Obstetric Anesthesia and Uncommon Disorders [3 ed.] 1009319760, 9781009319768

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Obstetric Anesthesia and Uncommon Disorders

Published online by Cambridge University Press

Published online by Cambridge University Press

Obstetric Anesthesia and Uncommon Disorders Third Edition Edited by

David R. Gambling

Past Head of Department of Anesthesiology, Sharp Mary Birch Hospital for Women and Newborns, San Diego; Clinical Professor Anesthesiology University of California, San Diego.

M. Joanne Douglas

Clinical Professor Emeritus, Department of Anesthesiology, The University of British Columbia

Grace Lim

Chief, Obstetric & Women’s Anesthesiology, UPMC Magee Women’s Hospital, University of Pittsburgh

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Shaftesbury Road, Cambridge CB2 8EA, United Kingdom One Liberty Plaza, 20th Floor, New York, NY 10006, USA 477 Williamstown Road, Port Melbourne, VIC 3207, Australia 314–321, 3rd Floor, Plot 3, Splendor Forum, Jasola District Centre, New Delhi – 110025, India 103 Penang Road, #05–06/07, Visioncrest Commercial, Singapore 238467 Cambridge University Press is part of Cambridge University Press & Assessment, a department of the University of Cambridge. We share the University’s mission to contribute to society through the pursuit of education, learning and research at the highest international levels of excellence. www.cambridge.org Information on this title: www.cambridge.org/9781009319768 DOI: 10.1017/9781009070256 © Cambridge University Press & Assessment 2024 This publication is in copyright. Subject to statutory exception and to the provisions of relevant collective licensing agreements, no reproduction of any part may take place without the written permission of Cambridge University Press & Assessment. First Edition W. B. Saunders 1997 Second Edition Published 2008 Third Edition 2024 Printed in Great Britain by Ashford Colour Press Ltd. A catalogue record for this publication is available from the British Library. Library of Congress Cataloging-in-Publication Data Names: Gambling, David R, editor. | Douglas, M Joanne, editor. | Lim, Grace, editor. Title: Obstetric anesthesia and uncommon disorders / edited by David R. Gambling, M. Joanne Douglas, Grace Lim. Description: Third edition. | Cambridge, United Kingdom ; New York, N.Y. : Cambridge University Press, 2023. | Includes bibliographical references and index. Identifiers: LCCN 2023040002 | ISBN 9781316513613 (hardback) | ISBN 9781009319768 (paperback) | ISBN 9781009070256 (ebook) Subjects: MESH: Anesthesia, Obstetrical | Pregnancy Complications Classification: LCC RG732 | NLM WO 450 | DDC 617.9/682–dc23/eng/20231002 LC record available at https://lccn.loc.gov/2023040002 ISBN 978-1-009-31976-8 Paperback Cambridge University Press & Assessment has no responsibility for the persistence or accuracy of URLs for external or third-party internet websites referred to in this publication and does not guarantee that any content on such websites is, or will remain, accurate or appropriate. Every effort has been made in preparing this book to provide accurate and up-to-date information that is in accord with accepted standards and practice at the time of publication. Although case histories are drawn from actual cases, every effort has been made to disguise the identities of the individuals involved. Nevertheless, the authors, editors, and publishers can make no warranties that the information contained herein is totally free from error, not least because clinical standards are constantly changing through research and regulation. The authors, editors, and publishers therefore disclaim all liability for direct or consequential damages resulting from the use of material contained in this book. Readers are strongly advised to pay careful attention to information provided by the manufacturer of any drugs or equipment that they plan to use.

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Cover Illustration “Strength in Pieces” by Lilly Soto This artwork represents the duality of human strength and fragility. The strength from structure, with all the components (organs and body systems) fitting together. but, like a stained glass window, potentially fragile. Outside of the body is a reinforcing network of pieces (services, personnel, social structures) that contributes to the strength of the individual. Each body has its own unique building blocks which speak to the array of conditions discussed in this book. Despite the fragility of the individual pieces, they create a thing of beauty when working together. “The whole is greater than the sum of its parts” - Aristotle.

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I would like to thank my family for their love and support throughout my career, for the collegiality of my coworkers over the years, and, as my career winds to an end, I give thanks for the opportunity to serve society through my work as a clinician and an educator. David R. Gambling To my family and particularly to my grandchildren, Erin, Sarah and Liam, much love. To my co-editors and the authors who contributed their expertise and time to the successful completion of this book, my many thanks. M. Joanne Douglas To Andrew, Nathan, and Emily who are the light of my life. To each of my past, present, future colleagues – anesthesia, obstetrics, nursing, residents, fellows, and students – who make every day not a day of work at all. And to all our mothers and children, everywhere: I hope that this work will help you, the most. Grace Lim

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Contents Preface to Obstetric Anesthesia and Uncommon Disorders, 3rd edition  ix Glossary of Common Abbreviations Used in this Text  x Gambling et al.: Obstetric Anesthesia: List of Contributors  xiii

1. Obstetric Anesthesia for the Parturient with Complex Medical Diseases  1 Jack M. Peace and Feyce M. Peralta 2. Point-of-Care Ultrasound for Obstetrics: Basics and Introductory Chapter  6 Elvera L. Baron and Daniel Katz 3. FoCUSed Cardiac Ultrasound for Cardiac Disorders  14 Clemens M. Ortner and M. Waseem Athar 4. Challenging Cardiac Disorders in Pregnancy  25 Hanna Hussey, Patrick Hussey, and Marie-Louise Meng 5. Uncommon Cardiac Dysrhythmias in Pregnancy  47 Ravishankar Agaram and Marie Davidson 6. Arterial Vascular Diseases  64 Ethan Jackson, Anitra Romfh, Yon K. Sung, and Natalie J. Bodmer

16. Peripheral Neuropathies  259 Cynthia A. Wong 17. Disorders of Intermediaries of Metabolism and Malignant Hyperthermia  273 David B. MacLean and Stephen H. Halpern 18. Hepatic Conditions  290 Arash Motamed, Thang Tran, and Mohamed H. Eloustaz 19. Renal Diseases in Pregnancy  305 Kate Petty 20. Rare Endocrine Disorders  315 Jill M. Mhyre, Jessica Merrill, and Waseem Athar 21. Disorders of Blood, Coagulation, and Bone Marrow  332 James P.R. Brown and M. Joanne Douglas

7. Uncommon Respiratory Disorders in Pregnancy  79 Alexandra Nicholas

22. Infectious Diseases in Pregnancy  367 C. Tyler Smith, Christina Megli, and Catherine A. Chappell

8. Airway Issues: Disorders Affecting the Airway  97 Roanne Preston and Clare E. G. Burlinson

23. Dermatologic Conditions in Pregnancy  389 David J. Berman

9. Use of Neuraxial Ultrasound for Axial Skeletal Conditions  110 Alexandria Papadelis and Carlo Pancaro

24. Psychiatric Disorders in Pregnancy  402 Allana Munro and Ronald B. George

10. Myopathies and the Parturient  122 Britany L. Raymond and Jeanette R. Bauchat 11. Parturients of Short Stature  140 Robert French-O’Carroll, Katherine M. Seligman, and Andrea J. Traynor 12. Disorders of the Vertebral Column  159 Robert Jee and Edward T. Crosby 13. Miscellaneous Skeletal and Connective Tissue Disorders  175 Caroline S. Grange and Sally Anne Shiels 14. Disorders of the Central Nervous System in Pregnancy  206 Lakshmi Ram and Rakesh Vadhera 15. Spinal Cord Disorders  231 Roanne Preston and Jonathan Collins

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25. Substance Use Disorder  413 Grace Lim 26. Autoimmune Disease  421 Caroline S. Grange and Annika Smith 27. Genetic Disorders  443 David J. Combs and Vesela P. Kovacheva 28. Anesthesia for Rare Fetal and Placental Conditions  456 Marla B. Ferschl and Mark D. Rollins.

Index  469 The color plate section can be found between  pp 252 and 253

vii

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Preface to Obstetric Anesthesia and Uncommon Disorders, 3rd edition This new edition describes uncommon diseases and disorders that have the potential to impact pregnancy, or to be impacted by pregnancy, and which are relevant to the anesthesiologist caring for parturients with these disorders. The primary focus of the book is the impact of rare medical conditions on the anesthetic management of these patients. We have removed some chapters from earlier editions and added others. It now contains 28 chapters, including new topics such as cardiac and neuraxial point of care ultrasound, substance abuse, rare inherited conditions, and anesthesia for rare fetal and placental conditions. Each chapter contains Valuable Clinical Insights which highlight important points from that section and help the reader assimilate the facts quickly. Tables, figures, and photographs provide visual aids to improve the readability of the book. After 14 years, figures and references were updated to make the book more current. Many practitioners rely on the internet for sources of contemporary

information but given the often-questionable quality of online resources, we believe that there remains a place for a peer reviewed textbook with expert contributions from around the globe. It will allow readers convenient access to up-to-date, relevant information about a range of conditions and a plan for the anesthetic management of such patients. In addition, this book highlights other issues important to the obstetric anesthesiologist and will be useful to perinatologists and other obstetric care providers. This text provides readers with otherwise hard-to-find information 24-7 to assist in the immediate management of complex patients. We welcome a new co-editor, Dr Grace Lim, whose contacts, knowledge, and insights were invaluable in creating this new edition. Finally, we would like to thank Dr Robert McKay, who co-edited the successful second edition, for his many contributions to the field of obstetric anesthesia.

ix https://doi.org/10.1017/9781009070256.001 Published online by Cambridge University Press

Glossary of Common Abbreviations Used in this Text AAGBI

Association of Anaesthetists of Great Britain and Ireland ABG Arterial blood gas ACOG American College of Obstetricians and Gynecologists ACTH Adrenocorticotropic hormone AD Autosomal dominant ADH Antidiuretic hormone ADP Accidental dural puncture AFE Amniotic fluid embolism AFLP Acute fatty liver of pregnancy AI Aortic insufficiency AMA Advanced maternal age APH Antepartum hemorrhage APLA Antiphospholipid antibody(ies) aPTT Activated partial thromboplastin time ARDS Acute respiratory distress syndrome AS Aortic stenosis ASA American Society of Anesthesiologists ASRA American Society of Regional Anesthesia ASD Atrial septal defect AV Arteriovenous AVM Arteriovenous malformation AAGBI Association of Anaesthetists of Great Britain and Ireland BMI Body mass index BP Blood pressure C Celsius CBC Complete blood count CC Closing capacity CD Cesarean delivery CDC Centers for disease control and Prevention CK Creatine kinase CNS Central nervous system CO Cardiac output CPAP Continuous positive airway pressure CPB Cardiopulmonary bypass Cr Creatinine

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CSA Continuous spinal analgesia/anesthesia CSE Combined spinal epidural CSF Cerebrospinal fluid CT Computerized tomography CVS Cardiovascular system CVT Cerebral venous thrombosis CVP Central venous pressure CXR Chest X-ray DDAVP Desmopressin DIC Disseminated intravascular coagulation DNA Deoxyribonucleic acid DP Dural puncture DPE Dural puncture epidural DVT Deep vein thrombosis EBL Estimated blood loss EBP Epidural blood patch ECG Electrocardiogram ECMO Extracorporeal membrane oxygenation EEG Electroencephalogram EGA Estimated gestational age EKG Electrocardiogram ERV Expiratory reserve volume ESR Erythrocyte sedimentation rate ESRD End Stage Renal Disease ETT Endotracheal tube F Factor FDA Food and Drug Administration FHR Fetal heart rate FNAIT Fetal neonatal alloimmune thrombocytopenia FRC Functional residual capacity FSH Follicle stimulating hormone FVC Forced vital capacity GA General anesthesia GDN Gestational diabetes mellitus GFR Glomerular filtration rate GHD Growth hormone deficiency GI Gastrointestinal

Glossary of Common Abbreviations Used in this Text

Hb Hemoglobin HELLP Hemolysis Elevated Liver enzymes Low Platelets HIV Human immunodeficiency virus HR Heart rate HUS Hemolytic uremic syndrome IC Inspiratory capacity ICH Intracranial hemorrhage ICP Intracranial pressure ICU Intensive care unit IgG Immunoglobulin G IHD Ischemic heart disease IIH Idiopathic intracranial hypertension IM Intramuscular INR International normalized ratio IT Intrathecal ITP Immune thrombocytopenic purpura IUFD Intrauterine fetal death IUGR Intrauterine growth restriction IUP Intrauterine pregnancy IV Intravenous IVC Inferior vena cava IVF In vitro fertilization IVH Intraventricular hemorrhage IVIG Intravenous immunoglobulin LA Local anesthetic LEA Lumbar epidural analgesia/anesthesia LFT Liver function tests LDH Lactic dehydrogenase LH Luteinizing hormone LMA Laryngeal mask airway LMWH Low molecular weight heparin LV Left ventricle, left ventricular LVH Left ventricular hypertrophy MAC Minimum alveolar concentration MI Myocardial infarction MRI Magnetic resonance imaging MS Mitral stenosis MV Minute volume NA Neuraxial analgesia/anesthesia NICU Neonatal intensive care unit NPO Nil per os or nothing by mouth NSAIDs Nonsteroidal anti-inflammatory drugs OAA Obstetric Anaesthetists Association OR Odds ratio OSA Obstructive sleep apnea

PA Pulmonary artery PACU Postanesthesia care unit PCA Patient controlled analgesia PCC Prothrombin complex concentrate PCEA Patient controlled epidural analgesia PDPH Postdural puncture headache PFT Pulmonary function testing PreE Preeclampsia PE Pulmonary embolism PH Pulmonary hypertension PIEB Programmed intermittent epidural bolus PMI Point of Maximal Impulse POCUS Point of care ultrasound PPH Postpartum hemorrhage PROM Premature rupture of membranes PT Prothrombin time PTT Partial thromboplastin time PVR Pulmonary vascular resistance r Recombinant RBC Red blood cells RCOG Royal College of Obstetricians and Gynaecologists RCT Randomized controlled trial RE Reticuloendothelial ROTEM Thromboelastometry RR Respiratory rate RV Right ventricle, right ventricular RVH Right ventricular hypertrophy SA Subarachnoid SAH Subarachnoid hemorrhage SGA Small for gestational age SMFM Society for Maternal Fetal Medicine SLE Systemic lupus erythematosus SOAP Society for Obstetric Anesthesia and Perinatology SOB Shortness of breath SpO2 Oxygen saturation SV Stroke volume SVC Superior vena cava SVD

Spontaneous vaginal delivery

SVR

Systemic vascular resistance

TAP

Transversus abdominis plane

TED

Thromboembolic disease

TEG Thromboelastography TIVA

Total intravenous anesthesia

TLC

Total lung capacity

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Glossary of Common Abbreviations Used in this Text

TSH

Thyroid stimulating hormone

TTE Transthoracic echocardiography TTP Thrombotic thrombocytopenic purpura TSH Thyroid stimulating hormone TV Tidal volume TXA Tranexamic acid UA Uric acid UFH Unfractionated heparin UK United Kingdom US Ultrasound

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USA UTI VC V/Q VSD VTE vWD vWF WBC WHO

United States of America Urinary tract infection Vital capacity Ventilation perfusion ratio Ventricular septal defect Venous thromboembolism von Willebrand disease von Willebrand factor White blood cells World Health Organization

Gambling et al.: Obstetric Anesthesia: List of Contributors Ravishankar Agaram Consultant Anaesthetist, Glasgow Royal Infirmary and Princess Royal Maternity

Marie Davidson Glasgow Royal Infirmary and Princess Royal Maternity, Glasgow, Scotland

Muhammad Waseem Athar Department of Anesthesiology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States

M. Joanne Douglas Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Canada

Elvera L. Baron Simulation Center, Louis Stokes Cleveland VA Medical Center, Cleveland; Department of Anesthesiology and Perioperative Medicine, Case Western Reserve University School of Medicine, Cleveland, United States

Mohamed H. Eloustaz Keck School of Medicine of USC, University of Southern California, California, United States

David J. Berman Johns Hopkins University School of Medicine; Department of Anesthesiology and Critical Care Medicine, Division of Obstetric, Gynecologic and Fetal Anesthesia; Johns Hopkins University School of Education, Baltimore, United States Natalie J. Bodmer Department of Anesthesiology, Stanford University Hospital, Stanford, United States James P.R. Brown BC Women’s Hospital, Vancouver, Canada, and Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Canada

Marla B. Ferschl University of California San Francisco, San Francisco, United States Robert French-O’Carroll BC Women’s Hospital and Health Centre, Vancouver, British Columbia David R. Gambling University of California San Diego and Sharp Mary Birch Hospital for Women and Newborns in San Diego, California, United States Ronald B. George UCSF Anesthesia & Perioperative Care, San Francisco, United States

Clare E. G. Burlinson Department of Anesthesia, British Columbia Women’s Hospital, Vancouver, Canada

Caroline S. Grange Nuffield Department of Anaesthetics, Oxford University Hospital NHS Trust, Oxford, United Kingdom

Catherine A. Chappell Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, United States

Stephen H. Halpern Department of Anesthesia, Sunnybrook Health Sciences Centre; University of Toronto, Toronto, Canada

Jonathan Collins Department of Anesthesia, BC Women’s Hospital, Vancouver, Canada David J. Combs Brigham and Women’s Hospital Department of Anesthesiology, Perioperative and Pain Medicine; Harvard Medical School, Cambridge, Massachusetts, United States Edward T. Crosby Department of Anesthesiology and Pain Medicine, University of Ottawa; Ottawa Hospital, Ottawa, Canada

Hanna Hussey Obstetric Anesthesiology, University of Alabama at Birmingham, United States Patrick Hussey Cardiothoracic Anesthesiology, University of Alabama at Birmingham, United States Ethan Jackson Division of Cardiothoracic Anesthesia; Chief, Adult Congenital Heart Disease Program; Chief, Cardio-Obstetric Program, Stanford University Medical Center, Stanford, United States

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Gambling et al.: Obstetric Anesthesia: List of Contributors

Robert Jee Department of Anesthesiology and Pain Medicine, University of Ottawa, Ottawa, Canada

Carlo Pancaro Department of Anesthesiology, University of Michigan, Michigan, United States

Daniel Katz Department of Anesthesiology, Pain, & Perioperative Medicine, The Icahn School of Medicine at Mount Sinai, New York, United States

Alexandria Papadelis Department of Anesthesiology, University of Michigan Medicine, Michigan, United States

Vesela P. Kovacheva Harvard Medical School, Cambridge, Massachusetts, United States Grace Lim University of Pittsburgh Department of Anesthesiology & Perioperative Medicine; University of Pittsburgh Department of Obstetrics & Gynecology; UPMC Magee-Women’s Hospital, Pittsburgh, United States David B. MacLean Department of Anesthesia, Sunnybrook Health Sciences Centre; University of Toronto, Toronto, Canada Christina Megli Division of Maternal Fetal Medicine, Division of Reproductive Infectious Disease, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, United States Marie-Louise Meng Cardiothoracic and Obstetric Anesthesiology, Duke University, Durham, United States Jessica Merrill Obstetric Anesthesiology, Ohio State University, Ohio, United States Jill M. Mhyre Department of Anesthesiology, The University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States Arash Motamed Liver Transplant Anesthesiology, Keck School of Medicine, University of Southern California, United States Allana Munro Department of Anesthesiology, Pain Management, and Perioperative Medicine, Dalhousie University, Canada Alexandra Nicholas Division of Obstetric and Women’s Anesthesiology, Division of Adult Cardiothoracic Anesthesiology, Department of Anesthesiology and Perioperative Medicine, University of Pittsburgh Medical Center, University of Pittsburgh School of Medicine, Pittsburgh, United States Clemens M. Ortner Department of Anesthesiology, Perioperative and Pain Medicine; Stanford University School of Medicine, Palo Alto, United States

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Jack M. Peace Temple University Lewis Katz School of Medicine, Philadelphia, United States Feyce M. Peralta Northwestern University Feinberg School of Medicine, Chicago, United States Kate Petty Department of Anesthesiology and Perioperative Medication, Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, United States Roanne Preston Department of Anesthesiology, Pharmacology & Therapeutics, Faculty of Medicine, The University of British Columbia, Vancouver, Canada Lakshmi Ram Obstetric Anesthesiology, The University of Texas Medical Branch, Galveston, Texas, United States Britany L. Raymond Vanderbilt University Medical Center, Department of Anesthesiology, Obstetric Division, Nashville, United States Mark D. Rollins Mayo Clinic, Rochester, United States Anitra Romfh Division of Cardiovascular Medicine and Pediatric Cardiology, Vera Moulton Wall Center for Pulmonary Hypertension, Stanford University School of Medicine, United States Katherine M. Seligman Department of Anesthesiology, Pharmacology & Therapeutics, University of British Columbia, Vancouver, Candad Sally Anne Shiels Nuffield Department of Anaesthesia, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom Annika Smith Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom C. Tyler Smith UPMC Department of Anesthesiology and Perioperative Medicine, University of Pittsburgh School of Medicine, Pittsburgh, United States

Gambling et al.: Obstetric Anesthesia: List of Contributors

Yon K. Sung Vera Moulton Wall Center for Pulmonary Vascular Diseases, Division of Pulmonary, Allergy; Critical Care Medicine, Stanford University School of Medicine, Stanford, United States Thang Tran Keck School of Medicine, University of Southern California, California, United States

Rakesh Vadhera The University of Texas Medical Branch, Galveston, Texas, United States Cynthia A. Wong University of Iowa, Iowa City, United States

Andrea J. Traynor Department of Anesthesiology, Perioperative, and Pain Medicine, Stanford University School of Medicine, Stanford, United States

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Chapter

1

Obstetric Anesthesia for the Parturient with Complex Medical Diseases Jack M. Peace and Feyce M. Peralta

Introduction Maternal mortality is on the rise in the United States (US) and other resource-rich countries.1 The reasons for this rise are debatable, but can be partly attributed to the increasing complexity of parturients.2,3 Undoubtedly, social determinants of health and systematic injustice also play a role in this phenomenon. Yet, data collected by the CDC suggest that as many as two out of three maternal deaths may be preventable.4 This rise in maternal mortality is occurring despite a decrease in the rate of anesthetic-related maternal mortality, though anesthetic techniques contribute to hundreds of maternal deaths every year. Advances in obstetric anesthesia, including improved labor analgesia techniques, anesthesia for cesarean delivery (CD), and peripartum hemorrhage management, have significantly impacted maternal safety. However, more remains to be done.5 The obstetric anesthesiologist has a major role to play in managing complex parturients during the peripartum period.6,7 This chapter will outline the part played by the obstetric anesthesiologist in caring for a parturient with complex medical diseases, including the obstetric anesthesia consultation, the value of the anesthesiologist in the multidisciplinary care team, and tools for putting into action a care plan for a complex patient. Valuable Clinical Insights • T he increasing prevalence of chronic medical conditions among pregnant women results in higher rates of maternal morbidity and mortality. • Proper planning and coordination of care can help minimize maternal harm. • An obstetric anesthesiology consultation is an essential tool for the early identification of medical issues vital to anesthesiologists. • Patients with complex medical diseases often understand their disease better than many of their healthcare providers.

The Obstetric Anesthesia Consultation Ideally, during the antepartum period, the anesthesiologist and the patient should discuss anesthetic options for vaginal or CD. Having the time to consider anesthetic choices while not in active labor, or worse, dealing with a peripartum emergency, can allow

a mother to have a more thorough understanding of the risks and benefits of anesthetic procedures in light of her personal preferences and medical history. However, in current practice, most obstetric preanesthetic evaluations are performed immediately before an anesthetic. For the parturient with complex medical diseases, such an evaluation is likely insufficient. An obstetric anesthesia consultation has emerged as a means of addressing anesthetically relevant medical issues before a woman’s delivery admission. The American College of Obstetricians and Gynecologists (ACOG) published a list of indications that should prompt antenatal consultation with an anesthesiologist.8 Their list encompasses a wide range of cardiac, hematologic, neurologic, and spinal pathologies that may influence anesthetic care during or after a woman’s pregnancy (Table 1.1). This list is not exhaustive, and individual institutions may wish to establish unique lists of conditions that deem anesthetic consultation appropriate. Some argue that a consultation with an obstetric anesthesiologist should be standard of care,9 so that every parturient arrives at her delivery equipped with full knowledge of the anesthetic options. This may be the optimal approach in many ways, as it removes the burden of determining anesthetically relevant medical conditions from obstetric providers. The form an obstetric anesthesiology consultation takes should address the needs of the patient, and the capabilities of the institution providing her care. Some minor conditions may be addressed with a phone consultation. In contrast, more complex issues (such as morbid obesity or congenital heart disease) are addressed better in-person, accompanied by a physical exam. Large academic centers may have groups of obstetric anesthesiologists or fellows in obstetric anesthesiology who can provide regular availability for antenatal consultations. Others may refer antepartum women to obstetrical triage offices where an anesthesiologist staffing a nearby labor and delivery unit can provide in-person consultation when not providing direct patient care. Institutions may choose to provide “walk-in” consultation hours where a woman can discuss anesthetic options with an obstetric anesthesiologist, regardless of whether she has preexisting medical conditions that would affect her care. For rural communities or communities without access to specialized obstetric care, telemedicine may be a powerful tool to leverage the expertise of obstetric anesthesiologists from academic institutions or larger delivery centers.10 If necessary, patients can be transferred to a

1 https://doi.org/10.1017/9781009070256.002 Published online by Cambridge University Press

Jack M. Peace and Feyce M. Peralta

Table 1.1  Indications for obstetric anesthesiology consultation Cardiac disease Congenital and acquired disorders such as repaired tetralogy of Fallot and transposition of the great vessels Cardiomyopathy Valvular diseases such as aortic and mitral stenosis, tricuspid regurgitation, and pulmonary stenosis Pulmonary hypertension and Eisenmenger syndrome Rhythm abnormalities such as supraventricular tachycardia and Wolff– Parkinson–White syndrome Presence of an implanted pacemaker or defibrillator Hematologic abnormalities or risk factors Immune and gestational thrombocytopenia Coagulation abnormalities such as von Willebrand disease Current use of anticoagulant medications Jehovah’s Witness Spinal, muscular, and neurologic disease Structural vertebral abnormalities and prior surgeries such as vertebral fusion and rod placement Prior spinal cord injury Central nervous system problems such as known arterial–venous malformation, aneurysm, Chiari malformation, or ventriculoperitoneal shunt Major hepatic or renal disease Chronic renal insufficiency Hepatitis or cirrhosis with significantly abnormal liver function tests or coagulopathy History of or risk factors for anesthetic complications Anticipated difficult airway Obstructive sleep apnea Previous difficult or failed neuraxial block Malignant hyperthermia Allergy to local anesthetics Obstetric complications that may affect anesthesia management Placenta accreta Nonobstetric surgery during pregnancy Planned cesarean delivery with a concurrent major abdominal procedure Miscellaneous medical conditions that may influence anesthesia management Body mass index of 50 or greater History of solid organ transplantation Dwarfism Sickle cell anemia Neurofibromatosis

center designated by the Society for Obstetric Anesthesia and Perinatology (SOAP) as a Center of Excellence. This designation recognizes a high standard of obstetric anesthesia care for parturients with complex diseases.11 When an obstetric provider identifies an anesthetically relevant condition, anesthesia consultation should occur as soon as possible. Pregnancy is highly unpredictable, and early

2 https://doi.org/10.1017/9781009070256.002 Published online by Cambridge University Press

planning can help ensure optimal care if a patient goes into labor early or experiences a complication in the antepartum period. Early consultation can also allow for venue and resource planning. For instance, a patient with pulmonary hypertension may require subspecialty clinic visits before delivery, as well as advanced monitoring (e.g., central line, arterial catheter) during her delivery; she may also require personnel (e.g., intensive care nurses) or critical care following delivery. These requirements may necessitate transfer to a larger urban center. The earlier a patient knows of this requirement, the earlier she can make transportation and housing decisions to ensure she and her family have access to the necessary facilities. An early consultation helps to anticipate the needs of parturients with complex medical diseases.

The Multidisciplinary Care Team This book aims to give those who provide anesthesia care for pregnant women insight into uncommon conditions during pregnancy. However, it is not a substitute for consulting with specialists and subspecialists who manage these conditions more often. Apart from the obstetric provider and anesthesiologist, many professionals may care for pregnant women with complex medical diseases. Maternal-fetal medicine physicians may be the first specialists involved in caring for high-risk pregnancies, due to their advanced training in maternal diseases. Cardiologists, especially those with expertise in obstetric patients, may advise on caring for women with congenital heart disease or pulmonary hypertension. Hematologists provide valuable insights on when it is safe to offer neuraxial analgesia (NA) to women with coagulopathies or how to manage postpartum hemorrhage (PPH) should it occur. Critical care specialists can assist with monitoring these women either before, during, or after pregnancy. In the patient with spinal pathology or prior spine surgery, neurologists and neurosurgeons can help minimize the risk of patient complications.12 Social workers may offer assistance for those parturients with challenging social situations or those with substance abuse disorders. Neonatologists and fetal surgeons can evaluate how fetal physiology can affect the physiology of a healthy mother with a medically complex fetus. In addition, the involvement and expertise of obstetric and critical care nurses are essential to the care of these patients. It is easy to see how the care of the parturient with a complex medical disease or critical illness can involve many different aspects of modern medical care. In consultation with these myriad specialists, it is crucial to consider the various contingencies that could arise over the peripartum period. What if a patient delivers early? What if a patient requires an operative delivery? What if a patient’s planned NA fails and she requires conversion to general anesthesia (GA)? What if a patient experiences a PPH? In institutions where it is feasible, in-person multidisciplinary meetings may provide a valuable opportunity to share expertise among specialists. Such sessions can help alert providers to the upcoming deliveries of patients with complex medical diseases and provide opportunities for this type of contingency planning to occur.

Obstetric Anesthesia for the Parturient with Complex Medical Diseases

Putting the Plan into Action After the multidisciplinary development of a plan for a medically complex parturient, the next task for team members is to disseminate the plan to those involved in the patient’s care. Detailed consultation notes, flags in the electronic medical record, phone trees, and email chains facilitate the implementation of a complex plan. Clinical simulation and practice runs may also be valuable tools in planning the care for a medically complex parturient, especially where providers may not use the processes or procedures involved very often.13 During a patient’s admission, maternal early warning systems can help alert providers to significant physiologic changes and warn of impending maternal morbidity or mortality.14 Such tools may lead to frequent false positives, however, especially in patients with some conditions already described. This means that constant vigilance is indispensable in averting harm to the parturient with complex medical diseases. Throughout the planning and implementation process, a patient’s involvement in her own care is crucial for ensuring the plan’s success. Patients with complex medical diseases often understand their disease more than many of their healthcare providers. Communication failures in obstetric anesthesia have not only been linked to adverse outcomes but also with malpractice claims.15 Patient–provider communication thus remains a critical part of caring for these patients.

Special Populations The complex patients that providers care for are an increasingly diverse group, many of whom have higher complication rates than the general population.16 Below are just several examples of patient populations contributing to the diversity of obstetric anesthesia practice and they require special consideration by their anesthetic providers (Table 1.2). Table 1.2  Special populations and anesthetic considerations

Patient population

Selected anesthetic considerations

Advanced maternal age

Increased incidence of PPH in patients > 45 years Increased risk of post-spinal hypotension

Parturients with physical/intellectual disabilities

Patient-specific concerns of failed/difficult NA Patient-specific concerns of anesthetic-related spinal injury Higher rates of CD and hypertensive disorders in women with intellectual disability

Cancer survivors/ parturients with cancer

Patients with cancer are more likely to deliver early and undergo GA for CD Chemotherapeutic agents may cause immunosuppression, thrombocytopenia, renal toxicity, and cardiac toxicity Cancers that affect the mediastinum (e.g., lymphoma) can have significant cardiac effects when combined with the hemodynamic changes of pregnancy

Patients affected by systemic racism

Minority patients are less likely to have the same access to care as nonminority patients Historical mistreatment of Black women in the USA may create an environment of distrust of medical providers Implicit or explicit bias is driving maternal health disparities between racial/ethnic groups

Patient population

Selected anesthetic considerations

Transgender/gendernonbinary parturients

Physiological effects of gender-affirming therapy on pregnancy are poorly understood Gendered language prevalent on delivery units may make nonfemale patients feel less supported Processes involved in birth (e.g., uterine contractions, cervical exams) may exacerbate gender dysphoria; this may be partially relieved by early NA

Advanced Maternal Age The birthrate in women older than 40 years has grown steadily since 1990, and now constitutes > 1 in 100 women delivering babies in the USA.17 Despite this, little is known about the anesthetic considerations specific to this population. Recent studies have demonstrated an increased risk for obstetrical complications (e.g., hypertensive disorders) and PPH in parturients older than 45 years. Increasing maternal age may also be a risk factor for post-spinal hypotension.18 Further studies are warranted to better define anesthetic considerations in this patient population. (See: Additional Reading below).

Women with Physical or Intellectual Disabilities Medical advances in recent decades have allowed many women with physical disabilities to survive well into childbearing years. As a result, the number of pregnant women with physical disabilities is increasing.19 These women require special consideration in the provision of anesthetic care, and providers must recognize the unique concerns in this population.20 Similarly, women with intellectual disabilities may be at increased risk for pregnancy complications in addition to the challenges they face in obtaining just, compassionate care.21

Cancer Patients Cancer survivors and women affected by cancer during pregnancy require a patient-specific multidisciplinary approach to obstetric care.22 Parturients who present with cancer are more likely to deliver early and to undergo GA for CD.23 While ­chemotherapeutic agents are often deferred during pregnancy, a thorough understanding of the effects of chemotherapy is necessary, as these agents may result in immunosuppression, thrombocytopenia, cardiac toxicity, or renal toxicity. Involvement of the mediastinum, such as by lymphoma, can result in deleterious effects when combined with the hemodynamic effects of pregnancy.

Patients Affected by Systemic Racism Significant racial disparities exist in maternal morbidity and mortality in the US. A recent CDC report reveals that pregnant or postpartum women of color are three to four times as likely to die as white women.24 Many racial and ethnic groups experience disparities, but the differences are more significant and well-studied among Black women. Racism undoubtedly plays a role in these disparities, which may be a product of the historical mistreatment of Black women in the US and implicit or

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Jack M. Peace and Feyce M. Peralta

explicit bias that these women may encounter in the peripartum period.25 As leaders in patient safety and team communication, the obstetric anesthesia team is well positioned to address these underlying disparities, eliminating biases that affect patient outcomes.

Transgender and Gender-Nonbinary Patients Patients who do not fit typical gender expectations may encounter substantial barriers to affirming care in the highly gendered labor and delivery environment.26,27 The physiological effects of gender-affirming therapies on pregnancy or birth are poorly studied. Moreover, the birth process or the procedures that surround it may exacerbate feelings of gender dysphoria for individuals who do not identify as female.28 To ameliorate this, early NA may serve the unique needs of this patient population. Additionally, efforts to adopt the use of gender-inclusive language and provide multidisciplinary education remain key roles of the anesthesia team.

Conclusion Parturients with complex medical diseases represent an increasing challenge in delivering safe obstetric anesthetic care. The role of the obstetric anesthesiologist in this process is indispensable as a key leader in the coordination and delivery of complex care. Armed with a thorough understanding of the conditions faced by these patients and the tools and resources required to manage them, the obstetric anesthesiologist can ensure that parturients with complex medical diseases,29 and those with critical obstetric illness,30 obtain the best possible care.

Additional Reading Advanced Maternal Age Magistrado L, Tolcher MC, Suhag A, et al. Lactation in a 67-year-old elderly gravida following donor oocyte in vitro fertilization. Case Rep Obstet Gynecol 2020;2020:9801565. Orbach-Zinger S, Aviram A, Ioscovich A, et al. Considerations in pregnant women at advanced maternal age. J Matern Fetal Neonatal Med 2015;28:59–62.

References 1. Creanga AA, Syverson C, Seed K, et al. Pregnancy-related mortality in the United States, 2011–2013. Obstet Gynecol 2017;130:366–373. 2. Mhyre JM, Bateman BT, Leffert LR. Influence of patient comorbidities on the risk of near-miss maternal morbidity or mortality. Anesthesiology 2011;115:963–972. 3. Wanderer JP, Leffert LR, Mhyre JM, et al. Epidemiology of obstetric-related ICU admissions in Maryland: 1999–2008*. Crit Care Med 2013;41:1844–1852. 4. Davis NL, Smoots AN, Goodman DA. Pregnancy-Related Deaths: Data from 14 U.S. Maternal Mortality Review Committees, 2008– 2017. In: Centers for Disease Control and Prevention USDoHaHS, ed. Atlanta, GA2019.

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  5. Lim G, Facco FL, Nathan N, et al. A review of the impact of obstetric anesthesia on maternal and neonatal outcomes. Anesthesiology 2018;129:192–215.   6. Abir G, Mhyre J. Maternal mortality and the role of the obstetric anesthesiologist. Best Pract Res Clin Anaesthesiol 2017;31:91–105.   7. Arnolds DE. Maternal safety: recent advances and implications for the obstetric anesthesiologist. Curr Opin Anaesthesiol 2020;33:793–799.   8. Practice Bulletin No. 177. Obstetric analgesia and anesthesia. Obstet Gynecol 2017;129:e73–e89.   9. Padilla CR. The obstetric anesthesia consultation: why the physician anesthesiologist consultation during pregnancy should be standard of care. ASA Monitor 2016;80:60–62. 10. Duarte SS, Nguyen TT, Koch C, et al. Remote obstetric anesthesia: leveraging telemedicine to improve fetal and maternal outcomes. Telemed J E Health 2020;26:967–972. 11. Carvalho B, Mhyre JM. Centers of Excellence for anesthesia care of obstetric patients. Anesth Analg 2019;128:844–846. 12. O’Neal MA. Obstetric anaesthesia: what a neurologist needs to know. Pract Neurol 2019;19:238–245. 13. Marynen F, Van Gerven E, Van de Velde M. Simulation in obstetric anesthesia: an update. Curr Opin Anaesthesiol 2020;33:272–276. 14. Shields LE, Wiesner S, Klein C, et al. Use of maternal early warning trigger tool reduces maternal morbidity. Am J Obstet Gynecol 2016;214: 527.e1–527.e6. 15. Douglas RN, Stephens LS, Posner KL, et al. Communication failures contributing to patient injury in anaesthesia malpractice claims. Br J Anaesth 2021;127:470–478. 16. Mangoubi E, Livne MY, Eidelman LA, et al. No longer rare diseases and obstetric anesthesia. Curr Opin Anaesthesiol 2019;32:271–277. 17. Hamilton BE, Hoyert DL, Martin JA, et al. Annual summary of vital statistics: 2010–2011. Pediatrics 2013;131:548–558. 18. Brenck F, Hartmann B, Katzer C, et al. Hypotension after spinal anesthesia for cesarean section: identification of risk factors using an anesthesia information management system. J Clin Monit Comput 2009;23:85–92. 19. Iezzoni LI, Yu J, Wint AJ, et al. Prevalence of current pregnancy among US women with and without chronic physical disabilities. Med Care 2013;51:555–562. 20. Smeltzer SC, Wint AJ, Ecker JL, et al. Labor, delivery, and anesthesia experiences of women with physical disability. Birth 2017;44:315–324. 21. Rubenstein E, Ehrenthal DB, Mallinson DC, et al. Pregnancy complications and maternal birth outcomes in women with intellectual and developmental disabilities in Wisconsin Medicaid. PLoS One 2020;15:e0241298. 22. McCoun KT, Fragneto RY. Cancer and pregnancy: a difficult combination requiring multidisciplinary care. J Clin Anesth 2012;24:521–523. 23. Tharmaratnam U, Balki M. Anesthetic management during labor and delivery: a 21-year review of women with cancer in a tertiary care center. J Clin Anesth 2012;24:524–530. 24. Petersen EE, Davis NL, Goodman DA, et al. Vital Signs: Pregnancy-Related Deaths, United States, 2011–2015, and Strategies for Prevention, 13 States, 2013–2017. Published 2019. Atlanta, GA: Centers for Disease Control and Prevention.

Obstetric Anesthesia for the Parturient with Complex Medical Diseases

25. Minehart RD, Jackson J, Daly J. Racial differences in pregnancyrelated morbidity and mortality. Anesthesiol Clin 2020;38:279–296. 26. Hoffkling A, Obedin-Maliver J, Sevelius J. From erasure to opportunity: a qualitative study of the experiences of transgender men around pregnancy and recommendations for providers. BMC Pregnancy Childbirth 2017;17(Suppl. 2):332. 27. Light AD, Obedin-Maliver J, Sevelius JM, et al. Transgender men who experienced pregnancy after female-to-male gender transitioning. Obstet Gynecol 2014;124:1120–1127.

28. Taylor MG, Scott PM, Premkumar A, et al. Peripartum considerations for the transgender parturient: a case report. A A Pract 2021;15:e01332. 29. Metzger L, Teitelbaum M, Weber G, et al. Complex pathology and management of the obstetric patient: a narrative review for the anesthesiologist. Cureus 2021;13:e17196. 30. Einav S, Leone M. Epidemiology of obstetric critical illness. Int J Obstet Anesth 2019;40:128–139.

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Chapter

2

Point-of-Care Ultrasound for Obstetrics: Basics and Introductory Chapter Elvera L. Baron and Daniel Katz

Introduction Over the last several decades, diagnostic ultrasound (US) served as a foundation in such medical subspecialties as radiology, cardiology, and obstetrics. Point-of-care ultrasound – POCUS – is a focused diagnostic ultrasound performed bedside at the point of care timepoint. With their increased portability, affordability, and image quality, POCUS devices have become one of the most significant recent advances in US technology. A growing literature supports its safe use and clinical utility, making POCUS a required and essential skill for obstetric anesthesiologists. It allows rapid diagnosis of relevant complications related to our practice, and helps to guide perioperative management. This chapter provides the basics of US physics, and transducers used in POCUS, reviews POCUS capabilities and indications for use in acute care settings, and summarizes its uses within the practice of obstetric anesthesiology.

What Is POCUS? The term POCUS refers to a surface US examination performed at the bedside or in the medical office, which serves as an extension of the physical examination. Unlike comprehensive extensive diagnostic US exams performed by US technicians and then interpreted by physicians, POCUS is a limited study examination, typically performed by the same clinician who makes treatment decisions. It rapidly diagnoses specific underlying conditions, reduces failure and complication rates during invasive line placements, and can improve clinical outcomes.1–3 Since images are acquired and interpreted in real-time, changes in patient condition can be detected quickly, images correlated with symptoms, and treatments rapidly initiated.4–6 The use of POCUS can be repeated to visualize the effects of interventions and treatments in real time. Therefore, this practice of image acquisition and interpretation in real time can reduce the time to diagnosis and allow for faster treatment.7 There are three categories of POCUS: screening, diagnostic, and interventional.4,5,7 Due to its value in clinical decision-making, POCUS is one of the required milestone competencies in numerous USA-based residencies, including emergency medicine (in 2012), family medicine (in 2018), anesthesiology (in 2018), and obstetrics (2014). For example, an emergency medicine graduating resident must show competency in performing

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US exams for suspected abdominal aortic aneurysm, abdominal trauma, focused cardiac exam, hepatobiliary and spleen, lung exam, and transabdominal and transvaginal pelvic US.8 Family medicine residents must demonstrate competency in obtaining limited obstetric and gynecologic evaluations, focused cardiac exam, assessment of abdominal free fluid or pneumothorax/ hemothorax, aorta basic US skills, pelvic US, limited vascular assessment for deep vein thrombosis, pulmonary exam, limited soft tissue/musculoskeletal exams, and procedural guidance.2 Anesthesiology residents must show competency in obtaining and interpreting images from the focused transthoracic echocardiography, lung exam, gastric exam (specific to gastric filling), trauma (FAST exam), and vascular access.9

Basic Point-of-Care Ultrasound Overview Brief Physics and Transducer Overview Knowledge of the fundamental physics of US, including artifacts, is essential to the correct interpretation of US images for accurate bedside diagnosis. Ultrasound technology uses sound waves to view different organs and tissues, without any radiation. Since the images are captured in real-time, internal organs, cardiac valves, and the direction of blood flow can be acquired and interpreted. The US machines send high-frequency waves (2.0–15.0 MHz) via vibrating piezoelectric crystals in the US transducers (i.e., probes). These sound waves bounce off body tissues generating echoes, which are received as reflected sound waves by the probes, enabling the computer to create images knowns as sonograms. The frequency of the sound waves determines the depth of penetration (Figure 2.1), where the highest frequency sound waves provide the highest resolution images with the lowest depth penetration, and vice versa. Therefore, selecting the correct transducer increases the chances of high-quality images, although more than one probe may be appropriate for a given exam. Anesthesiology is one of many disciplines that take advantage of POCUS examinations. In the acute care setting, probes used for POCUS studies include linear, curvilinear, and phased array (Figure 2.2). Linear probes are high frequency (5.0–15.0  MHz), which provides better resolution and less ­penetration – therefore, ideal for imaging superficial structures

Pressure

Point-of-Care Ultrasound for Obstetrics: Basics and Introductory Chapter

Time Period

Four cycles per second; f = 4Hz

Pressure

1 second

Time

Figure 2.1  Basic ultrasound physics, including sound waves, frequency, and wavelength. Transducer produces low-intensity mechanical sound waves, which result in tissue vibration. They are characterized by frequency (f) and wavelength (λ), where v = λ x f, such that velocity = frequency (Hz) x wavelength (mm). Ultrasound frequencies are between 2.0 and 10.0 MHz, which are above the range of audible sound. Frequency and wavelength are inversely proportional, resulting in high-frequency sound waves producing better image resolution.

Two cycles per second; f = 2Hz

Period Examining the frequency of sound waves Propagation of Sound Figure 2.2  Most used transducers and their frequencies, as they relate to image optimization. (A) Linear array probe, with frequency 5.0–15 MHz. High frequency leads to better resolution. Best for evaluating superficial structures, such as vascular access and superficial regional blocks. (B) Curvilinear array probe, with frequency 2.0–7.5 MHz. Low frequency leads to better penetration, making this the best probe for evaluating deep structures (i.e., FAST exam, deep regional blocks). (C) Phased array probe, with frequency 2.0–7.5 MHz. It contains many piezoelectric crystals, giving off a “fan” of signals. This probe has a small footprint, which is most suitable to fit between rib spaces. Most often used for transthoracic echocardiography, FAST, and lung examinations.

(A) Linear array probe

(B) Curvilinear array probe

(C) Phased array probe

and vessels. Curvilinear probes have a wider footprint (i.e., the part of the probe that is in contact with the body) and lower frequency (2.0–7.5  MHz) than linear probes. Consequently, they are better suited for imaging deeper structures, such as in transabdominal studies. A phased array probe uses a similar frequency to curvilinear probes (2.0–7.5 MHz), with a smaller footprint that fits between ribs, making it ideal for imaging cardiac and lung tissues. The linear probes generate rectangular images, while both curvilinear and phased array probes generate sector (“pie-shaped”) images, narrower in the near field and broader in the far field. There are multiple available modes to generate and display US images on the screen. The B-mode (brightness mode) is the primary and most used mode.10 In this mode, an array simultaneously scans a thin plane (~1  mm thickness) through the imaging structures that are viewed as a two-dimensional (2D) image on the screen and can be changed based on which probe is used. Another mode is M-mode (motion mode), where a onedimensional image is displayed to analyze moving body parts, such as cardiac structures. This mode is rarely used in POCUS studies since its interpretation requires specific knowledge and training. Since different tissues in the body have different densities, they lead to different tissue impedance – those tissues that reflect more waves appear more echogenic on the 2D image. For

example, fluid is anechoic (i.e., black), soft tissues are shades of gray, and bone or stones are white.

Basics of Knobology Each US machine has manufacturer-specific specifications. Knob organization varies from manufacturer to manufacturer, yet most have similar buttons and functions that perform similar operations. The size and location of each knob may vary from machine to machine; however, the function of a given knob will be similar across manufacturers. Learning the locations and functions of each knob is critical because selecting the incorrect settings could, at best, result in a low-quality image or, at worst, produce artifacts that are misinterpreted as findings. The following knobs and buttons exist on a wide variety of US machines. The first button to discuss is the power button, which must be depressed or switched to turn on the machine. To ensure proper functionality of the US machine, an adequate power source is needed and backup battery power in cases where no power outlet exists. Many power buttons serve dual functions as sleep buttons which do not turn off the machine but disable the monitor to save power. Machines in sleep modes can switch to scanning modes more rapidly than powered off machines. Most devices also have buttons to select a patient and manually enter demographic patient

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Elvera L. Baron and Daniel Katz

information whenever needed. If the practice supports these functions, this allows images to be saved into the patient electronic medical record (EMR) for reference, quality, and billing purposes. Ultrasounds also have buttons to change imaging modes depending on the type of analysis needed for a given image (Table 2.1). The details and appropriate modes for each exam are beyond the scope of this chapter. Most machines will have Motion Mode (M Mode), which displays a one-dimensional image of the US beam over time. The most used mode, as described earlier, is a 2D mode, whereby US pulses are fired sequentially across the sector displaying a 2D tomographic section that allows one to distinguish shape and lateral motion. Each scan line is sequentially activated within the frame, which repeats over and over to form motion (Frame rate). Advanced machines also have Color and Doppler imaging, which allows for interpretation of flow toward or away from the probe. Some images may appear darkened even when using other image optimization methods. At this point the operator can use the gain knob, button, or slider to increase the amplitudes of the waves, which will make the image appear brighter. Gain should be used with caution as certain findings may be “drowned out” by the stronger signal. Some machines allow only a universal gain adjustment, while others allow for a directional adjustment, which allows one to select different gain levels at different distances from the probes. As such, one can amplify the far field image, which would be darker since waves attenuate as they travel further away from the probe, but not cause distortion of near field images. Likewise, many machines allow the operator to change the depth of the image and the zoom, which allows selection of certain structures for further analysis. Several machines will have a measurement function and digital calipers to trace objects of interest or measure the distances between points. Finally, machines have a freeze button to create a still image from the 2D imaging mode and an acquire or capture knob to save either a video clip or still image to the internal storage or an external system. Table 2.1  Basic knobs or modes and their functions: these knobs or functions are common to any ultrasound equipment

Knob

Function

Power button

Turns the machine on

Motion mode (M Mode)

Displays a one-dimensional image of the ultrasound beam over time

Color and Doppler imaging

For interpretation of flow toward or away from the probe

Gain

Increases the amplitudes of the waves, which will make the image appear brighter

Depth

Changes visual field to focus on structures closer or further away

Zoom

Selects further functions for further analysis

Measurement function and Digital calipers

Trace objects of interest or measure the distances between points

Freeze

Creates a still image

Acquire or capture

Saves image or video clip to an internal or external storage system

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In summary, each US machine will have differently sized knobs and buttons in different locations. However, knob and button functions are relatively standard across manufacturers. Ensuring the operator is comfortable with each button and function on the machine is as important as selecting the correct probe to acquire and interpret the images correctly.

POCUS Capabilities, Indications, and Protocols Achieving competency in POCUS for specific organ systems is a priority for several subspecialties. Some professional bodies have established specific objectives to achieve competency in POCUS for airway, lung, gastrointestinal, cardiac tissue, and trauma evaluations. In addition, for invasive line placement, POCUS is useful in various clinical settings. Multiple clinical algorithms have been developed for diagnosis and rapid treatment, especially of patients in shock, respiratory distress, or cardiac arrest.11,12 Table 2.2 includes some of the major resuscitation protocols. Common exam components include cardiac and inferior vena cava (IVC) examinations. Cardiac POCUS emphasizes the evaluation of pericardial effusion and tamponade, left ventricular contractility and function, and right ventricular function (see Chapter 3). Intravascular volume is assessed with IVC US, which can help guide fluid resuscitation efforts. This is useful in sepsis, hemorrhage, heart failure, or other unexplained bouts of hypotension. Most recent POCUS protocols include lung US, which is helpful in the timely detection of respiratory complications and can help distinguish areas of lung consolidation (i.e., pneumonia), pleural effusion, collapse or atelectasis, interstitial disease, pleural effusion, or pneumothorax (PTX).

Advantages of POCUS Evidence demonstrates that using POCUS can be more accurate than physical examination alone,34–36 improve clinical outcomes,37 and decrease complication rates during procedures.38 Additionally, it lowers costs, shortens the time to definitive treatment, decreases the use of CT imaging, and improves patient satisfaction due to real-time patient–physician interaction during image acquisition and interpretation. During POCUS, acquisition and interpretation of images happen in real time, allowing for observation of dynamic changes that correlate with the symptoms.5 Additionally, POCUS may help elucidate the source of infection in a septic patient and guide use of more targeted antibiotics, determining the need for source control procedures and assisting with hemodynamic assessment and identification of sepsis mimics.35 Finally, the ability to visualize the effects of any treatment or intervention in real time as they occur makes this modality especially suitable for time-critical scenarios.4

Limitations of POCUS The use of POCUS has several limitations. One concern is that its use deprioritizes patient contact during the physical ­examination.39–41 Instead of listening to the patient’s symptoms and concerns, both the patient and clinician focus on US image

Point-of-Care Ultrasound for Obstetrics: Basics and Introductory Chapter

Table 2.2  Major resuscitation protocols for critically ill and trauma patients (modified from Seif et al.11)

Protocol abbreviation

Protocol name or cited study description

Components of POCUS exam, in order of performance

Indications for use

Reference

ACES

Abdominal and Cardiac Evaluation with Sonography in shock

Cardiac, IVC, aorta, FAST A/P, lung effusion

Shock, undifferentiated hypotension

Atkinson et al.13

BEAT

Bedside Echocardiographic Assessment in Trauma

Cardiac, IVC

Trauma, critical care

Gunst et al.14

BLEEP

Bedside Limited Echocardiography by the Emergency Physician

Cardiac, IVC

Critical care

Pershad et al.15

Boyd: ECHO

Goal-oriented Echocardiography

Cardiac, IVC

Critical care, hemodynamic monitoring

Boyd et al.16

EGLS

Echo-Guided Life Support

Lungs PTX, cardiac, IVC, lungs edema

Undifferentiated shock

Lanctot et al.17

Elmer/Noble

Evidence-based framework to integrate bedside US for the intensivist

Cardiac, IVC, FAST A/P, lungs PTX, lungs edema

Undifferentiated shock

Elmer et al.18

FALLS

Fluid Administration Limited by Lung Sonography

Lung edema, lung PTX, cardiac, IVC

Acute circulatory failure

Lichtenstein et al.19

FAST

Focused Assessment with Sonography in Trauma

Subxiphoid pericardial window, peri-splenic view, hepatorenal recess, suprapubic window

Trauma

Rozycki et al.20

Extended-FAST (e-FAST)

Extended-FAST

FAST + bilateral anterior thorax

Post-traumatic pneumothoraces, trauma

Kirkpatrick et al.21

FATE

Focus-Assessed Transthoracic Echocardiography

Cardiac, lungs effusion

Critical care

Jensen et al.22

FEEL: Resuscitation

Focused Echocardiographic Evaluation in Life support and peri-resuscitation

Cardiac

Emergency

Breitkreutz et al.23

FEER

Focused Echocardiographic Evaluation in Resuscitation management

Cardiac

Critical care, trauma, fluid status assessment

Breitkreutz et al.24

FREE

Focused Rapid Echocardiographic Examination

Cardiac

Emergency, advanced life support

Ferrada et al.25

POCUS-FAST and RELIABLE

POCUS in the hypotensive patient; FAST + Right ventricular strain, Effusion (pericardial), Left ventricular function, Inferior vena cava, Aorta, Blood clot (venous), Lungs, Ectopic pregnancy

FAST A/P, lungs PTX, cardiac, IVC, aorta, lungs edema, DVT, ectopic pregnancy

Undifferentiated hypotension

Liteplo et al.26

RUSH: HI-MAP

Rapid Ultrasound for SHock and Hypotension; Heart, Inferior vena cava, Morrison’s/FAST abdominal views, Aorta, Pneumothorax

Cardiac, IVC, FAST A/P, aorta, lungs PTX

Shock, hypotension

Weingart et al.27

RUSH: Pump/ Tank/Pipes

Rapid Ultrasound for SHock and Hypotension: Pump (heart), Tank (intravascular), Pipes (large arteries and veins)

Cardiac, IVC, FAST A/P, lungs effusion, lungs PTX, aorta, DVT

Critical care

Perera et al.28 Perera et al.29

Trinity

Hypotensive ultrasound protocol

Cardiac, aorta, FAST A/P

Undifferentiated hypotension

Bahner et al.30

UHP

Undifferentiated Hypotensive Patient

FAST A/P, aorta, cardiac

Undifferentiated hypotension

Rose et al.31

BLUE

Bedside Lung Ultrasound in Emergency

Lung u/s for pneumothorax, pulmonary edema, pulmonary consolidation, effusions

Acute respiratory failure

Lichtenstein et al.32

RADiUS

Rapid Assessment of Dyspnea with Ultrasound

Cardiac, IVC, focused pulmonary exam

Dyspnea

Manson et al.33

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Elvera L. Baron and Daniel Katz

acquisition and interpretations. Another limitation is a lack of universal access to portable US machines. The use of handheld and portable devices, which are becoming more available and less expensive, helps facilitate communication between clinician and patient. However, portable devices may pose the risk of transmitting harmful pathogens between patients. Finally, the use of US technology is operator dependent, contributing to the risk of misinterpretation of data derived from the exam. Training and practical experience are required to obtain highquality images consistently and properly interpret them for the institution of correct interventions. Specific training for proper image acquisition and interpretation and clinical decisionmaking improves operator use and minimizes inter-operator variabilities.4,42–45

POCUS Specifics in Obstetric Anesthesiology Practice There are numerous POCUS applications in the field of clinical anesthesia, including assessment of cardiac status, mechanisms of shock, procedural complications, causes of respiratory distress, airway management, gastric content, and trauma utilizing focused cardiac, pulmonary, airway, gastric, abdominal, and procedural US.46 Notably, gastric US (GUS) is an emerging diagnostic tool for determining pulmonary aspiration risk due to gastric contents at the bedside whenever NPO status is unknown.47–49 Obstetric anesthesiologists can successfully utilize the POCUS applications which facilitates rapid diagnosis, management, and clinical decision-making in common obstetric and maternal peripartum complications. Emergency use of POCUS in obstetrics and gynecology has a high sensitivity and specificity,50 so it assists in identifying the causes for patient abdominal pain, bleeding, pelvic mass, abdominal distension, or hemodynamic instability. Briefly, pregnancy itself is associated with an increased risk of difficult airway access, increased risk of aspiration, acute respiratory failure, and cardiovascular compromise.51 Specific pathologies faced by the obstetric anesthesiologist that may warrant POCUS examination include peripartum cardiomyopathy, PreE, amniotic fluid embolism (AFE) assessment, parturientspecific airway management, and peripartum hemodynamic instability.51–53 Additionally, procedural US guidance is beneficial in such interventions as vascular access (i.e., intravascular, central line), rapid neuraxial placement (i.e., spinal, epidural, CSE), and invasive monitoring techniques (i.e., arterial line, CVP monitoring, pulmonary artery pressure (PAP) monitoring). Cardiac and lung US is used to evaluate obstetric patients with hypoxemia; vascular and cardiac US can be used to assess hypovolemia; GUS can be used to assess aspiration risk; neuraxial US may aide in neuraxial placement (see Chapter 9), and optic nerve US may be used to identify patients with raised intracranial pressure and others. Protocols combining these individual exams exist and may be applied algorithmically in a crisis. Some are nonobstetric specific, such as e-FAST,21 and others are obstetric specific, such as the ROSE protocol.31 The general components of each exam are listed in Table 2.2, yet

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additional details are beyond the scope of this chapter. Principles of US for nonobstetric patients also apply to the parturient, but pregnancy may make image acquisition and interpretation more difficult. For example, obtaining a subxiphoid view in a woman in the third trimester can be challenging and uncomfortable for the patient. In other instances, pregnancy may make the US exam easier and image quality better – for example, as the heart is typically displaced anteriorly in the later stages of pregnancy, it becomes physically closer to the chest wall, making cardiac structures easier to visualize. Either way, to master POCUS in the obstetric patient, a significant amount of time must be spent acquiring and interpreting US images in a pregnant patient. Valuable Clinical Insights • During POCUS, acquisition and interpretation of images ­happen in real time, allowing for observation of dynamic changes that correlate with the symptoms. • POCUS allows assessment of cardiac status, mechanisms of shock, procedural complications, causes of respiratory distress, airway management, gastric content, and trauma using focused exams. • Since the heart is displaced anteriorly in the later stages of pregnancy, it becomes physically closer to the chest wall, making cardiac structures easier to visualize with POCUS. • Obtaining a subxiphoid view in a woman in the third trimester can be challenging and uncomfortable for the patient.

POCUS Certifications of Completion: Assessment-Based Programs and Future Directions Once a new clinical skillset is developed, primary issues to be addressed are standardization and measurement of competence. This has been a challenge for POCUS because it has origins in many specialties and clinical arenas. Over the past decade, numerous medical subspecialties have published position statements with evidence-based recommendations on the use of POCUS for diagnosis at the bedside.40,42,54–56 However, standards for teaching are highly variable and are rapidly changing. Many of these programs2,57,58 follow the framework of indication, acquisition, interpretation, and decision-making – beginning with knowing the anatomy and concluding with making appropriate clinical decisions and treatment recommendations based on the interpretation of the acquired images.40 To further the issue, the demonstration of competence in this skillset is also highly variable. Programs vary in the order of progression, number of required images submitted for portfolio review, and length of time required to complete the program. For the purposes of example, a recent consensus panel of over 20 POCUS experts has provided guidance on what they believe to be the minimum number of acceptable studies to demonstrate competence in various POCUS domains.59 Their recommendations are summarized in Table 2.3. Of note, the POCUS certification of completion is assessment-based, distinct from certificates earned for attendance of a POCUS-specific course, aimed at

Point-of-Care Ultrasound for Obstetrics: Basics and Introductory Chapter

Table 2.3  Summary of requirements for POCUS competency among organizations

Point-of-care ultrasound domain

Minimum number of supervised studies personally performed and interpreted

Minimum number of additional supervised studies interpreted but NOT personally performed

Focused Airway Ultrasound

30

20

Focused Assessment with Sonography in Trauma (FAST)

30

20

Focused Cardiac Ultrasound

50

100

Focused Gastric Ultrasound

30

20

Focused Pulmonary/Pleural Ultrasound

30

20

Focused Renal/ Genitourinary Ultrasound

30

20

Focus Ultrasound for Deep Venous Thrombosis

30

20

demonstrating evidence of specialized education achievement. A clear pathway for knowledge acquisition, interpretation, and reliable demonstration of competence is needed for many reasons including patient safety and proper reimbursement. No single standard exists, but a comprehensive program is offered by the American Society of Anesthesiologists (see below). Finally, no certificate program provides the credentialing necessary to practice POCUS in your institution. Guidelines for credentialing and privileging are driven by each institution and readers should consult their own hospital for more information.

The American Society of Anesthesiologists In 2020, the American Society of Anesthesiologists (ASA) has launched its first “Diagnostic POCUS Certificate Program,” aimed to expand anesthesiologists’ diagnostic POCUS skills.60 This course focuses on diagnostic US of the heart, lungs, abdomen (stomach, bladder, FAST exam). These organ systems were chosen for this pathway as these are the organ systems identified by the ABA61 and the ACGME (Accreditation Council for Graduate Medical Education)62 as core competencies in this area. This is a self-paced five-part program, which provides CME and MOCA credits and, ultimately, a Certificate of Completion. The parts include: (1) Quality improvement action plan, requiring reporting outcomes to earn MOCA credits; (2) Evidence of diagnostic POCUS training, with a minimum of 10 training hours obtained; (3) Image interpretation training, utilizing online 140 case-based POCUS modules; (4) Image acquisition training, requiring mentor-reviewed image portfolio submission; and (5) Comprehensive examination, composed of

cardiac, gastric, and lung POCUS exams. This open enrollment program is accessible to residents, fellows, and attending physicians. It requires the learner to identify a POCUS-certified local mentor or ASA faculty, who will review and sign-off on the log of acquired POCUS studies. The certificate of the program does not expire, as this program does not award credentials upon completion and does not require re-certification.63 In addition to the ASA POCUS Certification course, the ASA provides a list of approved POCUS courses on its website, including those offered at the member societies, such as Society of Cardiovascular Anesthesiologists, American Society of Echocardiography, American Society of Regional Anesthesiology and Pain Medicine, Society for Critical Care Medicine, Society of Pediatric Anesthesiology, as well as numerous university-affiliated POCUS courses.64 The structure, content, goals, and credits for these courses is highly variable.

Future Directions Given the heterogeneity of courses in their offerings, learning types (e-learning or in-person), scanning requirements and credits, standardization is needed. However, even in the event of a standardized curriculum, there may still be significant disagreement among certification standards, as we have seen in other areas of US. For example, in the United States, the National Board of Echocardiography has defined requirements for competency in perioperative TEE.65 In Canada, however, no certification is required, and only guidelines are presented.66 Furthermore, when summarizing the current state of POCUS as related to skills and assessments, the following summary of the consensus panel recommendations are prudent and are provided below.59 Ultrasound imaging is within the scope of practice of adequately trained physicians, and hospitals should grant privileges for US according to specialty-specific guidelines. • POCUS training programs should focus on the three primary POCUS applications (cardiac/lung/abdomen) and six secondary applications (airway, musculoskeletal, ocular, renal/genitourinary, transcranial, and deep venous thrombosis). • Minimum scanning numbers and training should be standardized and incorporated into anesthesiology training programs; ideally, with digital tracking and a certificate of competence. • Safe and ethical practicing of POCUS by recognizing limitations of POCUS, obtaining consent for images, and the archiving of images for documentation. A worldwide consensus on POCUS education and training will enhance the uptake and quality of POCUS in clinical practice.

Conclusion In summary, POCUS is an efficient, cost-effective, noninvasive, and portable surface US modality, particularly valuable in critical scenarios for time-sensitive clinical decision-making at the bedside.67,68 Competency in image acquisition and complete exam, interpretation, and differential diagnosis generation

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are critical to the safe and effective use of POCUS. With its increased clinical utilization, POCUS has developed into a lifesaving diagnostic tool employed by a subspecialist clinician for diagnosis, resuscitation, perioperative optimization, and acute care management.10

References   1. Kanji HD, McCallum J, Sirounis D, et al. Limited echocardiography-guided therapy in subacute shock is associated with change in management and improved outcomes. J Crit Care 2014;29:700–705.   2. American Academy of Family Physicians. Available at: www .aafp.org/dam/AAFP/documents/medical_education_residency/ program_directors/Reprint290D_POCUS.pdf [last accessed August 30, 2022].   3. Reynolds TA, Amato S, Kulola I, et al. Impact of point-of-care ultrasound on clinical decision-making at an urban emergency department in Tanzania. PLoS One 2018;13:e0194774.   4. Recker F, Weber E, Strizek B, et al. Point-of-care ultrasound in obstetrics and gynecology. Arch Gynecol Obstet 2021;303: 871–876.   5. Nielsen M, Cantisani V, Sidhu P, et al. The use of handheld ultrasound devices – an EFSUMB position paper. Ultraschall Med Eur J Ultrasound 2019;40:e1, 30–39.   6. Smallwood N, Dachsel M. Point-of-care ultrasound (POCUS): unnecessary gadgetry or evidence-based medicine? Clin Med 2018;18:219–224.   7. Moore CL, Copel JA. Point-of-care ultrasonography. N Engl J Med 2011;364:749–757.   8. Schmidt JN, Kendall J, Smalley C. Competency assessment in senior emergency medicine residents for core ultrasound skills. W J Emerg Med 2015;16:923–926.   9. ABA OSCE content outline. Available at: www.theaba.org/pdfs/ OSCE_Content_Outline.pdf [last accessed August 30, 2022]. 10. Abu-Zidan FM, Cevik AA. Diagnostic point-of-care ultrasound (POCUS) for gastrointestinal pathology: state of the art from basics to advanced. World J Emerg Surg 2018;13:47. 11. Seif D, Perera P, Mailhot T, et al. Bedside ultrasound in resuscitation and the rapid ultrasound in shock protocol. Crit Care Res Pract 2012;2012:503254. 12. Shrestha GS, Weeratunga D, Baker K. Point-of-care lung ultrasound in critically ill patients. Rev Recent Clin Trials 2018;13:15–26. 13. Atkinson PRT, McAuley DJ, Kendall RJ, et al. Abdominal and Cardiac Evaluation with Sonography in Shock (ACES): an approach by emergency physicians for the use of ultrasound in patients with undifferentiated hypotension. Emerg Med J 2009;26:87–91. 14. Gunst M, Ghaemmaghami V, Sperry J, et al. Accuracy of cardiac function and volume status estimates using the bedside echocardiographic assessment in trauma/critical care. J Trauma 2008;65:509–516. 15. Pershad J, Myers S, Plouman C, et al. Bedside limited echocardiography by the emergency physician is accurate during evaluation of the critically ill patient. Pediatrics 2004;114: e667–671. 16. Boyd JH, Walley KR. The role of echocardiography in hemodynamic monitoring. Curr Opin Crit Care 2009;15: 239–243.

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17. Lanctot YF, Valois M, Bealieu Y. EGLS: echo guided life support. An algorithmic approach to undifferentiated shock. Crit Ultrasound J 2011;3:123–129. 18. Elmer J, Noble VA. An evidence-based approach for integrating bedside ultrasound into routine practice in the assessment of undifferentiated shock. ICU Dir 2010;1:163–174. 19. Lichtenstein DA, Karakitsos D. Integrating ultrasound in the hemodynamic evaluation of acute circulatory failure (FALLS-the fluid administration limited by lung sonography protocol). J Crit Care 2012;27:e53–e64. 20. Rozycki G, Oschner MG, Schmidt JA. A prospective use of surgeon’s performed ultrasound as the primary adjunct modality for injured patient assessment. J Trauma 1995;39:879–885. 21. Kirkpatrick AW, Sirois M, Laupland KB, et al. Hand-held thoracic sonography for detecting post-traumatic pneumothoraces: the extended focused assessment with sonography for trauma (EFAST). J Trauma 2004;57:288–295. 22. Jensen MB, Sloth E, Larsen KM, et al. Transthoracic echocardiography for cardiopulmonary monitoring in intensive care. Eur J Anaesthesiol 2004;21:700–707. 23. Breitkreutz R, Price S, Steiger HV, et al. Focused echocardiographic evaluation in life support and periresuscitation of emergency patients: a prospective trial. Resuscitation 2010;81:1527–1533. 24. Breitkreutz R, Walcher F, Seeger FH. Focused echocardiographic evaluation in resuscitation management: concept of an advanced life support-conformed algorithm. Crit Care Med 2007;35(5, Suppl.): S150–S161. 25. Ferrada P, Murthi S, Anand RJ, et al. Transthoracic focused rapid echocardiographic examination: real-time evaluation of fluid status in critically ill trauma patients. J Trauma 2011;70:56–64. 26. Liteplo A, Noble V, Atkinson P. My patient has no blood pressure: point of care ultrasound in the hypotensive patient-FAST and RELIABLE. Ultrasound 2012;20:64–68. 27. Weingart SD, Duque D, Nelson B. Rapid Ultrasound for Shock and Hypotension (RUSH-HIMAP). Published 2009. Available at: https://emcrit.org/rush-exam/ [last accessed October 21, 2022]. 28. Perera P, Mailhot T, Riley D, et al. The RUSH exam: Rapid Ultrasound in SHock in the evaluation of the critically ill. Emerg Med Clin N Am 2010;28:29–56. 29. Perera P, Mailhot T, Riley D, et al. The RUSH exam: Rapid Ultrasound in SHock in the evaluation of the critically ill patient. Ultrasound Clin 2012;7:255–278. 30. Bahner DP. Trinity: a hypotensive ultrasound protocol. J Diagn Med Sonogr 2002;18:193–198. 31. Rose JS, Bair AE, Mandavia D, et al. The UHP ultrasound protocol: a novel ultrasound approach to the empiric evaluation of the undifferentiated hypotensive patient. Am J Emerg Med 2001;19:299–302. 32. Lichtenstein, DA, Mezière, GA. Relevance of lung ultrasound in the diagnosis of acute respiratory failure the BLUE protocol. Chest 2008;134:117–125. 33. Manson W, Hafez NM. The rapid assessment of dyspnea with ultrasound: RADiUS. Ultrasound Clin 2011;6:261–276. 34. Alonso JV, Martin D, Kinderman H, et al. Acute ischemic stroke what is hidden behind? J Cardiol Cases 2017;16:174–177. 35. Alonso JV, Chowdhury M, Borakati R, et al. Swimming-induced pulmonary oedema an uncommon condition diagnosed with POCUS ultrasound. Am J Emerg Med 2017;35:1986.e3–1986.e4.

Point-of-Care Ultrasound for Obstetrics: Basics and Introductory Chapter

36. Cortellaro F, Ferrari L, Molteni F, et al. Accuracy of point of care ultrasound to identify the source of infection in septic patients: a prospective study. Intern Emerg Med 2017;12:371–378. 37. Goldsmith AJ, Shokoohi H, Loesche M, et al. Point-of-care ultrasound in morbidity and mortality cases in emergency medicine: who benefits the most? West J Emerg Med 2020;21:172– 178. 38. Karakitsos D, Labropoulos N, De Groot E, et al. Real-time ultrasound-guided catheterization of the internal jugular vein: a prospective comparison with the landmark technique in critical care patients. Crit Care 2006;10:R162. 39. Haskins SC, Bronshteyn Y, Perlas A. American Society of Regional Anesthesia and Pain Medicine expert panel recommendations on point-of-care ultrasound education and training for regional anesthesiologists and pain physicians – part I: clinical indications. Reg Anesth Pain Med 2021;46:1048–1060. https://doi .org/10.1136/rapm-2021-102561 40. Haskins SC, Bronshteyn Y, Perlas A, et al. American Society of Regional Anesthesia and Pain Medicine expert panel recommendations on point-of-care ultrasound education and training for regional anesthesiologists and pain physicians – part II: recommendations. Reg Anesth Pain Med 2021;46: 1048–1060. 41. Veld HIMA, Allison MG, Bostick DS, et al. Ultrasound use during cardiopulmonary resuscitation is associated with delays in chest compressions. Resuscitation 2017;119:95–98. 42. Dietrich CF, Goudie A, Chiorean L, et al. Point of care ultrasound: a WFUMB position paper. Ultrasound Med Biol 2017;43:49–58. 43. Westerway SC. Comparing the effectiveness of training course formats for point-of-care ultrasound in the third trimester of pregnancy. Australas J Ultrasound Med 2019;22:45–50. 44. Haskins SC, Feldman D, Fields KG, et al. Teaching a point-of-care ultrasound curriculum to anesthesiology trainees with traditional didactic lectures or an online e-learning platform: a pilot study. J Educ Perioper Med 2018;20:E624. 45. Galjaard S, Baeck S, Ameye L, et al. Use of a pocket-sized ultrasound machine (PUM) for routine examinations in the third trimester of pregnancy. Ultrasound Obstet Gynecol 2014;44: 64–68. 46. Ramsingh D, Bronshteyn YS, Haskins S, et al. Perioperative pointof-care-ultrasound. Anesthesiology 2020;5:908–916. 47. Perlas A, Chan VW, Lupu CM, et al. Ultrasound assessment of gastric content and volume. Anesthesiology 2009;111:82–89. 48. Perlas A, Mitsakakis N, Liu L, et al. Validation of a mathematical model for ultrasound assessment of gastric volume by gastroscopic examination. Anesth Analg 2013;116:357–363. 49. Van de Putte P. Bedside gastric ultrasonography to guide anesthetic management in a nonfasted emergency patient. J Clin Anesth 2013;25:165–166. 50. Stein JC, Wang R, Adler N, et al. Emergency physician ultrasonography for evaluating patients at risk for ectopic pregnancy: a meta-analysis. Ann Emerg Med 2010;56: 674–683. 51. Zieleskiewicz L, Bouvet L, Einav S, et al. Diagnostic point-of-care ultrasound: applications in obstetric anaesthetic management. Anaesthesia 2018;73:1265–1279.

52. Weiniger CF, Sharoni L. The use of ultrasound in obstetric anesthesia. Curr Opin 2017;30:306–312. 53. King CH, Palmer LJ. Point-of-care ultrasound for obstetric anesthesia. Int Anesthesiol Clin 2021;59:60–77. 54. Chang WW, Hopkins AM, Rehm KP, et al. Society of Hospital Medicine Position on the American Board of Pediatrics Response to the Pediatric Hospital Medicine Petition. J Hosp Med 2019;10:589–590. 55. Soni NJ, Schnobrich D, Mathews BK, et al. Point-of-Care Ultrasound for Hospitalists: A Position Statement of the Society of Hospital Medicine. J Hosp Med 2019;14:E1–6. 56. Haskins SC, Tanaka CY, Boublik J, et al. Focused cardiac ultrasound for the regional anesthesiologist and pain specialist. Reg Anesth Pain Med. 2017;42:632–644. 57. Bornemann PH. Assessment of a novel point-of-care ultrasound curriculum’s effect on competency measures in family medicine graduate medical education. J Ultrasound Med 2017;36:1205– 1211. 58. American College of Emergency Physicians. Tayal V, Blaivas M, Mandavia D (Eds.), Emergency Ultrasound Guidelines. Published 2008. Revised 2016. Available at: www.acep.org/patient-care/ policy-statements/ultrasound-guidelines-emergency-pointof-care-and-clinical-ultrasound-guidelines-in-medicine/ [last accessed October 21, 2022]. 59. Bronshteyn YS, Anderson TA, Badakhsh O, et al. Diagnostic point-of-care ultrasound: recommendations from an expert panel. J Cardiothorac Vasc Anesth 2022;36:22–29. 60. ASA Pocus Certification. Available at: www.asahq.org/educationand-career/educational-and-cme-offerings/pocus [last accessed August 30, 2022]. 61. ABA. Initial Certification in Anesthesiology. Available at: www .theaba.org/pdfs/Initial_Certification_Content_Outline.pdf [last accessed August 30, 2022]. 62. ACGME. ACGME Program Requirements for Graduate Medical Education in Anesthesiology. Available at: www .acgme.org/Portals/0/PFAssets/ProgramRequirements/040_ Anesthesiology_2020.pdf [last accessed August 30, 2022]. 63. ASA. Diagnostic POCUS Certificate Program FAQs 2022. Available at: www.asahq.org/education-and-career/educationaland-cme-offerings/pocus/pocus-certificate-faqs [last accessed August 30, 2022]. 64. ASA. Approved POCUS courses. Available at: https://education .asahq.org/mod/page/view.php?id=25094 [last accessed August 30, 2022]. 65. National Board of Echocardiology. Available at: www.echoboards .org/ [last accessed August 30, 2022]. 66. Burwash IG, Basmadjian A, Bewick D, et al. 2010 Canadian Cardiovascular Society/Canadian Society of Echocardiography Guidelines for Training and Maintenance of Competency in Adult Echocardiography. Can J Cardiol 2011;27:862–864. 67. Abu-Zidan FM. Point-of-care ultrasound in critically ill patients: where do we stand? J Emerg Trauma Shock 2012;5:70–71. 68. Parks AR, Verheul G, LeBlanc-Duchin D, et al. Effect of a pointof-care ultrasound protocol on the diagnostic performance of medical learners during simulated cardiorespiratory scenarios. CJEM 2015;17:263–269.

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Chapter

3

FoCUSed Cardiac Ultrasound for Cardiac Disorders Clemens M. Ortner and M. Waseem Athar

Definition The definition of FoCUS is an ultrasound examination that is goaldirected, simplified, performed at the point of care, with a limited scope, and is problem oriented. A FoCUS exam is potentially suitable for all clinical settings as a targeted diagnostic test performed by the appropriately trained clinician treating the patient. A FoCUS exam is an extension of the physical examination and used to answer questions in a binary fashion (yes or no?) either qualitatively (e.g., is the right ventricle dilated or nondilated?) or semiquantitatively (e.g., the left ventricle is hyperkinetic, normokinetic, hypokinetic, or severely hypokinetic).1 Providing a detailed grading of cardiac size, function, or valve pathology is NOT a goal of FoCUS as defined. Instead, the results of a FoCUS examination are combined with other clinical findings to generate a differential diagnosis and a ­management plan. Defined diagnostic targets of the FoCUS examination are assessment of the following:2 1. Left ventricular (LV) dimensions 2. LV-systolic function

3. Right ventricular (RV) systolic function 4. Volume status 5. Presence of pericardial effusion and potential tamponade physiology 6. Gross signs of chronic cardiac disease 7. Gross valvular abnormalities 8. Gross intracardiac masses. After starting treatment, a FoCUS exam allows immediate assessment of treatment responses at the bedside.

Technique Recommended views (Figure 3.1, Table 3.1) for FoCUS examination3 include the: 1. Subcostal long axis (SLAX) view 2. Subcostal inferior vena cava (SIVC) view 3. Parasternal long axis (PLAX) view 4. Parasternal short axis (PSAX) view 5. Apical 4 Chamber (A4CH) view Figure 3.1  Recommended views for FoCUS examination: (1) Subcostal long axis view (SLAX); (2) Subcostal inferior vena cava view (SIVC); (3) Parasternal long axis view (PLAX); (4) Parasternal short axis view (PSAX); (5) Apical 4 Chamber view (A4CH). Abbreviations: IVC: inferior vena cave; LA: left atrium; LV: left ventricle; RA: right atrium; RV: right ventricle. (See color plate section).

* The videos for this chapter can be found in the resources at www.cambridge.org/9781009319768

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FoCUSed Cardiac Ultrasound for Cardiac Disorders

Table 3.1  FoCUS views, patient and probe positions, and clinical indications

FoCUS view

Patient and probe positioning

Obtainable clinical findings

Subcostal long axis (SLAX) view

Supine with slightly bent legs with probe marker pointed to left shoulder

Proper view to assess cardiac function or pericardial effusion. Very difficult to obtain in the presence of a gravid uterus but can be used in postpartum patients

Subcostal inferior vena cava (SIVC) view

Supine with slightly bent legs with probe marker pointed cephalad

Good view to assess volume status. May not be practical with gravid uterus, but valuable in postpartum patients

Parasternal long axis (PLAX) view

Left sternal edge between 2nd and 4th intercostal space with probe marker pointed to right shoulder

Helpful view to assess cardiac function, valvular disease (mitral or aortic) and pericardial effusion

Parasternal short axis (PSAX) view

Left sternal edge between 2nd and 4th intercostal space with probe marker pointed to left shoulder

Useful view to assess cardiac function and pericardial effusion

Apical 4 Chamber (A4CH) view

At PMI with probe marker pointed to left shoulder

Used to assess cardiac function, presence of regional wall motion abnormalities, valvular disease (mitral or aortic), and large pericardial effusion

Going through all or most views listed in a systematic and standardized way increases a FoCUS screening capability. However, a limited number of views can suffice to assess many diagnostic targets. Ideally, each target structure should be visualized in at least two different views to confirm the findings if the patient’s condition allows it. After each FoCUS exam, the findings should be well documented. This can be accomplished by the use of simplified, standardized forms (see Figure 3.2) with box checking and minimal free text.3

Limitations of FoCUS Anesthesiologists must differentiate a FoCUS exam from a comprehensive or limited echocardiographic exam. The FoCUS exam is not recommended to grade valvular pathology, assess diastolic function, or detect raised left ventricular end diastolic pressures (LVEDP). The entire clinical context should be considered rather than simply treating the images obtained. Patients in whom there is suspicion of undetected cardiac pathology or abnormalities beyond the scope of FoCUS examination should be referred for comprehensive standard echocardiographic evaluation. A practitioner performs a comprehensive echocardiographic exam with advanced image acquisition and interpretation skills and is trained to obtain supplementary echocardiographic views and use advanced ultrasound (US) tools such as three-dimensional (3D) or strain imaging. A limited echocardiographic exam is performed by a practitioner with the expertise to perform a comprehensive exam but collects a “limited” number of images. In contrast, a FoCUS exam is performed by a practitioner with a narrow scope of expertise answering a specific question by assessing diagnostic targets as defined above.

Protocols and Structured Approaches Various assessment protocols have been developed based on FoCUS and adapted to different clinical settings. Among these, to name a few, are the focused assessed transthoracic echocardiography protocol (FATE-protocol),1 focused assessment

with sonography in trauma protocol (FAST-protocol),4 rapid ultrasound in shock protocol (RUSH-protocol),5 or focused echocardiography in emergency life support protocol (FEELprotocol).6 All of these protocols are extensions of a FoCUS exam performed in different settings and are beyond the scope of this chapter. Notably, these protocols result from expert opinion and are not validated. Multiorgan ultrasonography (RUSH, FAST) examines the heart first, followed by ultrasound of the chest, abdomen and major blood vessels, whereas FoCUS involves heart examination only. The FATE protocol has been adapted to perioperative medicine needs and includes pleural scanning and obtaining basic cardiac views. The FAST protocol includes assessment for hemoperitoneum and hemothorax and getting pericardial views. The RUSH protocol combines FoCUS with lung ultrasound, inferior vena cava, aorta, pleura, bladder, and peritoneal windows and can help distinguish between hypovolemic, obstructive, cardiogenic, and distributive shock. FEEL protocol incorporates FoCUS into the Advanced Cardiac Life Support (ACLS) protocol, looking for potentially reversible causes of cardiac arrest and factors associated with prognosis. Echocardiography is performed during cardiac arrest synchronized with pulse checks to limit interruptions during CPR. The Rapid Obstetric Screening Echocardiography (ROSE) scan protocol has been developed specifically for the obstetric patient.7 This protocol considers the specific physiological and anatomical changes of pregnancy. The ROSE protocol includes qualitative and quantitative measurements that incorporate the basic views of a FoCUS scan. However, the ROSE scan also estimates CO using Doppler in the apical five-chamber view, and calculates diastolic function. Important distinctive principles of the ROSE scan are that the examination is performed in the left lateral decubitus position to avoid uterine aortocaval compression and improve maternal comfort. The protocol focuses on right heart dimensions and function to assess for embolic events (thrombotic or amniotic fluid embolism) as important causes of hemodynamic collapse in pregnancy. A distinguishing characteristic of the ROSE-protocol

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Clemens M. Ortner and M. Waseem Athar

Figure 3.2  Example of a FoCUS cardiac echo report form.

is the inclusion of fetal heart rate assessment. A nonreassuring FHR pattern may indicate compensated maternal status with no overt maternal hemodynamic instability. Once maternal compromise has been established, treatment should focus on the mother since maternal stabilization will improve the fetal condition. ROSE protocol does not include multimodal ultrasound, such as lower limb venous or lung ultrasound, which would improve the ability to diagnose pulmonary embolism or pneumothorax.

Specific Indications in the Obstetric Patient Performing a FoCUS exam has been shown to change medical management when screening for cardiovascular disease. It improves diagnostic accuracy in the assessment of the critically ill parturient who is hemodynamically unstable, has severe dyspnea, or is in cardiac arrest.

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FoCUS for Screening Cardiovascular Disease In the nonobstetric patient, FoCUS has shown promise in detecting unexpected relevant cardiac abnormalities and is a useful screening tool during preanesthetic evaluation and assessment.8,9 FoCUS accurately detects the following echocardiographic markers for cardiovascular pathology: • Left atrial enlargement • LV hypertrophy • LV dilatation • LV systolic dysfunction Depending on the clinical scenario, the observed ultrasound abnormalities help the clinician to identify the underlying pathology (Figure 3.3). FoCUS is not reliable in screening for coronary artery disease or rheumatic valve disease.

FoCUSed Cardiac Ultrasound for Cardiac Disorders

Figure 3.3  Perioperative use of FoCUS-assessed transthoracic ultrasound: important pathologies as seen on TTE, including pericardial effusion, hypertrophy, and/or dilatation of right atrium (RA), right ventricle (RV), left atrium (LA), and left ventricle (LV).1

FoCUS and Acute Dyspnea in Pregnancy Acute respiratory failure is a life-threatening event during pregnancy and one of the leading causes of intensive care unit admissions during pregnancy and the early postpartum period.10 Acute respiratory symptoms can be of cardiogenic and noncardiogenic etiology, and the use of FoCUS alone might be insufficient for a comprehensive diagnostic workup.11 A combined diagnostic approach using pulmonary ultrasound in conjunction with transthoracic echocardiography (TTE) is very successful.12–14 The following algorithm is used for the obstetric patient15 (Figure 3.4). FoCUS can identify RV-dilatation and decreased RV-systolic function indicating thromboembolism, pericardial effusion indicating tamponade

physiology, or pleural effusion by identifying effusion posterior to the descending aorta in PLA-view. However, differential diagnosis of acute dyspnea, such as pneumonia, bronchial disorder, acute respiratory distress syndrome (ARDS), or cardiogenic edema from elevated LVEDP will require pulmonary imaging or echocardiographic skills beyond the scope of a FoCUS exam. Valuable Clinical Insight A combined diagnostic approach using FoCUS and lung ultrasound is successful in differentiating between cardiogenic and noncardiogenic causes.

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Clemens M. Ortner and M. Waseem Athar

Clinical examination

Lung and pleural US

+

am

l tera

gr nc ho

re

ro

Atelectasis

l ia rd ef

lu e R DV V f T ai

a ric fu on si

Normal

Ac ut

cb

Pneumonia

St ati

TTE and venous US

l

Pe

ra

al

Pulmonary embolism ARDS

tion nsolida ural co Sub-ple bronchogram ic Dynam

te

Bila

Figure 3.4  Diagnostic approach using point-of-care pulmonary, cardiac, and venous ultrasound in work-up of acute respiratory failure in pregnancy.16 Abbreviations: ARDS: acute respiratory distress syndrome; DVT: deep venous thrombosis; RV: right ventricle; TTE: transthoracic echocardiography; US: ultrasound.

Lung consolidation

ila

rm No

d

Pneumothorax

Un

TTE filling pressure Elevate

Lu Lu ng p ng oi ab slidi nt olit ng ion

Normal parenchyma

B-lines

Cardiogenic oedema

Pleural effusion

Anechoic fluid

Tamponade Bronchial disorder

FoCUS and Cardiac Arrest FoCUS differentiates between electromechanical dissociation and organized myocardial activity in the setting of cardiac arrest. Distinguishing between an actual pulseless electrical activity (PEA) and a “Pseudo PEA” benefits the clinical management and outcome prediction. “Pseudo-PEA” states include severe hypovolemia, LV-dysfunction or RV-decompensation that appear clinically pulseless but are amenable to treatment and hence reversible. True PEA has worse outcomes, and cardiac standstill on FoCUS during cardiopulmonary resuscitation predicts death with 97–100% probability17,18 in the nonobstetric population. In cardiac arrest, FoCUS changes management in 89% of patients.6 It is more accurate than ECG interpretation or physical examination for diagnosing the cause of cardiac arrest and for assessing cardiac function. As a consequence, resuscitation guidelines published by the American Heart Association (AHA), European Resuscitation Council (ERC), American College of Emergency Physicians (ACEP), and American Society of Echocardiography (ASE) all advocate the use of point-of-care ultrasound in managing cardiac arrest while cautioning clinicians not to exceed 10-second pauses between chest compressions.19–21 In-hospital cardiopulmonary resuscitation during pregnancy is mainly associated with a nonshockable rhythm. An analysis of rhythms of 462 cases of maternal cardiac arrest in the United States and Canada reports PEA and asystole as the primary observed rhythm in 51% and 26%, respectively.22 Hemorrhage is the leading cause of maternal cardiac arrest, followed by embolic events, cardiovascular disease, sepsis, anaphylaxis, and anesthetic complications.23 Shockable rhythm (ventricular fibrillation/ventricular tachycardia) accounts for 12% of cardiac arrests,22 mostly from cardiovascular disease such as acute MI, acute aortic dissection, structural heart disease

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Pneumonia

and peripartum cardiomyopathy.24 FoCUS plays an important role in ruling out hemorrhage, embolic events, pericardial tamponade and cardiovascular disease as causes of maternal cardiac arrest. Although echocardiographic signs are nonspecific, FoCUS helps to diagnose sepsis or anaphylaxis as the cause for cardiac arrest. Valuable Clinical Insight FoCUS is a critical tool in ruling out hemorrhage, embolic events, pericardial tamponade, and cardiovascular disease as causes of cardiac arrest.

Video 3.1  Massive pericardial effusion displayed in subcostal long axis view.*

* Abbreviations: LA: left atrium; LV: left ventricle; RA; right atrium; RV: right ventricle.

FoCUSed Cardiac Ultrasound for Cardiac Disorders

FoCUS to Assess Shock and Hemodynamic Instability Hemodynamic compromise and unexplained hypotension are high acuity issues which happen, albeit infrequently, on labor and delivery units. The presentation and causes of shock vary with different degrees of physiological disturbance. When assessing a patient in shock, four main pathophysiologic entities must be differentiated. • Hypovolemic • Obstructive • Cardiogenic • Distributive shock The pathophysiological features of conditions such as hemorrhage and sepsis can overlap with the normal physiological changes of pregnancy, leading to a delayed diagnosis. It is often difficult to distinguish between various causes of hypotension and tachycardia but FoCUS assists with identifying different causes of shock (Table 3.2). Echocardiography for evaluating hypotension, shock, or hemodynamic instability of uncertain or suspected cardiac etiology meets the highest level of appropriateness or Class 1 recommendations from American, British, and European guidelines. According to both observational studies and randomized trials, a FoCUS exam allows clinicians to correctly diagnose the etiology of shock in 80% of patients. This is compared to 50% when ultrasound is not used,25 and leads to changes in patient management in approximately 66% of patients in shock.6 Hypovolemic shock is most common during the peripartum period and is usually related to severe bleeding. The highest-yield views for assessing hypovolemia are SIVC and PSAX views. A hypovolemic FoCUS pattern is described as the presence of small hyperdynamic ventricles with papillary muscles touching each other at end-systole (also called “kissing heart”) and a small IVC at end-expiration. Table 3.2  FoCUS features in different types of shock

Cause

FoCUS view

FoCUS signs

Cardiac tamponade (obstructive shock)

SLAX

Pericardial effusion Right cardiac chamber compression Swinging heart

Pulmonary embolism/ Amniotic fluid embolism (obstructive shock)

PSAX, SLAX, A4CH

Paradoxical septal motion Right ventricular dilation Thrombus

Hypovolemic or Distributive shock

PSAX, PLAX, SLAX, SIVC

Kissing heart IVC collapse > 40% Low VTI and cardiac output in hypovolemia but normal or increased VTI in distributive shock

Cardiogenic shock

PSAX, A4CH

Altered global systolic function Low VTI and cardiac output Reduced global or regional systolic function

Based on the overall clinical picture, patients may benefit from fluid resuscitation with crystalloid, colloid, or blood products. Serial FoCUS exams evaluate the efficacy of treatment. In hypovolemic shock, hemorrhage is often considered first, unless there are clinical indicators for dehydration or sepsis. Resuscitation goals in the PSAX view are to increase the LV end-diastole and systolic diameters. A FoCUS exam is used to identify hypovolemia in parturients prior to NA (e.g., in a patient with occult bleeding, as might exist in placental abruption). In this setting, NA might induce hemodynamic compromise leading to hypovolemic shock and cardiac arrest. Common causes of obstructive shock are pulmonary embolism followed by cardiac tamponade and AFE. Cardiac tamponade is caused by aortic dissection, trauma, or spontaneous pericardial effusion. It can occur during pregnancy or the peripartum period due to the combination of hormone-induced changes in connective tissue and hemodynamic stress. There will be a pericardial effusion and right ventricular chamber compression on SLAX views. Early performance of FoCUS can help identify RV failure and help differentiate AFE from other causes of acute cardiovascular collapse. In particular, the SLAX view can be performed during active chest compression, and will usually show dilated RV and RA, consistent with high RV pressure overload. When pulmonary embolism leads to obstructive shock, there are FoCUS signs of right ventricular dilation with flattening, or paradoxical motion, of the interventricular septum in PSAX view, also called “D-sign.” When assessing for PE, use an US exam of the legs to assess for the presence of DVT.26 A systematic review evaluating the accuracy of physician-performed US found a sensitivity of 96% and specificity of 97% for the diagnosis of DVT.26 Also, negative findings from leg scans, when accompanied by FoCUS assessment of RV function, can help rule out pulmonary embolism. Cardiogenic shock can be secondary to peripartum cardiomyopathy or an exacerbation of chronic heart disease. Gross contractility of the LV is assessed using FoCUS. In PSAX and A4CH views, there will be a low velocity-time integral (VTI), reduced cardiac output, and reduced global or regional systolic function. The term VTI is known as the stroke distance, which is the distance travelled by the sampled volume within each heartbeat. Multiplying the VTI measured in the left ventricular outlet tract (LVOT) by the cross-sectional area at the same location will give the stroke volume (SV). Multiplying the SV by the heart rate (HR) gives CO. In the parasternal views, one may see dilated LV end-diastolic diameter (> 5.6 cm) and decreased fractional shortening (FS). There may be increased LV and RV volume, and reduced LV and RV contractility in the apical views. Echocardiographic images in distributive shock secondary to decreased SVR, such as in sepsis, or anaphylaxis may be similar to hypovolemic shock showing a “kissing heart” in PSAX, and IVC collapse on SIVC. However, ejection fraction (EF), defined as a measure of the percentage of blood ejected during systole in relation to the end-diastolic volume, or VTI at the level of the LVOT, appears normal or increased. In addition,

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Clemens M. Ortner and M. Waseem Athar

as the volume status is normal, end-diastolic volume indicated by the end-diastolic area in PSAX remains unchanged and appears higher than in hypovolemic shock. Therefore, assessing CO and LVED area with TTE differentiates between hypovolemic or distributive shock.27,28 Valuable Clinical Insight FoCUS is useful for differentiating between various causes of unexplained hemodynamic instability and guiding clinical management and interventions.

FoCUS to Assess Fluid Responsiveness A primary clinical challenge in every hemodynamically unstable patient is to accurately differentiate between those patients that will respond to fluid administration with an increase in cardiac output versus those who will not respond and be at risk of fluid overload.29–31 In the nonobstetric, spontaneously breathing patient, a change in SV with passive leg raising (PLR) is the most accurate predictor of fluid responsiveness with a sensitivity of 80% (95% CI: 0.8–0.94) and specificity of 88% (95% CI: 0.8–0.94).32 In controlled ventilation, predictive accuracy further increases to an estimated sensitivity and specificity of 92% (95% CI: 0.82–0.97 and 0.86–0.96, respectively). In comparison, collapsibility of the IVC, a much used parameter that predicts fluid responsiveness in perioperative and critical care settings, predicts fluid responsiveness with a sensitivity of 31–70% and specificity of 80–97%.32 Despite the lower accuracy of IVC collapsibility, following the American Society of Echocardiography guidelines,33 an IVC size < 2 cm and collapsibility index > 50%, are used to predict low CVP in spontaneously breathing patients, and rule out high CVP (Figure 3.3, Table 3.1). In the obstetric population, Brun et al. have assessed stroke volume changes with PLR and IVC-collapsibility index (with and without PLR) to predict fluid responsiveness.34,35 In a population of 23 women diagnosed with preeclampsia (PreE) with severe features and oliguria, a change in VTI (ΔVTI) > 12% with PLR, predicted a 15% increase in SV after a fluid bolus of 500 ml normal saline (NS) with a sensitivity and specificity of 100% (95% CI: 0.74–1.00 and 0.75–1.00, respectively).34 Predictive accuracy of IVC collapsibility index was significantly lower and reported with an area under the curve receiver operating characteristics of 57% (95% CI: 0.32–0.82). Spinal hypotension in 40 healthy women at term undergoing elective cesarean delivery (CD), was predicted by a ΔVTI with PLR with a sensitivity, specificity, positive and negative predictive value of 94%, 73%, 70%, and 85%, respectively. Authors reported no spinal hypotension when ΔVTI with PLR was < 8%, but it always occurred if ΔVTI with PLR > 21%.35 To conclude, fluid responsiveness can be accurately predicted by measuring changes in stroke volume with PLR. However, this requires pulsed-wave Doppler flow measurements, which is beyond the scope of FoCUS and requires more advanced echocardiographic skills.

20 https://doi.org/10.1017/9781009070256.004 Published online by Cambridge University Press

Video 3.2  Loops 1 and 2 show a normal left ventricle followed by left ventricular failure from parasternal short axis view. Loops 3 and 4 show the same patients but viewed from subcostal long axis view.*

FoCUS in Preeclampsia Hypertensive disorders in pregnancy are the leading cause of maternal mortality in developed countries and Latin America and significantly contribute to pregnancy-related mortality in Asia and Africa.36,37 Following recommendations defined by the American College of Obstetrics and Gynecology, PreE is characterized by new onset arterial hypertension after 20 weeks gestation and proteinuria, or, in the absence of proteinuria, by new onset of arterial hypertension and signs of end-organ involvement, including renal insufficiency, impaired liver function, cerebral or visual symptoms, thrombocytopenia, or pulmonary edema.38 Hemodynamic studies revealed that women diagnosed with PreE initially present in a hyperdynamic state. After treatment with antihypertensive medications and parenteral administration of magnesium sulphate, some develop a reduction in LV-stroke work index, and increased LVEDP.39 Comparing cardiac function between women diagnosed with PreE and healthy pregnant volunteers, echocardiographic studies indicate an increase in CO, left ventricular mass, left atrial size, and preserved systolic function in most women.40–41 In a small subset of women, especially when PreE is diagnosed preterm, a significant reduction in systolic function occurs.42 In both preterm and term PreE, global diastolic dysfunction is found in 40–50% of patients. Pronounced diastolic dysfunction may lead to elevated LVEDPs, increasing the risk of pulmonary edema.11 A FoCUS exam can confirm preserved systolic function, but advanced echocardiography, including tissue and blood flow Doppler techniques, are needed to detect diastolic dysfunction and raised LVEDPs. Pulmonary US is highly sensitive in detecting increased extravascular lung water and pulmonary edema.43,44 Interstitial pulmonary edema, indicated by a B-pattern on lung US, can be found in 20–25% of women with PreE.45,46 Since pulmonary US seems to be an easier skill to learn than cardiac US,47 some authors suggest that absence of a B-pattern on lung US be * LV=left ventricle1

FoCUSed Cardiac Ultrasound for Cardiac Disorders

used to exclude the presence of raised LVEDPs or systolic dysfunction in PreE.16 As mentioned above, measuring a change in VTI with PLR is highly accurate in predicting fluid responsiveness in women with PreE and severe features.34 Valuable Clinical Insight The absence of a B-pattern on lung ultrasound is used to exclude the presence of raised LVEDPs and systolic dysfunction in PreE.

FoCUS in SARS-CoV2 (COVID-19) Cardiac complications of COVID-19 may include myocardial injury, heart failure, cardiogenic shock, and cardiac dysrhythmias, including sudden cardiac arrest48 (see Chapter 22). A valuable role for FoCUS has been to differentiate between primary cardiac disease or COVID-19-related myocardial damage. Heart failure can be precipitated by acute illness in COVID-19 patients with preexisting known or undiagnosed heart disease (e.g., coronary artery disease or hypertensive heart disease). In a case series of 154 pregnant women with COVID-19 infection, 15 women became critically ill requiring ICU admission. Decreased LVEF and elevated cardiac enzymes occurred in all of these critically ill patients, with a mortality rate of 13% (two patients) due to dysrhythmia.49 In a case report, two out of seven pregnant women developed cardiomyopathy (LV ejection fraction of 40–45%) during severe COVID-19 disease. Both of them were obese with elevated cardiac biomarkers, presenting at 33 and 39 weeks of pregnancy.50 FoCUS views recommended in COVID-19 patients include PSAX, PLAX, SLAX, or SIVC. The goal of a FoCUS exam is to qualitatively assess LV systolic function, RV size and contractility, gross regional wall motion abnormalities, and pericardial effusion. In prone position ventilation, one arm abducted above the shoulder allows an apical view. COVID-19 is also associated with activation of coagulation cascade leading to a hypercoagulable state, increasing the risk of DVT, pulmonary hypertension, and fulminant pulmonary embolism.51 RV dysfunction or signs of acute pulmonary hypertension can be rapidly assessed by FoCUS. Although FoCUS has a low sensitivity for the diagnosis of pulmonary embolism, it is highly specific in the setting of fulminant pulmonary embolism leading to cardiovascular collapse, especially in patients without any prior cardiovascular disease.52

Training Currently, there is no defined process to obtain certification in FoCUS in obstetric anesthesia or obstetric critical care. However, some critical care societies and physician groups worldwide have created the following framework for organizing training in basic and advanced critical care echocardiography.53,54 1. Examples of competencies in basic critical care echocardiography:

(a) Theoretical program: • 10 hours (minimum) of standard lectures or internet-based learning (b) Required number of examinations: • 30 fully supervised TTEs (minimum) defined as a reasonable target to teach image acquisition, but to be determined on an individual basis (c) Logbook: • Each study performed and interpreted by trainee is to be reported and documented by the trainee • Each report is to be cosigned by trainee and supervisor (d) Minimum number of cases of each clinical syndrome: • No consensus • Comprehensive panel of important abnormal images must be part of regular didactic training and image review (e) Training in transesophageal echocardiography (TEE) is optional (f) No certification is required 2. Examples of competencies in advanced critical care echocardiography: (a) Minimum theoretical program: • Estimated 40 hours of standard lectures or internet-based learning • Mastery of standard cardiology textbook (except complex congenital cardiac disease and stress echocardiography) (b) Required minimum number of examinations: • 100 personally performed TTEs, partially under direct supervision • Minimum of 35 full TEE studies (c) Logbook: • Each study performed and interpreted by trainee is to be reported and documented by the trainee • Each report is to be cosigned by trainee and supervisor (d) Minimum number of cases of each clinical syndrome: • No consensus • Comprehensive panel of important abnormal images must be part of regular didactical training and image review (e) Training in transesophageal echocardiography (TEE) is mandatory (f) Examination of Special Competence in Critical Care Echocardiography (CCEeXAM) offered by National Board of Echocardiography (NBE) (g) Certification available These are national and internationally suggested training frameworks to achieve basic competency in FoCUS or advanced competency in critical care echocardiography.

21 https://doi.org/10.1017/9781009070256.004 Published online by Cambridge University Press

Clemens M. Ortner and M. Waseem Athar

Focus Assessed Transthoracic Echo (FATE)

Focus Assessed Transthoracic Echo (FATE) Scanning through position 1–4 in the most favourable sequence

Basic FATE views º Point right (patient’s left)

Point right º (patient’s left back)

RA

LA

Pos 1: Subcostal 4-chamber

Dimensions and contractility: (LVDd - LVSd) FS = LVDd EF~2 × FS

LA

Pos 2: Apical 4-chamber Point right º (patient’s left shoulder)

º Point left (patient’s right shoulder)

RV LV

LV

RV

LV

LV

RV-wall ~5 mm RV 2.0–3.0 cm IVS 6–10 mm

RV AO

LV

LA

Left

Right

MSS< 1 cm

LV

LVDd 3.5–5.5 cm LVSd 2.0–4.0 cm

PW

6–10 mm

LA diam. ~3.5 cm

Start of QRS (LVDd)

Diaphragm

Systole: Preload Afterload Contractility Heart rate

3

Lung

2

1

4

4

Pos 4: Pleural scanning

Max. post wall contract (LVSd)

time

The global function of the heart is determined by the interaction between: Right ventricle

Liver/spleen

Aorta AO diam. ~3.5 cm

Pos 3: Parasternal long axis Pos 3: Parasternal LV short axis ° Point cranial

MV

Left ventricle

Diastole: Compliance Relaxation Heart rate

Systole: Preload Afterload Contractility Heart rate

Diastole: Compliance Relaxation Heart rate

Hemodynamic instability, perform a systematic evaluation of these determinants plus concomitant pathology: (e.g., pericardial effusion, pulmonary embolus, pleural effusion, pneumothorax, valvulopathy, dissection, defects)

Important pathology 1

2

Extended FATE views

3

º Point cranial

RV RA

RV

RV

RA

LV

LA

LA

LV

LV

RA LA

RA

Pos 1: Subcostal Vena Cava RV

LA

RA

LA

10

Pos 3: Dilated LV

AO

Pos 2: Apical Long - axis

LV

LV

LA

Pos 3: Dilated LV + LA

AO

LA

Pos 2: Apical 5 - Chamber

A3

A2

A1

º Point right Point right º (patient’s left (patient’s left shoulder) shoulder) P1

RV R

RA

P2

NC L

PA

LA

Pos 3: Parasternal short axis mitral plane Pos 3: Parasternal aorta short axis RV

LV

LA

Pos 3: Hypertrophy LV + Dilated LA

RV

P3

12

LV

LV

AO

Pos 3: Dilated RV

RV LV

LA

Point right º (patient’s back) RV

AO

11

RV

º Point left (patient’s right RV shoulder)

LV

Pos 2: Dilated LA + LV

RV

Pos 3: Pericardial effusion

0°

LV

9 RV

LV

Pos 2: Apical 2 - Chamber

120°

LV

8

RV

LA

Pos 1: Dilated LA + LV

Pos 2: Pericardial effusion Pos 2: Dilated RA + RV 7

LV

IVC

6 RV

Point right º (patient’s left shoulder)

RA

5 RV

LV

LA

Pos 1: Pericardial effusion Pos 1: Dilated RA + RV 4

LIVER

RA

60°

Pos 3: Hypertrophy LV

PATHOLOGY TO BE CONSIDERED IN PARTICULAR: Post OP cardiac surgery, following cardiac catheterisation, trauma, renal failure, infection. Pulmonary embolus, RV infarction, pulmonary hypertension, volume overload. Ischemic heart disease, dilated cardiomyopathy, sepsis, volume overload, aorta insufficiency. Aorta stenosis, arterial hypertension, LV outflow tract obstruction, hypertrophic cardiomyopathy, myocardial deposit diseases.

22 https://doi.org/10.1017/9781009070256.004 Published online by Cambridge University Press

2

CW: Peak pressure: V x 4; AO < 2 m/s; PA < 1 m/s; TI < 2.5 m/s PW: Mitral Inflow desc. time 140–240 ms; MAX E < 1.2 m/s; E/A > 1 (Age dependent) TVI: E/é < 8–10; IVC < 20 mm; 50% collaps during inspiration is normal Systolic Ventricular Function M-Mode Normal Ventricle 55 LV Pos 3, PS long EF (%) LV Pos 3, PS long FS (%) 25 LV Pos 3, PS long MSS (mm) < 10 LV Pos 2, AP 4ch Mapse (mm) 11 RV Pos 2, AP 4ch Tapse (mm) 16 – 20 Right and left ventricle Eye Balling use all views

Mild 45 – 54 20 – 24 7 – 12 9 – 10 11 – 15

Moderately 30 – 44 15 – 19 13 – 24 6–8 6 – 10

Severely < 30 < 15 > 24 100 mmHg, HR 120 beats/ min, a RR 30 breaths/min, oxygen saturation on room air < 95%, and urine output < 35 ml/h over 2 hours. Symptoms that meet the criteria include agitation, confusion, unresponsiveness, or patients with PreE reporting headaches or shortness of breath. When early warning signs are present, providers should obtain further data such as laboratory tests, echocardiography, chest imaging, and ECG.

Valuable Clinical Insights • Signs and symptoms of cardiac disease are similar to those of normal pregnancy. • There should be a lower threshold for additional evaluation of progressive fatigue, dyspnea, and orthopnea in patients with cardiac disease.

Challenging Cardiac Disorders in Pregnancy

General Management Principles of Pregnant Women with Heart Disease Preconception Counseling and Risk Stratification of the Maternal Cardiac Patient Contraceptive and preconception counseling is recommended for women of childbearing age with cardiac disease.25 Preconception counseling should address maternal cardiac risk, maternal obstetric risk, fetal and neonatal risks, maternal life expectancy, contraception safety and efficacy, cardiac status optimization, and pregnancy planning. Risk assessment should include a complete history and physical examination and, when indicated, ECG and TTE. Further clinical and imaging information may be part of the risk assessment and includes: cardiac computed tomography, cardiac MRI, exercise stress testing, and BNP.10 These patients should be seen regularly throughout their pregnancy and develop management plans early. Depending on the clinical progression of symptoms, a delivery plan may need adapting to meet the new demands of mother and baby. The coordination of the multidisciplinary care team is key to the successful management of women with cardiac disease.26

Table 4.4  Anticoagulation regimen recommendations in pregnancy

Anticoagulation regimen

Anticoagulation dosage

Prophylactic LMWH*

Enoxaparin, 40 mg SC once daily Dalteparin, 5,000 units SC once daily Tinzaparin, 4,500 units SC once daily Nadroparin, 2,850 units SC once daily

Intermediate-dose LMWH

Enoxaparin, 40 mg SC every 12 hours Dalteparin, 5,000 units SC every 12 hours

Adjusted dose (therapeutic) LMWH**

Enoxaparin, 1mg/kg every 12 hours Dalteparin, 200 units/kg once daily Tinzaparin, 175 units/kg once daily Dalteparin, 100 units/kg every 12 hours Target an anti-Xa level in the therapeutic range of 0.6–1.0 units/ml 4 hours after last injection for twice-daily regimen; slightly higher doses may be needed for a once-daily regimen.

Prophylactic UFH

UFH, 5,000–7,500 units SC every 12 hours in the third trimester, unless the aPTT is elevated.

Adjusted dose (therapeutic) UFH**

UFH, 10,000 units or more SC every 12 hours in doses adjusted to target aPTT in the therapeutic range (1.5–2.5 × control) 6 hours after injection.

Postpartum anticoagulation

Prophylactic, intermediate, or adjusted dose LMWH for 6–8 weeks as indicated. Oral anticoagulants may be considered postpartum based upon planned duration of therapy, lactation, and patient preference.

Surveillance

Clinical vigilance and appropriate objective investigation of women with symptoms suspicious of deep vein thrombosis or pulmonary embolism. VTE risk assessment should be performed prepregnancy or early in pregnancy and repeated if complications develop, particularly those necessitating hospitalization or prolonged immobility.

Anticoagulation during Pregnancy and Peripartum Pregnancy is generally a prothrombotic state. Women with low ejection fractions, mechanical valves, or dysrhythmias may require anticoagulation in pregnancy. There is a four- to fivefold increased risk of VTE in pregnancy. Approximately 75% of pregnancy-associated VTE are DVTs, and 25% are pulmonary emboli. About one-half of these events occur during pregnancy and one-half postpartum.27 The risk of VTE is highest in the third trimester, but the most critical risk factor is a personal history of VTE, followed by the presence of thrombophilia. Anticoagulation therapy in women during pregnancy poses potential maternal and fetal complications. Discuss the risks and benefits before initiating anticoagulation therapy. Common anticoagulation medications include LMWH, UFH, and warfarin. ACOG Practice Bulletin 196 describes a standard anticoagulation regimen for pregnancy27 (Table 4.4). Heparin compounds do not cross the placenta. Because of increased maternal blood volume, glomerular filtration, and protein binding, heparin compounds have shorter half-lives and lower peak plasma levels in pregnancy, so a therapeutic level may require higher doses. Pregnancy in women with prosthetic heart valves is associated with increased morbidity and mortality, and the choice between bioprosthetic and mechanical valves in young women is challenging. Bioprosthetic valves offer a lower risk of VTE and do not require anticoagulation; but, in women of childbearing age, structural valve deterioration can occur within two to three years.28 Mechanical valves offer excellent durability but require lifelong anticoagulation. Adequate anticoagulation during pregnancy is critical as the hypercoagulable state of pregnancy increases the risk of VTE. Recent recommendations by the European Society of Cardiology and the American College of Cardiology & American Heart Association for anticoagulation

Abbreviations: aPTT, activated partial thromboplastin time; INR, international normalized ratio; LMWH, low-molecular-weight heparin; SC, subcutaneously; UFH, unfractionated heparin; VTE, venous thromboembolism. * Although at extremes of body weight, modification of dose may be required. ** Also referred to as weight-adjusted, full treatment dose.

during pregnancy in women with mechanical heart valves are listed in Table 4.5.28 Planning neuraxial techniques around anticoagulation requires multidisciplinary planning, which assesses the risks of pausing anticoagulation given the type of valve and risk for a thrombotic event, versus the hemodynamic and airway risks of labor and delivery without NA. Valuable Clinical Insight As pregnancy is a hypercoagulable state, anticoagulation is essential in pregnant women with prosthetic heart valves. Decision to use NA requires input from cardiac team and hematologist.

Anesthetic Considerations An anesthetic-specific evaluation before delivery can assist in developing patient-centered plans and recommendations. An anesthetic evaluation allows the anesthesia provider to obtain

29 https://doi.org/10.1017/9781009070256.005 Published online by Cambridge University Press

Hanna Hussey, Patrick Hussey, and Marie-Louise Meng

Table 4.5  Guideline-recommended anticoagulation for pregnant patients with a mechanical prosthetic heart valve

American Heart Association/American College of Cardiology 2013 Class I 1. Therapeutic anticoagulation with frequent monitoring is recommended for all pregnant patients with a mechanical prosthesis (Level of Evidence: B). 2. Warfarin is recommended in pregnant patients with a mechanical prosthesis to achieve therapeutic INR in the second and third trimesters (Level of Evidence: B). 3. Discontinuation of warfarin with initiation of intravenous UFH (with an aPTT >2× control) is recommended before planned vaginal delivery in pregnant patients with a mechanical prosthesis (Level of Evidence: C). 4. Low-dose aspirin (75–100 mg) once per day is recommended for pregnant patients in the second and third trimesters with either a mechanical prosthesis or bioprosthesis (Level of Evidence: C). Class IIa 1. Continuation of warfarin during the first trimester is reasonable for pregnant patients with a mechanical prosthesis if the dose of warfarin to achieve a therapeutic INR is ≤5 mg/day, after full discussion with the patient about risks and benefits (Level of Evidence: B)* 2. Dose-adjusted LMWH at least twice per day (with a target anti-Xa level of 0.8 U/ml to 1.2 U/ml, 4–6 h post-dose) during the first trimester is reasonable for pregnant patients with a mechanical prosthesis if the dose of warfarin is >5 mg/day to achieve a therapeutic INR (Level of Evidence: B)* 3. Dose-adjusted continuous intravenous UFH (with aPTT at least 2× control) during the first trimester is reasonable for pregnant patients with a mechanical prosthesis if the dose of warfarin is >5 mg/day to achieve a therapeutic INR (Level of Evidence: B)*

European Society of Cardiology 20113 Class I C • OACs are recommended during the second and third trimesters until the thirty-sixth week. • Change of anticoagulation regimen during pregnancy should be implemented in hospital. • If delivery starts while on OACs, cesarean delivery is indicated. • OAC should be discontinued and dose-adjusted UFH (aPTT 2× control) or adjusted-dose LMWH (target anti-Xa level 4–6 h post-dose 0.8–1.2 U/ml) started at the thirty-sixth week of gestation. • In pregnant women managed with LMWH, the post-dose anti-Xa level should be assessed weekly. • LMWH should be replaced by intravenous UFH at least 36 h before planned delivery. UFH should be continued until 4–6 h before planned delivery and restarted 4–6 h after delivery if there are no bleeding complications. • Immediate echocardiography is indicated in women with mechanical valves presenting with dyspnea and/or an embolic event. Class IIa C • Continuation of OACs should be considered during the first trimester if the warfarin dose required for therapeutic anticoagulation is 3 mg/day or acenocoumarol >2 mg/day). Class IIb C • Discontinuation of OACs between weeks 6 and 12, and replacement by UFH or LMWH under strict dose control (as described earlier), may be considered on an individual basis in patients with a warfarin dose required for therapeutic anticoagulation >5 mg/day (or phenprocoumon >3 mg/day or acenocoumarol >2 mg/day).* • Continuation of OACs may be considered between weeks 6 and 12 in patients with a warfarin dose required for therapeutic anticoagulation >5 mg/day (or phenprocoumon 5 d

LMWHs (for treatment)

24 h

4 h

Platelets during treatment for >5d

Fondaparinux (for prophylaxis, 2.5 mg/d)

36–42 h

6–12 h

(Anti-factor Xa, standardized for specific agent)

Rivaroxaban (for prophylaxis, 10 mg daily)

22–26 h

4–6 h

(Anti-factor Xa, standardized for specific agent)

Apixaban (for prophylaxis, 2.5 mg BID)

26–30 h

4–6 h

(Anti-factor Xa, standardized for specific agent)

Dabigatran (for prophylaxis, 150–220 mg)

Contraindicated according to the manufacturer

6 h

TT

Coumarins

INR ≤1.4

After catheter removal

INR

Hirudin (desirubin)

8–10 h

2–4 h

aPTT, ECT (ecarin clotting time)

Argatroban

4 h

2 h

aPTT, ECT, ACT (activated clotting time)

Acetylsalicylic acid

None

None

Clopidogrel

7d

After catheter removal

Ticlopidine

10 d

After catheter removal

Prasugrel

7–10 d

6 h after catheter removal

Ticagrelor

5d

6 h after catheter removal

Cilostazol

42 h

5 h after catheter removal

NSAIDs

None

None

*All time intervals refer to patients with normal renal function. Prolonged time interval in patients with hepatic insufficiency. Adapted from Gogarten et al.39

cardiac disease on anticoagulants. The ASRA and European Society of Anesthesiology Guidelines39,40 (Table 4.8) and the SOAP consensus statement41 (Figures 4.1 and 4.2) can help guide decision-making. For NA, an epidural catheter technique (epidural, DPE, or CSE) allows incremental injection of LA to slow the onset of sympathectomy. At the same time, titration of vasopressors avoids hemodynamic alterations in women with cardiac disease. A CSE technique with intrathecal opioids facilitates rapid analgesia and sacral root coverage; one can slowly dose the epidural catheter with LA to the desired effect. A dural puncture not only aids sacral coverage but guides the correct placement of the epidural needle and subsequent catheter.42 The anesthesia provider must carefully select the test dose when using an epidural catheter. “Testing” the catheter by slowly titrating dilute LA and fentanyl may be appropriate depending on the severity and type of cardiac lesion. Avoid the typical test dose of 3 ml of lidocaine 1.5% or 2% with 1:200,000 epinephrine (15 mcg) in patients where epinephrine could have deleterious effects on the maternal cardiovascular system (i.e., stenotic heart lesions or aortic disease).43 One can maintain labor analgesia by either continuous epidural infusion or programmed intermittent boluses.

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When considering an anesthetic technique for the parturient with cardiac disease undergoing CD, it is vital to maintain baseline hemodynamic parameters, maintain preload, and avoid reflex tachycardia. Tachycardia increases myocardial oxygen demand and decreases diastolic coronary perfusion time. Avoiding shivering is imperative as it increases oxygen consumption. Using warmed IV fluids, forced air warmers, and increasing operating room temperature can help achieve this goal. Neuraxial anesthesia is also appropriate for CD. Depending on the cardiac lesion, spinal anesthesia may not be optimal for maintaining the baseline hemodynamic profile, since it induces rapid hemodynamic changes. A slowly titrated epidural anesthetic maintains a favorable hemodynamic profile in specific cardiac lesions. The decision to use spinal or epidural anesthesia requires consideration of block reliability, titratability, as well as the hemodynamic ramifications. Another option is a low-dose CSE consisting of low doses of subarachnoid LA or opioid-only subarachnoid dosing. A CSE allows an increased rate of successful catheter placement, use of intrathecal opioids, sacral LA coverage, decreased sympathetic stimulation from delivery or surgery, and the benefit of slowly and continuously titrating LA to a T4 to T6 surgical level.44–46 However, the duration of reliable

Challenging Cardiac Disorders in Pregnancy

UFH SQ INTERMEDIATE DOSE

UFH SQ HIGH DOSE

(5000U twice or three times daily)

(7500U or 10,000U twice daily) Total daily dose 20,000U

(individual dose > 10000U per dose) Total daily dose > 20000U

> 4–6 hours since last dose

12 hours since last dose

24 hours since last dose

UFH SQ LOW DOSE

Yes

No

Yes

Coagulation status available: aPTT within normal range or anti factor Xa level is undetectable Yes

No

No

Coagulation status available: aPTT within normal range or anti factor Xa level is undetectable

No

Yes

MINIMAL DATA TO GUIDE RISK ASSESSMENT

LIKELY LOW RISK TO

PROCEED WITH NEURAXIAL

Coagulation status available: aPTT within normal range or anti factor Xa level is undetectable

No

ASSESS DIFFICULT AIRWAY & BALANCE RELATIVE RISKS OF GA COMPARED TO SEH BASED ON URGENCY OF CLINICAL SITUATION & PATIENT COMORBIDITIES

Yes

No

Yes

CONSIDER NOT PROCEEDING WITH NEURAXIAL

MAY BE INCREASED RISK FOR SEH

Figure 4.1  Decision aid for urgent or emergent neuraxial procedures in the obstetric patient receiving UFH. *Assume normal renal function, body weight > 40 kg, and no other contraindications to neuraxial anesthesia. aPTT indicates activated partial thromboplastin time; GA, general anesthesia; SEH, spinal epidural hematoma; SQ, subcutaneous; UFH, unfractionated heparin. Note: This SOAP consensus statement is not intended to set out a legal standard of care and does not replace medical care or the judgment of the responsible medical professional considering all the circumstances presented by an individual patient. From Leffert L, Butwick A, Carvalho B, et al.41

LOW DOSE LMWH

INTERMEDIATE DOSE LMWH

HIGH DOSE LMWH

e.g. enoxaparin 40 mg SQ once daily or 30 mg SQ twice daily or dalteparin 5000U SQ once daily

e.g. enoxaparin > 40 mg SQ once daily or 30 mg SQ twice daily and < 1 mg/kg SQ twice daily or 1.5 mg/kg SQ once daily or dalteparin > 5000U SQ once daily and < 120U/kg SQ twice daily or 200U/kg SQ once daily

e.g. enoxaparin: 1 mg/kg SQ twice daily or 1.5 mg/kg SQ once daily or dalteparin: 120U/kg SQ twice daily or 200U/kg SQ once daily

12 hours since last dose

INSUFFICIENT PUBLISHED DATA TO RECOMMEND A

24 hours since last dose

SPECIFIC INTERVAL BETWEEN 12 AND 24 HOURS TO

No

Yes

DELAY NEURAXIAL ANESTHESIA

Yes

No

LIKELY LOW RISK TO PROCEED WITH NEURAXIAL

CONSIDER NOT PROCEEDING WITH NEURAXIAL BALANCE POTENTIAL INCREASED RISK FOR SEH WITH RISK OF GA

Figure 4.2  Decision aid for urgent or emergent neuraxial procedures in the obstetric patient receiving LMWH. *Assume normal renal function, body weight >40 kg, and no other contraindications to neuraxial anesthesia. GA indicates general anesthesia; LMWH, low molecular weight heparin; SEH, spinal epidural hematoma; SQ, subcutaneous. Note: This SOAP consensus statement is not intended to set out a legal standard of care and does not replace medical care or the judgment of the responsible medical professional considering all the circumstances presented by an individual patient. From Leffert L, Butwick A, Carvalho B, et al.41 https://doi.org/10.1017/9781009070256.005 Published online by Cambridge University Press

33

Hanna Hussey, Patrick Hussey, and Marie-Louise Meng

anesthesia with a low-dose LA block needs to be weighed against surgical considerations. CSE can be helpful in specific cardiac lesions due to superior reliability and symmetry of intrathecal LA with greater control of the level of sympathectomy compared to single-shot spinal anesthesia.47 Although one can treat thrombocytopenia with platelet administration before NA, this practice lacks consensus and requires individualized judgment.48 The anesthetic plan is highly dependent on the type of lesion and the severity of the cardiac symptoms.49 If GA is necessary use opioids and betablockers to blunt the cardiovascular response to endotracheal intubation and surgery. Use advanced hemodynamic monitoring if indicated by maternal physiology and current condition. An arterial line allows for beat-to-beat monitoring of BP for preload-dependent patients, such as aortic stenosis or hypertrophic obstructive cardiomyopathy, and arterial blood gas sampling. Central venous line placement allows administration of caustic vasoactive and inotropic agents, rapid infusion of blood products and can serve as an introducer for a pulmonary artery catheter. A pulmonary artery catheter can monitor central venous pressure, pulmonary artery pressures, CO and measure mixed venous oxygenation. In patients with cardiomyopathy or pulmonary hypertension, interpretation of these values, and delivery of vasoactive and inotropic agents, are valuable in emergent situations.50 For the patient requiring ECMO on standby, placement of 4F or 5F micropuncture catheters predelivery can facilitate ECMO deployment if required. The most significant hemodynamic changes in a CD occur immediately after delivery of the fetus and last for several days postpartum. After removing the fetus and placenta from the uterus, the uterus contracts and no longer compresses the IVC. This results in an immediate increase in preload, 500–1000 ml, to the right atrium and ventricle; maternal decompensation can occur if the right or left heart or pulmonary vasculature cannot accommodate this large preload. Postpartum inotropic support is imperative especially with those cardiac lesions impairing pulmonary and right heart function. Pulmonary vasodilators assist the accommodation of the large preload through the pulmonary circulation in women with pulmonary hypertension.10 Additionally, precordial Doppler changes indicate that air emboli occur in up to 65% of women undergoing CD.51 We recommend the surgical team avoid uterine exteriorization in women with high-risk lesions that would not tolerate acute increases in pulmonary artery pressure due to air emboli.

Uterotonic Agents When administering uterotonic agents, consider the medication and its possible side effects. Women with cardiac disease are twice as likely to experience PPH.52,53 Table 4.9 summarizes the cardiovascular effects of commonly used uterotonic agents. Oxytocin is the most common uterotonic used for active management of the third stage of labor, since it reduces hemorrhage, compared to deliveries where oxytocin is not used. Low-dose oxytocin infusions do not cause adverse cardiac outcomes.54 However, higher bolus doses of oxytocin (e.g., 5 or 10 units parenteral bolus) can cause severe hypotension and cardiovascular collapse, especially in volume-depleted states, so we recommend administering oxytocin via an infusion pump.55 Doses of oxytocin greater than the ED95 are not more effective than lower doses (16 U/h in nonlaboring women undergoing CD and 44 U/h in laboring women undergoing CD) but result in more hypotension without further augmentation of uterine contraction. Prostaglandin F derivatives may increase pulmonary vascular resistance by 100% and pulmonary artery pressures by 125%, detrimental in someone with asthma, heart failure, or pulmonary hypertension.56 Methylergonovine interacts with alpha-adrenergic receptors and causes coronary, peripheral, and pulmonary vasoconstriction. Methylergonovine is contraindicated in patients with hypertension, PreE, aneurysms, or coronary artery disease.57 Valuable Clinical Insight Use uterotonic agents cautiously as they may have undesirable side effects for many cardiac lesions.

Peripartum and Postpartum Monitoring Consider the severity of the cardiac lesion, the planned obstetric procedure, and anesthetic intervention when determining the level of monitoring. Appropriate cardiac monitoring is crucial when trying to prevent cardiac events. Pulse oximetry with a visible waveform can assist providers in assessing the accuracy of the reading. Consider five lead ECG telemetry for any patient Table 4.9  Cardiovascular effects of commonly used obstetric drugs

Medication

Cardiopulmonary effects

Relative CI

Oxytocin

Decrease SVR and MAP

Well tolerated with low-dose infusions

Valuable Clinical Insights

Misoprostol

Decrease SVR

• The hemodynamic changes of vaginal delivery are less than a CD. • Vaginal delivery with well-working NA is generally the best delivery technique, although some exceptions apply. • There should be a low threshold for intraarterial monitoring in patients with moderate to severe cardiac lesions undergoing labor and delivery.

Methylergonovine

Increase SVR and PVR

HTN/PEC, pulmonary HTN, coronary artery disease, aortopathy

Carboprost

Bronchospasm and increase PAP

Pulmonary HTN, intracardiac shunt

Terbutaline

Increase HR

HOCM, stenotic valvular lesions, tachydysrhythmias

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Challenging Cardiac Disorders in Pregnancy

with a history of malignant dysrhythmia or at risk for ischemia. Perform noninvasive BP monitoring at regular intervals but consider intraarterial BP monitoring in patients at risk for hemodynamic instability. Central venous pressure monitoring has low utility in labor. A peripherally inserted central venous line helps deliver inotropic and vasopressor agents. Internal jugular central lines may be reserved as conduits for pulmonary artery catheters when monitoring a patient with pulmonary hypertension or anticipating massive hemorrhage.58 Patients with mWHO class III/IV lesions or those who have experienced any complications may require advanced monitoring in intensive care or a step-down unit.59 Postpartum diuresis facilitates recovery with close monitoring of volume intake and urine output, in turn preventing late dysrhythmias and heart failure. A heart failure diet with low sodium helps prevent unwanted fluid accumulation. The postpartum period is the most critical time to monitor for maternal cardiac complications. Preload is increased in the postpartum period secondary to the relief of IVC obstruction from the gravid uterus and autotransfusion of blood from the contracting uterus. These physiologic changes can increase the risk for cardiac decompensation in high-risk patients. Patients at risk for postpartum decompensation include the following: pulmonary hypertension, right or left heart failure, significant diastolic dysfunction, and LV outflow tract obstruction.

Valvular Lesions In pregnancy, stenotic cardiac lesions are generally not well tolerated. Any symptomatic stenotic lesion warrants close attention and potential procedural correction before delivery.60,61 (Table 4.10) Mixed stenotic and valvular lesions often present a dilemma as to which lesion to treat and hemodynamic management goals to adopt. Generally, direct management to the most severe valvular lesion, but sometimes compromise is needed with these mixed valvular lesions. Women with preloaddependent valvular lesions (i.e., aortic, mitral stenosis) may not tolerate dysrhythmias, so treat promptly. As mentioned above, Table 4.10  Physiologic effects of and recommendations for valvular lesions in pregnancy

Valvular lesions

Effects on pregnancy and delivery

Management consideration

Mitral stenosis

Fixed preload, increased blood volume, increased HR increases left atrial pressure

Avoid tachycardia Maintain sinus rhythm Avoid beta agonist (i.e., terbutaline) Maintain normovolemia

Aortic stenosis

Decreased SVR can lead to decreased coronary perfusion

Maintain afterload Avoid tachycardia Maintain normovolemia

Mitral regurgitation Aortic regurgitation

Decreased SVR can lead to less regurgitant volume

Avoid bradycardia Maintain sinus rhythm Avoid increase in SVR Avoid decreases in contractility Consider afterload reduction

NA is an acceptable option for any of these patients, provided there is slow titration of LA and no contraindication (e.g., anticoagulation or patient refusal).

Valvular Repair and Prosthetic Valves There are many reports of successful pregnancy in patients with prior cardiac valvular surgery.62 The mWHO criteria can help risk-stratify which patients will tolerate the hemodynamic effects of pregnancy and delivery. Women who are asymptomatic at baseline often tolerate pregnancy well. Patients in mWHO groups III and IV need to receive care at Levels of Maternal Care 3 or 4.7 Women with prosthetic valves are at a higher risk of complications, including infection, thromboembolism, and bleeding, than those with repaired native valves.63 Women with valve disease who desire children may elect to receive bioprosthetic valves to avoid anticoagulation and thrombotic complications associated with mechanical valves.64 Unfortunately, bioprosthetic valves are accompanied by a higher rate of degeneration with corresponding stenosis or regurgitation.65 Should the patient have a mechanical valve, continue anticoagulation during pregnancy due to increased thrombotic complications from progesterone.63 In general, the risk of mechanical valve coagulation complications is highest with right-sided cardiac valves due to lower flow rates and lowest with the aortic valve due to its high flow rates.65 Maintain anticoagulation with warfarin if < 5 mg per day as low-dose warfarin is not associated with congenital deformities. Alternatively, bridging with heparin or LMWH is an acceptable option.65 Regardless of the patient’s age of valve replacement, a complete cardiac evaluation is essential to assess the functional status of a prosthetic valve. Prosthetic valves, well-functioning or not, can be associated with LV or RV dysfunction, pulmonary hypertension, and dysrhythmia.63 Consider invasive monitoring and tailor management goals and anesthetic considerations to the patient-specific lesion.

Cardiomyopathy Cardiomyopathy was responsible for 11.5% of pregnancyrelated deaths from 2014 to 2017.1 The New York Heart Association (NYHA) Functional Capacity and Objective Assessment (Table 4.11) categorizes patients with cardiomyopathy into different classes. It provides an objective numerical assessment of their functional status. Cardiomyopathy in pregnancy is classified as peripartum cardiomyopathy or preexisting cardiomyopathy. The latter includes ischemic cardiomyopathy, nonischemic cardiomyopathy, and hypertrophic obstructive cardiomyopathy.

Peripartum Cardiomyopathy Peripartum cardiomyopathy (PPCM) is a category of non­ ischemic cardiomyopathy. The National Institutes of Health defines PPCM based on four criteria: 1. Development of cardiac failure in six months (last month of pregnancy to within five months after delivery). 2. No identifiable cause of the cardiomyopathy.

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Hanna Hussey, Patrick Hussey, and Marie-Louise Meng

Table 4.11  New York Heart Association (NYHA) Functional Capacity and Objective Assessment

Functional capacity

Objective assessment

Class I: Patients with cardiac disease but without limitation of physical activity. Ordinary physical activity does not cause fatigue, palpitations, dyspnea or angina.

No objective evidence of cardiovascular disease.

Class II: Patients with cardiac disease resulting in slight limitation of physical activity. They are comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnea, or angina.

Objective evidence of minimal cardiovascular disease.

Class III: Patients with cardiac disease resulting in marked limitation of physical activity. They are comfortable at rest. Less than ordinary activity causes fatigue, palpitation, dyspnea, or angina.

Objective evidence of moderately severe cardiovascular disease.

Class IV: Patients with cardiac disease resulting in inability to carry on any physical activity without discomfort. Symptoms of heart failure or angina may be present even at rest. If any physical activity is undertaken, discomfort is increased.

Objective evidence of severe cardiovascular disease.

3. New diagnosis with no prior heart disease before the last month of pregnancy. 4. Ejection fraction 2.7cm/m2. The differential diagnosis includes alcoholism, toxins, thiamine deficiency, connective tissue disease, metabolic disorders, neuromuscular dystrophies, and infection. One must distinguish the signs and symptoms of heart failure from those of normal pregnancy. These symptoms include fatigue, dyspnea, orthopnea, and palpitations. Findings on physical examination can include crackles in the lungs, new regurgitant murmurs, raised jugular venous pressure and pitting edema. A CXR may reveal cardiomegaly and pulmonary edema, while an ECG may show dysrhythmias with nonspecific ST and T wave changes. Serial monitoring with echocardiography is recommended throughout the antepartum and postpartum periods.66 Peripartum cardiomyopathy may result from myocarditis secondary to viral or autoimmune etiology; however, it is a heterogeneous condition with multiple possible etiologies.67 Autopsies of women with PPCM demonstrate enlarged, dilated hearts with endocardial thickening and myocardial necrosis.68 Peripartum cardiomyopathy has a high mortality rate from cardiac failure, dysrhythmia, thromboembolism, or multiorgan failure. The prognosis worsens if the cardiac size and function do not return to baseline within 6 months of delivery.69 Fortunately, provided the PPCM patient receives full symptom support, 72% often recover full cardiac function (EF >50%) within 12 months.70 Takotsubo cardiomyopathy is like PPCM as it also is a diagnosis of exclusion, although associated with a psychosocial stressor.71 Also known as stress-induced cardiomyopathy, Takotsubo cardiomyopathy presents with similar symptoms (chest pain, palpitations, and dyspnea) to PPCM or dilated

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cardiomyopathy. It often resolves spontaneously within 1–2 months. Takotsubo cardiomyopathy is associated with specific echocardiographic findings of LV apical ballooning with normal basal contractility.72 Like dilated cardiomyopathy, Takotsubo cardiomyopathy is not associated with a single coronary artery territory.

Management Principles Treatment of PPCM is like managing any form of heart failure. The multidisciplinary team should manage care, including optimizing volume status with sodium and fluid restriction and diuretics. Loop diuretics are safe during pregnancy but avoid spironolactone.73 Afterload reduction with oral agents is the mainstay of medical management of PPCM. ACE inhibitors are contraindicated in pregnancy due to fetal renal teratogenicity but appear safe for breastfeeding women.74 All vasodilators have the potential to compromise uteroplacental blood flow. Inotropic agents such as digoxin, dopamine, dobutamine, or milrinone are safe in pregnancy. Beta-blockers improve outcomes in dilated cardiomyopathy. Patients with PPCM are at increased risk of sudden death due to dysrhythmias; implantable defibrillators have increased the survival rates in these patients.69 Importantly, in patients with Takotsubo cardiomyopathy, LV outflow obstruction can occur due to increased basal contractility, and inotropic agents may be contraindicated.75 Peripartum cardiomyopathy not only produces a low-flow state by reducing CO, but as these patients are on bed rest and have diuresis induced hemoconcentration, they are at risk of VTE. Adequate anticoagulation is necessary, especially if the LVEF is 95 beats per minute (bpm). Women with a HR >100 bpm require further investigation.49 The 2015 Heart Rhythm Society consensus defines Inappropriate Sinus Tachycardia (IST) syndrome as a sinus HR >100 bpm at rest (with a mean 24h HR >90 bpm not due to primary causes) associated with distressing palpitations.50 There are a few instances of untreated IST progressing to cardiomyopathy. However, this resolves with treatment. This condition exists in the general population with an incidence of 1.2%.50 Less well documented in pregnant women,51 IST can cause maternal anxiety due to its distressing symptoms. Some features of this condition in parturients, such as resolution postpartum, suggest that IST during pregnancy could be a distinct form of IST. Ivabradine has successfully controlled the HR with minimal effect on FHR.51

Valuable Clinical Insight A sustained resting heart rate of 100 bpm or higher can be abnormal in pregnancy (nonlaboring) and requires further investigation, especially if associated with other worrisome signs or symptoms.

Uncommon Cardiac Dysrhythmias in Pregnancy

Postural Orthostatic Tachycardia Syndrome Postural Orthostatic Tachycardia Syndrome (POTS) has an overall incidence of 0.2%; it predominantly affects young females. There are two types; dysautonomia  with tachycardia associated with an upright position and hyperadrenergic type with an exaggerated response to beta-adrenergic stimulation. These patients have a low circulating blood volume. Valsalva maneuvers can trigger syncope. Obstetric anesthetic implications include hemodynamic instability with the upright position for NA and straining (Valsalva maneuvers) during the second stage. There is also the possibility of an exaggerated response when treating hypertension in pregnancy with beta-blockers or using beta stimulants to treat hypotension or tocolysis. Hence, it is essential to monitor BP closely during labor and anesthesia.52,53

Atrial Fibrillation in Structurally Normal Hearts in Pregnancy Atrial fibrillation (AF) can occur in pregnant women with structurally normal hearts.9 The majority of affected women develop the paroxysmal form of AF. Medication for rate control and antithrombotic agents are the mainstays of management. The CHADS2 and CHA2DS2-VASC scores determine the need for antithrombotic agents but have not been validated for pregnancy.

Complete Heart Block in Pregnancy Complete heart block, characterized by the total absence of conduction between atria and ventricles, is rare in pregnancy. Most of the evidence is in the form of case series.54,55 Some women in these series had temporary pacing wires inserted; others had on-site service. Most authors suggest that pacemakers are not necessary during pregnancy. Suri et al. used GA for two CDs in their series.56 They justified this on a theoretical concern that spinal anesthesia, with the sudden onset of sympathetic block, might worsen hypotension and bradycardia in patients with complete heart block. However, the authors note that incremental epidural top-ups or a low-dose CSE may avoid this complication. Case reports have described the progression of first- and second-degree AV blocks to complete heart block in nonpregnant patients. There are reports of other uncommon dysrhythmias in pregnancy: Chagas disease57 and Uhl anomaly.58

Dysrhythmias Associated with Peripartum Cardiomyopathy Dysrhythmias are an uncommon presentation of peripartum cardiomyopathy (PPCM).59 In a series of 19 patients with PPCM who had 24-hour continuous ECG monitoring, 89% showed sinus tachycardia, 37% premature ventricular contractions, 21% nonsustained VT, and one patient had first-degree atrioventricular block. Dysrhythmias contribute significantly to morbidity and mortality in women with PPCM. Ventricular tachydysrhythmias were thought responsible for more than a quarter of deaths in this population. A primary tachydysrhythmia such as IST

rarely causes cardiomyopathy. In women hospitalized with PPCM, dysrhythmias were present in 18.7%. Ventricular tachycardia followed by bundle branch blocks, AF, atrial flutter, and SVT were the most common forms of dysrhythmia.60

Antidysrhythmic Drugs in Pregnancy As with all drug treatments in pregnancy, the biggest concern with antidysrhythmic drugs is safety for mother and baby, but there is little safety data available. Most evidence and guidance come from animal studies, case reports, limited case series, or consensus statements. Another difficulty in treating dysrhythmias is that drugs with the longest historical safety profile are rarely used in the nonpregnant population and physicians are unfamiliar with them.61 The Pregnancy and Lactation Labeling Rule (PLLR)62 (Table 5.6) replaced the former USA FDA five-letter classification system for drug safety in pregnancy.63 The new narrative structure for labeling drugs in pregnancy better communicates the risks to the fetus in utero and the neonate during breastfeeding. This change removed a rigid categorization system, often misinterpreted by clinicians, allowing for individualized decision-making. Some authors still refer to the former categories (Table 5.7). A general approach to antidysrhythmic drugs in pregnancy should ask the following questions: • Is the drug necessary now, or is there a safer alternative? • What are the maternal effects? • What are the fetal effects, including the risk of teratogenicity? • Are dose adjustments required due to altered pharmacokinetics in pregnancy? • Can breastfeeding be undertaken safely? If possible, avoid antidysrhythmic drugs in the first trimester during organogenesis, and use the lowest effective dose with regular follow-up.61,64 Caveats to this advice exist for high-risk dysrhythmias such as LQTS, where nonselective beta-blockers should be continued during pregnancy and postpartum.65 In treatment decisions, use a multidisciplinary team approach involving cardiologists, obstetricians, anesthesiologists, and midwifery staff. Also, involve mothers in the decision-making process and discuss the risks and benefits of the proposed treatments. Dysrhythmias that cause maternal hemodynamic compromise can have profound adverse effects on fetoplacental blood flow and fetal wellbeing. When managing clinical emergencies and advanced cardiac life support (ACLS), do not withhold any medications from the mother due to concerns about fetal effects.65,66 During ACLS, standard drug doses are recommended.66

Beta-blockers The most frequently used drugs for cardiac conditions in pregnancy are beta-adrenergic antagonists.67,68 Labetalol, a first-line treatment for hypertension in women with PreE, has no role in managing dysrhythmias.69 Beta-blockers (except atenolol) are the first-line treatment for preventing paroxysmal SVT in pregnancy.65 In parturients with congenital LQTS, beta-blockers

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Ravishankar Agaram and Marie Davidson

Table 5.6  Former FDA classification of drug safety in pregnancy

Category

Definition

A

Adequate and well-controlled studies in pregnant women have failed to demonstrate a risk to the fetus in the first trimester of pregnancy

B

Animal reproduction studies have failed to demonstrate a risk to the fetus, and there are no adequate and well-controlled studies in pregnant women, or animal reproduction studies have shown adverse effects, but well-controlled studies in pregnant women have shown no adverse effects to the fetus

C

Animal reproduction studies have shown an adverse effect on the fetus, or there are no animal reproduction studies and no well-controlled studies in humans

D

Positive evidence of fetal risk, but benefits may outweigh risks

X

Positive evidence of fetal risk, and risks clearly outweigh any possible benefit

Table 5.7  FDA PLLR information summary Pregnancy (including labor and delivery): • Pregnancy exposure registry • Risk summary • Clinical considerations • Data Lactation: (replaces “nursing mothers”): • Risk summary • Clinical considerations • Data Females and males of reproductive potential: • Pregnancy testing • Contraception • Infertility

reduce the incidence of cardiac events during pregnancy and postpartum.70,71 Maternal exposure to beta-blockers at the time of delivery increases the risk of neonatal hypoglycemia and bradycardia.72,73 Therefore, one should monitor for these neonatal effects. While generally considered safe in pregnancy, these drugs cross the placenta with the potential for physiological effects after neonatal exposure in utero.73 Differentiation of risk between beta selectivity and individual drugs is not well studied in pregnancy. Several observational studies noted an association between beta-blocker exposure in pregnancy and SGA infants.74,75 Most studies examined beta-blocker use for hypertension, which can also affect intrauterine fetal growth.76 When considering betablockers for dysrhythmias, Duan and colleagues found the risk of SGA infants with metoprolol or propranolol exposure was like an unexposed group. In contrast, there was a significant risk for SGA with labetalol and atenolol when administered for dysrhythmias. Of note, this study did not eliminate indication for use as a possible confounder.77 One meta-analysis showed an association between oral beta-blocker exposure in the first trimester and congenital cardiovascular defects.78 A subsequent retrospective populationbased cohort study spanned 11 years and included 379,238

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pregnancies. There was no association between maternal exposure to beta-blockers (1.3%) and fetal congenital cardiac anomalies after adjusting for maternal comorbidities.67 Similarly, a population-based case-control study failed to find an association between beta-blocker exposure and fetal congenital anomalies.79 Propranolol is a nonselective beta-blocker and a preferred agent for managing LQTS type 1 and 2.80 It has a long history of use in pregnancy and is considered safe. Metoprolol is a shorter-acting beta-1-selective agent. It is used to treat and prevent maternal dysrhythmias such as SVT but exhibits significant changes in pregnancy-induced pharmacokinetics.81 Atenolol carries a former FDA class D rating; the European Society of Cardiology guidelines do not support its use for managing dysrhythmias in pregnancy.65 While widely used in the nonpregnant population, bisoprolol is relatively new in terms of pregnancy. Data are limited, and study numbers are small, but it does not appear to be a major teratogen when used in the first trimester.82 Outcomes concerning SGA infants are inconsistent.82,83 Esmolol is a short-acting, cardioselective beta-1 antagonist. In addition to the short-term management of SVT, esmolol infusion can be used in labor to suppress polymorphic ectopic burden in mothers with CPVT.35,84

Calcium Channel Blockers Pregnant patients receive calcium channel blockers (CCBs) to manage fetal and maternal tachydysrhythmias and for tocolysis. Like beta-blockers, CCBs cross the placenta, but their use in pregnancy does not significantly increase the risk of major congenital disabilities in humans.85,86 One retrospective study found an apparent increase in the risk of neonatal seizures associated with third trimester CCB use.86 The authors proposed hypocalcemia resulting from CCBs crossing the placenta as a reason for this association. There was no such association in a subsequent controlled cohort study of late pregnancy exposure to CCBs.87 Verapamil is indicated in pregnancy for the treatment and prevention of maternal PSVT without preexcitation, rate control of atrial tachycardia (AT) or AF if beta-blockers fail, and for fascicular VT.65,88 Avoid verapamil in the treatment of AF with preexcitation, i.e., WPW syndrome due to the risk of rapid accessory pathway conduction and resultant ventricular fibrillation.89 Diltiazem causes skeletal abnormalities in animal studies and is not recommended in pregnancy if alternatives are available.65,90

Sodium Channel Blockers Quinidine and procainamide are class 1a sodium channel blockers. The former has >70 years of safe use in pregnancy; neither is teratogenic.91 Consider procainamide for the acute conversion of sustained, monomorphic VT in pregnancy and AF with preexcitation.65,92 For inherited primary dysrhythmia syndromes, use quinidine to manage Brugada syndrome, short QT syndrome where there is a contraindication to ICD (even though patients qualify), and in early repolarization syndromes

Uncommon Cardiac Dysrhythmias in Pregnancy

with recurrent appropriate ICD shocks.93 Because of their propensity to prolong the QTc interval, avoid these drugs in LQTS. Lidocaine is a class 1b sodium channel blocker. It is used extensively in pregnancy for its LA properties with epidural administration and pudendal nerve infiltration. It carries a former FDA category B, but experience with IV administration in pregnancy is limited.94 In the general population, physicians administer lidocaine acutely to manage hemodynamically stable ventricular tachydysrhythmia. Flecainide is a class 1c sodium channel blocker. Flecainide is appropriate for both supraventricular and ventricular dysrhythmias in the absence of structural heart disease and prevents SVT in pregnant patients with WPW.65 It successfully prevents malignant dysrhythmias in preexcitation AF during pregnancy without fetal compromise and suppresses ventricular dysrhythmias in CPVT.34,93,95,96 Flecainide terminates fetal SVT with equal or greater efficacy than digoxin, without increased maternal side effects.97,98 The reported maternal side effects include nausea, dizziness, and visual disturbance.

Potassium Channel Blockers Use amiodarone for fetal dysrhythmias and manage maternal SVT and ventricular dysrhythmias, such as monomorphic VT and ventricular fibrillation during ACLS. There is a report of its use in concurrently managing maternal and fetal tachydysrhythmias.99 Amiodarone was formerly an FDA class D drug due to its potential adverse fetal effects. It is usually reserved for dysrhythmias resistant to first- and second-line therapies. Amiodarone has a high iodine content and is structurally similar to thyroid hormones.100 Amiodarone, its metabolite desethylamiodarone, and iodine are capable of limited transplacental transfer.101 There are reports of neonatal hypo- and hyperthyroidism in pregnancies exposed to amiodarone; the former is more common with an incidence up to 23%.102 As well, amiodarone is possibly associated with neurodevelopmental delay.102–104 Sotalol has potassium channel blocker properties and is a nonselective beta-blocker. Consider using it for maternal SVT, AT, and AF if nodal blocking agents fail and in idiopathic sustained VT if other therapies fail.39,65,105 Given the dose-related potential for QTc prolongation and Torsade de Pointes, avoid its use in patients with known QTc prolongation. Sotalol easily crosses the placenta and so it is used in the treatment of fetal SVT and AF. There is no association with IUGR.106 In a case series of 30 fetal tachydysrhythmias, 28 received sotalol. There were no maternal syncopal episodes or dysrhythmias but maternal QTc interval increased.107 In those where QTc increased >20 ms, the mean increase was 38 ms. Therefore, it is important to monitor maternal ECG and QTc during therapy.

Other Drugs Adenosine Adenosine is an endogenous nucleoside. It exerts its antidysrhythmic properties by slowing sinus and atrioventricular nodal conduction.108 It has a very short plasma half-life. It is effective in terminating paroxysmal SVT in which the atrioventricular node

is an integral part of the reentrant circuit such as AVNRT and WPW.109 Well described in pregnancy, it is the first-line pharmacological treatment for paroxysmal SVT if vagal maneuvers fail.65 One can use adenosine to diagnose focal atrial tachycardia and terminate the dysrhythmia in 30% of cases.65 Since fetal bradycardia may occur after adenosine treatment of maternal PSVT, monitor FHR during adenosine administration.110 During pregnancy, levels of adenosine deaminase (the enzyme responsible for adenosine metabolism) decrease. However, plasma volume expansion in pregnancy balances this change,111 so use normal doses of adenosine; rapid IV administration of 6–12 mg is suggested.

Digoxin Digoxin is a cardiac glycoside used to manage SVT, particularly AF, and treat peripartum cardiomyopathy.112 It is considered one of the safest antidysrhythmic drugs used in pregnancy.61 Since it freely crosses the placenta, it is also used for fetal tachydysrhythmias. In pregnancy, one challenge of digoxin is that drug serum levels do not always correlate with toxicity. There is a report of digoxin toxicity (chest pain, shortness of breath, bigeminy on ECG), despite subtherapeutic serum drug levels in a mother receiving digoxin for fetal SVT.113 Like verapamil, avoid digoxin in WPW. See Table 5.8114, 115

Valuable Clinical Insights • Avoid unnecessary drugs in the first trimester but where indicated, use lowest effective dose, and provide regular follow-up. • Counsel women that while some antidysrhythmic drugs are associated with potential adverse fetal effects, the benefit of avoiding malignant maternal dysrhythmias and consequent fetal hypoperfusion mostly outweigh these risks. • During advanced life support, use standard drug doses and do not withhold drugs from the mother out of concern for fetal effects.

Nonpharmacological Treatments Direct Current Cardioversion Numerous case reports document the successful use of electrical cardioversion in pregnancy, and it is considered safe in all stages.116 Like nonpregnant patients, treat tachydysrhythmias that produce hemodynamic instability according to advanced life support protocols with DC cardioversion performed using standard pad placement.65,117 The MBRRACE-UK triennial report for 2015–2017 described two maternal deaths due to acute narrow complex tachycardia where DC cardioversion was delayed, emphasizing its importance.2 Tromp et al. reviewed 44 cases of electrical cardioversion during pregnancy, with 41 of those successfully converting to sinus rhythm.116 Only half reported neonatal outcomes; two required emergency CD due to fetal distress immediately post

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Table 5.8  Antiarrhythmic drugs in pregnancy

Drug name

Drug class

Indications

Adverse maternal effects and cautions

Former FDA category and fetal considerations

Breastfeeding 114, 115

Adenosine

Purine nucleoside

First-line drug for termination of PSVT Aid diagnosis and terminate focal AT

Bronchoconstriction – caution in asthmatics, chest discomfort, flushing, QT prolongation (contraindicated in LQTS)

C Generally considered safe in pregnancy, fetal bradycardia has been reported

Given short half-life, unlikely to be present in breastmilk

Amiodarone

K+ channel blocker

Treatment of refractory arrhythmias including AF/flutter, VT/VF

Hypotension with rapid injection, QT prolongation hyper/hypothyroidism, hepatic dysfunction, pneumonitis

D Avoid in pregnancy unless no alternative. Risk of neonatal hypothyroidism, goiter, growth restriction

Significant amount present in breastmilk, avoid

Digoxin

Cardiac glycoside

Rate control of AF and AT if betablockers fail, symptomatic SVT

Caution in WPW as may enhance conduction through accessory pathway

C Used for treatment of fetal tachydysrhythmia

Amount in breastmilk considered too small to be harmful

Flecainide

Na+ channel blocker (class 1 c)

SVT prophylaxis in WPW syndrome, rhythm control in SVT/AT/AF if AV node blocking drugs fail, idiopathic VT

Visual disturbance prolongation. Avoid in abnormal LV function

C Used for fetal tachydysrhythmia Infant hyperbilirubinemia reported

Significant amount present in breastmilk but not known to be harmful

Lidocaine

Na+ channel blocker (class 1b)

Alternative to amiodarone in shock refractory VT/VF or in monomorphic VT with structurally abnormal heart

Circulatory collapse, drowsiness/ loss of consciousness in systemic toxicity

B Can cause fetal bradycardia

Amount in breast milk considered too small to be harmful

Metoprolol

Beta-blocker

Management and prevention of SVT, rate control of AF or AT. Longterm management of idiopathic VT

Bradycardia, hypotension, exacerbation or precipitation of heart failure

C Possible association with SGA. Risk of bradycardia and hypoglycemia in neonate

Low levels in breastmilk, unlikely to be clinically significant for infants

Procainamide

Na+ channel blocker (class 1a)

Hemodynamically stable, sustained monomorphic VT

Risk of QTc prolongation, druginduced lupus-erythematosus-like syndrome with chronic use

C Limited data but no evidence of adverse fetal effects

Low levels in breastmilk, not known to be harmful

Sotalol

Beta-blocker, K+ channel blocker

Prevention of SVT/AF/AT if AV node blocking drugs fail, treatment and prevention of idiopathic VT

Risk of TdP due to QTc prolongation, caution in asthma

B Fetal bradycardia and hypoglycemia

Uncertain. Amount in breast milk likely too small to cause harm. Consider monitoring for neonatal hypoglycemia and bradycardia

Verapamil

Calcium channel blocker

Prevention of SVT in absence of preexcitation, AF rate control if beta-blockers fail, prevention of idiopathic VT associated with hemodynamic compromise

Caution in WPW as may enhance conduction through accessory pathway, avoid in significant LV impairment, hypotension, headache, flushing

C Neonatal seizure reported with third trimester use

Amount in breastmilk considered too small to be harmful

Uncommon Cardiac Dysrhythmias in Pregnancy

cardioversion. For women at viable gestations, the recommendation is to monitor the FHR with the ability to do an immediate CD.

Cardiac Implantable Electronic Devices Permanent Pacemakers Although implanted permanent pacemaker (PPM) insertion is increasing in the general population, it remains uncommon in parturients. In those with a prepregnancy implanted pacemaker, the commonest indication is congenital or acquired complete heart block (Table 5.9).118 There are reports of successful completion of pregnancy without a pacing device or lead complication.118,119 In patients with a PPM, it is crucial to evaluate their cardiovascular status carefully, assess the device, and be aware of device-related complications. A PPM consists of a pulse generator, and one or more pacing leads depending on the indication for pacing. The pulse generator is usually sited subcutaneously distal to the left clavicle but may be subpectoral or less commonly in the abdominal wall. Avoid abdominally sited pulse generators in young women due to the risk of lead fracture or dislodgement as the gravid uterus expands.120 A well-reported complication of subcutaneously placed chest wall pulse generators is skin irritation or ulceration due to breast tissue changes in pregnancy.120 Asymptomatic women with complete heart block have safely completed pregnancy without the need for a permanent or temporary pacemaker; however, the severity of AV block or bradydysrhythmia can increase as pregnancy progresses, necessitating close and frequent assessment.55,118–120 The postpartum period is a high-risk time for decompensation and cardiac complications, even in those with a permanent pacemaker.119 Class 1 recommendations exist for pacing high-risk dysrhythmias in the nonpregnant population, including bradycardia attributable to symptomatic, complete heart block, or Mobitz type II second-degree heart block.121 When patients present for the first time during pregnancy, and where indicated, it is possible to insert a permanent pacemaker without fluoroscopic techniques.122,123 Table 5.9  Assessment of patients with permanent pacemakers in situ Indication/ underlying rhythm

Symptomatic sinus node dysfunction, high-grade atrioventricular block. Assess degree of pacing dependence

Mode

Use recognized NAPSE/BPEG pacemaker nomenclature for clarity of communication: chamber paced, chamber sensed, response to pacing, rate modulation, multisite pacing124

Location

Pre-pectoral, subpectoral, abdominally placed

Model

Information obtainable from clinical notes or patient alert card

Last date of assessment and outcome

This confirms appropriate function and assessment of expected battery duration. PPM checked at least 12-monthly, ICD or CRT within six months (sooner if multiple discharges)

BPEG = British Pacing and Electrophysiology Group; CRT = cardiac resynchronization therapy; ICD = implantable cardioverter defibrillator; NAPSE = American Society of Pacing and Electrophysiology; PPM = permanent pacemaker;

Implantable Cardioverter Defibrillator The presence of an implantable cardioverter defibrillator (ICD) is not considered an absolute contraindication to pregnancy. Instead, the underlying cardiac condition necessitating its implantation, such as structural heart disease, should be the critical consideration in prepregnancy counseling. One multicenter retrospective analysis of 44 pregnant women with ICDs demonstrated no increase in device-related complications.125 Additionally, the incidence of preterm delivery, CD, spontaneous abortion, and IUGR were similar to the general population. Some recommend disabling the antitachydysrhythmia function of an ICD for operative delivery (Table 5.10). However, do this in consultation with a cardiologist as there is a risk of inappropriate discharge with electrocautery use. This risk, however, is less for subumbilical surgery and when bipolar diathermy is used.126 Clear communication and predelivery planning with a cardiologist allows for individualized patient management and, where indicated, minimizes deactivation time. Have an external defibrillation device available when the defibrillation function of an ICD is deactivated. Transcutaneous electrical nerve stimulation (TENS) can cause electromagnetic interference,127 so avoid it in pacingdependent patients or those with ICDs, given the availability of other analgesic alternatives.

Catheter Ablation Catheter ablation, either radiofrequency or less commonly cryothermic energy, can be used to interrupt aberrant conduction pathways and render the foci electrically inert. Usually, catheter ablation is performed under fluoroscopic guidance. Despite a considerable increase in the use of catheter ablation in the general population, concerns about radiation exposure in pregnancy restrict it to drug-refractory cases in experienced centers, preferably after the first trimester (a class IIb recommendation).65 Ideally, catheter ablation should be performed preconception in women with symptomatic SVT or VT. In a systematic literature review of catheter ablation in 27 pregnant patients, the most common presenting rhythms were AT and AVRT; the most frequent indication was recurrent symptomatic palpitations refractory to medical therapy.128 In pregnancy, catheter ablation was a successful rescue therapy for electrical storm in a patient with arrhythmogenic right ventricular cardiomyopathy and patients with drug-resistant right ventricular outflow tract VT.129–131 Nonfluoroscopic techniques using three-dimensional navigation systems have the potential to alter the threshold for performing ablations in pregnancy and avoid the need for potentially harmful medications.128,131 Descriptions of anesthetic techniques for catheter ablation in pregnancy are sparse or incompletely reported in the literature. Anesthetic agents may interfere with the inducibility of dysrhythmias, but in WPW, sevoflurane, propofol, alfentanil, and midazolam do not appear to affect sinoatrial node function or normal AV or accessory pathway conduction.132–134

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Table 5.10  Perioperative management of patients with cardiac implantable electronic devices

Preoperative considerations

Intraoperative considerations

Postoperative considerations

Detailed history and examination with focused history and assessment of implanted device and cardiac status

Full intraoperative monitoring with ECG activated to detect pacing spike

Postoperative monitoring in high-dependency ward

Establish level of pacing dependence

Use plethysmography to monitor heart rate if pacing spikes result in inaccurate heart rate count via ECG

Reactivation of defibrillation function as soon as possible

12-lead ECG

Consider intraarterial blood pressure monitoring if hemodynamic instability is present or anticipated

Interrogation of device if any prolonged monopolar diathermy is required

Correct any electrolyte abnormality such as hypomagnesemia or hypokalemia due to potential to alter stimulation or defibrillation threshold

Reduce electromagnetic interference by avoiding electrocautery if possible. Where possible, favor bipolar diathermy If monopolar must be used limit bursts to 4.5 cm in Marfan Syndrome and > 5.0 cm in bicuspid aortic valve aortopathy), and severe aortic coarctation. While pregnancy is contraindicated in Class 4 patients, there are rare situations where the pregnancy is continued despite medical counseling. As such, the bulk of this chapter will address some of the most challenging peripartum cardiovasculopathies to navigate. These parturients commonly fit within the WHO Class 3–4 risk categories, and therefore, they should be moved early to medical centers with an organized Cardio-Obstetric Team capable of providing the full gamut of cardiovascular medicine and surgical services including venoarterial extracorporeal membrane oxygenation (VA ECMO).9

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Physiology of Pregnancy Pregnancy’s impact on cardiovascular physiology demonstrates peak effect at approximately 28–32 weeks of gestation, coinciding with the beginning of the third trimester.10 Maternal systemic cardiac output (CO) increases by 30–50% of baseline by 32 weeks gestation.11 This effect is even more pronounced in a twin pregnancy, where CO increases an additional 20% over a singleton pregnancy.12 For simplicity, CO can be defined as heart rate (HR) times left ventricular stroke volume (SV). In turn, SV can be subdivided into two major influences – LV systolic function and LV diastolic preload. During the first half of pregnancy,

Arterial Vascular Diseases

an increase in SV through plasma volume expansion is primarily responsible for the observed increase in CO above its baseline. HR then takes over during the second half of pregnancy as the main booster of CO.13 There are several physiologic factors that allow for the increase in SV during pregnancy. During the systolic phase, the left ventricular ejection fraction (LVEF) is increased due to the dual presence of low systematic vascular resistance (SVR) and low placental vascular resistance. The mechanism underlying the low SVR is postulated to be arterial vascular indifference to the major sympathetically mediated pathways (adrenergic, angiotensin, +/– vasopressin). Progesterone, estrogen, prostacyclins, and relaxin are believed to play key roles in modulating this endothelial response; data for the role of nitric oxide are conflicting.14–17 The combination of low SVR and low placental vascular resistance combine to induce a hyperdynamic LV (hyper-LVEF) just as afterload reduction therapy improves ventricular performance in left ventricular systolic congestive heart failure (CHF) patients. The labor and delivery stage introduces other exogenous factors, such as neuraxial anesthesia (NA) and oxytocin administration, that acutely decrease SVR. As for diastolic function, a 40–50% increase in overall blood volume above prepregnancy levels serves to maintain LV preload, and hence SV, at a time when parturients must share an increasing proportion of their circulation with the placenta and fetus.12,18 Consistent with this pregnancy-induced volume expansion is the observation that the biomarker hormone B-type natriuretic peptide (BNP) and to a lesser extent its prohormone N-terminal BNP (NT-proBNP) can be used to diagnose cardiac complications, such as heart failure and preeclampsia (PreE).19 Serum levels of BNP allow the anesthesiologist to distinguish between cardiac and noncardiac conditions in pregnancy.20–25 The increase in blood volume outstrips a lesser increase in red blood cell proliferation, thus creating the “physiologic anemia of pregnancy.” The ensuing relative anemia stimulates a maternal central autonomic need for increased CO to maintain mixed venous oxygen saturation (MVO2) and thus prevent compromised oxygen delivery. Oxygen content is directly proportional to maternal hematocrit (HCT). Three factors that decrease maternal MVO2 – physiologic anemia, oxygen steal from a left-shifted hemoglobin F (HbF) oxygen dissociation curve, and the combined mother–baby elevated oxygen consumption serve as a driver to increase maternal CO. The four phases of labor and delivery usher in further hemodynamic changes. The active first stage of labor is defined by the WHO as the period of time characterized by regular painful uterine contractions from 5 centimeters (cm) of cervical dilatation until full dilatation in both nulliparous and multiparous women.26 The second stage of labor begins with full cervical dilatation and culminates when the child is delivered. CO is markedly augmented during the first two of these intrapartum phases by as much as 30% and 50%, respectively.27 Increased sympathetic activity, periodic autotransfusion into the central venous circulation due to uterine contractions, and intermittent decreases in central venous return, due to maternal Valsalva efforts or supine positioning, are the three major physiologic

factors that affect CO during this stage. Efforts to minimize these intrapartum physiologic stressors include aggressive analgesia with intravenous agents or NA, careful positioning to avoid aortocaval compression, early implementation of a facilitated second-stage of delivery, and early consideration of cesarean delivery (CD).28 Further acute increases in CO occur following delivery of the placenta during the third stage and the postpartum fourth stage of labor, when the tone of the uterus is reestablished. The major physiologic change that predominates at this point is an augmented central venous return with consequent increase in preload. The underlying mechanism is a composite mix of aortocaval decompression as well as the autotransfusion from a contracting uterine muscle and the loss of placental vascular bed capacitance. The third stage is defined as the time from child delivery until placental afterbirth. The average time of this period is 10–12 minutes, but it is highly dependent upon whether active or expectant management is employed.29 Active management of this stage may include the use of uterotonic agents, umbilical cord clamping strategies, uterine massage, etc. The rise in CO carries over into the postpartum fourth stage of labor for the next few hours. The increase in central venous return is balanced by maternal blood loss. Normal spontaneous vaginal delivery estimated blood loss (EBL) averages 600 milliliters (ml), and CD blood loss averages 1000 ml.30 The low SVR state of pregnancy will produce a trifurcated effect on BP – namely, low overall systolic (SBP), diastolic (DBP), and mean (MAP) arterial blood pressure (ABP). This effect is most prominent in the early–mid gestational window. Low placental vascular resistance, however, reduces DBP disproportionately compared to the other two components of ABP by allowing for passive runoff into the placental arterial tree specifically during diastole. Since coronary perfusion pressure (CPP) is equal to DBP minus left ventricular end diastolic pressure (LVEDP), the CPP will be mathematically lower in parturients. This same principle is seen with other run-off lesions such as chronic aortic valve insufficiency, where patients have retrograde run-off or “steal” into their left ventricles during diastole. They thus have lower DBPs and CPPs.13,31 Pulmonary arterial pressures (PAP) remain unaffected in parturients with no history of pulmonary hypertension. Despite the 30–50% increase in maternal CO (which translates to a 30–50% increase in maternal pulmonary arterial CO), the expected rise in PAP is offset by an adaptive decline in pulmonary vascular resistance (PVR) by about 25%.32 Hypoalbuminemia with associated low oncotic pressure is another known physiologic consequence of pregnancy. The mechanism is not entirely clear but may result from the dilutional effect of increased plasma volume without concomitant increased liver albumin production. The capillary-spill syndrome associated with PreE-mediated endothelial dysfunction will also be potentiated in the setting of hypoalbuminemia. Respiratory changes also occur during pregnancy. From an anatomical perspective, the growing fetus elevates the diaphragm and thoracic configuration. The major nonanatomic respiratory physiologic change of pregnancy is progesteronedriven central hyperventilation.33 Increased minute ventilation,

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hypocarbia (PaCO2 27–34 mmHg), and respiratory alkalemia (pH 7.40–7.45) are the net result. Some patients with pulmonary hypertension may experience respiratory-related hemodynamic compromise on top of their preexisting cardiovascular compromise. In such cases, the decision to deliver early may be warranted.

Table 6.1  Aortic dissection classifications

Stanford classification

Type A

Type A

Type B

DeBakey classification

Type I

Type II

Type III

Description

Dissection begins in the ascending aorta and includes at least the aortic arch

Dissection begins and is confined to ascending aorta

Dissection begins in the descending thoracic aorta and never propagates retrograde past the left subclavian artery

Management

Surgical emergency

Surgical emergency

Medical management with BP and HR control 

Valuable Clinical Insight Normal physiologic changes of pregnancy include: • High cardiac output • Low SVR • Minimally affected pulmonary artery pressures • Low oncotic pressure • Hyperventilation • Anemia

Major Thoracic Aortic Disease Introduction All major thoracic aortic diseases of any etiology impart an increased risk for aortic dilatation, dissection, and rupture. Some of the high-risk medical conditions associated with these catastrophic thoracic aortic events include systemic hypertension, bicuspid aortic valve, aortic coarctation, connective tissue disorders including Marfan Syndrome, Loeys-Dietz Syndrome, Ehlers-Danlos Syndrome, and Turner Syndrome. In addition, pregnancy, labor and delivery, and the postpartum state increase the risk of complications from aortopathy, including aortic dissection and rupture, due to elevated aortic wall tension from hyperdynamic and hypervolemic circulatory changes as well as the hormonal effects on aortic wall integrity.34,35 The most recent cohort data place the overall thoracic aortic dissection or rupture rate among all pregnancies at 5.5 per million.34 However, the mortality is high, ranging from 21% to 53%.36 The Stanford and DeBakey classification systems are the two most widely adopted classification schemes for thoracic aortic

dissections (Figure 6.1, Table 6.1). The Stanford system is the simpler of the two, classifying any dissection that involves the ascending aorta as Type A and all other dissections as Type B. Thus, the site of primary intimal tear is not the determining factor in this nomenclature system. In contrast, the DeBakey system is based upon the site of the original intimal tear. In Debakey Type I, the tear begins in the ascending aorta and extends forward to include at least the aortic arch. Debakey Type II originates in and is confined to the ascending aorta. Debakey Type III originates in the descending thoracic aorta and never propagates retrograde past the left subclavian artery. Uncomplicated Stanford Type B dissections are medically managed with BP and HR control therapy to decrease aortic shear stress. Indications for surgical intervention include major visceral artery ischemia, dissection propagation, and contained or impending rupture. In complete contrast, acute Type A dissections carry a 1–2% per hour mortality rate following the onset of symptoms and are always surgical emergencies. Clinical presentations are variable. These patients may present with acute onset severe chest or back pain and hemodynamic instability. Other presenting complaints such as gastro-esophageal reflux or uncontrolled hypertension, can be confounding since they might occur in any pregnancy. Thus, a high index of suspicion is required.36,37

Prenatal Categorization, Assessment, and Management of the Major Thoracic Aortic Diseases Systemic Hypertension DeBakey Stanford Management

Type I

Type II Type A

Surgical Emergency

Type III Type B Medical Management

Figure 6.1  Aortic dissection classification. (See color plate section).

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In the general nonpregnant population, systemic hypertension (HTN) is the most common predisposing risk factor for the development of aortic dissection and rupture.38,39 This statistic highlights yet another layer of concern for patients diagnosed with any of the three core hypertensive states of pregnancy – namely, chronic (preexisting) hypertension (CH), gestational hypertension (GH), and preeclampsia (PreE) (Figure 6.2). Chronic hypertension refers specifically to the existence of elevated BP prior to pregnancy or before 20 weeks gestation; its definition

Arterial Vascular Diseases

also extends to include hypertension that is first diagnosed during pregnancy with persistence for > 12 weeks postdelivery.40 The 2017 ACC/AHA Task Force endorses a numeric definition of CH as systolic BP > 130 mmHg and/or, DBP > 80 mmHg.41 The definition of GH is new-onset and sustained SBP > 140 mmHg and/or, DBP > 90 mmHg after 20 weeks gestation in the absence of proteinuria or new end-organ dysfunction.42 Lastly, PreE is characterized as new-onset GH plus proteinuria after 20 weeks gestation; or new-onset GH with end-organ dysfunction +/– proteinuria after 20 weeks gestation. By absolute numbers, PreE is considered severe when sustained SBP measurements reach > 160 mmHg and/or diastolic readings remain > 110 mmHg. The term eclampsia replaces that of PreE should seizures develop. HELLP Syndrome is a PreE variant that includes hemolysis, elevated liver enzymes, and low platelet counts. It is vitally important that any of the hypertensive states of pregnancy be managed aggressively, especially those with thoracic aortic disease. There are many categories of both oral and parenteral ­antihypertensive agents. Drug efficacy, acuity of need, and ­maternal–fetal safety profiles are balanced during their selections. Oral labetalol or nifedipine are considered the first-in-line medications for both CH and GH.43 For hypertensive emergencies requiring IV therapy, labetalol and hydralazine are favored options.44 Immediate release oral nifedipine and IV clevidipine

BP >140/90

Prior to 20 weeks, persistent >12 weeks post partum

Chronic HTN

Over 20 weeks

No proteinuria

Proteinuria with or without endorgan dysfunction

Gestation HTN

Pre eclampsia

BP >160/110

Severe Pre eclampsia Figure 6.2  Hypertension during pregnancy.

are next-line therapies. Calcium channel blockers should be used with caution in patients receiving magnesium sulfate for the prevention or treatment of eclampsia because the two agents can act synergistically to cause profound maternofetal hypotension. There are no guidelines for targeted BP-lowering therapy, but in general, individualize therapy according to the immediate physiologic needs and risks of mother and fetus. It is important to remember that the placenta has no auto-­regulatory mechanisms so over-aggressive antihypertensive therapy can result in decreased placental perfusion pressure. Importantly, all antihypertensive medications cross the placenta. Both angiotensin converting enzyme inhibitors (ACE inhibitors) and angiotensin 2 receptor blockers (ARBs) are of particular concern. They are known FDA Class D teratogens, meaning that there is definitive evidence of human fetal risks and thus, are contraindicated in pregnancy. The most common fetopathies include renal dysplasia/failure with secondary oligohydramnios, but ACE inhibitors and ARBs have also been associated with miscarriage, pulmonary hypoplasia, respiratory distress syndrome, intrauterine growth restriction (IUGR), cranial and limb anomalies, and arterial hypotension.45,46

Bicuspid Aortic Valve Bicuspid aortic valve (BAV) is the most common congenital heart anomaly with a prevalence of 1–2% within the general population.47 In addition to being highly associated with early-to-mid adulthood development of symptomatic aortic valve stenosis (AS), BAV is a major risk factor for aortic root and ascending thoracic aortic dilatation, and is associated with aortic coarctation.48,49 The dilation is due to an intrinsic connective tissue aortopathy.50 This theory is supported by the observation that dilatation often occurs independent of aortic valve replacement.51 Therefore, it is recommended that concomitant surgical aortic valve, root, and/ or, ascending thoracic aortic replacement be considered at the time of aortic valve replacement with aortic diameters > 4.5 cm.52 All BAV patients considering pregnancy should have prepregnancy advanced imaging in the form of CT or MRI to establish the ascending aortic dimensions as well as transthoracic echocardiography (TTE) to establish baseline aortic pathology along with LV function. A baseline aortic root < 4.0 cm is considered low risk for dissection. Since the aortic valve, root, and ascending aorta are predominantly anterior structures, TTE is used to follow patients during pregnancy once advanced imaging measurements have been established. Conversely, the posterior chest approach of transesophageal echocardiography (TEE) can be performed as an alternative imaging modality if TTE acoustic windows prove difficult to visualize. Unfortunately, TEE generally requires heavy sedation or a combination of oropharyngeal topicalization, light sedation, and a motivated patient to allow for a tolerable and successful exam. An additional TEE shortcoming is its inability to visualize the distal ascending thoracic aorta and the proximal aortic arch because of their anatomical positioning relative to the TEE probe. This aortic “blindspot” is created by a combination of two properties of the left main stem bronchus – (1) it is a large conducting airway filled with a medium (air) which does not propagate US waves and (2) its geographical location being interposed between the esophagus

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Table 6.2  Screening guidelines for aortic dilation in Marfan Syndrome and bicuspid aortic valve Aortic diameter

< 4.0 cm

> 4.0 cm

Frequency

3 months

1 month

and these aortic segments. If the patient has not had advanced imaging confirmation of these measurements prior to an active pregnancy, then a noncontrast MRI is recommended. MRI is favored as CT scanning predisposes to maternal and fetal radiation exposure. However, CT is allowed in pregnant women if the test is warranted, as the amount of ionizing radiation is lower than that which causes fetal harm.36 It is recommended that all pregnancies with documented aortic root and ascending dilated aortopathies be monitored throughout pregnancy and the postpartum period (Table 6.2). The frequency of imaging is dependent upon vessel dimensions.53 Maximal aortic diameters < 4.0 cm can be screened every 3 months. Those patients at high risk for dissection based on etiology or who have a baseline aortic measurement > 4.0 cm should be screened monthly. Indications for prophylactic surgical intervention include all BAV patients with aortic diameters > 5.0 cm who are planning pregnancies, since pregnancy is otherwise contraindicated. Planned BAV pregnancies with aortic diameters < 5.0 cm are monitored both during and after pregnancy.1,2,54,55

Aortic Coarctation Aortic coarctation (AoC) accounts for 6–8% of the congenital heart disease population. Most coarctations are located distal to the left subclavian artery and juxta-ductal to the remnant ductus arteriosus tissue (ligamentum arteriosum). Patients with unrepaired coarctation who reach adulthood develop large collateral vessels that allow for aortic perfusion distal to the narrowing. Chest X-ray demonstrates notching on the underside of the ribs to indicate such collateralization. Clinically, AoC patients requiring intervention may exhibit proximal HTN, an arm–leg pressure gradient > 20 mmHg, left ventricular hypertrophy (LVH), and LV diastolic dysfunction. Significant associated cardiovascular lesions include BAV. Late sequalae include recoarctation at the site of prior repair, premature coronary artery disease, and stroke due to the presence of berry aneurysms. Thoracic aortic aneurysm, dissection, and rupture development is increased for several reasons. The proximal thoracic aorta is burdened by HTN and a predisposition for disordered connective tissue. The proximal thoracic aorta may also become aneurysmal after open surgical grafts (particularly Dacron patch), endovascular stents, or balloon aortoplasty. Post intervention aneurysmal formation is particularly seen in patients with late repair and those with high preoperative pressure gradients. Proposed explanations include retention of unresected abnormal medial tissue, residual injured or weakened aortic tissue, and a predisposition to changes in the aortic wall protein matrix.56,57 It should be noted that patients with unrepaired severe coarctation or repaired patients with evidence of severe recoarctation should not undergo pregnancy. Pregnancy is contraindicated as per the mWHO 4 classification, as there is an extremely high risk or maternal mortality or severe morbidity.1 Should

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the pregnancy continue, there are several management issues to consider. In monitoring arterial BP invasively, the proximal BP (brain, heart, aorta) must be measured in the right upper extremity (assuming the site of coarctation is distal to the left subclavian) while distal BP (supplying the uterus, placenta, abdominal viscera, and lower extremities) is best measured in the femoral arteries.58 Pregnancy in patients with repaired coarctation also carries a slight increased risk of aneurysm formation.59 In general, aggressive upper extremity HTN treatment to mitigate aortic dissection risk needs to be balanced against the risk of hypotension below the level of the coarctation, which would cause uteroplacental insufficiency and fetal compromise.

Marfan Syndrome Marfan Syndrome (MFS) is an autosomal dominant multiorgan system connective tissue disease. It involves a myriad of mutations to the FBN1 gene which encodes the extracellular matrix protein fibrillin. The incidence is 1 in 3,000–5,000.60 The most concerning phenotypic expressions involve the cardiovascular system. Aneurysmal dilatation of the aortic root and ascending aorta is present in most adult MFS patients. Root dilatation in turn can cause AV annular dilatation and consequent chronic aortic valve insufficiency, which leads to LV volume overload with global LV dilatation. Ultimately global LV systolic dysfunction ensues with progression to left-sided systolic heart failure. Acute thoracic aortic dissection involving the root or ascending segments is a feared complication of MFS. Its overall rate of occurrence in pregnancy is approximately 3%. This dissection rate is estimated to be 1% in women with aortas < 4.0 cm and 10% when > 4.0 cm.61,62 The third trimester and early postpartum period are the most vulnerable.63 Composite guidelines emphasize an individualized surveillance imaging strategy. Serial echocardiograms are recommended every 1–3 months depending on baseline aortic root diameter, rapidity of root growth, use or nonuse of beta blockers, increased number of pregnancies, and family history of dissection. These recommendations also apply to the first six months postpartum.1,2,64 The therapies for aortic preservation include beta blockade to decrease the dP/dT shear forces and aggressive BP control with nonrenal angiotensinaldosterone system (RAAS) antihypertensives.65 Pregnancy is contraindicated if the aortic measurement is > 4.5 cm and women who meet this criterion should have surgery before pregnancy.1 Mitral valve regurgitation is another valvulopathy encountered in MFS. Its incidence is difficult to quantify since its presence and severity increase with age.66 Myxomatous degeneration of the mitral leaflets and the submitral apparatus (chordae tendinae) causes elongation and redundancy of the mitral tissues. Resultant unilateral or bilateral leaflet prolapse into the left atrium (LA) occurs because the leaflets and chordae do not possess enough connective tissue strength to stay anchored within the coaptation plane during systole. The chronicity of this mitral regurgitation leads to volume overload of the LV often with dilation of the LA. The early adaptation to the increase in LV preload results in a supranormal LVEF. However, with progression of disease, the LV will progressively dilate and develop global LV systolic dysfunction and heart failure symptoms. With longstanding severity, resulting elevated left atrial pressures can

Arterial Vascular Diseases

cause pulmonary venous hypertension, classified as WHO Group 2 PH. Atrial fibrillation may develop because of compensatory LA enlargement and high pulmonary venous pressures. Dural ectasia is an anesthesia-relevant manifestation of MFS. It describes an outpouching of the dura in the lumbosacral region where the cerebrospinal fluid pressure is the greatest. It is a common feature of MFS with an estimated prevalence of 63–92%.67,68 Clinical symptoms of dural ectasia often include low back pain, headaches, and proximal lower extremity neurologic symptoms; upright posture commonly intensifies these features.69 Case reports have described both unpredictable and inadequate spread of spinal local anesthetics. Increased lumbar CSF volume is a proposed mechanism for the observed inconsistent NA.70

Loeys-Dietz Syndrome Loeys-Dietz Syndrome (LDS) is a connective tissue disease caused by mutations in the transforming growth factor beta receptor genes, TGBR1 and TGBR2.71 Its cardiovascular profile includes thoracic aortic dilatation, dissection, rupture, and AV insufficiency at an intensity and frequency like that of MFS.72,73 The rates of myxomatous mitral valve disease and associated MR, however, are much lower than MFS. Prenatal risk stratification, thoracic aorta, valvular, and myocardial hemodynamic management goals mirror those previously described for MFS.

Ehlers-Danlos Syndrome Ehlers-Danlos Syndrome (EDS) is an umbrella term used to describe a multitude of genetic collagen protein connective tissue disorders of variable phenotypic presentation.74 The three highest-risk EDS subtypes vulnerable to aneurysmal dilatation, dissection, and rupture are Type IV vascular (vEDS), hypermobile, and kyphoscoliotic. Vascular EDS is by far the most serious of these subtypes. Aortic dissection can occur in the absence of dilation, and pregnant vEDS patients are estimated to have a 12% mortality rate from uterine rupture and thoracic aortic catastrophes. As a result, pregnancy in these women is contraindicated and, if required, early termination reommended.75

Turner Syndrome Turner Syndrome (TS) is a common chromosomal abnormality with an incidence of 1 in 2,000–2,500 live female births.76 It is caused by partial or full deletion of the X chromosome. Anesthesia concerns include the possibility of airway, spine, and cardiovascular issues. Predictors of a possible difficult airway include a short-webbed neck and palatal dysmorphia. Scoliosis and kyphosis occur in 20% and 50% of patients, respectively, and these curvatures may cause difficulties with NA.77 Congenital and early-onset cardiovascular diseases present the greatest overall threat, the most prevalent of which are BAV (30%), AoC (18%), HTN (50%), and aortopathies.58,78–81 The combination of hormonal and circulatory changes of pregnancy potentiates the aortic dissection risks already inherent in TS patients, particularly those with BAV, AoC, and HTN. Beta blockers and other antihypertensives are used to prevent aortic dilatation. It is recommended that aortic size index (ASI) (aortic diameter in cm divided by body surface area in meters squared

(m2)), is followed by serial TTEs and cardiac magnetic resonance imaging (CMRIs) for all TS patients 16 years or older. Guidelines place the highest risk on patients where the ASI exceeds 2.3 cm/ m2 when BAV, AoC, and/or HTN are concomitantly present. These TS patients should have repeat surveillance CMRIs every 6–12 months.82 Patients with an ASI > 2.7 cm/m2 should have prophylactic surgery prior to pregnancy. The prenatal anesthesia thoracic aortic, valvular, and myocardial hemodynamic management challenges of TS are the same as those previously described for BAV, AoC, and connective tissue aortopathy management.

Valuable Clinical Insights • The major risk factors associated with thoracic aortic catastrophes include:  Systemic hypertension (chronic preexisting hypertension, preeclampsia, gestational hypertension)  Bicuspid aortic valve  Aortic coarctation  Marfan Syndrome  Loeys-Dietz Syndrome  Ehlers-Danlos Syndrome  Turner Syndrome • Each of these entities has unique clinical presentations and anesthetic management concerns.

Intrapartum Management of Thoracic Aortic Disease Vaginal deliveries with NA are the preferred approach for parturients with high-risk thoracic aortic disease. This approach helps attenuate the hyper-catecholaminergic pain and anxiety state associated with labor, and it also decreases the quantity of blood loss otherwise associated with CD. The exact neuraxial technique employed is less important than the clinical effect and the safety factor of knowing that a functioning epidural catheter is already in place should an urgent or emergent CD be required. Options include lumbar epidural, combined spinal-epidural, and dural puncture epidural techniques. Intrathecal opioids and slowly titrated epidural local anesthetics allow the anesthesiologist more control over labor hemodynamics. The direct and indirect sympathectomy effects of NA, i.e., decreased SVR and decreased circulating catecholamines, can be offset by the anticipated coadministration of vasoconstrictors, such as phenylephrine and norepinephrine. Vasopressin is currently FDA Category C (not sufficiently studied to assess maternal or fetal harm) so it is reserved for only refractory vasoplegic situations. Since many of the cornerstone anesthetic management elements of thoracic aortic disease involve avoidance of hypertension as well as early detection of and preparation for potential dissection/rupture, arterial line monitoring is generally indicated. If these thoracic aortopathies have concurrent valvular dysfunction (AS, AI, MR) and consequent left ventricular systolic/diastolic myopathies, PH, and RV strain, then arterial line monitoring is mandatory. Central venous monitoring is generally reserved for those patients with a high likelihood of needing cardiopulmonary vasoactive support, not just epidural-related

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vasoconstrictor support. Pulmonary artery catheters (PACs) are particularly useful for direct numerical assessment of PA pressures to quantify RV afterload and to determine cardiac index, SVR, PVR, pulmonary capillary wedge pressures, and mixed venous oxygen saturations. TTE is an additional modality that can be useful to assess biventricular contractility and preload. As previously described, thoracic aortopathy hemodynamic goals include tight systemic BP and HR control, and valvulopathy management. Neuraxial anesthesia is ideal for aortic protection and can play a supportive role in the overall management of chronic AI and MR. In contrast, NA without vasoconstrictor support is poorly tolerated by such CPP-dependent lesions as BAV with AS and PH. Epidural test doses with epinephrinecontaining solutions should be avoided because systemic uptake of epinephrine could cause acute hypertensive and tachycardic aortic wall strain. Since AS, chronic AI, and chronic MR valvopathies coexist with many thoracic aortic disease states, it is important to determine the hemodynamic goals to anticipate changes and implement proactive management strategies, rather than being reactionary. Central to understanding its management, AS patients inherently exist in an unfavorable coronary supply– demand state (Table 6.3). Their high demand is dominated by strenuous pressure-work against a fixed stenotic valve. And the low supply is multifactorial – namely, poor relative subendocardial neocoronary vascular proliferation compared to LVH proliferation, decreased CO to the coronary vasculature from LV diastolic dysfunction, and decreased CPP secondary to elevated LVEDPs. Since CPP is equal to AoDP minus LVEDP, it is essential that AoDP be maintained with background vasoconstrictors, especially in the setting of the low intrapartum SVR ecosystem of NA and uterotonic agents. LV preload should be maintained to offset the expected blood losses related to SVD and CD as systemic hypovolemia is not tolerated well on top of LV diastolic dysfunction. Avoid tachycardia as it places additional demands on an already supply-compromised LV; and bradycardia decreases CO supply to the LV myocardium by summating with the decreased SV of LV diastolic dysfunction.

Table 6.3  Pathophysiology and management of aortic stenosis

Increased coronary demand state

Low supply state

- Increased pressure work - LVH

- Relative decrease of subendocardial neovascular coronary proliferation - Increased LVEDP - Low SVR ecosystem  - Decreased LV preload ecosystem

Management strategies 

• • •

Maintain AoDP to offset BP decreases from uterotonic agents and NA Maintain LV preload by anticipating volume loss associated with delivery Minimize extremes of tachycardia and bradycardia

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Chronic AI and chronic MR patients tend to benefit from the reduction in SVR produced by labor analgesia and oxytocin. In AI, this low SVR environment lessens the passive diastolic gradient driving blood backward from the aorta into the LV. In MR, the low SVR assures that during systole the LV will have more of a chance to eject its blood forward rather than backward into a low resistance LA. Keep HR on the upper side of normal for both valve lesions. In AI, high-normal HRs shorten the time that blood is available to passively “runoff ” into the LV from the aorta in diastole. Chronic AI and MR both eventually lead to LV volume overload, global LV dilatation, and global LV systolic dysfunction. As such, inotropic agents may be required to maintain contractility. The afterload reducing effects of NA will also assist with LV systolic function. Uterine tachysystole (excessively frequent uterine contractions in pregnancy) with nonreassuring fetal heart rate patterns is a cause of uteroplacental insufficiency corrected by tocolytic agents. Terbutaline is a predominantly beta 2 agonist with prochronotropy and pro-ino-dilator effects. Its vasodilatory qualities are beneficial for aortic preservation and chronic AI or MR. However, while its ino-chronotropic properties help stabilize chronic AI and MR, these same qualities are detrimental to aortopathies by increasing aortic wall shear forces. The chronodilator nature of terbutaline is not well tolerated by patients with AS. Nitroglycerine (NTG) is an alternative tocolytic. At clinically relevant doses, NTG primarily venodilates and increases subendocardial coronary blood flow. Hypotension associated with its use is potentially harmful in AS. More than 50% of aortic dissections in pregnancy occur in the third trimester and 33% in the postpartum period.83 Stanford Type A and medically unmanageable Type B dissections will require emergency surgery. The detailed anesthetic management and surgical options of such emergencies is beyond the scope of this chapter, as they require expertise and management at a specialized center. However, the important concepts are that in thoracic aortopathies, early dissection suspicion/detection (see above) and early involvement of Cardiothoracic Surgery, Cardiothoracic Anesthesia, and Perfusion are paramount. If cardiopulmonary bypass +/– circulatory arrest is required for aortic stabilization there are three major considerations: fetal viability, neonatal prematurity (if CD is performed), and maternal survival. Strategies to optimize fetal survival during cardiopulmonary bypass (CPB) include normothermia to avoid placental vasoconstriction, pulsatile flow to augment nitric oxide-mediated placental vasodilatation, high flows, high perfusion pressures, reasonable hematocrits to balance oxygen delivery with microvascular viscosity, and avoidance of vasoconstrictors. If circulatory arrest for aortic arch repair is required, then moderate hypothermia in conjunction with selective anterograde cerebral perfusion is recommended over retrograde cerebral perfusion because of concerns for maternal central venous backpressure on the placenta. If CD is part of the operative plan, then it should be performed before the CPB-phase of aortic repair. Rationale includes the danger of fatal hemorrhage from a combination of anticoagulation, the disorderly hematologic aspects of cardiopulmonary bypass, and uterine atonicity.84

Arterial Vascular Diseases

Valuable Clinical Insights • Most aortic dissections in pregnancy occur in the third trimester or postpartum period, and high-risk patients should have an anticipatory surgical plan with early involvement of a Cardio-Obstetrics Team. • The core of this team should consist of cardiologists, maternal–fetal medicine obstetricians, cardiothoracic anesthesiologists, obstetric anesthesiologists, cardiothoracic surgeons, interventional cardiologists, and mechanical-circulatory support perfusionists. • It is key to recognize the potential progressiveness of highrisk thoracic aortic scenarios and to transfer to an appropriate higher-level cardio-thoracic surgical center that can provide all necessary resources.

Postpartum Management of Thoracic Aortic Disease Postpartum bleeding from inadequate uterine tone is a risk in all parturients. However, in the thoracic aortopathy realm, the side-effect profile of the uterotonic medications is often just as important as the antihemorrhagic benefits. Oxytocin, for example, is a profound systemic arterial vasodilator, and it should be Table 6.4  Postpartum assessment of the patient with thoracic aortic disease

Acute subjective history

Physical exam

Labs and studies

- Back or subscapular pain - Chest pain - Shortness of breath - Abdominal pain - Extremity discomfort

- - - - - -

- Complete blood count - Chemistry panel  - Lactate - Coagulation panel - BNP - Active type and cross - Transthoracic echo

JVD Rales Murmurs (AI) Hypotension Poor capillary refill Mental status changes - Decreased breath sounds on lung oscillation - Lower extremity weakness - Loss of pulses

administered slowly or in conjunction with anticipatory vasoconstrictor support in patients intolerant to hypotension such as BAV with AS. Methylergometrine (methylergonovine) is an alternative uterotonic, but its untoward side effects include SVR elevation and coronary arterial vasospasm.85 Its routine use is therefore discouraged in parturients with thoracic aortic disease, CAD, AS, AI, MR, and hypertensive states of pregnancy. Prostaglandin F2-alpha is a third uterotonic choice. Its undesired side effects include bronchoconstriction and profound PVR augmentation. Preexisting asthma or high-LAP PH (from AS, AI, or MR) with secondary right ventricular dysfunction should preclude its use. Immediate postpartum care of the high-risk thoracic aortic patient should include Intensive Care or “Step-Down” Unit monitoring and management by appropriately matched subspecialists within the Cardio-Obstetrics Team. The initial postpartum phase is the apex of the high CO state, and biventricular preload increases from aortocaval decompression, uterine autotransfusion, and disappearance of the placental vascular tree. These intravascular volume increases are only partially offset by blood loss during delivery. As these preload issues begin to resolve, SVR normalization and oncotic pressure restoration begin to occur. Decompensation from CHF or dissection are the major concerns (Table 6.4). Daily subjective patient assessment includes listening for any mention of “ripping” back pain, chest pain, shortness of breath, abdominal pain, or extremity discomfort. Physical exam beyond routine vital signs should include close vigilance for jugular venous distention (JVD), SVC syndrome, rales, new or intensified diastolic runoff murmurs (AI), hypotension, mottled mal-perfused appearance, mental status changes, unilateral (typically left-sided unless patient has the rare right-sided aortic arch) decreased breath sounds (hemothorax), paraplegia, and/or loss of pulses. Screening labs and studies should include basic modalities as well as TTE and possibly BNP levels.

Prenatal Pulmonary Hypertension Management Pulmonary hypertension is defined as a mean pulmonary artery pressure (mPAP) > 20 mmHg.86 There are many causes of PH, and these are categorized into five WHO Groups (see Table

Table 6.5  Pulmonary Hypertension WHO Classification, abridged

Group 1 Pulmonary arterial hypertension

Group 2 Secondary to LV dysfunction

Group 3 Secondary to lung disease +/– hypoxia

Group 4 Secondary to pulmonary artery obstruction

Group 5 Secondary to unclear/ multifactorial mechanisms

- - - -

- Due to HFpEF - Due to HFrEF - Due to valvular heart disease

- COPD - Interstitial lung disease - Chronic hypoxemia (e.g. sleep disordered breathing)

- Chronic thromboemboli - Other pulmonary artery obstruction

- Chronic hemolytic anemia - Systemic disorders (e.g. sarcoidosis) - Langerhans histiocytosis - Chronic renal failure

- - - -

Idiopathic Heritable Drugs and toxins Collagen vascular diseases (e.g. systemic sclerosis, systemic lupus erythematosus, mixed connective tissue disease) Portal hypertension HIV Congenital heart disease Schistosomiasis

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6.5). WHO Group 1 PH is defined as patients with pulmonary arterial hypertension (PAH), previously called primary pulmonary hypertension, characterized by having a mPAP of > 20 mmHg with a pulmonary artery wedge pressure (PAWP) of ≤ 15 mmHg, with a PVR of > 3 Wood units. There are numerous causes of WHO Group 1 PAH including idiopathic, genetic mutations, certain drugs and toxins, portal hypertension, HIV, collagen vascular diseases most commonly systemic sclerosis, systemic lupus erythematosus, and mixed connective tissue disease, and congenital heart disease. While the causes of WHO Group 1 PAH are varied, they are all characterized by remodeling and occlusion of the small pulmonary arterioles. Progressive vascular remodeling leads to increasing pulmonary artery pressures and eventually right-sided heart failure. However, it should be noted that WHO Group 1 PAH is a rare condition with an estimated prevalence of 15 cases per 1 million. WHO Group 2 PH, which describes patients with PH secondary to left heart dysfunction, is the more common cause of PH. WHO Group 3 PH are patients who have PH secondary to underlying lung disease e.g., chronic obstructive pulmonary disease or interstitial lung disease, or hypoxemia e.g., sleep disordered breathing. WHO Group 4 PH includes patients with PH secondary to pulmonary artery obstruction, predominantly due to chronic thromboemboli. A review of outcomes in pregnancy and PAH states that peripartum mortality in women with PAH remains high. Publications from 1978 to 1996, which was in the era before pulmonary vasodilators were available, reported a maternal mortality rate of 38%. A subsequent review of cases from 1997 to 2007 reported a maternal mortality rate of 28%. A recent study analyzed 13 studies which included a total of 272 pregnancies from 2008 to 2018.87 They noted that only 214 pregnancies advanced beyond 20 weeks of gestation and 58% of pregnancies were premature with the median delivery at 34 weeks of gestation. Overall mortality in this combined cohort was 12% but was 20% for idiopathic PAH patients. Notably, 61% of these deaths occurred 0–4 days postpartum. The most common causes of death were right heart failure, cardiac arrest, PAH crises, PreE, and sepsis. Thus, even with modern treatment for PAH, maternal mortality remains high and current guidelines continue to recommend consideration for termination.88 It is recommended that women of childbearing age with PAH be on reliable birth control. Those who wish to have children are counseled to consider alternatives to pregnancy including adoption or surrogacy. However, for those women who elect to carry a pregnancy, referral to a maternal–fetal medicine and a PH center is essential. In the first trimester, most PAH patients feel well without any significantly worsening symptoms. However, as blood volume and cardiac output increase in the second and third trimesters, patients can develop shortness of breath and increasing edema. As noted above, normally in pregnancy, as the blood volume increases, the pulmonary vasculature dilates, and vessels are recruited. However, patients with PAH have no capacity to further vasodilate or recruit more vasculature. This will result in increases in PA pressures and RV afterload and if the RV is not able to accommodate the increased volume and afterload, acute

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RV failure ensues.89 This is managed with diuretics and escalation of pulmonary vasodilator therapy. Several medications used to treat PAH are teratogenic, specifically, all endothelin receptor antagonists (i.e., bosentan, ambrisentan, and macitentan), and riociguat. Thus, any patient who becomes pregnant, or is planning pregnancy, should stop these medications, and alternative therapies should be considered.

Intrapartum Pulmonary Hypertension Management The anesthetic management of obstetric patients with PH is challenging. There is a lack of evidence-based literature to guide management due to the rarity and variability of their clinical presentations. Furthermore, the anesthetic approach toward two parturients with the same cause of PH may require different levels of intensity reflecting the variability of disease (i.e., minimal cardiopulmonary compromise versus severe RV systolic failure). In all cases, the strategy should be to identify the etiology of PH, as for example, Group 1 PAH management will be vastly different from Group 2 PH (secondary to left heart disease). Hyper-controlled conditions emphasizing NA and targeted hemodynamics are central to PH management.1,90–93 The type of NA is less important than the overall theme of utilizing these modalities as vehicles to employ intrathecal opioids and slowly titrated epidural local anesthetics, thereby allowing the anesthesiologist pinpoint or “slow motion” control of labor hemodynamics. If CD is not planned from the outset, then it is reassuring to have a functioning epidural catheter in place should an emergent CD be required. The undesired sympathectomy of NA should be anticipated and neutralized with vasoconstricting agents. At the core of PH management is the preservation of RV function. Regardless of the cause, PH ultimately funnels into a pathway that causes excessive RV pressure work which can lead to RV hypertrophy, RV diastolic dysfunction with secondary LV diastolic impairment from RV diastolic intraventricular septal wall compression, elevated RVEDPs with consequent decreased right coronary artery perfusion pressures, RV systolic dysfunction, and right-sided heart failure. Therefore, the overall peripartum anesthetic goals will assemble around RV supply– demand optimization. Valuable Clinical Insight • Pulmonary hypertension causes a multitude of physiological cardiac derangements, which include:  RV systolic dysfunction  RV diastolic dysfunction with secondary LV diastolic preload impairment  Elevated RVEDPs  Congestive hepatopathy

On the RV-demand side, both chronic and acute variables influence the severity of the PH physiology. On the chronic side, the three potential contributors are LAP, PVR, and pulmonary

Arterial Vascular Diseases

blood flow (Qp). Mathematically, these three determinants are derived from the PVR relationship representing the pressure across the lungs (mPAP – LAP) divided by Qp. Rearranging the individual components demonstrates that the mPAP is directly proportional to LAP, PVR, and Qp. In the absence of a shunt, Qp equals CO. High LAPs are seen predominantly in four left heart disease states – namely, LV (or systemic ventricular) systolic dysfunction, LV diastolic dysfunction, MR, and MS; these are associated with WHO Group 2 PH. This elevation in LAP causes a hydrostatic backpressure on the pulmonary vasculature which culminates in a combination of fixed and variable PAP elevations. Other less commonly encountered entities include cor triatriatum sinister, pulmonary vein stenosis (secondary to atrial fibrillation ablation procedures or to stenotic heart/lung transplantation anastomosis sites), etc. High PVR states are often seen in such disease entities that comprise WHO Group 1 pulmonary arterial hypertension, although high PVR may also be seen in WHO Group 2 PH secondary to the pathological PA re-modeling changes of chronically elevated LAPs. Excessive Qp states such as those observed in intracardiac (VSD, ASD) and extracardiac (PDA) congenital heart disease which may or may not have concomitant WHO Group 1 PAH, are characterized by cardiopulmonary over-circulation. Less common sources of increased Qp include sizeable AV malformations and hemodialysis AV fistulas. These three main determinants (LAP, PVR, and Qp) should be optimized throughout pregnancy in conjunction with consulting cardiologists and pulmonologists specializing in pulmonary hypertension (Table 6.6). Treatment will include the continued administration of all chronic medications targeting treatable factors related to PH and heart failure (see PH prenatal section for full discussion on this topic). Perfusion to the RV is driven by several factors: CO, CPP to the RCA, and circulating oxygen-carrying capacity (HCT, O2 dissociation curve). Efforts to decrease RV demand while simultaneously augmenting RV supply are the cornerstones of lesionspecific PH management. Anesthesiologists must anticipate and treat acute elevations in PA pressure and subsequent RV-demand. These acute upticks in PA pressure are precipitated by exacerbations of existing left heart pathologies, acute increases in intrinsic PVR due to hypoxemia, hypercapnia, shunt pathologies, or thromboembolic events, especially given the hypercoagulable state of pregnancy. Table 6.6  Factors influencing severity of pulmonary hypertension

Increased LAP

High PVR

Elevated PA CO

•

•

•

• • • • •

LV (or systemic ventricular) systolic dysfunction LV diastolic dysfunction Mitral regurgitation Mitral stenosis Cor triatriatum sinister Pulmonary vein stenosis

• •

Pulmonary arterial HTN Chronic lung disease Chronic pulmonary emboli

• • • •

Intracardiac shunt (VSDs, ASDs) Extracardiac cardiac shunt (PDAs) Pregnancy AVMs AV fistulas

In patients with WHO Group 2 PH with LV dysfunction, acute on chronic severe LV systolic dysfunction is treated with inotropic support and afterload reduction. Mechanical support from an intraaortic balloon pump (IABP) increases coronary perfusion and reduces systolic-phase LV afterload. Inotropic options include epinephrine, dobutamine, dopamine, and milrinone. Dobutamine and milrinone may precipitate excessive SVR reduction, especially when combined with NA, and therefore, they may require co-administration of a vasoconstrictor to bring the SVR in balance with LV systolic failure needs and CPP goals. By deflating during systole, an IABP serves to create the equivalent of a “low SVR” environment which, in concert with inotropic support, maximizes LVEF. Inflation during diastole augments aortic diastolic pressure to the coronary arteries which is especially important for supply-side RCA CPP in the backdrop of PH. Contraindications to IABP placement include significant aortic valve insufficiency, thoracic aortic disease, and iliofemoral arterial disease. In addition, younger patients with more compliant aortas often fail to augment well with an IABP compared to stiffer, less compliant aortic walls of the older patient. These synergistic treatments collectively help prevent and treat any further LV systolic dysfunction-induced LAP increases and any consequent PH RV strain. Acute LAP elevations from chronic valvular MR exacerbations are managed by inotropic support for functional MR and afterload reduction. SVR reduction is achieved by the vasodilating effects of NA (in combination with vasoconstrictors to counterbalance excessive SVR reduction), chrono-ino-dilator therapy with dobutamine +/– vasoconstrictor adjuncts, inodilator therapy with milrinone +/– vasoconstrictor adjuncts, or IABP counter pulsation. Unfortunately, all nonmechanical methods of therapeutic SVR reduction are nonselective for systole versus diastole so there occurs an undesired decrease in AODP and hence RCA CPP. As such, parturients with significant MR along with severe PH and severe right-sided heart failure should be categorized as highly dependent on maximal RCA CPP and should be routinely considered for IABP placement. Hemodynamic goals of valvular MS include low HR to allow for decompression of LA volume (and LAP) into the LV, supraventricular dysrhythmia medications (beta blockers, amiodarone, adenosine) and cardioversion pads in place to immediately restore low HRs, and anticipatory vasoconstrictor therapy to maintain RCA CPP in the setting of NA systemic vasodilatation. As noted above, the physiology of patients with WHO Group 1 PAH is distinct from those with WHO Group 2 PH and is characterized by elevated PVR. Thus, management of PAH and RV failure focuses primarily on management of PVR. Patients should be continued on their PAH-specific medications throughout the peripartum period. Additionally, intrinsic PVR can be reduced by avoidance of hypoxemia, hypercarbia, acidemia, light anesthesia (pain, anxiety, stage two anesthesia), and nitrous oxide. It is unclear if ketamine provides beneficial RV and SVR sympathetic support or whether it has minimal or absent impact on PVR.94–99 Should these modalities prove to be insufficient to optimize PVR, then more advanced targeted PH therapies should be instituted. These include intravenous and inhalational pulmonary vasodilators. Inhaled nitic oxide (iNO) and epoprostenol (prostacyclin, PGI-2) are the two most prominent selective inhaled pulmonary

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arterial vasodilators.100 They are delivered by an endotracheal tube or high-flow nasal cannula.101 The phosphodiesterase inhibitor milrinone or the nitric oxide donors NTG, and nitroprusside (SNP), are the mainstay intravenous options. Both categories are administered with adjunct vasoconstrictor support in the setting of NA. In addition, NTG is a potent uterine relaxant, and, thus, it may be less applicable until uterine tone is established postdelivery. For patients who develop hemodynamic instability or cardiogenic shock, vasoactive agents will need to be used. Vasopressin is favored as it has minimal effects on PVR, while it is recommended to avoid phenylephrine as this agent theoretically promotes an unfavorable PVR/SVR ratio.102 For patients with severe shock, VA ECMO may be required. VA ECMO is a mechanical circulatory support (MCS) system that has been used with increasing frequency to support severe or complete cardiopulmonary failure in the peripartum period. High risk PH patients who may require this modality should be delivered in an operating room with CT Surgery, CT Anesthesia, Perfusion, and a “wet” VA ECMO circuit actively present. Femoral arterial and venous micropuncture catheters are often placed prophylactically for rapid-fire upgrade to ECMO cannulas should MCS be emergently needed for unresuscitatable RV failure ( see additional reading at end of references). For patients with WHO Group 2 PH with high PVR, potent pulmonary vasodilators such as iNO or inhaled epoprostenol should be avoided in certain fixed, noncompliant LAP lesions. Such an example would include mitral valve stenosis where these agents have the potentiality to increase pulmonary blood flow and consequently precipitate acute pulmonary edema. Excessive Qp parturients with predominant left-to-right shunting and minimal-to-no hypoxemia will benefit from NA to offload shunt severity and decrease PAPs and RV strain. Conversely, shunts that have progressed to Eisenmenger Syndrome physiology (right-to-left shunting with persistent hypoxemia) have fixed PAH with severe right-sided CHF from excessive RV strain. Aggressive pulmonary arterial vasodilator therapy is warranted to target any remaining plasticity within the pulmonary vascular bed to prevent any worsening of RV pressure demand work. Keeping the parturient’s baseline O2 saturation above their room air baseline with supplemental oxygen, systemic vasoconstrictor therapy to prevent further right-to-left shunting (in the setting of NA) and to augment RCA CPP, HR control to ensure sufficient time in diastole for coronary perfusion, and inotropic RV support are the mainstays of treatment. In patients with intracardiac shunts, being vigilant about not injecting air and the utilization of intravenous filters are highly emphasized.

Valuable Clinical Insights • Eisenmenger syndrome is the result of left-to-right shunts reversing course due to pulmonary hypertension. • Targeted therapy includes measures aimed at reducing PVR and maintaining RV cardiac output. • These therapies include:  Supplemental oxygen to maintain O2 saturation  SVR maintenance  Inotropic support  Pulmonary vasodilators

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Advanced invasive monitoring is essential for the management of parturients with significant PH and RV dysfunction.103 Arterial lines allow for titration of targeted vasoactive hemodynamic therapy, and intermittent blood gas sampling to ensure optimization of pH, PCO2, and PO2. Central venous pressure (CVP) catheters are indicated when there is a high likelihood of needing cardiopulmonary vasoactive support. They also generate a numerical CVP which can be trended for right heart preload optimization, especially when correlated with right heart echo imaging. The CVP tracing can also be used to look for the formation of “C-V” fusion waves which are indicative of severe tricuspid regurgitation, which may be a marker of actively progressing RV failure. Pulmonary artery catheters (PACs) supply real-time direct numerical assessment of PA pressures to help quantify RV afterload, and to determine cardiac index, SVR, PVR, pulmonary capillary wedge pressures, and mixed venous oxygen saturations, although this is generally not required for most PH patients. TTE and transesophageal echo (TEE) are modalities that can continuously provide qualitative image assessment of RV systolic function and preload. They can also provide an RV quantitative assessment such as tricuspid annular plane systolic excursion (TAPSE), fractional area change (FAC), dP/ dT, myocardial performance index (MPI), three-dimensional imagery, and global longitudinal strain.104 Echocardiography is also highly useful in the PH parturient to assess LV contractility, LV preload, mitral valve and tricuspid valve function, PAPs, and vascular resistances.

Postpartum Pulmonary Hypertension Management Despite advances in therapy, postpartum complication rates related to RV dysfunction remain high, particularly in those parturients with WHO Group 1 PAH.105 Moreover, as noted above, maternal mortality is highest in the few days postpartum. Thus, initial postpartum care of the high-risk PH patient should include Cardiovascular Intensive Care Unit monitoring and co-management by subspecialists in Cardiology, Pulmonary Hypertension, and Cardiothoracic Anesthesia.106 Intrapartum cardiopulmonary support is continued into the ICU setting with gradual de-escalation of support based upon advanced feedback monitoring. The initial postpartum phase is the apex of pregnancy’s high CO state. Specifically, there will be increased volume challenges placed on the RV from an admixture of aortocaval decompression, contracting uterine autotransfusion, and loss of the placental vasculature. These intravascular volume increases are only partially offset by blood loss during delivery. As these preload issues begin to resolve, SVR normalization and oncotic pressure restoration begin to occur. Thus, with so many imprecisely timed moving parts, decompensation from RV failure remains a major concern. In this period, close monitoring of RV preload and CO with CVP and MVO2 respectively is critical. With increases in CVP, patients should receive diuretics, and any support for a low CO. For PH patients with high PVR, pulmonary vasodilators such as inhaled nitric oxide or inhaled prostacyclins are continued until the patient has passed through the excess plasma volume phase. Deep vein thrombosis prophylaxis is paramount.

Arterial Vascular Diseases

Oxytocin is the uterotonic agent of choice for PH patients. However, its profound systemic arterial vasodilating effects necessitate that it be delivered slowly and in conjunction with anticipatory vasoconstrictor support as the right ventricles of severe PH patients are RCA CPP-dependent. Methylergometrine’s (methylergonovine) side effects include SVR elevation and coronary arterial vasospasm. It is not routinely used in WHO Group 2 PH parturients with LV systolic dysfunction, severe MR, or in PH patients where RCA coronary perfusion is marginal. Prostaglandin F2-alpha (carboprost) triggers both bronchoconstriction and profound increases in PVR. It should therefore be completely avoided in all PH parturients.

Splenic Arterial Aneurysms Splenic artery aneurysm (SAA) is rare, with an incidence of 0.16–0.78%.107 It represents the third most common abdominal visceral artery aneurysm.108 They are four times more common in females.109,110 It is associated with atherosclerosis, medial fibrodysplasia, autoimmune disorders, portal hypertension, collagen vascular diseases, and multiparity.110 Pregnancy is thought to contribute to growth and risk of rupture through both hormonal (estrogen, progesterone, relaxin) and mechanical mechanisms (increased CO, abdominal pressure, and plasma volume), although the exact pathway is not known. Rupture is associated with high mortality both maternally and in the fetus, 75% and 95% respectively.107,111 While most SAAs do not rupture when < 2 mm, during pregnancy there is no association between size and risk of rupture. Furthermore, 50% of the SAAs that rupture are documented to be during pregnancy.112 There is a 12% risk of rupture during the first and second trimesters, 13% during labor, 6% postpartum, and 69% during the third trimester.113 Therefore, vascular surgeons recommend prophylactic treatment of identified aneurysms, typically in the second trimester. There is an estimated risk of rupture of 25% for patients with SAA during pregnancy.114 Splenic artery aneurysms are usually asymptomatic, and more are being diagnosed incidentally with the wide use of abdominal CT scans. In the pregnant patient, symptomatic SAAs can present in similar ways to other obstetric emergencies, making their diagnosis very difficult. Therefore, being aware of this, identifying it early, and calling on vascular surgeons or gynecological oncologists is vital for the best outcome. For management, there are several approaches discussed in reported cases, including endovascular, laparoscopic, and open procedures. The personnel and approach will largely be dictated by the degree of bleeding. Endovascular surgery is typically performed by a combination of interventional vascular surgery and/ or interventional radiology (depending on the medical center) who access the splenic arterial aneurysm in an endovascular manner. Electively, these cases are typically performed during the second trimester when the uterus is still small, but most of the organogenesis is complete. In the case of a rupture, there is a need for blood products and readiness for massive transfusions to support hemodynamics. With rupture, about 40% of cases present with sudden cardiovascular collapse.113

References 1. Regitz-Zagrosek V, Roos-Hesselink JW, Bauersachs J, et al. 2018 ESC Guidelines for the management of cardiovascular diseases during pregnancy. Eur Heart J 2018;39: 3165–3241. 2. Hiratzka LF, Bakris GL, Beckman JA, et al. 2010 ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM guidelines for the diagnosis and management of patients with thoracic aortic disease: executive summary. A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, American Association for Thoracic Surgery, American College of Radiology, American Stroke Association, Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Society of Thoracic Surgeons, and Society for Vascular Medicine. Catheter Cardiovasc Interv 2010;76:E43–E86. 3. Mehta LS, Warnes CA, Bradley E, et al. Cardiovascular considerations in caring for pregnant patients: a scientific statement from the American Heart Association. Circulation 2020;141:e884–e903. 4. American College of Obstetricians and Gynecologists' Presidential Task Force on Pregnancy and Heart Disease and Committee on Practice Bulletins - Obstetrics. ACOG Practice Bulletin No. 212: Pregnancy and Heart Disease. Obstet Gynecol. 2019; 133:e320-e356. 5. O’Kelly AC, Scott N, DeFaria Yeh D. Delivering coordinated cardio-obstetric care from preconception through postpartum. Cardiol Clin 2021;39:163–173. 6. Thorne S, MacGregor A, Nelson-Piercy C. Risks of contraception and pregnancy in heart disease. Heart 2006;92:1520–1525. 7. Balci A, Sollie-Szarynska KM, van der Bijl AG, et al. Prospective validation and assessment of cardiovascular and offspring risk models for pregnant women with congenital heart disease. Heart 2014;100:1373–1381. 8. van Hagen IM, Boersma E, Johnson MR, et al. Global cardiac risk assessment in the registry of pregnancy and cardiac disease: results of a registry from the European Society of Cardiology. Eur J Heart Fail 2016;18:523–533. 9. Davis MB, Walsh MN. Cardio-Obstetrics. Circ Cardiovasc Qual Outcomes 2019;12:e005417. 10. Meah VL, Cockcroft JR, Backx K, et al. Cardiac output and related haemodynamics during pregnancy: a series of meta-analyses. Heart 2016;102:518–526. 11. Robson SC, Hunter S, Boys RJ, et al. Serial study of factors influencing changes in cardiac output during human pregnancy. Am J Physiol 1989;256:H1060–H1065. 12. Kametas NA, McAuliffe F, Krampl E, et al. Maternal cardiac function in twin pregnancy. Obstet Gynecol 2003;102:806–815. 13. Green LJ, Mackillop LH, Salvi D, et al. Gestation-specific vital sign reference ranges in pregnancy. Obstet Gynecol 2020;135:653–664. 14. Tkachenko O, Shchekochikhin D, Schrier RW. Hormones and hemodynamics in pregnancy. Int J Endocrinol Metab 2014;12:e14098. 15. Gant NF, Worley RJ, Everett RB, et al. Control of vascular responsiveness during human pregnancy. Kidney Int 1980;18:253– 258. 16. Weiner CP, Thompson LP. Nitric oxide and pregnancy. Semin Perinatol 1997;21:367–380. 17. Kristiansson P, Wang JX. Reproductive hormones and blood pressure during pregnancy. Hum Reprod 2001;16:13–17.

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18. Aguree S, Gernand AD. Plasma volume expansion across healthy pregnancy: a systematic review and meta-analysis of longitudinal studies. BMC Pregnancy Childbirth 2019;19:508. 19. Sheikh M, Ostadrahimi P, Salarzaei M, et al. Cardiac complications in pregnancy: a systematic review and metaanalysis of diagnostic accuracy of BNP and N-Terminal Pro-BNP. Cardiol Ther 2021;10:501–514. 20. Hameed AB, Chan K, Ghamsary M, et al. Longitudinal changes in the B-type natriuretic peptide levels in normal pregnancy and postpartum. Clin Cardiol 2009;32:E60–E62. 21. Tanous D, Siu SC, Mason J, et al. B-type natriuretic peptide in pregnant women with heart disease. J Am Coll Cardiol 2010;56:1247–1253. 22. Resnik JL, Hong C, Resnik R, et al. Evaluation of B-type natriuretic peptide (BNP) levels in normal and preeclamptic women. Am J Obstet Gynecol 2005;193:450–454. 23. Yoshimura T, Yoshimura M, Yasue H, et al. Plasma concentration of atrial natriuretic peptide and brain natriuretic peptide during normal human pregnancy and the postpartum period. J Endocrinol 1994;140:393–397. 24. Kampman MA, Balci A, van Veldhuisen DJ, et al. N-terminal proB-type natriuretic peptide predicts cardiovascular complications in pregnant women with congenital heart disease. Eur Heart J 2014;35:708–715. 25. Umazume T, Yamada T, Yamada S, et al. Morphofunctional cardiac changes in pregnant women: associations with biomarkers. Open Heart 2018;5:e000850. 26. WHO. WHO recommendations: intrapartum care for a positive childbirth experience. WHO Guidelines approved by the Guidelines Review Committee. Geneva, 2018. 27. Robson SC, Dunlop W, Boys RJ, et al. Cardiac output during labour. Br Med J (Clin Res Ed) 1987;295:1169–1172. 28. Kinsella SM, Lohmann G. Supine hypotensive syndrome. Obstet Gynecol 1994;83:774–788. 29. Jangsten E, Mattsson LA, Lyckestam I, et al. A comparison of active management and expectant management of the third stage of labour: a Swedish randomised controlled trial. BJOG 2011;118:362–369. 30. Ueland K. Maternal cardiovascular dynamics. VII. Intrapartum blood volume changes. Am J Obstet Gynecol 1976;126:671–677. 31. Green LJ, Kennedy SH, Mackillop L, et al. International gestational age-specific centiles for blood pressure in pregnancy from the INTERGROWTH-21st Project in 8 countries: a longitudinal cohort study. PLoS Med 2021;18:e1003611. 32. Clark SL, Cotton DB, Lee W, et al. Central hemodynamic assessment of normal term pregnancy. Am J Obstet Gynecol 1989;161:1439–1442. 33. LoMauro A, Aliverti A. Respiratory physiology of pregnancy: physiology masterclass. Breathe (Sheff) 2015;11:297–301. 34. Kamel H, Roman MJ, Pitcher A, et al. Pregnancy and the risk of aortic dissection or rupture: a cohort-crossover analysis. Circulation 2016;134:527–533. 35. Thalmann M, Sodeck GH, Domanovits H, et al. Acute type A aortic dissection and pregnancy: a population-based study. Eur J Cardiothorac Surg 2011;39:e159–e163. 36. Rimmer L, Heyward-Chaplin J, South M, et al. Acute aortic dissection during pregnancy: trials and tribulations. J Card Surg 2021;36:1799–1805. 37. Nienaber CA, Eagle KA. Aortic dissection: new frontiers in diagnosis and management: part I: from etiology to diagnostic strategies. Circulation 2003;108:628–635.

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38. Evangelista A, Isselbacher EM, Bossone E, et al. Insights from the International Registry of Acute Aortic Dissection: a 20-year experience of collaborative clinical research. Circulation 2018;137:1846–1860. 39. Landenhed M, Engstrom G, Gottsater A, et al. Risk profiles for aortic dissection and ruptured or surgically treated aneurysms: a prospective cohort study. J Am Heart Assoc 2015;4:e001513. 40. ACOG. ACOG Practice Bulletin No. 203 Summary: Chronic Hypertension in Pregnancy. Obstet Gynecol 2019;133:215–219. 41. Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/ AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: Executive Summary: A Report of the American College of Cardiology/ American Heart Association Task Force on Clinical Practice Guidelines. Circulation 2018;138:e426–e483. 42. ACOG. Gestational Hypertension and Preeclampsia: ACOG Practice Bulletin, No. 222. Obstet Gynecol 2020;135:e237–e260. 43. Halpern DG, Weinberg CR, Pinnelas R, et al. Use of medication for cardiovascular disease during pregnancy: JACC State-of-theArt Review. J Am Coll Cardiol 2019;73:457–476. 44. Committee Opinion No. 623: Emergent therapy for acute-onset, severe hypertension during pregnancy and the postpartum period. Obstet Gynecol 2015;125:521–525. 45. Weber-Schoendorfer C, Kayser A, Tissen-Diabate T, et al. Fetotoxic risk of AT1 blockers exceeds that of angiotensinconverting enzyme inhibitors: an observational study. J Hypertens 2020;38:133–141. 46. Bullo M, Tschumi S, Bucher BS, et al. Pregnancy outcome following exposure to angiotensin-converting enzyme inhibitors or angiotensin receptor antagonists: a systematic review. Hypertension 2012;60:444–450. 47. Hoffman JI, Kaplan S. The incidence of congenital heart disease. J Am Coll Cardiol 2002;39:1890–1900. 48. Hahn RT, Roman MJ, Mogtader AH, et al. Association of aortic dilation with regurgitant, stenotic and functionally normal bicuspid aortic valves. J Am Coll Cardiol 1992;19:283–288. 49. Fedak PW, Verma S, David TE, et al. Clinical and pathophysiological implications of a bicuspid aortic valve. Circulation 2002;106:900–904. 50. Tadros TM, Klein MD, Shapira OM. Ascending aortic dilatation associated with bicuspid aortic valve: pathophysiology, molecular biology, and clinical implications. Circulation 2009;119:880–890. 51. Keane MG, Wiegers SE, Plappert T, et al. Bicuspid aortic valves are associated with aortic dilatation out of proportion to coexistent valvular lesions. Circulation 2000;102:35–39. 52. Borger MA, Preston M, Ivanov J, et al. Should the ascending aorta be replaced more frequently in patients with bicuspid aortic valve disease? J Thorac Cardiovasc Surg 2004;128:677–683. 53. Erbel R, Eggebrecht H. Aortic dimensions and the risk of dissection. Heart 2006;92:137–142. 54. Verma S, Siu SC. Aortic dilatation in patients with bicuspid aortic valve. N Engl J Med 2014;370:1920–1929. 55. Borger MA, Fedak PWM, Stephens EH, et al. The American Association for Thoracic Surgery consensus guidelines on bicuspid aortic valve-related aortopathy: full online-only version. J Thorac Cardiovasc Surg 2018;156:e41–e74. 56. von Kodolitsch Y, Aydin MA, Koschyk DH, et al. Predictors of aneurysmal formation after surgical correction of aortic coarctation. J Am Coll Cardiol 2002;39:617–624.

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57. Pourmoghadam KK, Velamoor G, Kneebone JM, et al. Changes in protein distribution of the aortic wall following balloon aortoplasty for coarctation. Am J Cardiol 2002;89:91–93. 58. Stout KK, Daniels CJ, Aboulhosn JA, et al. 2018 AHA/ACC Guideline for the Management of Adults with Congenital Heart Disease: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2019;73:1494–1563. 59. Vriend JW, Mulder BJ. Late complications in patients after repair of aortic coarctation: implications for management. Int J Cardiol 2005;101:399–406. 60. Judge DP, Dietz HC. Marfan’s syndrome. Lancet 2005;366:1965– 1976. 61. Smith K, Gros B. Pregnancy-related acute aortic dissection in Marfan syndrome: a review of the literature. Congenit Heart Dis 2017;12:251–260. 62. Kuperstein R, Cahan T, Yoeli-Ullman R, et al. Risk of aortic dissection in pregnant patients with Marfan syndrome. Am J Cardiol 2017;119:132–137. 63. Elkayam U, Ostrzega E, Shotan A, et al. Cardiovascular problems in pregnant women with Marfan syndrome. Ann Intern Med 1995;123:117–122. 64. Donnelly RT, Pinto NM, Kocolas I, et al. The immediate and longterm impact of pregnancy on aortic growth rate and mortality in women with Marfan syndrome. J Am Coll Cardiol 2012;60:224– 229. 65. Shores J, Berger KR, Murphy EA, et al. Progression of aortic dilatation and the benefit of long-term beta-adrenergic blockade in Marfan’s syndrome. N Engl J Med 1994;330:1335–1341. 66. Rybczynski M, Mir TS, Sheikhzadeh S, et al. Frequency and agerelated course of mitral valve dysfunction in Marfan syndrome. Am J Cardiol 2010;106:1048–1053. 67. Pyeritz RE, Fishman EK, Bernhardt BA, et al. Dural ectasia is a common feature of Marfan syndrome. Am J Hum Genet 1988;43:726–732. 68. Fattori R, Nienaber CA, Descovich B, et al. Importance of dural ectasia in phenotypic assessment of Marfan’s syndrome. Lancet 1999;354:910–913. 69. Foran JR, Pyeritz RE, Dietz HC, et al. Characterization of the symptoms associated with dural ectasia in the Marfan patient. Am J Med Genet A 2005;134A: 58–65. 70. Lacassie HJ, Millar S, Leithe LG, et al. Dural ectasia: a likely cause of inadequate spinal anaesthesia in two parturients with Marfan’s syndrome. Br J Anaesth 2005;94:500–504. 71. Loeys BL, Chen J, Neptune ER, et al. A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2. Nat Genet 2005;37:275–281. 72. Loeys BL, Schwarze U, Holm T, et al. Aneurysm syndromes caused by mutations in the TGF-beta receptor. N Engl J Med 2006;355:788–798. 73. Attias D, Stheneur C, Roy C, et al. Comparison of clinical presentations and outcomes between patients with TGFBR2 and FBN1 mutations in Marfan syndrome and related disorders. Circulation 2009;120:2541–2549. 74. Malfait F, Francomano C, Byers P, et al. The 2017 international classification of the Ehlers-Danlos syndromes. Am J Med Genet C Semin Med Genet 2017;175:8–26. 75. Chetty SP, Shaffer BL, Norton ME. Management of pregnancy in women with genetic disorders, Part 1: Disorders of the connective

tissue, muscle, vascular, and skeletal systems. Obstet Gynecol Surv 2011;66:699–709. 76. Bondy CA, Turner Syndrome Study G. Care of girls and women with Turner syndrome: a guideline of the Turner Syndrome Study Group. J Clin Endocrinol Metab 2007;92: 10–25. 77. Elder DA, Roper MG, Henderson RC, et al. Kyphosis in a Turner syndrome population. Pediatrics 2002;109:e93. 78. Sachdev V, Matura LA, Sidenko S, et al. Aortic valve disease in Turner syndrome. J Am Coll Cardiol 2008;51:1904–1909. 79. Matura LA, Ho VB, Rosing DR, et al. Aortic dilatation and dissection in Turner syndrome. Circulation 2007;116:1663–1670. 80. Mortensen KH, Andersen NH, Gravholt CH. Cardiovascular phenotype in Turner syndrome – integrating cardiology, genetics, and endocrinology. Endocr Rev 2012;33:677–714. 81. Landin-Wilhelmsen K, Bryman I, Wilhelmsen L. Cardiac malformations and hypertension, but not metabolic risk factors, are common in Turner syndrome. J Clin Endocrinol Metab 2001;86:4166–4170. 82. Gravholt CH, Andersen NH, Conway GS, et al. Clinical practice guidelines for the care of girls and women with Turner syndrome: proceedings from the 2016 Cincinnati International Turner Syndrome Meeting. Eur J Endocrinol 2017;177:G1–G70. 83. Crawford JD, Hsieh CM, Schenning RC, et al. Genetics, pregnancy, and aortic degeneration. Ann Vasc Surg 2016;30:158 e5–e9. 84. Lansman SL, Goldberg JB, Kai M, et al. Aortic surgery in pregnancy. J Thorac Cardiovasc Surg 2017;153:S44–S48. 85. Lin YH, Seow KM, Hwang JL, et al. Myocardial infarction and mortality caused by methylergonovine. Acta Obstet Gynecol Scand 2005;84:1022. 86. Simonneau G, Montani D, Celermajer DS, et al. Haemodynamic definitions and updated clinical classification of pulmonary hypertension. Eur Respir J 2019;53:1801913. https://doi .org/10.1183/13993003.01913-2018 87. Low TT, Guron N, Ducas R, et al. Pulmonary arterial hypertension in pregnancy: a systematic review of outcomes in the modern era. Pulm Circ 2021;11:20458940211013671. 88. Galiè N, Humbert M, Vachiery JL, et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Respir J 2015;46:903–975. 89. Ballard W, Dixon B, McEvoy CA, et al. Pulmonary arterial hypertension in pregnancy. Cardiol Clin 2021;39:109–118. 90. Wang J, Lu J. Anesthesia for pregnant women with pulmonary hypertension. J Cardiothorac Vasc Anesth. 2021;35: 2201–11. 91. Rex S, Devroe S. Anesthesia for pregnant women with pulmonary hypertension. Curr Opin Anaesthesiol 2016;29:273–281. 92. Monagle J, Manikappa S, Ingram B, et al. Pulmonary hypertension and pregnancy: the experience of a tertiary institution over 15 years. Ann Card Anaesth 2015;18:153–160. 93. Zhang J, Lu J, Zhou X, et al. Perioperative management of pregnant women with idiopathic pulmonary arterial hypertension: an observational case series study from China. J Cardiothorac Vasc Anesth 2018;32:2547–2559. 94. Strumpher J, Jacobsohn E. Pulmonary hypertension and right ventricular dysfunction: physiology and perioperative management. J Cardiothorac Vasc Anesth 2011;25:687–704.

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95. Maxwell BG, Jackson E. Role of ketamine in the management of pulmonary hypertension and right ventricular failure. J Cardiothorac Vasc Anesth 2012;26:e24–e25; author reply e5–6.   96. Basagan-Mogol E, Goren S, Korfali G, et al. Induction of anesthesia in coronary artery bypass graft surgery: the hemodynamic and analgesic effects of ketamine. Clinics (Sao Paulo) 2010;65:133–138.   97. Williams GD, Philip BM, Chu LF, et al. Ketamine does not increase pulmonary vascular resistance in children with pulmonary hypertension undergoing sevoflurane anesthesia and spontaneous ventilation. Anesth Analg 2007;105:1578–1584.   98. Williams GD, Maan H, Ramamoorthy C, et al. Perioperative complications in children with pulmonary hypertension undergoing general anesthesia with ketamine. Paediatr Anaesth 2010;20:28–37.   99. Loomba RS, Gray SB, Flores S. Hemodynamic effects of ketamine in children with congenital heart disease and/or pulmonary hypertension. Congenit Heart Dis 2018;13:646–654. 100. Thunberg CA, Morozowich ST, Ramakrishna H. Inhaled therapy for the management of perioperative pulmonary hypertension. Ann Card Anaesth 2015;18:394–402. 101. Tremblay JA, Couture EJ, Albert M, et al. Noninvasive administration of inhaled nitric oxide and its hemodynamic effects in patients with acute right ventricular dysfunction. J Cardiothorac Vasc Anesth 2019;33:642–647. 102. Price LC, Wort SJ, Finney SJ, et al. Pulmonary vascular and right ventricular dysfunction in adult critical care: current and emerging options for management: a systematic literature review. Crit Care 2010;14:R169. 103. Pilkington SA, Taboada D, Martinez G. Pulmonary hypertension and its management in patients undergoing noncardiac surgery. Anaesthesia 2015;70:56–70.

104. Dutta T, Aronow WS. Echocardiographic evaluation of the right ventricle: clinical implications. Clin Cardiol 2017; 40:542–548. 105. Meng ML, Landau R, Viktorsdottir O, et al. Pulmonary hypertension in pregnancy: a report of 49 cases at four tertiary North American sites. Obstet Gynecol 2017;129:511–520. 106. Price LC, Martinez G, Brame A, et al. Perioperative management of patients with pulmonary hypertension undergoing noncardiothoracic, non-obstetric surgery: a systematic review and expert consensus statement. Br J Anaesth 2021;126:774–790. 107. Chookun J, Bounes V, Ducasse JL, et al. Rupture of splenic artery aneurysm during early pregnancy: a rare and catastrophic event. Am J Emerg Med 2009;27:898, e5–6. 108. Tcbc-Rj RA, Ferreira MC, Ferreira DA, et al. Splenic artery aneurysm. Rev Col Bras Cir 2016;43:398–400. 109. Al-Habbal Y, Christophi C, Muralidharan V. Aneurysms of the splenic artery – a review. Surgeon 2010;8:223–231. 110. Sadat U, Dar O, Walsh S, et al. Splenic artery aneurysms in pregnancy–a systematic review. Int J Surg 2008;6:261–265. 111. Nanez L, Knowles M, Modrall JG, et al. Ruptured splenic artery aneurysms are exceedingly rare in pregnant women. J Vasc Surg 2014;60:1520–1523. 112. Veterano C, Monteiro E, Rego D, et al. Laparoscopic resection of a splenic artery aneurysm with vascular reconstruction during pregnancy. Ann Vasc Surg 2021;72:666, e7–e11. 113. Jacobson J, Gorbatkin C, Good S, et al. Splenic artery aneurysm rupture in pregnancy. Am J Emerg Med 2017;35:935, e5–e8. 114. Samame J, Kaul A, Garza U, et al. Laparoscopic aneurysm resection and splenectomy for splenic artery aneurysm in the third trimester of pregnancy. Surg Endosc 2013;27: 2988–2991.

Additional Reading on VA ECMO 1. 2. 3. 4.

Lankford, AS, Chow JH, Jackson AM, et al. Clinical outcomes of pregnant and postpartum extracorporeal membrane oxygenation patients. Anesth Analg 2021; 132:777–787. Agerstrand C, Abrams D, Biscotti M. Extracorporeal membrane oxygenation for cardiopulmonary failure during pregnancy and postpartum. Ann Thorac Surg 2016; 102:774–9. Moore SA, Dietl CA, Coleman DM. Extracorporeal life support during pregnancy. J Thorac Cardiovasc Surg 2016;151:1154–60. Biderman P, Carmi U, Setton E. Maternal salvage with extracorporeal life support: Lessons learned in a single center. Anesth Analg 2017; 125:1275–1280.

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5. 6. 7.

Sharma NS, Wille KM, Bellot SC, et al. Modern use of extracorporeal life support in pregnancy and postpartum. ASAIO 2015; 61:110–114. Naoum EE, Chalupka A, Haft J. Extracorporeal life support in pregnancy: A systemic review. J Am Heart Assoc 2020; 913:e016072. Kapur NK, Esposito ML, Bader Y, et al. Mechanical circulatory support devices for acute right ventricular failure. Circulation 2017; 136:314–326.

Chapter

7

Uncommon Respiratory Disorders in Pregnancy Alexandra Nicholas

Acute Respiratory Distress Syndrome Epidemiology Acute respiratory distress syndrome (ARDS) is a distinct type of hypoxemic respiratory failure affecting approximately 190,000 patients in the United States each year.1 The incidence in parturients varies from 17 to 130 per 100,000 deliveries, with mortality ranging from 24% to 39%.2–4 Maternal ARDS is associated with high fetal death rates, preterm labor, perinatal asphyxia, and FHR abnormalities.5 In a series of 10 third trimester parturients ventilated for ARDS, only five neonates survived intact after delivery.2

Etiology Causes of ARDS in pregnancy (Table 7.1) include sepsis due to pyelonephritis, pneumonia, AFE, fat emboli, severe PreE, trauma, aspiration pneumonitis, inhalation injury, burns, Table 7.1  Causes of acute respiratory distress syndrome Sepsis Chorioamnionitis Pyelonephritis Endometritis Septic abortion Retained products of conception Pneumonia Aspiration Obstetric hemorrhage Massive blood transfusion Transfusion-related acute lung injury Trauma Severe PreE Embolism Thrombotic Amniotic fluid Venous air Trophoblastic Substance abuse Connective tissue disease Acute pancreatitis Near drowning

pancreatitis, and septic abortion.6,7 Another reported cause of ARDS is tocolytic-associated pulmonary edema that can develop with terbutaline. This phenomenon occurs in up to 10% of patients receiving beta-agonists (not specifically terbutaline) and is associated with the administration of multiple doses of tocolytic agents and hypervolemic states.5,6 Beta-agonistassociated pulmonary edema can result from fluid overload, decreased plasma oncotic pressure, physiologic alterations of pregnancy, and beta-agonist-induced increase in the secretion of antidiuretic hormone. However, the development of ARDS in these patients exposed to beta-agonists is proposed to be secondary to underlying infection leading to preterm labor. It may not be primarily due to the tocolytic itself.

Pathophysiology The pathologic stages of ARDS are exudative, proliferative, then fibrotic. The inciting injury leads to the release of proinflammatory cytokines such as tumor necrosis factor, interleukin (IL)1, IL6, and IL8. These cytokines release reactive oxygen species, proteases, and other toxic mediators that damage the capillary endothelium and alveolar epithelium.7 These toxic mediators lead to increased capillary permeability, interstitial and alveolar edema, and loss of surfactant with subsequent alveolar damage and collapse. Ventilation/perfusion mismatching, intrapulmonary shunting, decreased lung compliance, and hypoxemia result. PVR increases, and RV dysfunction can follow.5 These changes reduce LV preload and CO, further compromising oxygen delivery. Multisystem organ failure may occur and lead to maternal and/or fetal death.3–6

Diagnosis The Berlin Definition of ARDS (2012) has replaced the American European Consensus Conference’s definition of ARDS (1994). However, much of the literature on ARDS in pregnancy uses prior definitions.8 Table 7.2 lists current diagnostic criteria.

Anesthetic Management Management of ARDS in pregnancy starts with treating the primary cause, optimizing tissue oxygen delivery, and limiting further lung injury while providing supportive maternal care and monitoring the fetus for signs of distress that would prompt

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Table 7.2  Berlin diagnostic criteria for acute respiratory distress syndrome8 1. Timing of onset occurs within one week of a known insult or worsening respiratory symptoms 2. Chest imaging revealing bilateral infiltrates not fully explained by effusions, lobar collapse, or nodules 3. The radiographic opacities producing respiratory failure are not fully explained by cardiac failure or volume overload 4. Oxygenation deficits (with PEEP or CPAP 5 cm H2O): Mild: PaO2/FiO2 201–300 Moderate: PaO2/FiO2 101–200 Severe: PaO2/FiO2 < 100

delivery. Appropriate antibiotic selection and administration within the first hour of documented hypotension are associated with improved survival.6 While the overall treatment goals are similar in parturients and nonpregnant patients, there are some special considerations in pregnancy. Pregnant patients have increased oxygen and metabolic demands and therefore require increased CO. They have decreased FRC, resulting in a rapid decline in oxygenation in response to respiratory interventions, such as induction of anesthesia. Parturients also have a chronic compensated respiratory alkalosis, resulting in a decreased capacity for respiratory compensation and decreased buffering capacity for metabolic acidosis.5 Additionally, these patients are prone to pulmonary edema due to increased plasma volume with reduced plasma oncotic pressure. These considerations affect mechanical ventilation and oxygenation management. Noninvasive positive pressure ventilation (NIPPV) is used in pregnant patients with pulmonary edema and sleep apnea but has not been studied in ARDS.9 It may be considered in select patients with rapidly reversible causes of pulmonary edema but carries an increased risk of gastric aspiration during pregnancy. In addition, NIPPV is contraindicated when there is hemodynamic instability or impaired respiratory drive. Early endotracheal intubation is typically preferable. In general, intubation criteria for a parturient do not differ significantly from the nonpregnant population. Inability to maintain a PaO2 > 70 mmHg, SaO2 > 95%, and a normal nonpregnant PaCO2 all indicate impending respiratory failure.

Mechanical Ventilation Ventilation strategies for patients with ARDS focus on lung protection. Lung overdistention, atelectrauma, and high airway pressures can produce injury characterized by increased capillary permeability and noncardiogenic pulmonary edema. This may lead to a worsening systemic inflammatory response. The landmark ARDS Network trial showed a 22% relative risk reduction in mortality in a low tidal volume group (6 ml/kg of predicted body weight and targeted inspiratory plateau pressures ≤ 30 cmH2O) versus a higher tidal volume group (12 ml/ kg).10 There are no randomized trials examining lung protective strategies in pregnancy, While not well studied, changes in respiratory physiology during pregnancy warrant special consideration during mechanical ventilation. Increase the respiratory rate to maintain the pH and PaCO2 in ranges appropriate to the gestational age of pregnancy. Avoid

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respiratory alkalosis beyond normal for pregnancy because it may diminish uteroplacental blood flow. Most suggest a goal of PaCO2 < 45–50 mmHg. Permissive hypercapnia is a lung protective strategy often used in ARDS, but its use in pregnancy is not validated. Animal studies suggest that a rapid acute increase in maternal PaCO2 to > 60 mmHg increases uterine vascular resistance and decreases uteroplacental blood flow; however, this may not persist during a slower and controlled hypoventilation strategy in humans.5 Positive end expiratory pressure (PEEP) prevents atelectasis, recruits collapsed alveoli (increasing FRC) and improves oxygenation. However, excessive levels of PEEP can decrease CO, reduce oxygen delivery, and increase the risk of barotrauma. A beneficial strategy in parturients with ARDS is to use a low TV, maintain plateau pressure ≤ 30 cmH2O and apply PEEP to achieve PaO2 65 – 90 mmHg.5,6 Determining optimal PEEP is still a highly debated topic, as optimal PEEP likely depends on an individual’s amount of recruitable lung tissue. Various metrics are used for titrating PEEP in ARDS; however, there is no consensus for the ideal PEEP titration model, even in nonpregnant adults with ARDS.

Fluid Management Fluid restriction in the setting of capillary leak with extravasation plus intravascular hypovolemia can depress CO and compromise tissue oxygen delivery. Conversely, fluid administration to correct hypovolemia may precipitate pulmonary edema and worsen ARDS pathogenesis. Classically, invasive monitoring with pulmonary artery (PA) catheter was employed to titrate fluid administration and maintain adequate CO. The ARDS Network Fluid and Catheter Treatment Trial completed a randomized multicenter study with 1000 nonpregnant ARDS patients. The study found that guided fluid therapy using a PA catheter was not associated with improved survival or organ function compared to central venous catheter guided therapy and had more catheter-related complications.11 Comparing a liberal versus conservative (CVP < 4 mmHg) fluid management strategy, there was no significant difference in 60-day mortality; however, the conservative group had improved oxygenation and reduced ventilator-free days.12 These studies suggest that the best approach to fluid management includes avoiding volume overload, judicious diuresis, and fluid restriction. Simultaneously, avoid maternal hypotension and maintain end-organ perfusion to preserve uteroplacental blood flow.

Inhaled Nitric Oxide Nitric oxide (NO) relaxes smooth muscle and facilitates pulmonary vasodilation selectively in ventilated areas of the lung. This results in less intrapulmonary shunting and improved V/Q mismatch with enhanced oxygen delivery. Unfortunately, inhaled NO use in ARDS has not improved mortality, so is rarely used.13,14 However, consider a trial of NO in select obstetric patients with severe pulmonary hypertension.

Other Therapies Prone positioning may increase recruitment of previously atelectatic lung areas, increase FRC, and help to mobilize secretions,

Uncommon Respiratory Disorders in Pregnancy

all contributing to improved oxygenation. There is moderate evidence from RCTs and meta-analyses that the prone position reduces mortality, specifically in nonpregnant patients with severe ARDS.15,16 Reports utilizing prone positioning in patients with a gravid uterus are increasing, suggest that pregnancy is not a contraindication to prone positioning in severe ARDS.17–19 Systemic corticosteroid use in ARDS is controversial. Highdose corticosteroids given early in ARDS showed no improvement in outcomes and increased infection rates.20 In some small studies, moderate-dose corticosteroids showed some benefit when used in persistent ARDS (7 days after onset). However, in an ARDS Network multicenter, double blind, placebo-controlled, randomized trial in nonpregnant patients, there was no significant difference in 60-day mortality with methylprednisolone use. When started > 14 days after the onset of ARDS, mortality worsened at 60 and 180 days.21 Experts do not recommend the routine use of corticosteroids for ARDS. Studies of anti-inflammatory, antioxidant, and surfactant therapies have yet to show a clear benefit in ARDS treatment. Extracorporeal membrane oxygenation is an alternative modality in ARDS and cases of severe refractory hypoxemia. Case series and systematic reviews demonstrate favorable maternal and fetal outcomes with ECMO in pregnant and postpartum women with ARDS.22–24 Maternal 30-day survival was 75.4%, fetal survival 64.7% and the most common complications cited were maternal bleeding 18.4% and preterm delivery 48.5%.24

Obstetric Management Given the physiologic changes associated with pregnancy, some theorize that elective delivery for women in late pregnancy who have ARDS may improve maternal respiratory mechanics. There is minimal evidence to support this argument,25 and some evidence shows no benefit.26 At this time, standard obstetric indications for delivery and mode of delivery should apply to this patient population until further evidence is available. Efforts should focus on optimizing maternal oxygenation and pain control during delivery.

Cystic Fibrosis Epidemiology Data from newborn screening programs for cystic fibrosis (CF) reveal an incidence between 1:3000 and 1:6000 in populations of European descent. The incidence ranges from 1:1353 in Ireland to 1:3300 in Canada and 1:4000 in the United States. It appears rarer in Latin and South America, Asia, and Africa.27 Since first discovered, CF survival has improved dramatically, with the estimated median age of survival approximately 50 years.27,28 As more women with CF enter reproductive age, the incidence of pregnancy in this population has more than doubled over the last decade in the United States, with 137 pregnancies reported in 1999 and 310 in 2019.28

Pathophysiology The gene responsible for CF, an autosomal recessive disorder, codes for a protein product called cystic fibrosis transmembrane conductance regulator (CFTR). CFTR is responsible for

chloride ion transport across apical membranes of epithelial cells in the airway, intestine, pancreas, kidney, sweat glands, and male reproductive tract.29 There are more than 2000 variants of CFTR; some lead to more severe phenotypes than others, causing a broad spectrum of CF presentation and disease severity.30

Clinical Features Abnormal mucous secretion within the respiratory system causes small airway obstruction from increased adhesiveness and difficulty in clearance. Chronic airway obstruction and mucus retention lead to airway colonization and chronic infection. This chronic inflammation causes progressive tissue damage, fibrosis, bronchiectasis, and distal hyperinflation resulting in increased V/Q mismatching and hypoxemia. The respiratory effects of CF often start with a cough that gradually becomes persistent and productive. Over time, airway hyperreactivity is common, and PFT reveals an obstructive pattern. With advanced disease, respiratory failure occurs. Lung hyperinflation predisposes to spontaneous pneumothorax, and bronchiectasis causes hemoptysis, potentially massive. Pulmonary hypertension secondary to chronic hypoxemia and subsequent RV dysfunction appear as later complications. Exocrine gland dysfunction involving the pancreas is common and leads to maldigestion, malabsorption, and insulindependent diabetes mellitus. Subacute intestinal obstruction can also occur. In late disease, biliary cirrhosis and portal hypertension may occur with hepatic function abnormalities, hypoalbuminemia, and jaundice (Table 7.3).

Table 7.3  Clinical features of cystic fibrosis Respiratory Bronchiectasis with chronic infection Pneumothorax Hemoptysis Respiratory failure Chronic rhinosinusitis and nasal polyposis Gastrointestinal Intestinal obstruction Intussusception Rectal prolapse Malignancies Hepatobiliary Pancreatic insufficiency Recurrent acute pancreatitis Cholelithiasis Biliary cirrhosis Other Diabetes Chronic kidney disease Ureteric calculi Osteoporosis Oligomenorrhea Subfertility Malnutrition Vestibuloauditory disturbance Anxiety and depression

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Diagnosis Clinical signs and evidence of CFTR dysfunction lead to the diagnosis of CF. Sweat chloride testing with values ≥ 60 mmol/l has been the standard confirmatory test for CFTR dysfunction. With the advent of genetic and universal newborn screening, the diagnostic criteria have evolved and are outlined in Consensus Guidelines from the Cystic Fibrosis Foundation.31

Treatment The treatment of CF centers around airway clearance, bronchodilation, and prevention of acute exacerbations and infections. Inhaled hypertonic saline, inhaled recombinant human deoxyribonucleases, and chest physiotherapy all assist airway clearance. Some patients are candidates for a CFTR modulator, a class of drugs that improve the defective CFTR protein production, processing, and function.32 Inhaled beta 2 agonists are used before airway clearance therapy and as rescue therapy for acute symptoms. Patients with symptoms characteristic of asthma may require inhaled glucocorticoids. Use inhaled tobramycin to prevent acute exacerbation in patients with persistent Pseudomonas aeruginosa infection. Treatment of acute exacerbations requires systemic antibiotics, intensified airway clearance therapies, possible systemic glucocorticoids, and usually hospitalization. Patients with chronic hypoxemia may need continuous oxygen therapy and those with severe pulmonary compromise may need lung transplantation. In addition to respiratory treatments, CF patients may require replacement of pancreatic enzymes for pancreatic insufficiency, insulin replacement, nutritional counseling, and psychosocial support.

Cystic Fibrosis and Pregnancy Pregnancy is usually well tolerated in CF patients with mild disease. Those with severe CF may not tolerate the physiological changes of pregnancy. Women with poor pulmonary function, inadequate nutrition, and pulmonary hypertension are at greater risk for maternal and fetal morbidity and mortality.33 Overall, it does not appear that pregnancy accelerates the progression of CF. A large longitudinal study comparing pregnant to never pregnant matched CF patients showed declines in forced expiratory volume in 1 second (FEV1) over time that were not significantly different (6.8% vs. 4.7%).33 However, pregnancy is associated with increased annual rates of illness-related visits and more pulmonary exacerbations, likely reflecting the impact of the physical and emotional challenges on disease self-management.34 Prepregnancy lung function is essential in predicting pregnancy outcomes; several studies demonstrated a positive correlation between maternal FEV1 and gestational age at delivery.35 In one study of 71 women, 38% of infants were preterm. A FEV1 < 60% predicted correlated with increased risk of premature delivery, delivery by CD, and adverse fetal outcomes such as low birth weight and perinatal death.36 UK guidelines in 2008 recommended FEV1 < 50% predicted are considered an absolute contraindication to pregnancy.37 Basing this recommendation

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on FEV1 values alone may be misleading, as there are reports of successful pregnancies in patients with prepregnancy FEV1 values of 20–30% predicted.35

Management Preconception counseling is essential to optimize medical conditions and assess the need for psychosocial and physical support during pregnancy and postpartum. A multidisciplinary team (obstetrician, pulmonologist, anesthesiologist, and nutritionist) should follow these patients throughout pregnancy. Regular assessment of the cardiorespiratory system detects deterioration resulting from the changing demands of pregnancy. Bronchial toilet, early physiotherapy involvement, maintenance of CF medications and vigorous treatment of respiratory infections are mandatory. Advise women planning pregnancy to be 90% of ideal body weight before conception. Patients unable to achieve adequate weight gain orally may need nocturnal enteral nasogastric tube feeding.38 Monitor weight, blood glucose, Hb, protein, albumin, PT, and fat-soluble vitamins frequently. Patients with CF have a high incidence of developing diabetes and nutritional deficiencies during pregnancy and may require frequent adjustments in medications and supplements. Baseline PFTs and a TTE help monitor disease progression and diagnose pulmonary hypertension.38 Base the delivery plan on the severity of the disease, obstetric indications, and the patient’s wishes. Perform an anesthetic assessment and discuss options for labor analgesia and CD at an early stage. Monitor oxygen saturation continuously during labor and delivery and administer humidified oxygen if saturation falls below 94%. Maintenance of hydration, continuing CF medications, and monitoring insulin requirements are necessary. If cardiorespiratory function deteriorates or heart failure is suspected, consider TTE, intraarterial pressure, central venous pressure, and PA pressure monitoring. Diuresis may be required. Early LEA is essential for pain control which reduces the sympathetic response to labor and tachycardia, and in turn decreases oxygen demand. Avoid nitrous oxide for labor analgesia, given the increased risk of barotrauma due to air trapping. Parenteral opioids decrease respiratory drive and inhibit cough, so use them with caution in this patient population. In women with CF, Valsalva maneuvers in the second stage may cause a pneumothorax. Depending on this risk, consider assisted second stage delivery. Although usually reserved for obstetric indications, deterioration in maternal or fetal status may require rapid delivery by CD. Base the choice of GA or NA on individual circumstances. If GA is required, avoid preoperative anticholinergic agents that promote drying of airway secretions. As endotracheal intubation may provoke bronchospasm, and positive pressure ventilation may lead to barotrauma, consider the following: 1, Administer 100% FiO2 before intubation for a longer time for effective denitrogenation. 2. Employ techniques to reduce bronchospasm risk.

Uncommon Respiratory Disorders in Pregnancy

3. Humidify anesthetic gases to prevent inspissation of mucus. 4. Use positive pressure ventilation with adequate TV, PEEP, and frequent suctioning to minimize atelectasis. 5. Adjust ventilator settings to allow a long expiratory phase to prevent air trapping and reduce the risk of barotrauma. When NA is used, consider a continuous catheter technique (epidural or spinal) to control block height. A thoracic motor block may impair ventilation and the ability to mobilize secretions with cough. A continuous technique allows incremental administration of LA solution, avoiding this complication. It is prudent to aim for an upper sensory level of T6. Avoid NA in patients that do not tolerate lying flat. Single shot spinal anesthesia has a rapid onset and produces a dense motor and sensory block that is difficult to control. A sudden high block may precipitate a respiratory crisis in those with more severe respiratory disease. Hence, this technique is discouraged. A suitable alternative is CSE with a reduced intrathecal dose. Following CD, patients with CF require close attention to ensure pulmonary and hemodynamic stability. Encourage an early return to full mobility by providing adequate pain relief. Provide postoperative analgesia with parenteral or neuraxial techniques in conjunction with NSAIDs. Monitor clinical respiratory status regularly to detect opioid-induced respiratory depression.

Pneumothorax Introduction Primary spontaneous pneumothorax is likely due to rupture of subpleural blebs, causing air to leak into the pleural space leading to increased intrapleural pressure and lung collapse. Secondary spontaneous pneumothorax occurs in the setting of underlying lung pathology (Table 7.4). There are approximately 50 reports of spontaneous pneumothorax during pregnancy, but this event is underreported. In one case series, the mean gestational age for the first occurrence was 26 weeks, and 33% of cases occurred at or near term.39 Women with a history of pneumothorax are at increased risk of a recurrence in pregnancy, at delivery, or postpartum. Approximately half of the pneumothoraces reported during pregnancy are recurrent.40,41 Table 7.4  Causes of secondary pneumothorax Respiratory tract infection Asthma Prior history of pneumothorax Cocaine abuse Hyperemesis gravidarum Histoplasmosis Tuberculosis Lymphangioleiomyomatosis Alpha1 antitrypsin deficiency Chest trauma Iatrogenic

Clinical Features Patients usually present with sudden onset of dyspnea and pleuritic chest pain. The severity of symptoms is related to the volume of air in the pleural space, with dyspnea being more prominent if the pneumothorax is large. A large pneumothorax is associated with tachypnea, tachycardia, ipsilateral diminished breath sounds, hyperresonance to chest percussion, and hypoxemia. When hypotension is present, consider tension pneumothorax. Reliance on classical clinical findings may lead to misdiagnosis. Chest pain and dyspnea are often misattributed to other causes, especially during labor with its often-accelerated breathing pattern. Diagnosis is classically by CXR, but an alternative is POCUS (see Chapter 2). In a recent Cochrane meta-analysis, US for detection of pneumothorax in trauma patients had superior sensitivity and excellent specificity (91% and 99%) compared to supine CXR (47% and 100%),42 while posing little to no risk to the fetus. However, the fetus is not at substantial radiation risk from a CXR when the maternal abdomen is shielded. The estimated radiation dose to the uterus in this setting is one millirad per examination.

Treatment Maternal oxygen consumption increases by 20% during pregnancy and up to 50% during labor. Since the normal PO2 in fetal umbilical venous blood is 35–40 mmHg, there is little reserve if maternal oxygenation declines. Therefore, continuous pulse oximetry monitoring and early intervention are critical. Manage a stable asymptomatic pneumothorax with observation and administration of supplemental oxygen alone. Hospitalize all patients for at least 24 hours of monitoring. For patients with a symptomatic and stable large pneumothorax (> 15% of hemithorax), perform catheter aspiration or tube thoracostomy.41 Both interventions have similar rates of success and recurrence,43 but there may be a reduced hospital stay with needle aspiration.41 If a leak persists despite aspiration, perform tube thoracostomy. For unstable patients (e.g., women with tension pneumothorax and hemodynamic compromise), immediate decompression is necessary.41 Persistent air leaks with or without incomplete reexpansion of the lung is the usual reason for using suction; however, there is no evidence supporting its routine use. When these treatments have failed or pneumothorax recurs, the definitive treatment is thoracoscopy, bleb resection, and possible pleurodesis.41 Depending on individual circumstances, definitive therapy may be delayed in pregnant women until after delivery. However, long-term chest drainage predisposes to empyema, pain, and immobility.

Intrapartum Management Epidural analgesia is recommended early in labor for pneumothorax patients because it reduces maternal oxygen demand and tachypnea associated with pain. Increased intrathoracic pressure from Valsalva maneuvers can aggravate a pneumothorax, so elective assisted vaginal delivery is recommended.41 For CD, NA is

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highly desirable; avoid GA when possible. When GA is unavoidable, keep airway pressures as low as possible to minimize air leaks and avoid nitrous oxide. Valuable Clinical Insights • Increased MV may be required to maintain adequate ventilation in the presence of a continued leak when a thoracostomy tube is present. • Increase MV by increasing gas flow, TV, and/or RR.

Early LEA for labor is imperative, since expulsive efforts can lead to recurrence in patients with a history of prior pneumothorax or pneumothorax without definitive therapy.44 Similarly, NA is preferred to GA for CD when definitive therapy is incomplete. Patients that have undergone definitive surgical treatment may attempt spontaneous vaginal delivery, and there are successful cases without recurrence.45 Still, NA is recommended over GA for CD in definitively repaired cases.

Status Asthmaticus Introduction Status asthmaticus (SA) is very rare, occurring only in about 0.2% of pregnancies.46 However, asthma is prevalent in 3–12% of obstetric patients worldwide and is the most common chronic medical condition complicating pregnancy with increasing healthcare utilization and cost.47 Asthma is associated with PreE, placental abruption, placenta previa, obstetric hemorrhage, spontaneous abortion, gestational diabetes, and unplanned emergency CD.48,49 Asthma is also associated with poor pediatric outcomes such as low birth weight, and small for gestational age infants, with the severity of outcomes correlated with increasing asthma severity.49 It is important to note that patients with asthma often have higher rates of smoking, obesity, and other comorbidities independently associated with higher maternal and fetal risk.50 More prospective studies that control for these risk factors are needed to understand the relationship between asthma and pregnancy outcomes. Despite this, there is increasing evidence that improved asthma management leads to improved maternal and fetal outcomes. In a meta-analysis, Murphy et al. showed a reduction in preterm delivery and preterm labor when active asthma management was used.51 Similarly, Wang et al. demonstrated the risk of gestational diabetes was similar to nonasthmatic controls in women receiving active asthma management.48 Improved maternal asthma therapy also seems to improve pediatric outcomes. Mattes et al. demonstrated that reducing asthma exacerbations during pregnancy resulted in fewer episodes of bronchiolitis in infants at 12 months versus standard maternal asthma management.52 Pregnancy also impacts asthma. Kircher et al. showed that disease control was worse during pregnancy for 36% of asthmatic patients,53 but it may improve or stay the same. Most exacerbations occur in the second or third trimesters and rarely during labor.51 Pregnancy is also associated with new-onset

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asthma.54 Typically, an asthma course returns to a prepregnancy state within 3 months after delivery.51 These findings suggest that the obstetric anesthesiologist may encounter more pregnant women with asthma and should be prepared to encounter the rarer SA.

Pathophysiology Status asthmaticus is a severe, life-threatening exacerbation of asthma, refractory to standard therapy, requiring ICU admission and mechanical ventilation. Triggers for SA may include cigarette smoke, viral infections, aspirin, cold air, or exercise.55 Stimulated T helper lymphocytes release cytokines such as IL3, IL4, IL5, and granulocyte macrophage colony stimulating factors. These cytokines stimulate IgE production leading to mast cell activation. Mast cells produce cytokines, such as IL4 and IL5, and release histamine. Eosinophils also become activated and infiltrate the airways, releasing toxic proteins, leukotrienes, and platelet activating factor.55 Consequences include airway obstruction from bronchial smooth muscle contraction, mucus hypersecretion, airway infiltration, and mucosal edema. The result is severe airflow obstruction with mucous plugging, air trapping, and hypoxia. Increased MV and hypocapnia lead to dynamic hyperinflation (i.e., incomplete exhalation or auto-PEEP). Intrapulmonary shunting and worsening V/Q mismatch cause hypoxemia. Lung hyperinflation flattens the diaphragm and combined with increased MV, increases the metabolic demands on respiratory muscles. Subsequent respiratory muscle failure and worsening hypercapnia ensue.56

Management Ideally, optimal asthma management will prevent SA during pregnancy.52 Generally, treat pregnant women with asthma and asthma exacerbation in the same way as nonpregnant adults. The NIH National Asthma Education and Prevention Program Working Group Report recommends measures for managing asthma in pregnancy.57 Treatment goals include minimizing hypoxemia, hypercarbia, and alkalosis, all of which reduce fetal oxygenation. Intravenous fluid administration helps hydrate and clear pulmonary secretions. Administer supplemental oxygen by mask after obtaining an ABG; the recommendation is to maintain pO2 > 60 mmHg and SaO2 > 95%. Use continuous pulse oximetry and, when appropriate, FHR monitoring. First line therapy includes inhaled or subcutaneous betaadrenergic agonists and corticosteroids. If initial treatment fails or respiratory distress persists 30–60 minutes after treatment, this is SA, and ICU care is required. Elevated arterial pCO2 (> 38 mmHg) is an ominous sign in pregnancy but not in a nonpregnant woman. If the patient demonstrates progressive fatigue, continued increased work of breathing, or alterations in consciousness, intubation is indicated.58 Intubation and mechanical ventilation are critical for managing respiratory failure and alleviating some of the hemodynamic consequences of SA. With severe airway obstruction, patients can have a considerable negative inspiratory pressure that increases RV and PA pressures, and, in turn, decreases

Uncommon Respiratory Disorders in Pregnancy

SV and systolic pressure.59 Mechanical ventilation minimizes hyperinflation and barotrauma. Use a low TV with maximal expiratory time (this may require increasing inspiratory flow and decreasing RR); titrate the FiO2 for pO2 > 65 mmHg. To avoid auto-PEEP and barotrauma in mechanically ventilated SA patients, one may have to accept hypercapnia. Classically, one avoids maternal respiratory acidosis in pregnancy for fear of fetal acidosis and impaired oxygenation of fetal hemoglobin. In sheep models, PaCO2 > 60 mmHg can increase uterine vascular resistance and decrease uteroplacental blood flow,60 but in humans, adverse effects of maternal hypercapnia induced for the period of labor have not been demonstrated.61 Elsayegh and Shapiro published a series of five cases of SA in pregnancy.62 Cases occurred at 6-, 9-, 14-, 27-, and 28-weeks gestation. Four patients required mechanical ventilation and sedation. The severity of hypercapnia in SA patients ranged from pCO2 48–132 mmHg for durations of 30 minutes to ≥ 24 hours. The four patients who delivered had excellent pregnancy outcomes.62 Avoid maternal hypercarbia, when possible, but this report suggests that mother and fetus tolerate short periods of permissive hypercapnia. Effective sedation is crucial to ensure patient-ventilator synchrony and avoid excessive airway pressures. Propofol (category B) has the advantage of its short duration of action and bronchodilatory properties. Benzodiazepines (category D) have a controversial role; if used during organogenesis, there is conflicting evidence of benzodiazepine-associated congenital malformations. Third trimester use might lead to poor neonatal muscle tone and delayed feeding.63 Long-term use of opioids (category C/D) during pregnancy can have negative consequences,64 but short-term use of opioids for sedation is safe. In addition to sedation with mechanical ventilation, some patients may require muscle paralysis; this may cause prolonged weakness and myopathy. There are reports of successful short-term use of cisatracurium, atracurium, and vecuronium in pregnancy.65

Second Line Therapies When bronchodilators and systemic corticosteroids are ineffective, consider second line therapies. In the appropriate setting, use ipratropium (pregnancy category B). However, this is controversial as inhaled anticholinergic agents combined with betaagonists are not beneficial compared to beta-agonists alone.66 Anticholinergics can also thicken secretions making expectoration more difficult. Theophylline (category C) may be associated with cardiovascular anomalies, prematurity, and low birth weight,67 but is safe when used in the second and third trimesters.68 Monitor serum levels of theophylline during pregnancy, given the potential for toxicity and drug interaction. Leukotriene modifiers, such as zafirlukast and montelukast, are pregnancy category B. There is limited evidence of their use in pregnancy; the results of two notable studies are reassuring. Both studies found no increase in major congenital malformations.69,70 Omalizumab (category B) is used for moderate to severe persistent allergic asthma. A single-arm observational study

of women exposed to omalizumab during pregnancy and/or within 8 weeks of conception did not show any increased risk of congenital malformations or low birth weight.71 Further data are needed to establish safety. Inhaled helium-oxygen mixtures were used successfully in several studies for status asthmaticus, both in spontaneous and controlled ventilation. This mixture can reduce peak inspiratory pressures and improve hypercarbia.72,73 Helium is an inert gas with no direct interaction with living tissues, so the potential for toxicity in pregnant patients appears very low; however, there is limited evidence of use during pregnancy.74 Ketamine and magnesium sulfate infusions both aid bronchodilation. As ketamine has sympathomimetic effects and can lower the seizure threshold, it is likely inappropriate for the PreE patient. If administering magnesium, monitor serum levels closely to avoid toxicity. Inhaled anesthetics also appear to have a direct bronchodilatory effect and increase cholinergic tone. Although used successfully, the administration of halothane, isoflurane, and sevoflurane is limited by hypotension.58,75 A few reports describe the successful use of ECMO for SA in pregnancy,76,77 so its use should be considered if available.

Pulmonary Embolism Incidence The risk of venous thromboembolism is five- to six-fold higher in pregnant women than in nonpregnant women.78,79 Deep vein thrombosis (DVT) occurs in 1:300 to 1:5000 pregnancies, and possibly is more common antepartum.80,81 Pulmonary embolism (PE) occurs typically because of DVT and complicates 1 in 1000 to 1 in 2000 pregnancies, accounting for 1.49 deaths per 100,000 pregnancies (UK data from 2015 to 2017).82

Etiology The uterus can compress the inferior vena cava as pregnancy progresses, resulting in venous stasis. In pregnancy, blood is hypercoagulable. Procoagulants: fibrinogen, factor V, VII, VIII, X, XII, and von Willebrand increase, while anticoagulants such as antithrombin III and proteins C and S decrease.83 Enhanced thromboxane A2 production and platelet reactivity also contribute. Vascular trauma during CD or vaginal delivery and separation of the placenta may initiate a series of physiological events leading to accelerated coagulation activity and increased risk of thromboembolism. The risks of DVT and PE are 5–15 times higher after CD than vaginal delivery. Table 7.5 lists other risk factors for thromboembolism during pregnancy. Resistance to activated protein C, which is frequently associated with Factor V Leiden mutation, is the most common identified genetic predisposition to developing thrombosis.84

Pathophysiology Pulmonary embolism leads to obstruction of the pulmonary arterial tree; this obstruction increases PVR and RV afterload, leading to RV failure. In massive PE, acute RV dilation and failure cause a shift of the ventricular septum to the left, impeding LV filling leading to LV failure. Increased hydrostatic pressure

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Table 7.5  Coexisting factors and conditions that increase the risk of pulmonary embolism in pregnancy78,79,81,84 Smoking Obesity Preeclampsia Multiple gestation Previous thromboembolism Antiphospholipid antibody syndrome Protein C or S deficiency Antithrombin III deficiency Hyperhomocysteinemia Prothrombin gene mutation Factor V Leiden mutation

predisposes the patient to pulmonary edema. Pulmonary embolism also increases V/Q mismatching primarily due to increased dead space ventilation, causing hypoxemia and hypocapnia.

Clinical Presentation Most cases of PE are asymptomatic and not life-threatening. The classic triad of dyspnea, pleuritic pain, and hemoptysis occurs in only 25% of patients with PE. Patients are tachycardic and may show signs of RV failure, such as split-second heart sound, jugular venous distension, a parasternal heave, and hepatic enlargement. A low-grade fever, cyanosis, diaphoresis, altered mental status, and wheezing are possible clinical signs of PE. Rarely do patients have abdominal pain due to infarcted lung, or DIC.

Diagnosis Diagnosis of PE during pregnancy is particulary challenging. Studies that investigated pretest probabilities for PE excluded pregnant women and there is a lack of data, so clinical practice guidelines vary. Most suspected cases in pregnant women require imaging with a V/Q lung scan or CT pulmonary angiography (CTPA). While fetal radiation exposure is of concern, experts agree that the potential risks are lower than the risks of Table 7.6  Probability of PE: The revised Geneva score

undiagnosed PE or bleeding from misdiagnosed PE.85 The choice of V/Q lung scan versus CTPA is somewhat controversial. Both have similar levels of radiation exposure; however, CTPA exposes maternal breast tissue to a greater extent ( which can be be reduced with shielding).86 A positive result from lower limb compression ultrasonography (CUS) can negate the need for chest imaging.87 In nonpregnant adults, the revised Geneva score is a validated clinical tool for assessing the pretest probability of PE87 (Table 7.6). The score is a revised version of the tool from the landmark Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED) study.88 The advantage of this scoring system over the Wells criteria system is that it does not rely on subjective criteria. In a recent study by Righini et al., this tool was applied prospectively to pregnant women for the first time.89 Their algorithm for PE diagnosis is outlined in Figure 7.1. Using the revised Geneva scoring tool, the prevalence of PE in low, intermediate, and high probability groups was 3.6%, 9%, and 100%. A negative D dimer result in the low pretest probability group ruled out PE 100% of the time, allowing 11.6% of the women to avoid chest imaging.89 Since D dimer levels increase throughout pregnancy, the normal ranges for gestational ages could be redefined to identify more true negatives in the future.

Management Early intervention is paramount. Initial supportive management of PE consists of maintaining oxygenation, ventilation, and hemodynamic status. Oxygenation reduces RV afterload and improves hemodynamic status, so hypoxemia is treated with supplemental O2 or mechanical ventilation. Some patients may need vasopressor or inotropic support. Pregnant women with clinically suspected PE

Pretest probability assessment (revised Geneva score)

Low/Intermediate

Risk factors

Points

Age > 65 years

1

Previous DVT or PE

3

Surgery under GA or fracture within 1 month

2

Active malignancy, or cured for < 1 year

2

High

D-dimer test

Negative

Positive Bilateral leg CUS

Symptoms Unilateral lower limb pain

3

Hemoptysis

2

Negative

Positive

CTPA

Clinical Signs Heart rate 75–94 beats/minute >=95 beats/minute Pain on lower limb deep venous palpation and unilateral edema Clinical probability Low Intermediate High

Negative

3 5 4

0–3 total 4–10 total >=11 total

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No PE

Inconclusive

Positive

PE

Figure 7.1  PE diagnostic algorithm during pregnancy. With permission from Righini et al. Diagnosis of pulmonary embolism during pregnancy: a multicenter prospective management outcome study. Ann Intern Med 2018;169:766–773.89 Pretest probability in this tool is calculated using the revised Geneva score, which is outlined in Table 7.6.

Uncommon Respiratory Disorders in Pregnancy

Current treatment recommendations for PE are extrapolated from the nonpregnant population as clinical trials in pregnancy are lacking. Low molecular weight heparin is the treatment of choice for PE in pregnant and nonpregnant patients. Given the increased renal clearance during pregnancy and other physiologic changes, check antifactor Xa levels regularly for dosing adjustments. The target antifactor Xa level is 0.5–1.1 U/ml 3–6 hours post-dose.86 Low molecular weight heparin does not cross the placenta and compared to UFH during pregnancy, has a lower risk of bleeding complications, heparin-induced thrombocytopenia, and osteoporosis.90 Use intravenous UFH rather than LMWH for patients with renal failure or when one anticipates the need for urgent reversal of anticoagulation (i.e., during labor and delivery or imminent surgery). With UFH use in pregnancy, monitoring of antifactor Xa levels may be preferable to aPTT.86 Fondaparinux is an alternative to LMWH, but there is a higher risk of bleeding. Avoid vitamin K antagonists in the first trimester due to warfarin embryopathy (nasal hypoplasia and epiphysis stippling); avoid doses > 5 mg in later pregnancy due to increased risk of fetal ICH, spontaneous abortion, and IUGR.90 The new oral anticoagulants, dabigatran, rivaroxaban, and apixaban, have not been studied adequately in pregnancy. If an emergency CD is required, one can administer protamine to select patients who require reversal of UFH; it does not reverse LMWH. If the risk of preterm labor is high, transitioning from LMWH to UFH may be advised in late pregnancy. For vaginal births, women on anticoagulation should be induced, so interruption of anticoagulation can be minimized. To accomplish this goal and allow time for placement of NA, transition from LMWH to UFH prior to induction of labor. Refer to the latest ASRA guidelines for recommendations of timing and safety of neuraxial placement. Placement of an IVC filter is used for cases of thromboembolism diagnosed within 2 weeks of a planned induction or CD. Reversal of anticoagulation without IVC filter protection is strongly discouraged in this initial two-week period.91 Beyond this indication, there is no evidence to support routine IVC filter placement.92 Consider thrombolytic therapy for patients with massive PE and life-threatening decompensation. Recombinant tissue plasminogen activator (rtPA) has been used successfully in pregnancy and does not cross the placenta.93,94 A systematic review of pregnant patients receiving thrombolytic therapy found the following serious complications: hemorrhage (8.1%), preterm delivery (5.8%), pregnancy loss (5.8%), and maternal death (1.2%).94 Among all surgeries during pregnancy, pulmonary artery embolectomy has the highest maternal mortality rate (22%) and therefore is reserved as a last measure in moribund cases.95 Neuraxial anesthesia is never used in patients receiving fibrinolytic therapy.

Pathophysiology

Venous Air Embolism

Amniotic Fluid Embolism

Incidence Venous air embolism (VAE) is a common occurrence during CD and vaginal delivery. The incidence of VAE during CD ranges from 10% to 60%,96,97 and accounts for 1% of all maternal deaths in the United States.98

Subatmospheric venous pressure allows entrainment of air in the venous circulation. The volume and rate of air entrainment and site of embolization determine the outcome of VAE. During CD, the open uterine vessels allow an access point. Risk factors for VAE include left uterine displacement, uterine exteriorization, Trendelenburg position, placental abruption, placenta previa, manual extraction of the placenta, severe PreE, and hypovolemia.98 Pulmonary edema can develop following VAE, secondary to increased capillary permeability and hydrostatic pulmonary pressure. V/Q mismatching (increased dead space) occurs with hypoxemia and hypercarbia if a clinically significant amount of air embolizes to the pulmonary circulation. Dysrhythmias and hypotension may ensue. Volumes exceeding 3 ml/kg can obstruct the pulmonary circulation and be fatal.

Diagnosis Mild cases are asymptomatic, but severe cases can present with chest pain, dyspnea, and hypoxia. In an intubated patient, an acute decrease in end-tidal CO2 and an increase in end-tidal nitrogen may signal VAE. A “mill wheel” murmur is heard with a precordial or esophageal stethoscope. Patients may become hypotensive, tachycardic, bradycardic, or experience a dysrhythmia. Acute bronchospasm, pulmonary edema, elevated PA pressures, decreased CO, and even cardiac arrest can occur. Presentation can be similar to PE, pneumothorax, MI, and AFE. Transesophageal echocardiography is the most sensitive device for diagnosing air embolism but is invasive. Precordial Doppler US is almost as sensitive as TEE and is noninvasive, making it the tool of choice. One drawback, however, is false positive signals during CD.97 An increase of 25% from the baseline PA pressure is also diagnostic; however, PA pressure monitoring it is highly invasive and has lower sensitivity than end-tidal CO2 monitoring.98

Management Management is primarily supportive care, preventing further air entrainment by flooding the surgical field with saline. Position the patient in the Trendelenburg position, so the heart is dependent; this position minimizes the possibility of developing airlock while improving venous return. Discontinue nitrous oxide and administer 100% oxygen. Maintain coronary perfusion pressure to prevent deterioration of RV function.98 Transesophageal echocardiography or POCUS helps guide resuscitation decisions. If a central venous line is present, attempt to aspirate air from the right atrium. If the patient has altered mental status or delayed emergence from anesthesia, imaging is required to exclude the presence of intracerebral air.

Incidence Amniotic fluid embolism (AFE) is one of the most catastrophic pregnancy complications, estimated to be associated with 1 in 8000 to 1 in 80,000 deliveries. Amniotic fluid embolism is the second leading cause of maternal mortality in the United

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States;99 the estimated mortality rate is 20–25%, with only 50% of survivors neurologically intact.100

Pathophysiology The etiology of AFE is incompletely understood. Amniotic fluid embolism is a misnomer since it is more immunologic in origin than embolic or obstructive. Fetal cells are not consistently found in the pulmonary circulation of women who suffered AFE, and many women can have fetal cells in their circulation without suffering from AFE. Amniotic fluid contains vasoactive and procoagulant substances, such as platelet activating factor, cytokines, bradykinin, thromboxane, leukotrienes, and arachidonic acid.101 In theory, entry of fetal antigen into the maternal circulation triggers a massive inflammatory response, like anaphylaxis. Case reports that used TEE describe distinct hemodynamic phases of this syndrome. First, rapid and transient pulmonary and systemic hypertension leads to acute RV failure, hypoxia, and cardiac arrest. If the patient survives this phase, pulmonary hypertension resolves, and LV failure ensues.102 Finally, the third phase is coagulopathy. In some cases, patients may not experience cardiovascular collapse and instead present with DIC in isolation.103

Table 7.8  Diagnostic criteria for amniotic fluid embolism104 1. Sudden onset of cardiopulmonary arrest, or both hypotension (systolic blood pressure < 90 mmHg) and respiratory compromise (dyspnea, cyanosis, or SpO2 < 90) 2. DIC (not due to dilution or shock related consumptive coagulopathy) 3. Clinical onset during labor or within 30 minutes of delivery of the placenta 4. No fever (>=38.0°C) during labor

arachidonic acid metabolites, tryptase, urinary histamine, and markers of complement activation have not been validated.105

Management Valuable Clinical Insights • • • •

Treatment of AFE is primarily supportive Manage respiratory failure with intubation Anticipate the need for massive transfusion Use invasive intraarterial hemodynamic monitoring and regularly sample ABGs • TTE and TEE are excellent tools to guide fluid resuscitation • Data show worse outcomes in AFE patients who receive r­ FVIIa than those receiving blood component replacement only

Presentation and Diagnosis Amniotic fluid embolism usually occurs intrapartum or immediately postpartum.100 The most common presenting signs are listed in Table 7.7. Uniform diagnostic criteria do not exist; however, Clark et al. have published proposed criteria104 (Table 7.8). Presentation involves sudden dyspnea or respiratory arrest, hypotension, cardiovascular collapse, and bleeding. Symptoms can present in any sequence.103 Amniotic fluid embolism is essentially a diagnosis of exclusion. Objective findings may include: ABG with hypoxemia and metabolic acidosis; ECG with tachycardia, dysrhythmia, or RV strain; TEE with pulmonary hypertension, acute RV failure, and leftward shifted inter­ atrial and interventricular septum; prolonged PT and PTT with decreased fibrinogen.99 The detection of presumed fetal squamous cells in maternal pulmonary circulation was once considered diagnostic of AFE but has been identified since as a nonspecific finding seen both in patients with and without AFE.101,103 Diagnostic tests, such as Table 7.7  Common presenting symptoms in amniotic fluid embolism100 Hypotension Nonreassuring fetal status Pulmonary edema or ARDS Cardiac arrest Cyanosis Coagulopathy Dyspnea Seizure Uterine atony Bronchospasm Transient hypertension Cough Headache Chest pain

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Treatment of AFE is primarily supportive with rapid correction of maternal hemodynamic instability, hypoxia, and coagulopathy. After cardiac arrest, use Basic and Advanced Cardiac Life Support algorithms, and if indicated, perform a perimortem CD. Manage respiratory failure with intubation and employ lung protective ventilatory strategies anticipating the need for massive transfusion. Use invasive intraarterial hemodynamic monitoring and regularly sample ABGs to guide the correction of acid-base disturbances, oxygenation, ventilation, and fluid resuscitation. Central venous access is used to administer volume, vasopressors, and inotropes. Although PA catheter monitoring has been used, TTE or TEE may be better for guiding fluid resuscitation, choosing a vasoactive drug, and monitoring ventricular function.101 Follow PT, aPTT, and fibrinogen levels and use rapid viscoelastic testing of clotting function (TEG, ROTEM), if available, to guide treatment of coagulopathy. Do not delay administration of blood products if clinical signs of coagulopathy are present. Recent data show worse outcomes in patients with AFE who received recombinant factor VIIa than those who received blood component replacement only.106 Studies of AFE in some animal models found vagal stimulation, serotonin stimulation of 5HT receptors, and thromboxane activation of platelets may play a central role in triggering pulmonary vasoconstriction and coagulopathy.107,108 For this reason, a novel approach to treating AFE with atropine 0.2 mg, ondansetron 8 mg, and ketorolac 15 mg, termed “A-OK,” has been described in case reports.108,109 There are currently insufficient data to recommend this approach, but it likely poses little risk to the patient if used concurrently with other resuscitative measures. There are reports of successful use of ECMO, intraaortic balloon counterpulsation, RV assist device, inhaled

Uncommon Respiratory Disorders in Pregnancy

prostacyclin or nitric oxide, and cardiopulmonary bypass in AFE treatment.100,101,110,111 These treatments are experimental and should only be attempted at experienced centers with multidisciplinary physician teams.

Sickle Cell Embolism More than one-third of pregnancies in women with sickle cell syndromes terminate in abortion, stillbirth, or neonatal death.112 Maternal mortality due to sickle cell anemia is ~1%, mainly due to PE and infection.112 In sickle cell disease, erythrocytes undergo deformation when deoxygenated. The sickled cells are elongated, crescent-shaped, and form aggregates. Sickling depends on the presence of an abnormal hemoglobin (HbS), which is a hemoglobin variant (valine replaces glutamic acid in the sixth position of the beta chain). Increased sickling occurs when more than 50% of hemoglobin is HbS. Other factors that affect sickling include vascular stasis, hypothermia, hypovolemia, and acidosis. Sickle cells aggregate in circulation, leading to pulmonary vascular obstruction and pulmonary infarction. Sickle cell embolism presents with respiratory distress, chest pain, hypoxemia, V/Q mismatch, and pulmonary hypertension. Anesthetic management includes maintaining oxygenation while avoiding dehydration, acidosis, and vascular stasis.113 It is essential to avoid aortocaval compression, even in patients with sickle cell trait. One patient died from a massive sickle cell embolus following the release of aortocaval compression during CD.114

Miscellaneous Mediastinal Mass Mediastinal mass (MM) is a rare condition that can cause maternal circulatory and airway collapse, leading to severe maternal and fetal morbidity (see Chapter 8). Masses may be benign or malignant and may arise from the thymus, thyroid, lung, airway, pleura, pericardium, lymph, or other tissues. Patients may be asymptomatic or have severe orthopnea, dyspnea, stridor, cyanosis, superior vena cava syndrome, dysphagia, or hoarseness secondary to mass compression.115 Preoperative evaluation should include special attention to postural components of symptomatology. Symptoms are graded mild, moderate, or severe according to the tolerance of the supine position.116 Document positions where symptoms are alleviated. A paradoxical decrease in BP with a change in position from upright to supine may indicate significant impediment of RV filling or ejection, possibly secondary to tamponade physiology or SVC syndrome.115 A CXR followed by a CT scan is required to define the position and size of the mass. Use echocardiography if there is compression of the heart or vasculature. Spirometry is recommended by some but is not predictive of airway obstruction.115 A mixed obstructive and restrictive pattern on PFT is predictive of respiratory complications.117 Computerized tomography tracheal cross-sectional area (CSA) of < 50% of normal is associated with perioperative complications.115–117 Most of the literature regarding MM is from pediatric cases. Risk factors identified for acute airway collapse in this population are anterior mediastinal

location, SVC syndrome, lymphoma, vessel compression, pleural effusion, and pericardial effusion.118 Pregnancy in the setting of MM can worsen compression of vital structures given the upward displacement of the diaphragm from the gravid uterus. A potentially difficult airway, increased oxygen and CO requirements, and lower FRC place the mother in a tenuous state. Most catastrophic events occur with induction of anesthesia or with muscle paralysis. Relaxing a contracting diaphragm and loss of negative inspiratory force can collapse airways and major blood vessels. In some cases, sedation alone may lead to collapse.115,116 Advanced pregnancy with MM can cause acute respiratory distress. In some cases, NA is used for CD to relieve upward displacement of the diaphragm to improve maternal respiratory status.119 In some patients, this strategy can avoid progression to intubation. However, the anesthesiologist should still prepare for possible cardiorespiratory decompensation. Delivery planning includes a multidisciplinary team with the obstetrician, anesthesiologist, and cardiothoracic surgeon. When possible, avoid GA and sedation in obstetric patients with MM. If planning a vaginal delivery, the recommendation is for early LEA to decrease the cardiac and respiratory demands associated with pain. Women deemed high risk for compressive events are not candidates for an emergency CD with standard rapid induction of GA. Similarly, spinal anesthesia is associated with rapid hemodynamic changes and excessive motor blockade. To avoid a high thoracic block, consider using a slowly titrated epidural for a planned CD. In patients at high risk for mass compression who require GA, invasive arterial and central venous lines are inserted before inducing anesthesia. Femoral vessels are preferred, as the upper extremity vessels may be obstructed. Additionally, femoral access points can be dilated and cannulated if emergency ECMO is required. It is important to remember that emergency ECMO, even when the surgeon and perfusionist are ready at the bedside, will take at least 5–10 minutes to establish.115,116

Valuable Clinical Insights • If the anticipated need for ECMO is high, insert ECMO cannulas in the awake patient at the start of the case under nonemergent conditions. • If ECMO cannulas are unused, remove them at the end of the case.

Induction of anesthesia will depend on the individual. Usually, spontaneous ventilation is maintained until the airway is definitively secured. Selecting reversible agents or inhalational induction can be advantageous. Airway intervention and choice of ETT will vary according to mass location and degree of compression. Reinforced tubes, bronchial blockers, and hollow airway exchange catheters are potentially helpful.120 Difficult airway equipment with a fiberoptic bronchoscope and jet ventilation should be available. If airway or vascular compression occurs, wake the patient as rapidly as possible and explore other

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options. Airway compression usually responds to repositioning the patient in their preferred position or rigid bronchoscopy with ventilation distal to the obstruction (consider involving an otolaryngologist preoperatively).116 Sternotomy with manual lifting of the mediastinal mass is a last resort.115,120

Congenital Central Hypoventilation Syndrome Congenital central hypoventilation syndrome (CCHS) is a rare genetic disorder that manifests with hypoventilation and hypoxia, primarily during sleep. It stems from an abnormal or negligible physiologic response to hypercapnia and hypoxia.121,122 The estimated incidence is 1 per 200,000 live births, with individuals usually presenting as infants or during childhood.123 If untreated, chronic hypoxia can lead to pulmonary hypertension and eventually cor pulmonale. Most patients require lifelong ventilatory support during sleep or throughout the entire day. Ventilatory support may include positive pressure via tracheostomy, nasal or facemask, bilevel positive pressure (BiPAP), or diaphragmatic pacing.121 This population does not have the normal progesteronemediated increase in ventilation during pregnancy. Many develop deteriorating sleep-disordered breathing during pregnancy and need ventilatory and pacing adjustments. Patients should have regular intermittent pulse oximetry monitoring and at least one sleep study during pregnancy.122 Epidural anesthesia has been used for CD in parturients with CCHS receiving diaphragmatic pacing. In such patients, avoid CNS depressants. Furthermore, following CD, incisional pain often prevents diaphragmatic pacing, so BiPAP is used until the resumption of diaphragmatic pacing.122

Pulmonary Lymphangioleiomyomatosis Pulmonary lymphangioleiomyomatosis (LAM) is characterized by the hamartomatous proliferation of smooth muscle of the pulmonary bronchioles, arterioles, and lymphatic vessels. This results in progressive cystic degeneration of lung tissue with loss of pulmonary function.124 Disruption of pulmonary lymph drainage can lead to chylous ascites, hepatic and renal angiomyolipomas, and uterine leiomyomas.125 There is evidence that estrogen affects LAM; therefore, pregnancy may worsen disease progression.126 Rupture of peripheral lung cysts can lead to pneumothorax, a common presenting feature.125 These patients are at higher than usual risk for recurrent pneumothorax.126 There is no curative treatment for this condition. Treatment is supportive, including standard treatments for obstructive lung disease and pneumothorax (see earlier). Advanced disease may require lung transplantation.125,126 Hormonal therapies have been studied with variable results and insufficient data to recommend use.125 Epidural analgesia during labor will minimize fluctuations in intrathoracic pressure during painful contractions and facilitate emergency CD without needing GA.124 Assisted vaginal delivery is preferable to avoid high intrapleural pressures associated with pushing, especially in parturients with a history of surgically untreated pneumothorax. Avoid nitrous oxide if GA is used for CD.

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Restrictive and Interstitial Lung Disease Restrictive lung diseases are extrapulmonary (extrinsic) or parenchymal (intrinsic)127 (Table 7.9). In both, lung volumes are reduced. The characteristics of parenchymal or ILD are inflammation and fibrosis, resulting in loss of alveolar capillary units and lung volume leading to chronic hypoxia and pulmonary hypertension.128 Women with restrictive lung disease may not tolerate the increased oxygen demand and elevated diaphragm of pregnancy, especially during labor. Patients with extrinsic disease are at greater risk of ventilatory failure, whereas those with intrinsic disease are more at risk of oxygenation failure; most deliveries in this population occur preterm.129 Identify parturients with restrictive lung disease early to ensure appropriate monitoring and delivery planning, including anesthetic consultation. Obtain baseline PFT, and an echocardiogram to assess PA pressure and RV function.128 Optimize any medical comorbidities that stress pulmonary reserve, treat infections, and consider immunizations. Check oxygen saturation intermittently, starting at the second trimester, to evaluate the need for supplemental oxygen.129 In patients with extrinsic disease, such as kyphoscoliosis, pay special attention to neuromuscular assessment and review available imaging and candidacy for NA. The largest case series of women with severe restrictive lung disease in pregnancy (n = 15) showed that most women, even with FVC < 1.0 l, tolerated pregnancy with few complications.128,129 Route of delivery is typically based on obstetric criteria. Most women with intrinsic disease deliver vaginally, but most with extrinsic disease require CD.129 The goal of anesthesia during Table 7.9  Causes of restrictive lung disease127

Intrinsic

Extrinsic

Idiopathic pulmonary fibrosis Nonspecific interstitial pneumonia Cryptogenic organizing pneumonia Sarcoidosis Acute interstitial pneumonia Inorganic dust exposure: silicosis, asbestosis, talc, pneumoconiosis, berylliosis, coal worker’s lung Organic dust exposure: farmer’s lung, bird fancier’s lung, bagassosis, mushroom worker’s lung, humidifier lung, hot tub pneumonitis Hypersensitivity pneumonitis Systemic sclerosis Pulmonary vasculitis Pulmonary Langerhans cell histiocytosis Radiation therapy Medications: nitrofurantoin, amiodarone, gold, phenytoin, thiazides, hydralazine, bleomycin, cyclophosphamide, methotrexate

Kyphoscoliosis Obesity Neuromuscular disease: muscular dystrophy, amyotrophic lateral sclerosis, polio, and phrenic neuropathies Pleural conditions: effusions, trapped lung, chronic empyema, scarring, asbestosis Ascites

Uncommon Respiratory Disorders in Pregnancy

labor and delivery is to minimize pain and decrease oxygen consumption, best achieved with NA. GA has been used successfully, but can be associated with prolonged mechanical ventilation.128

Transfusion-related Acute Lung Injury Transfusion-related acute lung injury (TRALI) is a rare and life-threatening complication of transfusion, with an estimated incidence of 0.02% per unit transfused.130 A retrospective study found TRALI occurred in 11% of patients admitted to an ICU for obstetric hemorrhage, which agrees with previous suggestions that the obstetric population is at increased risk.131 The pathophysiology of TRALI is complex and incompletely understood, but the ultimate result is inflammatory damage to the pulmonary endothelium leading to hydrostatic pulmonary edema.132 The diagnosis is clinical and outlined in Table 7.10. TRALI occurs within 6 hours of transfusion but typically within 1–2 hours. Symptoms include dyspnea, tachypnea, cyanosis, and fever. There may be decreased breath sounds and rales; the CXR reveals diffuse, fluffy infiltrates, and PaO2/FiO2 is < 300 mmHg.133 Transfusion-related acute lung injury is self-limited, and management is supportive. Stop the transfusion immediately. Usually supplemental oxygen is sufficient, but mechanical ventilation may be indicated (and lung protective ventilation employed). Avoid diuretics; there is no indication for glucocorticoids.132

Transfusion-associated Circulatory Overload The pathophysiology of transfusion-associated circulatory overload (TACO) is even less clear than TRALI but is likely mediated via inflammatory cytokines. With TACO, there is a rapid increase in left atrial and pulmonary capillary pressures causing transudative fluid entry into the pulmonary interstitium.134 It may cause an acute hypertensive response. Risk factors are hypertension, cardiovascular disease, and renal impairment,135 but data are lacking in the obstetric population. Criteria for diagnosing TACO are listed in Table 7.11. Treatment of TACO includes respiratory support with supplemental oxygen or noninvasive ventilation. Unlike TRALI, reduce preload and afterload in TACO with diuresis and nitrates. In cases of severe renal impairment, consider renal replacement therapy.136 Table 7.10  Diagnostic criteria for transfusion-related acute lung injury133 TRALI Type I

No risk factors for ARDS (and no temporal relationship to an alternative risk factor for ARDS), and all the below are met: Acute onset Hypoxemia (PaO2/FiO2 50% or tracheal compression with associated bronchial compression Pericardial effusion or SVC syndrome

Adapted from Blank RS, de Souza DG. Anesthetic management of patients with an anterior mediastinal mass: continuing professional development. Can J Anesth 2011;58:853–867.12

The authors suggest that those in the low-risk category can safely receive a GA with positive pressure ventilation due to the lack of reported serious intraoperative complications. However, those in the intermediate and high-risk categories require an individualized management plan. There are no diagnostic or management principles specific to the pregnant patient with AMM. Classification of risk using the subjective grading of symptoms does not consider the confounding physiology of pregnancy, so an even more cautious approach is required. Management There is little guidance from the literature on one “correct” way to manage pregnant patients with an AMM above a handful of case reports with successful outcomes. Airway management is challenging due to the compression of mediastinal structures and SVC syndrome leading to facial and laryngeal edema. Management will depend on fetal gestational age at diagnosis and the maternal disease burden. Large AMMs are particularly challenging due to the risk of airway and respiratory compromise and possible cardiovascular collapse combined with a need to plan the timing for a safe delivery. General anesthesia is particularly risky due to a reduction in lung volume and tracheabronchial tree diameter, relaxation of bronchial smooth muscles leading to increased compressibility of large airways, and elimination of the negative transpleural gradient after paralysis and during positive pressure ventilation. Tracheal compression can render ventilation impossible after induction of GA. It also can lead rapidly to circulatory collapse due to a reduction in venous return and SVR, together with an increase in intrathoracic pressure. For this reason, NA is probably safer in patients with AMM requiring CD.9 Consideration should be given to treatment with cortico­ steroids, chemotherapy, and radiotherapy before delivery to achieve symptomatic relief and improve safety for labor or CD. Airway stenting, as described in nonpregnant patients,14 has been used as a temporizing measure, especially when ultimate treatment of the mass is nonsurgical.

Some suggest that patients with > 50% obstruction of the lower airway should have their femoral vessels cannulated before induction of anesthesia to prepare for ECMO if oxygenation becomes impossible.12 Several reports describe having ECMO or CPB teams “on standby.”8,9,15,16 The likelihood of complete airway obstruction must be carefully considered. Insertion of cannulas for ECMO will be significantly prolonged if not done preoperatively. When deciding on the anesthetic technique, consider the degree of airway and cardiovascular compromise and the experience of the ECMO team. Single-shot spinal causes rapid reduction in SVR and venous return and therefore cardiac compromise or instability with MMS. A CSE with a lowdose spinal gives the advantage of rapid onset with quality sacral blockade and the ability to slowly titrate and extend anesthesia with epidural boluses as required. In one case of relapsed, untreated lymphoma in pregnancy causing tracheal compression to the carina with only 5  mm diameter at the level of the clavicles, prophylactic ECMO cannulas were inserted before CD at 34 weeks after a dose of vinblastine to reduce the mass size. Thoracic surgeons were concerned that a rigid bronchoscope would not fit past the tracheal narrowing, impeding airway rescue. The CD was performed in a cardiac operating room under CSE.9 Another report described a 34-week pregnant patient who complained of dyspnea and an increasing inability to lie flat over the preceding two months and was diagnosed with a large AMM compressing the left pulmonary artery. Steroids were initiated to decrease the size of the tumor and a CD was performed in steep Trendelenburg position under a slowly titrated epidural block.10 Her care was provided by a team consisting of specialists from hematology/oncology, pulmonology, cardiothoracic surgery, anesthesiology, neonatology, and perinatology. This multidisciplinary team decided on the mode and timing of delivery, initiation of treatment, and the type of anesthetic. Another report described similar management with rigid bronchoscopy, jet ventilator, and thoracic surgeons immediately available.17 In cases where a GA was deemed unavoidable, awake fiberoptic intubation, with either a rigid laryngoscope18 or fiberoptic scope,19 was used to secure the airway before induction. Another case describes a patient presenting at 23 weeks gestation with malignant thymoma causing SVC syndrome requiring sternotomy and one-lung ventilation. The airway was secured with the patient under GA but breathing spontaneously, with positive pressure ventilation started only after sternotomy. Elective ECMO cannulas were not inserted because the surgical plan was to physically lift the tumor in the event of ventilatory failure after anesthetic induction.20 Many reports of AMM in pregnancy describe significant delays in diagnosis, by which point the airway and cardiovascular compromise were such that delivery had to be hastened to allow definitive treatment. By contrast, a patient diagnosed at 20 weeks gestation with a mediastinal mass causing compression of the trachea by > 70% was treated with high-dose oral steroids. This treatment reduced the size of the mass sufficiently to allow induction of labor and vaginal delivery at 34 weeks with LEA.21

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Structural Valuable Clinical Insights • Subglottic stenosis in pregnancy presents a significant challenge. Patients should be delivered in a center that provides obstetric care providers, anesthesiologists with advanced airway skills, and a surgeon to perform a tracheostomy if required, either preemptively or if airway compromise develops. • When managing patients with goiter, a plan must be made in the event of a “cannot intubate, cannot ventilate” situation. An enlarged thyroid may preclude front of neck access to the airway as a rescue technique. Availability of a rigid bronchoscope and jet ventilation with a skilled operator is necessary.

Subglottic Stenosis Subglottic stenosis (SGS) is the narrowing of the airway below the vocal folds. It may be congenital, idiopathic, or secondary to inflammatory or autoimmune disorders such as sarcoidosis and Wegener granulomatosis, gastroesophageal reflux disease, and prolonged intubation or previous tracheostomy. Idiopathic subglottic stenosis (ISS) is characterized by progressive fibrosis and annular stenosis of the subglottic larynx. The pathophysiology is unclear, and it is a diagnosis of exclusion. Although a rare disorder, it almost always occurs in women between 20 and 40 years old and can present, or worsen, during pregnancy due to physiological changes that promote airway edema.22 Autoimmune diseases that cause SGS show a female preponderance. Since SGS can be mistaken for asthma, diagnosis and treatment may be delayed. Treatment options include periodic dilatation, cricotracheal resection, and tracheostomy. The disease is recurrent, and therefore periodic retreatment, with endoscopic dilatation techniques, is often necessary. Due to an increased risk of aspiration and reduced respiratory reserve, clinical management of these women can be a challenge. The laryngoscopic view can be falsely reassuring as the stenosis is below the level of the cords. In a patient without a diagnosis, it may be impossible to perform an emergency endotracheal intubation. A parturient with a history of intermittent breathing difficulty required a stat CD under GA. There was a Cormack Lehane (CL) grade 1 view at laryngoscopy, but a 7.0 or 6.0 ETT could not be passed. The CD proceeded under LMA with high ventilatory pressure and eventually, after consultation with ENT, intubation was achieved with a size 4.0 microlaryngeal tube. Postpartum, she was admitted to ICU and 48 hours later had a trial of extubation. She required reintubation and subsequently had a tracheostomy. The eventual diagnosis was ISS.23 There is no clear consensus on airway and anesthetic management in patients with SGS in pregnancy. Evidence is limited to case reports which describe a variety of airway and oxygenation techniques.24 These included LA and sedation, GA with volatile or TIVA technique, jet ventilation, and high-flow nasal oxygenation. Four pregnant patients had laryngeal balloon dilatation with noninvasive ventilation.25 In one challenging case, a

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patient with SGS due to granulomatosis presented at 33 weeks gestation with progressive stridor and respiratory distress. Anesthesia included an inhalational spontaneous breathing induction and LMA placement, but jet ventilation was required via a rigid bronchoscope after desaturation occurred. A tracheostomy was required to provide a patent airway until delivery.26

Goiter The normal thyroid gland commonly enlarges during pregnancy by around 30%. Renal iodine clearance twice that of prepregnancy levels leads to relative iodine deficiency with compensatory follicular hyperplasia of the thyroid gland. Goiters are more common in areas of the world where iodine deficiency is endemic. A study conducted on women at an antenatal clinic in Nigeria found an incidence of thyroid enlargement of 93%.27 Preexisting thyroid disease worsens during pregnancy due to the impact of human chorionic gonadotrophin, one unit of which is identical to thyroid-stimulating hormone.28 Symptoms of airway compression due to goiter can be misdiagnosed as asthma, leading to a delay in diagnosis.29 A goiter may not be apparent on examination, especially if the patient has a high BMI. Goiter affects the trachea and the esophagus, so many affected women have feelings of pressure, dysphagia, and dyspnea, especially when supine. Upper airway obstruction due to goiter does not reliably correlate with the presence or extent of symptoms or with radiologic findings.30 Significant airway compression is often already present when symptoms occur. Pulmonary function tests with flow volume loops can give information not only to the degree of airway obstruction but also its location. The thyroid gland lies close to the boundary between extrathoracic and intrathoracic sections of the trachea. Depending on the degree of enlargement and the direction in which it expands, goiter can result in airway obstruction that is extrathoracic, intrathoracic, or both. In extrathoracic obstruction, flow limitation occurs during inhalation. If intrathoracic, flow limitation occurs during exhalation. Use CT/MRI to measure the size of the patent airway and help plan for the size of ETT if intubation is required.28,31 There are several case reports of goiter leading to acute airway obstruction during pregnancy and the immediate postpartum period.32 The management varied from awake fiberoptic intubation for combined CD and thyroidectomy,33,34 to planned CD at 32 weeks gestation under NA, followed by a thyroidectomy 4 weeks later,31 to emergency intubation for respiratory arrest and thyroidectomy in the second or early third trimester followed by normal delivery at term.28,35 One case involved LEA for CD before which the airway was anesthetized with lidocaine; after delivery, the cardiothoracic team placed femoral access for CPB under the existing epidural block, before doing an awake fiberoptic intubation and thyroidectomy.36 Heliox, steroids, and adrenaline nebulizers are useful as temporizing measures for an acute presentation of airway obstruction. Manage these patients in a center with access to ENT surgeons and specialized airway equipment. Awake fiberoptic intubation is often required, as well as a critical care bed. To prevent postoperative airway obstruction after thyroidectomy, one must determine whether tracheomalacia is present. Perform a

Airway Issues: Disorders Affecting the Airway

cuff leak test before emergence and extubation; if tracheomalacia is present, the trachea will collapse with inspiration, and there will be no leak. Tracheomalacia after thyroidectomy in parturients has led to overnight ventilation,28 and tracheostomy at day 6 post thyroidectomy.32 Patients with a prenatal diagnosis of goiter, or if they present with symptoms and are diagnosed during pregnancy, require an individualized management plan created by a multidisciplinary team.

Involvement of the genitourinary mucosa may cause vaginal and cervical strictures, requiring CD, but SVD is possible when the vaginal mucosa is not involved47 or after vaginal reconstruction.46 Severe bleeding and swelling of the oral and pharyngeal mucosa may require urgent intubation with sedation and ventilation, like patients with inhalation injury or airway burns. Consider transfer to the critical care unit early in the course of the disease.46

Infectious

Hereditary Angioedema

Deep Neck Infections/Ludwig Angina Pregnancy is associated with oral and dental changes that predispose to gingivitis and periodontal disease leading to orofacial infections.37 Infection can spread along fascial planes to the cranial base and mediastinum, leading to severe trismus that reduces mouth opening. Ludwig angina is a rapidly spreading cellulitis of the sublingual and submandibular spaces (usually secondary to a dental abscess) that leads to swelling of the floor of the mouth, elevation, and posterior displacement of the tongue. It can rapidly progress to airway obstruction if not treated promptly and aggressively. The high mortality rate is mainly attributable to airway complications rather than overwhelming sepsis,38 although necrotizing fasciitis may occur. The literature describes an increased risk of preterm delivery and IUFD and increased maternal morbidity and mortality in these patients.38–43 A review of 10 cases during pregnancy over 2 years in a single institution revealed a 20% mortality rate, a 60% rate of airway problems, and a 50% rate of trismus leading to reduced mouth opening. Three of the 10 patients suffered IUFD. and two had preterm deliveries. Two women required urgent CD at 32 and 40 weeks gestation with simultaneous debridement under GA after awake fiberoptic intubation; both had severe trismus.41,42 Awake tracheostomy44 is an option if fiberoptic intubation is deemed unfeasible or has failed. Also described is debridement under LA with superficial cervical plexus and mandibular nerve blocks allowing transection of the mylohyoid to decompress the airway.41

Dermatological Toxic Epidermal Necrolysis Toxic epidermal necrolysis (TEN) and Stevens Johnson Syndrome (SJS) are severe life-threatening dermatological conditions associated with acquired infections and medication reactions (see Chapter 23). In TEN, there is epidermolysis of > 30% total body surface area. The primary triggers are drugs such as allopurinol, antiepileptics, oxicam, NSAIDs, nevirapine and sulphonamides, and viral infections, especially when an altered immune response is present, such as in pregnancy. It has occurred secondary to ondansetron use in early pregnancy.45 Pregnant patients presenting with TEN/SJS are younger and more likely to be taking antiretroviral or anti­ epileptic drugs. It is postulated that pregnancy might induce TEN/SJS due to immunomodulation. However, the exact mechanism remains unclear.46

Three types of hereditary angioedema (HAE) are described; two resulting from C1 inhibiter deficiency (C1-INH-HAE types I and II), the third characterized by normal levels of C1 inhibitor (nC1-INH-HAE). Hereditary angioedema is rare; C1-INHHAE has a prevalence estimated to be between 1:10,000 and 1:50,000, and nC1-INH-HAE is likely even less common, although there are no prevalence studies.48 Angioedema develops peripherally in the subcutaneous tissues of the limbs, face, trunk, genitalia, or centrally in the submucosa of gastrointestinal and respiratory tracts. The swelling is caused by local bradykinin release and does not respond to conventional therapy with antihistamines, epinephrine, or corticosteroids. Hereditary angioedema can present for the first time in pregnancy, particularly the nC1-INH type. Despite autosomal dominant inheritance (meaning both sexes should suffer equally from C1 deficiency leading to HAE), severe disease is predominant in women, thought to be due to the influence of estrogen. There is also a lower penetrance of gene expression in males, so a higher proportion of them are asymptomatic carriers (90% vs. 40% in women).48 The influence of high estrogen levels in pregnancy can worsen the disease, and although some women improve, a higher proportion of pregnant women experience an increase in attacks.49,50 Hormone therapy, used in assisted reproduction, is also a risk factor for increased disease severity. Diagnosis is via blood complement levels (C4, antigenic C1 inhibitor, and functional C1 inhibitor) and genetic testing. Therapeutic options are limited by pregnancy; however, the recommended treatment is plasma-derived human C1-INH concentrate (pdhC1INH), which has the highest safety data for pregnancy and during lactation. If pdhC1INH is not available, fresh frozen plasma can be used, but rarely this can worsen HAE symptoms.51 There is little evidence to guide the best method of delivery in those with C1-INH-HAE. Although labor and delivery cause significant mechanical trauma, they seldom induce angioedema attacks. Routine prophylaxis with pdhC1INH concentrate is not recommended before uncomplicated vaginal delivery. However, it should be immediately available in the delivery room and considered for those with particularly severe disease, e.g., repeated or severe attacks during pregnancy.51 Neuraxial anesthesia is recommended for CD to avoid endotracheal trauma and local airway edema. Short-term prophylaxis with pdhC1INH concentrate is recommended before CD and treatment dose (20 U/kg) on hand in the event of acute complications.52

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Traumatic Cervical Spine Injury Further discussion of acute spinal cord injury in pregnancy can be found in Chapter 15.

Facial Fractures Trauma in pregnancy is a leading cause of nonobstetric mortality, most injuries being due to motor vehicle accidents or intimate partner violence. In general, management is the same as in facial trauma in the nonpregnant patient, with consideration given to an increased risk of difficult intubation and airway mucosa that is more prone to bleeding. Avoid nasal airways in cases where facial fracture is present or suspected.53

Physiologic Airway Changes in Labor Valuable Clinical Insight The airway of a term pregnant woman changes regardless of the mode of delivery, and these changes do not correlate with any known risk factors.

In 2008, Kodali et al. published the first prospective study documenting airway changes during labor and delivery,54 but the first published case report of this phenomenon appeared in 1994.55 In Kodali’s study, 70 women had photographs taken of their airway to document the modified Mallampati class (MMC) score using the same position at three time points. The first was on admission to the labor room; the second was 20 minutes after placental delivery, and the third was 36–48 hours postpartum. There were 30 women with Class III or IV scores post-labor compared with 17 Class III scores in early labor (no Class IV scores). Other authors have confirmed these findings using various assessment tools.56–58 For instance, 28 women had acoustic reflectometry to measure airway dimensions and volume, first on admission in labor and then 20 minutes postpartum. There was a significant decrease in oral and pharyngeal volume and mean pharyngeal area in the women from early labor to immediately postpartum.58 No study has found a correlation between increasing MMC scores and risk factors such as IV fluid administration or labor duration. No women received a GA, and the airway appears to return to normal at one month postpartum.58 Women having CD under NA can show these progressive airway changes as well. In a study by Sangkum et al., 104 women undergoing CD under SAB had MMC assessed at four time-points: pre-anesthesia, 1, 6, and 24 hours postoperatively.59 There was a high incidence of MMC III at baseline – 48%; and 52% had a change of one grade in the MMC between baseline and 24 hours postdelivery. A remarkable 85% had MMC III or IV after delivery, but again there was no correlation with risk factors such as fluid and oxytocin administration. The airway changes appear to be worse in women with PreE due to airway edema.60,61 Ultrasound demonstrated airway

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edema following labor and delivery in a study of normotensive and preeclamptic patients.62 Boutonnet et al. studied whether these airway changes could be predicted using airway US.57 They enrolled 87 pregnant women and assessed them four times, starting at 8 months gestation (baseline) until 48 hours postpartum. They evaluated several parameters including MMC.57 While 37% of participants exhibited no airway changes, a significant number were MMC III and IV when the LEA was requested (from 10.3% at baseline to 36.8%), and 20 minutes after delivery (51.7%), returning to a 20.7% incidence of MMC III/IV 48 hours postpartum. Again, no correlated risk factors were found. While the MMC on its own is insufficient as a predictor of difficult intubation, it does assess the relative tongue-to-mouth volume and, therefore, space available for direct laryngoscopy, VL, and supraglottic airway device placement.63,64 The MMC changes found in pregnant women around labor may result in a poor laryngeal view, as shown by Rocke et al. wherein view at laryngoscopy was more difficult with a relative risk of 7.6 for MMC III and 11.4 for MMC IV.65 Based on general surgical population data,66 bag and mask ventilation (BMV) may be more challenging with these changes in MMC. The relevance of these consistent findings of airway changes around labor and delivery is that one must assess the airway of all women before administration of any anesthetic and reassess if a woman has labored and is now presenting for intrapartum surgical intervention. Mallampati class scores of III and IV, if associated with any other abnormal airway tests, increase the likelihood of encountering a difficult intubation.65 Outside of PreE, life-threatening airway obstruction in a pregnant woman due to upper airway edema has been described once when there was massive hemorrhage and a substantial fluid resuscitation.67

Sleep-disordered Breathing Sleep-disordered breathing (SDB) includes a spectrum of sleeprelated breathing disorders. These include obstructive sleep apnea (OSA), central sleep apnea, sleep-related hypoventilation, and upper airway resistance syndrome (UARS). The most common form of SDB is OSA, characterized by a repetitive partial or complete collapse of the upper airway during sleep resulting in airway obstruction, hypoxemia, and sleep disruption. The severity is graded according to the apnea-hypopnea index (AHI); an AHI < 5 represents normal sleep, 5–15 mild OSA, > 15–30 moderate OSA, and > 30 severe OSA.68 Pregnancy significantly increases the risk for SDB; it often worsens as pregnancy progresses and is associated with adverse maternal and fetal outcomes.69 Physiological changes of pregnancy can precipitate or exacerbate OSA. Upper airways narrow during the third trimester when compared to postpartum and nonpregnant controls using acoustic reflectance. Increased estrogen causes mucosal edema, hypersecretion, gestational rhinitis, and increased nasal and oropharyngeal resistance. Weight gain of 10–15 kg contributes, with excess fat deposition noted under the mandible, within the tongue, soft palate, uvula, and pharynx, leading to airway compression. The increased respiratory drive caused by increased progesterone levels may increase negative intraluminal pressure of the upper airways and promote collapse.68

Airway Issues: Disorders Affecting the Airway

Third trimester snoring is as high as 34%, versus 4% in nonpregnant premenopausal women. The risk increases throughout pregnancy with polysomnography showing SDB rates of 11% in the first trimester and 27% in the third trimester. A prospective study of 1719 pregnant women found pregnancy-onset snoring was associated with gestational hypertension (odds ratio 2.4). Recurrent hypoxia caused by SDB may impact placental tissue oxygenation and activate pathways leading to PreE.70

Airway Management Valuable Clinical Insights • Airway assessment of any pregnant woman should be complete and include an upper lip bite test (ULBT), thyromental distance (TMD), and MMC. • Airway management of the pregnant patient should follow established current published guidelines. • Airway ultrasound is a new technique that holds promise for identifying the cricothyroid membrane (CTM) and possibly identifying a difficult airway. • High-flow nasal oxygen therapy (HFNO) does not provide good preoxygenation for the pregnant woman. However, when used for peroxygenation, it substantially increases the safe apnea time, except in those with BMI > 40.

Introduction The obstetric airway continues to challenge anesthesiologists despite advances in airway management techniques and focused education in the last two decades. The incidence of failed intubation in the pregnant woman remains at approximately 1:400, significantly higher than that in the general surgical population;71–75 and maternal mortality from a failed airway has not improved, at least in the United Kingdom.71 The incidence of failed intubation is considerably lower in countries like South Africa, where GA is used more often in obstetrics.76 It is also lower in tertiary care academic institutions despite low GA rates.77–79 There is ongoing concern that trainees are not being exposed adequately to the obstetric airway, as GA rates continue to fall: tertiary care centers typically have rates of 5–7%,73,78 and in the United Kingdom, the Royal College of Anesthesiologists has advocated for a GA rate < 3% for maternal safety reasons. Experience does matter, as shown at a busy inner-city United States maternity hospital,73 and ongoing Confidential Enquiry reports from the United Kingdom on maternal mortality. Unfortunately, the difficult airway in obstetrics proportionally results in considerable maternal, fetal, and neonatal morbidity and mortality in industrialized countries. Contributing factors are anatomical (weight gain, breast enlargement, dynamically changing airway with labor),54,57,62 physiological (pregnancy changes causing a shorter apnea time following induction),80,81 environmental (time pressure due to fetal distress, lack of regular exposure of the team to GA), and training. The increase in average BMI and age of parturients has resulted in a higher incidence of PreE and snoring.80,82 However, in the

general population neither OSA nor high BMI is a strong predictor of difficult intubation.83,84 There are no RCTs to guide us on what tools, processes, or algorithms work best in obstetrics. However, there are data supporting changes to how we historically managed the obstetric airway: rapid sequence induction (RSI) with endotracheal intubation: 1. Bag mask ventilation from time of administration of a neuromuscular blocking agent to the first attempt at intubation: The Canadian Airway Focus Group (CAFG)85 and the UK Difficult Airway Society (DAS) endorse the use of gentle BMV during RSI (www.das.uk.com/guidelines/ rsi.html).86–88 The optimal method for preoxygenation in the parturient is tidal volume breathing using a standard facemask at flows of 10–15 l/min for 3–4 minutes,89 the next best option is eight deep breaths over 60 seconds.87 Evidence for a benefit from HFNO for preoxygenation in the parturient is mixed to date (see below). 2. It is recommended to use a supraglottic airway early for airway rescue in a parturient; success rates are between 86% and 100%.72,90 A review of 45 years of obstetric airway management in the United Kingdom revealed a steady decade by decade increase in continuing with the CD following failed intubation in concordance with the rise of supraglottic airway use as a rescue device.71 When using a rescue supraglottic airway for CD, there are certain caveats: minimal fundal pressure with a generous uterine incision and use of a vacuum as necessary.91 Each case has unique considerations, and therefore a context-specific decision in advance of induction of GA should be made. There is no evidence at present to support or refute continuing with a well-functioning supraglottic airway. In the case of structural lesions affecting the airway, one should not assume a supraglottic airway will provide rescue, as a good fit is often impossible. 3. Optimal first attempt: consider using a videolaryngoscope (VL) as the first tool for intubation. All operating rooms in which pregnant women have surgery must have a VL immediately available, as highlighted in the DAS difficult obstetric airway guidelines,92 even though the limited evidence to date does not demonstrate superiority.93 In patients with known airway challenges, awake VL is an option for securing the airway as the field of view provided by many of them is superior to that of flexible bronchoscopy.

Airway Assessment Proactive assessment and documentation of all laboring women for potential airway challenges should be a goal for anesthesiologists providing care to parturients.94 No single test is sufficiently predictive of difficult intubation in a pregnant woman, either positively or negatively. Yildrim et al.95 recruited 255 women booked for elective CD under GA and measured five airway tests before induction of anesthesia: TMD, MMC, sternomental distance, inter-incisor distance, and ULBT. At direct laryngoscopy (DL), a modified CL score of 1–4 was assessed,

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and women classified as easy intubation (CL 1–2) or difficult (CL 3–4). The difference between predicted and actual difficult intubation was determined. The best combination, combining excellent sensitivity, specificity, and negative predictive value, with modestly good positive predictive value, was TMD and ULBT.95 If an airway is deemed challenging, evaluate difficulty with BMV and supraglottic placement,96 and identify the cricothyroid membrane (see below). Pregnant women presenting with structural, infectious, dermatological, and traumatic airway lesions should have a rigorous airway assessment using multiple airway tests and be managed in a setting where ECMO is available. Management principles for the anticipated difficult airway in an adult should be followed, with the addition of continuous FHR monitoring.96

The Unanticipated Difficult Airway in Pregnancy The endpoint is to limit attempts at DL, ensure oxygenation, and, if appropriate, wake the woman with a plan for either awake intubation or NA. Failure to oxygenate will quickly result in fetal compromise, altering the scenario and placing mother and fetus at increased risk of morbidity. Front of neck access must be rapidly performed if oxygenation continues to fall. An added element to consider in the “cannot ventilate, cannot oxygenate” situation in the parturient is that there is now sufficient information to state that identifying the CTM in this population is particularly challenging.97–101 Failure to identify the CTM may lead to maternal morbidity and mortality71 (see “Airway Ultrasound”). Reversing a deep neuromuscular block from rocuronium with sugammadex takes less time to return spontaneous breathing than spontaneous recovery from an intubating dose of succinylcholine, with less emergence agitation.102 However, the reality of waking the patient after either spontaneous recovery from an intubating dose of succinylcholine, or rescue reversal of rocuronium with sugammadex, is that neither option is fast. Succinylcholine takes 5–10 minutes for spontaneous reversal, and 16 mg/kg of sugammadex after rocuronium 1.2  mg/kg takes 3–4.5 minutes.103,104 Pregnancy is associated with longer spontaneous recovery from succinylcholine.105 Obesity puts patients at risk for prolonged, persistent respiratory depression with desaturation even after complete reversal with sugammadex.103 The most recent maternal mortality statistics from the United States and the United Kingdom show that the occurrence of difficult intubation or airway catastrophe has shifted to the postpartum period: both at emergence, shortly after anesthesia in the postanesthesia unit, or for postpartum tubal ligation procedures.106,107 Heightened vigilance and attention to these women are vital.

The Anticipated Difficult Airway in Pregnancy Women with a known or suspected difficult airway must be identified before delivery in order to fully assess and develop safe delivery and anesthetic plans. As noted above, labor may turn a potentially challenging maternal airway into a truly difficult airway. Time taken for consultation with specialists and

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the need for imaging is a priority, but that means obstetrical care providers must first recognize the risk. A discussion about the suitability of labor needs to occur in a multidisciplinary setting, ensuring all team members are aware of the evidence surrounding the effects of labor on the maternal airway and identifying available resources after hours at the proposed delivery site. The same principles apply to pregnant women as to all patients with a predicted difficult intubation. If airway avoidance is not possible, follow airway guidelines from the UK-DAS, CAFG, and ASA.92 Recent guidelines published on awake tracheal intubation apply to the obstetric population and have some specific cautions regarding parturients.108 Organize resources not usually available in the obstetric operating room, e.g., an ENT surgeon on standby. Continuous FHR monitoring during airway procedures is necessary and consider the maximum doses of topical LA allowed, given pregnancy-induced alterations in pharmacokinetics and possible recent use of neuraxial LAs.108 Calculate the recommended maximum dose of lidocaine with epinephrine of 7 mg/kg using prepregnancy weight for safety. Use IV sedation to facilitate securing the airway; in choosing medications, the anesthesiologist should consider the effects on the newborn. Reversible agents are preferable; inform the person responsible for immediate newborn care as to which agents were used. That being said, in most cases, 2 mg IV midazolam or 1 mcg/kg IV fentanyl has minimal neonatal impact. Dexmedetomidine is another option. In the case of structural airway lesions and respiratory failure, avoid sedation as it may lead to rapid decompensation. Open communication with all team members is vital, and the airway management plan discussed ahead of time. Newer techniques and equipment to consider are airway US to mark the CTM before intubation, flexible nasoendoscopy, and HFNO throughout the procedure.109,110

The Acutely Decompensating Airway As in nonpregnant patients, certain disorders impacting the airway (a bleeding vascular lesion, infectious process, or compressive mass) can rapidly change. Temporizing measures such as heliox may improve airflow; it has been used for asthma during pregnancy but not for airway obstruction from a structural lesion.111 Time permitting, one should always seek to manage the airway in the operating room setting, with all skilled hands present, and at a site with perinatal and ENT support, and ECMO.9

Airway Ultrasound Point of care US is proving to have yet another valuable use in the practice of anesthesia – assessment of the airway and precise location of the CTM. Failure to rescue airways with front of neck access has been documented by NAP4,112 and by Kinsella’s 45-year review of obstetric airway management.71 Risk factors for failure to identify the CTM correctly are female gender, obesity, and pregnancy, with only a 20–50% success rate from palpation compared to US.97–99,113 The evidence consistently demonstrates that US is superior to palpation. US is a skill rapidly learned but requires regular retraining if not used frequently.113–116

Airway Issues: Disorders Affecting the Airway

In our opinion, US identification of the CTM is a skill that obstetrical anesthesiologists should learn, and there are good publications, including videos, to guide skill acquisition.109,117 There are two well-described approaches to the CTM: transverse and paramedian. Both have advantages and disadvantages.118 As more anesthesiologists become experienced in the use of airway US, some experts advocate that it should be part of the preparation for a difficult airway.109 Ultrasound confirmation of the simple practice of palpation of the CTM may improve accuracy at locating the CTM in parturients.116 Be aware that when marking the US-guided CTM location, patient position affects skin localization, i.e., supine versus elevation of the head of the bed can alter the surface localization by a few millimeters.119 Ideally, locate the CTM with the neck extended.120 Predicting difficult laryngoscopy using airway US has also shown promise in the PreE population.121,122 Morbid obesity in pregnancy increases the depth to the CTM, so locating it with US is more challenging.100 A protocol for studying the role of airway US for predicting a difficult airway in the pregnant woman is underway in China (Chinese Clinical Trials Registry ChiCTR1800018949).123

High-flow Nasal Oxygen Therapy In the last several years, high-flow nasal oxygen therapy (HFNO) has been used frequently in the ICU population and even more recently in obstetric anesthesia. There are several reports of its use in high-risk pregnant women to manage hypoxemic respiratory failure124 and surgical management of SGS.25,125 However, evidence from RCTs in pregnant women examining the efficacy of HFNO for preoxygenation to increase safe apnea times (defined as time to desaturation < 90%) is contradictory. When a tight-fitting facemask, with flow rates of 10-15 L/min, is applied correctly it is superior to HFNO.89,126–128 The dilemma is that in the studies referenced, GA induction did not occur, so we do not know what happens during the apneic period before intubation. However, one published study randomized 34 healthy parturients with a mean BMI of 27, to HFNO or standard facemask preoxygenation, with the primary outcome PaO2 immediately after intubation.129 There was a clinically and statistically significantly higher PaO2 in the HFNO group. Physiologic modeling in the Nottingham Physiologic Simulator suggests that certain additional risk factors such as morbid obesity, labor, and sepsis decrease safe apnea times significantly during induction of GA. Women with these risk factors would likely benefit from using HFNO for peroxygenation.110 By peroxygenation, we mean providing optimal oxygenation from the preoxygenation period through the apneic period until the airway is secured.130 Data from the simulator and published case reports show a markedly prolonged safe apnea time with HFNO peroxygenation, although caution must be exercised in women with BMI > 40. If HFNO preoxygenation does not raise the ETO2 > 80% in these women, safe apnea time remains shockingly short (< 3 minutes).110 As post-extubation has been identified as a risk period for the obstetric patient, especially those who are obese, HFNO may prevent desaturation and need for reintubation. This premise is extrapolated from the general surgical literature.131,132

Summary • Subglottic stenosis in the pregnant patient presents a significant challenge; the most critical aspects of care are timely diagnosis and carefully planned multidisciplinary management in an appropriate center. • Goiter is endemic in certain parts of the world. The changes that occur in pregnancy can lead to acute airway obstruction following induction of GA, or secondary to tracheomalacia following resection. Front of neck access may not be possible in the event of failure to oxygenate. • Hereditary angioedema may worsen in pregnancy. Short-term prophylaxis with pdhC1INH concentrate is recommended prior to CD. • Management of the anticipated difficult airway should not differ from the general principles provided in recent guidelines from the United Kingdom, CAFG, ASA, and a specific review on awake tracheal intubation.108 • Airway US is proving to have value in the pregnant population, primarily for identifying the CTM, and assessing potential difficult laryngoscopy. • High-flow nasal oxygen therapy is not recommended for routine preoxygenation of pregnant women as it is inferior to standard facemask oxygenation. However, HFNO is excellent for peroxygenation, and therefore maintaining safe oxygenation, in predicted difficult intubations. The only caveat is that in the morbidly obese obstetric population, (BMI > 40), HFNO still provides a limited gain in safe apnea time.

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9. Mahmood A, Mushambi M, Porter R, et al. Regional anaesthesia with extracorporeal membrane oxygenation backup for caesarean section in a parturient with neck and mediastinal masses. Int J Obstet Anesth 2018;35:99–103. 10. Reeder CF, Hambright AA, Fortner KB. Dyspnea in pregnancy: a case report of a third trimester mediastinal mass in pregnancy. Am J Case Rep 2018;19:1536–1540. 11. Bechard P, Letourneau L, Lacasse Y, et al. Perioperative cardiorespiratory complications in adults with mediastinal mass: incidence and risk factors. Anesthesiology 2004;100:826–834; discussion 5A. 12. Blank RS, de Souza DG. Anesthetic management of patients with an anterior mediastinal mass: continuing professional development. Can J Anesth 2011;58:853–867. 13. Erdos G, Tzanova I. Perioperative anaesthetic management of mediastinal mass in adults. Eur J Anaesthesiol 2009;26:627–632. 14. Matsumoto R, Mitsuoka M, Hashiguchi T, et al. Temporary airway stenting for giant anterior mediastinal tumor biopsy: two case reports. Int J Surg Case Rep 2019;64:157–160. 15. Kusajima K, Ishihara S, Yokoyama T, et al. Anesthetic management of cesarean section in a patient with a large anterior mediastinal mass: a case report. JA Clin Rep 2017;3:28. 16. Chiang JC, Irwin MG, Hussain A, et al. Anaesthesia for emergency caesarean section in a patient with large anterior mediastinal tumour presenting as intrathoracic airway compression and superior vena cava obstruction. Case Rep Med. Published online 2010. https://doi.org/10.1155/2010/708481. Available from: www.hindawi.com/journals/crim/2010/708481/ [last accessed September 5, 2022]. 17. Dasan J, Littleford J, McRae K, et al. Mediastinal tumour in a pregnant patient presenting as acute cardiorespiratory compromise. Int J Obstet Anesth 2002;11:52–56. 18. Ferrari LR, Bedford RF. Anterior mediastinal mass in a pregnant patient: anesthetic management and considerations. J Clin Anesth 1989;1:460–463. 19. Boyne IC, O’Connor R, Marsh D. Awake fibreoptic intubation, airway compression and lung collapse in a parturient: anaesthetic and intensive care management. Int J Obstet Anesth 1999;8:138–141. 20. Ho AM, Pang E, Wan IPW, et al. A pregnant patient with a large anterior mediastinal mass for thymectomy requiring one-lung anesthesia. Semin Cardiothorac Vasc Anesth 2021;25:34–38. 21. Singh K, Balliram S, Ramkissun R. Perioperative anesthesia management of a pregnant patient with central airway obstruction: a case report. Braz J Anesthesiol 2021;71:281–284. 22. McCrary H, Torrecillas V, Conley M, et al. Idiopathic subglottic stenosis during pregnancy: a support group survey. Ann Otol Rhinol Laryngol 2021;130:188–194. 23. Karippacheril J. Idiopathic subglottic stenosis in pregnancy: a deceptive laryngoscopic view. Indian J Anaesth 2011;55:521. 24. Fang S, Pai BHP. Successful management of subglottic stenosis in pregnancy. BMJ Case Rep (online) 2021;14. http://dx.doi .org/10.1136/bcr-2020-236466 25. Damrose EJ, Manson L, Nekhendzy V, et al. Management of subglottic stenosis in pregnancy using advanced apnoeic ventilatory techniques. J Laryngol Otol 2019;133:399–403. 26. Walsh KJ, Shostak E. Supraglottic jet ventilation in a parturient with subglottic stenosis. J Clin Anesth 2019;58:98–99. 27. Adesunkanmi AR, Makinde ON. Goitre prevalence in pregnant women attending antenatal clinic in a teaching hospital. J Obstet Gynaecol 2003;23:156–159.

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28. El Jaouhari SD, Doghmi N, Najout H, et al. Acute respiratory failure secondary to a cervical goitre in a pregnant woman: a case report. BMC Emerg Med 2019;19:18. 29. Loo GH, Wan Mat WR, Muhammad R, et al. Obstructive retrosternal goitre mimicking severe bronchial asthma in pregnancy. BMJ Case Rep 2019;12:e229763. https://doi.org/ 10.1136/bcr-2019-229763 30. Albareda M, Viguera J, Santiveri C, et al. Upper airway obstruction in patients with endothoracic goiter enlargement: no relationship between flow-volume loops and radiological tests. Eur J Endocrinol 2010;163:665–669. 31. Al-Shammari L, Jemmett K, Wikner M, et al. Management of a parturient with a retrosternal goitre and tracheal compression. Int J Obstet Anesth 2015;24:201–202. 32. Okeke CI, Merah NA, Atoyebi OA, et al. Acute airway obstruction in the puerperium secondary to massive thyroid enlargement. Int J Obstet Anesth 2006;15:79–84. 33. Reid AW, Warmington AD, Wilkinson LM. Management of a pregnant patient with airway obstruction secondary to goitre. Anaesth Intensive Care 1999;27:415–417. 34. Hendrie MA, Kumar MM. Airway obstruction, caesarean section and thyroidectomy. Int J Obstet Anesth 2013;22:340–343. 35. Aloumanis K, Mavroudis K, Vassiliou I, et al. Urgent thyroidectomy for acute airway obstruction caused by a goiter in a euthyroid pregnant woman. Thyroid 2006;16:85–88. 36. Berg EV, Gomes HJ, Conturie CL, et al. Case report of multinodular goiter and airway compression in a preeclamptic patient. J Anesth Clin Res 2012 (online). https://doi.org/ 1.10.7243/2049-9752-1-10. Available from: www.hoajonline.com/ journals/pdf/2049-9752-1-10.pdf [last accessed September 5, 2022]. 37. Wong D, Cheng A, Kunchur R, et al. Management of severe odontogenic infections in pregnancy. Aust Dent J 2012;57:498– 503. 38. Osunde O, Bassey G, Ver-Or N. Management of Ludwig’s angina in pregnancy: a review of 10 cases. Ann Med Health Sci Res 2014;4:361–364. 39. Niederhauser A, Kirkwood D, Magann EF, et al. Ludwig’s angina in pregnancy. J Matern Fetal Neonatal Med 2006;19:119–120. 40. Kamath AT, Bhagania MK, Balakrishna R, et al. Ludwig’s angina in pregnancy necessitating premature delivery. J Maxillofac Oral Surg 2015;14:186–189. 41. Rahman T, Ahmed S, Rahman S. Decompression of Ludwig’s angina in a pregnant patient under bilateral superficial cervical plexus block. J Perioper Pract. Published online February 27, 2019. https://doi.org/10.1177/1750458919834195 42. Trahan MJ, Nicholls-Dempsey L, Richardson K, et al. Ludwig’s angina in pregnancy: a case report. J Obstet Gynaecol Can 2020;42:1267–1270. 43. Shamim F, Bahadur A, Ghandhi D, et al. Management of difficult airway in a pregnant patient with severely reduced mouth opening. J Pak Med Assoc 2021;71:1011–1013. 44. Abramowicz S, Abramowicz JS, Dolwick MF. Severe lifethreatening maxillofacial infection in pregnancy presented as Ludwig’s angina. Infect Dis Obstet Gynecol. Published online 2006. https://doi.org/10.1155/IDOG/2006/51931. Available from: www .ncbi.nlm.nih.gov/pmc/articles/PMC1581466/pdf/IDOG200651931.pdf [last accessed September 5, 2022]. 45. Shakoei S, Daneshpazhooh M, Nasimi M, et al. Toxic epidermal necrolysis in pregnancy due to ondansetron with a favorable

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outcome: a case report and review of the literature. J Clin Aesthet Dermatol 2021;14:46–49. 46. Struck MF, Illert T, Liss Y, et al. Toxic epidermal necrolysis in pregnancy: case report and review of the literature. J Burn Care Res 2010;31:816–821. 47. El Daief SG, Das S, Ekekwe G, et al. A successful pregnancy outcome after Stevens-Johnson Syndrome. J Obstet Gynaecol 2014;34:445–446. 48. Caballero T, Canabal J, Rivero-Paparoni D, et al. Management of hereditary angioedema in pregnant women: a review. Int J Womens Health 2014;6:839–848. 49. Czaller I, Visy B, Csuka D, et al. The natural history of hereditary angioedema and the impact of treatment with human C1-inhibitor concentrate during pregnancy: a long-term survey. Eur J Obstet Gynecol Reprod Biol 2010;152:44–49. 50. Martinez-Saguer I, Rusicke E, Aygoren-Pursun E, et al. Characterization of acute hereditary angioedema attacks during pregnancy and breast-feeding and their treatment with C1 inhibitor concentrate. Am J Obstet Gynecol 2010;203:131.e1–7. 51. Caballero T, Farkas H, Bouillet L, et al. International consensus and practical guidelines on the gynecologic and obstetric management of female patients with hereditary angioedema caused by C1 inhibitor deficiency. J Allergy Clin Immunol 2012;129:308–320. 52. Gonzalez-Quevedo T, Larco JI, Marcos C, et al. Management of pregnancy and delivery in patients with hereditary angioedema due to C1 inhibitor deficiency. J Investig Allergol Clin Immunol 2016;26:161–167. 53. Jain V, Chari R, Maslovitz S, et al. Guidelines for the management of a pregnant trauma patient. J Obstet Gynaecol Can 2015;37:553– 574. 54. Kodali BS, Chandrasekhar S, Bulich LN, et al. Airway changes during labor and delivery. Anesthesiology 2008;108:357–362. 55. Farcon EL, Kim MH, Marx GF. Changing Mallampati score during labour. Can J Anesth 1994;41:50–51. 56. Aydas AD, Basaranoglu G, Ozdemir H, et al. Airway changes in pregnant women before and after delivery. Ir J Med Sci 2015;184:431–433. 57. Boutonnet M, Faitot V, Katz A, et al. Mallampati class changes during pregnancy, labour, and after delivery: can these be predicted? Br J Anaesth 2010;104:67–70. 58. Leboulanger N, Louvet N, Rigouzzo A, et al. Pregnancy is associated with a decrease in pharyngeal but not tracheal or laryngeal cross-sectional area: a pilot study using the acoustic reflection method. Int J Obstet Anesth 2014;23:35–39. 59. Sangkum L, Apinyachon W, von Bormann B, et al. Modified Mallampati class rating before and after cesarean delivery: a prospective observational study. Asian J Anesthesiol. Published online April 30, 2021. https://doi .org/10.6859/aja.202104/PP.0001. Available from: www .airitilibrary.com/Publication/alDetailedMesh?DocI D=P20180503003-202106-202109030005-202109030005-51-57 [last accessed September 5, 2022]. 60. Heller PJ, Scheider EP, Marx GF. Pharyngolaryngeal edema as a presenting symptom in preeclampsia. Obstet Gynecol 1983;62:523–525. 61. Seager SJ, Macdonald R. Laryngeal oedema and pre-eclampsia. Anaesthesia 1980;35:360–362. 62. Ahuja P, Jain D, Bhardwaj N, et al. Airway changes following labor and delivery in preeclamptic parturients: a prospective case control study. Int J Obstet Anesth 2018;33:17–22.

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63. DI Filippo A, Adembri C, Paparella L, et al. Risk factors for difficult Laryngeal Mask Airway LMA-Supreme™ (LMAS) placement in adults: a multicentric prospective observational study in an Italian population. Minerva Anestesiol 2021;87:533–540. 64. Vannucci A, Rossi IT, Prifti K, et al. Modifiable and nonmodifiable factors associated with perioperative failure of extraglottic airway devices. Anesth Analg 2018;126:1959–1967. 65. Rocke DA, Murray WB, Rout CC, et al. Relative risk analysis of factors associated with difficult intubation in obstetric anesthesia. Anesthesiology 1992;77:67–73. 66. Kheterpal S, Martin L, Shanks AM, et al. Prediction and outcomes of impossible mask ventilation: a review of 50,000 anesthetics. Anesthesiology 2009;110:891–897. 67. Ushiroda J, Inoue S, Egawa J, et al. Life-threatening airway obstruction due to upper airway edema and marked neck swelling after labor and delivery. Braz J Anesthesiol 2013;63:508–510. 68. Johns EC, Denison FC, Reynolds RM. Sleep-disordered breathing in pregnancy: a review of the pathophysiology of adverse pregnancy outcomes. Acta Physiol 2020;229:e13458. 69. Pamidi S, Kimoff RJ. Maternal sleep-disordered breathing. Chest 2018;153:1052–1066. 70. Truong KK, Guilleminault C. Sleep-disordered breathing in pregnant women: maternal and fetal risk, treatment considerations, and future perspectives. Expert Rev Respir Med 2018;12:177–189. 71. Kinsella SM, Winton AL, Mushambi MC, et al. Failed tracheal intubation during obstetric general anaesthesia: a literature review. Int J Obstet Anesth 2015;24:356–374. 72. McDonnell NJ, Paech MJ, Clavisi OM, et al. Difficult and failed intubation in obstetric anaesthesia: an observational study of airway management and complications associated with general anaesthesia for caesarean section. Int J Obstet Anesth 2008;17:292– 297. 73. Tao W, Edwards JT, Tu F, et al. Incidence of unanticipated difficult airway in obstetric patients in a teaching institution. J Anesth 2012;26:339–345. 74. Rajagopalan S, Suresh M, Clark SL, et al. Airway management for cesarean delivery performed under general anesthesia. Int J Obstet Anesth 2017;29:64–69. 75. Pollard R, Wagner M, Grichnik K, et al. Prevalence of difficult intubation and failed intubation in a diverse obstetric communitybased population. Curr Med Res Opin 2017;33:2167–2171. 76. Djabatey EA, Barclay PM. Difficult and failed intubation in 3430 obstetric general anaesthetics. Anaesthesia 2009;64:1168–1171. 77. Palanisamy A, Mitani AA, Tsen LC. General anesthesia for cesarean delivery at a tertiary care hospital from 2000 to 2005: a retrospective analysis and 10-year update. Int J Obstet Anesth 2011;20:10–16. 78. Tsen LC, Pitner R, Camann WR. General anesthesia for cesarean section at a tertiary care hospital 1990–1995: indications and implications. Int J Obstet Anesth 1998;7:147–152. 79. McKeen DM, George RB, O’Connell CM, et al. Difficult and failed intubation: incident rates and maternal, obstetrical, and anesthetic predictors. Can J Anesth 2011;58:514–524. 80. Soens MA, Birnbach DJ, Ranasinghe JS, et al. Obstetric anesthesia for the obese and morbidly obese patient: an ounce of prevention is worth more than a pound of treatment. Acta Anaesthesiol Scand 2008;52:6–19. 81. McClelland SH, Bogod DG, Hardman JG. Pre-oxygenation in pregnancy: an investigation using physiological modelling. Anaesthesia 2008;63:259–263.

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82. Izci Balserak B. Sleep-disordered breathing in pregnancy Part 1. Am J Respir Crit Care Med 2019;200:18–19. 83. Neligan PJ, Porter S, Max B, et al. Obstructive sleep apnea is not a risk factor for difficult intubation in morbidly obese patients. Anesth Analg 2009;109:1182–1186. 84. Lundstrom LH, Moller AM, Rosenstock C, et al. High body mass index is a weak predictor for difficult and failed tracheal intubation: a cohort study of 91,332 consecutive patients scheduled for direct laryngoscopy registered in the Danish Anesthesia Database. Anesthesiology 2009;110:266–274. 85. Law JA, Duggan LV, Asselin M, et al. Canadian Airway Focus Group updated consensus-based recommendations for management of the difficult airway: part 1. Difficult airway management encountered in an unconscious patient. Can J Anesth 2021;68:1373–1404. 86. Mushambi MC, Kinsella SM, Popat M, et al. Obstetric Anaesthetists’ Association and Difficult Airway Society guidelines for the management of difficult and failed tracheal intubation in obstetrics. Anaesthesia 2015;70:1286–1306. 87. Chiron B, Laffon M, Ferrandiere M, et al. Standard preoxygenation technique versus two rapid techniques in pregnant patients. Int J Obstet Anesth 2004;13:11–14. 88. Tanoubi I, Drolet P, Donati F. Optimizing preoxygenation in adults. Can J Anesth 2009;56:449–466. 89. Au K, Shippam W, Taylor J, et al. Determining the effective preoxygenation interval in obstetric patients using high-flow nasal oxygen and standard flow rate facemask: a biased-coin up-down sequential allocation trial. Anaesthesia 2020;75:609–616. 90. Quinn AC, Milne D, Columb M, et al. Failed tracheal intubation in obstetric anaesthesia: 2-year national case-control study in the UK. Br J Anaesth 2013;110:74–80. 91. Habib AS. Is it time to revisit tracheal intubation for Cesarean delivery? Can J Anesth 2012;59:642–647. 92. Mushambi MC, Athanassoglou V, Kinsella SM. Anticipated difficult airway during obstetric general anaesthesia: narrative literature review and management recommendations. Anaesthesia 2020;75:945–961. 93. Howle R, Onwochei D, Harrison SL, et al. Comparison of videolaryngoscopy and direct laryngoscopy for tracheal intubation in obstetrics: a mixed-methods systematic review and meta-analysis. Can J Anesth 2021;68:546–565. 94. Boutonnet M, Pasquier P, Ausset S, et al. The difficult airway in obstetrical anesthesia: advocacy to improve the quality of assessment. Can J Anesth 2011;58:1053–1054. 95. Yıldırım İ, İnal MT, Memiş D, et al. Determining the efficiency of different preoperative difficult intubation tests on patients undergoing caesarean section. Balkan Med J 2017;34:436–443. 96. Law JA, Duggan LV, Asselin M, et al. Canadian Airway Focus Group updated consensus-based recommendations for management of the difficult airway: part 2. Planning and implementing safe management of the patient with an anticipated difficult airway. Can J Anesth 2021;68:1405–1436. 97. You-Ten KE, Desai D, Postonogova T, et al. Accuracy of conventional digital palpation and ultrasound of the cricothyroid membrane in obese women in labour. Anaesthesia 2015;70:1230–1234. 98. Aslani A, Ng SC, Hurley M, et al. Accuracy of identification of the cricothyroid membrane in female subjects using palpation: an observational study. Anesth Analg 2012;114:987–992. 99. Campbell M, Shanahan H, Ash S, et al. The accuracy of locating the cricothyroid membrane by palpation – an intergender study. BMC Anesthesiol 2014;14:108.

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100. Gadd K, Wills K, Harle R, et al. Relationship between severe obesity and depth to the cricothyroid membrane in third-trimester non-labouring parturients: a prospective observational study. Br J Anaesth 2018;120:1033–1039. 101. Hung KC, Chen IW, Lin CM, et al. Comparison between ultrasound-guided and digital palpation techniques for identification of the cricothyroid membrane: a meta-analysis. Br J Anaesth 2021;126:e9–e11. 102. Lee SJ, Sung TY, Cho CK. Comparison of emergence agitation between succinylcholine and rocuronium-sugammadex in adults following closed reduction of a nasal bone fracture: a prospective randomized controlled trial. BMC Anesthesiol 2019;19:228. 103. Naguib M, Brewer L, LaPierre C, et al. The myth of rescue reversal in “Can’t Intubate, Can’t Ventilate” scenarios. Anesth Analg 2016;123:82–92. 104. Chambers D, Paulden M, Paton F, et al. Sugammadex for reversal of neuromuscular block after rapid sequence intubation: a systematic review and economic assessment. Br J Anaesth 2010;105:568–575. 105. Dell-Kuster S, Levano S, Burkhart CS, et al. Predictors of the variability in neuromuscular block duration following succinylcholine: a prospective, observational study. Eur J Anaesthesiol 2015;32:687–696. 106. Hawkins JL, Chang J, Palmer SK, et al. Anesthesia-related maternal mortality in the United States: 1979–2002. Obstet Gynecol 2011;117:69–74. 107. Bamber JH, Lucas DN, on behalf of the MMBRACE-UK anesthesia chapter-writing group. Chapter 7: Messages for anaesthetic care. In Knight M, Nair M, Tuffnell D, Shakespeare J, Kenyon S, Kurinscuk JJ (Eds.) on behalf of MBRRACE-UK. Saving Lives, Improving Mothers’ Care – Lessons learned to inform maternity care from the UK and Ireland Confidential Enquiries into Maternal Deaths and Morbidity 2013–2015. Oxford: National Perinatal Epidemiology Unit, University of Oxford 2017: 67–73. 108. Ahmad I, El‐Boghdadly K, Bhagrath R, et al. Difficult Airway Society guidelines for awake tracheal intubation (ATI) in adults. Anaesthesia 2019;75:509–528. 109. Kristensen MS, Teoh WH. Ultrasound identification of the cricothyroid membrane: the new standard in preparing for front-of-neck airway access. Br J Anaesth 2021;126:22–27. 110. Stolady D, Laviola M, Pillai A, et al. Effect of variable preoxygenation endpoints on safe apnoea time using high-flow nasal oxygen for women in labour: a modelling investigation. Br J Anaesth 2021;126:889–895. 111. George R, Berkenbosch JW, Fraser RF, et al. Mechanical ventilation during pregnancy using a helium-oxygen mixture in a patient with respiratory failure due to status asthmaticus. J Perinatol 2001;21:395–398. 112. Cook TM, Woodall N, Frerk C. Major complications of airway management in the UK: results of the Fourth National Audit Project of the Royal College of Anaesthetists and the Difficult Airway Society. Part 1: anaesthesia. Br J Anaesth 2011;106:617– 631. 113. Lamb A, Zhang J, Hung O, et al. Accuracy of identifying the cricothyroid membrane by anesthesia trainees and staff in a Canadian institution. Can J Anesth 2015;62:495–503. 114. Oliveira KF, Arzola C, Ye XY, et al. Determining the amount of training needed for competency of anesthesia trainees in ultrasonographic identification of the cricothyroid membrane. BMC Anesthesiol 2017;17:74.

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115. Siddiqui N, Yu E, Boulis S, et al. Ultrasound is superior to palpation in identifying the cricothyroid membrane in subjects with poorly defined neck landmarks: a randomized clinical trial. Anesthesiology 2018;129:1132–1139. 116. You-Ten KE, Wong DT, Ye XY, et al. Practice of ultrasoundguided palpation of neck landmarks improves accuracy of external palpation of the cricothyroid membrane. Anesth Analg 2018;127:1377–1382. 117. Kristensen MS, Teoh WH, Rudolph SS, et al. Structured approach to ultrasound-guided identification of the cricothyroid membrane: a randomized comparison with the palpation method in the morbidly obese. Br J Anaesth 2015;114:1003–1004. 118. You-Ten KE, Siddiqui N, Teoh WH, et al. Point-of-care ultrasound (POCUS) of the upper airway. Can J Anesth 2018;65:473–484. 119. Arthurs L, Erdelyi S, Kim DJ. The effect of patient positioning on ultrasound landmarking for cricothyrotomy. Can J Anesth 2021;68:24–29. 120. Bowness J, Teoh WH, Kristensen MS, et al. A marking of the cricothyroid membrane with extended neck returns to correct position after neck manipulation and repositioning. Acta Anaesthesiol Scand 2020;64:1422–1425. 121. Adhikari S, Zeger W, Schmier C, et al. Pilot study to determine the utility of point-of-care ultrasound in the assessment of difficult laryngoscopy. Acad Emerg Med 2011;18:754–758. 122. Hui CM, Tsui BC. Sublingual ultrasound as an assessment method for predicting difficult intubation: a pilot study. Anaesthesia 2014;69:314–319. 123. Zheng BX, Zheng H, Lin XM. Ultrasound for predicting difficult airway in obstetric anesthesia: protocol and methods for a prospective observational clinical study. Medicine 2019;98:e17846.

124. Hengen M, Willemain R, Meyer A, et al. Transnasal humidified rapid-insufflation ventilatory exchange for preoxygenation before cesarean delivery under general anesthesia: a case report. A A Case Rep 2017;9:216–218. 125. Bourn S, Milligan P, McNarry AF. Use of transnasal humidified rapid-insufflation ventilatory exchange (THRIVE) to facilitate the management of subglottic stenosis in pregnancy. Int J Obstet Anesth 2020;41:108–113. 126. Shippam W, Preston R, Douglas J, et al. High-flow nasal oxygen vs. standard flow-rate facemask pre-oxygenation in pregnant patients: a randomised physiological study. Anaesthesia 2019;74:450–456. 127. Tan PCF, Millay OJ, Leeton L, et al. High-flow humidified nasal preoxygenation in pregnant women: a prospective observational study. Br J Anaesth 2019;122:86–91. 128. Al-Sulttan S, Bampoe S, Howle R, et al. A prospective, up-down sequential allocation study investigating the effectiveness of vital capacity breaths using high-flow nasal oxygenation versus a tight-fitting face mask to pre-oxygenate term pregnant women. Int J Obstet Anesth 2021;45:28–33. 129. Zhou S, Zhou Y, Cao X, et al. The efficacy of high-flow nasal oxygenation for maintaining maternal oxygenation during rapid sequence induction in pregnancy. Eur J Anaesthesiol 2020;37:1–7. 130. Murphy NE, Coursin DB, Pryde P. Efficacy vs efficiency using high-flow nasal oxygen in peri-intubation oxygenation of gravid women. Int J Obstet Anesth 2021;45:17–20. 131. Rochwerg B, Einav S, Chaudhuri D, et al. The role for high flow nasal cannula as a respiratory support strategy in adults: a clinical practice guideline. Intensive Care Med 2020;46:2226–2237. 132. Chaudhuri D, Granton D, Wang DX, et al. High-flow nasal cannula in the immediate postoperative period: a systematic review and meta-analysis. Chest 2020;158:1934–1946.

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Chapter

9

Use of Neuraxial Ultrasound for Axial Skeletal Conditions Alexandria Papadelis and Carlo Pancaro

Introduction Preprocedural spine ultrasound (US) is increasingly used in obstetric anesthesia because it facilitates neuraxial procedures predicted to be difficult and decreases the risk of the number of skin punctures, needle redirections, postpartum back pain, and headache.1 In addition, it can increase efficacy and reduce complications without significant prolongation of the total time required, regardless of the sonographer’s experience.1 Spinal US primarily identifies musculoskeletal structures. In rare axial skeletal conditions, preprocedural lumbar US can facilitate midline identification and proper interspace level, avoiding potential complications such as needle contact with the conus medullaris and consequent permanent nerve injury.2 The first report of the successful use of a spinal US-assisted technique was for single-shot spinal labor analgesia in an obese parturient with severe scoliosis and Harrington rods. In that case, spinous processes were not palpable, and the midline was not easily identifiable by physical examination alone.3 Other investigators describe using US to facilitate spinal injection by locating the only intervertebral space available in a parturient with poliomyelitis and previous spinal Harrington rod instrumentation.4 In axial skeletal conditions, there are two main goals for US use: (1) Enhancing safety by identifying the desired low-­lumbar interspace level for puncture, presumably below the termination of the conus medullaris; and (2) Facilitating success of the neuraxial technique by identifying the midline that may deviate significantly from one clinically estimated by physical examination.4

Lumbosacral Ultrasound Technique The time spent using US assessment can offset the time to perform a difficult neuraxial block, especially in patients with obesity, poorly palpable spinous processes, moderate to severe lumbar scoliosis, or those who have undergone previous lumbar spine surgery.5 Imaging the lumbosacral spine requires low frequency, curved US (2–5 MHz) array transducers. We recommend performing preprocedural scans, although some practitioners use real-time US-guided approaches successfully.

Determining the Desired Interspace Level After adjusting the US system settings for musculoskeletal-­ specific imaging, and with the patient in a flexed, sitting position,

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we apply the US probe 1–3 cm from the clinically estimated midline and in the paramedian longitudinal plane to visualize the sacrum and the space between the sacrum and the last lumbar vertebra.6 In females, the interlaminar space ranges between 21mm and 38  mm (average 30.6  mm) and is greatest when compared to the L4–5 (16–31  mm, average 23.7  mm), L3–4 (13–25 mm, average 18.8 mm), and L2–3 (12–23 mm average, 17.6 mm) interspaces.7 After identifying the interspaces and the surrounding musculoskeletal structures, we tilt the probe 20–45 degrees medially in the longitudinal paramedian oblique plane.8 We are looking for the lumbar vertebral laminae, the sacrum (displays hyperechoic (white) signals which give a “sawtooth”like appearance), and the interlaminar spaces. (Figure 9.1) Given its characteristic appearance as a horizontal, hyperechoic line, one can recognize sacral US anatomy (Figure 9.1). In some axial skeletal conditions, the L5–S1 interspace is the only one accessible for neuraxial blocks.4 The skin is marked at the probe’s midpoint by positioning the L5 lamina in the center of the screen. Moving the US probe cephalad, the sonographer counts upward from the L5–S1 junction to determine and mark all possible targeted intervertebral levels. Verify the levels by identifying the point where the T12 vertebra articulates with the twelfth rib and then sliding the probe in a caudad direction, visualizing and counting down each successive intervertebral space until reaching the lumbosacral junction.

Determining the Midline Spinous processes identify the midline of the spine. After marking all targeted interspaces in the paramedian oblique views, the probe is rotated 90 degrees into the transverse plane while sliding it cephalad or caudad as required to correspond to the L5–S1 interspace first. The transverse views obtained have the purpose of defining the spine midline and the corresponding targeted interspaces (Figure 9.2). After obtaining the best image, freeze the screen, and mark the skin at the midpoints of the right, left, cephalad, and ­caudad aspects of the probe and perpendicularly connect them in a cross-looking drawing, as previously described.9 Determine the puncture site by the intersection of these two lines (Figure 9.3). With the transverse approach, the anatomical structures give a view that resembles a “flying bat,” which is considered the optimal image. The direction of the needle should reproduce the angle of the US probe where the “flying bat” image was acquired.

Use of Neuraxial Ultrasound for Axial Skeletal Conditions

Figure 9.1  Longitudinal paramedian oblique approach identifying the sacrum and the lumbar interspaces. (A) Orientation of the ultrasound probe showing the corresponding sonogram of the sacrum and lumbo-sacral interspaces (B) The sacrum appears as a hyperechoic continuous line while the lumbar laminae confers the sawtoothlike appearance where the gaps are the interspaces and the teeth correspond to the laminae. When the ultrasound probe is moved cephalad (C), the corresponding sonogram (D) shows the two adjacent laminae, the posterior unit (formed by ligamentum flavum and the posterior dura mater), the intrathecal space, and the anterior unit (formed by the anterior dura mater, the posterior longitudinal ligament, and vertebral body). Source: Reprinted with permission from Husain T, Fernando R, Segal S. Obstetric Anesthesiology: An Illustrated Case-Based Approach. Chapter 6, “Spinal Ultrasound for Neuraxial Anesthesia Placement,” Figure 6.1, Talati and Carvalho. (See color plate section.)

Figure 9.2  Transverse approach at the tip of the spinous process identifies the midline of the spine. (A) Orientation of the ultrasound probe showing the corresponding sonogram of the L3 spinous process. (B) appearing as a small hyperechoic structure immediately beneath the skin, and determining a long vertical black hypoechoic shadow. When the probe is moved cephalad or caudad (C), the lumbar interspace allows the visualization of a “flying bat’ pattern with the first hyperechoic band corresponding to the posterior unit (ligamentum flavum and posterior dura mater) and the second band corresponding to the anterior unit (anterior dura mater, posterior longitudinal ligament and vertebral body). The articular and transverse processes can also be seen as paramedian hyperechoic structures and determine corresponding acoustic shadows. Source: Reprinted with permission from Husain T, Fernando R, Segal S. Obstetric Anesthesiology: An Illustrated Case-Based Approach. Chapter 6, “Spinal Ultrasound for Neuraxial Anesthesia Placement,” Figure 6.2, Talati and Carvalho. (See color plate section.)

The frozen image allows one to measure the distance between the skin and the posterior unit to estimate the depth to the epidural space. In normal anatomy, each spinous process generates one shadow, and the adjacent intervertebral space constitutes one acoustic window where the clinician can scan effectively. When one cannot easily visualize the shadow of the spinous processes,

we recommend using the symmetric US image generated by the paraspinal muscles to identify the midline.10 In adults, spine US does not reliably show the lower end of the spinal cord, the conus medullaris. If we need that information before targeting the desired intervertebral spaces and performing neuraxial blocks, we review other imaging techniques such as Computed Tomography (CT) or Magnetic Resonance Imaging (MRI) scans.

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Alexandria Papadelis and Carlo Pancaro

Figure 9.3  The insertion point is determined by the intersection of the extensions of the two marks on the skin in the vertical and horizontal planes, one for the midline, the other for the interspace. Source: Reprinted with permission from Husain T, Fernando R, Segal S. Obstetric Anesthesiology: An Illustrated CaseBased Approach. Chapter 6, “Spinal Ultrasound for Neuraxial Anesthesia Placement,” Figure 6.3, Talati and Carvalho. (See color plate section.)

Valuable Clinical Insights • In rare axial skeletal conditions, preprocedural spine US can facilitate midline identification and proper interspace level. • Preprocedural spine US helps avoid potential complications such as needle contact with the conus medullaris and consequent permanent nerve injury.

Spinal Dysraphisms and Tethered Spinal Cord Spinal dysraphisms are a heterogeneous group of developmental anomalies of the vertebral arches, spinal cord, meninges, and nerve roots that range from asymptomatic conditions to severe diseases. The most common open spinal dysraphism is the myelomeningocele, characterized by a cleft in the vertebral column, with a corresponding defect in the skin so that the meninges and spinal cord are exposed. Closed spinal dysraphisms manifest in many anatomic variations, including lipomyelomeningocele, a low-lying spinal cord, and a tethered spinal cord.11 Regardless of the type of dysraphism, most of these defects are usually surgically corrected early in childhood. The anesthesiologist faces the challenge of whether the neuraxial block is associated with an acceptable risk of morbidity and is technically feasible. The most common difficulties encountered during neuraxial blocks are locating the epidural space, asymmetric block, unintended dural puncture (DP), and multiple attempts by the

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operator.11 After determining that benefits exceed the risk of a neuraxial block, perform a spine US to define the best puncture level before proceeding to spinal, combined spinal epidural (CSE), or epidural block. A tethered spinal cord can be associated with spina bifida. The term “tethered spinal cord” was first used to describe an elongated spinal cord and a thick filum terminale in 31 children whose neurological symptoms improved following the release of the tethered spinal cord by sectioning the filum terminale.12 Tethered cord syndrome occurs when a tethered spinal cord, accompanied by a stretch-induced functional disorder results in neurologic abnormalities. Most patients with a tethered cord have a low-lying conus medullaris, while its position can be normal in some. However, most tethered cord syndrome patients with a normal conus medullaris position and vertebral abnormalities, intradural lipoma, and neurological abnormalities will improve pain and bowel or bladder incontinence following surgical untethering.13 In any case, with or without corrective surgery, the conus medullaris may remain abnormally low14 with the spinal cord more posterior than usual.15 It is prudent for patients with uncorrected tethered spinal cords to avoid neuraxial techniques due to the increased risk of direct needle trauma to the spinal cord and nerve roots. On the other hand, in patients with tethered cord following corrective surgery, the primary neurologist or neurosurgeon should assess if the current clinical condition could be associated with additional risks of spinal cord trauma following a neuraxial block. In addition, providers should review imaging for all patients

Use of Neuraxial Ultrasound for Axial Skeletal Conditions

with corrected spinal dysraphism or a tethered spinal cord to establish: • the location of the conus medullaris and spinal cord • the position of the spinal cord relative to the anteroposterior plane • whether the epidural space is likely anatomically normal • any postsurgical anatomical changes posing a challenge to performing a neuraxial block • the presence of neural elements between the corrected surgical site and the sacrum to avoid needle contact with such neural tissue, and • any paravertebral adipose tissue, or fat pads, that could be present following lipomyelomeningocele surgery. Lipomatous areas may contain neural structures that might innervate the bladder or lower extremities; needle contact with those could increase the risk of nerve injury following neuraxial block. Additionally, ask the consultant neurologist or neurosurgeon whether the current clinical condition is associated with the risk of spinal cord re-tethering following a possible neuraxial block in patients with surgically corrected dysraphisms who have undergone single or repeated spinal cord untethering procedures. Finally, to facilitate neuraxial block, the neurologist or neurosurgeon should determine the highest and the lowest acceptable interspace for performing a neuraxial technique. There is a report of successful labor epidural analgesia (LEA) following a preprocedural neuraxial US in a pregnant patient who had lipomeningocele and corrective surgery for tethered cord during childhood.14 This patient also had a second untethering procedure following her initial operation because of deteriorating neurological function, including urinary incontinence and leg weakness and numbness. At the time of admission for labor and delivery, the patient required braces and crutches to walk and needed self-catheterization. A lumbar MRI showed an L4–L5 lipomeningocele with surgical changes extending to the L3 area, neural elements around the sacrum, and an associated syrinx14 (Figure 9.4). With the aid of preprocedural US, a lumbar epidural catheter was inserted successfully above the level of the spinal operative site at the T12–L1 interspace. Subsequently, after labor failed to progress, she had a CD with effective ­epidural anesthesia.14

Valuable Clinical Insights • Patients with spinal cord dysraphisms and corrected tethered cord benefit from multidisciplinary management and preprocedural imaging (or postsurgical report) before undergoing neuraxial blocks. • Determine the highest and the lowest acceptable interspace before performing a neuraxial technique for spinal and epidural blocks. • Preprocedural spine US helps avoid potential complications such as needle contact with a low-positioned conus medullaris, a common abnormality in spinal dysraphism and tethered spinal cord.

Chiari Malformation Chiari malformations (CMs) are a heterogeneous group of disorders defined by anatomic anomalies of the cerebellum, brainstem, and craniocervical junction, with downward displacement of the cerebellum, either alone or together with the lower medulla, into the spinal canal.16 There are two types of malformations of interest to the obstetric anesthesiologist: CM Type I and CM Type II. Chiari malformation Type I involves abnormally shaped cerebellar tonsils displaced 5 mm or more below the foramen magnum. The normal cerebellar tonsils may lie up to 3  mm below the foramen magnum in adults. There is no direct correlation between how low the tonsils are lying and the clinical severity of this disease. The frequency of spinal cavitations, such as syringomyelia, hydromyelia, or syringohydromyelia, varies between 40% and 75% in CM Type I. In some patients, the syrinx can extend through the entire spinal cord.17 A CM Type I with concomitant syringomyelia implies an initial or persisting continuity between the syrinx and CSF in the cord’s central canal. Foramen magnum abnormalities cause intermittent obstruction of CSF outflow from the fourth ventricle, leading to craniospinal pressure dissociation, a higher CSF pressure in the head, and a lower pressure in the spine.18 CM-I is associated with hydrocephalus in up to 10% of patients. These patients typically present with headaches, neck and shoulder pain, sensorimotor impairments of the extremities, and mild Figure 9.4  Lumbar MRI showing postsurgical changes from L3–L5 with neural elements present to the sacrum with an associated syrinx. Figure adapted from O’Neal MA. A pregnant woman with spina bifida: need for a multidisciplinary labor plan. Front Med 2017;4:172.

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incoordination,19 though many are asymptomatic, and malformations are often discovered incidentally on the brain or cervical MRI.18 Characteristic of Type II CM is the downward displacement of the inferior cerebellar vermis, cerebellar tonsils, and medulla through the foramen magnum into the upper cervical canal, in association with a lumbosacral myelomeningocele. In these cases, the malformation variably obstructs CSF outflow through the posterior fossa, causing hydrocephalus in almost all patients. Patients may develop episodic apnea, cranial nerve dysfunction, and upper extremity weakness.19 Successful surgical correction of the CM with extra arachnoidal craniocervical decompression and duraplasty removes the obstruction and ameliorates these abnormal phenomena.19 Multiple reports and a case series of 30 deliveries documented successful neuraxial anesthesia (NA) or general anesthesia (GA) in women with CM Type I; none of the patients developed symptoms or had exacerbation of preexisting symptoms.19–21 A multicenter retrospective study found no increased risk of complications in parturients with CM Type I from 67 epidural procedures, 39 single-shot spinal anesthetics, and 29 CSEs.22 Of note, in the same study, one patient developed aspiration pneumonia after a GA.22 As such, it may be reasonable to provide NA in a parturient with CM Type I unless the patient presents with symptoms consistent with a risk of herniation. Following a thorough neurological exam and a review of imaging, if available, the neurosurgical team should assess whether a DP would increase the risk of iatrogenic cerebellar herniation, tentorial herniation with bulbar compression, or adversely alter intracranial pressure (ICP).23 It is prudent to perform regular neurological evaluations and assessments of sensory-motor function after delivery.23 Neuraxial US successfully aided the anesthetic management of a parturient with CM Type I and symptomatic multilevel lumbar disc prolapse.24 She experienced progressive worsening of occipital headaches with pain radiating to both arms, severe low back pain radiating to both legs, and weakness in both legs during her pregnancy. Using US guidance, an experienced anesthesiologist administered spinal anesthesia for an uncomplicated CD.24 Preprocedural spine US may be beneficial to target the desired intervertebral spaces before NA in CM patients, especially in cases associated with spina bifida or syringomyelia.

Syringomyelia Syringomyelia, a fluid-filled cavity within the spinal cord extending between C2 and T9, can descend further down to the conus medullaris or extend upward into the brainstem (syringobulbia). Syringomyelia occurs in the setting of CM Type I, in concomitance with spina bifida, Klippel-Feil syndrome, or tethered spinal cord. Syringomyelia can also follow transverse myelitis, multiple sclerosis, or trauma involving the spinal cord.25,26 Although a syrinx can be asymptomatic, most obstetric patients show signs and symptoms antepartum,27 such as neck and shoulder pain, muscle weakness, pain in the legs, numbness or decreased sensation, scoliosis, muscle contractions, and ataxia. Patients can also have progressive central cord deficits,

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including a prominent central pain syndrome in a segmental distribution.28 If the spinal syringomyelia is asymmetric, it can cause differential growth of the hemicords and the vertebral column leading to scoliosis.29 The recommendation for patients who present with neurologic deterioration or intractable pain is surgical decompression with shunt placement or fenestration. Neurologic deficits usually stabilize after intervention and occasionally improve.30 Individualize the obstetric management of the syringomyelia parturient in collaboration with the obstetric, neurology or neurosurgery, and anesthesiology teams. The recommendation may be for a CD or operative vaginal delivery to avoid Valsalva maneuvers during the second stage of labor. When increases in ICP do not endanger maternal safety, nonoperative vaginal delivery is an option. A case series and systematic review analyzed the anesthetic and obstetric management of 43 pregnancies in 39 patients affected by syringomyelia during labor and delivery.27 About half of these patients had CM; in most, the syrinx was in the cervicothoracic region (42%). For CD, 80% of the 39 patients had GA, 20% epidural anesthesia, and 10% spinal anesthesia. Most patients had LEA (n = 9/13, 69%) for vaginal delivery. Remarkably, no maternal or neonatal complications were associated with NA; however, three cases (14%) of those who had GA had complications (difficult intubation, transient worsening of neurological symptoms postpartum, prolonged muscle paralysis following nondepolarizing muscle relaxants).27 There were no cases where vaginal delivery aggravated the neurological condition associated with the preexisting syrinx; all anesthetic techniques were successful without any major, lasting complications.27 A 30-year-old woman with cervical syringomyelia secondary to a whiplash injury sustained 3 years earlier had a successful epidural anesthetic for CD following preprocedural US.31 Her symptoms were cervical spine pain, torticollis toward the right side, and back pain that increased significantly with Valsalva maneuvers. This back pain prevented her from walking normally or sitting upright in a chair. On physical examination, she had decreased sensation below C2 and diffuse, nonfocal ­weakness of her arms, mainly her left. She had a history of a few spontaneously resolving syncopal episodes that followed severe pain and dizziness. There were no other symptoms of autonomic dysfunction. A postaccident spine MRI showed a cervicothoracic syrinx of 2 mm in diameter extending from C4 to T1 with disc protrusions in the C4–C6 region, indenting the thecal sac without cord compression. The patient was obese, her vital signs were stable, and she had a Mallampati class II airway with limited neck movement in all directions due to torticollis and a firm mass in the left shoulder area. Spasms of her paravertebral muscles and her lordotic lumbar spine prevented palpation of the lumbar spinous processes. A recent MRI showed no change in the size of her syrinx. Consultation among the neurosurgeon, obstetrician, anesthesiologist, and the patient resulted in performing a CD at term. Reduced CSF pressure change and the ability to use an epidural catheter for postoperative pain management made titrated ­epidural anesthesia the preferred choice. Preprocedural

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US identified the L3–4 interspace, the needle insertion point, and the estimated depth to the epidural space. A senior anesthesiologist established epidural anesthesia with the patient in the sitting position. Slow, intermittent epidural administration of 25 ml of 2% lidocaine with epinephrine 1:200,000 and 50 μg of epidural fentanyl resulted in a bilateral sensory block height of T4. She received 2.5 mg of epidural morphine for postoperative pain, and the mother and newborn had uneventful recoveries.31

Currarino Syndrome Currarino syndrome is a rare hereditary condition characterized by anorectal malformation, sacral dysgenesis, and a presacral mass. This autosomal dominant syndrome has variable genetic penetrance and may be associated with CM Type I or tethered cord.32 A patient with Currarino syndrome, in whom NA was contraindicated, successfully received GA for CD, using elective videolaryngoscopy.33 To date, there are four case reports of patients with Currarino syndrome undergoing NA.32,34–36 In all cases, preprocedural spine MRI assessed the safety of neuraxial techniques; only one patient underwent preprocedural spine US to determine the targeted puncture intervertebral level.32 A 37-year-old woman underwent anesthesiology consultation at 31–3/7 weeks gestation.32 Her medical history included obesity, diabetes mellitus type 2, bicornuate uterus, and reconstructive surgery as a child for congenital vaginal-rectal anomalies. A lumbosacral MRI showed sacral dysgenesis, a large communicating anterior sacral meningocele (measuring 11 × 7 × 10 cm), and extension of the conus medullaris to the L2–3 interspace without evidence of tethered spinal cord. Based on the MRI, the L3–4 and L4–5 interspaces were the most feasible targets for NA.32 At 37–1/7 weeks gestation, she had a CSE in the lateral position for CD. Following preprocedural US, the anesthesiologist located the L3–L4 epidural space on the first attempt. The epidural catheter insertion occurred after intrathecal injection of hyperbaric bupivacaine (1.6 ml 0.75%), fentanyl (15 mcg), and preservative-free morphine (150 mcg). The patient was positioned supine with left uterine displacement and immediately complained of nausea, dizziness, and anxiety. After an examination found a sensory level of C8, she was placed in reverse Trendelenburg position and given supplemental oxygen. Fifteen minutes later, worsening dyspnea required the application of a tight facemask with 100% oxygen. She remained hemodynamically stable with spontaneous respiration and delivered a healthy newborn. Postoperatively, the patient developed vertigo associated with movement or eye-opening, but there was normal resolution of the block. The vertigo resolved spontaneously over the next day.32 Obesity and a spinal deformity were risk factors for high spinal anesthesia but did not affect the patient’s desire for an awake delivery or her safety. Although this is the only high spinal anesthetic reported in a patient with Currarino syndrome, there are reports of excessively high blocks with NA in patients with other spinal malformations, possibly due to alterations in the structure of the epidural space. Given the variation in neuroanatomic

abnormalities, such as a low-lying conus medullaris, MRI and preprocedural spinal US are indicated in these patients.

VACTERL Association Vertebral defects, Anal atresia, Cardiac defects, TracheoEsophageal, Renal, and Limb abnormalities characterize the VACTERL association, a rare multisystemic disorder with an estimated incidence of 1/10,000 – 1/40,000. The diagnosis of VACTERL association requires at least three of those abnormalities without other major congenital abnormalities.37 Affected women may have concomitant severe restrictive lung disease secondary to scoliosis.37 Epidural analgesia with preprocedural spine US was utilized for postoperative pain management in a woman with VACTERL association, scheduled for a CD.37 As she had a difficult airway (fixed neck in a right lateral flexed position, mildly reduced mandibular protrusion, and Mallampati class III), the decision was for GA with awake fiberoptic intubation, with postoperative epidural analgesia. There were concerns that a T5 block for CD with NA would interfere with her ventilation and oxygenation (restrictive lung disease and small stature). Given the severity of scoliosis, a preprocedural US identified the L2–3 interspace. After marking the L2–3 interspace in the longitudinal and transverse planes and approximating the spinal torsion, an epidural catheter was inserted on the first attempt. Postoperative analgesia was successful with good maternal and neonatal outcomes.37

Klippel-Feil Syndrome Klippel-Feil syndrome is a congenital condition characterized by vertebral anomalies in the cervical, thoracic, and lumbar spine. Klippel and Feil originally described a patient with a short neck, the resulting appearance of a low hairline at the back of the head, and limited neck range of motion.38 Most affected people have one or two of these characteristic features, while less than half show all three classic features. Moreover, missing cervical or upper thoracic vertebrae may be the reason for the short neck.39 There are three variants of this syndrome. Several cervical and upper thoracic vertebrae are fused in type I. In type II, the most common variant, failure of complete segmentation, occurs at one or two cervical interspaces. Type III variant includes type I or II abnormalities with coexisting segmentation errors in the lower thoracic or lumbar spine. Scoliosis (60% of cases), renal abnormalities (35%), deafness (30%), and congenital heart disease (14%) can be present, with the most common congenital heart disease being a ventricular septal defect.40 Some patients have mandibular abnormalities and micrognathia, increasing the risk of a difficult airway. Severe neurologic injury in this patient population can occur spontaneously or following minor trauma.41 As a result, many consider awake fiberoptic intubation for GA to minimize the risk of neurologic injury and failed intubation. While cervical vertebral fusion or instability can increase the risk of difficult airway, lumbar spine abnormalities can lead to midline deviation and difficulty when establishing a neuraxial block.42 In addition, asymptomatic tethered spinal cord43 and spina bifida

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occulta44 can occur with Klippel-Feil Syndrome. Other possible neuraxial abnormalities include Tarlov perineural cysts, ­low-lying spinal cord, and syrinx.43 A morbidly obese, pregnant patient with Klippel-Feil syndrome underwent a repeat CD.42 She had significant thoracic scoliosis and expressed a desire to be awake for her CD. Her two previous CDs were under GA with awake fiberoptic intubation due to her short neck with minimal range of motion, short thyromental distance, and a Mallampati class IV airway. Landmarks were difficult to palpate, but preprocedural US identified the midline and the L2–L3 interspace. During attempted epidural anesthesia, an unintentional DP with brisk CSF flow occurred during a difficult epidural. Unable to thread a catheter, the anesthesiologist removed the Tuohy needle. A second attempt was made at the same interspace with loss of resistance to saline at 9 cm and was successful. Lidocaine 2% with 1:200,000 epinephrine was given through the epidural catheter in fractionated doses to a total of 18 ml. After 25 minutes, the patient had a T4 level bilaterally to pinprick and was pain free upon incision. Her block resolved entirely within 4 hours, with no postoperative neurological complications.42 Given the technical challenges associated with neuraxial blocks and possible underlying spinal cord abnormalities in Valuable Clinical Insights • Low-lying and tethered spinal cord can occur in patients with Klippel-Feil syndrome. • Imaging and preprocedural spine US prior to neuraxial block can help avoid potential complications, such as needle ­contact with a low positioned conus medullaris.

Klippel-Feil Syndrome, imaging of the thoracolumbar spine and preprocedural US could potentially aid the clinician in establishing successful NA.

Klippel-Trénaunay Syndrome Klippel-Trénaunay Syndrome (KTS) is a rare, nonhereditary disorder characterized by a triad of venous malformations, cutaneous capillary malformations, and bony or soft tissue hypertrophy in affected limbs.45 Venous malformations (hemangiomata) can be associated with cerebral or spinal cord arteriovenous fistulae, increasing the risk of a neuraxial hematoma. Large varicosities in the vulvovaginal, and cervical uterine areas,46,47 predispose to PPH and DIC.45 Hemorrhage from AVMs can lead to a consumptive coagulopathy, known as the Kasabach–Merritt syndrome, characterized by thrombocytopenia, hypofibrinogenemia, and increased concentration of fibrinopeptide A and fibrinogen degradation products. This phenomenon is likely the result of trapping and destruction of platelets in the hemangiomata, activating the coagulation cascade.45 A 23-year-old parturient with KTS had deep hemangiomata, including an extensive area of abnormal vessels in the right thigh and the uterine fundus without involvement of the placenta, cervix, vagina, and labia. There were no abnormal vessels in the spinal canal or dural sac.45 The patient subsequently

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underwent serial MRIs (bimonthly during pregnancy) to establish the extent of the hemangiomata of the lumbar spine. After consultation with obstetric, radiology, and vascular surgery colleagues, labor induction occurred at 38 weeks. This decision was based on a lower risk of extensive blood loss with vaginal delivery than a CD.45 A labor epidural was sited at the L1–2 interspace with prompt pain relief; labor proceeded uneventfully, and she had vacuum-assisted delivery of a healthy infant.45 In patients with KTS, especially when cerebral or spinal cord arteriovenous fistulae are present, assess the proposed pathway of the NA needle with an MRI of the thoracolumbar area. A single-center study of 116 KTS patients who underwent spinal neuroimaging found neurovascular anomalies in 16%, including four patients with multiple anomalies.48 Paraspinal or epidural venous malformations were present in 12% of patients, and there was one conus medullaris AVM.48 Coordination among obstetric, radiology, vascular surgery and anesthesiology teams is necessary before labor or CD in KTS parturients. Consider asking for a neurosurgical consultation if there is involvement of cerebral or spinal cord vasculature and to assess the risks and benefits of NA. To date, there are no reports of preprocedural spine US in patients with KTS. However, it could play a critical role if the MRI shows vascular malformations around the thoracolumbar spinal cord or epidural space, especially if near the planned neuraxial block. Once MRI imaging determines suitable neuraxial block sites, preprocedural US can define the optimum intervertebral space for NA and minimize the risk of trauma to neurovascular structures.

Spinal Rods Spinal rods, commonly referred to as Harrington rods, are stainless steel, titanium alloy, or cobalt chromium.49 Consisting of a straight rod and a ratcheting mechanism, they are used in spinal fusion surgery to reduce the curvature of the patient’s spine.50 The rods are positioned in parallel along both sides of the curved spine and anchored to it by two hooks, one attached to a vertebra at the bottom and the other to a vertebra at the top of the curve. Spinal traction straightens the spinal curve into the desired position using a ratcheting mechanism.51 In patients with rods, anesthesia providers generally do not seek orthopedic, neurosurgical, or neurological consultations; however, they will review images or previous surgical records before NA, if available. Do a thorough clinical assessment and consider a preprocedural spine US for a planned neuraxial technique if these are unavailable. In patients with spinal rods, NA may be particularly challenging. A literature review on NA in parturients with scoliosis found a neuraxial failure rate of 31% in the 93 patients with surgically corrected scoliosis.52 Difficulties encountered by the anesthesiologist included inability to place the needle, multiple attempts, patchy or inadequate analgesia, and unintentional DP.52 Complications occurred more frequently in patients with fusions that extended to the lower lumbar interspaces than in those that ended at the upper lumbar spine. Similarly, a prospective case-matched study compared 41 women with previous corrective surgery to 41 healthy matched controls.53 The rate of NA failure was higher (12% vs. 0%), and the time to placement was longer (by 41%) in the surgical correction group. There were

Use of Neuraxial Ultrasound for Axial Skeletal Conditions

more needle redirections, more attempted interspaces, and a greater likelihood of switching to a more experienced provider in those who had corrective surgery. Of note, 11 parturients (27%) presented in labor without previous anesthetic consultation.53 Thus, in patients with surgically corrected scoliosis, one should anticipate technical difficulties during neuraxial placement and consider using preprocedural US. Visualizing the US image of the hyperechoic band (the ligamentum flavum–­ posterior dura mater unit) may be difficult in the patient with previous spine surgery. However, the lumbosacral area structures might be seen clearly, as most rods do not extend to the sacrum. To date, there are three reports of preprocedural US in patients with Harrington rods undergoing neuraxial blocks for CD and labor analgesia.3,4,54 In one account, preprocedural US facilitated successful spinal anesthesia for CD in a patient with T2 to L4 Harrington rods.4 The spinal processes of the lumbar spine could not be palpated, so an US scan of the lower back was done in longitudinal and transverse planes, at different intervertebral levels, and with the patient sitting. Scanning in the longitudinal paramedian plane revealed a hyperechoic shadow of a spinal rod extending from T2 to L4 and an inter­ spinous space at L5–S1 below the rods. This intervertebral space was the only one visible on US examination; the lower end of the rod obstructed the L4–5 interspace. Imaging in the transverse plane revealed the spinous process of L5 appearing as a hyperechoic signal underneath the skin, which continued as a long, triangular hypoechoic shadow, indicating the midline. Moving the US probe caudad enabled visualization of the L5–S1 interspace with its structures, including the ligamentum flavum, dura mater, transverse processes, articular processes, and the vertebral body.4 After capturing the best possible image of the interspace structures, the targeted puncture site was 3 cm lateral to the anticipated midline. The anesthetic provider marked the lowest level of the rods seen on US scanning. It was easy to identify the hyperechoic band corresponding to the ligamentum flavum–posterior dura mater. Holding the US probe perpendicular to the skin in the transverse plane, they determined the direction of the spinal needle by obtaining the best view of the L5–S1 interspace. The first attempt resulted in successful spinal anesthesia with subsequent delivery of a healthy infant.4 Similarly, preprocedural spinal US facilitated an intentional, continuous spinal anesthetic for a CD in a parturient with Harrington rods due to her severe thoracolumbar kyphoscoliosis and lumbar lordosis.54 She required a wheelchair. The surgical scar extended from her upper thoracic to lower lumbar spine. The longitudinal US parasagittal view showed the lower end of a Harrington rod and acoustic signals from the dura at the L1–2 intervertebral level. Acceptable acoustic windows with good dural signals were at the L2–3, L3–4, and L4–5 vertebral interspaces. With the patient in the right decubitus position, an epidural catheter was inserted uneventfully into the L3–4 sub­ arachnoid space through a Tuohy needle at the first attempt.54 After positioning the patient supine on three pillows to facilitate breathing and limit cephalad spread of the injectate, fentanyl 15 μg and 5 mg of 0.5% hyperbaric bupivacaine every 5 minutes up to a total of 20 mg was administered. After reaching a T6 level at 25 minutes, she had an uneventful CD.54

In the third case, a parturient with a history of severe congenital scoliosis, corrected partially with Harrington rods, requested epidural analgesia for labor pain.3 There were no palpable landmarks, and there was no available radiologic imaging. After two unsuccessful attempts at spinal analgesia, preprocedural US showed two Harrington rods in the thoracic region, extending down until the right rod disappeared just before the lumbar region. The anesthesia providers used the left rod as a lateral marker for the vertebral midline at the iliac crests. Cerebrospinal fluid was aspirated successfully with a 27 g Whitacre on the first attempt, and bupivacaine 2 mg with fentanyl 25 mcg injected. As the spinal block regressed, an epidural was successfully sited at the same location using a loss of resistance to saline. However, the epidural block was patchy and inadequate for pain control. After removing the epidural catheter, a 20-Gauge intrathecal catheter was introduced via an 18-Gauge Tuohy needle. Intermittent boluses of 2 mg bupivacaine with fentanyl 25 mcg resulted in excellent analgesia, with clonidine 30 mcg added to prolong the block. As labor failed to progress, four boluses of 1 ml of 0.5% hyperbaric bupivacaine (total 20 mg with fentanyl 15 mcg) over 20 minutes provided a surgical block to T3. An uneventful CD followed, and the patient did not develop a post dural puncture headache.3 Valuable Clinical Insights • Preprocedural US can sometimes visualize spinal rods. • Preprocedural US can help establish the vertebral midline when there is distorted anatomy following corrective spinal surgery, and US imaging does not show the classic anatomic pattern. • Spinal rods can also create challenges in identifying relevant spinal anatomy due to visual US artifacts created by the instrumentation.

Spinal Cord Stimulators Some patients with angina pectoris, peripheral vascular disease, and syndromes, such as complex regional pain syndrome, use spinal cord stimulation to manage chronic pain unresponsive to conventional treatment.55 Neuromodulation via stimulating electrodes diminishes chronic pain by activating dorsal column afferent neurons and inhibiting sympathetic efferent neurons. The result is a modification in neurotransmitter activity at segmental and supraspinal levels.55 Percutaneous or implanted electrodes are located in the epidural space and positioned to target the following vertebral levels in relationship to the a­ natomical pain site: neck – above C3; shoulder – above C5; hand – C5, C6; anterior thigh – T7, T8, T11/12; posterior thigh – T11 to L1; low back – T9 to T10; and foot – L1.56 Electrodes may become ­tethered to the adjacent supraspinous ligaments and extension tubing is tunneled subcutaneously to a pulse generator implanted in the buttock or abdomen.55 There are no known electrical interactions between spinal cord stimulators and the use of cardiotocography or fetal scalp monitoring.55 The pulse generator is generally implanted in the buttock to avoid damage to the electrodes from the increasing abdominal girth in ­pregnancy and damage to the extension wire, leads, or ­electromagnetic field from surgery or electrocautery.55

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Energy from electrocautery can alter, reprogram, or suppress neurostimulator output if components of the spinal cord stimulation system are in its path.57 One concern with spinal cord stimulators is that the electrodes might migrate, interfering with NA. Fortunately, fibrous deposits form an encapsulating sheath around the leads, which, combined with supraspinous sutures, decrease the possibility of migration.55 Anesthesia providers administering NA to parturients with SCSs should communicate with the team managing the spinal cord stimulator to determine lead placement, power source location, and path of the extension wire. Neuraxial blocks for labor analgesia or CD are feasible below the lead entry level. The risk of damaging the spinal cord stimulator system is less with prior knowledge or X-ray imaging of the implanted device’s exact location. Preprocedural US facilitates the identification of the best intervertebral spaces for neuraxial block, as well as confirming the location of leads, power source, and extension wires.55 Preprocedural US enabled successful spinal anesthesia for CD in a parturient with an SCS for chronic lumbosacral pain.57 The SCS leads were inserted at L2–3 and located at T8. The lead extensions and strain-relieving loops were below the device but above the L4 vertebra, and the pulse generator implanted on the left iliac crest. On admission at 32 weeks gestation, intrauterine growth restriction and absent placental end diastolic flow prompted an urgent CD. On examination, there was scarring from her previous SCS surgery, the lead extensions were palpable, and there was normal lower limb sensation and motor function. After reviewing her previous X-rays and turning off the SCS, the anesthetic provider did a preprocedural spine US in the sitting position. After identifying the L4–5 interspace, uncomplicated spinal anesthesia produced a T3 level. The obstetrician used only short bursts of bipolar electrocautery during the uneventful surgery. After recovery from the spinal anesthetic, the stimulator was reactivated.57 In another case, a parturient with an implanted spinal cord stimulator for chronic chest pain, secondary to a giant AVM that infiltrated several thoracic nerves, required an urgent CD.58 The location of the electrodes (thoracic) and pulse generator (left buttock) was determined on clinical examination as there was no available imaging. Using preprocedural US in the sitting position and after obtaining a left paramedian sagittal oblique view, the probe was moved cephalad from the sacrum to identify the L4–5 interspace. The midline was found by rotating the probe 90 degrees to obtain a transverse interlaminar view. The authors did not see any electrodes in the targeted interspace. The anesthesia provider established successful spinal anesthesia at L4–5, and the patient had an uneventful CD. Postoperatively a chest X-ray confirmed the thoracic placement of the electrodes and their entry point at the L2–3 interspace.58 Valuable Clinical Insights • In patients with spinal cord stimulators, preprocedural US facilitates identification of the best intervertebral spaces for neuraxial block. • Spinal US can also confirm the location of leads, power source, and extension wires.

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Lumboperitoneal Shunts Patients with pseudotumor cerebri and intractable headaches or progressive visual dysfunction unresponsive to conservative management often have a lumboperitoneal shunt.59 Although there are reports of successful NA in patients with lumboperitoneal shunts, some authors suggest lumboperitoneal shunts are a contraindication to NA, mainly based on theoretical considerations. Concerns include shunt trauma, potential loss of LA into the peritoneal cavity during spinal anesthesia,59 and entanglement or knotting between the shunt and the epidural catheter. Although there are no reports of the latter complication, ­consider the possibility of entanglement if there is abnormal resistance during epidural catheter removal and order appropriate imaging. If NA is judged reasonable, clinicians should review available imaging to determine the exact location of the shunt before proceeding with NA in patients with lumboperitoneal shunts. However, when imaging or records are unavailable, preprocedural US of the surgical scar from the shunt procedure and palpation of the lumboperitoneal shunt tubing will provide an approximate shunt position.59 Inserted into the dural sac at a low vertebral interspace, the lumboperitoneal shunt tubing runs laterally, tunneled under the skin (where it is palpable) to the peritoneal cavity. Preprocedural US can confirm the course of the shunt, and one can mark the points to avoid when performing neuraxial blocks. By approaching the epidural space from the midline, below or above the scar, there may be minimal risk of contact between the Tuohy needle and the shunt.59 Some anesthesiologists express concern that patients who have undergone back surgery and instrumentation will have ineffective epidural anesthesia, presumably because of scarring of the epidural space. As lumboperitoneal shunt insertion requires minimal instrumentation compared with more extensive spine orthopedic surgical procedures, ineffective epidural anesthesia is more likely due to catheter dislodgement than scar formation.59 During spinal anesthesia, local anesthetic (LA) may leak either into the dural hole (risking high neuraxial block) or into the peritoneal cavity via the shunt (risking inadequate or failed spinal block or one of shorter duration).60 Moreno-Duarte et al. suggest preprocedural US in parturients with a lumboperitoneal shunt to help determine the appropriate level for epidural insertion and potentially to avoid unexpected high block following epidural dosing.61 They describe a case where a 26-year-old woman underwent repeat CD in the setting of premature rupture of membranes. They attempted a CSE below the level of her lumboperitoneal shunt, but there was no CSF return through the spinal needle. The epidural catheter threaded easily and was dosed with 3 ml lidocaine with epinephrine and an additional 15 ml of 3% chloroprocaine in fractionated doses. The patient reported symptoms of shortness of breath, inability to move her upper extremities, and had decreased grip strength, consistent with a high block. She was hemodynamically stable and recovered motor function 30 minutes later. The authors hypothesized that the cause was the diffusion of the epidural LA through the preexisting dural lumbar hole. They recommend placing the epidural catheter above instead of below the lumboperitoneal

Use of Neuraxial Ultrasound for Axial Skeletal Conditions

shunt as LA preferentially spreads cephalad in the epidural space. Preprocedural US will help determine the intervertebral space to target and assess the anatomic characteristics to guide placement and dosing of the NA. Valuable Clinical Insights • Preprocedural US can assist in confirming the location and course of the lumboperitoneal shunt and marking structures to avoid the shunt when performing neuraxial blocks. • Performing neuraxial blocks in the vertebral midline, below or above the surgical scar, typically minimizes the risk of contact between the epidural/spinal needle and the shunt. • Exercise caution in dosing neuraxial catheters in patients with existing dural holes such as shunts because high neuraxial or inadequate blocks are possible.

Intrathecal Pumps Implantable intrathecal infusion systems (intrathecal pumps) treat chronic pain, severe spasticity, or dystonia by providing targeted drug delivery directly to the CNS, thus minimizing the amount of drug administered.62 The intrathecal catheter is typically placed in the high lumbar area for therapeutic pain purposes, and the radio-opaque catheter tip advanced under direct fluoroscopic visualization to the desired spinal level. Patients suffering from abdominal or pelvic pain have the catheter tip placed in the mid-thoracic levels or commonly higher. If there is no therapeutic effect, pulling the catheter to a lower level is typically simpler than replacing it. For patients with severe spasticity, the catheter is usually placed through a lumbar interlaminar space via a percutaneous puncture and advanced to the thoracic or cervical areas depending on the patient’s most affected limbs and where symptoms need relief. However, intraventricular baclofen and open approaches to the foramen magnum and cervical spine through a laminectomy or laminotomy are possible options for patients whose anatomy precludes the use of or makes the insertion of lumbar intrathecal catheters overly challenging.63 The pump is usually inserted in the abdomen and connected to the tunneled catheter. Sixteen children with baclofen pumps who underwent epidural catheter placement with fluoroscopic guidance for postoperative pain management experienced no significant complications or abnormalities in postoperative pump interrogation.64 Three reports describe LEA in parturients with intrathecal pumps. In two, there was successful, uncomplicated LEA placement without US guidance below the level of the scar through a midline65 or paramedian epidural approach.66 In another report, a parturient had an intrathecal baclofen pump inserted to control her spasticity and central post-stroke pain syndrome.67 She requested LEA. An abdominal X-ray showed an infusion pump in the right lower abdomen. The tubing was coiled posterior to the L2–3 spinous processes, entered the spinal canal between the L3–4 spinous processes, and terminated caudal to T8–9. The anesthesiology team consulted the neurosurgeon who placed the intrathecal pump. Transverse

and longitudinal views obtained with preprocedural spine US determined the estimated epidural depth and ensured the pump catheter was not in the pathway of the epidural needle. The patient had successful labor analgesia.67 Given the rarity of this condition, we suggest using preprocedural US in patients with intrathecal pumps to establish a neuraxial block for labor analgesia to decrease the risk of the epidural needle contacting the intrathecal pump tubing.

Summary The use of neuraxial US in uncommon axial skeletal conditions occasionally faced in the labor and delivery suite could facilitate the establishment of neuraxial analgesia and anesthesia. Certain conditions warrant subspecialty consultation and lumbosacral spine imaging before spine US use and performing neuraxial blocks.

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35. Heijden MWJ van der, Smits H, Willekes C, et al.Spinal anesthesia for a parturient with the triad of Currarino. Int J Obstet Anesth 2009;18:173–175. 36. McKenzie AG, Burns R, Cowan S. Combined spinal-epidural technique for caesarean delivery of a parturient with Currarino triad. Int J Obstet Anesth 2016;25:93–95. 37. Hilton G, Mihm F, Butwick A. Anesthetic management of a parturient with VACTERL association undergoing Cesarean delivery. Can J Anesth 2013;60:570–576. 38. Klippel M, Feil A. The classic: a case of absence of cervical vertebrae with the thoracic cage rising to the base of the cranium (cervical thoracic cage). Clin Orthop Relat Res 1975:109:3–8. 39. Naguib M, Farag H, Ibrahim A el-W. Anaesthetic considerations in Klippel-Feil syndrome. Can Anaesth Soc J 1986;33:66–70. 40. Hensinger RN, Lang JE, MacEwen GD. Klippel-Feil syndrome: a constellation of associated anomalies. J Bone Joint Surg Am 1974;56:1246–1253. 41. Michie I, Clark M. Neurological syndromes associated with cervical and craniocervical anomalies. Arch Neurol 1968;18:241– 247. 42. Smith KA, Ray AP. Epidural anesthesia for repeat cesarean delivery in a parturient with Klippel-Feil syndrome. J Anaesthesiol Clin Pharmacol 2011;27:377–379. 43. Stevens E, Williams B, Kock N, et al. Cord injury after spinal anaesthesia in a patient with previously undiagnosed Klippel-Feil syndrome. Anaesth Rep 2019;7:7–10. 44. Steinbok P. Dysraphic lesions of the cervical spinal cord. Neurosurg Clin N Am 1995;6:367–376. 45. Dobbs P, Caunt A, Alderson TJ. Epidural analgesia in an obstetric patient with Klippel-Trenaunay syndrome. Br J Anaesth 1999;82:144–146. 46. Zhang J, Wang K, Mei J. Late puerperal hemorrhage of a patient with Klippel-Trenaunay syndrome: a case report. Medicine 2019;98:e18378. 47. Watermeyer SR, Davies N, Goodwin RI. The Klippel-Trenaunay syndrome in pregnancy. BJOG 2002;109:1301–1302. 48. Larson A, Covington T, Anderson K, et al. Spinal neurovascular malformations in Klippel-Trenaunay syndrome: a single center study. Neurosurgery 2021;88:515–522. 49. Ohrt-Nissen S, Dahl B, Gehrchen M. Choice of rods in surgical treatment of adolescent idiopathic scoliosis: what are the clinical implications of biomechanical properties? Review of the literature. Neurospine 2018;15:123–130. 50. Harrington PR, Dickson JH. Spinal instrumentation in the treatment of severe progressive spondylolisthesis. Clin Orthop Relat Res 1976;117:157–163. 51. Walker CT, Kakarla UK, Chang SW, et al. History and advances in spinal neurosurgery. J Neurosurg Spine 2019;31:775–785. 52. Ko JY, Leffert LR. Clinical implications of neuraxial anesthesia in the parturient with scoliosis. Anesth Analg 2009;109: 1930–1934. 53. Bauchat JR, McCarthy RJ, Koski TR, et al. Labor analgesia consumption and time to neuraxial catheter placement in women with a history of surgical correction for scoliosis: a case-matched study. Anesth Analg 2015;121:981–987. 54. Majeed A, Ahmed I, Alkahtani GJ, et al. Ultrasound-guided continuous spinal anesthesia for cesarean section in a parturient with scoliosis corrected with Harrington’s rod surgery. Saudi J Anaesth 2017;11:479–482.

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55. Patel S, Das S, Stedman RB. Urgent cesarean section in a patient with a spinal cord stimulator: implications for surgery and anesthesia. Ochsner J 2014;14:131–134. 56. Barolat G, Massaro F, He J, et al. Mapping of sensory responses to epidural stimulation of the intraspinal neural structures in man. J Neurosurg 1993;78:233–239. 57. Sommerfield D, Hu P, O’Keeffe D, et al. Caesarean section in a parturient with a spinal cord stimulator. Int J Obstet Anesth 2010;19:114–117. 58. Zanfini BA, De Martino S, Frassanito L, et al. “Please mind the gap”: successful use of ultrasound-assisted spinal anesthesia for urgent cesarean section in a patient with implanted spinal cord stimulation system for giant chest wall arteriovenous malformation – a case report. BMC Anesthesiol 2020;20:122. https://doi.org/10.1186/s12871-020-01042-6 59. Bédard JM, Richardson MG, Wissler RN. Epidural anesthesia in a parturient with a lumboperitoneal shunt. Anesthesiology 1999;90:621–623. 60. Kaul B, Vallejo MC, Ramanathan S, et al. Accidental spinal analgesia in the presence of a lumboperitoneal shunt in an obese parturient receiving enoxaparin therapy. Anesth Analg 2002;95:441–443.

61. Moreno-Duarte I, Hall RR 3rd, Shutran MS, et al. Epidural anesthesia for cesarean delivery in a parturient with lumboperitoneal shunt: a case report. AA Pract 2019;12: 436–437. 62. Balaratnam MS, Donnelly A, Padilla H, et al. Reducing intrathecal baclofen-related infections: service evaluation and best practice guidelines. Neuromodulation 2020;23:991–995. 63. Dziurzynski K, Mcleish D, Ward M, et al. Placement of baclofen pumps through the foramen magnum and upper cervical spine. Childs Nerv Syst 2006;22: 270–273. 64. Eklund SE, Samineni AV, Koka A, et al. Epidural catheter placement in children with baclofen pumps. Paediatr Anaesth 2021;31:178–185. 65. Ali Sakr Esa W, Toma I, Tetzlaff JE, et al. Epidural analgesia in labor for a woman with an intrathecal baclofen pump. Int J Obstet Anesth 2009;18:64–66. 66. Tarshis J, Zuckerman JE, Katz NP, et al. Labour pain management in a parturient with an implanted intrathecal pump. Can J Anesth 1997;44:1278–1281. 67. Badve M, Shah T, Jones-Ivy S, et al. Ultrasound guided epidural analgesia for labor in a patient with an intrathecal baclofen pump. Int J Obstet Anesth 2011;20:370–372.

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Chapter

10

Myopathies and the Parturient Britany L. Raymond and Jeanette R. Bauchat

Introduction Myopathies are a group of clinical diseases that impair the function of skeletal muscle.1 The muscle fibers are affected directly, as the innervation and neuromuscular junctions remain intact. Although weakness is often a primary symptom, variable patterns of stiffness, contractures, or cramping may also be present. These symptoms can worsen due to the physiologic stress of pregnancy and labor, which may unmask a previously undiagnosed myopathy.2 The hereditary myopathies include muscular dystrophies, congenital myopathies, metabolic myopathies, and disorders of muscle membrane excitability. Inflammatory myopathies are a subset of acquired myopathy.1 Each classification has specific obstetric and anesthetic considerations, described below. Table 10.1 summarizes the general guidelines and principles.

Muscular Dystrophies and Other Hereditary Myopathies Muscular dystrophies are a group of genetic progressive muscle diseases that include fibrosis, variable muscle fiber size, and abnormal internalization of muscle nuclei in the respiratory,

cardiac, skeletal, and other organ systems (Table 10.2).3 In the past, many genetic muscular dystrophies were classified according to specific patterns of muscular weakness, but today, genetic testing forms the basis of the diagnostic criteria for nearly all muscular dystrophies. This section will focus on the most common genetic muscular dystrophies, including myotonic dystrophy, facioscapulohumeral dystrophy, Duchenne/Becker muscular dystrophy, and limb-girdle muscular dystrophy. Discussed briefly are other inherited muscular dystrophies such as congenital muscular dystrophy, including Emery-Dreifuss muscular dystrophy. The focus will be on the clinical manifestations of each disease, how pregnancy may affect the condition, and the anesthetic implications of treating this disease in the peripartum period. Muscular dystrophies can affect multiple systems, so the care provided must include neurologists, pulmonologists, gastroenterologists, endocrinologists, pain specialists, and cardiologists. Figure 10.1 summarizes some of the most common myopathies, the most common location of skeletal muscle weakness, and whether cardiac involvement is a predominant feature of the disease. Given the genetic and progressive nature of myopathies, the earlier that symptoms appear, the more likely

Table 10.1  Anesthetic considerations for myopathies in the peripartum period Peripartum period

Interventions

Antepartum

• • • • • • • • • • • • • • • • • •

Intraoperative for cesarean delivery

Postpartum

Consider consultation with neurologist, cardiologist, pulmonologist, and other subspecialty physicians involved in the patient’s care Thorough history and physical of underlying functional status and muscle weakness Consider cardiac or lung function testing if not done recently Plan for NA for labor to reduce labor exertion and avoid GA in emergencies Avoidance of respiratory depressants such as benzodiazepines NA is preferred Discuss awake extubation and possible postoperative ventilatory needs if general anesthesia is required Universal avoidance of succinylcholine Avoid halogenated agents for muscular dystrophies, core myopathy, CPT2 deficiency, and HypoPP Careful administration and monitoring of muscle relaxants Reversal with sugammadex Maintain normothermia Plan for multimodal analgesia and reduction of opioid use Consider respiratory monitoring for 24 hours with continuous pulse oximetry Consider ECG monitoring for 24 hours in those at risk for cardiac events Incentive spirometry Consider mechanical and/or chemical thromboprophylaxis Consider physical therapy and lactation consultation for infant care and fall safety assessments

Abbreviations: NA - neuraxial analgesia; GA - general anesthesia; CPT2 - Carnitine palmitoyltransferase II deficiency; HypoPP - Hypokalemic Periodic Paralysis; ECG - electrocardiogram

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Myopathies and the Parturient

Table 10.2  Inherited myopathies Disease

Inheritance + clinical course

Muscular involvement

Respiratory involvement

Cardiac involvement

Other comments

Myotonic Dystrophy Types 1 and 2

AD Type 1: can be severe and lead to death in childhood Type 2: presents later in life and is milder

Progressive muscular weakness Type 1: distal muscles and face, main feature myotonia Type 2: proximal muscles, main feature pain

Obstructive sleep apnea, respiratory failure

Worsens with age: • dysrhythmia • progressive AV block • a-fib/atrial flutter • vfib • left ventricular dysfunction

Cataracts, endocrine involvement (thyroid, lipid, diabetes), variable neurologic involvement (developmental delay)

Facioscapulohumeral Dystrophy

AD; variable expression Progressive symptoms

Progressive muscle atrophy and a descending pattern of asymmetric weakness (facial, scapular, and upper arm muscles)

Rare in ambulatory patients, but one-third of wheelchair bound individuals have respiratory compromise

Asymptomatic dysrhythmias

Early onset is associated with more severe weakness and central nervous system involvement (mental retardation, epilepsy, retinal vasculopathy, hearing loss)

Duchenne and Becker Muscular Dystrophy (DMD & BMD)

X-linked recessive allelic disorders from dystrophin gene mutations DMD: Severe in males BMD: Variable severity in males

Asymmetric upper and/or lower extremity weakness

DMD: scoliosis develops after loss of ambulation in males, which worsens FVC BMD: None

Dilated cardiomyopathy

Women carriers can manifest with weakness and dilated cardiomyopathy

Limb Girdle Muscular Dystrophy

Heterogeneous group of AD and AR disorders involving a variety of proteins in the muscle

Progressive proximal muscle weakness affecting hip and shoulder girdles

Respiratory compromise may occur depending on subtype

Cardiomyopathies and dysrhythmias may occur depending on subtype

Many women’s symptoms worsen with pregnancy without recovery to baseline

Emery-Dreiffus Muscular Dystrophy

AD X-linked

Cardiomyopathy and dysrhythmia

Abbreviations: AD: autosomal dominant; AR: autosomal recessive; AV: atrioventricular; a-fib: atrial fibrillation; BMD: Becker muscular dystrophy; CPT2-Carnitine palmitoyltransferase II deficiency; DMD: Duchenne muscular dystrophy; FVC: forced vital capacity; HypoPP:Hypokalemic Periodic Paralysis; v-fib: ventricular fibrillation.

the disease will involve multiple organ systems. Treatment for these diseases is primarily supportive for evolving skeletal muscle weakness, respiratory compromise, nutritional deficits from dysphagia or GI dysfunction, or ongoing endocrine dysfunction.4 Musculoskeletal deformity (scoliosis, kyphosis, rigid spine syndrome) may lead to chronic pain syndromes requiring symptom relief with analgesic medications and other pain alleviating interventions.4 Progressive cardiac disease typically requires ongoing surveillance and treatment by cardiac specialists, given that clinical symptoms may not precede fatal cardiac dysrhythmias or sudden death.4 Physical, occupational, and speech therapy can improve patients’ daily lives. Pregnancy requires obstetricians, maternal fetal medicine specialists, and anesthesiologists to collaborate with all of the specialist physicians consulted in order to optimize peripartum care. In the future, treatment for these genetic disorders may involve genealtering therapies currently under investigation. Valuable Clinical Insights • Women with myopathies often have involvement of other major organ systems including cardiac and pulmonary systems. • Early neuraxial labor analgesia for women with myopathy may decrease the stress responses that could trigger worsening musculoskeletal and cardiopulmonary symptoms and avoid

the negative respiratory consequences of general anesthesia for emergency cesarean delivery. • Avoid succinylcholine in any woman with a myopathy due to the potential risk of malignant hyperthermia (MH), hyperkalemia or rhabdomyolysis – although succinylcholine is not contraindicated in all myopathy subtypes. • If general anesthesia is required, use nondepolarizing neuromuscular agents sparingly, monitor neuromuscular weakness carefully, and ensure full and appropriate reversal with sugammadex. • Magnesium sulfate should be used in smaller doses, if at all, due to the risk of excessive muscle weakness and respiratory depression in women with myopathies. Women who receive this drug in the labor unit must receive appropriate ­monitoring and one-on-one nursing care.

Myotonic Dystrophy Type 1 and Type 2 Myotonic dystrophy is an autosomal dominant disorder that leads to progressive weakness, myotonia, and cataracts.5,6 Both type 1 and type 2 myotonic dystrophy are caused by repeat expansion of RNA-binding proteins that misregulate DNA splicing and subsequent protein formation. As a result, there are variable clinical presentations, including skeletal muscle, cardiac, gastrointestinal (GI), respiratory, skin, and endocrine abnormalities.6 Type 1 myotonic dystrophy (DM1) leads to an

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untranslated region on the DM1 protein kinase gene on chromosome 19; clinical manifestations appear early in life and can be severe enough to lead to death in childhood.6 Type 2 myotonic dystrophy (DM2) leads to an unstable expansion of the CNBP gene on chromosome 3; it manifests clinically later in life than DM1 and tends to be milder.6 The estimated prevalence of myotonic dystrophy in all age groups is 8/100,000.7 Type 1 myotonic dystrophy presents with distal muscle weakness, often manifesting in the distal finger flexors.6 With type 2 myotonic dystrophy DM2, there is proximal muscle weakness, including hip and neck flexors, and extensors (Figure 10.1). Myotonia occurs in both DM1 and DM2, but muscle pain is prominent in DM2. Cardiac manifestations lead to cardiac conduction abnormalities and tend to be more severe in DM1, with progressive atrioventricular node block as the leading cause of death.6 Respiratory, GI, AV, endocrine, and neurological manifestations are more common and severe in DM1 than type 2. The impact of DM1 and DM2 on respiratory function varies, but consensus guidelines for pulmonologists exist to guide pulmonary clinical care based on reported symptoms and diagnostic tests.8 Weakness of inspiratory and expiratory muscles can impair cough, which puts these women at risk of aspiration and pulmonary infections. Dysphagia also increases the risk of aspiration of food and drink, saliva, nasal secretions, and gastric contents. Fatigue is the most impactful symptom that patients notice, likely from obstructive sleep apnea, respiratory failure, and muscle weakness.6 The Myotonic Dystrophy Foundation, with affirmation from the board of the American Academy of Neurology, has released consensus-based care recommendations for adults with DM2 that include management of pain, skeletal muscle weakness, and myotonia, ocular, GI, endocrine, and neurological symptoms. In addition, these consensus guidelines include management of fatigue, daytime sleepiness, and recommendations for perioperative management.9

Pregnancy and Anesthetic Considerations: DM1 and DM2

Spontaneous miscarriage rates are not changed in DM1 or DM2, although there is increased risk of perinatal death in DM1, likely from overall genetic risk.10 Pregnancy can worsen myotonia and muscle weakness in DM1 and DM2, but most women spontaneously recover baseline functional status postpartum.2,10 Approximately 21% of women diagnosed with type 2 myotonic dystrophy first present with symptoms in pregnancy.11 Acute clinical deterioration frequently occurs at 28 weeks gestation, possibly due to progesterone’s effects on the skeletal muscle cell membrane potential.12 Particularly in DM1, women are at risk of preterm and prolonged labor, with an increased risk of instrumental vaginal delivery and CD.5,10,13 Polyhydramnios is welldescribed in women with myotonic dystrophy type 1.13,14 This likely contributes to preterm delivery but may also put patients at risk of PPH. Placenta previa is frequent, with women with DM1 having a 10-fold higher risk than the general population.15 Postpartum fall and mobility assessments may benefit women with DM1 and DM2 to assist with infant care. There is a risk of pseudo-ileus postpartum, so order bowel regimens for those with intractable irritable bowel syndrome. Postpartum, refer patients with upper and lower extremity weakness to lactation

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consultants for breastfeeding support and physical therapy specialists to facilitate infant care and fall safety. Anesthetic considerations and complications vary depending on the severity of ongoing or presenting symptoms. The Myotonic Dystrophy Foundation has a summary of anesthetic guidelines given the high risk of perioperative complications.16 In general, myopathies have similar anesthetic considerations within disease categories17 (Table 10.1). Neuraxial techniques are recommended to avoid GA and the related respiratory complications peripartum.18 Before NA for vaginal or CD, assess underlying lower extremity muscle weakness to accurately evaluate recovery from LA use by a NA technique. Consider early NA for vaginal delivery in any woman with underlying cardiac or respiratory compromise. Epidural analgesia reduces the stress response and increased demand on the cardiopulmonary system due to the sympathetic surges related to pain and exercise. With GA, avoid succinylcholine because of its potential for undesirable side effects such as hyperkalemia.19 Patients with central core and mini-core disease with ryanodine receptor mutations are at clear risk of malignant hyperthermia (MH). In all other neuromuscular disorders, an increased risk of MH is not well documented.10 In the case of muscular dystrophies, succinylcholine and halogenated agents can trigger anesthesiainduced rhabdomyolysis (AIR), which is unresponsive to dantrolene.20 Total intravenous anesthesia with propofol infusion is considered the most conservative method to manage myopathies requiring GA.17,20 Patients with myotonic dystrophy are at risk of pulmonary complications. Preoperative and postoperative pneumonia and aspiration can occur, especially in the presence of dysphagia or pseudo-obstruction. Therefore, obtain a baseline CXR. Theoretically, pregnancy may compound the risk of aspiration, although this is not proven. Be cautious with the use of muscle relaxants. For all myopathies, reduce the dose of muscle relaxants and closely monitor the train-of-four twitches.21 Sugammadex appears effective for muscle relaxant reversal in most patients with neuromuscular disease.21 Upon extubation, anticipate acute deterioration in the respiratory status of any woman with even mild myotonic dystrophy,22 but particularly in those with underlying respiratory failure given the worsening of disease symptoms in pregnancy. Prepare patients for awake extubation and the possible need for postoperative ventilation.17,20 Consider sleep apnea when administering GA, ­opioids, or other medications with respiratory depressant effects. During the hospital stay, encourage patients to use their CPAP with increased respiratory monitoring.23 Maximizing the use of multimodal analgesics and neuraxial techniques post-CD is essential. One case report demonstrated high sensitivity to even low-dose NA.24 The usual standard of neuraxial opioids may not be superior to systemic opioids, so maximally monitor respiratory function postpartum.23 Hypothermia can exacerbate muscle weakness. With underlying daytime sleepiness and fatigue, sedation and opioid analgesics may reduce the level of consciousness. The American Heart Association has clinical care recommendations for treating adults with myotonic dystrophy since cardiac disease worsens as patients age.25 Dysrhythmias found on routine ECG screening most commonly include AV nodal

Myopathies and the Parturient

block, atrial fibrillation, ventricular fibrillation, or atrial flutter. Peripartum, screen and monitor for dysrhythmias. Place women with myotonic dystrophy in labor and postpartum rooms with continuous pulse oximetry and ECG capabilities and equipment and medications to treat dysrhythmias nearby. Some patients will present with pacemakers that will require management peripartum and during CD.26 Patients may be on anticoagulation if they have experienced atrial fibrillation in the past. Left ventricular dysfunction occurs in up to 40% of myotonic dystrophy patients, so screen these women peripartum with an echocardiogram and, if over the age of 40, do yearly TTE.25

Facioscapulohumeral Muscular Dystrophy Type 1 and Type 2 The estimated prevalence of facioscapulohumeral muscular dystrophy (FSHD) in all age groups is 4/100,000, and FSHD type 1 (FSHD1) makes up 95% of the FSHD population.7 The cause of FSHD is a shortening of the D4Z4 region in the subtelomeric region of chromosome 4q leading to DUX4 open reading frame; DUX4 appears toxic to cells and leads to apoptosis, creating the constellation of FSHD clinical symptoms.3,27 The genetic expression of this D4Z4 expression alone is not sufficient. It is only when a specific 4qA haplotype containing a polyadenylation signal follows the last repeat of the D4Z4 array that the disease manifests.28 Facioscapulohumeral muscular dystrophy typically presents between 15 and 30 years, during a woman’s peak childbearing years. The typical presentation is an asymmetric weakness of the face and shoulder muscles, followed by truncal and extremity weakness27,28 (Figure 10.1). Patients’ eyes appear “wide open,” and they have difficulty puckering their lips and an asymmetric smile.27 The weakness in the scapular muscles will manifest as a winged scapula and inability to slowly abduct their arms.27 Musculoskeletal pain occurs in 88.6% of patients, usually in the shoulders and back,29 leading to poor quality of life. One-third of women who use a wheelchair have respiratory dysfunction, although the need for respiratory support is rare.30 Unlike other myopathies, FSHD is not associated with cardiomyopathy. Mild retinal vasculopathy occurs in half of all patients, with severe disease occurring in only 0.8% of FSHD patients.27 The FSHD Health Index31 and FSHD Composite Outcome Measure were developed to provide a comprehensive measure of function over time to understand treatment therapies better,32 and may help assess disease burden, improvement, or progression.

Pregnancy and Anesthetic Considerations The variable penetrance and variability in DUX4 expression complicate genetic counseling for women with FSHD.28 In patients with early-onset or rapidly progressive disease, about 12% to 24% will experience increased severity of symptoms during pregnancy, such as a general decrease in muscle strength, increased falls, and new-onset or worsening pain.28 Pregnancy outcomes such as miscarriages, mode of delivery, or preterm delivery do not appear affected by FSHD.13,33,34 However, these conclusions are based on small studies, and FSHD subtypes were not evaluated separately. One small study34 demonstrated a higher rate of forceps delivery, which would necessitate NA

for delivery. Many of the same postpartum concerns with infant safety and fall prevention for myotonic dystrophy apply to this patient population, with physical therapy and lactation consultation being essential in the setting of worsening symptoms in pregnancy. There are no guidelines for anesthetic care of women with FSHD in the general surgical or obstetric setting, but the usual anesthetic considerations delineated in the previous section on myotonic dystrophy and Table 10.1 apply. Neuraxial analgesia/ anesthesia is preferred in FSHD patients, although scoliosis may complicate the technique. Respiratory complications are rare, but among patients with underlying respiratory compromise, GA and paralysis require caution, given an increased risk of prolonged intubation, failed extubation, or sensitivity to medications used for muscle paralysis. Cardiac complications, if present, are benign dysrhythmias manifesting typically as asymptomatic right bundle branch blocks.35

Duchenne Muscular Dystrophy and Becker Muscular Dystrophy Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are X-linked genetic disorders affecting primarily males with mutations in the dystrophin gene. The overall pooled estimated prevalence among males worldwide for DMD is 4.78 (95% CI 1.94–11.81) per 100,000, and for BMD is 1.53 (95% CI 0.26–8.94) per 100,000.36 Although the clinical course for males with DMD is often progressive and devastating before reaching the age of having children, males with BMD tend to have mild disease.37 Women carriers are usually asymptomatic, but approximately 8% of women carriers of this X-linked gene can manifest clinical symptoms of weakness.38 In Duchenne and Becker dystrophy female carriers, the incidence of skeletal muscle damage is 2.5% to 19%.39 In carriers with muscular weakness, 81.8% have asymmetric weakness; 41% demonstrate upper extremity weakness, 23% lower extremity weakness, and 36% have both.38 With age, dilated cardiomyopathy incidence increases from 7.3% to 16.7% for DMD and 0% to 13.3% for BMD female carriers39 (Figure 10.1). Fifty-five percent of carriers under age 16 and 90% of carriers age 16 and older have either latent or clinical ­features of dilated cardiomyopathy.40 Another prospective cohort study of 77 genetically confirmed carriers of DMD/BMD mothers, 22 noncarrier mothers and 25 controls, demonstrated no difference in exercise capacity with cardiopulmonary exercise testing but more ventricular ectopy during the recovery phase for genetically confirmed carriers.41 Mild left ventricular (LV) dysfunction (left ventricular ejection fraction < 55%) was present in 11/77 (14.2%) of confirmed carriers, 1/20 (4.5%) of noncarriers, and 2/25 (8%) of control subjects on cardiac MRI (CMRI).41 In a study of cardiac involvement in DMD/BMD carriers, dilated cardiomyopathy was found in 8% carriers of DMD of whom one had concomitant muscle weakness. A high proportion (18%) had LV dilatation, but no phenotype-genotype correlation was found.38 If myocardial fibrosis is seen on CMRI, it does not always correlate with exercise tolerance or motor weakness.41

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Pregnancy and Anesthetic Considerations: DMD and BMD Given that Duchenne and Becker muscular dystrophy are rare, and few women manifest with the disease as carriers, we rely primarily on case reports and small studies to discern the impact of pregnancy on these women carriers.2 Women carriers rarely have muscular weakness severe enough to impact labor and delivery. One report of 13 women with 35 deliveries demonstrated a breech presentation rate of 14%42 (a five-fold higher rate than the national average); this may be due to differences in uterine or pelvic muscle tone, possibly increasing the risk of CD. Otherwise, vaginal delivery can be achieved in the presence of upper or lower extremity weakness, as uterine contractions primarily drive expulsion with a contribution from the Valsalva maneuver, which requires diaphragmatic and abdominal muscle strength.43 Given the high rates of cardiac fibrosis in carrier women,38,41 it is essential to evaluate prepregnancy cardiac reserve. In addition, peripartum ECG and echocardiography allows evaluation of the underlying dysrhythmias and LV dysfunction; this is important given the high rates of underlying cardiac fibrosis without clinical manifestations in carrier women. Knowing baseline cardiac function allows for a minimal delay in determining whether changes in exercise tolerance in pregnancy are expected or the result of worsening cardiac function from greater plasma volumes in the second and third trimesters of pregnancy. During labor, delivery, and postpartum, use

telemetry monitoring with ECG, given the high dysrhythmia potential in some carriers of DMD and BMD. In addition to the GA considerations listed in Table 10.1, DMD and BMD are two diseases that require avoiding halogenated agents, which could trigger AIR. Total intravenous anesthesia is the safest way to deliver GA and avoid halogenated agents that might trigger AIR.

Limb Girdle Muscular Dystrophy Limb girdle muscular dystrophy (LGMD) is a heterogeneous group of autosomal dominant and recessive disorders affecting proteins in the extracellular matrix, sarcolemma, cytoplasm, and nucleus of muscles.3,44 The estimated prevalence of LGMD is 1.63/100,000.7 The number of genetic conditions is extensive, and new ones are added regularly, with the old classification using LGMD 1X (from A to H) now classified as LGMD D for dominant disorders and LGMD 2X (from A to Q) now using LGMD R for recessive disorders.44 The most common forms of LGMD are the recessive group of disorders, with calpain-3 (CAPN3), dysferlin (DYSF), FKRP, and ANO5 as the most common protein (gene) mutations. An exhaustive list of LGMD subtypes and clinical descriptions is outside the scope of this review. Progressive muscle weakness occurs in the proximal hip and shoulder girdles, predominantly over distal skeletal muscles (Figure 10.1). Respiratory compromise, cardiomyopathies/­dysrhythmias, and

Figure 10.1  Illustration of the distribution of muscle weakness (shaded areas) for the inherited myopathies. The heart symbol indicates disorders that are also associated with cardiac involvement.

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Myopathies and the Parturient

dysphagia are highly variable depending on the LGMD subtype. Treatment for patients with LGMD will vary depending on the number of physiological systems affected and the severity of the patient’s clinical symptoms.4

Pregnancy and Anesthetic Considerations Most women with LGMD demonstrate progression of symptoms during pregnancy with strength not returning to baseline postpartum.33,45 Breech presentation and CD occur more often in women with LGMD.13 Anesthetic considerations vary depending on the subtype and clinical presentation of patients with LGMD. The preferred technique is NA (Table 10.1) but may be difficult due to spinal deformity from contractures from core muscle damage. Some patients carry an increased risk of aspiration due to dysphagia or impaired cough. A varying degree of respiratory compromise and further impairment from anesthetics and neuromuscular blocking drugs may make extubation difficult after GA. Similar to DMD and BMD, avoid halogenated agents.20

Congenital Muscular Dystrophies Congenital muscular dystrophies are a heterogeneous group of early-onset autosomal recessive childhood diseases. The estimated prevalence for congenital muscular dystrophies is 0.99/100,000.7 This group of diseases varies in severity, but the different forms typically have progressive hypotonia, muscle weakness, and reduced deep tendon reflexes. Respiratory and feeding issues are common, and neurological abnormalities, including cerebral malformation, microcephaly, eye anomalies, and joint laxity, can occur.

Emery-Dreifuss Muscular Dystrophy Once considered among the LGMD disorders, Emery-Dreifuss muscular dystrophy (EDMD) was reclassified because it does

not follow the pattern of muscle girdle weakness. The estimated prevalence of EDMD is 0.4/100,000,7 based on pooled data from diverse patient populations. There are dominant and recessive forms of EDMD and X-linked women carriers of EDMD.46 There are currently seven subtypes described with ongoing discoveries of previously unknown subtypes. Typically, the clinical presentation is skeletal muscle weakness of the arms and legs in the humeroperoneal distribution, with contractures involving neck extension, elbow flexion, and heel cord tightening.46 In EDMD, there are reports of contractures severely limiting cervical flexion. Cardiac dysrhythmias such as heart block, tachycardia, and sudden cardiac death from ventricular fibrillation are prominent features with cardiomyopathy developing later in life. Respiratory involvement is rare, but contractures of the spine can lead to restrictive respiratory disease.

Congenital Myopathies Congenital myopathies (CMs) (Table 10.3) are rare inherited disorders of musculature that are classified based on histologic abnormalities noted on muscle biopsy.47,48 These structural changes prevent the normal function of skeletal muscles, resulting in dysfunction rather than breakdown, which is more characteristic of muscular dystrophies. Therefore, the clinical course of myopathies is usually slow or nonprogressive and may even improve with strength and mobility therapy. There are five subtypes of CM based on muscle biopsy pathology:47 1. Core myopathy (most frequent) 2. Centronuclear myopathy 3. Nemaline myopathy 4. Congenital fiber type disproportion 5. Myosin storage myopathy

Table 10.3  Congenital myopathies Disease

Genetics

Muscular involvement

Respiratory involvement

Cardiovascular involvement

Core Myopathies (a) Central Core Disease (CCD)

AD mutation in the ryanodine receptor results in a single, central core inclusion that runs the entire length of a muscle fiber

Proximal hypotonia and weakness. Scoliosis and joint dislocations (particularly hip) are common

Rare

Rare

(b) Multiminicore Disease (MMD)

AR mutation in selenoproteins results in multiple smaller cores throughout various portions of muscle tissue

Hypotonia and weakness, with axial muscles most affected. Scoliosis is common

Occasional respiratory involvement with diaphragm and accessory muscle weakness

Rare

Centronuclear Myopathy

Variable genetics, but AD and AR defects are more common for surviving adults Centrally located nuclei in rows throughout the muscle fibers

Facial weakness and ophthalmoplegia is common. Weakness is preferentially proximal. Scoliosis, contractures, foot abnormalities, and arched palate may be present

Degree of respiratory impairment is often the most important prognostic factor for survivability

Rare

Nemaline Myopathy (includes core-rod, cap, and zebra body variants of myopathy)

AD or AR nemaline rods in the cytoplasm of the muscle fibers

Slowly progressive generalized weakness but may favor face and proximal muscles. Extraocular muscles are often spared.

Respiratory involvement is common; hypoventilation is the greatest risk for premature death

Rare

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Table 10.3  (Cont.) Disease

Genetics

Muscular involvement

Respiratory involvement

Cardiovascular involvement

Congenital Fiber Type Disproportion

Most cases occur spontaneously but can be expressed through AD or AR familial inheritance. Selective hypotrophy of type 1 muscle fibers

Axial and proximal muscles are most affected by weakness and hypotonia. Often have elongated faces and arched palates. Scoliosis, contractures, and hip dislocation are frequently present

One-third of patients may experience difficulty breathing or swallowing. Noninvasive ventilation assistance may be required at night

Rare

Myosin Storage Myopathies (previously known as hyaline body myopathy)

Accumulation of hyaline in type 1 muscle fibers and cardiac muscle

Predominately proximal weakness with slow progression. Calf hypertrophy is common. Occasional myopathic facies and scoliosis

Respiratory involvement is common

Occasional hypertrophic or dilated cardiomyopathy

Abbreviations: AD: autosomal dominant; AR: autosomal recessive.

These CMs may share common features of weakness, hypotonia, and decreased deep tendon reflexes, yet the severity and onset are highly variable.47,48 Although many types of CM are present at birth, some may not manifest physically until later in childhood or adulthood. While dysmorphic facial features, ptosis, and facial weakness are often present, affected individuals usually have average intelligence and a normal CNS. Respiratory and bulbar function is often affected, but cardiac involvement is rare.48 Any cardiac pathology is often a consequence of an indirect insult, such as severe respiratory compromise leading to hypoxia-induced coronary ischemia or cor pulmonale.

Obstetric Considerations: Congenital Myopathy Most patients with CM survive to adulthood and have childbearing potential.47 Unfortunately, there is a paucity of obstetric data from parturients with CM. The extensive heterogeneity of genetic mutations and phenotypes prohibits large studies, with most available data originating from case reports and series. A 2019 review of the literature summarized the clinical courses and outcomes of 29 pregnancies from 21 parturients with CM.49 The majority had a diagnosis of nemaline myopathy (n = 11), followed by central core disease (n = 6), multiminicore disease (n = 2), congenital fiber type disproportion (n = 1), and cytoplasmic body myopathy (n = 1). All but one of the patients were ambulatory at the time of pregnancy. Women with nemaline myopathy experienced stability and even improvement in their physical condition during pregnancy. In contrast, three (two central core, one multiminicore) of the eight women with core myopathy noted exacerbation of leg weakness, ankle instability, or increased pain from scoliosis. However, the vast majority of parturients reported no influence of gestation on their clinical course. Pulmonary and cardiac investigations were not routinely performed prenatally.49 There was no evidence of an increased risk of miscarriage or preterm birth. While 38% (11/29) of women elected to deliver via CD, the majority delivered vaginally. There was no prolongation of labor, and the incidence of assisted instrumentation was consistent with the general population. Additionally, obstetric complications, such as invasive placentation or PPH, were not elevated in this cohort. Neonatal measurements and outcomes were also favorable for infants

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unaffected by CM. Overall, the authors suggest that functional weakness is unaffected by gestation and that the risks of pregnancy and delivery are not increased in parturients with CM.

Anesthetic Considerations: Congenital Myopathy The increased demands of the cardiac and respiratory systems during pregnancy2 warrant caution with contributory exacerbating factors, such as magnesium therapy or prolonged second stage of labor. Early NA is preferred to reduce the physiologic burdens of labor, but scoliosis may pose significant challenges.20 Some suggest selecting ropivacaine to lessen the impact on motor weakness in parturients with CM.50,51 As with any primary muscle disease and weakness, administration of succinylcholine could result in hyperkalemia and life-threatening dysrhythmias.20 Additionally, susceptibility to MH is associated with the core disease subtype of CM due to mutations of the skeletal muscle ryanodine receptor (RYR1).48,52,53 While there is little evidence that MH is associated with other forms of CM, use MH precautions if the genetic mutation is unknown or histologic pathology is nonspecific. The advice is to avoid MH triggers when anesthetizing CM patients whenever possible given the extensive genetic variability present in CM syndromes.20,54

Metabolic Myopathies Metabolic myopathies are a group of disorders characterized by deficiencies in enzymes associated with muscle energy metabolism.55 Disruption of carbohydrate or fatty acid breakdown reduces a cell’s ability to generate adenosine triphosphate (ATP), thereby limiting the energy available for muscle contraction. However, ATP can be generated through various pathways, allowing for energy production that bypasses the enzymatic deficiency. Additionally, survivable metabolic myopathies often reflect only partial deficits in enzyme activity. Therefore, many patients with these diseases can live a normal life without significant limitations; in some, symptoms may not manifest until adulthood. The classic feature of all three groups is exercise intolerance, but myalgias, cramping, and myoglobinuria may also occur with activity. Symptoms usually resolve after short periods of rest. Disorders of carbohydrate metabolism typically present with early fatigue during high-intensity activity, such

Myopathies and the Parturient

as sprinting. In contrast, disorders of lipid metabolism usually present with fatigue after prolonged exercise or periods of fasting. Severe and premature fatigue out of proportion to the activity level are characteristic of mitochondrial disorders. There are three main categories of metabolic myopathies based on etiology:55 1. Glycogen storage disorders 2. Fatty acid oxidation disorders 3. Mitochondrial respiratory chain defects

Glycogen Storage Disorders There are 14 described glycogenoses, with types II (Pompe), V (McArdle), and VII (Tarui) associated with myopathy55,56 (Table 10.4). These diseases of carbohydrate metabolism include defects of enzymes involved in glucose storage, glucose degradation, or breakdown of glycogen.

Type II (Pompe) Disease Type II (Pompe) disease results from a genetic defect in acid maltase that impairs the ability to break down glycogen for energy.55,56 The build-up of glycogen can affect various tissues, including muscle, liver, and heart. Slowly progressive muscle weakness is the predominant symptom in contrast to the exercise intolerance that characterizes other glycogen storage disorders. Respiratory and proximal muscles are particularly affected, with diaphragmatic weakness occurring early in the disease. The severity of symptoms is inversely proportional to the onset. Lethal cardiomyopathy is common with infantileonset, yet cardiac involvement is notably absent in the disease’s

juvenile and adult-onset forms. Alternatively, respiratory complications are the primary cause of death for adult patients. The course of the disease dramatically improves with enzyme replacement therapy. Obstetric Considerations: Pompe Disease Most of the available obstetric data come from case series and reports of women with late adult-onset Pompe disease, where many pregnancies and deliveries occurred before receiving their diagnosis.57,58 Apart from an increased rate of stillbirth (3.8%), preterm birth rates, mode of delivery, and obstetric complications were consistent with the general population.58 Obstetric outcomes did not differ in the few cases involving symptomatic women, but there are reports of respiratory decline.57,59,60 Overall, pregnancy is generally considered safe in Pompe disease.61 The favorable outcomes in reported cases have even prompted some authors to recommend against routine elective CD for women with Pompe disease.60 Anesthetic Considerations: Pompe Disease62–64 Neuraxial anesthesia is the preferred analgesic and anesthetic for parturients with Pompe disease. Systemic administration of opioids may worsen hypoventilation, so utilize multimodal and regional techniques. Should GA be warranted, consider reducing doses of nondepolarizing muscle relaxants. Although there are no reported cases of lethal hyperkalemia, avoid succinylcholine due to the potential for rhabdomyolysis with fasciculations.

Type V (McArdle) Disease Type V (McArdle) disease is an autosomal recessive disorder resulting in a genetic defect in glycogen phosphorylase, which

Table 10.4  Glycogen storage disorders associated with myopathy Disease

Genetic defect

Muscular involvement

Respiratory involvement

Cardiovascular involvement

Pompe Disease (type II)

AR deficiency of acid maltase enzyme (acid alpha-glucosidase) prevents the proper breakdown of glycogen

Slowly progressive weakness of proximal muscle groups

Diaphragmatic involvement is often affected early and may precede skeletal muscle involvement. Respiratory complications are the primary cause of death in this population

Rare in surviving adults

Cori-Forbes Disease (type III)

AR abnormalities of glycogendebranching enzyme lead to accumulation of abnormal glycogen, particularly in the liver and muscle (skeletal and cardiac)

Subtype IIIa is characterized by progressive muscle weakness and atrophy of the distal limbs.

Respiratory weakness may lead to frequent infections

Cardiomyopathy is often present in subtype IIIa

Anderson Disease (type IV)

AR deficiency of glycogenbranching enzyme leads to accumulation of abnormal glycogen in the liver, muscle, and heart tissues.

Surviving adults generally have an isolated neuromuscular variant characterized by muscle cramps, weakness, fatigue, and atrophy

Rare

Dilated cardiomyopathy can be present

McArdle Disease (type V)

AR genetic defect of glycogen phosphorylase prevents the breakdown of glycogen

Exercise intolerance with cramps, pain, and weakness. May experience a “second wind” after a brief rest. Intake of exogenous glucose will improve symptoms. Serum CK is elevated at baseline. Propensity for rhabdomyolysis and myoglobinuria during periods of ischemia, such as intense exercise, tourniquets, or shivering.

Rare

Rare

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Table 10.4  (Cont.) Disease

Genetic defect

Muscular involvement

Respiratory involvement

Cardiovascular involvement

Tarui Disease (type VII)

AR mutation of phosphofructokinase inhibits glycolysis

Similar symptoms to McArdle of exercise intolerance with weakness, myalgias, and myoglobinuria. Nausea/vomiting is common with activity. In contrast to McArdle, exogenous glucose or carbohydrates exacerbates symptoms

Rare

Rare

Phosphoglycerate Mutase Deficiency (type X)

AR deficiency of phosphoglycerate mutase interrupts glycolysis and the ability to use glucose for energy

Type 2 primarily affects muscle tissue with exercise-induced cramps, weakness, and myoglobinuria. Usually not progressive or associated with weakness

Rare

Rare

Lactate Dehydrogenase Deficiency (type XI)

AR defect in lactate dehydrogenase prevents conversion of lactate to pyruvate to sustain energy during anaerobic activity

Type A is associated with exercise intolerance and cramping. Muscle breakdown with myoglobinuria occurs with high-intensity activity

Rare

Although type B primarily affects cardiac muscle, there appears to be no clinical significance

Aldolase A Deficiency (type XII)

AR defect in glucose metabolism results in primarily hemolytic anemia, but is also associated with myopathy

Muscle fatigue and fatal rhabdomyolysis has been reported with activity and febrile illness

Rare

Rare

ß-enolase Deficiency (type XIII)

AR defect in glycolysis

Strength and muscle bulk is normal. Early fatiguability and myopathy progressively worsen with age. Episodic rhabdomyolysis

Rare

Rare

Abbreviations: autosomal dominant, AD; autosomal recessive, AR; creatinine kinase, CK

impairs the breakdown of glycogen in skeletal muscle.55 Patients with McArdle disease can endure moderate exercise, but strenuous activity leads to a quick onset of fatigue and cramping. Symptoms will resolve with rest and may allow a “second wind” phenomenon with better tolerance of intense exercise. However, continued activity through painful symptoms may result in muscle damage, myoglobinuria, rhabdomyolysis, and kidney failure. Obstetric Considerations: McArdle Disease McArdle disease does not appear to affect pregnancy and childbirth.65–68 During labor, monitor and continuously administer (IV) glucose, as exogenous supplementation bypasses the need to break down glycogen.65,67,69,70 Uterine contractions do not contribute to symptoms because smooth muscle phosphorylase functions normally. Patients are at the highest risk of myopathy during the second stage of labor. The authors of one case report describing postpartum rhabdomyolysis recommend limiting pushing to two hours in women with McArdle disease.71 Anesthetic Considerations: McArdle Disease Take care to avoid exposure to skeletal muscle ischemia, such as prolonged tourniquets, shivering, and improper positioning.69 While there is no association of McArdle disease with MH, intense fasciculations after administration of succinylcholine could theoretically cause ischemic myopathy and subsequent rhabdomyolysis. The advice is to use nondepolarizing muscle relaxants when possible.72,73

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Type VII (Tarui) Disease Type VII (Tarui) disease is characterized by a mutation in phosphofructokinase (PFK), thereby inhibiting glycolysis. It is inherited in an autosomal recessive pattern and is more common in those of Japanese and Ashkenazi descent. Patients experience symptoms similar to McArdle disease, such as myalgias, stiffness, cramping, and myoglobinuria with intense activity. Nausea and vomiting may occur with exercise. Impaired activity of PFK in erythrocytes results in anemia and jaundice. Hyperuricemia may result from kidney damage due to frequent myoglobinuria. In contrast to McArdle disease, patients with Tarui disease are unable to use glucose, so intake of carbohydrates and exogenous glucose will worsen symptoms.70 Obstetric and Anesthetic Considerations: Tarui Disease There is a paucity of data regarding the obstetric and anesthetic implications of Tarui disease.72 Precautions similar to those above are likely warranted to prevent muscle ischemia. However, in contrast to the approach with McArdle patients, exogenous glucose supplementation is contraindicated.

Lipid Metabolism Disorders Fatty acid oxidation is an essential energy source for muscles during prolonged exercise, stress, or fasting (Table 10.5). In settings of inadequate glucose, patients with deficiencies in lipid metabolism are at risk for myopathy and rhabdomyolysis.55 Acute symptoms of myalgias, cramping, and myoglobinuria resolve with time, leaving the patient asymptomatic between

Myopathies and the Parturient

Table 10.5  Lipid metabolism disorders associated with myopathy Disease

Genetic Defect

Muscular Involvement

Respiratory Involvement

Cardiovascular Involvement

Carnitine Palmitoyltransferase II (CPT II) Deficiency

AR defects in CPT II inhibit the transport of long chain fatty acids into the mitochondria

The adult-onset form is most common and is predominately defined by myopathic symptoms Myalgias, cramping, and rhabdomyolysis with prolonged exercise and fasting. Most are asymptomatic between attacks, but progressive muscle weakness may occur if lipid accumulates in the muscle tissue

Rare in adult onset

Rare in adult onset

Trifunctional Protein Deficiency (TFP)

AR defects in the TFP inhibit the metabolism of long chain fatty acids

Late adult onset is characterized predominately by skeletal myopathy Peripheral neuropathy is common. Episodic myopathy, myalgias, and rhabdomyolysis with prolonged activity and fasting. High carbohydrate diets can improve symptoms

Common

Rare in adult onset

Very Long Chain Acyl-coenzyme-A Dehydrogenase Deficiency (VLCAD)

AR deficiency in VLCAD prevents the breakdown of very long chain fatty acids into consumable energy

The later onset myopathic form is the most common phenotype. It is associated with muscle pain, myoglobinuria, and rhabdomyolysis during fasting, illness, and exercise

Rare

Dilated or hypertrophic cardiomyopathy may be present, but it is not common in the myopathic phenotype

Carnitine Deficiency

AR genetic mutations alter the activity of the Organic Cation/ Carnitine Transporter 2, which is responsible for transferring carnitine across the plasma membrane into the cytoplasm

Variable presentations of myopathy. Proximal muscle weakness and neck/jaw muscles may also be affected

Rare

Cardiomyopathy and heart failure are common

Neutral Lipid Storage Disorder

AR enzymatic errors that cause excessive accumulation of triglycerides in various tissues such as skeletal muscle, heart, liver, and pancreas

Muscle atrophy, preferentially proximal, often asymmetric R>L

Respiratory and bulbar muscles are generally spared

Cardiomyopathy and heart failure are common

Phosphatidic Acid Phosphatase Deficiency

AR Lipin 1 mutations increase autophagy. The most common cause of recurrent rhabdomyolysis in childhood

Episodic rhabdomyolysis associated with fasting, exercise, and febrile illness. Weakness is uncommon, as patients are asymptomatic between crises

Rare

Cardiomyopathy is common

Carnitine-Acylcarnitine Translocase (CACT) Deficiency

AR defects in the carnitine/ acylcarnitine transporter impairs the import of long-chain fatty acids into the mitochondria. Patients experience hypoglycemia, hyperammonemia, hepatomegaly, muscle weakness, and cardiomyopathy

Later onset phenotypes are milder and more associated with muscle weakness when fasting or febrile

Apnea results in high neonatal mortality. Rare in surviving adults

Cardiomyopathy and dysrhythmias are common

Acyl-CoA Dehyrodgenase 9 (ACAD 9) Deficiency

AR defects of the ACAD 9 enzyme prevents proper metabolism of long-chain fatty acids. Cells that require the most energy are particularly affected, resulting in myopathy, cardiomyopathy, and intellectual disability

Nausea and exercise intolerance due to build-up of lactic acid during activity. Muscle weakness and hypotonia

Rare

Cardiomyopathy is common in severely affected individuals

Medium Chain AcylCoA Dehydrogenase Deficiency

AR most frequent disorder of fatty acid oxidation. Disrupts the ability to metabolize medium chain fatty acids. Results in metabolic crises of hypoglycemia

Weakness is less common than other lipid metabolism disorders. Fatigue and muscle pain with activity. Rhabdomyolysis with exercise and alcohol have been reported

Rare

Rare

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Britany L. Raymond and Jeanette R. Bauchat

Table 10.5  (Cont.) Disease

Genetic Defect

Muscular Involvement

Respiratory Involvement

Cardiovascular Involvement

Short Chain AcylCoA Dehydrogenase Deficiency

AR impairment in the ability to metabolize short chain fatty acids results in accumulation of fatty acids and ammonia in the body

Symptoms are variable, but a late onset phenotype is associated with progressive myopathy

Rare

Rare

Multiple Acyl-CoA Dehydrogenase Deficiency

AR defect in a flavoprotein transporter that transfers electrons to the respiratory chain

The late onset phenotype presents with exertional rhabdomyolysis and proximal myopathy. Myasthenia-type symptoms have also been reported

Rare

Cardiomyopathy and sudden death have been reported in the late onset phenotype

Abbreviations: AR: autosomal recessive; R: right; L: left.

attacks. Progressive muscle weakness may occur, however, as lipid accumulates in the skeletal muscle. Carnitine palmitoyltransferase II deficiency (CPT II) and two types of fatty acid oxidation disorders – trifunctional protein deficiency (TFP) and very long chain acyl-CoA dehydrogenase deficiency (VLCAD) – are the most common disorders of lipid metabolism associated with myopathy.

Patients diagnosed with MH, based upon anesthetic history, were later confirmed to have CPT deficiency.82 Nevertheless, the existence of several older case reports of CPT deficient patients experiencing MH symptoms under anesthesia prompted the Malignant Hyperthermia Association of the United States (MHAUS) to advise against using triggering anesthetics in this population.77,83–85

CPT II Deficiency

Fatty Acid Oxidation Disorders

The CPT II protein transports long-chain fatty acids into mitochondria for metabolism. Infantile presentation of symptoms is usually severe, involving multiple organ dysfunction and sudden death. However, the later adult-onset form of CPT II deficiency disease is more common and milder with predominately myopathic symptoms. Obstetric Considerations Increased metabolic demands of pregnancy can exacerbate the frequency of hypoglycemia.56 The biggest increase in carbohydrate requirements occurs during the first trimester.74 Patients with CPT II deficiency must eat frequent high carbohydrate meals to reduce the reliance on fat metabolism for energy. The stress of labor can precipitate rhabdomyolysis in patients with CPT II deficiency, as serum creatinine kinase (CK) levels are elevated postpartum, even in normal parturients. Monitor baseline and postpartum CK levels. The recommendation is to provide IV glucose continuously peripartum to avoid hypoglycemia. While available reports are limited, it appears that the progress of pregnancy is unaffected, and CD is only used for obstetric reasons.75–78 Anesthetic Considerations Early NA blunts the neuroendocrine response to pain, reducing the risk of developing rhabdomyolysis. As with most CD, NA is preferred. Exposure to propofol remains controversial. Patients with CPT deficiency may be susceptible to propofol-related infusion syndrome (PRIS), which is also characterized by disruption of fatty acid oxidation in the mitochondria.79 Data are limited, but there are reports of safe short exposures to propofol in related fatty acid oxidation disorders.80,81 Although CPT deficiency is unlikely to predispose patients to MH, the similarities to rhabdomyolysis under GA make diagnosis difficult.

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After transportation into the mitochondria, fatty acids undergo beta-oxidation metabolism.55 Defects in the enzymes involved in this process encompass a group of disorders known as fatty acid oxidation disorders (FAOD), the most common of which are TFP and VLCAD.86 The inability to metabolize fatty acids leads to their accumulation in organs, causing hepatomegaly, cardiomyopathy, and skeletal muscle myopathy. As with most metabolic myopathies, degree of severity correlates with age of onset of symptoms. The later adult-onset subtypes are predominately myopathic, presenting with prolonged exercise intolerance and rhabdomyolysis. Fasting and activity provoke episodic myopathy, weakness, and myoglobinuria. A high carbohydrate diet and supplementation with medium-chain fatty acids help avoid hypoglycemia and metabolic crises. Obstetric Considerations Interestingly, the placenta contains an unusually high expression of VLCAD enzymes, which may prove beneficial for deficient parturients.87,88 Although data are limited, one patient with VLCAD deficiency had complete resolution of her symptoms during pregnancy, which returned 2 months postpartum.89 Unfortunately, the converse relationship is detrimental, as fetal disorders of FAO negatively impact the obstetric course of a normal mother, including increased incidence of acute fatty liver and HELLP.90 Obstetric management of parturients with VLCAD deficiency includes strategies to avoid maternal exhaustion and hypoglycemia, which could prompt rhabdomyolysis. Vaginal delivery is preferred, with some authors advocating for assisted second stage of labor.89,91 Parturients should consume light carbohydrate snacks and juices, supplemented with IV dextrose solutions.89,91

Myopathies and the Parturient

Anesthetic Considerations As with other metabolic myopathies, early NA is highly encouraged to reduce the metabolic response to pain and stress. In one case report, serum CK-MB and urine myoglobin were assessed every 8 hours because of the concern that the epidural might mask subjective muscle weakness. Special considerations are imperative for patients undergoing GA. Since fasting is discouraged, the patient may have an elevated risk of aspiration. Avoid ketamine due to its sympathetic stimulation and release of endogenous catecholamines.92 There are reports of brief, safe exposures to propofol for patients with FAOD; however, avoid prolonged infusions because of the high concentrations of longchain fatty acids in its formulation.80,81 Volatile agents are safe, as concerns for rhabdomyolysis and susceptibility to MH are unfounded in this population.92 However, fasciculations due to succinylcholine administration can induce myopathy.

Mitochondrial Myopathies Mitochondrial myopathies are a group of maternally inherited disorders of oxidative phosphorylation and reduced generation of ATP.55 Tissues that consume higher amounts of energy, such as skeletal muscle, brain, and heart, are most impacted.93 In contrast to the exercise intolerance of other metabolic myopathies, mitochondrial myopathies are characterized by progressive muscle weakness. Other associated symptoms include diabetes, deafness, GI dysfunction, cardiomyopathy, and conduction disorders. While some genetic abnormalities are part of a syndrome, many mutations remain unclassified and present with a spectrum of symptom severity. Some common mitochondrial syndromes include progressive external ophthalmoplegia (PEO), mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS), myoclonus epilepsy with ragged-red fibers (MERRF), and Kearns-Sayre syndrome.

Obstetric Considerations Data are limited, but symptoms associated with mitochondrial myopathy in pregnancy appear well tolerated;56,94 however, exacerbations of proximal weakness and autonomic dysfunction have been reported.94,95 While rates of vaginal and CD are consistent with the general population,94 women with mitochondrial myopathies experience increased rates of miscarriage, gestational diabetes, and PreE.93,96 Carefully consider magnesium therapy for PreE, as magnesium interferes with mitochondrial oxidative phosphorylation.93 There are several reports of magnesium toxicity in women with mitochondrial disorders treated for PreE.93,97,98

Anesthetic Considerations Patients benefit from effective labor analgesia to limit oxygen consumption and acidosis.99 There is no increased risk of neurologic complications with NA in these patients, but placement may be challenging because of scoliosis and short stature.100 In addition to closely monitoring acid-base status and electrolytes, administer IV fluids judiciously, given the increased risk of pulmonary edema.100 Because some patients are unable to metabolize lactate effectively, avoid lactated ringers.101,102 The

most common complications of GA include hyperkalemia, hyponatremia, and renal dysfunction.103 A relationship between MH and mitochondrial disorders has not been confirmed, and MHAUS does not endorse avoiding volatile anesthetics.85 However, use succinylcholine with caution in myopathy because of the risk of hyperkalemia.104

Disorders Of Muscle Membrane Excitability The skeletal muscle membrane (sarcolemma) is a barrier to movement of ions in and out of the cell.105 At rest, the intracellular potassium concentration is high relative to the extracellular compartment. Conversely, sodium, calcium, and chloride ions are most prevalent extracellularly. Ions move down their concentration gradients across the membrane through ion channels, altering the membrane potential and ultimately propagating action potentials. Disruptions or mutations of these channels are pathophysiologically relevant for certain myopathic diseases (Table 10.6).

Chloride Channel Disorders Unlike nerve cells that are reliant upon potassium permeability, the skeletal muscle resting potential is determined predominately by conduction of chloride ions. After depolarization, a large influx of negatively charged chloride ions begins repolarization and prevents continued action potentials. Therefore, genetic disruptions of these chloride channels can result in hyperexcitability of the sarcolemma, especially immediately after depolarization and contraction. Myotonia congenita is a disease of disrupted chloride channels in the sarcolemma.105–107 Two forms exist, Thomsen disease (autosomal dominant inheritance) and Becker-type myotonia (recessive inheritance). The classic presentation includes painless myotonic contractions resulting in stiffness and sustained contraction after a patient initiates movement, particularly after rest (e.g., getting out of a chair). The stiffness subsides with continued activity. Patients with the recessive Becker-type myotonia will also experience generalized, flaccid weakness following myotonic attacks, not present in the dominant form. The frequent myotonic contractions can result in hypertrophy of the facial and proximal limb muscles, leading to the characteristic “Herculean” appearance. Mild, progressive weakness with wasting of distal muscle may also occur throughout life.

Sodium Channel Disorders The sarcolemma’s voltage-gated sodium channels begin to immediately close upon opening, resulting in a brief influx of sodium that produces a succinct depolarization event.106 With sodium channel myopathies, prolonged depolarization leads to muscle stiffness and weakness. In contrast to the painless myotonia of chloride disorders, patients with disruptions of sodium channels often experience painful stiffness and spasms, with or without weakness. As with most disorders, there is variable severity and symptoms, but considerable overlap exists. There are three categories of sodium channel myopathies: potassium-aggravated, paramyotonia, and hyperkalemic periodic paralysis.105–107

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Britany L. Raymond and Jeanette R. Bauchat

Table 10.6  Disorders of membrane excitability Thomsen Disease (myotonia congenita)

Becker Disease (myotonia congenita)

Paramyotonia Congenita

Hyperkalemic Periodic Paralysis

Hypokalemic Periodic Paralysis

Channelopathy

Chloride

Chloride

Sodium

Sodium

Sodium or Calcium

Genetics

AD

AR

AD

AD

AD

Clinical symptoms

Myotonia when initiating movement

Myotonia and transient weakness when initiating movement

Myotonia and episodic weakness during activity

Episodic weakness

Episodic weakness

Distribution

Upper > Lower limbs (Herculean appearance)

Lower > Upper limbs (Herculean appearance)

Bulbar, facial, neck, proximal muscles

Generalized

Generalized

Triggering factors

Cold, inactivity

Cold, inactivity

Cold, fasting, exercise

Cold, fasting, potassium ingestion, inactivity

Cold, carbohydrates, inactivity

Anesthetic considerations

For ALL channelopathies: • Maintain strict normothermia – consider active warming of IV fluid and environments • Avoid shivering, which can precipitate myotonic crises – consider pharmacologic intervention (e.g., meperidine, clonidine, etc.) • Succinylcholine is contraindicated as it can provoke severe myotonic crises Target normokalemia; frequent lab draws may be necessary for monitoring, consider continuous ECG in the peripartum period Encourage carbohydrate loading and avoid prolonged fasting Respiratory depression can lead to acidosis and provoke hyperkalemia

a. Potassium Aggravated: fluctuating (myotonia fluctuans) or persistent (myotonia permanens) symptoms of painful myotonia. Onset is usually delayed but most prominent after exercise. Weakness is not typically present. b. Paramyotonia: an autosomal dominant disorder characterized by muscle stiffness and weakness aggravated by exercise and cold exposure. Weakness may persist for hours or days following an attack. Bulbar, facial, and neck muscles are primarily affected. c. Hyperkalemic Periodic Paralysis (HyperPP): hyperkalemic episodes will provoke profound weakness of skeletal muscles, particularly after periods of rest following activity. Stress, fasting, and cold will trigger attacks. Ingestion of carbohydrates or engaging in activity may shorten and decrease the frequency of episodes. Additionally, medications that lower potassium (e.g., inhaled betaagonists, thiazide diuretics) can effectively prevent attacks.108 Systemic and cardiac manifestations are rare, as elevation in potassium levels are generally mild. d. Hypokalemic Periodic Paralysis, Type II: discussed below.

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Treat as though susceptible to MH, avoid known triggers Avoid large glucose and salt loads Hyperventilation and alkalosis can provoke hypokalemia. Treat anxiety and consider permissive hypercapnia intraoperatively Caution with medications known to decrease potassium (epinephrine, insulin, beta agonists) Oral repletion of potassium is preferred over IV

Calcium Channel Disorders Hypokalemic periodic paralysis (HypoPP) is an autosomal dominant disorder expressed through mutations of either the calcium (type I) or sodium channel (type II).105 The two phenotypes are virtually indistinguishable and likely linked, given the relationship between calcium and the expression of sodium channels on muscle membranes.109 Many patients with HypoPP are asymptomatic until adulthood and could present in pregnancy without a formal diagnosis.105,106 Episodic hypokalemia, generalized weakness, and hyporeflexia which may last for hours or days are characteristic of HypoPP. Similar to HyperPP, episodes generally occur after prolonged periods of rest following strenuous activity. These attacks are provoked by stress, carbohydrates, and cold temperatures. Patients should avoid triggers, and maintenance therapy with acetazolamide or carbonic anhydrase inhibitors can reduce the frequency of episodes.108 Should hypokalemia require treatment, oral potassium chloride is the preferred route for repletion because additives in the intravenous solutions may worsen symptoms in this population.105

Myopathies and the Parturient

Obstetric and Anesthetic Considerations: Membrane Excitability Myopathy Fluctuations in hormones during menstruation impact symptoms associated with channelopathies.110 This relationship is the proposed mechanism for the worsening of stiffness and myotonia experienced during pregnancy.107,111–113 Patients with sodium channel defects appear to be the most affected, with reports of worsened symptoms in up to 95% of patients.112 In contrast, parturients with calcium channelopathies (HypoPP) may be the least affected by a pregnancy, with 50% of patients reporting escalation of symptoms.112 Fortunately, patients often experience a rapid return to baseline status following delivery.112 There is no evidence that patients with channelopathies are at increased risk for obstetric complications.111,112 Therefore, unassisted vaginal delivery remains preferred, although stiffness or myotonia may affect patient positioning during the second stage of labor.107,111 Some common peripartum medications, such as beta-agonists and epinephrine, should be used with caution in myotonia congenita.107 Additionally, magnesium therapy may exacerbate preexisting weakness.107 Consider active warming of IV fluid and environments as cold temperature and shivering are known triggers to induce myotonic crises.106,107,112 Providers should aim for normokalemia and tailor strategies based upon the desired goal. For example, since the sodium channelopathies are sensitive to hyperkalemia, carbohydrate loading and avoidance of fasting can be helpful to lower potassium and prevent attacks.106,107 In contrast, large loads of glucose or salt may contribute to hypokalemia and provoke episodes of weakness in HypoPP.106,107 The physiologic stress of labor can precipitate attacks, so the recommendation is for early NA for all channelopathies.107,111 If GA is warranted, succinylcholine should not be used in order to avoid severe masseter spasm and myotonic crises, interfering with ventilation.114–116 Unfortunately, depolarizing and nondepolarizing muscle relaxants will not break the myotonic crisis, as the channel defects resulting in contraction occur downstream.106 There is no relationship between MH and the channelopathies of chloride and sodium.117 However, it cannot be excluded for patients with HypoPP, a calcium channelopathy, as genetic overlap may exist with the ryanodine receptors that release calcium from the sarcoplasmic reticulum. Until further evidence is available, the advice is to avoid triggering anesthetics in this population.106,112

Idiopathic Inflammatory Myopathies Idiopathic inflammatory myopathies (IIM) are an autoimmune response to defined or undefined muscle antigens leading to symmetrical proximal muscle weakness and rise in creatinine kinase as muscle is damaged.118–120 The degree of distal muscle weakness varies by IIM type. These idiopathic inflammatory myopathies are now reclassified based on serology testing and include dermatomyositis, inclusion body myositis, immunemediated necrotizing myopathy, and antisynthetase syndrome.119 Most IIM are treated initially with glucocorticoid therapy but agents such as chronic steroid-sparing immunosuppressive

drugs (methotrexate, azathioprine, cyclosporine), rituximab, and immunoglobulins are also used.120 “Polymyositis” will likely be discontinued as a diagnosis since patients diagnosed with this disease fall into one of two IIM subgroups, immune-mediated necrotizing myopathy or antisynthetase syndrome.119 Proximal muscle weakness manifests as difficulty with rising from a chair, climbing steps, or lifting objects.120 Tasks requiring fine motor skills, such as buttoning or holding objects, vary by disease but are typically involved late in dermatomyositis, immune-mediated necrotizing myositis, and antisynthetase syndrome but early in inclusion-body myositis. Neck-extensor and pharyngeal muscles can be involved in all subtypes. Cardiac involvement is uncommon, but pulmonary complications occur 10% to 40% of the time due mainly to interstitial lung disease. Different antibodies characterize IIM, but the antibodies antiARS and anti-MDA5 are associated most with myositis-related interstitial lung disease.121,122 Fever, arthralgias, and Raynaud syndrome can manifest in all but inclusion-body myositis.

Pregnancy and Anesthetic Considerations Like other autoimmune diseases, women with IIM have a higher risk of CD, a three-fold risk of preterm birth, and a six-fold risk of low birth weight than women without IIM.123 These results may be skewed as the study population was pregnant women with active disease who required hospital admission for their disease. One study examining both dermatomyositis and “polymyositis” together demonstrated an increased risk of hypertension during pregnancy, which may contribute to the increased risk of CD, preterm birth, and low birth weight.124 Consider NA for all laboring patients with IIM to reduce the stress of labor and avoid GA in emergencies. If GA becomes necessary, careful monitoring of neuromuscular blockade is essential. Avoid succinylcholine since immobilized muscle may act as denervated muscle resulting in hyperkalemia.125 One case report notes slow onset of rocuronium with slow recovery and slow reversal with sugammadex, perhaps due to inflammation at the neuromuscular junction impeding drug diffusion.126,127 Patients with underlying interstitial lung disease should have PFT before delivery and discuss respiratory reserve and mode of delivery with the pulmonologist and obstetrician.122 Because of higher CD rates, a discussion with an anesthesiologist should center on the potential for GA and subsequent risks of pulmonary complications, based on the severity of interstitial lung disease or presence of dysphagia.

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23. Bauchat JR, Weiniger CF, Sultan P, et al. Society for Obstetric Anesthesia and Perinatology Consensus Statement: Monitoring Recommendations for Prevention and Detection of Respiratory Depression Associated with Administration of Neuraxial Morphine for Cesarean Delivery Analgesia. Anesth Analg 2019;129:458–474. 24. Ogawa K, Iranami H, Yoshiyama T, et al. Severe respiratory depression after epidural morphine in a patient with myotonic dystrophy. Can J Anaesth 1993;40:968–970. 25. McNally EM, Mann DL, Pinto Y, et al. Clinical care recommendations for cardiologists treating adults with myotonic dystrophy. J Am Heart Assoc 2020;9:e014006. 26. Practice Advisory for the Perioperative Management of Patients with Cardiac Implantable Electronic Devices: Pacemakers and Implantable Cardioverter-Defibrillators 2020: An Updated Report by the American Society of Anesthesiologists Task Force on Perioperative Management of Patients with Cardiac Implantable Electronic Devices: Erratum. Anesthesiology 2020;132:938. 27. Wagner KR. Facioscapulohumeral muscular dystrophies. Continuum (Minneap Minn) 2019;25:1662–1681. 28. Vincenten SCC, Van Der Stoep N, Paulussen ADC, et al. Facioscapulohumeral muscular dystrophy: reproductive counseling, pregnancy, and delivery in a complex multigenetic disease. Clin Genet 2021 (online). https://doi.org/10.1111/ cge.14031 29. Moris G, Wood L, FernaNdez-Torro, et al. Chronic pain has a strong impact on quality of life in facioscapulohumeral muscular dystrophy. Muscle Nerve 2018;57:380–387. 30. Wohlgemuth M, Horlings CGC, van der Kooi EL, et al. Respiratory function in facioscapulohumeral muscular dystrophy 1. Neuromuscul Disord 2017;27:526–530. 31. Tawil R, Padberg GW, Shaw DW, et al. FSHD Workshop Participants. Clinical trial preparedness in facioscapulohumeral muscular dystrophy: clinical, tissue, and imaging outcome measures 29–30 May 2015, Rochester, New York. Neuromuscul Disord 2016;26:181–186. 32. LoRusso S, Johnson NE, McDermott MP, et al. Clinical trial readiness to solve barriers to drug development in FSHD (ReSolve): protocol of a large, international, multi-center prospective study. BMC Neurol 2019;19:224. https://doi .org/10.1186//s12883-019-1452-x 33. Rudnik-Schoneborn S, Glauner B, Rohrig D, et al. Obstetric aspects in women with facioscapulohumeral muscular dystrophy, limb-girdle muscular dystrophy, and congenital myopathies. Arch Neurol 1997;54:888–894. 34. Ciafaloni E, Pressman EK, Loi AM, et al. Pregnancy and birth outcomes in women with facioscapulohumeral muscular dystrophy. Neurology 2006;67:1887–1889. 35. van Dijk GP, van der Kooi E, Behin A, et al. High prevalence of incomplete right bundle branch block in facioscapulohumeral muscular dystrophy without cardiac symptoms. Funct Neurol 2014;29:159–165. 36. Mah JK, Korngut L, Dykeman J, et al. A systematic review and meta-analysis on the epidemiology of Duchenne and Becker muscular dystrophy. Neuromuscul Disord 2014;24:482–491. 37. Flanigan KM. Duchenne and Becker muscular dystrophies. Neurol Clin 2014;32:671–688, viii. 38. Hoogerwaard EM, Bakker E, Ippel PF, et al. Signs and symptoms of Duchenne muscular dystrophy and Becker muscular dystrophy among carriers in The Netherlands: a cohort study. Lancet 1999;353:2116–2119.

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39. Ishizaki M, Kobayashi M, Adachi K, et al. Female dystrophinopathy: review of current literature. Neuromuscul Disord 2018;28:572–581. 40. Politano L, Nigro V, Nigro G, et al. Development of cardiomyopathy in female carriers of Duchenne and Becker muscular dystrophies. JAMA 1996;275:1335–1338. 41. Mah ML, Cripe L, Slawinski MK, et al. Duchenne and Becker muscular dystrophy carriers: evidence of cardiomyopathy by exercise and cardiac MRI testing. Int J Cardiol 2020;316:257–265. 42. Geifman-Holtzman O, Bernstein IM, Capeless EL, et al. Increase in fetal breech presentation in female carriers of Duchenne muscular dystrophy. Am J Med Genet 1997;73:276–278. 43. Grimm MJ. Forces involved with labor and delivery: a biomechanical perspective. Ann Biomed Eng 2021;49:1819–1835. 44. Georganopoulou DG, Moisiadis VG, Malik FA, et al. A journey with LGMD: from protein abnormalities to patient impact. Protein J 2021;40:466–488. 45. Libell EM, Bowdler NC, Stephan CM, et al. The outcomes and experience of pregnancy in limb girdle muscular dystrophy type R9. Muscle Nerve 2021;63:812–817. 46. Heller SA, Shih R, Kalra R, et al. Emery-Dreifuss muscular dystrophy. Muscle Nerve 2020;61:436–448. 47. Papadimas GK, Xirou S, Kararizou E, et al. Update on congenital myopathies in adulthood. Int J Mol Sci 2020;21(10):3694. https:// doi.org/10.3390/ijms21103694 48. Claeys KG. Congenital myopathies: an update. Dev Med Child Neurol 2020;62:297–302. 49. Rudnik-Schoneborn S, Wallgren-Pettersson C. Pregnancy and delivery in women with congenital myopathies. Semin Pediatr Neurol 2019;29:23–29. 50. Saito O, Yamamoto T, Mizuno Y. Epidural anesthetic management using ropivacaine in a parturient with multi-minicore disease and susceptibility to malignant hyperthermia. J Anesth 2007;21:113. 51. Halpern SH, Breen TW, Campbell DC, et al. A multicenter, randomized, controlled trial comparing bupivacaine with ropivacaine for labor analgesia. Anesthesiology 2003;98: 1431–1435. 52. Jungbluth H. Central core disease. Orphanet J Rare Dis 2007;2:25. 53. Brislin RP, Theroux MC. Core myopathies and malignant hyperthermia susceptibility: a review. Paediatr Anaesth 2013;23:834–841. 54. Wang CH, Dowling JJ, North K, et al. Consensus statement on standard of care for congenital myopathies. J Child Neurol 2012;27:363–382. 55. Berardo A, DiMauro S, Hirano M. A diagnostic algorithm for metabolic myopathies. Curr Neurol Neurosci Rep 2010;10:118– 126. 56. Wilcox G. Impact of pregnancy on inborn errors of metabolism. Rev Endocr Metab Disord 2018;19:13–33. 57. Karabul N, Berndt J, Kornblum C, et al. Pregnancy and delivery in women with Pompe disease. Mol Genet Metab 2014;112:148–153. 58. Goker-Alpan O, Kasturi VG, Sohi MK, et al. Pregnancy outcomes in late onset Pompe disease. Life (Basel) 2020;10(9):194. https:// doi.org/10.3390/life10090194 59. Weida J, Hainline BE, Bodkin C, et al. Management of a pregnancy complicated by Pompe disease. Case Rep Obstet Gynecol 2012;2012:137861. https://doi.org/10.1155/2012/137861 60. Rohman PJ, Scott E, Richfield L, et al. Pregnancy and associated events in women receiving enzyme replacement therapy for

late-onset glycogen storage disease type II (Pompe disease). J Obstet Gynaecol Res 2016;42:1263–1671. 61. Plockinger U, Tiling N, Bosanska L, et al. Multiple, successful pregnancies in Pompe disease. JIMD Rep 2016;28:111–118. 62. Puthenveettil N, Issac JS, Kadapamannil D, et al. Anaesthetic management of caesarean section in a patient with Pompe disease. Indian J Anaesth 2021;65:418–420. 63. Dons-Sinke IJ, Dirckx M, Scoones GP. Anaesthetic management of two patients with Pompe disease for caesarean section. Case Rep Anesthesiol 2014;2014:650310. 64. Cilliers HJ, Yeo ST, Salmon NP. Anaesthetic management of an obstetric patient with Pompe disease. Int J Obstet Anesth 2008;17:170–173. 65. Cochrane P, Alderman B. Normal pregnancy and successful delivery in myophosphorylase deficiency (McArdle’s disease). J Neurol Neurosurg Psychiatry 1973;36:225–227. 66. Giles W, Maher C. Myophosphorylase deficiency (McArdle disease) in a patient with normal pregnancy and normal pregnancy outcome. Obstet Med 2011;4:120–121. 67. Quinlivan R, Buckley J, James M, et al. McArdle disease: a clinical review. J Neurol Neurosurg Psychiatry 2010;81:1182–1188. 68. Stopp T, Feichtinger M, Eppel W, et al. Pre- and peripartal management of a woman with McArdle disease: a case report. Gynecol Endocrinol 2018;34:736–739. 69. Coleman P. McArdle’s disease. Problems of anaesthetic management for Caesarean section. Anaesthesia 1984;39: 784–787. 70. Heller S, Worona L, Consuelo A. Nutritional therapy for glycogen storage diseases. J Pediatr Gastroenterol Nutr 2008;47:S15–21. 71. McMillan BM, Hirshberg JS, Cosgrove SC. McArdle disease causing rhabdomyolysis following vaginal delivery. Anaesth Rep 2019;7:73–75. 72. Gurrieri C, Sprung J, Weingarten TN, et al. Patients with glycogen storage diseases undergoing anesthesia: a case series. BMC Anesthesiol 2017;17:134. 73. Bollig G, Mohr S, Raeder J. McArdle’s disease and anaesthesia: case reports. Review of potential problems and association with malignant hyperthermia. Acta Anaesthesiol Scand 2005;49:1077– 1083. 74. Martens DH, Rake JP, Schwarz M, et al. Pregnancies in glycogen storage disease type Ia. Am J Obstet Gynecol 2008;198:646 e1–7. 75. Dreval D, Bernstein D, Zakut H. Carnitine palmitoyl transferase deficiency in pregnancy: a case report. Am J Obstet Gynecol 1994;170:1390–1392. 76. Moundras JM, Wattrisse G, Leroy B, et al. Anesthetic management of obstetrical labor in a parturient with muscular carnitine palmitoyl transferase deficiency. Ann Fr Anesth Reanim 2000;19:611–616. 77. Lilker S, Kasodekar S, Goldszmidt E. Anesthetic management of a parturient with carnitine palmitoyltransferase II deficiency. Can J Anaesth 2006;53:482–486. 78. Ramsey PS, Biggio JR. Carnitine palmitoyltransferase deficiency in pregnancy. J Matern Fetal Neonatal Med 2005;18:357–359. 79. Wolf A, Weir P, Segar P, et al. Impaired fatty acid oxidation in propofol infusion syndrome. Lancet 2001;357:606–607. 80. Vellekoop P, Diekman EF, van Tuijl I, et al. Perioperative measures in very long chain acyl-CoA dehydrogenase deficiency. Mol Genet Metab 2011;103:96–97.

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81. Martin JM, Gillingham MB, Harding CO. Use of propofol for short duration procedures in children with long chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) or trifunctional protein (TFP) deficiencies. Mol Genet Metab 2014;112:139–142. 82. Cumming WJ, Hardy M, Hudgson P, et al. Carnitine-palmityltransferase deficiency. J Neurol Sci 1976;30:247–258. 83. Katsuya H, Misumi M, Ohtani Y, et al. Postanesthetic acute renal failure due to carnitine palmityl transferase deficiency. Anesthesiology 1988;68:945–948. 84. Slater PM, Grivell R, Cyna AM. Labour management of a woman with carnitine palmitoyl transferase type 2 deficiency. Anaesth Intensive Care 2009;37:305–308. 85. States MHAotU. Sherburne, NY: MHAUS; 2021. Available from: www.mhaus.org/ 86. Finsterer J. Update review about metabolic myopathies. Life (Basel) 2020;10(4):43. 87. Oey NA, den Boer ME, Ruiter JP, et al. High activity of fatty acid oxidation enzymes in human placenta: implications for fetalmaternal disease. J Inherit Metab Dis 2003;26:385–392. 88. Oey NA, Ruiter JP, Attie-Bitach T, et al. Fatty acid oxidation in the human fetus: implications for fetal and adult disease. J Inherit Metab Dis 2006;29:71–75. 89. Mendez-Figueroa H, Shchelochkov OA, Shaibani A, et al. Clinical and biochemical improvement of very long-chain acyl-CoA dehydrogenase deficiency in pregnancy. J Perinatol 2010;30: 558–562. 90. Ibdah JA, Yang Z, Bennett MJ. Liver disease in pregnancy and fetal fatty acid oxidation defects. Mol Genet Metab 2000;71:182– 189. 91. Yamamoto H, Tachibana D, Tajima G, et al. Successful management of pregnancy with very-long-chain acyl-coenzyme A dehydrogenase deficiency. J Obstet Gynaecol Res 2015;41: 1126–1128. 92. Redshaw C, Stewart C. Anesthetic agents in patients with very long-chain acyl-coenzyme A dehydrogenase deficiency: a literature review. Paediatr Anaesth 2014;24:1115–1119. 93. Say RE, Whittaker RG, Turnbull HE, et al. Mitochondrial disease in pregnancy: a systematic review. Obstet Med 2011;4:90–94. 94. Karaa A, Elsharkawi I, Clapp MA, et al. Effects of mitochondrial disease/dysfunction on pregnancy: a retrospective study. Mitochondrion 2019;46:214–220. 95. Kovilam OP, Cahill W, Siddiqi TA. Pregnancy with mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes syndrome. Obstet Gynecol 1999;93:853. 96. de Laat P, Fleuren LH, Bekker MN, et al. Obstetric complications in carriers of the m.3243A>G mutation, a retrospective cohort study on maternal and fetal outcome. Mitochondrion 2015;25: 98–103. 97. Moriarty KT, McFarland R, Whittaker R, et al. Pre-eclampsia and magnesium toxicity with therapeutic plasma level in a woman with m.3243A>G melas mutation. J Obstet Gynaecol 2008;28:349. 98. Hosono T, Suzuki M, Chiba Y. Contraindication of magnesium sulfate in a pregnancy complicated with late-onset diabetes mellitus and sensory deafness due to mitochondrial myopathy. J Matern Fetal Med 2001;10:355–356. 99. Maurtua M, Torres A, Ibarra V, et al. Anesthetic management of an obstetric patient with MELAS syndrome: case report and literature review. Int J Obstet Anesth 2008;17:370–373.

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100. Bell JD, Higgie K, Joshi M, et al. Anesthetic management of mitochondrial encephalopathy with lactic acidosis and strokelike episodes (MELAS Syndrome) in a high-risk pregnancy: a case report. A A Case Rep 2017;9:38–41. 101. Parikh S, Saneto R, Falk MJ, et al. A modern approach to the treatment of mitochondrial disease. Curr Treat Options Neurol 2009;11:414–430. 102. Niezgoda J, Morgan PG. Anesthetic considerations in patients with mitochondrial defects. Paediatr Anaesth 2013;23:785–793. 103. Gurrieri C, Kivela JE, Bojanic K, et al. Anesthetic considerations in mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes syndrome: a case series. Can J Anaesth 2011;58:751–763. 104. Chow SY, Woon KL. General anesthesia for adults with mitochondrial myopathy. A A Case Rep 2015;4:52–57. 105. Ruff RL, Shapiro BE. Disorders of skeletal muscle membrane excitability: myotonia congenita, paramyotonia congenita, periodic paralysis, and related syndromes. In Katirji B KH, Ruff R. (Eds.), Neuromuscular Disorders in Clinical Practice. New York, NY: Springer; 2014: 1149–1185. 106. Bandschapp O, Iaizzo PA. Pathophysiologic and anesthetic considerations for patients with myotonia congenita or periodic paralyses. Paediatr Anaesth 2013;23:824–833. 107. Morton A. Myotonic disorders and pregnancy. Obstet Med 2020;13:14–19. 108. Desaphy JF, Altamura C, Vicart S, et al. Targeted therapies for skeletal muscle ion channelopathies: systematic review and steps towards precision medicine. J Neuromuscul Dis 2021;8:357–381. 109. Offord J, Catterall WA. Electrical activity, cAMP, and cytosolic calcium regulate mRNA encoding sodium channel alpha subunits in rat muscle cells. Neuron 1989;2:1447– 1452. 110. Charles G, Zheng C, Lehmann-Horn F, et al. Characterization of hyperkalemic periodic paralysis: a survey of genetically diagnosed individuals. J Neurol 2013;260:2606–2013. 111. Rudnik-Schoneborn S, Witsch-Baumgartner M, Zerres K. Influences of pregnancy on different genetic subtypes of nondystrophic myotonia and periodic paralysis. Gynecol Obstet Invest 2016;81:472–476. 112. Raja Rayan DL, Hanna MG. Managing pregnancy and anaesthetics in patients with skeletal muscle channelopathies. Neuromuscul Disord 2020;30:539–545. 113. Snyder Y, Donlin-Smith C, Snyder E, et al. The course and outcome of pregnancy in women with nondystrophic myotonias. Muscle Nerve 2015;52:1013–1015. 114. Thiel RE. The myotonic response to suxamethonium. Br J Anaesth 1967;39:815–821. 115. Vita GM, Olckers A, Jedlicka AE, et al. Masseter muscle rigidity associated with glycine1306-to-alanine mutation in the adult muscle sodium channel alpha-subunit gene. Anesthesiology 1995;82:1097–1103. 116. Farbu E, Softeland E, Bindoff LA. Anaesthetic complications associated with myotonia congenita: case study and comparison with other myotonic disorders. Acta Anaesthesiol Scand 2003;47:630–634. 117. Parness J, Bandschapp O, Girard T. The myotonias and susceptibility to malignant hyperthermia. Anesth Analg 2009;109:1054–1064.

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118. Farini A, Villa C, Tripodi L, et al. Role of immunoglobulins in muscular dystrophies and inflammatory myopathies. Front Immunol 2021;12:666879. 119. Mariampillai K, Granger B, Amelin D, et al. Development of a new classification system for idiopathic inflammatory myopathies based on clinical manifestations and myositisspecific autoantibodies. JAMA Neurol 2018;75:1528–1537. 120. Dalakas MC. Inflammatory muscle diseases. N Engl J Med 2015;372:1734–1747. 121. Kiely PD, Chua F. Interstitial lung disease in inflammatory myopathies: clinical phenotypes and prognosis. Curr Rheumatol Rep 2013;15:359. 122. Waseda Y. Myositis-related interstitial lung disease: a respiratory physician’s point of view. Medicina (Kaunas) 2021;57:599. 123. Che WI, Hellgren K, Stephansson O, et al. Pregnancy outcomes in women with idiopathic inflammatory myopathy, before

124. 125.

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and after diagnosis: a population-based study. Rheumatology (Oxford) 2020;59:2572–2580. Kolstad KD, Fiorentino D, Li S, et al. Pregnancy outcomes in adult patients with dermatomyositis and polymyositis. Semin Arthritis Rheum 2018;47:865–869. Martyn JA, Richtsfeld M. Succinylcholine-induced hyperkalemia in acquired pathologic states: etiologic factors and molecular mechanisms. Anesthesiology 2006;104:158–169. Suzuki T, Nameki K, Shimizu H, et al. Efficacy of rocuronium and sugammadex in a patient with dermatomyositis. Br J Anaesth 2012;108:703. You AH, Kang HY, Park SW, et al. Delayed recovery of limb muscle power after general anesthesia with cisatracurium in a dermatomyositis patient. J Clin Anesth 2018;50: 59–60.

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Chapter

11

Parturients of Short Stature Robert French-O’Carroll, Katherine M. Seligman, and Andrea J. Traynor

Dwarfism is defined as the inability to achieve a height of 4 feet 10 inches (148 cm) by adulthood and is now more commonly known as short stature.1 Short stature is a clinical entity with many forms and causes. These can be of genetic, constitutional, or metabolic origin. There are >400 different types of short stature, all of which are relatively rare. The most common variety, achondroplasia, occurs in 0.5 to 1.5 per 10,000 live births.2,3 There are two main classifications of short stature: (1) patients with proportionate short stature and have a typical trunk to limb ratio, and (2) patients who have disproportionate growth and have either short trunks relative to their limbs or short limbs relative to their trunks2 (Table 11.1). There are women at the lower extreme of height who meet the definition of short stature, but have no abnormal pathology. Their treatment must be individualized, understanding that there may be shared concerns with parturients with proportionate short stature. Table 11.1  Classification of short stature (formerly: Dwarfism) I. Proportionate short stature A. Endocrine etiology 1. Isolated growth hormone deficiency 2. Laron short stature 3. Congenital hypothyroidism 4. Precocious puberty B. Other genetic conditions 1. Turner syndrome 2. 3 M syndrome 3. Primordial short stature C. Normal variants of growth – constitutional, familial short stature, idiopathic short stature D. Chronic disease states – cystic fibrosis, Crohn disease, chronic renal insufficiency II. Disproportionate short stature A. Skeletal dysplasias* (osteochondrodysplasias) – abnormalities of cartilage +/– bone growth and development 1. Achondroplasia 2. Pseudoachondroplasia 3. Hypoachondroplasia 4. Spondyloepiphyseal dysplasia congenita 5. Spondyloepiphyseal dysplasia tarda 6. Spondylometaphyseal dysplasia 7. Diastrophic short stature 8. Osteogenesis imperfecta * Encompass over 400 conditions in over 40 groups (Mortier et al. 2019). More common conditions and those with reports of pregnancy in the literature are listed here.

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Since the founding of the Little People of America, a society for people of short stature, dedicated online dating services, and social media groups, more opportunities have been created for people with short stature to meet, socialize, and eventually have children. In addition, the increased use of assisted reproductive technology enables women of short stature, otherwise infertile, to achieve pregnancy. As a result, more pregnant patients with short stature are presenting for medical care, often with comorbidities, high-risk multiple gestation pregnancies, and frequent need for CD.4 It is essential in managing parturients of short stature that correct terminology, “short stature,” be used. There have been several reports of inappropriate or disrespectful terms used in the medical literature, which patients may find distressing. In the past, patients with short stature were often assumed to have a learning disability, which is typically not the case.5

Proportionate Short Stature Proportionate short stature refers to individuals who have short stature with a proportionate trunk to limb length ratio. Pregnancy in women with proportionate short stature is less often reported than in women with disproportionate short stature, primarily due to skeletal dysplasias.6 Generally, the preserved trunk height in patients with disproportionate short stature results in less cardiorespiratory compromise during pregnancy than individuals with proportionate short stature.7 Proportionate short stature may occur due to various conditions, including endocrine disorders, rare genetic conditions, chronic disease states, or normal growth variants such as familial short stature.8 This section will cover endocrine causes of proportionate short stature along with rare genetic conditions. Chronic disease states and normal growth variants are not covered, although many of the principles for management, including dosing for NA, will also apply to these patients.

Isolated Growth Hormone Deficiency Isolated growth hormone deficiency (IGHD) has four identified subtypes: 1A, 1B, 2, and 3. Subtypes 1A and 1B are autosomal recessive, Type 2 is autosomal dominant, and Type 3 is X-linked.9 IGHD has been referred to as “pituitary short stature.” Human growth hormone (hGH) is produced by the pituitary somatotroph cells. Other hormonal deficiencies can occur in conjunction with hGH deficiency (e.g., decreased levels of

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LH, FSH, TSH, and ACTH in panhypopituitarism), in which case puberty may not occur, making pregnancy unlikely.9 The other tropic hormones appear to be present in pregnant hGHdeficient women.10 Patients with hGH deficiency during childhood experience infertility at a higher rate, so preconception counseling and testing is recommended.11 Type 1A IGHD arises from homozygous deletions of the GH1 gene, resulting in undetectable hGH concentrations.12 Although often an average size at birth, affected individuals present with severe growth failure by 6 months of age and an undetectable hGH concentration. They can develop antibodies to hGH when receiving treatment in childhood. Adult height rarely exceeds 130 cm, the height of a typical eight-and-a-halfyear-old.1 Puberty may not occur until the late second or third decade of life. In addition to short stature, these individuals have soft, prematurely wrinkled skin, high pitched voices, and micrognathia. Some patients lack a normal lumbar lordosis.1,13 The pulsatile nature of hGH secretion during the day complicates testing and assessment of growth hormone deficiency. Human growth hormone stimulation tests, insulin-like growth factor, and insulin-like growth factor binding protein-3 levels aid in the diagnosis.9 Women with hGH deficiency may also have abnormal glucose metabolism and susceptibility to gestational diabetes as pregnancy progresses.1 These women should be thoroughly investigated in the antenatal period to detect and control any glucose perturbations during pregnancy. Pregnancy can occur in women with growth hormone deficiency.1,14–19

Laron Syndrome Primary growth hormone (GH) insensitivity (also known as Laron syndrome) is an autosomal recessive disorder in which the body cannot use the GH it synthesizes. The syndrome exhibits normal or high circulating hGH, deficient serum levels of insulin-like growth factor (IGF-I), and an abnormal hGH receptor.20 In addition to having an ordinarily proportioned trunk and extremities, these individuals may have frontal bossing, saddle nose, and hypoplasia of the extremities of the skeleton – the nose, jaws, fingers, and toes, a high pitched voice, and slow and sparse hair growth.21,22 Narrowing of the oropharynx and marked obesity place patients at increased risk of sleep apnea.20 Spinal stenosis may be present, especially in the cervical region, along with atlanto odontoid arthritis.20,23 Pregnancy can occur in women with Laron syndrome.21,24,25

Primordial Short Stature Primordial short stature is a rare cause of proportionate short stature characterized by intrauterine growth restriction (IUGR) that continues into the postnatal period. It is a heterogeneous group of conditions, classified according to specific phenotypic characteristics.26 The clinical subtypes described include Seckel syndrome, microcephalic osteodysplastic primordial short stature (MOPD I–III), Meier-Gorlin syndrome (MGS), and RussellSilver syndrome (RSS).26 There are several reports of primordial short stature in pregnancy reported in the literature. One report of primordial short stature (unknown subtype) described a woman delivered at 24 weeks gestation by emergency CD under

GA. Her pregnancy was complicated by difficult BP control, resting sinus tachycardia, hyperthyroidism, and insulin requiring gestational diabetes.7 Meier-Gorlin syndrome is primordial short stature characterized by microtia, facial abnormalities, and patellar aplasia/ hypoplasia.27 There are reports of pregnancy in women with MGS.28 In one report, a woman had two successful deliveries by CD, although there were no details of the type of anesthesia provided. Both pregnancies were complicated by postpartum hemorrhage, ultimately requiring a hysterectomy.28 Russell-Silver syndrome is a form of primordial short stature characterized by short stature, dysmorphic facial features, limb asymmetry, and endocrine abnormalities.29,30 Other associated anomalies include congenital heart disease, urogenital abnormalities, endocrinopathies, ocular and dental anomalies, and cognitive defects.29,31 Specific anesthetic considerations include risk of hypoglycemia in those with endocrinopathies, susceptibility to hypothermia, and potential airway difficulty due to facial abnormalities. The latter includes midface facial hypoplasia, facial hemiatrophy, and hypognathia.29 There are limited reports in the literature of pregnant women with RSS.4,32,33 One report describes a woman with RSS undergoing a scheduled CD at 36 weeks but without details of the anesthetic. Her antenatal course was complicated by gestational diabetes.33 Another report described a patient with RSS requiring a GA for an emergency CD for fetal indications.4

Turner Syndrome Turner syndrome results from a partial or absent X chromosome. Spontaneous pregnancy is rare in the most common karyotype 45X, but pregnancy can occur in women with mosaic karyotypes.34–36 Principal features include short stature, primary ovarian insufficiency, cardiovascular defects, cognitive defects, hypothyroidism, liver disease, diabetes, and cardiovascular disease. Principal concerns during pregnancy include the risk of cardiovascular malformations, including aortic coarctation and bicuspid aortic valve. There is a risk of worsening hypertension or aortic dissection, with several reports of death associated with pregnancy.37 Women with Turner syndrome should have a comprehensive cardiovascular examination and workup before pregnancy, which includes cardiac magnetic resonance imaging and echocardiography.34,37 Other anesthetic-related considerations include the risk of difficult airway due to short neck and micrognathia, musculoskeletal abnormalities (including scoliosis), and increased risk of gastroesophageal reflux.34,38 Cesarean delivery is also likely with rates twice that of the general population.36

3M Syndrome 3M syndrome is an autosomal recessive condition with proportionate short stature and distinct facial features. Skeletal and spinal abnormalities include tall vertebral bodies, thoracic kyphoscoliosis, and spina bifida. Intracerebral aneurysms are also possible.39,40 Women with 3M syndrome typically have a congenitally small pelvis, so they have a high risk of malpresentation, cephalopelvic disproportion, and the need for CD.41

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Robert French-O’Carroll, Katherine M. Seligman, and Andrea J. Traynor

Successful pregnancy has been reported in women with 3M syndrome, using both NA and GA for CD.41,42

Effects of Pregnancy in Proportionate Short Stature The physiologic changes of pregnancy can have profound implications for maternal health in women with proportionate short stature. The most concerning is the effect of uterine growth on cardiorespiratory parameters. The abdominal dimensions of these women are markedly smaller than averaged sized counterparts (Table 11.2). The uterus, therefore, becomes an intraabdominal organ earlier in gestation. These factors may cause significant mechanical dysfunction of the diaphragm and more aortocaval compression. The decrease in FRC seen during pregnancy causes worse respiratory compromise in women with proportionate short stature than those with disproportionate short stature.7,43 As a result, there may be decreased vital capacity, hypoxia, and acidosis, with tachypnea and tachycardia required to compensate for these physiologic derangements. As pregnancy progresses, patients may have such severe shortness of breath with movement that they require mobility aids, such as a scooter. Pulmonary decompensation may necessitate immediate delivery of the fetus to improve maternal condition.1,15 Valuable Clinical Insight Pregnancy in a person with short stature can affect cardiopulmonary physiology, and these changes can occur earlier in pregnancy compared to a person without short stature.

Obstetric and Neonatal Considerations Due to cephalopelvic disproportion, most women with proportionate short stature require CD, although there are rare reports of successful vaginal births.1 Other pregnancy complications include higher than standard rates of spontaneous abortion, stillbirth, and premature delivery.1,19,36 It is uncertain if these complications result from mechanical, genetic, or hormonal causes. Premature delivery is more likely when there are respiratory complications.1,7 It has been suggested that preterm delivery may be due to some unknown physiological actions of hGH in the first half of pregnancy, before placental production of a variant type of hGH. However, in a study of 173 pregnancies in women who were hGH deficient, different hGH replacement therapy regimens did not influence pregnancy outcomes.44 There are several reports of patients with proportionate short stature developing PreE with severe features during pregnancy,7,21,24,28

suggesting a higher risk of this condition in these patients. In addition, patients with hGH deficiency are at higher risk of gestational diabetes.1 Prepregnancy counseling and early presentation to high-risk antenatal units are essential to optimize outcomes for pregnant women with proportionate short stature. They should deliver in a hospital that can provide high risk obstetric care with access to an obstetric anesthesiologist and other subspecialists, including a pulmonologist and MFM expert. Since preterm delivery is frequent, these women should deliver their babies at an advanced neonatal unit. There may be a need for immediate neonatal resuscitation at delivery, given the risk of preterm delivery, IUGR, and maternal cardiorespiratory compromise during pregnancy.7 The risks to the newborn of inheriting the condition responsible for maternal short stature will depend on the type of short stature and inheritance pattern. Infants born to mothers with isolated hGH deficiency usually have average birth weight and length.10 A diagnosis of short stature in the offspring is made in infancy or later in childhood. At birth, infants with Laron syndrome have shorter lengths than average but normal birth weight.9 Valuable Clinical Insight Obstetric and neonatal outcomes in pregnant people with short stature include risks for cephalopelvic disproportion, premature delivery, stillbirth, spontaneous abortion, and complications related to cardiopulmonary compromise.

Anesthesia Considerations Anesthesia management in patients with proportionate short stature is less reported than in patients with disproportionate short stature (such as achondroplasia). Tables 11.3 and 11.4 contain an overview of anesthetic considerations in this patient population and a summary of reports that discuss anesthetic management. A multidisciplinary approach is required when planning the care and delivery of a woman with proportionate short stature. Considerations include maternal health optimization, delivery location, equipment availability, anesthetic technique, and postoperative pain relief.

Patient Optimization Preoperative anesthetic consultation should include a history and physical examination, emphasizing the airway and anatomy relevant to NA. Pulmonary decompensation will require arterial blood gas analysis, pulmonary function tests, and chest radiographs.

Table 11.2  Vertical and horizontal abdominal measurements in nonpregnant individuals (cm)

Achondroplasia

Growth hormone deficiency

SED & diastrophic

Normal

Xiphoid to symphysis

29

25

24

33

Intercristal

21

24

25

30

Reprinted with permission from Tyson JE, Barnes AC, McKusick VA, et al. Obstetric and gynecologic considerations of short stature. Am J Obstet Gynecol 1970;108:688–703. Abbreviation: SED = spondyloepiphyseal dysplasia.

1

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Parturients of Short Stature

Table 11.3  Anesthetic considerations for proportionate short stature

Characteristics

Anesthetic implications

Airway Upper airway   Micrognathia possible   Facial abnormalities   Smaller airway Neurologic Cervical spine Musculoskeletal Short stature Small pelvis Degenerative spinal changes

Possible difficult intubation May need smaller ETT Risk of sleep apnea

Cardiac Cardiac malformations Thoracic Uterine impingement on intrathoracic structures Abdominal Uterine impingement on abdominal structures Endocrine Endocrine abnormalities

High incidence of spinal stenosis Possible atlantoaxial instability Decreased dosage of local anesthetic for NA Continuous NA technique preferred High rate of cesarean delivery Regional anesthesia challenging Risk of worsening hypertension and aortic dissection (Turner syndrome) Respiratory compromise

Measuring oxyhemoglobin saturation with pulse oximetry and the patient in an upright and Trendelenburg position is a valuable screening test to detect potential deterioration with FRC reductions. Patients with proportionate short stature should be delivered at a tertiary care center with an onsite high acuity (step down) unit and critical care resources. Following delivery, these patients would benefit from recovery in a high acuity unit to monitor for respiratory and cardiac decompensation instead of the standard postpartum ward. If there are no comorbidities, these patients can be managed routinely during labor and delivery. If respiratory compromise is present, intraarterial catheter placement with oxygen monitoring, ventilation, and acid-base status is prudent. There are several considerations when performing NA or GA in patients with proportionate short stature. Valuable Clinical Insight

May not tolerate supine position or rapid IV fluid administration Risk of supine hypotension Risk of aspiration Risk of hypoglycemia Risk of gestational diabetes (growth hormone deficiency)

Patient optimization, including an antenatal anesthesiology consult, is critical to successful anesthetic management of a pregnant patient with proportionate short stature.

Table 11.4  Reports of anesthesia management of parturients with proportionate short stature

Author & year

Condition

Height (BMI) Mode of delivery, Anesthesia Anesthesia details gestation, and indication mode where reported

Maternal Complications

Ratner et al., 199814

Growth hormone deficiency

125 cm (22.5)

Scheduled CD at 39 weeks

Epidural

Test dose 2 ml 2% lidocaine with epinephrine 1/200 + 10 ml + 50 mcg fentanyl titrated + 2 mg epidural morphine T3 sensory block

Nil reported

Zaman et al., 201015

Growth hormone deficiency

124 cm

Emergency CD for maternal respiratory distress

Spinal

7.5 mg bupivacaine hyperbaric 0.5%

Nil reported

Li et al., 201716

Growth hormone deficiency

120 cm (21.5)

Scheduled CD at 37 weeks

Epidural

2 ml 2% lidocaine test dose + 8 ml 2% lidocaine

Hypotensive post epidural lidocaine

Cassar et al., 198017

Growth hormone deficiency

140 cm

Scheduled CD at 37 weeks for twin pregnancy

GA

Not reported

Nil reported

Bhatia et al., 201124

Laron syndrome

110 cm (41.3)

Emergent CD at 32 weeks

CSE

4 mg bupivacaine 0.5% T4 sensory block after second spinal

Severe preeclampsia during pregnancy First spinal failed

Vance et al., 20127

Primordial short stature (subtype not known)

97 cm (23.4)

Emergent CD at 24 weeks for uncontrolled HTN

GA

No airway difficulty

Uncontrolled HTN, severe preeclampsia, IUGR

Lange et al., 20164

Russell-Silver syndrome

142 cm, (15)

Emergent CD

GA

MAC 4 blade, size 6.5 ETT tube

Nil reported

Kalopita et al. 201834

Turner syndrome

155 cm, (23)

Scheduled CD at 37 weeks for CPD

CSE

1.2 ml 0.75% ropivacaine with 15 mcg fentanyl + two epidural doses of lidocaine 2%

Nil reported

Galea et al., 200842

3M syndrome

139 cm, (49)

Emergency CD at 36 weeks

GA

C&L Grade 3 view, successful with a bougie. Size 6 ETT tube

Nil reported

Cusimano et al., 201741

3M syndrome

132 cm, (25.2)

Scheduled CD at 38 weeks

Spinal anesthesia

US used for spinal anesthesia

Nil reported

Reports included in this table are those where the mode of anesthesia is reported in parturients with proportionate short stature. Abbreviations: BMI = body mass index; CD = cesarean delivery; C&L = Cormack and Lehane; CPD = cephalopelvic disproportion; HTN = hypertension; IUGR = intrauterine growth restriction; US = ultrasound.

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Neuraxial Anesthesia Principal concerns around neuraxial anesthesia (NA) relate to technical difficulties, risk of complications, and uncertainty around required intrathecal and epidural LA dosing for adequate labor analgesia and anesthesia for CD. Although patients with proportionate short stature have a lower risk of spinal abnormalities than those with disproportionate short stature, degenerative and anatomical spinal changes may be present, making NA more challenging and increasing the risk of complications. The spinal cord is assumed to be reduced in size relative to the spinal canal volume, but this is not known for sure. If the spinal cord is large compared to the size of the spinal canal or if it terminates at a lower-thanexpected level, an increased risk of neurologic damage with NA, especially spinal anesthesia, is possible. The use of neuraxial US to locate the lower lumbar interspaces (L4/5, L5/S1) may be beneficial.41 Furthermore, the possibility of spinal stenosis in patients with Laron syndrome, increasing the risk of complications, must be considered.45 Although a single dose spinal anesthetic is technically possible to perform in most patients, the appropriate dosage of LA is challenging to predict. Minimum effective doses for CD have been suggested as 0.06 mg per cm height,46 but studies determining an effective ED95 for hyperbaric bupivacaine have not included patients of short stature.47 There is debate around the effect of patient height on the intrathecal spread of LA,48 but there is a more apparent correlation between vertebral length, which is shorter in parturients of proportionate short stature, and LA spread; thus dosing should be reduced.49 Local anesthetic doses comparable to those used in the pediatric population50 may be appropriate, but no studies have been performed in this population to confirm this. There are some case reports available to guide anesthesiologists. One patient with Laron syndrome received a combined spinal epidural (CSE) for CD and obtained a bilateral T4 block after 4 mg of intrathecal bupivacaine.24 Furthermore, in patients with GHD, surgical anesthesia was achieved in one patient with a single intrathecal injection of 7.5 mg bupivacaine,15 in another patient with 12 ml of epidural 2% lidocaine,14 and another with 10 ml epidural 2% lidocaine.51 Potential problems with subarachnoid blockade include underdosing resulting in inadequate anesthesia for CD and overdosing resulting in high spinal anesthesia, loss of airway control, respiratory failure, and hemodynamic instability. For these reasons, a catheter technique is preferred because the LA can be titrated.14,34,51 A CSE technique, epidural alone technique, or a dural puncture epidural technique should be considered after weighing the risks and benefits of puncturing the dura when the interspace of spinal cord termination has not been confirmed. When administering epidural analgesia for labor, dilute LA, in combination with a short-acting opioid (e.g., fentanyl or sufentanil), can be titrated slowly to achieve adequate analgesia while avoiding a high block. Patient-controlled epidural analgesia can be used for maintenance with conservative bolus doses, beginning with approximately half to two-thirds of the initial bolus volume. A test dose is used to identify a misplaced epidural catheter into the subarachnoid space or an epidural vein in patients with

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proportionate short stature. Test doses for labor analgesia are controversial but may be helpful when surgical anesthesia is required. The optimal test dose in patients with short stature is unknown, but it is prudent to reduce the dose of LA and consider the dose of epinephrine based on patient weight. A previous case report described the safe use of a 2 ml test dose of 2% lidocaine with 1:200,000 epinephrine.14 In the event of an inadvertent subarachnoid injection, this dose would have likely provided evidence of spinal blockade without producing an excessive level. The appropriate dose of epinephrine to identify IV placement of an epidural catheter in a patient with short stature is unknown. Valuable Clinical Insight Neuraxial anesthesia and analgesia is possible in pregnant patients with proportionate short stature, albeit with some adjustments to routine administration such as dosing, technique, and anticipated complications.

General Anesthesia Patients with proportionate short stature are less likely to have difficulties in airway management and cervical spine instability than those with skeletal dysplasia conditions. That said, certain conditions may predispose to increased difficulty with airway management. A prospective study on Laron syndrome patients found a high incidence of cervical spinal stenosis, atlantoodontoid osteoarthritic changes, and decreased mediolateral diameter of the oropharynx. These findings led to a recommendation for routine cervical spine imaging (preferably MRI) in these patients if time permits.23 Regardless, caution should be used, and a thorough airway evaluation, including asking the patient about neurologic symptoms with flexion and extension of the neck, should be performed before induction of GA. If cervical spine imaging is not available, awake fiberoptic intubation should be considered, especially in patients with symptoms consistent with cervical spinal stenosis. Furthermore, attention should be paid to airway assessment and management in patients with Russell-Silver syndrome, 3M syndrome, and Turner syndrome because facial and anatomical airway alterations may predispose to problematic airway management. Predicting the appropriate size of ETT for patients with proportionate short stature is difficult. Whereas age is usually the best guide for ETT size in children, weight is likely a better predictor in patients with proportionate short stature.52 Some authors suggest using a pediatric tube based on the appropriate size for a child of similar height.14 Precautions against aspiration are necessary for pregnant patients with short stature because the uterus causes additional compression on intraabdominal structures.53,54 For the same reason, supine hypotension may be more significant than in an average-sized parturient. Although no literature exists on the optimal dose of vasopressors in parturients of short stature, is it prudent to titrate phenylephrine or other vasopressor infusions to maintain 10% of baseline BP55 and consideration should be given to dosing based on body weight.

Parturients of Short Stature

Valuable Clinical Insight General anesthesia is possible in pregnant patients with proportionate short stature, although considerations include the possibility of atlantoaxial instability and airway management concerns.

Table 11.5  Achondroplasia: anatomic and physical findings General                    Normal trunk length                                        Short limbs Craniofacial          Megalocephaly – large head size                                        Megalencephaly – large brain size                                        Brachycephaly – short head

Postoperative Management Pain management after CD should include scheduled weightbased multimodal analgesia and neuraxial morphine. Patients of short stature may benefit from a reduced intrathecal or epidural morphine dose, but no studies have determined the appropriate dose. Given the potential risk for respiratory depression, we recommend a high level of postoperative monitoring. Patients with proportional short stature should be deemed “high risk” for respiratory depression and monitored according to available guidelines.56

Disproportionate Short Stature Women with disproportionate short stature are potentially more problematic and have additional anesthetic considerations than patients with proportionate short stature. Disproportionate short stature is due mainly to skeletal dysplasia disorders, consisting of a heterogeneous group of over 450 different conditions, classified into 42 groups.6 While many of these disorders have specific implications for the anesthesiologist, several general considerations need to be taken into account when managing these patients. Below is a discussion of the more common skeletal dysplasia disorders which result in disproportionate short stature and the suggested anesthetic management during pregnancy and delivery.

Achondroplastic Short Stature Achondroplastic short stature is the most common type of short stature, with a prevalence rate of 0.5–1.5 per 10,000 births.3 Short stature in this condition results from abnormal endochondral bone formation. These patients with relatively preserved truncal lengths have shortened limbs which are primarily responsible for the short stature. Achondroplastic dwarfs are usually shorter than 130 cm.2 The condition, often diagnosed at birth, is caused by a fibroblast growth factor receptor gene mutation, decreasing endochondral ossification.57 The mode of inheritance is autosomal dominant, although 80% result from spontaneous mutations.57,58 The anatomic and physical characteristics of achondroplasia are listed in Table 11.5. There are craniofacial and airway abnormalities in addition to abnormalities of the spine and skeletal system. There may also be abnormalities of the CNS and the cardiorespiratory systems. Several features of achondroplasia have relevance for pregnancy and the resultant obstetric and anesthetic management. The nongravid achondroplastic patient has a reduced xiphoid to symphysis length (although greater than patients with proportionate short stature) as well as a decreased intercristal diameter (Table 11.2). These decreased pelvic measurements and the hyperlordotic features of achondroplasia make the uterus an abdominal organ even before pregnancy. Uterine enlargement

                                       Foramen magnum stenosis                                        Decreased atlanto-occipital distance                                        Frontal bossing                                        Depressed nasal bridge                                        Maxillary/facial hypoplasia                                        Macroglossia                                        Narrowed upper airways Central nervous system                                        Hydrocephalus                                        Hypotonia Spine/skeletal                                        Generalized spinal stenosis                                        Odontoid dysplasia                                        Atlanto-axial instability                                        Abnormally shaped vertebrae                                        Hyperplastic intervertebral discs                                        Lumbar hyperlordosis                                        Thoracolumbar kyphosis                                        Square ilia                                        Narrow sciatic notch                                        Horizontal sacrum Respiratory/cardiac                                        Chest deformities                                        Thoracic dystrophy/kyphosis                                        Rib hypoplasia                                        Upper airway obstruction                                        Obstructive sleep apnea                                        Cor pulmonale                                        Possible pulmonary hypertension

during pregnancy is exaggerated in an anterior and superior direction compared with parturients of average height and proportion.1 By the fourth month, these women look as though they are 30 weeks pregnant.1 Several anatomic features place patients with achondroplasia at risk of upper airway obstruction and complex airway management. These include brachycephaly (short head),22 a flattened nasal bridge, facial and maxillary hypoplasia, narrowed upper airways,59 a large mandible, and a large tongue.60 Other craniofacial abnormalities present include megalocephaly (large head size), megalencephaly (overgrowth of the brain), and frontal bossing.2,22 Obstructive sleep apnea syndrome is common61 secondary to these mechanical abnormalities but may also be secondary to generalized hypotonia of airway muscles59 and co-existing obesity.61 Although not typically the

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cause of sleep apnea,62 neurological or central causes may result in apnea and respiratory depression from medullary compression or compression of vertebral arteries at or near the cranio­ cervical junction secondary to foramen magnum stenosis.63 Herniation through an abnormally small foramen magnum has been reported in patients with achondroplasia with increased ICP from hydrocephalus59,64,65 in addition to upper cervical neurologic deficits. Limited hyperextension of the head is necessary not to worsen previous deficits and cause new cervical spinal cord injury.62,63,66–68 It is essential for the anesthesiologist to question the patient about neurologic symptoms before GA or performing direct laryngoscopy and intubation. The potential for complex airway management is reflected in the literature with several reports of difficult or failed intubation.69,70 These difficulties have been attributed to limited neck extension, 58,60 subglottic stenosis,71 and poor laryngeal view.72 There have been several case series of GA performed successfully without complex airway management,4,60,72 reflecting the variation in presentation and need for an individualized assessment. In addition to potential airway difficulties, respiratory complications commonly occur during pregnancy. In one survey, four out of 26 achondroplastic pregnant women had respiratory difficulties during the last 2 months of gestation.73 The causes of potential respiratory issues include chest deformities, upper airway obstruction, sleep apnea, neurologic disease, and other unrelated pulmonary conditions.3 Thoracic cage deformities, including rib hypoplasia and other rib deformities, can cause restrictive lung disease. These mechanical problems may be associated with recurrent respiratory tract infections.2,59,74 In patients without short stature, severe kyphoscoliosis can cause baseline hypoxemia and low lung volumes, which tend to worsen during sleep (or anesthesia).75 In adult patients with achondroplasia, Stokes demonstrated that the shape of the thorax differs most compared with the anatomy of women of average stature.76 The expansion of the uterus to become an intraabdominal organ very early in gestation limits respiratory mechanics, further worsened in individuals with significant kyphoscoliosis.54,65 Occasionally, cor pulmonale occurs due to these respiratory complications.2,59,77,78 However, corrective procedures performed early in childhood may reverse this process.59,61 Unfortunately, this problem is unlikely to be reversible in patients with chronic chest deformities and pulmonary hypertension who present for treatment while pregnant. More commonly, patients with achondroplasia are at increased risk of heart disease than the general population, with mortality rates ten times greater for young adults.79 This may be due to increased risk of hypertension, higher rates of obesity, reduced physical activity levels,61 or narrower arterial vessel caliber present in patients of short stature predisposing to severe atherosclerosis.80 Numerous spinal anomalies can occur in achondroplasia, including thoracolumbar stenosis and generalized spinal stenosis.66,81–83 Additional issues include lumbar hyperlordosis and thoracolumbar kyphosis, thoracic dystrophy, square ilia, a narrow sciatic notch, and a horizontal sacrum. Because of lumbar lordosis, the fifth lumbar vertebra will seem lower relative to the ilia than in patients of normal stature.84

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Spinal stenosis can occur at any spinal level, although the thoracolumbar and lumbar regions are the most commonly narrowed segments in achondroplasia.84 Spinal cord compression can result from narrowing due to abnormally shaped vertebrae or hyperplastic intervertebral discs.81 The narrowing of the spinal canal from underdeveloped vertebral arches and shallow vertebral bodies results in narrowed epidural and subarachnoid spaces,85 which has anesthetic implications for NA. The abnormal intervertebral discs may bulge laterally and posteriorly and cause neurologic deficits.2,86 Anatomic findings in one cadaveric achondroplastic spine from someone who had experienced nonvascular claudication revealed thickened pedicles, inferior facet encroachment, and nerve root stenosis.87 These physical findings were consistent with the symptomatology seen in this patient before death from an unrelated cause. Since the symptoms of neurologic compromise can progress to paralysis,81,83,84,87–90 the anesthesiologist must be aware of and document neurologic symptoms before an anesthetic intervention. In a series of 46 pregnant women with short stature, four out of 26 achondroplastic patients had symptoms of nerve root compression following delivery consisting of numbness and tingling in the lower limbs.73 Hypotonia and hydrocephalus are other features of achondroplasia.2,84 Progressive hydrocephalus with concomitant elevations in ICP may warrant shunting. The mechanism for hydrocephalus is from intracranial venous hypertension or CSF flow obstruction at the level of the stenosed foramen magnum.91–93 In such circumstances, anesthesiologists should be aware of the possibility of a lack of CSF flow despite correct needle placement.94 Valuable Clinical Insight Achondroplasia in pregnancy should prompt considerations around comorbidities, complex airway management, neuraxial anomalies such as kyphoscoliosis with or without corrective procedures or spinal stenosis, hypotonia, or hydrocephalus.

Nonachondroplastic Short Stature Pseudoachondroplasia Pseudoachondroplasia typically presents in early childhood, with affected individuals having similar stature to those with achondroplasia but with no craniofacial abnormalities. They may have lumbar hyperlordosis, genu valgum (”knock knees”), genu varum (knees are abnormally separated) and the lower extremities bowed inwardly, and scoliosis.22 As adults, they usually are less than 130 cm tall.2 Three cases of pregnant patients with pseudoachondroplasia were described in a survey of patients with short stature.73 No mention was made of anesthetic management or other complications encountered in these parturients.

Hypochondroplasia

Hypochondroplasia, from a mutation in the FGFR3 gene, like achondroplasia, is characterized by disproportionate short

Parturients of Short Stature

stature, mild joint laxity, and macrocephaly. Features tend to be like achondroplasia but milder. Spinal stenosis and obstructive sleep apnea tend to be less common, although intellectual disability and epilepsy may be more common.95 Management of pregnancy in patients with hypochondroplasia includes successful vaginal deliveries with epidurals.96 We have little other information on the anesthetic management of these patients. However, the approach should follow that of patients with achondroplasia, with an appreciation that the features are likely to be less severe.

Spondyloepiphyseal Dysplasia Spondyloepiphyseal dysplasia (SED) is a rare form of short stature, which has two variants. The SED congenita variant usually presents at birth, and individuals may have short limbs,2,97 whereas SED tarda variant is often diagnosed in late childhood and limb length is usually normal.2 SED arises either from a spontaneous mutation or may be X-linked or autosomal dominant inheritance.97 These patients have a short trunk with normal or shortened limb length and are usually 10 degrees with vertebral rotation in the usually straight vertical axis of the spine. Scoliosis is classified according to its cause and by describing the curve, including the magnitude, location, and ­direction.1,2 Scoliosis is divided into structural and nonstructural (functional) types based on the degree of spinal flexibility. Nonstructural curves are those seen in postural scoliosis or those related to sciatica or leg length discrepancies. Nonstructural curves are occasionally seen in parturients, developing as pregnancy progresses and resolving after delivery. They do not affect spine mobility, are nonprogressive, and resolve with attention to the underlying cause. Structural curves are those of idiopathic scoliosis or resulting from the conditions outlined in Table 12.1. Reduced spinal mobility is characteristic of the structural curves, as is asymmetry in lateral flexibility, which is best appreciated on left and right bending X-ray films. Structural curves are associated with a fixed prominence, the rib hump, on the convex side of the curve. This prominence is most evident in the forward-bend position. Kyphoscoliosis, a combination of kyphosis and scoliosis, is uncommon in parturients. It is usually a congenital disorder, although it may be related to progressive infantile scoliosis or paralytic forms of scoliosis.

Table 12.1  Conditions associated with scoliosis Congenital (vertebral) anomalies

• •

Hemivertebra Spina bifida

Neurologic disorders

• • • •

Spinal muscular atrophy Cerebral palsy Polio Neurofibromatosis

Myopathic disorders

• •

Myotonic dystrophy Muscular dystrophy

Connective tissue disorders

• •

Marfan syndrome Rheumatoid disease

Osteochondystrophies

• •

Achondroplasia/hypochondroplasia Osteogenesis imperfecta

Osteoporosis of pregnancy Infection

•

Tuberculosis

Post-traumatic

The magnitude of the curve of scoliosis is determined by the Cobb method. The curve’s upper and lower vertebrae are identified, and lines drawn through their endpoints; the Cobb angle is the intersection of perpendiculars to these lines (Figures 12.1 and 12.2). The Cobb angle allows the curve’s progression to be followed and determines the need for and type of any intervention. The anatomic area of the spine in which the curve’s apex is situated determines the location of the curve.2,3 The lower limit of curves involving the lumbar spine is usually L3 or L4, although relatively few curves extend this far caudad. The convexity determines the direction assigned to the curve, and right thoracic curves are the most common curves found in ­idiopathic scoliosis.

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Figure 12.1  Cobb angle-schematic representation. A line is drawn parallel to the superior cortical plate of the proximal end vertebrae and to the inferior cortical plate of the distal end vertebrae. A perpendicular line is erected to each of these lines. The angle of intersection is the (Cobb) angle of the curve. (From Preston R. Musculoskeletal disorders. In Chestnut DH, Wong CA, Tsen LC, et al. (Eds.). Chestnut’s Obstetric Anesthesia: Principles and Practice (6th ed.). Philadelphia: Elsevier; 2020, p. 1142. Reprinted with the permission of Elsevier.)

Etiological Considerations The cause of the majority (80%) of cases of scoliosis is unknown, and these are characterized as idiopathic. Idiopathic scoliosis is divided into three types: infantile, juvenile, and adolescent.1,2 The majority of infantile scoliosis arises before age three, does not progress beyond 30 degrees and resolves spontaneously. Juvenile scoliosis has its onset in the four- to nine-year-old age group, is less common than the adolescent form, and is not as well described. Adolescent idiopathic scoliosis (AIS) has its onset between age ten and the age of skeletal maturity and represents the most common form of idiopathic scoliosis, accounting for 90% of idiopathic cases.4 AIS is a complex genetic trait disorder; it usually occurs in an otherwise healthy child, often with a family history of the disease.2,5 Less common causes of scoliosis are found in Table 12.1. Of these rarer forms, the most common during pregnancy are deformities caused by neurological and myopathic conditions that result in paralytic scoliosis, and curves resulting from osteochondystrophies. Infectious causes of scoliosis, predominantly

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Figure 12.2  Cobb angle – chest radiograph. Cobb angles are represented on this radiograph of a young woman with a progressive spinal muscular atrophy (Kugelberg-Welander syndrome) and a 70-degree thoracic curve. Note should also be made of the rib separation on the right hemithorax compared with the left. This patient’s pelvic film is detailed in Figure 12.6.

tuberculosis-related, are reported primarily from underdeveloped countries.6

Incidence and Prevalence The prevention of poliomyelitis and the low prevalence of other conditions leading to scoliosis mean that surveys of scoliosis largely reflect the incidence and prevalence of AIS.3,7 The incidence in the United States of minor curves, as assessed radiographically, is four in 1000.8 The incidence of deformities that reach angles of 35 degrees is one in 1000, whereas deformities > 70 degrees are roughly 0.1 in 1000.9 The prevalence of AIS (Cobb angle > 10 degrees) in adolescents aged 10–16 is estimated at 2–3%, though only one in ten will require treatment. Females are affected more than males at a ratio of 3.6:1, and this ratio increases with increasing curve severity.2,3 Scoliosis screening programs and early interventions are indicated to prevent the natural progression of the disease. Early diagnosis and intervention have reduced the incidence of uncorrected major curves in adults.3 Severe scoliosis is very rare in parturients; however, pregnancy is common in women who have scoliosis. In a postal survey of women diagnosed with scoliosis in Minnesota, 72% of responders had been pregnant an average of 2.8 times each.10 Most of these women (68%) had idiopathic scoliosis with the majority adolescent-onset disease. Several other reviews confirm that pregnancy is common in women with scoliosis.11,12,13

Disorders of the Vertebral Column

Risk Factors for Curve Progression Curve progression is defined when the Cobb angle increases by 5 degrees or more, as measured over subsequent assessments. Progression is most likely to occur in the rapid adolescent growth phase in immature patients, in patients with larger curves (> 20 degrees) at the time of original diagnosis, and in patients with double curves at presentation.14 There is a threefold increase in the risk of progression if the initial curve is measured at > 20 degrees than if the curve is smaller, and thoracic curves are more likely to progress if the Cobb angle is large (> 50 degrees). Observation over decades has shown that curves > 30 degrees will progress following skeletal maturity. Thoracic curves of 50–75 degrees at skeletal maturity progress as much as 1 degree annually.3 The natural history of the severe untreated curve is progression of the deformity over time, resulting in early death from cardiopulmonary failure.7,15,16 Long-term ­follow-up of patients with significant, uncorrected curves demonstrated that the mortality rate was twice that of the general population, and the average age at death was 47 years.17 The overall mortality rate for AIS however, is comparable to the unaffected population.3,5

Skeletal Changes in Idiopathic Scoliosis The skeletal anatomic pathology that results from AIS is complex. Deformation of vertebrae is present when Cobb angles are > 40 degrees, as are abnormal relationships between vertebrae, excess curvature in the frontal plane, loss of typical sagittal plane curves, and rotation in the vertical axis.18 The vertebral bodies have shorter, thinner pedicles and laminae on the concave side and a narrower vertebral canal (Figure 12.3). The transverse processes are anatomically abnormal and asymmetric in their spatial orientation. The spinous processes are deformed and skewed from the midline. The rotatory component associated with the scoliotic curve is such that the axial rotation of the vertebral body is typically into the convexity of the lateral curve, and the spinous process is rotated back into the concavity (Figure 12.4A).19 As a result of the rotation of the vertebrae, the ribs on the side of the convexity are pushed backward, producing a prominent posterior angle – the rib hump (Figure 12.4B). The interlaminar space is shifted more toward the curve convexity than is the spinal process, and the usual anatomic relationship between these structures is altered.20 This change is important if major neuraxial block is considered, because the underlying structures no longer keep the same relationships to surface landmarks. Valuable Clinical Insight Scoliosis is a complex three-dimensional disease. Vertebral bodies are rotated laterally toward the convexity of the curve, while the spinous processes point toward the concavity.

Figure 12.3  Scoliotic deformation of the vertebral body. The vertebra diagrammed is from a spine with a moderate to severe right-sided curve. The body has shorter, thinner pedicles on the concave (left) side and a narrower vertebral canal. The transverse processes are abnormal and asymmetric in their spatial orientation. The spinous process is deformed and skewed from the midline. (See also Figure 12.7.)

Indications for Intervention and Principles of Corrective Surgery The goal of surgery is to fuse the spinal curve and prevent progression of the deformity. Modern surgical techniques consistently yield a 50% reduction of the deformity without excessive risk. In the past this was achieved with Harrington rods, though modern techniques including pedicle screws and rods provide better three-dimensional correction of scoliosis.21 Common to all the techniques described is the requirement for spinal instrumentation and extensive bone grafting in the axial spine (Figure 12.5). Surgical correction of AIS is usually indicated for thoracic curves that reach 45–50 degrees or more by skeletal maturity.5 Follow-up studies of patients receiving early operative correction of scoliotic curves demonstrated either improvement in lung volumes and function, or improved postoperative restrictive lung disease.22 Earlier correction of the curvature is superior to delaying correction until adulthood.23 Patients who undergo early instrumentation tend not to develop the cardiopulmonary complications seen in patients with severe, uncorrected disease.23–25

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A

B

Figure 12.4  Idiopathic scoliosis – lumbar spine. (A) X-ray study of the lumbar spine in a 26-year-old woman with idiopathic scoliosis. The spinous process and pedicles are rotated away from the curve convexity and into the concavity. The epidural space was entered easily by directing the needle about 15 degrees off the perpendicular at the skin level toward the convexity of the curve. (From Preston R. Musculoskeletal disorders. In Chestnut DH, Wong CA, Tsen LC, Ngan Kee WD, Beilin Y, Mhyre JM, Batemen BT (eds.). Chestnut’s Obstetric Anesthesia: Principles and Practice (6th ed.). Philadelphia: Elsevier; 2020, p. 1143. Reprinted with the permission of Elsevier.) (B) Rib hump-schematic. As a result of rotation of the vertebrae, the ribs on the side of the convexity are pushed backward, producing the prominent posterior angle, the rib hump. The intercostal gap is increased in the hemithorax with the rib hump (Figure 12.2).

Cardiopulmonary Pathophysiology in Idiopathic Scoliosis Respiratory Pathophysiology Scoliosis interferes with the formation, growth, and development of the lungs.20,26,27 The number of alveoli increases significantly between birth and age eight years, and the occurrence of scoliosis before lung maturity reduces the number of alveoli formed. The pulmonary vasculature develops in parallel with the alveoli and is likewise affected, resulting in increased pulmonary resistance, pulmonary hypertension, and, in severe cases, right heart failure. The pulmonary pathophysiology of scoliosis also includes the effects of the vertebral and rib-cage deformity on the mechanical function of the lung. The key findings that correlate with respiratory compromise are (1) thoracic curve, (2) thoracic lordosis, and (3) ribcage deformity. The most common abnormality is restrictive pulmonary dysfunction with a reduction in lung volume and compliance. This pattern occurs in all patients with thoracic curves > 70 degrees. Ventilatory

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reserve is limited, resulting in dyspnea on exertion and reduced exercise capacity in the early stages of the disease. Curve progression results in further respiratory compromise. Although the residual volume is not affected in most patients with restrictive lung disease, FRC is reduced. As a result, airways may close during normal tidal breathing, resulting in V/Q mismatch and arterial hypoxemia. Total lung capacity (TLC) and VC are also both reduced. Typical VC in adults is 70 to 80 ml/kg. When VC is reduced to < 15 to 18 ml/kg, expiratory airflow may become inadequate to produce an effective cough. Flow rates, as measured against lung volumes, provide a measure of the presence or absence of airway obstruction. These ratios tend to be unaffected in restrictive lung disease, implying that intrinsic airways disease is not typically associated with scoliosis. The work of breathing depends on many factors, most importantly, lung and chest wall stiffness and the airway resistance. In patients with thoracic scoliosis, the chest wall is stiff and larger trans-pulmonary gradients are required to achieve

Disorders of the Vertebral Column

Valuable Clinical Insights • Restrictive lung disease is the most common pulmonary abnormality in scoliosis and often occurs in patients with thoracic curves > 70 degrees. • Cardiorespiratory symptoms attributable to scoliosis are uncommon in patients with mild to moderate curves.

Cardiovascular Pathophysiology

Figure 12.5  Harrington rod instrumentation. Radiograph of the lumbar spine in a 31-year-old woman with thoracolumbar scoliosis corrected with spinal instrumentation. There is rotation of the vertebrae into the curve (toward the rod), and extensive bone grafting is evident adjacent to the rod. Two lumbar interspaces are not involved the fusion, L4–L5 and L5–S1. (From Preston R. Musculoskeletal disorders. In Chestnut DH, Wong CA, Tsen LC, Ngan Kee WD, Beilin Y, Mhyre JM (eds.). Chestnut’s Obstetric Anesthesia: Principles and Practice (5th ed.). Philadelphia: Elsevier Saunders; 2014, p. 1099. Reprinted with the permission of Elsevier.)

airflow; more work is necessary to expand the lungs to any volume. The actual work done is reduced if patients with scoliosis breathe faster and at smaller volumes. However, a normal dead space in conjunction with small-tidal-volume breathing results in increased wasted ventilation. Increased ventilatory requirements may result in a large increment in respiratory work, and, as the respiratory work increases, the risk of respiratory failure increases. Muscle fatigue and respiratory failure result if the respiratory muscles are forced to work at a sustained intensity of > 40% of maximum.20,28 Dyspnea on exertion occurs before the onset of alveolar hypoventilation. The degree of spinal deformity usually correlates with symptom severity. Cardiorespiratory symptoms are unusual with curves < 70 degrees. Dyspnea is more common as the deformity exceeds 100 degrees and alveolar hypoventilation occurs when angles exceed 120 degrees. In younger patients with moderate thoracic scoliosis (25–70%), impaired exercise capacity is more likely due to deconditioning and lack of regular aerobic exercise than intrinsic ventilatory impairment.29 Patients with severe scoliosis (curve > 90 degrees) frequently experience sleep-disordered breathing, night-time hypoxemia, and daytime hypercapnia.20,30

Scoliosis is associated with cardiac anomalies on a spectrum of severity.31 Most patients with AIS do not have congenitally abnormal hearts, but the incidence of mitral valve prolapse exceeds 25%. Children with congenital heart disease have an increased incidence of scoliosis.32 The cardiovascular abnormality most associated with scoliosis results from restrictive pulmonary disease. The consequences of impaired lung development and alveolar hypoxemia are increased pulmonary vascular resistance, pulmonary hypertension, and right ventricular hypertrophy. Permanent changes of the pulmonary vasculature are common with a thoracic curve > 70 degrees.20 Pulmonary hypertension arising from scoliosis is mainly attributable to increases in PVR resulting from chronic alveolar hypoxia (PaO2 < 60 mmHg), hypoxic pulmonary vasoconstriction, and anatomic vascular alteration. Fixed pulmonary hypertension, unresponsive to supplemental oxygen therapy, carries a grave maternal prognosis during pregnancy, and should prompt a discussion regarding maternal risks of continuing the pregnancy.33,34 Though mortality rates are still very high at 11.5/100 pregnancies, recent evidence suggests improvement in maternal outcomes in the setting of pulmonary hypertension due to improved management and treatment options.35 The evaluation and care of patients with pulmonary hypertension is discussed in detail in Chapter 6 and the reader is referred there for a more complete review. Valuable Clinical Insights • Severe scoliosis may induce pulmonary hypertension and cor pulmonale secondary to pulmonary vasculature abnormalities, restrictive lung disease, and alveolar hypoxemia. • Pulmonary hypertension in pregnancy carries a poor maternal and fetal prognosis.

Scoliosis Associated with Neuromuscular Disease – Cardiopulmonary Manifestations The pathophysiologic sequelae of scoliosis from a primary neurologic or myopathic disorder differ from those of idiopathic scoliosis. Neuromuscular disorders tend to present in early childhood when the thorax is highly compliant and pulmonary development is incomplete; severe anatomical distortion of the thorax and pulmonary hypoplasia may result. Unlike AIS, which tends to stabilize with skeletal maturity, scoliosis in neuromuscular disorders progresses incrementally with

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increasing muscle weakness. Abnormal respiratory function results from the skeletal deformity of scoliosis, abnormalities in the central control of respiration, and aberrant supraspinal innervation of muscles. Abnormal respiratory function also results from the loss of muscle function due to lesions of the motor neurons and peripheral nerves or a myopathy. Further compromise may result from impairment of the airway defense mechanisms caused by loss of control of the pharynx and the larynx, ineffective cough mechanisms, and infrequent or reduced large breaths. Recurrent aspiration pneumonitis may result from these compromised airway protective reflexes. Sleep-disordered breathing is also more prevalent compared to unaffected individuals. The prognosis for the patient with scoliosis caused by neuromuscular disease is determined predominantly by the progression of the primary disorder and is worse than that for idiopathic scoliosis. The neuromuscular disorders usually involve the inspiratory and expiratory muscles, resulting in moderate to severe decreases in inspiratory capacity (IC) and expiratory reserve volume (ERV). Functional residual capacity remains normal until the diseases are well advanced or a significant degree of thoracic scoliosis is superimposed. Diaphragmatic weakness or paralysis attributable to the underlying disorder can further compromise VC, and hypoventilation becomes a prominent feature. If rib-cage expansion is limited by neuromuscular involvement, respiratory function is severely compromised, and a restrictive pattern of lung disease develops. With advancing gestation, encroachment of the expanding uterus further compromises lung function resulting in respiratory insufficiency. Hypoxemia may be present for prolonged periods before the onset of hypercapnia. Pulmonary vasoconstriction, hypertension, and right heart failure occur owing to the same etiologic considerations as for idiopathic scoliosis. A primary myocardial impairment can be superimposed on the acquired cardiovascular derangements in conditions such as muscular dystrophy and Marfan disease (Chapters 10 and 7).20,36,37

Interaction of Pregnancy with Scoliosis Impact of Pregnancy on the Spinal Deformity Pregnancy may exacerbate both the severity of spinal curvature and cardiorespiratory abnormalities in patients with uncorrected scoliosis. The factors that predict curve progression are the same in pregnant and nonpregnant women. Thus, a young skeletally immature woman with uncorrected moderate to severe scoliosis would be at particular risk for curve progression during pregnancy. Curves that are mild and have been stable before the pregnancy tend not to progress during the pregnancy.3,38–41 More severe curves and those that have not yet stabilized may progress, although any curve progression during pregnancy usually is minor and of uncertain significance.12,13,41,42 There is no evidence of curve progression in women treated with bracing or surgery as adolescents, who then become pregnant.12,13,43 Some have linked maternal morbidity and mortality to the severity of the curve, but the actual correlation appears to be with the amount of functional impairment present before pregnancy.44 Patients with severe curves (Cobb angle ≥ 90 degrees)

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but good cardiopulmonary function tolerate pregnancy well.45 The incidence of gestational back pain is higher than expected in patients with uncorrected scoliosis and in patients who have undergone spinal fusion to L3 or L4.46,47 Valuable Clinical Insight Mild curves in skeletally mature women, and surgically stabilized curves do not progress in pregnancy.

Effect of Pregnancy on the Cardiopulmonary Pathophysiology of Scoliosis When evaluating the parturient with significant cardiopulmonary disease, the signs and symptoms consistent with normal pregnancy and advancing gestation should be distinguished from those that may herald deterioration in a chronic maternal condition. For example, although most parturients complain of dyspnea by the middle of the third trimester, exercise testing shows no deterioration in exercise response during moderate activity. A pathologic deterioration in respiratory function is associated with a significant decrease in exercise tolerance. Two features help differentiate physiologic from pathologic dyspnea.48,49 Physiologic dyspnea begins earlier in pregnancy and often reaches a plateau or improves as term approaches. It is rarely severe, and patients can usually maintain daily activities. The dyspnea of cardiopulmonary decompensation is progressive, becoming worse as gestation advances and physiologic demands increase. If dyspnea is extreme, has a limiting impact on everyday activity, occurs at rest or with minimal exertion, or is associated with a cough, then maternal cardiorespiratory decompensation should be ruled out.48 Dyspnea that is acute in onset or progressive and intractable, especially if coupled with other signs and symptoms (orthopnea, paroxysmal nocturnal dyspnea), is more likely to represent cardiopulmonary disease. The thoracic cage expands in circumference during normal pregnancy due to increases in both anteroposterior and transverse diameters. Little potential exists for further thoracic cage expansion during inspiration. Inspired volumes in the term pregnant woman are primarily attributable to diaphragmatic excursion. If the chest cage is fixed by scoliosis, the diaphragm is entirely responsible for all increments in minute ventilation. As the enlarging uterus enters the abdominal cavity in mid-­gestation, diaphragmatic activity is constrained, and FRC decreases to 70% (supine) to 80% (upright) of nonpregnant values by term gestation. There is also a reduction in closing capacity (CC). More than anticipated decreases in FRC and CC can be seen in patients with scoliosis, causing V/Q mismatch and reduced arterial oxygen content. Minute ventilation increases by 40% to 50% during pregnancy, and the increase is primarily a result of increased TV with RR relatively unchanged. In the scoliotic patient with restrictive lung disease, such increases in TV may not be possible, so increased MV would require an increased RR. This results in both wasted ventilation and increased work of breathing, so respiratory failure may result. The demands on the pulmonary

Disorders of the Vertebral Column

system peak by mid-third trimester but, because the uterus continues to grow through the third trimester, it may encroach further on the noncompliant thorax and cause further deterioration even though respiratory demand has stabilized. The onset of new respiratory symptoms or the exacerbation of preexistent symptoms during the antepartum period is associated with increased maternal morbidity and the need for assisted ventilation.50 Minute ventilation in an unmedicated parturient increases by 75% to 150% in the first stage of labor and by 150% to 300% in the second stage. These levels may be either unattainable or unsustainable by the scoliotic parturient with restrictive lung disease, and respiratory insufficiency or failure may result. In parturients with neuromuscular scoliosis, decreased lung volume with advancing pregnancy results in increased V/Q mismatching, decreased arterial oxygen content, and carbon dioxide retention. These effects may be accentuated during sleep because of a further reduction in lung volumes from loss of muscle tone and cephalad shift of the diaphragm in a supine position. Upper airway resistance increases during pregnancy from mucosal hyperemia, increased secretions, and, occasionally, nasal polyps. These changes predispose the patient to snoring and obstructive sleep apnea.51 Weakness of muscles that stabilize the upper airway is common in diffuse muscle disorders, and this weakness may increase the incidence, severity, and ­maternal–fetal implications of sleep apnea. These factors increase alveolar hypoxia and worsen pulmonary hypertension. Risk factors for ventilatory failure during pregnancy have been identified (Table 12.2).52 The use of noninvasive ventilation to reduce dyspnea and improve respiratory function has been reported.53 Cardiac output (CO) increases 40% by the end of the first trimester and is 50% above nonpregnant levels by the third trimester; HR and SV increase to augment CO. In scoliotic parturients with increased PVR, it may not be possible to achieve a higher CO without further increasing vascular pressures and right ventricular afterload. This may put an intolerable load on the right ventricle, precipitating right heart failure with low CO leading to poor myocardial perfusion and refractory failure. Death at the time of delivery or in the early postpartum period is not unusual in parturients with pulmonary hypertension.33,35

Outcome of Pregnancy in Scoliotic Parturients Isolated cases of maternal death during pregnancy and the postpartum period have been reported in patients with scoliosis, although pregnancy is usually well tolerated with few medical or obstetric complications.11,12 The reproductive experiences of women with scoliosis depend not only on the severity of the curve and the resulting cardiopulmonary sequelae but also on the presence of underlying neuromuscular disorders. Kafer Table 12.2  Risk factors for ventilatory failure in parturients with neuromuscular scoliosis Elevated PaCO2 Bilateral diaphragmatic impairment Extensive intercostal muscle weakness Vital capacity < 1.0 liter Cobb angle > 100 degrees

et al. suggested that complications are more likely in the older parturient (> 35 years) with severe scoliosis, in parturients with scoliosis associated with an underlying neuromuscular disease, and in primiparas who develop fatigue during prolonged labor.7 Premature labor has been reported to be more common in scoliotic parturients and to be independent of the severity of the curve.10,42,46,50 However, Danielsson and Orvomaa could not repeat this observation in two of the largest series of parturients with treated idiopathic scoliosis.11,12 Compared with population averages, the incidence of lowbirth-weight infants and congenital anomalies is not increased in women with moderate uncorrected or corrected curves.10,11,12 The likelihood of intrauterine fetal compromise rises with the frequency and severity of maternal hypoxic episodes.52 Malposition at delivery is not common; in patients without cephalopelvic disproportion, vaginal delivery occurs uneventfully at the same rate as controls. When scoliosis or other underlying disease distorts pelvic anatomy, operative or instrumented deliveries, perineal tears, and uterine prolapse occur with greater frequency, leading to a higher rate of maternal and fetal morbidity. In the second stage of labor, the diaphragm acts as a respiratory muscle and has a nonrespiratory function. With expulsive efforts, maximal isometric diaphragmatic contractions last for 10 to 20 seconds. Diaphragmatic fatigue has been demonstrated in healthy laboring women.50 However, in one report, the incidence of acute respiratory failure during delivery was sporadic in healthy parturients, but in the woman with a weak diaphragm from a neuromuscular disease, the potential for respiratory difficulties is greater.53,54 Expulsive forces are also decreased and may lead to a prolonged second stage or even failure of a trial of labor. Cesarean delivery is required in a significant proportion of scoliotic parturients. The indications may be related to the degree of skeletal deformity, maternal compromise, and cephalopelvic disproportion. In patients with severe curves, the rates for CD range up to 52%.6,55,56 Lebel also found higher rates (21.4% vs. 13.1%) of CD in patients with AIS, which was attributed to its association with nulliparity, labor induction, and maternal age; labor dystocia and cephalopelvic disproportion were not independent risk factors for CD.57 In contrast to these reports, Chan’s single-institution retrospective review of parturients with both corrected and uncorrected mild to moderate AIS did not find increased rates of CD.42 CD may be technically more difficult in patients with severe curves, especially those with lumbar spinal involvement. This difficulty is from acute ante-flexion of the uterus in the small abdominal cavity because the xiphisternum and the symphysis pubis are closer. The lower uterine segment may be inaccessible, making CD by vertical incision necessary,56 although Kopenhager, reporting on 25 CD in women with severe kyphoscoliosis, noted that classic CD was required in only one.6 Patients with corrected scoliosis tolerate pregnancy, labor, and delivery well, although some studies have demonstrated an increased incidence of operative delivery.42,47,58 Grabala et al. reported rates of CD in patients with surgically corrected AIS that were nearly twice that of the unaffected population (64% vs. 33% respectively); the risk of CD increased as the lower level of

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lumbar fusion increased. In Danielsson’s study, the rate of vacuum extractions was higher in surgically treated patients (16%) than in either the brace-treated (8%) or the control cohorts (5%).11 Others failed to demonstrate an increased requirement for operative delivery in patients with corrected scoliosis.12,13,40 Orvomaa et al. reported that rates of pregnancy or labor complications were similar to national statistics and although there was an increased requirement for CD, the indications for surgery were not typically scoliosis-related.12 In a report of 355 patients with scoliosis and prior posterior fusion, CD was necessary for only 2.5% of deliveries.40 In another review, there were 27 pregnancies in 17 women with kyphoscoliosis (idiopathic in nine women and post-traumatic scoliosis the next most frequent cause); their experience was similar to the unaffected population.13

Management Issues in the Scoliotic Parturient Antepartum Assessment and Medical Management Prepregnancy planning in women with scoliosis serves two purposes. It allows for counseling regarding the risk of inheritable disease in offspring when there is a significant genetic component, and it allows for evaluation of the maternal risk in carrying a gestation to term. Most patients with scoliosis have mild to moderate idiopathic curves, and the expectation is that they will tolerate pregnancy, labor, and delivery with a rate of complications comparable to that in the unaffected population. Maternal morbidity is predominantly due to cardiopulmonary failure and is related to the site (thoracic) of the curvature and degree of cardiopulmonary compromise before pregnancy. Morbidity and mortality increase if the VC is < 1 to 1.25 liters, if PaCO2 is elevated, or if pulmonary hypertension with ventricular compromise is present.33,52,53,59–62 These are considered indications for counseling regarding the maternal risk of commencing or continuing a pregnancy. However, Lapinsky noted that even in the setting of severe reductions (less than 1.0 liters) in FVC, pregnancy may be managed with few complications.53 Pregnancy is well tolerated if antenatal lung volumes exceed 50% of those predicted.38,44 Scoliosis secondary to a primary neuromuscular disorder might be associated with higher gestational morbidity than idiopathic scoliosis.52 Young women with uncorrected moderate to severe curves that are not yet stable should be advised that there is a risk of curve progression during pregnancy. Conversely, there seems little risk of progression if the curve is mild or has been stable, and little to no risk if the curve has been surgically stabilized.11,12,41,43 The antepartum maternal assessment focuses on the mother’s cardiorespiratory status with attention to the history and current status; the presence of coexistent disease; and type, status, and patient prognosis of associated neuromuscular disorders. If respiratory compromise is evident, there should be a formal respiratory evaluation. An assessment is made of the respiratory reserve, including inspiratory and expiratory muscle function and the integrity of the airway protective reflexes. Special attention should be paid to the presence of dyspnea, tachypnea, and exercise tolerance, and recent PFT reviewed. In pulmonary hypertension, serial six-minute walk tests are used to evaluate

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maternal functional class.33 Maternal oxygen saturation should be measured at all visits after the first trimester due to increasing oxygen demands. Nocturnal hypercapnia precedes daytime ventilatory failure, and can be measured during a sleep study.53 Further evaluation is made concerning the possible benefits of supplemental oxygen therapy, nocturnal continuous positive airway pressure (CPAP) and assisted ventilation. Patients with curves > 60 degrees or those with cardiac disease require formal cardiologic evaluation to assess ventricular size and function and pulmonary vascular pressures. Patients with known pulmonary hypertension require echocardiography for ongoing assessment of pulmonary pressures and RV function. Measurement of brain natriuretic peptide has been recommended in pulmonary hypertension; it is a valuable marker of RV function, and elevated levels are associated with worse outcomes.33 In women with severely compromised cardiopulmonary function, counseling regarding their risks of continuing the pregnancy is indicated. A shared decision-making approach with evidence-based information is advised.63 Despite the risk, many will choose to continue with pregnancy. The value of a team approach to these high-risk patients cannot be overstated. The team includes internal medicine, obstetrics, perinatology, neonatology, anesthesiology, and other consultants; the team is complemented by nursing and social services personnel. The team should meet, in whole and in part, at regular intervals to monitor maternal condition and progress of the pregnancy. This management approach helps to reduce morbidity and mortality even in very high-risk parturients.59 Patients with underlying neuromuscular disease or cardiopulmonary dysfunction related to scoliosis represent an exceptionally high-risk group for antepartum maternal decompensation. In the setting of pulmonary hypertension, the risk of maternal decompensation increases after 24 weeks estimated gestational age.33 These patients benefit from a high surveillance strategy; frequent outpatient assessments or even admission to hospital for the last weeks of pregnancy may be necessary to increase chances that maternal decompensation will be recognized early and morbidity or mortality prevented. Oxygen therapy, intermittently during the day and continuously overnight, may improve the maternal condition and reduce fetal risk. Noninvasive ventilatory support for respiratory insufficiency during pregnancy in parturients with severe kyphoscoliosis has been reported.53,64,65 Chronic hypoxemia and polycythemia combined with the hypercoagulable state of pregnancy increase the risk for thromboembolic events.33 Consideration should be given to antithrombotic therapy with subcutaneous LMWH.66 Cardiac monitoring during the peripartum period is recommended for those women with significant cardiopulmonary dysfunction. Continuous pulse oximetry and 5-lead ECG telemetry allow for ongoing assessment of maternal oxygenation, shunt deterioration, dysrhythmias, and cardiac ischemia. A radial arterial line allows for continuous assessment of maternal BP and serial arterial blood gases. Central venous pressure monitoring is of limited utility in laboring women.34 Point of care TTE is noninvasive and allows for rapid assessment of maternal hemodynamic compromise during labor and delivery.

Disorders of the Vertebral Column

Valuable Clinical Insight Antepartum echocardiography is recommended for pregnant women with thoracic curves > 60 degrees to measure pulmonary pressures and cardiac function.

Obstetric Management In parturients with little or no cardiopulmonary compromise at the onset of pregnancy, the expectation is for an uneventful pregnancy and delivery. As the pregnancy advances, the cardiopulmonary signs and symptoms of normal pregnancy must be differentiated from actual deterioration in function. The perinatologist is best positioned to monitor for untoward maternal responses during pregnancy by virtue of the frequency of antenatal visits. If there is concern that the maternal condition is deteriorating, re-evaluation by a medical consultant is required to quantify the change and initiate therapy. Although right heart failure may mimic PreE, peripheral edema being common in both, respiratory symptoms are usually profound in cor pulmonale and uncommon in PreE. Maternal decompensation early in the pregnancy is ominous. Decompensation in late pregnancy or during the early postpartum period is not unusual in women with borderline cardiopulmonary function. Obstetric intervention before full term is reserved for compelling maternal or fetal indications. At term, if maternal cardiopulmonary function and pelvic size are adequate and the fetal condition is good, a trial of labor is permitted and should be successful. Cesarean delivery is reserved for obstetric indications. A higher incidence of operative delivery may occur in patients with spinal fusion for scoliosis, but this has not been consistently reported.10–12,47,57,59,62 There is minimal alteration of the pelvic cavity in patients without major lumbosacral deformity, and malpresentation is not more frequent.6,10 In patients in whom the lumbar spinal deformity is prominent, however, malpresentation is common.56,67 Pelvic abnormalities are also more common when scoliosis is associated with neuromuscular disorders, which predisposes the fetus to malpresentation (Figure 12.6).52 Uterine function is typically normal in scoliosis; labor is not prolonged and SVD is anticipated. In patients with severe disease, those with scoliosis resulting from neuromuscular disease and especially in those with gestational decompensation, CD may be required due to maternal compromise. Patients with significant pulmonary hypertension should avoid bearing down, and an assisted vaginal extraction facilitates delivery in these patients. Oxytocin is a systemic vasodilator, and bolus doses should be avoided in parturients with pulmonary hypertension. Likewise, prostaglandin F2 alpha and ergot preparations should be avoided in the setting of advanced pulmonary hypertension due to their potential for further increasing PVR.33

Anesthetic Management Antepartum Assessment Patients who require antepartum anesthetic consultation include those with pulmonary hypertension, other cardiopulmonary findings, thoracolumbar scoliosis with a Cobb angle > 30 degrees, and spinal instrumentation and fusion for scoliosis.

Figure 12.6  Pelvic radiograph. X-ray study of the pelvis in a young woman with a progressive spinal muscular atrophy (Kugelberg-Welander syndrome) demonstrating an inadequate pelvic outlet. She delivered two children by CD under GA after failed attempts to perform regional anesthesia. Her chest film is detailed in Figure 12.2.

Initial anesthesiology contact should occur early in gestation, not later than the second trimester; the more severe the maternal condition, the earlier first contact is advised. Ongoing evaluation may be carried out via team conferences. A plan for anesthetic management should be created well before delivery, and the plan conveyed to the patient and the other team members. The underlying etiology of scoliosis and the location, severity, and stability of the curve should be elucidated. In patients with scoliosis resulting from neuromuscular disorders, anesthetic considerations specific to those disorders should be reviewed.68 Radiographic studies done before the pregnancy and operative notes related to surgical procedures on the spine should be assessed in any patient with significant scoliosis or previous major spinal surgery before consideration is given to NA. Reviewing diagnostic imaging taken in the past, even before pregnancy, is usually sufficient to determine the underlying anatomy and the residua of previous surgical interventions. If further diagnostic imaging is required, it should be deferred until there is little threat to the fetus (late second or third trimester). The spine should be examined, and a note made of the surface landmarks and the interspaces least involved in the deformity. Neuraxial ultrasound may be performed at the time of antenatal consultation to help facilitate planning for NA (Chapter 9).

Analgesia for Labor Modes of analgesia and anesthesia for labor and delivery are reviewed at the antepartum consultation. Patients with uncorrected thoracolumbar scoliosis may be offered NA for labor and delivery, even if the deformity is severe. Neuraxial procedures are technically more demanding than usual, and an increased incidence of complications should be anticipated and discussed. The midline of the epidural space is deviated toward the convexity of the curve, relative to the spinous process palpable at the skin level (Figure 12.7).69 The degree of lateral deviation is determined by the severity of the deformity. The needle should enter the selected interspace toward the convexity of the curve. Alternatively, Huang et al. have described a modified paramedian approach for epidural needle placement.70 The experienced clinician can track

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8. It may not be possible to perform an epidural blood patch if a significant postdural puncture headache occurs. 9. Persistent back pain is common in patients with surgically corrected scoliosis (correlates with increasing time since the surgery and extent of fusion).24,47,73 10. Patients often manifest high anxiety about their backs and may be reluctant to have a neuraxial procedure.

Apparent midline

True needle path

Plane of the back 35°

Figure 12.7  Vertebral displacement and rotation in moderate to severe scoliosis. The vertebral body deviates from the midline and undergoes rotation with the spinous process remaining closer to the true midline (defined as a line drawn from C7 to the sacrum). The interlaminar space is deviated toward the curve convexity. A needle entering the palpated interspinous gap must be directed toward the convexity of the curve to reach the interlaminar gap. Tracking the interspinous ligament can be used to determine the angle required; the angle is dependent on the magnitude of the curve.

the resistance of both the interspinous ligament and the ligamentum flavum to maintain a proper course into the epidural space. Structural curves < 30 degrees, and minor functional curves, seen commonly in term pregnant females, rarely result in much rotatory deviation of the vertebrae. Little change in technique is needed for successful needle or catheter placement. Some believe major spinal surgery represents a relative contraindication to NA; however, current evidence supports the provision of NA to parturients who have previously undergone spinal instrumentation. The incidence of successful block is reduced, and complications are more frequent, especially in patients who have had extensive surgeries involving the lumbar spine; however, it has been suggested that success rates may improve due to modern surgical techniques.69,71 When discussing NA with women who have undergone extensive spinal surgery, consideration should be given to the following: 1. Twenty percent of patients’ spines are fused to L4 and L5 levels, leaving few lumbar interspaces uninvolved.69 2. Reliable surface landmarks are absent following surgery. 3. Degenerative changes occur in the spine below the fusion area faster than usual, and these changes may increase the chance of technical difficulties entering the space or achieving a block.69 4. Insertion of an epidural needle by either the midline or paramedian approach in the fused area may not be possible because of the presence of instrumentation, scar tissue, and bone graft material.72 5. A false loss of resistance is common. 6. The ligamentum flavum may be injured during surgery, resulting in adhesions in, or obliteration of, the epidural space, which interferes with LA spread within the space.69 7. Obliteration of the epidural space may make accidental dural puncture inevitable in some patients.

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Placement of an epidural catheter is recommended early in labor. This will ensure adequate time for testing and troubleshooting, improve patient cooperation, and allow for bedside neuraxial US to facilitate the procedure. Parturients with cardiopulmonary disease also benefit from early and adequate labor analgesia to mitigate the physiologic stresses of labor. Painful labor results in hyperventilation, tachycardia, increased CO, and oxygen demands, all of which are undesirable in this population.34 In most parturients and in particular those with significant cardiovascular compromise, a dilute LA-opioid mixture (e.g., bupivacaine 0.0625–0.1% or ropivacaine 0.08–0.125% with fentanyl 2–4 mcg/ml) is more likely to provide excellent first-stage and good second-stage analgesia with fewer hemodynamic consequences compared with more concentrated LA solutions.74,75 Careful incremental titration of NA is warranted in the setting of cardiopulmonary disease to mitigate the degree and onset of hemodynamic changes.34 Bauchat et al. demonstrated that after modern surgical techniques, parturients with scoliosis and spinal instrumentation required similar hourly amounts of epidural solution and interventions compared with a control population.71 Combined spinal-epidural analgesia, DPE, and CSA are all options in patients in whom the intervertebral spaces can be reached. Compared with epidural analgesia alone, these techniques provide faster onset of analgesia, improved sacral block and block symmetry, and a lower risk of a failed block with confirmatory return of CSF. The advantages and disadvantages of each technique are well described.75,76 Intrathecal opioids represent another option for labor analgesia. Some reports suggest less hemodynamic compromise with opioids than with LA alone,77–81 whereas others have observed that the incidence and magnitude of hypotension is similar between the two therapies.82 Continuous subarachnoid infusion of sufentanil for effective labor analgesia has been described in normal populations and parturients with severe cardiac disease.83,84 If the opioid alone provides inadequate pain relief, small, hemodynamically innocuous does of dilute LA are usually adequate supplements. Valuable Clinical Insights • Neuraxial anesthesia can be offered to patients with advanced uncorrected scoliosis and surgically corrected scoliosis; higher rates of complications, including failure, are anticipated. • In cases of mild scoliosis, no adjustment to needle direction is usually required; with moderate to severe scoliosis the needle path should be directed toward the convexity of the curve. • Use of neuraxial US may facilitate needle placement (Chapter 9).

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Anesthesia for Operative Delivery in Parturients with Scoliosis Cesarean delivery may be indicated for maternal or fetal welfare or for obstetric reasons. Parturients with severe scoliosis often are small and frail. During surgery, the rib hump and bony prominences should be padded, with care taken to minimize heat loss. The patient’s small size may occasionally necessitate pediatric-sized equipment, such as BP cuff. General anesthesia or NA may be provided and there is no evidence that supports one over the other in this patient population. Neuraxial Anesthesia for Operative Delivery If NA is used, a slow and incremental extension of the block provides ideal conditions for operative delivery and postoperative analgesia. Because LA dose requirements are variable, an epidural, low-dose CSE or CSA is preferable to a single-shot subarachnoid injection. Particular attention should be paid to the dose of LA because the patient’s small size may render usual volumes excessive. In patients with severe curves, there is speculation that subarachnoid hyperbaric LA solution may pool in dependent portions of the spine, resulting in an inadequate block.76,85 Supplementing the block with isobaric formulations of LA may improve the quality of the block; supplementation is facilitated with an indwelling intrathecal catheter. Multiple reports exist about epidural anesthesia in parturients with severe scoliosis, including those with cardiopulmonary compromise and corrective instrumentation. Performance of NA in these patients is technically demanding and may be complicated by failed or inadequate block. Block quality may be enhanced by supplemental epidural injection of chloroprocaine when dose limits of the other agents have been reached or by intrathecal injection of small doses of LA.75,86 Publications exist that describe extensive spinal blocks causing profound hemodynamic instability after a full-dose subarachnoid injection is used following failure to convert a labor epidural into an anesthetic.87–90 If time permits, allowing the epidural block to regress before performing the spinal block is recommended.91 Alternatively, reducing the dose of LA agent injected into the subarachnoid space is recommended if an incomplete epidural block is present.90 The rate of mortality related to CD in patients with pulmonary hypertension is considerable.35 The high mortality rate is probably partly due to the presurgical status of the mother and reflects her poor condition. Prognosis is related to the preoperative maternal condition, with survivors demonstrating adequate RV function. There is evidence that NA is as safe as GA in parturients with pulmonary hypertension, but as noted earlier, this may be related to the severity of the disease.35 Both CSE and CSA have been reported with good outcome.92,93 When NA is used, a technique which permits cautious and incremental titration to achieve the required level of block is recommended. General Anesthesia General anesthesia may be used because of maternal preference or maternal cardiopulmonary decompensation, or technical difficulties related to NA. A complete maternal airway examination is required because several conditions associated with scoliosis, including severe scoliosis itself, are associated with difficult laryngoscopy and intubation. Many patients with scoliosis

resulting from neuromuscular diseases have preexisting airway obstruction and may have sleep apnea. Patients may be at risk for airway complications postoperatively, due to relaxation of the pharyngolaryngeal reflexes after GA.94 Elements of laryngeal incompetence and impaired swallowing may further decrease the integrity of the airway defense mechanisms, increasing the risk for postoperative decompensation. In unaffected patients, the FRC decreases at induction of anesthesia; this is attributable to cephalad shift of the diaphragm, ribcage dysfunction or instability, and increased intrathoracic blood volume. Abdominal surgery also produces persistent postoperative decreases in FRC that are progressive, becoming evident hours after surgery.95,96 The decreases in FRC are related to diaphragmatic dysfunction and may persist for up to one week. Atelectasis and V/Q abnormalities, which impair gas exchange and result in hypoxemia in normal subjects, may occur. However, in scoliotic parturients with underlying pulmonary pathology, these effects are augmented and may result in significant postoperative morbidity. Other causes of postoperative hypoxemia that are of particular importance to patients with scoliosis are included in Table 12.3. Anesthesia, tracheal intubation, and surgery result in mucociliary dysfunction and abnormal or retrograde mucous flow.97 Reduced competence of the larynx increases the potential for postextubation aspiration in patients already at risk because of pregnancy and underlying airway disorders. Coughing and bucking at the end of surgery may transiently and significantly reduce FRC, resulting in further V/Q mismatch and hypoxemia.98 Tracheal extubation after CD in those with gestational hypertension may result in increased systemic arterial and pulmonary artery pressures.99 These pressure rises take on added significance in the setting of preexisting pulmonary hypertension. Criteria for postoperative extubation must include assessment of preoperative respiratory function. An assessment of respiratory muscle strength and ability to support the airway should be made in all patients, but it is vital in patients with preexisting compromise. A preoperative FVC < 40% predicted or maximum inspiratory and expiratory pressures < 30 cm of H2O increase the likelihood of failed extubation.20 Potential hazards of GA in parturients with pulmonary hypertension include increased pulmonary artery pressures during laryngoscopy and intubation; adverse effects of positive-pressure ventilation on venous return; and negative inotropism of some anesthetic agents. These adverse effects can be attenuated by an opioidsupplemented induction and maintenance technique.100 Nitrous oxide should not be used because it increases PVR. The patient will require high surveillance care for up to a week following Table 12.3  Factors contributing to postoperative hypoxemia in scoliotic parturients Increased V/Q mismatch Increased alveolar-to-arterial oxygen gradient Inhibition of hypoxic pulmonary vasoconstriction Decreased CO Underlying preexistent pulmonary disease Restriction of chest wall movement

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delivery because major cardiopulmonary complications are common during this period.

Other Disorders of the Vertebral Column Lumbar disc herniation Back pain is a common complaint in pregnancy, affecting more than half of all pregnant women.101–103 Its occurrence during gestation seems most closely correlated with back symptoms in the prepregnant state, although new onset back pain is common in pregnancy. It is likely related to both changes induced by relaxin and estrogen and the biomechanical stresses imposed on the axial skeleton, including anterior displacement of the center of gravity, increased pelvic tilt, and lumbar lordosis. Low back pain is often overlooked in pregnancy and seemingly considered part of the natural history; however, it is not without morbidity and can seriously affect maternal function.103 Symptomatic lumbar disc herniation is a rare but notable cause of low back pain in pregnancy. Intervertebral discs function to disperse the axial stresses of the spine. They are composed of an outer annulus fibrosus and an inner nucleus pulposus; for a disc to herniate, there needs to be disruption of the annulus fibrosus. Traditionally herniation was attributed to trauma, but emerging evidence suggests genetics are a major contributing factor.104 Symptomatic lumbar disc herniation classically presents with radicular pain and sensorimotor weakness in the lumbosacral nerve roots. Lumbosacral disc bulges and herniations are common in women of childbearing ages, occurring in slightly more than half of all women in this age group.105 Despite the prevalence of back symptoms during pregnancy and the common occurrence of disc herniation in women of childbearing age, symptomatic lumbar disc herniation is rare during pregnancy, estimated to occur in one in 10,000 pregnancies.102 Pregnancy is not an independent risk factor for disc herniation. A systematic review of the management of symptomatic lumbar disc herniation in pregnancy identified 30 case reports and case series involving 52 patients.102 Most of the patients were treated conservatively at the outset but 39 subsequently received surgery due to intractable pain or progression of neurological deficits; 18 of the 39 had cauda equina syndrome. It is unclear whether conservative or surgical management has superior outcomes, but not surprisingly patients with more severe symptoms necessitating surgical management were less likely to have full resolution of their symptoms. Pregnancy outcomes were favorable for patients treated both conservatively and surgically. Neuraxial anesthesia has been employed for both the disc surgery as well as for the subsequent labors and deliveries without apparent sequelae.102,106–108 A conservative approach is warranted when disc herniation occurs in pregnancy; surgical intervention is reserved for women with significant neurological compromise (e.g., cauda equina syndrome). In the absence of progressive or significant neurological compromise or intractable pain, management is expectant.103,104 Conservative management may consist of oral analgesics, physical therapy, bracing, and (if symptoms persist) epidural steroid injections. Over 85% of patients will have resolution of symptoms within six weeks of conservative

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measures.102 Magnetic resonance imaging is considered to be the imaging modality of choice. If surgery is deemed necessary, NA may be used; both lateral and prone operative positions have been described. There is limited published obstetric experience managing labor and delivery in women with disc herniation. If symptoms worsen, CD may decrease intrathecal pressures and the risk of symptom exacerbation during labor and delivery.102 A multidisciplinary care plan should be tailored to each patient and a baseline neurological exam performed. A retrospective review by Hebl et al. examined NA success rates and neurologic outcomes in 937 patients (not specific to pregnancy) with a history of spinal stenosis, lumbar disc disease, or prior spine surgery. More than 75% of these patients had NA performed within two vertebral levels of their pathology. Fifty-eight percent of these patients had a spinal anesthetic, 38% an epidural, and the remainder a CSE or CSA. Block success was high. Ten patients (1.1%) experienced new deficits or worsening of preexisting symptoms; NA was presumed to be the contributing mechanism in five of these cases.109 Extrapolation of these results to the pregnant population is not clear. While symptomatic parturients may be at slightly higher risk of neurologic complications related to NA than previously thought, it is reassuring that it has a strong safety record in these parturients. Neuraxial anesthesia is appropriate for the provision of labor analgesia and surgical anesthesia in most women with lumbar disc disease.

Ankylosing Spondylitis Ankylosing spondylitis is a systemic inflammatory disease and the most common form of seronegative spondyloarthritis; over 90% of patients are HLA-B27 positive demonstrating a strong genetic association. Although men are more often affected at reported ratios of 2:1 to 9:1, over time the ratio has decreased as awareness of the condition in the female population has increased. The incidence and prevalence of ankylosing spondylosis are population dependent; one United States review placed the incidence at 7.2/100,000 and prevalence rates of 0.03–1.8% are reported.110,111 The peak incidence is in the second and third decades of life, which has obvious relevance to the obstetric population; however, advanced disease is very rare in the obstetric population. Symptoms typically include inflammatory back pain and associated enthesopathy and peripheral arthritis; extra-articular manifestations can include cardiac valvopathies (aortic insufficiency) and restrictive lung disease. Patients with ankylosing spondylitis may develop calcification of interspinous ligaments, vertebral column osteophytes, and ankylosis of the vertebral column with associated restriction of spinal flexion. Narrowing of the spinal canal and nerve root compression has been described.112 Diagnosis is made clinically (back pain and restricted spine mobility) with associated radiographic demonstration of sacroiliitis. There have been several reviews examining pregnancy outcomes in patients with ankylosing spondylitis.111,113,114 Unlike other autoimmune diseases, pregnancy has generally not shown to have a modulating effect on the course of ankylosing spondylitis. In fact, studies have demonstrated that disease flare in pregnancy and postpartum exacerbation of ankylosing spondylitis is common. Pregnant woman with ankylosing spondylitis may be

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at increased risk of preterm births and CD, though these findings have not been consistent across all studies. Advanced disease affecting the pelvis may act as a barrier to vaginal delivery.112 There are multiple anesthetic considerations relevant to the management of the parturient with ankylosing spondylitis. Advanced ankylosis of the vertebral column has obvious implications for both the provision of GA and NA. Ankylosis of the cervical spine may present severe limitations in neck mobility; there may also be concurrent cricoarytenoid or temporomandibular joint involvement and limited mouth opening. Awake intubation is commonly described in this population with advanced cervical spine involvement. Careful attention to patient positioning must be considered for neuraxial procedures and CD. Provision of NA and optimal positioning of the patient may be problematic given the changes to spinal ligaments and the vertebral column mentioned above. Spine imaging should be reviewed at the time of antenatal consultation. A paramedian approach can be considered if a midline approach is not possible.112 Higher neuraxial failure rates and complications have been described in the ankylosing spondylitis population.115–117 Due to the unpredictable spread of epidural LA solutions, placement of an intrathecal catheter has been advocated by some for both its reliability for labor analgesia as well as its utility should CD be required in a parturient with a nonreassuring airway.115 Neuraxial US is helpful for NA in this patient population.118 In advanced cases, antenatal and peripartum care should involve a multidisciplinary team. Extra-axial manifestations of ankylosing spondylitis should be explored at the time of antenatal visit, and cardiac or pulmonary involvement further investigated.

Spondylolysis and Spondylolisthesis Spondylosis is a defect of the pars interarticularis of the vertebral element; the neural arch is uninvolved in this anomaly. It may occur as either a congenital or acquired condition. If there is forward translation of the involved vertebrae with respect to the adjacent vertebrae, the condition is termed spondylolisthesis. Both conditions seem to be more common in women and occur frequently in women of childbearing age. Degenerative spondylolisthesis is most common at the L4/L5 level and in women.119 Pregnancy does not appear to constitute a risk for increased low back symptoms in women with spondylolysis or progression of spondylolisthesis.120 However, women who have had children have a significantly higher incidence of degenerative spondylolisthesis in later years.119 Pregnancy does not appear to complicate either spondylolysis or spondylolisthesis in most patients. The obstetrical and anesthetic management of individual patients with concurrent pregnancy and spondylolysis or spondylolisthesis is determined case-by-case.

Summary Most scoliotic patients will experience pregnancy, labor, and delivery with a similar incidence of complications as the general population. Within the population of scoliotic parturients, however, there is a subpopulation at high risk for morbidity and mortality. These patients include those with scoliosis resulting from neuromuscular disorders and those with severe restrictive

pulmonary disease complicated by pulmonary hypertension. A multidisciplinary team approach best serves these patients. Obstetric and anesthetic management is based on individual characteristics for patients with less common and less extreme syndromes affecting the vertebral column.

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65. Restrick LJ, Clapp BR, Mikelsons C, et al. Nasal ventilation in pregnancy: treatment of nocturnal hypoventilation in a patient with kyphoscoliosis. Eur Respir J 1997;10:2657–2658. 66. Chan WS, Rey E, Kent NE, et al. Venous thromboembolism and antithrombotic therapy in pregnancy. J Obstet Gynaecol Can 2014;36:527–553. 67. Chau W, Lee KH. Kyphosis complicating pregnancy. J Obstet Gynaecol Br Common 1970;77:1098–1102. 68. Lim G, Bader AM. Neurologic and neuromuscular disease. In Chestnut DH (ed.) Obstetric Anesthesia: Principles and Practice (6th ed.). Philadelphia: Elsevier; 2020, pp. 1160–1189. 69. Ko JY, Leffert LR. Clinical implications of neuraxial anesthesia in the parturient with scoliosis. Anesth Analg 2009;109:1930– 1934. 70. Huang J. Paramedian approach for neuroaxial anesthesia in parturients with scoliosis. Anesth Analg 2010;111:821–822. 71. Bauchat JR, McCarthy JR, Koski TR, et al. Labor analgesia consumption and time to neuraxial catheter placement in women with a surgical correction for scoliosis: a case matched study. Anesth Analg 2015;121:981–987. 72. Feldstein G, Ramanathan S. Obstetrical lumbar epidural anesthesia in patients with previous posterior spinal fusion for kyphoscoliosis. Anesth Analg 1985;64:83–85. 73. Sponseller PD, Cohen MS, Nachemson AL, et al. Results of surgical treatment of adults with idiopathic scoliosis. J Bone Joint Surg 1987;69A:667–675. 74. Chestnut DH, Owen CL, Bates IN, et al. Continuous infusion epidural analgesia during labor: a randomized, double-blind comparison of 0.0625% bupivacaine/0.0002% fentanyl versus 0.125% bupivacaine. Anesthesiology 1988;68:754–759. 75. Chau A, Tsen LC. Update on modalities and techniques for labor analgesia and anesthesia. Adv Anesth 2018;36:139–162. 76. Smith PS, Wilson RC, Robinson APC, et al. Regional blockade for delivery in women with scoliosis or previous spinal surgery. Int J Obstet Anesth 2003;12:17–22. 77. Cohen SE, Cherry SM, Holbrook RH Jr, et al. Intrathecal sufentanil for labor analgesia: sensory changes, side effects and fetal heart rate changes. Anesth Analg 1993;77:1155– 1160. 78. Ducey JP, Knape KG, Talbot J, et al. Intrathecal narcotics for labor cause hypotension (abstract). Anesthesiology 1992;77:A997. 79. Camann WR, Mintzer BH, Denney RA, et al. Intrathecal sufentanil for labor analgesia: effects of added epinephrine. Anesthesiology 1993;78:870–874. 80. Camann WR, Denney RA, Holby ED, et al. A comparison of intrathecal, epidural, and intravenous sufentanil for labor analgesia. Anesthesiology 1993;77:884–887. 81. Honet JE, Arkoosh VA, Norris MC, et al. Comparison among intrathecal fentanyl, meperidine and sufentanil for labor analgesia. Anesth Analg 1991;75:734–739. 82. D’Angelo R, Anderson MT, Philip J, et al. Intrathecal sufentanil compared to epidural bupivacaine for labor analgesia. Anesthesiology 1994;80:1209–1215. 83. Ransom DM, Leicht CH. Continuous spinal analgesia with sufentanil for labor and delivery in a parturient with severe pulmonary stenosis. Anesth Analg 1995;80:418–421. 84. Leicht CH, Evans DE, Durkan WJ. Intrathecal sufentanil for labor analgesia: results of a pilot study. Anesthesiology 1990;73:A980.

85. Moran DH, Johnson MD. Continuous spinal anesthesia with combined hyperbaric and isobaric bupivacaine in a patient with scoliosis. Anesth Analg 1990;70:445–447. 86. Crosby E, Read D. Salvaging inadequate epidural anaesthetics: the chloroprocaine save. Can J Anaesth 1991;38:136. 87. Beck GN, Griffiths AG. Failed extradural anaesthesia for Caesarean section. Complication of subsequent spinal block. Anaesthesia 1992;47:690–692. 88. Mets B, Broccoli E, Brown AR. Is spinal anesthesia after failed epidural anesthesia contraindicated for Cesarean section? Anesth Analg 1993;77:629–631. 89. Stone PA, Thorburn J, Lamb KSR. Complications of spinal anaesthesia following extradural block for Caesarean section. Br J Anaesth 1989;62:335–337. 90. Waters JR, Leivers D, Hullander M. Response to spinal anesthesia after inadequate epidural anesthesia. Anesth Analg 1994;78:1033–1034. 91. Pascoe HF, Jennings GS, Marx GF. Successful spinal anesthesia after inadequate epidural block in a parturient with prior surgical correction of scoliosis. Reg Anesth 1993;18:191–192. 92. Duggan AB, Katz SG. Combined spinal and epidural anesthesia for caesarean section in a parturient with severe primary pulmonary hypertension. Anaesth Int Care 2003;31:565–569. 93. Gandhimathi K, Atkinson S, Gibson FM. Pulmonary hypertension complicating twin pregnancy: continuous spinal anaesthesia for caesarean section. Int J Obstet Anesth 2002;11:301–305. 94. Miller KA, Harkin CP, Bailey PL. Postoperative tracheal extubation. Anesth Analg 1995;80:149–172. 95. Ali J, Weisel RD, Layug AB, et al. Consequences of postoperative alterations in respiratory mechanics. Am J Surg 1974;128:376–382. 96. Strandberg A, Tokics L, Brismar B, et al. Atelectasis during anaesthesia and in the postoperative period. Acta Anaesthesiol Scand 1986;30:154–158. 97. Gamsu G, Singer MM, Vincent H, et al. Postoperative impairment of mucous transport in the lung. Am Rev Respir Dis 1976;114:673–679. 98. Bickler PE, Dueck R, Prutow RJ. Effects of barbiturate anesthesia on functional residual capacity and ribcage/ diaphragm contributions to ventilation. Anesthesiology 1987;66:147–152. 99. Hodgkinson R, Husain FJ, Hayashi H, et al. Systemic and pulmonary blood pressure during Caesarean section in parturients with gestational hypertension. Can Anaesth Soc J 1980;27:389–394. 100. Wang J, Lu J. Anesthesia for pregnant women with pulmonary hypertension. J Cardiothorac Vasc Anesth 2021;35:2201–2211. 101. MacEvilly M, Buggy D. Back pain and pregnancy: a review. Pain 1996;64:405–414. 102. Whiles E, Shafafy R, Valsamis EM, et al. The management of symptomatic lumbar disc herniation in pregnancy: a systematic review. Global Spine J 2020;10:908–918. 103. Di Martino A, Russo F, Denaro L, et al. How to treat lumbar disc herniation in pregnancy? A systematic review on current standards. Eur Spine J 2017;26:s496–504. 104. Benzakour T, Igoumenou V, Mavrogenis AF, et al. Current concepts for lumbar disc herniation. Int Orthop 2019;43:841– 851.

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105. Weinreb JC, Wolbarsht LB, Cohen JM, et al. Prevalence of lumbosacral intervertebral disc abnormalities on MR images in pregnant and asymptomatic pregnant women. Radiology 1989;170:125–128. 106. Garmel SH, Guzelian GA, D’Alton JG, et al. Lumbar disc disease in pregnancy. Obstet Gynecol 1997;89(2):821–822. 107. Brown MD, Levi ADO. Surgery for lumbar disc herniation during pregnancy. Spine 2001;26:440–443. 108. LaBan MM, Rapp NS, Van Oeyen P, et al. The lumbar herniated disc of pregnancy: a report of six cases identified by magnetic resonance imaging. Arch Phys Med Rehabil 1995;76:476–479. 109. Hebl JR, Horlocker TT, Kopp SL, et al. Neuraxial blockade in patients with preexisting spinal stenosis, lumbar disk disease, or prior spine surgery: efficacy and neurologic complications. Anesth Analg 2010;111:1511–1519. 110. Zochling J, Smith EUR. Seronegative spondyloarthritis. Best Pract Res Clin Rheumatol 2010;24:747–756. 111. Timur H, Tokmak A, Turkmen GG, et al. Pregnancy outcome in patients with ankylosing spondylitis. J Matern Fetal Neonatal Med 2016;29:2470–2474. 112. Bourlier RA, Birnbach DJ. Anesthetic management of the parturient with ankylosing spondylitis. Int J Obstet Anesth 1995;4:244–247.

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113. Mokbel A, Lawson DO, Farrokhyar F. Pregnancy outcomes in women with ankylosing spondylitis: a scoping literature and methodological review. Clin Rheumatol 2021 (online). https:// doi.org/10.1007/s10067-021-05588-9 114. Jakobsson G, Stephansson O, Askling J, et al. Pregnancy outcomes in patients with ankylosing spondylitis: a nationwide register study. Ann Rheum Dis 2016;75:1838–1842. 115. Hoffman SL, Zaphiratos V, Girard MA, et al. Failed epidural analgesia in a parturient with advanced ankylosing spondylitis: a novel explanation. Can J Anesth 2012;59:871–874. 116. Mehrotra S, Gupta KL. Cesarean section in a patient with advanced ankylosing spondylitis. Int J Gyne Obstet 2005;89:272–273. 117. Schelew BL, Vaghadia H. Ankylosing spondylitis and neuraxial anesthesia – a 10-year review. Can J Anaesth 1996;43:65–68. 118. Vaghadia H, Germaine G, Tang R. Epidural analgesia in parturients with ankylosing spondylitis: a role for ultrasound surveillance and ultrasound-guided placement. Can J Anesth 2013;60:206–207. 119. Sanderson PL, Fraser RD. The influence of pregnancy on the development of degenerative spondylolisthesis. J Bone Joint Surg 1996;78-B;951–954. 120. Saraste H. Spondylolysis and pregnancy – a risk analysis. Acta Obstet Gynecol Scand 1986;65:727–729.

Chapter

13

Miscellaneous Skeletal and Connective Tissue Disorders Caroline S. Grange and Sally Anne Shiels

Introduction This chapter discusses miscellaneous skeletal and connective tissue conditions found during pregnancy, each with different degrees of rarity. It focuses on the pathophysiological changes that occur with each disease to highlight the impact of anesthetic and obstetric management. However, as some of the conditions described have wide and varied organ involvement, one cannot make firm management conclusions. Assess each case individually and evaluate the risk/benefit of any anesthetic choice for each patient.

Gorlin Syndrome (Basal Cell Nevus Syndrome or Gorlin-Golty Syndrome) Valuable Clinical Insights • Gorlin syndrome is a rare neurocutaneous syndrome with basal cell nevi, mandibular keratocytes, and other congenital abnormalities. • There is a predisposition for tumor formation. • Gorlin syndrome has no significant effects on pregnancy. • Potential anesthetic issues include: raised ICP (associated with CNS tumors), complex airway issues (related to orofacial deformities), challenging NA (associated with scoliosis), and cardiac issues (related to cardiac fibromas). • Beware of renin-secreting tumors and associated cardiovascular effects.

Gorlin syndrome, a rare neurocutaneous syndrome, was first described in 1960.1 Diagnosis is made clinically based on major and minor criteria.2 The characteristic features are multiple basal cell nevi, mandibular odontogenic keratocytes, and other congenital, primarily skeletal, abnormalities, i.e., multisystem involvement. There is a predisposition for tumor formation, including CNS tumors (mostly medulloblastomas), ovarian fibromas, skin, and cardiac tumors.3 Gorlin syndrome has an autosomal dominant mode of inheritance with complete penetrance and variable expression. However, up to 50% may arise from spontaneous mutations. The most common cause of Gorlin syndrome is a mutation of the PTCHI gene (on chromosome 9q 22.3), thought to act as a tumor suppressor gene; this results in an increased incidence of cancers. The estimated disease prevalence is 1: 56,000–256,000.3 There is no gender or ethnic predilection; however, black ethnic

groups develop fewer basal cell carcinomas, possibly due to the protective effect of melanotic pigmentation.4 Life expectancy is not significantly altered, although morbidity can be substantial. It is paramount to have a multidisciplinary approach to managing patients with Gorlin syndrome due to the myriad of clinical manifestations. Genetic counseling is essential, and antenatal diagnosis is possible. Fertility is not significantly reduced, despite the potential of ovarian cysts/fibromas/calcification, in addition to malignancies and use of chemotherapy.5 Ono et al.6 described a patient with Gorlin syndrome who required resection of bilateral ovarian fibromas. She subsequently had two consecutive spontaneous pregnancies and live births. Ultrasound scans during pregnancy may detect serious developmental complications. Some fetuses with Gorlin syndrome develop macrocephaly and may need an assisted forceps delivery or CD.7 Southwick and Schwartz8 followed a group of 36 patients with Gorlin syndrome, three of whom had severe bradycardic/ hypotensive reactions to GA. The authors postulated that these patients might have an unusual response to thiopental. However, there are no other similar reports in the literature which is reassuring, given that these patients require frequent surgery. Two reports of pregnant patients with Gorlin syndrome describe associated renin-secreting ovarian tumors.9,10 The first patient9 needed a laparotomy at 17 weeks gestation due to suspected malignant ovarian tumors. GA was induced with etomidate and succinylcholine and maintained with halothane, fentanyl, and pancuronium. The operation was uneventful except for hypertension, which occurred on handling the tumor. The patient made a good recovery but delivered prematurely at 27 weeks. The second pregnant patient10 had uncontrolled hypertension despite medical management and required a second trimester laparotomy to remove a renin-secreting ovarian tumor. Surgery was performed successfully under combined epidural and GA, and the patient was delivered at term. Both patients had mandibular cysts, but intubations were uneventful. Dasari et al.11 described the management of a parturient with Gorlin syndrome and Meig syndrome, who developed peripartum cardiomyopathy at 29 weeks gestation. Anesthetic management of her CD included a CSE, invasive arterial monitoring, and a phenylephrine infusion. After the baby was delivered, the parturient was managed successfully in the cardiothoracic unit.

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Table 13.1  Clinical features and anesthetic implications of Gorlin syndrome

Organ

Disease process

Potential anesthetic implications

CNS

CNS tumors Medulloblastomas (3–5%) Meningioma (1%) Congenital hydrocephalus Mild cognitive impairment (5%)

Raised ICP, seizures Consent issues

Skin

Basal cell carcinoma (50–97%) Mostly face/back and chest Palmar and/or plantar pits (90%)

No anesthetic implications

Orofacial

Odontogenic keratocytes (75–90%) Maxillary hypoplasia Mandibular hyperplasia Cleft lip/palate (5–7%) High arched palate (40%) Macrocephaly (40%) Frontal bossing (25%) Hypertelorism (5%) Widened nasal bridge (60%)

Potential airway issues

Spine/rib

Scoliosis Hemivertebrae Spina bifida occulta Fusion defects

Poor respiratory/CV function Difficulty with neuraxial blockade

Rib

Bifid/hypoplastic (38–60%) Chest wall deformities

Poor respiratory/CV function

Cardiac

Fibromas (3%)

Poor ventricular function Conduction defects Risk of endocarditis

Ovary/uterus

Fibroma (15%) (some renin secreting)

Hypertensive responses

Eye

Cataracts, cysts, nystagmus (10–25%)

Lung

Bullae (rare)

Skeletal

Potential for pneumothorax

Abbreviations: CNS = central nervous system; CV= cardiovascular; ICP = intracranial pressure.

The risks and benefits of NA and GA will depend on the patient’s individual features. If a renin-secreting tumor is suspected, anticipate managing a hypertensive crisis during tumor manipulation (Table 13.1).

Noonan Syndrome

• The most common cardiac abnormalities are pulmonary valve stenosis, atrial septal defect, and hypertrophic cardiomyopathy. • Improved outcomes from congenital cardiac surgery mean more cases are presenting in pregnancy. • A hematological deficit occurs in 50–89% of cases and may preclude the use of NA. • Other anesthetic issues include difficult airway management, challenging neuraxial blockade, and risk of hemorrhage.

First described in 1963,12 NS is a disorder characterized by abnormalities of the facial, cardiovascular, and skeletal systems. The incidence of NS is between 1:1000 and 1:2500 live births, and although inheritance is autosomal dominant, most cases are due to new mutations.13 Most involve a mutation of the PTPN11 gene on chromosome 12, and some involve the KRAS gene.13 Both sexes exhibit NS, but males have cryptorchidism and hypoplastic testes (hence are rarely fertile), whereas females are usually fertile, but often have a delayed menarche. Maternal transmission of the gene occurs three times as frequently as paternal transmission. The syndrome is similar to Turner syndrome: short stature, characteristic facies (ptosis, downward slanting eyes, hypertelorism, hooded eyelids, broad flat nose, high arched palate, micrognathia, and abnormal ears), shield-shaped chest deformity, and webbing (+/– fusion) of the neck.13,14 However, NS differs in that patients have a normal karyotype with a risk of cognitive disability, coagulation defects, skeletal abnormalities, and associated heart lesions (primarily right side rather than left, as in Turner syndrome). Although penetrance is thought complete, NS phenotypes show wide variability. Cardiac involvement occurs in 50–90% of patients affected by NS and is the second most common cause of congenital heart disease after trisomy 21. The most common cardiac abnormality is pulmonary stenosis (usually with a dysplastic valve), although many anomalies have been described, particularly atrial/ventricular septal defects, atrioventricular canal defects, and hypertrophic cardiomyopathy15 (Table 13.2). Although fertility is not an issue in women with NS, pregnancy and delivery complications largely depend on the occurrence and severity of associated organ dysfunction. Patients should be genetically counseled and assessed prenatally. Improved outcomes from congenital cardiac surgery have led to complex cardiac cases presenting in pregnancy. The Table 13.2  Cardiac abnormalities in patients with Noonan syndrome15

Type of cardiovascular disease

Incidence

None

Valuable Clinical Insights • Noonan syndrome (NS) is characterized by facial, cardiac, and skeletal abnormalities. • A complete evaluation is necessary as NS is a multisystem disease. • The effects of NS on pregnancy are due to associated cardiac and other abnormalities.

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10–16%

Congenital heart disease

Pulmonary valve stenosis Atrial septal defect Ventricular septal defect Atrioventricular canal defect Mitral valve disease Aortic coarctation

25–71% 4–57% 1–14% 1–13% 2–17% 2–9%

Other cardiovascular disease

Hypertrophic cardiomyopathy Arterial aneurysm

10–29% 5 mm in diameter in prepubertal and > 15 mm in postpubertal individuals • Freckling in the axillary or inguinal regions • Two or more iris hamartomas (Lisch nodules) • Two or more neurofibromas of any type or one plexiform neurofibroma • Optic glioma • A distinctive bony lesion, e.g., sphenoid dysplasia or medullary narrowing and cortical thickening of the long bone cortex • A first degree relative with NF1 (with the above criteria) Clinical features typically occur in a time-related way; initially café-au-lait spots, then axillary/inguinal freckling, Lisch nodules, and finally, neurofibromas.31 Café-au-lait spots are flat hyperpigmented macules, which increase in number and size during childhood but may fade in later life. Neurofibromas are benign peripheral nerve sheath tumors consisting of a mixture of Schwann cells, fibroblasts, perineural and mast cells. There are three distinct types of neurofibroma: cutaneous, nodular, and plexiform. Cutaneous (soft, fleshy) neurofibromas have no malignant tendencies but may cause major cosmetic issues. Nodular lesions (firm and rubbery) can cause compression effects due to increasing size, and although they do not infiltrate the surrounding tissue, they can be premalignant. In contrast, plexiform neurofibromas usually involve multiple and longer nerve segments; they can infiltrate and invade surrounding tissue and undergo malignant change. In addition to neurofibromas, patients with NF1 are at increased risk of developing benign and malignant tumors.32–34 Mutations of the NF1 gene result in loss of a functional protein (neurofibromin), which usually has a tumor-suppressor role. Malignancies associated with NF1 include optic glioma, astrocytoma, brainstem glioma, juvenile chronic myeloid leukemia, neurofibrosarcoma, rhabdomyosarcoma, breast cancer, medullary thyroid carcinoma, GI tumors, and pheochromocytoma. The estimated lifetime risk of cancer is up to 60% in NF1 patients, and this, combined with cardiovascular events, is the reason for reduced life expectancy.35 Other associated

Miscellaneous Skeletal and Connective Tissue Disorders

conditions include short stature, kyphoscoliosis, learning disabilities, hypertension, hydrocephalus, seizures, and various congenital abnormalities (pulmonary stenosis, spina bifida, rib and vertebral anomalies). Neurofibromatosis 2 (NF2) is genetically and clinically distinct from NF1, with the responsible gene located on chromosome 22q12.1. Pathological gene variants result in loss/reduced function of merlin (also known as schwannomin), which acts as a tumor suppressor. Manifestations include bilateral vestibular neuromas in 95% of cases and other CNS tumors such as meningiomas and ependymomas (gliomas). NF2 is considerably rarer than NF1, with an approximate incidence of 1:25,000 births.28 In common with NF1, it is inherited in an autosomal dominant manner, with 50% of cases resulting from spontaneous mutation. To diagnose NF2, one of the following criteria is needed:36 • Bilateral vestibular schwannomas age < 70 years OR • Unilateral vestibular schwannomas age < 70 years and firstdegree relative with NF2 OR • Multiple meningiomas and unilateral vestibular schwannomas or multiple meningiomas and any two of the following: – nonvestibular schwannoma, cataract, ependymoma OR • History of NF2 in first-degree relative plus any two of the following: ◦ meningioma ◦ nonvestibular schwannoma ◦ cataract ◦ ependymoma

The risk of CD is increased in NF1 patients, possibly due to pelvic or abdominal neurofibromas, causing an increased risk of cephalopelvic disproportion and NF1-related complications.47,48 Detrimental effects of NF to the parturient include predisposition to gestational hypertension, PreE, HELLP syndrome, vasculopathy, cerebrovascular disease, placental abruption, and shorter pregnancies.48,49 Risks to the fetus include an increased risk of spontaneous abortion, stillbirth, IUGR, and preterm labor.39,49 A possible explanation for the increased risk of stillbirths and spontaneous abortions is that a placental NF1associated vasculopathy causes abnormal placentation. There are a few case reports of fatalities, although overall maternal mortality is unchanged by pregnancy. Nelson et al.50 reported maternal and fetal demise in an NF1 parturient, presenting with an aggressive malignant mediastinal tumor. Unfortunately, the tumor recurred despite antepartum resection, resulting in airway compromise. The authors highlight the need for multidisciplinary care and the importance of a complete evaluation to exclude malignant transformation should the patient’s clinical condition change. Cecchi et al.51 reported a case of sudden death in a 37-yearold parturient with an uneventful pregnancy undergoing a CD. The patient suffered acute hypotension, supraventricular tachydysrhythmia, and pulmonary edema after delivery of the baby. Resuscitation was unsuccessful; autopsy revealed an unexpected pheochromocytoma (PHEO) and PHEO-induced cardiomyopathy. The authors highlight the need for awareness of associated PHEOs in these patients.

Cutaneous lesions (café-au-lait macules, neurofibromas) are seen in up to 70% of NF2 patients, although plexiform neurofibromas do not occur. Unlike NF1, there is no cognitive impairment with NF2, rarely are there Lisch nodules, and the schwannomas do not undergo malignant change. However, many patients with NF2 become completely deaf.37 Schwannomatosis38 is a rarer form of neurofibromatosis than either NF1 or NF2. It is characterized by multiple noncutaneous peripheral and intracranial schwannomas but without bilateral vestibular schwannomas.

Both GA and NA (spinal, epidural) have been used successfully in patients with NF.52–55 The choice of GA or NA may be complex. A thorough assessment of the patient is necessary to determine the dominant features of the disease and make a risk/ benefit analysis (Table 13.4).56,57

Pregnancy and Neurofibromatosis Neurofibromatosis does not have a detrimental effect on fertility in women.39 A study found that NF1 individuals are less likely to form cohabiting relationships than population comparisons and are older when they have their first relationship.40 Pregnancy in NF patients poses an increased risk to the parturient and her fetus. In multiple studies, neurofibromas increased in number and size during pregnancy and regressed postpartum.41–44 It is speculated that there may be a link between neurofibroma growth and levels of circulating hormones because progesterone, estrogen, and growth hormone receptors are all found in neurofibromatosis tissue.45 However, a recent study found plexiform and cutaneous neurofibroma growth in pregnant NF1 patients was not significantly different from matched nonpregnant NF1 controls.46 The study was limited as it was retrospective and had a small NF1 pregnant sample size.

Anesthetic Management

Table 13.4  Clinical features and anesthetic implications of neurofibromatosis 1

Organ

Disease process

Anesthetic implications

CNS

Neurofibromas Meningiomas, gliomas (5–10%) Cranial nerve fibromas Spinal nerve fibromas

Intellectual impairment (5–40% usually mild) Raised ICP, hydrocephalus, seizures (2–4%) Altered gag/swallowing reflexes Spinal cord compression/ peripheral neuropathy (4%) Concerns over insertion of neuraxial techniques

Skin

Café-au-lait spots (99%) Cutaneous neurofibroma Nodular neurofibroma Plexiform neurofibroma

Depending on site Difficult placement of IV access and neuraxial techniques due to position of lesions

Lungs

Mediastinal/intercostal neurofibromas Interstitial fibrosis

SVC obstruction Impaired respiratory function Right heart failure

Renal

Renal neurofibroma Renal carcinoma

Ureteric/urethral obstruction Impaired renal function

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Caroline S. Grange and Sally Anne Shiels

Table 13.4 (Cont.)

Organ

Disease process

Anesthetic implications

CVS

CHD (especially pulmonary stenosis) Hypertension Vasculopathy

Depends on lesion Risk of endocarditis Consider pheochromocytoma or renal artery stenosis Aneurysms, stenosis or malformation of arteries and veins – anesthetic implication depends on lesion

Airway

Pharyngeal/tongue neurofibroma Laryngeal neurofibroma

Airway obstruction Difficult intubation Dysphagia (increased risk of aspiration)

Bone

Fractures/long bone dysplasia Kyphoscoliosis (10–20%)

Difficult neuraxial techniques Impaired respiratory function

Adrenal

Pheochromocytoma (0.1–5.7%)

Hypertensive responses

GIT

GIT neurofibroma Carcinoid tumors

Pain, hemorrhage, perforation Carcinoid syndrome

Genitourinary

Neurofibroma of urinary tract

Ureteric/urethral obstruction Renal dysfunction

Abbreviations: CHD = congenital heart disease; CNS = central nervous system; CVS = cardiovascular system; GIT = gastrointestinal tract; ICP = intracranial pressure; IV = intravenous; SVC= superior vena caval obstruction.

If contemplating NA, key concerns include raised ICP, spinal tumors, and kyphoscoliosis. Dural puncture, in the presence of increased ICP, or direct trauma to a spinal/extradural neurofibroma from an epidural or spinal needle may have disastrous consequences. Although lumbar neurofibromas are usually unilateral, they can be large, asymptomatic, and extend toward the midline, making them vulnerable to direct needle trauma. There is a report of an epidural hematoma from unintentional puncture of a spinal neurofibroma during labor epidural placement.58 Although most asymptomatic patients do not have spinal involvement, it is prudent to avoid NA unless recent scans exclude a spinal lesion. Some also recommend MRI of the brain and spinal cord in late gestation as tumors may grow significantly during pregnancy.59 Clearly, vertebral abnormalities (either related to the disease or from surgical correction) may also complicate neuraxial placement. If considering peripheral nerve blocks (e.g., TAP blocks), perform US of the target nerves to avoid puncturing asymptomatic neurofibromas. Pheochromocytomas occur in 0.1–5.7% of patients with NF1, so it is vital to exclude them, particularly in patients with sustained or paradoxical hypertension resistant to treatment.60 If considering GA, the main areas of concern include the possibility of a difficult intubation and airway obstruction.61 Neurofibromas may involve the tongue, larynx, or trachea and cause airway obstruction and difficult intubation. Plexiform neurofibromas occur commonly in the cervical region and may distort the airway. Symptoms of dyspnea, stridor, or change in voice should alert the anesthesiologist to potential airway problems. Even if recognized early, elective awake fiberoptic tracheal intubation may not be successful due to the distorted anatomy.62 Previous reports of abnormal responses to neuromuscular blocking drugs are not

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substantiated. Due to NF-associated vasculopathy, it is essential to maintain cardiovascular stability and avoid pressor responses. There are reports of hemorrhage from vertebral AV fistulas.63

Von Hippel-Lindau Disease Valuable Clinical Insights • Von Hippel-Lindau disease (VHLD) is a rare, inherited, autosomal dominant disease. • It consists of many benign (hemangioblastomas) and malignant tumors. • Pheochromocytomas are found in 10–20% of VHLD patients and should be surgically removed before conception. • Hemangioblastomas may show increased growth during pregnancy. • Radiological scans are needed to evaluate CNS (intracranial and spinal) hemangioblastomas. • Neuraxial blockade is safe if increased ICP is ruled out, and spinal hemangioblastomas are remote from the insertion site. • Avoid hypertensive surges which could rupture intracranial hemangioblastomas.

Von Hippel-Lindau disease is a rare (incidence 1 in 36,000)64 multisystem disease characterized by various benign and malignant tumors (Table 13.5).65 Hemangioblastomas (benign vascular tumors) are the most common lesions associated with VLHD, occurring in 60–84% of patients. Although they are noninvasive and do not metastasize, they can bleed or cause pressure effects on surrounding structures. Hemangioblastomas commonly involve the retina, cerebellum, and spinal cord but can occur in other organs.66 Other associated features include renal cell carcinomas (clear cell), PHEOs, serous cystadenomas and neuroendocrine tumors of the pancreas, endolymphatic sac tumors of the middle ear, and papillary cystadenomas of the broad ligament and epididymis. Although autosomal dominant inheritance occurs, there is variable expression. A tumor suppressor gene located on chromosome 3p25–p26,67 is responsible for VHLD, but a second somatic mutation is required to develop cancer. The most common causes of death in VHLD patients are due to complications of renal cell carcinomas and CNS hemangioblastomas. There are types 1 and 2 VHLD, with type 2 much more likely to develop both PHEO and renal cell carcinoma than type 1.67 PHEOs associated with VHLD occur in 10–20% of patients.65 They tend to occur in younger patients, are often extradural, and are less likely to be associated with symptoms or biochemical evidence of catecholamine production than those in the general population.68 Before conception, evaluate patients with VHLD as to the extent and severity of the disease to determine VHLD ­pregnancy-related risks and whether they require genetic counseling. Exclusion of a PHEO is essential due to the potentially catastrophic risk of cardiovascular instability during pregnancy and labor.69 If found, the PHEO should be surgically removed before conception. Pregnancy will lead to increased blood volume and venous pressure within the vasculature of any hemangioblastoma. In

Miscellaneous Skeletal and Connective Tissue Disorders

Table 13.5  Clinical features and anesthetic implications of Von HippelLindau disease66

Organ

Disease process

Anesthetic implications

CNS

Hemangioblastomas (60–80%) involving: Cerebrum (2%) Cerebellum (38%) Brainstem (10%) Spinal Cord (51%)

Raised ICP Risk of CNS hemorrhage from disruption of a hemangioblastoma Seizures Risk of neurological damage by epidural/spinal needles or catheters

Retina

Hemangioblastomas (60–70%)

Risk of rupture and hemorrhage, loss of vision

Kidney

Hemangioblastomas (20%) Cysts Renal cell carcinoma

Kidney dysfunction (rare) Erythrocytosis/increased thrombotic risk

Adrenals

Hemangioblastomas Pheochromocytoma (10–20%)

Severe hypertensive response, dysrhythmias

Pancreas

Hemangioblastomas (20%) Cysts (77%) Neuroendocrine tumors (11–17%)

Altered glucose metabolism Abdominal pain/cholestatic jaundice Depends on peptide released, potential to metastasize

Face

Hemangioblastomas

Possible intubation problems

Lung

Hemangioblastomas

Pulmonary dysfunction Pulmonary hemorrhage

Liver

Hemangioblastomas

Liver dysfunction

Ear

Endolymphatic sac tumor of middle ear (15%)

Hearing loss

Abbreviations: CNS=central nervous system; ICP=intracranial pressure.

addition, further detrimental cardiovascular changes during labor and peripartum may cause hemangioblastoma rupture and, depending on the site, potential life-changing injury (e.g., hemangioblastomas in the CNS). Von Hippel-Lindau disease does not affect fertility in female patients.70 There are conflicting results on whether patients show new or accelerated growth of hemangioblastomas during pregnancy.71,72 Regardless of this, it is essential to evaluate VHLD lesions thoroughly preconception and continue surveillance during pregnancy. Maternal and fetal outcome data, from 29 women with 48 pregnancies, describe a favorable outcome, with no maternal mortality and only one fetal death (due to hypertension and maternal PHEO).73 Eight patients (17%) had VHLD-related complications; four had life-threatening events (two developed hydrocephalus secondary to cerebellar hemangioblastomas, and two had significant issues due to PHEOs). There were two premature CDs. Several case reports highlight VHLD-related complications in parturients.74–76 Mode of delivery remains controversial. Some suggest CD is the preferred mode of delivery due to the frequency of CNS involvement.77 Advantages of CD include avoiding the risks of CNS hemangioblastoma rupture and hemorrhage, secondary to increased cerebral blood pressure associated with the expulsive efforts of labor. However, there are reports of successful vaginal deliveries in VHLD parturients with cerebral hemangioblastomas.78 If considering

vaginal delivery, effective LEA will minimize fluctuations in BP and the potential for hemangioblastoma rupture. It is difficult to make firm recommendations regarding anesthetic technique as no anesthetic method is absolutely contraindicated. One must tailor management based on associated findings (e.g., PHEO, raised ICP, spinal hemangioblastomas) (Table 13.5). Some argue one should avoid NA because there may be asymptomatic spinal cord involvement, and a needle or catheter could cause a direct injury to a hemangioblastoma. Although spinal cord lesions can involve the lumbosacral region or even the cauda equina, most are cervicothoracic. Therefore, if a radiological scan shows the location of spinal cord lesions and they are distant from the neuraxial insertion site, one can safely initiate NA.79 A patient with multiple sclerosis and VHLD, with small hemangioblastomas in the dorsal spinal cord at T8/9 and L2 received epidural anesthesia without neurological sequelae.80 If there is a DP (either by a spinal or epidural needle), there is a risk of cerebellar herniation in patients with increased ICP secondary to intracranial hemangioblastomas.81 When considering NA, obtain a brain MRI scan in parturients with intracranial masses. When GA is needed (e.g., raised ICP/intracranial lesions, hemangioblastomas at the level of neuraxial insertion site), it is essential to blunt the pressor responses to tracheal intubation as hypertensive surges could cause CNS hemorrhage. Invasive arterial monitoring helps manage BP and guide treatment. Othmane et al.75 described a 30-week parturient requiring a craniotomy under GA to remove a symptomatic cerebellar hemangioblastoma. Premature delivery was averted, and the patient later delivered a healthy baby with LEA.

Ehlers-Danlos Syndrome Valuable Clinical Insights • Ehlers-Danlos Syndrome (EDS) is a heterogeneous group of conditions related to deficient/defective collagen. • EDS is characterized by skin hyperextensibility, joint hypermobility, and connective tissue fragility. • The subgroup indicates organ dysfunction and severity, but wide individual variation occurs. • Vascular EDS demonstrates significant maternal mortality and morbidity due to vessel/organ rupture so consider avoiding pregnancy. • Delivery should aim to minimize the risk of bleeding and tissue damage (e.g., perineal damage). • Carefully consider neuraxial risks, e.g., spinal hematoma (especially with vascular EDS), insertion difficulty due to scoliosis, and increased risk of DP. • General anesthesia goals include atraumatic airway management, avoidance of hypertensive episodes (to avoid vessel rupture), and low airway pressure ventilation (to prevent pneumothorax).

Ehlers-Danlos Syndrome is a group of inherited connective tissue disorders that differ clinically, genetically, and biochemically. The latest classification system differentiates EDS into 13 subgroups and relies on clinical findings (Table 13.6). 82

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Table 13.6  Classification of Ehlers-Danlos syndrome82

EDS subgroup

Previous classification

Inheritance

Clinical findings (mostly major criteria)

Classical EDS

Classical I and II

AD

Skin hyperextensibility, atrophic scarring Generalized joint hypermobility Easy bruising, skin fragility, soft doughy skin

Classical-like EDS

AR

Skin hyperextensibility, velvety skin, absence of atrophic scarring Generalized joint hypermobility Easy bruising Foot deformities Edema of legs in absence of cardiac failure

Cardiac-valvular EDS

AR

Severe progressive cardiac valvular defects (especially aortic and mitral valve) Skin hyperextensibility, atrophic scarring Thin skin, easy bruising Joint hypermobility (generalized or restricted to small joints)

Vascular EDS

Vascular EDS IV

AD

Arterial rupture at young age Intestinal rupture (in absence of bowel pathology) Uterine rupture during third trimester, in absence of previous CD Carotid-cavernous sinus fistula, in absence of trauma Positive family history of vascular EDS with gene mutation in COL3A1 Severe bruising unrelated to trauma

Hypermobile EDS

Hypermobility type, III

AD

Large and small joint, spine hypermobility Frequent joint dislocations (often patella, shoulder and temporomandibular joint) Chronic musculoskeletal pain, similar to fibromyalgia Soft or velvety skin, mild skin hyperextensibility, atrophic scarring

Arthrochalasia EDS

Arthrochalasia type, VIIA/VIIB

AD

Congenital bilateral hip dislocation Severe generalized joint hypermobility, multiple dislocations Extremity contractures Kyphoscoliosis Easily bruised skin

Dermatosparaxis EDS

Dermatosparaxis, VIIC

AR

Extreme skin fragility, cutis laxa Characteristic craniofacial features Severe bruising Short limbs, hands, and feet

Kyphoscoliotic EDS

Kyphoscoliosis, VI

AR

Congenital muscle hypotonia Congenital or early onset kyphoscoliosis Generalized joint hypermobility with dislocations/subluxations Skin hyperextensibility and easy bruising

Brittle Cornea syndrome

AR

Thin cornea, with or without rupture Early progressive keratoconus/keratoglobus Blue sclerae

Spondylodysplastic EDS

AR

Short stature, blue sclerae Muscle hypotonia (severe congenital to mild late onset) Bowing of limbs Thin, velvety, hyperextensible skin with atrophic scarring

Musculocontractural EDS

AR

Congenital multiple contractures (often adduction-flexion contractures or talipes equinovarus) Characteristic craniofacial features Skin hyperextensibility/fragility with atrophic scarring Easy bruising

Myopathic EDS

AD or AR

Congenital muscle hypotonia and/or muscle atrophy which improves with age Proximal joint contractures (knee, hip, elbow) Hypermobility of distal joints

AD

Severe and intractable periodontitis of early onset Lack of attached gingiva Pretibial plagues Positive family history

Periodontal EDS

VIII

Subgroups V, IX, X, XI are no longer in current EDS classification. Abbreviations: AD = autosomal dominant; AR = autosomal recessive.

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The main features of EDS consist of skin hyperextensibility (increased elasticity and extension of skin), joint hypermobility (increased laxity and extension of joints), and connective tissue fragility. Although sharing the cardinal features of the syndrome, the severity of these features varies widely among the subgroups.83 Definitive diagnosis depends on molecular confirmation with identification of the causative variant in the relevant gene, except for hypermobile EDS, as its complete genetic etiology is currently unknown. The estimated prevalence of EDS is 1:5000,84 and EDS is most prevalent among Caucasians, with men and women equally affected. The commonest subgroups of EDS are hypermobile (35%), classical (30%), and vascular EDS (5–10%).85 Some of the other subgroups of EDS are rare. The primary defect results in deficient or defective collagen due to mutations in structural collagen genes or genes coding for enzymes involved in their posttranslational modification. Many types of collagen occur. These proteins are essential for development and organogenesis, cell attachment, and platelet aggregation, in addition to providing tensile strength to connective tissue in skin, ligaments, tendons, and bone. The exact biochemical abnormality differs in the various subgroups. Depending on the type of EDS, these molecular lesions are associated with weakness of the supporting structure of the skin, joints, arteries, and visceral organs. The vascular subgroup of EDS is at particular risk of premature death from arterial rupture (either arising spontaneously or with trauma) and hollow organ (intestinal and uterine) rupture. Vascular EDS is associated with a defect in type III collagen, which is a major component of the arterial walls, intestine, and uterus. Rupture of arterial vessels accounts for the shortened lifespan (median age of death 48 years) in this subgroup of EDS patients.86,87 Lifespans for patients with classical and hypermobile EDS are unaltered; the lifespan of those with the kyphoscoliosis form is less due to the potential for restrictive lung disease and vasculopathy.

Pregnancy and Ehlers-Danlos Syndrome As EDS is a multisystem disease, it is paramount that there is a multidisciplinary approach (input from obstetricians, anesthesiologists, geneticists, cardiologists, and rheumatologists) to manage these patients. In addition, it is essential to know the particular EDS subgroup to determine pregnancy risk and offer prepregnancy genetic testing and counseling.

Effect of Pregnancy on Ehlers-Danlos Syndrome There are numerous reports of complications during pregnancy in women with EDS. Unfortunately, many of these reports are anecdotal and involve publication bias. In addition, the EDS subgroup is often unreported in these studies. This information is vital as pregnancy and delivery complications may be related to the subgroup involved and not to the whole spectrum of disease. Maternal and neonatal outcomes in EDS parturients are generally favorable; however, pregnancy can be associated with serious maternal complications in vascular EDS, predominantly due to spontaneous arterial rupture.

There is no evidence of altered fertility in these patients. Hormonal changes in pregnancy (e.g., increased relaxin production) increase ligamentous laxity, particularly in the hypermobile subgroup, resulting in increased joint instability and pain.88 For women with vascular EDS, pregnancy may precipitate vessel rupture of aneurysms, dissections, and arteriovenous malformations, as well as uterine rupture (due to contractions on a structurally weakened uterine wall). Risk of vessel rupture increases due to pregnancy-induced increases in CO and blood volume. Additionally, Valsalva maneuvers associated with contractions increase abdominal pressure, causing further elevation of vessel and organ transmural pressures. The estimated maternal mortality rate of vascular EDS is 5–12%.89 The 2018 European Society of Cardiology highlights the high risk of pregnancy in this subgroup, advising against pregnancy in patients with vascular EDS. Where pregnancy continues, the Society recommends administering celiprolol throughout pregnancy in patients with vascular EDS and thoracic aortic disease.90 Celiprolol reduces vascular complications, and its ß2 agonist action may prevent premature contractions and preterm delivery.

Effect of Ehlers-Danlos Syndrome on Pregnancy Ehlers-Danlos Syndrome parturients have an increased risk of preterm premature rupture of membranes (PPROM), cervical insufficiency, and preterm birth. The prevalence of preterm birth is 9% (all EDS patients), 19% (vascular EDS) compared with 6.5% in the general population.91 These findings may be due to the loss of structural integrity of the cervix caused by defective collagen. One study demonstrated that PPROM was twice as common in EDS patients with an EDS fetus compared to those whose fetus was unaffected by the disease.88 This suggests that defective amniotic fetal connective tissue (known to contain type I and V collagen – the collagen defects produced in Classical, Cardiac-Vascular, Vascular, and Arthrochalasia EDS) impacts PPROM. Prophylactic cervical cerclage is not necessary since it lacks documented benefit, and it could possibly harm fragile tissues. Interestingly, Sundelin et al.92 did not find a correlation between EDS and PPROM and prematurity in their patients; most were hypermobile EDS, where the collagen/ protein affected is still unknown. Other potential problems in EDS patients include increased risk of abnormal presentation, spontaneous abortions, and IUGR.93 Possible reasons for the increased risk of abnormal presentation include greater joint laxity and reduced muscle tone. There is no consensus as to the mode of delivery.94 Both ­vaginal delivery and CD have benefits and risks in EDS patients. Most clinicians prefer vaginal delivery in most cases, with more opting for CD in patients with vascular EDS. However, it is challenging to provide dogmatic recommendations on the management of delivery due to the varied manifestations of this disease and differences in subgroups of EDS and individual patients. Consider vaginal delivery unless obstetric contraindications or severe joint problems (e.g., hip dislocation/subluxation) preclude it. Labor and delivery are shorter in patients with hypermobile EDS compared with the general population.95 Therefore, there

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may be an increased risk of perineal damage/tears; a timely episiotomy may minimize this complication. If there is a perineal tear, an experienced obstetrician should assess and repair it to avoid defective healing. Forceps deliveries can induce severe perineal injury and bladder/vaginal avulsion, so should be avoided if possible. Vacuum extraction carries less risk of perineal injury, although there are concerns over an increased risk of cephalohematomas if the disease affects the fetus. Early CD may minimize labor-related risks of uterine/vessel rupture and perineal lacerations (particularly in vascular EDS); however, weigh this against the risk of arterial damage, hemorrhage, and bowel damage, associated with fragile vessels and organs. In addition, there is an increased risk of wound dehiscence ­following CD. Have blood products available, as there are increased risks of APH and PPH due to increased tissue and capillary fragility.95 In addition to uterotonic drugs, tranexamic acid (TXA) and deamino-8-D arginine vasopressin (DDAVP) may be useful. Wound healing is abnormal, with an increased risk of dehiscence,96 so close skin wounds in two layers with sutures remaining in situ for twice as long as usual. Postpartum, uterine, and bladder prolapse can occur, as can extensions of episiotomies. There is an increased prevalence of VTE in EDS patients (0.86%) compared with the general population (0.32%),91 so use appropriate thromboprophylaxis.

Ehlers-Danlos Syndrome and Anesthesia Choice of anesthesia is controversial since the EDS subgroup, and individual variability, will influence the risks. Manage patients with EDS in a high-risk pregnancy unit with multidisciplinary input. Table 13.7 highlights the anesthetic and surgical implications of EDS. Evaluation of coagulation status and cardiovascular function is vital to assess the anesthetic implications (Table 13.8). Although hematological test results are usually normal, there are reports of platelet aggregation abnormalities in 26% of patients.97 An echocardiogram is advantageous. Friable arteries are easily damaged, making cardiac catheterization hazardous. The investigations of choice for coronary insufficiency are stress echocardiography and MRI scans. Before any procedure, patients should have adequate IV access. Even with careful IV insertion, bleeding may occur at the insertion site due to the vessel wall connective tissue defects and a lack of tamponade from surrounding tissues. Review IV sites regularly to reduce the risk of extravasation. To minimize the risk of vascular wall dissection, use ultrasound for arterial cannulation if required for arterial BP monitoring in patients with vascular EDS. Carefully pad and position patients to avoid tissue damage, especially those with reduced sensory and motor modalities, following NA or GA.

Table 13.7  Clinical features of Ehlers-Danlos syndrome and anesthetic/surgical implications

Organ

Dysfunction

Anesthetic/surgical implications

Skin

Hyperextensibility/fragility

Scarring – difficult IV access Poor wound healing – sutures hold poorly Careful taping/padding/positioning needed perioperatively

Musculoskeletal

Hypermobility of joints effusions hemarthrosis dislocations premature degenerative joint disease Cervical spine instability/spondylolisthesis due to lax ligaments Kyphoscoliosis Chronic pain

Careful positioning of joints Careful manipulation of airway/intubation Technical difficulties with neuraxial blockade/increased risk of inadvertent dural puncture due to ligamentous laxity Cardiovascular/respiratory compromise Difficulties achieving adequate analgesia Use of chronic pain medications

Hematologic

Bruising after minor trauma, due to defective vessel wall Hemostasis tests are usually normal although abnormal platelet function and coagulopathy have been described in some patients with vascular EDS Increased risk of aneurysm and spontaneous rupture of arteries and veins, due to abnormalities in walls of large/small blood vessels (mostly vascular EDS)

Perioperative hemorrhage/blood products should be available Possible contraindication to spinal/epidural and risk of spinal hematoma Awareness of possibility of vessel rupture Prevention and treatment of hypertension e.g., PreE, hypertension related to laryngoscopy and intubation

Gastrointestinal tract

Hiatus hernia GIT bleeding

Risk of aspiration Anemia

Viscera

Spontaneous rupture of viscera (e.g., uterus/GIT)

Shock – depends on organ involved

CVS

Mitral valve prolapse/regurgitation Proximal aortic dilatation Dysautonomia/autonomic dysfunction e.g., postural orthostatic tachycardia syndrome

Dysrhythmias Bacterial endocarditis prophylaxis Rupture Careful use of vasopressors/titration of neuraxial block and IV fluids

Respiratory system

Increased risk of pneumothorax

Low airway pressures when ventilating patient

Eyes

Thin cornea

Careful protection to prevent globe rupture

Abbreviations: CVS = cardiovascular system; GIT = gastrointestinal tract; IV=intravenous.

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Table 13.8  Obstetric anesthetic checklist for parturients with EhlersDanlos syndrome 1. Genetic assessment for severity and type of disease (and prognosis for fetus) 2. Careful preoperative assessment (particularly cardiac and bleeding tendency) 3. Multidisciplinary approach to medical care 4. Exclude concomitant coagulopathy 5. Ensure blood available for transfusion if needed 6. Ensure adequate IV access 7. Careful cannulation/intubation to avoid damage to friable tissues 8. Careful insertion of spinal/epidural (if not contraindicated) 9. During GA, maintenance of low airway pressure during ventilation to reduce risk of pneumothorax 10. Avoidance of hypertension, which may result in the rupture of occult aneurysm 11. Immediate availability of methods of uterine contraction (oxytocin, methylergonovine, prostaglandin) especially for CD to minimize blood loss. Use TXA and DDAVP as needed

General anesthesia and NA (epidural/spinal) have been used successfully in patients with EDS. Discuss the benefits and risks of each type of anesthesia with the patient. There may be an increased risk of nerve injury, inadvertent DP, and spinal hematoma with NA. Due to the perceived increased risk of vessel rupture in vascular EDS patients, Wiesmann et al.98 recommend avoiding NA in this subgroup, mainly due to concerns of spinal hematoma. However, there are several reports of successful epidural and spinal anesthesia in this subgroup of patients.99–102 Large trials would help evaluate the actual risk of these issues. On a personal note, if there were a history of prior bleeding problems (e.g., prolonged epistaxis or excessive bleeding after dental extraction) or documented laboratory clotting abnormality, this author would prefer not to insert an epidural in a parturient with vascular EDS. Neuraxial blockade in the other subgroups is less of an issue. The risk of epidural hematoma and neurologic complications may be higher due to the rupture of vessels from hypertensive responses to painful stimuli. Therefore, avoid sudden increases in arterial pressure and consider administering antihypertensive therapy to prevent vessel wall rupture. Although subarachnoid block with a small gauge needle may minimize the risk of a spinal hematoma, it may be challenging to secure hemostasis in these patients, prolonging surgery for CD. Brighouse and Guard102 reported a case of pregnancy in women with EDS type IV, who produced virtually no type III collagen. Before pregnancy, there were no bleeding problems, although the authors postulated that bleeding into the hepatic and splenic capsules caused abdominal pain in the third trimester. After obtaining a normal coagulation screen and a complete discussion of the risks and benefits of GA versus NA, the patient consented to a CSE for CD. The perioperative period was uncomplicated. The authors argued that a CSE offers a rapid, reliable block with the benefit of prolonged anesthesia should protracted surgery occur. Some have reported LA resistance (particularly in hypermobile EDS patients), suggesting this may account for poor block

quality following local infiltration for episiotomy, perineal repair, or NA.103–105 However, others feel this concern is unwarranted.106 Scoliosis may make NA more difficult, and there may be an increased risk of inadvertent DP due to lax ligaments. Tarlov cysts (cysts filled with CSF) have been reported in EDS patients and may be a contraindication to NA, although most cysts are found in the S1–4 region and therefore unlikely to be a problem. With GA, carefully perform atraumatic intubation (to avoid oral/tracheal trauma and cervical injury), pad vulnerable pressure areas (to prevent tissue injury) and avoid hypertensive episodes (to prevent major vessel rupture). Maintain low airway pressure or spontaneous ventilation (to prevent pneumothorax from cyst rupture). Due to temporomandibular dysfunction, spondylosis, and cervical instability, airway management could be problematic.107 The use of videolaryngoscopy or fiberoptic intubation may mitigate the risks. There is a report of difficult intubation during rapid sequence induction in a hypermobile EDS patient. The authors describe a failed attempt to insert an ETT with bougie but upon release of cricoid pressure intubation was successful. It was thought that application of cricoid pressure collapsed both the fibroelastic tissues and the lower adjoining C-shaped cartilages.108 They speculated that this problem would not happen in nonhypermobile EDS patients. Hypermobile EDS is associated with dysautonomia and orthostatic intolerance, namely postural orthostatic tachycardia syndrome.109 Careful use of vasopressors, titration of NA and IV fluids are required. Many EDS patients have chronic pain and require regular analgesia, physiotherapy, and input from a chronic pain team, especially those having a CD.

Tuberous Sclerosis Valuable Clinical Insights • Hallmarks of tuberous sclerosis are benign hamartomas, which precipitate complications by disturbing tissue function or obstructing outflow. • Cardiac rhabdomyomas are associated with outflow obstruction, ventricular dysfunction, and dysrhythmias. • Lymphangioleiomyomatosis affects pulmonary function and may worsen in pregnancy. • Psychiatric and psychological disorders are common in TS. • Patients with sudden onset abdominal pain should have urgent investigations to exclude renal angiomyolipoma rupture. • New therapies (sirolimus and everolimus) are changing disease outcomes and appear to be safe in pregnancy.

Tuberous sclerosis (TS) is a multisystem disease characterized by benign hamartomas of the brain, spinal cord, skin, kidney, eyes, heart, lungs, and bones. The incidence is 1 in 6,000–10,000 births; however, as there is a broad expression of disease severity, the true incidence is unknown. TS presents typically in early childhood and affects males and females equally. This slowly progressive disease is inherited in an autosomal dominant manner in 30% of cases, although spontaneous

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mutation causes most cases. Causative mutations are in either the TSC1 gene (chromosome 9 and encoding for the protein hamartin) or the TSC2 gene (chromosome 16 and encoding for tuberin, more commonly found in de-novo cases).110 In normal physiology, both proteins inhibit the mechanistic target of rapamycin (mTOR) pathway, thereby regulating cell proliferation and growth. Pathological gene mutations result in overactive mTOR pathways, leading to unrestrained cell proliferation. In 15% of patients, there is no gene mutation.111 Hamartomas are mesenchymal tissue: cartilage, fat, nerve, connective tissue, or smooth muscle. Complications occur due to outflow obstruction (e.g., in the CSF or the renal and cardiac systems) or disturbance of organ function. Most TS patients have neurologic abnormalities, including cognitive deficits, learning disabilities, and seizures. Cortical tubers occur in the gray-white matter interface with cerebral dysfunction directly related to the number, size, and location of tubers. Recent research suggests a molecular basis for TS-associated neuropsychiatric disorders (TAND).112 In 90% of patients, nodules are in the ventricular system. When obstruction to CSF flow occurs, hydrocephalus can develop slowly and insidiously and may require foramen magnum decompression. Ten percent of TS patients have a neuromalignancy; a subependymal giant cell astrocytoma (SEGA) is the most common.113 Pulmonary manifestations include lymphangioleiomyomatosis (LAM), whereby smooth muscle proliferation in the respiratory bronchioles, pulmonary arterioles, and lymphatic vessels destroy lung tissue and cause pulmonary dysfunction. LAM predominantly affects women, often presenting between ages 30 and 40, coinciding with the childbearing years.114 Only 10% of TS men have LAM, and most are asymptomatic. Although women with TS and LAM have variable disease progression, the prognosis is generally poor. The most common presentations are dyspnea and pneumothorax (from rupture of peripherally located cysts into the pleural space).115 Cardiac rhabdomyomas are present in up to 70% of patients and can cause intraventricular obstruction, cardiac dysfunction, and dysrhythmias (e.g., Wolf Parkinson White syndrome).110 There are reports of coarctation of the aorta, arterial stenosis (e.g., renal arterial stenosis), and aortic aneurysms. Rupture or hemorrhage is present in 55–80% of TS patients with renal angiomyolipomas.114 The majority of patients with TS have classical dermatological lesions; these form many of the major diagnostic criteria. A 2021 consensus on the diagnosis of TS requires at least two major features or one major and two minor features (Table 13.9).110 Genetic diagnosis confirms if a pathogenic variant of TSC1 or TSC2 is present. Treatment of TS has dramatically altered in the past decade with the introduction of mTOR inhibitors (e.g., rapamycin, sirolimus, everolimus).116 The first prospective trial with mTOR inhibitors reported a reduction in the size of angiomyolipomas and improved lung function with minimal side effects after 12 months of treatment with sirolimus.117 Longer-term studies show good outcomes with improvements in exercise tolerance, oxygen saturation, and pulmonary function.118,119 Treating SEGA with mTOR inhibitors showed a dose-response effect on

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Table 13.9  Diagnostic criteria in tuberous sclerosis110

Major criteria

Minor criteria

Hypomelanotic macules or “ash-leaf spots” (> 3, > 5 mm diameter)

“Confetti” skin lesions (small hypopigmented macules usually found distally on limbs)

Angiofibroma (small pink papules usually found in center of face)

Dental enamel pits (> 3)

Ungal fibromas

Intraoral fibromas (> 2)

Shagreen* patch (oval shaped, nevoid, orange peel texture, skin-colored lesions usually on lower back)

Retinal achromic patch

Retinal hamartoma

Nonrenal hamartoma

Multiple cortical tubers

Sclerotic bone lesions

Subependymal nodules (> 2) Subependymal giant cell astrocytoma Cardiac rhabdomyoma Lymphangioleiomyomatosis (LAM) Angiomyolipomas (> 2) *shagreen is a type of untanned roughened leather Diagnosis = 2 major criteria or 1 major + 2 minor

tumor regression,120 potentially minimizing the need for neurosurgery. Further trials are exploring mTOR inhibitors as a treatment for TAND.112 There is emerging evidence that sirolimus and everolimus are safe in pregnancy.121

Pregnancy and Tuberous Sclerosis Many reported cases of TS in pregnancy are associated with serious maternal and fetal complications. The most common adverse event is renal angiomyolipoma rupture, which can cause fetal demise due to maternal blood loss.122 Although most lesions are asymptomatic, consider the possibility of rupture if there is sudden abdominal or flank pain. Due to the inheritance pattern of TS, fetal cardiac rhabdomyomas are common and affect two out of three newborns with TS. They can cause fetal demise if > 3 cm and are associated with fetal cardiac dysrhythmias.121 Women with TS can also present with seizures, which may confound a diagnosis of eclampsia. Pregnancy management is complicated by TAND and should be a key consideration for the multiprofessional team. Impaired cognitive function can affect the parturient’s ability to process birth options during the consent process. Psychiatric disorders may worsen in pregnancy, particularly postpartum. Pregnancy accelerates the progression of LAM, worsens lung function, and increases the risk of pneumothorax.110 As a result, parturients should know that pulmonary symptoms may worsen. Regular assessment of lung function is essential during pregnancy; treat patients proactively with bronchodilators (if responsive).110 Despite these concerns, many women with TS have uncomplicated pregnancies. Prior knowledge of the full extent of the disease and organ involvement allows preparation for potential complications. Table 13.10 highlights those organ systems of particular relevance in pregnancy.

Miscellaneous Skeletal and Connective Tissue Disorders

Table 13.10  Organ systems affected in tuberous sclerosis relevant to pregnancy complications

Body system

General advice

Neurology ▪ Seizures ▪ Raised ICP caused by subependymal cysts or astrocytoma obstructing CSF flow

▪ Continue antiseizure medication ▪ MRI brain within 1–3 years in asymptomatic patients (more frequent if symptomatic) ▪ If neuraxial technique considered: MRI spine + brain, ensure ICP not raised

Tuberous-sclerosis-associated neuropsychiatric disorder (TAND):110 ▪ Behavioral: aggression, selfinjury, anxiety ▪ Psychiatric: autism spectrum, depressive disorder, personality disorder ▪ Intellectual disability ▪ Psycho-social: relationship difficulties

▪ Appropriate and regular psychological, psychiatric, or social care input to guide treatment and communication

Pulmonary ▪ Tuberous sclerosis LAM: poor exercise tolerance, low oxygen saturation, pneumothorax

▪ Lung function tests, CXR or CT chest (clear need for diagnosis may outweigh radiation risk) ▪ Careful consideration of treatment options (balance of symptom control with potential fetal impact)

Renal ▪ Angiomyolipoma rupture causing hemorrhage compromising mother and fetus

▪ MRI abdomen to assess size ▪ Intervention if large (surgical or radiological) ▪ Rapid resuscitation and treatment for rupture

Cardiac ▪ Cardiac rhabdomyoma: obstruction, decreased function or arrhythmias ▪ Aortic coarctation and/or aneurysm

▪ ECHO and ECG in pregnancy ▪ Increased surveillance of known aortic aneurysm

Fetal risks • Cardiac rhabdomyomas • Risk of preterm delivery, IUGR, perinatal death

Ultrasonography, genetic testing, and counseling as appropriate

Anesthetic Management A limited number of case reports describe the anesthetic management in adult patients with TS. Although several parturients required labor analgesia or anesthesia for instrumental delivery, specific anesthetic details are lacking. Of importance to the anesthesiologist is a history of seizures, focal neurological signs, hydrocephalus, renal dysfunction, cardiac dysfunction, dysrhythmias, pulmonary dysfunction, and neuropsychiatric symptoms. It is crucial to ensure surveillance investigations are up to date, particularly abdominal MRI, to detect any expansion of renal angiomyolipomas. Anesthesiologists should know that patients with TS and neurological disease likely have coexisting renal, cardiac, and pulmonary diseases. Assess each parturient on an individual basis and tailor the anesthetic accordingly. It is essential to continue anticonvulsant medication and prevent any reduction in

seizure threshold (e.g., avoid hyperventilation with effective labor analgesia). Brain lesions (e.g., large subependymal nodules) may increase ICP, obstruct the ventricles, and cause difficulty with seizure control. Prior neurosurgery (such as foramen magnum decompression) may make NA safer. However, even in the context of previous foramen magnum decompression, subsequent cerebellar herniation can still occur, increasing the risk of further herniation with neuraxial techniques.123 When considering NA, ensure there are no changes to existing or new lesions by brain and spine imaging and exclude raised ICP. If GA is preferable, it is crucial to obtund the pressor responses (e.g., during laryngoscopy) and prevent a further rise in ICP. If there is a renal angiomyolipoma, adequate IV access is essential during labor, as is the availability of cross-matched blood. In patients with LAM, effective LEA reduces hyperventilation and excessive changes in intrathoracic pressure during contractions. Elective instrumental delivery during the second stage may be preferable to avoid excessive straining, especially if there is a history of a previous nonsurgically treated pneumothorax, as the recurrence rate is high.118 In addition, avoid nitrous oxide when there is evidence of noncommunicating cystic lung disease or a closed pneumothorax.

Myasthenia Gravis Valuable Clinical Insights • It is crucial for an anesthesiologist to clearly understand the factors that exacerbate myasthenia gravis (MG) in the peri­ operative period. • Continue anticholinergic drugs peripartum and adjust neuromuscular blocking medications accordingly. • Myasthenic crisis is rare in pregnancy. • Sugammadex can be used in MG. • Monitor neonates born to mothers with MG for transient neonatal MG.

Myasthenia gravis (MG) is a chronic autoimmune disease involving the postsynaptic neuromuscular junction (NMJ). The hallmarks of the disease are weakness and rapid fatigability of striated muscle with repetitive use, followed by partial recovery with rest.124 The reported worldwide incidence is between 0.3 and 3/100,000 births,125 with a bimodal peak of incidence. Women are affected two to three times as often as men and are more likely to be diagnosed with early-onset disease.126,127 Recent evidence suggests that the mean diagnostic age of MG has increased over the past 40 years from the third to the fifth decade, with an older onset being most common.125 While there is some speculation that this could be a change in disease pattern, as the frequency of autoimmune diseases is increasing worldwide, most studies indicate improved detection.128 Myasthenia gravis is divided into subgroups based on autoantibodies, clinical characteristics, and severity (Table 13.11). There are three main autoantibodies that act on the following specific areas of the NMJ129:

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Table 13.11  Subgroups of myasthenia gravis127,129,130

Anti-AchR

Anti-MuSK

Anti-LRP4

Seronegative

Prevalence

80–85%

5%

2%

5%

Age/gender predilection

Early < 50 yrs F > M Late > 50 yrs M > F

Any age F > M 2:1

Any age

Any age

Severity

All grades

Usually moderate to severe

Mild to moderate

Mild

Skeletal muscle distribution

Generalized but predominately proximal Ocular (10%)

Generalized (rare to have ocular involvement)

Generalized

Generalized

Thymic Pathology

Yes (15%) Early onset responds to thymectomy

No

No

Variable

Antibody titer correlates with disease severity

No

Yes

No

No

Testing

Widely available

Available in specialized centers

No commercial test available yet

n/a

1. Acetylcholine receptor (AchR): postsynaptic ligand-gated ion channel 2. Muscle-specific kinase (MuSK): membrane protein responsible for the coordinated assembling of the receptors at the NMJ 3. Lipoprotein-related protein 4 (LRP4): membrane protein essential for the functioning of MuSK Additional antibodies emerging from MG research are the ryanodine receptor, potassium channel subunit KV1.4, and various key proteins in the NMJ: titin, agrin, cortactin, and collagen Q. In most cases (85%), autoantibodies bind to the AchR, activating the complement pathway disrupting the receptor membrane, rendering it ineffective.127 A reduction in endplate potential is directly related to the decrease in functioning receptors and the complement-mediated disruption to the voltagegated sodium channels.124 Approximately 5% of patients are seronegative. Table 13.12 reviews the clinical classification of the severity of MG.131 Sixty percent of patients present with ocular symptoms (ptosis or diplopia), usually asymmetrical.130 The most uncommon presentation is limb weakness, usually more pronounced in the proximal muscle groups and generally symmetrical.127 The diagnosis is clinical (i.e., fatigable muscle weakness without loss of

deep tendon reflexes or other neurological symptoms), coupled with pharmacologic, serological, radiological, and, if needed, electrophysiologic tests. Understanding the specific autoantibodies associated with MG has changed the diagnosis and treatment of MG. Anticholinesterase challenge testing (Tensilon or edrophonium test) and electromyography may not be necessary for patients with clinical symptoms and a positive autoantibody result.130 However, these tests can help identify MG in seronegative patients. The edrophonium test can distinguish between a “myasthenic” and a “cholinergic” crisis (Table 13.13). The course of MG is usually variable over time, although the initial presentation can predict the course of the disease. Treated patients with mild or moderate disease may experience full symptom resolution, while those with severe disease rarely reach remission.130 The progression of weakness in MG usually occurs in the cranial-to-caudal direction: ocular symptoms progress to facial and bulbar muscles, while bulbar symptoms progress to truncal and limb muscles. Good prognostic indicators include rapid diagnosis (< 1 year from symptom onset) and early age of onset.132 If MG goes undiagnosed and untreated, it has a 50% 10-year mortality.133 Table 13.13  Myasthenic and cholinergic crises in myasthenia gravis

Myasthenic crisis

Cholinergic crisis

Table 13.12  Clinical classification of myasthenia gravis

Cause

Disease exacerbation or undermedication

Overmedication

MGFA Class

Respiratory

Distress, increased RR

Bronchoconstriction, apnea

I

Secretions

Normal

Increased, lacrimation

Abdominal

None

Cramping, incontinence (fecal and urinary)

Cardiac

Tachycardia, hypertension

Bradycardia

Moderate weakness +/– ocular IIIa limb and/or axial involvement IIIb oropharyngeal and/or respiratory involvement

Pupils

Normal or dilated

Constricted

Muscles

Weak

Weak but with fasciculations

Severe weakness +/- ocular IVa limb and/or axial involvement IVb oropharyngeal and/or respiratory involvement

Edrophonium test

Improves

Worsens

Treatment

Anticholinergic drugs, steroids, mechanical ventilation +/– plasmapheresis, IVIG

Atropine

131

II

III

IV

V

Only ocular involvement Causing ptosis, diplopia Mild weakness +/– ocular IIa limb and/or axial involvement IIb oropharyngeal and/or respiratory involvement

Severe Requiring respiratory support (noninvasive ventilation or intubation). Not in the context of planned perioperative care Requiring the use of a feeding tube

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Abbreviation: IVIG = intravenous immunoglobulin.

Miscellaneous Skeletal and Connective Tissue Disorders

Current treatment modalities for MG include symptomatic, immunosuppressive, and surgical therapies. Anticholinesterases, which act by increasing the amount of Ach available at the NMJ, are the first-line symptomatic treatment for most patients with MG.134 Pyridostigmine is the drug of choice due to its pharmacological profile (onset 10–15 minutes, offset 4 hours). Immunosuppressive therapy is started if symptoms fail to resolve with pyridostigmine. Azathioprine (AZA) works by blocking cell proliferation through inhibition of T lymphocytes. It has a prolonged time to clinical effect (6–15 months). Therefore, corticosteroids (e.g., prednisolone) are usually coadministered to accelerate symptom control (2–3 weeks).130 The prednisolone dose can be reduced once symptom control is optimal. Mycophenolate, a second-line drug, can be used for mild to moderate symptoms.130 For patients with more severe disease, rituximab improves symptoms in 68% of patients and is also recommended for patients with antiMuSK, unresponsive to first- and second-line drugs.135 Use IVIG therapy and plasma exchange for short-term, life-threatening MG. They are equally effective, reaching peak effect within 2–5 days.130 Elective thymectomy is recommended for all patients aged 18–50 years who have AchR autoantibodies with or without overt disease.135 This recommendation is based on evidence from the MGTX trial (Thymectomy Trial in Non-Thymomatous Myasthenia Gravis Patients Receiving Prednisone Therapy).136 This multicenter, randomized, rater-blinded study found that thymectomy reduced symptoms, drug doses, and hospitalizations over 3 years. The reason for the improvement following thymectomy is not fully understood. However, cell-mediated immunity, expressed through the T lymphocyte system and dependent on the thymus, plays a role in the pathogenesis of MG.

Table 13.14A  Physical factors that may exacerbate myasthenia gravis Environmental

Excessive heat or cold Exertion Exhaustion Emotional stress

Physiological

Systemic infection Menstruation Surgery Trauma Malnutrition

Table 13.14B  Pharmacological factors that may exacerbate myasthenia gravis

Pharmacological Drugs that will definitively* or probably† cause an adverse drug reaction

Comments

Drugs that have autoimmune reaction at NMJ - Immune checkpoint inhibitors* Used in metastatic cancer treatment (such as: pembrolizumab, nivolumab, avelumab, atezolizumab)

Consider use of steroids, IVIG before treatment initiation. Not advised in patients who have recently had life-threatening MG

- D-Penicillamine* Used in the treatment of rheumatoid arthritis

Consider alternative therapies

- Statins†

Discontinue if MG worsens

Drugs that interfere with neuromuscular transmission - Macrolides* (i.e., erythromycin, clarithromycin)

Consider alternative where possible and monitor symptoms if required

Myasthenia gravis does not affect fertility, and it has an estimated prevalence of 1 in 20,000 during pregnancy. The disease has no impact on pregnancy outcomes, such as prematurity or operative delivery.137 Although perinatal mortality in women with MG is unchanged, transplacental transfer of antiAchR antibodies to the fetus may be responsible for transient neonatal MG (TNM), found in approximately 10% of newborns.133 Of note, the incidence of TNM is not related to the level of maternal anti-AchR antibodies. Carefully monitor all babies born to mothers with MG for signs of muscle weakness (poor sucking, hypotonia, feeble cry, ptosis, respiratory distress). Symptoms commonly occur in the first 12–24 hours postpartum and last up to 3 months.127 Anticholinesterase drugs and ventilatory support may be necessary in some cases. Rarely, TNM can lead to arthrogryposis due to the limited movement of the fetus in utero.

- Aminoglycosides* (gentamicin, streptomycin)

Consider alternative where possible and monitor symptoms if required

- Beta blockers †

Can be used in stable disease, monitor closely

- Sodium channel blockers in Class 1a antidysrhythmics* (quinine, procainamide)

Avoid use, seek alternative

- Magnesium*

Caution and close monitoring

- L-type Calcium channel blockers † (i.e., amlodipine, nifedipine, verapamil)

Can be used in stable disease, monitor closely

- Depolarizing neuromuscular blockers (NMB) *

Avoid succinylcholine. NMBs discussed further in the text

- Antipsychotics † (i.e., haloperidol, olanzapine, risperidone, chlorpromazine)

Can be used in stable disease, monitor closely as can worsen MG symptoms

Effect of Pregnancy on Myasthenia Gravis

- Lithium (has been reported to cause de-Novo MG)

Can be used in MG patients as MG exacerbation is rarely reported

- Corticosteroids*

Start with low dose and increment. If high dose is required then pretreat with IVIG

- Botulinum toxin *

Avoid if possible but can be used to treat blepharism or cervical dystonia in low dose

Effect of Myasthenia Gravis on Pregnancy

There is no clear consensus about the effect of MG on pregnancy, most likely due to the rarity of the disease, spectrum of symptoms, and lack of prospective cohort studies. During pregnancy, MG is unpredictable, with 50% deteriorating, 30% improving, and 20% remaining static.138 Factors such as puerperal infection, pain, and stress are well-known factors that can worsen symptoms. Tables 13.14A and 13.14B cover the physical and

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pharmacological factors that may exacerbate MG. Myasthenic crisis in pregnancy is rare.133

Obstetric Management A multidisciplinary approach involving obstetricians, anesthesiologists, pediatricians, and neurologists is essential to manage these high-risk pregnancies. Management includes134: • Prompt treatment of infection • Careful titration of medication • Alertness for exacerbations • Avoidance of exacerbating factors Continue pyridostigmine throughout pregnancy as it does not cross the placenta and poses no fetal risk. During pregnancy, frequent medication adjustments may be necessary as erratic GI absorption, nausea, vomiting, or increased bulbar symptoms may compound the expanded plasma volume, increased renal excretion, and hepatic stasis. Anticholinesterases may have to be administered parenterally during the first trimester if emesis is an issue. Parenteral administration avoids the problem of variable gastric absorption and minimizes breakthrough symptoms caused by subtherapeutic levels (Table 13.15). Prednisolone is the first-choice immunosuppressive treatment in MG in pregnancy. Azathioprine is generally deemed safe in pregnancy, although there are differing opinions. In Europe, the consensus is to continue AZA in pregnancy, whereas advice is more cautious in the United States due to unfavorable animal studies and case reports.134 As methotrexate, mycophenolate, and cyclophosphamide are teratogenic, do not administer them to women of childbearing age. Plasmapheresis and IVIG are safe in pregnancy.126 If thymectomy is necessary, plan it before conception, as there is no therapeutic advantage in incurring the added operative risk during pregnancy. Myasthenia gravis does not affect the first stage of labor because the uterus consists of nonstriated muscle. However, the second stage uses striated muscles, and fatigue may mandate instrumental delivery.126 Consider CD for obstetric reasons only. Supplemental doses of corticosteroids may be required during labor or instrumental delivery.139 Hypermagnesemia causes neuromuscular block by inhibiting the release of Ach, reducing the depolarizing action of Ach at the endplate, and depressing muscle fiber membrane excitability. Therefore, do not administer magnesium sulfate (MgSO4) to patients with severe MG (for tocolysis or PreE), and if considered in patients with mild MG, use with great caution.135 Consider treating an eclamptic seizure with magnesium; have the anesthesiologist standby as the patient may require respiratory support. Table 13.15  Equivalent dosages of anticholinesterase medication

Drug

Duration Intravenous Intramuscular Oral of action dose dose dose

Pyridostigmine

4–6 hours 1–2 mg

1–2 mg

30–60 mg

Neostigmine

2–3 hours 0.5 mg

1.5 mg

15 mg

Physostigmine is not used as it crosses the blood–brain barrier and causes central stimulation. Pyridostigmine is preferred anticholinesterase as it has fewer muscarinic side effects than neostigmine.

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Most mothers can safely breastfeed even when taking pyridostigmine, prednisolone, or AZA. In addition, breast milk only contains 2% of the IgG content from maternal serum, thus representing a negligible risk of transmission and neonatal MG symptoms. Moreover, breastfeeding reduces the risk for many autoimmune diseases.140

Anesthetic Management The obstetric anesthesiologist faces many challenges in caring for the parturient with MG (Table 13.16). It is essential to perform an extensive, early evaluation of the patient. Pay particular attention to the onset, duration, severity (especially bulbar and respiratory muscle involvement), disease treatment, and associated diseases. As there are reports of focal myocardial necrosis in some MG patients, obtain an ECG. Counsel patients with prior respiratory or bulbar problems as they may have a higher rate of postsurgical myasthenic crisis.141 Preoperative lung function testing (FVC < 2.9 liters or 40 ml/kg) may identify patients with a risk of requiring prolonged respiratory support.141 Therapeutic optimization will decrease the risk of surgery and improve outcomes. The anesthesiologist should be aware of the factors that exacerbate MG, (Table 13.14A), particularly the pharmacological factors (Table 13.14B). Controversy exists around anticholinesterase medication, whether to maintain or discontinue it preoperatively.141 Discontinuation may facilitate dosage and reversal of neuromuscular blocking agents. Issues with continuation include potentiation of vagal responses, inhibition of plasma cholinesterase (hence prolongation of ester LA and succinylcholine), and possible cholinergic crisis. It is better to continue medication in patients with MG who are physically or psychologically dependent on the therapy. Neuraxial anesthesia is the preferred method of analgesia for labor and delivery.139 It reduces the exacerbating factors of labor pain, avoids opioid-induced respiratory depression, and allows flexibility should operative delivery be necessary. Epidural anesthesia might be preferred over spinal in the elective operative setting to prevent the risk of respiratory depression if a high spinal occurs.137 Expect exaggerated vagal responses to neuraxial blockade with concurrent pyridostigmine treatment, requiring prompt treatment with atropine. Thrombocytopenia can be associated with MG, so check platelet levels before NA.142 Table 13.16  Associated problems in patients with myasthenia gravis Muscle weakness

Bulbar/oropharyngeal → pooling of secretions and saliva → respiratory obstruction and aspiration Respiratory → difficulty in clearing secretions → respiratory failure

Associated conditions

Thymus hyperplasia (75%) Thymoma (10–25%) and other malignancies Thyroid disease (3–15%) Systemic lupus erythematosus (2%) Rheumatoid arthritis (4%) Ankylosing spondylitis Crohn disease Hypertension Diabetes mellitus Myocarditis → cardiomyopathy, dysrhythmias Seizures

Miscellaneous Skeletal and Connective Tissue Disorders

General anesthesia may be necessary for failed NA or to prevent aspiration in those patients with severe bulbar disease. Inhalational agents have been used safely but can cause neuromuscular blockade.143 Some anesthesiologists exploit this effect to avoid using neuromuscular blocking agents in the elective surgical setting.143,144 Depolarizing and nondepolarizing muscle relaxants (NDMR) are safe, although in altered doses. Responses to depolarizing muscle blockers may be variable. The ED50 for succinylcholine in MG patients is 2.6 times the normal due to the reduction in AchR in the motor endplate.145 In obstetric anesthesia, succinylcholine is usually used at the rapid sequence induction dose of 1–1.5 mg/kg (three to five times the ED50), but this may be insufficient in MG patients. After choosing the rapid sequence induction dose, the onset of the block should be normal. There is the potential for a prolonged (Phase II block) due to preoperative treatment with anticholinesterases.145 Myasthenic patients are more sensitive to NDMRs, so use agents with a short or intermediate half-life. Dosing should depend on disease severity and start at 50% of the usual dose.141 Sugammadex is a safe reversal agent for rocuronium and is changing clinical practice in MG patients requiring GA.137,146,147 Rapid, sustained recovery from neuromuscular blockade means that one does not have to compromise safe intubating conditions with subtherapeutic dosing in the emergency setting. To avoid an overdose, calculate the doses based on ideal weight and anticipate that some GA patients with MG will need a period of prolonged ventilatory support. Finally, it is essential to perform preoperative muscle strength measurement for postoperative comparison. The disease, rather than the neuromuscular block, may prevent patients with MG from reaching full strength, despite treatment. A control electromyograph or train-of-four should be recorded (warn the patient of the expected uncomfortable sensation) before administering any anesthetic drugs that interfere with neuromuscular transmission.

inheritance and caused by a point mutation in the FXN gene on chromosome 9.150 This mutation causes a reduction in the protein product of FXN (frataxin), required for efficient regulation of cellular iron homeostasis. Frataxin is normally found in high quantities in the brain, spinal cord, heart, and pancreas, the organs most affected by FA. Deficiencies in this protein lead to mitochondrial accumulation of iron, reducing adenosine triphosphate production and oxidative stress. This causes cardiac hypertrophy and fewer contractile fibers in the cardiomyocyte. In the nervous and endocrine systems, there is cellular atrophy. Tables 13.17 and 13.18 describe the diagnostic criteria and clinical problems of FA. Table 13.17  Diagnostic criteria for Friedreich ataxia Autosomal recessive inheritance Age of onset < 25 years Progressive gait and limb ataxia Absent tendon reflexes in lower limbs Electrophysiological evidence of axonal sensory neuropathy (with normal/ slightly raised motor nerve conduction velocity) Dysarthria* Areflexia* in all four limbs Pyramidal leg weakness* Distal loss of joint position and vibration sense* Criteria, except as marked, within 5 years of symptom onset. *  Eventually universal but generally not found in patients within 5 years of onset of symptoms. Table 13.18  Clinical features of Friedreich ataxia148,151

Organ Disease process

Anesthetic implications

CNS

Ataxia Dysarthria Loss of deep tendon reflexes Posterior column signs Weakness/decreased muscle tone, bulbar dysfunction Distal muscle wasting (50%) Extensor plantar response (90%)

Altered response to muscle relaxants Hyperkalemic response to succinylcholine ? Unpredictable response to nondepolarizing muscle relaxants Muscle weakness Increased risk of aspiration/ chest infection

CVS

Cardiac muscle disease Hypertrophic cardiomyopathy

Dysrhythmias (atrial fibrillation) Cardiac compromise

Spine

Kyphoscoliosis (mostly thoracic) Possible corrective surgery (e.g., Harrington rods)

Decreased cardiopulmonary reserve Technical problems with spinal/epidural block

Eyes

Optic atrophy (25%) Nystagmus (20%) Abnormal extraocular movements

Ears

Sensorineural deafness (10%)

Feet

Pes cavus ± equinovarus deformity (75%)

Friedreich Ataxia Valuable Clinical Insights • Friedreich ataxia (FA) is an inherited, progressive, cardio/neurodegenerative disease. • The main issues are cardiomyopathy, progressive neuropathy (central/peripheral), diabetes, and kyphoscoliosis. • FA patients have reduced life expectancy, with cardiac failure being the leading cause of death. • FA does not affect pregnancy; however, the physiological effects of pregnancy may worsen cardiac status. • Pregnancy is recommended only in the early stages of the disease.

Friedreich ataxia affects the central and peripheral nervous systems. It is the most frequent hereditary ataxia with an estimated prevalence of 3–4 cases per 100,000 individuals.148 It is mainly found in Caucasian populations and rarely seen in Sub-Saharan Africa or the Far East.149 It is transmitted by autosomal recessive

Associated diseases include diabetes mellitus (10%), impaired glucose tolerance (20–30%), and increased incidence of seizures. Abbreviations: CNS = central nervous system; CVS = cardiovascular system.

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The manifestations vary with the number of point mutations, also known as GAA expansions. Longer GAA repeats cause a more profound frataxin deficiency. They are associated with earlier onset, shorter time to loss of ambulation, greater frequency of cardiomyopathy, and increased disease severity.151 The major clinical manifestations of FA are neurological dysfunction, cardiomyopathy, and diabetes mellitus. The most frequent presenting symptom is an ataxic gait, although scoliosis or cardiac symptoms may precede it. The average age of onset is 15 years (range 2–51 years); most patients require a wheelchair within 11 years of diagnosis (range 1–25 years). The estimated life expectancy is 35–40 years. Mortality is caused by cardio­ respiratory problems related to scoliosis and cardiac abnormalities, with more than 50% of FA patients dying from heart failure.152 There are ECG abnormalities in up to 95% of patients with FA, the most common being T wave inversion or flattening in the left chest leads. Eighty percent of FA patients have echocardiographic findings of LV wall remodeling, with 35% showing concentric hypertrophy.152 Approximately one-third of FA patients have overt diabetes mellitus or impaired glucose tolerance, likely associated with the mitochondrial defects associated with the damaged FXN gene in pancreatic ß cells.153 Treatment of FA involves symptomatic support and antioxidants to reduce free radicals. However, as with many rare diseases, treatment options are based on low-quality evidence. A Cochrane review concluded that, while these treatments are not harmful, they are equivocal in improving the neurological status of FA patients.154

Pregnancy and Friedreich Ataxia Advances in medical management have resulted in more women with FA attaining reproductive age. FA appears to have little effect on the fetus or mother. In a series of 65 pregnancies in 31 women with FA, there was no increased risk of spontaneous abortion, PreE, or preterm labor.155 Despite the weakness associated with FA, 78% delivered vaginally. There is no consensus on changes in FA symptoms during pregnancy. However, superimposed physiological changes of pregnancy potentially aggravate cardiorespiratory problems in parturients with FA, so review these patients regularly. Addressing a woman’s concerns about worsening symptoms or weakness affecting their ability to care for an infant is vital during the consultation.

Obstetric Management Patients with FA do not have an increased risk of obstetric complications. Some studies recommend pregnancy in earlier stages of the disease to facilitate the care of young children. In later stages of the disease, weakness and cardiorespiratory compromise might interfere with that care. Perinatal care of FA patients, especially those with cardiac complications, requires full multidisciplinary involvement in a tertiary center. Consider CD for obstetric reasons only, as there is no evidence that a planned CD improves outcomes for mothers with cardiac conditions or their fetuses.156 There is one documented case report of profound weakness after magnesium administration.157 However, one must balance the risks of magnesium in FA parturients against its benefits for neuroprotection of the premature fetus and eclampsia in the parturient.

Anesthetic Management The primary considerations for the anesthesiologist caring for a patient with FA are cardiorespiratory compromise, kyphoscoliosis, diabetes, and pharmacological interactions. The main perioperative risk in women with FA is the presence of hypertrophic cardiomyopathy. Global systolic function is maintained in most patients for a considerable time until a dysrhythmia or, more commonly, cardiac failure results in death. Nevertheless, concentrate preoperative evaluation on cardiac and pulmonary function with an ECG and echocardiogram in all patients. Document baseline neurologic deficits, especially if contemplating NA. As spinal anesthesia may cause precipitous hypotension, use it only in those patients with FA who have had an extensive cardiac assessment. Epidural anesthesia is a good alternative with a slow incremental onset and greater hemodynamic stability in patients with known cardiac compromise.158 Combining intraarterial BP monitoring with incremental doses of peripheral vasopressors can improve the safety of this technique. Progressive kyphoscoliosis may restrict pulmonary function by decreasing vital capacity and total lung capacities. In addition, corrective surgery for scoliosis may make NA difficult. Table 13.19 reviews the relative advantages and disadvantages of NA versus GA in FA patients. If GA is required, a “cardiostable induction” using highdose opioids is prudent to avoid the loss of CO associated with

Table 13.19  Advantages and disadvantages of different anesthetic techniques in patients with Friedreich ataxia

Epidural

Spinal

General

Advantages

↓perioperative respiratory problems unless high block Cardiovascular stability with slow administration Provides excellent postoperative analgesia preventing ↓SVR and ↑HR (especially with cardiac patients)

Rapid onset Easier technique than epidural Provides good postoperative analgesia

Good airway control in patients with gross muscle weakness

Disadvantages

Technical difficulties in patients with kyphoscoliosis ↑incidence of patchy block in patients with kyphoscoliosis

Technical difficulties in patients with kyphoscoliosis Sudden sympathetic block may compromise patients with hypertrophic cardiomyopathy

Possible succinylcholine-induced hyperkalemia ? ↑sensitivity to NDMR

Abbreviations: HR = heart rate; NDMR = nondepolarizing muscle relaxant; SVR = systemic vascular resistance.

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Miscellaneous Skeletal and Connective Tissue Disorders

the profound vasodilatory effects of traditional IV anesthetics. One can reduce the effect of opioids on the fetus by ensuring the induction to delivery time is minimized by having the team ready to operate at the point of confirmed intubation. Although most studies indicate normal responses, reports of patient responses to NDMR in FA vary. However, it is prudent to use an appropriate dose of NDMR for safe intubation and to monitor neuromuscular blockade intraoperatively. The use of rocuronium and sugammadex can help mitigate potential issues with NMJ blocking agents.159 Although there are reports of succinylcholine use in patients with FA, it has the potential to induce hyperkalemia. In cases of severe muscle wasting or rapid progression of weakness, do not use succinylcholine.

Table 13.20  Clinical features of Marfan syndrome Eyes

Ectopia lentis, myopia, retinal detachment, cataracts, enophthalmos

Skin

Striae (not associated with pregnancy or weight gain) Incisional hernia

Neural fibrous tissue

Dural ectasia (of particular importance for the anesthesiologist)

Musculoskeletal

Arachnodactyly Pectus deformity Kyphoscoliosis Increased bone length/tall stature Joint hypermobility High narrow palate* Mandibular retrognathia* Malar hypoplasia* *implications for airway management

Pulmonary

Spontaneous pneumothorax Obstructive sleep apnea

Cardiovascular

Mitral valve prolapse Aortic dilatation (60%), dissection and rupture Premature coronary disease Electrical conduction defects

Marfan Syndrome Valuable Clinical Insights • Pathophysiology of Marfan syndrome is related to factors associated with cell signaling rather than exclusive architectural deficiencies of the fibrillin protein. • MFS can take years to diagnose due to the complexity and, at times, the subtlety of symptomology. • Mortality is directly related to aortic root size and is caused mainly by dissection and rupture. • With an aortic root diameter: < 4 cm vaginal delivery, 4–4.5 cm CD, > 4.5 pregnancy not recommended. • Key anesthetic concerns include minimization of hemodynamic stress (prevention of acute aortic dissection) and difficulties with neuraxial blockade (scoliosis/dural ectasia).

First diagnosed by Antoine-Bernard in 1896, Marfan syndrome (MFS) has an incidence of 0.19 in 100,000 and a prevalence of 1 in 5,000 individuals.160 The median age of diagnosis is 19 years; however, identification of this disease can occur at any age.161 There is no predilection for gender, nationality, or race. Although there is often a family history, 25% of cases arise as new mutations.161 Previously, MFS was considered directly related to mutations in one gene: the fibrillin-1 (FBN1) gene on chromosome 15.162 This large protein, FBN1, is a central component of the extracellular matrix, maintaining the strength and integrity of cells and tissues. However, the connection between mutation and disease is not simple. The current thought is that fibrillins have a crucial role in cellular signaling: regulating homeostasis, immune response, and inflammation.163 In fact, many genetic disorders are linked to this gene, including multiple forms of dwarfism, pointing toward the complex nature of the FBN1 gene.164 Research studies in mice have described an overexpression of transforming growth factor-beta (TGF-ß) in those tissues linked to the pathology of MFS.165 The molecular mechanism linking TGF-ß, and FBN1 in MFS suggests errors of the intracellular signaling function of FBN1 rather than disrupted cellular architecture. Marfan syndrome is a multisystem disease with abnormalities in the eyes, skin, neural fibrous tissue, musculoskeletal, pulmonary, and cardiovascular systems. Table 13.20 summarizes the clinical features of MFS.

It is difficult to diagnose MFS and often takes anywhere from 1.5 to 4 years to do so. Eighty percent of patients are initially misdiagnosed, with some patients having to consult over 20 doctors before reaching a diagnosis.166 The international classification system for MFS has been revised twice since the original Berlin criteria. Aortic dilatation is one of the essential clinical diagnostic features of MFS. The most recent criteria, Ghent-2, rests heavily on aortic root dilatation combined with family history and key physical characteristics.167 Genetic testing can be helpful in some cases, but it is only considered part of the diagnostic criteria in the absence of family history. The Ghent-2 criteria are complex, so most use simple screening tools to evaluate MFS risk for a particular patient. One such tool is the “seven signs of MFS,” where a score of > 3.5 suggests a high probability of MFS161,168: 1. Family history of MFS (2 points) 2. Previous thoracic aorta surgery (1 point) 3. Pectus excavatum (1 point) 4. Wrist and thumbs sign (arachnodactyly) (1 point) 5. History of pneumothorax (1 point) 6. Skin striae (1 point) 7. Ectopia lentis (displaced lens) (4 points) Advances in surgical and medical therapy have decreased the mortality of MFS. Affected individuals have a normal life expectancy if the diagnosis is made early and appropriate treatment is received. Early detection of aortic root dilatation is critical for the success of beta-blocker therapy in slowing the rate of progress. In randomized controlled trials, losartan is equally as effective as beta-blockers in treating aortic disease in young adults.169 Losartan, as an angiotensin-II type 1 receptor (AT1) blocker, acts to prevent TGF-ß signaling. Prophylactic cardiovascular intervention in MFS is required when aortic root dilatation is > 5.0 cm due to a four-fold increase in the

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Caroline S. Grange and Sally Anne Shiels

risk of death or dissection.170 This recommendation changes to > 4.5 cm in the pregnant population and those with rapid progression in size.

Effect of Marfan Syndrome on Pregnancy Marfan syndrome is associated with an increased risk of obstetric complications. Cervical incompetence can lead to preterm rupture of membranes and labor (> 40% of MFS pregnancies).171 The risk of PPH is higher in MFS, and there are reports of poor fetal outcomes.172

Effect of Pregnancy on Marfan Syndrome The cardiovascular and hormonal changes of pregnancy can profoundly affect women with MFS. The critical consideration is the worsening of aortic disease. Cardiac output increases 40% by the second trimester due to higher HR and stroke volume, worsening shear stress across the vessel wall. This is further impacted by the estrogen- and progesterone-mediated collagen changes seen in pregnancy. While more likely to occur in the third trimester, acute aortic dissection (AAD) can happen at any stage of pregnancy. The risk of acute AAD in pregnancy for patients with MFS is on average 4%, rising to 10% in higher risk women with an aortic diameter > 4 cm.173 Women with MFS are 20,000 times more likely to have AAD than the general population.174 Management of AAD depends on the area of the aorta affected and the stage of pregnancy. Type B AAD occurs more commonly and affects the descending aorta. Pharmacological agents successfully manage most cases by lowering BP and preventing further dissection. Type A AAD involves the ascending aorta and usually requires intervention. The preferred treatment is thoracic endovascular repair (TEVAR) in Type A AAD patients without MFS. However, endografts have a high failure rate when used for definitive repair in MFS.175 This is likely due to the pathological architecture of the vessels, causing further dilatation in the MFS aorta. A joint statement from the European Cardiology Society and Thoracic Surgery Society suggests using TEVAR in patients with MFS only as “a bail-out procedure or bridge to definitive open surgical therapy.”176 There are reports of successful use of TEVAR in pregnant patients with MFS with good short- to medium-term outcomes for both mother and baby.177 However, no long-term studies have looked at the success of endografts over decades, suggesting that most patients will ultimately require an open procedure. There are reports of open repair of AAD in pregnancy, but as expected, it is associated with high fetal mortality (27–80%) and carries a risk of maternal death up to 8.7%.173

Obstetric Management Cardiovascular disease is the primary cause of maternal mortality in the United States and United Kingdom. Early care by a multidisciplinary team can improve mortality and morbidity outcomes for women with preexisting cardiovascular disease.178 Caring for women with MFS in a tertiary-referral obstetric center with a dedicated cardiac clinic can ensure holistic patientcentered care from preconception to postpartum (see Chapter 6).

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Prepregnancy counseling is essential in patients with ascending aortic measurements of > 4.0 cm, as elective root repair may be prudent before considering pregnancy. European guidelines suggest intervention at > 4.5 cm or a growth rate of > 0.3 cm per year179; American guidelines are more conservative at > 4 cm.180 Genetic counseling is crucial in MFS and usually takes place before conception, given the autosomal dominant nature of inheritance. Preimplantation diagnosis reduces the incidence of in utero diagnosis and the otherwise difficult decisions that would have to be made.173 Once pregnant, the risk of an adverse cardiac outcome is associated with an enlarged aortic root, rate of root expansion, multiple pregnancies, lack of beta-blocker usage, and the absence of appropriate follow-up.181 Measure the aortic root using echocardiography in women with MFS; measure it monthly in those with a root > 4 cm or where the size is rapidly progressing. Hypertension is the most significant modifiable factor to prevent AAD; in most cases, start beta-blockers in pregnancy. However, there is no proof that beta-blockers reduce AAD risk in pregnancy.182 In addition, beta-blockers carry a risk of IUGR. The decision to start beta-blockade in pregnancy should consider baseline root diameter, growth rate, fetal status, and patient preference.181 Ensuring the patient and family are aware of the symptoms and signs of dissection can facilitate prompt treatment before catastrophic rupture.182 Consider a vaginal delivery in women with an aortic root diameter of < 4 cm. However, when > 4 cm, advise women to have a CD and deliver in a center with cardiothoracic surgical provision.180 Avoid ergot derivatives as they cause hypertension and vasoconstriction. Postpartum care should be enhanced for up to a year with ongoing imaging, especially for those in the high-risk group.

Anesthetic Management It is crucial to involve an obstetric anesthesiologist in the perinatal care of women with MFS, especially during intrapartum planning. This involvement ensures safer anesthetic delivery in elective and emergency situations and provides an opportunity to discuss anesthetic preferences with the patient. Table 13.21 covers the foremost considerations for the anesthesiologist assessing a woman with MFS. In elective and emergency settings, anesthetic management aims to minimize aortic root shear forces and wall stress through invasive monitoring, pharmacologic intervention, and adequate analgesia.

Neuraxial Anesthesia Epidural and spinal anesthesia has been used safely in parturients with MFS.183 In patients with a metallic cardiac valve, bridge anticoagulation appropriately if considering NA. Initiate LEA early to prevent pain-induced catecholamine release, elevated BP, and increased CO. An IV infusion of crystalloid solution can be administered slowly in 250 ml aliquots as required. Slow titration of the epidural level to a T10 sensory level will help prevent a sudden fall in SVR and BP. Treat significant hypotension with phenylephrine (avoiding the beta-agonist effect of ephedrine).

Miscellaneous Skeletal and Connective Tissue Disorders

Table 13.21  Anesthetic concerns in patients with Marfan syndrome

General Anesthesia

System

Concern

Key points

Airway

Potential for difficult airway

History: Previous difficult intubation, neck pain, dizziness, previous neck surgery Examination: Crowding of the teeth, high-arch palate, cervical spine instability, retrognathia, cervical pathology limiting neck movement Investigation: Neck radiograph, MRI

Respiratory

Perioperative respiratory compromise

History: Previous respiratory compromise, recurrent pneumothorax, untreated scoliosis causing restrictive lung disease, symptoms of obstructive sleep apnea Investigation: Chest radiograph, pulmonary function tests, sleep studies

Attenuate the hypertensive response to tracheal intubation with opioids and IV beta-blockers. Volatile agents for these parturients are helpful because they decrease cardiac contractility. For optimum BP control and intraoperative analgesia, consider TIVA (e.g., using propofol and remifentanil). Use positive pressure ventilation carefully to avoid inducing pneumothorax. In all high-risk cases (aortic root > 4 cm), use invasive cardiovascular monitoring and central venous access.

Cardiovascular

Aortic dissection Cardiac failure Dysrhythmia

History: Previous cardiac surgery (valve repair/replacement, dissection repair) Investigations: ECG conduction defect ECHO to identify cardiac function, structural abnormalities, and diameter of aorta

Hematological

Anticoagulation therapy – impact on NA

Anticoagulation treatment (i.e., for metallic heart valve) may require bridging therapy with short-acting agents to facilitate NA in labor. Choice of agent in pregnancy should be chosen in consultation with cardiology/hematology team

Neuraxial anesthesia

Ability to provide effective NA

History: Previous back surgery, symptoms of dural ectasia (low back or leg pain, headache, or lower limb paresthesia) Examination: Anatomical abnormalities of back (scoliosis) Investigation: Plain radiograph of thoraco-lumbar region if metalwork in situ, MRI spine to quantify dural ectasia

Musculoskeletal

Joint dislocation

History: Elucidate joints of concern Ensure careful intrapartum and perioperative positioning

Another unique concern in MFS is dural ectasia (DE), the expansion of the dural sac surrounding the spinal cord. Dural ectasia is present in most patients with MFS (63–92%)184 and is often asymptomatic. However, DE can cause low back pain, headache, proximal leg pain, weakness and numbness above and below the knee, and genital/rectal pain.185 These symptoms can be moderate to severe, typically occur daily or several times a week, exacerbated by the upright posture but not always relieved by recumbency. Their presence effectively increases CSF volume making drug dosing for NA difficult. There is a higher chance of DP during epidural insertion, but DE is not an absolute contraindication for NA. As DE worsens with age, previous successful NA is not necessarily reassuring. MRI is the best modality to identify and quantify DE, helping inform the anesthesiologist and patient of the risk of conversion to GA if NA fails.

Arthrogryposis Multiplex Congenita Valuable Clinical Insights • The primary consideration in pregnancy is the risk of preterm delivery due to respiratory compromise. • Patients are likely to have a difficult airway and complex anatomy making neuraxial techniques challenging. • Incorporate the multidisciplinary team in planning for surgery. • Carefully position these patients for all anesthetic and obstetric techniques due to contractures.

Arthrogryposis multiplex congenita (AMC) is a heterogeneous group of disorders characterized by contractures affecting two or more joints with associated hypotonia and muscle mass wasting. The name is Greek for joint (arthron) and hooked or crooked (gryposis), denoting the curvature of the joints in this disorder. It has an incidence of 1 in 2– 3,000 births.186 The deformities are present at birth and are not progressive. Arthrogryposis multiplex describes over 350 contracture disorders; as a result, there is a considerable disease spectrum.187 Most cases are sporadic, and the natural history and prognosis are challenging to predict. Therefore, it is not surprising that we do not yet know the underlying genetic mutations that lead to AMC. Recent studies, however, have located five potential candidate genes that may cause the AMC phenotype.188 The exact etiology, inheritance, and pathogenesis of AMC are unknown in most cases, but all causes of AMC are associated with decreased fetal movements (fetal akinesia). The origin of the joint deformities is primarily neurogenic in 70–80% of AMC, resulting from peripheral and central nerve dysfunction such as spinal muscular atrophy.189 The nonneurogenic causes of AMC are classified as amyoplasia or distal arthrogryposes.190 Amyoplasia is more common, occurs sporadically, does not affect intelligence, and has distinct contractures affecting the arms and legs, usually in a symmetric pattern.191 Distal arthrogryposes affect the distal parts of the limbs and have an autosomal dominant inheritance. Some reports suggest an association between fetal akinesia and uterine abnormalities (e.g., fibroids or septate uterus); these abnormalities may limit the space in which the fetus can move. However, a study by Hall suggests that this is not causative but only worsens contractures in fetuses with existing AMC.192 Another cause of AMC is abnormal amniotic fluid levels.192 Maternal MG may produce neonatal MG resulting in AMC. The reduction in fetal movement affects the normal development of the joint, shortening tendons

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and causing contractures.191 Therefore, the earlier in gestation that reduction in movement begins, the more severe the contractures. Frequently there are accompanying developmental defects in the neurological system and various viscera191,193,194 (Table 13.22).

Effect of Arthrogryposis Multiplex on Pregnancy Arthrogryposis multiplex is seen primarily in the pediatric population. Parturients with AMC are unusual due to the rarity of the disease, the chronic disability, and the incidence of other associated abnormalities. However, women who reach childbearing age are likely to have adapted to their physical disabilities and may wish to consider pregnancy. The primary consideration of the effect of AMC on pregnancy is the risk of preterm delivery due to maternal respiratory compromise. This risk is related to limited respiratory reserve and early encroachment of the uterus into the thorax associated with spinal deformities and short stature. There are limited case reports from which to draw evidence of the effect of AMC on pregnancy. In one report,195 the uterine fundus reached the xiphisternum at 30 weeks; in another, it reached the xiphisternum at 16 weeks.196 Both required preterm CD at 31 weeks and 30 weeks, respectively, due to respiratory complications.195,196 Reduced mobility due to AMC can increase VTE risk during pregnancy. Consider prophylaxis against VTE in all pregnant women with AMC.

Effect of Pregnancy on Arthrogryposis Multiplex As AMC is nonprogressive, the effect of pregnancy on the disease process is minimal. However, it is probably worth considering Table 13.22  Associated abnormalities in arthrogryposis multiplex congenita191,193,194

the toll that pregnancy takes on the longer-term respiratory function of women with AMC who carry infants to term.

Obstetric Management Most women with AMC who are considering pregnancy will benefit from pregnancy counseling to discuss the physical, mental, and social aspects of their disease on the ultimate success of pregnancy. The risk of preterm and operative delivery, coupled with the high likelihood of needing GA, is not without risk for the mother or fetus. Of the nine published case reports, all but one woman required a CD due to the anatomical limitations associated with their existing contractures and pelvic proportions.195,197–203 Depending on the extent of their contractures, many women will need help postpartum with some aspects of infant care.199

Anesthetic Management Table 13.23 outlines the challenges presented to the anesthesiologist by patients with AMC. The primary areas to address preoperatively are the airway, patient anatomy, respiratory system, and medication choice. Intubation difficulties in AMC patients are due to micro­gnathia, limited neck extension, and abnormal facial anatomy. Most cases of anesthetic management of AMC patients describe a difficult airway scenario in pediatric patients. While bag/mask ventilation may be uncomplicated, visualization of the larynx may be impaired due to its apparent anterior position.204 For GA in adults, many consider awake fiberoptic intubation essential. When this technique is not acceptable, videolaryngoscopy can Table 13.23  Anesthetic concerns in patients with arthrogryposis multiplex congenita

Concern

Abnormality

Organ

Abnormality

Airway

Joints/extremities

Contracture-limited or fixed flexion Absence of patella Syndactylism Bilateral club foot

Difficulty due to micrognathia, high-arched palate, cervical spine deformities, facial abnormalities, muscle contractures

Associated conditions

Congenital heart disease-reduced cardiovascular reserve Pulmonary disease due to myopathy and scoliosis Renal abnormalities-altered drug handling, renal function Seizures

Intravenous access

Joint contractures and scarring from surgery can make intravenous access difficult

General anesthesia

Induction agents ↑sensitivity due to ↓muscle mass Muscle relaxants Nondepolarizing ↑sensitivity due to ↓muscle mass Succinylcholine Possible hyperkalemic response Inhalation agents ↑sensitivity due to ↓muscle mass Increased incidence of hypermetabolism on exposure to anesthetic agents rather than actual link with malignant hyperthermia

Neuraxial anesthesia

Difficulty due to skeletal abnormalities – kyphoscoliosis Abnormalities in spinal cord Altered spread of LAs Abnormalities in cerebrospinal fluid production and reabsorption Medicolegal consequences of neuronal damage Decreased accessibility to nerves due to contractures

Head/neck

Micrognathia High-arched palate Mandibulofacial dysostosis Craniosynostosis Facial abnormalities Tracheal stenosis

Cardiovascular system

Congenital heart disease (10%) e.g., PDA, AS, coarctation of aorta, cyanotic heart disease

Spine

Vertebral abnormalities Kyphoscoliosis Spina bifida Sacral agenesis

Respiratory system

Restrictive lung disease Hypoplastic lungs Tracheoesophageal fistula

Genitourinary system

Renal abnormalities Absence of vagina/uterus

Central nervous system

CNS abnormalities Increased incidence of seizures

AS = aortic stenosis; CNS = central nervous system; PDA = patent ductus arteriosus.

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Miscellaneous Skeletal and Connective Tissue Disorders

improve the safety of securing the airway.197 Although helpful in the elective, nonobstetric setting, using the LMA is not considered safe in the obstetric population due to the high risk of regurgitation of gastric contents with pulmonary aspiration. To avoid GA, early use of NA is recommended. Advantages of LEA include excellent analgesia, maintenance of cardiovascular and respiratory function, flexibility to provide anesthesia (top-up) without resorting to GA and airway manipulation. However, identifying the epidural space may be difficult because of scoliosis or corrective surgery, and skeletal contractures may make positioning difficult. A possible reason for epidural block failure in AMC is the increased incidence of spina bifida occulta and sacral agenesis, which may affect the spread of LA. Five of ten case reports of parturients with AMC describe successful NA with varying difficulty.197,199,202,203,205 In the remaining five cases, one had failed NA resulting in GA,200 and the others elected to use GA for anatomical reasons. Respiratory problems may arise from myopathy and skeletal deformities. These include alveolar hypoventilation, atelectasis, decreased ability to cough, and an increased incidence of aspiration. The presence of significant scoliosis may lead to reduced lung volumes, increased work of breathing, abnormal ventilation/perfusion ratios, and hypoxemia, which may proceed to carbon dioxide retention, pulmonary hypertension, and cor pulmonale. In addition, AMC patients may be more sensitive to the respiratory depressant effects of opioids. Patients with AMC may react abnormally to induction agents, inhalational agents, and muscle relaxants.206 There have been several reports of hyperthermia in some AMC children, but it is not malignant hyperthermia (MH). In a case series of 398 anesthetics in patients with AMC, there were no cases of MH, although all GA cases used inhalational induction agents.207 More recent case reports describe planned GA due to anticipated difficult neuraxial access based on physical examination. In one case, severe contractures forced the patient to walk on all four limbs.201 Despite this, her pregnancy went to 36 weeks when she had a successful GA for CD. The team, in this case, emphasized the importance of accessing previous anesthetic records (most women have had previous corrective surgery) and how this helped in planning for awake tracheal intubation to secure the airway safely before GA induction. Benonis and Habib197 describe a woman with AMC who required an ex utero intrapartum treatment (EXIT) procedure in her second pregnancy. Unfortunately, her first pregnancy resulted in the death of twins after their failed intubation at birth for suspected Pierre Robin syndrome. Complications of the anesthetic for that procedure (CD) included failed spinal anesthesia, failed awake tracheal intubation (due to anxiety), and difficult direct laryngoscopy (grade III, Cormack and Lehane classification). She had limited flexion and extension of her back and mild lumbar scoliosis but reasonable neck movement. She expressed a preference for NA for the EXIT procedure. The technique was complicated by an inadvertent spinal catheter which was used successfully for the operation. This case captures the potential problems the anesthesiologist may face in caring for patients with AMC and the importance of early shared decision making with patients where possible.

Osteogenesis Imperfecta Valuable Clinical Insights • Bone fragility is the hallmark of the disease, and depending on the variant of the disease, this can be mild or extremely debilitating. • Other systemic manifestations of the disease are hearing loss, mitral valve prolapse, hyperthyroidism, and a predisposition to bleeding. • Congenital malformations are common. • Patients with severe forms of OI are likely to have a difficult airway and potentially complex anatomy making NA and surgery challenging.

Osteogenesis imperfecta (OI), or brittle bone disease, is a rare inherited connective tissue disorder with a variable clinical spectrum of disease severity. The incidence of OI is approximately 1 in 10,000 births.208 Bone fragility is the hallmark of the disease, resulting in an increased risk of fractures. The underlying condition involves osteopenia with primary defects in the protein matrix of bone and other connective tissue. Pathogenic variants of the COL1A1 and COL1A2 genes on chromosomes 17 and 7, respectively, link to osteopenia in approximately 85% of cases.209 These genes encode the α1 and α2 chains of the collagen type 1 protein and, as the main organic component of bone, contribute to its elastic properties. Over 20 genes associated with OI affect collagen production, osteoblast and osteoclast function, and bone mineralization.208,210 Most cases of OI are inherited in an autosomal dominant pattern, although some are autosomal recessive or X-linked. Clinical manifestations of OI include excessive bone fragility with a predisposition to fracture, short stature, scoliosis, triangular facial configuration (large vault, small jaw), cervical and basilar skull deformities, hearing loss, blue sclerae (decreased collagen content results in pigmented choroid becoming visible), dentinogenesis imperfecta, predisposition to bruising, and increased laxity of other connective tissue (e.g., skin, ligaments, heart valves). The original classification of OI in 1979 by Sillence et al. used the severity and physical manifestations of the disease.211 Since then, advances in the understanding of OI’s genetic and molecular basis led to a reclassification of the disease (Table 13.24). The diagnosis is made after physical examination, genetic and biochemical tests, and skin biopsy (to assess collagen properties). Treatment involves a multidisciplinary approach to maximize functional capacity and minimize fracture rates, deformity, and chronic pain. Recent treatment developments include gene therapy and in utero stem cell transplantation.212

Effect of Osteogenesis Imperfecta on Pregnancy Fertility in patients with OI in Group A is unaffected by the disease, and women should expect to reach childbearing age. There are more white women in the OI parturient population,213 which might be because black children with OI are three times more

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Table 13.24  Classification of osteogenesis imperfecta208–210

Obstetric Management

Type Manifestations

Women with OI are seven times more likely to have a fetus with congenital malformations.213 As a result, offer genetic counseling and prenatal diagnosis to all affected mothers. The precise risk of OI in the fetus depends on the inheritance characteristics of the maternal OI and whether it has been mapped to a specific gene. Antenatal diagnosis involves a detailed anomaly scan, chorionic villus sampling, and extensive genetic screening. Concern exists over the risk of fractures with vaginal delivery in the fetus with OI; however, there is no evidence to support this. Therefore, only consider CD for obstetric reasons in mild cases of OI.215 Specifically, a CD did not decrease fetal fracture rates at birth.219 Preterm CD is associated with more severe forms of OI and may be necessary for those parturients with crippling skeletal deformities and absolute cephalopelvic disproportion.218,220

Inheritance

Prevalence

Group A: Mild to moderate severity 1

Blue sclera Nondeforming Fracture frequency > 1/year Conductive hearing loss (60%) Normal stature Joint hypermobility

AD

46–71%

4

Normal sclera Variable degree of long bone and spine deformities Recurrent fractures May be of short stature Posterior fossa compression syndrome

AD AR XL

12–28%

5

Calcification in intraosseous membrane in forearms and legs Dislocation of radial head Hyperplastic callus

AD

2–5%

Anesthetic Management

Group B: Progressively deforming and perinatally lethal 3

Severe progressive deformity May have blue sclera Wheelchair-bound with life expectancy 30 years

AD AR XL

12–28%

2

Lethal in perinatal period Long bone fracture, crushed vertebrae and small thorax Usually stillborn

AD AR

12%

AD = autosomal dominant; AR = autosomal recessive; XL = X-linked.

likely to die in childhood.214 Parturients with OI are at increased risk of APH and PPH, placental abruption, gestational diabetes, and increased neonatal morbidity/mortality.213,215 Di Lieto and coworkers found diminished collagen content in the uterine myometrium of a patient with type I OI compared with normal controls.216 They postulated that the underlying myometrial biochemical modifications were responsible for an increased risk of uterine rupture. However, larger population studies and case reviews failed to show an increased risk of uterine rupture in patients with OI.217

Effect of Pregnancy on Osteogenesis Imperfecta Musculoskeletal problems, particularly back pain, are common in parturients with OI and may result from pregnancy-induced joint laxity.217 Pregnancy and breastfeeding may accelerate osteoporosis, resulting in an increased risk of fractures during pregnancy or early postpartum. Calcium and vitamin D supplementation are essential preventative measures. Of note, stop bisphosphonates in the conception period. In severe disease, where the gravid uterus worsens cardiopulmonary complications, parturients may need an early expedited operative delivery. Kawakita et al.218 described a woman with severe OI who required premature delivery of both of her children due to severe respiratory compromise. This compromise was secondary to severe kyphoscoliosis compounded by uterine compression.

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As OI is heterogeneous, individualize the anesthetic management. To successfully address the needs of these women with complex disabilities, ensure there is sufficient time to have a clear and in-depth discussion about analgesic/anesthetic options.221 Given the rarity of this disease, evidence for best anesthetic practice is derived from case reports; these inevitably focus on rare complications with successful outcomes. Anesthetic concerns include patient fragility, airway abnormalities, vertebral column abnormalities, and a bleeding predisposition. Care is needed when transferring and positioning patients. One case report illustrates the successful use of supportive layers of foam padding to help position and support a parturient with severe anatomical deformities for CD.218 Positioning also affected the operative field and required a subumbilical incision to deliver the preterm infant. Use tourniquets and noninvasive BP cuffs cautiously. Invasive monitoring may be less traumatic than repeated excessive inflation with an automatic BP cuff. Table 13.25 reviews the anesthetic implications of OI. The spine in OI can be affected from cervical to lumbar levels resulting in neuraxial and airway difficulties. NA may be challenging due to kyphoscoliosis, short stature, and problems positioning patients with fracture deformities or surgical interventions. Spinal US may improve NA success in patients with impalpable spinous processes or severe scoliosis, decreasing the number of failed attempts during placement.222–224 Patients with OI may have shortened cervical vertebrae, malformed teeth, micrognathia, and previous fracture deformities. Therefore, airway examination is essential to establish potential difficulty with intubation. Patients with unstable cervical spinal anatomy likely had surgical intervention before childbearing age. While minimizing the risk of spinal injury, surgical intervention can limit cervical flexion/extension, making intubation challenging. If contemplating GA, secure tracheal intubation with minimal trauma and manipulation to avoid fractures in vulnerable vertebrae, mandible, and teeth. Awake fiberoptic intubation or videolaryngoscopy may minimize this risk. The patient and anesthesiologist may prefer NA but should consider the possible need to convert to GA if unsuccessful

Miscellaneous Skeletal and Connective Tissue Disorders

Table 13.25  Osteogenesis imperfecta and anesthetic implications

Organ

Dysfunction

Anesthetic/surgical implications

Musculoskeletal

Bone fragility Kyphoscoliosis (due to joint hyperdistensibility and vertebral collapse) Fragile cervical spine/airway/teeth Cervical instability (odontoid hypoplasia) Chest wall deformities (from previous fractures)

Care with handling patient, protection of pressure areas during anesthesia Care with use of tourniquet Avoid automated BP devices in severe OI Use manual BP devices or invasive monitoring Possible neurological deficit (from nerve compression) NA – technically challenging, unpredictable spread Reduced respiratory reserve Avoidance of trauma to cervical spine/jaw/teeth during intubation Fiberoptic intubation may be necessary Reduced respiratory reserve

Hematologic

Predisposition to bleeding (possible quantitative/ qualitative platelet abnormality, vessel fragility)

Spinal hematoma risk Increased risk of perioperative hemorrhage

Thyroid

Hyperthyroidism (40%)

Awareness and correction of thyroid function

Cardiovascular

Aortic incompetence, aortic root widening, mitral valve prolapse

Dysrhythmias, bacterial endocarditis prophylaxis, rupture

Auditory

Deafness

Communication problems

Cellular metabolism

Probable deranged cellular energy metabolism (? hypermetabolic state – hyperthermia during GA)

Intraoperative temperature monitoring ETCO2 monitoring

BP = blood pressure; ETCO2 = end tidal carbon dioxide.

NA, respiratory compromise, or high block occurs. One report describes preoperative visualization of the airway with a laryngoscope after topicalizing the mucosa to determine ease of intubation before initiating NA.218 OI is not associated with malignant hyperthermia.225

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statement from the American Heart Association. Circulation 2020;141:e884–e903. Erbel R, Aboyans V, Boileau C, et al. 2014 ESC Guidelines on the diagnosis and treatment of aortic diseases. Eur Heart J 2014;35:2873–2926. Hiratzka LF, Bakris GL, Beckman JA, et al. 2010 ACCF/AHA/ AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM Guidelines for the diagnosis and management of patients with thoracic aortic disease. Circulation 2010;2010:121. https://doi.org/10.1161/ CIR.0b013e3181d4739e Donnelly RT, Pinto NM, Kocolas I, et al. The immediate and long-term impact of pregnancy on aortic growth rate and mortality in women with Marfan syndrome. J Am Coll Cardiol 2012;60:224–229. Smith K, Gros B. Pregnancy-related acute aortic dissection in Marfan syndrome: a review of the literature. Congenit Heart Dis 2017;12:251–260. Weinstein J, Shinfeld A, Simchen M, et al. Anesthesia in parturients presenting with Marfan syndrome. Isr Med Assoc J 2021;23:437–440. Mesfin A, Ahn NU, Carrino JA, et al. Ten-year clinical and imaging follow-up of dural ectasia in adults with Marfan syndrome. Spine J 2013;13:62–67. Yang HJ, Baek IC, Park SM, et al. Inadequate spinal anesthesia in a parturient with Marfan’s syndrome due to dural ectasia. Korean J Anesthesiol 2014;67:s104–105. Navti OB, Kinning E, Vasudevan P, et al. Review of perinatal management of arthrogryposis at a large UK teaching hospital serving a multiethnic population. Prenat Diagn 2010;30:49–56. Filges I, Hall JG. Failure to identify antenatal multiple congenital contractures and fetal akinesia – proposal of guidelines to improve diagnosis. Prenat Diagn 2012;33:61–74. Pehlivan D, Bayram Y, Gunes N, et al. The genomics of arthrogryposis, a complex trait: candidate genes and further evidence for oligogenic inheritance. Am J Hum Genet 2019;105:132–150. Kalampokas E, Kalampokas T, Sofoudis C, et al. Diagnosing arthrogryposis multiplex congenita: a review. ISRN Obstet Gynecol 2012;2012:264918. https://doi.org/10.5402/ 2012/264918 Bamshad M, van Heest AE, Pleasure D. Arthrogryposis: a review and update. J Bone Joint Surg 2009;91:40–46. Hall JG, Aldinger KA, Tanaka KI. Amyoplasia revisited. Am J Med Genet Part A 2014; 164A:700–730. Hall JG. Uterine structural anomalies and arthrogryposis-death of an urban legend. Am J Med Genet Part A 2013;161A:82–88. Ma L, Yu X. Arthrogryposis multiplex congenita: classification, diagnosis, perioperative care, and anesthesia. Front Med 2017;11:48–52. Oberoi GS, Kaul HL, Gill IS, et al. Anaesthesia in arthrogryposis multiplex congenita: case report. Can J Anaesth 1987;34:288–290. Duffy J, Iyer J. Successful management of pregnancy in arthrogryposis multiplex congenita. Internet J Gynecol Obstet 2006;7:2. Hardwick JCR, Irvine GA. Obstetric care in arthrogryposis multiplex congenita. BJOG 2002;109:1303–1304. Benonis J, Habib AS. Ex utero intrapartum treatment procedure in a patient with arthrogryposis multiplex congenita, using continuous spinal anesthesia and intravenous nitroglycerin for uterine relaxation. Int J Obstet Anesth 2008;17:53–56.

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198. Castro J, Abreu-Silva J, Godinho C, et al. Successful pregnancy in a woman with arthrogryposis multiplex congenita. BMJ Case Rep 2013;2013:bcr2013201621. 199. Hackett A, Giles W, James S. Successful vaginal delivery in a woman with amyoplasia. Aust N Z J Obstet Gynaecol 2000;40:461–463. 200. Quance DR. Anaesthetic management of an obstetrical patient with arthrogryposis multiplex congenita. Can J Anaesth 1988;35:612–614. 201. Rani Singhal S, Paul A, Nanda S, et al. Successful pregnancy outcome by caesarean section in a woman with arthrogryposis multiple congenita (AMC). Afr J Reprod Health 2010;14:233–234. 202. Rozkowski A, Smyczek D, Birnbach D. Continuous spinal anesthesia for cesarean delivery in a patient with arthrogryposis multiplex congenita: a clinical report. Reg Anesth 1996;21:477–479. 203. Spooner L. Caesarean section using a combined spinal epidural technique in a patient with arthrogryposis multiplex congenita. Internet J Gynecol Obstet 2000;9:282–285. 204. Isaacson G, Drum ET. Difficult airway management in children and young adults with arthrogryposis. World J Otorhinolaryngol Head Neck Surg 2018;4:122–125. 205. Sadacharam K, Ahmad M. Epidural anesthesia for labor pain and cesarean section in a parturient with arthrogryposis multiplex congenita. J Anaesthesiol Clin Pharmacol 2016;32:410–411. 206. Martin S, Tobias JD. Perioperative care of the child with arthrogryposis. Paediatr Anaesth 2006;16:31–37. 207. Baines DB, Douglas ID, Overton JH. Anaesthesia for patients with arthrogryposis multiplex congenita: what is the risk of malignant hyperthermia? Anaesth Intensive Care 1986;14:370–372. 208. Marini JC, Forlino A, Bächinger HP, et al. Osteogenesis imperfecta. Nat Rev Dis Primers 2017;3:1–19. 209. Zhytnik L, Simm K, Salumets A, et al. Reproductive options for families at risk of osteogenesis imperfecta: a review. Orphanet J Rare Dis 2020;15:1–20. 210. Van Dijk FS, Sillence DO. Osteogenesis imperfecta: clinical diagnosis, nomenclature and severity assessment. Am J Med Genet A 2014;164:1470–1481. 211. Sillence DO, Senn A, Danks DM. Genetic heterogeneity in osteogenesis imperfecta. J Med Genet 1979;16:101–116. 212. Götherström C, Westgren M, Shaw SWS, et al. Pre- and postnatal transplantation of fetal mesenchymal stem cells in osteogenesis imperfecta: a two-center experience. Stem Cells Transl Med 2014;3:255–264. 213. Ruiter-Ligeti J, Czuzoj-Shulman N, Spence AR, et al. Pregnancy outcomes in women with osteogenesis imperfecta: a retrospective cohort study. Am J Perinatol 2016;36:828–831. 214. Byers PH, Pyott SM. Recessively inherited forms of osteogenesis imperfecta. Annu Rev Genet 2012;46:475–497. 215. Rao R, Cuthbertson D, Nagamani SCS, et al. Pregnancy in women with osteogenesis imperfecta: pregnancy characteristics, maternal, and neonatal outcomes. Am J Obstet Gynecol MFM 2021;3:1000362. 216. Di Lieto A, Pollio, F, de Falco M, et al. Collagen content and growth factor immunoexpression in uterine lower segment of type IA osteogenesis imperfecta: relationship with recurrent uterine rupture in pregnancy. Am J Obstet Gynecol 2003;189:594–600. 217. Cozzolino M, Perelli F, Maggio L, et al. Management of osteogenesis imperfecta type I in pregnancy: a review of

Miscellaneous Skeletal and Connective Tissue Disorders

218. 219. 220. 221.

literature applied to clinical practice Arch Gynecol Obstet 2016;293:1153–1159. Kawakita T, Fries M, Singh J, et al. Pregnancies complicated by maternal osteogenesis imperfecta type III: a case report and review of literature. Clin Case Rep 2018;6:1252–1257. Bellur S, Jain M, Cuthbertson D, et al. Cesarean delivery is not associated with decreased at-birth fracture rates in osteogenesis imperfecta. Genet Med 2016;18:570–576. Yimgang DP, Shapiro JR. Pregnancy outcomes in women with osteogenesis imperfecta. J Matern Fetal Neonatal Med 2015;29:2358–2362. Long-Bellil L, Mitra M, Iezzoni LI, et al. Experiences and unmet needs of women with physical disabilities for pain relief during labor and delivery. Disabil Health J 2017;10:440–444.

222. Creaney M, Mullane D, Casby C, et al. Ultrasound to identify the lumbar space in women with impalpable bony landmarks presenting for elective caesarean delivery under spinal anaesthesia: a randomised trial. Int J Obstet Anesth 2016;28:12–16. 223. Perlas A, Chaparro LE, Chin KJ. Lumbar neuraxial ultrasound for spinal and epidural anesthesia. Reg Anesth Pain Med 2016;41:251–260. 224. Bowens C, Dobie KH, Devin CJ, et al. An approach to neuraxial anaesthesia for the severely scoliotic spine. Br J Anaesth 2013;111:807–811. 225. Bojanić K, Kivela JE, Gurrieri C, et al. Perioperative course and intraoperative temperatures in patients with osteogenesis imperfecta. Eur J Anaesthesiol 2011;28:370–375.

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Chapter

14

Disorders of the Central Nervous System in Pregnancy Lakshmi Ram and Rakesh Vadhera

Introduction Valuable Clinical Insights • Disorders of the central nervous system (CNS) are a significant cause of maternal morbidity and mortality. • Neurological disorders are the second most common cause of indirect maternal deaths in the United Kingdom.

Disorders of the central nervous system (CNS) in pregnancy continue to be a common reason for maternal morbidity and mortality. The study, “Mothers and Babies: Reducing Risk through Audits and Confidential Enquiries across the UK,” which looked into maternal deaths between 2016 and 2018, reported that after cardiac diseases, neurological disorders were the second most common cause of indirect maternal deaths and the third most common cause of all maternal deaths.1 With all causes of CNS deaths combined, CNS diseases were responsible for 29 of the 217 total deaths and 125 indirect causes, a slight increase compared to the prior triennium.2 MBRRACE-UK reported an increase in peripartum deaths from epilepsy and stroke, comprising 13% of total deaths.2 During 2016–2018, there were 22 deaths among women throughout the course, or within one year, of pregnancy from epilepsy, compared to 13 women dying from epilepsy during 2013–2015. This represents a mortality rate that increased from 0.52 (95% CI 0.28–0.8) to 0.91 per 100,000 maternities (95% CI 0.84–3.79, p = 0.1082).2 Some chronic neurological diseases (e.g., epilepsy, Parkinson disease, multiple sclerosis, intracranial lesions, benign intracranial hypertension, migraine) predate pregnancy; other cerebrovascular disorders, including hemorrhagic or vaso-occlusive strokes, are more likely to emerge and cause adverse outcomes during pregnancy. Since these conditions are uncommon, few medical centers have extensive experience treating these CNS disorders. Basic physiological principles, isolated case reports or small case series, and common clinical sense usually guide clinical management. Medico-legal and ethical dilemmas arise with unconscious pregnant patients in vegetative states or brain death situations (Table 14.1).

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Table 14.1  Issues to consider during care of a parturient with CNS disorder

Neurological lesion

Fetal and maternal safety

Communication

Pathophysiology of lesion Effect of lesion on pregnancy Effect of pregnancy on lesion

Avoid aortocaval compression Protection during imaging Airways protection against aspiration in obtunded patient Impact of monitoring and medical and surgical management on the fetus Maternal versus fetal priority, with respect to timing for surgical plan and delivery

Among patient, family, and medical team Multidisciplinary communication between neurology, neurosurgeon, obstetrician, neonatal, and anesthesia care providers

Diagnostic Tests Many intracranial conditions produce similar signs and symptoms in the parturient, making a careful and discriminating diagnosis critical to manage and optimize care, ensuring the best possible outcome (Table 14.2). Special imaging techniques like ultrasonography, MRI, CT scan, and cerebral angiography help diagnose neurological diseases (Table 14.3). During these procedures, the patient must stay still and immobile; most do not require anesthesia unless uncooperative or unstable. During anesthesia, possible technical problems are difficulty positioning the pregnant patient in the scanning apparatus, shielding the patient, fetus, Table 14.2  Common symptoms and signs of intracranial conditions

Symptoms

Signs

Headache

Nuchal rigidity

Nausea, vomiting

Altered consciousness

Diplopia or blurring of vision

Focal neurological signs

Photophobia or orbital pain

Ataxia

Epigastric pain

Bruits

Dizziness

Disseminated intravascular coagulation

Mental changes

Hypertension or bradycardia

Taken from the previous edition of Obstetric Anesthesia and Uncommon Disorders, chapter 9.

Disorders of the Central Nervous System in Pregnancy

Table 14.3  Recommendations for head MRI and CT during pregnancy

Table 14.4  Classification and differential diagnosis of epileptic seizures

•

Classification

Differential diagnosis

1. Seizure types a. Focal b. Generalized c. Unknown 2. Epilepsy types a. Focal b. Generalized c. Combined generalized and focal d. Unknown

1. Cerebrovascular a. Stroke b. Syncope c. Migraine d. Eclampsia e. Mass lesions f. Infections 2. Drugs a. LA toxicity b. Intoxication or withdrawal (morphine, cocaine) 3. Metabolic a. Hypoglycemia b. Acute intermittent porphyria 4. Cardiovascular a. Stokes-Adam attacks 5. Obstetric a. Amniotic fluid embolism b. Acute fatty liver of pregnancy 6. Others a. Hysteria

• • • • •

Discuss and document indications, risks, benefits, and alternatives with patient MRI may be preferable to CT, although conclusive data are not available Delay elective diagnostic imaging until after delivery, if possible Avoid diagnostic imaging in the first trimester unless no alternative exists Iodinated contrast is rated by the FDA as a category B drug Avoid gadolinium, an FDA category C drug, in pregnancy unless no alternative exists

Abbreviations: CT = computerized tomography; FDA = Food and Drug Administration; MRI = magnetic resonance imaging.

anesthesiologist, and remote access to the patient. Position the pregnant patient in a left lateral tilt with a wedge under the hip to avoid hypotension from aortocaval compression. The presence of aortic pulsations from any obstruction may degrade the image quality.3 CT scanning is preferred for detecting a recent hemorrhage and is quick. The ACOG Committee Number 723 opinion is not to withhold CT from a pregnant patient, if clinically indicated and readily available. The CT scan adds additional information to US and MRI, and the benefits outweigh the risks.3,4 The area of neuroimaging for CNS disorders is away from the fetus; compared to an abdominal scan, there is less scatter resulting in lower fetal risk.5 MRI is often preferred as it does not expose the mother or fetus to radiation. MRI is used to diagnose vascular malformations, demyelinating diseases, congenital and developmental nervous system abnormalities, posterior fossa lesions, and spinal cord diseases.3 If an appropriate diagnostic alternative, a timely MRI scan is safe.5 Angiography is invasive and more traumatic. It can alter neurological function, so ideally, perform it in an awake patient. Complications of angiography include vessel occlusion from subintimal vascular dissection from dye, hematoma formation, irritation of cerebral vessels including arterial necrosis, cerebral embolism from hyperosmolar contrast media, sepsis and temporary vasodilation with intense pain. Hyperosmolar solutions produce an osmotic diuresis, leading to dehydration, reduced fetal perfusion, and fluid shifts in the fetal brain.

Neuronal Tissue Disorders Seizure Disorders A seizure is a paroxysmal disorder of the CNS characterized by an abnormal neuronal discharge, with or without loss of consciousness. See Table 14.4 for the classification and differential diagnosis of seizures. The most common cause is epilepsy, a condition characterized by recurrent seizure activity in the absence of metabolic disorders or acute brain disease. For every 1000 pregnancies, two to five babies are born to mothers with epilepsy.6 For these mothers, pregnancy may be stressful due to maternal and fetal health concerns.7 MBRRACE-UK found that more women died due to a seizure disorder during or within a year of delivery than died from hypertensive disorders in pregnancy.2 Of particular concern, the 2020 triennial publication reported sudden unexpected death in epilepsy (SUDEP) during 2016–2018 more than doubled when 18 women died from SUDEP, a mortality rate of 0.74 per 100,000 pregnancies

(95% CI 0.44–1.18). This compared to 2013–2015 when there were eight maternal deaths, a mortality rate of 0.32 per 100,000 maternities.2

Effect of Pregnancy on Epilepsy Valuable Clinical Insights • Seizure activity does not increase during pregnancy for most epileptic women. • Ninety-six percent of epileptic women deliver a healthy child. • More women die from a seizure disorder during or within one year after delivery than die from hypertensive disorders in pregnancy.

Most women with epilepsy will not experience increased seizure frequency during pregnancy, and 96% of them will deliver a healthy child. However, some women with epilepsy, between 14 and 32 per 100, experience increased seizure frequency. Various pregnancy-associated physiological and other factors may cause inadequate seizure control8 (Table 14.5). Epilepsy can affect pregnancy adversely, with maternal and fetal consequences9,10 (Table 14.6). The MBRRACE report emphasized that the occurence of night time seizures, presence Table 14.5  Pregnancy-associated factors causing inadequate seizure control8 Reduced sleep during pregnancy, labor, and post-partum period Stress and anxiety Hormonal changes of pregnancy: increase in estrogen level related to increased seizure activity Altered pharmacokinetics with AEDs during pregnancy Reduced compliance with medication due to fear of adverse fetal outcomes Changes in medication to lower potency drugs, presumably with lower risk of teratogenicity AEDs = antiepileptic drugs.

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Table 14.6  Effect of epilepsy on pregnancy and fetus9,10 Maternal adverse outcomes noted in pregnant women with epilepsy Spontaneous miscarriage APH PPH Hypertensive disorders Induction of labor CD Preterm birth before 37 weeks of gestation

of uncontrolled seizures, and ineffective treatment of seizures were the biggest reasons for concern with SUDEP.2

Effect of Epilepsy on Fetus and Neonate The effect of maternal epilepsy on the fetus and neonate may be due to the condition itself, antiepileptic drug (AED) use, or a combination of both. Seizures during pregnancy, especially status epilepticus, expose the fetus to the risk of blunt trauma, hypoxia, and acidosis, all of which may produce neurological damage. As seizures increase the risk of fetal and maternal morbidity, they require rapid intervention. Applying a fetal scalp electrode carries the risk of scalp bleeding through AEDs’ effect on fetal coagulation. Neonates born to mothers taking an enzyme-inducing AED may develop life-­threatening hemorrhagic disease from vitamin K ­deficiency11 that responds to vitamin K given intramuscularly at birth. Infants with abnormal cord blood prothrombin and activated partial thromboplastin time can be treated with fresh frozen plasma or factor concentrates, as appropriate. Infants of epileptic mothers have a twofold increased (to 6%) risk of congenital malformations such as orofacial clefts, congenital heart defects, microcephaly, intellectual disability, hypospadias, distal limb hypoplasia, and nail dysplasia. Most AEDs are implicated in teratogenic congenital defects12 (Table 14.7). Certain drugs are associated with a higher relative risk for congenital defects than others. Sodium valproate is associated with significantly higher rates of major malformations.13 Newer agents (e.g., lamotrigine, gabapentin, felbamate, topiramate, tiagabine, levetiracetam, pregabalin) have fewer teratogenic effects.12 There may be a genetic component as children of epileptic fathers have a similar increase in malformations.

Table 14.7  Congenital defects associated with antiepileptic medications12

Drug

Anomaly

Phenytoin

Fetal hydantoin syndrome

Valproate

Neural tube defects, developmental delay, cardiac anomaly

Phenobarbital

Cleft lip or palate or both, cardiac anomaly

Lamotrigine

Cleft lip or palate or both

Topiramate

Cleft lip or palate or both

Levetiracetam

Skeletal anomalies

Derived from Tomson T, Battino D. Teratogenic effects of antiepileptic drugs. Lancet Neurol 2012;11:803–813. https://doi.org/10.1016/ s1474-4422(12)70103-5

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Management of Seizures in Pregnancy The principles of seizure management are straightforward – to stop the seizure, maintain an unobstructed and protected airway, ensure oxygenation of both mother and fetus, and prevent aspiration. Plasma concentrations of AEDs drop during pregnancy. Reasons for this include: 1. Decrease in compliance (due to anxiety, nausea and vomiting, and missed doses in labor) 2. Decreased absorption and protein binding of the drug 3. Increased volume of distribution, hepatic and renal clearance, and body weight. Folic acid supplements prescribed during pregnancy may also cause lower AED levels. Maternal and fetal risks are high, including irreversible maternal brain injury and fetal hypoxia, ischemia, bradycardia, and death. In a recent report from the International Registry of Antiepileptic Drugs in Pregnancy (EURAP), there were 36 cases of status epilepticus with no maternal deaths and only one stillbirth.14 If seizures present during pregnancy, imaging (CT scan or MRI) will rule out intracerebral pathology that is amenable to early neurosurgical intervention. Assess the fetus using US and cardiotocography to determine the need for obstetric intervention and operative delivery.

Obstetric Management Pregnancies in epileptic mothers are considered high risk. MBRRACE focused on requiring every epileptic patient to have urgent and early access to specialized care and counseling. This access is necessary to optimize the AED regimen, primarily if seizures are uncontrolled, the patient lives alone or is noncompliant. Counseling also provides information on the risk of fetal malformations and possible infant withdrawal symptoms.2 Ideally, before conception, the goals are AED withdrawal or conversion to monotherapy and minimal doses of AEDs for seizure control. During labor, maintain AED levels; IV administration may be necessary due to decreased GI absorption. These measures minimize fetal drug exposure while maintaining maternal seizure control (Table 14.8). Obstetric management goals include abolishing seizures during pregnancy and a seizure-free delivery of a healthy infant. There is no contraindication to breastfeeding unless the infant shows signs of lethargy. The epileptic parturient is at higher risk for emergency obstetric intervention due to generalized seizures during labor, fetal bradycardia following a grand mal seizure, maternal postictal drowsiness and CNS depression, and loss of FHR variability following rapid IV control of seizures. Table 14.9 contains the indications for elective and emergency CD. Table 14.8  Considerations for epilepsy management

• • • • • •

Commonly used antiepileptic drugs (AEDs) have adverse effects Monotherapy is considered safer Discuss teratogenic potential of AED & risk of major & minor birth defects Prepregnancy and pregnancy folic acid (0.5 mg daily) supplementation Eliminate other risk factors – smoking, drugs, alcohol Consider vitamin K predelivery

Disorders of the Central Nervous System in Pregnancy

Table 14.9  Criteria for cesarean delivery in the epileptic parturient

Elective

Emergency

• •

• • •

• •

Neurologic deficit Deterioration in third trimester seizure control Occurrence of seizures with exercise and stress Unable to cooperate

Generalized seizure in labor Threat of fetal asphyxia Maternal somnolence and lack of cooperation in labor

Anesthetic Management and Antiepileptic Drugs There are significant interactions between AEDs and anesthetic agents because of their site of action. Some AEDs, such as carbamazepine, phenytoin, phenobarbital, and primidone, have potent enzyme-inducing properties that could decrease plasma concentrations of many medications, including neuromuscular blockers, beta-adrenergic receptor antagonists, and calcium entry blocking agents.15 Sodium valproate is an inhibitor of hepatic microsomal enzyme systems and may reduce the clearance of many concurrently administered medications. Tricyclic antidepressants lower the seizure threshold. Opioids in high doses cause neuroexcitatory phenomena in animals but not in humans. Meperidine, and its metabolite normeperidine with its long halflife, can cause CNS excitability. Laudanosine, a metabolite of atracurium, can be epileptogenic, but this is unlikely in humans. Low serum concentrations of amide LA are anticonvulsant but cause convulsions at high serum concentrations. The concomitant use of AEDs may enhance the action of nondepolarizing neuromuscular blockers; however, with chronic phenytoin use, there may be resistance to pancuronium but not to atracurium. The anesthesiologist must also consider the side effects of AEDs. Phenytoin has multiple side effects: hematological (leukopenia, anemia, agranulocytosis, aplastic anemia) and neurological (peripheral neuropathy). Barbiturates have similar neurological and hematological (megaloblastic anemia) side effects. Carbamazepine’s side effects include an antidiuretic hormone (ADH) effect that may induce water retention (producing emesis and mental confusion), transient and sometimes persistent leukopenia, and, rarely, agranulocytosis and aplastic anemia.

Anesthetic Management in Labor Communication among the obstetrician, neurologist, and anesthesiologist is essential. The goals of anesthetic care are prevention and prompt treatment of intrapartum seizures and provision of adequate labor analgesia to reduce anxiety and hyperventilation. Evaluate the adequacy of seizure control, side effects of therapy, the patient’s mental and physical status, and proposed obstetric management. Parenteral opioid analgesia can be used. Modify the dose to prevent worsening CNS depression in the parturient sedated from anticonvulsant therapy. Epidural analgesia instituted within accepted guidelines provides superior pain relief and does not depress the CNS. Patients with evidence of a bleeding diathesis require coagulation assessment before initiating NA. Establish epidural analgesia incrementally, avoiding high plasma concentrations of LA, which are epileptogenic.

Anesthetic Management during Cesarean Delivery A combination of maternal, fetal, and obstetric factors determines whether to use GA or NA. Post-seizure and drug-induced somnolence and status epilepticus mandate GA, recognizing the potential interaction between anesthetic agents and AEDs, and the need to protect the airway. Neuraxial anesthesia is appropriate for elective CD in a medically stable patient. As there is a questionable association between spinal anesthesia and potentiation of seizure activity, epidural anesthesia may be preferred. However, the risk for LA toxicity is more with an epidural technique. Despite the potential problems facing the pregnant epileptic woman, most will have a stable gestational course and deliver a healthy infant.

Parkinson Disease Parkinson disease (PD), a progressive neurodegenerative disease, is caused by widespread diffuse lesions in the basal ganglia and cerebral cortex, with loss of dopaminergic fibers. Depletion of dopamine produces the unopposed action of neuroexcitatory acetylcholine resulting in the symptom complex of tremor at rest, rigidity, bradykinesia, and posture disturbances. In addition, affected patients may become mentally depressed and develop cognitive and memory deficits that can progress to delirium. Parkinson disease, more commonly seen in males above 60 years of age, is uncommon during reproductive years and pregnancy.16 Generally, women develop the disease on average about two years later than men.16 In 5% of total cases of PD, it presents < 40 years of age. It is rare in women of childbearing age, with an estimated 400 women < 50 years of age diagnosed with PD every year in the United States. The current incidence of pregnancy in PD is unknown. As advances in assisted reproductive technology allow more older women to become pregnant, the incidence of PD may increase during pregnancy.17

Effect of Parkinson Disease on Pregnancy Idiopathic PD in itself does not affect fertility, conception, or delivery.18 Compared to the current American CD rate of 32% among all parturients, only 15% of patients with PD underwent a CD,17 indicating that PD does not increase the risk for operative deliveries and need not influence the mode of childbirth. A literature review of pregnancy in women with PD found no increase in the spontaneous abortion rate since only 5% of pregnancies ended in a miscarriage.17

Effect of Pregnancy on Parkinson Disease Seier and Hiller found that symptoms worsened in 48% of pregnant patients with PD, while in 52%, symptoms improved or did not change.17 That contradicted some earlier studies but was consistent with data presented by Hagell et al. in 1998.19 Factors contributing to exacerbations of PD in pregnancy include altered drug metabolism and sub-therapeutic dosing of antiparkinson medications, diet modifications, and changes in drug absorption, and physical and psychological stress.

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Effect of Parkinson Disease on Fetus and Neonate Medications used to manage PD in pregnancy also confound the disorder’s impact on pregnancy. In a literature review of 75 babies born to women with idiopathic PD, there were three fetal malformations (osteomalacia, ventricular septal defect, and inguinal hernias). The three mothers were taking antiparkinson medications.15 Dopamine agonists inhibit lactation and may affect breastfeeding.20

Management in Pregnancy Though there seem to be no standardized clinical guidelines for PD management during pregnancy, the recommendation is to use antiparkinson medication to improve or stabilize symptoms. A literature review combined with a survey of patients, neurologists, obstetricians, L&D nurses, and midwives suggests optimization of motor symptoms, levodopa monotherapy, and vaginal delivery unless indicated by obstetric causes.21 Clinical features of PD can deteriorate in pregnancy, and data suggest better symptom control if PD treatment continues throughout the entire pregnancy.17 Young et al. found insufficient safety evidence regarding the use of dopaminergic therapy.21 Levodopa, a dopamine agonist, remains an effective and favorite drug in treating PD.20,21 Carbidopa inhibits dopa decarboxylase preventing the peripheral breakdown of levodopa in the liver. The combination of levodopa and carbidopa allows a higher concentration of dopamine to breach the blood–brain barrier. Although data suggest its safety in pregnancy, use levodopa cautiously as it crosses the placental barrier and gets metabolized in fetal tissues, including the brain and spinal cord. Early fetal exposure to levodopa or dopamine may alter normal fetal neuronal development.

Anesthetic Management in Parkinson Disease The potential interaction between anesthetic drugs and anti PD medications will determine anesthetic management. Be aware of any worsening signs and symptoms of PD, the need to optimize PD treatment, and use of anesthesia drugs that possess antidopaminergic activity. Avoid acetylcholinesterase inhibitors, or those with serotonergic activity that may cause Parkinson hyperpyrexia syndrome and serotonin toxicity.22 Continue therapy for PD on the morning of surgery to decrease perioperative complications like drooling, difficulty in swallowing, impaired cough reflex with the potential for aspiration, and reduced ventilatory function. Avoid drugs, such as phenothiazines, butyrophenones (droperidol), and perhaps large doses of opioids that inhibit dopamine release or compete with dopamine at receptors in the basal ganglia. If the anesthetic technique includes antidopaminergic drugs (metoclopramide, droperidol), patients can develop neuroleptic malignant syndrome (NMS) if they did not receive levodopa before anesthesia. Opioid-induced rigidity of the chest wall warrants caution. Laryngospasm and airway collapse can occur during induction of GA.23 Reinstituting therapy soon after surgery is crucial as the half-life of levodopa is short. Treatment interruption for > 6–12  hours can result in severe skeletal muscle rigidity and reduced ventilatory function.23

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Orthostatic hypotension, cardiac dysrhythmias, hypo­ volemia, and even hypertension can occur during NA and GA in patients treated with levodopa.23 A combination of fentanyl and droperidol in patients on levodopa may result in rigidity and pulmonary edema. Morphine inhibits dyskinesia in lower doses and increases it in higher doses.24 The interaction of MAO inhibitors and meperidine may cause profound respiratory depression, hypotension, agitation, excitement, restlessness, hypertension, headache, rigidity, convulsions, hyperpyrexia, and coma.23 The use of ketamine is controversial in patients treated with levodopa as it can result in tachycardia and hypertension24 or possibly worsen the rigidity due to interaction with the opioid receptor. Despite these concerns, ketamine has been used without complication. One should avoid metoclopramide because of its antidopaminergic effects.24

Neuraxial Anesthesia Though autonomic dysfunction and orthostatic hypotension are not unusual in patients with PD,23 NA for CD has some apparent advantages over GA: there are fewer drug interactions, NA avoids neuromuscular blocking agents, confusion with residual neuromuscular block, masking of tremors, prevention of postoperative nausea and vomiting, and prolonged ventilation.24 The use of NA (combined spinal epidural (CSE) or epidural) for labor pain is advantageous. It will reduce leg stiffness, although epidural placement could be difficult in a rigid parturient with tremors. Intrathecal or epidural morphine might worsen rigidity through a central effect due to its low lipid solubility. During induction of NA, decreased intravascular fluid volume and levodopa treatment may cause hypotension and cardiac dysrhythmias,23 requiring aggressive administration of crystalloid or colloid solutions and vasopressors. Spinal anesthesia with intrathecal morphine and fentanyl was used successfully for CD in a woman with advanced PD (right-sided weakness and altered gait) despite optimizing antiparkinson medications.25

General Anesthesia Patients with severe tremors, rigidity, or dementia may require GA, as NA may lead to inadequate surgical conditions and be technically challenging.24 The anesthesiologist should ensure optimal preoperative control of PD symptoms. Aspiration of pharyngeal contents into the trachea may result from dysphagia compounded by excessive salivation. These patients benefit from a rapid sequence induction of anesthesia with appropriate measures to prevent pulmonary aspiration. Famotidine given an hour before induction, reduces acid production, and sodium citrate, a nonparticulate antacid, administered 20 minutes before induction neutralizes stomach acid. Atropine, an anti-sialagogue, and ipratropium, a bronchodilator, administered perioperatively will reduce pulmonary secretions and relieve airway obstruction resulting from the excess parasympathetic activity. Chest wall rigidity and hypokinesia cause a restrictive pattern of respiratory deficit, while postoperative spasticity may result in airway obstruction requiring ventilation.23 Involuntary movements after GA can be confused with worsening PD

Disorders of the Central Nervous System in Pregnancy

symptoms, residual muscle paralysis, or thermoregulatory shivering. Postoperative shivering is mostly transient. Patients with PD may become confused and develop hallucinations postoperatively, especially the day after surgery.23,24

Brain Neoplasms Although brain neoplasms during pregnancy have a similar incidence to nonpregnant patients, the physiologic changes of pregnancy may cause differences in symptoms and management. Most neoplasms are gliomas (39%), meningiomas (35%), pituitary adenomas (7%), and schwannomas (7%) (Table 14.10).26 Prognosis varies according to the type of tumor. Gliomas arise from astrocytes and oligodendrocytes and vary clinically from slow growing to highly anaplastic; their sequelae range from a mass effect to producing local tissue damage. Meningiomas are benign tumors that grow slowly from the membranes covering the brain and spinal cord, ultimately causing a mass effect. Pituitary tumors are benign and slow growing, producing various hormones (growth hormone, adrenocorticotrophic hormone, prolactin) and visual field defects from compression of the optic chiasma. Schwannomas arise in the Schwann cells surrounding the nerve. In patients with neurofibromatosis, acoustic neuromas can affect the eighth cranial nerve. A significant number of brain neoplasms are metastatic carcinomas. Primary cancers commonly causing brain metastasis are lung, breast, and colon.27

Clinical Presentation and Diagnosis Nonspecific symptoms from brain tumors include constant headache and persistent nausea and vomiting secondary to increased ICP. To differentiate from the common headache and morning sickness associated with pregnancy, look for lateralizing signs, including hemiparesis, sensory loss, visual field defects, and aphasia. Seizures, focal or generalized (with or without a focal onset), are possible with low-grade gliomas and meningiomas and must be differentiated from other causes. Magnetic resonance imaging to define a mass lesion is preferred to CT, which is less sensitive and requires shielding.

Effect of Pregnancy on Neoplasms Valuable Clinical Insights • Pregnancy hormones may facilitate brain tumor growth. • Ninety percent of meningiomas and some gliomas have progesterone receptors.

Pregnancy may enlarge meningiomas and acoustic neuromas, possibly from fluid retention, increased blood volume, and engorgement of blood vessels. Pregnancy hormones may Table 14.10  Classification of brain neoplasms and their incidence in women

Benign

Malignant

• • •

• • •

Meningioma – 35% Schwannoma – 7% Pituitary adenomas – 7%

Gliomas – 39% Lymphoma – 2% Medulloblastoma – 2%

facilitate tumor growth since 90% of meningiomas and some gliomas have progesterone receptors.27 In a population-based study, malignant brain tumors were associated with higher maternal mortality, adverse pregnancy outcomes, and CNS neoplasms were associated with higher CD rates. The OR for a CD was 6.4 in those with malignant neoplasms, compared to 2.8 in those with benign tumors.28

Obstetric Management Control seizures and maternal hypertension throughout pregnancy, especially during labor, to prevent increases in ICP. The appropriate delivery method for a parturient with a brain tumor remains controversial and likely will be influenced by high ICP. Many obstetricians prefer to deliver women with brain tumors and increased ICP by CD. However, similar maternal and fetal outcomes can be achieved with a pain-free labor and an assisted vaginal birth.27 When drug therapy controls symptoms, Bonfield and Engh recommend CD in the early third trimester followed immediately by neurosurgical intervention.27

Neurosurgical Management The safety of the mother and fetus is the primary goal of managing brain tumors during pregnancy.29 Low-grade gliomas are slow-growing and often surgically removed electively after delivery. High-grade gliomas are surgically removed without delay, followed by radiotherapy and chemotherapy. Since these treatments pose a significant risk to the fetus, individualize treatment decisions. In the case of a slow-growing meningioma, typically, about 30% can be resected entirely, while the rest require subtotal resection or radiation. Pituitary tumors require trans-sphenoidal resection or, in the case of prolactinomas, bromocriptine therapy. Radiation and chemotherapy are used mainly for choriocarcinoma, with surgery reserved for those with a single metastatic lesion to the brain or those requiring decompression. When indicated, anticonvulsants and cortico­ steroids are additional treatments.

Anesthetic Management Valuable Clinical Insights • Before anesthesia, carefully evaluate parturients with a history of brain tumor resection for any residual tumor. • Normal ICP does not mean a low risk of herniation.

A comprehensive study by Leffert et al. concluded that not all space-occupying lesions are associated with raised ICP.30 As well, normal ICP necessarily does not mean a low risk of herniation. Guide anesthetic management by the presence or absence of symptoms and signs of elevated BP and ICP. Pain during labor and pushing can increase ICP, while effective pain control by NA helps minimize fluctuations. Balance this analgesic benefit against the risk of brainstem herniation following an inadvertent dural puncture (DP). Rapid epidural injection of LA increases epidural space pressure, possibly worsening symptoms. For CD in a parturient with raised ICP, preinduction measurement and control of ICP and BP are mandatory. Inserting

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an arterial line and an ICP pressure transducer via ventriculostomy allows the anesthesiologist to control the hypertensive response to tracheal intubation by titrating antihypertensive drugs, hyperventilation, and mannitol. Ghaly et al. suggest that a detailed review is essential before any anesthetic technique in a patient with a history of brain tumor resection to assess for residual tumor.31

Central Nervous System Infections Valuable Clinical Insight An urgent lumbar puncture with CSF analysis is essential to diagnose infections of the CNS.

Anesthetic Management There is little research to guide our use of NA in patients with an active meningeal infectious process. Infection at the spinal puncture or epidural catheter insertion site may contraindicate NA. Single-puncture techniques can be safe. Available information indicates that the insertion of catheters requires antibiotic pretreatment of the infection, followed by a clinically appropriate response.36 In a case report by Baidya et al., GA was administered to a patient for an emergency CD with seizures and signs of raised ICP due to tuberculous meningitis.37 The patient was moved to the ICU, intubated, and made a full recovery after four days in the ICU. Valuable Clinical Insights

Meningitis, an inflammation of meninges covering the brain and spinal cord, is a clinical syndrome characterized by headache, fever, photophobia, and neck stiffness. Bacteria, viruses, or other microorganisms may be responsible for the inflammation. When infection crosses the pial cell lining and spreads to the brain parenchyma, the correct term is meningoencephalitis.32 Bacterial meningitis is uncommon during pregnancy; when it occurs, otitis media and sinusitis are major contributing factors.33 Adriani et al. reviewed 42 cases of meningitis in pregnancy; 25 were caused by Streptococcus. pneumoniae and seven by Listeria. monocytogenes.33 All parturients who developed pneumococcal meningitis were multiparous, had an average age of around 33 years, and had frequent first-trimester miscarriages. There was a high rate of neonatal death with L. monocytogenes infection.33 Therefore, antibiotic therapy for bacterial meningitis in pregnant women should cover S. pneumoniae and L. monocytogenes. Despite optimal antibiotic treatment, bacterial meningitis during pregnancy can have a rapidly fatal outcome for mother and child and requires treatment as a medical emergency.

Clinical Presentation and Diagnosis It is critical to perform a lumbar puncture urgently in suspected cases and analyze the CSF to confirm the diagnosis of a CNS infection, identify the responsible organism and the location of the infection (encephalitis vs. meningitis). The CSF analysis helps in the differential diagnosis of other conditions with a similar presentation, like an inflammatory process, subarachnoid hemorrhage, or malignancy. CSF analysis is also invaluable in monitoring the effects of antibiotic therapy. Neuroimaging may help diagnose underlying risk factors for meningeal and brain infections or associated complications such as generalized cerebral edema.33,34

Medical and Surgical Management Early identification of the organism causing meningitis helps start goal-directed antibiotic therapy more quickly. The physiologic changes in pregnancy cause an increase in glomerular filtration rate, total blood volume, and enhanced cardiac output. These changes may lead to pharmacokinetic alterations in antibiotics requiring dose adjustment or careful monitoring and assessment.35 Four of the six meningitis patients reported by Adriani et al. received urgent CD.33

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• In patients with systemic infection, single-shot neuraxial techniques are considered safe after appropriate treatment with antibiotics. • Before a neuraxial catheter technique in parturients with a systemic infection, ensure there is an appropriate response to antibiotics

Central Nervous System Vascular Disorders Stroke A stroke is defined as a syndrome of acute neurological injury following rupture or occlusion of vessels in the CNS and is classified as hemorrhagic or ischemic; Table 14.11 outlines common causes of both.38 Pregnancy is a hypercoagulable state, which increases the risk of stroke threefold compared to nonpregnant women.39 Strokes affect 30 per 100,000 pregnancies, leading to 1.6 maternal deaths with ischemia, cerebral venous sinus thrombosis, and hemorrhage causing roughly equal numbers.40 The highest risk of stroke occurs peripartum and postpartum.39,40 Most strokes occur from hypertensive disorders or heart disease. Among pregnancy-related deaths in the United States in 2011–2013, 6.6% were due to cerebrovascular accidents, and 7.4% by PreE/eclampsia.41

Central Nervous System Hemorrhage Intracranial hemorrhage (ICH) is either intraparenchymal, subarachnoid, or subdural. Common causes of ICH during pregnancy are vascular anomalies, PreE/eclampsia, and coagulopathy (Table 14.11) Subarachnoid hemorrhage from a ruptured aneurysm is uncommon during pregnancy, labor, or the Table 14.11  Etiology of stroke in a parturient38

Hemorrhagic stroke

Ischemic stroke

• • • • • • •

• • • • •

Choriocarcinoma Eclampsia Cerebral venous thrombosis Hypertension Aneurysm Vascular malformation Cerebral angiopathy

Amniotic fluid embolism Eclampsia Cerebral angiopathy Peripartum cardiomyopathy Air embolism

Adapted from The Stroke Book. Stroke in Consultation. Cambridge: Cambridge University Press, pp. 257–304.38

Disorders of the Central Nervous System in Pregnancy

puerperium. Intraparenchymal hemorrhage (IPH) and subdural hemorrhage (SDH) usually have a known etiology. However, in 24% of ICHs, the cause is unknown. Cases of bleeding where the etiology is unknown are called “spontaneous” ICH.40 The pathophysiologic effects of ICH result from a compressive mass effect and irritation from blood and its breakdown products. Intracerebral structures are relatively noncompressible, so even a tiny bleed can result in significant anatomic distortion, a large increase in ICP, and a reduction in cerebral perfusion. Subarachnoid Hemorrhage The Nationwide Inpatient Sample found pregnancy-associated subarachnoid hemorrhage (SAH) occurred in 5.8 per 100,000 pregnancies, leading to 4.1% of all pregnancy-related deaths.42 The mortality rate seems to be lower among parturients than other groups, with half occurring postpartum.43 Intracranial aneurysms result from the weakening of the internal elastic lamina of large arteries at the base of the brain, usually at a bifurcation. Often the vessel wall is thinnest at the dome of the aneurysm and ruptures into the subarachnoid space of the basal cisterns, the subdural space, or directly into the underlying brain parenchyma. Aneurysms can leak spontaneously. Precipitating factors for SAH during pregnancy include bleeding disorders, hypertension, cocaine abuse, advancing age, African-American or Hispanic ethnicity, sickle cell disease, and intracranial venous thrombosis.30,44 Arteriovenous malformations, thin-walled communications between the arterial and venous systems, occur in most parts of the brain and spinal cord and are prone to rupture.42 Clinical Presentation and Diagnosis Unruptured aneurysms are usually asymptomatic; large aneurysms can cause headaches and focal neurologic signs depending on their location. Subarachnoid hemorrhage may produce severe headache, photophobia, nausea and vomiting, periorbital pain, nuchal rigidity, and a positive Kernig sign. Throbbing headaches, changing sensorium, and seizures are more characteristic of IPH from an arteriovenous malformation (AVM). Vasospasm is seen more commonly in patients with a bleeding aneurysm than a bleeding AVM. When significant hemorrhage occurs, the following can happen. - ICP approaches the mean arterial pressure, thereby decreasing cerebral perfusion, resulting in a transient loss of consciousness. - A severe headache occurs either before the loss of consciousness or upon awakening. - Rarely, acute vascular spasm leads to additional focal neurologic signs with stupor and impaired autoregulation. - The electrocardiogram (ECG) often shows ST and T wave changes like those of myocardial ischemia, along with a prolonged QRS complex, increased QT interval, and prominent peaked or inverted T waves. The ECG changes are possibly secondary to intense sympathetic activity. The ECG changes generally do not correlate with the extent of cardiac injury. The grade of SAH may correlate with wall motion abnormalities on echocardiography.

After a bleed, the following complications can occur. - Rebleeding in 10–30% of patients during the first three weeks following aneurysmal rupture, with a 50–60% mortality rate with each rebleed. - Vasospasm in 35% of patients 4 to 11 days following SAH, leading to further neurological deterioration. - Fifteen to twenty percent develop hydrocephalus following SAH from blood and cellular exudate blocking efflux of CSF. Hydrocephalus produces a gradual decrease in the level of consciousness. - Cerebral edema or hyponatremia from inappropriate ADH (SIADH) secretion may happen. Subarachnoid hemorrhage is life-threatening, and surgery can be lifesaving. So, promptly carry out a CT scan, MRI, and possibly lumbar puncture to detect the presence of blood/­ xanthochromia. Angiography will define the lesion for surgical intervention. Effect of Pregnancy on Vascular Malformations As pregnancy advances, aneurysms and AVMs are more likely to bleed, possibly due to pregnancy’s hemodynamic and hormonal changes. This explanation does not account for the rarity of ICH during labor and delivery when hemodynamic changes are maximal. Hemorrhage resulting from AVMs does not cluster during any particular trimester; the incidence of bleeding increases in subsequent pregnancies. The incidence and mortality from ICH in parturients are like that of the general population. Neurosurgical Management As ruptured AVMs can lead to significant neurological deficits, treatment is usually based on neurological urgency. During pregnancy, their management requires a multidisciplinary approach among the neurosurgeon, obstetrician, and anesthesiologist, to determine the best course for neurosurgical intervention and the timing and mode of delivery to ensure the best fetal and maternal outcome. The risk of rebleeding and associated mortality is 27% and 40%, higher than in a similar age-matched group of nonpregnant women. Therefore, the principal management goal of a ruptured brain AVM is to minimize the risk of rebleeding until delivery.45 The management of patients with symptomatic AVM during pregnancy is challenging. There is no consensus regarding the optimal timing for AVM treatment, delivery, the most appropriate delivery method, or the anesthetic technique.46 Controversy exists over the optimal time to operate on a parturient with SAH. Early surgery reduces the incidence of vasospasm and rebleeding and seems to be associated with lower maternal and fetal mortality. However, the patient may be unstable, and surgery can induce vasospasm. Surgery may or may not be of benefit after an AVM bleed. The decision to operate is based primarily on neurosurgical considerations, although advances in the maintenance of normotension, normovolemia, hemodilution, and improved treatment of vasospasm, favor early clipping of aneurysms to prevent rebleeding. Obstetric Management There are no established protocols for managing a parturient with an unruptured intracranial aneurysm. Patients with

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sentinel headaches are at risk of aneurysmal rupture; however, the mode of delivery does not appear to increase the risk.47 There is no increased risk from vaginal delivery with a clipped aneurysm. If the aneurysm is untreated however, the risk of intrapartum rebleeding is most likely when the initial bleed occurs in the third trimester.46 An uncorrected AVM is more likely to bleed during labor and delivery than an aneurysm. Some authors recommend elective CD at 38/39 weeks gestation, but others found no advantage over a vaginal delivery.47,48 Most recommend operative delivery with an unclipped and previously ruptured aneurysm. When indicated, do a combined CD and neurosurgical procedure.40 If urgent, the neurosurgical procedure is carried out before delivery. If there are obstetrical reasons for expeditious delivery, delay the neurosurgical procedure until an appropriate time postpartum. Anesthetic Management Postpone aneurysm clipping in unstable patients. Among other goals (Table 14.12), it is essential to minimize transmural pressure (mean arterial pressure – ICP) across the aneurysm wall to reduce the risk of rebleeding. General anesthetic considerations for CD are the same as those for other neurosurgical procedures. Epidural anesthesia for CD and vaginal delivery has been reported in women with a medically managed intracranial aneurysm.46,49 Intracerebral Hemorrhage Leading causes of intracerebral hemorrhage are vascular anomalies, PreE/eclampsia, and coagulopathy (Table 14.13). A significant number (24%) of spontaneous intracerebral hemorrhages arise from undeterminable causes.50 Risk factors for intra­ cerebral hemorrhage are migraine headache, thrombophilia, systemic lupus erythematosus (SLE), heart disease, sickle-cell disease, thrombocytopenia, PPH, PreE, transfusion, gestational hypertension, and postpartum infection. AVMs are the commonest cause of IPH,51 but Moyamoya disease and cerebral Table 14.12  Anesthetic goals for clipping a cerebral aneurysm in the parturient

• • • • • • • • •

Minimize transmural pressure (mean arterial pressure–intracranial pressure) a Prevent hypertension and maintain normal mean arterial and intracranial pressure Maintain normal oxygen saturation and normocarbiab Maintain appropriate analgesia, muscle relaxation, and amnesia Close monitoring of volume status Mild hypothermia (26–35°C) may be considered to reduce cerebral metabolic rate – brain protection (prevent shivering with muscle relaxation) Vasospasm may require nimodipine treatment and triple “H” therapy, i.e., hypervolemia, hypertension, and hemodilution Head elevation Left uterine displacement to minimize aortocaval compression Early awakening

 It is imperative that ICP not be lowered until the dura mater is opened to minimize changes in the transcranial pressure gradient on the aneurysm wall and associated bleeding. a

 Hypocarbia potentially reduces placental perfusion.

b

Taken from the previous edition of Obstetric Anesthesia and Uncommon Disorders, chapter 9.

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Table 14.13  Causes of intracerebral hemorrhage in pregnancy40 Arterial – vasculitis, aneurysms, hypertension (PreE/eclampsia), AVM Bloody – hemorrhagic transformation of infarct Cardiac – embolus from endocarditis Drugs – amphetamines, cocaine Coagulopathy – anticoagulation medications, thrombocytopenia

venous sinus thrombosis are infrequent etiologies. The pathophysiology and etiology of spontaneous intracerebral hemorrhage differ from the other types of intracerebral hemorrhage since there is no specific structural abnormality. Clinical Presentation and Diagnosis Pregnant patients with intracerebral hemorrhage present with an abrupt onset neurological deficit referable to the bleed site, commonly accompanied by headache, nausea, and vomiting. A noncontrast CT scan is the most sensitive test to diagnose acute intracerebral hemorrhage. A contrast CT scan, MRI scan, or angiography help exclude a structural etiology. One should rule out a bleeding disorder and differentiate intracerebral hemorrhage from SAH because treatment differs significantly. Neurosurgical Management Intracerebral hemorrhage often is not amenable to surgical correction and has a poor prognosis. Treatment is supportive, with control of BP and ICP. Reserve surgery for life-threatening elevations of ICP, brainstem herniation, and evacuation of a welldefined expanding hematoma. Effect of Pregnancy and Obstetric Management Obstetric considerations should determine the mode and timing of delivery. Pain and pushing during labor and delivery may elevate ICP and BP, worsening the ICH. An attempt to limit hemodynamic stress by doing a CD offers no advantage over a painless vaginal delivery, modified with limited pushing during the second stage. Sometimes, a perimortem CD is required. Anesthetic Management Anesthetic goals are to provide hemodynamic and ICP stability. BP must be controlled before surgery to reduce the risk of rebleed but may be challenging to manage in the hypertensive or PreE parturient. Hypertensive patients often have a low intravascular volume, increasing the risk of severe hypotension and decreased placental perfusion following anesthetic induction. In these cases, central venous pressure will guide optimal fluid replacement or use one of the new noninvasive stroke volume and cardiac output devices. Intraoperative mannitol and furosemide help reduce edematous brain bulk and facilitate surface exposure. Mannitol increases fetal osmolality significantly, so use with caution. Control ICP preoperatively. Stress and the hypertensive response to intubation, extubation, and emesis are responsible for the detrimental effects of GA during CD. Neuraxial anesthesia is preferred in hypertensive parturients, providing the coagulation status is normal, as it avoids the hypertensive response to intubation and reduces the risk of regurgitation and pulmonary aspiration.52 If administering GA, it is essential to control hypertensive responses with labetalol or sodium nitroprusside and use an arterial line to

Disorders of the Central Nervous System in Pregnancy

assess the response to therapy on a beat-to-beat basis. Observe PreE patients for postpartum convulsions and manage them with magnesium sulfate and benzodiazepines. Hayashi et al. described a case of a successful GA for CD in a patient with a brainstem cavernous malformation.53 Although there was no lesion at the possible lumbar puncture site, the authors avoided NA, as they could not rule out the chance that NA might affect the brainstem cavernous malformation. In another report, Le et al. used a CSE for CD in a term parturient with a posterior inferior cerebellar aneurysm rupture.54 The patient had no neurological deterioration and was conscious during the procedure.

Cerebral Ischemia Ischemic stroke is uncommon in women of childbearing age. It results from occlusion of the cerebral circulation (venous or arterial) due to various causes. (Table 14.14) The rate of ischemic and hemorrhagic stroke was 12.2 in 100,000 pregnancies, whereas for cerebral venous sinus thrombosis, the rate was 9.1 in 100,000 pregnancies.55 Cerebral venous thrombosis (CVT) occurs mainly during the early postpartum period. There are multiple underlying precipitating factors for CVT (Table 14.15). Thrombosis of the sagittal sinus with extension to the cortical veins is not uncommon. Sagittal sinus thrombosis blocks the reuptake of CSF, causing intracranial hypertension. Cortical vein thrombosis produces focal cerebral ischemia and edema, and, when extensive, bland or hemorrhagic infarction. In the parturient, the etiology of arterial occlusion is like in other young adults. Clinical Presentation and Diagnosis The presentation of CVT is a gradual onset of focal deficits, while arterial emboli produce more sudden onset of symptoms. Cerebral venous thrombosis usually presents with a progressive headache, nausea and vomiting, blurred or double vision, and altered sensorium secondary to increased ICP. Cerebral venous thrombosis may be mistaken for eclampsia (or be associated Table 14.14  Etiology of arterial occlusion

Type

Association (risk factors)

•

Arteriopathies

•

•

Hematological

•

Embolism

• • • • • •

• •

Idiopathic Miscellaneous

• • •

Premature atherosclerosis (smoking, hypertension, diabetes, hypercholesterolemia, homocystinuria, radiation to the neck, and a family history of arteriosclerosis) Arterial dissection (inflamed cerebral arteries) Sickle cell crises (ischemic injury to the vessel wall) Systemic lupus erythematosus (SLE) Thrombotic thrombocytopenic purpura (TTP) Embolism from artificial valves, mitral valve prolapse, atrial fibrillation, and subacute bacterial endocarditis Others: air, fat, and amniotic fluid embolism, as well as paradoxical emboli from veins in the presence of a patient foramen ovale No cause found in 25% Migraine-related Drug-induced (cocaine, heroin, and amphetamines)

Taken from the previous edition of Obstetric Anesthesia and Uncommon Disorders, chapter 9.

Table 14.15  Precipitating factors for cerebral venous thrombosis Excessive blood loss during delivery Infection Hyperviscosity syndromes Sickle cell disease Malignancy Polycythemia rubra vera Paroxysmal nocturnal hemoglobinuria Dehydration Procoagulation syndromes Antiphospholipid antibody syndrome Deficiency of protein C and S Arteriovenous malformation Endothelial injury Venous stasis Taken from the previous edition of Obstetric Anesthesia and Uncommon Disorders, chapter 9.

with it) or a ruptured aneurysm. Cortical vein occlusion produces focal or generalized seizures and lateralizing signs that affect the proximal extremities. Differentiate ischemic strokes from hemorrhagic strokes or structural lesions that may be surgically treatable. Stroke recurrence is not unusual, so it is critical to diagnose and treat any underlying medical condition. Base the diagnosis on clinical information, laboratory investigations (including coagulation studies), CT, MRI, and angiography where indicated. Treatment of patients with CVT is supportive with the administration of anti-seizure medication. These patients usually recover rapidly and spontaneously without neurological sequelae. Effect of Pregnancy and Obstetric Management Pregnancy and the postpartum period are associated with an increased risk of ischemic stroke and intracerebral hemorrhage, thought to occur in 30 in 100,000 pregnancies.56 Obstetric considerations should determine the mode of delivery. Medical Management Base treatment on the underlying etiology. Treat an acute thrombotic episode with anticoagulants. There are reports of the successful use of urokinase, IV tissue plasminogen activator (TPA), and heparin (LMWH or UFH) in pregnancy. Many obstetric providers use LMWH as it has a predictable anticoagulant effect, less frequent dosing, and minimal monitoring. After an acute episode, these medications often are changed to subcutaneous heparin (UFH) and aspirin to minimize recurrence. Postpartum, switch the heparin to warfarin, aspirin, or clopidogrel. Ventriculoperitoneal shunting and placement of ICP monitors are needed if there is hemorrhagic transformation of the infarct with mass effect and increased ICP. Anesthetic Management During labor, prevent hypertension and elevated ICP by carefully inducing epidural analgesia and using an assisted vaginal delivery to avoid pushing in the second stage. Systemic hypotension may reduce cerebral perfusion and blood flow to an already compromised, injured area. In patients receiving anticoagulants, follow the precautions outlined in the ASRA guidelines.57 To administer NA safely, it may be necessary to reverse

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therapeutic anticoagulation. Month et al. describe a case of CVT in a pregnant woman who had a CD under uneventful spinal anesthesia.58 Iqbal et al. reported on a pregnant woman with an ischemic cerebrovascular event at 32 weeks gestation; 10 days later, she had a CD under GA with no neurological deterioration.59 Postoperatively, observe the patient for recurrence or extension of local thrombus or increased ICP.

Disorders of Intracranial Pressure The Monroe-Kellie principle explains the dynamics of ICP when there is intracranial pathology. As the intracranial compartment and vertebral canal volumes are constant, the sum of all intracranial volumes, brain, blood, and CSF, is fixed. It shows how ICP rises in a predictable manner. A rise in the volume of one compartment or the addition of a new pathologic mass requires a compensatory decrease in the volume of other parts. Among these three components, the brain is least compressible, so blood and CSF offer the best options for adjustment to compliance. This compliance permits ICP to increase marginally with small increases in the volume of intracranial components; however, once this compensation fails, ICP will rise.60

Benign Intracranial Hypertension Benign idiopathic intracranial hypertension (IIH) or “pseudotumor cerebri” is defined as an increase in ICP without a demonstrable etiology and is a diagnosis of exclusion. The incidence among pregnant patients is 0.9 per 100,000, similar to that in the general population.60 Idiopathic intracranial hypertension is more common in obese women of childbearing age, suggesting a hormonal etiology,61 but it may occur after chronic use of some medications, such as tetracycline. Overproduction and underabsorption of CSF are proposed mechanisms. The disease is usually benign, but high ICP can lead to optic nerve atrophy and blindness.

Clinical Presentation and Diagnosis Headache, stiff neck, papilledema, and visual disturbances occur from increased ICP, but consciousness is not affected. Other findings are CSF pressure elevated to > 200 mm H2O, normal CSF composition, and unremarkable imaging studies.61

Impact of Pregnancy and Obstetric Management Pharmacologic management of uterine muscle tone can potentially impact ICP. Administering oxytocin too rapidly or as a bolus may cause transient hypotension and tachycardia, affecting cerebral perfusion pressure and ICP.62 Accepted practice for pregnant women with IIH is for a vaginal delivery; IIH is not an indication for CD. Treatment of IIH during pregnancy is the same as for nonpregnant patients, except use caution with calorie restriction and diuretics (acetazolamide). The condition usually resolves postpartum. Valuable Clinical Insight Oxytocin may cause transient hypotension and tachycardia, potentially affecting cerebral perfusion pressure and ICP.

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Medical and Neurosurgical Management Treatment goals are to preserve vision and control symptoms by reducing ICP. Medical management includes diuretics (primarily acetazolamide), steroids, and serial lumbar punctures to drain CSF and lower the ICP. Brainstem herniation usually does not occur with a lumbar puncture as the increase in ICP is uniformly distributed throughout the brain and spinal cord. However, there are reports of cerebellar tonsillar herniation after a diagnostic lumbar puncture in nonpregnant patients with this syndrome.63,64 These patients presented with severe headache, neck pain, and focal neurologic signs. If medical measures fail to improve visual function, surgical techniques like optic nerve sheath fenestration may be needed to preserve vision.64,65 If visual symptoms worsen after optic nerve sheath fenestration in patients with IIH, insert a lumbo­ peritoneal or ventriculoperitoneal shunt.65,66 Many recommend limiting weight gain during pregnancy as it may worsen IIH.67

Anesthetic Management Valuable Clinical Insights • Neuraxial anesthesia can be used safely in parturients with IIH. • Concerns include increasing ICP by injecting a large volume of LA into the epidural space. • Use systemic opioids with caution as they may depress respiration, causing an increase in ICP.

There are reports of complication-free neuraxial labor analgesia in pregnant women with IIH.66,68-70 Some anesthesia providers question whether injecting a large volume of LA into the epidural space might increase ICP further in patients with IIH and advocate vaginal delivery with an intrathecal catheter.67,68 Heckathorn et al. described a case of a pregnant woman with intractable symptoms from benign IIH. An indwelling intrathecal catheter provided spinal anesthesia for an urgent CD.69 Avoid analgesic drugs, primarily opioids, that might cause respiratory depression and a subsequent increase in ICP. There are some concerns about whether GA or NA is better for patients with a lumboperitoneal shunt.60 The main concern is possible damage to the shunt catheter by the epidural or spinal needle. There are reports of quick offset of block after repeated doses of intrathecal lidocaine, possibly by rapid washout of lidocaine through the shunt into the peritoneal cavity.70 The primary goal during anesthesia is to avoid further increases in ICP. Thus, the recommendation is to use GA for CD in IIH patients only when necessary.71 As parturients with benign IIH often undergo a diagnostic spinal tap, they have the potential to develop a PDPH and may require an epidural blood patch.71 Blood placed in the epidural space may increase ICP through compression of the dura mater, so slow injection may be warranted.

Hydrocephalus with Shunt Hydrocephalus is an abnormal accumulation of CSF in the brain. The CSF is often under increased pressure, which can compress and damage the brain. There are many causes of hydrocephalus (Table 14.16). Some patients require ventriculoperitoneal or

Disorders of the Central Nervous System in Pregnancy

Table 14.16  Causes of hydrocephalus and increased intracranial pressure

Hydrocephalus

Increased intracranial pressure

• •

• • • • • • •

•

• •

Congenial aqueductal stenosis Noninherited - Dandy-Walker anomaly Acquired, secondary to: - Subarachnoid hemorrhage - Infection - Tumor Inherited neural tube defect Arnold-Chiari malformation

Traumatic brain injury Pseudotumor cerebri Arnold-Chiari malformation Brain tumor or other mass lesion Hydrocephalus Lyme disease Severe hypertension

Taken from the previous edition of Obstetric Anesthesia and Uncommon Disorders, chapter 9.

ventriculoatrial shunts to relieve raised ICP. Many women with cerebrospinal shunts are now reaching childbearing age and may have shunt malfunction during pregnancy.72

Clinical Presentation and Diagnosis In patients with shunts, hydrocephalus may recur due to shunt malfunction, commonly due to infection or mechanical damage. Perform a physical examination and a CT or MRI scan to rule out other causes. Use transcranial US to monitor hydrocephalus closely, thus avoiding exposure to ionizing radiation in a pregnant patient.73 Valuable Clinical Insights • Hydrocephalus may recur from shunt malfunction. • Infection or mechanical damage may cause shunt malfunction. • Use US to monitor hydrocephalus through pregnancy.

Effect of Pregnancy on Hydrocephalus The failure rate of CSF shunts is high during pregnancy. In a literature search spanning the last 30 years, shunt malfunction occurred in 28 of 97 women (29%) who presented with a shunt during pregnancy.74 Of these cases, 71% required a shunt revision during pregnancy. A gravid uterus may cause a mechanical or functional obstruction to the shunt by either direct pressure or by raising intraabdominal pressure.75 Any further increase in intraabdominal pressure, as seen with uterine contractions and pain during the first stage of labor and Valsalva during the second stage, can result in a sudden rise of ICP due to failure of the shunt. Neurological symptoms like headache, confusion, nausea, vomiting, cranial nerve palsies, seizures, and disordered mentation can occur in pregnancy. If ICP is normal, there are no specific obstetric considerations. However, prophylactic antibiotics reduce the risk of shunt infection, especially after entering the peritoneum during CD or tubal ligation.

Neurosurgical Management Shunts may need initial placement or a revision if the patient develops signs of raised ICP. Neurosurgeons prefer ventriculoperitoneal shunts as they are the most resistant to infection. Administer prophylactic antibiotics to prevent infection of the shunt during revision.

Anesthetic Management In a literature review of parturients with cerebrospinal shunts, 56% delivered vaginally vs. 44%, who had a CD. Forty percent of women having a vaginal delivery had an epidural, and 44% had a GA for a CD. The data suggest that NA is safe in women with patent shunts and normal ICP. General anesthesia may be safer than NA in patients with shunt failure due to an increased risk of brain herniation with NA.74 Damage to an existing shunt catheter may occur during NA, and some of the LA injected into the CSF could be lost via the lumboperitoneal shunt reducing its spread, effectiveness, and duration of action.70 Valuable Clinical Insights • Neuraxial anesthesia is safe in parturients with working shunts and normal ICP. • There is a risk of brain herniation with NA when there is shunt failure and increased ICP. • Concerns with NA include damage to the shunt catheter and potential LA loss via the shunt.

Increased Intracranial Pressure Brain trauma and various other conditions may increase ICP, leading to a reduction in cerebral perfusion. An elevated ICP correlates directly with poor neurological outcomes. The symptoms of raised ICP are headache, nausea and vomiting, ataxia, papilledema, visual disturbances, and a decreasing level of consciousness. An acute increase in ICP due to an expanding intracranial lesion can lead to brainstem herniation, but a loss of consciousness may occur before signs of herniation are seen. Signs and symptoms of brainstem herniation include a decreasing level of consciousness, lateralizing neurologic signs (“unilateral blown pupil,” abducens nerve palsy), sudden changes in BP, and HR (Cushing triad), vomiting, irregular respiration, respiratory collapse (CheyneStokes respiration), and seizures. The differential diagnosis includes acute obstetric disasters, such as AFE. In the parturient, increased ICP can occur secondary to uterine contractions and increases in arterial and venous pressure from pain and Valsalva maneuvers.

Monitoring and Management of Increased Intracranial Pressure Normal ICP is 23 weeks gestation, and Rh isoimmunization.79,80 As there is a lack of specific guidelines for the pregnant population with TBI,79 follow the Maternal Fetal Medicine Committee guidelines.80

Neurosurgical Management Neurosurgical management of the parturient with TBI includes control of BP, ICP, ventilation, maternal cerebral perfusion, and fetal perfusion. Indications for surgical intervention are subdural and epidural hematomas, intracerebral hematomas associated with a mass effect and neurological deterioration, symptomatic ICP >25 mmHg that is not responding to treatment, depressed skull fractures, hydrocephalus, and the need to place ICP monitors.

Anesthetic Management Anesthetic management for neurosurgery in pregnancy is similar to that in nonpregnant patients, bearing in mind those factors important in dealing with nonobstetric surgery during pregnancy.82 Exposure to teratogens is concerning, but judicious use of commonly used agents is safe in the absence of hypoxemia, acidemia, and hypercarbia. Anesthetic

management for delivery is similar to that in pregnant patients suffering from ICH.

Uncommon Disorders Sturge-Weber Syndrome Sturge-Weber syndrome (SWS), also known as Krabbe Weber Dimitry disease, is a rare neurocutaneous syndrome, with an incidence of 1:50,000,83 with only a small number of cases recorded in the literature.84 The cardinal features of this disease are localized atrophy and calcification of the cerebral cortex with an associated intracranial venous malformation (angiomatosis) and an ipsilateral port-wine colored facial nevus usually located in the ophthalmic and maxillary distribution of the trigeminal nerve. The atrophic process may affect any portion of the cerebral cortex, but the occipital and parietal regions are the most involved.

Clinical Presentation Clinical manifestations may range from localized, superficial skin lesions to extensive systemic involvement (Table 14.18). Occasionally the combination of a port-wine facial nevus and localized cortical atrophy exists without clinical symptoms, but in most cases, convulsions are present from infancy. Many patients have intellectual disability, contralateral hemiplegia, or hemianopia without cerebral infarction.85 Ipsilateral exophthalmia, glaucoma, buphthalmos, angiomas of the retina, optic atrophy, and dilated vessels in the sclera may also be present.

Diagnosis

Valuable Clinical Insights • Parturients with a seizure disorder and a port-wine stain nevus in the ocular trigeminal nerve distribution should have an MRI with contrast. • This will rule out an ipsilateral intracranial vascular malformation.

One can diagnose Sturge-Weber disease without difficulty from the clinical syndrome. In most patients, the appearance of characteristic shadows on the X-ray identifies the cortical lesion. Lesions in the occipital and parietal lobes are usually more calcified than those in the frontal lobe. When there is minimal cerebral involvement, make the diagnosis using angiography or contrast-enhanced CT scan. Any parturient with a port-wine nevus in the ocular trigeminal nerve distribution should have an MRI with contrast to rule out an ipsilateral intracranial vascular malformation, especially if a seizure disorder is present.86

Management Evaluate any patient presenting with complaints of seizure disorder, facial nevus, ocular manifestations, or an intracranial vascular malformation early in pregnancy. A multidisciplinary team should manage their obstetric care. The treatment of patients with SWS is essentially symptomatic. Control of seizures follows

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the principles outlined above and requires optimal control with anticonvulsive drugs. Subarachnoid and subdural hemorrhage may occur but are uncommon. Heart failure rarely occurs and is due to shunting through the intracranial angiomas. Many patients will have had AVMs or other anomalies treated surgically, but not all pregnant patients with SWS require surgery.84

Anesthetic Management

Valuable Clinical Insights • Rule out spinal AVMs or hemangiomas before deciding to administer NA. • Prevent an increase in intraocular or ICP.

Evaluate the signs and symptoms of associated anomalies to determine the choice of anesthetic technique. Carefully plan anesthesia to avoid trauma to the hemangiomatous lesions and prevent any rise in intraocular or intracranial pressure87 (Table 14.18). See above for anesthetic concerns for the epileptic parturient. Pay special attention to intubation and extubation as difficulties with tracheal intubation and ventilation may occur due to angiomas of the lip, oral cavity, tongue, larynx, and trachea.87 Perforation of vascular lesions may cause uncontrolled bleeding, so use soft, unstyleted, well-lubricated endotracheal tubes for atraumatic intubation. Care during tracheobronchial suction is mandatory. During induction and intubation, avoid sudden increases in BP, which could rupture the malformations. Ocular manifestations require avoiding anesthetic agents that may increase intraocular pressure. Straining, bucking, and obstructed airways during induction or emergence may increase intraocular and intracranial pressure.87 Increased ICP can result in intracranial hemorrhage from associated vascular malformations. Neuraxial techniques (e.g., spinal, epidural, CSE) are a safe and logical choice in most cases, especially when localized superficial skin lesions exist without clinical symptoms. Epidural analgesia was used successfully for labor in a patient with a prior total left hemispherectomy.88 If an epidural is not in place, administer spinal anesthesia (saddle block) to facilitate an Table 14.18  Clinical manifestations and anesthetic concerns in a parturient with Sturge-Weber syndrome87

Clinical manifestations

Anesthetic concerns

• • • • • • • • • •

• • • •

Seizures Contralateral hemiparesis Contralateral hemianopia Headaches Developmental delay Intellectual disability Glaucoma Choroidal hemangioma Stroke Bilateral cerebral involvement

• •

Control of seizures ↑ICP ↑Intraocular pressure Difficult intubation from airway hemangiomas Uncontrolled hemorrhage, from rupture of hemangiomas Uncommon Subarachnoid/subdural hemorrhage Heart failure from shunting Recurrent thrombotic episode

Taken from the previous edition of Obstetric Anesthesia and Uncommon Disorders, chapter 9.

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assisted vaginal delivery. Two concerns with an epidural block are the potential for increased ICP caused by the injection of anesthetic drugs into the epidural space and the catastrophic consequences of sudden CSF loss from an accidental DP in the presence of an intracranial lesion. The slow continuous leak of CSF after withdrawing the needle may lead to some cases of delayed neurological deterioration. A preexisting neurological disease of the spinal cord or peripheral nerves is a relative contraindication to NA. Epidural or spinal anesthesia is preferred for CD if time permits and ICP is normal. Spinal anesthesia after a failed epidural was used successfully for CD in a patient with SWS.89 General anesthesia is an option for cases of extreme urgency, increased ICP, an uncooperative patient, or obstetric considerations. One can minimize perioperative hypertension and improve postoperative analgesia by combining epidural anesthesia with GA for CD.

Arnold–Chiari Malformation Herniation of the cerebellar tonsils through the foramen magnum into the upper cervical spinal canal characterizes adult-onset Arnold–Chiari malformation (ACM). Chiari I malformations, a herniation < 10 mm, are relatively common in neuroimaging studies (0.6% of the population).90 Table 14.19 lists the classification and clinical manifestations of ACM.

Clinical Features Symptoms of ACMs are due to increased ICP from obstruction of CSF flow from the fourth ventricle or pressure effects of displacement, or entrapment of cranial nerves, resulting in occipital headache, shoulder and arm pain with cutaneous dysesthesia, visual disturbances, intermittent vertigo, and ataxia. Symptoms become worse with head movement and coughing. Neuronal impairment of the medulla can cause sleep apnea, respiratory failure, and death.91 Rarely, syncopal episodes are described and attributed to either compression of the midbrain ascending reticular system, or vascular compromise (vertebrobasilar artery compression, hypotension).92 Syringomyelia, a slow-onset progressive myelopathy characterized by cystic degeneration within the spinal cord, is Table 14.19  Classification and clinical manifestations of Arnold–Chiari malformation

Type

Signs

Symptoms/ presentation

Associated morbidities

I

Cerebellar tonsils extend into foramen magnum

Adolescence and adulthood

Headache, most cerebellar signs present later in life

II

Cerebellum and brainstem herniation into upper cervical canal

Presents at birth or early infancy

Myelomeningocele with partial or complete paralysis below the spinal opening

III

Smaller cerebellum with entire cerebellar herniation into cervical canal

Presents at birth

Severe neurological deficits, developmental delays and seizures

IV

Cerebellar hypoplasia

Presents at birth

Rare

Disorders of the Central Nervous System in Pregnancy

Table 14.20  Anesthetic concerns in Arnold–Chiari malformation ↑ICP

Worsening symptoms and possible brainstem herniation During pushing Inadvertent dural puncture General anesthesia: at induction, intubation, and extubation During epidural injection

Scoliosis/ syringomyelia

Technical difficulty Spread of local anesthetics (LA) Possibility of enhanced LA neurotoxicity Damage to spinal cord: if higher space chosen for regional anesthesia

Meningomyelocele

Nerve/spinal cord damage Space may be shallower

Lower motor neuron lesion

Possibility of hyperkalemia with succinylcholine Prolonged nondepolarizing neuromuscular block

Autonomic dysfunction

Hypotension In hypovolemic patients with an increase in intrathoracic pressure Vasodilation caused by spinal or epidural anesthesia

Shunts

Leakage of drug into peritoneal cavity Shorter action of LA Difficult to calculate dose of spinal LA

Taken from the previous edition of Obstetric Anesthesia and Uncommon Disorders, chapter 9.

documented in 50% of ACM patients.91 Symptoms of syringomyelia include skeletal muscle weakness, wasting, areflexia with or without thoracic scoliosis, and severe neurological deficits. Women with Chiari I malformation, with or without syringomyelia, are of concern due to the potential risk for increased ICP during pregnancy and delivery.93 Involvement of the autonomic nervous system is not uncommon.94

Effect of Pregnancy Physiological increases in CSF pressure during pregnancy can have a detrimental effect on patients with ACM-I. A rise in ICP during uterine contractions and labor pain, with further increases of 25–51 mmHg CSF pressure during the second stage of labor, puts a parturient at greater risk of complications.95 In one report, seven pregnant patients suffering from an ACM, with and without syringomyelia, had no significant increase or recurrence of ACM-related symptoms during delivery or postpartum.93

Neurosurgical Management The treatment of patients with an ACM includes posterior fossa decompression surgery, ranging from freeing adhesions, enlarging the foramen magnum, suboccipital craniectomy, laminectomy of C1, and dural patch grafting to dural splitting of the craniocervical junction.96

Obstetric Management Avoiding a sudden or persistent increase in CSF pressure during delivery is ideal. The method of delivery needs careful planning involving a multidisciplinary team. Consider vaginal delivery in an asymptomatic ACM patient and one already treated surgically. In the second stage of labor, avoid increasing ICP during pushing and Valsalva maneuvers, as it may worsen neurological

symptoms.97 A transient increase in ICP could impede CSF flow around the foramen magnum, producing cerebellar/brainstem herniation and or syrinx formation.97 Early pain control and passive second stage of labor contribute to successful vaginal delivery.97 In patients with neurological symptoms or uncorrected malformations, CD may be the best option.

Anesthetic Management Anesthetic options depend on the presence and severity of symptoms and a history of decompression surgery (Table 14.20). There are reports of successful spinal anesthesia,98 epidural anesthesia,93 and GA94 for CD in pregnant patients with ACMI. In a retrospective cohort study of 185 deliveries in patients with ACM-I from four academic medical centers in the United States, symptoms did not worsen after NA.99

Moyamoya Disease Moyamoya disease (MMD) is a noninflammatory cerebral vasoocclusive disease process of an unknown etiology. It mainly affects the terminal part of the intracranial internal carotid artery and circle of Willis. Bilateral stenosis leads to spontaneous or progressive occlusion of the internal carotid artery and abnormal collateral vessels at the base of the skull.100 Though the condition is prevalent worldwide, MMD is most prevalent in Japan (3.16–6.03 per 100,000 population)101 and Korea.102 MMD is more common in women and commonly seen between 10 and 30 years of age.103 MMD-related vaso-occlusion presents as a hemorrhagic or ischemic stroke or epilepsy. Thus, it is not unusual to detect MMD for the first time during pregnancy or postpartum.103

Effect of Pregnancy on Moyamoya Disease Maragkos et al. reported a maternal mortality rate of 13.6% in women with MMD.104 Pathophysiological changes during pregnancy and labor increase the risk of hemorrhagic and ischemic strokes. A 30–60% increase in blood volume during pregnancy, associated with hemodynamic changes during bearing down and breath-holding, can transiently raise ICP, making a parturient susceptible to hemorrhagic shock. During labor, pregnancyassociated hypercoagulation, hypocapnia, and metabolic alkalosis from hyperventilation can reduce cerebral blood flow, precipitating an ischemic event.

Management of Moyamoya Disease in Pregnancy No known medical management for MMD will slow or reverse the disease process. Most treatment strategies are surgical and designed to bypass the vaso-stenotic fragile vessels. Described techniques are superficial temporal artery to middle cerebral artery bypass, encephaloduroarteriosynangiosis, and encephalomyosynangiosis. However, their efficacy in preventing morbidity and mortality in pregnant women is unknown.104 It may be prudent to consider antithrombotic therapy in women at a high risk of an ischemic stroke.

Obstetric Management Obstetric management favors CD in Japan,105 and vaginal delivery in the United States.103 A Japanese national survey found a rate of CD between 70–76% in patients with MMD. Fujimura

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et al. recommended CD for patients with established MMD.106 This recommendation arose from concerns that sudden hemodynamic changes associated with Valsalva maneuvers during the second stage of labor, and increased ICP while bearing down, might injure friable vessels.106 The current literature does not support either CD or vaginal delivery in known MMD patients.104

Anesthetic Management Anesthetic management in a parturient with MMD for CD is not standardized. During GA, laryngoscopy, intubation, and extubation can increase cerebral metabolic rate, oxygen consumption, and ICH from rupture of collaterals or aneurysms. Inhalational halogenated agents can negate cerebrovascular autoregulation. General anesthesia reduces cerebral metabolic rate and oxygen consumption, possibly protecting from cerebral ischemia, a possible advantage.107 Neuraxial anesthesia allows monitoring of cerebral function. Hypotension due to sympathetic block with NA may decrease cerebral perfusion pressure, causing cerebral ischemia. Epidural anesthesia may be more desirable than spinal anesthesia due to its gradual onset of sympathetic block and less severe hypotension.107

Tourette Syndrome Tourette syndrome (TS) is a habitual, repetitive, involuntary neuropsychiatric movement disorder, described as a tic, with a worldwide prevalence of 1%.108,109 Patients with TS develop motor and phonic tics and behavioral disorders before age 18. There is a reduction in the severity of the tics after that age; hence it is uncommon to see these movement disorders in pregnancy years. The prevalence of TS is nearly equal among men and women.110

Effect of Pregnancy on Tourette Syndrome Current clinical data indicate that tic frequency does not increase during pregnancy.111 In a retrospective study of eight TS patients with 11 pregnancies, there was no unfavorable effect on pregnancy.109 TS symptoms improved in five pregnancies but worsened in three. TS severity and occurrence of tics remained unchanged in the remaining three pregnancies.

Management In a parturient with nondisabling tics, consider withdrawal or a decrease in medication dose during pregnancy or optimally before pregnancy. A treatment plan should be revisited and optimized in women with disabling tics. Neuroleptic drugs, the primary management option for TS patients, are lipophilic and readily cross the placenta to the fetus. The most commonly used neuroleptics (olanzapine, risperidone, quetiapine) for pregnant women with TS do not cause fetal malformations.112 Some pregnant women with TS receive anti-dopamine drugs (tetrabenazine, category C), benzodiazepines (category B), clonidine (category C), and pimozide (with fluoxetine, category C).

Obstetric Management Unless there are obstetrical indications, consider vaginal delivery in all pregnant patients with TS. There is a single case report of GA and CD in a woman with TS who developed worsening

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motor tics during delivery, likely due to discontinuing medical management.113

Anesthetic Management Motor tics may cause technical problems in performing NA, increasing the risk of nerve damage or DP. Consider judiciously titrated sedation, with prior informed consent, during attempted NA or administer GA to avoid agitation and unwanted movements. Be aware of any possible interaction between anesthetic medications and the patient’s neuroleptic and anti-dopamine medications.

Narcolepsy Narcolepsy is an unusual chronic clinical syndrome of excessive daytime sleepiness, possibly accompanied by cataplexy, hypnagogic hallucinations, and sleep paralysis. Narcolepsy may happen with or without cataplexy and affects approximately one in 3000 individuals in the United States.114 Narcolepsy commonly arises between adolescence and into the early twenties, so women with narcolepsy may become pregnant.

Effect of Narcolepsy on Pregnancy Irregular and excessive sleep attacks and cataplexy are safety concerns for the mother and her fetus because of increased chances of accidents, falls, or trauma. A European multinational retrospective cohort study of 249 pregnant women with narcolepsy found anemia and glucose intolerance were more common in women with narcolepsy than in the general population.115 In 40% of women with narcolepsy who stopped medication in the first trimester, the severity of sleepiness increased during pregnancy.115 In the same study, less than 1% of pregnant women with narcolepsy and cataplexy reported symptoms during delivery, but they required more CDs.115 Possibly, labor triggers cataplexy due to pain and interrupted sleep.116 Ping et al. reported a case of status cataplecticus during labor. This woman had a history of cataplexy caused by sexual intercourse, indicating genital stimulation during labor might cause a cataplectic event.117

Management during Pregnancy The use of nonpharmacological and behavioral therapy for narcolepsy is significant in pregnancy.  The mainstays of medical management in narcolepsy are stimulants and wake-promoting agents like modafinil and methylphenidate (FDA category C in pregnancy).118,119 On an individual basis, one must balance the danger of the uncontrolled condition against the risk of fetal exposure in deciding to withhold or continue medications. Women with minor symptoms might not need medical treatment. If symptoms are disruptive, the decision becomes challenging. Decreased fetal growth occurs with some medications that are unlikely teratogenic. Counsel women with narcolepsy before pregnancy about the risks associated with the condition and its medical treatment.116

Obstetric Management The chance of a cataplectic episode during labor is only 1%,115 suggesting that an elective CD is unnecessary in women with cataplexy.  Adequate analgesia, avoiding individual triggers, and adequate sleep reduces the risk of cataplexy during childbirth.

Disorders of the Central Nervous System in Pregnancy

Anesthetic Management There are no increased anesthetic or surgical risks if a CD is required.120 Anesthetic concerns for pregnant women with narcolepsy include the choice of anesthetic technique and sitting position for NA. Soltanifar et al. reported successful NA in a patient with narcolepsy.121 They suggest that NA with neuraxial opioids is the first choice for CD in patients with narcolepsy. There may be a risk of delayed awakening after GA in patients with narcolepsy and apneic episodes.

The Comatose Parturient Coma, a deep state of unconsciousness, has a multitude of etiologies, all of which may complicate pregnancy and pose a significant threat to the mother and her fetus (Table 14.21). Further in the continuum of CNS deficits are the entities of chronic vegetative state and brain death, posing medical, ethical, and legal dilemmas, especially when considered in the context of a viable pregnancy.

Management The immediate treatment goals are prevention of further nervous system damage, rapid correction of hypotension, hypoglycemia, hypoxia, hypercapnia, hyperthermia, and control of seizures. The unconscious parturient may require endotracheal intubation and ventilation to protect the airway and correct hypoventilation. Assess fetal viability after maternal stabilization. History and a thorough clinical examination with neurological and laboratory evaluation will indicate the need for neuroimaging techniques such as CT scanning, MRI, MR angiography, and conventional angiography. Accurate diagnosis allows the development of an individualized management plan, utilizing a multidisciplinary approach and a direct specific treatment toward the cause of coma. Long-term management goals are adequate nutrition and avoiding complications like infections, bedsores, and contractures. Table 14.21  Differential diagnosis of coma

Intracranial

Extracranial

Vascular Hemorrhage (subarachnoid) Cerebral infarction (embolus, thrombus, or vasculitis) Tumor Hemorrhage Edema Abscess Hemorrhage Edema Infection Meningitis Encephalitis Trauma Edema Hemorrhage (subdural, extradural, or intracerebral) Epilepsy Postictal Status epilepticus

Hypotension Hemorrhage Myocardial infarction Septic shock Hypertension Encephalopathy eclampsia Metabolic Endocrine Hepatic Renal Hypoxia Hypercarbia Drug/Toxins Physical Hypothermia Electrocution

Taken from the previous edition of Obstetric Anesthesia and Uncommon Disorders, chapter 9.

In general, neurosurgical considerations dictate management in the case of life-threatening ICH while basing obstetric decisions on fetal viability. Administration of steroids may enhance fetal lung maturity. Hypoglycemic coma, not associated with insulin therapy, is rare because pregnancy confers insulin resistance. Insulinoma may be diagnosed with simultaneous determination of plasma glucose, insulin, and C-peptide levels in the fasting state. In one case report, treatment consisted of a 50% glucose infusion and supportive care until postpartum excision of the pancreatic tumor.122 Prolonged maternal hypoglycemia may cause precipitous fetal compromise. Short-term maternal hypoglycemia changes the FHR pattern but after treatment, FHR monitoring rapidly shows a reassuring pattern.123

Management of Maternal Vegetative State and Brain Death The definition of a chronic vegetative state is a subacute or chronic condition that sometimes occurs after brain injury and consists of a return of wakefulness accompanied by an apparent total lack of cognitive function. The vital functions of respiration, BP, and thermal regulation are retained and may be subject to periods of overactivity. Artificial life support will preserve cardiorespiratory function when a total cessation of cerebral blood flow results in brain death, a diagnosis made according to strict criteria. Brainstem and hypothalamic centers do not function, resulting in a lack of spontaneous respiration, hypotension, hypothermia, and panhypopituitarism. Advances in intensive care, life support systems, and neonatology mean the continuation of pregnancy is possible in the vegetative or brain-dead parturient. Moral and ethical problems exist when considering the removal of support from the vegetative mother postpartum. Make management decisions on a case-bycase basis with liaison among family members, legal advisors, institutional ethics committee, and the multidisciplinary care team. Romagano et al. describe the management of a pregnant patient with irreversible anoxic brain damage who was in a persistent vegetative state from 20 weeks gestation until CD at 39 weeks.124 The authors stressed a multidisciplinary team approach to decision-making, with each case assessed individually regarding the likelihood of maternal survival and fetal prognosis with continued life support. Administer betamethasone to stimulate fetal lung maturation if indicated. Base the delivery timing on maternal condition and fetal maturity. Case reports in the literature outline scenarios and management issues. Ceccaldi et al. describe the management of a 28-year-old female who developed encephalitis of unknown origin and went into a persistent vegetative state at 22 weeks gestation.125 The patient went into labor at 37 weeks and had an assisted vaginal delivery of a healthy neonate. The patient subsequently improved with intensive rehabilitation.125

Considerations for Neurosurgery during Pregnancy Monitoring It is essential to monitor oxygen saturation, ECG, end-tidal CO2, oxygen saturation, temperature, FHR, direct arterial and central

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venous pressures, ICP, and, occasionally, electroencephalogram (EEG) and sensory-evoked potentials.

Fluid Management In unconscious patients and those with intracranial lesions, fluid and electrolyte balance can be problematic due to decreased fluid intake, vomiting, and hyperosmolar dyes for angiography. Severe fluid restriction minimally reduces ICP because fluid loss is isotonic; the downside is that it decreases uteroplacental perfusion. One can use IV fluid loading to maintain BP, cerebral perfusion, and fetal perfusion. Hypotension and hypovolemia can exacerbate intracranial vasospasm, so careful fluid administration is appropriate while monitoring ICP and FHR.

Blood Pressure Control Control BP throughout the perioperative period to maintain ICP, cerebral perfusion, and fetal perfusion. Select vasopressors and antihypertensives with the fetus in mind. Although ephedrine benefits fetal perfusion by increasing myocardial contractility and constricting capacitance and resistance vessels, it may increase shear stress on sensitive intracranial vessels, so administer cautiously. Multiple studies show that phenylephrine, which increases afterload, is safe for the fetus.126 However, in large doses, phenylephrine may reduce uteroplacental perfusion secondary to its alpha-adrenergic effect on the uterine vasculature. In normal doses, antihypertensive agents such as labetalol, hydralazine, nifedipine, nitroglycerin, and brief infusions of nitroprusside are safe for the fetus.127 The lack of placental autoregulation means that placental perfusion is directly related to maternal mean BP. Be aware of how volume expanders, diuretics, vasopressors, or vasodilators impact cerebral perfusion, maternal end-organ perfusion, and placental perfusion.

Brain Protection Avoiding hypoxia, and hypercarbia, maintaining euglycemia, and providing therapeutic hypothermia may minimize further neurological damage perioperatively. Many of these methods are experimental, and the effects on the fetus are unknown.

Anesthetic Management The wellbeing of the mother determines fetal outcome; select surgical procedures with the safety of the parturient in mind. Consider the impact of preoperative therapy and anesthetic intervention on the mother and fetus when formulating an anesthetic plan. Urgent surgical intervention is required only in the most severe cases (massive trauma, epidural hematoma, brainstem herniation). Major considerations include neurological status (level of consciousness, ICP), diagnosis, cardiorespiratory compromise, and fetal condition. The maternal condition should be as stable as possible before surgery with appropriate monitoring in place. Goals of anesthetic management include control of BP, cerebral blood flow, ICP, prevention of aspiration, and maintenance of fetal perfusion.128 Anesthetic management for a neurosurgical procedure during pregnancy is similar to that for a nonpregnant patient with the following exceptions: surgery is best deferred until the second trimester; assess fetal wellbeing

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throughout surgery by monitoring FHR; and ensure left uterine displacement to avoid aortocaval compression, especially during the late third trimester. After preoxygenation and induction, apply cricoid pressure until the endotracheal tube is secured. Succinylcholine (100–120 mg) remains the most reliable neuromuscular blocker for intubation. The resulting fasciculations may temporarily increase ICP and BP but have little clinical consequence. If there is a contraindication to succinylcholine and the woman has an adequate airway, use rocuronium in a dose of 0.6–1.0 mg/kg. Most anesthetic drugs are safe for the fetus,82 but second-trimester surgery negates concerns about teratogenesis. Premature labor can occur following any nonobstetric surgery. The risk is greater following abdominal or pelvic surgery compared to neurosurgery. Early detection with continuous monitoring for uterine contractions and treatment of premature labor is essential. Induced hypotension to control bleeding during clipping of an intracerebral aneurysm may adversely affect the fetus. Limit the depth and duration of induced hypotension; adjust the mean BP upwards if the FHR pattern becomes unfavorable.

Summary Because CNS disorders are not common during pregnancy, retrospective reviews and case reports guide most management decisions.129 With advances in neurosurgical, obstetric, and anesthetic management and, since fetal wellbeing ultimately depends on maternal health, there is a trend to treat the parturient aggressively for any neurological condition during pregnancy. Appropriate monitoring, rational, preemptive control of physiological variables, communication, a coordinated team approach, and timely intervention based on predetermined triage priorities are essential to optimal management. This chapters covers a lot of material, but many rare syndromes contain CNS lesions that could not be incorporated into this long chapter. As a result the editors chose to provide a list of additional topics with a brief description and some up to date references in order to be more thorough. However, there will continue to be case reports published that contain other very rare conditions affecting the CNS and other systems, and some no doubt we have missed.

Additional Topics Cerebral Palsy

A congenital disorder of movement, muscle tone, or posture. Cerebral palsy arises from abnormal brain development, often in utero. Aiudi CM, Sharpe EE, Pasternak JJ, et al. Anesthetic management of two parturients with cerebral palsy and prior selective dorsal rhizotomy. Int J Obstet Anesth 2018;34:105–108. Tanqueray TA, Dob DP. Spinal anesthesia for caesrean section in a patient with cerebral palsy. Int J Obstet Anesth 2010;19:238.

Phace(S) Syndrome

PHACE syndrome is a rare disorder of unknown etiology affecting multiple body systems. P – Posterior fossa and other structural brain malformations H – Hemangiomas of face, neck or scalp

Disorders of the Central Nervous System in Pregnancy

A – Arterial anomalies (cerebral and cervical) C – Cardiac anomalies and Coarctation of the Aorta E – Eye abnormalities (S) Sternal anomalies occasionally. Martel C, Robertson R, Williams FB, et al.Anesthetic management of a parturient with PHACE syndrome for cesarean delivery. AA Case Rep 2015;5:176–178.

Cerebral Autosomal Dominant Arteriopathy Subcortical Infarcts and Leukoencephalopathy (CADASIL)

This is the most common form of hereditary stroke disorder, caused by mutations of the Notch 3 gene on chromosome 19. Clinical manifestations include migraines, transient ischemic attacks, or stroke. There are characteristic MRI findings, but skin biopsies are often used to make a diagnosis. CADASIL does not appear to be associated with poor maternal or fetal outcomes. Dorbad MA, Creech TB, Jain S, et al. Epidural management for obstetric patient with Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) undergoing emergent cesarean section. J Clin Anesth 2018;45: 88–89. Donnini I, Rinnoci V, Nannucci S, et al. Pregnancy in CADASIL. Acta Neurol Scand 2017;136:668–671.

Anti-N-Methyl-D-Aspartate (NMDA) Receptor Encephalitis

Anti-NMDA receptor encephalitis was first identified in 2007. It is an autoimmune disease where the body produces antibodies against brain NMDA receptors. Normal brain signaling is disrupted by the antibodies, resulting in brain swelling and encephalitis. Patients may present with abnormal behavior, cognitive defects, memory loss, speech disorders, loss of consciousness, movement disorders, seizures, and autonomic dysfunction. Further information can be found at https://www.med.upenn.edu/autoimmuneneurology/ nmdar-encephalitis.html. A study of pregnancy outcomes in women with this condition found that obstetric complications often occurred but that newborn outcomes were usually good. Another report described the use of NA for CD in a woman with anti-NMDA receptor encephalitis. Joubert B, Garcia-Serra A, Planaguma J, et al. Pregnancy outcomes in anti-NMDA receptor encephalitis. Neurol Neuroimmunol Neuroinflamm 2020;7:e668. https://doi.org/10.1212/ NXI.0000000000000668 Demma L, Norris S, Dolak J. Neuraxial anesthesia in a patient with anti-N-methyl-D-aspartate receptor encephalitis in pregnancy: management for cesarean delivery and oophorectomy. Int J Obstet Anesth 2017;31:104–107.

Hyperekplexia

Hyperekplexia is a rare hereditary neurological disorder often misdiagnosed as a form of epilepsy, which can delay the diagnosis. It is characterized by an extreme startle reaction to sudden noises, movement, or touch. Jerking movements can also occur as the patient is trying to fall to sleep (hypnagogic myoclonic jerks).

Patients can be treated with clonazepam. For further information go to rarediseases.org (NORD). Chau A, Roitfarb M, Carabuena JM, et al. Anesthetic management of a parturient with hyperekplexia. AA Case Rep 2015;4:103–106.

Posterior Reversible Encephalopathy Syndrome (PRES)

Posterior reversible encephalopathy syndrome is a rare complication associated with headache, hypertension, and cortical blindness. Delay in diagnosis and treatment can lead to death or permanent neurologic deficits. It can be associated with seizures and so is often confused with PreE and eclampsia. Postpartum the headache may be misdiagnosed as PDPH. Treatment includes antihypertensives, magnesium infusion, and supportive therapy. Diagnosis is made by axial FLAIR MRI which shows foci of high signal intensity of cortical and subcortical white matter in various parts of the brain. Marcoccia E, Piccioni MG, Schiavi MC, et al. Postpartum posterior reversible encephalopathy syndrome (PRES): three case reports and literature review. Case Rep Obstet Gynecol 2019 (online). https://doi.org/10.1155/2019/9527632 Poma S, Delmonte MP, Gigliuto C, et al. Management of posterior reversible syndrome in preeclamptic women. Case Rep Obstet Gynecol 2014 (online). https://doi.org/10.1155/2014/928079

CNS Complications Associated with Neuraxial Anesthesia Velickovic IA, Pavlik R. Pneumocephalus complicated by postdural puncture headache after unintentional dural puncture. Anesth Analg 2007;104:747–748. Cohen S, Hunter CW, Sakr A, et al. Meningitis following intrathecal catheter placement after accidental dural puncture. Int J Obstet Anesth 2006;15:172. Liu G, Lee A, Withanawasam N, et al. Subdural hemorrhage post obstetric epidural: an MRI case report. Radiol Case Rep 2020;15:1584–1586. Lim G, Zorn JM, Dong YJ, et al. Subdural hematoma associated with labor epidural analgesia: a case series. Reg Anesth Pain Med 2016;41:628–631. Kapessidou Y, Vokaer M, Laureys M, et al. Case report: cerebral vein thrombosis after subarachnoid analgesia for labour. Can J Anaesth 2006;53:1015–1019. Green MS, George S, Green P, et al. Subdural hematoma following labor analgesia utilizing an intrathecal catheter. J Anesth 2014;28:302–303. Coll S, Murillo E, Serra B, et al. Postpartum meningitis by E. faecalis secondary to neuraxial anesthesia. Enferm Infecc Microbiol Clin 2020;2020:S0213005X(20)30247-0 Elshanawany AM, Wahab AHA. Intracranial acute subdural hematoma following spinal anesthesia: our experience with six patients. J Neurol Surg A Cent Eur Neurosurg 2020;81:44–47. Richa F, Chalhoub V, El-Hage C, et al. Subdural hematoma with cranial nerve palsies after obstetric analgesia. Int J Obstet Anesth 2015;24:390–391. del-Rio-Vellosillo M, Garcia-Medina JJ, Fernandez-Rodriguez LE, et al. Subdural hygroma accompanied by parenchymal and subarachnoid haemorrhage after epidural analgesia in an obstetric patient.Acta Anaesthesiol Scand 2014;58:897–902.

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Intracranial Tumors Paech MJ. An unusual presentation of a pituitary tumor in the early postpartum period. Anaesth Intensive Care 2006;34:79–82. Dyamanna DN, Bhakta P, Chouhan RS, et al. Anesthetic management of a patient with pituitary adenoma for caesarean section. Int J Obstet Anesth 2010;39:951–953. Remadevi R, Babu DD, Sureshkumar K, et al. Epidural anesthesia for caesarean section in a pregnant patient with pituitary macroadenoma. J Clin Diagn Res 2014;8:GD01–2. https://doi .org/10.7860/JCDR2014/9666.4552 Smith IF, Skelton V. An unusual intracranial tumor presenting in pregnancy. Int J Obstet Anesth 2007;16:82–85. Kasper EM, Hess PE, Silasi M, et al. A pregnant female with a large intracranial mass: reviewing the evidence to obtain management guidelines for intracranial meningiomas during pregnancy. Surg Neurol Int 2010;1:95. Jayasekera BA, Bacon AD, Whitfield PC. Management of glioblastoma multiforme in pregnancy. J Neurosurg 2012;116;1187–1194. Unterrainer AF, Steiner H, Kundt MJ. Caesarean section and brain tumor resection. Br J Anaesth 2011;107:111–112.

Anesthetic Techniques for Patients with Intracranial Pathology Allen G, Farling P, MaAtamney D. Anesthetic management of the pregnant patient for endovascular coiling of an unruptured intracranial aneurysm. Neurocrit Care 2006;4:18–20. Month RC, Vaida SJ. A combined spinal-epidural technique for labor analgesia and symptomatic relief in two parturients with idiopathic intracranial hypertension. Int J Obstet Anesth 2012;21:192–194. Rupasinghe MM, McLoughlin L, Singaraju V. Intracranial arachnoid cyst: anesthetic management in pregnancy. Int J Obstet Anesth 2007:16:265–268. Larkin C, Murphy F, Browne I. Anaesthetic management of pregnancy complicated by a symptomatic arachnoid cyst. Int J Obstet Anesth 2009;18:291–292. Month R, Vaida S, Budde A. Combined spinal-epidural anesthesia for cesarean delivery in a parturient with capillary pontine telangiectasia. Int J Obstet Anesth 2012;21:196–197. Month RC, Vaida SJ. Spinal anesthesia for cesarean delivery in a patient with cerebral venous sinus thrombosis. Can J Anaesth 2008;55:658–659. O’Neal MA. Obstetric anaesthesia: what the neurologist needs to know. Pract Neurol 2019;19:238–245. Hopkins AN, Alshaeri T, Akst SA, et al. Neurological disease with pregnancy and considerations for the obstetric anesthesiologist. Semin Perinatol 2014;38:359–369.

Other References

Arora G, Sahni N. Anesthetic management of a patient with Sheenan’s syndrome and twin pregnancy while undergoing a cesarean section. J Postgrad Med 2020;66:51–53. Kanani N, Goldszmidt E. Postpartum rupture of an intracranial aneurysm. Obstet Gynecol 2007;109:572–574. Ladhani NNN, Swartz RH, Foley N, et al. Canadian Stroke Best Practice Consensus Statement: Acute Stroke Management during Pregnancy. Int J Stroke 2018;13:743–758.

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62. Thomas JS, Koh SH, Cooper GM. Haemodynamic effects of oxytocin given as i.v. bolus or infusion on women undergoing Caesarean section. Br J Anaesth 2007;98:116–119. https://doi .org/:10.1093/bja/ael302 63. Hoffman KR, Chan SW, Hughes AR, et al. Management of cerebellar tonsillar herniation following lumbar puncture in idiopathic intracranial hypertension. Case Rep Crit Care 2015;2015:895035. https://doi.org/:10.1155/2015/895035 64. Paruchuri SR, Lawlor M, Kleinhomer K, et al. Risk of cerebellar tonsillar herniation after diagnostic lumbar puncture in pseudotumor cerebri. Anesth Analg 1993;77:403–404. https:// doi.org/:10.1213/00000539-199308000-00039 65. Julayanont P, Karukote A, Ruthirago D, et al. Idiopathic intracranial hypertension: ongoing clinical challenges and future prospects. J Pain Res 2016;9:87–99. https://doi .org/:10.2147/JPR.S60633 66. Worrell J, Lane S. Impact of pseudotumor cerebri (idiopathic intracranial hypertension) in pregnancy: a case report. AANA J 2007;75:199–204. 67. Aly EE, Lawther BK. Anaesthetic management of uncontrolled idiopathic intracranial hypertension during labour and delivery using an intrathecal catheter. Anaesthesia 2007;62:178–181. https://doi.org/:10.1111/j.1365-2044.2006.04891.x 68. Gragasin FS, Chiarella AB. Use of an intrathecal catheter for analgesia, anesthesia, and therapy in an obstetric patient with pseudotumor cerebri syndrome. A A Case Rep 2016;6:160–162. https://doi.org/:10.1213/xaa.0000000000000279 69. Heckathorn J, Cata JP, Barsoum S. Intrathecal anesthesia for cesarean delivery via a subarachnoid drain in a woman with benign intracranial hypertension. Int J Obstet Anesth 2010;19:109–111. https://doi.org/:10.1016/j.ijoa.2009.07.010 70. Kaul B, Vallejo MC, Ramanathan S, et al. Accidental spinal analgesia in the presence of a lumboperitoneal shunt in an obese parturient receiving enoxaparin therapy. Anesth Analg 2002;95:441–443. https://doi.org/:10.1097/00000539200208000-00038 71. Karmaniolou I, Petropoulos G, Theodoraki K. Management of idiopathic intracranial hypertension in parturients: anesthetic considerations. Can J Anaesth 2011;58:650. https://doi .org/:10.1007/s12630-011-9508-4 72. Freo U, Pitton M, Carron M, et al. Anesthesia for urgent sequential ventriculoperitoneal shunt revision and cesarean delivery. Int J Obstet Anesth 2009;18:284–287. https://doi .org/:10.1016/j.ijoa.2009.02.011 73. Geraldini F, De Cassai A, Ciccarino P, et al. Ultrasound as a useful tool in hydrocephalus management during pregnancy: a case report. A A Pract 2021;15:e01451. https://doi.org/:10.1213/ xaa.0000000000001451 74. Rajagopalan S, Gopinath S, Trinh VT, et al. Anesthetic considerations for labor and delivery in women with cerebrospinal fluid shunts. Int J Obstet Anesth 2017;30:23–29. https://doi.org/:10.1016/j.ijoa.2017.01.005 75. Liakos AM, Bradley NK, Magram G, et al. Hydrocephalus and the reproductive health of women: the medical implications of maternal shunt dependency in 70 women and 138 pregnancies. Neurol Res 2000;22:69–88. https://doi.org/:10.1080/01616412.2 000.11741040 76. Reschke M, Sweeney JM, Wong N. Spinal anesthesia performed for cesarean delivery after external ventricular drain placement in a parturient with symptomatology from an intracranial mass. Int J Obstet Anesth 2019;37:122–125. https://doi.org/:10.1016/ j.ijoa.2018.08.010

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77. Taylor CA, Bell JM, Breiding MJ, et al. Traumatic brain injuryrelated emergency department visits, hospitalizations, and deaths – United States, 2007 and 2013. MMWR Surveill Summ 2017;66:1–16. https://doi.org/:10.15585/mmwr.ss6609a1 78. Mendez-Figueroa H, Dahlke JD, Vrees RA, et al. Trauma in pregnancy: an updated systematic review. Am J Obstet Gynecol 2013;209:1–10. https://doi.org/:10.1016/j.ajog.2013.01.021 79. Leach MR, Zammit CG. Traumatic brain injury in pregnancy. Handb Clin Neurol 2020;172:51–61. https://doi.org/:10.1016/ B978-0-444-64240-0.00003-9 80. Jain V, Chari R, Maslovitz S, et al. Guidelines for the management of a pregnant trauma patient. J Obstet Gynaecol Can 2015;37:553–574. https://doi.org/:10.1016/s17012163(15)30232-2 81. Kazemi P, Villar G, Flexman AM. Anesthetic management of neurosurgical procedures during pregnancy: a case series. J Neurosurg Anesthesiol 2014;26:234–240. https://doi .org/:10.1097/ANA.0000000000000029 82. Lim G, Bader AM. Neurologic and neuromuscular disease. In: Chestnut DH, Wong CA, Tsen LC, et al. (Eds.), Chestnut’s Obstetric Anesthesia Principles and Practice (6th ed.). Philadelphia: Elsevier, 2020: 1160–1189. 83. Pandey A DP, Jadhav B, Nandanway YS. A rare case of pregnancy with Sturge-Weber syndrome. Int J Reprod Contracept Obstet Gynecol 2015;4:866–868. https://doi .org/:10.18203/2320-1770.ijrcog20150112 84. Luo Y, Yang Y, Chen X. A case report of a pregnant woman with Sturge-Weber syndrome. J Int Med Res 2020;48:300060520913708. https://doi.org/:10.1177/0300060520913708 85. Chabriat H, Pappata S, Traykov L, et al. Sturge-Weber angiomatosis responsible for hemiplegia without cerebral infarction in term pregnancy. Rev Neurol (Paris) 1996;152:536–541. 86. Dolkart LA, Bhat M. Sturge-Weber syndrome in pregnancy. Am J Obstet Gynecol 1995;173:969–971. https://doi .org/:10.1016/0002-9378(95)90383-6 87. Batra RK, Gulaya V, Madan R, et al. Anaesthesia and the SturgeWeber syndrome. Can J Anaesth 1994;41:133–136. https://doi .org/:10.1007/bf03009806 88. Aziz AS, Hui D, Chinnappa V, et al. Successful pregnancy, epidural anaesthesia, labour, and delivery in a woman with Sturge-Weber syndrome and previous hemispherectomy. J Obstet Gynaecol Can 2013;35:917–919. https://doi.org/:10.1016/ S1701-2163(15)30814-8 89. Tadrous R, Ni Mhuirchteagh R, McCaul C. Anaesthesia for caesarean section in a patient with Sturge-Weber syndrome following acute neurological deterioration. Int J Obstet Anesth 2011;20:259–262. https://doi.org/:10.1016/j.ijoa.2010.11.011 90. Waters JFR, O’Neal MA, Pilato M, et al. Management of anesthesia and delivery in women with Chiari I malformations. Obstet Gynecol 2018;132:1180–1184. https://doi.org/:10.1097/ aog.0000000000002943 91. Botelho RV, Bittencourt LR, Rotta JM, et al. Adult Chiari malformation and sleep apnoea. Neurosurg Rev 2005;28: 169–176. https://doi.org/:10.1007/s10143-005-0400-y 92. Prilipko O, Dehdashti AR, Zaim S, et al. Orthostatic intolerance and syncope associated with Chiari type I malformation. J Neurol Neurosurg Psychiatry 2005;76:1034–1036. https://doi .org/:10.1136/jnnp.2004.048330 93. Mueller DM, Oro J. Chiari I malformation with or without syringomyelia and pregnancy: case studies and review of the literature. Am J Perinatol 2005;22:67–70. https://doi .org/:10.1055/s-2005-837271

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94. Agustí M, Adàlia R, Fernández C, et al. Anaesthesia for caesarean section in a patient with syringomyelia and ArnoldChiari type I malformation. Int J Obstet Anesth 2004;13: 114–116. https://doi.org/:10.1016/j.ijoa.2003.09.005 95. Ghaly RF, Tverdohleb T, Candido KD, et al. Management of parturients in active labor with Arnold Chiari malformation, tonsillar herniation, and syringomyelia. Surg Neurol Int 2017;8:10. https://doi.org/:4103/2152-7806.198737 96. Limonadi FM, Selden NR. Dura-splitting decompression of the craniocervical junction: reduced operative time, hospital stay, and cost with equivalent early outcome. J Neurosurg 2004;101(2 Suppl):184–188. https://doi.org/:10.3171/ ped.2004.101.2.0184 97. Janjua MB, Haynie AE, Bansal V, et al. Determinants of Chiari I progression in pregnancy. J Clin Neurosci 2020;77:1–7. https:// doi.org/:10.1016/j.jocn.2020.05.026 98. Kuczkowski KM. Spinal anesthesia for Cesarean delivery in a parturient with Arnold-Chiari type I malformation. Can J Anaesth 2004;51:639. https://doi.org/:10.1007/bf03018412 99. Gruffi TR, Peralta FM, Thakkar MS, et al. Anesthetic management of parturients with Arnold Chiari malformation-I: a multicenter retrospective study. Int J Obstet Anesth 2019;37:52–56. https://doi.org/:10.1016/j.ijoa.2018.10.002 100. Hashimoto N, Tominaga T, Miyamoto S, et al. Guidelines for diagnosis and treatment of moyamoya disease (spontaneous occlusion of the circle of Willis). Neurol Med Chir (Tokyo) 2012;52:245–266. https://doi.org/:10.2176/nmc.52.245 101. Kuriyama S, Kusaka Y, Fujimura M, et al. Prevalence and clinicoepidemiological features of moyamoya disease in Japan: findings from a nationwide epidemiological survey. Stroke 2008;39:42–47. https://doi.org/:10.1161/ strokeaha.107.490714 102. Ahn IM, Park DH, Hann HJ, et al. Incidence, prevalence, and survival of moyamoya disease in Korea: a nationwide, population-based study. Stroke 2014;45:1090–1095. https://doi .org/:10.1161/strokeaha.113.004273 103. Church EW, Qaiser R, Bell-Stephens TE, et al. Pregnancy after direct cerebral bypass for moyamoya disease. J Neurosurg 2021;134:10–16. https://doi.org/:10.3171/2019.8.jns191372 104. Maragkos GA, Ascanio LC, Chida K, et al. Moyamoya disease in pregnancy: a systematic review. Acta Neurochir (Wien) 2018;160:1711–1719. https://doi.org/:10.1007/s00701-0183597-6 105. Takahashi JC, Ikeda T, Iihara K, et al. Pregnancy and delivery in moyamoya disease: results of a nationwide survey in Japan. Neurol Med Chir (Tokyo) 2012;52:304–310. https://doi .org/:10.2176/nmc.52.304 106. Fujimura M, Akagi K, Uenohara H, et al. Moyamoya disease in pregnancy: a single institute experience. Neurol Med Chir (Tokyo) 2013;53:561–564. https://doi.org/:10.2176/ nmc.53.561 107. Dutta B, Dehran M, Sinha R. Anaesthetic management of a parturient with moyamoya disease. Singapore Med J 2011;52:e108–110. 108. Robertson MM, Eapen V, Cavanna AE. The international prevalence, epidemiology, and clinical phenomenology of Tourette syndrome: a cross-cultural perspective. J Psychosom Res 2009;6:475–483. https://doi.org/:10.1016/j .jpsychores.2009.07.010 109. Stern JS, Orth M, Robertson MM. Gilles de la Tourette syndrome in pregnancy: a retrospective series. Obstet Med 2009;3:128–129.

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110. Lewin AB, Murphy TK, Storch EA, et al. A phenomenological investigation of women with Tourette or other chronic tic disorders. Compr Psychiatry 2012;53:525–534. https://doi .org/:10.1016/j.comppsych.2011.07.004 111. Ba F, Miyasaki JM. Movement disorders in pregnancy. Handb Clin Neurol 2020;172: 219–239. https://doi.org/:10.1016/ b978-0-444-64240-0.00013-1 112. Einarson A, Boskovic R. Use and safety of antipsychotic drugs during pregnancy. J Psychiatr Pract 2009;15:183–192. https:// doi.org/:10.1097/01.pra.0000351878.45260.94 113. Sener EB, Kocamanoglu S, Ustun E, et al. Anesthetic management for cesarean delivery in a woman with Gilles de la Tourette’s syndrome. Int J Obstet Anesth 2006;15:163–165. https://doi.org/:10.1016/j.ijoa.2005.07.004 114. Longstreth WT, Jr., Koepsell TD, Ton TG, et al. The epidemiology of narcolepsy. Sleep 2007;30:13–26. https://doi .org/:10.1093/sleep/30.1.13 115. Maurovich-Horvat E, Kemlink D, Högl B, et al. Narcolepsy and pregnancy: a retrospective European evaluation of 249 pregnancies. J Sleep Res 2013;22:496–512. https://doi .org/:10.1111/jsr.12047 116. Oyiengo D, Louis M, Hott B, et al. Sleep disorders in pregnancy. Clin Chest Med 2014;35:571–587. https://doi.org/:10.1016/ j.ccm.2014.06.012 117. Ping LS, Yat FS, Kwok WY. Status cataplecticus leading to the obstetric complication of prolonged labor. J Clin Sleep Med 2007;3:56–57. 118. McLafferty LP, Spada M, Gopalan P. Pharmacologic treatment of sleep disorders in pregnancy. Sleep Med Clin 2018;13: 243–250. https://doi.org/:10.1016/j.jsmc.2018.02.004 119. Thorpy M, Zhao CG, Dauvilliers Y. Management of narcolepsy during pregnancy. Sleep Med 2013;14:367–376. https://doi .org/:10.1016/j.sleep.2012.11.021 120. Calvo-Ferrandiz E, Peraita-Adrados R. Narcolepsy with cataplexy and pregnancy: a case-control study. J Sleep Res 2018;27:268–272. https://doi.org/:10.1111/jsr.12567

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121. Soltanifar S, Russell R. Neuraxial anaesthesia for caesarean section in a patient with narcolepsy and cataplexy. Int J Obstet Anesth 2010;19:440–443. https://doi.org/:10.1016/ j.ijoa.2010.07.015 122. Galun E, Ben-Yehuda A, Berlatzki J, et al. Insulinoma complicating pregnancy: case report and review of the literature. Am J Obstet Gynecol 1986;155:64–65. https://doi .org/:10.1016/0002-9378(86)90079-7 123. Confino E, Ismajovich B, David MP, et al. Fetal heart rate in maternal hypoglycemic coma. Int J Gynaecol Obstet 1985;23:59–60. https://doi.org/:10.1016/0020-7292(85) 90013-x 124. Romagano MP, Scorza WE, Lammers SE, et al. Treatment of a pregnant patient in a persistent vegetative state. Obstet Gynecol 2017;129:107–110. https://doi.org/:10.1097/ aog.0000000000001759 125. Ceccaldi PF, Bazin A, Gomis P, et al. Persistent vegetative state with encephalitis in a pregnant woman with successful fetal outcome. BJOG 2005;112:843–844. https://doi.org/:10.1111/ j.1471-0528.2004.00543.x 126. Lee JE, George RB, Habib AS. Spinal-induced hypotension: incidence, mechanisms, prophylaxis, and management: summarizing 20 years of research. Best Pract Res Clin Anaesthesiol 2017;31:57–68. https://doi.org/:10.1016/ j.bpa.2017.01.001 127. Bellos I, Pergialiotis V, Papapanagiotou A, et al. Comparative efficacy and safety of oral antihypertensive agents in pregnant women with chronic hypertension: a network metaanalysis. Am J Obstet Gynecol 2020;223:525–537. https://doi.org/:10.1016/ j.ajog.2020.03.016 128. Qaiser R, Black P. Neurosurgery in pregnancy. Semin Neurol 2007;27:476–481. https://doi.org/:10.1055/s-2007-991129 129. Hopkins AN, Alshaeri T, Akst SA, et al. Neurologic disease with pregnancy and considerations for the obstetric anesthesiologist. Semin Perinatol 2014;38:359–369. https://doi.org/:10.1053/ j.semperi.2014.07.004

Chapter

15

Spinal Cord Disorders Roanne Preston and Jonathan Collins

Valuable Clinical Insights • P regnant women with spinal cord disorders are uncommon. However, with improved acute injury care and surgical repair of open spinal dysraphism, there is an increasing number of adult women with chronic spinal cord disorders. • Neuroimaging techniques have vastly improved in quality and accessibility, and MRI is acceptable in pregnancy; this has led to a substantial increase in diagnoses of spinal cord tumors and vascular malformations. • Adult tethered cord syndrome is an increasingly recognized entity and poses specific considerations for neuraxial anesthesia. • Many infectious agents can cause transverse myelitis, most notably Zika virus, and if untreated, may result in permanent neurologic impairment.

Spinal Cord Injury Introduction The incidence of spinal cord injury (SCI) is 54 per million in the United States, or approximately 17,900 new cases annually. Around half are aged between 16 and 30, and 20% are female.1 Advances in acute and rehabilitative care have led to improved outcomes, with those affected able to attain higher levels of independent function after SCI than was previously possible; SCI patients are encouraged to work, establish relationships, and start or continue families. Regardless of the level of injury, transient disturbance of the hypothalamic pituitary axis appears to cause around half of the women to experience 5–12 months of temporary amenorrhea after SCI,2,3 with approximately 15% becoming menopausal.4 However, long-term fertility usually is not affected, and pregnancy in SCI patients is not rare. In a 1999 survey of 472 women with SCI,4 14% became pregnant after their injury (60% for the first time). In a case series of 68 pregnancies in 50 women with SCI from the United Kingdom,5 five sustained SCI during pregnancy, and the other 63 pregnancies were conceived at least one year after SCI, the majority > 10 years post injury. Since the first published report of successful pregnancy in a quadriplegic patient in 1953,6 there have been numerous articles on caring for the pregnant SCI patient, alongside regularly updated guidelines published by ACOG.7 While much of the literature focuses

on chronic SCI, there are reports on the management of pregnant women with acute SCI.8–14 Knowledge of the pathophysiology of SCI and the implications of pregnancy on the medical complications of SCI are paramount to caring for this complex population.

Acute Spinal Cord Injury during Pregnancy Motor vehicle crashes are the most common cause of SCI in the United States.1 Although the physiological changes of pregnancy appear to reduce trauma-related mortality compared to nonpregnant female counterparts,15 trauma remains the leading cause of nonobstetric maternal mortality.16 There are several considerations unique to the pregnant trauma patient, including the risk of Rhesus alloimmunization, placental abruption, and preterm labor. Traumatic SCI sustained during pregnancy may lead to pregnancy loss or fetal abnormalities.17 Injury during or after the second trimester is associated with worse outcomes, possibly from uterine trauma and placental abruption16 or, rarely, direct fetal trauma (< 1%).18 Less common causes of acute SCI include compression from epidural hematoma, abscess, tumor, and degenerative disease.

Pathophysiology The initial phase of acute SCI is well described, with an immediate onset and a duration of three to six weeks. Below the level of the lesion, there is flaccid paralysis, loss of sensory and motor function, and “spinal shock” caused by the sudden interruption of sensory, motor, and sympathetic neurons. There is accompanying loss of temperature regulation and spinal reflexes. Cardiovascular effects include profound hypotension, marked bradycardia due to unopposed parasympathetic tone, and other dysrhythmias. In the acute resuscitation of the obstetric trauma patient, fetal heart rate (FHR) monitoring provides reassuring information about the fetus and may contribute to maternal hemodynamic assessment.16 Due to loss of vasomotor tone, the extremities lose heat rapidly if left exposed, and dependent edema develops. There may be prolonged paralytic ileus. Cervical injuries above C5 usually mandate prolonged or permanent ventilatory support,19 while lower cervical lesions may require ventilation until the thoracic cage muscles recover. Acute phrenic nerve injury may follow cervical spine trauma, leading to transient unilateral diaphragmatic paralysis.20 Patients sustaining high thoracic injuries may

231 https://doi.org/10.1017/9781009070256.016 Published online by Cambridge University Press

Roanne Preston and Jonathan Collins

be unable to cough or clear the airway of secretions, increasing their susceptibility to aspiration and pneumonia. Following the stage of flaccid paralysis, SCI patients usually develop exaggerated reflexes with muscle spasms, upper motor neuron injury-pattern tendon reflexes, and autonomic dysreflexia.

surrounding early intervention include hemodynamic instability from spinal shock and difficulties with positioning. A threequarters prone position has been used for patients in the latter stages of pregnancy.27 High-dose corticosteroids, once a mainstay of SCI management, remain controversial due to conflicting evidence supporting both beneficial and deleterious effects.28 Pregnancy is not considered a contraindication to this therapy. Serial clinical examination using the American Spinal Injury Association (ASIA) International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI) allows for characterization of the extent of the injury according to the fivepoint ASIA scale (Figure 15.1). Note that the ASIA classification may be inaccurate during the very early period (8–12 hours), as the primary (traumatic disruption of spinal cord fibers) and secondary (inflammation and progression of axonal damage) phases occur. The true extent of the injury may become apparent later.23

Acute Management Management of the patient with suspected SCI starts at the injury scene and should ideally result in transfer to a major trauma center.21 Spinal cord injury is likely to coexist with other major, potentially life-threatening injuries.22 Canadian guidelines16 state that one must consider all female trauma patients of reproductive age pregnant until proven otherwise. The primary survey of the pregnant trauma patient with a viable fetus should include FHR monitoring. When SCI is confirmed, early patient transfer to a specialist SCI center is associated with improved outcomes.21 In nonpregnant patients, early decompressive surgery may improve neurological outcomes.23 While there is a paucity of literature regarding the neurosurgical management of acute traumatic SCI in patients with viable pregnancies, most authors favor early surgical intervention according to the same principles as the nonpregnant population.8,9,11,24–26 Concerns

MOTOR

KEY SENSORY POINTS

KEY SENSORY POINTS

Light Touch (LTR) Pin Prick (PPR)

Light Touch (LTL) Pin Prick (PPL)

C2 C3 C4

C2 C3

C4 T2 C5

T4 T5 T6

L2 L3 L4 Long toe extensors L5 S1

(Lower Extremity Right)

T8

T1

T9

Dorsum

C6

T10 T11 T12 L1

Palm

S3

L 2

S2

L3

L 3

SENSORY

(SCORING ON REVERSE SIDE) 0 = Absent 1 = Altered 2 = Normal

(50)

(56)

S2 S3 S4-5 (56) SENSORY SUBSCORES

(56)

= UEMS TOTAL

NEUROLOGICAL LEVELS

(50) 1. SENSORY 2. MOTOR

+ LEL

LER

(25)

R

MAX (25)

L

LTR

= LEMS TOTAL (25)

3. NEUROLOGICAL LEVEL OF INJURY (NLI)

(50)

MAX

+ LTL (56)

(56)

4. COMPLETE OR INCOMPLETE?

Incomplete = Any sensory or motor function in S4-5

5. ASIA IMPAIRMENT SCALE (AIS)

LEFT TOTALS (MAXIMUM)

PPR (112)

LEL

(Lower Extremity Left)

(DAP) Deep Anal Pressure (Yes/No)

(50)

= LT TOTAL (56)

NT = Not testable 0*, 1*, NT* = Non-SCI condition present

L2 L3 Knee extensors L4 L5 Long toe extensors S1

S1

MOTOR SUBSCORES

Page 1/2

MOTOR

(SCORING ON REVERSE SIDE)

L5

L5

S2 S3 S4-5

UEL

(Upper Extremity Left)

0 = Total paralysis 1 = Palpable or visible contraction 2 = Active movement, gravity eliminated 3 = Active movement, against gravity 4 = Active movement, against some resistance 5 = Active movement, against full resistance NT = Not testable 0*, 1*, 2*, 3*, 4*, NT* = Non-SCI condition present

L4

RIGHT TOTALS (MAXIMUM)

as on reverse

Key Sensory Points

L2

S4-5

L 4

(VAC) Voluntary Anal Contraction (Yes/No)

+UEL

T2 T3 T4 T5 T6 T7 T8 T9 T10 T11 T12 L1

T7

C8

T2 T3 T4 T5 T6 T7 T8 T9 T10 T11 T12 L1

Knee extensors

LER

MAX (25)

C5 C6 Wrist extensors C7 Elbow extensors C8 T1

C3

T3

LEFT

MOTOR

KEY MUSCLES

C2 C3 C4

C2

C4

Comments (Non-key Muscle? Reason for NT? Pain? Non-SCI condition?):

UER

Signature

SENSORY

C6

(Upper Extremity Right)

Examiner Name

C7

UER

Date/Time of Exam

SENSORY

KEY MUSCLES

C5 Wrist extensors C6 Elbow extensors C7 C8 T1

Following the initial period of spinal shock, the situation stabilizes as chronic SCI. Nearly 50% of SCIs are classified as

Patient Name

INTERNATIONAL STANDARDS FOR NEUROLOGICAL CLASSIFICATION OF SPINAL CORD INJURY (ISNCSCI)

RIGHT

Medical Complications in Chronic Spinal Cord Injury and the Impact of Pregnancy

+ PPL

MAX (56)

= PP TOTAL (112)

(56)

(In injuries with absent motor OR sensory function in S4-5 only)

6. ZONE OF PARTIAL SENSORY PRESERVATION MOTOR

R

L

Most caudal levels with any innervation

This form may be copied freely but should not be altered without permission from the American Spinal Injury Association.

REV 04/19

Figure 15.1  American Spinal Injury Association: International Standards for Neurological Classification of Spinal Cord Injury, revised 2019; Richmond, VA. Reprinted with permission.

232 https://doi.org/10.1017/9781009070256.016 Published online by Cambridge University Press

Spinal Cord Disorders

Muscle Function Grading

0 = Total paralysis 1 = Palpable or visible contraction 2 = Active movement, full range of motion (ROM) with gravity eliminated 3 = Active movement, full ROM against gravity 4 = Active movement, full ROM against gravity and moderate resistance in a 5 = (Normal) active movement, full ROM against gravity and full resistance in a

functional muscle position expected from an otherwise unimpaired person NT = Not testable (i.e. due to immobilization, severe pain such that the patient cannot be graded, amputation of limb, or contracture of > 50% of the normal ROM) 0*, 1*, 2*, 3*, 4*, NT* = Non-SCI condition present a

Sensory Grading

0 = Absent 1 = Altered, either decreased/impaired sensation or hypersensitivity 2 = Normal NT = Not testable 0*, 1*, NT* = Non-SCI condition present a Note: Abnormal motor and sensory scores should be tagged with a ‘*’ to indicate an impairment due to a non-SCI condition. The non-SCI condition should be explained in the comments box together with information about how the score is rated for a

When to Test Non-Key Muscles:

A = Complete. No sensory or motor function is preserved in the sacral segments S4-5. B = Sensory Incomplete. Sensory but not motor function is preserved below the neurological level and includes the sacral segments S4-5 (light touch or pin prick at S4-5 or deep anal pressure) AND no motor function is preserved more than three levels below the motor level on either side of the body.

C = Motor Incomplete. Motor function is preserved at the most caudal sacral segments for voluntary anal contraction (VAC) OR the patient meets the criteria for sensory incomplete status (sensory function preserved at the most caudal sacral segments S4-5 by LT, PP or DAP), and has some sparing of motor function more than three levels below the ipsilateral motor level on either side of the body. (This includes key or non-key muscle functions to determine motor incomplete status.) For AIS C – less than half of key muscle functions below the single NLI have a muscle grade ≥ 3. D = Motor Incomplete. Motor incomplete status as

more than 3 levels below the motor level on each side should be tested to most accurately classify the injury (differentiate between AIS B and C).

Movement

ASIA Impairment Scale (AIS)

Root level

Shoulder: Flexion, extension, adbuction, adduction, internal and external rotation Elbow: Supination

C5

Elbow: Pronation Wrist: Flexion

C6

Finger: Flexion at proximal joint, extension Thumb: Flexion, extension and abduction in plane of thumb

C7

Finger: Flexion at MCP joint Thumb: Opposition, adduction and abduction perpendicular to palm

C8

Finger:

T1

Hip: Adduction

L2

Hip: External rotation

L3

Hip: Extension, abduction, internal rotation Knee: Flexion Ankle: Inversion and eversion Toe: MP and IP extension

L4

functions below the single NLI having a muscle grade ≥ 3.

E = Normal. If sensation and motor function as tested with the ISNCSCI are graded as normal in all segments, and the without an initial SCI does not receive an AIS grade.

Using ND: To document the sensory, motor and NLI levels,

Hallux and Toe:

L5

Hallux: Adduction

S1

the ASIA Impairment Scale grade, and/or the zone of partial preservation (ZPP) when they are unable to be determined based on the examination results.

individuals with SCI.

1. Determine sensory levels for right and left sides.

The sensory level is the most caudal, intact dermatome for both pin prick and light touch sensation.

2. Determine motor levels for right and left sides.

least 3 (on supine testing), providing the key muscle functions represented by segments above that level are judged to be intact (graded as a 5). Note: in regions where there is no myotome to test, the motor level is presumed to be the same as the sensory level, if testable motor function above that level is also normal.

3. Determine the neurological level of injury (NLI).

This refers to the most caudal segment of the cord with intact sensation and antigravity (3 or more) muscle function strength, provided that there is normal (intact) sensory and motor function rostrally respectively. The NLI is the most cephalad of the sensory and motor levels determined in steps 1 and 2.

4. Determine whether the injury is Complete or Incomplete.

(i.e. absence or presence of sacral sparing) If voluntary anal contraction = No AND all S4-5 sensory scores = 0 AND deep anal pressure = No, then injury is Complete. Otherwise, injury is Incomplete.

5. Determine ASIA Impairment Scale (AIS) Grade. Is injury Complete? If YES, AIS=A Is injury Motor Complete? If YES, AIS=B (No=voluntary anal contraction OR motor function more than three levels below the motor level on a given side, if the patient has sensory Are at least half (half or more) of the key muscles below the neurological level of injury graded 3 or better?

If sensation and motor function is normal in all segments, AIS=E

INTERNATIONAL STANDARDS FOR NEUROLOGICAL CLASSIFICATION OF SPINAL CORD INJURY

Page 2/2

Note: AIS E is used in follow-up testing when an individual with a documented cits are found, the individual is neurologically intact and the ASIA Impairment Scale does not apply.

6. Determine the zone of partial preservation (ZPP).

The ZPP is used only in injuries with absent motor (no VAC) OR sensory function (no DAP, no LT and no PP sensation) in the lowest sacral segments S4-5, and refers to those dermatomes and myotomes caudal to the sensory and motor levels that remain partially innervated. With sacral sparing of sensory function, the sensory ZPP is not applicable and therefore “NA” is recorded in the block of the worksheet. Accordingly, if VAC is present, the motor ZPP is not applicable and is noted as “NA.”

Figure 15.1 (cont.)

incomplete, meaning that some motor power and sensation remain below the level of injury. Most of the remainder are complete injuries that functionally resemble complete cord transection. Fewer than 1% of patients have complete neurological recovery at the time of hospital discharge.1 Most neurological improvement is made within the first year post injury, although some patients continue to make slow progress over subsequent years;29 complications are related to the final level of injury (Figure 15.2). Patients with cervical and high thoracic injury levels typically have impaired pulmonary function with decreased respiratory reserve. This results in poor cough and predisposes to recurrent pulmonary infection. There is an increase in the standardized mortality ratio for pneumonia and influenza in SCI patients, with the risk of death increasing with higher injury levels (greater ventilatory dysfunction).30,31 Chronic or recurrent UTI, secondary to neurogenic urinary tract dysfunction nearly ubiquitous in SCI patients, may lead to deterioration in renal function.32 Intermittent catheterization for neurogenic bladder dysfunction results in less morbidity than indwelling catheters, but catheterization frequency often increases as gestation advances. Deep vein thrombosis and decubitus ulcers are persistent concerns in wheelchair bound patients. Anemia of chronic disease is common,33 and iron supplements may cause deterioration in bowel function. Most SCI patients have low BP

due to sympathetic nervous system dysfunction, altered baroreceptor activity, lack of skeletal muscle pump activity, cardiovascular deconditioning, and contracted plasma volume secondary to altered sodium and water homeostasis.34 Pregnancy may aggravate many of these conditions. In addition to the complications of SCI not exclusive to pregnancy (UTI, falls, pneumonia, anemia, VTE, and increased spasticity), pregnant patients with SCI present an increased risk of preterm labor, unattended delivery, and postpartum depression.35 As weight increases and ligaments become more lax, mobility gets more difficult. In one study, 11% of SCI women were unable to transfer independently at the end of their pregnancy, and 4.5% could not propel their wheelchairs.36 Cough mechanics with SCI are further compromised by the respiratory changes of pregnancy, such as low functional residual capacity and expiratory reserve volume. The expanding uterus limits diaphragmatic excursion. This is particularly important in the patient with cervical cord injury who may depend entirely upon her diaphragm for respiratory function due to loss of intercostal muscle function. Of note, however, and in contrast to patients without SCI, patients with tetraplegia frequently report less breathlessness in the supine position than when seated; the weight of the abdominal contents displaces the diaphragm into a higher resting position such that its contraction produces greater excursion and increases vital capacity (VC).37 Even in the

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Figure 15.2  Complications of pregnancy in the SCI patient both specific and unrelated to level of injury.

non-SCI patient, labor puts a huge demand on ventilation and may cause acute diaphragmatic fatigue.38 Although such fatigue does not cause clinical deterioration in a healthy parturient, labor may not be tolerated in the SCI patient. Conversely, much of the increased minute ventilation in labor is brought on by pain, and patients with cord injuries may be spared both the pain and the resultant increased ventilatory demands.

Management of the Parturient with Chronic Spinal Cord Injury Patients with chronic SCI should have a multidisciplinary medical assessment before conception to assess the impact of their SCI on pregnancy and vice versa.7 Many SCI patients take medications for spasticity, such as baclofen, diazepam, tizanidine, and dantrolene. Though baclofen has been used during pregnancy without untoward effects, animal studies have demonstrated fetal abnormalities.39 A neonatal baclofen withdrawal syndrome is described,40 and a personal risk/benefit analysis must be made regarding its

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continuation. Of note, baclofen may be delivered intrathecally via an implanted pump;41 this may have implications on decision-making regarding the provision of NA. Benzodiazepines have been associated with increased incidence of oral clefts, although a meta-analysis is reassuring about other major malformations.42 A Norwegian cohort study associated gestational benzodiazepine exposure with small reductions in birth weight and gestational age at the time of birth and an increased risk of preterm labor.43 Recognizing the addictive potential of these drugs, decisions regarding ongoing use during pregnancy are individualized. Like baclofen and diazepam, tizanidine and dantrolene belong to the USA FDA Category C, meaning that when considering their use, the benefit should outweigh the risk. Evaluate pulmonary function early in pregnancy to identify women at risk of respiratory deterioration during later stages of pregnancy and labor. Pulmonary function tests and respiratory consultation are required if there is evidence of compromise.

Spinal Cord Disorders

Some patients, previously able to breathe independently, will require ventilator assistance during late pregnancy. As in the non-SCI population, smoking contributes to respiratory problems, and every effort is made to assist the SCI patient to stop smoking. Obstetrical Management Women with SCI may deliver vaginally, with one case series demonstrating a 77% vaginal delivery rate (14% instrumental delivery).5 Cesarean delivery is reserved for obstetrical indications. Preterm labor is more common in SCI parturients and is treated with beta adrenergic tocolytics and magnesium sulfate; there is a risk of precipitating respiratory failure with the latter due to its muscle relaxant effects. Women with complete lesions above T10 are at risk for an unexpected and unattended delivery, especially if labor begins while asleep.35 If awake when labor begins, other symptoms, such as increased spasticity during contractions or symptoms of autonomic dysreflexia, may alert the woman to the onset of labor. Some centers offer routine admission at 37 weeks gestation to prevent unattended delivery,44 others use frequent tocodynamometry and cervical examination as term approaches.12 Home uterine activity monitoring starting at 26–28 weeks gestation is a monitoring method that enables the woman to remain at home.45 During labor, continue specific nursing care for SCI, such as frequent turning to prevent pressure sores and optimal bladder care.

Autonomic Dysreflexia Autonomic dysreflexia (also called autonomic hyperreflexia or the mass autonomic response) was first recognized in 1890,46 but was not well described until 1947 when Guttmann and Whitteridge reported on the effects of bladder distension in SCI.47 It is a life-threatening reflex caused by a massive unbalanced sympathetic response to noxious stimuli below the level of the injury. Most seen in patients with complete spinal cord injuries at T6 or above 48 (up to 90% incidence), it is less common in patients with lesions between T5 and T9 (50–65%) and is rare with lesions below T10. While autonomic dysreflexia usually presents in the first three to six months after SCI, some patients will present with symptoms within a month of injury. Some patients are asymptomatic for over a decade before features first present.49,50 The consequences of untreated autonomic dysreflexia are severe: systolic BP may rise to 200–300 mmHg, giving rise to complications including MI, intracranial and retinal hemorrhage, cardiac dysrhythmias, and fetal hypoxemia.51 The reflex is often brought on by a noxious stimulus below the level of the injury. Recurrent episodes of autonomic dysreflexia without an obvious precipitant may point toward undetected pathology.48 An exaggerated thoracolumbar sympathetic response follows due to hyperexcitability below the lesion and a lack of descending modulation. There is mass vasoconstriction of the splanchnic, cutaneous, and muscular circulations. In the spinal levels above the lesion, compensatory reflex vasodilation occurs but with lesions above the midthoracic level, there is insufficient vasodilator reserve to counteract the vasoconstriction, and severe systemic hypertension ensues. The baroreceptor reflex causes bradycardia and vasodilation above

the lesion. Clinical signs and symptoms include severe hypertension, bradycardia, headache, diaphoresis, blurred vision, increased skin temperature, facial flushing, and nasal congestion. While triggers for autonomic dysreflexia are numerous and frequently include stimuli to the genitourinary tract, bowel, and lower extremities, common precipitants in obstetric patients include pelvic examinations and uterine contractions. Autonomic dysreflexia can occur for the first time during parturition. Because maximal noxious stimulation occurs in the perineal region, it may not present until the late first stage or early second stage of labor. Autonomic dysreflexia may manifest as episodic headaches synchronous with contractions,50 with headache resolution an indicator of NA efficacy. ACOG guidelines emphasize the importance of NA for the prevention of autonomic dysreflexia.7 If lumbar epidural analgesia (LEA) is not immediately available, parenteral vasodilators should be available. For labor induction, patients at high risk for autonomic dysreflexia should have a preinduction epidural. Avoid ergonovine in the third stage because the side effects of hypertension and dysrhythmias mimic the diagnosis of autonomic dysreflexia. The differential diagnosis of hypertension in SCI parturients is PreE, but SCI patients do not appear predisposed to it. The two syndromes are usually distinguishable clinically because of the sudden onset of autonomic dysreflexia, and the hypertension is often episodic in autonomic dysreflexia, coinciding with contractions. The presence or absence of laboratory findings characteristic of PreE help to confirm the diagnosis.50 Acute hypertension is treated with a variety of agents. First-line agents in pregnant patients include nifedipine (oral or sublingual), nitroglycerin (sublingual or transdermal), hydralazine, prazosin, and labetalol.52 As nitroprusside may cause fetal cyanide toxicity and, alongside ganglion blockers such as trimethaphan, severe hypotension,53 these agents are used rarely and with extreme caution. Clonidine may be helpful when spasticity is a concurrent problem.19 Magnesium sulfate has been used to treat autonomic dysreflexia.54 Because the hypertension may be episodic in labor-induced autonomic dysreflexia, maternal BP may be very high during contractions despite antihypertensive medication, then very low in the intervening period before the onset of the next contraction. Beta blockers are generally not recommended because of concerns about fetal hypoxemia,55 but the combined alpha and beta blocking agent labetalol is commonly used.

Anesthetic Management of Labor and Delivery Problems in SCI patients of relevance to the anesthesiologist include: • an increased incidence of premature labor and painless precipitous labors • the need for pain relief in labor • the occurrence of muscle spasms in labor • the requirement for assisted delivery • prophylaxis for autonomic dysreflexia • potential for hypotension, and • hyperkalemia with succinylcholine in those with subacute injury.

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Antepartum anesthesia consultation should be routine for parturients with SCI. During this visit, the requirement and options for analgesia including the risk and benefits of the different methods are discussed. Address concerns about worsening symptoms following NA. The risk of major neurological injury in healthy patients is very low, usually secondary to direct cord trauma, epidural hematoma, or neurotoxic effects of agents. Spinal-cord-injured patients are not at increased risk of these methods of injury, and the benefits of NA, especially in those at risk of autonomic dysreflexia, are highly significant. Patients with an injury level below T10 generally experience labor pain. Those with incomplete lesions between T6 and T10 may not have typical labor pain but may have spasms with contractions. Patients with complete injury levels above T6 have painless labors and are at high risk for autonomic dysreflexia. There remains the question as to when to initiate LEA. Given the potential for serious morbidity resulting from autonomic dysreflexia, the prevalent opinion is that prevention is the best cure and that NA is instituted early.7 If planned, induction of labor starts after placing an epidural. It is reasonable to begin with dilute LA solutions to minimize hypotensive effects. Bupivacaine has been used extensively in varying concentrations. A solution of 0.08–0.125% with or without added fentanyl and using the institutional method (PCEA, PIEB) is appropriate. Epidural fentanyl as the sole agent was ineffective in one report;56 therefore if fentanyl is employed it should be used as an adjunct to LA. Regular BP checks and assessments of the upper extent of the block are important. If the block’s upper extent is below the level of the lesion, it may be difficult to define unless segmental abdominal reflexes are still intact. In these cases, lightly stroking the sides of the abdomen above and below the umbilicus will initiate muscular contraction, causing the umbilicus to move toward the stimulus. While NA will stop this reflex activity, it may be difficult to determine in practice. In patients with spasticity, the block level becomes apparent with a change in muscle tone from spasticity to flaccid paralysis. Invasive monitors are not routinely required. Pulse oximetry is useful in patients with high cord lesions receiving neuraxial opioids. Securing the epidural catheter well is essential, due to the likelihood of increased sweating secondary to autonomic dysreflexia. Autonomic dysreflexia may occur up to 48 hours postpartum, so the epidural catheter should remain in situ after delivery.53 Notably, unlike patients with open spinal dysraphism, adults with SCI do not appear susceptible to latex sensitization or allergy and therefore do not require special protocols when presenting for medical interventions.57 Valuable Clinical Insights • Pregnancy in spinal-cord-injured patients is not rare. • Safe obstetrical management of the SCI patient requires a multidisciplinary approach, ideally starting prior to conception. • Autonomic dysreflexia is a life-threatening complication of spinal cord injury, which may be prevented by effective neuraxial anesthesia. • Succinylcholine is contraindicated from approximately two days to one year after injury.

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Neuraxial Anesthesia in Spinal Cord Injury Neither stable neurological disease nor a history of major spinal surgery represents an absolute contraindication to NA. Abnormal anatomy and the presence of surgical hardware may cause technical difficulties. While many patients undergo uncomplicated procedures,58 epidural fibrosis59 may increase the risk of accidental dural puncture (ADP) or inadequate and failed blocks. Although the combined effects of SCI and pregnancy mean that hypotension is a risk with NA, patients with SCI are already near maximally vasodilated at baseline. Therefore, modern low concentration LEA negates the need for a mandatory pre-epidural fluid bolus. Treatment of hypotension involves IV fluids and, if needed, careful administration of vasopressors. Both ephedrine and phenylephrine are safe. If the woman has autonomic dysreflexia and has received antihypertensive agents, care is needed with subsequent use of vasopressors. Ephedrine may have reduced efficacy in the presence of beta-blockade and an exaggerated effect with ganglion blocking agents. An inadvertently high thoracic block is not tolerated in patients with preexisting ventilatory dysfunction. In these patients, techniques that allow LA titration are best: epidural and spinal catheters. Spinal anesthesia can be employed for SCI parturients, with the caveat that it may be harder to control anesthesia levels, and hypotension may be more problematic. However, a spinal block consistently provides better sacral anesthesia than an epidural block, which may represent an advantage when reliable sacral anesthesia is required. Given the inherent difficulties with assessing the extent of NA in an insensate patient, the ability to identify and aspirate CSF is reassuring. Nursing assistance will be required to position and support the patient for epidural and spinal insertion. Patient assessment of mobility, and the presence of contractures or spasms, will determine the best position for NA administration. This author (JC) has found that for nonpregnant wheelchair users, it can be helpful to seat the patient at the head end of a stretcher with side rails, instructing her to lean forward and hold the rails in the same way that she would propel herself in her chair. This helps to counter the lumbar lordosis, although a gravid uterus may make this challenging. Once an epidural block is established, the patient should be repositioned frequently to prevent pressure sores. Anesthesia for Cesarean Delivery The choice of anesthetic technique for CD is determined by maternal condition and whether anesthesia is required for autonomic dysreflexia prophylaxis alone or for pain relief. A neuraxial block is required to provide autonomic dysreflexia prophylaxis in patients with high cord injury (above T6). Encourage gentle surgical manipulation of the viscera to minimize visceral stimulation and avoid uterine exteriorization, thereby reducing the risk of inducing autonomic dysreflexia. Neuraxial anesthesia has benefits in the postpartum period as effective analgesia is obtained with neuraxial opioids, and epidural catheters can remain in place for postoperative analgesia. Spinal anesthesia may be technically easier to perform than epidural anesthesia, and CSF identification is a more reliable

Spinal Cord Disorders

confirmation of needle placement. However, the concern about further impairment of respiratory mechanics by a high block must be acknowledged. Deep GA prevents autonomic dysreflexia. Tracheal intubation will not initiate autonomic dysreflexia but may cause bradycardia due to vagal stimulation. Rapidly acting IV antihypertensive agents must be available. Succinylcholine is associated with massive hyperkalemia when administered between 72 hours post injury and up until six months or more after the injury. Hyperkalemia likely results from the proliferation of extrajunctional neuromuscular receptors on muscle, denervated by the neurological injury. Nondepolarizing muscle relaxants (or muscle relaxant free techniques) are recommended for tracheal intubation and maintenance during GA for all SCI patients in the first year post injury. Patients with high cord lesions require intensive management and should be cared for in centers offering such treatment. Staff must be educated about the issues relating to care of the SCI patients, in particular autonomic dysreflexia.

Anatomic Disorders Spinal Cord Tumors and Vascular Malformations Introduction Spinal cord tumors are rare in women of childbearing age, representing < 12% of nervous system tumors diagnosed during pregnancy.60 Diagnosis of spinal tumors in pregnancy is complicated by a high incidence of lumbar, pelvic, and sciatic pain in pregnancy, plus the typical discomfort and fatigue that many women experience while pregnant. The diagnosis may not be apparent until spinal cord compromise occurs. In high income countries, average maternal age is rising. So, a higher likelihood of encountering the most common malignant tumors in women exists: breast, colon, and lung, all of which can metastasize to the spine. Cancer diagnoses during pregnancy are fortunately rare at 0.02–0.1%.61,62 If the woman chooses to continue pregnancy, management is complex due to limitations on safe imaging and treatment modalities. Spinal tumors may be extradural or intradural in location; the intradural tumors are extramedullary (70%) or intramedullary (30%).63 In a small series by Meng et al., 21 pregnant women were diagnosed with spinal tumors over 11 years in China.62 The majority presented in the second and third trimesters and were benign, distributed evenly between the cervical, thoracic, and lumbar spine segments; however, nine were malignant with three secondary to metastases. Most were extradural tumors, commonly involving the vertebrae with destruction causing spinal cord compression or overt mass effect. Only five were intradural tumors. Three patients presented with paralysis, and of those, two underwent immediate spinal decompressive surgery; one had spine surgery postpartum. Three patients chose preterm delivery prior to spine surgery. Four required urgent surgery one day postpartum for worsening symptoms during delivery (two had a CD and two vaginal delivery). Pain was a frequent issue for these women, and while usually manageable with analgesic agents, it may prompt earlier surgical intervention.62

Benign Tumors The benign tumors affecting the spinal cord are meningiomas, neurofibromas, and schwannomas; those of a vascular nature are hemangiomas, angiolipomas, and hemangioblastomas. The tumors most commonly needing urgent intervention are those of metastatic origin.62 However, hemangiomas, angiolipomas, and meningiomas are influenced by pregnancy,64,65 as are hemangioblastomas.66 The term “pregnancy-related spinal tumors” was coined to describe unusual spinal tumors diagnosed during pregnancy or within one year postpartum.67 It is postulated that the combination of hormonal angiogenic placental growth factor (PGIF), its receptor vascular endothelial growth factor receptor 1 (VEGFR 1) are expressed at increased quantities by the endometrium, placenta, and decidua in pregnancy – and hemodynamic changes secondary to venous congestion in the epidural venous plexus, create a milieu that promotes the growth of certain tumors.66 Smaller lesions without substantive neurologic compromise may be monitored, as there is evidence of tumor regression postpartum.66 Spinal meningiomas comprise 25–45% of intradural (extramedullary) spinal tumors and are uncommon in the childbearing years. However, in one review, 8% of meningiomas presenting in pregnancy were in a spinal location.60 In another series of 122 spinal meningiomas, 1.5% presented in pregnancy.68 Clinical presentation is typically that of a slow growing lesion, with sensory changes (80%), gait instability (68%), and back pain or radicular pain. However, as spinal meningiomas may be adversely influenced by pregnancy they may present with rapidly progressive neurological deficits.63 Neurofibromatosis type 1 (NF1) causes spinal neurofibromas in 40% of those afflicted, but only 2–5% of those develop neurologic symptoms, typically in older patients. Unfortunately, pregnancy hormones cause accelerated growth of neurofibromas in 80% of women.69 There is one report of a patient who had a lumbar CT scan at 30 weeks gestation showing a lesion at L2; at 36 weeks gestation she had successful LEA at L4–5.70 The associated commentary by two obstetric anesthesiologists indicated significant reservations about the use of NA in a parturient with a known spinal cord neurofibroma without a very recent MRI. In another case, a woman presented two weeks postpartum with acute paraparesis from a T12 extradural mass. She had urgent surgery to remove the large neurofibroma and was subsequently diagnosed with NF1 and had an excellent recovery.69 Intramedullary Tumors Intramedullary tumors are uncommon; typically caused by ependymomas, meningiomas astrocytomas, and rarely glioblastoma multiforme.71 There is one report of a spinal glioblastoma in pregnancy, presenting at 20 weeks gestation with lower limb followed by upper limb weakness. She had a C6–T3 lesion on MRI and underwent urgent spinal surgery with incomplete tumor removal. At 28 weeks, she had a CD under GA to facilitate further therapy but unfortunately died nine months later. There are eight reported cases of ependymomas in pregnancy. One case was that of a 37-year-old woman who presented at 18 weeks gestation with lower back and right lower limb pain.

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There was a lesion at L1, which proved to be an ependymoma of the conus medullaris.72 She had spinal surgery in the lateral position and subsequent term delivery. An even rarer holocord ependymoma diagnosed at six months’ gestation presented with two months of urinary incontinence and tight/weak legs for one month. Spinal surgery to excise this T10–12 tumor resulted in good neurologic recovery prior to delivery. Unfortunately, she presented with extensive neurologic deterioration and respiratory compromise three months postpartum. She had an intramedullary tumor extending from the conus to C3 and died shortly thereafter.67 Hemorrhage into a tumor is another cause of sudden onset of neurological symptoms. A 26-year-old woman presented two days post vaginal delivery with severe lower back pain, bowel and bladder dysfunction, and rapidly progressive sensorimotor deficits of her lower limbs.73 MRI with contrast revealed a mass at T9–12 and spinal cord compression. Emergency spinal surgery revealed a large hematoma under the dura mater. A tiny mass in the middle of the clot turned out to be a spinal cord neurinoma. Vascular Malformations There are various ways to classify vascular lesions of the spinal cord.74,75 If using pathophysiology and location, one can categorize as tumor, aneurysm, or arteriovenous malformation (AVM) and intradural vs. extradural. Each has specific neuroimaging features, and treatment is guided by symptomatology, location, and pathophysiology. Spinal angiolipomas are unusual extradural tumors, representing 2–3% of spinal-epidural tumors, ordinarily slow growing and presenting with progressive myelopathy. The association with pregnancy is even rarer, with only 15 cases reported.65 Angiolipomas are usually located in the thoracic spine and present with back and interscapular pain. Expectant management is often an option, given the slow growth of spinal angiolipomas, with some tumors regressing postpartum. However, some spinal angiolipomas grow rapidly during pregnancy, causing severe progressive myelopathy requiring spinal decompression. In addition, given the typical thoracic location of these tumors, a vascular “steal” phenomenon may occur as the tumor has a dense vascular structure and is in the watershed area of the mid thoracic spine vascular supply. Hemangioblastomas (HBs) are benign vascular tumors and the most common CNS tumor associated with von Hippel Landau disease (vHLD). However, only 3% are in the spinal cord.76 Despite their benign nature, the location of these tumors, in the cerebellum or upper cervical spinal cord, often causes neurological complications, and intervention is required. Lesions in pregnancy arise in unusual locations, such as the filum terminale.77 The diagnosis and treatment of HBs now occur earlier during vHLD thanks to superior neuroimaging. In pregnancy, there is accelerated growth because of the increased production of PGIF and VEGFR 1.66,76 Changes in spinal venous pressure may result in cord compression and potentially spinal cord ischemia.76 Sporadic spinal cord HBs

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often present due to tumor growth or because of hemorrhage within the lesion.78,79 Vertebral hemangiomas are benign vascular tumors with high prevalence in the general population at 10%, but only symptomatic in 1% of cases. Spinal cord compression occurs due to bone expansion in the vertebral canal with mass effect, vascular shunting effect with ischemia, or spinal epidural hemorrhage.79 Pregnancy predisposes a patient with a vertebral hemangioma to symptom development. Most vertebral hemangiomas present in the third trimester and, according to a review of 27 cases, are commonly located in the upper thoracic spine.79 It is postulated that increased blood flow through the vertebral venous plexus as the gravid uterus expands and compresses the vena cava may be the critical factor causing the hemangiomas to become symptomatic. Chi et al. proposed a management algorithm for vertebral hemangiomas in pregnancy based upon gestational age at diagnosis.80 While many patients have good recovery despite delaying surgical intervention, some maintain that spinal surgery in the third trimester can be managed safely for mother and fetus. Radiotherapy and embolization are other therapeutic options.81

Valuable Clinical Insights • Spinal cord tumors presenting in pregnancy require interdisciplinary planning as some require urgent surgical intervention and others require premature delivery of the fetus to facilitate ongoing care of the patient. • Management of vascular spinal cord lesions often requires neurosurgical procedures in pregnancy due to their accelerated growth and development of neurological compromise. • Neuroimaging with CT scan and MRI should not be withheld because of pregnancy, and use of contrast media is not ­absolutely contraindicated but requires discussion with a neuroradiologist and the patient. • Conditions that may cause multiple CNS lesions mandate complete neuroaxis imaging prior to NA administration. Spontaneous hemorrhage into spinal cord lesions is unpredictable in many of these conditions. Informed consent of anesthetic risk, NA, or GA, should be detailed and done in a team setting.

Cerebral cavernous malformations (CCMs) are lesions influenced by pregnancy hormone changes; there are many reported cases of hemorrhage from a CCM in pregnancy.82,83 Databases on women of childbearing age who have CCMs provide evidence for their behavior in pregnancy.82–84 Cerebral cavernous malformations are low flow vascular lesions that comprise 9% of CNS vascular malformations; they hemorrhage unpredictably. Alterations in venous hemodynamics may precipitate rupture of a fragile thin-walled CCM, but the pathophysiology of CCM hemorrhage is not well delineated. Brainstem lesions are more likely to hemorrhage than CCMs in other locations.85 Cerebral cavernous malformations appear as “popcorn” lesions on MRI,

Spinal Cord Disorders

and with improved neuroimaging, are diagnosed more readily as a cause of focal neurologic deficits, epilepsy, or stroke.86 Spinal cavernous malformations comprise only 5% of CCM lesions and are more likely to occur in patients with the familial (AD) form of CCMs; they account for 5–12% of spinal vascular tumors.87,88 Spinal cavernous malformations are found in the extradural, intramedullary, or intradural extramedullary spaces.89,90 A large case series could not demonstrate a higher risk of CCM hemorrhage during pregnancy.82 Pregnancy is acceptable in women with CCM, and hemorrhage of a lesion during pregnancy does not mean avoiding vaginal delivery.83,89 Due to the potential presence of spinal cord cavernous malformations, NA is controversial in a pregnant woman diagnosed with a CCM, either prior to pregnancy or during pregnancy following a symptomatic cerebral hemorrhage.89 Spinal cord cavernous malformations may be tiny and difficult to locate even with contrast-enhanced MRI. Risk factors for repeat hemorrhage are female gender and elapsed time since the first hemorrhage of < 5 years.86 In 2017, the Angioma Alliance Scientific Advisory Board published consensus guidelines for the clinical management of CCMs.91 On the other hand, spinal cord AVMs are at risk for hemorrhage during pregnancy and delivery. They are rare vascular intramedullary lesions that may cause neurological symptoms via direct mass effect, venous congestion, or hemorrhage. They are difficult to manage surgically because of the multiple arterial and venous connections with spinal cord vasculature.92,93 Central nervous system arteriovenous shunts are rare, with 10% having a spinal location. The presentation may be either slow evolution of neurologic deficit or acute compromise secondary to hemorrhage or venous thrombosis.94 Diagnosis in pregnancy is not different; typically, they present in the third trimester most frequently with spinal cord compromise from hemorrhage. Embolization of the lesions during pregnancy was effective in the small number of known cases. The recommendation is that women with known intradural spinal cord arteriovenous shunts avoid future pregnancies due to the risk of spinal cord hemorrhage.94

Obstetrical and Surgical Management Collaborative team planning with spine surgeons, anesthesiologists, and neonatologists is necessary. Spinal surgery during pregnancy requires the additional considerations of positioning, FHR monitoring, and plans for intervention for fetal compromise that does not respond to intrauterine resuscitative measures.61 Use neuroimaging as needed for accurate diagnosis and surveillance during pregnancy. Gadolinium contrast dye used with MRI is not associated with direct fetal effects. However, how much gadolinium crosses the placenta and is absorbed by the fetus directly and via swallowing amniotic fluid is unknown.95 After informed discussion with the patient, use contrast MRI for those cases in which benefit is clear. Renal impairment is a relative contraindication to the use of gadolinium due to nephrotoxic effects and possible development of nephrogenic systemic fibrosis. Iodine-based dyes for CT are associated with a very low incidence of fetal

hypothyroidism. Therefore the previous relative contraindication of using contrast-enhanced CT should be downgraded to a caution, and the risks and benefits of its use discussed with the patient.95,96 Radiotherapy can be administered in the second half of the pregnancy to control malignant growth; however, it is associated with childhood leukemia and neurocognitive deficits.97 Chemotherapy administered in pregnancy after the period of organogenesis is remarkably well tolerated by the fetus; adverse effects of cancer on the neonate are related more to preterm delivery than exposure to chemotherapy.98 The collaborative team should decide on the mode of delivery, taking into account clinical, radiological, and patient preferences. While there is no clear evidence that vaginal delivery with the fluctuating increased intraabdominal pressure associated with second stage pushing worsens spinal-tumor-induced compression of neurologic structures, it is a concern expressed in many articles on spinal tumors in pregnancy. Five cases developed progressive neurological decline peripartum in one series, with four requiring surgery within 24 hours of delivery. Of those four patients, two had an elective CD.62

Anesthetic Management See Table 15.1. All modern anesthetic agents are safe for spinal surgery during pregnancy, so the primary focus is providing safe anesthesia in the prone position. Bolsters ensure the pregnant abdomen is free from compression. Discuss other positions (lateral, semi prone, or three-quarters prone) with the surgeon, but many opt for the prone position for visualization and precision. A systematic review of positioning options includes a description of the modified three-quarters prone position.27 Provide mechanical venous thromboprophylaxis and discuss the need for neuromonitoring with the surgeon. A qualified healthcare professional for FHR and tocodynamometer monitoring should be present in the operating room. Anesthetic considerations for CD in a patient with a spinal cord tumor depend on neurologic status and stability, general medical status, especially in cases of metastatic cancer, and patient preference. Usually, active and deteriorating neurologic compromise is a contraindication to the use of NA. However, in the challenging case of metastatic cancer, the patient’s preference to to be awake may outweigh other considerations.99 Back pain in a pregnant woman with a known cancer diagnosis requires investigation with MRI prior to any discussion about NA. Evaluate risks and benefits on an individual case basis. Vascular lesions, such as CCMs, may be more challenging to manage because of the unpredictable risk of hemorrhage. Interdisciplinary team meetings, including the patient and family, need to occur regularly. While most CCMs do not require acute neurosurgical intervention due to the nature of the hemorrhage, neurosurgical access should be organized prior to delivery. Neuraxial anesthesia in the absence of a recent contrast-enhanced MRI of the spine is controversial due to the ­potential presence of a spinal CM.

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https://doi.org/10.1017/9781009070256.016 Published online by Cambridge University Press

Table 15.1  Presentation and management of spinal cord tumors and vascular malformations in pregnancy

Tumor type

Number of cases reported/ incidence

Metastatic

Spine location

Influenced by pregnancy

Presentation

Surgery while pregnant?

Mode of delivery

Neuraxial anesthesia

C/T/L/S

Possibly

Pain and neurologic deficits, fatigue

Often needed; combined procedure with GA

Preterm CD

Lesion- and patient-status-dependent

Primary malignant

Rare; 0.02–0.1% pregnant women

T/L

Unknown

Pain and neurologic deficits, fatigue

Often needed; combined procedure with GA

Preterm CD

Location- and patient-status-dependent

Meningioma

122: 1.5% presented in pregnancy

8% in spine: extramedullary

Yes: growth with rapidly progressive neurological deficits

Sensory changes, gait instability, back pain

Yes

Obstetric indications

Not if progressive neurologic deficits

May regress postpartum

Pelvic neurofibromas may cause obstruction

Yes, with reservation and need for recent neuroimaging

May regress postpartum

Obstetric indications

Vascular “steal” may occur and result in spinal cord ischemia

Neurofibroma Angiolipoma

Yes, in 80% of women with NF1 15 cases 2–3% of spinal tumors

Schwannoma Ependymoma

2

Glioblastoma multiforme

T

Yes: growth (usually slow growing)

Back pain, intrascapular pain

C

Yes: growth

Not usually

Obstetric indications

Unusual locations such as filum terminale

Yes: rapid progression

Back pain and neurologic deficits

Yes

Obstetric indications

C/T

Unknown

Progressive weakness

Yes

Preterm CD

Hemangioma

27 cases 10% prevalence general population

Upper T

Yes: growth

May regress postpartum

Obstetric indications: management algorithm by Chi et al.

Management algorithm by Chi et al.80

HB: vHLDassociated

3% of lesions in spinal cord

Unusual locations such as filum terminale

Yes: accelerated growth

Combined procedure

Preterm CD

Spinal cord ischemia may occur

HB: sporadic

Yes; growth and hemorrhage

Back pain and neurologic deficits

CCM

Brainstem vs other. Spinal CMs only 5% of CCM lesions

Recent literature supports not a risk for hemorrhage82

Stroke, neurologic deficit

Spinal AVMs

10% have spinal location

Yes, hemorrhage; mass effect

Slow neurologic deficit from compression; acute compromise from hemorrhage

Preterm CD Surgery rarely indicated

Vaginal delivery acceptable

Only if MRI imaging, especially in familial form of CCM

CD. Future pregnancies to be avoided.

Not recommended

Abbreviations: AVM = arteriovenous malformation; C = cervical; CCM = cerebral cavernous malformation; CD = cesarean delivery; chemo = chemotherapy; L = lumbar; HB = hemangioblastoma; NF1 = neurofibromatosis type 1; S = sacral; T = thoracic; vHLD = von Hippel Landau Disease; XRT = radiation therapy.

Spinal Cord Disorders

Spinal Dysraphism, Including Tethered Cord Syndrome Valuable Clinical Insights • M ore cases of spinal dysraphism and tethered cord syndrome are being diagnosed in adults, but more subtle forms of closed spinal dysraphism (CSD) are not easily found on physical examination. Cutaneous stigmata are present in only 30–50% of CSD without a subcutaneous mass.100 • Tethered cord is present in 70% of dysraphic lesions involving the spinal cord. • The presence of midline cutaneous stigmata, such as a hairy tuft or capillary hemangioma, in a pregnant patient with minor neurologic, orthopedic, urologic complaints, or back pain mandates MRI imaging prior to NA due to the risk of an abnormally positioned conus or tethered cord.

Introduction Neural tube defects (NTD) are a group of congenital malformations of the CNS that arise from failures in neurulation. They remain one of the most common birth defects worldwide and are a significant health problem in developing countries, at rates of 1–3/1000 births.101,102 Despite longstanding recommendations for folate supplementation, the prevalence of NTD in high income countries holds steady. Data from Canada showed a rate of 0.37/1000 births from 2001 to 2015.103 In the United States, prevalence is similar at 0.35/1000 births.104 The United States’ National Spinal Bifida Registry distributed a survey exploring the characteristics of their population with a diagnosis of NTD. Survey responses from 852 patients revealed a preponderance of female sex at 73.6%, ethnicity (primarily white) at 83.7%, and a mean age of 37 years.104 Less than 50% were employed, and only 13.3% did not require some form of assistive device to mobilize. Concerning medical conditions, 43% suffered from skin breakdown, 47% had chronic pain, especially in the lower back and legs, 54% a shunt for hydrocephalus control, and 33% a UTI in the prior 12 months. Spinal Dysraphism The term “dysraphism” refers to a NTD closure but also includes all congenital midline disorders of the spinal cord. High quality neuroradiologic imaging permits a much better understanding of the nature of these defects. The confusing terms of “spina bifida occulta” and “spina bifida cystica” were eliminated, and a classification system was created based on a mix of clinical and neuroradiologic information.105 The classification system divides lesions into two main categories: open spinal dysraphism (OSD) and closed spinal dysraphism (CSD). Open spinal dysraphism abnormalities are NTDs that are open to the environment and contain spinal cord malformations. In contrast, CSD abnormalities are covered by skin, always midline in location, and in up to 50% of cases, heralded by the presence of cutaneous stigmata such as subcutaneous patches, dimples, hairy tufts or nevi.105,106 The finding of an isolated bony neural arch defect (usually at L5–S1) is common enough (5–36% of the

population) to be considered a normal variant of human anatomy.107 Patients with isolated vertebral arch anomalies usually have neither cutaneous stigmata nor underlying cord anomalies despite older reports of associations with chronic back problems, enuresis, and neurological problems; these likely represented cases of undiagnosed spinal dysraphism.108,109 Adults with OSD have shortened life spans. A single center review of 487 patients in the United States found an average age at death of 44.4 years,110 which agrees with a 50-year prospective cohort study of 117 patients with NTD in the United Kingdom.111 The primary causes of death were infection, respiratory failure, renal failure, and shunt malfunction. A history of hydrocephalus and Chiari II malformation was significantly associated with death at a younger age. Chronic neurologic, orthopedic, and urologic complications occur in all adults with repaired OSD.112 In addition, premature cardiovascular disease secondary to hypertension and diabetes is of concern in this population.113 As the prevalence of OSD in women of childbearing age rises, large-scale cohort studies to examine pregnancy outcomes are possible. Ongoing issues, related to shunts to control hydrocephalus, kyphoscoliosis, neurological impairment, and the genitourinary system, impact pregnant women’s care with surgically closed OSD.107 Pregnancy outcomes in women with OSD reveal substantive effects on the woman and the fetus/neonate. A Canadian study of 397 pregnant women with OSD, compared to > one million women delivered without spinal dysraphism, identified a need for peripartum ICU admission, respiratory morbidity, neonatal ICH, birth hypoxia and congenital abnormalities (oral clefts and abdominal wall defects).114 Women with OSD were twice as likely to have a CD, 23 times more likely to require intubation and ICU admission, and three times more likely to die. Women with OSD suffer from urological complications at a high rate during pregnancy, including UTI, incontinence, and cystotomies at emergency CD.115 Women with OSD have chronic medical problems and these studies reveal that extensive interdisciplinary planning is required to manage pregnancy and delivery in order to reduce adverse outcomes. Closed spinal dysraphism lesions are further divided into those with or without a subcutaneous mass (Figure 15.3). Masses are usually located in the lumbosacral region and are frequently lipomas with dural defects or posterior meningoceles, which are essentially herniated sacs of CSF. The overlying skin is not normal, providing a clue to an underlying abnormality.116 Closed spinal dysraphism without a subcutaneous mass is a group of mixed conditions, some of which are simple such as an abnormally long spinal cord or tight filum terminale. Others are more complex, including split cord malformations, neurenteric cysts, and dermal sinus tracts. Typical cutaneous stigmata are sacral dimples, hypertrichosis, capillary hemangioma, and caudal appendage (pseudotail).100,106 Frequently, bony vertebral abnormalities are present, from simple transitional vertebrae to grossly abnormal bony structure.117,118 Lumbosacral lipomas are the most common form of CSD, and often result in adult onset of tethered cord syndrome (TCS). Surgical resection is advised, but patients are often left with ongoing pain, neurologic deficits, urinary complaints, and

241 https://doi.org/10.1017/9781009070256.016 Published online by Cambridge University Press

Roanne Preston and Jonathan Collins

Figure 15.3  Closed spinal dysraphism lesions.

Closed Dysraphism Lesions

With Subcutaneous Mass

Lipomas with Dural Defects: lipomyelomeningocele lipomyelocele Myelocystocele: terminal non-terminal

Without Subcutaneous Mass

Simple

Complex intraspinal lipoma tight filum terminale

split cord malformation

abnormally long spinal cord

neurenteric cyst segmental spinal dysgenesis

persistent terminal ventricle

Meningocele

retethering.119 Split cord malformations are associated with rare spinal cord teratomas and other spinal cord tumors, such as lipomas and dermoids.120 Dermal sinuses are actual tracts from the skin to the spine, with 60–70% reaching the subarachnoid space, posing a risk of infection. The tract may end in an intradural dermoid or epidermoid cyst, rarely a teratoma. The dermal sinus appears as a midline dimple above the buttock cleft. The challenge is differentiating them on clinical exam from the more common coccygeal dimple or pilonidal cyst. If the dimple is off midline and caudad to the buttock crease, it is not a dermal sinus.106,121 A dermal sinus may be associated with other skin markers such as hypertrichosis or skin pigmentation. Anterior sacral meningocele (ASM) is an unusual form of CSD that typically presents later in life, often in women during pelvic examination. Presentation is often nonspecific with symptoms such as chronic constipation, dysmenorrhea, low back pain, and rarely perineal or lower extremity sensorimotor changes.122 The finding of an ASM mandates focused neuroimaging as the association with low-lying conus, tethered cord, and Chiari malformation is of concern for NA. Currarino syndrome is an autosomal dominant disorder comprised of ASM and sacral teratoma, partial agenesis of the sacrum, and anorectal malformations, arising from a failure of secondary neurulation. Cutaneous stigmata are usually absent.123 The presence of the ASM results in substantial obstetric management issues due to the size of the ASM obstructing labor, possible rupture during labor, and surgical complexity at CD. There are four reports on the anesthetic management of Currarino syndrome with or without ASM in which NA was provided.122–124 Patients with CSD, especially the complex lesions, often have orthopedic issues such as scoliosis and neurologic symptoms, particularly those affecting bowel and bladder.106,125,126 Patients with cord abnormalities frequently have a tethered cord, which has implications for NA (see below). Magnetic resonance imaging has improved the diagnosis of CSD when a patient presents with cutaneous stigmata and typical orthopedic or neurologic complaints. In addition, with the

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dorsal dermal sinus

caudal regression syndrome anterior sacral meningocele

increased use of US imaging prior to NA and improved equipment, scanning experts may see bony structural abnormalities such as absent spinous processes, alerting the imager to the potential presence of CSD lesions.127

Medical and Obstetric Management The long-term outlook for patients with OSD has improved since the first large study published in 1943 noted a 48% early mortality rate.128 There are several features of OSD which affect the course of pregnancy and delivery; the management of patients with significant kyphoscoliosis can be found in Chapter 12. Patients have a complex set of physical, psychosocial, and cognitive needs, and preconception counseling helps formulate a complex care plan. Respiratory function is assessed, and followed in those patients with compromise or who are at risk for decompensation during pregnancy. Patients with shunt-controlled hydrocephalus require assessment of shunt function, noting the sites of peritoneal drainage. A survey of shunt-dependent women found nine out of 70 women had more headaches during pregnancy.129 Seven women required shunt revisions during pregnancy, and 23 patients experienced shunt failures in the first six months postpartum. There is a lower incidence of TCS due to improved closure techniques, although by age ten years, 19% of patients experience some cord tethering.130 Common complications include preterm labor, UTIs, and problems in patients with uretero-ileostomies (damage during CD).131 Assess the pelvis early in pregnancy as many OSD patients have short stature and a contracted pelvis that may preclude vaginal delivery.131 If exposed to latex since birth, up to 23% of adults with OSD have latex sensitization and latex allergy.131,132 Recognition of this serious problem led to latex avoidance measures in this population, resulting in a considerable decrease (from a high of 72%) in the prevalence of latex sensitization. Women who are more mobile before pregnancy are more likely to have a vaginal delivery. In a series of 32 women with SCI, 69% secondary to spinal dysraphisms, most had a CD.133 So, while consensus is that CD is performed for obstetric reasons,

Spinal Cord Disorders

many women with OSD have substantial indications for operative delivery. Multidisciplinary planning throughout pregnancy is essential.

Anesthetic Management There are few implications for obstetric anesthesia management of the patient with a lumbosacral isolated bony arch defect. Neuraxial anesthesia is not contraindicated, and the only recommendation is to perform the block at a site remote from the level of the anomaly. It is more likely that ADP will occur because the supporting ligaments, specifically the interspinous ligament and the ligamentum flavum, may be abnormal at the level of the lesion.134 The epidural space may be discontinuous and inadequate or failed block may result.135 Patients with CSD often have cutaneous signs and neurological signs and/or symptoms. Assess these patients in the anesthesiology clinic to obtain relevant neurological data and consultations. This also provides an opportunity to discuss issues relating to NA, such as direct trauma to the low-lying tethered cord, increased potential for problem blocks, and ADP. Obtain an MRI before attempting NA if there is symptomology suggesting a TCS, such as leg pain and weakness with or without cutaneous stigmata.136,137 This allows a determination of spinal cord termination. Patients with spinal dysraphism may have decreased LA requirements. This may be a result of altered dural permeability and a small volume epidural space surrounding the lesion.135 Murphy et al. reviewed 139 published cases of spinal dysraphism and use of NA. Epidural anesthesia was provided in 52 cases and spinal or CSE in 15. Complications occurred in 36.5% of the epidural group and 80% in the spinal/CSE group, ranging from asymmetric blocks to neural trauma.107 Among 102 cases of neurologic conditions in the 1997–2002 United Kingdom Registry of High Risk Obstetric Anesthesia, there were 23 patients with spinal dysraphism.138 Of these, eight had an isolated bony arch defect, leaving 15 true cases of dysraphism. Epidural anesthesia was provided in eight cases, although nine other women planned to have NA. In the series by Sterling et al.,133 24% of the 32 women had a contraindication to NA, and 57% received a GA for CD. Therefore, while NA is used in these patients, variation in block success and challenges in neuraxial placement are common. Obtain detailed informed consent as the risks of a failed block, ADP, high block, and direct neural trauma are undoubtedly higher than in the healthy parturient. There is no evidence that one technique is safer or superior to another. Ultrasound imaging of the terminal part of the cord is not helpful as it is challenging in adults, unlike in pediatric patients.127 However, handheld US can determine the level for needle insertion in the presence of low-lying and possibly tethered cord.

Adult Tethered Cord Syndrome Tethered cord syndrome (TCS), also known as “tight filum terminale,” “cord traction syndrome,” “filum terminale syndrome,” and “tethered conus,” was first described in 1953.118 It is a neurological syndrome caused by longitudinal traction on the ­frequently low-lying conus medullaris, producing chronic cord

ischemia. Initially recognized in pediatric post meningomyelocele repair patients, CSD lesions cause the majority of adult onset TCS. It is not the same syndrome as that seen in the post OSD repair population.116,139 The diagnosis of TCS in the developed world is increasing due to superior neuroimaging modalities; MRI is the imaging modality of choice for diagnosis. The conus may be as low as S1 and located posteriorly, and in most cases, there is a thickened filum terminale.125 There are published cohorts of patients with adult TCS, providing specific case information and reviews of this syndrome. There is a preponderance of female sex and age at diagnosis is mid-twenties to early thirties. Half of the reported cases have a thickened filum terminale and low-lying conus only, with no mass such as lipoma or complex cord anomaly.125 The most common presenting symptoms of TCS in adults are back and lower limb pain (70–80%), lower limb sensorimotor deficits (35–75%), and urological problems (50– 80%).117,124,126,140,141 Some patients present with acute symptoms after a precipitating event that stretched the spinal cord, such as heavy lifting, placement in the lithotomy position, and childbirth.118 Progressive neurological deterioration and development of scoliosis are common with a tethered cord.106,142 Studies and meta analyses found that only 30–40% of patients had cutaneous stigmata.125,137 Detethering surgery provides substantial improvement in symptoms of pain, weakness, and sensory impairment but with less improvement in bladder dysfunction.125,140,141,143 Retethering occurs in approximately 20% of patients,141 and surgical success seems more likely if done before age 50.137 Most neurosurgeons now recommend surgical intervention in adults diagnosed with TCS.137,144,145

Anesthetic Management of Parturients with Tethered Cord Syndrome Information on the anesthetic management of confirmed adult TCS in a parturient is sparse, even when combined with OSD lesions (Table 15.2). Murphy et al. reviewed 84 parturients with spinal dysraphism, including some with tethered cord, but given the high proportion of OSD patients, it is unclear how many had adult TCS.107 Review of neuroimaging and use of US at the time of NA limits neurologic trauma.124,146 This is important given that anesthesiologists tend to be one level higher than they imagine when performing NA, if not using preprocedural US.147 There are a few reports of neurologic injury after NA for delivery in women subsequently diagnosed with closed spinal dysraphism; typically, there was no history or cutaneous stigmata.148–151 Childbirth may be a precipitating event of an undiagnosed CSD lesion, and NA may be implicated in the development of new onset neurologic symptoms. As TCS is not diagnosed until adulthood, take a careful history and perform a neurological examination in all parturients requesting NA who complain of significant back pain or neurological symptoms. In patients with known TCS, NA is not contraindicated but should be performed below the level of the conus if known. Informed consent in these patients should include discussing the increased risk of spinal cord trauma. Direct needle trauma to the conus does not necessarily produce typical

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https://doi.org/10.1017/9781009070256.016 Published online by Cambridge University Press

Table 15.2  Neuraxial anesthesia in adult tethered cord syndrome and pregnant women with spinal dysraphism

Author

Patients N: F/M

Mean age (range)

Pregnant: Y/N

Surgery

Neuraxial technique

Presentation

Preoperative findings

MRI results

Liu 2016148

4:3/1

(28–52)

Y: 2

CD: 2 Hyst:1 Append: 1

CSE: 3 Spinal: 1

Radiating pain in lower extremities or perineum with dural puncture Onset of paresthesias, pain or weakness 2–3d postop

1: Pain, right leg 2: Occasional back and perineal pain 1: Bladder symptoms 1: Difficulty bending

Conus at: Inferior body L3 Superior body L4 Mid body L4 Mid body L5 Diastematomyelia and syringomyelia in 1. Sacral cyst in 1

Xue 2013149

1F

25

Y

CD

Spinal

n/a

L4 body Conus edema

Valente 2012155

1F

35

Y

CD

Spinal

Slow onset spinal anesthesia and rapid offset with standard dose

Dysmorphic foot Plain films: bifid lumbar vertebra and abnormal sacrum Cutaneous stigmata: skin discoloration and hairy tuft

Conus at L2/3 Dural ectasia

Ahmad 2006150

1F

26

Y

CD

Spinal

R Foot drop: at 1 month PP, found to have sensory loss R lateral ankle and foot drop with absent ankle reflex

none

Conus at L4 Fatty filum terminale and intradural cyst with tethering at S3

Ali 2005156

1F

32

Y

none

Neuraxial avoided

SBO with bladder surgery as child

Tethered cord at S1 with intraspinal lipoma

Wenger 2001151

1F

38

Y

CD X 2

Spinal

1st CD: Paresthesia R leg during spinal injection. Followed by intermittent R leg weakness 2nd CD: paresthesia R leg. 5 days PP weakness L leg with absent ankle reflex and 4/5 weakness dorsiflexion

Kyphosis, weakness right leg, pelvic deformity

Conus at L3–4 Diastematomyelia Bifid spines L2–5

Tidmarsh 1998135

16 F

Y

CD: 3 Forceps: 3

10 epidurals: 7 behaved normally, 1 asymmetric 1 high block 1 poor sacral analgesia

1 ADP

8 CSD – no neurologic symptoms 8 OSD – “mild” symptoms

No MRIs

Wood 1997157

1F

N

TKR

Spinal

Postop D4: bilateral leg weakness and T10 sensory deficit. Subarachnoid hematoma T12–L5 at laminectomy

Skin dimple at L5–S1 Dx as CSD as child

Tethered cord at L4 body (at surgery)

77

https://doi.org/10.1017/9781009070256.016 Published online by Cambridge University Press

Author

Patients N: F/M

Mean age (range)

Pregnant: Y/N

Surgery

Neuraxial technique

Presentation

Preoperative findings

MRI results

Davies 1996158

1 M

53

N

TURP

Spinal unknown level

R leg paresthesia and weakness with dural puncture. 4h postop: pain and weakness R leg

R foot deformities and shorter R leg

Conus at L4/5 Diastematomyelia Intradural cystic tumor L2–3 Bifid L5S1 and absent spinous process T12

Morgenlander 1994159

1F

30

Y

SVD

Epidural

L leg weakness and pain 2 m PP exam: 4/5 strength L hip/knee R foot smaller than L and absent ankle reflex

Lumbar giant hairy nevus excised as child

Diastematomyelia L1 with tethering Lipoma of conus

Nuyten 1990160

1F

33

Y

CD

Spinal with 18g Tuohy at T7–8

Uneventful

OSD: surgery as infant, paraplegia with extensive sensory impairment Substantial lumbosacral scarring and kyphoscoliosis

No imaging

Broome 1989161

1F

26

Y

CD

Spinal 26g at T10–11

TL MMC repaired as infant. Significant sensorimotor dysfunction below T10 and kyphosis

No MRI

Vaagenes 1981162

1F

26

Y

Epidural: difficult placement and poor sacral analgesia

LS meningocele excised as infant L leg spasticity and sensory impairment L4–S1 Foot abnormalities Hairy tuft

Plain X-ray: bifid L5, fusion L3–4

Abbreviations: append. = appendectomy; CD = cesarean delivery; CSE = combined spinal-epidural; F = female; hyst. = hysterectomy; L = left; LS = lumbosacral; M = male; MMC = myelomeningocele; N = number; OSD = open spinal dysraphism; PP = postpartum; R = right; SBO = spina bifida occulta; SVD = spontaneous vaginal delivery; TKR = total knee replacement; TL = thoracolumbar; TURP = transurethral resection of prostate.

Roanne Preston and Jonathan Collins

lancinating pain,152,153 but such pain on performing NA mandates immediate removal of the needle or catheter.154 Epidural anesthesia may be safer than spinal anesthesia because of the low fixed spinal cord. Intrapartum management of patients with known TCS should include avoidance of prolonged lithotomy position and squatting. Valuable Clinical Insight Individual assessment of each patient with Chiari 1 malformation (CM1) and/or syringomyelia involves a multidisciplinary team, including a neurosurgeon. For minimally symptomatic patients, vaginal delivery and use of NA does not influence the natural history of the disease.

Syringomyelia Syringomyelia is a neurological disorder characterized by cystic cavities within the spinal cord, typically in the cervicothoracic regions. Syringomyelia most often is congenital, associated with CM1, and more common in women by a factor of 2:1.163 The pathogenesis is unclear. However, 84% of patients have cranio­ cervical junction abnormalities, which may be the initiating cause of the cystic lesions from a craniospinal pressure gradient. A retrospective review of a spinal cord database of 3206 patients with spinal cord pathologies found 1535 had syringomyelia.163 Other causes of syringomyelia include trauma, arachnoiditis, degenerative disc disease with extradural compression, and spinal cord tumors. In Klekamp’s study, 61% of the syringomyelia cases did not have pathologies at the craniocervical junction.163 In those non-CM1-associated cases, 69 (7.4%) had TCS with the syrinx starting at the level of the tethering; the majority of these cases had a low positioned conus medullaris.163 Traumatic syrinxes following obstetric NA are described with

all patients suffering neurological symptoms from the cystic lesion.153 Syringomyelia is either communicating (with CSF pathways) or noncommunicating. Communicating syringomyelia is more susceptible to deterioration when exposed to raised ICP.164 Syringobulbia is when the syrinx extends cephalad into the medulla. Typical symptoms of syringomyelia are progressive sensorimotor deficits of the upper limbs and neuropathic pain. Pain and temperature are commonly affected, while the senses, touch and position, are preserved. Sensory disturbances and pain often occur with coughing, sneezing, and Valsalva maneuvers. Diagnosis is based on clinical features, supported by MRI, and often missed until patients are in their third or fourth decade. Secondary kyphoscoliosis due to weakness of the paraspinal muscles is common but the development of this structural abnormality is reduced by early suboccipital craniectomy.163 Syringomyelia is progressive in two-thirds of affected patients. The physiological changes of pregnancy and labor pose a theoretical risk of brainstem herniation and cord compression,165 although neither has been reported. It is uncertain if the Valsalva maneuver creates a cervicolumbar CSF pressure differential which could cause a syrinx to expand. In healthy volunteers, no gradient is created, but women with syringomyelia have not been studied. It is reasonable to assess the patient based on whether coughing or sneezing exacerbates their typical symptoms.166 The obstetric and anesthetic management of 500 pregnancies with CM1, with or without syringomyelia, is detailed in the most extensive case series to date165 (Table 15.3). In women with CM1 with or without syringomyelia, CD is required to avoid Valsalva maneuvers.165,166 Neuraxial anesthesia appears to be more acceptable than in the past, especially if the woman is asymptomatic.167 Mode of delivery and anesthetic type (GA vs.

Table 15.3  Syringomyelia in pregnancy

Author

Cases Births/patients

CM1 present

Mode of delivery

Neuraxial anesthesia

Knafo 2021 (own cases)165

83/83

59: 27 with syringomyelia

Before Dx: CD 38% After Dx: CD 54% If CMI present: CD 84–67% elective Note: 76% diagnosed after pregnancy

Before Dx: epidural 60%, spinal 9%, GA 20% After Dx: GA 75%

Knafo 2021 (literature review) 165

73/70

39 CM1 only 18 CM1 with syringomyelia 12 syringomyelia only

50% VD 50% CD Note: 80% diagnosed pre-pregnancy

39% NA 33% GA

Gruffi 2019168

185/148

All, 17 births/14 patients had syringomyelia

VD 43%

78%

Roper 2018169

21/21

All, 19% syringomyelia

VD 65% CD 35%

VD: Epidural 22% CD: 50% GA

Waters 2018167

95/63

All 3% syringomyelia

54% VD 46% CD

VD: epidural 40%, spinal 26% CD: GA 23%

Garvey 2017166

43/39

50%

70% CD

CD: 10% spinal 20% epidural 70% GA VD: 69% epidural

Abbreviations: CM1 = Chiari malformation 1; CD = cesarean delivery; Dx = diagnosis; GA = general anesthesia; NA = neuraxial anesthesia; VD = vaginal delivery.

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Spinal Cord Disorders

NA) do not influence clinical deterioration, as assessed using a standardized clinical severity score, which is confirmed by other case series.168 In Gruffi’s series, NA was not associated with increased risk of ADP nor PDPH in patients with CM1 alone, but the PDPH rate was higher in the small cohort (three patients) who also had syringomyelia. Consequently, no conclusions can be made about the risk of PDPH in these patients.168 The decision about mode of delivery should be made in consultation with neurosurgery and will depend upon maternal symptoms during pregnancy.165–169 Ghaly proposed a scoring system that assigns points to the presence of symptoms from CM1, the presence and degree of tonsillar herniation, and the presence of syringomyelia or syringobulbia to determine whether multidisciplinary team planning and elective CD are indicated.170

Anesthetic Considerations for Labor and Delivery The key pathophysiological features are neurologic dysfunction and respiratory impairment secondary to kyphoscoliosis. Clinical symptoms consistent with raised ICP must be elicited before NA. While sudden clinical deterioration following a short period of Valsalva maneuver can occur in patients with syringomyelia, vaginal delivery and NA are most often safe. The presence of a shunt for hydrocephalus is not a contraindication to NA. However, 13–23% of parturients may experience shunt problems during pregnancy, some requiring revision, others waiting until postpartum.129 Syringomyelia (especially if syringobulbia is present) may alter the normal cardiovascular responses to vasodilation and hypovolemia due to involvement of the autonomic system. Cautious induction of NA in these ­patients is recommended.164,171 Considerations for GA are multiple and, when chosen because of advanced disease, some authors recommend awake intubation.170 Avoid drugs and procedures that cause sharp increases in ICP, and consider using prophylactic measures to control ICP, such as osmodiuresis (preferably postdelivery) and hyperventilation.170 There are reports of increased sensitivity to neuromuscular blocking agents in those with CM1 and syringomyelia.172 Pregnant women with advanced pathology should receive care in a center with immediate neurosurgical access.

There are reports of pregnancy in SEL patients. With MRI confirmed diagnosis, one had new onset back, hip, and thigh pain in the third trimester leading to a decision to avoid NA.173 Another parturient with SEL had unpredictable spread of NA, essentially from the reduced epidural compartment. After an uneventful labor epidural, this woman developed a high block with an epidural top-up for CD.175 Acute disc herniation has to be ruled out by neuroimaging before diagnosing SEL, and an abnormal extradural fat content ratio helps confirm the diagnosis. It is theorized that venous impedance may contribute to spinal nerve compression in patients with high BMI. However, laminectomy and resection of extradural fat may be indicated in SEL patients presenting with sudden neurologic deficits.174

Vascular Disorders Anterior Spinal Artery Syndrome The spinal cord derives its blood supply from the single anterior and paired posterior spinal arteries (Figure 15.4). The single anterior spinal artery supplies the anterior two-thirds of the spinal cord, responsible for motor and coarse sensory function. It originates from the vertebral arteries at the foramen magnum and, as it tracks in a caudad direction, receives contributions from various radicular arteries, including the artery of Adamciewicz, which enters the cord around T9–L2.176 As several spinal levels do not receive radicular branches and, connection between anterior and posterior spinal arteries is poor, the spinal cord is susceptible to ischemia. Anterior spinal artery syndrome (ASAS) (previously known as Beck syndrome) is a rare neurological syndrome caused by occlusion of the anterior spinal artery, usually in the lower thoracolumbar cord. It was originally described in a pregnant patient in 1938.177 Anterior spinal artery syndrome describes a constellation of neurological symptoms, including loss of sensory function with preservation of proprioception and light touch, loss of motor function, and intact vibration sense. Pathophysiological events leading to ASAS can include vessel occlusion, marked vasoconstriction, or mechanical interference with spinal cord

Spinal Epidural Lipomatosis Spinal epidural lipomatosis (SEL) is a rare condition in which spinal nerve root compression occurs secondary to adipose tissue hypertrophy in the epidural space. It may effectively lead to spinal canal stenosis, with subsequent motor and sensory compromise. It is seen most in obese patients or those on longterm steroids.173 A small case series of nine SEL patients, one of whom was 25 weeks pregnant,174 revealed substantial neural compromise, ranging from lumbar radiculopathy to cauda equina syndrome. In this series, patients presenting with acute cauda equina syndrome were on average 37 years old and had an extradural fat to spinal canal ratio of 47%. Patients with chronic cauda equina symptoms were older (mean age 61 years) and had a much higher extradural fat to spinal canal ratio at 72%. Treatment was laminectomy and excision of extradural fat, with a high recovery rate over several months (up to four years).

Posterior column (deep touch, vibration, and proprioception)

Posterior spinal arteries

Descending motor tracts

Anterolateral spinothalamic tract (pain and temperature) Anterior spinal artery

Area of possible anastomosis between anterior and posterior arteries

Figure 15.4  Anatomy of spinal cord arterial supply.

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Roanne Preston and Jonathan Collins

blood flow. While most frequently seen in an older atherosclerotic population, it is classically associated with surgery (including aortic and spinal surgery) in which aortic blood flow is interrupted. Other risk factors are hypotension during GA or NA,178 vasoconstriction caused by epinephrine-containing LA solutions,179 and the hypercoagulable state of pregnancy.180 The diagnosis of ASAS is made after a sudden onset of progressive paraparesis, bladder dysfunction, and sensory loss to pain and temperature. Some experience neck or back pain before onset of neurological symptoms. The best diagnostic modality is MRI. Treatment is supportive, with specific therapies to reverse the process limited to high dose corticosteroids, anticoagulants, and antiplatelet drugs. Recovery is limited if there are occlusive lesions, aortic disorders, and angiomas. Residual bladder dysfunction often persists even when there is improvement in motor and sensory function. There is a handful of cases of ASAS presenting in the peripartum period.178–184 Not all patients had NA, and, in some cases, the only identifiable risk factor was pregnancy-associated hypercoagulability. Adding vasoconstrictors, such as epinephrine, to LA may constrict the anterior spinal artery. However, animal studies demonstrate that clinically relevant concentrations of epinephrine in the epidural space do not cause sufficient impairment of spinal cord blood flow to result in ASAS.185,186 Other animal studies implicate neuraxial opioid agonists in neurotoxicity,187 although decades of uneventful neuraxial opioid administration refute this. Despite an aging childbearing population, it is rare to find significant arteriosclerosis, but diseases with a vasculitic component, such as SLE, may affect spinal cord blood flow.188 In these patients, avoid epinephrine or other vasoconstrictors in the epidural or subarachnoid spaces. Close attention to maternal BP is, as always, paramount. Effective management of ASAS emphasizes early diagnosis and treatment of correctable factors. Pregnancy increases susceptibility to reduced spinal cord blood flow from engorged venous plexuses, exacerbated during the second stage of labor. Epidural catheter-induced vasospasm may present with a clinical picture like ASAS and should be considered in the differential diagnosis. Immediate management involves epidural catheter removal and urgent neurological evaluation.189

Degenerative Disorders Valuable Clinical Insights • N eurodegenerative diseases, while rare, are seen more often in parturients due to improving medical and rehabilitative therapies. • Thorough and frequent assessment of cardiorespiratory function is vital in predicting and managing decompensation. • Neuraxial anesthesia is mostly safe, but requires close attention to worsening of ventilatory dysfunction. • Succinylcholine is not to be used with most neuromuscular disorders. Response to nondepolarizing muscle relaxants may be unpredictable. Sugammadex appears safe.

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Spinal Muscular Atrophy Spinal muscular atrophy (SMA), a neurodegenerative disorder characterized by progressive destruction of anterior horn neurons in the spinal cord and brainstem, causes symmetrical proximal muscle weakness and atrophy. The incidence is approximately 1 in 11,000,190 with an AR inheritance pattern ­resulting from homozygous mutations in the Survival Motor Neuron 1 (SMN1) gene.191 Now recognized as a spectrum of phenotypes rather than discrete disease entities, the condition was previously classified into subtypes with an inverse relationship between disease severity and age at onset (Table 15.4). Spinal muscular atrophy does not appear to affect fertility. With more women with SMA reaching childbearing age, the ability to detect SMA in the fetus prenatally, and the availability of specific therapies for SMA, it is likely that the number considering pregnancy will increase. The classic features of SMA are progressive symmetrical proximal weakness typically affecting the lower limbs more than the upper, accompanied by fasciculations. Gait instability leading to wheelchair dependence is common. There is often respiratory impairment due to involvement of the intercostal and accessory muscles, with secondary kyphoscoliosis (and subsequent spinal instrumentation) contributing to the restrictive respiratory defect. Although cranial nerve involvement is uncommon (< 20% of cases), there is a report of a parturient with SMA 2 and vocal cord paralysis.192 This woman, diagnosed at age six, had a forced vital capacity of 2.1 L, 54% of the predicted value. She had a low forceps extraction under LEA, as vocal cord paralysis prevented Valsalva maneuvers. A review described 100 pregnancies in 67 patients with SMA; of these 25% had SMA type 2, 66% had SMA type 3, and two women had SMA type 4.190 All patients with the ability to walk had SMA type 3, while most of those with SMA type 2 were wheelchair dependent. Similarly, 70% of patients with SMA type 2 had scoliosis vs. none with SMA type 3. The incidence of fetal (polyhydramnios, IUGR, macrosomia) and maternal complications (gestational diabetes, hypertensive disorders) is unchanged compared to a reference population. Preterm ­delivery is more likely in parturients with SMA; one series reported a mean of Table 15.4  Spinal muscular atrophy subtypes

SMA subtype

Eponymous syndrome

SMA 0

Age at onset

Life expectancy

In utero, requires respiratory support from birth

Few weeks

SMA 1

Werdnig Hoffmann disease

Onset in infancy

Fatal by 2 years

SMA 2

Dubowitz disease

Onset at 6–18 months, unable to stand or walk independently

Lifespan 2–30 years

SMA 3

Kugelberg Welander disease

Onset in childhood, slow progression

Normal life expectancy

Onset in adulthood

Normal life expectancy

SMA 4

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36.1 completed gestational weeks.193 Although vaginal delivery is possible, the risk for operative delivery is higher in SMA, particularly for wheelchair users. Distortion of the bony pelvis caused by longstanding neuromuscular dysfunction may prompt pelvic assessment and CD. Operating table positioning, and surgical access, may be challenging in such cases.

of cases reported support using slowly titrated NA or GA with tracheal intubation and avoidance of muscle relaxants. One group reported GA plus bilateral TAP blocks to reduce postoperative narcotic requirement and respiratory dysfunction.200 Sugammadex has been used with varying degrees of success but without apparent adverse effects.201

Anesthetic Considerations

Friedreich Ataxia

Restrictive lung disease is frequently present in SMA, which poses a significant challenge to the obstetric anesthesiologist. A detailed assessment of pulmonary function should be made at the earliest opportunity and repeated during the third trimester since deterioration may occur, and perioperative noninvasive ventilation may be necessary. Spinal muscular atrophy does not contraindicate NA, but patient positioning can be challenging due to spinal instrumentation or chronic lower limb contractures. Single shot spinal, continuous spinal, CSE, and de novo epidural techniques have been described.192,194–196 Close attention must be paid to the cranial extent of the block in the presence of respiratory insufficiency since intercostal muscle paralysis may result in acute ventilatory decompensation. General anesthesia may be associated with difficult intubation due to restricted neck movement. As with other neuromuscular disorders, succinylcholine may cause acute hyperkalemia and sensitivity to nondepolarizing muscle relaxants. The combination of residual neuromuscular blockade and lower abdominal surgery may require extended postoperative ventilation. In patients with predictors of difficult laryngoscopy, awake fiberoptic intubation followed by maintenance with titratable short acting agents, such as propofol and remifentanil, may be ideal. Postoperative care requires a setting with the capability to institute and titrate advanced ventilatory support.

Amyotrophic Lateral Sclerosis Although amyotrophic lateral sclerosis (ALS) (previously known as Lou Gehrig disease) typically presents in older male patients (mean age at onset is 60 years), the onset of this progressive motor neuron disease has occurred in pregnancy,197 and there are successful pregnancies in known sufferers.198 Affecting the anterior horn cells of the spinal cord, ALS is the most common motor neuron disease, with an incidence of 2 per 100,000 population per year. It typically presents with loss of fine motor function in the upper limbs, with fasciculations and cramping. The disease progresses to involve the lower limbs, followed by the muscles of the tongue, pharynx, and larynx. Higher cortical function remains intact. Parasympathetic activity for bowel and bladder function remains relatively intact, as does ocular activity. Death usually occurs because of respiratory failure within 3–5 years of diagnosis, though disease severity and progression of ALS pregnant patients varies.199 Treatment includes riluzole and ridaravone, but safety data in pregnancy and lactation are limited. Peripartum anesthetic and obstetric management depend on the degree of respiratory compromise; the small number

Friedreich ataxia (FA) is an autosomal recessive neurodegenerative disease of the spinocerebellar tracts with a prevalence of 1:100,000. It consists of ataxia, dysarthria, muscle weakness, loss of tendon reflexes, and nystagmus. Most patients carry a GAA triplet repeat on both alleles of the FXN gene. The repeat length corresponds to patient age at disease onset (usually late childhood or early adolescence).202 Common complications include scoliosis, cardiomyopathy, myocarditis, complete heart block, and diabetes (15%).203 Survival beyond the second decade is unusual, with death frequently occurring due to cardiac complications. However, advances in supportive medical therapies mean that more women survive to childbearing years. There are a handful of reports of successful pregnancies in women with FA, with the largest series to date including 61 pregnancies in 31 women.202 Successful vaginal delivery occurred in most cases, although elective CD occurred for a variety of reasons, including deteriorating respiratory status in the third trimester.204 Respiratory compromise secondary to kyphoscoliosis and the high incidence of cardiac complications mandate multispecialty consultation and investigation (PFTs, ECG, echocardiography, glucose tolerance test) before and during pregnancy. Reported complications of pregnancy, labor, and delivery include PreE and preterm labor, although FA does not appear to increase the risk.202 There are reports of pulmonary embolism205 and profound weakness following magnesium sulfate (MgSO4) bolus administered for preterm labor.203 Preeclampsia may be challenging to treat in parturients with FA as extreme caution must be taken with magnesium; some authors assert that it is not an acceptable therapy.203,205 There is no evidence that pregnancy worsens the neuromuscular effects of the disease, nor the cardiomyopathy, though a proportion of patients report worsening symptoms postpartum.202 As with other degenerative conditions, the respiratory changes of pregnancy may be a challenge for patients with borderline respiratory reserve preconception.

Anesthetic Considerations Although reports are limited, both NA and GA have been used with success in parturients with FA. Each case must be individually assessed for respiratory function, cardiac status, severity and treatment of kyphoscoliosis, and associated pregnancy conditions such as PreE and TED. There is no evidence that spinal anesthesia exacerbates the disease.206 Avoid succinylcholine for GA, and sensitivity to nondepolarizing muscle relaxants is possible. Postoperative ventilatory support may be required.

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Postpolio Syndrome Postpolio syndrome (PPS) is also a degenerative disease of the anterior horn cells of the spinal cord. It typically develops 15 or more years after the initial illness in 15–80% of paralytic polio survivors.207 It is estimated that there are 15–20 million polio survivors worldwide. Despite the 1994 declaration that poliovirus was eradicated in the Western hemisphere, over half a million survivors remain in the United States.208 The diagnosis of PPS is one of exclusion, after ruling out other adult-onset motor neuron diseases. The hallmark of PPS is new muscle weakness or fatigability, persistent for at least one year. Pain is common (> 50% of PPA patients report daily pain), as is generalized fatigue, though these features are not required for diagnosis. Other symptoms include muscle atrophy in all four limbs, fasciculations and cramping, cold intolerance, dysphagia, and dysphonia secondary to bulbar muscle atrophy. Complete vocal cord paralysis has been described.209 Like the other degenerative motor neuron diseases, the respiratory muscles are often significantly affected in PPS. In combination with bulbar weakness, this may result in dyspnea and hypoventilation. A Norwegian registry study investigating perinatal outcomes in polio survivors found that prior polio infection increased the likelihood of PreE, UTI, APH, CD, (OR 2.7) and low birth weight.210 Although many women in both the developed and developing world must have completed pregnancies with PPS, there is a paucity of reports detailing anesthetic management. Important anesthetic considerations are the potential for significant respiratory compromise, bulbar dysfunction, sensitivity to anesthetic agents, and cold intolerance. Anesthetic management is based upon the patient’s physiologic and neurologic status. There are no data to support theoretical concerns of increased susceptibility to neurotoxicity of LA agents in patients with PPS; therefore, choice of NA versus GA is an individual decision.

Transverse Myelitis Transverse myelitis (TM) is a rare inflammatory disease of the spinal cord, associated with autoimmune disorders and a variety of bacterial and viral infections (including Covid-19).211 Most commonly presenting in the thoracic spinal cord, symptoms include back pain and progressive paraparesis with varying degrees of severity and symmetry. Management strategies during pregnancy include specific therapies for the underlying disease, high dose corticosteroids,212 and plasma exchange.213 Historically, around one-third of patients with TM make a full neurological recovery, with half of the remainder suffering severe permanent disability or death.214 It is controversial whether NA is associated with TM or not. Postulated mechanisms include misdirected immune response to direct needle trauma and LA mediated neurotoxicity.212,215–219 Successful pregnancies, with term vaginal deliveries, have been described in TM.220 Anesthetic management principles are similar for other acquired spinal cord injuries, including precautions against autonomic dysreflexia221 and avoidance of succinylcholine.

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Infectious Diseases Valuable Clinical Insights • Many microbial agents exhibit neurotropism, as highlighted by the incidence of Guillain-Barré Syndrome (GBS) and acute myelitis/encephalitis during the 2015 Zika Virus (ZIKV) epidemic. Global travel means that infectious causes such as ZIKV and schistosomiasis are possible in cases of myelitis in pregnancy. • Varicella Zoster Virus (VZV) reactivation is associated with a 1% incidence of acute myelitis secondary to direct viral invasion of the spinal cord. If left untreated, it may result in permanent neurologic impairment.

Introduction Many microorganisms display neurotropism, and therefore, cause spinal cord lesions, by inflammation, mass effect, and autoimmune mechanisms (Table 15.5). Infectious diseases are responsible for 20–40% of cases of transverse myelitis, and varicella zoster virus (VZV) is the most common cause.222–225 This section will cover the microorganisms most associated with spinal cord neurotropism in pregnancy: Zika, Varicella Zoster, and Schistosomiasis (see Chapter 22). Both Zika and Schistosomiasis are endemic in specific areas of the world, however global travel means cases are seen worldwide. Varicella Zoster causing zoster, or shingles, may occur in any adult who had an original chickenpox infection. Diagnosis of the specific microorganism is vital for targeted therapy, and therefore patient location and travel history are essential factors when dealing with an acute myelopathy. Magnetic resonance imaging of the spinal cord with contrast is the gold standard imaging technique for myelopathies.224

Zika Virus Zika virus (ZIKV) was studied extensively in early 2015 because of the sudden rise in neonates born with microcephaly in South America, the southern United States, and the Caribbean. A mosquito-borne flavivirus, transmitted mainly by Aedes aegypti mosquitoes, it may cause minor illness in the pregnant woman with fever, rash, joint pain, and conjunctivitis but have significant effects on the fetus. It was first isolated in 1947 from a monkey in Uganda, and in 1952 the first human Zika infection was diagnosed.228 Maternal fetal transmission is common, perinatal infection less frequent; it is also sexually transmitted. What became apparent after the first outbreak of Zika in French Polynesia in 2013 was the high associated incidence of Guillain-Barré syndrome (GBS) in adults (two- to ten-fold increase over baseline incidence of GBS). When one examines ZIKV neurological effects, there is a high incidence of encephalopathy, encephalitis, meningitis, seizure disorders, and myelitis in adults.229 In the few published cases of myelitis or myelopathy, MRI revealed extensive longitudinally located lesions throughout the spinal cord. Unlike ZIKV-associated GBS, a predominantly post infectious immune-mediated demyelinating process, the myelitis and myelopathy appear secondary to

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Table 15.5  Most common infectious diseases causing spinal cord compromise

Infectious agent

Diagnosis

Mass effect

Myelitis/ transverse myelitis

SCHM

CSF serology Eggs in feces

Yes

Yes

ZIKV

RT-PCR IgG antibodies

Yes

VZV

CSF VZV DNA and/or IgG antibodies

Yes

Staph Aur

Back pain, fever, blood culture

Cjejuni

Blood culture

TB

CSF culture CSF PCR

Lyme

Lyme IgG CSF and blood

Yes; rare

EBV

CSF EBV PCR Serologic tests

Yes

Yes

HSV

CSF and blood serology

Yes

Yes

CMV

CSF PCR and blood serology

Yes

Yes

Enteroviruses

CSF PCR

Yes

Yes

Fungal

MRI CSF fungus-specific antibodies

COVID-19

CSF SARS-CoV-2 RNA

Yes: pyogenic

BrownSequard syndrome

Spinal cord infarction

Yes

Yes

Yes

Yes

Yes

Yes Yes

Guillain-Barré syndrome

Yes

Yes: mainly thoracic

Yes Yes

Cjejuni = Campylobacter jejuni; CMV = cytomegalovirus; CSF = cerebrospinal fluid; EBV = Epstein-Barr virus; HSV = herpes simplex virus; MRI = magnetic resonance imaging; PCR = polymerase chain reaction; RT-PCR = reverse transcriptase polymerase chain reaction; SCHM = schistosomiasis; Staph Aur = Staphylococcus aureus; TB = Mycobacterium tuberculosis; VZV = varicella zoster virus; ZIKV = Zika virus. Created from references 223–227.

­euroinflammation via cytokines and macrophages versus n direct ZIKV infection of neurons.228 Genetic susceptibility to neurologic effects from ZIKV is not ruled out as a causative factor, but ZIKV appears to be neurotropic. This fits with the neurotropism seen with other flavivirus infections such as West Nile and dengue.230 It appears that ZIKV may cause simultaneous central and peripheral nervous system effects, given the number of reports of GBS with encephalitis and myelitis.231 Diagnosis of infection requires reverse transcriptase polymerase chain reaction (RT-PCR) analysis of bodily fluids and convalescent ZIKV IgG antibodies.231 Treatment of neuroinflammation is with high dose methylprednisolone, whereas GBS is treated with immunoglobulin therapy.232 Pregnant women presenting with symptoms congruent with acute myelitis and/or encephalitis who are either from an endemic ZIKV area or with history of recent travel from one of those areas should receive a ZIKV test. Because of the scale of the outbreak in 2015–2016, and the significance of its neurological effects, WHO declared ZIKV an international public health emergency and supported the rapid development of vaccines and antiviral drugs specifically for ZIKV. As of 2021, however, there is still no specific treatment or vaccine for ZIKV.

Varicella Zoster Virus Varicella zoster virus (VZV) is known for the painful blistering dermatomal skin rash called herpes zoster or shingles that occurs after reactivation from the dorsal root ganglia where it had been dormant after an active chickenpox infection. The

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most common factor implicated in viral reactivation is stress. Neurological complications are varied, and while uncommon (acute myelitis occurring in < 1% of cases), they can ­result in permanent neurological impairment. Myelitis usually occurs in the same dermatomes as the typical skin rash, often spreading to the contralateral side.222,233 Patients present with rapidly progressive spinal tract weakness and sensory loss, often with sphincter ­impairment days to weeks after a classic VSV rash appears. There are numerous reports of VZV myelitis presenting as Brown-Sequard syndrome, characterized by ipsilateral weakness and loss of proprioception below the level of a spinal cord lesion and contralateral loss of pain and temperature sensation.234,235 The cause of myelitis is believed to be a ­direct neural invasion by the virus versus an allergic or vascular cause, and cases demonstrate that multiple ganglia are invaded. Cerebrospinal fluid analysis typically shows pleocystosis, and VZV DNA or anti VZV IgG can be detected.236 Extensive longitudinal TM develops in many patients, although recovery is typically good if immunocompetent.222 Management of VZV myelitis usually involves antivirals (e.g., acyclovir) and cortico­ steroids, although this therapy combination does not always produce good outcomes. Plasmapheresis has been tried. The earlier that treatment is initiated, the more likely a full neurological recovery will occur.236 Relapses of TM can occur in the absence of a new rash. Herpes zoster occurs in pregnancy, with one study ­describing an incidence of 3.5 per 1000 women undergoing CD; GA was reported to be a risk factor.237 Another sporadic

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complication of VZV reactivation is spinal cord stroke. One report described a 28-year-old woman at 22 weeks gestation, presenting with severe interscapular pain in an itchy rash, followed by rapid flaccid paralysis of arms and legs.238 On examination, she had a typical T3 dermatomal vesicular rash on the right. Cerebrospinal fluid analysis did not show inflammation as one sees with myelitis, nor VZV DNA. Initial MRI was normal, but at 48 hours showed classic ASAS from C6 to T2. Treatment of herpes zoster infection in pregnancy is no different than for other adults; the development of severe neurologic complications such as myelitis mandates hospitalization and high-dose corticosteroid treatment.237

Schistosomiasis Schistosomiasis is a parasitic infection caused by several species of schistosomes that affects > 200 million people worldwide, mainly in subSaharan Africa, with 20 million severely affected.239,240 Schistosomiasis-induced spinal cord lesions account for 6% of cases of nontraumatic myelopathy in endemic areas. Because of global travel, cases occur in nonendemic areas, often with a delayed or initially incorrect diagnosis. The infectious cycle begins when the forked tail cercariae form enters the human body directly, usually via the feet. Once inside the body, the cercariae lose their tails and differentiate into the larval form. These schistosomulae migrate to the lung, then to the liver, and mate in the blood. Their eggs are excreted in urine and feces. Most of the infection effects are from the human immune response to the egg-secreted antigens, but the eggs may become entrapped in the intestinal wall or other organs, creating a mass effect. Neuroschistosomiasis occurs when eggs deposit in the CNS, triggering an immune reaction; it is estimated to occur in 1–4% of people with systemic infection.240 While S. japonicum eggs may reach the brain, S. mansoni and S. haematobioum usually stay in the spinal cord, causing myelopathy, radiculopathy, and occasionally anterior spinal artery occlusion. Spinal cord symptoms may take years to develop following infection by the cercariae. Spinal schistosomiasis has three forms: ­medullary, myeloradicular, and cauda equina syndrome; classic clinical presentation is acute/ subacute lower spinal cord symptoms.240,241 The mean age of neuroschistosomiasis presentation is 28 years for S. mansoni, and is predominantly in men. However, cases have occurred in women of childbearing age.240 Unfortunately, in nonendemic areas, the MRI findings may lead to the erroneous diagnosis of neoplasm, and in one case, this resulted in pregnancy termination.242 Serum and CSF schistosomal serology facilitate the diagnosis but eggs are never found in the CSF. However, there is frequently CSF eosinophilia. On MRI, typical granulomatous spinal cord lesions and swelling of the conus medullaris are seen.239 Treatment of the spinal cord lesions consists of antiparasitic therapy (praziquantel) and corticosteroids. In cases with significant mass effect, prevention of permanent spinal cord damage may require spinal surgery.243 Neuroschistosomiasis, manifesting mostly as myeloradiculopathy or transverse myelitis, can lead to severe and permanent neurological disability if not diagnosed and treated.

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Summary Diseases of the spinal cord in women in the childbearing years range from the very rare to the merely uncommon. As the average age of parturients rises in many countries, some diseases have become more prevalent, or the disease state, such as spinal dysraphism, has more women surviving to adulthood. Spinal cord tumors and vascular malformation, while rare, are prone to progression during pregnancy. A remarkable number of infectious disease agents affect the spinal cord. For this reason, more cord-compromised patients will present for obstetric anesthesia care in the future. Appropriate management decisions stem from an appreciation of the disease processes and the interaction of these processes with pregnancy. Diagnostic imaging should never be withheld because of pregnancy, and it is clear that many required therapies are safe for the pregnant woman and the fetus. The challenge is to achieve outcomes in these patients comparable to the general obstetric population. This is most likely with interdisciplinary care in specialty centers. Providing care to these women is a tremendously gratifying experience.

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170. Ghaly RF, Tverdohleb T, Candido KD, et al. Management of parturients in active labor with Arnold Chiari malformation, tonsillar herniation, and syringomyelia. Surg Neurol Int 2017;8:10. 171. Parker JD, Broberg JC, Napolitano PG. Maternal Arnold-Chiari type I malformation and syringomyelia: a labor management dilemma. Am J Perinatol 2002;19:445–450. 172. Ghaly RF, Candido KD, Sauer R, et al. Anesthetic management during cesarean section in a woman with residual ArnoldChiari malformation type I, cervical kyphosis, and syringomyelia. Surg Neurol Int 2012;3:26. 173. Billings F, Hoyt MR. Epidural lipomatosis causing new debilitating back pain in a patient with human immunodeficiency virus on highly active antiretroviral therapy. Int J Obstet Anesth 2012;21:367–370. 174. Kellett CG, Siva V, Norman ICF, et al. Symptomatic idiopathic spinal epidural lipomatosis in 9 patients: clinical, radiologic, and pathogenetic features. World Neurosurg 2019;126:e33–e40. 175. Smith MK, Martin R, Robblee J, et al. A case of epidural lipomatosis in pregnancy: management during labour and caesarean section. J Obstet Gynaecol Can 2018;40:1182–1185. 176. Demondion X, Lefebvre G, Fisch O, et al. Radiographic anatomy of the intervertebral cervical and lumbar foramina (vessels and variants). Diagn Interv Imaging 2012;93:690–697. 177. Barré J DAC. Paraplegia par ramollissement aigu unisegmentaire de la moelle, survenue au cours de la grossesse. Rev Neurol 1938;69:133–135. 178. Zaphiratos V, McKeen DM, Macaulay B, et al. Persistent paralysis after spinal anesthesia for cesarean delivery. J Clin Anesth 2015;27:68–72. 179. Ackerman WE, Juneja MM, Knapp RK. Maternal paraparesis after epidural anesthesia and cesarean section. South Med J 1990;83:695–697. 180. Dunn DW, Ellison J. Anterior spinal artery syndrome during the postpartum period. Arch Neurol 1981;38:263. 181. Gong J, Gao H, Gao Y, et al. Anterior spinal artery syndrome after spinal anaesthesia for caesarean delivery with normal lumbar and thoracic magnetic resonance imaging. J Obstet Gynaecol 2016;36:855–856. 182. Soda T, Shimizu I, Takagaki M, et al. A case of benign postpartum anterior spinal artery syndrome with thrombocytosis and high fibrolytic activity. Brain Nerve 2011;63:1125–1129. 183. Eastwood DW. Anterior spinal artery syndrome after epidural anesthesia in a pregnant diabetic patient with scleredema. Anesth Analg 1991;73:90–91. 184. Ben-David B, Vaida S, Collins G, et al. Transient paraplegia secondary to an epidural catheter. Anesth Analg 1994;79:598– 600. 185. Usubiaga JE. Neurological complications following epidural anesthesia. Int Anesthesiol Clin 1975;13:1–153. 186. Dohi S, Takeshima R, Naito H. Spinal cord blood flow during spinal anesthesia in dogs: the effects of tetracaine, epinephrine, acute blood loss, and hypercapnia. Anesth Analg 1987;66:599– 606. 187. Kakinohana M, Nakamura S, Fuchigami T, et al. Mu and delta, but not kappa, opioid agonists induce spastic paraparesis after a short period of spinal cord ischaemia in rats. Br J Anaesth 2006;96:88–94.

188. Markusse HM, Haan J, Tan WD, et al. Anterior spinal artery syndrome in systemic lupus erythematosus. Br J Rheumatol 1989;28:344–346. 189. Ben-David B, Vaida S, Collins G, et al. Transient paraplegia secondary to an epidural catheter. Anesth Analg 1994;79:598– 600. 190. Abati E, Corti S. Pregnancy outcomes in women with spinal muscular atrophy: a review. J Neurol Sci 2018;388:50–60. 191. Prior TWLM, Leach ME, Finanger E. Spinal muscular atrophy. In Adam MP, Everman DB, Mirzaa GM, et al. (Eds.), GeneReviews® [Internet]. Seattle, WA: University of Washington, 1993–2022. Available from: www.ncbi.nlm.nih .gov/books/NBK1352/ [last accessed October 25, 2022]. 192. Weston LA, DiFazio CA. Labor analgesia and anesthesia in a patient with spinal muscular atrophy and vocal cord paralysis. A rare and unusual case report. Reg Anesth 1996;21:350–354. 193. Awater C, Zerres K, Rudnik-Schoneborn S. Pregnancy course and outcome in women with hereditary neuromuscular disorders: comparison of obstetric risks in 178 patients. Eur J Obstet Gynecol Reprod Biol 2012;162:153–159. 194. Buettner AU. Anaesthesia for caesarean section in a patient with spinal muscular atrophy. Anaesth Intensive Care 2003;31:92–94. 195. Harris SJ, Moaz K. Caesarean section conducted under subarachnoid block in two sisters with spinal muscular atrophy. Int J Obstet Anesth 2002;11:125–127. 196. Wilson RD, Williams KP. Spinal muscular atrophy and pregnancy. Br J Obstet Gynaecol 1992;99:516–517. 197. Solodovnikova Y, Kobryn A, Ivaniuk A, et al. Fulminant amyotrophic lateral sclerosis manifesting in a young woman during pregnancy. Neurol Sci 2021;42:3019–3021. 198. Porto LB, Berndl AML. Pregnancy 5 years after onset of amyotrophic lateral sclerosis symptoms: a case report and review of the literature. J Obstet Gynaecol Can 2019;41:974–980. 199. Huston JW, Lingenfelder J, Mulder DW, et al. Pregnancy complicated by amyotrophic lateral sclerosis. Am J Obstet Gynecol 1956;72:93–99. 200. Li J, Zeng H, Li M, et al. Anesthetic management of a parturient with amyotrophic lateral sclerosis undergoing cesarean section. Chin Med J (Engl) 2020;133:1371–1372. 201. Gurunathan U, Kunju SM, Stanton LML. Use of sugammadex in patients with neuromuscular disorders: a systematic review of case reports. BMC Anesthesiol 2019;19:213. 202. Friedman LS, Paulsen EK, Schadt KA, et al. Pregnancy with Friedreich ataxia: a retrospective review of medical risks and psychosocial implications. Am J Obstet Gynecol 2010;203:224 e1–5. 203. Bruner JP, Yeast JD. Pregnancy associated with Friedreich ataxia. Obstet Gynecol 1990;76:976–977. 204. Leone M, Bottacchi E, Bussolino S, et al. A case of successful pregnancy in a woman with Friedreich ataxia. Ital J Neurol Sci 1992;13:439–441. 205. Armstrong BA, Howat PW. Pregnancy in a woman with Friedreich’s ataxia complicated by pulmonary embolism. Aust N Z J Obstet Gynaecol 2002;42:88–90. 206. Kubal K, Pasricha SK, Bhargava M. Spinal anesthesia in a patient with Friedreich’s ataxia. Anesth Analg 1991;72:257–258. 207. Lo JK, Robinson LR. Postpolio syndrome and the late effects of poliomyelitis. Part 1: Pathogenesis, biomechanical

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208. 209. 210. 211. 212.

213. 214. 215. 216.

217. 218. 219. 220. 221. 222. 223. 224. 225.

considerations, diagnosis, and investigations. Muscle Nerve 2018;58:751–759. Groce NE, Banks LM, Stein MA. Surviving polio in a post-polio world. Soc Sci Med 2014;107:171–178. Cannon S, Ritter FN. Vocal cord paralysis in postpoliomyelitis syndrome. Laryngoscope 1987;97:981–983. Veiby G, Daltveit AK, Gilhus NE. Pregnancy, delivery and perinatal outcome in female survivors of polio. J Neurol Sci 2007;258:27–32. Fumery T, Baudar C, Ossemann M, et al. Longitudinally extensive transverse myelitis following acute COVID-19 infection. Mult Scler Relat Disord 2021;48:102723. Kitazaki Y, Ueno A, Maeda K, et al. A case of longitudinally extensive transverse myelitis with an isolated pontine lesion following epidural and spinal anesthesia for cesarean section. eNeurologicalSci 2020;21:100264. https://doi.org/10.1016/j .ensci.2020.100264. Moranne O, Hachulla E, Valat AS, et al. Longitudinal myelitis in a pregnant patient with SLE. Am J Med 2004;116:355–357. Berman M, Feldman S, Alter M, et al. Acute transverse myelitis: incidence and etiologic considerations. Neurology 1981;31:966– 971. Hosseini H, Brugieres P, Degos JD, et al. Neuromyelitis optica after a spinal anaesthesia with bupivacaine. Mult Scler 2003;9:526–528. Hsu MC, Hung MH, Chen JS, et al. Acute transverse myelitis after thoracic epidural anesthesia and analgesia: should anesthesia and analgesia be blamed? Acta Anaesthesiol Taiwan 2013;51:37–39. Martinez-Garcia E, Pelaez E, Roman JC, et al. Transverse myelitis following general and epidural anaesthesia in a paediatric patient. Anaesthesia 2005;60:921–923. Seok JH, Lim YH, Woo SH, et al. Transverse myelitis following combined spinal-epidural anesthesia. Korean J Anesthesiol 2012;63:473–474. Shimada T, Yufune S, Tanaka M, et al. Acute transverse myelitis arising after combined general and thoracic epidural anesthesia. JA Clin Rep 2015;1:4. Thomas S, Massey S, Douglas J, et al. Obstetric anaesthesia and transverse myelitis. Int J Obstet Anesth 2010;19:467–468. Berghella V, Spector T, Trauffer P, et al. Pregnancy in patients with preexisting transverse myelitis. Obstet Gynecol 1996;87:809–812. Wang X, Zhang X, Yu Z, et al. Long-term outcomes of varicella zoster virus infection-related myelitis in 10 immunocompetent patients. J Neuroimmunol 2018;321:36–40. Grill MF. Infectious myelopathies. Continuum (Minneap Minn) 2018;24:441–473. Yokota H, Yamada K. Viral infection of the spinal cord and roots. Neuroimaging Clin N Am 2015;25:247–258. Rodríguez Y, Rojas M, Pacheco Y, et al. Guillain-Barré syndrome, transverse myelitis and infectious diseases. Cell Mol Immunol 2018;15:547–562.

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226. Duca LM, Beckham JD, Tyler KL, et al. Zika virus disease and associated neurologic complications. Curr Infect Dis Rep 2017;19:4. https://doi.org/10.1007/s11908-017-0557-x 227. Nanthakumar MP, Sood A, Ahmed M, et al. Varicella Zoster in pregnancy. Eur J Obstet Gynecol Reprod Biol 2021;258:283– 287. 228. Muñoz LS, Parra B, Pardo CA. Neuro viruses emerging in the Americas study. Neurological implications of Zika Virus infection in adults. J Infect Dis 2017;216:S897–S905. 229. Reid S, Rimmer K, Thakur K. Zika virus and neurologic disease. Neurol Clin 2018;36:767–787. 230. Mécharles S, Herrmann C, Poullain P, et al. Acute myelitis due to Zika virus infection. Lancet 2016;387:1481. 231. Mancera-Páez O, Román GC, Pardo-Turriago R, et al. Concurrent Guillain-Barré syndrome, transverse myelitis and encephalitis post-Zika: a case report and review of the pathogenic role of multiple arboviral immunity. J Neurol Sci 2018;395:47–53. 232. Nascimento OJM, da Silva IRF. Guillain-Barré syndrome and Zika virus outbreaks. Curr Opin Neurol 2017;30:500–507. 233. Abbas SA, El Helou J, Chalah MA, et al. Longitudinal extensive transverse myelitis in an immunocompetent older individual – a rare complication of varicella-zoster virus reactivation. Medicina (Kaunas) 2019;55:201. 234. Hosaka A, Nakamagoe K, Watanabe M, et al. Magnetic resonance images of herpes zoster myelitis presenting with Brown-Sequard Syndrome. Arch Neurol 2010;67:506. 235. Young-Barbee C, Hall DA, LoPresti JJ, et al. Brown-Séquard syndrome after herpes zoster. Neurology 2009;72:670–671. 236. Nagel MA, Gilden D. Complications of varicella zoster virus reactivation. Curr Treat Options Neurol 2013;15: 439–453. 237. Hayward K, Cline A, Stephens A, et al. Management of herpes zoster (shingles) during pregnancy. J Obstet Gynaecol Can 2018;38:887–894. 238. McNamara JF, Paterson DL, Allworth A, et al. Re-activation of varicella zoster virus associated with anterior spinal cord stroke in pregnancy. Infect Dis (Lond) 2016;48:705–707. 239. Algahtani HA, Aldarmahi AA, Al-Rabia MW, et al. Acute paraplegia caused by Schistosoma mansoni. Neurosciences (Riyadh) 2014;19:47–51. 240. de Wilton A, Aggarwal D, Jäger HR, et al. Delayed diagnosis of spinal cord schistosomiasis in a non-endemic country: a tertiary referral centre experience. PLoS Negl Trop Dis 2021;15:e0009161. 241. Ferrari TC, Moreira PR. Neuroschistosomiasis: clinical symptoms and pathogenesis. Lancet Neurology 2011;10: 853–864. 242. Palin MS, Mathew R, Towns G. Spinal neuroschistosomiasis. Br J Neurosurg 2015;29: 582–584. 243. Salim AD, Arbab MA, El Hassan LA, et al. Schistosomiasis of the spinal cord: report of 5 cases from Sudan. East Mediterr Health J 2012;18:294–297.

Chapter

16

Peripheral Neuropathies Cynthia A. Wong

Introduction Valuable Clinical Insights • A peripheral neuropathy occurs as a primary condition or as one manifestation of multisystem diseases. • Causes of peripheral neuropathies include genetic, inflammatory, traumatic, metabolic, vasculitic, neoplastic, dietary, and toxic triggers. • Pregnancy exacerbates some neuropathies or directly ­causes acute compression neuropathy. • A peripheral neuropathy does not usually directly impact anesthetic care but associated systemic disease manifestations may complicate peripartum anesthetic care. • The presence of a peripheral neuropathy, by itself, is not a contraindication to neuraxial anesthesia (NA).

Peripheral neuropathy takes many forms and occurs as a primary condition or as a component of many diseases with multisystem manifestations. There are manifold etiologies, including genetic, inflammatory, traumatic/compressive, metabolic, vasculitic, neoplastic, dietary, and toxic/drug-induced. They may be classified as mononeuropathy, multifocal neuropathy (mononeuropathy multiplex), or polyneuropathy.1 Peripheral neuropathies primarily affect the cell body and the axon (neuropathy, axonopathy) or the myelin sheath (demyelinating neuropathy/neurapraxia). As these categories are confusing and of little use to the anesthesiologist, a simple etiological classification is used here (Table 16.1). Neuropathies may affect sensory, motor, autonomic nerves, or a combination. Longer neurons are usually the most

susceptible, so a predominantly distal distribution is typical. Signs and symptoms may include muscle weakness and wasting, peripheral in onset, usually affecting the lower limbs first, with loss of tendon reflexes, and sometimes with fasciculation, glove and stocking sensory loss, paresthesias, spontaneous pain, and autonomic dysfunction.2 Pregnancy can exacerbate some neuropathies, while pregnancy or parturition can be a direct or indirect cause of a variety of mononeuropathies and plexopathies,3 many of which may be wrongly attributed to NA.4 The presence of peripheral neuropathy does not usually directly impact anesthetic care, but associated systemic disease manifestations can complicate peripartum anesthetic care. Some peripheral neuropathies alter drug sensitivity or impair respiration, presenting unique challenges to the anesthesiologist. In general, the presence of peripheral neuropathy is not a contraindication to the use of NA for CD. However, the neuropathy should be well-documented in the medical record, including a thorough neurologic examination. Carefully position the patient and protect pressure points, as the underlying neuropathy or sensorimotor blockade of NA might mask acute compression or stretch injury of peripheral nerves. Valuable Clinical Insight A peripheral neuropathy is not a contraindication to the use of NA; however, careful patient positioning is required, as the underlying neuropathy or the sensorimotor blockade of NA might mask acute compression or stretch injury of peripheral nerves.

Table 16.1  Classification of peripheral neuropathies

HEREDITARY NEUROPATHIES Hereditary Sensory Motor Neuropathies (HSMN) Charcot-Marie-Tooth disease type 1 (subtypes A–F)

Autosomal dominant demyelinating neuropathies

Charcot-Marie-Tooth disease type 2

Autosomal dominant axonal neuropathies

Charcot-Marie-Tooth disease type 3 (HSMN type 3)

Demyelinating polyneuropathy

Charcot-Marie-Tooth disease type 4

Autosomal recessive neuropathies

X-linked HSMN Hereditary neuropathy with liability to pressure palsy

Autosomal dominant demyelinating neuropathy

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Cynthia A. Wong

Table 16.1  (Cont.) Hereditary Sensory Autonomic Neuropathies (HSAN) HSAN type 1

Autosomal dominant

HSAN type 2

Autosomal recessive or sporadic

HSAN type 3 (Riley-Day syndrome, familial dysautonomia)

Autosomal recessive, primarily in Ashkenazi Jews

Neurofibromatosis type 1

Autosomal dominant

Neurofibromatosis type 2

Autosomal dominant

INFLAMMATORY DEMYELINATING POLYNEUROPATHIES Guillain-Barré syndrome

Acute demyelinating and axonal forms, autoimmune

Chronic inflammatory demyelinating polyneuropathy

Demyelinating

TRAUMATIC/COMPRESSIVE MONONEUROPATHIES AND PLEXOPATHIES Cranial nerve lesions Cranial nerve VII (Bell palsy) Other cranial nerves (V, IV, VI, VIII) Upper limb neuropathies Radial nerve palsy Carpal tunnel syndrome Obstetric palsies Lumbosacral plexopathy Femoral neuropathy Obturator neuropathy Lateral femoral cutaneous neuropathy (meralgia paresthetica) Sciatic neuropathy Peroneal neuropathy Lumbosacral plexopathy NEUROPATHIES SECONDARY TO OTHER CONDITIONS Diabetes

Polyneuropathy, autonomic neuropathy

Porphyria

Peripheral and autonomic neuropathy

Infection Vasculitis Sarcoidosis Poisoning (heavy metals and solvents) Deficiency states Drug-induced Conditions are listed in the order in which they appear in the text.

Hereditary Sensory Motor Neuropathies Hereditary sensory motor neuropathies (HSMN) are a heterogeneous group of inherited neuropathies. Historically grouped together and called Charcot-Marie-Tooth disease (CMTD), classification has become increasingly confusing as novel gene sequencing technology has led to a better understanding of the disease inheritance.5,6 Multiple different genes are associated

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with HSMN, and several phenotypes can arise from different mutations of the same gene.7

Charcot-Marie-Tooth Disease Types 1 and 2 Charcot-Marie-Tooth disease (CMTD), often used synonymously with HSMN, refers to a group of inherited peripheral neuropathies. Although most CMTD is familial, mutations

Peripheral Neuropathies

may occur de novo.6 Historically, CMTD has been classified into types 1 and 2, although it is now clear that both types are heterogeneous entities caused by mutations of different genes. Charcot-Marie-Tooth disease type 1 (CMTD1) refers to the autosomal dominant demyelinating/dysmyelinating neuropathies. CMTD1A is the most common subtype of CMTD, accounting for 60–70% of CMTD1 disease; it is associated with duplication of peripheral myelin protein-22 gene (PMP22).5 CMTD1A presents in childhood with difficulty walking, sometimes accompanied by pes cavus. There is weakness and wasting of the lower legs, foot drop, steppage gait, reduced tendon reflexes, later involvement of the hands and trunk, and variable distal sensory loss. The condition is slowly progressive. Other, less common types of CMTD1 (B, C, D, E, F) are associated with different genetic mutations. For example, CMTD1B arises from a mutation in the myelin protein gene (MPZ), the major myelin protein. The phenotypes for the subtypes differ. Some patients present with early severe disease, while others have minimal disability throughout life, even within a subtype.6 Charcot-Marie-Tooth disease type 2 (CMTD2) refers to the autosomal dominant axonal neuropathies that often present later in life than CMTD1. It, too, has proven to be a heterogeneous mix of disorders with different subtypes.6 Clinically, it is difficult to distinguish between CMTD1 and CMTD2; nerve conduction studies are helpful. Conduction velocity is slowed in CMTD1, whereas it is normal or near-normal in CMTD2. Overall, the symptoms of CMTD tend to progress slowly over decades. The hands may become involved in some cases. Autonomic function is maintained; walking difficulty is usually the primary disability.2

X-linked Charcot-Marie-Tooth Disease X-linked Charcot-Marie-Tooth disease (CMTDX) is the second most common type of CMTD, accounting for 10–16% of CMTD cases. It is caused by mutations in the X chromosome-linked gene connexin32kd (Cx32).6 Because they only have one X chromosome, men have worse disease than women. Individuals start to develop symptoms in the late second or early third decade of life. The disease is slowly progressive and is not associated with a shortened lifespan.

Hereditary Sensory Motor Neuropathy Type 3 Formally known as Dejerine-Sottas disease, HSMN type 3 (also known as CMTD3) is a severe demyelinating polyneuropathy of early infancy inherited as autosomal dominant or recessive, depending on the gene mutation involved. This disease may present at birth with severe hypotonia, weakness, feeding difficulty, and joint contracture.7

Charcot-Marie-Tooth Disease Type 4 Charcot-Marie-Tooth disease type 4 (CMTD4) is a heterogeneous group of autosomal recessive neuropathies. Clinical deficits may be severe with significant proximal muscle weakness and skeletal deformities.6

Obstetric and Anesthesia Management in Women with Charcot-Marie-Tooth Disease Data are scarce regarding obstetric and anesthetic management of women with CMTD. Several small cohort studies have assessed pregnancy outcomes in women with CMTD. In a study using data from the Medical Birth Registry of Norway (1967–2002) identifying 49 women and 108 births, the operative delivery rate was higher in women with CMTD than women without CMTD.8 The incidence of postpartum hemorrhage was also higher. In contrast, in two studies from Germany with non­ overlapping patient populations, no differences in obstetric outcomes were identified.9,10 Approximately one-third of women reported worsening symptoms during pregnancy. Spinal anesthesia used in 80% of CD produced no adverse anesthetic effects. The type of anesthesia did not correlate with worsening postpartum disease.10 Other case reports and case series describing peripheral and neuraxial nerve blocks in patients with CMTD document uneventful recovery without worsening the disease.11 Despite concerns about succinylcholine use in patients with CMTD, a review of 86 cases of patients with CMTD who received succinylcholine had zero instances of symptomatic hyperkalemia or other untoward effects.12 The authors postulated that denervation is much slower than muscle atrophy; thus, the amount of muscle available to release potassium is small. CMTD is not associated with a risk of malignant hyperthermia. Rarely, CMTD may be associated with scoliosis. These patients may develop restrictive lung disease with significant pregnancy compromise.13 Neuraxial anesthetic procedures may be technically challenging (see Chapter 12).

Valuable Clinical Insight Charcot-Marie-Tooth disease is not associated with increased risk for malignant hyperthermia or hyperkalemia following administration of succinylcholine.

Hereditary Neuropathy with Liability to Pressure Palsies Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal dominant disorder with variable penetrance that can present at any age. The cause of HNPP is deletion of the distal segment of chromosome 17p, which contains the gene for PMP22.6 Mechanical stressors, such as stretching, compression, or repetitive movement, may injure peripheral nerves.6 Such nerve injuries lead to areas of local demyelination and cause episodes of numbness or weakness of varying duration. Many individuals with HNPP have an underlying, slowly progressive, demyelinating sensory neuropathy.2 The condition may exacerbate neuropathies associated with pregnancy and delivery, such as lumbosacral plexus, femoral, lateral femoral cutaneous, obturator, or peroneal nerve palsies, more often than is appreciated.14

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Anesthetic Management of Hereditary Neuropathy with Liability to Pressure Palsies Management principles for pregnant patients with HNPP can be found in Table 16.2. The HNPP website advises on positioning during surgical procedures.15 Dense LA blockade should be avoided as it may mask or contribute to compression neuropathy.16 One report describes a patient with HNPP who presented for CD with a history of temporary loss of arm function after using a noninvasive BP cuff during her last CD.17 An arterial catheter was placed for continuous BP monitoring instead of a BP cuff during uneventful spinal anesthesia for delivery. Valuable Clinical Insight Dense sensory and motor blockade during neuraxial labor analgesia should be avoided in parturients with hereditary neuropathy with liability to pressure palsies. Extremities should be well padded, especially during surgical anesthesia.

Hereditary Autonomic Neuropathies Peripheral autonomic dysfunction is a prominent manifestation of many neuropathies, including specific hereditary neuropathies.18 Signs and symptoms of autonomic dysfunction include impairment of cardiovascular, gastrointestinal, urogenital, thermoregulatory, sudomotor, and pupillomotor functions. In clinical practice, dysautonomia is more likely a complication of diabetes than a genetic condition. Like HSMN, autonomic neuropathies are a heterogeneous group of disorders. Sensory loss with dysautonomia is characteristic of hereditary sensory and autonomic neuropathies (HSAN).18 The autonomic dysfunction Table 16.2  Peripartum management of parturients with hereditary neuropathy with liability to pressure palsies16

Antepartum

• •

Consultation with a neurologist Assessment of neurologic status

Peripartum

• • • •

Avoid prolonged immobilization during labor Avoid dense epidural labor analgesia Avoid operative vaginal delivery Consider CD if pressure palsy develops during labor

Cesarean deliverya

• • • • • •

Position arms to sides, angle < 90 degrees Consider positioning while awake Extensively pad arms and legs Tape endotracheal tube centrallyb Move arms (supinate/pronate) every 15 minutes under GA Avoid leaning on the patient

a  From the HNPP website (https://web.archive.org/web/20161126113558/) [last accessed October 15, 2022].15

 Fully support the endotracheal tube with tape so that it is not pulling on the mouth. Tape other tubing in a similar manner. b

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of Shy-Drager syndrome does not typically affect women of childbearing age. Type 1 HSAN is associated with an autosomal dominant mutation in the gene that encodes subunit 1 of the serine palmitoyltransferase (SPTLC1). Patients usually present in the second decade of life with distal pain and sensory loss (primarily nociceptive and thermal perception) that gradually evolve to include anhidrosis, trophic ulcers, acral injuries, stress fractures, and osteomyelitis. Type 2 HSAN (hereditary sensory and autonomic neuropathy or Morvan disease) presents in early childhood. Autonomic dysfunction includes episodic hyperhidrosis, tonic pupils, constipation, and apneic episodes.18 Type 3 HSAN, also known as Riley-Day syndrome or familial dysautonomia (FD), is an autosomal recessive genetic disorder caused by a mutation in the gene that expresses I-kappa B kinaseassociated protein (ELP1).19 The incidence is 1 in 3700 live births among Ashkenazi Jews.18 Presenting in infancy, it features autonomic instability (abnormal sweating, loss of vasomotor control, labile blood pressure), sensory involvement (impaired taste with absence of fungiform papillae, diminished pain and temperature sensation, hyporeflexia), unexplained fever, vomiting attacks, impaired respiratory reflexes with frequent episodes of aspiration pneumonia, blunted responses to hypoxia and hypercarbia, dry eyes, and corneal anesthesia with ulceration.2,18 The disease progresses through life. Orthostatic hypotension, lack of compensatory tachycardia, and supine hypertension are key components of the disease. By age 20 years, 80% of individuals have some degree of kyphoscoliosis.19 Renal function deteriorates with age. Craniofacial findings include micrognathia, malocclusion, and dental crowding. Upper airway obstruction and restrictive lung disease are common. Autonomic crisis (hypertensive vomiting attacks), caused by sympathetic outflow leading to the uncontrolled release of catecholamines, can be triggered by emotion, illness, abdominal discomfort, and a full bladder. Individuals are at increased risk for sepsis. Viable pregnancies with normal offspring have been described in women with FD,20 although pregnancies are considered high-risk because of BP lability.19 Hypertension ­secondary to FD must be distinguished from pregnancy-related hypertension.

Anesthetic Considerations for Parturients with Dysautonomia A woman with dysautonomia is at increased risk in pregnancy and parturition. She may suffer from repeated vomiting, blunted respiratory responses, and inability to compensate for intravascular volume depletion. There may also be reduced respiratory reserve. Since pain during uterine contractions is typical, NA is indicated.19 Because of chronic exposure to low levels of catecholamines, there is hypersensitivity to exogenous transmitter substances but insensitivity to indirect-acting vasopressors such as ephedrine. Peripartum, histamine2-receptor blockers (e.g., ranitidine), and prokinetics (e.g., metoclopramide) are recommended for aspiration prophylaxis. Early recognition and treatment of fluid depletion can reduce hemodynamic instability. Inadequate analgesia may precipitate an autonomic crisis, while norepinephrine

Peripheral Neuropathies

deficiency and an unpredictable vasopressor response may complicate NA. One alternative is to induce labor analgesia with intrathecal opioids, with appropriate respiratory monitoring, while gradually introducing epidural LA for late first-stage and second-stage analgesia (combined spinal-epidural analgesia). Cesarean delivery may be performed with epidural anesthesia or CSE using a low dose of bupivacaine or ropivacaine with fentanyl. Fluid loss must be scrupulously replaced, irrespective of the anesthetic technique. Direct arterial pressure monitoring, and postoperative ventilation should be considered if GA is used.

Valuable Clinical Insight Parturients with familial dysautonomia are at risk for peripartum hemodynamic lability. They have increased sensitivity to direct-acting vasoactive drugs but decreased sensitivity to indirect-acting drugs.

Neurofibromatosis Types 1 and 2 Neurofibromatosis is a common hereditary disease that affects the central and peripheral nervous systems (see Chapter 13). Both neurofibromatosis type 1 (NF1) and neurofibromatosis type 2 (NF2) are autosomal dominant diseases with variable penetrance; familial inheritance can be identified in approximately half of the cases. Both types tend to form tumors associated with nervous tissue and other organs.21 NF1 (von Recklinghausen disease) arises from a mutation in the neurofibromin gene (NF1), and NF2 (also known as acoustic neurofibromatosis) is caused by mutation in the merlin gene (NF2) (also called schwannomin). Skin and peripheral nerve lesions are more common in NF1, and CNS lesions are more common in NF2. Café au lait spots, together with freckling, are the hallmarks of NF1, while in NF2 acoustic neuromas are present in > 90% of individuals, and skin plaques are typical. Spinal deformities may be present in both conditions. Pregnancy can stimulate tumor growth in both diseases. Large pelvic or genital neurofibromas may interfere with vaginal delivery. NF1 is associated with an increased risk of hypertension and cerebrovascular complications.22 The most crucial anesthetic consideration is whether lesions in the spinal canal will interfere with NA and whether NA will cause bleeding. However, neurofibromas also occur in the oropharynx and larynx, potentially interfering with tracheal intubation.23 Magnetic resonance imaging of the spine is recommended before neuraxial procedures and US is useful in identifying a clear path to the epidural space.24,25 Restrictive respiratory impairment, if present, requires particular attention.

Valuable Clinical Insight Antepartum preanesthetic evaluation of parturients with neurofibromatosis should include assessment for neuraxial and airway neurofibromas.

Inflammatory Demyelinating Polyneuropathies Guillain-Barré Syndrome (Acute Inflammatory Polyneuropathy) Guillain-Barré syndrome (GBS), the most common cause of acute paralysis, is an acute inflammatory polyneuropathy, with an annual incidence of 0.4–1.7 cases per 100,000.2,7 The incidence is similar in pregnancy.26 Both acute demyelinating and acute axonal forms of the disease occur. Typically, the disease is idiopathic or triggered by infections such as Campylobacter jejuni, cytomegalovirus, Epstein-Barr virus, mycoplasma, hepatitis B, HIV, chlamydia, upper respiratory tract infection, and, rarely, after vaccine administration.2 Recently, Zika virus26 and SARS-CoV-227 infections have been associated with GBS. GBS affects both sexes and all ages, but with peak incidences in young adults and the elderly. Guillain-Barré syndrome is an autoimmune disease. Evidence supports a cell-mediated immunologic reaction directed at peripheral nerves, but the humoral immune system is likely also involved.2 The condition develops over a few days to weeks, during which time the patient’s condition may deteriorate rapidly. The first symptom is usually severe upper and lower back pain, followed by progressive symmetrical weakness starting in the legs, progressing to the trunk, and sometimes to the cranial nerves, with facial and bulbar weakness. There may be some sensory loss, but more commonly, paresthesia. Dysautonomia is typical, usually short-lived, manifesting as sinus tachycardia or bradycardia, facial flushing, profuse or absent sweating, labile BP, ileus, and urinary retention. Approximately one-quarter of patients may require mechanical ventilation. There is increased CSF protein in the acute phase of the disease. The patient usually recovers within weeks or months. There may be residual muscle weakness in 10–40% of cases. Most mortality is due to autonomic instability, although respiratory and bulbar failure may contribute. The mortality rate, therefore, varies depending on the quality of care.2 The presence of a gravid uterus increases the risk for ventilatory assistance and exacerbates circulatory instability.26 Guillain-Barré syndrome is associated with an increased relapse rate and high maternal morbidity in pregnancy and the puerperium. The outlook for the fetus is good if maternal homeostasis is maintained.

Management of Guillain-Barré Syndrome Pregnancy does not alter the management of GBS, and GBS does not alter the process of pregnancy and labor, although these patients certainly require particular attention.26 In general, patients should be monitored in the hospital during the initial phases of the syndrome. It is vital to treat both respiratory weakness and swallowing difficulty promptly. Forced vital capacity (FVC) should be monitored since it is desirable to treat respiratory weakness before the blood gases are seriously disturbed. While noninvasive respiratory support has obvious advantages, the presence of bulbar weakness may necessitate tracheal intubation to prevent aspiration pneumonitis,

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provide safe mechanical ventilation, and tracheobronchial suction. Circulatory support, attention to electrolyte balance, and thromboprophylaxis are also needed. Severe cases (defined as those unable to walk without assistance), including those in pregnancy, may be treated with plasma exchange or immunoglobulins (IVIg).2,26 Intravenous immunoglobulins have become the treatment of choice because of convenience and the ability to infuse via a peripheral intravenous catheter.26 Corticosteroid administration has not shown a benefit.

Anesthetic Considerations in a Parturient with Guillain-Barré Syndrome Both epidural28–30 and CSE31 techniques have been used successfully for labor analgesia and CD anesthesia in patients with active GBS and those in the recovery phase. Sensitivity to NA with LA may be increased29,32; hypotension and bradycardia may be excessive. Small, gradually titrated doses of low-dose local anesthetic and opioid combinations are therefore advisable, with the administration of small doses of a direct-acting vasopressor if needed. Responses to the latter drugs are erratic. When NA is used for CD, respiratory reserve should be thoroughly assessed. General anesthesia may be used in the parturient with GBS, but succinylcholine may cause dangerous hyperkalemia, even in the recovery phase of the disease.32 Autonomic instability may provoke severe hypotension from the induction agent. There is increased sensitivity to all neuromuscular blocking agents, and respiratory depressant drugs should be administered with care.29 Bulbar weakness necessitates aspiration pneumonia prophylaxis to mitigate the danger of pulmonary aspiration during both induction and recovery from anesthesia.

Traumatic/Compressive Mononeuropathies and Plexopathies Most mononeuropathies and plexopathies that arise in pregnancy or parturition have a physical origin, but some, such as brachial plexus palsy, may have an inflammatory element.

Cranial Nerve Lesions Idiopathic facial (VII) nerve palsy (Bell palsy), the most common cranial nerve palsy seen in pregnancy, is about three times more common in pregnancy than in the nonpregnant population. Most cases arise in the third trimester and the first two weeks postpartum.3 The etiology is poorly understood; relative immunosuppressive allowing reactivation of herpes viruses in the geniculate ganglion, increased extracellular water, hypertension, hypercoagulation, and altered hormone levels are possible causes of Bell palsy. It appears to be associated with PreE, diabetes mellitus, migraine, and other cranial nerve palsies in pregnancy. The presentation does not differ from that in nonpregnant individuals, although the course may be more severe. The sufferer cannot wrinkle the brow, raise the eyebrow, close the eye, purse the lips, whistle, or smile on the affected side. There may also be dribbling and dysphagia; involvement of the chorda tympani branch may cause a partial loss of taste in the tongue and altered lacrimal and salivary secretion.34 Permanent dysfunction is unusual; recovery within the first three months postpartum is the norm. Treatment with prednisone, recommended when initiated within three to seven days of symptom onset, has been successful with no apparent adverse effect on the mother or fetus.

Valuable Clinical Insight Valuable Clinical Insight Dysautonomia and respiratory compromise are common in pregnant patients with Guillain-Barré syndrome. Succinylcholine may cause dangerous hyperkalemia, and increased susceptibility to anesthetic agents (causing cardiopulmonary compromise) is likely.

Chronic Inflammatory Demyelinating Polyneuropathy Chronic inflammatory demyelinating polyneuropathy (CIDP) is a condition that appears similar to GBS but is chronic or relapsing, with widespread demyelination.7 Dysautonomia and respiratory failure are rare. In a systematic review of 24 women with CIDP, 17 developed the disease during their first pregnancy, and 8 had a relapse during a subsequent pregnancy.33 The treatment of CIDP includes plasmapheresis or immunoglobulin therapy, but, unlike GBS, the chronic condition responds to corticosteroids. The fetus and neonate are not affected by CIDP. Obstetric and anesthetic management is similar to GBS.

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Bell palsy in pregnancy is treated with corticosteroids, initiated within three to seven days of symptom onset.

Involvement of the spinal nucleus of the trigeminal (V) cranial nerve in the cervical cord, causing transient facial weakness, has been reported in association with a high epidural block during labor.35,36 Because of the inverted representation of the fibers, the upper division is involved first, requiring special care of the eye as the corneal reflex may be lost. Trigeminal, facial, abducent (VI), and vestibulocochlear (VIII) nerve palsies may occur from loss of CSF after an unintended dural puncture in parturients,37–39 and even after puncture with a 25-gauge pencilpoint needle.40 The response of these palsies to epidural blood patch is not always encouraging. However, a cranial nerve palsy associated with a dural puncture is an indication for an epidural blood patch.39

Upper Limb Neuropathies Radial Nerve Palsy The radial nerve is vulnerable in the spiral groove at the mid humeral region. Radial neuropathy, resulting in upper arm

Peripheral Neuropathies

weakness and commonly known as Saturday night palsy, has been described following prolonged use of a birthing bar.41

Carpal Tunnel Syndrome Carpal tunnel syndrome, the most common mononeuropathy occurring during pregnancy, results from compression of the median nerve beneath the flexor retinaculum at the wrist.3 Estimates of incidence during pregnancy vary widely from 1% to 60%. The most likely etiology is edema in the tissues of the carpel tunnel, although other factors may contribute.3 Numbness, tingling, and burning sensations in the hand may radiate up the arm and worsen at night, often causing sleep disturbance. There may also be thenar wasting. The symptoms may be relieved by shaking the hand or otherwise keeping it moving. Although it usually resolves postpartum, it may arise de novo at this time (lactational carpal tunnel syndrome) and resolve only after weaning.

Neuralgic Amyotrophy Neuralgic amyotrophy is an inflammatory disorder, primarily of the upper extremity nerve trunks.3,42 An autosomal dominantly inherited disorder has been linked to mutations in the septin (SEPT9 ) gene and presents with recurrent episodes of plexopathy. Precipitating events occur in ~ 50% of idiopathic cases, including trauma, infection, vaccination, and pregnancy. The condition may be unilateral or bilateral and exhibits severe pain and weakness in the arm and shoulder girdle. Treatment is with corticosteroids if the diagnosis is within one month of the start of symptoms.42 The mode of delivery does not appear to be a risk factor for postpartum episodes.3 Overall, complete recovery occurs in 75% of cases within three years.

Obstetric Palsies In the past, when labor might continue for several days, and CD, like anesthesia, was rare, obstetric palsies were well recognized. Several surveys between 1935 and 1965 reported incidences ~ 1 in 2000 deliveries.43–45 The classical syndrome, once termed traumatic neuritis of the puerperium, arose from pressure of the fetal head on the lumbosacral trunk as it crossed the pelvic brim.3,46 The current incidence of postpartum neuropathy is difficult to determine because survey studies are too small to detect what has become a rare event, and there is a lack of control groups and relevant recorded data. Neuraxial anesthesia frequently gets blamed for many neurologic disorders, although they are about five times more likely to result from obstetric factors.47 Any form of anesthesia, signifying as it does a complicated labor, may be associated with an increased incidence of neurologic sequelae.48 Transient neurapraxia involving the femoral, lateral femoral cutaneous, obturator, peroneal, and sciatic nerves can occur after vaginal delivery.49,50 As in the past, nulliparity, prolonged second stage, prolonged lithotomy position, and assisted delivery, rather than NA, are associated factors.50 However, the parturient with neuraxial labor analgesia should be encouraged to change positions at regular intervals as sensory blockade may block the symptoms of nerve compression.50–52

Root damage, usually mild and causing only paresthesia, may follow epidural analgesia. One survey detected one case among 13,000 women receiving epidural labor analgesia,47 while the incidence following spinal anesthesia is probably tenfold higher.53

Lower Limb Neuropathies Lumbosacral Plexus Injury Lumbosacral plexus injury is a cause of postpartum foot drop. The lumbosacral plexus is created by L4, L5, and sacral roots. However, it is only the lumbosacral trunk (the union of the L4 and L5 roots) that crosses the pelvic brim where it is maximally vulnerable to compression from the fetal head during labor. There may be sciatic-type pain during labor, with postpartum foot drop due to weakness of the anterior tibial and peroneal muscles, and paresthesias or numbness of the outer leg and foot, for months after. Gluteal involvement may occur, and the condition is occasionally bilateral. Sufferers are often primiparous, have long labors, difficult vaginal deliveries, and deliver large babies.43–45, 50

Femoral Nerve Palsy Transient femoral neurapraxia is not uncommon after vaginal delivery.49,50 The femoral nerve is vulnerable to stretching injury as it passes beneath the inguinal ligament, especially with prolonged flexion, abduction, or external rotation of the hip joint. Femoral neuropathy may follow prolonged and excessive lithotomy position54 and occurs after a difficult vaginal delivery.55 Signs and symptoms are weak straight leg raising, a diminished patella reflex, and numbness of the anterior thigh. Some hip flexion is usually present as iliopsoas muscle function is preserved; walking is, therefore, possible, but mounting stairs is not.

Obturator Nerve Palsy The obturator nerve may be compressed where it crosses the brim of the pelvis or within the obturator canal, so it is vulnerable during difficult vaginal deliveries.3 Nevertheless, cases are rarely reported among parturients, suggesting the diagnosis is often missed. Three cases were detected when sought prospectively.50 The mother may complain of pain and weakness of hip adduction and internal rotation, with sensory disturbance over the upper inner thigh.

Meralgia Paresthetica Meralgia paresthetica arises from compression of the lateral femoral cutaneous nerve as it passes between the two divisions at the lateral end of the inguinal ligament where they attach to the anterior superior iliac spine. It is one of the most frequently encountered neuropathies in childbirth.47–50 It may occur both during pregnancy, typically about the thirtieth week of gestation, and intrapartum. The presence of edema may contribute. It may recur during successive pregnancies.56 Symptoms are unpleasant and include numbness, tingling, burning, or other paresthesias, affecting the anterolateral aspect of the thigh. The distribution is quite unlike a root lesion, yet when the condition is noted de novo postpartum, it is commonly attributed to neuraxial blockade by those unfamiliar with neuroanatomy. The symptoms usually resolve following childbirth, but if they are

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Cynthia A. Wong

severe during pregnancy, they may be relieved by local infiltration analgesia or the application of lidocaine patches.3 In severe and persistent cases, surgical nerve release has been advocated.

Anterior cutaneous branches (intercostal nerves)

T10

Sciatic Neuropathy

Lateral cutaneous branches (intercostal nerves)

Sciatic neuropathy has not generally been recognized as a complication of childbirth, possibly because it is mistaken for a lumbosacral palsy. It has, however, been described in women delivered by CD.57–59

T12 Subcostal nerve L1

S 4

Peroneal Neuropathy Peroneal neuropathy results from compression of the common peroneal nerve as it winds around the fibular head. It may arise during labor from incorrect and prolonged positioning in stirrups or compression of the lateral side of the knee against any hard object. It may follow sustained knee flexion or prolonged squatting.60 Signs of nerve compression may go unnoticed in the presence of neuraxial blockade. The resulting foot drop may be profound, but plantar flexion and inversion at the ankle are preserved, unlike an L4/5 lesion. Sensory impairment spares the lateral border of the foot, which distinguishes it from sciatic nerve palsy.

Ilioinguinal nerve Lateral femoral cutaneous nerve

L2

Obturator nerve L3

Anterior cutaneous nerve Femoral nerve

L4 Saphenous nerve Lateral cutaneous nerve

L5

Anesthetic Implications Neuraxial anesthesia or analgesia is often blamed for postpartum neurologic deficits, so it is essential to be aware of any preexisting deficit and accurately diagnose the lesion site. A diagnosis does not necessarily involve conduction studies and imaging; it is often possible to distinguish between peripheral and central lesions by simple clinical means. For example, dermatomes (the spinal segments involved in the sensory supply to the skin) bear no relation to the peripheral nerve distribution to the skin (Figure 16.1).61 At the same time, segmental motor supply also has a characteristic pattern (Figure 16.2).62,63 Anesthesiologists cannot wholly absolve themselves from responsibility for peripheral nerve injuries if the dangers of stretch or compression under GA or NA are overlooked. Moreover, among those with a HLPP, even brief periods of immobility or pressure at any site must be avoided. Obstetric palsies must be differentiated from other postpartum neuropathies caused by spinal-epidural hematoma or abscess. Thus, complaints of symptoms should be evaluated expeditiously to rule out reversible pathology. Nerve compression may result from a pelvic hematoma, and pelvic imaging is required if this is suspected. Most obstetric palsies are associated with numbness and weakness, but not pain. Symptoms usually, but not always, resolve in weeks to months.50 Electromyography may help localize the lesion site and predict the timing of recovery. Patients with residual weakness should be referred for physical therapy evaluation and taught to compensate until the motor deficit resolves.

Femoral branch (genitofemoral nerve)

Common peroneal nerve

Superior peroneal nerve Sural nerve/ tibial nerve Deep peroneal nerve

S 1

Figure 16.1  The segmental (right leg) and peripheral (left leg) sensory nerve distributions; useful in distinguishing central from peripheral nerve injury. (From Redick LF. Maternal perinatal nerve palsies. Postgrad Obstet Gynecol 1992;12:1-6; by permission of the author and publisher61).

L1 L2 L3 L4 L5 S1 S2 S3 S4 Hip

flexion extension abduction adduction medial rotation lateral rotation

Knee

flexion

Ankle

dorsiflexion

extension

plantar flexion Big toe dorsiflexion Levator ani

Valuable Clinical Insight Obstetrical palsies – lower extremity peripheral nerve injuries that result from the birthing process and usually resolve within weeks or months – are common. They must be differentiated from other critical causes of acute, postpartum lower extremity sensory and motor deficits, such as spinal-epidural or pelvic hematoma.

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Coccygeus Figure 16.2  The spinal segments involved in the movements of joints in the leg. (Reproduced from Sviggum H, Reynolds F. Neurologic complications of pregnancy and neuraxial anesthesia. In Chestnut DH, Wong CA, Tsen LC, et al. (Eds.), Obstetric Anesthesia: Principles and Practice (6th ed.). Philadelphia: Elsevier, 2020: 752–776; by permission of the publisher63. Data from Russell R. Assessment of motor blockade during epidural analgesia in labour. Int J Obstet Anesth 1992;4:230–234.62

Peripheral Neuropathies

Neuropathies Secondary to Other Conditions Diabetes Mellitus Diabetes mellitus (DM) is the commonest cause of peripheral neuropathy and is present in approximately 50% of patients with DM.64 The prevalence appears higher in individuals with type 2 DM than type 1; prevalence and severity increase with disease duration and age. Any type or combination of neuropathies can be a feature of diabetes.65 Distal symmetric polyneuropathy commonly presents as burning, numbness, tingling, pain, and weakness in the distal lower extremities, which progress to neuropathic pain in 10–30% of affected individuals. Autonomic neuropathies of DM affect the cardiovascular, urogenital, and gastrointestinal systems.64 Unfortunately, there is currently no simple test or biomarker for diagnosing diabetic neuropathy, and diabetic neuropathy is a diagnosis of exclusion. The American Diabetes Association recommends that patients are screened for neuropathies at the time of diagnosis of type 2 DM and five years after the onset of type 1 DM.65 Diabetes requires meticulous attention during pregnancy for many reasons, and peripheral neuropathy, if present, can only benefit from this. Pregnancy does not induce or worsen peripheral nerve dysfunction in women with insulin-­dependent diabetes.66 Diabetic autonomic neuropathy, however, is particularly dangerous in pregnancy.67 It may be associated with postural hypotension, disordered baroreceptor reflexes and diarrhea, gustatory sweating, bladder dysfunction, gastroparesis and lack of awareness of hypoglycemia.

Management Pregnant women with diabetes are checked for diabetic neuropathy, and signs and symptoms of dysautonomia are sought in all patients with peripheral diabetic neuropathy. Painful diabetic neuropathy is associated with a greater risk for autonomic dysfunction.68 Anesthetic considerations mirror those for other women with dysautonomia. Epidural, spinal, or combined spinal-epidural analgesia and anesthesia are all used for vaginal birth and CD, but anesthesiologists should expect peripartum hemodynamic lability. Gastroparesis may increase the risk for aspiration pneumonia.

of the neurotoxic heme precursors, delta-aminolevulinic acid (ALA) and porphobilinogen (PBG). The neurologic symptoms of acute porphyria arise from heme deficiency and ALA neurotoxicity.69 Acute attacks, usually heralded by visceral symptoms, may be accompanied by autonomic and peripheral neuropathy. Autonomic neuropathy usually precedes the onset of motor neuropathy by several weeks. Sensory neuropathy is the least common. Typically, the motor neuropathy is manifested first by proximal muscle weakness in the upper extremities; the most severe cases may progress to respiratory paralysis. Mild cases regress in a few weeks; severe and slowly progressing cases leave significant sensorimotor paralysis that takes months to improve. Pregnancy may provoke an attack.70 The porphyrias are addressed in more detail in Chapter 17.

Infection Infectious neuropathies are important preventable causes of peripheral neuropathy.71 Infectious agents associated with neuropathy include human immunodeficiency virus (HIV), human T-lymphotropic viruses, hepatitis B and C, and varicella zoster virus. Chagas disease (caused by the parasite Trypanosoma cruzi), Lyme disease (Borrelia burgdorferi), and leprosy (Mycobacterium leprae) are also associated with neuropathies. Finally, drugs used to treat infections may also cause peripheral neuropathy.

Leprosy With increasing global travel, leprosy (or Hansen disease) has become a worldwide problem; it is endemic in South America, Asia, and Africa. It is a chronic infection producing multiple mononeuropathies that affect superficial nerves, particularly the median, ulnar, peroneal, and facial and trigeminal nerves.71 Transmission is by direct contact or via respiratory mucosa, with low infectivity and a long incubation period of three to five years. Multidrug therapy with dapsone, a folate antagonist, rifampin, and clofazimine are the mainstay of therapy and are continued during pregnancy.72 Because of the relative suppression of cell-mediated immunity during pregnancy, pregnancy may increase the risk of disease relapse. One case describes CSE anesthesia, used successfully for CD in a patient with leprosy.73

HIV Valuable Clinical Insight Parturients with diabetic neuropathy are at increased risk for dysautonomia and accompanying hemodynamic lability and gastrointestinal dysfunction.

Porphyria The porphyrias are inherited metabolic disorders resulting from genetic mutations in the eight enzymes in the heme biosynthesis pathway. Enzyme deficiencies result in the overproduction of heme precursors, including porphyrins, which are nonfunctional and potentially neurotoxic.69 Triggers such as smoking, alcohol, porphyrinogenic drugs, and pregnancy increase heme demands or production and upregulate the rate-limiting enzyme, aminolevulinic acid synthase-1, and the production

Many types of peripheral neuropathy occur in HIV-infected patients. The most common is distal symmetric polyneuropathy.71,74 Rarely, an acute inflammatory demyelinating polyneuropathy, chronic inflammatory demyelinating polyneuropathy, and mononeuritis multiplex, as well as toxic neuropathy due to antiviral drugs, are found in individuals with HIV.71 Infectious diseases are discussed more fully in Chapter 22.

Diphtheria Diphtheria is now a rare cause of peripheral neuropathy. The exotoxin produces segmental demyelination. Palatal weakness may follow two to three weeks after pharyngeal diphtheria, and local muscle paralysis a similar interval after cutaneous diphtheria.71 The condition may then spread to cranial nerves followed by generalized, predominantly motor neuropathy. In severe cases, the respiratory muscles may be affected.

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Vasculitis

primary immune disorders with axonal loss, and less commonly, demyelinating abnormalities.77 Sarcoidosis is a multisystem disease.78 Pulmonary infiltration results in restrictive lung disease with decreased vital capacity. Myocardial involvement may produce heart block, heart failure, paroxysmal dysrhythmias, and cor pulmonale. Uveitis, keratoconjunctivitis sicca, parotitis, hepatosplenomegaly, lupus pernio of the skin, and generalized lymphadenopathy also occur. Hypercalcemia develops in 10% of patients. The main treatment of sarcoidosis is corticosteroids. Sarcoidosis usually does not influence pregnancy outcomes, and pregnancy has no effect on the course of the disease.79 Obstetric and anesthetic management are dictated by the cardiopulmonary status of the mother.

Vasculitic neuropathies are a heterogeneous group of neuropathies that may be nonsystemic (only affecting the peripheral nerve) or systemic (Table 16.3).75 The common pathology is inflammation of the vasa nervorum, primarily the epineural arteries, ultimately resulting in thrombosis and ischemia. There may be a multifocal mononeuropathy, a distal sensory neuropathy sometimes restricted to the digital nerves, or, in rheumatoid arthritis, an entrapment neuropathy. Most of these conditions are multisystem diseases that may interact with pregnancy.76

Sarcoidosis The nervous system manifestations of sarcoidosis result from the anatomic location of the sarcoid granulomas. Cranial neuropathies are common, including the optic (I), facial (VII), and vestibulocochlear (VIII) nerves.77 Parenchymal brain, spinal cord, and meningeal involvement also result in nervous system pathology. Symptomatic involvement of peripheral nerves is rare. Granulomas cause infiltration, direct compression, or vasculitis symptoms and EMG findings may mimic those of other

Poisoning with Heavy Metals and Solvents Heavy metals accumulate in the body and exert toxic effects by combining with one or more reactive groups essential for physiological function. They produce a variety of peripheral neuropathies (Table 16.4). Exposure may come from high concentrations in soil or water, leaching from utensils and cookware, industry, and mining, use of pesticides and therapeutic agents, burning fossil fuels containing heavy metals, and the addition of tetraethyl lead to gasoline. Neuropathies from chronic exposures to environmental toxins may be classified using electrophysiologic features – sensory or motor predominant and with or without conduction slowing.80

Table 16.3  Examples of vascular neuropathies

Disease

Proportion with neuropathy

Primary systemic vasculitis Polyarteritis nodosa

65−85%

Churg-Strauss disease

65−80%

Cryoglobulinemia

30−70%

Lead Poisoning Lead poisoning affects the gastrointestinal, neuromuscular, central nervous, hematological, and renal systems. Lead neuropathy is rare and thus not well characterized in the modern era.80 Classically considered a motor neuropathy of the wrist and finger extensor muscles, other sensorimotor neuropathies with autonomic involvement can occur. Increased levels of lead in maternal blood are associated with hypertension in pregnancy and increased risk for spontaneous abortion.81 Lead crosses the placenta; the consequences of prenatal lead exposure are poorly understood, but may lead to cognitive impairment in offspring.82

Secondary systemic vasculitis Rheumatoid arthritis

15−70%

Systemic lupus erythematosus

20−27%

Sarcoidosis

5−10%

Systemic sclerosis

5−30%

Summarized from Blaes F. Diagnosis and therapeutic options for peripheral vasculitic neuropathy. Ther Adv Musculoskel Dis 2015;7:45–55.75

Table 16.4  Poisoning with heavy metals

Effects Substance

CNS

Peripheral nerve

Fetal

Other

Lead

Intellectual disability, headache

Motor (lead palsy) - wrist drop - foot drop - extraocular

Adverse effects assumed

GI Renal Hematologic

Thallium

Late convulsions and coma

Painful sensory followed by motor, ocular, and autonomic palsies

Arsenic

Headache, confusion, and convulsions

Sensorimotor neuropathy

Chromosomal breaks

GI Alopecia All organs

Mercury

Tremor, irritability, memory loss

Sensorimotor neuropathy

Cortical/cerebellar atrophy

Gingivitis GI Renal damage

Abbreviations: CNS = central nervous system; GI = gastrointestinal tract.

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GI Dermatologic

Peripheral Neuropathies

Thallium Poisoning Thallium is used as an insecticide and rodenticide, a catalyst in fireworks, in the manufacture of optical lenses, in industry as an alloy, and in cardiac perfusion imaging.80 Thallium is absorbed across multiple membranes and distributed widely in the body leading to multisystem dysfunction. Thallium neuropathy differs from most other neuropathies; symptom onset occurs within hours to days of exposure. Stinging pain usually starts in the feet and progresses up the leg. There is a stockingglove distribution of sensory loss and preserved reflexes. Some patients have dysautonomia with accompanying abdominal pain, anhidrosis, and cardiovascular lability.80 Thallium crosses the placenta and is transferred into breast milk83 and may cause clinically significant fetal poisoning.

B3 (niacin or nicotinic acid), B6 (pyridoxine), B12 (cobalamin), E, and copper and folate.

Alcoholic Neuropathy

Inorganic arsenic interferes with cellular energy metabolism and disrupts protein and enzyme activity.80 In the peripheral nervous system, arsenic causes axonal degeneration of largediameter nerve fibers. Following a single massive exposure, symptoms, including paresthesias, burning pain, distal numbness, and weakness, appear within five to ten days and progress over weeks.80 The neuropathy is part of multisystem dysfunction that includes cardiac, gastrointestinal, renal, hematologic, and dermatologic involvement. Arsenic crosses the placenta. There is evidence that chronic arsenic exposure during p ­ regnancy (e.g., in drinking water) is associated with an increased risk for spontaneous abortion, stillbirth, and low birth weight.84 There are no reports of neuropathy following chronic exposure to arsenic.80

Alcoholic neuropathy affects almost 90% of individuals with alcohol abuse disorder.86 Neuropathy may result from direct neurotoxic effects of alcohol (likely mechanism for small nerve-fiber neuropathy) and indirectly through vitamin deficiency (vitamin B1). Thiamine deficiency primarily affects large nerve fibers, resulting in motor weakness and sensory ataxia. Together, these neuropathies present as a mixed sensorimotor neuropathy.86 The neuropathy does not affect the course of pregnancy, but other alcohol-related organ dysfunction places the mother at increased risk. Alcohol use disorder results in many acute and chronic complications such as withdrawal seizures, aspiration pneumonitis, cardiomyopathy, liver dysfunction, peptic ulcer, malabsorption, pancreatitis, esophageal varices, coagulopathy, endocrine effects, and immunologic suppression. The adverse fetal effects of alcohol include fetal alcohol syndrome, increased rate of prematurity and infant mortality, and adverse perinatal outcomes.87 Obstetric and anesthetic considerations are not determined by the neuropathy, but the deficit must be documented. The presence of dysfunction in other organs should determine management. Coagulopathy may preclude NA, while anxiety and acute intoxication may dictate the need for GA. Nevertheless, GA may need to be modified to account for the altered pharmacokinetics and pharmacodynamics associated with chronic alcoholism.

Chronic Mercury Poisoning

Neuropathy Following Bariatric Surgery

Inorganic Arsenic

Chronic mercury poisoning may produce a sensorimotor neuropathy with insidious onset of stocking-distribution sensory loss, absent ankle reflexes, and postural tremor of outstretched hands.80 Organic or methyl mercury is highly lipid soluble and readily crosses the blood–brain barrier and placenta and into breast milk. Elemental mercury is poorly absorbed by the gastrointestinal tract but is readily absorbed as a vapor via the lungs. Inorganic mercury salts are absorbed through the gastrointestinal tract and skin. Prenatal poisoning produces cerebral palsy due to cortical and cerebellar atrophy. Those intending to become pregnant should follow official advice about eating fish.81 Treatment of the multisystem disturbances, including peripheral neuropathy, associated with heavy metal and solvent poisoning is directed at life-threatening acute complications. Anesthetic management of the parturient is determined by the obstetric situation and organ dysfunction.

Deficiency States In the Western world, nutritional polyneuropathy is often a result of alcoholism. Malnutrition is seen in the setting of eating disorders, prolonged vomiting (e.g., hyperemesis gravidarum), and following bariatric surgery.85 Nutritional deficiency neuropathies may result from deficiencies of vitamins B1 (thiamine),

In general, women who lose weight following bariatric surgery have improved maternal and neonatal outcomes.88 However, bariatric surgery may cause nutritional malabsorption, particularly after bypass procedures.85 The reported incidence of neurologic complications following bariatric surgery was 4% in one prospective study.89 The most common presentation was peripheral neuropathy (62%), both poly- and mononeuropathies. The polyneuropathy is predominantly sensory.85 Deficiencies in Vitamins A, B1, B12, and copper have been linked to neuropathy following bariatric surgery. One report describes five neonates delivered to women with a history of bariatric surgery; intra­ cranial bleeding in the infants was caused by severe Vitamin K deficiency.90

Drug-induced Neuropathies Many drugs are known to produce neuropathy (Table 16.5). Causative agents include chemotherapeutic agents, antimicrobials, cardiovascular drugs, psychotropic, and anticonvulsant drugs.91 Risk factors for drug-induced neuropathy include preexisting neuropathy. A major problem is the diagnosis, and once established, further exposure must be avoided. After determining the neurologic deficit, anesthetic options depend on the obstetric, maternal, and fetal needs.

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Table 16.5  Drug-induced peripheral neuropathy

References

Drug

Effect

Isoniazid

Sensorimotor neuropathy

Pyridoxine

Sensory neuropathy (in large doses)

Nitrofurantoin

Sensorimotor neuropathy; also caused by uremia

Vincristine

Dose-related sensorimotor neuropathy; may develop foot drop

Cisplatin

Sensory neuropathy

Chloramphenicol

Mild sensory; optic neuropathy associated

Phenytoin

Mild sensorimotor neuropathy

Dapsone

Motor neuropathy

Amiodarone

Sensorimotor neuropathy in 5%

Perhexiline

Sensory neuropathy

Metronidazole

Mild sensory neuropathy

Lithium

Sensorimotor neuropathy

Flecainide

Sensory neuropathy

  1. Donofrio PD. Clinical approach to the patient with peripheral neuropathy. In Donofrio PD (Ed.), Textbook of Peripheral Neuropathy: New York, NY: Demos Medical Publishing, 2012: 1–7.   2. Ropper AH, Samuels MA, Klein JP, et al. Diseases of the peripheral nerves. Adams and Victor’s Principles of Neurology. London: McGraw-Hill, 2019.   3. Massey EW, Massey JM. Mononeuropathies in pregnancy. Handb Clin Neurol 2020;172:145–151.   4. Wong CA. Neurologic deficits and labor analgesia. Reg Anesth Pain Med 2004;29:341–351.   5. Pareyson D, Saveri P, Pisciotta C. New developments in CharcotMarie-Tooth neuropathy and related diseases. Curr Opin Neurol 2017;30:471–480.   6. Li J. Inherited peripheral neuropathies (Charcot-Marie-Tooth disease). In Donofrio PD (Ed.), Textbook of Peripheral Neuropathy. New York, NY: Demos Medical Publishing, 2012: 107–116.   7. McMillan HJ, Jones HR. Peripheral neuropathies in childhood. In Donofrio PD (Ed.), Textbook of Peripheral Neuropathy. New York, NY: Demos Medical Publishing, 2012: 339–362.   8. Hoff JM, Gilhus NE, Daltveit AK. Pregnancies and deliveries in patients with Charcot-Marie-Tooth disease. Neurology 2005;64:459–462.   9. Rudnik-Schöneborn S, Röhrig D, Nicholson G, et al. Pregnancy and delivery in Charcot-Marie-Tooth disease type 1. Neurology 1993;43:2011–2016. 10. Rudnik-Schöneborn S, Thiele S, Walter MC, et al. Pregnancy outcome in Charcot-Marie-Tooth disease: results of the CMTDNET cohort study in Germany. Eur J Neurol 2020;27:1390–1396. 11. Kopp SL, Jacob AK, Hebl JR. Regional anesthesia in patients with preexisting neurologic disease. Reg Anesth Pain Med 2015;40:467– 478. 12. Antognini JF. Anaesthesia for Charcot-Marie-Tooth disease: a review of 86 cases. Can J Anaesth 1992;39:398–400. 13. Greenwood JJ, Scott WE. Charcot-Marie-Tooth disease: peripartum management of two contrasting clinical cases. Int J Obstet Anesth 2007;16:149–154. 14. Peters G, Hinds NP. Inherited neuropathy can cause postpartum foot drop. Anesth Analg 2005;100:547–548. 15. Surgery and HNPP. 2000. Available from: https://web.archive.org/ web/20161126113558/ [last accessed October 15, 2022]. 16. Lepski GR, Alderson JD. Epidural analgesia in labour for a patient with hereditary neuropathy with liability to pressure palsy. Int J Obstet Anesth 2001;10:198–201. 17. Samuel K, Mead K, Cominos T, et al. Spinal anaesthesia for elective caesarean section in a patient with hereditary neuropathy with liability to pressure palsies. Int J Obstet Anesth 2019;40:162– 163. 18. Freeman R. Autonomic peripheral neuropathy. In Donofrio PD (Ed.), Textbook of Peripheral Neuropathy: New York, NY: Demos Medical Publishing, 2012: 421–437. 19. Bar-Aluma BE. Familial dysautonomia. In Adam MP, Ardinger HH, Pagon RA, et al. (Eds.), GeneReviews(®). Seattle (WA): University of Washington, 1993 (updated 2021). 20. Porges RF, Axelrod FB, Richards M. Pregnancy in familial dysautonomia. Am J Obstet Gynecol 1978;132:485–488.

Summary In general, the presence of a peripheral neuropathy does not usually directly impact anesthetic care, but associated systemic disease manifestations may complicate peripartum anesthetic care. For example, women with a peripheral neuropathy may have concurrent neuropathy affecting the muscles of respiration (e.g., GBS, HSMN). Some neuropathies are associated with scoliosis and the resultant restrictive lung disease (e.g., HSAN type 3). Pregnancy and the gravid uterus may further impede respiratory function in these patients. These patients may not tolerate midthoracic NA for CD, and GA may be needed. Bulbar weakness (e.g., associated with GBS) is associated with increased risk for pulmonary aspiration. Dysautonomia, commonly associated with DM, and a component of many other neuropathic diseases, is associated with cardiovascular lability (e.g., supine hypertension, profound hypotension after induction of NA) and gastrointestinal dysfunction (increased risk for pulmonary aspiration). Increased sensitivity to direct-acting vasopressors may be present, while the response to indirect-acting vasopressors may be suboptimal. Childbirth may result in compressive neuropathies, commonly called obstetric palsies. These mononeuropathies (usually) or plexopathy of the lower extremities may be mistakenly attributed to a complication of NA. Timely assessment is necessary to rule out rare causes of postpartum lower extremity sensorimotor impairment (e.g., spinal-epidural, or pelvic hematoma). A comprehensive history and physical examination are necessary for parturients with peripheral neuropathy. Consent for NA and GA involves a thorough discussion of risks and benefits with the patient, as both are influenced by the presence of ­neurologic disease.

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Peripheral Neuropathies

21. Ropper AH, Samuels MA, Klein JP, et al. Developmental diseases of the nervous system. Adams and Victor’s Principles of Neurology. London: McGaw-Hill, 2019. 22. Terry AR, Barker FG, 2nd, Leffert L, et al. Neurofibromatosis type 1 and pregnancy complications: a population-based study. Am J Obstet Gynecol 2013;209:46.e1–e8. 23. Hirsch NP, Child CS, Wijetilleka SA. Paraplegia caused by spinal angioma–possible association with epidural analgesia. Anesth Analg 1985;64:937–940. 24. Dounas M, Mercier FJ, Lhuissier C, et al. Epidural analgesia for labour in a parturient with neurofibromatosis. Can J Anaesth 1995;42:420–422. 25. Spiegel JE, Hapgood A, Hess PE. Epidural anesthesia in a parturient with neurofibromatosis type 2 undergoing cesarean section. Int J Obstet Anesth 2005;14:336–339. 26. Pacheco LD, Saad AF, Hankins GD, et al. Guillain-Barré syndrome in pregnancy. Obstet Gynecol 2016;128:1105–1110. 27. Makhluf H, Madany H. SARS-CoV-2 infection and Guillain-Barré syndrome. Pathogens 2021;10:936. 28. Wiertlewski S, Magot A, Drapier S, et al. Worsening of neurologic symptoms after epidural anesthesia for labor in a Guillain-Barré patient. Anesth Analg 2004;98:825–827. 29. McGrady EM. Management of labour and delivery in a patient with Guillain-Barré syndrome. Anaesthesia 1987;42:899. 30. Alici HA, Cesur M, Erdem AF, et al. Repeated use of epidural anaesthesia for caesarean delivery in a patient with Guillain-Barré syndrome. Int J Obstet Anesth 2005;14:269–270. 31. Vassiliev DV, Nystrom EU, Leicht CH. Combined spinal and epidural anesthesia for labor and cesarean delivery in a patient with Guillain-Barré syndrome. Reg Anesth Pain Med 2001;26:174–176. 32. Brooks H, Christian AS, May AE. Pregnancy, anaesthesia and Guillain-Barré syndrome. Anaesthesia 2000;55:894–898. 33. Kohle F, Kuwabara S, Lehmann HC. Chronic inflammatory demyelinating polyneuropathy and pregnancy: systematic review. J Neurol Neurosurg Psychiatry 2021;92:473–478. 34. Farrar D, Raoof N. Bell’s palsy, childbirth, and epidural analgesia. Int J Obstet Anesth 2001;10:68–70. 35. Collier CB. Trigeminal nerve palsy and Horner’s syndrome following epidural analgesia for labour: not a subdural block. Int J Obstet Anesth 2008;17:92–93. 36. Sprung J, Haddox JD, Maitra-D’Cruze AM. Horner’s syndrome and trigeminal nerve palsy following epidural anaesthesia for obstetrics. Can J Anaesth 1991;38:767–771. 37. Carrero EJ, Agustí M, Fábregas N, et al. Unilateral trigeminal and facial nerve palsies associated with epidural analgesia in labour. Can J Anaesth 1998;45:893–897. 38. Martin-Hirsch DP, Martin-Hirsch PL. Vestibulocochlear dysfunction following epidural anaesthesia in labour. Br J Clin Pract 1994;48:340–341. 39. Hofer JE, Scavone BM. Cranial nerve VI palsy after duralarachnoid puncture. Anesth Analg 2015;120:644–646. 40. Chohan U, Khan M, Saeed UZ. Abducent nerve palsy in a parturient with a 25-gauge Sprotte needle. Int J Obstet Anesth 2003;12:235–236. 41. Roubal PJ, Chavinson AH, LaGrandeur RM. Bilateral radial nerve palsies from use of the standard birthing bar. Obstet Gynecol 1996;87:820–821. 42. Seror P. Neuralgic amyotrophy. An update. Joint Bone Spine 2017;84:153–158.

43. Murray RR. Maternal obstetric palsies. Am J Obstet Gynecol 1964;88:399–403. 44. Tillman AJB. Traumatic neuritis in the puerperium. Am J Obstet Gynecol 1935;29:660–666. 45. Chalmers JA. Traumatic neuritis of the puerperium. J Obstet Gynaecol Br Emp 1949;56:205–216. 46. Feasby TE, Burton SR, Hahn AF. Obstetrical lumbosacral plexus injury. Muscle Nerve 1992;15:937–940. 47. Holdcroft A, Gibberd FB, Hargrove RL, et al. Neurological complications associated with pregnancy. Br J Anaesth 1995;75:522–526. 48. Ong BY, Cohen MM, Esmail A, et al. Paresthesias and motor dysfunction after labor and delivery. Anesth Analg 1987;66:18–22. 49. Dar AQ, Robinson APC, Lyons G. Postpartum neurologic symptoms following regional blockade: a prospective study with case controls. Int J Obstet Anesth 2002;11:85–90. 50. Wong CA, Scavone BM, Dugan S, et al. Incidence of postpartum lumbosacral spine and lower extremity nerve injuries. Obstet Gynecol 2003;101:279–288. 51. Cohen DE, Van Duker B, Siegel S, et al. Common peroneal nerve palsy associated with epidural analgesia. Anesth Analg 1993;76:429–431. 52. Kahn L. Neuropathies masquerading as an epidural complication. Can J Anaesth 1997;44:313–316. 53. Holloway J, Seed PT, O’Sullivan G, et al. Paraesthesiae and nerve damage following combined spinal epidural and spinal anaesthesia: a pilot survey. Int J Obstet Anesth 2000;9:151–155. 54. Warner MA, Warner DO, Harper M, et al. Lower extremity neuropathies associated with lithotomy positions. Anesthesiology 2000;93:938–942. 55. Gherman RB, Ouzounian JG, Incerpi MH, et al. Symphyseal separation and transient femoral neuropathy associated with the McRoberts’ maneuver. Am J Obstet Gynecol 1998;178:609–610. 56. Van Diver T, Camann W. Meralgia paresthetica in the parturient. Int J Obstet Anesth 1995;4:109–112. 57. Silva M, Mallinson C, Reynolds F. Sciatic nerve palsy following childbirth. Anaesthesia 1996;51:1144–1148. 58. Umo-Etuk J, Yentis SM. Sciatic nerve injury and caesarean section [letter]. Anaesthesia 1997;52:605–606. 59. Roy S, Levine AB, Herbison GJ, et al. Intraoperative positioning during cesarean as a cause of sciatic neuropathy. Obstet Gynecol 2002;99:652–653. 60. Babayev M, Bodack MP, Creatura C. Common peroneal neuropathy secondary to squatting during childbirth. Obstet Gynecol 1998;91:830–832. 61. Redick LF. Maternal perinatal nerve palsies. Postgrad Obstet Gynecol 1992;12:1–5. 62. Russell R. Assessment of motor blockade during epidural analgesia in labour. Int J Obstet Anesth 1992;1:230–234. 63. Sviggum H, Reynolds F. Neurologic complications of pregnancy and neuraxial anesthesia. In Chestnut DH, Wong CA, Tsen LC, et al. (Eds.), Chestnut’s Obstetric Anesthesia Principles and Practice. Philadelphia, PA: Elsevier, 2020: 752–776. 64. Carmichael J, Fadavi H, Ishibashi F, et al. Advances in screening, early diagnosis, and accurate staging of diabetic neuropathy. Front Endocrinol (Lausanne) 2021;12:671257. 65. Pop-Busui R, Boulton AJ, Feldman EL, et al. Diabetic neuropathy: a position statement by the American Diabetes Association. Diabetes Care 2017;40:136–154.

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66. Lapolla A, Cardone C, Negrin P, et al. Pregnancy does not induce or worsen retinal and peripheral nerve dysfunction in insulindependent diabetic women. J Diabetes Complications 1998;12: 74–80. 67. Macleod AF, Smith SA, Sönksen PH, et al. The problem of autonomic neuropathy in diabetic pregnancy. Diabet Med 1990;7:80–82. 68. Gandhi RA, Marques JL, Selvarajah D, et al. Painful diabetic neuropathy is associated with greater autonomic dysfunction than painless diabetic neuropathy. Diabetes Care 2010;33:1585–1590. 69. Gandhi Mehta RK, Caress JB, SR, et al. Porphyric neuropathy. Muscle Nerve 2021;64:140–152. 70. Farfaras A, Zagouri F, Zografos G, et al. Acute intermittent porphyria in pregnancy: a common misdiagnosis. Clin Exp Obstet Gynecol 2010;37:256–260. 71. de Freitas MRC, de Mendonca Cardoso F. Infectious neuropathies. In Donofrio PD (Ed.), Textbook of Peripheral Neuropathy. New York, NY: Demos Medical Publishing, 2012: 259–272. 72. Ozturk Z, Tatliparmak A. Leprosy treatment during pregnancy and breastfeeding: a case report and brief review of literature. Dermatol Ther 2017;30:e12414. 73. Hempenstall K, Holland R. Regional anaesthesia for emergency caesarean section in a patient with lepromatous leprosy. Anaesth Intensive Care 1997;25:168–170. 74. Aziz-Donnelly A, Harrison TB. Update of HIV-associated sensory neuropathies. Curr Treat Options Neurol 2017;19:36. 75. Blaes F. Diagnosis and therapeutic options for peripheral vasculitic neuropathy. Ther Adv Musculoskelet Dis 2015;7:45–55. 76. Machen L, Clowse ME. Vasculitis and pregnancy. Rheum Dis Clin North Am 2017;43:239–247. 77. Pawate S. Sarcoidosis and the nervous system. Continuum (Minneap Minn) 2020;26:695–715. 78. Drent M, Crouser ED, Grunewald J. Challenges of sarcoidosis and its management. N Engl J Med 2021;385:1018–1032. 79. Freymond N, Cottin V, Cordier JF. Infiltrative lung diseases in pregnancy. Clin Chest Med 2011;32:133–146.

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80. Albers JW. Occupational, biologic, and environmental toxic neuropathies. In Donofrio PD (Ed.), Textbook of Peripheral Neuropathy. New York, NY: Demos Medical Publishing, 2012: 87–105. 81. United States Centers for Disease Control. Guidelines for the identification and management of lead exposure in pregnant and lactating women. 2010. Available from: www.cdc.gov/nceh/lead/ publications/leadandpregnancy2010.pdf [last accessed September 28, 2021]. 82. Allen KA. Is prenatal lead exposure a concern in infancy? What is the evidence? Adv Neonatal Care 2015;15:416–420. 83. Hoffman RS. Thallium poisoning during pregnancy: a case report and comprehensive literature review. J Toxicol Clin Toxicol 2000;38:767–775. 84. Milton AH, Hussain S, Akter S, et al. A review of the effects of chronic arsenic exposure on adverse pregnancy outcomes. Int J Environ Res Public Health 2017;14:556. 85. Chin RL, Langsdorf J, Feuer N, et al. Nutritional and alcoholic neuropathies. In Donofrio PD (Ed.), Textbook of Peripheral Neuropathy. New York, NY: Demos Medical Publishing, 2012: 69–85. 86. Hammoud N, Jimenez-Shahed J. Chronic neurologic effects of alcohol. Clin Liver Dis 2019;23:141–155. 87. Oei JL. Alcohol use in pregnancy and its impact on the mother and child. Addiction 2020;115:2148–2163. 88. Magdaleno R, Jr., Pereira BG, Chaim EA, et al. Pregnancy after bariatric surgery: a current view of maternal, obstetrical, and perinatal challenges. Arch Gynecol Obstet 2012;285:559–566. 89. Koffman BM, Greenfield LJ, Ali II, et al. Neurologic complications after surgery for obesity. Muscle Nerve 2006;33:166–176. 90. Eerdekens A, Debeer A, Van Hoey G, et al. Maternal bariatric surgery: adverse outcomes in neonates. Eur J Pediatr 2010;169:191–196. 91. Vilholm OJ, Christensen AA, Zedan AH, et al. Druginduced peripheral neuropathy. Basic Clin Pharmacol Toxicol 2014;115:185–192.

Chapter

17

Disorders of Intermediaries of Metabolism and Malignant Hyperthermia David B. MacLean and Stephen H. Halpern

Introduction Many inherited conditions result from disorders of intermediary metabolism, with more discovered annually using advanced gene sequencing and other tools. These diseases cause symptoms due to the accumulation of precursors, the absence of the final product, an excess of toxic intermediaries, or a combination of these mechanisms. Many are fatal in childhood, but some are compatible with adult life and pregnancy. A better understanding of the enzymatic deficiencies and new technologies has made recombinant enzyme replacement therapy (ERT) available for some diseases. Along with early diet manipulation, current management allows many to live relatively normal lives. As fertility may not be affected, the obstetric anesthesiologist will encounter some of these women at a time when physiologic stress may cause severe metabolic derangements or cardiopulmonary decompensation. This chapter discusses some of the more common inherited metabolic diseases compatible with fertility. However, these conditions are relatively rare and often described as “orphan diseases.” The most recent reliable information about these diseases are found at www.orpha.net/consor/cgi-bin/index.php [last accessed September 28, 2022]. Specific issues related to anesthesia can be found at www.orphananesthesia.eu/en/ [last accessed September 28, 2022]. Plasma pseudocholinesterase deficiency and inherited hematological, endocrine, connective tissue, or bone disorders are discussed elsewhere in the book.

For all these rare disorders, a basic tenet of management is to provide a multidisciplinary approach to the patient from (where possible) preconception extending past the postpartum period. Specialists in the relevant fields of medicine, genetics, and dietary services should be involved early in pregnancy. The obstetric and anesthesia team will determine the best mode of delivery and appropriate monitoring during labor and delivery or operative delivery. The neonatal team will determine the impact of any metabolic derangements on the fetus and newborn, appropriate newborn testing, and plan for breastfeeding and newborn care.

Glycogen Storage Diseases Glucose metabolism plays a fundamental role in supplying energy for most cellular metabolic processes. Glycogen, the storage form of glucose, is composed of a branched polymer of glucose residues. Rare inborn errors of glycogen metabolism may result in defects in glycogen breakdown affecting the liver, brain, muscle, and heart (Figure 17.1). The classification of glycogen storage diseases (GSD) is based on the primary enzyme defect, resulting in 20 unique conditions (Table 17.1).1 Those compatible with adult life exhibit an autosomal recessive (AR) pattern of inheritance.2 The main manifestations are primarily related to the liver or muscle, and it is helpful to categorize them according to the primary organ involved.3

Table 17.1  Glycogen storage diseases

Disease

Other names

Defect

Metabolic manifestations

Inheritance

Incidence

Implications

GSD 0

Aglycogenosis

Glycogen synthetase

Fasting ketosis and hypoglycemia, postprandial hyperglycemia, and hyperlactatemia4 5

AR

40 cases in the literature; 2 obstetric patients

Symptoms controlled with high protein diet

GSD Ia Ib Ic (Id)

von Gierke disease

Glucose-6phosphatase translocase

Ia – hypoglycemia, lactic acidemia

AR

1:20,000 to 1:100,000

Ia: Long-term complications: short stature, adenomas, nephropathy, impaired platelet function, polycystic ovary disease Ib–Ia + neutropenia and inflammatory bowel disease Ic/Id – may not be phenotypically distinguishable from Ib4

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David B. MacLean and Stephen H. Halpern

Table 17.1 (Cont.)

Disease

Other names

Defect

GSD II

Pompe disease

Alpha-1–4glucosidase

GSD III a & b IIIc IIId

Cori disease

Phosphorylase Glucosidase Transferase activity loss

GSD IV

Andersen disease

GSD V

Inheritance

Incidence

Implications

AR

1:14,000 to 1:300,000

All tissues affected including cardiac, skeletal muscle, liver, leukocytes and fibroblasts. May result in limb/girdle weakness and respiratory failure6

AR

1:100,000 live births

Cardiac failure from cardiomyopathy, enlarging adenomas. Respiratory failure from progressive myopathy

Amylo-1,4 to 1,6-transgluosidase

AR

< 1% of all GSD

Death in early childhood

McArdle disease

Muscle glycogen phosphorylase (Myophosphorylase)

AR

1:100,000 to 1:350,000

Wide spectrum of disease. Muscle weakness and cramping after exercise. Myoglobinuria may lead to renal failure

GSD VI

Hers disease

Liver glycogen phosphorylase E

AR

1:100,000 in general population 1:1000 in Mennonite population no obstetric cases described. Generally benign

Hepatomegaly and IUGR

GSD VII

Tauri disease

Phosphofructokinase enzyme

AR

90 cases worldwide, none in obstetric patients

GSD VIII and IX

Phosphorylation activation defects

Various

X-linked and AR, multiple types

Cyclic 3’,5’ AMPdependent kinase

AR

Glucose transporter

AR

Aldolase deficiency

AR

GSD X GSD XI GSD XII

Fanconi-Bickel syndrome

Metabolic manifestations

Hypoglycemia and ketosis. IIIa most common

Fasting hypoglycemia7

This section will consider the GSD already described or which could occur in obstetric patients. Those diseases that primarily affect muscle include Pompe disease (GSD II), McArdle disease (GSD V), and Tarui disease (GSD VII). Tarui disease is extremely rare and is phenotypically similar to GSD V. There are no known obstetric cases of GSD VII, so it does not merit further discussion. The GSD that primarily affect the liver are Von Gierke disease (GSD Ia and Ib), Cori-Forbes disease (GSD III), and Hers disease (GSD VI).

support for at least part of the day and may have insufficient strength to clear secretions and cough. Obstructive sleep apnea may occur from macroglossia, and tongue weakness secondary Lysosomal acid maltose (GSD II)

Branching enzyme (GSD IV )

274 https://doi.org/10.1017/9781009070256.018 Published online by Cambridge University Press

Branched 4 glucose residues

Glucose-1-phosphate

Pompe Disease

GLUCOSE

Phosphorylase (GSD V ) (GSD V I )

Glycogen synthase

Diseases that Affect Muscle Pompe disease or type II GSD is a deficiency of α-glucosidase and has an incidence of about 1 in 100,000. In 2008, the first case report of Pompe disease in pregnancy was published.8 It is often misdiagnosed as muscular dystrophy, although a specific biochemical test is available to help differentiate the two. Cardiomyopathy is not a feature of the disease. Weakness, fatigue, muscle cramps, and back pain are common initial complaints. Patients may become debilitated and require walking aids or a wheelchair in early adult life. Some require respiratory

Lysosomal degradation

GLYCOGEN

Debranching enzyme (GSD III )

GLUCOSE GLUCOSE

Glycose-6-phosphate Glucose-6-phosphatase (GSD I) Fructose-6-phosphate Phosphofructokinase (GSD VII )

Fructose-1-6-diphosphate

PYRUVATE

Figure 17.1  Metabolic pathways associated with glycogen storage diseases.

Disorders of Intermediaries of Metabolism and Malignant Hyperthermia

to glycogen infiltration may cause respiratory obstruction.9 Thus, careful preoperative assessment of respiratory function, including ABG analysis and pulmonary function testing, is necessary before deciding on the anesthetic management for surgery during pregnancy. Specific ERT with alglucosidase alfa may be beneficial; however, experience in pregnancy is limited. It should be noted that recombinant alglucosidase alfa (Lumizyme ®) is classified by the American FDA as Category B1. These are “Drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus. Studies in animals have not shown evidence of an increased occurrence of fetal damage.” Alglucosidase alfa is unlikely to cause damage during breastfeeding as it is a large molecule that is destroyed by the infant’s gastrointestinal tract. (www.drugs.com/pregnancy/ alglucosidase-alfa.html; last accessed September 22, 2022). Obstetric and Anesthetic Considerations Many women with Pompe disease are asymptomatic until later in life. One series describes 23 women with Pompe disease; 21 women had a diagnosis made after they had completed their families. This group of women had the same obstetric complication rates as reported in the national database (United States).10 However, some women with Pompe disease have muscular weakness leading to respiratory compromise, although deterioration is not usual during pregnancy. Limb-girdle weakness from kyphoscoliosis may further compromise the respiratory system. If anesthetic management is necessary, NA is preferred, provided a high block does not impair respiratory function. Epidural analgesia with low concentrations of LA is ideal for preserving muscle function and reducing exhaustion during labor. Neuraxial anesthesia is preferable if operative delivery is required, although there may be technical challenges because of kyphoscoliosis. Lumbar US may help place the block.11 General anesthesia is safe, provided one anticipates postoperative respiratory failure. Always examine the airway for macroglossia which could make endotracheal intubation difficult. While succinylcholine has been used safely in patients with Pompe disease,12 some authors advise against its use if there is significant muscle wasting.8 Nondepolarizing muscle relaxants should be used in reduced doses and completely reversed before extubation.

McArdle Disease McArdle disease or GSD V is a rare AR hereditary myopathy due to a deficiency of glycogen myophosphorylase, vital for converting glycogen to lactate during anaerobic exercise.2 Although more prevalent in males, affected females are otherwise healthy, and fertility is unaffected. The accumulation of glycogen in skeletal muscle produces muscle fatigue and cramping during exercise. The diagnosis is often made in early adulthood, and affected individuals who remain sedentary may be asymptomatic. Ingestion of glucose or fructose before exercise can reduce symptoms. A history of myoglobinuria is usually present after heavy exercise but rarely precipitates acute renal failure. The myocardium and myometrium are usually unaffected. There are case reports of ECG changes and cardiomyopathy, but these are likely coincidental.13 The liver is normal, and muscle wasting is uncommon, except in

older patients who may exhibit upper limb wasting. Diagnosis is based on assays of serum lactate (with failure to rise), pyruvate, muscle enzymes, and myoglobin during ischemic exercise testing. Confirmation is by muscle biopsy and genetic studies. Obstetric and Anesthetic Considerations Pregnancy in women with McArdle disease has been described and is usually relatively uneventful.14 The primary goal is to avoid undue muscular activity resulting in rhabdomyolysis and renal failure.12 A source of carbohydrates, such as sports drinks, will reduce the risk of rhabdomyolysis.15 Neuraxial anesthesia confers its usual advantages, although GA has been used successfully. Avoid succinylcholine due to the risks of myoglobinemia, myoglobinuria, and possible renal failure, but it has been used safely in some patients. Response to nondepolarizing muscle relaxants appears normal. A modified rapid sequence induction using a nondepolarizing drug, with monitoring of neuromuscular block, is appropriate. Rocuronium is the preferred agent because of its rapid onset and intermediate duration. While there is only a weak link between McArdle disease and malignant hyperthermia, some patients may have a positive in vitro contracture test. While the possibility that the contracture test in these patients is nonspecific, one should probably avoid triggering agents.16 The risk of compromised postoperative respiratory function secondary to myopathy is low in the reproductive age group. The use of tourniquets or frequent repeated noninvasive BP recordings is inadvisable since repeated use of an automated BP device has precipitated muscle cramps.17 The use of a manual BP cuff may reduce tourniquet time. Sequential leg compression devices and compression stockings to prevent thrombosis are not used as cases of compartment syndrome requiring leg fasciotomies have occurred.17 When possible, one should avoid pyrexia, hypothermia, and shivering because of poor temperature compensatory mechanisms and the risk of myoglobinemia from severe shivering. The perioperative administration of IV dextrose as a substrate is recommended but requires titration to maintain normoglycemia since there are fetal and neonatal consequences of maternal hyperglycemia. Valuable Clinical Insights (McArdle Disease) • While most patients have uneventful pregnancies, they must avoid excess muscular activity and exhaustion. • Rhabdomyolysis is a serious concern. Prevent it by avoiding shivering, compression devices, and supplying appropriate nutrition.

Diseases that Affect the Liver Von Gierke Disease (Glycogen Storage Diseases Type Ia, Ic, Id) The cause of Von Gierke disease is a deficiency of glucose ­6-phosphatase (type Ia) or its transporter, G6P translocase (type Ib), resulting in an inability to hydrolyze glycogen into glucose and phosphate. Types Ic and Id GSD are like Ib and are not considered further.4 Survival into adulthood and pregnancy in patients with GSD Ia has been possible since the introduction in the 1970s of

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continuous glucose therapy and other diet manipulation. The main challenge is to prevent hypoglycemia, as glucose requirements change throughout pregnancy. There is an increased need for cornstarch in the first trimester, but the changes are variable as pregnancy progresses.18,19 Frequent meals, uncooked cornstarch, or continuous gastric drip feeding of glucose satisfy the glucose requirements. Lactic acidosis may occur during fasting. Other metabolic derangements such as hypertriglyceridemia and hyperuricemia may occur. Platelet function defects may cause ecchymoses and recurrent epistaxis. Hepatic adenomas are at risk for rupture and hemorrhage, so if present, their size is monitored. Renal function may also deteriorate.18 Patients with GSD Ib have immune system compromise, in addition to all the metabolic derangements mentioned above. As a result, they often have severe neutropenia, are susceptible to infections, and have a high incidence of inflammatory bowel disease. Obstetric and Anesthetic Considerations Increased lactate levels can lead to nausea, vomiting, and preterm labor. However, with careful monitoring and treatment, most pregnancies in patients with GSD Ia go to term.20 Metabolic control may be challenging during labor. Intravenous glucose is a substitute for oral feeds. Starting requirements are approximately 10–15 gms of glucose (10% dextrose at 125 ml/hr) adjusted according to frequent blood glucose sampling. Lactate-containing IV solutions are not used. Early institution of LEA for labor pain relief will reduce the stress-induced increase in lactate levels unless there is a contraindication, such as a coagulopathy.21 If CD is required, NA may be preferable as early return to oral feeding is more likely. If hepatomegaly is present, the obstetric team should avoid pressure on the upper abdomen during delivery. Since they are immunocompromised, many patients with GSD Ib have severe aphthous gingivostomatitis that could complicate airway management. Patients diagnosed with a platelet function defect may require platelet transfusion if abnormal bleeding occurs. Desmopressin does not reliably reverse platelet dysfunction. (Glycogen storage disease type I; www.­orphananesthesia.eu): last accessed October 1, 2022).

Cori Disease (Glycogen Storage Disease Type III) Cori disease (GSD type III), also known as Forbes disease or debrancher enzyme deficiency, is a rare hepatic-hypoglycemic form of GSD that occurs in about 1:100,000 live births. There are two predominant phenotypes. The most common is GSD type IIIa, accounting for 85% of cases. In addition to hypoglycemia and other liver manifestations, type IIIa patients may suffer from skeletal muscle weakness and hypertrophic cardiomyopathy. Type IIIb patients have only liver manifestations. Types IIIc and IIId are extremely rare and are caused by partial reductions in debrancher activity.2 Obstetric and Anesthetic Considerations Most patients do well during pregnancy with close monitoring.22 Patients with GSD type III are at high risk for hypoglycemia during fasting and stress. To prevent hypoglycemia, administer frequent meals with uncooked cornstarch,

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supplemented with IV infusions of 10% dextrose when oral feeding is not possible. Screen type IIIa patients for hypertrophic cardiomyopathy. Important additional anesthetic considerations are the high risk of hypoglycemia with fasting and the presence of cardiac myopathy.

Hers Disease (Glycogen Storage Disease Type VI) Hers disease or GSD type VI results from a deficiency in liver glycogen phosphorylase E and is extremely rare, with only one pregnancy recorded in the literature.23 Symptoms are variable, and many patients become asymptomatic in adulthood. Hepatomegaly is common. As in the other liver GSD, hypoglycemia is the primary concern during pregnancy. Dietary treatment with uncooked cornstarch and IV dextrose is similar to that described above. Valuable Clinical Insights (Glycogen Storage Disease) • A change in enteral feeding may upset the metabolic balance in these patients. • Where possible, continue enteral feeding throughout labor and delivery. • Change IV supplementation in consultation with the clinical team. • Monitor metabolic status frequently.

Lysosomal Storage Diseases Introduction Lysosomal storage diseases are a group of monogenetic disorders of lysosomal catabolism. Of the 70 described disorders, all but three exhibit an AR pattern of inheritance. The diseases result from an inadequate breakdown of substrate leading to accumulation in the lysosomes. The disorders are heterogeneous and often present in the pediatric population as neurodegenerative diseases. Over the last 20 years, research into these diseases has led to specific treatment with ERT and other interventions. This section will cover Gaucher and Fabry diseases, as they are the most common disorders of lysosomal catabolism in which pregnancy is possible or well described.24,25

Gaucher Disease Gaucher disease, the most common sphingolipidosis, is caused by deficiency of the lysosomal enzyme glucocerebrosidase leading to an accumulation of glucocerebroside in macrophages. These cells, known as Gaucher cells, infiltrate various organs and are responsible for the clinical manifestations of the disease.26,27 Caused by a single gene mutation, the clinical manifestations vary, ranging from asymptomatic to patients who experience lifelong debilitating disease. The most common form of Gaucher disease in adults, type 1, does not involve the CNS. Type II and type III, however, involve the CNS, but only patients with type III survive to adulthood. Fertility is not directly affected by Gaucher disease, but very few patients with

Disorders of Intermediaries of Metabolism and Malignant Hyperthermia

type III have had normal pregnancies.28 Gaucher disease is especially prevalent among the Ashkenazi Jewish population, with a gene frequency of about 1:16. It is present in other ethnic groups with a disease frequency between 1:50,000 to 1:100,000 in the general population.26 Patients with Gaucher disease typically present with organomegaly caused by infiltration of Gaucher cells. Extramedullary hematopoiesis, infarction, and fibrosis are hallmarks of the disease. Hemorrhage, related to thrombocytopenia and a platelet function defect, is common. Immune phenomena such as autoimmune hemolytic anemia and thrombocytopenia can occur. Skeletal involvement may include osteopenia, avascular necrosis of the large joints, pathological fractures, and lytic lesions. Visceral involvement may consist of lung parenchymal disease, abnormal pulmonary function, and in severe cases, pulmonary hypertension.29 Enzyme replacement therapy has been available clinically since the early 1990s. Where available (the treatment is expensive), ERT has significantly reduced organ volumes and improved cytopenia and skeletal symptoms. Of note, ERT does not cross the blood–brain barrier and therefore has no impact on the neurologic symptoms of type III Gaucher disease. Velaglucerase-α is an ERT produced using gene-activation technology with human fibroblasts. It is available in North America, Europe, and Israel and is used extensively in pregnancy.28 It is considered a category B drug for pregnancy and lactation (no evidence of risk in humans). Substrate reduction therapy (SRT) can reduce the build-up of lysosomal material by inhibiting production. Eliglustat is approved for use by the FDA, and compared to ERTs, it has the advantages of oral administration, potential cost benefits, and may reduce neurologic symptoms. However, variable absorption and metabolism, and side effects, limit its use. Eliglustat is not used in pregnancy (category C, no well-controlled trials in humans).26

Obstetric and Anesthetic Considerations The effect of pregnancy is variable. Some women experience improvement, although more frequently those mildly affected show no change;30 others experience worsening hematologic parameters, such as anemia and thrombocytopenia. Women who were taking ERT before conception should continue the drug during pregnancy.29 In one series, thrombocytopenia or a defect in platelet function caused PPH requiring transfusion in five of 16 pregnancies.31 Hepatosplenomegaly may worsen during pregnancy. One must be careful during CD to avoid injuring these organs. Bone crises occur in pregnancy. Evidence suggests ERT reduces the incidence of bone crises and PPH. In one study, PPH, organomegaly, thrombocytopenia, and bone complications were the most common complications of Gaucher disease.32 The same study reported a high CD rate. Neonatal outcome was good for most patients, although two had type I Gaucher disease, and one had type III. Some complications, such as pulmonary hypertension, may be exacerbated by pregnancy.29

While vaginal delivery is preferred, CD may be required because of pelvic bony abnormalities. Many patients with Gaucher disease are at risk for injury, so require careful positioning. Neuraxial anesthesia may be appropriate if coagulation is normal,31 and TEG might be helpful before NA.33 Pulmonary involvement in Gaucher disease may be lifethreatening. Some authors recommend that patients on ERT have an echocardiogram to assess the severity of pulmonary hypertension.34 Valuable Clinical Insight (Gaucher Disease) • While enzyme replacement therapy has reduced the severity of the clinical manifestations, some patients are at risk for PPH and bleeding due to platelet dysfunction.

Fabry Disease Unlike most lysosomal storage diseases, Fabry disease involves X-linked inheritance. A defect in lysosomal α-galactosidase A leads to a build-up of glycosphingolipid globotriaosylceramide. Gene expression and symptoms are highly variable because of the X-linked inheritance. Once thought to be a rare disorder with an incidence of 1:50,000, newborn genetic screening shows the incidence is between 1:1250 and 1:8500. Many patients are asymptomatic until adulthood, and patients presenting with neuropathic pain may be misdiagnosed as having fibromyalgia or a rheumatic disease.35 While most women with Fabry disease have some enzyme activity and are asymptomatic, others have cardiovascular symptoms (palpitations, shortness of breath), abdominal pain, myalgias, joint pain, and painful acroparesthesias. Patients may present with proteinuria and renal failure requiring dialysis. Cardiac disease, such as hypertrophic cardiomyopathy, cardiac dysrhythmia, and valvular heart disease, is a feature of Fabry disease. Transient ischemic attacks and ischemic strokes may occur.35 Osteoporosis, eye lesions, and neuropsychiatric disturbances are common.

Obstetric and Anesthetic Considerations There are few case reports of pregnant patients with Fabry disease. Most pregnancies are uncomplicated, provided there is no antenatal vital organ involvement. Nonlife-threatening symptoms such as headaches, and GI complaints may increase during pregnancy,36 although some suggest these symptoms improve.37 Patients with cardiovascular and pulmonary compromise may worsen because of the increased demands of pregnancy and should be monitored carefully for decompensation and dysrhythmia. Proteinuria is common but usually does not lead to renal failure during pregnancy. However, renal function requires close evaluation.37 Patients with severe disease benefit from continuing ERT throughout pregnancy.38 There are no specific anesthetic considerations in asymptomatic patients. Patients with severe end-organ damage require appropriate monitoring and pain management optimized for chronic neurologic, joint, or gastrointestinal pain.

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Disorders of Amino Acid Metabolism and Storage Phenylalanine Hydroxylase Deficiency (Phenylketonuria) Phenylalanine hydroxylase deficiency (PAH), formerly called phenylketonuria, is an AR disorder that results in toxic phenylalanine levels in the blood and brain.39 The severity of the disease is highly variable, but if left untreated, it may result in profound, irreversible mental disability. Dietary treatment started just after birth prevents this complication. With neonatal screening, early detection and continued childhood dietary control, many affected women reach childbearing age free of mental handicap. Treatment with sapropterin dihydrochloride is used to control phenylalanine levels. Phenylalanine hydroxylase deficiency does not affect fertility.

six weeks postpartum. The obstetric anesthesiologist should see these women in consultation and, in conjunction with the obstetric and medical teams, formulate a management plan that preserves the option of NA according to the most recent guidelines.44 Communication among caregivers is necessary to determine the optimum time to discontinue prophylactic anticoagulation before delivery. There is a theoretical risk of nitrous oxide causing neurologic damage in patients with hyperhomocysteinemia by causing severe methionine deficiency in the brain. Therefore, it should not be used in these patients if possible.45 Valuable Clinical Insights (Homocystinuria) • Patients with homocystinuria are at high risk for thromboembolism. • Inquire about prophylactic anticoagulants before NA.

Obstetric and Anesthetic Considerations Although the fetal outcome is not affected by the inheritance of PAH, elevated maternal phenylalanine and subsequent fetal accumulation cause severe damage in a normal (non-PAH) fetus. Phenylalanine crosses the placenta by active transport, increasing the risk to the fetus. High serum phenylalanine levels result in developmental delays, microcephaly, congenital heart defects, growth delay, and seizures.40 A phenylalanine restricted diet should start before conception to avoid fetal anomalies. Sapropterin hydrochloride is classified as an FDA Class C drug during pregnancy and should be used if required to control phenylalanine levels.40,41 There are no specific anesthetic implications for parturients with PAH.

Homocystinuria Homocystinuria, caused by cystathionine beta-synthase deficiency, has an incidence of 1:200,000 to 1:335,000 but varies widely among populations.42 Increased plasma levels of homocysteine and methionine and decreased cystine lead to manifestations such as intellectual disability, seizures, dislocated optic lens, osteoporosis, and thromboembolism. Early diagnosis and treatment of homocystinuria with pyridoxine (vitamin B6) in pyridoxine-responsive patients usually result in a benign clinical course. Methionine restriction may also be required. Unresponsive patients may require high-dose pyridoxine, vitamin B12, and other dietary manipulation. Pyridoxinenonresponsive homocystinuria is also treated with betaine, a methyl donor in the reaction converting homocysteine to methionine.42 There are reports of successful pregnancies in women with pyridoxine nonresponsive homocystinuria treated with betaine and anticoagulants.43 Of note, betaine has not yet been assigned an FDA grade for pregnancy because of insufficient data.

The Porphyrias The porphyrias are a group of eight metabolic disorders associated with specific enzyme defects in the heme synthetic pathway that result in the overproduction of heme precursors and subsequent clinical signs and symptoms46 (Table 17.2). All are inherited, although porphyria cutanea tarda (PCT) occurs after exposure to environmental stressors, iron overload, or other triggers.47 The defect occurs at various steps in the heme biosynthetic pathway, with numerous mutations identified at each site (Figure 17.2). Table 17.2  Clinical manifestations of acute porphyria

Site

Manifestation

Autonomic neuropathy

Abdominal pain Tachycardia Hypertension Constipation Vomiting Abnormal sphincter function Diarrhea Cardiac dysrhythmia

Peripheral, central, or motor neuropathy

Back and extremity pain Numbness of hands and/or feet Muscle weakness Respiratory muscle paralysis Pneumonia Cranial nerve neuropathy Bulbar Facial weakness

Central nervous system

Mental changes Insomnia Anxiety Depression Hallucinations Convulsions (may be multifactorial) Decreased level of consciousness Extensor plantar signs

Metabolic changes

Dark/red urine Hyponatremia Liver dysfunction

Obstetric and Anesthetic Considerations Thromboembolism is a significant concern, and there are reports of cerebrovascular disease. Since normal pregnancy is a hypercoagulable state, these women may require prophylactic anticoagulation antenatally (e.g., subcutaneous UFH or LMWH), with therapy continued after delivery and up to

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Disorders of Intermediaries of Metabolism and Malignant Hyperthermia

Type of porphyria

Heme synthesis

Enzyme

Glycine+ succinyI-CoA Aminolevulinate dehydratase deficiency porphyria (plumboporphyria)

δ-aminolevulinic acid synthase δ-aminolevulinic acid δ-aminolevulinic dehydratase

Acute intermittent porphyria Porphobilinogen

Porphobilinogen deaminase

Congenital erythropoietic porphyria HydroxymethyIbilane

Uroporphyrinogen III Synthase

Porphyria cutanea tarda Uroporphyrinogen III

Uroporphyrinogen decarboxylase

Hereditary coproporphyria Coprotoporphyrinogen III

Coprotoporphyrinogen oxidase

Variegate porphyria Protoporphyrinogen IX

Protoporphyrinogen oxidase

Erythropoietic protoporphyria Protoporphyrin IX

Ferrochelatase

+Fe

Heme

Figure 17.2  Enzyme defects at various stages in heme synthesis.

The classification of porphyrias is based on the main clinical features. Acute neurovisceral (hepatic) porphyrias include acute intermittent porphyria (AIP), variegate porphyria (VP), hereditary coproporphyria (HCP), and delta-aminolevulinic acid dehydratase deficiency porphyria (ADP).48 All but the sporadic ADP show an autosomal dominant (AD) inheritance pattern with incomplete penetrance.49 Patients with porphyria are at risk of acute attacks that are life-threatening. As photosensitivity and other cutaneous symptoms are the main clinical features of congenital erythropoietic porphyria, PCT, and erythropoietic protoporphyria, there are no anesthetic or obstetric considerations for these three disorders other than meticulous skin care. However, PCT is associated with an increased incidence of diabetes, antinuclear antibodies, hepatitis C, and poor liver function. Patients with HCP and variegate VP have acute attacks (see below) and skin manifestations.

Epidemiology Porphyrias associated with acute attacks are pan-ethnic, with an incidence between five and 60 per 100,000.50 Variegate porphyria is more common in the Afrikaner community in South Africa, with a frequency of up to one in 250.51 The genetic mutations are well studied, and there are many variants of each gene. Many patients with the genetic defect may not manifest the disease

and are not diagnosed without screening. Therefore, other factors such as modifying genes or environmental factors may play a crucial role in determining the phenotypic manifestations.

Clinical Manifestations of an Acute Attack Precipitating factors for acute attacks increase aminolevulinic acid synthase activity resulting in increased production of porphyrinogens. These factors include physiologic hormonal fluctuations, ethanol, fasting, dehydration, stress, and infection. Administration of enzyme-inducing drugs is the most important trigger under the direct control of the anesthesiologist (Table 17.3). The pathogenesis of acute porphyria is unclear but probably involves direct neurotoxicity of δ-aminolevulinic acid, porphobilinogen, or both. The clinical manifestations of acute porphyria result from the effects of toxic metabolites (Table 17.2). Many symptoms are nonspecific, leading to delays in diagnosis and treatment. The symptoms vary in severity from mild to life threatening. A family history of the disease is of prime importance in making the diagnosis. Acute attacks often begin with abdominal pain, autonomic instability, and electrolyte disturbances. Neuropsychiatric symptoms such as hallucinations and anxiety may also occur. Neuromuscular weakness is potentially fatal and may lead to quadriparesis and severe respiratory failure. Seizures and cranial nerve palsies may result from CNS involvement. Rarely are these defects permanent. In addition to neurotoxicity, porphyrin precursors may cause vascular damage with increased permeability of the blood–brain barrier resulting in focal brain edema and seizures. The reduced heme in neural tissue may cause additional symptoms. This reduction may lead to a lower concentration of heme-containing enzymes, causing deficiencies in neurotransmitters, e.g., serotonin. Various biochemical markers such as δ-aminolevulinic acid and porphobilinogen are diagnostic if found in the urine.48

Treatment of an Acute Attack If the diagnosis of an acute attack of porphyria is likely (based on clinical and biochemical features), treatment should begin as soon as possible. Manage mild attacks conservatively with an increased intake of oral carbohydrates. However, more aggressive therapy is needed if the attack progresses to include severe abdominal pain, vomiting, and neurologic symptoms. Severe abdominal pain may require high doses of opioids; antiemetics, such as ondansetron and prochlorperazine, can be added to treat nausea. Hyponatremia is common, but the exact mechanism is unclear. Gastrointestinal sodium loss or the syndrome of inappropriate antidiuretic hormone release may exacerbate hyponatremia. Severe hyponatremia causing seizures requires treatment with hypertonic saline. Other electrolyte imbalances may require IV therapy. Symptomatic hypertension and tachycardia are safely treated with beta-adrenergic blockers and nifedipine.49 Several preparations of IV hemin are available and are given in doses of 3 to 4 mg/kg/day. Hemin is classified as “Category C” for pregnancy and breastfeeding mothers by the American FDA. (www.rxlist.com/panhematin-drug .htm#precautions; last accessed September 28, 2022).

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Table 17.3  Examples of commonly used anesthetic and obstetric drugs and their recommended use in porphyria

Drug class

Agent

American Porphyria Foundation (APF)

Drug database for PorphyriaUK(DDP)

Comments

Local anesthetics

Bupivacaine

OK!

NP

Safe

Levobupivacaine

No data

NP

Safe

Chloroprocaine

No data

PNP

Safe

Ropivacaine

OK?

PNP

Probably safe

Lidocaine

OK?

PNP

Probably safe, possible disease activation: 2 poorly documented cases

Nitrous oxide

No data

PNP

Safe

Sevoflurane

OK!

PNP

Safe, nausea may reduce carbohydrate intake

Isoflurane

OK!

PNP

Safe

Desflurane

OK!

PNP

Safe

Propofol

OK!

NP

Safe

Thiopental

BAD!

P

Avoid all barbiturates

Etomidate

BAD!

No data

Avoid

Ketamine

BAD!

PSP

Avoid if possible

Dexmedetomidine

OK?

PSP

Avoid if possible, side effects due to abnormal glucose metabolism

Acetaminophen (paracetamol)

OK!

PNP

Safe

Fentanyl and derivatives

OK? No data for sufentanil or remifentanil

PNP (fentanyl and derivatives)

Probably safe

Morphine

OK!

NP

Safe

Hydromorphone

OK!

PNP

Safe

Nalbuphine

OK!

PNP

Safe

Ketorolac

BAD!

PNP

Very little data. Use with caution if necessary

Naproxen

OK!

PNP

May be used

Diclofenac

BAD?

PNP

Use with caution if necessary

Celecoxib

BAD?

PNP

Use with caution if necessary

Naloxone

OK!

PNP

Safe

Rocuronium

No data

NP

Safe

Succinylcholine

OK?

NP

Safe

Cisatracurium

No data

NP

Probably safe

Pancuronium

OK!

PNP

Safe

Vecuronium

OK!

PNP

Safe

Atropine

OK!

PNP

Safe

Glycopyrrolate

No data

PNP

Probably safe

Sugammadex

No data

PNP

Probably safe

Esomeprazole

OK!

PNP

All current proton pump inhibitors are probably safe

Droperidol

No data

PNP

Probably safe

Inhalational agents

Intravenous induction agents

Analgesics

Neuromuscular blocking agents

Reversal agents

Anti-emetics and agents to reduce gastric acidity

Ranitidine

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Disorders of Intermediaries of Metabolism and Malignant Hyperthermia

Drug class

Cardiovascular

Obstetric

Sedatives

Anticonvulsants

Agent

American Porphyria Foundation (APF)

Drug database for PorphyriaUK(DDP)

Comments

Dimenhydrinate

BAD!

No data

Avoid if possible

Ondansetron

OK!

PNP

Safe

Labetolol

OK!

NP

Safe

Propranolol

OK!

NP

Safe

Hydralazine

BAD!

P

Avoid

Verapamil

OK?

PRP

Probably safe

Nifedipine

BAD!

PNP

Avoid if possible

Oxytocin

OK!

NP

Safe

Methylergometrine

BAD!

P

Avoid ergot preparations if possible

Carboprost

No data

PNP

Probably safe

Misprostol

OK?

No data

Probably safe

Carbetocin

No data

No data

?

Magnesium

No data

No data

Probably safe

Diazepam

OK?

PNP

Probably safe

Midazolam

OK?

PNP

Probably safe

Phenytoin

BAD!

P

Avoid

Gabapentin

OK!

PNP

Safe

Key to rating APF: OK! = safe; OK? = probably safe, inconsistent/scant evidence; BAD? = probably unsafe, inconsistent/scant evidence; BAD! = very likely to be unsafe. Key to rating DDP: NP = not porphyrinogenic, safe; PNP = probably not porphyrinogenic, safe; PSP = possibly porphyrinogenic, can use when no safer alternative available; PRP = probably porphyrinogenic, prescribe for strong/urgent indication when no other alternative available; P = porphyrinogenic, prescribe only for urgent, life-saving indication.

Obstetric and Anesthetic Considerations As with many rare diseases, conflicting reports make it difficult to determine whether pregnancy affects the incidence of attacks or the disease’s natural history. When well controlled, most parturients with porphyria experience uneventful pregnancies.52 However, hormonal changes and other stressors, such as hyperemesis, may increase the incidence of acute attacks during pregnancy.53 Many patients, previously asymptomatic, may have their first attack in pregnancy. Parturients with symptoms of active acute porphyria are at high risk for adverse pregnancy outcomes, including death, particularly during first deliveries.54 In general, avoid prolonged fasting and stress, and where possible, administer supplemental carbohydrates either orally or IV. Use drugs known to be safe, but life-threatening circumstances may dictate the use of other medications.49

Drug Pharmacology Much interest lies in drug-induced attacks since many drugs commonly used during pregnancy and in anesthetic practice may induce excess porphyrin production (Table 17.3). Several drug databases which list drugs that are safe to use in porphyria are available online. The American Porphyria Foundation (https://porphyriafoundation.org/drugdatabase/; last accessed

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September 28, 2022) and the drug database for acute porphyria (www.drugs-porphyria.org/index.php; last accessed September 28, 2022) are the most extensive. Because of interpatient variation in susceptibility, each of these databases rate drugs on a scale from “OK!” or definitely not porphyrinogenic (NP) to “Bad!” or definitely porphyrinogenic (P), with gradations in between. Use drugs with the latter designation only in the most urgent clinical circumstances. These databases help the clinician decide on the risk versus benefit for each drug.

Neuraxial Anesthesia Because LEA can prevent fatigue and reduce stress, many authors recommend its use in parturients with porphyria.49,55 Bupivacaine and ropivacaine are classified as “probably not porphyrinogenic” (PNP) and are safe (www.drugs-porphyria .org; last accessed September 28, 2022). Fentanyl and sufentanil are also classified as PNP and can be used as additives. Intravenous lidocaine is classified as unsafe by Porphyria South Africa because it is porphyrinogenic in animals. However, epidural lidocaine is considered safe by the European Porphyria Initiative based on human clinical experience. Whether or not NA is appropriate must be judged at the time of presentation. It is essential to see these women early in pregnancy to document

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neurologic deficits (if any) and discuss an analgesic plan. Further assessment on admission to the labor floor identifies any changes to the neurologic or metabolic status. One can safely use IV PCA with parenteral opioids in patients where NA is inappropriate. Morphine, fentanyl, or remifentanil are safe for IV PCA as they are classified as NP or PNP. Inhaled nitrous oxide is PNP and considered safe (www .drugs-porphyria.org) [last accessed October 1, 2022].

General Anesthesia With the possible exception of sodium citrate, no drugs are completely safe for prophylaxis against pulmonary aspiration of gastric contents. Based on case reports, metoclopramide was considered unsafe in the past, and current databases contain conflicting safety ratings. Therefore, metoclopramide cannot be recommended as safe (www.drugs-porphyria.org) [last accessed October 1, 2022]. Ranitidine and proton pump inhibitors are rated as PNP and are safe. Propofol is the induction agent of choice, while one should avoid thiopental and etomidate. There are no reported acute attacks caused by ketamine, and although it has been used safely, it is still rated as “possibly porphyrinogenic” and “Bad!” by the European and American databases, respectively. However, as ketamine has been used successfully, consider its use in patients with hemodynamic instability due to hemorrhage. For safe, rapid sequence induction and endotracheal intubation, use propofol and succinylcholine or rocuronium. Atropine, glycopyrrolate, neostigmine, and sugammadex are rated as PNP and are safe. All current inhalational agents (isoflurane, sevoflurane, desflurane, nitrous oxide) are rated as PNP and are safe. Opioids and acetaminophen are appropriate for postoperative analgesia. Naproxen is probably not porphyrinogenic and should be used instead of diclofenac, where possible. Many drugs commonly used by obstetricians should be avoided, including the ergot derivatives, some calcium channel blockers (e.g., nicardipine), hydralazine, clonidine, and α-methyldopa. Midazolam, temazepam, lorazepam, droperidol, and the phenothiazine antiemetics are likely safe. Oxytocin is not porphyrinogenic and is safe. Prostaglandin F2-alpha (Hemabate®), instead of ergometrine, can be used if oxytocin is insufficient. However, in cases of life-threatening bleeding, ergotamine can be used.49 Tranexamic acid is not porphyrinogenic.

Summary Acute porphyrias are rare but are triggered by some medications commonly used in anesthesia and obstetrics. Labor and delivery place the susceptible parturient at risk. Stress, fatigue, and carbohydrate deficiency are important triggers of acute attacks, so mitigate where possible. While it is impossible to catalog or remember which drugs are safe, updated prescribing information is available on reliable websites. Despite best efforts to reduce the risk in susceptible individuals, acute attacks may occur. Consider the diagnosis and initiate supportive treatment early in parturients with a history of porphyria.

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Valuable Clinical Insights (Porphyrias) • Acute attacks can be avoided during labor and delivery. • Stress avoidance and appropriate caloric intake are essential aspects of clinical care. • A list of safe drugs should be available to all clinicians caring for these patients to reduce the risk of triggering an attack.

Conclusion Increasing numbers of women with inherited metabolic disorders survive into adulthood and, with new therapies, can become pregnant and have successful outcomes. However, advances in managing inherited metabolic disorders during pregnancy are ongoing. Some of these disorders can significantly affect the mother and the fetus. It is essential to consider the possibility of an inherited metabolic disorder in fetuses of pregnancies affected by nonimmune hydrops, HELLP syndrome, or acute fatty liver of pregnancy. There is a need for ongoing data collection within registries to improve our understanding of these conditions.

Malignant Hyperthermia Introduction Malignant hyperthermia (MH) is a skeletal myopathy affecting intracellular calcium regulation. MH-susceptible (MHS) patients may develop a rapid and sustained rise in intramyoplasmic calcium (Ca2+) upon exposure to triggering agents, leading to hypermetabolic crisis and high mortality without treatment.56 Early recognition of an MH reaction and initiation of treatment is paramount to reduce mortality, as is the identification of MHS individuals to allow avoidance of triggers. Known pharmacologic triggers include the depolarizing muscle relaxant succinylcholine and the potent inhalational agents such as sevoflurane, desflurane, and isoflurane.56 The combination of succinylcholine with volatile agents appears to increase the risk of MH.57 Given the routine use of these agents to provide GA during obstetric care, thorough knowledge of the management of MHS parturients is fundamental to the safe provision of obstetric anesthesia. Malignant hyperthermia is a heritable condition. Familial transmission follows an AD pattern, although causative mutations may also arise de novo. MH exhibits incomplete penetrance and variable expressivity, likely owing to locus and allelic heterogeneity and possible modulating factors.58 More than 70% of the mutations associated with MHS occur on the RYR1 gene,59 which encodes the ryanodine receptor subtype 1 (RyR1) protein responsible for facilitating skeletal muscle contraction via its effect on calcium release from the sarcoplasmic reticulum. Of the myriad potential RYR1 mutations implicated with MHS, only 50 have been fully characterized as pathogenic variants thought to be causative for MH, called diagnostic mutations (https://emhg.org/diagnostic-mutations) [last accessed October 1, 2022]. Forty-eight of these are mutations within RYR1, while the remainder occurs within CACNA1S, which encodes the α-1S subunit of the voltage-gated calcium channel

Disorders of Intermediaries of Metabolism and Malignant Hyperthermia

known as the dihydropyridine receptor.60 Successful interaction among these and other proteins allows for normal functioning of the excitation-contraction mechanism in skeletal muscle. Data from population-level genomic studies suggest the prevalence of known MH pathogenic variants lies between 1:200 and 1:3,000.58 Despite this, clinical MH episodes remain rare. The estimated prevalence of MH reactions varies widely from between 1:16,000–100,000 among medical and surgical inpatients61 to as low as 1:500,000 among ambulatory surgical patients.62 Female patients account for one-third or less of MH reactions,61 though the mechanism leading to this disparity remains unknown. Discordance between the rates of genetic mutations and observed MH reactions is from a reduced or incomplete penetrance.59 A large, multicenter case-control study estimated the overall penetrance of MH to be 40% among those who carried one of a subset of RYR1 diagnostic mutations.63 Penetrance among those with a diagnostic mutation without a history of MH reaction was 25%; this increased to 76% among probands who survived an MH reaction. This change supports the notion that epigenetic or nongenetic factors may play a role in modulating the MH phenotype in patients with a known MH genotype. Guglielminotti et al. conducted a retrospective review encompassing 12 years of data from the United States National Inpatient Sample from 2003 to 2014. The overall rate of MH reactions among obstetric patients was approximately 1:200,000 deliveries. Despite high rates of NA in obstetric care, the rate of MH reaction during CD (nearly 1:125,000) was comparable to that of nonobstetric surgical patients. Interestingly, the authors noted that the presence of coding errors in the ICD-9-CM dataset may have led to overestimating reactions, whereby the ICD code intended for an MH reaction may also indicate MHS status or an unrelated fever. It is not possible to say whether the MH reactions recorded in the vaginal delivery group were due to an overestimation error or exposure to triggering anesthetics during the management of postpartum complications.64 Regardless, the risk of an MH reaction was significantly greater in parturients undergoing CD versus vaginal delivery (adjusted OR 2.88; 95% CI, 2.19 to 3.80). This difference is likely attributable to a greater risk of exposure to MH triggering agents during the performance of GA for CD. Multivariate analysis also identified lower rates of MH reactions among Hispanics versus nonHispanic White patients and geographic variation in MH rates among census data regions.64 There is some minimal regional geographic variation in the prevalence of MH.61

Presentation of Malignant Hyperthermia The classic clinical picture of MH is that of uncontrolled muscular rigidity, severe hypercapnia, hypoxemia, mixed respiratory and metabolic acidosis, and eventual rhabdomyolysis resulting in creatine kinase (CK) release, myoglobinuria, and hyperkalemia. Fulminant cases may progress to acute kidney injury (AKI), disseminated intravascular coagulation, multiorgan failure, and death. Clinical signs develop according to the fundamental pathophysiology of uncontrolled hypermetabolism; hypercapnia, tachycardia, and lactic acidosis are among the first manifestations. An unexplained rise in end-tidal CO2 under

anesthesia (or tachypnea if spontaneously breathing) is an early sign with high sensitivity and specificity.65 Although the speed of onset of symptoms is variable, most patients will develop muscular rigidity or cardiac dysrhythmias. Hyperthermia is a late sign of MH, but its severity correlates with the likelihood of complications.65 The Malignant Hyperthermia Association of the United States (MHAUS) defines masseter muscle rigidity (MMR) as difficulty in manual mouth opening that impedes direct laryngoscopy and tracheal intubation in the absence of temporomandibular joint dysfunction. After succinylcholine administration, MMR may be the initial presenting sign of MH.66 Women experiencing MMR should be observed closely for additional signs of MH or rhabdomyolysis related to other myopathies. They will require MH susceptibility testing or workup of a myopathy as necessary. A trigger-free anesthetic is prudent in those with a history of severe MMR but without an MHS workup.66 Reports of MH in obstetrics are rare.67 All parturients (MH and nonMH) have a lower resting PaCO2 and higher baseline metabolic rate than nonobstetric patients. These pregnancy changes may initially mask symptoms of MH but lead to earlier decompensation. The higher baseline glomerular filtration rate and attendant decrease in serum Cr during pregnancy are also important when evaluating renal function during a suspected MH reaction. Maternal serum lactate rises in labor but not in nonlaboring parturients.68 Compared to parturients undergoing elective CD, maternal lactate levels are higher at the time of vaginal delivery (4.9 ± 1.6 vs. 1.2 ± 0.3 mmol/L at CD), potentially contributing to lactic acidosis in the setting of MH.69

Differential Diagnosis The presentation of several diseases and syndromes may overlap with that of MH. These include neuroleptic malignant syndrome, serotonin syndrome, sympathomimetic toxidrome (including cocaine intoxication), thyroid storm, and pheochromocytoma.70 Inadvertent intrathecal injection of high ionic, water-soluble radiologic contrast agents can cause seizures and hyperthermia.71 Other conditions more common to obstetric practice, such as maternal sepsis, pain, anxiety, or iatrogenic hyperthermia, may mimic MH, making the clinical diagnosis more difficult. Using the classical signs and some of the biochemical markers noted above to predict MH susceptibility, Larach et al. developed a clinical grading scale (CGS) to aid the definition of MH and its research.71 This scale assigns points to various indicators based on their predictive value for MH; however, the CGS has not been used to evaluate an MH reaction during pregnancy. If exposed to triggering agents, several congenital myopathies, including central core disease, multi minicore disease, nemaline myopathy, Evans syndrome, STAC3 disorder (formerly Native American myopathy), and King-Denborough syndrome, are at risk of actual MH reactions and significant rhabdomyolysis.72 Thus, treat patients with these disorders as MHS. Exertional rhabdomyolysis and exertional heat illness are associated with MHS, although there is no consensus on the best methods to identify at-risk patients.73 Lastly, several mitochondrial myopathies, myotonic syndromes, and

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muscular dystrophies (most notably Duchenne and Becker muscular dystrophy) are at risk of severe hyperkalemia and rhabdomyolysis upon exposure to triggering anesthetic agents; however, these patients are not at increased risk for a true MH reaction.72

Confirmation of Malignant Hyperthermia Diagnosis There are two similar protocols for in vitro testing of muscle biopsy specimens from suspected MHS patients, the caffeine halothane contracture test (CHCT) in North America and the in vitro contracture test (IVCT) in Europe. Both are viewed as the gold standard for diagnosing MHS. The sensitivity of both tests approaches 100%, meaning a negative result effectively rules out MH.70 However, testing is invasive, requiring surgery to collect a muscle biopsy specimen large enough to facilitate multiple in vitro experiments.74 Additionally, biopsy and testing must be performed at one of the 30 specialized MH testing centers worldwide, potentially requiring travel or additional expense to the patient. There is no specific contraindication to muscle biopsy collection during pregnancy, although a thorough discussion of risks and benefits is warranted. With the advent of lower-cost genetic testing, DNA screening is a viable, less invasive alternative to in vitro testing. DNA screening only confirms MHS after identifying a known diagnostic mutation. In cases where no variant or a variant of unknown significance is identified, in vitro testing remains the only accepted method to rule out MHS.70,74 Therefore, a definitive diagnosis of MHS can only be made by identifying a diagnostic mutation on molecular genetic testing or a positive in vitro test on exposure to caffeine, halothane, or both.

General Treatment of Malignant Hyperthermia Discontinue the trigger agent immediately, remove vaporizers, and hyperventilate the patient with 100% oxygen at fresh gas flows of 10 L/minute. Consider inserting activated charcoal filters to assist with breathing circuit decontamination.75 Change the anesthetic technique to a TIVA technique. As mortality increases with a delay in giving dantrolene,76 immediately administer 2–2.5 mg/kg.75,77 Provide additional doses to abate symptoms; the total dose may exceed 10 mg/kg in 24 hours.77 As soon as possible, institute active cooling if the temperature exceeds > 39°C or rises rapidly. Supportive care involves the administration of glucose, fluids, and bicarbonate for severe acidosis and the treatment of dysrhythmias, rhabdomyolysis, and hyperkalemia.75,77 Closely monitor urine output, CK, and blood gases. Administer furosemide, mannitol, and additional fluids as needed to keep urine output > 1–2 mL/kg/h. The surgical procedure should be aborted or completed as soon as possible. Once stable, transfer the patient to ICU for a minimum 24 hours of monitoring, including CK every six hours, looking for rhabdomyolysis. The MHAUS maintains a 24-hour MH telephone hotline to advise clinicians managing an acute MH crisis and for post-crisis counseling (1–800–644–9737, or 001–209–417–3722 outside North America, last accessed August 10, 2021). Following a suspected episode, refer all patients to determine the need for further testing to establish MHS status. The clinician should also consider submitting a report to the North American Malignant

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Hyperthermia Registry (NAMHR) of MHAUS or an MH unit of the European Malignant Hyperthermia Group (EMHG).

Obstetric and Anesthetic Considerations The obstetric anesthesia provider should question every parturient regarding a personal or family history of MH. Provide a trigger-free anesthetic to the patient with a possible MH history unless she has undergone contracture testing with a negative result. Given the Mendelian and AD nature of MH inheritance,58 each child of an MHS-proven individual has a 50% chance of being MHS. Therefore, treat children or siblings of a known MHS individual as MHS unless the patient themselves underwent negative contracture testing. In the case of a sibling proband, that relative and both parents are tested to establish a de novo (rather than inherited) pathogenic variant in the sibling proband.70 Ideally, the parturient with known MH susceptibility will be seen in consultation before hospital admission. This consultation allows a complete discussion of the implications of the MH diagnosis on the management of labor and delivery. As the highest risk relates to GA, an early epidural for labor allows adequate analgesia and quick conversion for operative delivery, if needed. In the absence of a dedicated volatile-free workstation for use in an MHS parturient, follow the manufacturer’s recommendation for decontamination of volatile anesthetics. At a minimum, guidelines56 recommend the removal of vaporizers and all disposables (tubing, soda lime canister, reservoir bag) and replacement with uncontaminated equipment, followed by flushing at the maximum allowable fresh gas flow (minimum 10 L/min) with any air/oxygen mixture (Figure 17.3). In an emergency where time does not permit preparation of the workstation, activated charcoal filters can facilitate rapid removal of volatile anesthetic gases after flushing for 90 seconds.56 Oxytocin remains the first-line uterotonic in pregnancy and is safe in the MHS parturient.78,79 Knowledge of the side effects of other uterotonics is essential when assessing a patient for a possible MH episode. Prostaglandins may increase body temperature and oxygen consumption, while ergot preparations and beta-sympathomimetics may cause tachycardia, hypertension, and dysrhythmias.80 The EMHG recommends immediate availability of dantrolene at any location that uses volatile anesthetics or succinylcholine. Thirty-six vials of dantrolene sodium should be immediately available, with an additional 24 vials (60 total) available within one hour.76 The MHAUS also recommends dantrolene be available within ten minutes wherever MH-triggering agents are used, including facilities that only stock succinylcholine for emergency use.66 Though some debate exists regarding the amount of dantrolene stocked in maternity units,81 the first dose must be administered and not be delayed more than ten minutes after diagnosing an MH reaction. Use of prophylactic dantrolene is not recommended, nor is elective admission to the ICU.56 Concerns regarding exposure to expired volatile anesthetics in the recovery room appear to be unfounded;82 standard postanesthetic care is sufficient56 in the absence of other issues. Monitoring of the MHS parturient for CD should follow local anesthesia society guidelines. However, at a minimum,

Disorders of Intermediaries of Metabolism and Malignant Hyperthermia

Figure 17.3  Preparation of the anesthesia workstation for an MHS parturient. With permission from Ruffert et al., Consensus guidelines on the perioperative management of malignant hyperthermia suspected or susceptible patients from the European Malignant Hyperthermia Group. Br J Anesthesia 2021;126:120–130.

Patient undergoing anesthesia who has a known or suspected increased risk of developing malignant hyperthermia Yes Clean anesthetic workstation available? Yes

No Still enough time to prepare the workstation?

Anesthetic workstation is ready to use Yes

• Remove vaporizers from anesthetic workstation • Change anesthetic breathing circuit (T-circuit, circle circuit, and reservoir bag) and soda lime canister for uncontaminated equipment • Flush circuit with oxygen or air with maximum flow rate for workstation-specific time*

Anesthetic workstation is ready to use • Maintain maximum fresh gas flow • Avoid standby mode

No

• Remove vaporizers from anesthetic workstation

• Flush circuit with oxygen or air with maximum flow rate, for 90 s

• Insert activated charcoal filters (ACFs) on both inspiratory and expiratory limbs • Change anesthetic breathing circuit (T-circuit, circle circuit, and reservoir bag) and soda lime canister for uncontaminated equipment

Anesthetic workstation is ready to use

• Keep filters in place • Decrease fresh gas flow to 3 L min–1, *Proposed ventilatory pattern: 600 mL tidal volume; ventilatory frequency of 15 min–1

but not below 1 L min–1

• Change ACFs after 12 h

monitoring must include continuous pulse oximetry, ECG, noninvasive BP monitoring, neuromuscular monitoring (where indicated), end-tidal and waveform capnography, and core temperature monitoring during GA.56 The distal esophagus or tympanic membrane are two preferred core temperature monitoring sites.83 Although hyperthermia remains a late sign of MH, lack of any temperature monitoring is associated with a doubling of the risk of death during an MH reaction versus core temperature monitoring.84 Routine arterial cannulation is not warranted, though placement during a suspected MH reaction can facilitate serial monitoring of arterial gases, potassium, lactate, and other parameters. Avoidance of the MH triggers succinylcholine and volatile anesthetics is mandatory. None of the other medications used in anesthesia are known to trigger MH, including propofol, ketamine, opioids, local anesthetics, benzodiazepines, phenylephrine, ephedrine, or nitrous oxide.70 Neuraxial anesthesia is the best option for emergency CD in the MHS patient.79 If the situation, time, failed block, or contraindications to NA necessitate a GA, then prepare TIVA as the primary technique for induction and maintenance of anesthesia. During induction, the primary risk is pulmonary aspiration of gastric contents, so use gastric acid prophylaxis. Instead of succinylcholine, a higher dose of a nondepolarizing muscle blocker (NDMB) such as rocuronium can facilitate rapid tracheal intubation. A Cochrane systematic review of succinylcholine versus rocuronium for rapid sequence induction found no statistical difference between the two drugs in providing excellent intubating conditions when using highdose rocuronium (0.9–1.2 mg/kg). Onset times between succinylcholine 1.0 mg/kg (50 seconds) and rocuronium 1.2 mg/kg (55 seconds) are similar in nonpregnant patients.85

Proponents of the high-dose NDMB approach argue that the unnecessarily long duration of high-dose rocuronium or vecuronium may be rapidly antagonized with the newer reversal agent sugammadex ≥ 4 mg/kg.86 Although it is unknown if the volume of distribution is altered by pregnancy, a single dose of sugammadex 2–4 mg/kg is sufficient for complete reversal of NDMB after CD, including patients with profound neuromuscular block.87 The Society for Obstetric Anesthesia and Perinatology (SOAP) recommends not using sugammadex in early pregnancy as it binds and encapsulates progesterone. However, it can be used at term, provided its use is justified, and the patient is made aware that its impact on lactation is unknown (soap.org/assets/docs/SOAP_statement_sugammadex_during_ pregnancy_lactation_approved.pdf). The USA FDA does not provide a specific pregnancy category for sugammadex, while the Australian Therapeutic Goods Administration (TGA) has assigned category B2.

Management of the Malignant-HyperthermiaSusceptible Fetus Given the AD inheritance pattern of MH, consider a fetus as MHS if the parturient or biological father is MHS. Therefore, include questions about family history of MH to include the biological father. A valid concern about the anesthetic management of an MH-negative mother exists, when the father of the fetus is MHS.88 All anesthetic agents cross the placenta to some degree89; thus, MH-triggering agents administered to an MH-negative mother may pose a risk to an MHS fetus in utero. Guidelines for managing MH in pregnancy specify that MH-negative parturients with a possible MHS fetus be treated like those parturients identified as MHS.79 The highly lipophilic volatile anesthetics

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readily cross the placenta89 and are considered unsafe in the setting of a possible MHS fetus. Clearance of sevoflurane and isoflurane is less during placental hypoperfusion in vitro,90 which would prolong fetal exposure in cases of maternal extremis. Succinylcholine exhibits significantly less placental transfer than the volatile anesthetics,91 although one should expect some fetal exposure. A case of maternal succinylcholine administration was believed to have caused respiratory depression in an infant born with pseudocholinesterase deficiency.92 Although it remains unclear whether the placental transfer of succinylcholine is sufficient to trigger an MH reaction in the fetus, consider the steroid NDMBs rocuronium and vecuronium and their rapid reversal agent sugammadex as alternatives. Despite these concerns, case reports of MH in the fetus or newborn are fortunately rare. There remains only one report of an infant exposed to MH triggers in utero who was born presenting with rigidity and metabolic derangements consistent with a diagnosis of MH, although the diagnosis was not confirmed.93 An additional report documented an uncomplicated, trigger-free anesthetic for an MHS fetus.94 There is currently a lack of consensus regarding maternal administration of succinylcholine for an MHS fetus;79 the anesthesia provider must weigh risks and benefits for each case.

Dantrolene in Pregnancy Dantrolene is the only approved agent for treating an MH episode. Although it antagonizes calcium release at the sarcoplasmic reticulum via intracellular action at the RyR1 channel,95 the precise mechanism remains unclear. Evidence suggests magnesium is necessary to facilitate RyR1 receptor inhibition by dantrolene via an ATP-dependent mechanism,96 suggesting a potential future role for magnesium administration. As dantrolene may prolong the action of NDMBs, the obstetric anesthesia provider must ensure adequate neuromuscular recovery.97 The USA FDA has assigned dantrolene pregnancy category C, while the Australian TGA has assigned category B2. Calculate the dosing of dantrolene using actual body weight.76 Currently, available formulations include the older dantrolene sodium powder (Dantrium, Revonto) and a lyophilized formulation (Ryanodex). While both contain mannitol and dantrolene and are reconstituted in sterile water, the lyophilized formulation contains significantly more dantrolene per vial, thus allowing faster reconstitution and delivery (Table 17.4). The newer formulation also contains less mannitol, notable due to limited evidence that mannitol, but not dantrolene, causes dose-dependent uterine relaxation of human myometrium in vitro.98 Despite this concern, only one report exists of PPH due to uterine atony associated with prophylactic dantrolene sodium administration.99 In that case, there were multiple other risk factors for PPH. There were no maternal or neonatal adverse events in a study of 20 MHS patients receiving prophylactic lowdose oral dantrolene for several days before and after delivery.100 According to data from the NAMHR, the most common complications of dantrolene administration in the general population are muscle weakness (22%), phlebitis (9%), GI upset (4%), and respiratory failure (4%).101 Although females accounted for 25% of MH episodes, the risk of complications was five-fold

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higher in the obstetric and gynecologic population. However, the authors attributed this potential overestimation to the small sample size. The risk of an untreated MH reaction far outweighs that of dantrolene administration. Table 17.4  Comparison of dantrolene formulations

Dantrolene sodium powder (Dantrium, Revonto)

Lyophilized dantrolene (Ryanodex)

Dantrolene per vial

20 mg

250 mg

Mannitol per vial

3000 mg

125 mg

Sterile water needed to reconstitute one vial

60 mL

5 mL

Vials to provide 2.5 mg/kg dose to a 70 kg patient

9 vials

2 vials

Effects on the fetus and newborn are also worthy of consideration. Dantrolene crosses the placenta leading to a fetal–maternal ratio between 0.48 in gravid ewes and 0.69 in ­humans.100,102,103 This prompts concern for neonatal hypotonia, which has not been found in previous studies despite an estimated 20 hour half-life of dantrolene in the fetal-newborn circulation.100 Dantrolene is secreted into breastmilk. In a case of a MH reaction treated with dantrolene after fetal delivery, the half-life of dantrolene in breastmilk was found to be nine hours, leading the authors to recommend resuming breastfeeding two days after the last dose of dantrolene.104

Summary Although MH episodes are rare during pregnancy, there is no evidence that pregnancy alters the response to triggering agents. The overall rate of MH episodes in obstetric practice seems to be like that of nonpregnant patients undergoing surgery, though episodes are more likely with CD. The obstetric anesthesia provider must know how to provide anesthesia to an MHS parturient and be able to diagnose and manage an unexpected MH episode. The management principles of an MH episode are the same as those in the nonobstetric patient. For up-to-date recommendations and guidelines, the reader is referred to the excellent websites maintained by the MHAUS (www.mhaus.org) and EMHG (www.emhg.org). Valuable Clinical Insights (Malignant Hyperthermia) • Diagnosis and treatment of MH in the parturient are similar to nonpregnant patients. • Dantrolene is safe to treat an MH episode during pregnancy. • MH in the fetus is possible but is extremely rare.

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pathologic features, and treatment. Ultrastruct Patho. 2011;35:183–196.   3. Ferns JM, Halpern SH. Glycogen storage diseases. In Mankowitz SKW (Ed.), Consults in Obstetric Anesthesiology. New York, NY: Springer, 2018: 235–240.   4. Veiga-da-Cunha M, Gerin I, Van Schaftingen E. How many forms of glycogen storage disease type I? Eur J Pediatr 2000;159:314–318.   5. Grunert SC, Rosenbaum-Fabian S, Hannibal L, et al. Three successful pregnancies in a patient with glycogen storage disease type 0. JIMD Rep 2021;57:38–43.   6. Karabul N, Berndt J, Kornblum C, et al. Pregnancy and delivery in women with Pompe disease. Mol Genet Metab 2014;112:148–153.   7. Aeppli TRJ, Rymen D, Allegri G, et al. Glycogen storage disease type VI: clinical course and molecular background. Eur J Pediatr 2020;179:405–413.   8. Cilliers HJ, Yeo ST, Salmon NP. Anaesthetic management of an obstetric patient with Pompe disease. Int J Obstet Anesth 2008;17:170–173.   9. Shah NM, Sharma L, Ganeshamoorthy S, et al. Respiratory failure and sleep-disordered breathing in late-onset Pompe disease: a narrative review. J Thorac Dis 2020;12:S235–S247. 10. Goker-Alpan O, Kasturi VG, Sohi MK, et al. Pregnancy outcomes in late onset Pompe disease. Life 2020;10:194. 11. Park S-K, Bae J, Yoo S, et al. Ultrasound-assisted versus landmark-guided spinal anesthesia in patients with abnormal spinal anatomy: a randomized controlled trial. Anesth Analg 2020;130:787–795. 12. Gurrieri C, Sprung J, Weingarten TN, et al. Patients with glycogen storage diseases undergoing anesthesia: a case series. BMC Anesthesiol 2017;17:134. https://doi.org/10.1186/s12871-0170428-x 13. Moustafa S, Patton DJ, Connelly MS. Unforeseen cardiac involvement in McArdle’s disease. Heart Lung Circ 2013;22:769– 771. 14. Carballeira EMC, Vila EF, Martíneza MJC. Pregnancy control and management of labor in McArdle’s disease. Prog Obstet Ginecol 2008;51:307–310. 15. Johnson MS. McArdle disease. Anästh Intensivmed 2020;61:S378– 385. 16. Bollig G, Mohr S, Raeder J. McArdle’s disease and anaesthesia: case reports. Review of potential problems and association with malignant hyperthermia. Acta Anaesthesiol Scand 2005;49:1077– 1083. 17. Findlay S, Liu D, Rijhsinghani A. Acute compartment syndrome: clinical course and laboratory findings in pregnant patients with McArdle’s Disease. Pain Med 2014;15:481–482. 18. Martens DH, Rake JP, Schwarz M, et al. Pregnancies in glycogen storage disease type Ia. Am J Obstet Gynecol 2008;198:646 e1–7. 19. Dagli AI, Lee PJ, Correia CE, et al. Pregnancy in glycogen storage disease type Ib: gestational care and report of first successful deliveries. J Inherit Metab Dis 2010;33:S151–S157. 20. Ferrecchia IA, Guenette G, Potocik EA, et al. Pregnancy in women with glycogen storage disease Ia and Ib. J Perinat Neonatal Nurs 2014;28:26–31. 21. Reynolds F. Fetal and maternal lactate increase during active second stage of labour (what about the effect of maternal analgesia?). BJOG 2003;110:86. 22. Ramachandran R, Wedatilake Y, Coats C, et al. Pregnancy and its management in women with GSD type III – a single centre experience. J Inherit Metab Dis 2012;35:245–251.

23. Grunert SC, Rosenbaum-Fabian S, Hannibal L, et al. Successful pregnancy in a woman with glycogen storage disease type 6. Mol Genet Metab Rep 2021;27:100770. 24. Bouwman MG, Rombach SM, Schenk E, et al. Prevalence of symptoms in female Fabry disease patients: a case-control survey. J Inherit Metab Dis 2012;35:891–898. 25. Platt FM, d’Azzo A, Davidson BL, et al. Lysosomal storage diseases. Nat Rev Dis Primers 2018;4:27. https://doi.org/10.1038/ s41572-018–0025–4 26. Gary SE, Ryan E, Steward AM, et al. Recent advances in the diagnosis and management of Gaucher disease. Expert Rev of Endocrinol Metab 2018;13:107–118. 27. Stirnemann J, Belmatoug N, Camou F, et al. A review of Gaucher disease pathophysiology, clinical presentation and treatments. Int J Mol Sci 2017; 18(2):441. https://doi.org/10.3390/ijms18020441 28. Lau H, Belmatoug N, Deegan P, et al. Reported outcomes of 453 pregnancies in patients with Gaucher disease: an analysis from the Gaucher outcome survey. Blood Cells Mol Dis 2018;68:226–231. 29. Rosenbaum H. Management of women with Gaucher disease in the reproductive age. Thromb Res 2015;135:S49–S51. 30. Elstein Y, Eisenberg V, Granovsky-Grisaru S, et al. Pregnancies in Gaucher disease: a 5-year study. Am J Obstet Gynecol 2004;190:435–441. 31. Ioscovich A, Elstein Y, Halpern S, et al. Anesthesia for obstetric patients with Gaucher disease: survey and review. Int J Obstet Anesth 2004;13:244–250. 32. Komninaka V, Flevari P, Marinakis T, et al. Outcomes of pregnancies in patients with Gaucher disease: the experience of a center of excellence on rare metabolic Disease-Gaucher disease, in Greece. Eur J Obstet Gynecol Reprod Biol 2020;254:181–187. 33. Tharp WG, Farhang B. Thromboelastography before epidural placement in a thrombocytopenic parturient with Gaucher disease treated with imiglucerase: a case report. A A Pract 2018;11:16–18. 34. Elstein D, Klutstein MW, Lahad A, et al. Echocardiographic assessment of pulmonary hypertension in Gaucher’s disease. Lancet 1998;351:1544–1546. 35. Miller JJ, Kanack AJ, Dahms NM. Progress in the understanding and treatment of Fabry disease. Biochimica Et Biophysica Acta-Gen Subj 2020;1864:129437. 36. Holmes A, Laney D. A retrospective survey studying the impact of Fabry disease on pregnancy. In Zschocke J, Baumgartner M, Morava E, et al. (Eds.), JIMD Reports, Vol. 21. London: Springer, 2015: 57–63. 37. Parent E, Wax JR, Smith W, et al. Fabry disease complicating pregnancy. J Matern Fetal Neonatal Med 2010;23:1253–1256. 38. Madsen CV, Christensen EI, Nielsen R, et al. Enzyme replacement therapy during pregnancy in Fabry patients: review of published cases of live births and a new case of a severely affected female with Fabry disease and pre-eclampsia complicating pregnancy. JIMD Rep 2019;44:93–101. 39. Blau N, van Spronsen FJ, Levy HL. Phenylketonuria. Lancet 2010;376:1417–1427. 40. Anonymous. Management of women with phenylalanine hydroxylase deficiency (phenylketonuria): ACOG Committee Opinion, No. 802. Obstet Gynecol 2020;135:e167–e170. 41. Muntau AC, Adams DJ, Belanger-Quintana A, et al. International best practice for the evaluation of responsiveness to sapropterin dihydrochloride in patients with phenylketonuria. Mol Genet Metab 2019;127:1–11.

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42. Sacharow SJPJ, Levy HL. Homocystinuria caused by cystathionine beta-synthase deficiency. In Adam MPAH, Pagon RA (Eds.). GeneReviews® [Internet]. 1993–2021. Updated May 18, 2017. Seattle (WA): University of Seattle. 43. Manta-Vogli PD, Schulpis KH, Dotsikas Y, et al. Nutrition and medical support during pregnancy and lactation in women with inborn errors of intermediary metabolism disorders (IEMDs). J Pediatr Endocrinol Metab 2020;33: 5–20. 44. Horlocker TT, Vandermeuelen E, Kopp SL, et al. Regional anesthesia in the patient receiving antithrombotic or thrombolytic therapy: American Society of Regional Anesthesia and Pain Medicine Evidence-Based Guidelines (4th ed.). Reg Anesth Pain Med 2018;43:263–309. 45. Luzardo GE, Karlnoski RA, Williams B, et al. Anesthetic management of a parturient with hyperhomocysteinemia. Anesth Analg 2008;106:1833–1836. 46. Puy H, Gouya L, Deybach JC. Porphyrias. Lancet 2010;375:924–937. 47. Singal AK. Porphyria cutanea tarda: recent update. Mol Genet Metab 2019;128:271–281. 48. Gandhi Mehta RK, Caress JB, Rudnick SR, et al. Porphyric neuropathy. Muscle Nerve 2021;64:140–152. 49. Wilson-Baig N, Badminton M, Schulenburg-Brand D. Acute hepatic porphyria and anaesthesia: a practical approach to the prevention and management of acute neurovisceral attacks. BJA Educ 2021;21:66–74. 50. Elder G, Harper P, Badminton M, et al. The incidence of inherited porphyrias in Europe. J Inherit Metab Dis 2013;36:849–857. 51. Hift RJ, Meissner PN. An analysis of 112 acute porphyric attacks in Cape Town, South Africa: evidence that acute intermittent porphyria and variegate porphyria differ in susceptibility and severity. Medicine (Baltimore) 2005;84:48–60. 52. Marsden JT, Rees DC. A retrospective analysis of outcome of pregnancy in patients with acute porphyria. J Inherit Metab Dis 2010;33:591–596. 53. Shenhav S, Gemer O, Sassoon E, et al. Acute intermittent porphyria precipitated by hyperemesis and metoclopramide treatment in pregnancy. Acta Obstet Gynecol Scand 1997;76:484– 485. 54. Tollanes MC, Aarsand AK, Sandberg S. Excess risk of adverse pregnancy outcomes in women with porphyria: a populationbased cohort study. J Inherit Metab Dis 2011;34:217–223. 55. Harris C, Hartsilver E. Anaesthetic management of an obstetric patient with variegate porphyria. Int J Obstet Anesth 2013;22:156– 160. 56. Rüffert H, Bastian B, Bendixen D, et al. Consensus guidelines on perioperative management of malignant hyperthermia suspected or susceptible patients from the European Malignant Hyperthermia Group. Br J Anaesth 2021;126:120–130. 57. Dexter F, Epstein RH, Wachtel RE, et al. Estimate of the relative risk of succinylcholine for triggering malignant hyperthermia. Anesth Analg 2013;116:118–22. 58. Biesecker LG, Dirksen RT, Girard T, et al. Genomic screening for malignant hyperthermia susceptibility. Anesthesiology 2020;133:1277–1282. 59. Robinson R, Carpenter D, Shaw MA, et al. Mutations in RYR1 in malignant hyperthermia and central core disease. Hum Mutat 2006;27:977–989. 60. Beam TA, Loudermilk EF, Kisor DF. Pharmacogenetics and pathophysiology of CACNA1S mutations in malignant hyperthermia. Physiol Genomics 2017;49:81–87.

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61. Lu Z, Rosenberg H, Li G. Prevalence of malignant hyperthermia diagnosis in hospital discharge records in California, Florida, New York, and Wisconsin. J Clin Anesth 2017;39:10–14. 62. Lu Z, Rosenberg H, Brady JE, et al. Prevalence of malignant hyperthermia diagnosis in New York State ambulatory surgery center discharge records 2002 to 2011. Anesth Analg 2016;122:449–453. 63. Ibarra Moreno CA, Hu S, Kraeva N, et al. An assessment of penetrance and clinical expression of malignant hyperthermia in individuals carrying diagnostic ryanodine receptor 1 gene mutations. Anesthesiology 2019;131:983–991. 64. Guglielminotti J, Rosenberg H, Li G. Prevalence of malignant hyperthermia diagnosis in obstetric patients in the United States, 2003 to 2014. BMC Anesthesiol 2020;20:19. https://doi .org/10.1186/s12871-020-0934-0 65. Schneiderbanger D, Johannsen S, Roewer N, et al. Management of malignant hyperthermia: diagnosis and treatment. Ther Clin Risk Manag 2014;10:355–362. 66. Litman RS, Smith VI, Larach MG, et al. Consensus statement of the Malignant Hyperthermia Association of the United States on unresolved clinical questions concerning the management of patients with malignant hyperthermia. Anesth Analg 2019;128:652–659. 67. Johnson C. Pregnancy and malignant hyperthermia. J Clin Anesth 1992;4:173. 68. Kern-Goldberger AR, Polin M, Bank TC, et al. Searching for a biochemical correlate of critical illness in obstetrics: a descriptive study of maternal lactate in patients presenting for acute care in pregnancy. J Matern Fetal Neonatal Med 2020;2020:1–3. 69. Zaigham M, Helfer S, Kristensen KH, et al. Maternal arterial blood gas values during delivery: effect of mode of delivery, maternal characteristics, obstetric interventions and correlation to fetal umbilical cord blood. Acta Obstet Gynecol Scand 2020;99:1674–1681. 70. Rosenberg H, Pollock N, Schiemann A, et al. Malignant hyperthermia: a review. Orphanet J Rare Dis 2015;10:93. 71. Larach MG, Localio AR, Allen GC, et al. A clinical grading scale to predict malignant hyperthermia susceptibility. Anesthesiology 1994;80:771–779. 72. Schieren M, Defosse J, Böhmer A, et al. Anaesthetic management of patients with myopathies. Eur J Anaesthesiol 2017;34:641–649. 73. Capacchione JF, Muldoon SM. The relationship between exertional heat illness, exertional rhabdomyolysis, and malignant hyperthermia. Anesth Analg 2009;109: 1065–1069. 74. Hopkins PM, Rüffert H, Snoeck MM, et al. European Malignant Hyperthermia Group guidelines for investigation of malignant hyperthermia susceptibility. Br J Anaesth 2015;115:531–539. 75. (MHAUS) Managing a crisis: emergency treatment for an acute MH event: Malignant Hyperthermia Association of the United States (MHAUS). 2021. Available from: www.mhaus .org/healthcare-professionals/managing-a-crisis/ [last accessed September 29, 2022]. 76. Glahn KPE, Bendixen D, Girard T, et al. Availability of dantrolene for the management of malignant hyperthermia crises: European Malignant Hyperthermia Group guidelines. Br J Anaesth 2020;125:133–140. 77. Glahn KP, Ellis FR, Halsall PJ, et al. Recognizing and managing a malignant hyperthermia crisis: guidelines from the European Malignant Hyperthermia Group. Br J Anaesth 2010;105:417–420.

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78. Sim AT, White MD, Denborough MA. The effect of oxytocin on porcine malignant hyperpyrexia susceptible skeletal muscle. Clin Exp Pharmacol Physiol 1987;14: 605–610. 79. Schuster F, Johannsen S. Maligne Hyperthermie und Schwangerschaft – Empfehlungen der Europäischen Malignen Hyperthermie Gruppe. Anasthesiol Intensivmed Notfallmed Schmerzther 2021;56:367–372. 80. Gallos ID, Williams HM, Price MJ, et al. Uterotonic agents for preventing postpartum haemorrhage: a network meta-analysis. Cochrane Database Syst Rev 2018;4:Cd011689. 81. Ho PT, Carvalho B, Sun EC, et al. Cost-benefit analysis of maintaining a fully stocked malignant hyperthermia cart versus an initial dantrolene treatment dose for maternity units. Anesthesiology 2018;129:249–259. 82. Heiderich S, Thoben C, Dennhardt N, et al. Low anaesthetic waste gas concentrations in postanaesthesia care unit: a prospective observational study. Eur J Anaesthesiol 2018;35:534–538. 83. Cork RC, Vaughan RW, Humphrey LS. Precision and accuracy of intraoperative temperature monitoring. Anesth Analg 1983;62:211–214. 84. Larach MG, Brandom BW, Allen GC, et al. Malignant hyperthermia deaths related to inadequate temperature monitoring, 2007–2012: a report from the North American malignant hyperthermia registry of the malignant hyperthermia association of the United States. Anesth Analg 2014;119:1359– 1366. 85. Tran DT, Newton EK, Mount VA, et al. Rocuronium versus succinylcholine for rapid sequence induction intubation. Cochrane Database Syst Rev 2015;2015:CD002788. 86. Duvaldestin P, Kuizenga K, Saldien V, et al. A randomized, doseresponse study of sugammadex given for the reversal of deep rocuronium- or vecuronium-induced neuromuscular blockade under sevoflurane anesthesia. Anesth Analg 2010;110: 74–82. 87. Richardson MG, Raymond BL. Sugammadex administration in pregnant women and in women of reproductive potential: a narrative review. Anesth Analg 2020;130:1628–1637. 88. Nestor CC, Kearsley R, Irwin MG. Anaesthetic implications for a malignant hyperthermia-susceptible fetus. Anaesthesia 2021;76:1281–1282. 89. Griffiths SK, Campbell JP. Placental structure, function and drug transfer. CEACCP 2014;15:84–89. 90. Ueki R, Tatara T, Kariya N, et al. Effect of decreased fetal perfusion on placental clearance of volatile anesthetics in a dual perfused human placental cotyledon model. J Anesth 2014;28:635–638.

  91. Pacifici GM, Nottoli R. Placental transfer of drugs administered to the mother. Clin Pharmacokinet 1995;28:235–269.   92. Cherala SR, Eddie DN, Sechzer PH. Placental transfer of succinylcholine causing transient respiratory depression in the newborn. Anaesth Intensive Care 1989;17:202–204.   93. Sewall K, Flowerdew RM, Bromberger P. Severe muscular rigidity at birth: malignant hyperthermia syndrome? Can Anaesth Soc J 1980;27:279–282.   94. Hersch PE, Matheson KH. Anaesthetic considerations for a possible malignant hyperthermia susceptible fetus. Anaesthesia 1996;51:99.   95. Zucchi R, Ronca-Testoni S. The sarcoplasmic reticulum Ca2+ channel/ryanodine receptor: modulation by endogenous effectors, drugs and disease states. Pharmacol Rev 1997;49:1–51.   96. Diszházi G, Magyar Z, Mótyán JA, et al. Dantrolene requires Mg(2+) and ATP to inhibit the ryanodine receptor. Mol Pharmacol 2019;96:401–407.   97. Driessen JJ, Wuis EW, Gielen MJ. Prolonged vecuronium neuromuscular blockade in a patient receiving orally administered dantrolene. Anesthesiology 1985;62:523–524.   98. Shin YK, Kim YD, Collea JV, et al. Effect of dantrolene sodium on contractility of isolated human uterine muscle. Int J Obstet Anesth 1995;4:197–200.   99. Weingarten AE, Korsh JI, Neuman GG, et al. Postpartum uterine atony after intravenous dantrolene. Anesth Analg 1987;66:269–270. 100. Shime J, Gare D, Andrews J, et al. Dantrolene in pregnancy: lack of adverse effects on the fetus and newborn infant. Am J Obstet Gynecol 1988;159:831–834. 101. Brandom BW, Larach MG, Chen MS, et al. Complications associated with the administration of dantrolene 1987 to 2006: a report from the North American Malignant Hyperthermia Registry of the Malignant Hyperthermia Association of the United States. Anesth Analg 2011;112:1115–1123. 102. Craft JB, Jr., Goldberg NH, Lim M, et al. Cardiovascular effects and placental passage of dantrolene in the maternal-fetal sheep model. Anesthesiology 1988;68:68–72. 103. Morison DH. Placental transfer of dantrolene. Anesthesiology 1983;59:265. 104. Fricker RM, Hoerauf KH, Drewe J, et al. Secretion of dantrolene into breast milk after acute therapy of a suspected malignant hyperthermia crisis during cesarean section. Anesthesiology 1998;89:1023–1025.

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Chapter

18

Hepatic Conditions Arash Motamed, Thang Tran, and Mohamed H. Eloustaz

Introduction The hormonal changes of pregnancy induce changes in the liver’s anatomy, physiology, and function. These can lead to diagnostic difficulties if liver disease is present during pregnancy. For example, spider nevi and palmar erythema are signs of liver disease but exist in some healthy pregnant women. However, liver size is unchanged in pregnancy, so the presence of hepatomegaly suggests liver disease. Even though the proportion of cardiac output flowing to the liver is reduced by 35%, hepatic blood flow remains unchanged from the nonpregnant state because of the overall increase in blood volume and cardiac output associated with pregnancy. Splanchnic, portal, and esophageal venous pressures are increased toward the end of pregnancy. Indeed, 60% of pregnant women develop esophageal varices that resolve postpartum. Clearance of drugs dependent on hepatic blood flow is reduced because of the larger volume of distribution. The changes to albumin, serum globulins, liver enzymes, cholesterol and triglycerides, fibrinogen, and other clotting factors can be found in Table 18.1.

Viral Hepatitis A diverse group of viruses causes viral hepatitis, the number one cause of hepatic dysfunction and jaundice in pregnancy.1 Hepatotropic viruses replicate within hepatocytes and include Table 18.1  Liver function in normal pregnancy

No change

Increased levels

Decreased levels

Aspartate aminotransferase (AST)

Alkaline phosphatase (2–3x) with maximum change in third trimester

Gallbladder contractility

Alanine aminotransferase (ALT)

Clotting factors: I, II, V, VII, VIII, X, & XII

Antithrombin III and protein S

γ-glutamyltranspeptidase (GGT)

Ceruloplasmin

Albumin and total protein

Bilirubin

Transferrin

Uric acid

Bile acids

Cholesterol

Fibrinogen with maximum change in second trimester

Lactate dehydrogenase

Triglycerides

Hemoglobin

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Hepatitis A, B, C, D, E, and G. Nonhepatotropic viruses are a less common cause of hepatitis and include cytomegalovirus, herpesvirus, Epstein-Barr virus, and influenza virus.2

Hepatitis A Virus Hepatitis A virus (HAV) is a single-stranded RNA virus transmitted via the fecal-oral route and is the most common cause of acute hepatitis.3 Viral transmission occurs most commonly in areas with poor sanitation and is endemic in parts of Asia, Africa, Central America, and Oceania. Infections are selflimited, often asymptomatic, or subclinical, and rarely lead to mortality.4 Hepatitis A infection is relatively uncommon in pregnancy (incidence: 1 in 1000). Although there are no reports of maternal or fetal mortality secondary to hepatitis A, there is an association with preterm labor and other gestational complications such as premature rupture of membranes and uterine bleeding.3 Vertical transmission is sporadic, with only a few documented cases.4 Vaccine and immunoglobulin are safe in pregnancy.5

Hepatitis B Virus Hepatitis B virus (HBV) is a double-stranded DNA virus transmitted via exposure to body fluids, sexual contact, or vertical transmission.6 Most infections are subclinical but may present early with flu-like symptoms and later with nausea, vomiting, jaundice, and abdominal pain.6 Approximately 24,000 infants are born to mothers with hepatitis B, and vertical transmission occurs in approximately 1000 newborns annually in the United States.7 Acute infection can cause liver injury in both mother and baby, so consider antiviral therapy in pregnant women with evidence of active infection. Chronic hepatitis B infection in pregnant women does not appear to increase maternal or fetal mortality, but there may be an increased risk of gestational diabetes, APH, and preterm labor.7 Most vertical transmission occurs during or shortly after birth; vaginal birth does not increase the risk of vertical transmission.7 Infants born to mothers with HBV should receive hepatitis B immunoglobulin and HBV vaccine.7

Hepatitis C Virus Hepatitis C virus (HCV) is a single-stranded RNA virus that infects 1.6% of the global population. It is transmitted primarily

Hepatic Conditions

via percutaneous exposure to blood (e.g., through shared needles) and vertical transmission from mother to child; transmission via sexual contact is rare.8 Acute infections in pregnancy are sporadic, and patients are mostly asymptomatic.9 Those with symptoms experience nausea, malaise, abdominal pain, and jaundice. Fifty-five percent to 85% of those infected will develop a chronic infection that can cause cirrhosis and hepatocellular carcinoma.8 Multiple studies have shown that HCV is associated with low birth weight and small for gestational age infants.8 Furthermore, HCV-infected parturients have a 20-fold increased chance of developing intrahepatic cholestasis of pregnancy.8 Interestingly, Di Martino et al. demonstrated a decrease in the progression of hepatic fibrosis during pregnancy, thought to be secondary to the downregulation of the maternal immune response leading to infrequent immune-mediated liver damage.8,10 Vertical transmission occurs in 3–5% of women who are HIV negative and HCV positive on polymerase chain reaction (PCR). With HIV coinfection, vertical transmission increases to 19.4%.9 Up to one-half of vertical transmission occurs in utero.8,9 Risk factors for vertical transmission include high viral load, HIV coinfection, invasive procedures, prolonged rupture of membranes (> 6 hours), internal fetal monitoring, and episiotomy.8,9 Mode of delivery and breastfeeding are not associated with vertical transmission.8 The goal of HCV treatment is to achieve a state of sustained virological response, in which the virus is undetectable 12–24 weeks following treatment.8 Treatment of HCV consists of a combination of drugs, with the most effective combinations including direct-acting antivirals (DAAs), which prevents replication of HCV. Treatment regimens that include DAAs achieve a sustained viral response in 60–100% of patients.8 DAAs are not approved yet for pregnancy, and treatment regimens that include ribavirin (category X) are not used in pregnancy.8

Hepatitis D and Hepatitis E Hepatitis D virus (HDV) is an incomplete RNA virus that requires coinfection with HBV for replication. The virus is highly prevalent in Africa, Asia, the Pacific Islands, and the Middle East.11 Coinfection with HDV and HBV is associated with severe disease, causing fulminant hepatitis in 2.3% of cases in pregnancy.11 Vertical transmission of HBV occurs more often when there is coinfection with HDV.11 Treatment in pregnancy is supportive. Hepatitis E virus (HEV) is a single-stranded, nonenveloped RNA virus. It is endemic in areas of Africa, India, and Mexico. Over half of HEV infections occur during the third trimester, and its presentation can range from subclinical disease to fulminant hepatitis.11 Seventy-five percent of fulminant hepatitis is secondary to HEV. Vertical transmission occurs in up to 46% of HEV IgM-positive mothers and results in neonates who can present with jaundice, hepatosplenomegaly, respiratory distress syndrome, and sepsis.11 Treatment is mainly supportive.

Management and Anesthetic Implications of Viral Hepatitis Presentation of hepatitis varies, ranging from asymptomatic to fulminant liver failure. Symptomatic patients present with

largely nonspecific pregnancy symptoms such as fatigue, nausea, vomiting, and abdominal pain. More specific signs of liver injury include jaundice and dark urine. Hepatic encephalopathy and hepatorenal syndrome have a higher incidence during pregnancy. Laboratory findings in hepatitis include anemia, vitamin K deficiency, lymphocytosis, and coagulation abnormalities. Halogenated anesthetics can cause hepatotoxicity.12 In the past, halothane and enflurane were associated with fulminant liver failure. There are case reports of sevoflurane-, isoflurane-, and desflurane-induced liver injury. However, modern halogenated anesthetic-induced liver injury is exceedingly rare, and these agents are considered safe in patients with liver injury. Avoid acetaminophen in patients with severe liver disease, as it causes oxidant stress to hepatocytes.13 General anesthesia does not affect the survival of patients with advanced liver disease, so it is a good technique in pregnant women with liver disease.13 Similar to other parturients, NA is preferable for surgical procedures. Obtain appropriate laboratory tests before NA in those with advanced liver disease, as they may have thrombocytopenia or coagulopathy.

Hyperemesis Gravidarum Nausea and vomiting are very common in pregnancy, occurring as early as six weeks and lasting up to 20 weeks post-conception.14 Hyperemesis gravidarum (HG) is a severe form of pregnancyinduced nausea and vomiting that includes signs of dehydration and weight loss of 5% or more.14 It occurs in upwards of 1% of pregnancies. This condition is rarely fatal; however, it is a significant cause of morbidity and is the most common cause of hospitalization in the first half of pregnancy.15,16 Outcomes of neonates born to mothers with HG are generally good, but these babies can present with low birth weight. Severe vomiting may lead to dehydration, ketosis, weight loss, and reflux esophagitis. Risk factors for HG include nulliparity, younger age, high saturated fat intake and obesity, female fetus, twins, and hydatidiform mole. Patients can present with dehydration and malnutrition. Laboratory tests may show hyponatremia, hypokalemia, and hypochloremia. Up to 50% of women also have increased serum aminotransferases and total bilirubin.17 The etiology and mechanism of liver disease in HG is uncertain, but it may be related to impaired fatty acid oxidation.18 Synthetic liver function remains normal, and abnormalities reverse with treatment.

Management and Anesthetic Implications of Hyperemesis Gravidarum Dehydrated patients need fluid resuscitation as well as electrolyte replacement. Malnourished patients may require total parenteral nutrition. To prevent complications from central pontine myelitis, be cautious with fluid resuscitation in women with hyponatremia. In rare cases, women with HG can present with Wernicke encephalopathy, so supplement with vitamins B6 and B12. Patients with a history of HG have a higher incidence and severity of postoperative nausea and vomiting after CD.19 So, it is essential to take a multimodal approach to antinausea medication administration in HG patients undergoing CD or any

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Arash Motamed, Thang Tran, and Mohamed H. Eloustaz

other surgical procedure. First-line treatments for HG include doxylamine and pyridoxine. Other possible medications include ondansetron, metoclopramide, diphenhydramine, and promethazine.17

Intrahepatic Cholestasis of Pregnancy Intrahepatic cholestasis of pregnancy (IHCP) is a disease characterized by pruritus and elevated serum bile acids, often in the presence of other signs of liver dysfunction20 (Table 18.2). It is the most common pregnancy-specific liver disorder, affecting 0.3–5.6% of pregnancies in the United States.21 The incidence is variable and based highly on ethnic group and geography, with South Americans and Northern Europeans most affected. Other risk factors include multiple gestations, advanced maternal age, in vitro fertilization pregnancies, hepatitis C infection, and family history.20 The cause of IHCP is poorly understood but is possibly due to dysfunction of bile secretion by active hepatocellular transporters.22 The onset of IHCP is typically in the second and third trimester but may present as early as eight weeks gestation.23 The usual presentation is pruritus, most intense on the palms of the hands and the soles of the feet. The differential diagnosis of pruritus includes atopic eruption of pregnancy (the most common pruritic disorder of pregnancy), polymorphic ­eruption of pregnancy, and pemphigoid gestationis (see Chapter 23 for more details). Other symptoms include abdominal pain, nausea, mild jaundice, and steatorrhea.24 The main laboratory abnormality in IHCP is an increased bile acid level; aminotransferases, gamma-glutamyl transferase, and alkaline phosphatase can also be elevated.24 Pregnant women have good outcomes with relatively minor symptoms of pruritus and excoriations secondary to scratching that resolve shortly after delivery. On the other hand, fetal outcomes can be poor with complications including preterm labor, meconium staining of amniotic fluid, fetal asphyxia events, and IUFD.23 The risk of fetal complications increases with bile acid levels > 40 μmol/L, and the risk of stillbirth is 3.4% with bile acid levels > 100 μmol/L.25

Management and Anesthetic Implications of Intrahepatic Cholestasis of Pregnancy Serial testing for bile acid levels (e.g., weekly) is not recommended but if the patient has pruritus, bile acids are checked and rechecked if initially normal but with persistent pruritus. The risk of fetal demise increases with increasing gestational age, so ACOG recommends delivery between 36- and 37-weeks gestation. There is no effective therapy. Ursodeoxycholic acid (UDCA) is the most common treatment, as it reduces maternal bile acid levels and itching. However, UDCA does not improve fetal outcomes.23,25 Second-line therapies include cholestyramine or rifampin; if using cholestyramine, it is essential to administer prophylactic vitamin K. Dexamethasone and ondansetron reduce pruritus.20,26 Neuraxial anesthesia is the preferred technique for analgesia in childbirth in normal gestations and IHCP. DeLeon et al. evaluated 319 parturients with IHCP and found that coagulopathy was rare and that there was no increased incidence of abnormal bleeding or epidural hematoma.27 If there is time, a complete blood count could be obtained before NA, and coagulation studies done when there is any indication.

Valuable Clinical Insights • Consider IHCP in women presenting with itching during second and third trimesters. • Perform liver function tests, including serum bile acids, which will all be significantly elevated. • If these tests are normal and the itching persists, then repeat liver function tests (LFTs) weekly, since pruritus can precede changes in LFTs. • Increased risk of gallstones. • Treat with ursodiol. • Delayed diagnosis increases the risk of stillbirth, and ­induction of labor from 36 to 37 weeks gestation reduces this risk.

Table 18.2  Liver diseases unique to pregnancy (excluding preeclampsia)

Liver disorder

Clinical features

Obstetric implications

Anesthetic concerns

Hyperemesis gravidarum (HG)

Extreme vomiting and dehydration in early pregnancy Minor liver dysfunction Occasionally severe complications

Increased early fetal loss

Optimal antiemetic therapy Correct fluid and electrolyte imbalances

Intrahepatic cholestasis of pregnancy (IHCP)

Late pregnancy pruritus, malaise, and jaundice Treat pruritus with ursodiol Rapid resolution postpartum

Monitor fetal status Increased risk of preterm delivery and poor fetal outcomes

Monitor liver function and coagulation status

Acute fatty liver of pregnancy (AFLP)

Third trimester malaise, nausea, abdominal pain, and jaundice Hypoglycemia, metabolic acidosis, coagulopathy, liver failure

Intensive fetal monitoring Expedite delivery PreE in 40% Intensive therapy to include dextrose, antibiotics, and vitamin K Complete postpartum resolution

Invasive monitors Good IV access Correct coagulopathy if present Prepare for peripartum hemorrhage GA vs. RA: weigh risks & benefits

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Hepatic Conditions

Acute Fatty Liver Disease of Pregnancy Introduction Acute fatty liver disease of pregnancy (AFLP) is an obstetric emergency whereby fatty infiltration of the liver can lead to acute maternal liver failure, potentially resulting in maternal and fetal death.28,29 It is relatively rare, occurring in about 1:13,000 pregnancies, and while it can present in the second trimester, it typically occurs in the third trimester.28–31 The incidence is around 1:9,300 in Caucasians, but all ages, races, and ethnicities can be affected.32 Early diagnosis is critical, and treatment can range from expedited delivery of the fetus and supportive care of the mother to multiple blood transfusions, dialysis, and orthotopic liver transplantation.29,33 Risk factors28,34,35 may include: • multifetal gestation (potentially due to increased fatty acid metabolites from more than one fetus) • male fetuses • underlying maternal metabolic disorders such as diabetes • fetal long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency. While causation and association are not delineated, a significant number of women with PreE and HELLP syndrome are also diagnosed with AFLP.35,36

Clinical Features and Diagnosis Clinical findings and correlation with laboratory data are the main methods to diagnose AFLP. AFLP can have vague and frequently overlapping symptoms, such as jaundice, nausea, vomiting, encephalopathy, polydipsia, polyuria, and abdominal pain. These symptoms can quickly progress to acute liver failure with coagulopathy, hypoglycemia, and acute renal insufficiency.37 True liver dysfunction, rather than just elevated liver enzymes, may occur with AFLP.38 For example, hypoglycemia, elevated international normalized ratio, and evidence of liver dysfunction, such as disseminated intravascular coagulation (DIC) and encephalopathy, can help distinguish AFLP from HELLP syndrome and PreE.38 It is crucial to note that multiple disease processes, such as AFLP, HELLP, and IHCP, can coincide, making early diagnosis difficult. Up to 20% of patients with AFLP have concurrent HELLP syndrome and 40% PreE.34 The Swansea criteria are a potential diagnostic tool for AFLP with a reported 100% sensitivity, 57% specificity, 85% PPV, and 100% NPV for AFLP when meeting six of the 15 criteria. However, their utility as an early diagnostic tool has been questioned as: • they are designed to be used in the absence of other liver diseases • the criteria can overlap with the diagnosis of HELLP syndrome, and • it appears these criteria are most helpful for already critically ill patients when it may be too late for treatment.30,39,40 While liver biopsies are not necessary to diagnose AFLP, they can expedite the treatment plan in uncertain cases.41 The hallmark histologic finding of AFLP is microvesicular fatty infiltration

of hepatocytes involving the pericentral zone and sparing the periportal hepatocyte; this differs from other liver diseases of pregnancy, suggesting different underlying pathophysiology.42 Various radiologic studies in AFLP have not demonstrated high utility.28

Pathophysiology A group of disorders called fetal fatty acid oxidation defects (FAOD) is associated with the risk of liver disease in ­pregnancy, including AFLP. There is a lack of enzymes involved in the mitochondrial metabolism of fatty acids with FAOD. In AFLP, the most common deficiency is long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD),43,44 although deficiencies in other enzymes involved in fatty acid oxidation may have similar effects. Increased maternal hormone-sensitive lipase activity and increased insulin resistance cause increased triglyceride levels in pregnancy. These triglycerides are broken down into free fatty acids (FFAs) in maternal blood. Fetal and ­placental enzymes, such as LCHAD, break down these FFAs for growth and development. Deficiencies in such enzymes, and the increased FFAs due to the maternal metabolic changes of pregnancy, can result in the accumulation of intermediate products in maternal blood and maternal hepatocytes, creating toxic effects on the mother.29,45 Fatty acids and their metabolites create reactive oxygen species (ROS) that can injure hepatocytes via inflammation and cellular necrosis, ultimately manifesting as AFLP.28,29,46

Management, Implications, and Outcomes While there is no standardized approach to diagnosing AFLP, emergent fetal delivery and supportive care are essential if characteristic clinical and laboratory findings suggest the diagnosis. While women with AFLP may recover normal function within a week, early diagnosis is still crucial, as fulminant hepatic failure may be irreversible. Hepatic rupture and hematoma can occur immediately postpartum, but the most common life-threatening conditions associated with AFLP are acute liver failure, DIC, GI bleeding, and acute renal failure.47 In severe cases, admit women with AFLP to ICU for correction of hypoglycemia, administration of blood products for coagulopathy, mechanical ventilation, and dialysis. If there is no improvement, consider the possibility of simultaneous sepsis or hypoxic-ischemic liver injury.48,49 Liver transplantation is the last measure. Maternal mortality rates for AFLP, once over 80%, dropped to about 7–18% by the 2000s.50 Women receiving prompt, adequate care can improve in one to three weeks. Unlike PreE, there is no demonstrated pattern of recurrence of AFLP in women who had it during a prior pregnancy. Once AFLP has subsided, there are relatively few long-term maternal complications.29,51 However, fetal mortality is as high as 23%, possibly due to maternal acidosis, complications of prematurity, and FAOD.29,34

Anesthesia Implications Due to the emergent nature of AFLP, the anesthesiologist may be unable to optimize the electrolytes, coagulation profile, or NPO status of the patient. Although described in this situation, current or impending coagulopathy may contraindicate NA

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use due to the increased risk of paralysis. Ensure large-bore IV access and consider arterial cannulation for close hemodynamic monitoring, as there may be considerable blood loss secondary to coagulopathy. Depending on the severity of the liver disease, one should have blood, fresh frozen plasma, cryoprecipitate, and platelets readily available. Before any procedure, administer aspiration prophylaxis, (an H2 receptor antagonist, metoclopramide, and sodium citrate). For GA, do a rapid sequence induction with videolaryngoscopy available in the event of airway edema. Either succinylcholine or rocuronium is appropriate for muscle paralysis for intubation, providing there is normokalemia. Cisatracurium or rocuronium are suitable to maintain paralysis. Neuromuscular monitoring is essential as impaired hepatic function may decrease the dose required. The goals of GA are to maintain liver and renal blood flow, while avoiding hepatotoxicity. Poor metabolism in the presence of hepatic failure will yield exaggerated responses to anesthetics, paralytics, and opioids, so one will likely need to reduce their dose. Valuable Clinical Insights • Acute fatty liver disease of pregnancy causes nausea, vomiting, abdominal pain, malaise, jaundice, and hypoglycemia. • PreE often coexists. • Less commonly, AFLP presents with headache, backache, hematemesis, necrotizing enterocolitis, and fulminant liver failure – i.e., severe hypoglycemia, hyperammonemia, metabolic acidosis, GI bleeding, impaired or loss of consciousness, or encephalopathy.

Liver Tumors While a specific incidence is unknown, hepatic tumors in pregnancy are rare. However, they may result in significant diagnostic and therapeutic challenges when they occur.52

Diagnosis Depending on the nature of the mass, the clinical presentation can range from asymptomatic to hemorrhagic shock, which can mimic ruptured ectopic pregnancy. Common symptoms such as nausea and anorexia may also be mistaken for pregnancy symptoms. Ultrasound and non-contrast MRIs are the imaging modalities of choice; use CT and angiography only as needed, as they can expose the fetus to radiation.

Malignant Neoplasms of Pregnancy Primary malignancies of the liver are exceedingly rare during pregnancy. Hepatocellular carcinoma (HCC) accounts for 90% of these lesions. Seventy percent of patients with HCC have elevated alpha-fetoprotein (AFP) levels. When diagnosed early in pregnancy, termination of pregnancy is encouraged due to the aggressive nature of HCC, which has a median survival of eight weeks, and an overall one-year survival rate of 23%52–54 About 5–10% of primary malignant liver neoplasms of pregnancy are accounted for by cholangiocarcinoma, a cancer of the extrahepatic biliary tract. The median survival time is three to

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six months, and while reported in pregnancy, it is exceedingly rare. In contrast with HCC, AFP levels are not typically elevated in patients with cholangiocarcinoma.54,55

Nonneoplastic Liver Masses Nonneoplastic liver masses can be due to infections caused by echinococcosis, amebiasis, schistosomiasis, and brucellosis. They can ultimately result in abscesses, cysts, and granulomas. History and physical examination, especially travel history, help diagnose these conditions.52

Benign Neoplasms of Pregnancy Hemangiomas are the most common benign liver tumors, but the incidence in pregnancy is unknown.52,56 Rupture, leading to life-threatening hemorrhage, occurs in 1–4%.57 During pregnancy, treatment depends on size, symptomatology, and risk of rupture. Treatments include corticosteroids, radiation, surgical excision, and embolization.58 Liver cell adenomas are solid tumors that usually consist of hepatocytes, are encapsulated, and vascular with a tendency to bleed spontaneously, and are associated with oral contraceptive pill (OCP) use.52,59 One can treat asymptomatic adenomas < 5 cm in size conservatively, as they have a lower chance of rupture.60 Focal nodular hyperplasias (FNH) contain hepatocytes and proliferating bile ducts, are not associated with OCPs, are not encapsulated, and have a central fibrous scar with radiating septa. If small and asymptomatic, resection is not required. However, if large and symptomatic, resection holds risks of rupture and premature delivery.52,61 Regardless of the cause of the mass, carefully consider the risks and benefits of medical management, surgical management, or termination of pregnancy, as a rupture is associated with high maternal and fetal mortality. If the decision is for surgery, consider intraoperative fetal monitoring depending on the gestational age. Ensure large-bore IV access with packed RBCs on standby and prepare for cell salvage.

Other Liver Diseases Budd–Chiari Syndrome In Budd–Chiari syndrome (BCS), hepatic vein or terminal IVC thrombosis results in hepatic venous outflow obstruction.62 Thrombophilia, such as protein C or protein S or Antithrombin III deficiency, are risk factors for BCS. As pregnancy induces a hypercoagulable state, it is not surprising that there is a close relationship between BCS and pregnancy,63,64 with a prevalence likely between 3.9% and 10.5%.63 Clinically, hepatomegaly, ascites, and even acute liver failure may be present. Diagnosis is made with Doppler flow studies, MRI, or venography, while liver biopsy reveals congestion and centrilobular liver necrosis. In the past, maternal and fetal outcomes in pregnant women with BCS were poor (with maternal mortality as high as 50%). Multidisciplinary management, early detection, decompressive treatment, and anticoagulation with heparin or warfarin have improved outcomes in patients in well-controlled BCS.65 However, if the obstruction is resistant to interventions and

Hepatic Conditions

revascularization is unsuccessful, the only other option is liver transplantation.

is a higher incidence of preterm delivery, the most frequently reported obstetric complication in AIH.85,86

Peliosis Hepatitis

Hydatid Disease

Peliosis hepatitis is characterized by various sized, blood-filled, cystic spaces in the liver parenchyma.66–68 It has many etiologies, including infectious agents such as the gram-negative bacteria genus Bartonella, tumors, or anabolic steroids. One hypothesis is that problems with blood outflow from the liver lead to increased sinusoidal pressure, hepatocyte necrosis, sinusoidal wall weakness, and portal hypertension.66 The clinical spectrum ranges from asymptomatic to severe portopulmonary hypertension necessitating liver transplantation, as well as life-­threatening hepatic rupture.67,69 Liver biopsy is needed to confirm the diagnosis, by demonstrating round intralobular cavities randomly distributed throughout normal hepatic parenchyma.70 Rarely, it is described in pregnancy and improvement can occur with antibiotics and hepatic artery embolization.71

Hydatid disease, or cystic echinococcosis, is a worldwide parasitic disease where canine feces transfer adult worms to humans. The larvae of these worms develop in the intestine and enter the liver through the portal circulation, where they form hydatid cysts.52 Often asymptomatic, US can diagnose hydatid cysts. Hydatidosis during pregnancy is rare. Even where hydatid disease prevalence is high (e.g., Mediterranean, South American, and Middle Eastern regions), its incidence is about 1 in 20,000 to 1 in 30,000 births.87–90 Surgical resection of liver hydatid cysts carries the risk of anaphylaxis, dissemination, and recurrence. Surgery combined with chemotherapy can serve as an alternative. Drug treatment with benzimidazoles alone or concurrently with surgery is effective in nonpregnant patients with decreased recurrence or stopping further disease progression. Some sources suggest that drug therapy is a suitable initial alternative to surgery in uncomplicated hydatid liver disease.91–93 However, there is no consensus on using these medications during pregnancy. Mebendazole and albendazole are teratogenic in some animal models, and mebendazole may be associated with hemangiomas.52 In bovine models, a low dose of albendazole is safe, but results are inconsistent in humans.52,90,94 Therefore, consider drug therapy in pregnancy only when surgical intervention is impossible, or the disease is recurrent.

Autoimmune Hepatitis Characterized by hepatocellular inflammation and necrosis, autoimmune hepatitis (AIH) can cause liver cirrhosis in the absence of viral, alcoholic, hepatotoxic, or genetic disorders.72–74 Clinical manifestations range from asymptomatic hepatitis to acute fulminant liver failure.75,76 Disease activity may improve during pregnancy because of an immune shift with increased anti-inflammatory cells and cytokines.77,78 However, if the disease is severe with preexisting cirrhosis, the patient is at increased risk during exacerbations. Prednisolone and azathioprine are the leading medical treatments in AIH. As prednisolone is safe during pregnancy, it can be used to treat and prevent AIH exacerbations.74,79 There is no consensus on azathioprine, classified as a category D drug, but exposure in humans does not increase congenital anomalies.80,81 While the older literature demonstrated unfavorable pregnancy outcomes, management of preexisting comorbidities (portal hypertension, concurrent disorders) and complex medical management by multidisciplinary teams have vastly improved maternal and fetal outcomes.82–84 The birthrate in AIH patients is like that of the general population, but there

Wilson Disease (Hepatolenticular Degeneration) Wilson disease is a rare autosomal recessive disorder of copper metabolism, causing liver disease and neural copper accumulation. Patients may be asymptomatic, present with acute liver failure (see below), or chronic liver disease – with or without neuropsychiatric and movement abnormalities. Fertility is reduced, and therapy should be started before conception and continued throughout pregnancy.95 The preferred treatment is zinc sulfate 50 mg t.i.d. (FDA category C) because of its efficacy and fetal safety profile. The anesthetic implications are listed in Table 18.3.

Table 18.3  Rare liver diseases

Liver condition

Clinical features

Obstetric issues

Anesthetic issues

Budd–Chiari syndrome

Hepatic vein obstruction causing ascites, hepatomegaly, and liver failure

Consult with hepatologist Patient may require anticoagulation and occasionally portocaval shunt Poor maternal and fetal outcomes

Monitor liver function and coagulation status Intraoperative management appropriate for patients with liver failure NA not appropriate if significant coagulopathy GA with sevoflurane, propofol, atracurium, and short-acting opioids

May be associated with inherited thrombophilias, e.g., Factor V Leiden, Protein C or S deficiency, MTHFR mutation Wilson disease

Copper accumulates in body causing liver dysfunction, motor, and psychiatric disturbances Copper levels controlled with zinc therapy

Favorable pregnancy outcomes in those who get regular therapy and remain asymptomatic

As above Be wary of esophageal varices, bulbar involvement, and drug effects Prepare for PPH

Primary biliary cirrhosis

Variable presentation from asymptomatic to cirrhosis Diagnosis based on mitochondrial antibodies and liver biopsy

Pregnancy and the fetus unaffected if there is well-compensated disease

As above

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Diseases of the Biliary Tract Diseases of the gallbladder are common and predominantly impact women, with a prevalence of 58% compared to 42% in men.96 They often present during pregnancy and are the most common nonobstetric cause of hospitalization up to 60 days postpartum.97 Pregnancy factors that influence gallbladder disease prevalence include parity (increased in multiparous women), prepregnancy obesity, elevated serum leptin, and increasing gestational age.98,99 Studies in the nonpregnant population demonstrate a link between estrogen and the increased incidence of gallstone formation, while progesterone is linked to biliary stasis.100–102 Cholelithiasis, the presence of stone(s) within the gallbladder, is the commonest gallbladder disease during pregnancy, with an incidence of 3%.103 While most patients are asymptomatic, biliary colic (the painful contraction of the gallbladder) is the likeliest presentation.99,104 Acute cholecystitis, inflammation due to physical gallstone obstruction in the cystic duct, is the most common complication of cholelithiasis, occurring in about 0.1% of pregnancies.103,105 Choledocholithiasis, obstruction of the common bile duct by gallstone(s), is another complication of cholelithiasis. While less frequent, gallstone pancreatitis, pancreatic inflammation from gallstone obstruction, is the most common type of pancreatitis during pregnancy. Acute pancreatitis, of all etiologies, occurs in approximately 1 in 3000 pregnancies, frequently presenting during the third trimester or in the early postpartum period.106 Clinical evaluation, laboratory testing, and imaging can help differentiate various gallbladder diseases. Clinically, right upper quadrant pain should alert the clinician to the possibility of biliary colic and cholecystitis. If a gallstone causes obstruction, it may increase liver transaminases, alkaline phosphatase, and bilirubin. Fever and an elevated white blood cell count may occur with significant inflammatory conditions, such as acute cholecystitis. Ultrasound is the diagnostic tool of choice in pregnancy, given its safety profile, lower cost, availability, and accuracy. One must consider the risks and benefits of nonsurgical and surgical approaches in treating gallbladder disease, including the associated anesthetic risks. A nonsurgical approach has a higher recurrence rate, especially during the second trimester, with possibly a worse outcome for the fetus or mother.107,108 Conversely, surgical intervention during pregnancy has a small but significantly higher risk of surgical complications such as bile leak and septic shock.109 Nevertheless, laparoscopic surgery appears safe in all stages of pregnancy.110 While surgery has a favorable safety profile, more pregnant women with acute cholecystitis are treated nonsurgically than the general population.109 Other techniques such as extracorporeal shock wave lithotripsy and percutaneous cholecystostomy are not well studied in pregnant patients. Consequently, the treatment approach may result in a challenging decision that must consider factors such as gestational age, resource availability, the severity of illness, presence of other concomitant diseases, and surgical approach (laparoscopic vs. open). While IV hydration, antibiotic therapy, and pain medication may represent the initial approach to these

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diseases, acute complications related to the gallbladder require definitive surgical treatment.111 Gallbladder disease represents the second most common indication for surgery after appendicitis.112 Approximately 40% of patients presenting with symptomatic cholelithiasis during pregnancy require cholecystectomy,113 with an overall rate of 1 in 1600 to 10,000 pregnancies.112 In a meta-analysis that did not consider gestational age, laparoscopic cholecystectomy (mean 18 weeks gestation) had fewer maternal and fetal complications than open cholecystectomy (mean 24 weeks gestation).114 Furthermore, in the pregnant population, there are more maternal and fetal complications, longer lengths of stay, and higher hospital costs with open compared to laparoscopic cholecystectomy.107 Endoscopic retrograde cholangiopancreatography (ERCP) is another modality employed for patients with choledocholithiasis. ERCP relieves obstruction, potentially resolving associated obstructive jaundice, pancreatitis, or cholangitis. Aside from the need for sedation and anesthesia, the primary concern with ERCP is the need for radiation with fetal exposure. However, in pregnancy, there are reports of ERCP with acceptable doses of ionizing radiation,115,116 or nonradiation ERCP.117 Two other biliary tract diseases that may impact pregnancy are primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC).118 The inflammation and bile duct fibrosis associated with both may ultimately result in liver cirrhosis, with liver transplantation the definitive treatment. Furthermore, in approximately 70% of patients, PSC is strongly associated with inflammatory bowel disease.118 Both PBC and PSC during pregnancy are well tolerated, although the rate of preterm births has been found to increase.119,120 The prognosis for a pregnant patient with gallbladder disease and her fetus has improved significantly. Overall, there is a significant reduction in fetal loss,121 but gallstone pancreatitis causes an increase in fetal mortality and preterm delivery.122

Anesthetic Implications In a pregnant patient requiring nonobstetric surgical intervention related to biliary tract disease, maintaining maternal and fetal hemodynamic stability through appropriate monitoring and management is critical. Liver function and coagulation are often affected in patients with PBC or PSC, depending on the severity and chronicity of each disease. In parturients with chronic liver disease, liver function abnormalities may impact the pharmacokinetic and pharmacodynamic effects of medications, which are compounded by hypoalbuminemia.

Liver Emergencies Liver emergencies are rare in the parturient. Early recognition of a liver emergency and its management has a significant impact on maternal and fetal survival. Unfortunately, all liver emergencies during pregnancy carry a high morbidity and mortality rate. While diagnostic and therapeutic interventions should ensure maternal and fetal safety, in life-or-death scenarios, maternal wellbeing takes precedence. Given the paucity of literature on the topic, most recommendations come from case reports, case series, and anecdotal evidence.

Hepatic Conditions

Hepatic Rupture There are only about 200 published cases of spontaneous hepatic rupture. Mainly observed in PreE, hepatic rupture is frequently associated with HELLP syndrome.123–126 While there are reports of hepatic rupture in earlier stages of pregnancy, it typically occurs late in the third trimester and multiparous patients over age 30. The hematoma occurs most frequently in the liver’s right lobe,127–130 and is often limited to the anterior/superior regions.129 If suspected, a CT scan is the imaging modality of choice. If a liver hematoma is diagnosed before rupture, then consult with an interventional radiologist who might recommend hepatic vessel embolization. Unfortunately, the characteristic presentation of hepatic rupture is nonspecific and may range from vague epigastric discomfort and nausea to right upper quadrant discomfort or severe right shoulder pain. With significant blood loss, there may be abdominal distension and hypovolemic shock. Laboratory findings are nonspecific and like those associated with HELLP syndrome, such as elevation of liver transaminases and alkaline phosphatase, along with thrombocytopenia and abnormal coagulation. While early detection and management (surgical or nonsurgical) may impact the outcome, prognosis remains poor with a 40–60% maternal and perinatal mortality.130,131 Recent reports suggest better outcomes, likely due to general improvements in medical diagnosis, monitoring, and management. Given the nonspecific nature of this disease, identification may first occur during an emergency CD. When rupture occurs, it may lead to shock requiring resuscitation, emergency surgery, and termination of pregnancy. If the patient is stable, monitor the mother and fetus closely, followed by CD and liver inspection. Surgical interventions are used when hemodynamic compromise is anticipated despite aggressive medical management. Reported surgical techniques include hepatic compression and packing, hepatic artery ligation, recombinant factor VIIa administration, argon beam coagulation, hepatic lobectomy, and emergency transplantation.132–136 A comparison of these approaches suggests better outcomes with hepatic packing instead of lobectomy.131

Acute Liver Failure Acute liver failure presents another form of complicated liver emergency with a poor prognosis. While studies are limited, nearly half of the presenting cases have been in patients with HELLP syndrome, while most of the others were diagnosed with AFLP.137 Other etiologies related to or exacerbated by pregnancy include PreE/eclampsia with liver infarction, acute hepatic rupture, viral hepatitis, BCS with portal vein thrombosis, and gallstone disease.138 The accepted definition of acute liver failure is coagulation abnormalities and encephalopathy in a patient without preexisting cirrhosis and an illness of 26 weeks or less.139 Given the loss of hepatic synthetic function, hypoalbuminemia, hypoglycemia, and lactic acidosis are common. In addition, affected individuals are at increased risk of hyperammonemia and cerebral edema. The management of acute liver failure requires a comprehensive multidisciplinary approach guided by its etiology. The recommended treatment for AFLP or HELLP syndrome is

expeditious delivery.140 The stage of pregnancy during which acute liver failure occurs will affect fetal wellbeing, with worse outcomes in earlier gestations. Emergency liver transplant is reserved for a small subset of patients.141

Anesthetic Approach for Liver Emergencies Pregnant patients with liver emergencies are among the most challenging cases for the obstetric anesthesiologist. Anesthetic management depends on the nature of the emergency. Preoperatively evaluate the degree of liver impairment (presence of ascites, levels of plasma proteins and ammonia, coagulation parameters), other organ involvement, and degree of urgency. Expeditious transfer of patients who require liver transplantation to liver transplant health centers is vital. The parturient with acute liver failure secondary to PreE/ eclampsia or HELLP syndrome requires delivery, most likely CD under GA, as coagulopathy will contraindicate NA. For a patient in extremis due to hemorrhage from liver rupture, the primary anesthetic concern is maintenance of intravascular volume and organ perfusion. General anesthesia is mandatory in this situation. These patients benefit from invasive hemodynamic monitoring, TTE (or other noninvasive cardiac monitoring), and neuromuscular blockade monitoring. Be prepared for significant blood loss, coagulopathy, massive transfusion, and organ dysfunction. Resuscitation will require IV fluids, blood products, and replacement of factor deficiencies until there is hemostasis and surgical control of blood loss. Tools such as ROTEM and TEG are important aids in this setting. Vasopressors may be required to sustain BP and SVR. Correct electrolytes and glucose abnormalities and provide seizure prophylaxis. Given the potential metabolic derangement and perfusion injury to the liver and kidneys, titrate medications to effect. As with most critical situations, effective communication with other providers is key to a successful outcome. In patients with underlying liver disease, select anesthetic agents based on (1) their effect on liver function, and (2) the effect of liver disease on their metabolism and duration of action. Volatile anesthetic agents are mostly excreted via the lungs, but being lipophilic, some absorption occurs, requiring hepatic metabolism. Older agents, such as halothane, undergo significantly more metabolism than the newer agents, sevoflurane or desflurane. Trifluoroacetylate, the result of this metabolism, can cause an immune-mediated reaction leading to liver damage. Newer agents, such as sevoflurane or desflurane, are safer agents for patients with liver disease. Propofol is an appropriate induction agent because of its rapid redistribution, but it could decrease liver blood flow due to its vasodilatory effects. As thiopental is protein bound, use cautiously in patients with decreased plasma proteins. As all opioids are metabolized in the liver, titrate short-acting opioids, such as fentanyl, sufentanil, or remifentanil. Avoid long-acting agents, such as morphine. It is essential to monitor neuromuscular blockade in patients with severe liver disease. The duration of succinylcholine is likely to be prolonged due to decreased plasma cholinesterase, so it is best to avoid it. Atracurium is the neuromuscular blocker of choice since it does not undergo hepatic metabolism.

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Postoperatively, consider transferring these patients to the ICU for ventilation and ongoing management. Not only is there the risk of rebleeding, liver failure, hemodynamic instability, and cerebral edema, there is also the risk of complications such as septic shock, DIC, and acute renal failure.

Liver Cirrhosis and Pregnancy Cirrhosis in pregnancy  occurs in approximately 1 in 6000 pregnancies. Alcohol-related cirrhosis represents only 5% of these cases. An article by Dr. Jennifer Flemming illustrates that the number of women with cirrhosis who become pregnant is increasing, with 50% of such pregnancies associated with adverse outcomes for mother and infant142 (Figure 18.1). Despite this increased incidence, the need for liver transplant and death are still rare. Like all complex cases, a multidisciplinary approach to these cases is essential with early consultation and a well-designed care plan. Such cases require an abundance of resources and a broad skill set. Liver disease must be recognized early to avoid undesirable outcomes. Liver cirrhosis can present with the following: 1. Preterm labor and IUGR. 2. Coagulopathy. 3. Anasarca and ascites. 4. Chronic anemia. 5. Limited or no prenatal care. 6. Caput medusa and esophageal varices from portal hypertension 7. Decompensated liver disease. 8. Hyperammonemia requiring treatment with lactulose enemas and rifaximin. 9. Hepatic coma. 10. Other co-morbidities, e.g., hypertension, morbid obesity, and diabetes.

These patients have a significant bleeding risk from coagulopathy and varices, so adequate IV access is essential and, if possible, avoid instrumentation of the esophagus. Blood products must be readily available, and the patient will require a postoperative ICU bed. The neonates often require NICU care as they can have multiple problems related to fetal alcohol syndrome and prematurity. The anesthetic implications for all women with liver and biliary disease are well reviewed.143,144

Liver Transplantation The first reported case of pregnancy in a liver transplant recipient took place in 1978.145 Since then, a successful pregnancy after a liver transplant is more likely. Fertility is restored soon after transplantation, and menstruation can occur as early as the first month.146–149 Nevertheless, the current recommendation is to wait at least one year, with some centers advocating two years after liver transplant before planning pregnancy.150–153 At the author’s institution, the current recommendation is to wait one year with a minimum wait time of six months. Time ensures proper graft function and recovery from surgery, less likelihood of acute cellular rejection and opportunistic infections while allowing for reduced dosages of immunosuppressive drugs.152 Those with post-liver transplant complications, such as acute cellular rejection or graft failure, require longer periods of observation. A multidisciplinary team must care for these complex patients throughout pregnancy. Compliance with the designed immunosuppression medication regimen is vital for graft function. The results of a meta-analysis reviewing 1496 pregnancies in 1073 liver transplant recipients found rates of live birth (85.6%), induced termination of pregnancy (5.7%), miscarriage (7.8%), and stillbirth (3.3%). Obstetric complications included pregnancyinduced hypertension (PIH), PreE, and gestational diabetes.154 Others have reported complications such as PPH, prematurity, and IUGR.155,156 Of these, the most common complication is PIH.

Figure 18.1  Outcomes of pregnancy in women with cirrhosis. Reprinted with permission from Flemming JA, Mullin M, Lu J, et al. Outcomes of pregnant women with cirrhosis and their infants in a population-based study. Gastroenterology 2020;159:1752–1762.

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Immunosuppression is required to maintain adequate graft function and prevent failure. Careful dosing and titration of immunosuppression is key to maximizing maternal benefit while minimizing fetal exposure. Current doses of corticosteroids are not teratogenic and do not cause a cleft lip.157,158 Azathioprine crosses the placenta but has good safety data for pregnancy without long-lasting sequelae.159 Cyclosporine also crosses the placenta and, despite a moderate risk for IUGR, is not associated with congenital anomalies.160–162 Tacrolimus, considered the ideal monotherapy, is also safe, but one must monitor levels closely. Mycophenolate Mofetil is not used during pregnancy due to its association with congenital anomalies.163 Graft loss during pregnancy is uncommon; when rejection occurs, it is likely due to discontinuation or reduction of immunosuppressive drugs. The increased plasma volume in pregnancy may also play a role by diluting the levels of immunosuppressive medication.

Anesthetic Considerations Multidisciplinary collaboration is essential in managing pregnancy in post-liver transplant patients. Ideally, an anesthesiologist will see these women in consultation early in the third trimester as many deliver preterm. A thorough evaluation that focuses on the status of the grafted organ, other preexisting conditions, and current medications is crucial. In the United States, liver transplant patients tend to have a higher rate of CD (42%) than the general population (32%).154,156 Neuraxial anesthesia may be appropriate, following the same general guidelines as for other pregnant patients. General anesthesia is required for graft dysfunction, coagulopathy, or persistent portal hypertension with extensive venous collaterals. Large-bore IV access for rapid resuscitation is essential, given the possibility of extensive collaterals.

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113. McKellar DP, Anderson CT, Boynton CJ, et al. Cholecystectomy during pregnancy without fetal loss. Surg, Gynecol Obstet 1992;174:465–468. https://pubmed.ncbi.nlm .nih.gov/1595022/ 114. Sedaghat N, Cao AM, Eslick GD, et al. Laparoscopic versus open cholecystectomy in pregnancy: a systematic review and meta-analysis. Surg Endosc 2017;31:673–679. https://doi .org/10.1007/S00464-016-5019-2 115. Kahaleh M, Hartwell GD, Arsenau KO, et al. Safety and efficacy of ERCP in pregnancy. Gastrointest Endosc 2004;60:287–292. https://doi.org/10.1016/S0016-5107(04)01679-7 116. Tham TCK, Vandervoort J, Wong RCK, et al. Safety of ERCP during pregnancy. Am J Gastroenterol 2003;98:308–311. https:// doi.org/10.1111/J.1572-0241.2003.07261.X 117. Shelton J, Linder JD, Rivera-Alsina ME, et al. Commitment, confirmation, and clearance: new techniques for nonradiation ERCP during pregnancy (with videos). Gastrointest Endosc 2008;67:364–368. https://doi.org/10.1016/j.gie.2007.09.036 118. de Vries AB, Janse M, Blokzijl H, et al. Distinctive inflammatory bowel disease phenotype in primary sclerosing cholangitis. World J Gastroenterol 2015; 21:1956–1971. https://doi.org/ 10.3748/wjg.v21.I6.1956 119. Trivedi PJ, Kumagi T, Al-Harthy N, et al. Good maternal and fetal outcomes for pregnant women with primary biliary cirrhosis. Clin Gastroenterol Hepatol 2014; 12:1179–1185.e1. https://doi.org/10.1016/j.cgh.2013.11.030 120. Cauldwell M, Mackie FL, Steer PJ, et al. Pregnancy outcomes in women with primary biliary cholangitis and primary sclerosing cholangitis: a retrospective cohort study. BJOG 2020;127:876–884. https://doi.org/10.1111/14710528.16119 121. Glasgow RE, Visser BC, Harris HW, et al. Changing management of gallstone disease during pregnancy. Surg Endosc 1998;12:241–246. https://doi.org/10.1007/S004649900643 122. Date RS, Kaushal M, Ramesh A. A review of the management of gallstone disease and its complications in pregnancy. Am J Surg 2008;196:599–608. https://doi.org/10.1016/ j.amjsurg.2008.01.015 123. Barton JR, Sibai BM. Care of the pregnancy complicated by HELLP syndrome. Gastroenterol Clin North Am 1992;21: 937–950. 124. Gonzalez-Martinez G, Aguirre-Suarez J, Alarcon-Sandoval A, et al. [Hepatic and splenic rupture associated with severe preeclampsia: a case report]. Invest Clin 2004;45:63–68. https:// pubmed.ncbi.nlm.nih.gov/15058759/ 125. Pilco P, McCormack L, Perez D, et al. [Ruptured subcapsular hepatic hematoma associated with HELLP syndrome]. Rev Gastroenterol Peru 2006; 26:207–210. https://pubmed.ncbi.nlm .nih.gov/16865169/ 126. Araujo ACPF, Leao MD, Nobrega MH, et al. Characteristics and treatment of hepatic rupture caused by HELLP syndrome. Am J Obstet Gynecol 2006;195:129–133. https://doi.org/10.1016/ j.ajog.2006.01.016 127. Han GH, Kim M-A. Recurrent spontaneous hepatic rupture in pregnancy: a case report. Medicine (Baltimore) 2018;97:e11458. https://doi.org/10.1097/MD.0000000000011458 128. Hakim-Elahi E. Spontaneous rupture of the liver in pregnancy: report of a case and review of the literature. Obstet Gynecol 1965;26:435–440. https://pubmed.ncbi.nlm.nih .gov/14341220/

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129. Henny CP, Lim AE, Brummelkamp WH, et al. A review of the importance of acute multidisciplinary treatment following spontaneous rupture of the liver capsule during pregnancy. Surg Gynecol Obstet 1983;156:593–598. https://pubmed.ncbi.nlm .nih.gov/6845122/ 130. Bis KA, Waxman B. Rupture of the liver associated with pregnancy: a review of the literature and report of 2 cases. Obstet Gynecol Surv 1976;31:763–773. https://doi .org/10.1097/00006254-197611000-00001 131. Smith LG Jr, Moise KJ Jr, Dildy GA 3rd, et al. Spontaneous rupture of liver during pregnancy: current therapy. Obstet Gynecol 1991;77:171–175. https://doi.org/10.1097/00006250199102000-00001 132. Poo JL, Gongora J. Hepatic hematoma and hepatic rupture in pregnancy. Ann Hepatol 2006;5:224–226. https://pubmed.ncbi .nlm.nih.gov/17060889/ 133. Gyang AN, Srivastava G, Asaad K. Liver capsule rupture in eclampsia: treatment with hepatic artery embolisation. Arch Gynecol Obstet 2006;274:377–379. https://doi.org/10.1007/ S00404-006-0179-2 134. Merchant SH, Mathew P, Vanderjagt TJ, et al. Recombinant factor VIIa in management of spontaneous subcapsular liver hematoma associated with pregnancy. Obstet Gynecol 2004;103:1055–1058. https://doi.org/10.1097/01 .AOG.0000127943.68645.96 135. Shrivastava VK, Imagawa D, Wing DA. Argon beam coagulator for treatment of hepatic rupture with hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome. Obstet Gynecol 2006;107:525–526. https://doi.org/10.1097/01 .AOG.0000187954.45956.F1 136. Hunter SK, Martin M, Benda JA, et al. Liver transplant after massive spontaneous hepatic rupture in pregnancy complicated by preeclampsia. Obstet Gynecol 1995;85:819–822. https://doi .org/10.1016/0029-7844(94)00348-H 137. Westbrook RH, Yeoman AD, Joshi D, et al. Outcomes of severe pregnancy-related liver disease: refining the role of transplantation. Am J Transplant 2010;10:2520–2526. https:// doi.org/10.1111/J.1600-6143.2010.03301.X 138. Pandey CK, Karna ST, Pandey VK, et al. Acute liver failure in pregnancy: challenges and management. Indian J Anaesth 2015;59:144–149. https://doi.org/10.4103/0019-5049.153035 139. Trey C, Davidson CS. The management of fulminant hepatic failure. Prog Liver Dis 1970;3:282–298. https://pubmed.ncbi .nlm.nih.gov/4908702/ 140. Polson J, Lee WM. American Association for the Study of Liver Disease. AASLD position paper: the management of acute liver failure. Hepatology 2005;41:1179–1197. https://doi.org/10.1002/ hep.20703 141. Sato H, Tomita K, Yasue C, et al. Pregnant woman with non-comatose autoimmune acute liver failure in the second trimester rescued using medical therapy: a case report. Hepatol Res 2015;45:349–355. https://doi.org/10.1111/hepr.12344 142. Flemming JA, Mullin M, Lu J, et al. Outcomes of pregnant women with cirrhosis and their infants in a population-based study. Gastroenterology 2020;159:1752–1762. 143. Hansen JD, Perri RE, Riess ML. Liver and biliary disease of pregnancy and anesthetic implications: a review. Anesth Analg 2021;133:80–92. https://doi.org/ 10.1213/ ANE.0000000000005433

144. Griffiths S, Nicholson C. Anaesthetic implications for liver disease in pregnancy. BJA Education 2016;16:21–25. doi.org/10.1093/bjaceaccp/mkv008 145. Walcott WO, Derick DE, Jolley JJ, et al. Successful pregnancy in a liver transplant patient. Am J Obstet Gynecol 1978;132: 340–341. https://doi.org/10.1016/0002-9378(78)90906-7 146. Cundy TF, O’Grady JG, Williams R. Recovery of menstruation and pregnancy after liver transplantation. Gut 1990;31:337–338. https://doi.org/10.1136/gut.31.3.337 147. Mass K, Quint EH, Punch MR, et al. Gynecological and reproductive function after liver transplantation. Transplantation 1996;62:476–479. https://doi.org/ 10.1097/00007890-199608270-00009 148. Jabiry-Zieniewicz ZJ, Kaminski P, Bobrowska K, et al. Menstrual function in female liver transplant recipients of reproductive age. Transplant Proc 2009;41:1735–1739. https:// doi.org/10.1016/j.transproceed.2009.03.073 149. de Koning ND, Haagsma EB. Normalization of menstrual pattern after liver transplantation: consequences for contraception. Digestion 1990;46:239–241. https://doi.org/ 10.1159/000200352 150. McKay DB, Josephson MA, Armenti VT, et al. Reproduction and transplantation: report on the AST Consensus Conference on Reproductive Issues and Transplantation. Am J Transplant 2005;5:1592–1599. https://doi.org/10.1111/J.1600-6143 .2005.00969.X 151. Blume C, Pischke S, von Versen-Hoynck F, et al. Pregnancies in liver and kidney transplant recipients: a review of the current literature and recommendation. Best Pract Res Clin Obstet Gynaecol 2014;28:1123–1136. https://doi.org/10.1016/ j.bpobgyn.2014.07.021 152. Rahim MN, Long L, Penna L, et al. Pregnancy in liver transplantation. Liver Transpl 2020;26:564–581. https://doi .org/10.1002/lt.25717 153. Nagy S, Bush MC, Berkowitz R, et al. Pregnancy outcome in liver transplant recipients. Obstet Gynecol 2003;102:121–128. https://doi.org/10.1016/S0029-7844(03)00369-7 154. Marson EJ, Kamarajah SK, Dyson JK, et al. Pregnancy outcomes in women with liver transplants: systematic review and metaanalysis. HPB (Oxford) 2020; 22:1102–1111.https://doi .org/10.1016/j.hpb.2020.05.001 155. Coffin CS, Shaheen AA, Burak KW, et al. Pregnancy outcomes among liver transplant recipients in the United States: a nationwide case-control analysis. Liver Transpl 2010;16:56–63. https://doi.org/10.1002/lt.21906 156. Deshpande NA, James NT, Kucirka LM, et al. Pregnancy outcomes of liver transplant recipients: a systematic review and meta-analysis. Liver Transpl 2012;18:621–629. https://doi .org/10.1002/lt.23416 157. Hviid A, Molgaard-Nielsen D. Corticosteroid use during pregnancy and risk of orofacial clefts. CMAJ 2011;183:796–804. https://doi.org/10.1503/cmaj.101063 158. Skuladottir H, Wilcox AJ, Ma C, et al. Corticosteroid use and risk of orofacial clefts. Birth Defects Res A Clin Mol Teratol 2014;100:499–506. https://doi.org/10.1002/bdra.23248 159. Casanova MJ, Chaparro M, Domenech E, et al. Safety of thiopurines and anti-TNF-α drugs during pregnancy in patients with inflammatory bowel disease. Am J Gastroenterol 2013;108:433–440. https://doi.org/10.1038/ajg.2012.430

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Arash Motamed, Thang Tran, and Mohamed H. Eloustaz

160. Jain A, Venkataramanan R, Fung JJ, et al. Pregnancy after liver transplantation under tacrolimus. Transplantation 1997;64:559–565. https://doi.org/10.1097/00007890199708270-00002 161. Jain AB, Reyes J, Marcos A, et al. Pregnancy after liver transplantation with tacrolimus immunosuppression: a single center’s experience update at 13 years. Transplantation 2003;76:827–832. https://doi.org/10.1097/01 .TP.0000084823.89528.89

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162. Kainz A, Harabacz I, Cowlrick IS, et al. Analysis of 100 pregnancy outcomes in women treated systemically with tacrolimus. Transpl Int 2000;13:S299–S300. https://doi .org/10.1007/S001470050347 163. Women in Hepatology Group; Italian Association for the Study of the Liver (AISF). AISF position paper on liver transplantation and pregnancy. Dig Liver Dis 2016; 48:860–868. https://doi.org/10.1016/j.dld.2016.04.00

Chapter

19

Renal Diseases in Pregnancy Kate Petty

Renal Adaptations to Pregnancy Anatomical Changes There are clinically important changes to the upper urinary tract anatomy throughout pregnancy. Progressive uterine enlargement displaces both kidneys in a cephalad direction.1 Throughout gestation, the kidneys increase in length and volume after activation of the renin aldosterone angiotensin system. Activation of this system during pregnancy increases the plasma volume by 20–30% via enhanced sodium and water reabsorption. The increase in plasma volume contributes to increased renal blood flow and interstitial volume. Typically, there is a 30% growth in renal volume and an increase in renal length of 1–1.5 cm.2 Changes of the upper urinary tract during pregnancy also include physiologic dilation of the collecting system. This dilation occurs from mechanical compression of the ureter before entering the pelvis.2 In pregnancy, approximately 80% of women will develop hydronephrosis and hydroureter, secondary to the acute trajectory into the pelvis and proximity to the iliac and ovarian vessels. Progesterone plays a role in renal pelvis dilation by reducing ureteral tone, peristalsis, and contraction pressure.1 Dilation of the collecting system can result in urinary stasis and pyelonephritis.2 Knowledge of pregnancy-induced urinary tract changes helps further understand the pathophysiology of renal diseases in pregnancy.

Physiologic Changes Glomerular Function Vascular vasodilation occurs during pregnancy, associated with an average BP reduction of 10 mmHg. Systemic vascular vasodilation produces a decrease in renal vascular resistance resulting in increased renal blood flow (RBF). This increase in RBF may reach levels > 75% of prepregnancy values.3 During pregnancy, an increase in RBF creates an increase in the glomerular filtration rate (GFR) from prepregnancy values of 120 mL/min to a range of 150–200 mL/min.3 The augmentation of GFR during pregnancy is not fully explained by increases in RBF alone. In addition, there is an increase in plasma volume and a lower oncotic pressure. Oncotic pressure is the force that opposes glomerular filtration, and a decrease in oncotic pressure during pregnancy results in a greater GFR. There is also a modest change in glomerular permeability, contributing to an increased GFR4 (Table 19.1).

The increase in RBF is more than the proportional increase in GFR, resulting in a decreased filtration fraction during pregnancy.3 The increase in GFR is reflected during pregnancy by a lower serum creatinine. The standard for determining the GFR in pregnant women is a 24-hour urine collection to calculate creatinine clearance because the modification of diet in renal disease (MDRD) equation grossly underestimates a pregnant woman’s GFR. However, due to difficulties collecting a 24-hour urine specimen, clinicians often follow serum creatinine levels. The increased GFR and elevated creatinine clearance persist until 8–12 weeks postpartum.3,4

Tubular Function Tubular alterations occur during pregnancy to deal with increased waste products and nutrients. An increased protein and albumin excretion in the urine is greatest beyond 20 weeks gestation. With proteinuria being common in uncomplicated pregnancies, it is crucial to recognize abnormal proteinuria thresholds. Abnormal proteinuria is defined as a level > 300 mg/24 hours or a protein to creatinine ratio of > 0.3 mg/ mg.5 This threshold is two times the upper limit of normal values found in nonpregnant patients. Routinely, we use the urine protein to creatinine ratio to determine the level of proteinuria present, but the gold standard remains the 24-hour urine collection.2 In pregnant women, glycosuria results from glucose filtered by the glomerulus that exceeds the tubular reabsorption capacity resulting in urinary excretion. Glycosuria during pregnancy is due to a reduction in tubular reabsorption capacity, and does not correlate with coexisting diabetes.4 Glycosuria typically resolves one week postpartum.3 Other serum markers that change throughout pregnancy include uric acid serum levels. There is increased uric acid clearance during the first and second trimesters due to increased GFR and decreased proximal tubular reabsorption. This higher clearance helps handle the increased production from the placenta and fetus during early pregnancy. Serum uric acid levels fall and reach a nadir at 22–24 weeks gestation, rising after that toward typical prepregnancy values at term.2 The acid-base status is altered during pregnancy due to increased minute ventilation from progesterone stimulation of the brain’s respiratory center. The respiratory alkalosis is due to reduced pCO2, and the kidneys compensate by increasing renal

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excretion of bicarbonate. In turn, there is a reduction in serum levels of bicarbonate, 4 mEq/L lower than prepregnancy values.6

Water and Electrolyte Balance Women tend to retain water more than salt during pregnancy, resulting in lower serum osmolality.2 There is a complex hormonal interplay regulating the serum sodium levels during pregnancy. There is an overall increase in total body sodium throughout pregnancy. However, there is a decrease in serum sodium levels resulting from natriuresis, which is due to an increased GFR resulting in sodium filtration, increased atrial natriuretic peptide, and elevated progesterone levels. In addition to increased natriuretic forces, antinatriuretic hormones, such as aldosterone and deoxycorticosterone, promote sodium retention.4 This intricate balance is beyond the scope of this text. However, it is essential to know that pregnant women have serum sodium levels 4–5 mEq/L below prepregnancy values and have a lower serum osmolality.2 Valuable Clinical Insights • There are clinically important changes to the upper urinary tract anatomy throughout pregnancy. • Knowledge of pregnancy-induced urinary tract changes helps further understand the pathophysiology of renal diseases in pregnancy. • An increased GFR and elevated creatinine clearance during pregnancy persist until 8–12 weeks postpartum. • Abnormal proteinuria is defined as a level > 300 mg/24 hours or a protein to creatinine ratio of > 0.3 mg/mg • Acid-base status is altered during pregnancy due to renal compensation for the increased minute ventilation.

Urologic Infectious Diseases: Obstructive Pathology Asymptomatic Bacteriuria The urinary tract, excluding the urethra, is considered a sterile environment void of bacteria. Asymptomatic bacteriuria is the presence of bacteriuria without clinical signs or symptoms Table 19.1  Renal anatomic and physiologic changes in pregnancy

Anatomic alterations

Physiologic alterations

Renal size

Increased length and volume

Plasma volume

Renal location

Cephalic displacement

SVR

Collecting system

Dilation

GFR RBF   Filtration Fraction

GFR = glomerular filtration rate; RBF = renal blood flow; SVR = systemic vascular resistance.

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of an active infection. The pathogenesis of asymptomatic bacteriuria and acute cystitis starts with bacteria entering the urinary tract via the distal urethra and migrating proximally to the bladder. Pregnant women with asymptomatic bacteriuria have an increased risk of developing acute pyelonephritis, preterm delivery, and low birth weight if left untreated.7 Diagnosis of asymptomatic bacteriuria requires a midstream urine sample that grows >100,000 colony-forming units of a single identifiable pathogen. Usually, the most common pathogen is Escherichia coli (E. coli), with less common pathogens including Klebsiella, Proteus, Staphylococcus saprophyticus, and Enterococcus.8 The treatment for confirmed asymptomatic bacteriuria in a pregnant woman is a short course of antibiotic therapy,9 typically with a beta-lactam, nitrofurantoin, or a sulfonamide. A short period of antibiotic treatment is beneficial because it minimizes the risk associated with adverse drug effects, limits microbial resistance, and ensures medication compliance.7 Treating asymptomatic bacteriuria limits the risk of acute pyelonephritis throughout pregnancy and its potential complications.

Acute Cystitis In contrast to asymptomatic bacteriuria, acute cystitis is a clinical syndrome characterized by urinary urgency, frequency, dysuria, and suprapubic pain without the presence of systemic signs of infection.10 The frequency of acute cystitis in pregnancy is 0.3–1.3%.8 Risk factors for developing acute cystitis include being sexually active and having a history of prior cystitis. A clean midstream urine sample will confirm acute cystitis if there is pyuria and concurrent symptoms. A urine culture will provide confirmation. The urine dipstick has replaced microscopic evaluation in many hospitals due to convenience and rapid results. If the dipstick is negative and the woman is symptomatic, acute cystitis cannot be excluded without a urine culture.8 Due to the risk of ascending infection in pregnant women with acute cystitis, antibiotic therapy must begin before the culture results are available. In pregnant women, a three-day course of antibiotics is superior to a single dose. A longer treatment period of seven to ten days is often used for recurrent infections. The pathogens and therapies are the same as previously mentioned for asymptomatic bacteriuria. Once the antibiotic treatment is complete, the patient should have an additional urine culture to prove successful treatment.7

Acute Pyelonephritis Acute pyelonephritis is a clinical diagnosis that encompasses a constellation of features, including fever, flank pain, costovertebral angle tenderness, and the presence of bacteriuria.11 In those pregnancies with untreated asymptomatic bacteriuria, about 40% progress to acute pyelonephritis.7 Pregnant women have an increased risk of developing pyelonephritis due to anatomic and physiologic changes in the urinary system described previously.8 In one study, most cases of acute pyelonephritis occurred during the second trimester, with the predominant pathogen being E. coli. While other common pathogens included Proteus, Klebsiella, and Enterobacter.11 The treatment of acute pyelonephritis is the administration of appropriate antibiotic therapy. Typically, ceftriaxone is the

Renal Diseases in Pregnancy

drug of choice, which has adequate coverage for most uropathogens, except enterococcus. Antibiotic treatment is dependent on the sensitivities and local microbial resistances of each institution, and treatment may vary. In pregnancy, outpatient management is sufficient for mild cases of pyelonephritis. However, many experts recommend 24 hours of assessment before using outpatient care. This recommendation is out of concern for renal dysfunction and multiorgan dysfunction in the setting of sepsis.8 When there is resolution of acute pyelonephritis, initiate suppressive antibiotic therapy to avoid recurrence.10

Vesicoureteral Reflux Vesicoureteral reflux (VUR) is retrograde urine flow from the bladder into the upper urinary tract, a risk factor for renal damage. Vesicoureteral reflux can be due to congenital abnormalities of the ureterovesical junction flap, functional anomalies such as neurogenic bladder, or anatomic outlet obstruction. Those with severe VUR may require surgical correction with ureteric reimplantation. Several complications can develop from VUR, including frequent urinary tract infections, renal scarring, hypertension, and renal impairment.12 Pregnant women with VUR have an increased risk of UTIs compared to women without VUR. Interestingly, those women who underwent childhood correction of VUR have a higher incidence of UTIs than those managed conservatively.12 Maternal complications associated with VUR in pregnant women include associated renal scarring, increased risk of developing gestational hypertension, PreE, and renal impairment.13 There is no increased risk of maternal or fetal complications in the absence of renal scarring.14 Women with VUR, renal dysfunction, and scarring require coordinated care between obstetrician and nephrologist to determine optimal management.

Nephrolithiasis Nephrolithiasis, or renal calculi, are one of the most common indications for hospitalizations during pregnancy, typically occurring during the second and third trimester. Typical symptoms of renal colic include flank pain and associated hematuria. Determining the presence of a renal stone poses unique challenges in the parturient.15 The diagnostic gold standard is a noncontrast computed tomography (CT) of the abdomen. Though radiation exposure in pregnancy is of concern, many opt for a renal ultrasound with limited sensitivity for diagnosis. Another modality for diagnosis includes a magnetic resonance urography (MRU) that can help distinguish stone-related obstruction in almost 90% of cases. In cases where MRI is not available, a transvaginal US or low-dose CT scan is used to detect distal stones.15,16 From a clinical perspective, diagnosis of renal colic should also include a clinical evaluation of the patient to assess for infectious complications and end-organ dysfunction. Treatment of women with renal colic includes supportive care and expectant management.15,16 In the absence of concurrent infection, analgesia, hydration, and monitoring are employed. Most renal stones pass without intervention. There is an increased risk of preterm labor, low birth weight, and infant death in women with renal colic. Indications for intervention include intractable symptoms, infectious complications,

progressive hydronephrosis, and obstetrical complications. Interventions depend on the clinical picture, but a ureteral stent can alleviate the obstruction, and a percutaneous nephrotomy tube is sometimes required.15 Do not use shockwave lithotripsy and percutaneous nephrolithotomy in pregnancy.16

Acute Renal Failure Acute renal failure (ARF) in pregnancy encompasses a wide array of disorders that varies based on geographic location, socioeconomic class, and stage of pregnancy.17 The incidence of ARF during pregnancy has significantly declined in developed nations, with less than 1/20,000 pregnancies requiring hemodialysis.18,19 The diagnosis and treatment of ARF pose challenges in the obstetric population. ARF shows a rapid decline in GFR with the accumulation of nitrogenous waste products.18,19 The diagnosis of ARF is likely if two of the three following criteria exist: (1) a rapid rise of serum creatinine > 1.0 mg/dL, (2) development of anuria or oliguria, and (3) initiation of dialysis.17 The causes of ARF are prerenal, intrinsic, or obstructive renal failure.19 The timing of renal injury provides clinical clues that suggest a diagnosis. Those with a prerenal cause usually have a sudden decline in renal function due to decreased renal perfusion. Decreased renal perfusion during pregnancy has several causes. In the first trimester, hyperemesis gravidarum can lead to volume depletion,18,19 and if sepsis is present (e.g., septic abortion) both may lead to inadequate renal perfusion.17–19 In comparison, in the third trimester, the leading causes of renal injury are postpartum hemorrhage and bleeding from placenta previa or placental abruption.17–20 Volume resuscitation and correction of the underlying pathology can reverse these causes of renal injury within the first 24–36 hours.19 Intrinsic causes of ARF during the latter half of pregnancy include hypertensive disorders of pregnancy, such as PreE and HELLP, which account for 75% of ARF during pregnancy. Lastly, obstructive nephropathy can lead to renal failure and requires immediate therapy to alleviate the obstruction. In pregnant women with ARF, the management aims to diagnose and treat the underlying disease state. Acutely, treatment involves supportive measures such as renal replacement therapy.17

Chronic Kidney Disease Chronic kidney disease (CKD) increases maternal and fetal risks throughout pregnancy, present in around 4% of women of childbearing age.21 Adverse pregnancy outcomes occur in women with renal insufficiency at conception and those with significant proteinuria.21,22 The term CKD encompasses a heterogeneous group of diseases classified by the disease site: renal, glomerular, or tubointerstitial. Glomerular disorders can be either nephrotic or nephritic. A nephritic syndrome involves hematuria, red blood cell casts, white cell casts, mild proteinuria, and hypertension. In contrast, nephrotic syndrome demonstrates proteinuria > 3 grams in 24 hours with associated edema.23 Glomerulonephritis (GN) can be a primary disease or secondary to a systemic disease such as hypertension or diabetes mellitus in women of childbearing age. It is essential to

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recognize that women with CKD are at increased risk for developing PreE compared to the general population.23,24 Below are common GNs seen in women of childbearing age, with a more comprehensive list depicted in Table 19.2.

Diabetic Nephropathy Diabetic nephropathy affects around 6% of women with type 1 diabetes mellitus. Although not common in pregnancy, obese women with type two diabetes are more likely to present with nephropathy. Management focuses on ensuring strict glycemic control throughout pregnancy. In addition, many women with preexisting diabetes and renal disease take an angiotensin converting inhibitor (ACEi) or an angiotensin receptor blocker agent. Discontinue these medications before conception since they have fetal toxic effects.21

IgA Nephropathy Typically, IgA nephropathy (IgAN) is a primary GN diagnosed during the second or third decade of life, affecting women of childbearing age.21 Women with IgAN, whose prepregnancy renal function is preserved, will maintain their renal function after becoming pregnant. Women with renal insufficiency and hypertension have worse pregnancy outcomes, including perinatal death, preterm delivery, and low birth weight.23,24 Most women with stable or slowly progressing IgAN do not require immunosuppression but should discontinue ACEi during pregnancy.25

Lupus Nephritis Lupus nephritis (LN) is a GN that is common in women of childbearing age. Systemic lupus erythematosus (SLE) is a multiorgan system autoimmune disease that affects connective tissues.22

Frequently, women with SLE have clinically evident renal disease. Diagnosis involves a renal biopsy, and those with evidence of proliferative renal disease have an increased incidence of hypertensive disorders of pregnancy.21 In addition, women with LN, have an increased risk of miscarriage, fetal prematurity, and small for gestational age babies.22 The primary treatment for women with LN is immunosuppressant medicines. Before conception, alterations to therapy are often out of concern for toxicity, especially with methotrexate and mycophenolate. Treatment throughout pregnancy aims to control active disease and prevent flares.26 About a quarter of pregnancies experience a flare. In addition, women with nephrotic range proteinuria, antiphospholipid antibodies, or prior thrombotic complications should all receive chemoprophylaxis throughout pregnancy.22 The most important predictors for maternal complications include the presence of LN, active lupus at the time of conception, and the presence of antiphospholipid antibodies.24

Anesthetic Management Kidney disease in pregnancy can be either a known chronic disease present before conception or may have been unappreciated before pregnancy then diagnosed after conception.27 The management of pregnant women with CKD has implications for the anesthesiologist. Chronic kidney disease affects both the cardiovascular and vascular systems. Generally, these patients have hypertension leading to concentric LVH and diastolic dysfunction. In conjunction with the increased plasma volume of pregnancy, the development of diastolic dysfunction predisposes patients to a hypervolemic state resulting in pulmonary edema and possible

Table 19.2  Glomerular diseases

Clinical disease

Clinical presentation

Treatment

Outcomes

Membranous nephropathy

Presence of diffuse basement membrane thickening Nephrotic syndrome

Immunosuppression with calcineurin inhibitors Anticoagulation Aspirin

Increased fetal loss Increased risk of worsening maternal renal function

Minimal change disease

Electron microscope with podocyte foot process effacement Nephrotic syndrome

Blood pressure control, volume management. Corticosteroids until proteinuria is controlled. Consider calcineurin inhibitors or azathioprine

Limited evidence in pregnancy, steroids may have fetal consequences on growth

Focal segmental glomerular nephritis (FSGS) Primary and secondary etiologies

Nephrotic syndrome Can be due to infectious complications or vasculitis-related conditions

Blood pressure control Volume management Secondary causes work up for FSGS Corticosteroids, up to 16 weeks to achieve remission Calcineurin inhibitors

Increased spontaneous abortions, preterm labor, perinatal death in those with hypertension and impaired renal function

Vasculitis Takayasu arteritis and granulomatosis with polyangiitis

Renal insufficiency, hypertension, stroke, congestive heart failure, multiorgan involvement

Corticosteroids Calcineurin inhibitors With active disease consider cyclophosphamide (fetal implications) Consider pregnancy termination with active disease

Active disease increases risk of pulmonary hemorrhage, worsening renal function, and myocarditis

Atypical hemolytic uremic syndrome

Complement consumption

Plasma exchange Anti-complement agents

Increased fetal demise, PreE, progression to ESRD

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CHF. Fluid management should be goal directed to ensure adequate euvolemia while avoiding the use of excessive IV fluids. In addition, women with CKD are at increased risk for advanced atherosclerosis, putting them at an elevated risk for premature coronary artery disease that is unmasked during the high cardiac output state of pregnancy and subsequent delivery. Careful evaluation of functional status and assessment of an EKG for evidence of myocardial ischemia should be part of the anesthetic evaluation. Hypertension in this population should be managed appropriately with nonteratogenic medications. The diagnosis of PreE in women with preexisting CKD can be challenging.28 In women at risk for superimposed PreE, ensure hemostasis before NA by obtaining coagulation studies. The hemoglobin level should be measured to rule out anemia. If anemia is present, treatment involves ensuring adequate iron stores and possibly using an erythropoiesis-stimulating agent targeting a goal hemoglobin level of 10–11 mg/dL.29 Lastly, magnesium sulfate is a common medication for women with premature labor or PreE. Toxic levels of magnesium are more likely in those with renal insufficiency, as a result of decreased renal excretion. In addition, those with renal disease are at increased risk of fluid overload in the setting of oxytocin administration.30

Genetic Diseases with Renal Implications Alport Syndrome Alport syndrome is a disorder of the genes encoding collagen that results in a defect of the basal membrane of different organs. This defect leads to neurosensorial deafness, hematuria, proteinuria, and end stage renal disease (ESRD). Frequently, it is an X-linked autosomal dominant disorder that affects men more often than women. Typically, affected women have less severe clinical manifestations than males. There are few known cases of women with Alport syndrome who become pregnant. Available reports describe worsening (nephrotic range) proteinuria, and the mothers suffer anasarca, deteriorating renal function, hypertension, and superimposed PreE requiring urgent delivery.31–34 Valuable Clinical Insight Alport syndrome in pregnancy is associated with worsening proteinuria, maternal anasarca, deteriorating renal function, hypertension, and superimposed PreE requiring urgent delivery.

Autosomal Dominant Polycystic Kidney Disease Autosomal dominant polycystic kidney disease (ADPKD) is an autosomal dominant disease characterized by fluid-filled cysts in the kidneys and other organs. It presents early in life with bilateral renal cysts,35 with 50% of individuals reaching ESRD by age 60. In addition, there is a greater risk of intracranial aneurysm development, pancreatic cysts, aortic root dilation, and liver cysts.36

Women with ADPKD who become pregnant are more likely to develop renal insufficiency, proteinuria, hypertension, infectious complications, and PreE. Despite an elevated risk of hypertensive diseases of pregnancy, fetal outcomes in women with ADPKD are like control pregnancies with similar renal function. However, as with all pregnancies involving CKD, there is an elevated risk for small for gestational age (SGA) infants, prematurity, NICU admission, and stillbirths.35,37 Management of women with ADPKD includes a multidisciplinary team approach, with regular monitoring of BP, renal function, proteinuria, bacteriuria, and fetal growth.36–37 The anesthetic management should mirror that for CKD in pregnancy.

Tuberous Sclerosis Complex Tuberous sclerosis complex (TSC) is an autosomal dominant disorder described by the classic triad of seizures, mental retardation, and facial angiofibromas.38 Tuberous sclerosis is a neurocutaneous syndrome that affects multiple organ systems due to a mutation in the TSC1 or TSC2 gene, causing dysregulation of cellular growth. This mutation creates cellular overgrowth or hamartomas of the heart, brain, and kidneys.39 With aging, renal angiomyolipomas increase, and renal disease is the most common cause of death for adults with TSC.40 There are limited cases of TSC and pregnancy, with various outcomes, but some complications encountered include acute intraabdominal bleeding due to a renal tumor, ruptured renal cyst, and severe PreE.38 However, pregnancy does not increase the risk of developing renal complications in women with TSC.41 This condition has implications for the developing fetus, and fetal cardiac ECHO is advisable after 24 weeks gestation.42 The management and prognostic outcomes are based on renal function preconception, highlighting the importance of a renal evaluation before conception. In addition, there may be renal and retroperitoneal masses.43

Bartter Syndrome Bartter syndrome (BaSy) demonstrates metabolic alkalosis, defective salt reabsorption, hypokalemia, and hypomagnesemia due to renal tubular abnormalities. In the past, the term BaSy referred to a spectrum of renal tubular disorders causing metabolic alkalosis, including Gitelman syndrome.44 Those affected with BaSy present with a broad spectrum of clinical and biochemical presentations. It can range from someone who is entirely asymptomatic to someone with marked muscle weakness, polyuria, polydipsia, and tetany.45 This disorder is rare in pregnancy, with those affected requiring a prompt diagnosis and treatment, especially for significant hypokalemia. Women require potassium supplementation and the use of potassium-sparing diuretics. Before conception, many receive ACEi or prostaglandin inhibitors, neither of which can be used during pregnancy.46 The many biochemical abnormalities in BaSy can be a challenge when using GA. There may be difficulties in fluid and electrolyte management, acid-base imbalance, and a decreased response to vasopressors. Renal function is carefully monitored, and dose adjustments made for those drugs dependent on renal

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excretion. Metabolic alkalosis alters drug protein binding for some anesthetic agents. Women with BaSy may also have platelet dysfunction after prolonged therapy with NSAIDs, hence NA might be problematic in such patients.47

Gitelman Syndrome Gitelman syndrome (GS) is an autosomal recessive disorder that results in abnormal sodium-chloride-transport in the distal convoluted tubule resulting in metabolic alkalosis, hypokalemia, hypercalciuria, and hypomagnesemia. Rarely this condition progresses to CKD. Treatment involves magnesium supplementation, which can be challenging when there is diarrhea.48 Prior case reviews of GS during pregnancy found oligohydramnios to be the most common complication. Oligohydramnios is caused by chronic urinary water and electrolyte loss. Neonatal outcomes were good in 15 cases of GS in one study. One case described a woman with GS who developed HELLP without hypertension and proteinuria, perhaps due to GS patients having lower BP from associated renal salt loss. This is an example of different clinical presentations for GS pregnant patients with possible hypertensive disorders.49 Case reports have described the anesthetic management for vaginal birth and CD in women with GS.50,51

End Stage Renal Disease Conception In women with ESRD, pregnancy is unusual and associated with high fetal morbidity and mortality. However, in the past few decades, ESRD has been occurring more frequently. Before 1976, The Australian and New Zealand Dialysis and Transplant Registry reported no pregnancies in women with ESRD. The incidence increased to 3.3 pregnancies per 1000 from 1996 to 2008, which indicates an increasing rate of conception in women with ESRD.29 Conception in women requiring dialysis remains a challenge due to infertility complications related to derangements in the hormonal axis. As the GFR declines, menstrual cycle irregularities increase in women with CKD.29 Reportedly, 42% of women on dialysis indicated they had menses.30 Despite this report, many women with ERSD fail to ovulate due to dysregulation in the hypothalamic-pituitary-gonadal axis. This leads to elevated luteinizing hormone (LH) levels, and a lack of estradiol-stimulated cyclic release of LH – necessary for ovulation. Additionally, women on dialysis have elevated prolactin levels due to reduced clearance leading to hyperprolactinemia which further inhibits ovulation. The hormonal derangements in women on dialysis contribute to low rates of conception. Furthermore, women report high levels of sexual dysfunction and loss of libido, which also contributes to low rates of conception.29 Overall, the conception rates in women with ESRD are low, further influenced by the type of dialysis used. Women who undergo intermittent hemodialysis (iHD) compared to peritoneal hemodialysis (PD) have higher conception rates, though the exact mechanism is still unknown.30

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Additionally, there is difficulty in confirming an intrauterine pregnancy for women with ESRD due to limited renal clearance of beta human chorionic gonadotropin (B-HCG). This results in elevated levels of B-HCG in nonpregnant women on dialysis, so urine pregnancy tests are unreliable. Serum B-HCG testing is also unreliable, so pregnancy needs to be verified with an early US in patients with ESRD.30 Valuable Clinical Insights • Women with ESRD have low conception rates, but those receiving peritoneal dialysis have a lower conception rate than those on intermittent hemodialysis. • ESRD in pregnancy has increased maternal and fetal complications. • Infants who survive to delivery are likely to be premature or SGA. • Most ESRD pregnancies are complicated by hypertension.

Fetal Complications Pregnant women with ESRD have an increased risk of maternal and fetal complications. Despite advances in obstetric care for those with ESRD, the number of pregnancies producing a surviving infant to women on dialysis continues to be low. Those infants who survive to delivery are likely to be premature or SGA. In the National Registry for Pregnancy in Dialysis Patients during the 1990s, there were 116 live births out of 222 pregnancies. Further analysis of these 116 live births found that 85% of the infants had a premature delivery and a mean gestational age of 32.4 weeks, and most required neonatal intensive care.30 Despite this analysis, there are significant improvements in the live birth rate. The improved birth rate stems from intensive hemodialysis management. A landmark study from Toronto compared 22 Canadian pregnancies to 70 American ESRD pregnancies and found that those women in Canada had a live birth rate of 80% compared to 61% in the American cohort. This improved birth rate was due to more frequent and intense dialysis sessions. The Canadian cohort received around 37 hours of dialysis a week compared to the cohort in the United States, who only received 17 hours per week. In addition, those women with more frequent and intense dialysis sessions had older gestational ages and higher birth weights.52 Frequent dialysis aims to create a less uremic fetal environment allowing improved fetal growth and avoiding hypotension that can compromise uteroplacental blood flow. Continuous fetal monitoring is required during dialysis since changes in amniotic fluid volume can lead to fetal heart rate changes.28,53

Maternal Complications One of the most common maternal complications during pregnancy is hypertension. Most women with ESRD will experience BP > 140/90 mmHg requiring antihypertensives throughout pregnancy. Of those women with hypertension > 50% experience BP > 170/110 mmHg.30 In the setting of significant preconception hypertension and concomitant oliguria/anuria, it

Renal Diseases in Pregnancy

creates significant challenges in diagnosing hypertensive disorders of pregnancy. Despite the difficulty in diagnosing hypertensive disorders of pregnancy, it is essential to distinguish PreE from preexisting renal disease since the two frequently coexist. Ideally, before pregnancy or before 20 weeks gestation, proteinuria is discovered. Though, in women with ESRD, the diagnosis of proteinuria is of limited utility to diagnose PreE. For women with PreE, monitor for nonrenal manifestations of PreE such as worsening liver function tests or fetal effects of PreE.49 Other frequent complications of ESRD include anemia associated with renal disease, which coincides with anemia of pregnancy. Management of anemia in renal disease involves erythropoietin, and its requirements increase 50–100% once a pregnancy is confirmed. In addition, serum iron and ferritin levels typically decrease, requiring iron supplementation. Those dialysis patients not treated with erythropoietin almost always require red blood cell transfusions at some point during their pregnancy.30 For those women who receive PD, it is important to recognize possible infectious complications, including exitsite infections and peritonitis. Other complications related to PD catheter placement include placental abruption and uterine trauma.29

Anesthetic Evaluation and Management A parturient with ESRD undergoes physiologic changes in all organ systems, further affected by pregnancy. Women with ESRD have similar management considerations as discussed for CKD. This section will highlight critical aspects of an anesthetic evaluation specifically for the pregnant woman with ESRD requiring dialysis (Table 19.3).

Fluid Balance A tertiary care center is required to provide the necessary care, including dialysis, to a pregnant woman with renal disorders.29 A multidisciplinary team involving a nephrologist, obstetrician,

and anesthesiologist will ensure the best maternal and fetal outcomes. The anesthetic evaluation includes a complete history and physical examination, including the patient’s dry weight. Also, one must determine the modality of renal replacement therapy and examine the vascular access port to ensure it is functioning. If the patient has a tunneled dialysis line, keep the site sterile and appreciate that these lines are often locked with a heparin-containing solution. A critical aspect for the anesthesiologist is the parturient’s current fluid balance. The laboring patient is prone to several fluid shifts during labor. Ideally, management of women on dialysis will involve frequent sessions before delivery to optimize the fluid status and uremia associated with renal failure.28,29–30 Review the most recent dialysis session and ultrafiltrate removed. If feasible, consider a small volume dialysis session for optimizing the mother before delivery. Give careful consideration to avoid iatrogenic volume overload with IV fluids and oxytocin administration. Commonly, oxytocin is administered before and after delivery and can mimic anti-diuretic hormone (ADH), which may bind to ADH receptors and worsen volume overload.30 Within 24 hours of delivery, hemodialysis may be warranted after significant fluid shifts and iatrogenic fluid administration within 24 hours of delivery. Volume overload can contribute to hypertension, pulmonary edema, and possible respiratory compromise.54

Neuraxial Analgesia/Anesthesia Neuraxial anesthesia appears to be a safe option for women with ESRD on iHD after carefully assessing the coagulation status. In the setting of thrombocytopenia, defined as a platelet count of less than 70,000, there is an increased risk of epidural hematoma formation.54 In addition, platelet dysfunction can occur in the setting of significant uremia.28,54 Women on iHD with heparinization should have NA delayed for six hours to ensure heparin clearance, with normal prothrombin and partial thromboplastin times.

Table 19.3  Anesthetic medications in chronic renal disease: clinical implications

Anesthetic medications

Implications

Propofol

Renal disease does not markedly change the dosing required, nor is recovery prolonged

Etomidate

No adjustment for renal dosage necessary. Multiple dosing, even one dose may result in adrenal suppression

Ketamine

Safe pharmacologic profile in renal disease

Dexmedetomidine

Shorter elimination half-life, and decreased protein binding in the setting of renal disease. There may be an enhanced sedation effect in renal disease

Neuromuscular blocking drugs

Benzylisoquinoliniums: cisatracurium, atracurium no dose adjustment, not reliant on renal clearance Aminosteroids: rocuronium, vecuronium, pancuronium have partial renal clearance with a prolonged duration of action

Neuromuscular reversal

Neostigmine: reduced clearance, prolonged half-life. Possible prolonged cholinergic effects compared to short-acting muscarinic antagonists Sugammadex: complex with rocuronium is eliminated renally, so remains in circulation longer. Limited clinical data about the safety for patients with ESRD

Opioids

Morphine: metabolites 3- and 6-glucuronide can accumulate, increased risk of respiratory depression Meperidine: normeperidine accumulation, can precipitate seizure Fentanyl, hydromorphone: no dose adjustments

Acetaminophen

Safe to use in renal disease, no dose adjustment necessary

Local anesthetics

Prolonged duration, and delayed onset is common. Lidocaine and ropivacaine metabolites have a prolonged clearance

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After NA, the administration of LA should occur with caution. The low serum bicarbonate levels and decreased protein binding in renal disease may lead to delayed onset and prolonged anesthetic effects. This combination makes those with ESRD prone to LA toxicity. Women with ESRD who receive a NA usually have coexisting autonomic dysfunction making them susceptible to profound hypotension after a sympathetic block. Gradual epidural dosing can mitigate profound hypotension associated with a sympathetic blockade.28

Electrolyte Derangements As mentioned previously, magnesium sulfate administration in CKD should be monitored carefully due to potential toxicity in the setting of impaired clearance. There is a higher incidence of premature delivery and PreE requiring magnesium sulfate administration in the ESRD population.28, 29–30 Most recommend avoiding continuous magnesium infusions to avoid the risk of toxicity.28 For those patients who develop magnesium toxicity, treatment is supportive and may require dialysis to augment magnesium clearance.29 Monitor serum electrolytes throughout labor and delivery since these women are prone to hyponatremia, hyperkalemia, hypercalcemia, and hyperphosphatemia.

Renal Transplant and Pregnancy Solid organ transplantation for ESRD has become a ubiquitous treatment therapy over the last few decades.55,56 In the United States, during 2011, > 3,500 solid organs were allocated to women of childbearing age. Still, there were even more female pediatric patients.56 Obstetric considerations need to be a part of transplantation counseling, especially as the number of solid organ transplants continues to grow in women with reproductive potential. Once a renal transplant has been implanted with adequate function, fertility improves, the hormonal axis is restored, rendering conception a viable option.55 However, those receiving a renal transplant should have perioperative contraception since pregnancy is not advisable in the peri-transplantation period. The CKD nephrology guidelines highlight that conception should wait until adequate renal allograft function and that immunosuppression dosing is stable, which generally takes > one year to achieve.57 In addition, the American Society of Transplant (AST) consensus states that pregnancy is allowable if there has been stable graft function, defined as < 500 mg/24 hours of proteinuria, regular immunosuppression regimen, no rejection in the past year, and no acute infections.55 These guidelines arose from worse maternal and fetal outcomes experienced before AST promoted them.

Maternal Outcomes There are several considerations for women with a renal allograft who become pregnant, including pregnancy’s effects on acute allograft function and long-term function. Before pregnancy, ensure stable allograft function because those with serum creatinine levels < 1.3 mg/dL have a low risk of worsening allograft function during pregnancy. In contrast, women with

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a serum creatinine > 1.5  mg/dL with associated proteinuria (> 500 mg/dL) have an increased risk of allograft failure during pregnancy. In addition to alterations in allograft function, clinicians should be aware of the risk of possible organ rejection. Immunosuppressive medications for solid organ transplants may be challenging to dose in the setting of dynamic maternal changes associated with pregnancy. There is no consensus on the correct immunosuppression regimen, but the recommendation remains to avoid graft rejection by maintaining immunosuppression dosing at prepregnancy levels. Adequate immunosuppression can be disturbed by alterations in dosing regimens to avoid fetal teratogenic effects. If there are concerns about developing rejection, a renal biopsy is performed, and if confirmed, rejection is treated with high-dose steroids.55–58 Commonly, women with a renal allograft have preexisting hypertension before conception. Pregnancy leads to an elevated risk of gestational hypertension in this patient population. An extensive meta-analysis of > 6700 pregnancies in mothers with a renal transplant found that 24% of pregnancies experienced gestational hypertension59 and an elevated risk of PreE.55 The development of PreE can lead to severe maternal complications, including renal failure, HELLP syndrome, pulmonary edema, liver failure, and death. Throughout pregnancy, the hemodynamic goal is to aim for normotension.55 In addition to hypertension, other comorbidities of the renal transplant patient include gestational diabetes mellitus (GDM), anemia, and infection secondary to opportunistic infections. Screening for GDM occurs every trimester,51 with standard anemia screening and management occurring throughout pregnancy. Due to immunosuppression, mothers are at increased risk of contracting opportunistic infections such as cytomegalovirus (CMV). Antiviral prophylaxis is not used in pregnancy.49,51 Having a transplanted kidney is not an indication for CD.56 Despite this, > 60% of cases receive a CD.52 Despite the high prevalence of CD, the delivery method is decided based on obstetric indications and maternal preferences.55,56

Fetal Outcomes A systematic review of 4000 pregnancies in women with prior renal transplants estimated the live birth rate to be 73%.53 Those neonates born to mothers with solid organ transplants have an increased risk of preterm delivery and low birth weights.56 Using immunosuppressive medications to prevent solid organ rejection has the risk of in utero exposure during organogenesis. After a solid organ transplant, exposing the fetus to immunosuppressants is tolerated to ensure adequate allograft function.56 The FDA classifies most immunosuppressants as category C, meaning no animal studies show adverse fetal effects. Immunosuppressants with no documented increase in birth defects include cyclosporine, tacrolimus, sirolimus, rapamycin, thymoglobulin, and methylprednisone.56,58 In contrast, women on mycophenolate (MMF) are advised to change medications six weeks before conception.51 Exposure to MMF (category D drug) is thought to increase the incidence of spontaneous abortions and is associated with a pattern of structural abnormalities.53

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In conclusion, the risks to the fetus and mother with a solid organ transplant, in the setting of immunosuppressive medications, require a multidisciplinary team to ensure the best maternal and fetal outcomes.

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42. Sharma N, Sharma S, Thiek JL. Maternal and fetal tuberous sclerosis: do we know enough as an obstetrician. J Reprod Infertil 2017;18:257–260. 43. Gounden YP. Tuberous sclerosis in pregnancy: a case report and review of the literature. Aust N Z J Obstet Gynaecol 2002;42:551–552. 44. Cunha T, Heilberg IP. Bartter syndrome: causes, diagnosis, and treatment. Int J Nephrol Renovasc Dis 2018;11:291–301. 45. O’Sullivan E, Monga M, Graves W. Bartter’s syndrome in pregnancy: a case report and review. Am J Perinatol 1997;14:55–57. 46. Deruelle P, Dufour P, Magnenant E, et al. Maternal Bartter’s syndrome in pregnancy treated by amiloride. Eur J Obstet Gynecol Reprod Biol 2004;115:106–107. 47. Frassetto LA, Lo LJ. Bartter syndrome treatment and management. Available from: https://emedicine.medscape.com/ article/238670-treatment [last accessed October 26, 2022]. 48. Gjata M, Tase M, Gjata A, et al. Gitelman’s syndrome (familial hypokalemia-hypomagnesemia). Hippokratia 2007;11:150–153. 49. Lee M, Kim DI, Lee KH, et al. HELLP syndrome in a pregnant patient with Gitelman syndrome. Kidney Res Clin Pract 2017;36: 95–99. 50. Micha G, Kalopita K, Theodorou S, et al. Peripartum management of Gitelman syndrome for vaginal delivery: a case report and review of literature. Anesth Essays Res 2021;15:146–148. 51. Shanbhag S, Neil J, Howell C. Anaesthesia for caesarean section in a patient with Gitelman’s syndrome. Int J Obstet Anesth 2010;19:451–453.

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52. Hladunewich MA, Hou S, Odutayo A, et al. Intensive hemodialysis associates with improved pregnancy outcomes: a Canadian and United States cohort comparison. J Am Soc Nephrol 2014;25:1103–1109. 53. Luders C, Castro MC, Titan SM, et al. Obstetric outcome in pregnant women on long-term dialysis: a case series. Am J Kidney Dis 2010;56:77–85. 54. Kanda H, Hirasaki Y, Iida T, et al. Perioperative management of patients with end-stage renal disease. J Cardiothorac Vasc Anesth 2017;31:2251–2267. 55. Deshpande NA, Coscia LA, Gomez-Lobo V, et al. Pregnancy after solid organ transplantation: a guide for obstetric management. Rev Obstet Gynecol 2013;6:116–125. 56. McKay DB, Josephson MA. Pregnancy in recipients of solid organs: effects on mother and child. N Engl J Med 2006;354: 1281–1293. 57. Wiles K, Chappell L, Clark K, et al. Clinical practice guideline on pregnancy and renal disease. BMC Nephrol 2019;20:401. https:// doi.org/10.1186/s12882-019-1560-2 58. McKay DB, Josephson MA. Pregnancy after kidney transplantation. Clin J Am Soc Nephrol 2008;3(Suppl. 2):S117–S125. 59. Shah S, Venkatesan RL, Gupta A, et al. Pregnancy outcomes in women with kidney transplant: meta-analysis and systematic review. BMC Nephrol 2019;20:24. https://doi.org/10.1186/ s12882-019-1213-5

Chapter

20

Rare Endocrine Disorders Jill M. Mhyre, Jessica Merrill, and Waseem Athar

Introduction Several endocrinopathies may complicate pregnancy with significant adverse effects on the mother and fetus. Diagnosis may prove difficult because of a long differential, and pregnancy can mask or mimic signs and symptoms of endocrine disease. Thyroid disease and diabetes are relatively common during pregnancy; however, serious complications such as thyroid storm and diabetic ketoacidosis are rare. This chapter discusses uncommon complications of hyperthyroidism and diabetes, and other less common endocrinopathies.

Thyroid Hyperthyroidism Hyperthyroidism occurs in 0.2–0.7% of pregnancies. It is defined by a decreased thyroid stimulating hormone (TSH) level and an increased free T4 level.1 The signs and symptoms of hyperthyroidism include tachycardia, palpitations, hypertension, nervousness, tremors, frequent bowel movements, excessive sweating, heat intolerance, weight loss, goiter, and insomnia. While there is a significant overlap between symptoms of hyperthyroidism and pregnancy symptoms, the results of serum thyroid function tests help differentiate between them. Graves disease accounts for 95% of cases during pregnancy;2 other causes include transient gestational hyperthyroidism, toxic thyroid adenoma, toxic goiter, thyroiditis, drug-induced thyroiditis, and exogenous thyroid hormone. Characteristic features of Graves disease are ophthalmic signs, including lid lag and lid retraction, and dermatological signs, including pretibial myxedema. Postpartum thyroiditis is a very common complication within the first three months after delivery, especially in Graves disease. Therefore, close monitoring of thyroid function tests is crucial during this time frame. Subclinical hyperthyroidism, reported in 0.8–1.7% of pregnant women, is characterized by an abnormally low serum TSH concentration and normal T4 levels and is not associated with adverse pregnancy outcomes.3 Treatment is not recommended for these patients. Maternal outcomes depend on whether one achieves metabolic control before and during pregnancy.4 If left untreated or poorly treated, maternal thyrotoxicosis increases the risk of PreE

with severe features, LV dysfunction, high output heart failure and thyroid storm as compared to well-treated thyrotoxicosis.5 Left ventricular dysfunction is reversible. However, it may persist for a few weeks even after achieving a euthyroid state.

Valuable Clinical Insight Thyrotoxicosis is associated with increased rates of PreE, spontaneous abortion, and preterm delivery.

Fetal and neonatal risks associated with Graves disease are related either to the disease itself or to its treatment with thioamides (propylthiouracil or methimazole).  Inadequately treated hyperthyroidism is associated with an increase in preterm deliveries, low birth weight, placental abruption, miscarriage, and stillbirth.1,5,6 Because of the persistence of maternal antibodies, consider the possibility of fetal thyrotoxicosis in all women with a history of Graves disease.7

Anesthetic Management Early epidural placement is encouraged during labor for vaginal delivery to avoid pain and potential thyroid crisis. Both GA and NA are safe for CD in patients with uncontrolled hyperthyroidism. Neuraxial anesthesia may be preferred over GA because it avoids airway management and allows direct monitoring of the parturient’s mental state throughout the perioperative period. Adequate hydration before NA helps minimize hemodynamic changes, and phenylephrine administration avoids and treats post-spinal hypotension. Before GA, it is essential to check for an enlarged thyroid gland that could cause airway distortion or obstruction. If a patient has a goiter, it may extend behind the sternum. Assess for the presence of stridor, tracheal deviation, positional dyspnea, and range of neck movement. Distended neck veins may indicate SVC obstruction. Imaging, including CXR and chest CT, helps delineate the site and degree of airway obstruction and measure the diameter of the ETT required. Consider preoperative endoscopy to assess for any laryngeal displacement. If anticipating a difficult airway, perform awake fiberoptic intubation. An ENT surgeon should be present during induction and extubation in these cases.

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Valuable Clinical Insights • P atients with goiter can have a challenging airway. • A thorough airway assessment is required. • Have a backup plan in place for airway management.

Avoid drugs that may worsen tachycardia, such as sympathomimetics, anticholinergic agents, and ketamine. The combination of neostigmine and atropine or glycopyrrolate can cause tachycardia, so use sugammadex to reverse neuromuscular block from rocuronium. Avoid epinephrine-containing solutions due to the risk of exaggerated tachycardia from absorption. In patients with exophthalmos undergoing GA, prevent corneal abrasions with protective eye care.

Thyroid Storm and Thyrotoxic Heart Failure Thyroid storm, a rare, acute, and life-threatening condition, occurs in 2% of pregnancies complicated by hyperthyroidism with a mortality rate of 10–30%.8,9 Thyroid storm is diagnosed clinically, based on a combination of the following signs and symptoms in the setting of severe thyrotoxicosis: fever (temperature > 40°C/104°F), tachycardia, cardiac dysrhythmia, and CNS dysfunction.3 In women with Graves disease, it can

be precipitated by common obstetric complications such as hemorrhage, severe PreE, and sepsis. The differential diagnosis includes malignant hyperthermia, pheochromocytoma, neuroleptic malignant syndrome, and sepsis. Thyrotoxic heart failure and pulmonary hypertension, secondary to the cardiomyopathy caused by the myocardial effects of excessive T4, are more common in pregnancy than thyroid storm. Thyrotoxic heart failure and pulmonary hypertension occur in 9% of pregnant women with uncontrolled hyperthyroidism.1 Preeclampsia, anemia, sepsis, or a combination of conditions can precipitate decompensation. Frequently, T4-induced cardiomyopathy and pulmonary hypertension are reversible. If thyroid storm or thyrotoxic heart failure are suspected, evaluate serum free T4, total T3, and TSH levels to confirm the diagnosis, but do not withhold therapy pending the results. Treatment is similar for both conditions (Table 20.1). Treat these patients in an ICU setting using a multidisciplinary team that includes an anesthesiologist, endocrinologist, critical care physician, obstetrician, and neonatologist. Treat any underlying cause (e.g., infection, trauma). It is important to note that emergent delivery can worsen maternal outcomes during acute thyroid storm. Any nonreassuring fetal status is likely to improve with maternal treatment, so usually defer delivery until the mother is stable.

Table 20.1  Management protocol for pregnant women with thyroid crisis General supportive measures

• • • • • • • •

Cooling blanket and ice Chlorpromazine (25–50 mg IV) or meperidine (pethidine) (25–50 mg IV) to diminish shivering IV fluids Glucose and electrolyte replacement Acetaminophen (paracetamol) Oxygen Glucocorticoids: dexamethasone (2 mg IV q6h) or hydrocortisone (100 mg IV q8h) for three doses B-complex multivitamins

Reduction of synthesis and secretion of thyroid hormones

• • •

Antithyroid medications: propylthiouracil (1000 mg as loading dose and then 200 mg orally q6h) or methimazole (20–25 mg orally q6h) Iodine: sodium iodide (500-1000 mg IV or Lugol’s solution 10 drops orally q8h) or supersaturated potassium iodide solution (5 drops orally q6h) Glucocorticoids

Reduction of peripheral conversion of thyroxine (T4) to 3,5,3´-Triiodothyronine (T3)

• • • •

Propylthiouracil Glucocorticoids Radiographic contrast agents Propranolol

Decrease in the metabolic effects of thyroid hormones

•

Beta-blockers (propranolol, esmolol)

Other therapeutic maneuvers

•

Plasma exchange

Diagnosis and treatment of the underlying illness that precipitated the thyroid storm Adapted from Thyroid Disease in Pregnancy: ACOG Practice Bulletin, No. 223. Obstet Gynecol 2020;135:e261–274.10

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Valuable Clinical Insight Do not withhold therapy while awaiting results if thyroid storm or thyrotoxic heart failure is suspected.

Hypothyroidism Overt hypothyroidism complicates 2–10 per 1,000 pregnancies, whereas subclinical hypothyroidism is more common, occurring in 2.0–2.5% of pregnancies.2 Overt hypothyroidism is diagnosed when TSH is above the upper limit of normal and a free T4 is below the lower limit of normal; in subclinical hypothyroidism, there is an elevated serum TSH concentration and a normal free T4 concentration.10 Hypothyroidism can present with nonspecific clinical findings that may be indistinguishable from common signs or symptoms of pregnancy, such as fatigue, constipation, cold intolerance, muscle cramps, and weight gain. Other clinical findings include edema, dry skin, hair loss, and a prolonged relaxation phase of the deep tendon reflexes. Myxedema, the most severe complication of hypothyroidism, is rare and, if untreated, can lead to myxedema coma. The etiology of hypothyroidism includes autoimmune thyroiditis (Hashimoto disease), subtotal thyroidectomy, radio­ iodine therapy, and primary hypothyroidism. In pregnancy, Hashimoto thyroiditis is the most common cause of hypothyroidism, arising from glandular destruction by autoantibodies, particularly antithyroid peroxidase antibodies. Goiter may or may not be present but is more likely to occur in women who have Hashimoto thyroiditis or who live in areas of iodine deficiency. A requisite for maternal and fetal synthesis of T4 is adequate maternal iodine intake.

Obstetric Management Untreated hypothyroidism can result in adverse perinatal outcomes such as spontaneous abortion, PreE, preterm birth, placental abruption, and stillbirth.11 Early diagnosis and adequate thyroid hormone replacement therapy during pregnancy minimize the risk of adverse outcomes in women with overt hypothyroidism.

Anesthetic Management Patients with overt hypothyroidism present several potential problems important to the anesthesiologist: 1. They may be sensitive to induction agents, opioids, and sedatives. Use opioids judiciously for postoperative analgesia in these patients. 2. Depressant drugs, such as induction agents and volatile anesthetics, may aggravate cardiac depression and bradycardia. Fortunately, hypothyroid patients respond well to IV fluids and exogenous catecholamines. Nevertheless, there may be an indication for invasive hemodynamic monitoring, particularly in the presence of hypovolemia and abnormal baroreceptor reflexes. 3. Reduced skeletal muscle activity may worsen respiratory efforts and increase the risk of pulmonary complications following GA.

4. Abnormal respiratory control mechanisms and impaired central neurologic responses to hypoxia and hypercarbia mandate monitoring of oxygen saturation and end-tidal CO2 perioperatively.12 5. Other complications of severe hypothyroidism include fibrinolysis and acquired von Willebrand syndrome, putting these patients at increased risk of coagulopathy and PPH.5,13 Additional physiologic changes include altered metabolism and inactivation of drugs, primary adrenal insufficiency, electrolyte and free-water clearance abnormalities, hypoglycemia, and delayed gastric emptying. Neuraxial analgesia and anesthesia appear to be safe provided volume and cardiac status are carefully monitored and maintained. Evaluate coagulation status before NA block initiation. Abnormal coagulation and fibrinolysis may improve with thyroxine replacement; desmopressin (DDAVP) appears to correct the coagulation defect of acquired von Willebrand disease.13 Neurologic examination before block placement may reveal any preexisting neurologic weakness or paresthesias. The stress of labor or surgery may unmask reduced adrenal cortical function, warranting steroid supplementation. Valuable Clinical Insight Both NA and GA are safe anesthetic choices if hypothyroidism is well-controlled.

Pancreas Diabetic Ketoacidosis Diabetic ketoacidosis (DKA) is uncommon during pregnancy, although diabetes itself is relatively common. Approximately 0.5–3% of diabetic pregnant women develop DKA, and previously undiagnosed diabetes may present with DKA.14 Precipitating events include hyperemesis gravidarum, severe infection, insulin pump dysfunction, and neglect of care (Table 20.2). Treatment of premature labor with corticosteroids and ß-sympathomimetics can also precipitate DKA.

Clinical Features Presenting symptoms may include polyuria, polydipsia, marked fatigue, nausea, vomiting, abdominal pain, and dyspnea. Signs Table 20.2  Risk factors and precipitants of diabetic ketoacidosis in pregnancy

• • •

New onset diabetes

•

Insufficient insulin administration (impaired absorption of insulin, insulin pump failure, poor patient compliance)

• •

Antenatal corticosteroids

Anorexia, vomiting, starvation Infection (e.g., mastitis, pyelonephritis, respiratory infection, chorioamnionitis, endometritis, cellulitis)

Antenatal B-mimetic tocolytic medications

From: American College of Obstetricians and Gynecologists’ Committee on Practice Bulletins – Obstetrics. ACOG Practice Bulletin No. 201: Pregestational Diabetes Mellitus. Obstet Gynecol 2018;132:e228–248.

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include evidence of dehydration, hyperventilation, breath with a “fruity” odor, and altered mental status that can progress to coma. Hypotension with tachycardia indicates significant dehydration and electrolyte depletion. Mild hypothermia is usually present, so normothermia or hyperthermia should raise suspicion of infection. Although severe acidosis and hyperosmolarity can lead to altered mental status, consider other etiologies, including hypoglycemic coma, hyperosmolar coma, central neurologic event, pharmacologic effects, infection, and sepsis. The triad of hyperglycemia, ketonemia or ketonuria, and anion gap metabolic acidosis is pathognomonic for DKA (Table 20.3). Normoglycemia does not rule out DKA since up to onethird of pregnant women in DKA present with blood sugar levels < 200  mg/dL, a condition termed euglycemic DKA.15 Significant ketonemia and an anion gap may be present with mild acidosis (pH 7.3–7.35) if the DKA is early in its clinical course.15 Leukocytosis as high as 25,000/µL with a left shift may occur with or without associated infection. Valuable Clinical Insight The triad of hyperglycemia, ketonemia/ketonuria, and anion gap metabolic acidosis is characteristic of DKA.

Management For both maternal and fetal wellbeing, stabilize DKA before attempting delivery. Nonreassuring FHR patterns are common in pregnant women with DKA, with late decelerations and decreased or absent beat-to-beat variability. Once dehydration, acidosis, and electrolyte imbalance are corrected, the FHR typically reverts to a normal pattern.14 Treatment of DKA includes correction of dehydration, acidosis, hyperglycemia, and electrolyte imbalance16 (Table 20.4). Initial hydration consists of 1–2 L of balanced crystalloid solution over 1–2 hours to restore intravascular volume. One can use normal saline 0.9%, but the resulting hyperchloremic acidosis delays resolution of DKA.17,18 Subsequent fluids administered at 250–500 mL/h should restore renal and uteroplacental blood flow, as evidenced by good urine output (> 0.5 mL/kg/hour) and an improved FHR pattern. This improvement frequently requires 6–10 L of crystalloid (or 100 mL/kg of body weight) over 24 hours. Valuable Clinical Insights • Start treating DKA before considering delivery. • Treatment includes rehydration and correction of electrolyte imbalance and hyperglycemia.

Table 20.3  Diagnostic criteria for diabetic ketoacidosis

• • • •

Acidosis with blood pH < 7.3 Anion gap [Na – (K + Cl ) > 10 mEq/L] +

+

–

Serum bicarbonate < 15 mEq/L Ketonemia or ketonuria (acetoacetate and ß-hydroxybuterate)

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Do not administer insulin until obtaining initial serum electrolyte values and starting rehydration. After a bolus of 0.1–0.2 U/kg of IV insulin, start a continuous insulin infusion at an initial rate of 0.1 U/kg per hour. Once the blood sugar falls to < 250 mg/ dL, decrease the insulin infusion to 0.05 U/kg per hour, and start a dextrose infusion (100 mL/h of 5% dextrose in normal saline). Continue therapy until the acidosis resolves and the serum bicarbonate and the anion gap normalize. If the blood sugar remains elevated, ensure adequate volume replacement before increasing the insulin infusion rate. Add potassium if the level is < 5.0 mEq/L and there is adequate urine output. Bicarbonate replacement is appropriate only if the pH falls < 6.90. An underlying cause of the DKA, such as infection, should be sought and treated. Tracheal intubation may be necessary if the patient is comatose.

Hyperglycemic Hyperosmolar State The hyperglycemic hyperosmolar state (HHS) is far less common than DKA. There are two case reports of HHS in pregnant women, both of whom had severe PreE with no previous history of diabetes.19,20 One woman reverted to a normoglycemic state after delivery.19 Hyperglycemic hyperosmolar state is characterized by serum osmolality > 310 mOsm/kg, blood glucose level > 600 mg/dL, and normal blood pH (> 7.3). Hyperglycemia leads to profound osmotic diuresis, dehydration, and hyperosmolality in women with HHS. Coma can occur if osmolality exceeds 320–330 mOsm/kg. Typically, an event such as infection, glucocorticoid therapy, stroke, pulmonary embolism, or recent surgery precipitates HHS. Table 20.4  Treatment for diabetic ketoacidosis in pregnancy Fluid resuscitation

• •

Administer 1–2 L balanced crystalloid solution within 1–2 hours

•

When glucose reaches 200 mg/dL, change to 5% dextrose with 0.45% NaCl at 150–250 mL/hour

Continue crystalloid 250–500 mL/hour for 8–24 hours to correct a fluid deficit

Potassium

• •

Measure serum potassium every 2 hours

•

Hold insulin for potassium 50 mL/hour, titrate potassium supplementation to maintain serum potassium > 4 mEq/L and four times the upper limit of normal yield close to 100% sensitivity and 90% specificity for PPGL.63 Collect blood samples in a supine patient with left uterine displacement, at least 20 minutes after IV catheter insertion, and after the patient has avoided food, caffeine, strenuous physical activity and smoking for at least eight hours.54,63 Medications, such as tricyclic antidepressants, may yield false-positive results. Patients with PreE may have elevated urinary catecholamines (up to three-fold), while

plasma catecholamines usually are decreased or normal.55 There is a potential for plasma catecholamines to be elevated in eclampsia.54 Valuable Clinical Insight It is difficult to clinically differentiate pheochromocytoma from PreE as many symptoms overlap both conditions.

Locate PPGL tumors with MRI, CT, and 123iodinated metaiodobenzylguanidine (123I-MIBG) scans, all of which have excellent sensitivity (95–100%). The advantage of MRI is avoidance of ionizing radiation in pregnancy; an ultrasound is a less sensitive alternative. Although most tumors are pheochromocytomas located in the adrenal medulla, approximately 15% are paragangliomas found in the sympathetic ganglia located along the superior and inferior paraaortic areas, the bladder, thorax, head, neck, or pelvis.54,64 Finally, if cardiomyopathy or congestive heart failure is suspected, echocardiography will define the extent of cardiac dysfunction. Between 20% and 40% of patients with PPGL have a hereditary disorder, so offer all patients genetic counseling.54,55,64 PPGLs appear to develop in 50% of patients with multiple endocrine neoplasia  (MEN) 2A and 2B, 25% of patients with von HippelLindau syndrome (vHL), and 5% of patients with neurofibromatosis.65 Patients with familial PPGLs are typically younger at diagnosis, and more likely to develop multifocal disease, tumors outside the adrenals and paraganglia, and metastases. Underlying susceptibility genes include the rearranged during transfection oncogene (RET, associated with MEN-2), the VHL tumor suppressor gene, succinate dehydrogenase subunits (SDHA, SDHB, SDHC, SDHD, associated with paraganglioma syndromes 1 through 5), the neurofibromatosis type 1 (NF-1) tumor-suppressor gene, MYC-associated factor X (MAX), and transmembrane protein 127 (TMEM127).54,56,64  Each genetic disorder creates a different pattern of non-PPGL tumors, anatomic distribution of PPGLs, and risk of metastasis, so genetic diagnosis is essential for tumor surveillance in both the patient and her family members. For example, hemangioblastomas of the retina, CNS, and viscera are characteristic of vHL. Neurofibromatosis-1 is associated with nerve sheath tumors in the spine. Spinal MRI is the best modality to check for a highrisk spinal lesion before NA in patients with vHL and NF-1.

Medical Management For first-line treatment, use effective sympathetic blockade with an α-antagonist to control the hemodynamic response to catecholamines. Phenoxybenzamine, a long-acting α-antagonist, is given orally, 10 mg twice daily and increased by 10 mg/day every three days, until sympathetic blockade is established and symptoms controlled.56 Prazosin (titrated from 2 mg/day up to 20 mg daily in divided doses two to three times per day) or doxazocin (titrated from 2 mg/day up to 16 mg/day in divided doses two to three times per day) are equally effective and may be associated with less reflex tachycardia and postoperative hypotension than phenoxybenzamine due to a shorter half-life.56

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Add labetalol (α- and ß-blocker) if tachycardia persists but do not administer it until there is α-blockade. Calcium channel blockers will minimize orthostatic hypotension but do not prevent hypertensive crises without established α-adrenergic blockade. Methyldopa may worsen BP control and cause false elevations in urinary metanephrines, so discontinue it once there is a diagnosis of PPGL. Phenoxybenzamine crosses the placenta,56 but plasma catecholamines do not cross due to metabolism by placental catechol-O-methyl transferase and monoamine oxidase.54,56 Monitor the FHR regularly while increasing the dose of antihypertensive medications.66 Neonates exposed to long-term phenoxybenzamine may experience hypotension and respiratory distress in the first few days of life, although multiple case reports confirm good long-term outcomes.56

Surgical Preparation Defer surgical resection and CD until there is an effective sympathetic blockade for at least 10–14 days.63,64 Table 20.7 lists criteria for adequate preoperative preparation in the nonpregnant patient. In pregnancy, the BP goal of < 160/90 mmHg may represent inadequate preparation, so plan for 10–15 mmHg below this value. Avoid orthostatic hypotension because it impairs uteroplacental perfusion and contributes to oligohydramnios.56 One group has proposed a phenylephrine infusion challenge in which an arterial line monitors the hemodynamic response to escalating doses of phenylephrine; an absence of any hypertensive response suggests effective alpha-adrenergic blockade.67

Tumor Removal In nonpregnant patients, the preference is for laparoscopic resection of an abdominal PPGL tumor; extra-abdominal paragangliomas may require open resection depending on their size and location. Other treatment options include external radiation therapy, radioactive isotope therapy (e.g., iodine-131 metaiodobenzylguanidine), and long-term medical management.63,64 For pregnant women, therapeutic options include laparoscopic resection in the first half of pregnancy or medical management with resection, either at the time of delivery or postpartum. A systematic review of case reports and data from the International Pheochromocytoma and Pregnancy Registry indicate that surgery during pregnancy does not improve maternal or perinatal survival.57,58 Nevertheless, nonreassuring FHR patterns and preterm birth were more common when the tumor was not resected before delivery.56,57 Decisions about surgical resection during pregnancy depend on the characteristics of the PPGL disease, the gestational age, and anticipated Table 20.7  Criteria for optimal preoperative preparation in pheochromocytoma

• • • •

No BP >160/90 mmHg in the 72 hours prior to surgery

•

Hematocrit decreased by ~ 5%

Orthostatic hypotension should be present, but not < 80/55 mmHg The ECG should be free of ST-T segment changes Premature ventricular contractions should be no more frequent than once every five minutes

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ability to comply with effective medical therapy for the duration of pregnancy.  Before 24 weeks, patients usually are offered a choice between medical management and laparoscopic surgical resection of the pheochromocytoma. After 24 weeks, patients are typically managed medically with phenoxybenzamine or an alternative α-adrenergic antagonist until obstetric reasons mandate delivery.

Mode of Delivery Traditionally, the recommendation is for a CD, possibly combined with open resection of an abdominal PPGL. Fetal signs of uteroplacental insufficiency may mandate CD. As uterine contractions and the maternal Valsalva maneuver may precipitate catecholamine release, some caution against attempting vaginal delivery. Nevertheless, a minority of PPGL patients have delivered vaginally.58 Even when antepartum PPGL control has been suboptimal, vaginal delivery is possible with dense epidural anesthesia, minimal maternal pushing, vacuum-assisted delivery, manual delivery of the placenta, and ongoing hemodynamic monitoring and management.68

Anesthetic Management Patients with pheochromocytoma accumulate norepinephrine in nerve terminals and develop an exaggerated sympathetic response when stress and pain stimulate norepinephrine release. Either NA or GA is appropriate for CD with or without a combined PPGL resection. Take care to limit the physiologic response to anxiety and pain and monitor and treat hemodynamic lability.69 Titration of a low-dose preoperative anxiolytic may reduce activation of the sympathetic nervous system. Neuraxial anesthesia or opioid infusion for GA helps control the exaggerated physiologic response to pain. In addition to the usual monitors (ECG, pulse oximetry, and urinary bladder catheter), cannulate the radial artery using local anesthesia to measure BP directly. A second, large-bore peripheral IV cannula (14 or 16 gauge) permits rapid infusion of warmed crystalloid and colloid fluids intraoperatively. Some authors recommend preoperative placement of a central access sheath in case catecholamine-induced cardiomyopathy becomes apparent intraoperatively. When administering GA, take care to minimize the hemodynamic effects of intubation.69 Alfentanil (20–30 µg/kg) or fentanyl (2–3 µg/kg), and lidocaine (1–2 mg/kg) reduce the incidence of ventricular dysrhythmias and prevent or attenuate the pressor response to tracheal intubation. Propofol or etomidate are appropriate agents to induce GA; avoid ketamine due to its sympathomimetic effects.56 If the tumor is embedded in skeletal muscle, use rocuronium instead of succinylcholine. Avoid drugs that release histamine, such as atracurium and morphine, because histamine releases catecholamines from chromaffin granules. Also, avoid droperidol and metoclopramide as they may block inhibitory dopaminergic input to chromaffin cells. There are reports of the successful use of NA for combined CD and open pheochromocytoma resection. During neuraxial sympathetic blockade, postsynaptic receptors still respond to the direct effects of catecholamines, so do not add epinephrine to the test dose solution. It is essential to anticipate hypotension

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following tumor vein ligation and inadequate anesthesia if there is a need for cephalad exploration of the abdomen. An alternative anesthetic strategy is to use LEA for the CD followed by GA for the pheochromocytoma resection.66 With either NA or GA, expect periods of paroxysmal tachycardia and hypertension before tumor resection and profound hypotension after tumor removal. Therefore, prepare shortacting vasoactive infusions for intraoperative hemodynamic management. Valuable Clinical Insights • W ith either NA or GA, expect periods of paroxysmal hypertension before tumor resection and profound hypotension after tumor removal. • Prepare short-acting vasoactive infusions for intraoperative hemodynamic management.

A sodium nitroprusside solution (SNP, 50 mg added to 500 mL of 5% dextrose solution infused at 1 µg/kg/min) will control BP intraoperatively. If surgery includes pheochromocytoma removal, stop SNP after clamping the adrenal vein. Typically, recovery from the SNP infusion occurs within one to two minutes, thus preventing a rapid fall in BP following tumor removal. Fetal cyanide toxicity from SNP can become a problem if using higher doses or maternal tachyphylaxis develops. Magnesium sulfate (2–2.5 gms/min) is clinically helpful in maintaining cardiovascular stability during pheochromocytoma resection. Magnesium sulfate has a direct vasodilator effect, reduces the sensitivity of the alpha-adrenergic receptors to catecholamines, and inhibits the release of catecholamines from the adrenal medulla and peripheral adrenergic nerve terminals.70 Magnesium has the additional benefit of being familiar to obstetric care providers. If using magnesium, carefully monitor neuromuscular function with the expectation of impaired recovery. Other helpful vasoactive medications include phentolamine IV bolus (1–5 mg), nitroprusside IV bolus (1–2 µg/kg), esmolol, labetalol, and propranolol. Following resection, treat hypotension unresponsive to volume expansion with crystalloids or blood, with an infusion of epinephrine, norepinephrine, or phenylephrine. Avoid using indirect sympathomimetics such as ephedrine.

Adrenal Insufficiency Adrenal insufficiency results from primary adrenal insufficiency (Addison disease), or secondary to pituitary failure/ destruction, or from exogenous steroid therapy that suppresses adrenal production of corticosteroids and mineralocorticoids. Intrapartum hemorrhage, traumatic breech delivery, or fulminant sepsis in the perinatal period may lead to primary adrenal insufficiency. Autoimmune adrenal insufficiency occurs at a rate of 10–15 in 100,000 as an isolated abnormality or as a part of an autoimmune polyglandular deficiency syndrome (types I and II).71 In type II, women aged 20 to 40 years have chronic immune thyroiditis and insulin-dependent diabetes mellitus.

Other scenarios that cause mineralocorticoid insufficiency include prolonged administration of corticosteroids, congenital 21-hydroxylase deficiency, and acquired immunodeficiency syndrome. The antifungal drug ketoconazole may result in adrenal insufficiency because it inhibits mitochondrial cytochrome P450 enzymes such as cholesterol desmolase, 11 ß-hydroxylase, and aldosterone synthase.

Clinical Features Hyponatremia, hyperkalemia, and volume depletion typify aldosterone insufficiency, but the classic combination of hyponatremia and hyperkalemia is not always present. After prolonged vomiting, patients may develop hypokalemia and alkalosis.72 In patients with Addison disease, hyperpigmentation, weakness, fatigue, nausea, anorexia, weight loss, hypotension, and hypoglycemia accompany cortisol deficiency. Since nausea, vomiting, fatigue, weakness, and hyperpigmentation are common symptoms of pregnancy, the diagnosis of adrenal insufficiency can be difficult.73 Clinical and laboratory features of adrenal insufficiency indicate deficiencies in cortisol and aldosterone.71 Plasma cortisol levels and cortisol-binding globulin levels increase during normal pregnancy, but patients with Addison disease fail to show the expected rise in cortisol following adrenocorticotrophic hormone (ACTH) stimulation.71

Maternal and Fetal Effects Historically, Addison disease had a maternal mortality rate of 45%.74 With adequate steroid replacement, pregnancy should present minimal risks.60 Overall, the prognosis for the fetus and newborn is good, although there are reports of preterm delivery, IUGR, and fetal distress.60

Management Use standard doses of glucocorticoids (hydrocortisone 20–30  mg/day) and mineralocorticoids (fludrocortisone 0.05–0.1 mg/day) during early pregnancy. Glucocorticoid dose requirements increase 20–40% in the second half of pregnancy;71 additional glucocorticoid medication covers any increased mineralocorticoid requirements.73 Hydrocortisone is inactivated by the placenta, so is preferred over dexamethasone.71 Most women tolerate labor and vaginal delivery well, but there is the potential for an Addisonian crisis. The recommendation is to administer a hydrocortisone bolus during the active phase of labor.71 Optimize fluid balance, glucose, and electrolyte levels.

Anesthetic Implications Use standard techniques of NA when appropriate but GA will require certain modifications. Administer incremental or low doses of anesthetic agents to avoid the risk of drug-induced myocardial depression. Avoid etomidate because of the potential transient inhibition of cortisol synthesis. As skeletal muscle weakness is a typical feature of the disease, use a peripheral nerve stimulator to monitor neuromuscular blockade and titrate neuromuscular blocking agents. During an emergency surgery, administer hydrocortisone 100 mg every six hours for 24 hours. Invasive hemodynamic monitoring will guide volume replacement.

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Addisonian Crisis The stress of labor and delivery, infection, and surgery may precipitate an Addisonian crisis, a life-threatening condition. The presentation commonly includes abdominal pain, nausea, vomiting, and shock.75 Hence it can be misdiagnosed as an acute surgical abdomen. Circulatory collapse in Addisonian patients under stress has several possible mechanisms: loss of an enhanced response to catecholamines linked to steroids, altered receptor affinity, increased catecholamine metabolism, increased calcium uptake, and altered electrolyte milieu, loss of cardiac glycogen, and decreased adenosine triphosphatase [ATPase] activity. Therapy includes: • treatment of the inciting cause • a bolus of 100 mg hydrocortisone followed by 300–400 mg of IV hydrocortisone given as an infusion over 24 hours, and • replacement of water and sodium deficits with normal saline.

Cushing Syndrome Pregnancy in patients with Cushing syndrome is rare due to the effect of elevated cortisol on the reproductive axis, often leading to anovulation, impaired follicle development, and infertility.76 Cushing syndrome is divided into two main categories: (1) Cushing disease, adrenal corticotropin hormone (ACTH) dependent hypercortisolism, most often caused by ACTH-secreting pituitary adenoma, which in turn stimulates the adrenal cortex to produce markedly elevated cortisol levels or (2) Cushing syndrome, which is ACTH-independent excessive production of adrenocortical tissue, most often caused by an adrenal adenoma.

Clinical Features As many typical features of Cushing syndrome overlap with those of normal pregnancy, including weight gain, fatigue, abdominal striae, edema, and hyperpigmentation, it is possible to miss the diagnosis. Abnormal glucose tolerance and hypertension can be misattributed to gestational diabetes and PreE. Symptoms that make Cushing syndrome more likely include pathological fracture, muscle weakness, purple striae, and hypokalemia.77 Additionally, cortisol levels are elevated twoto three-fold during normal pregnancy confounding the biochemical diagnosis. Dexamethasone suppression tests (DST) are unreliable in pregnancy, with 80% of healthy pregnant women displaying an abnormal DST peripartum. Instead, one diagnoses Cushing syndrome in pregnancy based on an unfractionated free cortisol (UFC) level > 3 times the upper limit of normal in the second and third trimester and loss of diurnal variation in cortisol levels. Determining the etiology of the cortisol excess can also be challenging. Initially, use an adrenal US to look for an adenoma, then if none is identified, perform an MRI with and without contrast of the abdomen and brain.77,78

Maternal and Fetal Effects Cushing syndrome has significant morbidity and mortality for mother and fetus. Women with Cushing syndrome have higher rates of PreE, gestational diabetes, spontaneous abortion, preterm delivery, and CD.76 Cushing syndrome is also associated with congestive heart failure, pathologic fractures, impaired wound healing, and psychiatric symptoms.76,78 Fetal risks include IUGR, hypoglycemia, respiratory distress, and infection/sepsis. If the Cushing syndrome has been treated, then the risks are markedly decreased.76 Valuable Clinical Insight

Valuable Clinical Insight Cushing disease is the most common form of endogenous Cushing syndrome in nonpregnant individuals. However, during pregnancy it only causes Cushing syndrome ~30% of the time. Cushing disease always involves an ACTH-secreting pituitary adenoma. Other causes of endogenous Cushing syndrome include adrenal adenoma, pregnancy-induced hypercortisolism and, rarely, adrenal carcinoma. Exogenous Cushing syndrome is usually caused by excessive prednisone intake.

  Outside of pregnancy, Cushing syndrome is most commonly (~ 70%) caused by an ACTH-secreting pituitary adenoma (Cushing disease). However, in pregnancy, Cushing syndrome is more commonly caused by an adrenal adenoma (~ 50% of cases), followed by a pituitary adenoma (~ 30%) or even pregnancy-induced hypercortisolism, thought to be secondary to increased expression of LH/hCG receptors on adrenal tumors (~ 15%) and rarely an adrenal carcinoma (1–3%).55,76,77

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Pregnant women with Cushing syndrome have higher rates of PreE, gestational diabetes, spontaneous abortion, preterm delivery, and CD.

Management For cortisol-secreting adrenal adenomas, laparoscopic surgical resection in the second trimester is the treatment of choice. After adrenalectomy, patients will likely have some degree of adrenal insufficiency requiring treatment. Medical management includes metyrapone, a cortisol synthesis inhibitor that blocks conversion of 11-beta-hydroxylase. However, it can worsen hypertension and possibly increase the PreE risk due to the accumulation of mineralocorticoid precursors. Ketoconazole, an antifungal with anti-steroidogenesis properties, is another option that has been used with some success. ACTH-dependent pituitary Cushing syndrome is usually managed medically with dopamine agonists, namely cabergoline. If these patients have severe symptoms, then transsphenoidal hypophysectomy is indicated during the second trimester.78

Anesthetic Implications It is essential to evaluate coagulation, cardiovascular function, plasma glucose, electrolyte levels, and acid-base parameters in these patients before initiating any form of anesthesia.

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Valuable Clinical Insight In parturients with Cushing syndrome, severe hypertension is the most significant hazard during labor and delivery.

Since severe hypertension is a significant risk during labor and delivery, monitor BP frequently and start appropriate treatment promptly. Control BP with hydralazine or labetalol. Severe or malignant hypertension may be associated with cardiac failure and necessitates invasive monitoring. Polyuria and diabetes mellitus are frequent complications of Cushing syndrome so treat appropriately. Other complications include fluid retention, hypokalemia, and alkalosis. For patients with post-surgical adrenal insufficiency, give IV hydrocortisone 100 mg at the onset of labor, followed by immediate initiation of a continuous infusion of hydrocortisone 200 mg/24 hours or 50 mg IM every six hours.79 Neuraxial anesthesia is safe in pregnant women with Cushing syndrome. Before initiating NA, it is essential to elicit a thorough musculoskeletal history; patients with uncontrolled hypercortisolism are at risk of pathologic fracture, including the pelvis and lumbar spine.80 Coagulation abnormalities or psychiatric disturbances may preclude NA. There may be an exaggerated hemodynamic response to vasopressors, endogenous catecholamines, or sympathectomy. Many of these women require operative delivery. Either NA or GA is appropriate, depending on the clinical context. Hemodynamic lability may be significant. Intraoperatively, invasive hemodynamic monitoring can assist in the management of serious complications, such as cardiac failure and increased bleeding. For GA, consider awake fiberoptic intubation because central obesity, a buffalo hump, increased fatty tissue of the neck and sternal areas, and delicate mucosa may contribute to a difficult airway. Muscle weakness may reduce the dose requirements for neuromuscular blocking agents; a peripheral nerve stimulator is essential for GA with pharmacologic paralysis. After cord clamping, IV opioids control, but do not eliminate, the release of cortisol resulting from surgical stimulation.

Primary Hyperaldosteronism/Conn Syndrome In primary hyperaldosteronism, also known as Conn syndrome, excess mineralocorticoid secretion produces diastolic hypertension, hypernatremia, hypokalemia, kaliuresis, and metabolic alkalosis. Symptoms include headache, fatigue, weakness, and muscle cramps. Primary hyperaldosteronism is rare in pregnancy, with < 50 cases reported.55 Patients present with hypertension resistant to therapy and may develop uteroplacental insufficiency resulting in premature delivery, placental abruption, IUGR, or IUFD. There are reports of pulmonary edema and acute renal failure. Proteinuria is present in 43% of cases, complicating the diagnosis of superimposed PreE.81 Other potential complications include congestive heart failure, aortic dissection, dysrhythmias secondary to hypokalemia, hyperglycemia, hypercoagulability with thromboembolism, and pathologic fractures. The majority of cases are due to bilateral adrenal hyperplasia or aldosterone-producing adenoma, although adrenal cortical carcinoma, ectopic production of aldosterone,

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unilateral adrenal hyperplasia, and familial hyperaldosteronism are also possible.77,82 Conservative management with BP control and potassium supplementation is the mainstay of primary aldosteronism in pregnancy. Spironolactone is the preferred agent for mineralocorticoid hypertension. However, it should be discontinued in pregnancy out of concern for feminizing effects.  Amiloride or eplerenone are alternatives that do not appear to have any adverse fetal effects. Methyldopa, beta-adrenergic blockade, or calcium channel blockade are the preferred antihypertensives.77,83 Use potassium when necessary to correct hypokalemia. If medical therapy fails, the preferred treatment is laparoscopic adrenalectomy in the second trimester.

Anesthetic Implications It is safe to administer NA or GA but pay attention to hemodynamic monitoring, volume status, glucose levels, and electrolytes. Consider invasive cardiovascular monitoring if congestive heart failure is suspected, or the intravascular volume status is unclear. Hypokalemia may lead to dysrhythmias and potentiate the effects of neuromuscular blockade.

Congenital Adrenal Hyperplasia Congenital adrenal hyperplasia (CAH) includes a family of genetic disorders of steroidogenesis.84 The most common is 21-hydroxylase deficiency, resulting in impaired cortisol production. Mineralocorticoid production may be affected as well. In response to impaired synthesis of cortisol, the hypothalamus increases ACTH secretion. The ACTH stimulates adrenal precursors leading to excess androgen production. Start dexamethasone to the mother before the ninth week of gestation to avoid virilizing the female fetus. Use preimplantation genetic testing to select embryos without the genetic disorder; alternatively, genetic testing with cell-free DNA, amniocentesis or chorionic villus sampling can identify the need to continue steroid therapy throughout pregnancy for women carrying an affected female fetus.85 Women with CAH often have amenorrhea but may become pregnant with adequate steroid therapy and pharmacologic induction of ovulation. Cesarean delivery rates may be as high as 80% in women with CAH because of the increased rates of gestational diabetes, abnormal maternal external genitalia, prior genitourinary surgery, or cephalopelvic disproportion.86 Women on dexamethasone therapy need steroid supplementation during labor and delivery. Even in unaffected neonates, chronic steroid therapy in pregnancy may suppress the fetal adrenals, leading to transient neonatal adrenocortical insufficiency.

Parathyroid Glands Up to 30 grams of calcium are delivered across the placenta to the fetus during a normal pregnancy. The fetus and placenta release PTH-related peptide (PTHrP), which shares a common receptor with parathyroid hormone (PTH) and regulates the active transport of calcium across the placenta. It is also found in uterine smooth muscle, where it regulates myometrial tone and blood flow. High levels of PTHrP may suppress maternal parathyroid release of PTH. Nevertheless, maternal ionized calcium

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levels usually are homeostatically regulated and stable through pregnancy at 1.5–2.5 mEq/dL. Close to half of the circulating calcium is bound to albumin, and total blood calcium levels fall because plasma albumin falls.

Hyperparathyroidism Hyperparathyroidism is characterized by overactivity of the parathyroid glands, resulting in high plasma PTH levels, leading to hypercalcemia. It is a rare condition with an approximate incidence of 0.03% in pregnancy.87 Primary hyperparathyroidism (PHPT) is diagnosed based on an elevated calcium level associated with a normal or inappropriately high PTH level.88 Symptoms include lethargy, weakness, nausea, vomiting, polyuria, and polydipsia (Table 20.8). As these symptoms overlap with the usual physiological changes of pregnancy, approximately 80% of pregnant women with PHPT may not be aware of them.88 Maternal effects are directly related to serum calcium levels. As mild hypercalcemia is not associated with an increased risk of obstetrical complications, it can even go undiagnosed.87 Severe hypercalcemia in hyperparathyroidism during pregnancy is associated with several maternal complications, including hyperemesis gravidarum, PreE, hypertension, nephrolithiasis, and pancreatitis.88,89 In some nonpregnant patients, thromboembolism was the initial presentation, possibly due partly to the role of calcium in activating several clotting factors.90 When calcium levels are > 13 mg/dL the patient can have mental status changes and dysrhythmias. A level > 14 mg/dL may induce coma and cardiac arrest.91 The highest risk period Table 20.8  Presenting symptoms of hypercalcemia Cardiovascular       

Hypertension

                                 Dysrhythmias Neuropsychiatric   

Depression

                                 Psychosis                                  Seizures                                  Obtundation                                  Coma Gastrointestinal      

Peptic ulcer disease

                                

Hyperemesis gravidarum

                                 Constipation                                  Anorexia                                  Nausea/vomiting                                  Pancreatitis Urinary                   

Nephrolithiasis

                                 Nephrocalcinosis                                  Polyuria Neuromuscular      

Weakness

Skeletal                  

Osteoporosis

                                

Pathologic fracture

Miscellaneous        

Thirst

                                 Pruritis

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may be postpartum after transplacental shunting of calcium to the fetus stops. Fetal complications include hypocalcemia, tetany, polyhydramnios, IUGR, and fetal demise.92  The fetus exposed to maternal hypercalcemia may have impaired fetal parathyroid development, leading to either temporary or permanent neonatal hypoparathyroidism. In asymptomatic women, the first sign of maternal hyperparathyroidism may be neonatal hypocalcemia and tetany in the 48 hours following delivery.93,94 The most common cause of primary hyperparathyroidism is parathyroid adenoma (accounting for ~ 85% of cases).88 Secondary hyperparathyroidism is due to excessive PTH secondary to hypocalcemia, mostly caused by vitamin D deficiency or chronic renal failure. Women who rely on calcium carbonate antacids to control gastroesophageal reflux symptoms may present with exogenous hypercalcemia with normal or decreased PTH levels.

Management Manage asymptomatic patients and those with mild symptoms conservatively with oral hydration, oral phosphates, limitation of calcium and electrolyte intake, and fetal surveillance.95 Patients with life-threatening complications such as pancreatitis, mental status changes, dysrhythmias, or hypercalcemic crisis should be hospitalized and treated more aggressively. Therapy includes fetal surveillance, IV fluid resuscitation followed by IV furosemide, electrolyte, cardiac monitoring, and surgical consultation. Consider further treatment with calcitonin, oral phosphates, and bisphosphonates. If symptoms persist, parathyroidectomy is 95% successful; the safest time for surgery is during the second trimester for patients with a single adenoma.91

Anesthetic Management Women with hyperparathyroidism may receive standard NA or GA but assess volume status and correct calcium levels preoperatively as hypovolemia and hypercalcemia may lead to hemodynamic instability and cardiac dysrhythmias. Perioperative ECG monitoring for prolonged PR interval, wide QRS complex, or a shortened QT interval may help identify physiologically significant hypercalcemia. During GA, the action of nondepolarizing neuromuscular blockers is likely prolonged; therefore, administer smaller doses with neuromuscular monitoring in place. Use cardiac monitoring to detect dysrhythmias secondary to hypercalcemia. Postoperatively, muscle weakness and increased drowsiness can lead to pulmonary complications and increased risk of aspiration.

Hypoparathyroidism Hypoparathyroidism presents with low calcium levels, secondary to absent or inappropriately low PTH. Most cases are secondary to accidental removal or injury to the parathyroid glands during neck surgeries.95 Other etiologies include genetic, hypomagnesemia, chronic renal failure, or autoimmune-related dysfunction. Hypocalcemia leads to numbness or tingling in the face, hands, feet, muscle cramping, or confusion. Severe hypocalcemia can lead to tetany, stridor, laryngospasm, bronchospasm,

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seizures, heart failure, and dysrhythmias.7 Chronic hypocalcemia may lead to symptoms of fatigue, skeletal muscle cramping and weakness, lethargy, and personality changes. Signs of hypocalcemia include the Chvostek sign (facial muscle spasm after tapping the facial nerve) and the Trousseau sign (carpopedal spasm after inflating a BP cuff for three minutes). Cardiovascular consequences of hypocalcemia include: • hypotension • elevated LV pressure • myocardial dysfunction • cardiac dysrhythmias with prolongation of the QT interval and • congestive heart failure. Hypocalcemia during pregnancy can cause low birth weight and IUFD. Maternal hypocalcemia can lead to fetal hypocalcemia, which stimulates fetal parathyroid glands, triggering compensatory hyperparathyroidism. Subsequent demineralization of the fetal skeleton may result in intrauterine rib and limb fractures. Neonatal hyperparathyroidism produces transient hypercalcemia.95

Management Calcium, phosphate, and magnesium levels should be checked and corrected before any type of anesthesia. Correct symptomatic or severe hypocalcemia (< 3.5 mg/dL) with calcium gluconate (5–10 mL of a 10% solution) until signs of neuromuscular irritability or cardiovascular dysfunction subside. Neuraxial analgesia and anesthesia are safe in these patients, and good analgesia will help prevent maternal hyperventilation. Maternal hyperventilation can lead to respiratory alkalosis and hypocapnia, resulting in decreased calcium levels. In the case of GA, the duration of neuromuscular blocking agents is likely prolonged; therefore, it is necessary to monitor neuromuscular function. Hypocalcemia can augment the  effects of induction agents and volatile anesthetics on the cardiovascular system leading to myocardial depression, vasodilatation, and hypotension.96 Avoid hyperventilation during GA. Use cardiac monitoring to detect dysrhythmias secondary to hypocalcemia. Calcium monitoring is critical if rapid transfusion of citrated blood becomes necessary. Hypocalcemia also may impair coagulation, and a review of coagulation parameters before NA is prudent. Finally, laryngospasm may occur during extubation in patients with acute hypocalcemia.

Conclusions Rare endocrine disorders are often a manifestation of a multisystem disorder resulting from altered hormone regulation. Circulating hormone levels are increased in pregnancy, resulting from placental production. Management of pregnant patients with rare endocrine disorders must consider maternal and fetal wellbeing. Life-threatening emergencies, for example, thyroid storm and diabetic ketoacidosis, need immediate and effective treatment, best managed by a coordinated team that includes an endocrinologist, with early consultation of an obstetric anesthesiologist, to facilitate medical management.

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41. Passannante AN, Kopp VJ, Mayer DC. Diabetes insipidus and epidural analgesia for labor. Anesth Analg 1995;80:837–838. 42. Pazhayattil GS, Rastegar A, Brewster UC. Approach to the diagnosis and treatment of hyponatremia in pregnancy. Am J Kidney Dis 2015;65:623–627. 43. Fleseriu M, Hashim IA, Karavitaki N, et al. Hormonal replacement in hypopituitarism in adults: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2016;101:3888–3921. 44. Vila G, Fleseriu M. Fertility and pregnancy in women with hypopituitarism: a systematic literature review. J Clin Endocrinol Metab 2020;105:e53–e65. https://doi.org/10.1210/clinem/ dgz112 45. Overton CE, Davis CJ, West C, et al. High-risk pregnancies in hypopituitary women. Hum Reprod 2002;17:1464–1467. 46. Hall R, Manski-Nankervis J, Goni N, et al. Fertility outcomes in women with hypopituitarism. Clin Endocrinol 2006;65:71–74. 47. Caturegli P, Newschaffer C, Olivi A, et al. Autoimmune hypophysitis. Endocr Rev 2005;26:599–614. 48. Joshi MN, Whitelaw BC, Carroll PV. Mechanisms in endocrinology: hypophysitis: diagnosis and treatment. Eur J Endocrinol 2018;179:R151–R163. 49. Sheehan HL. Post-partum necrosis of the anterior pituitary. Trans Edinb Obstet Soc 1938;58:13–28. 50. Diri H, Karaca Z, Tanriverdi F, et al. Sheehan’s syndrome: new insights into an old disease. Endocrine 2016;51:22–31. 51. Matsuzaki S, Endo M, Ueda Y, et al. A case of acute Sheehan’s syndrome and literature review: a rare but life-threatening complication of postpartum hemorrhage. BMC Pregnancy Childbirth 2017;17:188. 52. See T-T, Lee S-P, Chen H-F. Spontaneous pregnancy, and partial recovery of pituitary function in a patient with Sheehan’s syndrome. J Chin Med Assoc 2005;68:187–190. 53. Arora G, Sahni N. Anesthetic management of a patient with Sheehan’s syndrome and twin pregnancy while undergoing a cesarean section. J Postgrad Med 2020;66:51–53. 54. Lenders JWM, Langton K, Langenhuijsen JF, et al. Pheochromocytoma and pregnancy. Endocrinol Metab Clin North Am 2019;48:605–617. https://doi.org/10.1016/j.ecl.2019.05.006 55. Affinati AH, Auchus RJ. Endocrine causes of hypertension in pregnancy. Gland Surg 2020;9:69–79. 56. Prete A, Paragliola RM, Salvatori R, et al. Management of catecholamine-secreting tumors in pregnancy: a review. Endocr Pract 2016;22:357–370. 57. Langton K, Tufton N, Akker S, et al. Pregnancy and phaeochromocytoma/paraganglioma: clinical clues affecting diagnosis and outcome – a systematic review. BJOG 2021;128:1264–1272. 58. Bancos I, Atkinson E, Eng C, et al. International Pheochromocytoma and Pregnancy Study Group. Maternal and fetal outcomes in phaeochromocytoma and pregnancy: a multicentre retrospective cohort study and systematic review of literature. Lancet Diabetes Endocrinol 2021;9:13–21. 59. Weerd K van der, Noord C van, Loeve M, et al. Endocrinology in pregnancy: pheochromocytoma in pregnancy: case series and review of literature. Eur J Endocrinol 2017;177:R49–58. 60. Kamoun M, Mnif MF, Charfi N, et al. Adrenal diseases during pregnancy: pathophysiology, diagnosis and management strategies. Am J Med Sci 2014;347:64–73.

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61. Cermakova A, Knibb AA, Hoskins C, et al. Postpartum phaeochromocytoma. Int J Obstet Anesth 2003;12:300–304. 62. van Zwet CJ, Rist A, Haeussler A, et al. Extracorporeal membrane oxygenation for treatment of acute inverted Takotsubo-like cardiomyopathy from hemorrhagic pheochromocytoma in late pregnancy. AA Case Rep 2016;7:196–199. 63. Lenders JWM, Duh Q-Y, Eisenhofer G, et al. Pheochromocytoma and paraganglioma: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2014;99:1915–1942. 64. Neumann HPH, Young WF Jr, Eng C. Pheochromocytoma and paraganglioma. N Engl J Med 2019;381:552–565. 65. Bravo EL, Tagle R. Pheochromocytoma: state-of-the-art and future prospects. Endocr Rev 2003;24:539–553. 66. Cammarano WB, Gray AT, Rosen MA, et al. Anesthesia for combined cesarean section and extra-adrenal pheochromocytoma resection: a case report and literature review. Int J Obstet Anesth 1997;6:112–117. 67. Reitman E, Monteleone M, Smiley RM. Phenylephrine infusion test to evaluate alpha blockade in a pregnant patient with pheochromocytoma. Int J Obstet Anesth 2016;25:90–91. 68. Strachan AN, Claydon P, Caunt JA. Phaeochromocytoma diagnosed during labour. Br J Anaesth 2000;85:635–637. 69. Ramakrishna H. Pheochromocytoma resection: current concepts in anesthetic management. J Anaesthesiol Clin Pharmacol 2015;31:317–323. 70. Lord MS, Augoustides JGT. Perioperative management of pheochromocytoma: focus on magnesium, clevidipine, and vasopressin. J Cardiothorac Vasc Anesth 2012;26:526–531. 71. Bornstein SR, Allolio B, Arlt W, et al. Diagnosis and treatment of primary adrenal insufficiency: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2016;101:364–389. 72. Husebye ES, Allolio B, Arlt W, et al. Consensus statement on the diagnosis, treatment and follow-up of patients with primary adrenal insufficiency. J Intern Med 2014;275:104–115. 73. Oliveira D, Lages A, Paiva S, et al. Treatment of Addison’s disease during pregnancy. Endocrinol Diabetes Metab Case Rep 2018;2018:EDM170179.https://doi.org/10.1530/edm-17-0179 74. Brent F. Addison’s disease and pregnancy. Am J Surg 1950;79: 645–652. 75. MacKinnon R, Eubanks A, Shay K, et al. Diagnosing and managing adrenal crisis in pregnancy: a case report. Case Rep Womens Health 2021;29:e00278. 76. Caimari F, Valassi E, Garbayo P, et al. Cushing’s syndrome and pregnancy outcomes: a systematic review of published cases. Endocrine 2017;55:555–563. 77. Eschler DC, Kogekar N, Pessah-Pollack R. Management of adrenal tumors in pregnancy. Endocrinol Metab Clin North Am 2015;44:381–397. 78. Brue T, Amodru V, Castinetti F. Management of endocrine disease: management of Cushing’s syndrome during pregnancy: solved and unsolved questions. Eur J Endocrinol 2018;178:R259–R266. 79. Woodcock T, Barker P, Daniel S, et al. Guidelines for the management of glucocorticoids during the peri-operative period

for patients with adrenal insufficiency: Guidelines from the Association of Anaesthetists, the Royal College of Physicians and the Society for Endocrinology UK. Anaesthesia 2020;75:654–663. 80. Tajika T, Shinozaki T, Watanabe H, et al. Case report of a Cushing’s syndrome patient with multiple pathologic fractures during pregnancy. J Orthop Sci 2002;7:498–500. 81. Morton A. Primary aldosteronism and pregnancy. Pregnancy Hypertens 2015;5:259–262. 82. Riester A, Reincke M. Progress in primary aldosteronism: mineralocorticoid receptor antagonists and management of primary aldosteronism in pregnancy. Eur J Endocrinol 2015;172:R23–R30. 83. Malha L, August P. Secondary hypertension in pregnancy. Curr Hypertens Rep 2015;17:53. 84. Merke DP, Auchus RJ. Congenital adrenal hyperplasia due to 21-hydroxylase deficiency. N Engl J Med 2020;383:1248–1261. 85. Simpson JL, Rechitsky S. Prenatal genetic testing and treatment for congenital adrenal hyperplasia. Fertil Steril 2019;111:21–23. 86. Hagenfeldt K, Janson PO, Holmdahl G, et al. Fertility and pregnancy outcome in women with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Hum Reprod 2008;23:1607–1613. 87. Hirsch D, Kopel V, Nadler V, et al. Pregnancy outcomes in women with primary hyperparathyroidism. J Clin Endocrinol Metab 2015;100:2115–2122. 88. Ali DS, Dandurand K, Khan AA. Primary hyperparathyroidism in pregnancy: literature review of the diagnosis and management. J Clin Med Res 2021;10:235713859.https://doi.org/10.3390/ jcm10132956 89. Rigg J, Gilbertson E, Barrett HL, et al. Primary hyperparathyroidism in pregnancy: maternofetal outcomes at a quaternary referral obstetric hospital, 2000 through 2015. J Clin Endocrinol Metab 2019;104:721–729. 90. Koufakis T, Antonopoulou V, Grammatiki M, et al. The relationship between primary hyperparathyroidism and thrombotic events: report of three cases and a review of potential mechanisms. Int J Hematol Oncol Stem Cell Res 2018;12:175–180. 91. Schnatz PF, Curry SL. Primary hyperparathyroidism in pregnancy: evidence-based management. Obstet Gynecol Surv 2002;57:365–376. 92. Norman J, Politz D, Politz L. Hyperparathyroidism during pregnancy and the effect of rising calcium on pregnancy loss: a call for earlier intervention. Clin Endocrinol 2009;71:104–109. 93. Jaafar R, Yun Boo N, Rasat R, et al. Neonatal seizures due to maternal primary hyperparathyroidism. J Paediatr Child Health 2004;40:329. 94. Beattie GC, Ravi NR, Lewis M, et al. Rare presentation of maternal primary hyperparathyroidism. BMJ 2000;321:223–224. 95. Ali DS, Dandurand K, Khan AA. Hypoparathyroidism in pregnancy and lactation: current approach to diagnosis and management. J Clin Med Res 2021;10(7):1378.https://doi .org/10.3390/jcm10071378 96. Aguilera IM, Vaughan RS. Calcium and the anaesthetist. Anaesthesia 2000;55:779–790.

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Chapter

21

Disorders of Blood, Coagulation, and Bone Marrow James P.R. Brown and M. Joanne Douglas

Introduction Hematological Changes with Normal Pregnancy Term pregnancy is usually associated with a hypercoagulable state resulting from an increase in most clotting factors. At the same time, there is a decrease in natural anticoagulants and fibrinolytic activity (Table 21.1).1,2 There are inherited or acquired abnormalities that upset this equilibrium resulting in thrombotic or bleeding risk.

Hematological Testing in Pregnancy Routine complete blood count (CBC) during early pregnancy is important to identify common, preexisting hematological disorders that may impact pregnancy.3 In uncomplicated pregnancies, a repeat CBC in the third trimester might reveal anemia or thrombocytopenia, which requires peripartum planning.4 Coagulation screening in pregnancy is required: • to investigate personal or family history of significant bleeding

Table 21.1  Normal hematological changes with pregnancy1,2

Change

Notes

Increase

45–55% Peak 34–36 weeks

Blood volume Red cell mass Hemoglobin

Decrease

Platelet count Clotting Factors

Hemodilution and increased destruction Nadir 32–36 weeks Fibrinogen (I)

Marked increase (can double)

V VII VIII

Marked increase (up to ten times) Increase

von Willebrand factor (vWF) X XII Prothrombin (II)

Increases in early pregnancy, normal at term

XIII

Increases in first trimester, decreases to below prepregnancy levels by term

IX

Conflicting evidence

XI Thrombotic Control

Fibrinolysis

Antithrombin Protein C

Unchanged

Protein S

Decrease

Tissue Plasminogen Activator (tPA)

Decrease

Plasminogen Activator Inhibitor 1,2 (PAI-1 and -2) Thrombin Activatable Fibrinolysis Inhibitor (TAFI)

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Level unchanged 50% resistance to activated Protein C

Most PAI-2 produced by placenta Increase

Disorders of Blood, Coagulation, and Bone Marrow

• to follow factor levels in those with established bleeding disorders • during acute peripartum complications such as PreE, abruption, massive hemorrhage or DIC • to monitor anticoagulation therapy. Coagulation screening includes platelet count (CBC), PT or INR, aPTT, and fibrinogen. Prothrombin time and INR measure the extrinsic and common coagulation pathways; aPTT measures the intrinsic and common pathways. These are in vitro tests and are not reflective of in vivo reality, better described by the cell-based model of hemostasis.5 Activated partial thromboplastin time and PT are often unchanged until massive blood loss occurs; severe morbidity and mortality from hemorrhage may occur before these values change.6 Therefore, aPTT and PT are not reliable to guide therapy. Bleeding time is an in vivo measure of platelet function but lacks sensitivity and specificity to predict clinical bleeding.7 Several options are available for “near-patient” or “point of care (POC) testing” of Hb and coagulation. Only a tiny sample of blood is needed. Results are available quickly and can be

used to assess platelet function in parturients with thrombocytopenia, or those with a history of clinical bleeding, or to finesse blood product replacement in massive hemorrhage. Point of care devices use a blood sample (e.g., HemoCue®) or a noninvasive continuous measurement through pulse co-­oximetry (e.g., Radical-7™).8 HemoCue® was shown to be more accurate (90% samples within 1g/dL of laboratory value) than Radical-7™ (40%).8 Point of care tests of coagulopathy include thrombo­ elastography (TEG) and thromboelastometry (ROTEM).9,10 Thromboelastography or ROTEM is superior to conventional coagulation testing to demonstrate the hypercoagulable state of normal pregnancy.11 Suggested reference ranges for the term pregnant population are published: TEG,12,13 ROTEM,11,14,15 and ROTEM for postpartum after vaginal or CD (Table 21.2).16 Amgalan et al. reviewed the evidence for TEG and ROTEM use in obstetrics.10 The platelet function analyser (PFA 100) measures primary hemostasis, represented as closure time (CT). There is a reference range for CT in pregnancy.12 PFA and CT are more sensitive than TEG at identifying platelet dysfunction in PreE.12

Table 21.2  TEG and ROTEM obstetric parameters and their interpretation (adapted from Amgalan et al.)10

Parameter

Definition

TEG

Clot time

Time to initiation of clot

R (reaction time) Non-pregnant

Term pregnancy

Postpartum

Clot kinetics

Time from initiation to width of 20 mm

ROTEM CT (clotting time) *14.3 (2.4)13

*7.2 (1.9) *4.5 (1.8)12 13

*6.3 (2)13

Mild PreE

*4.9 (1.9)

Severe PreE

*5.2 (2.5)12

Term pregnancy

†159 (138–189)14 ∑151 (113–266)11

EXTEM

†51 (45–55)14 ∑48 (30–91)11

FIBTEM

†51 (44–53)14 ∑48 (29–92)11

APTEM

†63 (56–67)14

INTEM

†155 (132–186)14 ∑140 (86–168)11

EXTEM

†53 (47–62)14 ∑47 (31–80)11

FIBTEM

†52 (46–65)14 ∑49 (20–95)11

APTEM

†57 (51–84)14

EXTEM

†44 (44–52)16

FIBTEM

†47 (42–52)16

APTEM

†51 (49–55)16

12

K (kinetics) Non-pregnant

INTEM

CFT (clot formation time) *4.4 (1.2)13

*2.5 (0.5) *1.4 (0.5)12 13

INTEM

†78 (65–98)14 ∑54 (35–120)11

EXTEM

†101 (88–121)14 ∑61 (37–104)11

APTEM

†96 (78–116)14

INTEM

†66 (58–78)14 ∑48 (33–108)11

EXTEM

†74 (66–89)14 ∑50 (34–86)11

APTEM

†74 (64–96)14

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James P.R. Brown and M. Joanne Douglas

Table 21.2 (cont.)

Parameter

Alpha angle (clot formation rate)

Definition

Angle of curve plotting clot initiation

TEG *2.3 (0.4)13

Mild PreE

*1.4 (0.4)

Severe PreE

*2.0 (1.7)12

Term pregnancy

Postpartum

Maximum amplitude of curve in mm

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*73.4 (4.2) *70 (9)12

13

*74.2 (5.3)

Severe PreE

*66 (11)12

APTEM

†73 (63–84)16

13

INTEM

∑79 (63–83)11

EXTEM

∑78 (66–83)11

FIBTEM

∑69 (16–81)11

INTEM

∑81 (71–83)11

EXTEM

∑80 (64–83)11

FIBTEM

∑78 (33–86)11

EXTEM

†76 (73–77)16

FIBTEM

†75 (72–77)16

APTEM

†75 (73–77)16

MA (maximum amplitude)

MCF (maximum clot firmness)

Non-pregnant

INTEM

†58 (54–62)14 ∑64 (57–73)11

EXTEM

†59 (57–62)14 ∑66 (53–74)11

FIBTEM

†13 (11–16)14 ∑17 (11–37)11

APTEM

†58 (56–62)14

INTEM

†66 (63–69)14 ∑71 (55–79)11

EXTEM

†67 (64–71)14 ∑73 (66–92)11

FIBTEM

†19 (17–23)14 ∑25 (15–38)11

APTEM

†67 (64–70)14

EXTEM

†66 (63–70)16

FIBTEM

†22 (18–25)16

APTEM

†67 (63–71)16

*61.5 (4.5)13

*71.7 (4.5)13 *73 (5)12

*72.4 (2.8)

Mild PreE

*73 (5)12

Severe PreE

*71 (8)12

13

Ly 30 or Ly60

CL30 or CL60 (%)

Non-pregnant

INTEM

CL30 †98 (98–100)14

EXTEM

CL30 †99 (99–100)14

APTEM

CL30 †99 (97–99)14

INTEM

CL30 †100 (99–100)14

EXTEM

CL30 †100 (99–100)14

APTEM

CL30 †100 (99–100)14

Term pregnancy

334

*64 (6.1)

*71 (6)12

Postpartum

% loss of clot at either 30 mins or 60 mins after Max amplitude

†73 (61–87)16

α 13

Mild PreE

Term pregnancy

Fibrinolysis

EXTEM

12

Α Non-pregnant

Clot strength

ROTEM

Postpartum

Disorders of Blood, Coagulation, and Bone Marrow

Table 21.2 (cont.)

Parameter

Definition

TEG

ROTEM

Postpartum

EXTEM

CL30 †100 (99–100)16 CL60 †95 (92–97)16

APTEM

CL30 †100 (100–100)16 CL60 †96 (94–98)16

 Values are mean (+/– SD)

*

 Values are median (IQR)

†

∑ Values are median and 95% reference limit INTEM – Evaluates intrinsic pathway EXTEM – Evaluates extrinsic pathway FIBTEM – Evaluates fibrinogen component of clotting APTEM – Evaluates fibrinolysis Ly30 = CL30 = Clot lysis % at 30 minutes Ly60 = CL60 = Clot lysis % at 60 minutes

In reality, no test predicts the risk of clinical bleeding reliably in all settings. Point of care tests complement the medical history and conventional coagulation tests.11 There is a lack of RCTs investigating POC testing in obstetrics, and there are unanswered questions.10 Valuable Clinical Insights Management of Postpartum Hemorrhage • Traditional coagulation testing is of limited use in massive obstetric hemorrhage. • Point of care testing can help focus and protocolize blood product replacement.6 • If POC testing is not available, use formula-driven/empirical fixed ratio resuscitation.

Apheresis (Therapeutic Plasma Exchange) Therapeutic plasma exchange (TPE), the most commonly used apheresis technique that separates blood into its components, is used during pregnancy. It treats autoimmune diseases (systemic lupus erythematosus (SLE), multiple sclerosis, myasthenia gravis); thrombotic microangiopathies (hemolysis elevated liver enzymes low platelets (HELLP), thrombotic thrombocytopenic purpura (TTP)); red cell alloimmunization, and metabolic disorders. Wind et al. present a review of TPE in pregnancy.17

Red Cell Abnormalities and Anemias Antepartum anemia is common during pregnancy. It is frequently due to hemodilution (physiologic anemia) or dietary deficiencies (iron, folate, B12).4 Alternate causes of anemia in pregnancy include hemoglobinopathies, thalassemia, hemolytic or aplastic anemias, chronic disease (e.g., renal failure), and infections (e.g., HIV, parasitic).

Anemia in pregnancy is defined as mild (100–109 g/L), moderate (70–99 g/L), or severe (< 70 g/L).4 Globally, iron deficiency is the most typical cause (60%).4

Management of Anemia in Pregnancy Screen for anemia (CBC) in the first trimester (12 weeks) and early in the third trimester (28 weeks; allows time for treatment). A normal Hb level is not sensitive for diagnosing iron deficiency. Screen women at risk (e.g., vegans, hemoglobinopathies, history of anemia, chronic disease) with serum ferritin.4,18 Ferritin (< 30 mcg/L) is the best single marker of iron deficiency.4 Anemia investigations include: mean cell volume, mean cell Hb concentration, ferritin, iron saturation, total iron-binding capacity, reticulocyte count, folate, vitamin B12, blood film, Hb electrophoresis, haptoglobin, bilirubin, lactic dehydrogenase (LDH), Coombs test.4 Anemia is associated with maternal and neonatal morbidity and obstetric intervention.19 One large multinational study found that severe antenatal anemia more than doubles the risk of maternal death.4 Antenatal anemia increases the risk of peripartum blood transfusion. Women with a Hb of < 90g/L were 11 times more likely to receive a transfusion.4 Oral iron supplementation is the first line of management for iron deficiency. Routine supplementation is not recommended but most providers agree on treating women with mild or moderate anemia.4 Valuable Clinical Insights: Oral Iron Supplementation 4,18,20 • Most prenatal vitamins do not contain adequate iron for correcting deficiency (commonly 30–60 mg). • Ferrous is better absorbed (e.g., fumarate, sulfate, gluconate). • Absorption is best with an empty stomach (1–2 hours before food).

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James P.R. Brown and M. Joanne Douglas

Table 21.3  Common considerations with inherited anemias

• Target response (10 g/L increase in 2–3 weeks). • Compliance is an issue because of intolerance of side effects (a common reason for failed therapy). ◦ Side effects are dose-related ◦ Start with lower dosing (elemental iron) 60–100 mg (as effective as high dose). ◦ Every other day dosing (better absorption) ◦ Take at night • Supplement for three months after reaching target Hb and at least six weeks postpartum.

Hemolysis Severe anemia May be first presentation Require folic acid supplementation Gallstone disease Multiple blood transfusions may result in A.  Iron overload which can cause a.  Cardiac siderosis  Cardiomyopathy

Intravenous iron replenishes stores faster than oral, increasing Hb levels more quickly. Intravenous iron is contraindicated in the first trimester from concerns of teratogenicity.20 As there is a rare risk of anaphylaxis, resuscitation equipment should be immediately available. Indications for IV iron in pregnancy:4 • inadequate response to oral supplementation • severe anemia • rapid treatment in the third trimester • optimizing women at high risk of PPH (e.g., abnormal placentation) • optimizing women who decline RBC transfusion. Evidence to support erythropoietin optimizing Hb in pregnancy is limited; reserve erythropoietin for moderate to severe anemia unresponsive to IV iron.21 Rarely, or if patients present late to maternity care, antepartum blood transfusions may be required. There is no absolute Hb level below which transfusion is required; base decisions on individual case assessment (e.g., significant symptoms or severe anemia).21

Anesthetic Considerations for Anemic Parturients Anesthesiologists have a role in reducing adverse perinatal outcomes by optimizing Hb and iron status. Patients with compensated, stable anemia tolerate anesthesia well. Choice of anesthetic technique and drugs are guided by underlying disease, e.g., safety of NA will depend on degree of thrombocytopenia with aplastic anemia. Specific anesthetic considerations are outlined below.

Inherited Anemias Inherited anemias arise from genetic defects in production (erythropoiesis) or RBC structure that affect function or reduce RBC half-life. Inherited anemias are rare. More women with these conditions are surviving to childbearing age due to advances in medical care.22 Offer patients with severe disease prepregnancy genetic counseling. Taher et al. present a review of recommendations for pregnancy in rare inherited anemias.22 Table 21.3 lists important general considerations concerning inherited anemias for obstetric anesthesiologists.

Thalassemias and Hemoglobinopathies Thalassemia Thalassemia syndromes are inherited disorders that lead to quantitative defects in synthesizing globin chain subunits (alpha

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  Cardiac arrhythmias Iron deposition and complications exacerbated during pregnancy (ongoing transfusion dependence, chelation therapy discontinued), cardiovascular physiological changes with pregnancy. b.  Endocrine disorders Diabetes Thyroid Parathyroid Hypogonadism (may have had IVF) c.  Hepatic disorders d.  Immune compromise Decreased T cell neutrophil and macrophage function B. Alloimmunization C.  Infectious complications Hypersplenism Associated thrombocytopenia Splenectomy Infection risk (encapsulated bacteria) Inheritance Possibility fetus affected Severe anemia or hydrops Paternal screening (carrier status) Antenatal diagnosis Prothrombotic Abnormal RBC Endothelial damage from siderosis Predisposition to PreE

or beta). Most patients with thalassemia have a benign carrier state (heterozygous). Thalassemia patients usually present with mild anemia and have uncomplicated pregnancies although the starting Hb and nadir is lower. Folic acid supplementation is used in all patients with thalassemia.22 Thalassemias are classified as transfusion-dependent (e.g., beta thalassemia major) or non-transfusion dependent (e.g., beta thalassemia minor, HbH disease23), which helps stratify the severity of thalassemia and probability of associated complications. Transfusion of RBCs, monitoring for iron overload, and iron chelation therapy are mainstays of treatment.22 Women with transfusion-dependent thalassemia tend to present in childhood and are at risk of endocrine

Disorders of Blood, Coagulation, and Bone Marrow

abnormalities: hypogonadism and infertility, diabetes, hypothyroidism, and hypoparathyroidism.22 They are also at risk of cardiac, liver, and immune issues. Cardiac complications are the lead cause of death and can worsen during pregnancy, especially peripartum. All pregnant women with beta-thalassemia should be assessed by a cardiologist and have a baseline ECG, echocardiogram, and T2 weighted cardiac MRI to assess cardiac siderosis.24 Serial transfusions will likely be required during pregnancy, although iron chelation is usually discontinued (at least in the first trimester).22 Restarting chelation in the third trimester is a recommended option.25,26 Fetal problems include spontaneous abortion, hydrops, preterm labor, and IUGR.25 The RCOG in the United Kingdom offers guidelines on managing beta-­thalassemia in pregnancy.26 Non-transfusion-dependent disease is less severe, presents later, and is less likely to require IVF. Major complications in pregnancy are iron overload and VTE (up to 30%). Prophylactic LMWH is often used during pregnancy and aspirin is used in patients with a splenectomy. These patients are at risk of alloimmunization with blood transfusion in pregnancy. Patients with hypersplenism should undergo a splenectomy before conception.22 HbE and HbC are beta-thalassemia variants. The morphology of RBCs in the heterozygous state is close to normal and does not cause significant anemia or poor maternal or fetal outcomes.27,28 Homozygous states cause mild anemia in most patients; the Hb is unstable and at risk of hemolysis. Hemoglobin E has been linked to IUGR but not with other poor pregnancy outcomes.29 There are no reports of pregnancy with homozygous HbC. Anesthesia in Pregnant Women with Thalassemia Butwick et al. discuss the anesthetic management of a pregnant patient with beta-thalassemia.30 • The primary anesthetic concerns relate to cardiac disease. • Characteristic facial changes can occur from extramedullary erythropoiesis (frontal bossing and maxillary hypertrophy), predictors of a difficult airway. • A rarely reported complication is spinal cord compression from neuraxial extramedullary erythropoiesis, in extreme cases leading to paraparesis.31,32 Such cases are treated with repeated RBC transfusions. • No contraindication to any particular anesthetic technique. • Pay careful attention to fluid balance. A woman with placenta accreta and beta-thalassemia intermedia refused RBC transfusion (EBL 9000 mL) and received intraoperative cell salvage.33 Sickle Cell Disease Sickle cell disease (SCD) arises from a point mutation on the beta globulin gene resulting in HbS. Polymerization of the beta chain under deoxygenated stress damages cell membranes producing sickled RBCs (Figure 21.1). Patients with SCD are either homozygous for HbS or have compound heterozygous disease, i.e., HbS combined with another abnormal Hb (e.g., beta thalassemia, HbC). SCD is associated with chronic hemolytic anemia, vaso occlusive crises (e.g., acute chest syndrome,

Figure 21.1  Typical peripheral blood smear with sickle cell disease demonstrating numerous sickle cells and a rare target cell. (See color plate section) .

pain, acute renal insufficiency, or stroke), and an increased risk of infection.22,34 Heterozygous disease (sickle cell trait) is usually asymptomatic. Pregnant women with SCD are screened for complications of the disease or its treatment: cardiac dysfunction, restrictive lung disease, pulmonary hypertension, obstructive sleep apnea, proteinuria, renal impairment, sepsis, iron overload, liver dysfunction, PreE, and RBC antibodies.22,34 Increased metabolic demands, prothrombotic changes, and blood flow changes from aortocaval compression are risk factors for sickle-related complications.34 Acute pain syndrome may be the first presentation of SCD; overall, 57% suffer a pain episode during pregnancy.34 Sickle cell disease is associated with obstetric complications: • IUGR (23%), frequent fetal assessment recommended • PreE (placental vaso occlusive events) • Early spontaneous abortion • Preterm delivery (5–6%)22 • Increased CD rate (38%)34 Parturients with SCD are over-represented in the UK Triennial Confidential Enquiries into Maternal Deaths with estimated maternal mortality 1–3% and perinatal 1–8%.34 They recommend that these women be cared for at specialist SCD centers.34 Hydroxyurea and iron chelation are the mainstays of therapy for SCD in the nonpregnant population. Ideally, these are stopped three months before conception. Prophylactic RBC transfusion reduces the concentration of HbS and potentially the associated maternal and fetal complications (RCTs are ongoing).22 It is not recommended for uncomplicated pregnancies, but it may benefit high-risk pregnancies, e.g., twins.34 Theoretical benefits include increased oxygen delivery, suppression of sickle erythropoiesis, and reduced sickle-related ­complications (HbS is diluted). Fewer events occur when HbS is < 30%.34,35 Hemoglobin F protects neonates with SCD during the first six months of life.

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Other sickling syndromes (HbSD, HbSF, HbSE) produce milder disease and generally better maternal and fetal outcomes. Sickle cell trait is the heterozygous form of sickle cell disease (HbAS). Most patients are asymptomatic. In pregnancy, these patients have increased demands for erythropoiesis and should receive supplemental folic acid. Anesthesia and Sickle Cell Disease Pregnant women with SCD should have antenatal assessments for chronic effects on organ function (e.g., CBC, antibody screen, echocardiogram, PFT, sleep polysomnography). Perioperative anesthetic management aims to avoid sickling and sickle-related complications from hypothermia, acidosis, dehydration, and hypoxemia. Recommendations include: • minimize perioperative and labor fasting • measure core temperature (active warming) • supplementary oxygen (aim SpO2 ≥ 94%) • if not contraindicated, use NA to reduce sickling via pain relief and sympathetic drive and improving peripheral blood flow34 • avoid prolonged second-stage as it may precipitate sickling.35 Crossmatch in parturients with SCD can be challenging (20– 50% are alloimmunized).35 Intraoperative cell salvage is a good option, but hemoglobinopathies are a relative contraindication. There is a theoretical risk that salvaged blood will sickle in the relatively hypoxic collection reservoir and, if reinfused, precipitate sickling. Cell salvage has been used successfully in sickle cell trait36 or patients with SCD when mixed with autologous blood.37 There are no studies of tranexamic acid (TXA) in pregnant women with SCD. One author recommends its use based on experience in the nonpregnant population and a lack of reports of harm.35 Postpartum pain may be challenging to manage, especially in women with chronic pain related to SCD. Assess parturients with postoperative pain to exclude sickle-related complications. A decrease in oxygen saturation (acute chest syndrome) or an increase in temperature may herald sickle crises; continue regular monitoring of vital signs postpartum.34 Lumbar epidural analgesia and ketamine have successfully managed acute pain syndromes in pregnancy that did not respond to opioids.38–40 Continue postoperative thromboprophylaxis for six weeks, as parturients with SCD are at risk of VTE. Consider the timing of NA, and encourage postpartum hydration with early mobilization. Parturients with SCD are more likely to require high dependency or intensive care, especially following GA (23% in one survey).34 Anesthesia complications with sickle cell trait are rare. Intraoperative death has occurred during CD (HbAS).41 In that instance, death was attributed to severe, concealed aortocaval compression: once relieved, a large volume of hypoxemic, acidotic blood returned to the circulation causing cardiac arrest.41 A parturient with SCD (HbSS) developed progressive neurologic symptoms post CD under spinal anesthesia. She

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experienced bilateral motor and sensory deficits (T11–S2). MRI excluded an epidural hematoma; symptoms were attributed to vaso occlusive disease. She subsequently developed pleuritic chest pain and dyspnea, and it was uncertain if this was from SCD or a pulmonary embolus. The woman was anticoagulated, making a full recovery.42 Another woman with SCD (HbSS) had a PDPH following spinal anesthesia and then had a successful epidural colloid patch. The authors were reluctant to do an epidural blood patch (EBP) due to theoretical concerns over precipitating a medullar vaso occlusive crisis.43

Hemolytic Anemias Hemolytic anemia is either inherited or acquired. • Inherited: ◦ membrane disorders ◦ metabolic abnormalities ◦ abnormal Hb • Acquired: ◦ immune-mediated ◦ mechanical stresses (e.g., mechanical heart valves) or microangiopathic Hemolysis can occur in the intravascular space causing free Hb release with resulting hemoglobinuria and hemosiderinuria, or more commonly extravascularly in the RE system (primarily liver, spleen). Indicators of ongoing chronic hemolysis include a raised reticulocyte count, LDH, and unconjugated bilirubin. In specific disorders, morphologic abnormalities are seen on a peripheral smear.

Inherited Hemolytic Disorders Red Cell Membrane Disorders These disorders cause hemolytic anemia either from erythrocyte membrane structural (hereditary spherocytosis) or transport function abnormalities (e.g., dehydrated hereditary stomatocytosis). Hereditary Spherocytosis Hereditary spherocytosis (HS) is the most common nonimmune cause for hemolytic anemia. The phenotypic expression varies significantly from asymptomatic to transfusion-dependent. The pathognomonic features are spherocytes in peripheral blood. Increased destruction of abnormal cells in the RE system results in hemolytic anemia, jaundice, splenomegaly, reticulocytosis, and gallstone disease. In severe disease, splenectomy may improve RBC half-life. Although hemolytic crises occur during pregnancy (30% require transfusion), most patients with HS tolerate pregnancy well.22 Initial diagnosis of HS may occur during pregnancy. The fetus can be affected; severe fetal anemia may require intrauterine transfusion.22 Transport Function Abnormalities These are RBC membrane abnormalities that frequently present with mild chronic hemolytic anemia. They include hereditary elliptocytosis44,45 (pregnancy can precipitate severe hemolysis),44 and dehydrated hereditary stomatocytosis (autosomal dominant, (AD)) (fetal ascites, hydrops).46,47

Disorders of Blood, Coagulation, and Bone Marrow

Red Cell Enzyme Deficiencies The most common hereditary deficiencies are pyruvate kinase and glucose-6-phosphate dehydrogenase. Both make RBC susceptible to oxidative stress and hemolysis.

Recommend prophylactic antibiotics for CD, prompt identification and treatment of any infection, and good multimodal analgesia postpartum.50

Pyruvate Kinase Deficiency Usually an autosomal recessive (AR) defect (AD also reported) in the glycolytic pathway causes chronic hemolysis and anemia. Blood transfusion leads to iron overload.48 There are over 300 mutations causing pyruvate kinase deficiency (PKD), and the degree of hemolysis varies.22 Mohamed et al. discuss aspects of pregnancy in patients with PKD.48 Pregnancy can trigger hemolysis; most require transfusion.22 Fetal growth can be affected; regular monitoring is recommended.48

Autoimmune Hemolytic Anemia Autoimmune hemolytic anemia (AIHA) results from RBC autoantibodies which are classified by the temperature at which they optimally bind to RBCs (60% “warm,” predominantly IgG; 27% “cold,” predominantly IgM; remainder mixed, or atypical).52 Usually, AIHA occurs secondary to drugs (e.g., methyldopa) or with other diseases (25%, rheumatological or lymphoproliferative). Patients with IgG autoantibodies present with anemia, mild icterus, and splenomegaly from extravascular hemolysis. Laboratory findings include reticulocytosis and spherocytes on the peripheral smear. IgG autoantibodies may cross the placenta causing fetal anemia. Patients with idiopathic AIHA usually respond to corticosteroids. Avoid transfusion unless the patient is very symptomatic or there is fetal compromise. IgA causing warm AIHA in pregnancy has been reported and the disease course is like IgG “warm” AIHA. The patient may respond to corticosteroids and intravenous immunoglobulin (IVIG).53 Evan syndrome (ES) is a combination of AIHA and immune thrombocytopenic purpura (ITP). Lefkou et al. reviewed all cases of ES in pregnancy (n = 16).54 Compared with nonpregnant women, all ES patients who had IgG “warm” disease had a benign course, responding to corticosteroids and IVIG, and resolving postpartum. A splenectomy is an option for affected pregnant women who do not respond to treatment. Some patients with ES have coexisting neutropenia, although this is rarer in pregnancy. Anesthetic considerations are those of ITP. The pathophysiology of hemolysis in patients with “cold” AIHA differs. Fixation of complement on the RBC membrane results in intravascular hemolysis. Reticulocytes are present, but not spherocytes. This condition is rare in pregnancy and does not respond well to corticosteroids or IVIG. If the anemia is severe, management is supportive with warming, hydration, and RBC transfusion (warmed).55 IgM does not cross the placenta, so the fetus is unaffected.

Glucose 6 Phosphate Dehydrogenase Deficiency X-linked; heterozygous females (carriers) can be affected due to lyonization (random inactivation of one chromosome). There is a spectrum of diseases with nearly 200 different mutations identified. Glucose 6 phosphate dehydrogenase (G6PD) deficiency is responsible for the first step of the pentose phosphate pathway, which maintains intracellular glutathione protecting against oxidative damage. Most cells manufacture glutathione by other pathways that RBC cannot.49 A WHO classification is based on the extent of deficiency and severity of hemolysis, ranging from Class I with severe deficiency and chronic hemolytic anemia to Class V, increased activity. Hemolysis typically presents one to three days after the precipitating event and progresses until day seven.49 Most patients are asymptomatic unless exposed to triggers. Prevention by avoiding precipitants is ideal (Table 21.4). Most crises are self-limiting; remove precipitant, supportive care (e.g., transfusion, manage hemoglobinuria).49 Anesthetic Management of G6PD Deficiency Anesthetic management includes avoiding precipitants. Neuraxial anesthesia is ideal for reducing pain and anxiety (situational precipitants). Avoid ester LAs in patients with G6PD as para-aminobenzoic acid (in ester LA) and methylene blue, used to treat methemoglobinemia (caused by ester LA), precipitate hemolysis.50 Some recommend avoiding lidocaine; however, there are no reports of hemolysis with lidocaine epidural top-ups, and any effect is likely dose-dependent.50 Anesthetic agents considered safe in G6PD deficiency include:50 propofol, fentanyl, ketamine, benzodiazepines, sevoflurane, bupivacaine. Table 21.4  Precipitants for hemolysis with G6PD deficiency

•

Drugs (e.g., nitrofurantoin,51 sulfonamides, co-trimoxazole, quinolones, dapsone, methylene blue)*

• • • •

Infection (most common) Metabolic conditions e.g., diabetic ketoacidosis Dietary e.g., fava beans Situational e.g., stress, pain, anxiety

* Drug list is not exclusive; represents common medications associated with hemolysis in G6PD deficiency. High-level evidence is limited. Individual drugs should be checked for latest advice with respect to G6PD.

Acquired Disorders of the Red Blood Cells Leading to Hemolysis

Pregnancy-induced (Unexplained) Hemolytic Anemia This rare condition presents as hemolytic anemia during the third trimester and remits spontaneously postpartum. More than 20 cases have demonstrated that anemia is often severe and life-threatening.56 Corticosteroids and IVIG have been used without much success. The underlying etiology is unclear, and treatment is empirical; spontaneous resolution usually occurs postpartum.52,56

Miscellaneous Causes of Hemolysis Trauma to normal RBCs from prosthetic heart valves or fibrin deposition in the microvasculature (microangiopathic hemolytic anemia) may cause hemolysis. In the former situation, chronic hemolysis during pregnancy causes raised LDH, mild icterus, reticulocytosis, and hemosiderinuria with decreased plasma haptoglobin. Folic acid and iron supplementation help bone marrow compensate for ongoing losses. Microangiopathic

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hemolytic anemia is associated with DIC, PreE, and vasculitis; treatment targets the underlying disorder.

Congenital Methemoglobinemia Congenital methemoglobinemia is a rare AR disease where iron in Hb is ferric (Fe3+) rather than ferrous (Fe2+). Hence, there is a left-shift in the oxygen dissociation curve resulting in reduced tissue oxygen delivery.57 Type 1 presents with cyanosis from birth, and type 2 with severe neurological deficits and early death.57 Clinical outcomes are related to the percentage of methemoglobin; significant harm occurs with levels > 20%.57 Intrapartum management involves monitoring methemoglobin levels (ideally continuously by co-oximetry), preventative ascorbic acid, and treating exacerbations with methylene blue and dextrose. Drugs to avoid are those associated with oxidation and increased methemoglobinemia: bupivacaine, nitrous oxide, nitroglycerin, aspirin, and metoclopramide. Safe drugs: propofol, depolarizing and nondepolarizing muscle relaxants, reversal agents, sevoflurane, oxytocin, prostaglandin F2-alpha, magnesium, labetalol, hydralazine, phenylephrine, ephedrine, and remifentanil. (In theory, chloroprocaine and ropivacaine are safe, although literature describing their safety is limited).57 Controversial: lidocaine (may be safe at lower doses; reports of methemoglobinemia at 7mg/kg),57 fentanyl, acetaminophen, and dexmedetomidine. Yin et al. reviewed the obstetric anesthetic considerations for congenital methemoglobinemia type 1, including IV remifentanil PCA for labor analgesia.57 There is no report of NA in pregnant women with congenital methemoglobinemia. However, there is a case report of GA for an emergent CD in a patient with undiagnosed congenital methemoglobinemia complicated by perioperative hypoxia.58

Abnormalities of the Bone Marrow Bone Marrow Failure Aplastic Anemia Aplastic anemia (AA) is a life-threatening disorder caused by hypocellular bone marrow (without abnormal infiltrate or fibrosis), resulting in pancytopenia. Etiology is varied, with acquired forms more common than inherited (80% idiopathic). Known precipitants include: radiation, cytotoxic drugs, immune mediated, infections (especially viral hepatitis).59 Patients with AA can develop paroxysmal nocturnal hemoglobinuria (PNH), or the conditions can overlap.59 Inherited syndromes associated with AA are Fanconi anemia (FA) and Shwachman Diamond syndrome (SDS): see below. The British Society for Standards in Haematology has published guidelines on managing patients with AA.60 RiverosPerez et al. review obstetric and anesthetic considerations for AA during pregnancy.59Aplastic anemia frequently progresses during pregnancy, or pregnancy can be the first presentation.59 AA is associated with increased maternal and fetal morbidity and mortality: IUGR, sepsis, preterm delivery, PPH. There are reports of remission after delivery.59 Those with severe

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thrombocytopenia are at risk of complications, with a six-fold increase in composite outcomes: PreE, preterm delivery, neonatal death.61 McGowan et al. describe a series of 19 pregnancies in nine women (complication rate 79% maternal and fetal; from disease and treatment), with no deaths.62 Management during pregnancy:59,60 • preconception risk counseling • multidisciplinary approach • identify and treat the underlying cause • supportive: transfuse RBCs (restrictive; based on patient status), platelets (aim: > 20 x 109/L) • immunosuppressive therapy: cyclosporine, corticosteroids (both safe in pregnancy) • hematopoietic stem cell transplantation • therapeutic abortion allows treatment of severe maternal disease in the first trimester • other therapies with reported success: granulocyte colony stimulating factor, antithymocyte globulin • monitor for IUGR • Table 21.8 outlines the anesthetic management in the setting of thrombocytopenia

Congenital Red Cell Aplasias Pure Red Cell Aplasia Pure red cell aplasia (PRCA) is a rare disease associated with normocytic, normochromic anemia, marked reticulocytopenia, and an almost complete absence of bone marrow RBC precursors. Precursors and production of leukocytes and platelets are normal. Acquired PRCA is associated with thymoma, malignancies, viral infections (especially parvovirus B19), pregnancy, and autoimmune disorders.63 A report on 21 pregnancies in 15 women with PRCA found: present at any point in pregnancy; all needed RBC transfusion (most multiple); eight received corticosteroids; all recovered within three months postpartum; frequently recurred with subsequent pregnancies.63 Diamond-Blackfan Anemia Diamond-Blackfan anemia (DBA) is the name given to inherited PRCA. Treatment includes regular RBC transfusion, iron chelation, corticosteroids, and hematopoietic stem cell transplantation in resistant cases. Pregnancy in women with DBA is associated with: IUGR, premature delivery, and CD,64,65 and rarely hydrops fetalis, and mirror syndrome.66,67 An international consensus on DBA treatment includes a section on pregnancy management.68 Fanconi Anemia Fanconi anemia (FA), a rare inherited RBC aplasia, causes progressive bone marrow failure, skeletal and urogenital malformations, skin hyperpigmentation, reduced fertility, and predisposition to malignancy (especially leukemia).69,70 Hematological parameters frequently worsen during pregnancy.64 Baseline pregnancy rate with FA before bone marrow failure is ~ 15%.70 One pregnancy occurred following bone marrow failure without transplantation. That patient required intensive support with leukocyte-depleted, irradiated RBC, and

Disorders of Blood, Coagulation, and Bone Marrow

platelet transfusions. Pancytopenia progressed during pregnancy with systemic Campylobacter jejuni and E. coli infections on a background of severe neutropenia. She required GA for CD at 36 weeks with multiple transfusions. Staphylococcal infection occurred postpartum. The patient received 42 units RBCs and 22 units platelets during her pregnancy.69 There is a report of 14 pregnancies in ten women with FA following hematopoietic stem-cell transplantation.70 Obstetric anesthetic considerations relate to the management of pancytopenia and its consequences in collaboration with a hematologist. Shwachman-Diamond Syndrome This rare AR inherited disorder is associated with pancreatic insufficiency and malabsorption, pancytopenia, short stature, bony and hepatic abnormalities.64,71 Management is usually supportive depending on disease manifestation: RBC and platelet transfusions, granulocyte colony stimulation factor, rarely hematopoietic stem cell transplantation.71 There are four pregnancies reported in three women with SDS:64,71,72 Case 1: Anemia and thrombocytopenia worsened through pregnancy (no transfusions), poor weight gain (pancreatic insufficiency, malabsorption). CD was required as platelets were falling but with no comment on anesthetic technique.64 Case 2: Two pregnancies; extensive prepregnancy counseling. a. uneventful vaginal delivery, no particular intervention. b. twins, mild neutropenia without consequence, scheduled CD (obstetric reasons) with moderate PPH (atony, no transfusion).71 Case 3: Uncomplicated pregnancy, emergency CD (failure to progress), required two units RBC postpartum.72

Paroxysmal Nocturnal Hemoglobinuria Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired disorder of one or more lines of hematopoietic stem cells. Abnormal erythrocyte, leukocyte, or platelet clones are susceptible to lysis because of dysregulation of complement activation.73 Cell surface membranes are affected in PNH as a result of phosphatidylinositol glycan gene (PIG-A) mutation.73 This leads to acute and chronic intravascular hemolysis (classically nocturnal), intermittent hemoglobinuria (classically in the morning), and a thrombotic tendency. Associated with PNH are AA, pancytopenia (thrombocytopenia frequently, neutropenia less often), and myelodysplasia. There are limited reports of PNH in pregnancy; pregnancy exacerbates hemolytic anemia with PNH,74 with significant maternal and neonatal mortality (8–20%).73 Long-term prognosis is poor without hematopoietic stem cell transplantation; 10-year survival 50%.73 Major complications of PNH in pregnancy are acute hemolytic anemia (21%), major vessel thrombosis (12%; e.g., intraabdominal or intracerebral), infection, and hemorrhage (14%), abortion, and IUFD (30%).73,75 There are several reports of obstetric anesthesia and PNH.73–76 Anesthetic considerations for pregnancy with PNH are listed below.

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• Venous thromboprophylaxis: LMWH, first trimester to six weeks postpartum. • Suitability of NA depends on degree of thrombocytopenia and timing of LMWH administration. Consider conversion to UFH to facilitate NA. If platelets fall during pregnancy, this might be from heparin-induced thrombocytopenia. Hold LMWH in severe thrombocytopenia. • PPH risk; may need RBC, platelet transfusion peripartum. • RBC transfusion may decrease defective RBC production and thrombosis.73 Thrombosis risk proportional to percentage of affected RBC.74 • Prophylactic antibiotics, strict asepsis, low index of suspicion for infection, and early intervention. • Labor stress may precipitate acute hemolytic anemia,74 so effective analgesia is essential; LEA if possible, alternatively opioid PCA. Avoid nitrous oxide.74 • Corticosteroids may help acute hemolytic anemia but are ineffective for chronic hemolytic anemia.73 • If deterioration occurs, consider superimposed PreE (increased incidence ~ 12%); difficult to distinguish from PNH. • Maintain homeostasis and avoid dehydration, hypothermia, and acidosis, which may precipitate acute hemolytic anemia. • Thiopental may activate complement release, so use propofol. Volatile agents decrease complement levels.74 Eculizumab, a monoclonal antibody against complement protein, has been used to treat PNH.77 In nonpregnant populations, it prevents complications and improves quality of life; there is less evidence in pregnant women, but available data suggest it is safe. There is little consensus on dosing, but there appears to be a promising reduction in PNH complications; notably reduced maternal and neonatal mortality.78,79

Sideroblastic Anemia Sideroblastic anemia is a descriptive term for a spectrum of disorders unified by defective heme synthesis and iron overload. Bone marrow biopsy shows “ring sideroblasts.” Hypochromic microcytic and normal erythrocytes are present on a blood film.80 Sideroblastic anemia can be inherited (usually X-linked) or more commonly acquired. Acquired can be primary (chronic myeloproliferative disorder) or secondary (drugs, toxins, alcohol). Obstetric management is supportive: • remove precipitant where appropriate • circumspect transfusion of RBC as required • iron chelation when necessary (but not during the first trimester) • administration of supplemental iron is not normal practice unless iron deficiency is proven. There are reports of pregnancy with sideroblastic anemia.80,81

Anesthesia for Parturients with Bone Marrow Failure Disorders The management principles in patients with bone marrow failure include adequate oxygenation, preventing infection, and maintaining hemostasis. A multidisciplinary approach

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(obstetrician, hematologist, anesthesiologist) is essential for optimal management of labor and delivery (Table 21.5). Irradiated, leukodepleted blood products with a restricted approach to replacement are used in cases requiring hematopoietic stem cell transplantation.73 Leukodepletion reduces the risk of nonhemolytic transfusion reactions and transmission of cytomegalovirus. Irradiation reduces lymphocytes and transfusion-associated graft versus host disease (GVHD). ABO-Rhesus matched platelets are recommended.73 In patients with human leukocyte antigen (HLA) alloimmunization, HLA matched platelets are required. Apheresis platelets carry less risk than pooled. A transfusion target of 10 g/L Hb is often cited, but a restrictive approach is recommended given the risks of alloimmunization and iron overload. Use transfusion based on maternal symptomatology, fetal wellbeing, and anticipated blood loss.60 The supply of matched blood may be limited; cell salvage reduces donor blood required at CD. Neutropenia places patients at increased risk of infection. Observe strict asepsis for invasive procedures. Special considerations for bone marrow recipients are described below.

Primary Marrow Malignant Disorders Myeloproliferative Neoplasms This group of distinct disorders with shared genetic mutations (JAK2, CALR, MPL) comprises essential thrombocythemia/ thrombocytosis (ET), polycythemia vera (PV), and primary myelofibrosis (PMF). PV and PMF tend to occur later in life; therefore, ET is the most common myelproliferative neoplasm (MPN) in pregnancy.82 Since advanced maternal age is on the rise, the incidence of MPN will likely increase. These are collectively known as Philadelphia chromosome negative MPN; Philadelphia chromosome positive MPN suggests chronic myeloid leukemia (CML). Myeloproliferative neoplasms and pregnancy increase thrombotic risk (arterial and venous) and cause the most complications; paradoxically, hemorrhage can be secondary to anticoagulant therapy.82 Fetal complications include spontaneous abortion, IUGR with placental insufficiency, and PreE.83 In a prospective study of pregnancy with MPN (n = 58) (most had ET),84 the findings were: • No thrombotic events • 3.5% major hemorrhage rate • 1.7% spontaneous abortion • 1.7% stillbirth • 9% PreE • 9% PPH • 15% Preterm • 45% CD • 22% small for dates (< 10th percentile) • 13% NICU • Prophylaxis during pregnancy, 88% aspirin, 38% prophylactic LMWH, 3% therapeutic LMWH These outcomes were better than in retrospective studies:82,85 A meta-analysis of published cases (1210 pregnancies) found a live birth rate of 71% and improved rates (~9 times) with

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aspirin or interferon therapy; LMWH alone or combined with aspirin did not improve rates.85 The physiological changes seen during a normal pregnancy can improve parameters, e.g., normalizing Hb and platelet counts with PV and ET, respectively.82 Postpartum levels may return rapidly to prepregnancy levels. Robinson et al. present a pragmatic approach to managing MPN in pregnancy.83 Management includes aspirin and heparin (if any additional risk factors for thrombosis), phlebotomy, and possible use of cytoreductive therapy interferon-alpha).83 Gangat et al. include a flow chart with treatment recommendations based on risk factors.82 Currently, there are no RCTs to guide practice. Table 21.5 ­summarizes the anesthetic implications for bone marrow malignancies in pregnancy.

Table 21.5  Summary of anesthetic implications for bone marrow malignancies in pregnancy

•

Require multidisciplinary input (e.g., obstetric, hematology, anesthesiology)

• • •

Most require specialist/tertiary hospital Many diseases rare; evidence is limited Thrombotic risk ◦ Hyperviscosity ◦ Placental insufficiency/infarction (PreE risk) ◦ Thromboprophylaxis ◦ Aspirin ◦ LMWH – management peripartum; timing of NA

•

Pancytopenia ◦ Thrombocytopenia ■■

Hemorrhage (APH, abruption, PPH)

■■

NA contraindicated

◦ Anemia ■■

Impaired oxygen delivery

◦ Leukopenia/neutropenia ■■

Recurrent infection/immunosuppression

■■

Strict asepsis

■■

Prophylactic antibiotics

■■

Active screening for infection

◦ Previous transfusions; risk of alloimmunization and difficult crossmatch ◦ May require leukocyte-depleted/irradiated products

•

Functional deficiency/dysfunction ◦ Thrombocytosis – ineffective lineage ◦ Acquired vWD

•

Pregnancy interaction with underlying disease ◦ Normal physiological changes (e.g., decrease in RBC, platelets) may improve or worsen underlying disease ◦ Changes in immune surveillance during pregnancy can exacerbate disease

•

Malignant cells (blasts) in blood ◦ Risk of seeding into neuraxial space with DP (e.g., AML)

Disorders of Blood, Coagulation, and Bone Marrow

Table 21.5 (cont.)

•

Splenomegaly or splenectomy ◦ Risk infection with encapsulated bacteria

•

Compressive lesions ◦ Cardiovascular – respiratory compromise (e.g., anterior mediastinal mass; NHL) ◦ Spinal, vertebral fracture (e.g., MM)

•

Avoid nitrous oxide ◦ Theoretical marrow suppression

Patients with MPN (platelet count > 1000 x 109/L) are at risk of hemorrhage. Increased platelets absorb more vWF and can cause acquired vWD due to a functional deficiency.86 It often improves with pregnancy-induced increases in vWF and decreased platelets, in contrast to inherited vWD type 2a. One should exclude acquired vWD in pregnancy in patients with MPN:87,88 • Test vWF (and FVIII) activity early in pregnancy (hold aspirin if vWF activity < 30%). • Repeat vWF and FVIII in the third trimester (to confirm anticipated correction). The only potentially curative treatment for MPN disorders is hematopoietic stem cell transplantation. Essential Thrombocythemia Essential thrombocytopenia (ET) is an acquired MPN that can cause both thrombosis and hemorrhage. Thrombosis can be arterial or venous and involves the macro (stroke, MI, DVT) or micro vasculature (visual disturbance, digital paresthesia). It is the commonest MPN in pregnancy.89 Hemorrhagic complications are less common, occurring at extreme platelet counts. Diagnostic criteria for ET:90 • Platelet count consistently > 450 x 109/L • Bone marrow shows proliferation of megakaryocytes (no increase in neutrophil or erythropoiesis) • Does not meet WHO criteria for alternate diagnosis (e.g., PV, PMF, CML) • Demonstration of a genetic marker (e.g., JAK2) • If there is no genetic marker and no identified cause for reactive thrombocytosis There are reports of 1266 pregnancies in 765 patients with ET.82 Patients with ET are often asymptomatic, particularly if platelets < 1000 x 109/L. Point of care testing of platelet function has been described in ET: • “Plateletworks” (a rapid POC test of platelet count and function) in an ET patient on aspirin before LEA.86 The test demonstrated 21–40% of platelets responded to activation testing and were deemed “functional thrombocytes.” This highlights that the number of functional platelets is important, not the total platelet count. • TEG to support LEA insertion.91 When ET is associated with bleeding, it may be from acquired vWD (type 2a).87 One paper presents 24 pregnancies in 18 women with ET; 83% had type 2a vWD at baseline, by the third

trimester, no patient had vWD (71% received NA, 33% CD, no complications or special treatment).87 Polycythemia Vera Polycythemia vera (PV) can occur during pregnancy (less commonly than ET) and is associated with thrombosis and hemorrhage. An increase in all cell lines (erythrocytosis, leukocytosis, thrombocytosis) occurs in PV, and patients may develop splenomegaly.88 There are reports of 174 pregnancies in 79 women with PV.82 Patients improved when PV diagnosis was known and treated with a combination of aspirin, LMWH, phlebotomy, and interferon. The British Society for Haematology guidelines for managing PV in pregnancy include:92 • multidisciplinary care • avoid cytoreductive therapy for three months before conception (if needed, use interferon) • phlebotomy to achieve normal hematocrit for stage of pregnancy (95% range: first trimester: 0.31–0.41; second trimester: 0.3–0.38; third trimester: 0.28–0.39)92 • use aspirin with LMWH and interferon for high-risk pregnancies* • regular fetal growth scans and Doppler studies after 20 week estimated gestational age • use LMWH for six weeks postpartum. * Defined as a prior history of thrombosis or hemorrhage, or pregnancy complications (> 3 spontaneous abortions in the first trimester, > 1 in the third trimester, low birthweight (< 5th centile), IUFD, stillbirth or PreE), extreme thrombocytosis > 1500 x 109/L, diabetes or hypertension requiring medication. In one report, a patient with PV and PreE received LEA for CD.88 Primary Myelofibrosis Primary myelofibrosis (PMF) is relatively rare in pregnancy (286 pregnancies in 179 patients). It carries a worse prognosis than ET, or PV,82 and is characterized by chronic myeloproliferation, bone marrow fibrosis, severe anemia (with extramedullary hemopoiesis), and splenomegaly. ET can progress to PMF, and PMF may progress to acute myeloid leukemia (AML).93 Leukemia Lishner et al. present an international consensus on managing hematological malignancies in pregnancy.94 Given the rarity (incidence 0.02%) and ethical consideration of trials in pregnancy, prospective RCTs are not feasible; expert consensus and retrospective or observational studies are used to create clinical guidelines. Pregnancy can delay the diagnosis of malignancy as symptoms can overlap with normal pregnancy (e.g., fatigue, dyspnea). Prognosis is related to prompt staging and treatment. Avoid delays in imaging because of fetal concerns, as it may further delay treatment. Pregnancy does not appear to alter the incidence or prognosis of acute or chronic leukemia. Shliakhtsitsava et al. reported on pregnancy outcomes in survivors of leukemia and lymphoma.95

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Acute Leukemia Acute leukemia occurs in one of every 75,000–100,000 pregnancies.96 Most leukemias in pregnancy are acute; two-thirds are myeloid (AML), one-third is lymphoblastic (ALL).96 Treatment in early pregnancy is complicated by concerns for teratogenic effects on the fetus.96 Maternal outcomes are better the sooner treatment starts; therefore, termination is recommended in the first trimester to allow conventional chemotherapy.94 Chemotherapy is relatively safe for the fetus during the second and third trimester, although linked with IUGR, premature delivery, increased IUFD, and neonatal hematopoietic suppression.96 There are no long-term effects from chemotherapy in children of mothers who received treatment in pregnancy.96 Complications can occur as part of leukemia or as a consequence of therapy; thrombosis, thrombocytopenia, hemorrhage, neutropenia, and sepsis.94,96 Plan delivery of the baby > 3 weeks after the last dose of chemotherapy. As fetal metabolism is immature, the delay allows drug excretion via the placenta and time for bone marrow recovery.96 Remission rates are high (75%).96 Mothers receiving cytotoxic drugs should not breastfeed. Additional challenges are associated with ALL as treatment requires CNS therapy with fetotoxic drugs (e.g., methotrexate).94 Spontaneous abortion rates are higher in ALL survivors who received radiation therapy.95 Acute promyelocytic leukemia (APL) may present as an obstetric emergency; it is often associated with DIC and has worse maternal and fetal outcomes.94,96 There are sporadic cases of maternal malignant cells metastasizing to the fetus via the placenta, so the placenta should be examined by a pathologist.94,96 Thomas et al. review acute leukemia and pregnancy, including all published cases and outcomes of AML (n = 232) and APL (n = 38).96 Elterman et al. describe the anesthetic considerations for a pregnant patient with AML.97 There is an increased risk of hemorrhage and thrombosis. Neuraxial anesthesia is not used due to the risk of introducing malignant cells (blasts) into the CNS with DP.97 An EBP was avoided in an AML parturient with a PDPH out of a similar concern.98 Chronic Leukemia Chronic Myeloid Leukemia Chronic myeloid leukemia (CML) is the commonest (1:100,000) chronic leukemia in pregnancy (90%) and is associated with the Philadelphia chromosome (95%).94,99 Classically, CML presents with weight loss and night sweats. In the nonpregnant patient, tyrosine kinase inhibitors are the mainstay of treatment, with significantly improved outcomes. However, these are teratogenic.94 Stopping treatment during pregnancy may be life-threatening (disease progression, blast crisis).99 Other supportive treatments considered in pregnancy are leukapheresis and interferon alpha.94 One should approach CML in the blast phase as acute leukemia.94 Rebahi et al. describe anesthetic considerations for CD in CML.99 In that case, 32% of the leukocytes were blast cells at the time of the CD. The patient had a GA, avoiding NA out of

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concern of seeding malignant cells.99 A cut-off < 5% blast cells is considered safe for NA.99 Chronic Lymphocytic Leukemia Predominantly a disease of older (median 72 years) males (twothirds), chronic lymphocytic leukemia (CLL) is seen rarely in pregnancy (seven cases reported).100 CLL may present in pregnancy with leukocytosis or immune compromise and infection. Treatment is described as “watch and wait” in pregnancy, as the typical course is “indolent.”100 If the leukocyte count is very high, leukostasis can cause placental insufficiency and IUGR.100 Treatment options include leukapheresis for cytoreduction (leukocyte count < 100 x 109/L),100 and in advanced disease, rituximab and tyrosine kinase inhibitors. Supportive care: • Immune compromise associated with CLL may contribute to spontaneous abortion and prematurity. Reactivation of CMV or herpes may also affect the neonate. • Autoimmune hemolytic anemia can be seen with CLL and responds to corticosteroids. • Anemia can occur from marrow failure, requiring transfusion and potentially B12, iron, and folate supplementation. • Platelet transfusion for thrombocytopenia. Chronic Neutrophilic Leukemia One report of chronic neutrophilic leukemia in pregnancy describes the risks of hemorrhage and thrombosis.101 Lymphoma Hodgkin lymphoma (HL) is the most common hematological cancer in pregnancy (6%), and non-Hodgkin lymphoma (NHL) is the second most common (5%).94,102 Diagnosis is from lymph node biopsy (prognostic indicators: erythrocyte sedimentation rate, LDH). Chest CT (with abdominal shielding) and abdominopelvic MRI are used to stage HL during pregnancy. Management depends on gestational age, risks from chemotherapy, disease staging, and the impact of delaying treatment. If possible, delay treatment until the second trimester. However, this is not ideal for high-grade lymphomas (e.g., Burkitt lymphoma), which can rapidly progress and require aggressive intervention. There is no difference in maternal and fetal outcomes in patients with HL and NHL treated with standard multiagent chemotherapy in the second or third trimester. In one study, 64% of women achieved complete remission.102 In nonpregnant patients, local radiation therapy is given to reduce relapse, but this is deferred to the postpartum period. Rituximab has been used successfully as an alternate treatment in pregnancy.102 Survival from HL in pregnancy appears similar to matched (nonpregnant) controls.94 There are several subtypes of NHL; diffuse B-cell lymphoma is the commonest in pregnancy, outcomes are worse than HL, and heterogeneous depending on subtype.94 Mediastinal NHL during pregnancy can cause cardiorespiratory compromise; Roze des Ordons et al. report a CD in a parturient with a large B-cell lymphoma and an anterior mediastinal mass (with cardiac tamponade, SVC obstruction, and

Disorders of Blood, Coagulation, and Bone Marrow

airway compression) performed under epidural anesthesia (spontaneous ventilation a priority), with cardiopulmonary bypass on standby.103 Rare Hematological Malignancies Hairy Cell Leukemia There are few reports in pregnancy; supportive therapy and specific treatment with chemotherapy, interferon alpha, rituximab, or splenectomy are described.94 Myelodysplastic Syndrome These are clonal marrow stem cell disorders that result in ineffective hematopoiesis and pancytopenia; it can be considered “preleukemia” and can transform to AML.94 Supportive management in pregnancy includes: repeated RBC and platelet transfusions or recombinant erythropoietin.104 There are reports of pregnancy-induced myelodysplastic syndrome, and several cases briefly entered remission after therapeutic abortion.96,104 Christiaens et al. report anesthetic management for CD in a parturient with an acute myelodysplastic syndrome.104 Multiple Myeloma Although rare in pregnancy, multiple myeloma (MM) is the most common primary bone malignancy. Of 32 cases, five initially presented in pregnancy.94,105 It is a neoplastic bone tumor that leads to a proliferation of plasma cells and an overproduction of monoclonal immunoglobulins (most commonly IgG, but also IgA, and possibly IgD).105 Clinical presentation is with bone pain (lytic lesions or pathologic fractures), neurologic deficits (compression), recurrent infections (immunodeficiency), or symptoms of anemia, hypercalcemia, or renal failure.105 Marrow infiltration can cause pancytopenia. Renal failure occurs in the later stages. Spinal cord compression secondary to vertebral collapse from MM may occur in pregnancy.106 MM patients can develop hyperviscosity syndrome, causing stroke or MI. Amyloid deposition (15%) can lead to macroglossia and cardiomyopathy.105 Cryoglobulinemia in patients with MM can cause vasculitis or contribute to renal impairment.105 Bence Jones proteins in the urine (paraprotein band on electrophoresis), malignant infiltration on bone marrow biopsy, and staging with an X-ray skeletal survey will help confirm the diagnosis.105 There are no guidelines for managing MM in pregnancy. Chemotherapy commonly used for treatment is considered unsafe; thalidomide is teratogenic, there is no safety information available for lenalidomide or bortezomib. Corticosteroids may temporize until delivery.107 Bisphosphonates to treat lytic bone lesions/fractures in pregnancy is controversial.94 Dabrowska et al. discuss the anesthetic management of an uncomplicated scheduled CD with combined spinal epidural (CSE) with MM in pregnancy.105 Most reported cases of MM parturients had a CD, possibly because of concerns of pelvic disease.107 Waldenstrom Macroglobulinemia This disorder exhibits IgM monoclonal gammopathy. It presents with anemia and is associated with hepatosplenomegaly,

purpura, and renal insufficiency. It is rare in pregnancy (two reported cases).108,109 One pregnancy, complicated by IUGR (secondary to placental infarction from hyperviscosity), culminated in CD under GA for fetal distress.108 The other had uncomplicated LEA and forceps delivery for abnormal FHR.109 Potential anesthetic concerns include thrombosis, pancytopenia (anemia, bleeding, infection), amyloidosis, and hyperviscosity. Cold hemagglutinin disease, cryoglobulinemia, and acquired vWD also occur.109 Hemophagocytic Lymphohistiocytosis Syndrome Hemophagocytic lymphohistiocytosis syndrome, HLS110,111, is a rare, life-threatening condition caused by unregulated immune activation (macrophages, T lymphocytes) producing widespread cytokine release and inflammation. It presents with fever, hepatosplenomegaly, cytopenia, hypertriglyceridemia, hypofibrinogenemia, elevated ferritin, and hemophagocytosis in reticuloendothelial tissues. Untreated HLS can be life-threatening, progressing to multiorgan failure over months. There are reports of HLS in pregnancy associated with infection (e.g., Epstein Barr), autoimmune or underlying neoplastic disease; pregnancy may also trigger HLS.110–112 HLS has a high fetal and maternal mortality.112 Yip et al. make recommendations for modifying treatment in pregnancy (corticosteroids, interleukin-1 receptor antagonist).111 Chien et al. report anesthetic management (GA) of CD in a patient with HLS.112

Hematopoietic Stem Cell (Bone Marrow) Transplantation Myeloablative therapy (total body irradiation and chemotherapy) can cause pulmonary fibrosis and cardiomyopathy; anesthetic assessment should focus on the cardiovascular and respiratory systems, and appropriate investigation used as indicated (e.g., PFT, echocardiogram). All bone marrow transplant patients will have residual immunodeficiency, in particular susceptibility to viral, fungal, and gram-positive bacterial infections.113 Graft versus host disease (GVHD) complicates some hematopoietic stem cell transplants, where allogenic competent T-lymphocytes are injected into immunosuppressed individuals.113 Chronic GVHD occurs in 20–40% of transplant recipients.114 Effects depend on which organ systems are targeted: gastroenterological, hepatic, immune, skin. Patients may require long-term immunosuppression.114 Transplantation may fail, or there may be a recurrence of malignancy. Stein et al. review the anesthetic implications of hematopoietic stem cell transplantation,113 and Venkatesan et al. review GVHD.114 Prior to hematopoietic stem cell transplantation, total body irradiation frequently causes ovarian failure and infertility.115 Subsequent spontaneous pregnancies are possible, but IVF is often necessary.113

Coagulation Disorders A concern of most anesthesiologists is whether NA will cause an epidural hematoma leading to permanent neurological damage. However, the incidence of coagulopathy in parturients

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Table 21.6  Principles of anesthetic management of patients with a known (or suspected) coagulation disorder 1. Take personal and family bleeding history: easy bleeding or bruising? (e.g., perioperatively or following dental work). 2. Perform physical examination: bruising, bleeding, petechiae (BP cuff, IV sites). 3. Lab work: CBC, specific testing dependent on patient’s history and clinical course. 4. Multidisciplinary approach: anesthesiologist, obstetrician, and hematologist. Confirm diagnosis, agree monitoring requirements throughout pregnancy, optimize condition (e.g., IVIG or corticosteroids for ITP). Include neonatology if newborn possibly affected (e.g., AD, X-Linked, or IgG immune mediated conditions). 5. Assess airway, feasibility/risk of alternate techniques (e.g., risk of neuraxial bleeding with coagulopathy vs. risk from emergency GA with a predicted difficult airway). 6. Discuss and document risks/benefits of procedure and alternatives e.g., remifentanil PCA.116 7. Discuss and document risks/benefits of any required blood products. 8. Proceed with NA if appropriate; minimize impact (spinal less risk than epidural, most experienced anesthesiologist, consider preprocedural US). 9. If NA is contraindicated, caution with pudendal block, IM injections, NSAIDs. 10. Active management third stage (prophylactic uterotonics). 11. Consider conditions and timing of epidural catheter removal. 12. Monitor and document lower limb neurological recovery post NA. 13. Consider primary and secondary PPH risk: need for continued monitoring (clinical or lab based), specific product replacement, or TXA.

is extremely low, and the relationship between NA, epidural hematoma, and coagulopathy is unknown. There is no evidence for the best anesthetic management in pregnant women with coagulopathies. However, Table 21.6 outlines some general principles for anesthetic management of the parturient with a coagulation disorder.

Platelet Disorders Thrombocytopenia Thrombocytopenia (platelet count < 150 x 109/L) is the most common (12%) hematologic condition in pregnancy, 1% have a platelet count < 100 x 109/L).117,118 Normally, the platelet count decreases throughout pregnancy until 32–36 weeks; this is associated with a consistent increase in mean platelet volume.

Anesthetic management of the parturient with thrombocytopenia varies with the underlying pathophysiology and its effect on platelet function (Table 21.7). As platelet counts decrease, the risk of epidural hematoma increases (Table 21.8). A SOAP consensus statement reviewed and analyzed available pertinent literature.118 One study found five spinal hematomas in 7509 neuraxial procedures: two epidural, three spinal (platelet range 44–91 x 109/L). One patient had an arteriovenous malformation, one was coagulopathic at the time of epidural catheter removal, and three had PreE (two HELLP).118 The upper 95% confidence interval (CI) for risk of epidural hematoma among 1995 obstetric patients with thrombocytopenia is:118 Platelet count (range) 70–100 x 109/L 50–69 x 109/L ≤ 50 x 109/L

Upper 95% CI 0.19% 2.6% 9%

A systematic review concluded that platelet transfusion before NA did not improve outcomes.118 In the United Kingdom, platelet transfusions were responsible for 34% of adverse transfusion events.118 Non-steroidal anti-inflammatory drugs, including aspirin, impair platelet function, but ASRA guidelines state NSAIDs do not increase the risk of epidural hematoma following NA.118 In patients with platelet disorders, the administration of NSAIDs should be based on the clinical context.118 Gestational Thrombocytopenia Gestational thrombocytopenia is the most typical cause of thrombocytopenia in pregnancy (~ 8%). It is generally mild, and platelet counts rarely fall < 80 x 109/L. There is no associated increased bleeding risk in patients, and neonates are not at increased bleeding risk. In most cases, platelet count returns to normal three to five days postpartum. The diagnosis of gestational thrombocytopenia is one of exclusion. Immune Thrombocytopenic Purpura Eslick et al. reviewed the management of ITP in pregnancy,122 and Bailey et al. reviewed NA in ITP.123 Immune thrombocytopenic purpura is an autoimmune mediated disease that increases platelet destruction leading to thrombocytopenia. Laboratory findings usually include isolated thrombocytopenia (before or in early pregnancy) with large well-granulated platelets that function well, and so hemostasis

Table 21.7  Acquired disorders of platelets during pregnancy

Disorder

Thrombocytopenia

Abnormal platelet function

Physiological

Gestational thrombocytopenia

Yes

No

Autoimmune

ITP

Yes

No

Antiphospholipid syndrome

Yes

Not typically

HIV

Yes

No

COVID-19119 (including mild disease)

Yes

No

Microangiopathic syndromes

Yes

Only if significant decrease in fibrinogen

Viral

TTP, hemolytic uremic syndrome (HUS), HELLP

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Table 21.8  Platelet count and neuraxial anesthesia for obstetrics; based on an amalgamation of National Guidelines118,120,121 Platelet count

Generalized recommendations

> 100 x 10 /L

Considered safe, unless history of bleeding suggests abnormal platelet function

> 70 x 109/L and < 100 x 109/L

If platelet count stable (not falling precipitously, e.g., with HELLP) considered low risk

> 50 x 109/L and < 70 x 109/L

Unless ITP risks probably outweigh benefits

< 50 x 109/L

Avoid. Risks likely outweigh benefits.

9

is expected. Often there is a family history of autoimmune disease, but ITP can be secondary to SLE, HIV infection, and some medications (e.g., heparin).117 In some, corticosteroids or IVIG are administered at 37–38 week gestation to increase platelets for delivery. If successful, this facilitates safe NA and reduces PPH risk. It may take several days for platelets to increase, and effects last up to six weeks.2 Occasionally, splenectomy is required during pregnancy, preferentially in the second trimester.124 Anesthetic management of women with ITP is usually straightforward as typically platelet function is normal. A history of a lack of bleeding at a given platelet count is reassuring. ACOG recommends intervention (IVIG, corticosteroids, or both) in ITP if there is active bleeding, platelets are < 30 x 109/L, or to cover procedures. Other ACOG recommendations are > 70 x 109/L for NA and > 50 x 109/L for CD.121 Some anesthesiologists are comfortable administering NA to parturients with ITP and platelet counts as low as 50 x 109/L. The AAGBI considers ITP patients with platelets of 50–75 x 109/L at increased risk for epidural hematoma and a platelet count of 20–50 x 109/L high risk.120 For platelet transfusions in ITP, ACOG recommends using two to three times normal platelet dosing and infusing with high-dose corticosteroids or IVIG.121 As IgG antibodies cross the placenta, ~ 10–15% of neonates born to mothers with ITP have thrombocytopenia at birth and an associated rate of ICH of 1.5%.117 Neonatal thrombocytopenia can develop postpartum, so follow neonates born to ITP mothers until platelet count stabilizes (~ 3 days). Maternal treatment of ITP does not influence neonatal outcome.117 Other Causes of Thrombocytopenia Some causes of thrombocytopenia are not specific to pregnancy. • Spurious: platelets are clumped, leading to a low automated count. Rule out with visual inspection of a blood smear (Figure 21.2).125 • Viral infections: (HIV, hepatitis C, cytomegalovirus, Epstein Barr virus, or COVID-19119). • Drug therapy: (heparin, sulphonamides, penicillin, rifampicin, quinine). • Immune mediated: thrombocytopenia associated with antiphospholipid syndrome (APLS). Approximately 25% of patients with these antibodies have concomitant thrombocytopenia; however, thrombosis rather than hemorrhage is the overriding risk. There is a risk of adverse

Figure 21.2  Peripheral blood smear demonstrating platelet clumping showing comparative size of the clump with a white blood cell. (See color plate section.)

outcomes from placental compromise; IUGR, abruption, severe and early onset PreE (< 26 week gestation), IUFD, placental infarction, recurrent abortion. Rarely platelet defects (thrombocytopenia, platelet dysfunction) are genetic in origin (Table 21.9). Bolton-Maggs et al. reviewed the inherited platelet disorders using a flow-chart to assist diagnosis.126 These are rare conditions with a paucity of Table 21.9  Congenital platelet disorders (modified from Bolton-Maggs 2006)126

Disorder

Estimated cases world-wide

Notes

MYH9 disorder Includes previous classifications: May-Hegglin anomaly Sebastian syndrome Fechtner syndrome Epstein syndrome

< 1000

AD Often asymptomatic Individual bleeding history variable in those with same genetic defect Associated sensorineural hearing loss, glomerulonephritis, cataracts

Congenital amegakaryocytic thrombocytopenia

< 100

AD Associated sensorineural deafness, pancytopenia

Thromobocytopenia absent radius syndrome (TAR)

< 100

Most AR (AD described) Platelet count improves with age, may have platelet dysfunction

Thrombocytopenia

Severe platelet dysfunction Bernard-Soulier syndrome

< 1000

AR Associated macrothrombocytopenia Moderate to severe bleeding

Glanzmann thrombasthenia

< 1000

AR Normal platelet count Severe bleeding High-risk maternal alloimmunization, associated fetal thrombocytopenia

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Chediak Higashi syndrome

< 1000

AR

Hermansky-Pudlak syndrome

< 100

AR

cases of severe bleeding with thrombocytopenia.128 A personal bleeding history is vital to assess individual risk. Hussein et al. reviewed 75 pregnancies in 40 patients with May Hegglin anomaly.128 Of note, in 25%, the first presentation was an incidental finding of thrombocytopenia in pregnancy. Five were misdiagnosed as ITP (three had splenectomy for misdiagnosed ITP). Prophylaxis with platelets, desmopressin, or cryoprecipitate occurred in 15%. There was no hemostatic prophylaxis in 79% of patients, and two women had PPH. Cesarean delivery occurred in 36% of women (two out of three scheduled), and 4% had assisted forceps. Mean EBL was 600 mL. Overall, there was a 10% PPH rate; one required blood transfusion and another platelets with cryoprecipitate. Although 12% of scheduled CD were for potential neonatal bleeding, none (n = 78) had severe morbidity.128 Patients with MYH9, both with prophylactic platelet transfusion,129,130 and without (despite platelet counts as low as 14 and 26 x 109/L),131 have received uncomplicated NA for labor and CD. A patient with MYH9 disorder received Eltrombopag (thrombopoietin receptor agonist) to stimulate third trimester platelet production (increased platelets from 30 to 179 x 109/L) for CD with spinal anesthesia.132

Idiopathic dense-granule storage pool disease

< 1000

Inheritance unclear

Severe Platelet Dysfunction

Gray platelet syndrome

< 100

AR, AD described

Jacobsen/ParisTrousseau syndrome

< 100

AD Thrombocytopenia

Quebec platelet syndrome

40 (1 family)

AD

Table 21.9 (cont.)

Disorder

Estimated cases world-wide

Notes

Wiskott-Aldrich syndrome

< 1000

X-linked Associated microthrombocytopenia Unlikely to have maternal consequences Male neonates at risk

Receptor and signal transduction disorders ADP receptor defect

< 100

Thromboxane synthase deficiency

< 100

Thromboxane A2 receptor defect

< 100

Platelet cyclooxygenase deficiency

< 100

AR

Platelet granule disorders Dense-granule

Alpha-granule

Disorder of phospholipid exposure Scott syndrome

< 10

AR Severe bleeding tendency

Abbreviations: AD = autosomal dominant; AR = autosomal recessive.

data on anesthetic management. Significant variables to consider are associated bleeding risk and likelihood of the neonate being affected (AD or X-linked inheritance). Neuraxial anesthesia is probably inappropriate for pregnant women with rare platelet function disorders, but the anesthetic technique is decided after weighing the risks and benefits for each case. The evidence is limited and may guide discussion with the patient, but ultimately expert opinion will drive practice. These patients should be seen early in pregnancy, managed by a multidisciplinary team, and have their condition optimized. MYH9-related Thrombocytopenia Disorders Several eponymous syndromes (May-Hegglin, Sebastian Fechtner, and Epstein) have been reclassified as MYH9-related syndromes, accounting for 30% of cases of genetic macrothrombocytopenia.127 Laboratory findings are macrothrombocytopenia and specific leukocyte inclusion (Döhle-like) bodies.126 Bleeding tendency varies between individuals with the same genetic mutation. Most are asymptomatic, although there are

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Bernard Soulier Syndrome There is qualitative and quantitative platelet dysfunction of the membrane glycoprotein Ib-IX-V complex in Bernard Soulier syndrome. This complex is an essential functional binding site on the platelet membrane for vWF. Clinically, patients with this disorder have moderate to severe bleeding, and laboratory studies show thrombocytopenia, prolonged BT, and giant platelets. During 30 pregnancies in 18 women, complications included intrapartum bleeding and PPH (primary 33%, secondary 40%).133 One-third had antiplatelet antibodies, either following platelet transfusion or sensitization during exposure to fetal platelet antigen during a previous pregnancy. These women were treated with IVIG, corticosteroids, or plasmapheresis to improve transfused platelet half-life and reduce the neonatal autoimmune thrombocytopenia (NAIT) risk.133 There was a high risk of bleeding for mother and neonate; 7% hysterectomy, 20% NAIT (one IUFD, one neonatal death).133 However, a reporting bias may exist due to small numbers of subjects. Sixteen pregnancies had CD, three had forceps or vacuum-assisted deliveries, but the anesthetic technique was not described. They advised avoiding NA and using GA for operative deliveries. These authors recommend rFVIIa and TXA prophylaxis in uncomplicated vaginal deliveries, HLA-matched platelets and TXA for CD, active management of the third stage, and continuing TXA for six weeks postpartum.133 Glanzmann Thrombasthenia This rare, severe bleeding disorder arises from qualitative or quantitative abnormalities of the platelet glycoprotein GPIIb/ GPIIIa complex. These glycoproteins form a complex in the platelet membrane and act as the fibrinogen receptors, adhesive glycoproteins, vWF, and fibronectin.126 Normal platelet count

Disorders of Blood, Coagulation, and Bone Marrow

and morphology characterize Glanzmann thrombasthenia (GT). There is an increased bleeding time (or increased CT with PFA-100).126 There are three types of GT: type I < 5% normal GPIIb/IIIa (78% of patients); type II 5–20% normal GPIIb/IIIa (14%); type III has a qualitative defect in GPIIb/IIIa complex (8%).134 There are reports of acquired GT presenting with no previous bleeding history and a normal platelet count but a prolonged BT. Acquired GT is often associated with lymphoproliferative or autoimmune disorders. Some antithrombotic therapy (e.g., abciximab, tirofiban) can induce GT.135 Siddiq et al.136 reviewed 40 pregnancies in 35 women with GT. Fifty percent had APH, 61% intrapartum bleeding, 34% primary PPH, 24% secondary PPH. The average time to secondary PPH was ten days. They recommended close postpartum observation and TXA for two weeks.136 Seventy-three percent received prophylaxis with platelet transfusion and a few rFVIIa. Maternal alloimmunization against platelets (73%) resulted in fetal thrombocytopenia and four neonatal deaths. Sixteen women had CD, but the anesthetic technique was not described.136 Neuraxial anesthesia is contraindicated in patients with GT.126 Prophylaxis with rFVIIa and TXA is recommended for vaginal delivery with platelet transfusion for CD.126 If platelet antibodies are present, plasma exchange may reduce neonatal risk. Wiskott-Aldrich Syndrome Wiskott-Aldrich syndrome (WAS) (X-linked) has a poorly understood pathophysiology. It occurs mainly in males and is associated with developmental defects of platelets, lymphocytes, and possibly other cell lineages resulting in immunodeficiency, thrombocytopenia, eczema, and susceptibility to malignancies. Platelets are typically small, and thrombocytopenia may cause severe bleeding requiring platelet transfusion. Typically, female carriers have no clinical signs, but occasionally females have microthrombocytes without other findings of the syndrome.125 There is one reported pregnancy with no delivery details; she had a preimplantation genetic diagnosis to select a female offspring.137 This disorder is more likely to have consequences for male neonates than pregnant carriers.

Receptor and Signal Transduction Disorders This heterogeneous group of inherited platelet disorders (normal platelet count and morphology, but abnormal function) occurs due to membrane receptor and cell signaling defects. Platelet aggregation or granule secretion can occur, but most have only mild bleeding.126 There are few published cases and even fewer with a pregnancy focus; collagen receptor defects are linked to recurrent spontaneous abortion,138 and thromboxane A2 receptor defects to IUGR.139 Due to their heterogeneous nature, specific recommendations cannot be given.126

Abnormalities of Platelet Granules There are three sub-sets of platelet storage pool deficiencies: dense granules, alpha granules, or both. Often these defects are seen as part of a more complex disease affecting multiple organ systems.126

Dense Granule Disorders Hermansky-Pudlak Syndrome This AR disorder manifests as oculocutaneous albinism, platelet granule abnormalities, and “ceroid” metabolism disorder.140 It is highly prevalent in Puerto Rico.126 Platelet count is normal, but platelet aggregation is impaired. Other clinical manifestations are pulmonary fibrosis, granulomatous colitis, and renal impairment.141 Severity of bleeding tendency is variable and can be life-threatening.141 At least eight different distinct genetic defects can cause the syndrome.126 Obeng-Tuudah et al. reviewed 29 pregnancies in 15 women with Hermansky-Pudlak syndrome (HPS):141 PPH led to a diagnosis in 29%; 44% had primary PPH. Of the 17 where HPS diagnosis was already known, nine had prophylaxis with DDAVP, and eight received a platelet transfusion; 33% had massive PPH (all in the DDAVP group, no PPH in platelet group). Thirteen cases described the anesthetic technique, and in 12 cases NA was avoided. One parturient with an unknown diagnosis, had an uncomplicated epidural, and four had GA for CD.141 Chediak-Higashi Syndrome This rare disease usually results in early death. It is an AR immunological disorder of neutrophil function. The syndrome exhibits oculocutaneous albinism, decreased leukocyte chemotaxis, susceptibility to infection, and childhood death. Neurological abnormalities also occur. There is one report of uneventful pregnancy and vaginal delivery with no mention of anesthesia.142 Alpha Granule Disorders Gray Platelet Syndrome A rare inherited qualitative disorder of platelet function, gray platelet syndrome (GPS) is associated with increased bleeding risk. The name derives from the gray appearance after Wright staining. The platelets are large with decreased or absent cytoplasmic (alpha) granules, and thrombocytopenia may be present. There is one report of anesthesia in two sisters.143 The first sister had thrombocytopenia and a GA for emergency CD. A postpartum investigation following PPH led to a diagnosis of GPS. Before that diagnosis was made, the second sister had a primary CD for oligohydramnios under spinal. She had another pregnancy after the GPS diagnosis requiring emergency CD under GA. Despite a platelet transfusion, she had a massive PPH (5200 mL).143 Another report discussed the possibility of using a TEG platelet mapping assay to provide reassurance before performing a spinal for CD.144 Despite a hypercoagulable result, GA was used. Jacobsen and Paris-Trousseau Syndrome Easley at el. summarize the anesthetic considerations for a patient with Jacobsen syndrome (JS) based on its associations: Paris-Trousseau thrombocytopenia (95%), dysmorphic features, cardiac anomalies (most frequently ventricular septal defect), and developmental delay.145 Paris-Trousseau syndrome is named for patients with JS who have the inherited platelet abnormality.

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Paris-Trousseau is associated with thrombocytopenia in infancy; platelet count improves with age, but platelet function does not. Platelets do not mature properly, and giant alphagranules are present. Associated bleeding is usually relatively mild.126 Few cases have been reported, just ten in children but none in pregnancy.126 Quebec Platelet Syndrome Factor V Quebec manifests as decreased Factor V in platelet alpha-granules but normal circulating levels.126 There are no obstetric cases described in the literature. Most present with severe hemorrhage following trauma.146 Alpha and Dense-granule Disorders This is a rare heterogeneous group, with few reports and little information specific to pregnancy to base recommendations.126

Disorder of Phospholipid Exposure Scott Syndrome Platelets in affected individuals have less ability to activate clotting factor on their surface. There have been no case reports in pregnancy. Mucosal bleeding is treated with TXA; platelet transfusion should correct the defect, and rFVIIa is an effective second-line therapy.126

Thrombotic Microangiopathies in Pregnancy Thrombotic microangiopathies (TMAs) seen in pregnancy are classified as pregnancy-related (PreE, HELLP, acute fatty liver of pregnancy (AFLP)) or pregnancy-associated (TTP, hemolytic uremic syndrome (HUS), lupus nephritis, sepsis). Microangiopathic hemolytic anemia (MAHA) and consumptive thrombocytopenia are key features of TMA; they cause microvascular thrombosis, resulting in end-organ ischemia and damage. The peripheral blood smear in these syndromes shows hemolysis (schistocytes and fragmented cells) and thrombocytopenia (Figure 21.3). Undetectable haptoglobin, high reticulocyte count, and disproportionately elevated LDH are also indicative.147

Figure 21.3  Peripheral blood smear with a microangiopathic syndrome demonstrating fragmented cells, schistocytes, and thrombocytopenia. (See color plate section).

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Pregnancy-related Thrombotic Microangiopathies Preeclampsia and Hemolysis, Elevated Liver Enzymes, and Low Platelets (HELLP) Twenty-one percent of parturients with thrombocytopenia have PreE: 50% of preeclamptic patients are thrombocytopenic.148 A subset of preeclamptic patients (2–12%) develops HELLP, a TMA associated with endothelial injury, fibrin deposition, platelet consumption, and hepatic hemorrhage with necrosis.149 Hypertension and proteinuria are not always prominent features of HELLP, even in those cases with severe thrombocytopenia. Complications include DIC (6%), placental abruption, acute kidney injury, pulmonary edema, cerebral hemorrhage, hepatic failure, liver rupture,150 and associated maternal (3–4%), and neonatal (25%) mortality.149 There is no absolute level of platelets regarded as safe for NA. In HELLP, the rate at which the platelet count falls is important as it may drop precipitously. Blood results need to be within six hours of NA.118,120 A stable platelet count of 70 x 109/L is likely more reassuring than a count that falls from 150 x 109/L to 80 x 109/L over six hours. In patients undergoing labor induction to manage severe PreE with evolving HELLP, there may be a time window to insert an epidural as platelet numbers decrease. The timing of epidural catheter removal is also vital as it presents a similar risk to insertion.118 There is insufficient clinical experience to show that TEG correlates or predicts neuraxial bleeding in cases of HELLP.150 Specific concerns with GA in severe PreE are precipitating pulmonary edema or maternal ICH with an exaggerated hypertensive response to intubation. Intracranial hemorrhage is the single most common cause of mortality in severely preeclamptic patients.151 Control of BP before anesthesia, short-acting agents to reduce pressor response (e.g., lidocaine, remifentanil) at induction and, if time allows, invasive arterial BP monitoring may reduce GA risk. In addition to avoiding the risks associated with GA, NA potentially improves fetal oxygen delivery by reducing uteroplacental resistance and increasing intervillous blood flow.150 Koyama et al. reported a subarachnoid hematoma in a patient with severe PreE and HELLP.152 Preoperative blood work two hours before surgery was reassuring (platelets 91 x 109/L, coagulation normal), so a spinal was inserted “without difficulty.” The platelet nadir (26 x 109/L) occurred on day 1, necessitating a platelet transfusion. The patient initially had full neurological recovery but developed urinary retention and mild flaccid paraparesis on day two. MRI demonstrated a hematoma with cauda equina compression. Conservative management led to a full recovery in three months. Several retrospective reviews report neuraxial outcomes in patients with HELLP.153–156 Overall there were 248 patients; 52 GA (platelet range 27–140 x 109/L), 75 epidurals (19–143 x 109/L), 53 CSE (46–149 x 109/L) and 20 spinals (55–146 x 109/L). One epidural hematoma was reported (platelets 93 x 109/L).155 A report from Sweden described four spinal hematomas in obstetric patients. All had signs of coagulopathy: two HELLP, one post spinal, and one after epidural catheter removal.157 ACOG recommends platelet transfusion in PreE for active bleeding or to aim for a platelet count > 50 x 109/L before CD.

Disorders of Blood, Coagulation, and Bone Marrow

ACOG noted that the half-life of transfused platelets in PreE is decreased because of destruction.121 Acute Fatty Liver of Pregnancy A rare disease, AFLP has significant morbidity and mortality (1:20,000 pregnancies).149 Similar to PreE, AFLP is more common in primiparous women or multi-gestation pregnancies and likely results from underlying mitochondrial dysfunction.149 Presentation is often nonspecific but may progress rapidly to overt liver failure with jaundice and coagulopathy. It can mimic PreE and HELLP. The Swansea diagnostic criteria are helpful, and antithrombin levels (< 65%) may distinguish AFLP from HELLP.149 Fifteen to twenty percent of cases of AFLP are associated with MAHA.158 Management of AFLP is supportive; treating hypoglycemia, coagulopathy, renal impairment, and neurological symptoms (encephalopathy, confusion, seizures, and coma) (Chapter 14). Pregnancy-associated Thrombotic Microangiopathies These can all also occur in nonpregnant women. Thrombotic Thrombocytopenic Purpura and Hemolytic Uremic Syndrome Thrombotic thrombocytopenic purpura and hemolytic uremic syndrome have similar pathophysiology. Neurological dysfunction is more likely with TTP, and renal dysfunction is more likely with HUS. These disorders can occur at any time during pregnancy (incidence 1:200,000). Although TTP is the commonest cause of TMA in early pregnancy, it most frequently occurs in the third trimester, while HUS tends to occur in the postpartum period.159,160 In TTP, there is a deficiency in ADAMTS13, which is required to cleave vWF. Although TTP is usually an autoimmune phenomenon (90%), the rarer congenital form (5–10%) is more common in pregnancy.159 Pregnancy is associated with up to 5% of cases of TTP.160 It is postulated that the increase in vWF seen during pregnancy triggers TTP, as it decreases ADAMTS13 to below a critical level.147,160 Diagnosis of TTP/HUS in pregnancy can be challenging. The presentation can be nonspecific and challenging to distinguish from more prevalent diagnoses (e.g., HELLP); TTP can coexist with these diseases.159,160 The correct diagnosis is essential for deciding when to deliver the baby; the maternal condition will improve with delivery in HELLP, but not TTP. Features supporting TTP over HELLP include more profound thrombocytopenia (< 50 x 109/L) that does not rebound postpartum, a markedly elevated LDH, and normal coagulation studies. Diagnosis of TTP in pregnancy requires ADAMTS13 activity levels < 10%. ADAMTS13 antibodies may be demonstrated in autoimmune mediated disease, while confirmation of congenital TTP requires genetic analysis.159 Thrombotic thrombocytopenic purpura may be underdiagnosed. One study suggests 5% of pregnant women with a platelet count < 75 x 109/L had congenital TTP.159 Thrombotic thrombocytopenic purpura is associated with poor pregnancy outcomes due to placental infarction and insufficiency related to the disease process (40–50% risk of spontaneous abortion). Regular plasma therapy (infusion or exchange) can reduce these risks.159

Treatment of autoimmune TTP in pregnancy includes plasma exchange and immunosuppressants, so consider biological agents in resistant cases (e.g., rituximab).159 If fetal compromise (IUGR) exists, consider low dose aspirin and prophylactic heparin after platelet counts recover. Manage congenital TTP with regular plasma infusions and continue therapy postpartum. As TTP can recur, early prophylactic plasma infusions are beneficial in subsequent pregnancies.159,160 Theoretically, platelet transfusions may worsen TTP by precipitating widespread thrombosis. However, before receiving a TTP diagnosis, many patients receive platelets without untoward effects.147 Treatment of HUS is partly supportive. In one study, 80% of pregnant women with HUS required renal replacement therapy at presentation; 60% developed end stage renal disease within one month.159 Plasma exchange and immunosuppressive therapy (including biological agents) are useful.159 A parturient with undiagnosed TTP had a platelet count of 277 x 109/L during pregnancy. Following spinal anesthesia for emergency CD, the platelet count was 7x109/L. Once known, the patient received a platelet transfusion. Postpartum, transient neurological symptoms, and acute kidney injury developed. Treatment was a nine-day course of corticosteroids and plasmapheresis. She required two further treatment courses plus rituximab for relapses.147 Antiphospholipid Syndrome Antiphospholipid syndrome (APLS) is associated with predominantly recurrent large vessel venous and arterial thrombotic events, although microangiopathic thrombosis can occur.161 There appears to be crossover and an increased risk of HELLP and DIC in patients with APLS.161 A pregnant woman with APLS had a history of recurrent spontaneous abortion and VTE. She presented with APH and abruption and subsequently developed HELLP.161 She was successfully managed with plasmapheresis and IVIG.

Miscellaneous Platelet Disorders Sticky Platelet Syndrome The molecular cause of sticky platelet syndrome (SPS) (an AD disorder associated with arterial and venous thrombosis) is unknown.162 Presentation of SPS may be acute MI or transient cerebral ischemic attacks. Obstetric complications include IUGR and recurrent spontaneous abortion.162 There is one report of a 24-year-old woman who had a MI during the third trimester.162 She had a cardiac family history; her mother had MI during pregnancy, and an 18-year-old brother, angina. Her platelets and those of her symptomatic family members were hyperaggregable with ADP and epinephrine, diagnostic for SPS. Low-dose aspirin is adequate prophylaxis for platelet aggregation. Anesthetic management of pregnant women with SPS on low-dose aspirin is the same as normal parturients. Fetal and Neonatal Alloimmune Thrombocytopenia Fetal and neonatal alloimmune thrombocytopenia (FNAIT) occurs similarly to Rhesus incompatibility and hemolytic disease of the newborn but involves platelets, not RBCs. Maternal platelet-specific alloantibodies cross the placenta and act against

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paternal antigens on fetal platelets.163 The fetus/neonate may develop severe thrombocytopenia; 10–20% of severely affected newborns have ICH, 80% in utero.163 A diagnosis of FNAIT often occurs while investigating a neonate with unexplained thrombocytopenia, hemorrhage, or ICH.121 Maternal prophylactic corticosteroids and regular IVIG (weekly) can increase fetal platelet count.163 Although multiple platelet antigens can cause FNAIT, the most severe disease is associated with HPA-1ab polymorphism (not present in those with Chinese or Japanese ethnic origins).163 There are no specific anesthetic considerations for the mother of a fetus/neonate with FNAIT. It will, however, influence obstetric delivery planning and neonatal management (potential platelet transfusion or IVIG).163

Table 21.10  Considerations for pregnant patients with factor deficiencies

Factor Deficiencies

Associated neonatal disease

There are several reviews on factor deficiencies in pregnancy164-174 and anesthetic concerns.120,175–179 Valuable Clinical Insights Anesthetic Management of Patients with Congenital Coagulopathies • All patients diagnosed with a congenital coagulopathy benefit from early consultation with a hematologist and anesthesiologist. This allows for disease assessment and planning for labor and delivery. • Suitability of NA is based on a risk benefit analysis and clinical manifestations for that particular woman. Assess the phenotypic expression of the deficiency, changes in factor levels throughout pregnancy, and response to treatment.

Except for vWD, most inherited clotting deficiencies are rare, and there is a paucity of high-level evidence on specific obstetric anesthetic management. Case reports, series, and expert consensus provide management guidance (Table 21.10). Peterson et al. reported cases of NA in adults with bleeding disorders.180 If there is evidence of clinically significant bleeding, you should avoid NA. However, do not deny the benefits of NA to women with factor deficiencies who have no history of a bleeding tendency, who have received appropriate product replacement, and have normal coagulation parameters (aPTT, INR, and possibly TEG/ROTEM). If proceeding with NA, additional precautions to reduce maternal risk include: • written documentation of discussions (including alternative techniques) and consent • most experienced anesthesiologist • preprocedural US • for LEA, use the lowest concentration and dose that is effective (reduce motor blockade) • spinal is less risk than an epidural (smaller needle, no residing catheter) • avoid NSAIDs peripartum • active, regular monitoring and documentation of lower limb neurological recovery • if unanticipated motor block or inadequate recovery: urgent MRI.

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Disease-specific

•

Phenotypic expression, severity of associated bleeding tendency (personal or family history)

• •

Is factor level predictive of bleeding risk (quantitative vs. qualitative)?

• •

What options are available for factor replacement?

Monitoring the disease: formal coagulation tests or POC testing (TEG, ROTEM)? What is the factor half-life, how frequently is replacement required?

Obstetric complications

• • • • •

Spontaneous abortion APH PPH Antepartum screening Risk of ICH - relative trauma from mode of delivery - avoid vacuum or midcavity forceps-assisted deliveries

•

Avoid fetal scalp electrode

Anesthetic complications

• • • •

Risk of epidural hematoma with NA Care with IM injections and hematoma risk Care with NSAIDs Consider TXA

Fibrinogen (Factor I) Deficiency Fibrinogen, factor I (FI), is a protein synthesized in the liver, with a half-life of approximately four days. Thrombin catalyzes the conversion of fibrinogen to fibrin, and FXIIIa helps polymerize fibrin into an insoluble, stable clot. Inherited fibrinogen deficiency can be either quantitative: afibrinogenemia (total absence), hypofibrinogenemia (decreased levels [< 1g/L]), or qualitative: dysfibrinogenemia (abnormal function). Plasma fibrinogen levels normally increase from a baseline of 2–4 g/L to 4–6g/L in pregnancy.6 Periodic transfusions of fibrinogen may prevent spontaneous abortion (aim to maintain > 0.6g/L).181 Regular US assessments monitor for concealed abruption. Dysfibrinogenemia can be associated with a bleeding tendency or a prothrombotic state. Patients with a personal or family history of thrombotic events may need heparin prophylaxis. Valuable Clinical Insights Acquired Hypofibrinogenemia is Associated with Hemorrhage • Hypofibrinogenemia is the most common clotting defect with PPH; levels fall proportional to EBL. • Placental abruption is associated with hypofibrinogenemia. • After PPH is diagnosed, a fibrinogen level predicts disease severity.6 • Rapid identification and correction of hypofibrinogenemia (< 2g/L) improves outcomes.6 • Mean fibrinogen with hemorrhage6 EBL > 2000 mL < 4g/L

Disorders of Blood, Coagulation, and Bone Marrow

• •

• • •

EBL > 4000 mL < 2g/L Predictor of outcome6 Fibrinogen < 2g/L early in PPH is associated with: Fall in Hb of 4 g/L Requiring > 4 units RBC or massive transfusion Replacement Fibrinogen concentrate (50 mg/kg increases levels by 1 gm/L)181. Cryoprecipitate (10–20 units increase levels by 0.6–1.2 gm/L).165

Fresh frozen plasma (FFP) is not used to replace fibrinogen since12 mL/kg FFP only increases plasma fibrinogen by 0.4 g/L. In acute PPH, plasma fibrinogen levels may decrease because of a dilutional effect from the volume of FFP required.6

Factor II (Prothrombin) Deficiency Factor II (FII) (prothrombin) is vitamin K-dependent and synthesized in the liver. Factor II is necessary for converting fibrinogen to fibrin, aggregation of platelets, activation of plasminogen, thrombin activatable fibrinolysis inhibitor, factors V, VIII, XI, and XIII, and Protein C in the presence of thrombomodulin. Factor Xa activates FII on the surface of platelets in the presence of FV and calcium. Factor II deficiency can be quantitative: type I (hypoprothrombinemia), or qualitative: type II (dysprothrombinemia). Patients with prothrombin deficiency typically present with mucosal, soft tissue, joint, and surgical bleeding.165,167

Factor V Deficiency Factor V (FV) is made in the liver and megakaryocytes; it plays a key role in coagulation. Platelets usually contain ~ 20% of circulating FV. Thrombin activates Factor V which then acts as a cofactor for FXa, converting prothrombin to thrombin (FII to FIIa). Protein C downregulates Factor Va in order to maintain normal hemostasis.165,167 Test for FVIII in patients with FV deficiency to rule out a combined defect.

Factor VII Deficiency Factor VII (FVII) is a vitamin K-dependent plasma glycoprotein. Circulating FVII binds to tissue factor, exposed when there is endothelial damage. FVII then becomes activated and, in turn, activates FX and FXI, generating thrombin and initiating coagulation. FVII levels increase during pregnancy, but whether this happens in women with FVII deficiency is unclear. There is a poor correlation between laboratory values and bleeding risk; clinical history of bleeding best predicts PPH risk.165,167

Von Willebrand Disease Von Willebrand factor (vWF) facilitates platelet adhesion and is a carrier protein for FVIII. There are three main subtypes of vWD.182,183 Type 1 (80%) is a quantitative deficiency; levels usually normalize during pregnancy, returning to baseline rapidly postpartum. There are four subsets of type 2, all qualitative, so although levels may increase in pregnancy, the abnormality will persist (2a, 2b, 2m, 2n). Type

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3 (5–10%) is the most severe form where vWF is absent; the associated decrease in FVIII presents similarly to hemophilia. When needed, DDAVP 0.3 mcg/kg is the treatment of choice, except for type 2b. In type 2b an increase in vWF function leads to platelet aggregation and thrombocytopenia, both worsened by DDAVP. In type 3, DDAVP will not increase vWF. Infusion of DDAVP results in the release of vWF from the endothelium and an immediate two- to three-fold rise in plasma levels of both vWF and FVIII. A DDAVP challenge investigates the magnitude and duration of response. A subgroup of type 1 patients respond to DDAVP but the increase is not sustained, since their deficiency results from increased clearance.184 In patients with significant disease who respond to DDAVP, vWF:FVIII concentrates (e.g., Humate-P) are recommended. Pacheco et al. summarize the clinical care of vWD in pregnant women, including a suggested treatment algorithm.185 James and Kouides are valuable resources on vWD in pregnancy.186,187

Factor VIII Deficiency (Hemophilia A) Women are carriers of this X-linked recessive disease. Although anticipated to have 50% of normal levels, some women have lower levels because of lyonization (inactivation of gene expression).167,182 Low levels may cause bleeding in 10–30%. FVIII levels usually increase markedly in pregnancy, up to ten times.182 A combination of activated FVII and activated FIX forms the “tenase” complex, which activates FX. If the fetus is affected there is a risk of ICH, so delivery plans may need to be modified. The risk is greater with vacuumassisted delivery and lowest with CD; consider the mode of delivery in the context of maternal risks. The risk of ICH is relatively low in unassisted vaginal delivery.188 “Hemophilia with inhibitors” refers to a disease caused by antibodies directed against FVIII. There are acquired forms of hemophilia sometimes associated with an underlying medical disorder (e.g., lymphoproliferative, autoimmune disease). About 14% of acquired cases of hemophilia are “postpartum,” possibly triggered by exposure to fetal FVIII. This is a rare condition (0.2–1 cases/million).189 Up to one-third of patients with severe hemophilia develop antibodies (or inhibitors) to blood products (rFVIII, plasma concentrates). Patients with inhibitors may require immunosuppressive therapy or plasmapheresis.190 Dewarrat et al. reviewed postpartum acquired hemophilia (174 cases): 57% needed FFP, factor concentrate, or bypassing agents (activated prothrombin complex concentrates or rFVIIa); most received corticosteroids; 25% required other immunosuppressive therapy; 22% had a relapse in subsequent pregnancies. 191

Factor IX Deficiency (Hemophilia B, Christmas Disease) This X-linked recessive bleeding disorder is clinically indistinguishable from FVIII deficiency (hemophilia A). Unlike hemophilia A, factor IX (FIX) levels do not rise during pregnancy, so pregnant carriers with low FIX levels are at increased risk of bleeding peripartum and are more likely to require factor replacement.164 DDAVP is of no benefit.

Factor X Deficiency Factor X (FX) is activated by activated FVII and the tenase complex (activated FVIII and IX). Activated FX with activated FV

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forms a prothrombinase complex which triggers thrombin production from prothrombin. The severity of disease in FX deficiency strongly correlates with plasma levels, < 1 iu/dL is severe (spontaneous bleeds), moderate 1–5 IU/dL (PPH, bleeding after trauma, surgery), and mild 6–10 IU/dL (usually asymptomatic). FX levels typically increase with pregnancy. FX replacement is generally unnecessary if the FX > 10 IU/dL or a lower level with no bleeding history.165,167

Factor XI Deficiency The bleeding tendency does not correlate well with plasma levels; the patient’s risk involves a detailed personal and family history.165,167 Factor XI (FXI) deficiency is associated with Noonan syndrome, Gaucher syndrome, vWD, FVIII deficiency, and FVII deficiency. Factor XI levels typically decrease during pregnancy, in contrast to most other factors. Depending on the level of FXI at term, these patients may require factor replacement. Replacement factors are used if there is a history of bleeding. Wheeler et al. present an algorithm for product replacement based on disease severity, mode of delivery, and NA considerations.192 Pregnant women who are heterozygous for FXI deficiency have been evaluated with TEG.193 In one study where plasma levels of FXI were lower, coagulopathy was not demonstrated with TEG, and the results were normal for term pregnancy. The use of TEG may support NA in these patients, but it is not clear if TEG results reflect a clinical bleeding risk. Several studies have shown that ROTEM does not distinguish between clinical “bleeders” and “non-bleeders.”193

Factor XII Deficiency The clinical effects of Factor XII (FXII) deficiency are debatable, and potentially prothrombotic.

Factor XIII Deficiency Thrombin activates Factor XIII (FXIII), which in turn promotes fibrin polymerization to create a stable thrombus that is more resistant to fibrinolysis. FXIII also has a role in wound healing and placental attachment.165,167 Factor XIII consists of two subunits, and depending on which subunit is deficient, there are three subtypes. Severe deficiency without treatment often causes spontaneous abortion; factor replacement throughout pregnancy can lead to a viable newborn.194

Combined Deficiencies Combined Factor V and Factor VIII Deficiency A point mutation on a protein common to FV and FVIII leads to deficiencies in both factors.167 Typically, the levels of FV and FVIII in the combined deficiency are higher than those seen in isolated deficiencies; therefore, the associated bleeding is usually less severe. There are limited data regarding pregnancy. Bleeding is more likely dependent on FV levels as FV does not consistently increase during pregnancy, unlike FVIII levels. FFP contains both FV and FVIII, but with replacement, FVIII has a shorter half-life. Higher plasma levels are ideal for hemostasis, so additional or more regular FVIII supplementation may be needed.165,167

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Vitamin K-dependent Clotting Factors Inherited Deficiency (VKCFD, Borgschulte-Grigsby Deficiency) There are few case reports of an AR combined deficiency of the vitamin K-dependent clotting factors (FII, FVII, FIX, FX) and anticoagulants (protein C and S). Individuals with this disorder experience a wide variation in bleeding tendency. There is prolongation of PT and aPTT, dependent on how much the activity of the different factors is reduced. Most individuals show some improvement with vitamin K therapy. Occasionally factor replacement is necessary. A single report of vitamin K-dependent clotting factors inherited deficiency (VKCFD) during pregnancy, managed with oral vitamin K, described FFP use for persistent bleeding after an episiotomy.195 Table 21.11 summarizes the various factor deficiencies, the obstetric considerations and the details for blood product replacement. Table 21.12 contains notes on the available literature on various factor deficiencies in pregnancy and their management.

Disseminated Intravascular Coagulation Thachil et al. and Montagnana et al. reviewed disseminated intravascular coagulation (DIC) in pregnancy.245,246 Disseminated intravascular coagulation occurs when the process of hemostasis becomes unbalanced. It involves widespread activation of coagulation, resulting in fibrin deposition, microvascular thrombosis, and multiorgan failure. A consumptive coagulopathy and thrombocytopenia follow. Hemorrhage or thrombosis are both possible presentations of DIC.247 Pregnancy is a hypercoagulable state which predisposes to DIC as physiological anticoagulant pathways are impaired; coagulation is already “not normal.” 245,248 A 30-year retrospective database review of DIC found an incidence of 3:10,000 deliveries (n = 151, 678),247 with high maternal and fetal morbidity and mortality: 41% ICU admission 6% required renal replacement therapy 6% maternal death (1:50,000 deliveries) 25% stillbirth (placental abruption highest risk) 5% neonatal death 72% of neonates required NICU. The International Society on Thrombosis and Haemostasis defines DIC with a scoring system based on the severity of thrombocytopenia, elevated fibrin marker, prolonged PT, and the severity of hypofibrinogenemia.249 Applying this to the pregnant population can be challenging since fibrin degradation products are unreliable, and baseline fibrinogen levels are higher in pregnancy. In pregnancy, the trend over time is more valuable than results at a single time point.250 The placenta is a rich source of tissue factors responsible for activating the extrinsic coagulation pathway. Fetal trophoblastic cells within the placenta also suppress fibrinolysis (plasminogen activator inhibitor) and alter anticoagulant function.245 The DIC process is relatively localized to the uteroplacental unit, which

https://doi.org/10.1017/9781009070256.022 Published online by Cambridge University Press

Table 21.11  Summary of factor deficiencies including obstetric considerations and details for product replacement

Factor deficiency

Incidence and inheritance

Testing

Obstetric considerations

Product replacement and other therapeutic options

Bleeding severity correlation with laboratory testing165

Half-life of clotting factor

PT

aPPT

Specific

FI Fibrinogen

Afibrinogenemia and hypofibrinogenemia AR 1:1,000,000 Dysfibrinogenemia can be AD, incidence unknown, more common than afibrinogenemia

Increased

Increased

Fibrinogen concentration Immunoassay and functional testing (Clauss method)

Spontaneous abortion181 APH PPH Impaired wound healing Afibrinogenemia Severe hemorrhage Hypofibrinogenemia Milder symptoms, may be asymptomatic Dysfibrinogenemia196 Asymptomatic (55%) Hemorrhage (25%) Thrombosis (20%)

Acute hemorrhage aim > 2g/L Fibrinogen Concentrate 50 mg/kg increases levels by 1 g/L Cryoprecipitate 10–20 units increases levels by 0.6–1.2 g/L (FFP)

Quantitative Strong Qualitative Weak

2–4 days

FII Prothrombin

Rarest inherited bleeding disorder AR 1:2,000,000

Increased

May be increased

FII assay FII antigen (distinguish qualitative and quantitative)

Type I Spontaneous abortion APH PPH Type II Variable May be asymptomatic or mild bleeding

PCC 20–30 IU/kg will increase 4–6 IU/dL FFP 15–20 mL/kg will increase by 3–4 IU/dL

Strong

2–3 days

FV Owren disease Parahemophilia

AR 1:1,000,000

Increased

May be increased

FV assay FV antigen (distinguish qualitative and quantitative)

PPH (55–75%)164,167

FFP 15 mL/kg increases plasma level by 1.5 IU/dL (maintain 5–7 days post CD for wound healing)

Weak

16–36 hours

FVII

Most common of rare inherited deficiencies AR 1:300,000 to 1:500,000

Increased

Normal

FVII assay FVII antigen (distinguish qualitative and quantitative)

Homozygotes most at risk of severe bleeding (typically levels < 10 IU/dL) Spontaneous abortion APH PPH 10% in those with a history of bleeding165 (15% risk ICH in affected neonates)167

rFVIIa FVII Concentrate PCC FFP Short half-life, needs regular redosing 4–6 hourly for 3 days after vaginal or 5 days after CD

Weak PPH correlates with history of other significant bleeding events (10% risk)165,197

2–8 hours

vWD

Commonest inherited deficiency AD 1% of the population (clinically significant disease 1 in 10,000)182

Subtype diagnosis:198 Amount: vWF:Ag Function: ristocetin cofactor activity assay (vWF:RCo)199 vWF:Collagen binding activity (2 n) FVIII assay

Spontaneous abortion APH (especially first trimester) PPH (OR 1.5) (Type 1 secondary PPH, type 2 primary and secondary PPH)164

DDAVP (responders, not type 2b) vWF:FVIII concentrates (e.g., Humate-P®, Wilate®, Alphanante®) Cryoprecipitate FFP (platelets in Type 2b)

n.b. type 1c – increased “clearance” of vWF leads to decreased half-life184

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Table 21.11 (cont.)

Factor deficiency

Incidence and inheritance

Testing

PT

aPPT

Specific

Obstetric considerations

Product replacement and other therapeutic options

Bleeding severity correlation with laboratory testing165

Half-life of clotting factor

FVIII Hemophilia A

X-linked Most affected women have 50% normal levels, some less (lyonization) 1 in 5000 male births167

Normal

Increased

FVIII assay Distinguish from vWD: vWF:Ag and vWF:RCo Screen for inhibitors

Women with low factors risk of APH mostly first trimester (levels usually increase during pregnancy) 48% risk of PPH especially secondary PPH as levels fall back to baseline rapidly postpartum200 Male fetus 50% chance of disease and 4% chance of ICH164

DDAVP rFVIII FVIII concentrate

Strong

10–14 hours

Combined FV and FVIII

AR 1:2,000,000

Increased

Increased

FV assay FVIII assay

Spontaneous abortion Abruption PPH

FFP and rFVIII or FVIII concentrate DDAVP

Weak

FV 16–36 hours FVIII 10–14 hours

FIX Hemophilia B

X-linked Most affected women have 50% normal levels, some less (lyonization) 1 in 30,000 male births167

Normal

Increased

FIX assays Screen for inhibitors

PPH

rFIX FIX concentrate

Weak

25 hours

FX StuartPrower Factor deficiency

AR 1 in 1 million

Increased

Increased

FX Assay FX:Ag (distinguishes qualitative from quantitative)

Spontaneous abortion APH PPH

FX Concentrate PCC FFP

Strong

30–40 hours

FXI Hemophilia C

Mostly AR 1 in 1 million 1 in 190 individuals of Ashkenazi Jewish Heritage (Rarely AD)

Normal

Usually Increased

FXI assay FXI:Ag (distinguishes qualitative from quantitative)

PPH primary and secondary

FXI Concentrate rFVIIa (especially if inhibitors present) TXA FFP

Very weak Personal history of bleeding better predictor than plasma level201

45–50 hours

FXII

AR Mild deficiency 1.5–3%202 Clinically significant disease rare

Normal

Increased

FXII assay

Not normally associated with clinically significant bleeding Spontaneous abortion Possible link to thrombosis

FFP

Weak

60 hours

FXIII

AR 1 in 2 million

Normal

Normal

FXIII assay Immunoassay for FXIII-A and B subunits.

Spontaneous abortion (type 2 deficiency 90%)165 APH Abruption170 PPH (especially Type 1 and 3)

rFXIII FXIII concentrate Cryoprecipitate FFP

Strong

10–20 days

Abbreviations: FFP = fresh frozen plasma (all clotting factors); PCC = prothrombin complex concentrate (FII, FIX, FX (some preparations also contain FVII)).

Disorders of Blood, Coagulation, and Bone Marrow

Table 21.12  Summary of available literature for specific factor deficiencies in pregnancy

Factor deficiency

Notes on reported cases in the literature

FI Fibrinogen

Uncomplicated epidural insertion in woman with afibrinogenemia with regular replacement throughout pregnancy203 Spinal anesthesia in a patient prior to diagnosis or recognition of dysfibrinogenemia204 Hypofibrinogenemia (0.4 g/L) who had uneventful epidural analgesia180 Case series of 4 asymptomatic women (diagnosed because of sibling or offspring history, or recurrent spontaneous abortions). All received fibrinogen and FFP prophylaxis for uncomplicated CSE for elective CD205

FII Prothrombin

One report: 8 pregnancies in one woman. 4 spontaneous abortions, 1 complicated by PreE and PPH despite FFP prophylaxis (required further FFP and PCC for treating PPH), remaining 3 vaginal deliveries with prophylactic PCC. The mother had a spontaneous subarachnoid hemorrhage in 1 pregnancy206

FV Owren disease Parahemophilia

Case series207 Heterozygotes: 15 pregnancies in 11 women; uneventful Homozygotes: 5 women with 3 pregnancies 1 CD with prophylactic FFP, no discussion anesthetic technique 1 patient diagnosis was made following a PPH (no prophylaxis) Summary of case reports207 11 of 18 required FFP for PPH (7 received prophylactic FFP) Concluded bleeding most commonly seen at < 25% activity, and rare in heterozygotes One report of 10 pregnancies in 5 homozygous patients. 4 CD under neuraxial with FFP (continued 3–8 days postpartum)208

FVII

Comprehensive summary of cases with obstetric rather than anesthetic focus (56 cases)197 Multiple reports of uncomplicated neuraxial procedures in pregnant women. 5 with FVIIa infusion,164,209 8 before diagnosis made209 Four cases identified in a retrospective review having NA, all without prophylaxis, or complication.180 One report of 2 pregnancies in same mother with inhibitors causing deficiency210

vWD

One analysis identified 18 studies investigating NA in obstetric patients with vWD.180 Five studies reported patients with type 1, 2 in type 2, rest unspecified In total 134 procedures (mix of spinal, epidurals, one CSE) Prophylaxis with DDAVP or vWF/FVII concentrate variable, details of rationale for use not always included Overall procedures were performed at ranges of plasma levels: vWF 10–198 IU/dL and FVIII 38–249 IU/dL. No epidural hematomas Only one study reported consideration of levels for epidural catheter removal Majority of reviews recommended a threshold for vWF and FVIII of 50 IU/dL for NA180 Largest case series published, with a specific anesthesia focus (published after Peterson review)211 No anesthetic complications observed. Type 2 higher risk and more likely to receive Humate-P® Type 1 vWD Out of 87 deliveries Vaginal delivery 39 epidurals, 5 CSE, 1 Spinal: 18 received DDAVP and 1 Humate-P® CD 10 epidurals, 3 CSE, 21 Spinals Type 2 vWD Out of 7 deliveries Vaginal delivery 2 epidurals, 5 received Humate-P® CD 1 CSE, 2 GAs Unknown Type vWD Out of 12 deliveries Vaginal delivery 4 epidurals, 2 CSEs: 3 received DDAVP CD 1 CSE, 5 spinals Separate systematic review of type 3 vWD212 28 pregnancies in 17 women with type 3 vWD 19 received factor concentrate pre-delivery, 8 postpartum. 48% primary PPH, 56% secondary PPH. 11% received LEA (no reported complications), 32% NA was avoided because of concerns for epidural hematoma. Specific case reports of interest Case report and discussion: Type 2a (uncomplicated labor epidural after Humate-P® infusion (previously no response to DDAVP), patient failed to progress and required a CD under epidural-top-up, given further doses of Humate P® prior to CD and for treatment of PPH)213 Case report and discussion: Type 2b, CD for breech presentation under GA (platelets 30 x 109/L), given rFVIII and platelets214 Case report and discussion: Type 2m previous CD under GA, minimal bleeding history, Mallampati 4 airway noted, uncomplicated spinal (given DDAVP after delivery)215 Case report Type 3 vWD in 2 CDs (same patient). Both under spinal without complication. Received prophylaxis with Humate P® (bolus 60 IU/kg and infusion 3 IU/kg/hr) targeting vWF and FVIII levels > 0.5 IU/mL, as well as TXA216 Case report of subtype: Type 1C, deficiency caused by rapid clearance of vWF, reducing its half-life. Repeated doses of FVIII/vWF concentrate required during labor to facilitate safe LEA184

FVIII Hemophilia A

Multiple cases of NA (> 100). Most follow guidelines169 that NA is safe if coagulation screen is normal and target FVIII replacement > 50 IU/dL180,182,217–219 Lowest factor level that NA reportedly was performed is 76 IU/dL180

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James P.R. Brown and M. Joanne Douglas

Table 21.12 (cont.)

Factor deficiency

Notes on reported cases in the literature

Combined FV and FVIII

Four case reports in pregnancy. Both received product replacement (one FFP and FVIII concentrate,220 one FFP, DDAVP and FVIII concentrate,221 one rFVIII and TXA222) One case, no mention of anesthetic technique.221 One case, received fentanyl.220 One case, NA considered too high-risk despite factor replacement and normalization of coagulation studies, patient given remifentanil PCA222 There is a report from nonobstetric practice of rFVIIa treating resistant surgical bleeding223

FIX Hemophilia B

Several cases of pregnancy reported, anesthetic management is not mentioned224,225 One study reported three LEA insertions 1 with rFIX and 2 without prophylaxis Proposed minimum level for neuraxial procedure 50 IU/dL180

FX Stuart-Prower factor deficiency

One report epidural with PCC administration guided by thrombin assay226 Two CD under GA with FFP227,228 Several case reports of pregnancy/deliveries without mention of anesthesia175 Five CD with PCC229–232 (2 placental abruption),229,231 1 CD with prophylactic FFP233 Vaginal delivery Seven no prophylaxis,234–236 2 FFP,237,238 4 PCC,226,239,240 3 PPH, one with hysterectomy236,238,240 Of note: 1 fetus suffered subdural hemorrhage235

FXI Hemophilia C

113 reports of uncomplicated NA summarized in Wheeler192 and Davies241 61 with product replacement (FFP, FXI concentrate, rFVIIa, TXA). Remainder (those without bleeding history) had no prophylaxis Many instances diagnosis not known at the time of NA One review found LEA placed at 5–74 IU/dL without epidural hematoma180 Consensus that bleeding history most important factor when considering NA180 One CD with GA for deficiency with inhibitor treated with rFVIIa242

FXII

No reported obstetric cases found

FXIII

There are several reports of CD, generally anesthetic technique is not described243 One report suggesting that NA safe if FXIII “adequately” replaced, not further defined180 One report uncomplicated spinal for CD combined hypofibrinogenemia and FXII deficiency (48%). With product replacement (fibrinogen and rFXIII) guided by ROTEM244

Abbreviations: FFP = fresh frozen plasma (all clotting factors); PCC = prothrombin complex concentrate (FII, FIX, FX (some preparations also contain FVII)).

spills into the systemic circulation rather than a true disseminated process.245 Hence, removing the placenta is key to treating DIC.245 Management of DIC in pregnancy is based on expert consensus and tailored to the individual patient and clinical scenario. The primary aim is to treat the underlying obstetric condition, with additional therapy to support coagulation provided as indicated.245,248 When there is no bleeding, plasma or clotting factor replacement is unnecessary. Suggested triggers for replacement in DIC with active bleeding are: • platelets < 50 x 109/L (if not bleeding, tolerate lower threshold 20 x 109/L) • PT or APTT > 1.5 (administer FFP 10–20 mL/kg, if volume overload a concern use non-activated PCC) • Fibrinogen > 1 g/L (potentially higher in pregnancy, use fibrinogen concentrate or cryoprecipitate)245,246 A review investigating rFVIIa in patients with DIC from amniotic fluid embolism (AFE), demonstrated increased mortality in those receiving rFVIIa, perhaps because they had more severe disease.248 Hemorrhage from DIC is common in obstetrics, but thrombotic complications are rare. Several anticoagulant therapies (heparin, anticoagulant factor concentrates, antithrombin) exist in obstetrics. However, no one therapy has shown better clinical outcomes.245,246 Anticoagulants are reserved for overt thromboembolic events from DIC or for prophylaxis in patients with DIC without overt hemorrhage or thrombosis.251

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Disseminated intravascular coagulation is not a disease in itself but a complication of other diseases. Several obstetric conditions precipitate the imbalance in hemostasis via different mechanisms, leading to DIC (Table 21.13). Up to 10% of placental abruptions are associated with DIC.247,248 Hemorrhage occurs when the placenta prematurely separates, allowing placental tissue factor into the maternal circulation, precipitating DIC.245 Following an abruption, the degree of fibrin formation and thrombocytopenia is proportional to the extent of placental separation.245,248 In massive PPH, tissue factor released from traumatized endothelium, clotting factor consumption, volume resuscitation, Table 21.13  Conditions associated with disseminated intravascular coagulation in pregnancy Placental abruption (37%) * [1.1%] † Massive hemorrhage (29%) * [0.2%] † PreE/HELLP (14%) * [0.2%] † Acute fatty liver (8%) * Sepsis (6%) * AFE (6%) * IUFD Retained products of conception * Percentage of DIC cases by diagnosis. From Rattray et al.; 30-year retrospective analysis; one Tertiary centre.247 † Percentage of cases with the underlying obstetric condition that developed DIC.247

Disorders of Blood, Coagulation, and Bone Marrow

hypocalcemia, acidosis, and hypothermia conspire to cause DIC. Aggressive, timely, formula-driven resuscitation (1:1:1, RBCs: FFP: platelets) and early fibrinogen replacement reduces progression to DIC.245 In an extensive review, 64% of DIC from PPH had a hysterectomy to manage blood loss.247 Although not commonly associated with PreE, the cytokines and proinflammatory mediators implicated in the primary disease process can activate the coagulation system, precipitating DIC.246 In AFE, amniotic fluid enters the maternal circulation through tears in the chorioamniotic membranes, uterine veins, or the result of uterine rupture (Chapter 7). Tissue factor present in the amniotic fluid triggers DIC with coagulopathy typically occurring in the second phase of the process. Fifty percent of patients with AFE develop DIC.246 In sepsis, the inflammatory cytokine response activates coagulation pathways, precipitating DIC.245 Disseminated intravascular coagulation from IUFD is relatively rare in those countries where prompt diagnosis and treatment occur. Coagulation disturbances tend to take time to develop, typically over a month.245,246 Thromboplastic material release from the dead fetus is the likely etiology of DIC in this setting.246 DIC is “incompatible with safe neuraxial blockade.”120

Tayler et al. (CSE for CD) and Xu et al. (GA for CD) describe the anesthetic considerations for mirror syndrome:255,256 • assess maternal cardiac status and reserve (echocardiogram) • consider invasive BP and CO monitoring • anatomical landmarks may not be apparent making NA difficult • risk of fetal distress during labor, consider early epidural to reduce the need for GA • increased likelihood of operative delivery • airway edema may make laryngoscopy more challenging (one report of awake fiberoptic intubation in a parturient with mirror syndrome)257 • may not tolerate supine positioning (orthopnea) • restrict IV fluids • possible increased incidence of PPH.

Mirror Syndrome

The hypercoagulable state of pregnancy reduces hemorrhage at birth. This may result in the improvement of some underlying bleeding disorders. Parturients with coagulation disorders that do not improve during pregnancy are at risk of significant hemorrhage.  The obstetric anesthesiologist must understand the pathophysiology of these conditions, optimize where possible, and balance the risks and benefits of neuraxial procedures.

Mirror syndrome is rare, with uncertain etiology. It features maternal hydrops combined with placental edema and hydrops fetalis (“triple edema”). Mirror syndrome, previously known as Ballantyne syndrome, is also referred to as pseudotoxemia because of its similarity to PreE; it is often misdiagnosed as PreE, leading to underreporting.252 Mirror syndrome presents earlier in pregnancy (mean gestational age 27 weeks)253 than PreE and, unlike PreE, is often associated with hemodilution.254 Causes of hydrops fetalis can be immune mediated (Rhesus isoimmunization) or nonimmune: cardiovascular (21%), hematological abnormalities (especially alpha thalassemia),254 infection (viral, especially parvovirus), twin-to-twin transfusion, inborn errors of metabolism.252 Sacrococcygeal teratoma is the most typical congenital tumor linked to fetal hydrops, secondary to high output cardiac failure.252 Approximately 20–30% of hydrops fetalis develop mirror syndrome.252,254 A systematic review found 113 case reports of mirror syndrome from 1956 to 2016.253 The maternal clinical presentation includes shortness of breath from pulmonary edema, anemia, polyhydramnios with pressure on the diaphragm, and ascites. Women are commonly hypertensive at presentation (60%).253 Pregnant women with mirror syndrome have higher uric acid, LDH, and creatinine levels and lower hematocrit.254 Maternal morbidity is secondary to pulmonary edema and renal failure. Mirror syndrome is associated with high fetal mortality (67%) from hydrops fetalis.252 Treatment of fetal hydrops (in utero transfusion) improves fetal survival and maternal condition.253 Maternal outcome improves with delivery and is required if intrauterine fetal treatment is not possible.254 Anesthesia may be needed to facilitate in utero procedures or labor analgesia.

Local anesthesia and sedation (compared with NA or GA) for percutaneous laser therapy to treat twin-to-twin transfusion syndrome have better maternal outcomes and may decrease the risk of maternal pulmonary edema.258,259

Summary

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251. Levi M, ScullyM. How I treat disseminated intravascular coagulation. Blood 2018;131:845–854. 252. Trad A, Czeresnia R, Elrefaei A, et al. What do we know about the diagnosis and management of mirror syndrome? J Matern Fetal Neonatal Med 2021;2021:1844656. 253. Allarakia S, Khayat H, Karami M, et al. Characteristics and management of mirror syndrome: a systematic review (1956– 2016). J Perinat Med 2017;45:1013–1021. 254. Chen R, Liu M, Yan J, et al. Clinical characteristics of mirror syndrome: a retrospective study of 16 cases. J Obstet Gynaecol 2021;41:73–76. 255. Tayler E, DeSimone C. Anesthetic management of maternal Mirror syndrome. Int J Obstet Anaesth 2014;23:386–389. 256. Xu Z, Huan Y, Zhang Y, et al. Anesthetic management of a parturient with mirror syndrome: a case report. Int J Clin Exp Med 2015;8:14161–14165. 257. Zlotnik A, Gruenbaum S, Gruenbaum B, et al. Awake fiberoptic intubation and general anesthesia in a parturient with mirror syndrome and a predicted difficult airway. Isr Med Assoc J 2011;13:640–642. 258. Rossi A, Kaufman M, Bornick P, et al. General vs local anesthesia for the percutaneous laser treatment of twintwin transfusion syndrome. Am J Obstet Gynecol 2008;199: e1–e7. 259. Davies S, Mordani K. Anesthetic management of laparoscopic surgery for twin-to-twin transfusion syndrome. Can J Anesth 2004;51:945–946.

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22

Infectious Diseases in Pregnancy C. Tyler Smith, Christina Megli, and Catherine A. Chappell

Physiologic Considerations of Infectious Diseases in Pregnancy Infections cause direct maternal morbidity and remain a leading cause of maternal morbidity in the United States and globally. Infection, such as chorioamnionitis, can have indirect effects leading to obstetric hemorrhage, stillbirth, prematurity, and hypertensive disorders. These outcomes may not be attributed to an infectious cause in epidemiologic studies,1 but are important considerations when caring for the pregnant patient. Pregnant women have increased susceptibility to morbidity and mortality from select pathogens,2 likely due to alterations in the immune response. During pregnancy, there are alterations to the immune system, presumably a physiologic adaptation (the Medwar hypothesis3), so the maternal “host” will not reject foreign genetic material (i.e., the fetus). Changes occur locally at the maternal fetal interface and in immune cells in the systemic circulation and reflect differences in the innate immune responses to pathogens. The many immune differences are reviewed elsewhere,4–6 and may be related to hormonal changes. Some of the changes during pregnancy involve innate immune cells (monocytes, macrophages, dendritic cells, NK cells) and adaptive immune cells (T cell populations, regulatory T cells). These immune alterations combined with physiologic changes to the respiratory and cardiovascular systems lead to differences in the virulence of specific pathogens. Important anesthetic considerations in the setting of infection during pregnancy result from altered physiology and several infection-related concerns.

Fever Fever during pregnancy can result from various infections, tissue trauma, malignancy, epidural analgesia, drug administration, and endocrine or immunologic disorders. In some animals, advanced pregnancy attenuates the pyrogenic response, suggesting that the physiologic state of pregnancy alters the sensitivity of the CNS responses to stressors.7–9 Fever can be associated with uterine contractions and fetal heart rate changes during a Jarisch-Herxheimer reaction. This reaction (fever, chills, worsening skin lesions) is transient, occurring within the first 24 hours of antibiotic treatment for spirochete disease

(e.g., syphilis).10,11 Regardless of the etiology of fever, clinical suspicion for infectious etiologies should remain high and fever treated with acetaminophen and fluids. A variety of pathogens cause antepartum fever in pregnancy. Fever and hyperthermia in early pregnancy may be linked to congenital anomalies (particularly neural tube defects and cleft lip),8,12 but fever after the first trimester does not produce adverse neurodevelopmental outcomes.13,14 In retrospective analyses, the most common cause of antepartum maternal fever was viral in etiology (50–57%), followed by bacterial and unknown etiologies.15,16 Antibiotics are often empirically administered for fever without a clear cause.16 One should have a high clinical suspicion for infection, and the differential diagnosis should remain broad. Before starting antibiotics, a detailed history, physical examination, and infectious workup are necessary. Labor induction agents (e.g., misoprostol), epidural analgesia, or infection can cause maternal fever. Recent guidelines suggest that a single temperature above 39°C or two measurements above 38°C taken 30 minutes apart should be the threshold for administering antibiotics on the presumption of intrauterine infection. Avoid NSAIDs to reduce fever due to the potential for premature closure of the ductus arteriosus. Fever within the first 24 hours postpartum may be due to lactogenesis, pyelonephritis, a thromboembolic event (DVT or pulmonary embolism), and infection.

Initiation of Labor as a Physiologic Response to Infection As classically described with pyelonephritis, systemic infection is associated with preterm labor. Pyelonephritis increases preterm delivery without vertical transmission of the etiologic bacterial agent.17–19 For this reason, it is essential to screen pregnant patients for asymptomatic bacteriuria and administer appropriate treatment. Preterm birth occurs with other systemic infections, and almost half of the preterm births are associated with inflammation (in the absence of infection) at the maternal fetal interface.20 The mechanisms underlying labor initiation are unknown, making this an active area of investigation. Obstetric providers must be vigilant for signs and symptoms of labor in any patient with disseminated infection.

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Increased Severity or Dissemination Select infections have increased systemic dissemination in pregnancy, including tuberculosis, malaria, and Group B Streptococcus (GBS).2,21,22 Increased severity occurs with SARSCo-V2, influenza, hepatitis E, varicella, and herpes simplex virus (HSV).2,23 The underlying mechanisms for increased dissemination or increased severity remain unclear. Alterations in the innate immune response may enhance susceptibility to cytokine storms with select pathogens. In the pregnant patient, be alert for sepsis and severe disease.

Alterations in Pregnancy Response to Infections Anatomical/Physiologic Adaptations The physiologic changes of pregnancy alter the presentation and physiologic response to infectious disease. Several cardiopulmonary changes occur in response to infection. The expanding gravid uterus alters the right ventricle and FRC, which have important clinical implications for GA during induction and ventilation. The fetal/maternal exchange of oxygen and carbon dioxide leads to a mild maternal metabolic alkalosis and increased respiratory rate. Accumulation of carbon dioxide during sepsis and respiratory failure can lead to difficulty in fetal gas exchange with subsequent fetal compromise. Monitoring the fetal heart tracing after viability reflects the metabolic state of the fetus and maternal respiratory compromise.24,25 Obtain an arterial blood gas early during respiratory decompensation and consider fetal gas exchange when adjusting ventilator settings. Progesterone increases secretions that may be difficult to clear with infection. Equally important are the hemodynamic changes of pregnancy and how they affect infection. The increased blood volume, decreased vascular resistance, and enhanced postural hemodynamic changes may increase the parturient’s sensitivity to the volume contraction seen with many infections. This sensitivity is well documented in animal models,26,27 and is consistent with the authors’ clinical experience. There is an increased susceptibility to pulmonary edema28 from decreased protein binding and enhanced capillary leakage, so closely monitor oxygenation. The hypercoagulable state of pregnancy may increase the risk of thromboembolic complications from an infection. Moreover, the placenta mediates several alterations in the clotting cascade.29 Valuable Clinical Insight Physiologic and anatomic adaptations to pregnancy can alter the response to, and presentation of, an infection.

Changes in Immune Cell Populations The complete immunologic alterations of pregnancy are reviewed elsewhere.4–6 The leukocyte count can increase as high as 25,000/mm3 in pregnancy and during physiologic stress, such as surgery or labor, without underlying infection. The circulating

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populations of monocytes, granulocytes, and lymphocytes change slightly with advancing gestation with increasing numbers of monocytes and granulocytes.30,31 In the past, some studies suggested that pregnancy was a state of complete immunosuppression. More recent studies and enhanced susceptibility to select infections indicate that pregnancy is a state of immunomodulation, not immune suppression. In pregnancy, the adaptive immune system is an area of active research, with the maternal fetal interface and the systemic responses to antigens being key areas. A woman’s T cell populations are altered in pregnancy. Historically, research suggested that maternal tolerance to fetal antigens in pregnancy was due to an alteration of the T helper (Th1-Th2) cell balance, but recent information indicates that the process is more complex.32 Successful pregnancy is associated with differential regulation of T regulatory cells FOXP3+ Th 17 cells, and Th1 Th2 cells.32,33

Immune-related Signaling at the Maternal Fetal Interface The maternal fetal interface, including the placenta and maternal decidua, is rich in immunoactivity. An influx in macrophage and NK cells occurs with implantation and is essential for placentation.34,35 At the maternal fetal interface, there are multiple layers of immunologic defenses.36–39 The fetus has an antimicrobial placenta with embedded immune cells (Hofbauer macrophages) that can defend against vertical transmission of infection.40 The placenta is resistant to infection by bacteria, viruses, and parasites and has a rich immune secretory profile preventing vertical infection.36 The maternal decidua is rich in immune cells, and cross talk between maternal immune cell populations, stromal tissue, and prostaglandins is essential to maintain a healthy pregnancy and responses to pathogens.41–43 The coordination of maternal and fetal immune cell populations and signaling with embedded stroma are precisely regulated. This coordinated response restricts infection at the maternal fetal interface and regulates systemic immune responses.

Fetal Immune Response The fetal immune system can respond to vertical pathogens. Fetal inflammation can be teratogenic, and the fetal inflammatory response can be completely segregated from the maternal compartment. The fetal inflammatory response to pathogens may produce adverse neonatal outcomes and congenital anomalies.44 In contrast, the contribution of fetal-based immune signaling to the maternal response to infection is less well characterized. There are no specific anesthetic concerns for fetal immune alterations in pregnancy. Medications that cross the placenta and affect the adrenals (e.g., etomidate, betamethasone) may modulate the response, but this is poorly studied.

Sepsis in Pregnancy The estimated incidence of maternal infection during labor is about 3%.45 Severe sepsis is less common, presenting as the primary problem in < 1% of patients. However, sepsis remains a significant cause of maternal death in locations with poor resources.46

Infectious Diseases in Pregnancy

Maternal complications of sepsis are similar to those in nonpregnant adults. These complications include pneumonia, ARDS, DIC, pulmonary edema, septic pulmonary emboli, septic shock, decreased LV function, and cardiac arrest. Additional complications specific to the parturient include preterm delivery, stillbirth, and fetal/neonatal loss. Maternal sepsis outcomes are associated with preexisting medical conditions and differ from age matched pregnant controls.28,47–49 The diagnosis of sepsis is made by considering the history, physical examination, and laboratory findings (Table 22.1). The changes to vital signs and laboratory values in pregnancy and parturition can render the diagnosis difficult, despite diagnostic criteria. Failure to recognize and address sepsis in pregnancy is a risk factor for maternal death.50 Sepsis scoring systems, such as the maternal early warning criteria (MEW),51 the systemic inflammatory response syndrome (SIRS), and the quick sequential organ failure assessment (qSOFA), were developed to enable the practitioner to recognize impending sepsis, and so initiate treatment quickly. A case control multicenter study comparing the three sepsis screening tools found that the sensitivity and specificity differed. SIRS had the highest sensitivity at 0.93, while qSOFA had the most specificity at 0.95. The authors concluded that all three systems showed limited utility, and currently, there is no ideal tool to identify sepsis in a laboring patient.52 Valuable Clinical Insights • Sepsis is a significant cause of maternal mortality in resourceconstrained settings. • Maternal complications of sepsis are similar to those in nonpregnant adults. • Changes to vital signs and laboratory values in pregnancy and parturition can make the diagnosis difficult. • There is no ideal tool to identify sepsis in a laboring patient. Table 22.1  Scoring criteria for sepsis

SIRS criteria

qSOFA criteria

Body temperature < 36°C or > 38°C

Respiratory rate > 22 breaths/min

Heart rate > 90 BPM

Systolic BP < 100 mmHg

White blood count < 4 or > 12 (10^3/µL)

Glasgow Coma Score < 13

Respiratory rate > 20 breaths/min MEW criteria Systolic BP: < 90 or > 160 mmHg Diastolic BP: > 100 mmHg Heart rate: < 50 or > 120 beats/min Respiratory rate: < 10 or > 30/min Oxygen saturation on room air, at sea level < 95% Oliguria: < 35 mL/h for ≥ 22 h Maternal agitation, confusion, or unresponsiveness; patient with PreE reporting a nonremitting headache or shortness of breath

Anesthetic Management of the Septicemic Parturient Anesthetic management of a patient with septicemia and potential multiorgan system failure is complex due to serious physiological changes. A thorough evaluation of a patient with sepsis includes: • a detailed history and physical examination • identifying the source of infection • identifying any multiorgan involvement • assessing hemodynamic and intravascular volume status • assessing fetal condition. Bedside point of care US may help assess fluid volume, but there are limited data on its use in the parturient with compression of the inferior vena cava by the gravid uterus as a confounding factor.53 Invasive monitors benefit a hemodynamically unstable parturient. Consider the physiological changes of pregnancy when interpreting intravascular volume and SVR data. As mortality is associated with rapid decompensation, the recommendation is for a multidisciplinary team to manage sepsis in an ICU. There are no guidelines about providing NA to a febrile pregnant patient. Sepsis is not an absolute contraindication to NA in the setting of corrected hypovolemia, normal coagulation, and following initiation of antibiotic treatment. Evaluate the intravascular volume and coagulation status before considering NA, as pregnancy and pregnancy-related diseases can disrupt maternal hemodynamics and coagulation. Sympathetic blockade with NA can potentiate hemodynamic compromise and increase mortality in patients with hypovolemia. Evaluate coagulation (especially fibrinogen) in the septic parturient before NA, as sepsis is associated with coagulopathy, resulting in hemorrhagic complications. After weighing risks and benefits, NA is a reasonable option, but start antibiotic therapy first as many experts consider untreated systemic infection to be a contraindication to NA.54–57 The same applies to a parturient with a fever of unknown origin.57 The recommendation to avoid NA in patients with untreated systemic infection (level of evidence C) stems from potential cardiovascular instability, coagulopathy, and introducing pathogens into the CNS.58 After initiation of antibiotic therapy, there is reasonable evidence that dural puncture is safe (level of evidence A).58 Conversely, catheter insertion (epidural or spinal) remains controversial. Current guidelines suggest considering single shot spinal anesthesia in the absence of bacteremia (level of evidence B).58 Hemodynamic compromise from sepsis places the pregnant patient at elevated risk for fetal compromise. Accordingly, there is a higher CD rate in septic patients.59 In the case of an emergency CD, the provider must consider the physiological changes of ­sepsis. If a functional indwelling epidural catheter is in place, dosing with a fast-acting LA (e.g., 3% 2-chloroprocaine) will provide a rapid surgical block. However, vasopressor support may be necessary as sympathectomy and hypovolemia cause a rapid decrease in mean arterial pressure. The Society of Maternal Fetal Medicine recommends norepinephrine as the

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C. Tyler Smith, Christina Megli, and Catherine A. Chappell

first-line vasopressor to treat sepsis-induced hypotension,60 but vasopressin and steroids are also beneficial.61 Due to unknown coagulation or volume status, GA may be preferred for emergent delivery, despite an increased hemorrhage risk. If GA is required, use a rapid sequence induction with an agent causing minimal decreases in SVR, such as ketamine or etomidate. Ketamine may be undesirable if there is catecholamine depletion and cardiac depression, while etomidate may result in hypotension secondary to adrenal insufficiency as it inhibits cortisol production. Many avoid propofol in a septic patient with hemodynamic instability due to decreased SVR. Succinylcholine or rocuronium are suitable for muscle paralysis during rapid sequence induction.62 Maintenance of anesthesia should include a combination of volatile agents, including nitrous oxide and IV agents, to reduce uterine atony and limit changes in SVR. Have uterotonics readily available. Continue to assess the patient for complications of sepsis, including ARDS and DIC. Valuable Clinical Insights • A nesthetic management of a patient with septicemia and potential multiorgan system failure is complex due to serious physiological changes. • The CD rate is elevated in septic patients. • After initiation of antibiotic therapy, there is reasonable evidence that dural puncture is safe in the septic patient. • Sepsis is not an absolute contraindication in the setting of corrected hypovolemia, normal coagulation, and following response to antibiotic treatment.

Bacterial Pathogens of Concern Presenting with Sepsis Group A Streptococcus Group A streptococcus (GAS), more specifically known as Streptococcus pyrogenes, is an important cause of infection in pregnancy. It is a frequent cause of minor illness, such as acute pharyngitis, scarlet fever, or erysipelas. Invasive GAS (characterized by the release of exotoxins) has a 20-fold higher incidence in postpartum women than in nonpregnant women.63 There are two proposed mechanisms by which GAS causes infection in pregnant women: (1) ascending infection from the lower genital tract to the upper genital tract or (2) hematogenous seeding of the placenta from the upper respiratory tract. Not all Streptococcus pyrogenes strains cause invasive disease. Virulence mechanisms for invasive GAS in pregnancy are not well defined. Pregnant patients with invasive GAS typically present with fever and significant abdominal pain, followed rapidly by shock with hypotension, tachycardia, leukocytosis, and organ dysfunction, including renal failure and ARDS. Timely diagnosis and intervention are critical as the mortality rate is > 50% once there is shock and organ dysfunction.64,65 Treatment of GAS consists of aggressive fluid resuscitation, antibiotic therapy, and source control. Preferred antibiotic therapy is IV penicillin G with clindamycin or gentamicin to suppress exotoxin release. Source control is critical for patients with sepsis and

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may require wound debridement, vulvar debridement, or hysterectomy, depending on the source of GAS.

Clostridial Toxic Shock Syndrome Clostridium sordellii and Clostridium perfringens are anaerobic gram-positive bacteria frequently found in the soil and women’s’ GI and genital tracts.66 Similar to invasive GAS, the virulence of clostridial infections is related to the production of exotoxins, which cause tissue edema and necrosis, leading to shock. The characteristics of clostridial toxic shock are rapid onset of severe illness, including profound leukocytosis, edema, capillary leak, hemoconcentration, and finally, multiorgan failure in an otherwise healthy individual. Therapy for clostridial toxic shock syndrome is IV penicillin G and clindamycin, and surgical source control. Mortality from clostridial toxic shock syndrome is high; one review of 45 cases reported a 69% mortality.67

Polymicrobial Flora Associated with Ascending Infection Chorioamnionitis and endometritis are frequent sources of sepsis. The etiology for these infections can be polymicrobial, consisting of flora from the genitourinary tract. Common pathogens include E. coli, GBS, and Bacteroides.68 The clinical presentation for these infections is not as drastic as exotoxin mediated GAS and clostridial infections; however, there still is significant morbidity and mortality.1,69 Treatment is with broad spectrum antibiotics covering gram-negative, GBS, and anaerobic flora.

Antimicrobial Considerations in Pregnancy Antimicrobial administration, both pathogen directed and empiric therapy, has several considerations in pregnancy (Table 22.2). The first consideration is that maternal administration results in fetal administration of the drug with potential fetal/neonatal toxicity. For example, fluoroquinolones and tetracyclines are avoided in pregnancy due to possible fetal effects. Fluoroquinolones are associated with bone, muscle, and neurologic toxicity in animal fetuses, while tetracyclines cause permanent teeth discoloration. Use extra caution in patients with G6PD mutations as administration of trimethoprim-sulfasalazine and nitrofurantoin close to delivery may cause neonatal hyperbilirubinemia. In general, cephalosporins and penicillins are efficacious and have a favorable safety profile. Secondly, the protein binding capacity and the volume of distribution are altered in pregnancy, and renal clearance of medications is enhanced. These changes alter the pharmacokinetics and pharmacodynamics of most medications. For example, peak serum concentrations of penicillin and gentamicin are lower in pregnant patients than nonpregnant patients. It may be difficult to achieve therapeutic vancomycin concentrations due to enhanced renal clearance in pregnancy. Thus, one may need to alter the dose of these medications during pregnancy. Lastly, in general, data on antimicrobials are collected retrospectively; this means that safety outcomes and pharmacodynamic and kinetic measurements are often missing. Recommendations on medication use in pregnancy are mostly extrapolated from animal and retrospective studies. Overall, it is essential to assess the risk for each medication (Table 22.2).

Infectious Diseases in Pregnancy

Table 22.2  Considerations for antimicrobial therapy during pregnancy

Antimicrobial agent

Maternal risks

Fetal risks

Penicillins

Hypersensitivity, antimicrobial resistance

Altered microbiome, freely crosses placenta

Second and third generation cephalosporins

Hypersensitivity, bone marrow suppression

Altered microbiome, freely crosses placenta

Combination vancomycin with pipercillin tazobactam

Nephrotoxicity

Vancomycin

May be difficult to achieve drug levels with enhanced GFR in pregnancy

Does not cross placenta, limited data

Clindamycin

C. diff infection, driving antimicrobial resistance

None

Tetracyclines

Renal toxicity

Tooth enamel

Gentamicin

Renal toxicity

Renal toxicity, ototoxic

Fluoroquinolones

C. diff infection

Concern for connective tissue defects

Macrolides (Azithromycin/ erythromycin)

QT prolongation, nausea and vomiting (erythromycin)

None

Trimethoprim-sulfamethoxazole

Drug fever, skin manifestations, agranulocytosis hemolysis with G6PD deficiency, lactic acidosis, ARDS

Kernicterus of the newborn if used in the third trimester, particularly with G6PD deficiency

Nitrofurantoin

Hemolysis with G6PD deficiency, interstitial pneumonitis with prolonged therapy

Kernicterus of the newborn if used in the third trimester, particularly with G6PD deficiency

Amphotericin B (preferred agent for disseminated infection)

Multiple

None

Azoles

Hepatotoxicity

Miscarriage

Oseltamivir

Skin reactions

None

Interferon alpha

Multiple

Growth restriction, neonatal lupus

Tenofovir (TAF/TDF)

GI intolerance

Crosses placenta, no evidence of toxicity

Emtricitabine (FTC)

Lactic acidosis

None

Integrase inhibitors

Elevated glucose intolerance

Neural tube defects (only if taking during conception)

Acyclovir/valcyclovir

Elevated creatinine, neurotoxicity

None

Protease inhibitors

Drug interactions (particularly with uterotonics), hepatotoxicity

None

Bacterial agents

Anti-fungal agents

Antiviral agents

Use the same principles to guide antimicrobial prophylaxis and treat the presumed infection as in nonpregnant women (i.e., antibiotic therapy selected on presumed infection risk) (Table 22.3). For CD, cefazolin is the recommended agent for prophylaxis.70 Weight-based dosing alters serum concentrations but does not change infection-associated morbidity.71 Interestingly, adding prophylactic azithromycin lowers the incidence of wound infection in patients at higher risk for infection, such as obesity or labor/ruptured membranes.72,73 Valent et al. found that continuing cefoxitin and metronidazole for 24 hours postpartum lowered infectious complications after CD.74 As the average blood loss of a CD can be higher than other scheduled procedures, be prepared to repeat antibiotics in complicated cases. Additionally, cephalosporins are recommended for fundal exploration, as part of managing a retained placenta or PPH,70 and for severe obstetric lacerations. Do not use antibiotics for a routine vaginal delivery. As sepsis or a disseminated infection may be secondary to ascending intrauterine infection, treat with a broad-spectrum

antibiotic. The genital tract is polymicrobial, and antibiotic treatment must cover anaerobic flora, E. coli, GBS, and other atypical gram-negative pathogens.

Viral Infections Viral infections in pregnancy are of concern to the obstetric anesthesiologist. Clinically relevant viruses include human immunodeficiency virus (HIV), hepatitis viruses, coronaviruses, herpes simplex viruses, cytomegaloviruses, papillomaviruses, parvoviruses, and the viruses that cause chickenpox, measles, influenza, and rubella. Maternal viral infection is associated with an increased risk for adverse perinatal outcomes. The acronym TORCH applies to agents known to cause serious congenital infections. Except for Toxoplasma gondii and Treponema pallidum, all TORCH agents are viruses: rubella, cytomegalovirus, herpes simplex, varicella zoster, and HIV (Table 22.4). To prevent transmission, at a minimum, wear surgical gloves and use eye protection when doing procedures or handling blood and body fluids. Specific considerations for aerosol-dispersed microbes are discussed below.

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Table 22.3  Antimicrobial recommendations for common pathogens in pregnancy

Indication

Preferred

Alternative

Other considerations

Cesarean delivery

Cefazolin 2g IV x1 (+Azithromycin 500 mg IV x1 if laboring or ruptured membranes)

Clindamycin 900 mg IV x1 + Gentamicin 5 mg/kg IV x1 (+Azithromycin 500 mg IV x1 if laboring [rupture of membrane])

- Give preoperative dose within 60 minutes of incision - Patients with procedure > 2 half-lives of the antibiotic (cefazolin = 4 hours) or those who have EBL > 1000 mL should receive additional intraoperative dose of same antibiotic - MRSA coverage with vancomycin recommended if MRSA colonized (however, screening for MRSA colonization is not recommended)

Asymptomatic bacteriuria

Nitrofurantoin 50 mg PO QID

Cefuroxime 500 mg PO q12h

- Duration 7 days

Pyelonephritis

Ceftriaxone 1-2 g q24h

Gentamicin 5 mg/kg IV q24h

- Treatment duration 14 days - Narrow per antibiotic resistance profile of urine culture

Chorioamnionitis/ suspected intraamniotic infection/triple I

Cefoxitin 2 g IV q 6hr OR Cefotetan 1 g Ampicillin 2 g IV q6h + Gentamicin 5 mg/kg IV x1 (+ metronidazole 500 mg IV x1 or clindamycin 900 mg IV x1 if patient required CD)

Cefazolin 2g IV q8h+ Gentamicin 1.55 mg/kg xq8 OR Vancomycin 15 mg/kg IV q12h+ Gentamicin 1.5 mg/kg q8hr + Metronidazole 500 mg q8

- At least 1 or more doses is recommended postpartum after CD, not necessary after vaginal delivery - If fever continues postpartum for > 48 hours consider endometrial biopsy & culture - Placental cultures should be evaluated post delivery - Antimicrobial use should be guided by local drug resistance patterns of E. coli and GBS

Third/fourth degree laceration repair

Consider Cefoxitin 1 g IV x1 OR Cefotetan1 g IV x1

Clindamycin 900 mg IV x1 OR Cefazolin 2 g IV x 1 can be considered

- ACOG recommends a single dose of antibiotics to prevent perineal wound infections but the optimal regimen has not been elucidated. Start the patient on a bowel regimen postpartum and inspect the wound after a short interval

Postpartum endometritis

Cefoxitin 2 g q8hr OR cefotetan 1 g q12hr

Gentamicin 5 mg/kg IVx1 +metronidazole IV 500 mg q8hr +Ampicillin 2 g q 6 hr if GBS positive OR Vancomycin 15 mg/kg IV q12h+ Gentamicin 1.5 mg/kg q8hr + Metronidazole 500 mg q8

If suspicious for Group A strep: Ceftriaxone 2g q24 hr +clindamycin 900 mg q8hr - No role for routine blood cultures in guiding therapy. Consider routine blood cultures if critically ill. Duration of therapy is suggested as 7–10 days with discontinuation of parenteral antibiotics after 24–48 hours if afebrile. Suggested oral regimen is amoxicillin clavulanate or cefalexin or cefuroxime

PPROM

Azithromycin 1 g po x1 + Ampicillin 2 g q6 hr x 48 hrs followed by Amoxicillin 250 mg q8 x 5 days OR Erythromycin IV 250 mg q6h + Ampicillin 2g q 6 hr x 48 followed by Erythromycin 333 mg q 8h + Amoxicillin 250 mg q8 x 5days

Azithromycin 1g po x1 + Clindamycin IV 900 mg q 8 + Gentamicin IV 5 mg/kg q 24 x 48 hours followed by Clindamycin po 300 mg q 8 hr x 5 days

- Antibiotics are to establish latency, not to treat infection. If there is evidence of infection, delivery is recommended - Can also do amoxicillin 875 mg BID - Alternatives in women with a penicillin allergy are not well established, if penicillin allergy GBS positive and clindamycin resistant vancomycin should be used

Community-acquired pneumonia

Ampicillin/sulbactam 3 g IV q6h + Azithromycin 500 mg IV q24h

Aztreonam 2 g IV q8h + Vancomycin 15-20 mg/kg IV q12h

Sepsis of unknown origin

Cefepime 2 gm q 12 hr + metronidazole 1 gm loading dose followed by 0.5 gm q 6hr OR Piperacillin-Tazobactam 4.5 g loading dose followed by 3.375 g q8hr + Vancomycin 15–20 mg/Kg IV q8–12hr

Consider infectious diseases consultation – Carbapenem may be reasonable Vancomycin 15 mg/kg IV q12h+ Gentamicin 1.5 mg/kg q8hr + Metronidazole 500 mg q8

- Send blood cultures and request L. monocytogenes evaluation - Non-Beta lactam antibiotics are inferior to Beta lactam antibiotics, consider desensitization, allergy testing or use of non-cross-reactive side chains - If high prevalence of extended spectrum betalactamase producing Gram-negative bacteria, then combination Piperacillin Tazobactam is not appropriate

MRSA = methycillin-resistant Staphyloccus aureus.

Human Immunodeficiency Virus Epidemiology: Incidence Human immunodeficiency virus (HIV) has had a profound impact on women worldwide. Estimates of global HIV prevalence in 2020 found that 50% among the 37.7 million people

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living with HIV were women or girls. In 2020, women and girls of reproductive age accounted for 42% of new HIV infections, indicating an urgent need for prevention strategies in this population.75 The end result of HIV infection is acquired immunodeficiency syndrome (AIDS), defined as a CD4 count < 200 cells/mL or an AIDS-defining illness such as invasive cervical

Infectious Diseases in Pregnancy

Table 22.4  Pathogens that can cause congenital infection

Pathogen

Classification Mode of maternal transmission

Mode of fetal/neonatal transmission

Hallmarks of congenital infection

L. monocytogenes

Bacterial

Contaminated food

Transplacental Contamination with parturition

Stillbirth/pregnancy loss Preterm delivery Neonatal sepsis

S. agalactiae (GBS)

Bacterial

Commensal

Ascending infection Contamination with parturition

Neonatal sepsis

E. coli

Bacterial

Commensal

Ascending infection Contamination with parturition

Neonatal sepsis

T. pallidum

Bacterial

Sexual

Transplacental

Stillbirth/pregnancy loss Low birth weight Hepatosplenomegaly Saddle nose deformity Rhinitis Dental deformities Chorioretinitis Rash Dilated bowel Skin thickening Periostitis, bone fractures and demineralization

Cytomegalovirus

Viral

Ingestion of contaminated fluids

Transplacental Breastfeeding (less common)

Hearing loss Low birth weight Chorioretinitis Developmental delay Anemia/thrombocytopenia Rash Stillbirth/pregnancy loss Ventriculomegaly Intracerebral calcification Echogenic bowel/abdominal calcifications

HSV-1/HSV-2

Viral

Sexual or oral contact

Transplacental Viral shedding with parturition

Parturition Neonatal meningitis Transplacental Dermatologic lesions Ventriculomegaly Microcephaly Intracerebral calcifications Chorioretinitis Optic atrophy Limb dysplasia

ZIKV

Viral

Arbovirus: Aedes species, sexual, blood borne

Transplacental Possible ascending

Microcephaly IUGR Hepatosplenomegaly Intrahepatic calcifications Ventriculomegaly Intracerebral calcifications Echogenic bowel Stillbirth/pregnancy loss

Parvovirus B-19

Viral

Respiratory droplets

Transplacental

Anemia Hydrops Stillbirth/pregnancy loss

HIV

Viral

Bloodborne, sexual

Transplacental, contact with vaginal secretions

Neonatal HIV, increased transmission of CMV

Hepatitis B

Viral

Bloodborne, sexual, vertical

Contact with vaginal secretions

Neonatal hepatitis

T. gondii

Parasitic

Ingestion of contaminated food or oocytes

Transplacental

Ventriculomegaly Hydrocephalus Intracerebral calcifications Choroid plexus cysts Hydrocephalus Ascites IUGR Hepatosplenomegaly

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Table 22.4 (cont.)

Pathogen

Classification Mode of maternal transmission

Mode of fetal/neonatal transmission

Hallmarks of congenital infection

P. falciparum P. vivax

Parasitic

Arthropod vector

Placental

IUGR Preterm delivery Severe hypoglycemia

T. cruzi

Parasitic

Arthropod vector

Transplacental

Symptomatic at birth IUGR Respiratory failure Hepatosplenomegaly Meningitis Heart failure Hydrops Asymptomatic at birth Chronic Chagas disease

cancer, pneumocystis jiroveci pneumonia, or Kaposi sarcoma. Despite being 40 years into the HIV epidemic, AIDS remains the worldwide leading cause of death of women of reproductive age.76 After the first recognition of AIDS in 1981, there was a rapid rise in HIV prevalence among women of reproductive age who acquired HIV from heterosexual intercourse. Women are twice as likely to contract HIV compared to their male counterparts. This discrepancy results from several factors, including increased anatomic susceptibility (male-to-female transmission is more efficient than female-to-male transmission) and the socio-economic challenges of gender inequity and social violence. The overlapping social, cultural, environmental, and economic factors responsible for health inequities or social determinants of health play an important role during the HIV epidemic in the United States. Health inequities explain the disproportionate burden of HIV in specific populations, such as African Americans.77

HIV Screening Screening for HIV is the first critical step in the HIV care continuum and is the gateway for linkage to HIV care. Routine HIV care and specifically the initiation of antiretroviral therapy (ART) is critical to the survival of persons with HIV by preventing the progression to AIDS or death and preventing them from transmitting HIV to others. In 2006, the CDC recommended routine HIV screening for all persons 13 through 64 years of age in all health settings in the United States, including all sexually active women and during preconception care. The CDC recommends screening all pregnant women for HIV as early as possible prenatally. They also recommend repeating HIV screening in the third trimester for pregnant women at increased risk of acquiring HIV, including those in facilities with an HIV prevalence of ≥ 1 case per 1000 pregnant women per year.78 All HIV unscreened pregnant women presenting to labor and delivery should undergo rapid HIV testing. This testing should be available 24 hours a day, with the results available within one hour. The recommended initial HIV test should be a laboratory-based HIV-1/-2 antigen-antibody immunoassay, which can detect HIV-1 and HIV-2 antibodies as well as HIV-1 p24 antigen. This test can determine HIV status as long as there was no exposure within four weeks. A recent exposure to, or

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symptoms of, acute HIV infection (flu-like illness, lymphadenopathy), requires an HIV RNA test (viral load). If a pregnant woman is identified with HIV infection, immediately consult with an infectious diseases specialist. This consultation is essential to initiate ART to improve maternal health and prevent perinatal transmission of HIV. A new diagnosis of HIV infection in pregnancy is one of the few cases where urgent ART initiation is warranted.

Therapy and Prognosis Without the advent of ART, HIV infection would almost universally lead to AIDS and then death. However, a well-controlled HIV infection with ART results in a similar life expectancy as a person without HIV.79 Furthermore, if a person living with HIV is taking ART and has an undetectable viral load, they cannot transmit HIV to their sexual partner.80,81 Similarly, the management of pregnant women with HIV infection has evolved significantly with advances in drug development and better understanding of perinatal transmission. All pregnant women with HIV should receive combination ART regardless of CD4 count or HIV viremia. ART for pregnant women should include three active antiretroviral drugs, ideally antiretroviral drugs with a high placental transfer rate, like tenofovir. When choosing an ART regimen, one must consider numerous factors, including the virus’s resistance profile, the safety of the antiretroviral drugs in pregnancy, and dosing. Therefore, consult a specialist with expertise in HIV care to ­initiate HIV treatment. There are guidelines for ART during pregnancy that are updated regularly.82 After starting ART, monitor the HIV viral load at intervals of two to four weeks, then monthly until RNA levels are undetectable, and then at least every three months during pregnancy. Additionally, assess HIV viral load at 34 to 36 weeks. If a pregnant woman on ART has detectable HIV viremia, contact the HIV care provider immediately to ensure that the ART modification is unnecessary. Worldwide, about 500 children acquire HIV infection daily, and 90% of those are due to perinatal (maternal-to-child) transmission of HIV-1.83 Before the routine use of ART during pregnancy, perinatal HIV transmission occurred in up to 60% of all pregnancies, including pregnancy and breastfeeding.84 Antiretroviral therapy significantly reduces the risk of transmission to < 1% risk in the United States.82 Maternal HIV

Infectious Diseases in Pregnancy

viral load is the biggest risk factor for transmitting HIV perinatally.85 Perinatal HIV transmission can occur as early as the first trimester,86 so start ART once HIV is diagnosed in pregnancy to achieve viral suppression as quickly as possible. Integrase strand inhibitors are highly potent and result in rapid viral suppression.

Intrapartum HIV Management The majority of perinatal HIV transmission occurs intrapartum in the setting of unsuppressed HIV infection. There is a significant increase in maternal–fetal blood exchange with fetal exposure to HIV in the genital tract during this time.87 As it is critical to know the HIV status of every pregnant woman presenting in labor, those without prenatal care should have rapid HIV testing. If the rapid HIV test is positive, manage the patient as HIV positive until obtaining the results of a definitive test. Many maternity hospitals can conduct definitive HIV testing rapidly. When HIV is detected late in pregnancy, and HIV viral load cannot be suppressed < 1000 copies/mL, the recommendation is for CD before labor onset. Start IV zidovudine (ZDV) three hours before CD.82 A CD before labor onset significantly reduces HIV infection in the newborn.88 However, if the membranes were ruptured > 4 hours, or there is active labor, the benefits of CD decline significantly. Administer ZDV with an IV loading dose of 2 mg/ kg over one hour, followed by a continuous ZDV infusion of 1 mg/kg for two hours (minimum of three hours).82 For pregnant HIV-positive women on ART, it is critical to continue oral ART throughout the intrapartum period, even during periods of NPO. Another recommendation is to avoid fetal scalp electrodes, early amniotomy, and operative delivery, as these interventions might increase maternal-to-infant blood exchange.

Anesthetic Considerations Thoroughly assess parturients with HIV/AIDS looking for systemic manifestations and opportunistic infections. Systemic manifestations may include: encephalitis, meningitis, increased ICP with infection, neuropathy, myelopathy, neuritis, pneumocystis pneumonia, tuberculosis, cardiomyopathy, enteropathy, anemia, thrombocytopenia, neutropenia, dermatological disease, or tumors. Use these findings to determine the anesthetic management. A decision about mode of delivery is based on viral load, systemic manifestations, and comorbidities. Document any antepartum laboratory tests, and obtain a CBC before NA procedures. Patients with cardiopulmonary manifestations may benefit from further testing, including ECG, TTE, and radiological imaging. Most HIV-positive patients in the United States will be on ART. Knowing the patient’s current medications is essential, as certain ART medications interact with uterotonics and other drugs. This is particularly true for patients on salvage regimens with long-standing HIV infection, often those who acquired HIV perinatally. For example, ritonavir-boosted protease inhibitors, which are cytochrome P450 3A4 inhibitors, affect the action of midazolam, fentanyl, and antidysrhythmic medications. Methylergonovine is also affected by ART, with reports of cerebral vasospasm leading to cerebral ischemia.89

Assuming no other contraindications, NA is safe in patients with HIV/AIDS on ART, with no risk of facilitating CNS disease.90 Similarly, NA is safe in patients with neuropathic symptoms.91,92 There is no contraindication to an EBP for a PDPH in HIV/AIDS patients.93 As with any pregnant patient, one wants to avoid GA, if possible.94 In the case of an emergent CD or a contraindication to NA, GA may be necessary, but patients with CNS involvement may be more sensitive to anesthetic medications. Avoid succinylcholine due to possible hyperkalemia in severe cases of neuropathic muscle wasting. Since opioids may reactivate latent CNS disease,95,96 use opioid-sparing techniques, such as regional analgesia, scheduled acetaminophen, and ketorolac, in the absence of a contraindication. Opioids may also contribute to HIV-associated neurocognitive disorders.97 If intracranial hypertension and coagulopathy are not present, NA is suitable for surgical procedures in parturients with AIDS, independent of gestational age. However, it is necessary to explain the risks and benefits of GA versus NA so that the woman participates in the decision. Neuraxial opioid use in HIV patients has not been thoroughly studied.

Viral Hepatitis Acute viral hepatitis is the most common cause of jaundice in pregnancy. The course of most viral hepatitis infections (hepatitis A, B, C, and D) is unaffected by pregnancy. Hepatitis E causes a more severe course of viral hepatitis in pregnancy98 (see also Chapter 18).

Viruses Associated with Epidemics or Pandemics Influenza Virus Influenza is highly contagious and a significant cause of respiratory disease in adults. Influenza infections are more severe in pregnancy, as evidenced in the H1N1 influenza epidemic when pregnant women constituted a significant portion of influenzaassociated morbidity and mortality.99,100 The influenza vaccine is recommended for all pregnant women. Before providing anesthesia to a parturient with influenza, consider the possibility that she may have viral pneumonia or septicemia. There are reports of patients with influenza receiving GA and NA (epidural, CSE, DPE).101 Consider the alterations to the respiratory system in pregnancy complicated by severe disease, and take appropriate precautions.

Coronaviruses Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-Co-V-2, COVID) Most data on coronavirus infections during pregnancy is from the ongoing SARS-Co-V-2 pandemic. Initially, pregnancy data had been extrapolated from experience with Middle East Respiratory Syndrome (MERS) and SARS-Co-V (SARS). With increased case numbers and low vaccine uptake in pregnancy, more data on COVID are now available, resulting in changing guidelines. The complications of SARS-Co-V-2 infection

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in pregnancy include preterm delivery,102,103 stillbirths,104 and placental chronic histiocytic intervillositis with associated adverse neonatal outcomes.105–107 Additionally, there are reports of placental insufficiency, IUGR, increased maternal mortality, and severe morbidity in symptomatic cases.108,109 There is some evidence that the delta variant poses additional risk to obstetric patients,110–112 such as ARDS, sepsis, ICU admission, renal failure, cardiac events, and thromboembolic complications.102 Maternal death is less frequent, and immunologic complications (Multisystem Inflammatory Syndrome in Adults, MIS-A) can occur following COVID. There is an increased incidence of hypertensive disorders of pregnancy in the parturient after symptom resolution.113 Most therapies for SARS-Co-V-2 in pregnancy are unstudied, and their risks to the fetus and pregnant woman are unknown. However, the risks of severe COVID-19 disease often outweigh any theoretical risk of treatment.109 Maternal vaccination is safe and leads to improved outcomes.109,114,115 Management of the severely ill SARS-Co-V-2 infected pregnant patient requires a multidisciplinary team, including critical care, pharmacy, maternal-fetal medicine, and other specialty providers. There are no clear guidelines regarding the delivery timing, but respiratory compromise and fetal oxygenation are critical factors. Manage severely ill patients in the ICU with ­sepsis precautions. Anesthetic considerations include minimizing exposure to health care providers and ensuring the most experienced provider performs all necessary procedures. Peng et al. having described patient and procedure room preparation, personal protective equipment (PPE) issues, and minimization of aerosol generation.116 SOAP has released a document, “Interim Considerations for Obstetric Anesthesia Care related to COVID-19,” available to members on their website (www .soap.org) (Table 22.5). Patients with COVID can receive NA.117 Early LEA with frequent block assessment helps reduce the risk of GA for an emergency CD due to failed block. There are reports of successful NA for CD in parturients with COVID.117,118 In the case of GA, the most skilled provider should perform a rapid sequence induction. Limit the number of personnel caring for the patient and follow hospital policies on COVID infection. A CBC is warranted before NA in COVID parturients, as thrombocytopenia may occur.119 Nitrous oxide analgesia should not be used if the patient appears hypoxic or symptomatic. As the virus is present in droplets, it is crucial to consider the delivery system. Due to sanitization and infection control concerns, some hospitals and medical systems do not offer nitrous oxide analgesia in this setting.

Middle East Respiratory Syndrome (MERS) There is little information on the anesthetic management of the parturient with MERS, even though they have required anesthetic care. The anesthetic concerns are similar to those for COVID (Table 22.5). There is a case report of a MERS parturient having an urgent CD under CSE one day after clinical improvement.120 The authors discuss the risks of viral spread and their rationale for using NA. As MERS is a respiratory virus, assess the

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Table 22.5  Anesthetic management of COVID-19 obstetric patients Pre-delivery

Assess the patient for symptoms of COVID Assess accompanying person(s) for COVID

If COVID positive

Transfer to a room that is adequately ventilated – preferably negative pressure Patient/support person(s) should wear a facemask at all times Staff should use PPE; practice hand hygiene Limit the number of staff caring for the patient

Management

Do a CBC as thrombocytopenia possible Try to anticipate emergency Consider early LEA, to avoid GA for urgent delivery There are no contraindications to NA specific to COVID-19

Minimize aerosol generation

Most experienced anesthesiologist should manage the airway High efficiency (HEPA) filter between facemask and breathing circuit Avoid manual ventilation if possible by preoxygenation and rapid sequence induction Avoid awake fiberoptic intubation if possible as coughing may disperse virus particles Consider videolaryngoscopy Use tracheal intubation rather than laryngeal mask airway

Postpartum

Consider the risks and benefits of dexamethasone and NSAIDs prior to their use for postoperative nausea and vomiting or pain

Other

Create COVID-19 kits with drugs and equipment needed to care for a patient Create scenarios for care of COVID-19 patients so staff can practice

respiratory status and need for respiratory support before determining the anesthetic technique. Some MERS patients have nausea, vomiting, and diarrhea, requiring volume replacement before NA. A catheter technique (e.g., epidural, CSE, continuous spinal) to control the anesthetic level may benefit patients whose respiratory status is compromised by weak accessory muscles. As there is a risk of thrombocytopenia and IVH,121 assess the coagulation status and perform a neurological exam as part of the anesthetic workup.

Severe Acute Respiratory Syndrome Coronavirus (SARS Co-V, SARS) Severe acute respiratory syndrome, a highly contagious infection caused by a strain of coronavirus, produced numerous deaths during an epidemic in Hong Kong and Toronto in 2003. Yudin et al. reported a case of a pregnant woman with SARS who delivered an uninfected, healthy baby.122 Overall, however, adverse perinatal outcomes in mothers with SARS are usual. First trimester miscarriage, preterm delivery, and IUGR were common in one study.123 Pregnant women with SARS have poorer outcomes with more renal failure and DIC than nonpregnant women with SARS.124 There are stepwise protocols for handling outbreaks.125 Anesthetic considerations are similar to those for SARS Co-V-2.

Flaviviridae Japanese Encephalitis Virus Japanese encephalitis virus is a mosquito-borne flavivirus endemic to Asia. The risk of infection is very low for most

Infectious Diseases in Pregnancy

travelers, with vaccination recommended for rural travel or travel to areas with an outbreak. There is little evidence on anesthetic management in the parturient with Japanese encephalitis virus. Most patients are asymptomatic. If asymptomatic, NA may be acceptable. Severe virus cases may result in neck rigidity, cachexia, hemiparesis, convulsions, and fever, necessitating endotracheal intubation for airway protection. Avoid NA in patients with neurological changes.

West Nile Virus West Nile virus (WNV) is another arthropod borne flavivirus. Like avian influenza, it is primarily a disease of birds but is spread by mosquitoes. National blood donor screening for WNV RNA suggests asymptomatic infections are widespread, with approximately 735,000 cases occurring in the United States in 2003.126 WNV causes significant neurologic disease in a small portion of infections (one per 256 cases).127 There currently is no evidence for congenital transmission of WNV.128,129 There is little evidence on the anesthetic management of the parturient with WNV. Most people infected with WNV are asymptomatic, so routine anesthesia care is reasonable. Severe cases with neurologic manifestations, including altered mental state, may necessitate GA. One may want to consider avoiding NA in parturients with neurological changes.

in 2017, there were more respiratory complications in pregnant women than nonpregnant women (21% vs. 9%) during a measles outbreak.135 A selected literature review found that pregnant women were more likely to be hospitalized and have pneumonia than nonpregnant women.136 Although preterm birth and IUFD occur, the risks are not well defined. Congenital transmission from the mother to her fetus can happen, usually when the mother develops measles within ten days of delivery, but the mode of transmission is unclear. Treatment for measles in pregnancy is supportive. Susceptible pregnant women exposed to measles can receive immunoglobulin within six days of exposure. Infants born to infected mothers should also receive immunoglobulin. If administering NA to parturients with active measles infection, ensure the proposed insertion site is clear of the rash. There are no other special considerations for anesthetic management.

Parvovirus B19 (Fifth Disease)

Members of the family Filoviridae include the Ebola and Marburg viruses, which cause viral hemorrhagic fever. The presentation and mortality rates are similar in pregnant and nonpregnant patients; most have high GI losses and hypovolemia.130 The fetal loss rate is nearly 100% for these infections best characterized by the Ebola virus. Pregnancy increased the severity of disease and morbidity during Ebola virus outbreaks in Western Africa.131 There is evidence of vertical transmission to the fetus with associated preterm delivery and stillbirth in women who recover.132,133 Concerns around providing NA to parturients with Ebola include the risk to the provider (recommended to keep invasive procedures to a minimum)130,134 and coagulopathy. When anesthesia is required, GA with endotracheal intubation is often preferred due to clinical disease severity, coagulopathy, and risk of massive hemorrhage.

Parvovirus B19, the causative agent of Fifth disease, is associated with hydrops fetalis. Approximately 35–50% of the general population is susceptible to the virus, while 20% will become infected after exposure.137Approximately 1–5% of pregnant women will be affected, with most having a normal outcome.138 The risk of IUFD from placental transmission of parvovirus ranges from 1% to 15%,137 with an increase in adverse outcomes when maternal infection occurs in the first two trimesters. Maternal symptoms include malaise, low-grade fever, maculopapular rash (“slapped-cheeks”), and symmetric poly­ arthralgia of the hands, wrists, and knees that resolve spontaneously. Maternal symptoms do not correlate with the presence or severity of fetal infection. The fetus can be normal or suffer from aplastic anemia, myocarditis, nonimmunologic hydrops, and increased perinatal mortality. The US signs of fetal infection arise from severe anemia, heart failure, and hydrops. The anemia is secondary to infection of erythroblast precursors, leading to bone marrow suppression. If there is no evidence of fetal anemia, treatment is supportive, but a fetal transfusion is needed if there is US evidence of fetal anemia. Anesthesia for this procedure may include light maternal sedation and fetal administration of a muscle relaxant (rocuronium) to the fetus. There are no other special anesthetic considerations for parvovirus.

Rubeola (Measles)

Rubella (German Measles)

Filoviridae

Measles is a highly contagious exanthematous viral illness caused by a paramyxovirus (Morbillivirus). Its incidence worldwide decreased dramatically with the introduction of effective vaccines. Nevertheless, outbreaks still occur among unvaccinated individuals, especially young adults. Measles in pregnancy is an illness in a pregnant woman that meets the definition for “probable measles” by the CDC. This clinical definition includes generalized rash, which coincides with the onset of the effector phase of the antiviral immune response, cough, coryza, conjunctivitis, and temperature > 101°F during three or more days. ELISA can determine antibody status. Outbreaks in Europe and the United States resulted in a contemporary update of pregnancy-associated outcomes. In Italy

Rubella is a self-limiting maternal viral infection139 caused by a togavirus of the genus Rubivirus. Rubella can cause serious fetal disease, including congenital rubella syndrome (CRS). Maternal postauricular adenopathy may be detectable a week before the characteristic maculopapular rash appears and may persist for one to two weeks after the rash disappears. A high incidence of arthritis among young women is described.140 Successful vaccination campaigns have made CRS very rare in the United States, and transmission requires prolonged exposure. Mothers infected during the first half of pregnancy can infect the fetus, resulting in miscarriage, stillbirth, intellectual disability, sensorineural deafness, cataracts, and heart disease. In one study, the intrauterine infection rates were 10%, 11.8%,

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2.9%, and 6.5% after maternal infection at 1–10, 11–14, 15–19, and 20–29 weeks gestation.139 Six of 95 fetuses from rubellainfected mothers had serologic evidence of congenital infection. Among the six fetuses, one had CRS with sensorineural deafness, two were terminated at midtrimester, two were normal, and one was lost to follow-up. There were no rubella deficits in the other 81 children during a two- to four-year follow-up.139 The only possible anesthetic consideration is to avoid needling a rash during NA.

Zika Virus Zika virus flavivirus caused an epidemic with the epicenter in South America in 2009. The Zika virus is transmitted through an arthropod vector (mosquito), sexual contact, transfusion of blood, or blood products. Symptoms of the infection range from asymptomatic to rash, conjunctivitis, fever, and malaise to the development of Guillain-Barré syndrome. Zika virus infection in pregnancy can be vertically transmitted and cause congenital Zika syndrome in approximately 3% of cases. Characteristics of congenital Zika syndrome are microcephaly, developmental delay, and IUGR. Since the initial report, Zika cases have dropped off sharply, suggesting that the development of humoral immunity is protective and that epidemic potential exists only with the introduction of the virus into a naïve population. There are no clear guidelines on anesthesia for parturients with the Zika virus. In the absence of Guillain-Barré, neurological manifestations, or coagulopathy, NA is reasonable.141

Herpesviruses There are > 100 known herpesviruses; however, only three are of interest in pregnancy: herpes simplex virus types 1 and 2, varicella-zoster virus, and cytomegalovirus.

Herpes Simplex Viruses Herpes simplex virus (HSV) infection of the genital tract is one of the most common sexually transmitted infections. Transmission occurs through direct skin-to-skin contact into the mucosa or breaks in the skin. Herpes simplex virus is a ­double-stranded DNA virus differentiated into HSV type 1 (HSV-1) and HSV type 2 (HSV-2), based on the glycoproteins in the lipid bilayer envelope. Infection with HSV results in lifelong infection with latent infection in the dorsal root ganglia and lytic growth phases indicated by outbreaks of painful ulcerative lesions. Asymptomatic shedding of HSV is characteristic. Most HSV-infected individuals are unaware that they have contracted the virus. Only approximately 5–15% of infected individuals report recognition of their infections.142 A serologic screening study found a seroprevalence of 21% for HSV-2 antibodies,143 however, this is undoubtedly an underestimate because HSV-1 is an increasing cause of genital herpes.144 Transmission of HSV to the infant results from ascending infection after rupture of the membranes or passage of the neonate through an infected birth canal, but transplacental transmission also occurs. Neonatal genital herpes from an infected mother is high (30–50%) if acquired near the time of delivery. The risk is low (< 1%) among women with prenatal recurrent

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herpes or who acquire genital herpes during the first half of pregnancy,145 possibly due to the passive transfer of maternal HSV antibodies to the infant. These antibodies protect the infant from HSV acquisition during delivery. Neonatal HSV infections can manifest as a disseminated disease (22.9%), CNS disease (33.7%), and disease limited to the skin, eyes, or mouth (SEM) (43.4%).146 Despite significant advancements in managing neonatal HSV infection with high-dose intravenous acyclovir, mortality is 29% for disseminated disease and 4% for CNS disease;147 20% of neonatal herpes survivors have long-term neurologic sequelae.146 Due to the significant morbidity and mortality associated with neonatal HSV infection, pregnant women with a history of HSV should take antiviral therapy with valacyclovir starting at 36 weeks gestation to prevent an outbreak. If an HSV lesion is present at the time of delivery or if a primary outbreak occurs in the third trimester, the recommendation is for a CD to avoid exposing the infant to HSV.148 General, epidural, and spinal anesthesia have been used safely in women with active, recurrent herpes simplex lesions. There is concern that NA might introduce the virus into the CNS during primary infection due to viremia. However, there is only one report of a transient postpartum neurologic deficit associated with NA and primary infection.149 Nonetheless, some caution against NA during primary infection because herpes encephalitis is devastating. Herpes encephalitis is part of the differential diagnosis of seizures during pregnancy.150 One report describes the failure of acyclovir to prevent neonatal infection in a parturient with HSV type 2 encephalitis.151 In a parturient with active genital herpes, discuss the mode of delivery with the obstetrician. Neuraxial anesthesia is contraindicated in patients with untreated primary HSV, as transient neurological symptoms might occur from the virus accessing the intrathecal space.149 Patients may receive NA if treated for primary HSV or secondary HSV.149 Disseminated HSV could result in multiorgan failure, prompting immediate evaluation for possible hemodynamic and respiratory support. Start antiviral medication and consult an infectious disease specialist as soon as possible. There is evidence that epidural morphine,152 epidural fentanyl, and intrathecal morphine may reactivate HSV.153 The mechanism is unclear, but opioid activity within the spinal nucleus of the trigeminal nerve may be responsible. Inform the parturient with an HSV history about a possible postpartum outbreak when contemplating using neuraxial opioids.

Other Herpesviruses Cytomegalovirus Cytomegalovirus (CMV) is the most common vertically transmitted infection. Congenital CMV is the leading cause of hearing loss and developmental delay in children.154 Cytomegalovirus is often asymptomatic and can reactivate to cause congenital transmission. Primary CMV infection is more frequently associated with vertical transmission, but reactivation and reinfection cause most cases.155 To date, there is no effective intervention to prevent congenital transmission for CMV. Clinical manifestations of virus replication are seldom seen, except in immunocompromised individuals who may develop

Infectious Diseases in Pregnancy

encephalitis, pneumonia, and multiorgan failure. However, pregnant or postpartum women may have transaminitis and pancytopenia. Consider any organ involvement when tailoring the anesthetic plan. In asymptomatic patients, anesthetic management will often involve routine care.

Varicella-Zoster Virus (Chickenpox) Varicella-zoster virus (VZV) is highly contagious with 80–90% secondary attack rates and a seroprevalence rate of > 98%.156 In Canada, primary maternal varicella infection is estimated to complicate three to five per 1000 pregnancies.157 The average incubation period of varicella is 14 days, occurring more frequently during late winter and early spring.158 A day after the onset of fever, a nonsynchronous maculopapular rash appears on the skin and mucosa. The lesions undergo vesiculation and appear as pruritic, superficial thin-walled vesicles, arising in crops. The incidence of VZV is no higher in pregnant than in nonpregnant women. VZV primary infection or chickenpox during pregnancy is associated with increased maternal morbidity and mortality. Pregnant women are more likely to develop hypoglycemia, pneumonia, encephalitis, hepatitis, pancreatitis, and nephritis after chickenpox infection. Most cases of varicella pneumonia in pregnancy occur in the third trimester. Before antiviral therapy (e.g., acyclovir), 65% of pregnant women with varicella developed varicella pneumonia, with a maternal mortality rate of 41% compared to 17% in nonpregnant patients.159 After the introduction of antiviral therapy, there were no maternal deaths in a study of 18 pregnant women with varicella pneumonia.160 This result suggested that antiviral treatment is effective, although it does not prevent the fetal effects. Although prior VZV infection confers immunity, medical personnel (and others) should avoid or minimize their exposure to infectious patients since secondary infections are more common than previously thought.161 Transplacental infection can produce congenital varicella syndrome in < 2% of cases. Affected newborns are likely to be small for gestational age and have skin changes, e.g., hypertrophy, erythema, and scar formation (cicatrix). They may also have brain malformations (e.g., cortical atrophy and dilated ventricles), hypoplastic limbs, and an array of other defects, depending on the timing of infection related to organogenesis. Congenital varicella syndrome occurs in 0.4–2% of infected mothers.157,162 Varicella-zoster immune globulin is given to exposed VZVseronegative pregnant patients to prevent infection. The CNS is the most common site for extracutaneous involvement with varicella. Infection of the CNS can lead to acute cerebellar ataxia, encephalitis, meningitis, or GuillainBarré syndrome. Brown and colleagues speculated that a pencil-point spinal needle was less likely than an epidural needle to core tissue, potentially introducing infected cells into the neuraxis.161 They recommend administering GA when active lesions are present. For patients with active varicella infection, examine the proposed site of neuraxial insertion, and if active lesions are present, avoid NA and consider alternatives. If a CD is necessary, administer GA. A report describes successful spinal anesthesia for an

elective CD in a parturient one week following treatment with varicella immunoglobulin.161 Another case report describes a paramedian approach for NA, avoiding active lesions.163 There are no studies that compare NA to GA for CD in these patients.

Maternal Bacterial Infections Invasive Bacterial Infection Associated with Intravenous Drug Use The increase in opioid use has paralleled a rise in intravenous drug use (IVDU)-associated infections in the United States.164 In pregnancy, these infections also continue to increase, particularly cellulitis, infectious arthritis, osteomyelitis, and endocarditis,165,166 where the infectious source may be an atypical pathogen. Pregnancy outcomes in the setting of these disseminated infections remain unclear, but the physiology of pregnancy complicates their management and antimicrobial treatment. Bacteremia is a hallmark of deep infections (septic arthritis, osteomyelitis, and endocarditis), which often require prolonged antibiotic administration.164,165,167–169 If there is ongoing bacteremia, administer GA for CD. Opioid tolerance may complicate postpartum pain management. Management of infective endocarditis requires a multidisciplinary approach.170

Syphilis

Treponema pallidum is the causative agent of syphilis and is transmitted sexually as well as vertically. Vertical transmission occurs in upwards of 50% of untreated maternal infections. Congenital and maternal syphilis is on the rise in the United States and across the globe.171,172 Syphilis is treated with penicillin G. Because congenital syphilis is preventable with maternal treatment, the recommendation is that all women are screened for syphilis and rescreened in the third trimester. There are no particular anesthetic concerns for a pregnant patient with syphilis. As syphilis can present in any organ system with secondary dissemination, consult with neurology for any neurologic manifestations and discuss the possibility of NA. The presence of spirochetal bacteria in the CSF may prolong treatment and increase the risk for vertical transmission with secondary dissemination.

Listeria

Listeria monocytogenes, the etiologic agent of listeriosis, is transmitted through contaminated food and can be transmitted vertically. Listeriosis is more common in pregnant women than in the general population (12/100,000 vs. 0.7/100,000).173 An infection often has mild symptoms, the most common being fever, but patients may also have nausea, vomiting, and diarrhea. There are rare reports of meningitis during pregnancy. Listeria is a vertical pathogen associated with congenital infection, stillbirth, and pregnancy loss. The placenta often displays significant inflammation. Amoxicillin is the treatment for listeria in pregnancy. If there are neurologic symptoms, consult with an infectious disease specialist. One anesthetic concern is hypovolemia which requires treatment before NA. In the event of an IUFD, coagulopathy could preclude NA.

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Q Fever

Coxiella burnetii during pregnancy may manifest as acute pneumonia, hepatitis, or a flu-like illness. A severe chronic form exists, characterized by endocarditis, chronic hepatitis, and chronic fatigue syndrome.174 The impact of Q fever on pregnancy is unclear. Fetal death at 24 weeks gestation was reported in a woman with chronic infection.175 The obstetrician who treated the infected patient developed pneumonia shortly after the fetal demise, possibly resulting from the aerosolization of organisms from the infected placenta. The treatment of the mother was cotrimoxazole and the obstetrician, doxycycline.175 Most cases of Q Fever are asymptomatic or mild. Standard anesthesia management may be appropriate; however, severe cases of Q Fever can progress to ARDS, hepatitis, and endocarditis. Tailor the anesthetic management to account for those sequelae in severe cases.

Tropical Diseases Mycobacterium tuberculosis ( Tuberculosis) Tuberculosis (TB) is estimated to infect one-third of the world’s population, with most of those affected living in developing countries.176 About 10% of infected patients develop symptoms, but this number is rising due to HIV co-infection.177 Individuals in certain occupations (e.g., health care workers) have an increased risk of TB.178 Clinical manifestations of TB include an unremitting cough, fatigue, weight loss, loss of appetite, fever, hemoptysis, and night sweats. In one study of TB in pregnancy, 38% had pulmonary TB, 53% had extrapulmonary TB, and 9% had both.179,180 Pregnancy does not change the course of tuberculosis, but TB poses a risk to the pregnant woman and her fetus unless treated. Screen pregnant women for TB in high-risk populations (immigrants, HIV-positive, homeless, or intravenous drug users.)181 Management of TB in pregnancy should be multidisciplinary, with treatment initiated at diagnosis. Most treatment options are safe in pregnancy. Before neuraxial placement, assess the parturient for systemic manifestations. Barring no absolute contraindications, NA is acceptable. However, there are reports of NA unmasking extrapulmonary disease in parturients.182–184 A carefully titrated NA technique might be beneficial in preventing respiratory muscle weakness in a patient at risk of postoperative respiratory failure and mechanical ventilation.

Vibrio cholerae (Cholera)

Vibrio cholerae is the causative agent of cholera, a severe and devastating diarrheal disease. After an incubation period of a few hours to three days, severe diarrhea and vomiting (equivalent to a loss of one liter of fluid per hour) occur, resulting in dehydration. Preoperative care involves intense rehydration, correction of electrolytic disturbances, and improvement in nutritional status. Hospitalize a pregnant patient with cholera during the acute phase. Anesthetic considerations in the acute phase relate primarily to managing clinical shock with rehydration via peripheral and central lines.

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Typhoid Fever Typhoid is predominantly a GI gram-negative bacterial disease caused by Salmonella (S) typhi and S. paratyphi. Ingestion of contaminated food is followed in 6–48 hours by abdominal cramps, sustained bacteremia, high fever, vomiting, diarrhea, and occasionally colonic perforation.185 This may lead to multiorgan involvement with renal failure, hepatitis, meningitis, diffuse cerebral edema, brain abscesses, and epidural abscesses.186,187 A 14-day-course of chloramphenicol or 3-day-course of ceftriaxone is effective,188 along with supportive therapy. The possibility of CNS spread of disease (meningitis, epidural, cerebral abscess) contraindicates epidural and spinal anesthesia during the acute phase of the disease. Abnormal liver function may mimic HELLP syndrome.

Parasitic Diseases Plasmodium species (Malaria) Malaria is a tropical parasitemia transmitted by mosquitoes (Anopheles species) infected with Plasmodium (P) species (vivax, falciparum, malariae, or ovale). P. falciparum and P. vivax cause most of the cases in pregnancy. Malaria in pregnancy causes different clinical presentations in endemic areas and during epidemics in nonendemic areas. Both are associated with maternal and neonatal morbidity. Fried and Duffy reviewed the epidemiology and burden of disease.189 In endemic areas, women are semi-immune and may have mild or no symptoms. However, erythrocytes containing mature forms of the parasite can sequester in the placental intervillous space. This reservoir of parasites leads to severe maternal anemia, low birth weight, and prematurity.190 Pregnancy in a woman without preexisting immunity predisposes her to severe disease, including cerebral malaria, respiratory distress, and death. Consider chemoprophylaxis for travelers and patients in endemic areas. WHO recommends quinine and clindamycin in the first trimester for pregnant women with uncomplicated falciparum malaria and artemisinin-based combination therapies (ACT) in the second and third trimesters.191 As severe malaria can progress rapidly to death, initiate treatment as soon as possible. Treatment of severe malaria in the parturient is IV artesunate, similar to nonpregnant patients.191,192 Complications from IV artesunate, such as hemolytic anemia, are rare.192 Base the anesthetic management of a patient with malaria on clinical manifestations.193 In severe cases, malaria can cause pancytopenia, cerebral edema, pulmonary edema, renal failure, and hepatitis, necessitating urgent CD under GA. There is a report of successful spinal anesthesia for emergency CD in a parturient with malaria,194 and another of a parturient with cerebral edema and pancytopenia who had a successful vacuum-assisted vaginal delivery under monitored anesthesia care.195

Toxoplasmosis Toxoplasmosis is an infection caused by a protozoan parasite, Toxoplasma gondii. A primary infection occurring during pregnancy or in the immunocompromised host (mainly HIVpositive mothers) puts the fetus and newborn at risk due to

Infectious Diseases in Pregnancy

vertical transmission. It is crucial to prevent toxoplasmosis as untreated infants with subclinical disease at birth may develop seizures, significant cognitive and motor deficits, and diminution in cognitive function over time. Further, infants treated for a year with pyrimethamine and sulfadiazine have poorer cognitive function than their uninfected siblings.196 Pregnant women should avoid exposure to risk factors such as raw or undercooked meat, unwashed fruits or vegetables, and cat excrement (especially in cat litter). Most cases of maternal toxoplasmosis are asymptomatic or have only nonspecific lymphadenopathy, fever, myalgia, or prostration. Ocular toxoplasmosis is less common. Screening may be the only way to identify infection. A woman with toxoplasmosis received successful LEA, but following an IV infusion of spiramycin (to treat toxoplasmosis), she developed numbness, tingling, a metallic taste, and fetal bradycardia.197 The epidural was working well, but the anesthesiologist administered a GA for an emergency CD over concerns of LA toxicity. Subsequently, the authors concluded that the adverse reaction was due to spiramycin.

Trypanosoma cruzi (Chagas Disease)

Transmission of Trypanosoma cruzi to humans occurs following infected reduviid bug bites; contamination of the bite or mucosa results from feces containing trypomastigotes. Acute Chagas disease is usually mild (lymphadenopathy and unilateral periorbital edema known as the Romaña sign). After the acute illness resolves, the patient enters the indeterminate phase, after which life-long parasitemia may occur. Ten to thirty percent of those infected will develop chronic Chagas disease years later. Characteristics of chronic disease are denervation of the cardiac conducting system resulting in cardiomyopathy,198 and denervation of digestive tract smooth muscle, resulting in megacolon or megaesophagus. Forty percent of patients with Chagas disease develop impairment of the cardiac conducting system, mainly left anterior hemiblock or anterior fascicular block. Clinical manifestations of GI tract denervation include constipation, gastroesophageal reflux disease, and dysphagia. The incidence of maternal transmission to her fetus in the chronic phase is 0.7%.199 Congenital disease occurs in 2–10% of infants born to infected mothers200,201 and may result in spontaneous abortion, fetal hydrops, stillbirth, or premature birth. In pregnancy, multiple maternal reinfections from repeated reduviid bug bites increase maternal parasitemia and worsen congenital Chagas disease.202 Diagnosis of congenital Chagas is by histologic evidence of placental villitis. There are no satisfactory drug therapies to prevent the transmission of the parasite to the offspring. The cure rate of congenital Chagas disease is > 90% following treatment begun in the first year of infection. Patients who develop chronic Chagas disease tolerate NA and GA without significant difficulties and may have less postoperative pain than healthy patients. As a subset of pregnant women from endemic areas will have dilated cardiomyopathy and potentially lethal ventricular dysrhythmias,203,204 evaluate functional status, ECG, and echocardiography. A parturient with Chagas disease received GA for an emergency hysterectomy due to PPH; the authors did not report the details of the anesthetic.205 In a series of nonobstetric patients with chronic

Chagas disease, etomidate and vecuronium were used for GA induction.206 Telemetry may be warranted peripartum.

Leishmaniasis Leishmaniasis can occur in three forms, cutaneous, mucocutaneous leishmaniasis, and visceral leishmaniasis (kala-azar). Cutaneous is the most common form and causes skin lesions, mainly ulcers. Usually, the mucocutaneous form of leishmaniasis is self-limiting. Destructive lesions of the nasal, ­pharyngeal, and laryngeal mucosa can occur in the advanced stages of the disease and may lead to mutilation of the face and difficult endotracheal intubation. Visceral leishmaniasis (VL)207 is a rare disease in pregnancy with only anecdotal reports. It is life-threatening for mothers and infants, endemic in tropical and sub-tropical areas, and vertical transmission can occur.207 Characteristics of maternal VL are insidious fever, shivering, anorexia, nausea, vomiting, hepatosplenomegaly, cutaneous lesions, anemia, and leukopenia. The usual presentation of neonates with congenital disease is fever, pancytopenia, and splenomegaly.208 Treatment of the mother with amphotericin B is safe and effective for her and the baby.209 Evaluate parturients with leishmaniasis for skin lesions at the site of neuraxial placement. As thrombocytopenia is a possibility, obtain a CBC in these patients.210

Infectious Complications from Anesthesia There is no direct evidence that lumbar puncture, using proper sterile technique, facilitates CNS disease by introducing viruses or bacteria from blood into the CSF. The incidence of meningitis after lumbar puncture appears similar to spontaneous meningitis in bacteremic patients,211,212 although it is controversial.213 The incidence of epidural abscess after lumbar epidural catheterization in obstetric patients is estimated at one in 505,000,214 as opposed to the rate of spontaneous epidural abscess formation in the general hospital population, which is estimated at 0.2–1.2 per 10,000.215 Hence, it may be challenging to differentiate spontaneous complications from lumbar puncture-induced complications. An epidural abscess can develop spontaneously postpartum, as described after GA.216 However, a disproportionate number of epidural abscesses follow thoracic epidural block.217 Patients having concomitant systemic or epidural steroids are at increased risk.218 Subdural empyema has occurred after spinal anesthesia.219 The most likely pathogen in spinal meningitis after NA is Staphylococcus aureus, but 2.5% of CNS infections are from Klebsiella pneumoniae. One case report described an epidural infection secondary to cervical vertebra osteomyelitis.220 Factors in the development of meningitis include the use of opioids,96 integrity of the immunologic system, bacterial/viral count, and virulence in blood/CSF. An epidural abscess may have a variable presentation, making diagnosis difficult. For example, a patient with a spinal epidural abscess may be normothermic and have normal white blood cell counts. Consider the diagnosis in any patient who demonstrates signs of infection, back pain, postspinal headache, radicular pain, weakness, paralysis, or bladder dysfunction.221

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The incidence of spinal epidural abscess is rising. It is crucial to consider the diagnosis early. Although increased awareness has led to decreased mortality, morbidity remains unacceptably high, with rapid deterioration of neurological status if there is delayed treatment. The outcome is related to erythrocyte sedimentation rate, muscle strength at presentation, and speed of intervention. Age, sex, comorbidities, C-reactive protein levels, and degree of thecal sac compression have no prognostic value. The most important factors for a good outcome in spinal epidural abscess are high clinical suspicion, prompt investigation, and immediate intervention. Urgent surgery is more likely to be offered to patients presenting with neurologic deficits than pain alone. Patients treated without early surgery were significantly more likely to deteriorate and suffer poor outcomes.221 In rats, a dural puncture is associated with the development of meningitis, provided the animals are bacteremic at the time of the puncture. Antibiotic treatment before the puncture appears to eliminate this risk.222 In one report, three of eight bacteremic obstetric patients received epidural anesthesia following antibiotic therapy, with none developing infectious complications, such as epidural abscess or meningitis.223 However, there are reports of meningitis and epidural abscess after spinal anesthesia, despite preoperative administration of antibiotics.224,225 In the absence of guidelines, the anesthesiologist must consider the risk for NA versus GA individually, as no risk is acceptable unless there is a clear benefit. For a localized infection away from the site of needle placement, the use of extradural catheters appears relatively safe.223,226 For patients with evidence of systemic infection, GA is recommended in emergencies. If the patient has responded to antibiotic therapy and the intravascular volume is optimized, NA is acceptable. Valuable Clinical Insights • T here is no direct evidence that dural puncture, using proper sterile technique, introduces viruses or bacteria from the blood into the CSF. • An extradural abscess can develop spontaneously postpartum. • The presentation of an extradural abscess varies (may be normothermic, have a normal white blood cell count), making diagnosis difficult. • Morbidity is unacceptably high with an epidural abscess, with rapid deterioration of neurological status if treatment is delayed.

Conclusion Many infectious diseases, including those caused by emerging organisms, have sudden and devastating effects on the mother and fetus. The role of the obstetric anesthesiologist may be limited to life support and/or the containment of the infectious agent. Many infectious agents, particularly those causing tropical diseases, lead to chronic infections, often with fetal transmission. Reports detailing the anesthetic management of these patients are rarely published, so the obstetric anesthesiologist must understand the pathophysiology of the disease and its clinical features to make

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rational decisions relating to anesthesia. The usual contraindications to NA or GA apply. Intravenous and LA techniques that preserve cardiorespiratory function are recommended for high-risk patients with contraindications to NA and GA. The most effective means to control infectious diseases is prevention. Good hygiene and sterile precautions limit the spread of infectious agents. Political and economic support for preventive health measures, including proper sanitation, is paramount, especially in developing countries. While vaccination against disease is a helpful control measure, many are hesitant to be vaccinated in pregnancy. Vaccines in the context of pregnancy and the peripartum state are largely understudied.

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23

Dermatologic Conditions in Pregnancy David J. Berman

Introduction The physiologic state of pregnancy is associated with various changes to several organ systems, often in drastic and notable ways. While the integumentary system is not usually the first consideration for physicians taking care of pregnant women, skin changes in pregnancy can be memorable and potentially exacerbate chronic skin conditions. Additionally, patients with chronic skin conditions may become pregnant, altering the course of their disease. This chapter will review some common physiologic skin changes in pregnancy and discuss dermatoses specific to pregnancy. It will then review chronic skin conditions in pregnant patients, followed by a brief overview of dermatologic drug safety in pregnancy. The anesthetic implications of various disorders will be discussed in their relevant sections. It is important to note that some systemic diseases, such as autoimmune conditions, have skin effects in pregnancy. While the skin changes involved in these diseases may be significant, they will not be the focus of this chapter. A note of caution regarding nomenclature: skin conditions have been categorized and named by gross appearance, histologic characteristics, molecular markers, or responses to treatment. These names have changed as further information and descriptors become available. To the extent possible, the conditions in this chapter have been categorized based on currently accepted nomenclature focusing on the pathophysiology of skin lesions rather than their appearance.

Functions of the Skin The integumentary system comprises approximately 16% of body weight. It is a system containing multiple tissues, including skin itself (epidermis, dermis, and hypodermis), glands (sudoriferous and sebaceous), hair, nails, nervous tissue, blood vessels, and even muscle (piloerector muscles). Although considered a single organ, the skin serves multiple discrete and interactive functions. As a barrier, skin protects the body from physical agents, mechanical injury, dehydration, and ultraviolet radiation. The proper balance of collagen and elastic fibers gives skin flexibility while preventing overstretching. The skin’s secretory glands, fat, and vascular system help regulate body temperature. Likewise, when present, hair and the air pockets produced by piloerection may help maintain body temperature. Skin plays a significant role in vitamin D production. It contains numerous

receptors that interact with the nervous system to affect the entire body. Anesthesiologists frequently use the skin to monitor temperature, oxygenation, hydration, blood pressure, and even blood sugar (shivering, color, tone, diaphoresis, etc.). Careful skin evaluation can lead to the detection of many systemic disease processes, including connective tissue disease, infection, diabetes mellitus, and vascular disease. Although skin changes rarely have anesthetic implications for the pregnant woman, the underlying conditions associated with such changes are often significant to the anesthesiologist. This chapter will focus on such associations to help the clinician distinguish benign conditions from those with morbid potential. Of note, some of the conditions discussed are rare and will receive only passing mention when the anesthetic implications are trivial. The essential roles of skin during anesthesia are often neglected, with the anesthesiologist trained to concentrate on internal organ homeostasis (e.g., the cardiopulmonary system). Nevertheless, the integrity of skin functions in the perioperative period is critical to a good outcome. Thus, a plan for proper skincare must be part of the anesthetic management. This is the case whenever the skin is compromised by either disease or invasive techniques, in other words, in practically every anesthetic procedure. An anesthetic plan for managing normal skin includes simple measures such as avoiding prolonged skin ischemia through careful positioning, minimizing dermal trauma, and avoiding excessive heat or cold application. Perhaps the most important preventative measure in skincare is skin preparation for invasive procedures: salient points about skin preparation are discussed in Table 23.1.

Relevant Skin Changes in Pregnancy The skin undergoes several changes during pregnancy, related primarily to hormonal influences. Such changes may be marked but are usually benign, nonproblematic, and temporary, although some (such as striae gravidarum or “stretch marks”) may persist long after delivery. These common skin changes, seen in many or most of the gravid population, are listed in Table 23.2.

Common Dermatoses Specific to Pregnancy Several common dermatoses of pregnancy are discussed individually below. As an adjunct to this section, Figure 23.1 (an

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David J. Berman

Table 23.1  Skin preparation for invasive procedures in anesthesiology

Skin preparation/ Scrub

There is no universally accepted method for skin preparation. Cutaneous antiseptics in common use include: 10% povidone-iodine, 70% alcohol, iodophor in alcohol, and 2% aqueous chlorhexidine (Hibiclens®). As povidone-iodine multiuse bottles may become contaminated, it is recommended that only singleuse containers of this antiseptic be used.1 Of these preparations, only chlorhexidine and iodophor in alcohol have significant residual antimicrobial activity once the skin has dried. There are concerns that chlorhexidine, despite its use as a plaque-controlling mouthwash, is toxic to various eukaryotic cells and that its use near mucous membranes should be limited. Although rubbing increases the antiseptic effects,2 blisters or bullae should not be vigorously scrubbed as tissue damage and spread of some types of lesions may occur. Topical antiseptics dry the skin and this may exacerbate eczematous lesions. Treatment with skin moisturizers, e.g., petroleum jelly, may be beneficial following the procedure. Certain pathologic lesions, e.g., psoriasis and sarcoid, may be reactivated by trauma (Koebner response). Similarly, infection of the skin may be spread by instrumentation. Thus, avoid instrumentation of blistered, raw, open, or otherwise infected skin. Malignant melanoma lesions should not be instrumented.

Needle instrumentation

Inflammatory sites may be instrumented, but like eczematous patches, they may harbor Staphylococcus aureus and therefore are best left undisturbed, if possible. Historical concerns had existed about tattoo ink deposition if tattoos are traversed during NA, and specifically regarding neurologic complication of these dyes: this concern has not come to fruition and placing a sterile needle through a healed tattoo is now a widely accepted practice.

Table modified from McKay RS, Schlicher JE. Dermatoses. In Gambling, DR, Douglas MJ, McKay RS (Eds.), Obstetric Anesthesia and Uncommon Disorders (2nd edn.). Philadelphia, PA: W. B. Saunders, 2014: 342.3

algorithm to help distinguish various causes of pruritus in pregnancy), and Table 23.3 (an overview of the salient clinical pearls of commonly conflated pruritic dermatoses) may prove helpful.

Pregnancyrelated

Non-pregnancyrelated

Without rash

Skin Hyperpigmentation Increased vascularity (spider angiomas, hemangiomas) Palmar erythema Nonpitting edema Pruritus Changes to existing skin lesions due to hormonal changes (keloids, leiomyomas, dermatofibromas, neurofibromas) Hair Frontal hair thinning Postpartum hair loss Mucosal Hyperemia of gingiva/oral mucosa Vaginal erythema Nail Brittleness Rapid growth Transverse grooves

Intrahepatic Cholestasis of Pregnancy Unlike other pregnancy-specific dermatoses discussed in this text, intrahepatic cholestasis of pregnancy is not associated with any skin changes. This diagnosis is based on patient reports of intense pruritus, predominantly in the palms and soles, which often leads to vigorous itching and excoriations.4 The diagnosis of intrahepatic cholestasis of pregnancy is critical since there is significant morbidity associated with fetal exposure to elevated maternal bile acids. The fetus is at risk for intrauterine demise, respiratory distress, meconium-stained amniotic fluid, and premature delivery. While controversial, maternal intrahepatic cholestasis of pregnancy may lead to chronic liver disease.5

Anesthetic Implications When caring for patients with intrahepatic cholestasis of pregnancy, anesthetic concerns include the degree of liver dysfunction and associated coagulopathy. Reduced bile acid excretion Early-onset in pregnancy ( 11 mmol/L; liver function tests and serology evaluated

Skin biopsy for histologic changes, ELISA for BP180 antibodies

None required; clinical diagnosis

None required; clinical diagnosis

Maternal prognosis

Higher hemorrhage risk, gallstone risk; potential for liver disease later in life

Resolution in weeks to months postpartum; may recur with hormonal contraception or menstruation

No change compared to baseline pregnancy risk

No change compared to baseline pregnancy risk; high risk of hand and nipple eczema postpartum

Recurrence in subsequent pregnancies

Significant

Yes, often more severe

Rare

Yes, but severity unchanged

Fetal effects/ prognosis

Increased risk of prematurity, fetal distress, stillbirth

Increase in growth restriction; some neonates born with mild self-limited disease

No known effects, no skin changes in the newborn

No direct effects to fetus, but fetus likely to develop atopic changes due to multifactorial (environmental, genetic) risk factors

Table adapted from Massone C, Cerroni L, Heidrun N, et al. Histopathological diagnosis of atopic eruption of pregnancy and polymorphic eruption of pregnancy. Am J Dermatopathol 2014;36:812–21.

may also be associated with decreased fat-soluble vitamin absorption, contributing to coagulopathy.6 While rare, neuraxial hematomas can occur in patients with cholestasis of pregnancy.7 Additionally, neuraxial opioids may exacerbate pruritus in this patient population. There may be a role for ondansetron to treat pruritus in this condition.8 Valuable Clinical Insight Intrahepatic cholestasis of pregnancy is among the most common dermatologically related conditions the clinician encounters, but is not associated with visible skin changes. Diagnosis is made based on laboratory testing and clinical history of intense pruritus.

Pemphigoid Gestationis Pemphigoid gestationis (formerly known as herpes gestationis) is a rare autoimmune disorder targeting the bullous pemphigoid antigen, an antigen found in the basement membrane zone of the skin. It causes intense pruritus, often followed by the appearance of urticarial plaques or papules (Figure 23.2). These lesions typically begin on the trunk and spread throughout the body, almost always sparing mucous membranes.9 This rare entity occurs in approximately 1 in 50,000 pregnancies and occurs exclusively in pregnancy or in the setting of gestational trophoblastic tumors.10 The onset of this condition is typically in the second or third trimester, and relapse in subsequent pregnancies is common.

Figure 23.2  Pemphigoid gestationis.Figure originally from Agostinis P, Antonello RM. Pemphigoid gestationis. N Engl J Med 2020;383:e61. Used with permission. (See color plate section). A: Clustered tense vesicles and bullae B: Truncal areas of urticated erythema

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Additionally, the disease may flare in the immediate postpartum period. Diagnosis comes from direct visual observation, characteristic findings on skin biopsy, and circulating anti-BP180 antibodies. Treatment for pemphigoid gestationis typically involves suppressing the immune system, thereby reducing antibody-­ mediated basement membrane destruction.11 Immunosuppression is achieved with topical corticosteroids, oral systemic corticosteroids, or other immunosuppressive regimens (cyclosporine,12 rituximab,13 plasmapheresis14) for refractory cases.15 Antihistamines can be helpful to relieve pruritus. Fetal effects of pemphigoid gestationis typically involve preterm delivery and SGA neonates, thought to be due to placental insufficiency. Passage of antibodies to the fetus can result in blisters, which are mild and resolve without treatment.16

Anesthetic Implications As a noninfectious process, areas of skin with mild disease may be used for procedures (ECG lead placement, securing an epidural or IV catheter), if necessary. However, use caution when handling skin with blisters, as secondary infection and permanent scarring may occur. A recent case report highlighted the difficulty of anesthetic planning in a patient with lesions covering her lower back, requiring GA for CD.17 Unlike other bullous diseases of pregnancy, the mucous membranes are typically unaffected, and therefore, no specific airway management precautions are required. However, care is required when securing airways to affected areas, due to blister disruption from tape removal. Valuable Clinical Insight Pemphigoid gestationis is a blistering dermatosis of pregnancy, diagnosed on skin biopsy, and typically spares mucosal surfaces.

Polymorphic Eruption of Pregnancy Polymorphic eruption of pregnancy (PEP), also called pruritic urticarial papules and plaques of pregnancy (PUPPP), is a relatively common gestational dermatosis. It usually occurs in the last few weeks of gestation or immediately postpartum.18 A selflimited, mild pruritic inflammation, PEP is relatively common, occurring in approximately one in 300 pregnancies. Historical terms such as Nurse’s late-onset prurigo, Bourne’s toxemic rash of pregnancy, and linear IgM dermatosis of pregnancy are historical names that are likely the same disease entity histologically.19 The pathogenesis of PEP is unknown but may be related to stretching of the skin given its increased likelihood in multiple gestation and nulliparous patients, and its predilection for the abdomen. There may be a component of immune response to circulating fetal antigens, as numerous case series highlight a preponderance of this condition in women pregnant with male fetuses.20,21 Commonly presenting as pruritic, erythematous papules within striae (Figure 23.3), this rash usually spares palms, soles, and face. Polymorphic eruption of pregnancy is self-limiting, resolving within two to six weeks postpartum and often not

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Figure 23.3  Polymorphic eruption of pregnancy. Used under a creative commons license, originally published by Brandão P, Portela-Carvalho AS, Melo A, et al. Post-partum polymorphic eruption of pregnancy. Obstet Gynaecol Cases Rev 2018 (online). https://doi.org/10.23937/2377-9004/1410139 (See color plate section).

requiring treatment. If treatment is needed, moderate to high potency topical corticosteroids may be used: rare cases necessitate systemic corticosteroid therapy. Delivery is rarely a treatment measure, and this condition poses no maternal or neonatal risk beyond pruritus. Recurrence in subsequent pregnancies is uncommon.22

Anesthetic Implications Given the relatively benign nature of this common condition, it will likely not significantly impact anesthetic care. For maternal comfort, histamine-releasing agents should be avoided, and affected skin should not be used for procedures if possible. Valuable Clinical Insight Polymorphic eruption in pregnancy is a benign, self-limiting skin condition commonly affecting the periumbilical region. It rarely recurs in subsequent pregnancies.

Atopic Eruption of Pregnancy Atopic eruption of pregnancy (AEP) is a term that includes a variety of historical disease states thought to be along the same spectrum of atopic diathesis. This pruritic disorder typically presents as an eczematous or papular lesion in patients prone to atopy. Most cases occur early in pregnancy, and this disease spectrum has a high rate of disease recurrence in subsequent pregnancies. The prior disease classifications eczema in pregnancy, prurigo of pregnancy (also called prurigo gestationis of Besnier, Nurse’s early-onset prurigo of pregnancy, Spangler’s papular dermatitis of pregnancy, and linear immunoglobulin M [IgM] disease of pregnancy), and pruritic folliculitis of pregnancy were previously considered independent entities, but have shared clinical features and therefore are discussed together here and elsewhere.23 This amalgamation of disease categories remains controversial but is increasing in acceptability.24

Dermatologic Conditions in Pregnancy

The most common of the pregnancy-associated dermatoses, the unstudied incidence for AEP is likely relatively high. It occurs in the first or second trimester with atopic skin changes, especially in patients with a history of atopic disease (rhinitis, asthma, atopic dermatitis). These lesions are usually located along the face, neck, and flexural areas and appear as either eczematous patches or papules. These may be follicle-based, grouped, or scattered and are strongly associated with skin dryness. Alternative forms of AEP (prurigo of pregnancy or P-type AEP, as well as pruritic folliculitis of pregnancy) may alter the clinical presentation of this heterogeneous spectrum. Regardless of the presentation, these lesions typically clear before or within two to six weeks of delivery.25 Diagnosis of AEP is mainly clinical, as there is limited utility in the often-nonspecific skin biopsy findings. A biopsy can rule out pemphigoid gestationis or confirm another disease where a specific treatment depends on an accurate diagnosis. If patients present with folliculitis, culture is often performed to delineate bacterial or fungal infection. While laboratory testing is generally not indicated, about two-thirds of patients may have elevated IgE levels.26 Like nonpregnant patients with eczema, the treatment involves the relief of symptoms. Skin hydration is crucial for symptom control, and low potency corticosteroids and systemic antihistamines are often required. There is no association with adverse fetal effects.25 Patients should be informed that recurrence in subsequent pregnancies is very likely.10

Anesthetic Implications Like PEP, this condition will not significantly impact anesthetic care. For the sake of maternal comfort, avoid histamine-­ releasing agents. While the back is an unlikely location for AEP, care should be taken to avoid folliculitis (if present) during NA. Like other pruritic states, neuraxial opioids are associated with the development of significant pruritus and can be problematic. Valuable Clinical Insight Atopic eruption of pregnancy describes eczematous or papular lesions in patients prone to atopy. It is a relatively benign condition that is often responsive to topical corticosteroids.

Hypocalcemia is also associated with PPP. Its exact mechanism is unclear but might be due to hypoparathyroidism. Diagnosis is often made clinically, but a skin biopsy is recommended since accurate diagnosis can alter the disease management and could influence delivery decisions. The pathologic appearance of skin biopsy specimens is consistent with nonpregnancy pustular psoriasis, including spongiform pustules with neutrophils and parakeratosis. Parakeratosis is a mode of keratinization characterized by retention of nuclei in the stratum corneum. Parakeratosis is normal in mucous membranes but not in skin where it leads to an abnormal replacement of annular squames with nucleated cells. Fetal growth restriction and placental deficiencies can result,28 and therefore, fetal testing is indicated with routine nonstress or biophysical profile testing and growth ultrasounds. Maternal electrolyte and fluid imbalances should be corrected, and early delivery considered for symptom relief or fetal safety.29 Medical treatment includes high-dose systemic corticosteroid therapy, cyclosporine monotherapy,30 and infliximab.31 In cases of severe disease in postpartum non-breastfeeding women, methotrexate or systemic retinoid therapy is an option.32

Anesthetic Implications The anesthesiologist should evaluate the location and extent of lesions in women presenting with PPP. Examine the pharyngeal mucosa for these lesions, and have a high index of suspicion for esophageal involvement in severe cases. Avoid lesions during the placement of NA, and be careful when placing orogastric tubes, esophageal, and nasopharyngeal temperature probes. As hypocalcemia is associated with PPP, pay attention to calcium and fluid management in the peripartum period, focusing on the cardiovascular effects of hypocalcemia and metabolic alkalosis during labor hyperventilation. Other metabolic and electrolyte changes (hyperglycemia, hypokalemia) can result from high-dose systemic corticosteroid therapy and impact anesthetic management. Finally, calcium gluconate therapy may alter the effects of magnesium sulfate if being used for preeclampsia. While NA can be used in patients with this condition, experience is limited: there is one report of an acutely decompensated patient who ultimately recovered well.33 Valuable Clinical Insight

Pustular Psoriasis of Pregnancy Pustular psoriasis of pregnancy (PPP), formerly known as impetigo herpetiformis, is a rare pregnancy-associated dermatosis with significant risk for maternal harm. It typically presents in the third trimester of pregnancy but may occur earlier or in the immediate postpartum period.26 It presents clinically as symmetric, erythematous plaques studded at the periphery with sterile pustules. This evolves into central erosion and plaque enlargement. This rash usually starts on the trunk and extremities and may involve oral and esophageal erosions as well.26 While pruritus is typically absent, generalized systemic symptoms such as fever, malaise, nausea, vomiting, diarrhea, and tetany are common.27 This reflects an underlying inflammation, often accompanied by leukocytosis and an elevated ESR.

Pustular psoriasis is a rare but morbid dermatosis of pregnancy associated with large plaques on the skin and mucous membranes. It is associated with significant electrolyte disturbances, uteroplacental insufficiency, and may require high-dose corticosteroids or biologic therapies.

Common Skin Diseases during Pregnancy Inflammatory Conditions Acne Vulgaris Acne vulgaris typically improves in early pregnancy but worsens toward the end of pregnancy from maternal exposure to circulating fetal androgens. As in nonpregnant patients, mild disease is treated with topical benzoyl peroxide. While retinoids

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are often considered first-line therapy (either topical or systemic), they are teratogenic and are not used in pregnancy.34,35 Antibiotic therapy is often used, either topically or systemically; several small studies showed a higher rate of fetal cardiac defects associated with erythromycin exposure in early pregnancy, though this may reflect underlying conditions rather than the exposure to the medication itself.36,37 For this reason, azithromycin or clarithromycin are the preferred agents for acne treatment in the first trimester. Ultraviolet (UV) light therapy is a second-line treatment with excellent efficacy and safety.38 Acne vulgaris should have minimal effect on anesthetic care beyond rigorous attention to skin hygiene.

Psoriasis Vulgaris The disease course of psoriasis in pregnancy is remarkably variable. Most women improve due to the immune tolerance associated with pregnancy. However, a minority of patients require escalation of therapy during pregnancy.39 Large populationbased datasets show no change in neonatal outcome with mild or moderate disease but an increased risk of preterm delivery, low birthweight infants, and hypertensive disorders of pregnancy with severe disease.40,41 Typical treatment of psoriasis in pregnancy involves topical corticosteroid therapy and emollients. More severe cases require systemic corticosteroids and UV-B therapy, a protocol well studied in pregnancy.42 Drugs such as methotrexate and retinoids, mainstays of treatment in nonpregnant psoriatic patients, should be avoided as these drugs are known teratogens. Immune modulating therapy such as cyclosporine43 and tumor necrosis factor-alpha inhibitors44,45 is used for severe disease after balancing maternal and neonatal risks and benefits. Anesthetic Implications Psoriasis changes skin flora, leading to an increase in bacterial counts and less normal skin flora than healthy controls.46 Neuraxial procedures require a meticulous sterile technique and appropriate skin preparation. There is limited data for the performance of NA in the setting of plaque psoriasis but one case report described successful NA after topical corticosteroid optimization, skin cultures of the surrounding affected tissue, and avoidance of the psoriatic plaque.47

Pityriasis Rosea This inflammatory skin condition can present during pregnancy and is often confused with guttate psoriasis or tinea corporis. It is associated with human herpesvirus 6 infection, and management is typically conservative, and the rash fades rapidly. One case series of 38 women showed a high risk of preterm delivery and fetal loss, though an etiologic relationship was not established.48 While there is a concern about NA through an active skin lesion in a patient with pityriasis rosea, literature exists to support this approach.49

Urticaria Urticaria, colloquially known as hives, commonly presents during pregnancy. It can mimic other pregnancy-specific dermatoses and often appears as early pemphigoid gestationis. If

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urticaria persists, typical treatments are oral antihistamines. These medications have a long safety record in pregnancy.50

Erythema Nodosum Erythema nodosum presents as a reactive inflammatory rash in the lower extremities, typically in the anterior portion. This rash may be associated with fever, fatigue, and arthralgias. These symptoms usually last for several weeks and remit spontaneously, but severe or bothersome cases may require a short course of systemic corticosteroids if conservative therapy (rest, elevation, bandaging, and systemic analgesics) fails.51

Infections and Infestations Varicella Zoster Herpes zoster reactivation in pregnancy is not associated with viremia, and therefore the fetus is not affected. Primary varicella infections are uncommon in pregnancy but may be associated with fetal varicella syndrome and major neurological and growth defects.52 Varicella vaccination is relatively contraindicated in pregnancy, and therefore seronegative women with exposure to varicella are recommended for passive immunization with varicella zoster immunoglobulin.53 Acyclovir is used to treat varicella in pregnancy.54 This is also the treatment of choice for neonatal varicella.55

Herpes Simplex Primary herpes simplex virus occurs in 1–2% of pregnancies and may be associated with a more severe disease course than nonpregnant patients. Additionally, patients with active genital herpes simplex lesions should deliver by CD to decrease the risk of neonatal transmission, which can be associated with severe neonatal disease.56 Acyclovir remains the treatment of choice for herpes simplex in pregnancy, with an excellent safety record.57

Anesthetic Implications Primary herpes simplex virus outbreaks are associated with a high degree of viremia, which typically do not cross into the CNS. Therefore, the traditional approach has been to avoid NA in patients with primary HSV, though the data for this practice are lacking. The risk appears low for those with reactivation of HSV.58 Neuraxial opioids have been shown to increase HSV recurrence postpartum,59 though the incidence and effect size are debated.60–63 Neonatal transmission appears low. Despite this small increased risk, expert consensus is to use neuraxial morphine in patients with a history of herpes simplex, as the benefits appear to outweigh the risks.64

Scabies Scabies infestation is relatively common in pregnancy. The preferred treatment is topical permethrin, associated with minimal systemic absorption and a strong safety record in pregnancy. For treatment failures or intolerance, benzyl benzoate can be used.65 Antihistamines and mild topical corticosteroids relieve itching.

Dermatologic Conditions in Pregnancy

Autoimmune Diseases Pemphigus Vulgaris The pemphigus family of diseases produces autoimmune blistering of the skin and mucosae due to antibodies against epidermal protein, namely desmoglein 1 and 3. These rare diseases are potentially fatal and are associated with a high degree of maternal and neonatal morbidity.66 The most common of these diseases, pemphigus vulgaris, is characterized by flaccid blisters or erosions on the trunk and limbs (initially presenting as blisters but becoming erosions when scratched). Orogenital mucosal surfaces are often involved as well. This disease can occur or flare during pregnancy, and the fetus can be affected: the extent of maternal disease is not well associated with the degree of fetal involvement.67–69 Direct fluorescence via skin biopsy or serum antibodies70 will confirm the diagnosis. Systemic treatment is often required for this condition, initially with high-dose corticosteroids and potentially progressing to other immunosuppressive agents such as dapsone or azathioprine. In severe disease, plasmapheresis or plasma exchange may be necessary, and IV immune globulin also has been used successfully.71,72

Systemic Lupus Erythematosus While lupus is discussed later in the section on autoimmune disease (Chapter 26), this condition can present with skin symptoms in both the neonate and fetus and is associated with poor pregnancy outcomes in the setting of severe disease.73 Additionally, congenital heart block remains a concern for neonates born to women affected with lupus.

C1-Esterase Inhibitor Deficiency (Hereditary Angioedema) C1-esterase inhibitor (C1-INH) deficiency is a rare disorder of the complement system characterized by episodes of cutaneous or mucosal edema of the skin, GI tract, and upper airway.74 Airway instrumentation or minor trauma may cause life-threatening airway edema. Gastrointestinal obstruction may occur. The consensus is that NA is the safest anesthetic technique for parturients with C1-INH deficiency and that airway instrumentation should be avoided if possible.75 Elective CD should be considered if a problematic vaginal birth is anticipated. Prophylactic FFP can be used before labor or ­obstetric surgery to temporarily elevate serum levels of C1-INH, although this exposes mother and fetus to transfusion risks. C1-esterase inhibitor concentrate can be used for acute angioedema and before major surgery, so it should be available in the operating room.

Mastocytosis Mastocytosis comprises several diseases characterized by an abnormal increase in tissue mast cells. Cutaneous mastocytosis (CM) or urticaria pigmentosa is the most common form and presents as a mast cell hyperplasia limited to the skin. In the United States, 0.1–0.8% of new patients visiting dermatology clinics have some form of mastocytosis. Most cases (75%) occur

in children, but a second peak occurs between 30 and 49 years of age. Males and females are equally affected.76 Systemic mastocytosis (SM) comprises multiple distinct entities in which mast cells infiltrate the skin and other organs. The diagnosis of SM is based on one major criterion and one minor criterion, or three minor criteria. Major criteria include the presence of multifocal dense infiltrates of > 15 mast cells in the bone marrow and other extracutaneous organs. Four minor criteria include the presence of elevated serum alpha tryptase levels > 20 ng/mL, the expression of specific mast cell surface markers, the presence of a c-kit mutation on mast cells, and the presence of > 25% abnormal spindle-shaped mast cells. Cutaneous symptoms of CM include pruritus, flushing, urticaria, and dermatographism. It is essential to distinguish these symptoms from LA (or other drug) allergies so that these agents are not given in error.77 Symptoms of SM include syncope, gastric distress, nausea and vomiting, diarrhea, bone pain, and neuropsychiatric symptoms. There is no cure for mastocytosis but the majority of children with pediatric CM regress at puberty. Women with mastocytosis are fertile, and pregnancy and delivery have successfully blocked mast-cell-mediated symptoms.76,77 Pregnancies in women with mastocytosis may proceed normally. However, symptoms will worsen in approximately one third, likely because of decreased medication use (antihistamines, mast cell stabilizing agents, e.g., sodium cromolyn and corticosteroids are the usual therapies). Labor and delivery may progress normally with NA reportedly used.78,79 However, marked histamine excretion has occurred in a pregnant woman with a particularly rare form of mastocytosis (telangiectasia macularis eruptiva perstans). She had an anaphylactoid reaction, rash, uterine contractions, and vaginal bleeding and was successfully treated with tocolytics and antihistamines. Cardiovascular collapse has also been reported. Notably, in some cases including the case of cardiovascular collapse, the authors specifically reported that the patients lacked supporting signs of histamine release such as cutaneous flushing and bronchospasm.80,81 Interferon alpha, corticosteroids, and purine analogs also reduce mast cell burden, with varying results. Future directions include tyrosine kinase inhibitors and bone marrow transplantation.77 Avoidance of histamine-releasing drugs is essential, and GA using remifentanil and sevoflurane has been described.81 Valuable Clinical Insight Autoimmune skin conditions typically improve in pregnancy but can worsen in the immediate postpartum period.

Skin Tumors Benign Melanocytic Nevi Due to hormonal changes of pregnancy, specifically, an increase in circulating melanocyte-stimulating hormone, preexisting nevi may darken in pregnancy.82 In the case of a pregnant woman with suspicious lesions or those with changing appearances,

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close dermatologic examination with dermoscopy and potentially a skin biopsy is recommended.83

Malignant Melanoma Melanoma is among the most common tumors in pregnant women. While somewhat controversial, recent data suggest similar survival rates between pregnant and nonpregnant patients with melanoma.84–86 While treatment of melanoma is beyond the scope of this text, postpartum placental examination will rule out transplacental metastatic spread.86,87 A recent case report of a parturient with melanoma in pregnancy described a fetus with numerous congenital anomalies, but these appeared to be unrelated.88 The ABCDEs of melanoma are important for clinicians to remember (Table 23.4). Valuable Clinical Insight Skin tumors, such as melanoma, can occur or recur during pregnancy. Any pregnant patient with a suspicious lesion should be referred to a dermatologist for evaluation and skin biopsy, as delays can result in disease progression.

Other Dermatologic Conditions Epidermolysis Bullosa Epidermolysis bullosa (EB) is a rare inherited disease marked by fragile skin and debilitating recurrent bullae or blister formation following minimal mechanical trauma. The defect is in the genes regulating keratin formation, and at least 18 different mutations occur, all of which produce a fragile cell phenotype.89 At least ten of these mutations lead to EB. Dystrophic nails and flexion contractures of the joints can lead to deformities. Carious teeth are common, and microstomia caused by scarred contractures of the lips may complicate intubation. Ocular, gastrointestinal, genitourinary, and musculoskeletal complications can occur. All types of EB have variable expression, which accounts for a broad range of clinical presentations. The most severe forms of EB include the recessive dystrophic EB (RDEB), junctional EB (JEB), EB with pyloric atresia (EB-PA), and EB simplex (EBS).90 DNA-based prenatal diagnosis is available, and genetic counseling is offered. Treatment is symptomatic for most types, although high-dose IV immunoglobulin, immunosuppressants, and corticosteroids are used in a similar disease, epidermolysis bullosa acquisita. Aggressive squamous cell carcinoma often occurs, particularly in patients with severe dystrophic EB.91 Pregnancy rarely affects the course of EB, but specific alterations in obstetric care are necessary to assure maternal and fetal safety.92 Table 23.4  Melanoma ABCDEs A

Asymmetry

B

Border irregularity

C

Color variation or dark black color

D

Diameter > 0.6 cm

E

Evolving behavior (changes in appearance over time)

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Anesthetic Implications Anesthesia for pediatric and young patients with EB has been well described.93–96 Airway complications are uncommon, and GA is often used. Various authors have summarized the special anesthetic considerations for patients with EB.97–100 Optimal patient positioning to avoid pressure points or tangential friction is necessary. Avoid scrubbing the skin, subcutaneous infiltration, surgical tape, and adhesive electrodes. The eyes should be lubricated but not taped. Electrocardiographic monitoring using leads placed over sheets with water as the conductive media has been reported.101 Skin beneath a BP cuff is protected by adequate padding and maximum intervals between measurements chosen. Nasal, oral, laryngeal, and tracheal manipulations should be minimized to protect the upper airway. Fiberoptic intubation is preferred because of the possibility of microstomia and the simultaneous direct examination of the airway for lesions. In addition, oro- or nasopharyngeal tubes and catheters should be avoided. With care, serious complications did not occur in 67 procedures using standard anesthetic techniques, including GA and NA.100 Specifically in obstetric anesthesia, recent articles have highlighted the challenges associated with caring for these patients with EB, both for vaginal delivery and CD.102,103

Erythema Multiforme, Stevens-Johnson Syndrome, and Toxic Epidermal Necrolysis Erythema multiforme (EM) is an acute, sometimes recurrent, inflammatory disease of the skin and mucous membranes. EM minor features typical target lesions, no mucosal involvement, and constitutional symptoms of fever, malaise, and arthralgias. EM major is a more serious, and potentially life-­threatening, disease with mucosal lesions and occasional multisystem involvement. EM is manifested as purpuric vesiculobullous target lesions accompanying macules, papules, and an urticarialappearing rash. The lesions may occur on any part of the body and may arise suddenly, lasting one to four weeks. Target lesions show necrotic keratinocytes, dermal endothelial swelling, and papillary edema. Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are similar diseases, but they generally involve more extensive skin involvement than EM with potentially high mortality rates.104–106 Patients with SJS may develop large bullae with ulcerated erosions of the nose, mouth, and tracheobronchial tree. The conjunctiva, gastrointestinal mucosa, and genitourinary mucosa may be involved, leading to stenoses, including vaginal stenosis. Bacterial secondary infections are common. Serious but rare complications include hepatitis, glomerulonephritis, cardiac involvement, and pneumonia. Fluid and electrolyte imbalance and anemia may occur. Toxic epidermal necrolysis is defined by the presence of a more extensive detachment of skin (> 30%). Both EM major and SJS can involve internal organs. EM minor usually follows recurrent herpes simplex infections and tends to be self-limiting. EM major is mainly related to herpes virus infection. In contrast, precipitating factors of SJS and TEN include drug reactions (barbiturates, antibiotics, NSAIDs, salicylates, anticonvulsants, and digitalis),107 herpes simplex virus (HSV), mycoplasma, human immunodeficiency virus (HIV), bacterial (especially

Dermatologic Conditions in Pregnancy

Staphylococcus), fungal, and parasitic infections. SJS may also be a manifestation of a collagen vascular or neoplastic disease. Erythema multiforme occurs primarily in young, healthy persons. Although mortality in SJS is between 3% and 18%, SJS may have its ominous prognostic connotation more from inadequate treatment rather than the disease itself. High-dose systemic corticosteroid therapy (oral dosage starting at > 80 mg/ day) will usually resolve most cases of SJS. Erythema multiforme and SJS, like all subepidermal bullous dermatoses, must be managed with extreme caution regarding possible airway lesions and with meticulous care to avoid friction on the affected skin. Specific guidelines for anesthetic care are similar to those discussed above for epidermolysis bullosa. Neuraxial anesthesia is feasible and may be the preferred approach for these patients.108

dermatologic drugs in pregnant patients as the data remains limited. However, the potential for these medications to improve the quality of life of pregnant women is significant, and therefore it is essential to address the safety of specific medications helpful in the management of the above conditions.50,110 Most women take routine medications during pregnancy, with a recent study showing that 86% of women take an average of three medications during pregnancy.111 While drug safety is an essential topic throughout pregnancy, it is crucial in early pregnancy when organogenesis occurs. This is important, as many women may be unaware of their pregnancy early on. However, the abrupt discontinuation of effective medications due to pregnancy may be associated with maternal and fetal harm from worsening disease. This requires a discussion of risks and benefits between the patient and her physicians: ideally, this involves coordinated care between dermatologists and obstetricians for high-risk patients.

Neurofibromatosis

Topical Corticosteroids

Anesthetic Considerations

Neurofibromatosis (NF) is an autosomal dominant genetic disorder that causes tumors of the nervous system. This progressive disorder affects all races, all ethnic groups, and both sexes equally. There are two genetically distinct forms: NF1 and NF2. While NF is further discussed in Chapter 13 detailing musculoskeletal diseases, its implications for the anesthesiologist can be crucial. Patients with neurofibromas can exhibit CNS symptoms or have neurofibromas in the neuraxial space, predisposing to numerous complications from NA. Patients with NF should undergo careful pre-procedural screening to assess the extent and location of neurofibromas, including airway and lower back. Some anesthesiologists prefer imaging studies in pregnancy before initiation of NA. Table 23.5 summarizes key NF signs and symptoms.

Dermatologic Drug Safety in Pregnancy While a thorough discussion of drug safety in pregnancy and lactation and a discussion of FDA classes is beyond the scope of this text, specific attention should be paid to the safety of Table 23.5  Neurofibromatosis signs and symptoms

As the most-often used dermatologic drug in pregnancy, a discussion of topical corticosteroid therapy is relevant to pregnant women with skin conditions. Topical steroids come in various formulations and are classified based on potency (Table 23.6). Recent guidelines looked at the use of topical corticosteroids in pregnancy based on the best available evidence.112 While the review showed no association between maternal topical corticosteroid use and a number of pregnancy complications (including craniofacial abnormalities, preterm delivery, or fetal death), they identified an association between fetal growth restriction and treatment with potent or ultrapotent topical corticosteroids. Further study has elucidated that the risk of impaired fetal growth depended on the total amount of dispensed corticosteroid throughout the pregnancy. The risk of growth restriction was greater for women who were dispensed potent or very potent corticosteroids, with a total of > 300 g corticosteroid equivalent throughout the pregnancy.113 This finding was not seen in patients prescribed < 200 g of topical corticosteroid, nor confirmed in systematic reviews.114 Current recommendations limit corticosteroids to the mildest effective formulation necessary for clinical improvement. If a higher potency corticosteroid is necessary, the total dose should be kept to a minimum, and fetal surveillance with growth ultrasonography is recommended.

CNS

Seizures, headaches, brain tumors, brain vascular defects, learning disabilities, cognitive delays, macrocephaly, cancer, Chiari-I malformation109

Ophthalmic

Visual impairment/blindness, optic glioma, Lisch nodules (benign iris hamartomas)

Table 23.6  Corticosteroid potency classes

Laryngeal

Speech impairments and delays

Steroid class

Examples

Café-au-lait spots and neurofibromas of varying sizes may occur anywhere. Freckling where skin meets skin (armpits, groin, under breasts), intense pruritus

Mild

1% hydrocortisone

Moderate

Betamethasone valerate 0.025% (Betnovate-RD) and clobetasone butyrate 0.05% (Eumovate), Trimovate, Daktacort

Cardiovascular

Hypertension, vessel fragility and rupture, coagulopathy

Potent

Musculoskeletal

Kyphoscoliosis, short stature, pseudoarthrosis (false joints), bone deformities

Betamethasone valerate 0.1% (Betnovate), hydrocortisone butyrate 0.1% (Locoid), mometasone furoate 0.1% (Elocon, Fucibet, Lotriderm)

Endocrine

Delayed puberty, increase in number and size of tumors during pregnancy

Ultrapotent

Clobetasol propionate 0.05% (Dermovate)

Gastrointestinal

Chronic constipation, vomiting, diarrhea, pain

Skin

This table is adapted from McAleer MA, Flohr C, Irvine AD. Management of difficult and severe eczema in childhood. BMJ 2012;345:e4770.115

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David J. Berman

Valuable Clinical Insight Mild or moderate potency corticosteroids are generally considered safe in pregnancy, but larger doses of higher potency corticosteroids are associated with intrauterine growth restriction.

Topical Antibiotics Systemic Medications Topical and oral retinoids have been strongly associated with multiple fetal anomalies and should be avoided in pregnancy.35 Additionally, the systemic administration of methotrexate or mycophenolate is associated with teratogenic effects. The use of these medications in women of childbearing age should include explicit warnings against pregnancy.116,117 Systemic corticosteroid therapy is occasionally required, either as a pulse dose to induce disease remission or as a chronic dose when necessary to control disease activity. Systemic corticosteroids are associated with a wide variety of neurohormonal, electrolyte, and cardiovascular changes due to their mechanism of action. While this has been demonstrated in pregnancy, maternal and neonatal outcomes have not been well studied. Earlier studies showed a potential association between craniofacial abnormalities and maternal corticosteroid use, but recent data are conflicting, and underlying maternal disease may also contribute to this effect. Little data exist to support the notion that systemic corticosteroids alone will increase the risk of preterm birth, growth restriction, preeclampsia, or gestational diabetes.118

Summary Dermatologic disease, both pregnancy-related and coincident with pregnancy, can have a significant effect on maternal and fetal health. Even relatively benign conditions such as eczematous states can have broad effects on quality of life. In pregnant patients presenting with skin changes, it is crucial to take a thorough history and perform a physical examination to rule out potentially dangerous conditions. Referral to a dermatologist should be considered when the diagnosis is questionable, when the standard response to therapy is inadequate, when a skin biopsy is necessary, or when traditional therapies are not acceptable in pregnancy. Cooperative management of the parturient with skin disease between the obstetrician and dermatologist is crucial in high-risk skin conditions. Anesthesiologists should be familiar with the above conditions, as these diseases (or their resultant treatments) can significantly impact anesthetic management.

Additional Topics Multiple Pterygium Syndrome

Multiple pterygium syndrome (MPS) is a cutaneous condition inherited in an autosomal dominant fashion. The following case describes a pregnant woman with MPS who presented for elective CD. Neuraxial anesthesia failed, and the back-up plan of awake intubation was extremely difficult.

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Daga V, Mendonca C, Choksey F, et al. Anaesthetic management of a patient with multiple pterygium syndrome for elective caesarean section. Int J Obstet Anesth 2017;31:96–100.

Harlequin Ichthyosis

Harlequin ichthyosis (HI) is a rare disorder of defective lipid transport resulting in severe epidermal hyperkeratosis producing large plate-like scales. Mortality is high, but improved treatments have allowed some with HI to survive into their third and fourth decades. Until this case, there were no known reports of pregnancy followed by the birth of a healthy neonate to a mother with HI. This was one of approximately 25 known current HI survivors worldwide unique in having carried a pregnancy to full term, and it outlines the ­challenges for the anesthesiologist during labor and delivery. Rosenbaum T, Rosenbaum ER, Lienhart KL, et al. Obstetric anesthesia for harlequin ichthyosis: a unique challenge. A A Case Rep 2015;4:19–21.

Pregnant Women with Burn Injuries

Pregnant patients with burn injuries present a unique challenge and require special anesthetic considerations. One case published by Radosevich et al. describes a woman at 28 weeks gestation, who suffered 45% total burn surface area partial and full-thickness burns. Anesthetic management included preparation and care ­during excision and skin grafting procedures and during emergency CD. The management plan was developed by a multidisciplinary team of personnel from burn surgery, obstetrics, anesthesiology, neonatology, and nursing. Radosevich MA, Finegold H, Goldfarb W, et al. Anesthetic management of the pregnant burn patient: excision and grafting to emergency Cesarean section. J Clin Anesth 2013;25:582–586. Correia-Sa I, Marques M, Horta R, et al. Experience in management of burn injury during pregnancy in a burn unit. J Burn Care Res 2021;42:232–235.

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103. Araújo M, Brás R, Frada R, et al. Caesarean delivery in a pregnant woman with epidermolysis bullosa: anaesthetic challenges. Int J Obstet Anesth 2017;30:68–72. 104. Farthing P, Bagan J-V, Scully C. Mucosal disease series. Number IV. Erythema multiforme. Oral Dis 2005;11: 261–267. 105. Bastuji-Garin S. Clinical classification of cases of toxic epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme. Arch Dermatol 1993;129:92–96. https:// doi.org/10.1001/archderm.129.1.92 106. Sehgal VN, Srivastava G. Toxic epidermal necrolysis (TEN) Lyell’s syndrome. J Dermatolog Treat 2005;16:278–286. 107. Roujeau JC. Stevens-Johnson syndrome and toxic epidermal necrolysis are severity variants of the same disease which differs from erythema multiforme. J Dermatol 1997;24:726–729. 108. Ahiskalioglu A, Yayik AM, Erguney OD, et al. Combined spinal-epidural anaesthesia for urgent caesarean section in a parturient with Stevens-Johnson syndrome. Int J Obstet Anesth 2017;30:78–79. 109. Tubbs RS, Rutledge SL, Kosentka A, et al. Chiari I malformation and neurofibromatosis type 1. Pediatr Neurol 2004;30:278–280. 110. Butler DC, Heller MM, Murase JE. Safety of dermatologic medications in pregnancy and lactation: Part II. Lactation. J Am Acad Dermatol 2014;70:417.e1–10; quiz 427. 111. Collaborative group on drug use in pregnancy (C. G. D. U. P.). Medication during pregnancy: an intercontinental cooperative study. Int J Gynecol Obstet 1992;39:185–196. https://doi .org/10.1016/0020-7292(92)90656-4 112. Chi C-C, Kirtschig G, Aberer W, et al. Evidence-based (S3) guideline on topical corticosteroids in pregnancy. Br J Dermatol 2011;165:943–952. 113. Chi C-C, Wang S-H, Mayon-White R, et al. Pregnancy outcomes after maternal exposure to topical corticosteroids: a UK population-based cohort study. JAMA Dermatol 2013;149:1274–1280. 114. Chi C-C, Wang S-H, Wojnarowska F, et al. Safety of topical corticosteroids in pregnancy. Cochrane Database Syst Rev 2015;2015:CD007346. 115. McAleer MA, Flohr C, Irvine AD. Management of difficult and severe eczema in childhood. BMJ 2012;345:e4770. 116. Zip C. A practical guide to dermatological drug use in pregnancy. Skin Therapy Lett 2006;11:1–4. 117. Anderka MT, Lin AE, Abuelo DN, et al. Reviewing the evidence for mycophenolate mofetil as a new teratogen: case report and review of the literature. Am J Med Genet A 2009;149A:1241–1248. 118. Bandoli G, Palmsten K, Forbess Smith CJ, et al. A review of systemic corticosteroid use in pregnancy and the risk of select pregnancy and birth outcomes. Rheum Dis Clin North Am 2017;43:489–502.

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Chapter

24

Psychiatric Disorders in Pregnancy Allana Munro and Ronald B. George

Valuable Clinical Insights • The most common psychiatric disorders encountered peripartum include depression, anxiety, bipolar disorder, posttraumatic stress disorder, and schizophrenia. • Peripartum psychiatric disorders are commonly underdiagnosed and undertreated but may have grave maternal and neonatal consequences. • Obstetric anesthesiologists need to know how psychiatric disorders and their associated treatment can affect the mother, baby, and anesthetic care. • There are specific anesthetic considerations for pregnant patients with psychiatric disorders and interactions between anesthesia and the medical management of these disorders. • There are a variety of interventions and prevention techniques to improve patient care and manage postpartum ­psychiatric sequelae.

Introduction The peak incidence of psychiatric disorders in women occurs between 23 and 44 years of age, which coincides with childbearing years. The peripartum period may coincide with relapses of earlier mental disorders or the development of a new psychiatric disturbance. Newly diagnosed postpartum psychiatric disorders (PPPD) are a common consequence of pregnancy. Some link PPPD to labor analgesia, operative anesthesia, and peripartum management. It is imperative that obstetric anesthesiologists be familiar with common psychiatric disorders presenting in pregnancy, become an essential member of the multidisciplinary care team for these patients, and be aware of opportunities to prevent PPPD. Pharmacological treatment for psychiatric patients may increase the risk of perioperative complications. The anesthesiologist should consider the specific psychiatric illness, drug type, duration of therapy, drug interactions, and dose management in the preoperative assessment and perioperative management of psychiatric patients. When psychosocial and psychological treatments are insufficient and do not provide timely resolution, pharmacological therapy is required. This chapter considers the anesthetic implications of psychiatric conditions that arise de novo and existing illnesses that may be affected by obstetrical anesthesia practice.

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Depression Depression is a common complication of pregnancy and the postpartum period and includes some or all symptoms listed in Table 24.1. Pregnancy-related medical conditions such as anemia, gestational diabetes, and thyroid dysfunction may mimic depression, delaying accurate diagnosis. A systematic review of 25,771 women found a depression prevalence rate in pregnancy of 16%.1 Depression was most prevalent in the last trimester of pregnancy and least in the second trimester, indicating late pregnancy may be a risk factor.1 Postpartum depression has prevalence rates reported at 10–20%.2 Depression and antidepressants can pose risks for preterm birth, low birth weight, IUGR, postnatal adaptation syndrome, and postnatal cognitive and emotional complications.3 Women need to consider the risks of untreated depression in pregnancy, including suicidal behavior, poor nutrition and poor weight gain, cognitive impairment, comorbid substance use disorders, poor self-care, and nonadherence with prenatal care. Also, antenatal depression is a risk factor for postpartum depression (PPD), so proactively counsel women about their risk, follow them closely to monitor symptoms, and initiate treatment early postpartum. One study showed that 75% of women who stopped taking antidepressants had relapses, often in the first trimester, with symptoms severe enough to require retreatment.4 There is no Table 24.1  Features of depression 1.  Depressed mood most of the day, nearly every day 2. Markedly diminished interest or pleasure in all, or almost all, activities most of the day 3.  Significant weight loss, weight gain, or decreased appetite 4.  Insomnia or hypersomnia 5.  Psychomotor agitation or retardation 6.  Fatigue or loss of energy 7. Feelings of worthlessness or excessive or inappropriate guilt (which may be delusional) 8.  Diminished ability to think or concentrate or indecisiveness 9.  Recurrent thoughts of death, or of suicidal ideation From the Diagnostic and Statistical Manual of Mental Disorders (5th edn.). Copyright © 2013. American Psychiatric Association.

Psychiatric Disorders in Pregnancy

Table 24.2  Antidepressants

Selective serotonin reuptake inhibitors (SSRIs)

Serotonin-norepinephrine reuptake inhibitors (SNRIs)

Atypical agents

Tricyclics (TCAs)

Monoamine oxidase inhibitors (MAOIs)

Citalopram

Desvenlafaxine

Bupropion

Amitriptyline

Phenelzine

Escitalopram

Duloxetine

Mirtazapine

Amoxapine

Selegiline

Fluoxetine

Levomilnacipran

Nefazodone

Clomipramine

Tranylcypromine

Fluvoxamine

Milnacipran

Trazodone

Desipramine

Paroxetine

Venlafaxine

Vilazodone

Doxepin

Vortioxetine

Imipramine

Sertraline

Maprotiline Nortriptyline Protriptyline Trimipramine From Lexicomp Online. Copyright © 1978–2021 Lexicomp, Inc. All Rights Reserved.

compelling evidence that the safety of fetal exposure differs among antidepressants, and women should generally receive the same drug during pregnancy. A meta-analysis found that women taking antidepressants in pregnancy had a shorter gestation but no significant difference in infant weight than women with untreated depression.5 However, do not use monoamine oxidase inhibitors during pregnancy. Table 24.2 lists common antidepressants.

Tricyclic Antidepressants Tricyclic antidepressants (TCAs) inhibit the reuptake of neurotransmitters into the presynaptic terminal, increasing the amount available for synaptic transmission. TCA sideeffects result from nonspecific interactions with cholinergic, histaminergic, serotonergic, and dopaminergic receptors. Anticholinergic side-effects occur in up to 15% of patients and are prominent in overdose. Overdose features include dilated pupils, agitation, delirium, convulsions, hyperpyrexia, and prolonged QT and QRS segments. Treatment of overdose includes hyperventilation and sodium bicarbonate to help correct the acidosis.6 All TCAs lower the seizure threshold, so use caution when administering them to PreE patients and following large volumes of LA. Women treated with TCAs do not seem to have a higher risk of spontaneous abortion or preterm birth rates.7 However, multiple studies have found an association between TCAs and PreE8 and PPH.9 The risk of teratogenicity with TCAs is low, and most studies suggest that prenatal drug exposure is not associated with congenital anomalies.10 Antenatal clomipramine use may be an exception. A study of pregnant women taking antidepressants, primarily clomipramine, found a modestly elevated risk of severe malformations, including cardiovascular defects.11 Peripartum exposure to TCAs may result in transient neonatal withdrawal symptoms, hypoglycemia, respiratory distress, and jaundice.12 These antidepressants are secreted into breastmilk, although there are no reports of adverse effects to the infant.

Selective Serotonin Reuptake Inhibitors Selective serotonin reuptake inhibitors (SSRIs) are the most used antidepressants in pregnancy. Serotonin inactivation occurs by reuptake, which is selectively blocked by SSRIs, increasing neurotransmission.13 SSRIs cross placental and blood–brain barriers and transfer into breastmilk, possibly affecting fetal brain development and function. However, SSRIs are not associated with specific patterns of congenital anomalies. A systematic review of more than nine million births found no increased risk of congenital anomalies with SSRI use in pregnancy when the analysis was restricted to women with a psychiatric diagnosis.14 A small risk of congenital malformations may exist, but SSRIs have no substantial teratogenic effects.15 However, fluoxetine has a long half-life predisposing it to accumulate in breastfeeding infants,15 and observational studies suggest there is a small risk of congenital cardiac defects associated with paroxetine use.16 Up to 30% of infants exposed to SSRIs develop a spectrum of symptoms known as neonatal withdrawal syndrome3 (Table 24.3). Cytochrome P450 2D6 is inhibited by SSRIs, potentially increasing the plasma concentration of drugs dependent on hepatic metabolism for clearance. Table 24.3  Symptoms of neonatal withdrawal from selective serotonin reuptake inhibitors

• • • • • • • • • •

Agitation/jitteriness Poor feeding Hypotonia Sleepiness/lethargy GI symptoms Convulsions Tremor Fever Respiratory disorders (respiratory depression, apnea, tachypnea) Extensor posturing (back-arching)

From Australian Adverse Drug Reactions Bulletin 2003;22(4).

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Allana Munro and Ronald B. George

Serotonin-Norepinephrine Reuptake Inhibitors Serotonin-norepinephrine reuptake inhibitors (SNRIs) block presynaptic serotonin and norepinephrine transporter proteins, increasing stimulation of postsynaptic receptors.  They have minimal effect on cholinergic or histaminergic receptors. SNRIs are not associated with an increased risk of congenital malformations,15 but the evidence is conflicting whether SNRIs  are associated with spontaneous abortion.7,17 Some observational studies suggest that SNRIs are associated with increased risk of hypertensive disorders in pregnancy and PPH.18,19

Monoamine Oxidase Inhibitors Monoamine oxidase inhibitors (MAOIs) block the enzyme monoamine oxidase, increasing the concentration of dopamine, norepinephrine, and serotonin within neuronal synapses. Due to concerns about drug and food interaction with MAOIs, they are generally used to treat refractory depression. First generation MAOIs, which bind irreversibly to both A and B subtypes of MAO, can produce lethal excitatory or depressive interactions with meperidine. The former interaction, called type I, results from serotoninergic activity and is characterized by agitation, headache, rigidity, hyperthermia, convulsions, and coma.20 Type II is depressive, characterized by hypotension, respiratory depression, and coma.21 Administration of indirect-acting vasopressor agents, such as ephedrine, in patients taking MAOIs, may cause severe hypertension, requiring vigorous α-adrenoreceptor blockade (e.g., with phentolamine).22 Infusion of direct-acting agents, such as epinephrine, is preferred for maintaining BP. Caution is needed because receptor hypersensitivity may develop in these patients.21 Combining an MAOI with an SSRI produces a hyper serotoninergic state. This synergistic interaction is rare but occasionally leads to death from rhabdomyolysis, DIC, ARDS, and cardiovascular collapse.23 Treat the resulting hyperthermia and muscle rigidity with muscle relaxation, sedation, and controlled ventilation.

levels rapidly. ECT is efficacious in treating depression, schizophrenia, catatonia, and mania, but its primary use is for treatment-resistant depression. ECT is well tolerated with a rapid response postpartum.24 Treatment allows breastfeeding to continue and is effective for severe postpartum psychiatric disorders.25 Pregnant patients may need ECT for urgent symptom control, with implications for the anesthesiologist. ECT may induce premature contractions and labor bradydysrhythmias in the fetus.26 With appropriate precautions, ECT is usually safe in pregnancy. Deciding to embark on ECT during pregnancy should occur after consultation with the obstetrician, psychiatrist, and anesthesiologist. In utero exposure to ECT has not been implicated as a causal factor in teratogenesis.27 Table 24.4 lists recommendations for ECT during pregnancy.

Postpartum Depression The peripartum period is a vulnerable time to develop a mood disorder due to significant physical and hormonal changes. Postpartum, mothers are challenged by sleep deprivation, breastfeeding, pain, and neonate care. If symptoms of baby blues fail to resolve after two weeks, include psychotic features, or significantly impact daily functioning, PPD may be present. PPD is depression that occurs during pregnancy or within four weeks after delivery.28 The highest rates of PPD occur in the first few months after delivery.29 PPD is one of the most common childbirth complications, with an estimated risk of 18%.30 The rate of PPD in women with a history of depression is 25–40%,31 and the recurrence rate in subsequent pregnancies is 50%.32 The most significant risk factor for PPD is a history of depression. Children of mothers with PPD may show emotional detachment that can negatively impact brain development and hinder cognitive and motor milestones.33 Table 24.4  Recommendations for electroconvulsive therapy during pregnancy   1. Hold anticholinergic medications

Valuable Clinical Insights • First generation MAOIs can produce lethal excitatory or depressive interactions with meperidine. • Administration of indirect-acting vasopressor agents, such as ephedrine, in patients on MAOIs may cause severe hypertension, requiring vigorous α-adrenoreceptor blockade (e.g., with phentolamine). • Infusion of direct-acting agents, such as epinephrine, is preferred for maintaining BP. • Combining an MAOI with an SSRI synergistically can produce a hyper serotoninergic state.

Electroconvulsive Therapy Electroconvulsive therapy (ECT) involves the electrical stimulation of neurons in the CNS. An electric current, which triggers a brief seizure, is thought to increase neurotransmitter

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  2. Sodium citrate prior to procedure   3. IV access, adequate hydration   4. Lateral uterine displacement (after 20 weeks gestation)   5. Pretreatment fetal monitoring (after 20 weeks gestation)   6. Hyperventilation with 100% oxygen (enhance the quality of the seizure) but severe respiratory alkalosis must be avoided   7. Maintain normocapnia (avoid severe respiratory alkalosis)   8. Rapid sequence induction with cricoid pressure and tracheal intubation (after first trimester)   9. Induction of anesthesia with IV anesthetic agent such as propofol and a small dose of succinylcholine (e.g., 0.5 mg/kg) to modify the peripheral expression of the seizure 10. Uterine contractions and FHR must be monitored after ECT 11. Observe for vaginal bleeding after treatment From Ward HB, Fromson JA, Cooper JJ, et al. Recommendations for the use of ECT in pregnancy: literature review and proposed clinical protocol. Arch Womens Ment Health 2018;21:715–722.

Psychiatric Disorders in Pregnancy

Anesthetic Implications Childbirth is one of the most painful experiences a woman may have to endure, and labor analgesia and anesthesia can influence the pain experience. There is a growing body of research on the influence of analgesia on PPD risk.34 A few studies suggest that LEA decreases the risk of PPD.35–37 Another study showed that women who received LEA had reduced serum cortisol levels and lower PPD rates at six weeks postpartum.38 On the contrary, other studies have found no protective effect from LEA use and PPD risk.39,40 While there was no statistical association between LEA and the risk of PPD in a systematic review and meta-analysis,41,42 a recent multicenter prospective cohort study with propensity score matching found neuraxial labor analgesia was associated with a reduced risk of PPD, highlighting the ongoing controversy.43 Acute pain such as childbirth may be associated with PPD. In one study, women with severe postpartum pain had a 2.5-fold increase in the risk of chronic pain and a 3.0-fold increase in the risk of developing PPD.44 A prospective observational study found that perinatal pain was independently linked to PPD at six weeks postpartum.45 Based on these findings, labor pain and analgesia may contribute to the onset of PPD. The anesthetic choice for CD may influence PPD. For example, women undergoing GA for CD had increased odds of PPD, suicidal ideation, and self-inflicted injury than patients who had NA.46 A RCT showed those given 0.5 mg/kg ketamine ten minutes post-CD had less PPD.47 These findings suggest that labor and CD pain and analgesia may affect PPD risk. Further research is required to understand better the clinical significance of obstetric anesthesia and PPD. The development of novel, synthetic, neuroactive steroid treatments has led to their use for PPD. Brexanolone, administered as a continuous IV infusion over 60 hours, is effective in treating PPD.48 Valuable Clinical Insight It is uncertain whether LEA reduces postpartum depression risk.

Anxiety Disorders Peripartum anxiety symptoms have the highest incidence during pregnancy and often decrease after birth.49 The pooled prevalence during pregnancy is 15.2% for any anxiety disorder and 22.9% for anxiety symptoms.50 Patients suffering from anxiety disorders during pregnancy are at increased risk for PPD. Screening often misses postpartum anxiety, with only one in three women identified.51 Understanding the effects of anxiety on maternal and infant outcomes is essential, yet there is little information to guide evidence-based treatment decisions during pregnancy. A meta-analysis found significant associations between antenatal anxiety and perinatal complications such as preterm birth, low birth weight, small for gestational age, and small head circumference at birth.52 There are limited studies on an association between postpartum anxiety and obstetric anesthesia. A 2017

multi-phase study found significant decreases in anxiety after the institution of LEA.53 However, another prospective study found no association between the use of LEA and anxiety four months postpartum.54 Further research is required to understand the effect of LEA throughout the postpartum period.

Post-Traumatic Stress Disorder The childbirth experience can cause psychological trauma, manifesting as postpartum post-traumatic stress disorder (PTSD). Symptoms of postpartum PTSD follow the same criteria as the Diagnostic and Statistical Manual (DSM-5),28 and are grouped into three clusters: 1. Re-experiencing of traumatic events. 2. Avoidance and numbing of responsiveness; and 3. Hyperarousal, hypervigilance, and difficulties in concentration. A cross-sectional multicenter study showed that the prevalence of a traumatic birth experience was as high as 37%.55 An estimated prevalence of PTSD after childbirth was 3.1% overall and 15.7% in high-risk groups.56 Prevalence rates for postpartum PTSD increase over time from 1.2% at four to six weeks postpartum to 3.1% at 24 weeks postpartum.57 Women requiring an emergency team response during labor and delivery may have higher postpartum PTSD risk.58 Interestingly, one of the significant risk factors for a traumatic experience was the absence of labor analgesia.55 In a 2019 study, GA was identified as a risk factor for postpartum PTSD. However, the study was based exclusively on emergency cases, making it difficult to determine if anesthesia type affects the development of PTSD.59 Neuraxial anesthesia may prevent postpartum PTSD, serving as a protective measure for pain-induced trauma during delivery.59 However, complications associated with neuraxial placement, such as PDPH or inadequate block, increase the risk of postpartum PTSD.60 Non-pharmacologic treatment should be the first-line treatment in pregnant women with anxiety disorders.61 Psychotherapy, such as cognitive behavioral therapy (CBT), is as effective as antidepressants in managing symptoms of postpartum psychiatric disorders.62 SSRIs and TCAs are the most commonly prescribed medications for managing anxiety. Other commonly prescribed drugs are benzodiazepines (BZDs). BZDs act by mimicking γ–aminobutyric acid (GABA) in the brain and glycine in the spinal cord and brainstem. BZDs are potentially harmful to the fetus, although evidence from studies is scarce. Exposure to BZDs in the first four months of pregnancy does not significantly increase the risk of oral clefts, as determined by a case-control study.63 Table 24.5 includes recommendations for BZD use in pregnancy.

Anesthetic Implications Monitors, infusions, epidural lines, and other pieces of apparatus may precipitate anxiety for patients in labor and delivery. Sympathetic support is essential, perhaps with pharmacologic assistance, such as small doses of short-acting BZDs. Pregnant patients on BZDs are likely tolerant of other drugs in that class. The central sedative properties of BZD may potentiate those of

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Table 24.5  Recommendations for benzodiazepine use during pregnancy

Table 24.6  Common oral and injectable antipsychotics

1. Before conception, carefully re-evaluate pharmacotherapeutic regimens.

First-generation antipsychotics (FGAs)

2. Taper the dose of benzodiazepines to avoid breakthrough symptoms of panic and/or withdrawal.

Oral

Injectable

Potency

Haloperidol

x

x

High

3. For patients on short-acting agents (e.g., alprazolam) who develop recurrence, consider adding a tricyclic antidepressant.

Chlorpromazine

x

x

Low

4. Consider switching patients to a longer half-life agent to decrease the incidence of rebound anxiety.

Fluphenazine

x

x

High

Loxapine

x

x*

High

Perphenazine

x

High

Pimozide

x

High

Thiothixene

x

High

Thioridazine

x

Low

Trifluoperazine

x

High

epidural opioids, whereas the GABAergic activity may lower the pain threshold. Constraint posed by pieces of equipment may precipitate a panic attack for patients in labor. Again, shortacting BZDs in small doses may help (e.g., IV midazolam, 1 mg IV boluses to achieve symptom control).

Schizophrenia Schizophrenia affects 1% of the general population, and pregnancies occur in 50% of women with schizophrenia.65 Decreased institutionalization, increased early intervention psychosis programs, and fertility-sparing second-generation antipsychotic medications have enabled more women with schizophrenia to have the opportunity of motherhood.66 However, pregnant women with schizophrenia and their newborns are vulnerable to adverse outcomes. The characteristic features of schizophrenia are delusions, hallucinations, disorganized speech, grossly disorganized or catatonic behavior, and negative symptoms.67 Impaired functioning may present as not attending antenatal appointments, lack of prenatal vitamins, folate, and thyroid hormone supplementation, increased rates of unplanned and unwanted pregnancy, limited social support, and increased domestic abuse and poverty rates.68 Women with schizophrenia may experience more obstetric complications.69 Specifically, hypertensive disorders of pregnancy, placental abruption, and APH are more common in women with schizophrenia.69,70 Additionally, they more commonly have a fetus with distress at delivery, IUGR, and an increased risk of cardiovascular anomalies.69 Babies of women with schizophrenia have elevated risks of prematurity, reduced birth weight, and reduced Apgar at one  minute.71 Women taking antipsychotics in pregnancy are at higher risk of CD and should consider delivering in a setting with enhanced monitoring and intervention.72,73 Approximately half of the patients with schizophrenia relapse without medication, suggesting treatment is needed during pregnancy to prevent a recurrence.74 In the past decade, antipsychotics have been shown to be relatively safe in pregnancy, and their avoidance poses more significant risks, such as suicide and infanticide.75 Maintenance therapy for schizophrenia consists of first- or second-generation antipsychotics, in either oral or injectable form (Table 24.6). When choosing an antipsychotic for use in pregnancy, guidelines recommend high potency first-generation antipsychotics (FGAs) to minimize maternal anticholinergic, hypotensive, and antihistaminergic effects associated with low potency FGAs.76 They can produce extrapyramidal side-effects, so it is common to co-administer 64

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Second-generation antipsychotics (SGAPs) Olanzapine

x

x

Quetiapine

x

Risperidone

x

x

Ziprasidone

x

x

Aripiprazole

x

x

Asenapine

x

Brexpiprazole

x

Cariprazine

x

Clozapine

x

Iloperidone

x

Lumateperone

x

Lurasidone

x

Paliperidone

x

Pimavanserin

x

x

* Not available in the United States. From: Lexicomp Online. Copyright © 1978–2021 Lexicomp, Inc. All Rights Reserved and Jibson MD. First-generation antipsychotic medications: pharmacology, administration, and comparative side effects. In Marder S, Friedman M (Eds). UpToDate. Waltham, MA: UpToDate. Available from: www.uptodate.com/contents/first-generation-antipsychotic-medicationspharmacology-administration-and-comparative-side-effects [last accessed October 27, 2022].

atropine-like antiparkinsonian agents such as benztropine with FGA. However, most generally avoid routine antiparkinsonian agents in pregnancy. Others advocate using the lowest effective antipsychotic dose in pregnancy or cautious discontinuation of medication in the first trimester.77 Resumption of antipsychotic medication should begin immediately postpartum. There is limited information available on how pregnancy affects the relapse of schizophrenia. While a small prospective study reported worsening mental health postpartum,78 a larger trial identified no increased risk of acute relapse.79 Factors known to increase risk outside of the perinatal period should be addressed, such as stress and sleep deprivation.80 Women who

Psychiatric Disorders in Pregnancy

suffer from peripartum psychoses have considerable potential for self-harm and harming their neonates. While poorly controlled studies suggest an increased risk of congenital malformations associated with FGAs, it appears the risk is minimal overall.77,81,82 A systematic review77 and a large cohort study83 have not implicated any antipsychotic as a major teratogen. However, exposure to FGAs is associated with an increased risk of premature delivery, and exposure in the third trimester may cause transient extrapyramidal symptoms and neonatal withdrawal symptoms.83 Second-generation antipsychotics (SGAPs) differ from FGAs in side effects, especially their potentially higher risk of metabolic syndrome and VTE.84 There is some evidence that fetal exposure to SGAPs may increase infant birth weight (large for gestational age)85 and the risk of neonatal hypoglycemia.86 One large study found that women prescribed SGAPs in pregnancy did not have a higher risk of gestational diabetes, hypertensive disorders of pregnancy, VTE, preterm birth rate, and low or high neonatal birth weight than women not exposed.72 Valuable Clinical Insights • Women with schizophrenia may experience more obstetric complications. • Consider treatment during pregnancy as 50% will relapse. • The risk of congenital malformations with first-generation antipsychotics is minimal. • There is a higher risk of metabolic syndrome and VTE with second-generation antipsychotics.

Neuroleptic Malignant Syndrome Neuroleptic malignant syndrome (NMS) is an uncommon but sometimes fatal side effect of antipsychotic agents with a prevalence between 0.02% and 2.4%.87 NMS occurs typically early in treatment, and fever, muscular rigidity, autonomic dysfunction, leukocytosis, and impaired level of consciousness are characteristic and may last from hours to weeks. Symptoms result from a sudden reduction in dopamine activity, either from the withdrawal of dopaminergic agents or from blockade of dopamine receptors in the hypothalamus, nigrostriatal, and spinal pathways.87 Differential diagnoses include serotonin syndrome, heatstroke, malignant hyperthermia (MH), cocaine use, and amphetamine overdose.88 In addition to antipsychotics, other drugs may cause NMS. These include droperidol, succinylcholine, haloperidol, and metoclopramide, so use them cautiously.88 Treatment of NMS includes resuscitation with IV fluids, aggressive cooling, and dantrolene administration following MH management guidelines. Valuable Clinical Insights • Neuroleptic malignant syndrome is an uncommon side effect of antipsychotic agents used to treat schizophrenia. • Differential diagnosis includes serotonin syndrome, heatstroke, MH, cocaine use, and amphetamine overdose. • Treatment is similar to MH with IV fluids, aggressive cooling, and dantrolene administration.

Anesthetic Implications of Schizophrenia Communicating with patients with schizophrenia may be difficult if the patient exhibits aggressive behavior. The team providing care should address the individual’s decision-making capacity. A contraindication to NA is the failure of the woman to provide consent to treatment. Emotional support and a quiet environment are essential, and the need for urgent psychiatric consultation may become evident. Continue antipsychotic medication perioperatively as abrupt withdrawal may result in psychotic symptoms and postoperative confusion.89 However, antipsychotics may potentiate hypotensive and sedative effects of general anesthetic agents. The action of antipsychotics on the anticholinergic and α-1 adrenergic receptors causes side effects such as hypotension, sedation, and anticholinergic effects.90 Antipsychotics, specifically the FGAs, may have synergistic effects when combined with opioids and may increase the risk of respiratory depression.90 Antipsychotic agents may block the vasopressor effect of norepinephrine and alpha-adrenergic stimulating drugs, intensifying the impact on beta-adrenergic receptors. The anticholinergic effects of FGAs are additive with other anticholinergic agents. Some recommend avoiding central acting anticholinergic medications in the patient taking FGAs. Ondansetron may cause QT interval prolongation,91 and metoclopramide may cause extrapyramidal side effects92 in patients taking antipsychotics. It is best to avoid metoclopramide in schizophrenic patients. All currently used inhalational anesthetic agents are considered safe for schizophrenic patients taking antipsychotics.88 Inhaled anesthetics combined with FGA may cause hypotension, which is treatable with alpha-adrenergic vasopressors and IV fluid.90 All routine IV induction anesthetic agents are acceptable in patients with schizophrenia. One exception may be ketamine, which can cause prolonged hallucinations and delirium and induce transient positive psychotic symptoms.93 In the anesthetized patient, hypotension, heat loss, and inadequate compensation for blood loss are complicating factors. Therefore, maintain normothermia by adequate warming.88 There are reports of severe hypotension with the combination of FGA and NA. The effects of the sympathetic blockade following NA are additive with the hypotensive effects of FGAs. Evaluate and restore circulating blood volume in patients taking antipsychotic drugs when hypotension occurs during NA in patients taking antipsychotic drugs.90 Patients requiring SGAPs are at higher risk for adverse maternal outcomes such as gestational diabetes, hypertensive disorders of pregnancy, and VTE.72 Monitor these women for metabolic complications, including assessment of HbA1c, glucose tolerance testing, cholesterol and triglyceride levels, and weight gain.77 There are specific recommendations for the labor and delivery plan for mothers with psychotic disorders.94 It is suggested that a psychiatric nurse be present in the labor room to help mediate the psychosocial environment. An early CSE may be preferred to minimize pain and avoid any pain-induced anxiety the patient may experience. Premedication with lorazepam before epidural placement may prevent worsening anxiety.

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Intrapartum telemetry is advised as Q-T interval prolongation may occur secondary to medication use. Have parenteral haloperidol, lorazepam, and benztropine immediately available for acute psychiatric symptoms.94 The postoperative and immediate postpartum periods also require the particular attention of the anesthesiologist. Schizophrenic patients have higher pain thresholds due to hypofunctioning  N-methyl D-aspartate receptors and a decreased conduction by C fibers.88 These patients may be at risk of pain, confusion, and delirium postoperatively. Surgical stress may worsen psychotic symptoms and postoperative delirium due to hypersecretion of cortisol and norepinephrine. Administer IV haloperidol 0.5–2 mg to reduce postoperative delirium.88 Valuable Clinical Insights • Communication with the schizophrenic patient may be difficult. • A team approach is essential in managing these patients; have an anesthetic plan before their admission for labor and delivery. • Most anesthetic agents are safe for patients with schizophrenia; the one exception is possibly ketamine. • Hypotension is a potential complication from the combination of antipsychotic agents and anesthesia (both NA and GA), while hypothermia is a risk with GA. • Avoid metoclopramide in psychotic patients due to the risk of extrapyramidal side effects. • Psychotic patients may be at risk of pain, confusion, and delirium postoperatively. Treat postoperative delirium with haloperidol.

Bipolar Disorder Characteristics of bipolar disorder are marked mood swings from depressive episodes to manic episodes. While pregnancy may be protective with low rates of both new onset and relapse of bipolar disorder,95 some studies report high recurrence rates in pregnancy.96 Complications of bipolar episodes include poor prenatal care, insomnia, substance abuse, obsessions, delusions, and hallucinations. These may result in poor infant bonding, inability to care for the infant, suicide, and infanticide.80 Approximately 50% of women with a pre-existing bipolar disorder have a mood episode following childbirth.97 Depressive symptoms or mixed episodes are most prevalent postpartum97 and are associated with a higher risk of postpartum psychosis.98 However, compared with pregnancy, more hypomanic symptoms can occur in the immediate postpartum period.99 Postpartum, the symptoms of depression and/or hypomania may be attributed to normal physiological changes following childbirth.97 Bipolar disorder symptoms can be difficult for clinicians to identify, and misdiagnosis as unipolar disorder sometimes occurs.97 However, carefully consider the diagnosis because the treatment of bipolar disorder differs from unipolar depression. For example, administering an antidepressant to a patient with bipolar disorder may induce a manic episode. Instead, treat a bipolar disorder with mood stabilizers and possibly a newer SGAP.100

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Lithium The most common mood stabilizer is lithium, but it freely crosses the placenta, equilibrating between maternal and fetal circulations.101 While there were initial reports of an association between lithium exposure and Ebstein anomaly,102 there is no evidence of a causal relationship. A recent prospective observational study with first trimester lithium exposure was not associated with an increased risk of cardiovascular anomalies.103 However, sedation and “floppy infant syndrome” characterized by poor muscle tone and cyanosis may occur.101 There are reports of neonatal hyperbilirubinemia, cardiac rhythm disturbances, hypothyroidism, and diabetes insipidus.101 Carefully monitor exposed newborns during the first 48 hours. During pregnancy, maintain maternal serum levels in the therapeutic range, remembering that the lithium dose may require increasing because of increased clearance rates. There is also the ­potential for lithium toxicity in the presence of complications such as PreE.100

Valproic Acid Valproic acid use during the first trimester is associated with a 0.6–2% incidence of neural tube defects and an increased rate of total congenital malformations.104 Valproic acid malformations are dose related. Facial clefts, cardiac defects, limb defects, hypospadias, and abnormal facial features are part of a fetal syndrome.101 As a result, limit valproic acid in pregnancy to when other treatments are not effective or not acceptable.

Lamotrigine Lamotrigine is an anticonvulsant approved for treating bipolar disorder, but there is an increased risk for oral clefts when used in pregnancy.100 Clinical response usually guides lamotrigine dosing, but a preconception lamotrigine serum level may direct the need for increasing the dose during pregnancy.100

Second-generation Antipsychotics Newer antipsychotics, including olanzapine, risperidone, quetiapine, are increasingly used to treat bipolar disorder.100 As mentioned previously, the SGAPs are generally safe for use during pregnancy.

Anesthetic Implications Check maternal lithium levels in early labor, and ensure adequate hydration. Avoid nephrotoxic drugs in women taking lithium.100 Non-steroidal anti-inflammatory drugs may increase lithium levels up to 40%.105 Lithium toxicity presents with confusion, sedation, muscle weakness, tremors, and slurred speech. Cardiac problems may include sinus bradycardia, sinus node dysfunction, AV block, T wave changes, hypotension, and ventricular irritability.105 Lithium may decrease anesthetic requirements if GA is required because it blocks the brainstem release of norepinephrine, epinephrine, and dopamine.105 As the duration of depolarizing and non-depolarizing muscle relaxants may be prolonged in the presence of lithium, neuromuscular m ­ onitoring is advised.105

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The usual dose of propofol may be excessive for patients receiving valproic acid, delaying anesthetic recovery. In patients taking valproic acid, some recommend lowering the propofol dose.106

Conclusion Psychiatric disorders may present perinatally and need assessment and management by the obstetric anesthesiologist. Patients with these conditions will be on medications that may interact with anesthetic and analgesic agents. In addition, the women themselves can be challenging given their abnormal psychology, the stress of pregnancy, and the pain of labor. Collaborative consultation with the obstetrician and attending psychiatrist may be necessary for optimal care. Not all anesthesiologists are skilled in this area, and time spent in consultation before entering the labor suite may be invaluable. Involving the obstetric anesthesiologist early in the peripartum care of a patient with psychiatric illness may enhance prompt action and treatment and better long-term outcomes. Perinatal consultation may facilitate perioperative management and a plan to help reduce the risk of p ­ sychiatric disorders in the postpartum period.

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77. Gentile S. Antipsychotic therapy during early and late pregnancy. a systematic review. Schizophr Bull 2010;36:518–544. https://doi .org/10.1093/schbul/sbn107 78. McNeil TF, Kaij L, Malmquist‐Larsson A. Women with nonorganic psychosis: mental disturbance during pregnancy. Acta Psychiatr Scand 1984;70:127–139. https://doi.org/ 10.1111/j.1600-0447.1984.tb01190.x 79. Trixler M, Gati A, Tenyi T. Risks associated with childbearing in schizophrenia. Acta Psychiatr Belg 1995;95:159–162. 80. Jones I, Chandra PS, Dazzan P, et al. Bipolar disorder, affective psychosis, and schizophrenia in pregnancy and the post-partum period. Lancet 2014;384(9956):1789–1799. https://doi .org/10.1016/S0140-6736(14)61278-2 81. Pearlstein T. Use of psychotropic medication during pregnancy and the postpartum period. Womens Health (Lond) 2013;9:605– 615. https://doi.org/10.2217/WHE.13.54 82. ACOG. ACOG Practice Bulletin: Clinical management guidelines for obstetrician-gynecologists No. 92, April 2008. Use of psychiatric medications during pregnancy and lactation. Obstet Gynecol 2008;111:1001–1020. https://doi.org/10.1176/ foc.7.3.foc385 83. Habermann F, Fritzsche J, Fuhlbrück F, et al. Atypical antipsychotic drugs and pregnancy outcome: a prospective, cohort study. J Clin Psychopharmacol 2013;33: 453–462. https:// doi.org/10.1097/JCP.0b013e318295fe12 84. Newcomer JW. Antipsychotic medications: metabolic and cardiovascular risk. J Clin Psychiatry 2007;68(Suppl. 4):8–13. 85. Newham JJ, Thomas SH, MacRitchie K, et al. Birth weight of infants after maternal exposure to typical and atypical antipsychotics: prospective comparison study. Br J Psychiatry 2008;192:333–337. https://doi.org/10.1192/bjp .bp.107.041541 86. Gentile S. Clinical utilization of atypical antipsychotics in pregnancy and lactation. Ann Pharmacother 2004;38:1265–1271. https://doi.org/10.1345/aph.1D485 87. Kornhuber J, Weller M, Riederer P. Glutamate receptor antagonists for neuroleptic malignant syndrome and akinetic hyperthermic parkinsonian crisis. J Neural Transm Park Dis Dement Sect 1993;6:63–72. https://doi.org/10.1007/ BF02252624 88. Constance LSL, Lansing MG, Khor FK, et al. Schizophrenia and anaesthesia. BMJ Case Rep 2017 (online). https://doi.org/10.1136/ bcr-2017-221659 89. Kudoh A, Katagai H, Takase H, et al. Effect of preoperative discontinuation of antipsychotics in schizophrenic patients on outcome during and after anaesthesia. Eur J Anaesthesiol 2004;21:414–416. https://doi.org/10.1017/ S026502150422511X 90. Janowsky EC, Risch C, Janowsky DS. Effects of anesthesia on patients taking psychotropic drugs. J Clin Psychopharmacol 1981;1:14–20. https://doi.org/10.1097/00004714-19810100000004 91. Baguley WA, Hay WT, Mackie KP, et al. Cardiac dysrhythmias associated with the intravenous administration of ondansetron and metoclopramide. Anesth Analg 1997;84:1380–1381. 92. Ganzini L, Casey DE, Hoffman WF, et al. The prevalence of metoclopramide-induced tardive dyskinesia and acute extrapyramidal movement disorders. Arch Intern Med 1993;153:1469–1475. https://doi.org/10.1001/ archinte.1993.00410120051007

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100. Khan SJ, Fersh ME, Ernst C, et al. Bipolar disorder in pregnancy and postpartum: principles of management. Curr Psychiatry Rep 2016;18:13. https://doi.org/10.1017/s11920-015-0658-x 101. Newport DJ, Viguera AC, Beach AJ, et al. Lithium placental passage and obstetrical outcome: implications for clinical management during late pregnancy. Am J Psychiatry 2005;162:2162–2170. https://doi.org/10.1176/appi.ajp.162 .11.2162 102. Nora JJ, Nora AH, Toews WH. Lithium, Ebstein’s anomaly, and other congenital heart defects. Lancet 1974;304(7880):594–595. https://doi.org/10.1016/S0140-6736(74)91918-7 103. Diav-Citran O, Shechtman S, Tahover E, et al. Pregnancy outcome following in utero exposure to lithium: a prospective, comparative, observational study. Am J Psychiatry 2014;171:785–794. https://doi.org/10.1176/appi.ajp .201412111402 104. Werler MM, Ahrens KA, Bosco JLF, et al. Use of antiepileptic medications in pregnancy in relation to risks of birth defects. Ann Epidemiol 2011;21:842–850. https://doi.org/10.1016/j .annepidem.2011.08.002 105. Attri JP, Bala N, Chatrath V. Psychiatric patient and anaesthesia. Indian J Anaesth 2012;56:8–13. https://doi.org/10.4103/00195049.93337 106. Hızlı Sayar G, Eryılmaz G, Semieoğlu S, et al. Influence of valproate on the required dose of propofol for anesthesia during electroconvulsive therapy of bipolar affective disorder patients. Neuropsychiatr Dis Treat 2014;10: 433–438. https://doi.org/ 10.2147/NDT.S59375

Chapter

25

Substance Use Disorder Grace Lim

Introduction Perinatal substance use disorder (SUD) is a significant risk factor for pregnancy-associated deaths.1 The American Psychological Association defines SUD as, “a complex condition in which there is uncontrolled use of a substance despite harmful consequences”2 which can have a devastating impact on patients, families, and communities. Between 2010 and 2020, SUD, including opioid use disorder (OUD), has risen four-fold among pregnant women, and opioid overdose deaths in women have increased.3 Reasons for substance abuse in pregnancy range from nonpain-related initial substance encounters or a remote shortterm acute event that acted as a pathway to abuse.4 Estimates of drug use among pregnant women suggest an annual prevalence of 5–6%. Maternal health and fetal development are affected by SUD, with an associated risk for neonatal abstinence syndrome, and poor childhood cognitive development and academic performance. In addition to the direct effects of substances on fetal-­ neonatal development, indirect effects impact the risk behaviors and poor maternal health associated with SUD childhood outcomes. These considerations underscore the critical importance of treating SUD in pregnancy. This chapter will identify and summarize the available literature on peripartum anesthetic management in women with SUD.

Screening Some estimates place 1.6% of pregnant women as meeting criteria for a SUD.5 Marijuana, cocaine, opioids, and methamphetamines are the most used substances in pregnant women with SUD.6,7 Screening for SUD and brief interventions in outpatient primary care settings (e.g., general medicine, obstetrics and gynecology, pediatric practices) is considered effective in reducing substance use in pregnant women.8 Effective treatments for SUD are available, but there is a disparity in treatment uptake in that < 20% of women who need treatment for SUD receive it.9 These disparities may be secondary to social limitations affecting women, such as childcare needs, stigmas, or other barriers. Both men and women respond similarly to treatment when therapy is engaged. Depression and other mental health disorders are common comorbidities of SUD. Therefore, routinely screening for depression of pregnant and

postpartum women, with and without SUD, is recommended10 because screening for depression allows early intervention with referrals for support services and may reduce symptoms of depression. Valuable Clinical Insights • Screening for perinatal SUD during antenatal visits is imperative to de-stigmatize and identify SUD early, so as to engage patients in effective therapies for SUD. • Depression screening is also vital for any pregnant or ­postpartum patient with SUD.

Benzodiazepines Anxiety is a common condition among women of reproductive age, present in an estimated 15% of pregnant women.11 Benzodiazepines can be used as a short-term approach for the treatment of anxiety or depression, until other specific therapies are introduced, and which are often maintained during pregnancy (see Chapter 24). Alternatively, some may use these agents without oversight by a medical provider and subsequently develop a SUD. The estimated prevalence of benzodiazepine use in pregnancy is 1–4%.12,13 Fetal exposure to maternal benzodiazepines may interfere with fetal brain maturation due to effects on the γ-aminobutyric acid receptor.14 Associations between prenatal benzodiazepine exposure and impaired motor development have been observed in toddlers and children. However, the main limitations of existing data include confounding by indication and small sample sizes.15,16 The potential long-term ramifications on childhood neurocognitive development after intrauterine ­exposure to benzodiazepines – and other GABAergic substances – are the subject of active and ongoing research. One sizeable Norwegian cohort study of over 41,000 pregnancy-child dyads found no significant link between chronic prenatal benzodiazepine exposure and fine motor or attention deficit hyperactivity disorder symptoms in children.17 Neonates with intrauterine acute or chronic benzodiazepine exposure will need to be monitored for respiratory depression, sedation, or withdrawal symptoms.

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Valuable Clinical Insights • Perinatal benzodiazepine exposure may reflect an underlying anxiety disorder. • Neonates exposed to intrauterine benzodiazepines, acute or chronic, should be monitored for respiratory depression or withdrawal.

Stimulants Cocaine Cocaine (the methyl ester of benzoylecgonine) is a CNS stimulant with LA properties.18 It binds to dopamine, serotonin, and norepinephrine proteins and inhibits their presynaptic reuptake, which leads to the accumulation of these neurotransmitters in the cleft, resulting in receptor activation. The result is sympathomimetic activity: tachycardia, sweating, hypertension, and euphoria. An estimated 750,000 cocaine-exposed pregnancies occur every year.19 Pregnant women who use cocaine often manifest symptoms such as migraines, seizures, PROM, and placental abruption.20 Acute cocaine toxicity can lead to hypertensive crises, spontaneous abortion, preterm labor, or complications in labor and delivery.19 Neonatal outcomes associated with maternal use of cocaine during pregnancy include low birth weights, smaller head circumferences, and shorter lengths than babies born to mothers not using cocaine.19

Amphetamines Amphetamines are synthetic stimulants that result in increased wakefulness and attention with reduced appetite and fatigue.21 These effects result from the chemical modulation of dopamine, serotonin, and norepinephrine. Amphetamine users develop rapid tolerance and dependence due to impaired serotonin neurotransmission after chronic exposure. Globally, an estimated 53 million people use amphetamines or about 2.1% of the population.22 Amphetamines transfer through the maternalfetal circulation and are quantifiable in the umbilical cord, the placenta, and amniotic fluid.21 Maternal use of amphetamines is associated with placental hemorrhage, uterine contractions, and preterm labor. The highest concentrations of fetal amphetamines are in the lungs, placenta, kidney, intestine, liver, brain, and heart. Although amphetamines are not known teratogens, they are known to reduce folic acid uptake leading to potential fetotoxicity.23 Amphetamines affect multiple areas of the maternal and fetal brains, including the hippocampus, prefrontal cortex, striatum, and dopaminergic/serotonergic systems. Amphetamines induce adverse fetal outcomes, including cleft palate and exencephaly. In addition, movement disorders, physical tension, EEG changes, IUGR, and reduced neonatal brain volumes can also result from maternal amphetamine use.24 Some studies have found lower results in cognitive testing, emotional instability, and attention disorders among offspring of amphetamine-using mothers.24 However, there are also complex social interactions. The maternal social factors associated with amphetamine use – unemployment, lack of parental engagement in childcare

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and development, lack of social support – can also influence ­neonatal-childhood neurocognitive development.

Peripartum Anesthetic Management Pregnant patients who use stimulants acutely or chronically are at risk for multiorgan dysfunction, hypertensive crises, abruption and coagulopathy, and emergency obstetric needs. Early NA can assist in airway avoidance for potential emergent CD. The timing of NA should be weighed against available coagulation studies and the urgency of delivery. Other considerations include airway risks, aspiration risks, and patient preferences. Neuraxial anesthesia and analgesia mitigate the effects of acute stimulant toxicity by reducing BP and sympathetic activity. However, hypotension will more likely occur after initiation of NA, so be prepared to treat with an appropriate vasopressor such as phenylephrine. Placental perfusion requires a higher BP in women who use amphetamines regularly, so vasopressors should be titrated to maintain BP close to their baseline to ensure fetal perfusion. When GA is used, hypertensive crises are likely in cocaineusing patients during laryngoscopy and intubation.25,26 It is prudent to consider a benzodiazepine or opioid to attenuate these acute physiologic effects of cocaine before initiating laryngoscopy. Pure beta blockers should be avoided in acute cocaine ­toxicity because they may exacerbate coronary vasospasm and the toxic effects of cocaine by creating “unopposed” alpha-­ adrenergic stimulation.27 Valuable Clinical Insights • Stimulant use in pregnancy encompasses cocaine and amphetamines. • Peripartum risks include placental abruption, preterm delivery, and hypertensive crises. • Anesthesia evaluation assesses the broad differential diagnosis for a patient presenting with acute hypertension and abruption. Careful planning includes readily available agents to treat hypertensive crises.

Opioids Opioid use disorder in pregnancy is associated with neonatal abstinence syndrome, fetal growth restriction, low birth weight, and poorer neonatal outcomes.28–30 Comorbidities often associated with OUD in pregnancy include trauma histories (sexual abuse, child abuse, domestic abuse) or other mental health disorders (which incur risk for psychiatric medication interactions with opioids), and co-existing polysubstance use disorder.31–38 Pain sensitivity and pain responses were significantly different in women with OUD from those not maintained on opioids,31 although available evidence to guide patient care for these patients is limited.

Synthetic Opioids (Heroin and Fentanyl) Heroin (diamorphine) is a highly addictive analog of morphine, and an estimated one in three adults who try heroin will become addicted to it.39,40 Its onset ranges from less than one

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minute (parenteral administration, 37% of heroin abusers) to 15 minutes (smoked or administered intranasally). The elimination half-life is typically one to two hours. Given its high lipid solubility, it rapidly crosses the blood–brain barrier. Heroin is metabolized by cytochrome P450 in the liver and excreted in the urine, where it is detected in toxicology screens. Due to poor peripheral venous access, it may be necessary to place central venous access in patients with IV opioid use disorder. Fentanyl is a highly potent synthetic opioid delivered by intravenous, transmucosal, intranasal, buccal, epidural, intrathecal, or inhalational routes.41,42 It has a rapid onset time, but its length of action is limited by redistribution. Increasing contextsensitive half-times depend upon the duration of exposure and administration (half-life ranging from 3.1 to 7.9 hours). Fentanyl is highly lipophilic, metabolized by the liver, and excreted by the kidneys. If there is intrapartum exposure, the detection of fentanyl in postpartum urine toxicology screens may be of limited value.

Methadone and Buprenorphine The mainstay for effective treatment of OUD in pregnancy includes medication for opioid use disorder (MOUD) because medical stabilization with MOUD is associated with better prenatal care compliance and birth outcomes.43 In pregnancy, MOUD typically includes opioid agonist or mixed agonistantagonist therapy (i.e., methadone, buprenorphine). Chronic use of these medications, both under medical supervision and in periods of abuse, can impact pain management during and after labor and delivery. As of a result of their strong affinity for mu-opioid receptors, it is often thought that higher doses of opioids are needed to control pain during labor and after delivery. In contrast, some caution against opioid exposure out of concern for a return to abuse.44 Notably, lower rates and severity of neonatal abstinence syndrome are noted in women receiving buprenorphine versus methadone.45,46 Available evidence on the management of methadone or buprenorphine during labor and delivery exists in reviews, case reports, opinions, a cross-sectional survey, retrospective cohort studies, and one randomized trial.32,34,36,45–75 Many publications note the lack of high-quality evidence and recommendations based on expert opinion. One review highlighted that opioid replacement therapy should continue in women with OUD and is not a contraindication to breastfeeding.52 Others noted that maintenance with buprenorphine or methadone is effective in pregnancy.53,57 One randomized trial compared women maintained on methadone versus buprenorphine. Those on either buprenorphine or methadone had adequate pain control with opioids and ibuprofen. However, the methadone group used more ibuprofen postpartum.56 A survey of practicing obstetricians concluded that there is a need to improve clinician confidence in managing pain for patients with OUD.59 Most available evidence recommends continuing methadone and buprenorphine therapy throughout pregnancy and labor, rather than reducing doses or stopping these therapies. Suboxone® is a combination of 2–12 mg buprenorphine and 0.5–3 mg naloxone prescribed as a sublingual tablet.67 The naloxone is only activated if the tablet is injected instead of dissolved in the mouth

as directed. This would result in uncomfortable withdrawal symptoms in the opioid-dependent individual. All references to buprenorphine in this chapter also apply to suboxone.

Peripartum Anesthetic Management Available publications on anesthetic and pain management during labor and delivery for patients with OUD consist of retrospective reviews, narrative reviews, case reports, and a practice guideline.45,46,48,71,74,76,77 A multidisciplinary approach to patient management is necessary, and prenatal anesthesia consultation is recommended. Multimodal approaches to pain management include the scheduled use of acetaminophen and nonsteroidal anti-inflammatory drugs during hospitalization.71 Studies conflict on whether patients receiving MOUD have increased pain and analgesia needs after CD. One retrospective study found that opioid-naïve patients have less pain and use fewer morphine equivalents than women on opioid agonist therapy. However, they did not find that women on buprenorphine had more pain or used more morphine equivalents than patients maintained on methadone.73 Retrospective studies have found that patients on buprenorphine or methadone had similar outcomes after CD in terms of opioid requirements, complications, and length of stay.78 Also, post-CD pain scores were similar between buprenorphine- and methadone-maintained patients.79 A review article noted pain sensitivity was not different between patients maintained on methadone and patients who were not on opioids.31 In contrast, other studies have found evidence for increased pain and analgesic requirements after CD for patients on OUD treatment. Retrospective studies found that patients on methadone and buprenorphine have 70% and 47% more opioid needs (respectively) after CD, compared to no opioid maintenance.65 80,81 A case report describes clinicians anticipating more post-CD pain in a patient on methadone therapy and stopping methadone therapy to use postoperative intravenous opioid patientcontrolled analgesia.82 Others have found that methadone and buprenorphine can be used safely during labor, delivery, and postpartum with other analgesics regardless of the mode of delivery.83 A retrospective cohort found that return to use and opioid abuse was common after delivery and that CD was associated with higher rates of post-discharge opioid misuse in the month after delivery, compared to vaginal delivery.84 Longer duration of MOUD treatment before delivery was associated with lower rates of opioid misuse in the month after delivery. The use or avoidance of opioids for pain control in patients with OUD for labor and delivery pain is debatable. A case series described the safe ongoing use of MOUD (buprenorphine or methadone) after CD and described the effective use of oral opioids for breakthrough pain.83 However, the authors caution on the potential need for higher than typical doses of opioids, although there was no data to support this conclusion. Another review article made explicit recommendations that no opioids should be used in the perioperative period, although the evidence to support this statement was also not provided.47 A retrospective study assessed post-CD opioid analgesic requirements in women receiving MOUD (methadone or buprenorphine) and found women receiving

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buprenorphine had lower opioid requirements than those receiving methadone.85 Engaging non-medical providers can potentially improve outcomes for patients with OUD, particularly those with histories of trauma or abuse. In one qualitative study, doula engagement led to perceptions of increased emotional support, health literacy, and self-advocacy in maternal health among women with OUD.86 Other studies find similarly positive perspectives among women with OUD if care providers are perceived to be engaged in recovery and personal growth or if non-medical support persons are present and engaged in their care team.87,88

agents for pain management, even though its use for pain management is a topic of ongoing investigation and controversy. For patients with chronic cannabis exposure requiring surgery under GA, anesthetic doses may be increased, hemodynamic instability is possible, and some medications such as ketamine, ephedrine, and atropine may cause extreme additive effects.97 There are some reports of increased propofol dose requirement, increased doses needed for benzodiazepines and opioids, and possible delayed metabolism of other medications as cannabis is a CYP450 inhibitor.

Valuable Clinical Insights Valuable Clinical Insights • The mainstay for OUD treatment in pregnancy is MOUD, often methadone or buprenorphine. • Anesthetic management of peripartum pain can be challenging, with little evidence-based treatment guidance; the best treatment approaches are individualized to patient priorities and treatment goals, including considerations around the use or avoidance of opioids for pain control. • Non-medical provider support of women with OUD, such as doulas, has improved outcomes.

Marijuana (Cannabis) Marijuana use occurs in 5% of pregnancies and will increase in the United States after legalization in several states.89 It exerts an effect on cannabinoid receptors in the central nervous system resulting in anxiolysis, analgesia, appetite stimulation, and euphoria. Its effects on the pregnancy, and on the fetus, are difficult to discern since multiple other substances are often used with cannabis during pregnancy. Some reports suggest risks for stillbirth, preterm birth, and neurocognitive deficits, although others do not report associations with prenatal cannabis exposure and low birth weights or Apgar scores.90,91 Cannabis use in pregnancy is associated with placenta previa, preterm labor, and rupture of membranes.89 Acute cannabis intoxication with low doses can present with tachycardia and elevated cardiac output, while higher doses can manifest as bradycardia and hypotension from sympathetic depression and parasympathetic stimulation.92 In pregnancy, concerns around cannabis exposure include potential placental changes, oxytocin-induced myometrial contractions, and uterine signaling.93–96 Chronic maternal prenatal alcohol and marijuana exposure can independently lead to cognitive and academic performance deficits in the offspirng.28

Peripartum Anesthetic Management Anesthetic management for pregnant patients exposed to prenatal cannabis focus on pain control and intoxication management. Neuraxial analgesia is preferred and is safe for patients using cannabis. Atropine, pancuronium, and ketamine should be used with caution, if at all, as these agents exacerbate tachycardia in the setting of acute cannabis intoxication.97 Since cannabinoid therapy has become prevalent for acute and chronic pain, some pregnant patients may also continue using these

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• Cannabis use in pregnancy is increasing. • Anesthetic management for pregnant patients with chronic cannabis use should avoid medications that exacerbate cardiovascular effects. • Higher doses of anesthetic agents may be required.

Other Drugs of Abuse and Designer Drugs These drugs include, MDMA (Methylenedioxy methamphetamine, “Ecstasy”), LSD (Lysergic acid diethylamide, “Acid”), and PCP (Phenylcyclohexyl piperidine, “Angel Dust”). The well-known recreational drug MDMA is a hallucinogen with stimulant properties. Cardiovascular effects are similar to cocaine and include vasoconstriction, tachycardia, and elevated BP.98 In addition, MDMA can induce hyperthermia, hyponatremia, and seizures92 and can induce neurohormonal changes such as cortisol and oxytocin increases. Another hallucinogen, LSD, is a psychedelic agent that creates or facilitates intense thoughts, emotions, and sensory perceptions. Using LSD increases the incidence of spontaneous abortion, cataracts, and retinal problems. The contribution of LSD to developing preterm delivery or low birth weight is questionable. It is more likely due to other maternal behaviors associated with LSD use, such as polysubstance abuse or alcohol use.99–101 The third hallucinogen in this section, PCP, is a dissociative agent (related to ketamine) that causes distorted perceptions and sometimes violent behavior. Overdose can lead to tremendous hemodynamic lability, with sudden malignant hypertensive episodes followed, shortly after treatment, by profound hypotension, which in turn requires pressor therapy and so on, in a cyclical fashion. Neonatal symptoms of maternal PCP use are hypertonus, vomiting, and diarrhea, requiring a period of intense neonatal monitoring.102 Fetal exposure to MDMA, LSD, or PCP has been linked with retinal defects, cleft palate, fetal malformations, growth restriction, impaired motor development, preterm birth, abruption, hypertension, PreE, fetal death, aggressive behavior, and attention deficits.103–105 Anesthetic management of patients using MDMA, LSD, or PCP is similar to that for cocaine toxicity.106 Increased MAC requirements for volatile anesthetics are possible in acute toxicity, while chronic use may manifest as catecholamine depletion and cardiac arrest during GA.107 For these reasons, chronic stimulant use in the perioperative period is discouraged.

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Kratom (Mitragyna speciosa)

Kratom (Mitragyna speciosa) is derived from a tropical plant related to the coffee bean and is used in herbal medicines for its opioid and stimulant-like properties. It is a mu-opioid receptor agonist and a delta- and kappa-opioid receptor antagonist and is an emerging drug of abuse in the United States.108 Although people describe using it for chronic pain, opioid withdrawal symptom management, or recreationally for its opioid-like “high,” the United States FDA has stated that there is no evidence that kratom is safe or effective for treating any condition. In 2017 the FDA issued a public health advisory for kratom.109 Adverse effects from chronic kratom use include respiratory depression, liver toxicity, and death. Rapid discontinuation can be associated with opioid withdrawal symptoms. Very little is known about kratom interactions with anesthetic medications, despite being used more frequently in pregnancy. One perioperative case report described GA in a patient with chronic pain using kratom.110 Perioperative medications included lidocaine, fentanyl, gabapentin, midazolam, sevoflurane, ketamine, acetaminophen, ketorolac, fentanyl, dexamethasone, and ondansetron for a lumbar laminectomy. Post-extubation, the patient required intermittent jaw thrust until fully awake. Overnight, hydromorphone intravenous PCA (demand 0.3 mg, total use 5.4 mg over 18 hours), gabapentin 400 mg TID, naproxen 500 mg BID, and acetaminophen 1000 mg TID were given, with monitoring including continuous EKG and end-tidal carbon dioxide, the latter of which was elevated during the first postoperative night. In another report, two pregnant women with kratom dependence presented with symptoms consistent with opioid withdrawal.111 They were initiated on opioid replacement therapy with successful treatment of symptoms. Another case report of a pregnant patient with chronic kratom use described postpartum opioid replacement and eventual discontinuation, driven by patient motivation to discontinue all use.112 The authors also described a need to monitor kratom withdrawal in neonates. Altogether, the management considerations for labor and delivery management of a parturient using kratom are like that of an opioid-dependent patient. Valuable Clinical Insights • MDMA, PCP, LSD, and kratom are substances of abuse across the lifespan and in pregnancy. • Anesthetic management considerations in labor and delivery focus on acute intoxication and withdrawal management.

Conclusions Estimates suggest that up to 5% of pregnant women use one or more addictive substances, which has serious implications for the mother, her baby, and their caregivers.113 Peripartum anesthetic management in patients with SUD should consider individual patient circumstances, obstetric concerns, and patient goals for pain management. These considerations must be balanced with

the desires of the patient to avoid or judiciously use controlled substances for anxiolysis and analgesia. Prenatal anesthesiology consultation to clarify perinatal care goals can assist in peripartum planning and preparation. Multidisciplinary care facilitates support and longitudinal planning for these patients, including coordinating appropriate transitional care ­services and followup to treat their chronic addiction conditions.

Acknowledgments I am deeply grateful to Ms. Carol Hunn for her assistance with this chapter.

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52. Gopman S. Prenatal and postpartum care of women with substance use disorders. Obstet Gynecol Clin North Am 2014;41:213–228. 53. Harter K. Opioid use disorder in pregnancy. Ment Health Clin 2019;9:359–372. 54. Jones CW, Terplan M. Pregnancy and naltrexone pharmacotherapy. Obstet Gynecol 2018;132:923–925. 55. Jones HE, Finnegan LP, Kaltenbach K. Methadone and buprenorphine for the management of opioid dependence in pregnancy. Drugs 2012;72:747–757. 56. Jones HE, O’Grady K, Dahne J, et al. Management of acute postpartum pain in patients maintained on methadone or buprenorphine during pregnancy. Am J Drug Alcohol Abuse 2009;35:151–156. 57. Klaman SL, Isaacs K, Leopold A, et al. Treating women who are pregnant and parenting for opioid use disorder and the concurrent care of their infants and children: literature review to support national guidance. J Addict Med 2017;11: 178–190. 58. Kliman L. Drug dependence and pregnancy: antenatal and intrapartum problems. Anaesth Intens Care 1990;18: 358–360. 59. Ko JY, Tong VT, Haight SC, et al. Obstetrician-gynecologists’ practice patterns related to opioid use during pregnancy and postpartum – United States, 2017. J Perinatol 2020;40: 412–421. 60. Landau R. Post-cesarean delivery pain. Management of the opioid-dependent patient before, during and after cesarean delivery. Int J Obstet Anesth 2019;39:105–116. 61. Ludlow J, Christmas T, Paech MJ, et al. Drug abuse and dependency during pregnancy: anaesthetic issues. Anaesth Intensive Care 2007;35:881–893. 62. Lugo RA, Satterfield KL, Kern SE. Pharmacokinetics of methadone. J Pain Palliat Care Pharmacother 2005;19:13–24. 63. Mahoney K, Reich W, Urbanek S. Substance use disorder: prenatal, intrapartum, and postpartum care. MCN Am J Matern Child Nurs 2019;44:284–288. 64. McNicholas LF, Holbrook AM, O’Grady KE, et al. Effect of hepatitis C virus status on liver enzymes in opioid-dependent pregnant women maintained on opioid-agonist medication. Addiction 2012;107(Suppl. 1):91–97. 65. Meyer J, Wagner K, Benvenuto A, et al. Intrapartum and postpartum analgesia for women maintained on methadone during pregnancy. Obstet Gynecol 2007;110:261–266. 66. Mozurkewich EL, Rayburn WF. Buprenorphine and methadone for opioid addiction during pregnancy. Obstet Gynecol Clin North Am 2014;41:241–253. 67. Pan A, Zakowski M. Peripartum anesthetic management of the opioid-tolerant or buprenorphine/suboxone-dependent patient. Clin Obstet Gynecol 2017;60:447–458. 68. Pritham UA, McKay L. Safe management of chronic pain in pregnancy in an era of opioid misuse and abuse. J Obstet Gynecol Neonatal Nurs 2014;43:554–567. 69. Raymond BL, Kook BT, Richardson MG. The opioid epidemic and pregnancy: implications for anesthetic care. Curr Opin Anaesthesiol 2018;31:243–250. 70. Sen S, Arulkumar S, Cornett EM, et al. New pain management options for the surgical patient on methadone and buprenorphine. Curr Pain Headache Rep 2016;20:16.

71. Soens MA, He J, Bateman BT. Anesthesia considerations and postoperative pain management in pregnant women with chronic opioid use. Semin Perinatol 2019;43:149–161. 72. Tran TH, Griffin BL, Stone RH, et al. Methadone, buprenorphine, and naltrexone for the treatment of opioid use disorder in pregnant women. Pharmacotherapy 2017;37:824–839. 73. Wendling AL, Garvan C, Roussos-Ross D, et al. Pain outcomes among patients after cesarean consuming buprenorphine or methadone and opioid-naive patients. J Clin Anesth 2020;65:109905. 74. Wong S, Ordean A, Kahan M ; Society of Obstetricians and Gynecologists of Canada. SOGC clinical practice guidelines: substance use in pregnancy: No. 256, April 2011. Int J Gynaecol Obstet 2011;114:190–202. 75. Young JL, Lockhart EM, Baysinger CL. Anesthetic and obstetric management of the opioid-dependent parturient. Int Anesthesiol Clin 2014;52:67–85. 76. Cassidy B, Cyna AM. Challenges that opioid-dependent women present to the obstetric anaesthetist. Anaesth Intensive Care 2004;32:494–501. 77. Reddi D, Mehta A, Patel N, et al. Perioperative pain management for cesarean section in the mother with severe acute on chronic pain and opioid dependence. Eur J Anaesthesiol 2013;30:178 (abstract). 78. Vilkins AL, Bagley SM, Hahn KA, et al. Comparison of postcesarean section opioid analgesic requirements in women with opioid use disorder treated with methadone or buprenorphine. J Addict Med 2017;11:397–401. 79. Parad R, McBride C, Garofalo F, et al. Equivalent post-cesarean pain and analgesic requirements in women maintained on methadone versus buprenorphine during pregnancy. Am J Obstet Gynecol 2020;222:S309. 80. Meyer M, Paranya G, Keefer Norris A, et al. Intrapartum and postpartum analgesia for women maintained on buprenorphine during pregnancy. Eur J Pain 2010;14:939–943. 81. Shainker SA, Saia K, Lee-Parritz A. Opioid addiction in pregnancy. Obstet Gynecol Surv 2012;67:817–825. 82. Boyle RK. Intra- and postoperative anaesthetic management of an opioid addict undergoing caesarean section. Anaesth Intensive Care 1991;19:276–279. 83. Jones HE, Johnson RE, Milio L. Post-cesarean pain management of patients maintained on methadone or buprenorphine. Am J Addict 2006;15:258–259. 84. Ellis JD, Cairncross M, Struble CA, et al. Correlates of treatment retention and opioid misuse among postpartum women in methadone treatment. J Addict Med 2019;13:153–158. 85. Vilkins A, Wachman EM, Bagley SM, et al. Comparison of post-cesarean opioid analgesic requirements in methadoneand buprenorphine-maintained women. Obstet Gynecol 2016;127:107S. 86. Gannon M, Short V, Becker M, et al. Doula engagement and maternal opioid use disorder (OUD): experiences of women in OUD recovery during the perinatal period. Midwifery 2021;106:103243. 87. Alexander K, Short V, Gannon M, et al. Identified gaps and opportunities in perinatal healthcare delivery for women in treatment for opioid use disorder. Subst Abus 2021;42:552–558. 88. Peacock-Chambers E, Paterno MT, Kiely D, et al. Engagement in perinatal outpatient services among women in recovery from opioid use disorders. Subst Abus 2021;42:1022–1029.

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  89. Gesterling L, Bradford H. Cannabis use in pregnancy: a state of the science review. J Midwifery Womens Health 2021 (online). https://doi.org/10.1111/jmwh.13293   90. Fried PA. Marijuana use during pregnancy: consequences for the offspring. Semin Perinatol 1991;15:280–287.   91. Varner MW, Silver RM, Rowland Hogue CJ, et al. Association between stillbirth and illicit drug use and smoking during pregnancy. Obstet Gynecol 2014;123:113–125.   92. Hernandez M, Birnbach DJ, Van Zundert AA. Anesthetic management of the illicit-substance-using patient. Curr Opin Anaesthesiol 2005;18:315–324.   93. Das SK, Paria BC, Chakraborty I, et al. Cannabinoid ligandreceptor signaling in the mouse uterus. Proc Natl Acad Sci U S A 1995;92:4332–4336.   94. Feinshtein V, Erez O, Ben-Zvi Z, et al. Cannabidiol changes P-gp and BCRP expression in trophoblast cell lines. PeerJ 2013;1:e153.   95. Feinshtein V, Erez O, Ben-Zvi Z, et al. Cannabidiol enhances xenobiotic permeability through the human placental barrier by direct inhibition of breast cancer resistance protein: an ex vivo study. Am J Obstet Gynecol 2013;209:573.e1–e15.   96. Houlihan DD, Dennedy MC, Morrison JJ. Effects of abnormal cannabidiol on oxytocin-induced myometrial contractility. Reproduction 2010;139:783–788.   97. Davidson EM, Raz N, Eyal AM. Anesthetic considerations in medical cannabis patients. Curr Opin Anaesthesiol 2020;33: 832–840.   98. Figurasin R, Maguire NJ. 3,4-MethylenedioxyMethamphetamine Toxicity. [Updated July 26, 2021]. In StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing, 2022. Available from: www.ncbi.nlm.nih.gov/ books/NBK538482 [last accessed October 2, 2022].   99. Holmes LB. Letter: ocular malformations associated with maternal LSD usage. Arch Ophthalmol 1975;93:1061. 100. Aase JM, Laestadius N, Smith DW. Children of mothers who took LSD in pregnancy. Lancet 1970;1(7663):100–101. 101. Chan CC, Fishman M, Egbert PR. Multiple ocular anomalies associated with maternal LSD ingestion. Archi Ophthalmol 1978;96:282–284.

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102. Strauss AA, Modaniou HD, Bosu SK. Neonatal manifestations of maternal phencyclidine (PCP) abuse. Pediatrics 1981;68: 550–552. 103. Eze N, Smith LM, LaGasse LL, et al. School-aged outcomes following prenatal methamphetamine exposure: 7.5-year follow-up from the infant development, environment, and lifestyle study. J Pediatr 2016;170:34–38.e1. 104. Gorman MC, Orme KS, Nguyen NT, et al. Outcomes in pregnancies complicated by methamphetamine use. Am J Obstet Gynecol 2014;211:429.e1–e7. 105. Wouldes T, LaGasse L, Sheridan J, et al. Maternal methamphetamine use during pregnancy and child outcome: what do we know? N Z Med J 2004;117:U1180. 106. Fischer SP, Healzer JM, Brook MW, et al. General anesthesia in a patient on long-term amphetamine therapy: is there cause for concern? Anesth Analg 2000;91:758–759. 107. Johnston RR, Way WL, Miller RD. Alteration of anesthetic requirement by amphetamine. Anesthesiology 1972;36:357–363. 108. Demick DS, Lee TT, Summers AT, et al. Kratom: a growing substance of abuse in the United States. Ann Clin Psychiatry 2020;32:275–280. 109. U.S. Food and Drug Administration. FDA and Kratom. Available from: www.fda.gov/news-events/public-health-focus/ fda-and-kratom [last accessed October 2, 2022]. 110. Vermaire DJ, Skaer D, Tippets W. Kratom and general anesthesia: a case report and review of the literature. A&A Practice 2019;12:103–105. 111. Smid MC, Charles JE, Gordon AJ, et al. Use of Kratom, an opioid-like traditional herb, in pregnancy. Obstet Gynecol 2018;132:926–928. 112. Mackay L, Abrahams R. Novel case of maternal and neonatal kratom dependence and withdrawal. Can Fam Physician 2018;64:121–122. 113. National Institute on Drug Abuse (NIDA). Substance abuse while pregnant and breastfeeding. Available from: www .drugabuse.gov/publications/research-reports/substance-usein-women/substance-use-while-pregnant-breastfeeding [last accessed October 2, 2022].

Chapter

26

Autoimmune Disease Caroline S. Grange and Annika Smith

Introduction Autoimmune disease represents a pathological condition caused by an immune response directed against an antigen within the host’s body. The incidence and activity of autoimmune diseases are exceptionally high in young women, and hence their occurrence in parturients is not uncommon. The objective of this chapter is to discuss the implications of the following autoimmune diseases in pregnancy: - rheumatoid arthritis - systemic lupus erythematosus - polyarteritis nodosa - systemic sclerosis - antiphospholipid syndrome - multiple sclerosis

Rheumatoid Arthritis

Table 26.1  Criteria for diagnosis of rheumatoid arthritis1 Presence of synovitis in at least one joint Exclusion of other diseases with similar clinical features (e.g., psoriatic arthritis, polyarticular gout, acute viral polyarthritis, systemic lupus erythematosus (SLE) or calcium pyrophosphate deposition disease) A score of > 6 points from the following four domains: Number and site of joints involved 2–10 large joints = 1 point 1–3 small joints = 2 points 4–10 small joints = 3 points > 10 joints (including 1 small joint) = 5 points Elevated rheumatoid factor (RF) and anticitrullinated peptide/protein antibody (ACPA) Above upper limit of normal = 2 points > 3 x upper limit of normal = 3 points Elevated C-reactive protein (CPR) levels or erythrocyte sedimentation rate (ESR) = 1 point Symptoms present > 6 weeks = 1 point The highest score in each domain is used for the calculation

Valuable Clinical Insights • Rheumatoid arthritis (RA) is a multisystem disease. • Fifty to seventy percent of patients with RA improve during pregnancy, although 50% deteriorate postpartum. • Rheumatoid arthritis parturients have an increased risk of hypertensive diseases, gestational diabetes, PROM, and preterm delivery.

Rheumatoid arthritis (RA) is a chronic multisystem, autoimmune disease. Etiology is unknown, although likely due to a combination of genetic predisposition and various environmental/lifestyle choices (e.g., smoking, lower socioeconomic class). Base the diagnosis of RA on the 2010 ACR/EULA classification criteria1 (Table 26.1). Characteristics of RA are symmetrical polyarthritis (usually affecting small joints), with possible joint destruction and deformity. The joints primarily affected include the meta­ carpal-phalangeal/interphalangeal joints of the fingers and thumbs, wrists, elbows, shoulders, and knees. Although the axial skeleton is mainly spared, cervical spine involvement is relatively common in long-standing disease. Rheumatoid arthritis is a multisystem disease; extra-articular manifestations include fatigue, anemia, weight loss, muscle weakness,

lung involvement, cardiac involvement, subcutaneous nodules (rheumatoid nodules), lymphadenopathy, vasculitis, neuropathy, renal disease, and Sjögren syndrome (parotid and lacrimal hypertrophy, keratoconjunctivitis, vaginitis, xerostomia) and Felty syndrome (Rheumatoid Factor (RF) +ve, splenomegaly, neutropenia, possibly associated with anemia, thrombocytopenia, and splenomegaly) (Table 26.2). The disease usually follows a slowly progressive course with exacerbations (RA flares) and remissions, although the prognosis is highly variable. The prevalence of the disease is 1% in the United States with a female to male ratio of approximately 2:1.2 Rheumatoid factor is found in 70–80% of patients with RA but can occur in other autoimmune conditions and unaffected patients. Although anticitrullinated peptide/protein antibody (e.g., anti-cyclic citrullinated peptide, anti-CCP) is more specific for RA, neither RF nor anti-CCP has specificity alone to establish the diagnosis. However, the presence of RF and anti-CCP does predict a poorer functional and radiological outcome.3 Early diagnosis of RA is essential as early intervention with disease-modifying antirheumatic drug (DMARD) therapy improves outcomes and prevents long-term disability.4

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Caroline S. Grange and Annika Smith

Table 26.2  Clinical features and anesthetic implications of rheumatoid arthritis

Organ

Disease process

Anesthetic implications

Airway

Temporomandibular dysfunction Cricoarytenoid involvement Cervical spine involvement Micrognathia

Possible difficult intubation

Cervical spine

Subluxation

Avoidance of excessive airway manipulation during intubation Use of videolaryngoscopy/FOI

Joints

Joint destruction / deformity

Care with positioning Additional padding Difficult IV/arterial cannulation Risk of TE (decreased mobility)

Lumbar spine

Calcification of ligaments Joint deformity

Potentially difficult NA

Cardiovascular

Pericarditis/myocarditis Vasculitis Increased risk of IHD/HF/AF Myocardial rheumatoid nodules

Limited cardiac reserve Conduction disturbances/dysrhythmias

Blood vessels

Vasculitis

End-organ damage Peripheral vascular disease

Respiratory

Interstitial fibrosis Pulmonary nodules Bronchiolitis obliterans Pneumonia

Limited pulmonary reserve

Neurological

Peripheral nerve root compression Cervical nerve root compression Psychiatric (e.g., depression)

Awareness of neurological abnormalities prior to NA

Hematological

Anemia Felty syndrome (associated with neutropenia/thrombocytopenia)

Reduced oxygen transport Increased risk of infectious complications Increased risk of spinal hematoma

Eye

Episcleritis Scleritis Sjogren disease

Eye care, especially during GA

Renal

Glomerulonephritis Drug toxicity (e.g., NSAIDs, Cyclosporine)

Altered drug handling

Abbreviations: AF = atrial fibrillation; FOI = fiberoptic intubation; HF = heart failure; IHD = ischemic heart disease; IV = intravenous; NSAIDs = non-steroidal anti-inflammatory drugs; TE = thromboembolism.

Valuable Clinical Insights • Disease-modifying antirheumatic drugs (DMARDs) cause fetal concerns, and there is limited human safety data available for newer biological DMARDs. • Immunosuppressive therapy may increase the risk of sepsis.

The primary tools to achieve clinical remission or a state of minimal disease activity are DMARDs, whereas anti-­ inflammatory drugs are used as bridging therapies. Once DMARDs control disease activity, anti-inflammatory drugs can be discontinued. Drug treatments for RA sufferers include analgesics (e.g., aspirin, acetaminophen, NSAIDs, opioids), glucocorticoids (e.g., prednisolone), and DMARDs. Diseasemodifying antirheumatic drugs used to treat RA include: 1. Non-biological agents, e.g., methotrexate, azathioprine, hydroxychloroquine, sulfasalazine, leflunomide 2. Biological agents

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• TNF alpha inhibitors, e.g., infliximab, etanercept, adalimumab, certolizumab, golimumab • IL-6 receptor antagonists, e.g., tocilizumab • T-cell costimulation blocker, e.g., abatacept • Anti-CD20 B cell depleting antibody, e.g., rituximab

Effect of Pregnancy on the Disease Most studies show that approximately 50–70% of patients with RA improve during pregnancy. The reduced cellular immune response seen in pregnancy may ameliorate disease activity. Disease characteristics, such as disease duration, RF titer levels, and functional class, are not predictive of improvement during pregnancy. However, RA parturients who were seronegative (for RF and anti-CCP) are more likely to improve during pregnancy than women positive for either or both antibodies. Similar patterns of disease change recur in individuals during future pregnancies. For those patients who demonstrate a reduction in symptoms, improvement usually starts in the first

Autoimmune Disease

trimester and continues throughout pregnancy. Unfortunately, approximately 50% of parturients experience an exacerbation of their disease postpartum.5 This relapse usually occurs within six months, with the peak incidence at around 12 weeks postpartum.6 In addition, there may be an increased risk of developing RA in this early postpartum period, especially in those mothers following their first pregnancy.7

Table 26.3  Drug therapy used in rheumatoid arthritis

Effect of Disease on Pregnancy Women with RA have reduced fertility, and those attempting to conceive have a longer time to pregnancy than controls.8 Increased age, nulliparity, higher disease activity, preconception use of NSAIDs, and preconception daily prednisolone dose of > 7.5 mg are risk factors for infertility. Regarding pregnancy outcomes, women with RA have a higher incidence of hypertensive diseases, gestational diabetes, premature rupture of membranes, APH, preterm delivery, IUGR, and CD.9 Postpartum RA-complicated pregnancies have an increased risk of wound complications and thromboembolic disease (TED).10 It is postulated that exposure to maternal autoimmune diseases in utero is a risk factor for developing neurodevelopmental disorders (e.g., developmental delay, autism spectrum disorders, and attentiondeficit/hyperactivity disorder) in the offspring. In animal models, maternal autoantibodies alter fetal brain development and induce behavioral anomalies.11 Knudsen12 reported a higher risk of these outcomes in humans, although there may be reporting bias. A significant concern in parturients with RA is the potential risk from drug therapy, both during pregnancy (for mother and fetus) and during lactation (for the neonate). Many drugs currently utilized in RA therapy are not licensed for pregnancy, creating a dilemma for the obstetrician and anesthesiologist. There is often limited knowledge regarding toxicities and teratogenic effects due to the ethics of drug testing in pregnant women. Fortunately, improvement in RA symptoms during pregnancy may permit a reduction in medication dose and revision of therapy used, thus diminishing side effects to mother and fetus. Use the lowest effective dose during pregnancy and avoid those drugs that adversely affect the fetus. Where evidence of adverse effects is inconclusive, the drugs’ benefits should significantly outweigh any potential risks; otherwise, choose a safer alternative. Table 26.3 summarizes the effects of analgesics and nonbiological DMARDs on the parturient and the fetus. Nonsteroidal anti-inflammatory drugs (NSAIDs) are generally safe in the first and second trimester and breastfeeding. However, women with fertility issues may wish to avoid these drugs. Avoid NSAIDs in the third trimester due to the risk of premature closure of the ductus arteriosus. Corticosteroid therapy can be continued during pregnancy and breastfeeding, although there appears to be an increased risk of premature rupture of the membranes.13 Reduce fetal exposure by using the lowest effective dose of maternal corticosteroids and avoiding fluorinated preparations (e.g., dexamethasone, betamethasone), as they readily cross the placenta. Unlike the non-fluorinated corticosteroids (e.g., prednisolone,

Drug

Maternal effects

Fetal effects

NSAIDs

Prolonged gestation/ labor Bleeding risk

Bleeding risk Premature closure of ductus arteriosus Oligohydramnios/renal dysfunction

Glucocorticoids

Weight gain Cushingoid features Increased infection risk Adrenal suppression Diabetes mellitus Hypertension Osteoporosis

Possible risk of cleft lip/ palate

Hydroxychloroquine

Retinopathy Hepatic/renal dysfunction

? Small risk of congenital abnormalities. However, no particular pattern of abnormalities identified

Methotrexate

Hepatotoxicity Leukopenia Interstitial lung disease

Multiple congenital abnormalities, cleft palate, hydrocephalus, anencephaly, long bone abnormalities

Sulfasalazine

Neutropenia Thrombocytopenia Stevens-Johnson syndrome

No adverse fetal outcomes if mother taking folic acid

Azathioprine

Nausea and vomiting Hepatotoxicity

No congenital abnormalities Low birth rate, jaundice Prematurity

Leflunomide

Renal impairment Hepatotoxicity Bone marrow depression

Congenital abnormalities

Cyclosporine

Hypertension Nephrotoxicity Hepatotoxicity

Low risk of congenital abnormalities Prematurity Small for gestational age

hydrocortisone), they are not metabolized by placental dehydrogenase. This policy also minimizes any increased risk of neonatal adrenal suppression and infection. Stop methotrexate before conception as it causes miscarriage and is teratogenic. As methotrexate can cause folate deficiency, administer supplemental folic acid to avoid neural tube defects in women recently treated with this agent. Methotrexate is contraindicated in breastfeeding, as it can accumulate in neonatal tissue. One can continue hydroxychloroquine, sulfasalazine, and azathioprine during pregnancy, and they are thought safe during breastfeeding. Patients on sulfasalazine require folate supplementation preconception and throughout pregnancy. As cyclosporine does not increase the risk of congenital abnormalities, one can continue it throughout pregnancy, but it is essential to monitor renal function. In contrast, leflunomide causes miscarriage and is profoundly teratogenic, so stop it before conception and avoid it during breastfeeding.14 An active

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Caroline S. Grange and Annika Smith

metabolite is detected in plasma for up to two years following cessation; the recommendation is that women planning to become pregnant undergo a cholestyramine washout, measuring leflunomide levels to ensure they are negligible before conception.15 Unfortunately, as the biological DMARDS are relatively new, human safety data in pregnancy are limited. The most studied are the tumor necrosis factor (TNF) inhibitors (e.g., infliximab, etanercept, adalimumab, certolizumab, golimumab). Initial concerns surrounded the use of infliximab and etanercept due to congenital abnormalities (vertebral abnormalities, anal atresia, cardiac defects, trachea-­esophageal, renal, and limb abnormalities). Since this report, multiple studies have not replicated this association.14.15 However, due to the potential immunosuppressive effect of these drugs on the baby, the recommendation is to postpone live vaccines until the infant is six months old. Of the commonly used TNF inhibitors, certolizumab has the lowest levels of placental transfer; it is safe to continue throughout pregnancy and during breastfeeding. Certolizumab is the only TNF inhibitor licensed by the European Medicines Agency and the FDA for administration during pregnancy and breastfeeding.16 Due to low drug transfer, administration of infliximab, etanercept, and adalimumab is considered safe in early pregnancy and for breastfeeding. However, do not administer golimumab due to a concern over congenital malformations. In pregnancy, avoid biological agents, such as tocilizumab, abatacept, and rituximab, due to a lack of safety data. Some suggest discontinuing rituximab six months before conception, as it is associated with neonatal B cell depletion and a pausity of safety data.

Obstetric Management Prepregnancy counseling is essential to optimize disease control and amend medications that may be detrimental to the fetus. Manage the disease using a multidisciplinary approach involving obstetricians, anesthesiologists, neonatologists, and rheumatologists. As RA is a multisystem disease, evaluate all affected organs and seek advice from appropriate medical specialists. In parturients with RA, ligamentous relaxation from estrogen, progesterone, and relaxin, may place increasing strain on weight-bearing joints. As pregnancy progresses, the increasing uterine mass accentuates lumbar lordosis and compensatory thoracic kyphosis so remind RA patients about the importance of correct posture and exercises to relieve discomfort. The usual obstetric and medical indications apply to the mode of delivery. Although rare, severely diseased hips/ lower spine and limitation of hip abduction may impede vaginal delivery and require CD. Patients with hip replacements are at greater risk of dislocation, so take care to avoid excessive flexion or rotation of the hips. Patients taking corticosteroids may require additional doses during labor and delivery due to possible suppression and atrophy of the hypothalamic-­ pituitary-adrenal axis. Women, particularly those with Sjogren syndrome, should be screened for anti–Ro and anti-La ­antibodies due to the risk of neonatal lupus.

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Anesthetic Management Valuable Clinical Insights • Airway concerns require a thorough pre-anesthetic evaluation, avoidance of excessive airway manipulation, and use of video-laryngoscopy/fiberoptic intubation. • Spinal deformity and calcification of ligaments make NA challenging. Consider the more accessible paramedian approach.

The affected organ systems in RA, which may influence anesthetic choice, are summarized in Table 26.2. Preanesthetic assessment should focus on an airway evaluation and cervical spine mobility. Patients with RA may have mandibular hypoplasia, temporomandibular joint dysfunction, cricoarytenoid arthritis, and/or cervical issues resulting in airway problems. It is essential to examine the airway carefully, as urgent delivery under GA may become necessary. Clearly, an early functioning labor epidural is prudent in patients with a difficult airway, so if an operative delivery is required, the neuraxial block can be rapidly extended. The obstetric team should have a clear management plan for emergency operative delivery. Administer pharmacological prophylaxis against aspiration in patients perceived as having a difficult airway. Concerns over the use of cricoid pressure in patients with atlantoaxial subluxation (AAS) are unfounded.17 Identify temporomandibular joint involvement by history and assessment of mouth opening, Mallampati score, and mandibular protrusion. Note symptoms of stiffness or discomfort, and the amount of cervical flexion and extension. Most neck extension occurs at the atlantooccipital joint, and average extension is approximately 35 degrees. If this value is 1 clinical criterion and a total score of > 1030 (Table 26.4). Disease pattern includes a Table 26.4  EULAR/ACR classification criteria for systemic lupus erythematosus30

Clinical domains and criteria

Score

Constitutional • Fever

2

Hematogical • Leukopenia • Thrombocytopenia • Autoimmune hemolysis

3 4 4

Neuropsychiatric • Delirium • Psychosis • Seizure

2 3 5

Mucocutaneous • Nonscarring alopecia • Oral ulcers • Subacute cutaneous or discoid lupus • Acute cutaneous

2 2 4 6

Serosal • Pleural or pericardial effusion • Acute pericarditis

5 6

Musculoskeletal • Joint involvement

6

Renal • Proteinuria > 0.5 g / 24 hours • Renal biopsy Class II or V lupus nephritis • Renal biopsy Class III or IV lupus nephritis

4 8 10

Immunology domains and criteria Antiphospholipid antibodies • Anticardiolipin or anti-beta-2GP1 antibodies or lupus anticoagulant

2

Complement proteins • Low C3 or low C4 • Low C3 and low C4

3 4

SLE specific antibodies • Anti-dsDNA antibody or anti-Smith antibody

6

The presence of positive antinuclear antibodies (ANA) and > 1 clinical criterion and a total score of > 10 is required to diagnose SLE

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mixture of constitutional complaints (e.g., fatigue, fever, weight loss) with musculoskeletal (e.g., arthralgia, arthritis), skin, cardiac, renal, pulmonary, neuropsychiatric, hematological, and serological involvement. Ultraviolet light, infections, drugs, or pregnancy may precipitate exacerbations.

Effect of Pregnancy on the Disease Most studies show that SLE deteriorates during pregnancy, with a widely variable exacerbation rate of 25–65%.31 This considerable variation may be due to different definitions of flares and heterogeneous study designs. Pastore et al.32 found that SLE flares were diagnosed in 23.5% of parturients and occurred more frequently during the second trimester. Renal and hematological are the most common organ flares, although exacerbations arise in other organs.33 Most flares are mild to moderate; however, a small percentage are severe. Risk factors for developing flares include prior lupus nephritis, active disease six months before conception, primigravid status, and discontinuation of hydroxychloroquine.31 Unlike RA, SLE does not deteriorate in the postpartum period.

Effect of Disease on Pregnancy Systemic lupus erythematosus does not affect fertility in the absence of active disease or exposure to cyclophosphamide (causes 33% of patients to have premature ovarian failure). However, as mycophenolate mofetil is now the preferred treatment of lupus nephritis, rather than cyclophosphamide, one does not see this effect.34 Patients with SLE have fewer children than non-SLE patients, possibly due to patient choice or increased risk of miscarriage.35 Pregnancies in SLE patients are high risk and result in ­elevated maternal and fetal morbidity and mortality. Predictors of adverse pregnancy outcomes include active disease, lupus nephritis, antiphospholipid antibodies, thrombocytopenia, primigravida status, and antihypertensive therapy.36

Effect on Mother Active disease at conception is a strong predictor of adverse maternal and obstetric outcomes in SLE pregnancies.37 Parturients with SLE have an increased risk of PreE, occurring in 13–18% (compared with 5–8% in the normal pregnant population).38 Distinguishing between PreE and nephritic lupus flare may be difficult but essential, as treatment regimens are very different (i.e., delivery for PreE and immunosuppressive therapy for nephritic flare). Both conditions can cause proteinuria, hypertension, thrombocytopenia, and worsening renal function. However, rising anti-dsDNA titer, presence of RBC/casts in the urine, a relative reduction of C3/C4, normal liver function tests, and stable uric acid levels favor lupus nephritic flare. In addition, the increased sFLT1/PLGF ratio seen in PreE further helps differentiate the two diagnoses,39 as would renal biopsy. The two conditions may be superimposed, adding to the difficulty in differentiation. Risk factors for developing PreE in these patients include lupus nephritis (two to four times higher risk), elevated Cr, hypertension, thrombocytopenia, prednisolone therapy, and antiphospholipid antibodies (lupus anticoagulant

Autoimmune Disease

and anti-β-2 glycoprotein 1).38 The use of antimalarial drugs is associated with a lower risk of PreE in lupus pregnancy.40 The risk of gestational diabetes increases in SLE pregnancies, particularly if treated with high-dose prednisolone. There is an increased risk of unplanned CD.41

Effect on Fetus Fetal risks in SLE pregnancies include increased fetal loss (spontaneous abortions/stillbirths), preterm birth, IUGR, and premature rupture of membranes. Despite these increased risks, most pregnancies result in a live birth. In an observational study of 385 SLE patients with inactive, mild, or moderate disease at conception, 81% had uncomplicated pregnancies.42 Fetal loss rates have declined over recent times, probably due to better obstetric management of SLE pregnancies. In the study by Buyon et al.42 there was a fetal loss of 5% in SLE patients. Predictors of fetal loss include active maternal SLE, proteinuria, thrombocytopenia, hypertension, and the presence of lupus anticoagulant in the first trimester.43 Intrauterine growth restriction occurs in 10–30% of SLE pregnancies compared to 10% in the general obstetric population, and low birth weight at every gestation is more prevalent. Long-term outcomes of children born to SLE mothers include increased risk of learning disabilities in male offspring, although data are limited.11 There is no evidence for increased risk of autistic spectrum disorders in these children. There is a risk of neonatal lupus (NL), a passively acquired autoimmune disease resulting from the transfer of maternal antibodies (Anti-Ro/SSA and Anti-La/SSB) to the fetus. These antibodies, which present in approximately 30–40% of women with SLE, predominantly affect the neonatal skin and heart. Less commonly, they cause transient hepatic, hematological, and neurological manifestations. The precise pathogenesis is unknown. The cardiac manifestations largely involve the c­ onduction system and may result in first-, second-, and ­third-degree heart block. Approximately 2% of offspring of anti-Ro/SSA and antiLa/SSB-positive women develop complete heart block. In fact, NL is responsible for up to 90% of cases of congenital heart block in the neonatal period.44 Complete heart block is irreversible and is unresponsive to medical treatment, although first- and second-degree heart block are treatable. Treatment of complete heart block is largely expectant, and neonates may require cardiac pacing. Cutaneous NL commonly affects the periorbital and scalp region and develops in approximately 5% of anti-Ro/SSA and anti-lupus anticoagulant/SSB-positive mothers. It is self -limiting and resolves by age six months.

Medical Management The cornerstone to the successful management of SLE parturients is to reduce or prevent end-organ damage (Table 26.5). On presentation, evaluate SLE patients as to disease activity (magnitude and intensity of inflammatory process), disease severity (organs involved and degree of dysfunction), and possible associated conditions (e.g., accelerated atherosclerosis, antiphospholipid syndrome, osteoporosis, pulmonary hypertension). Ask as to their treatment for maintenance and flares. All SLE

Table 26.5  Broad treatment strategies for systemic lupus erythematosus Nonpharmacological Avoid exposure to ultra violet light as may exacerbate SLE manifestations Supplemental vitamin D (as less sun exposure) Appropriate immunizations prior to immunosuppressive treatment Avoid pregnancy during active disease Pharmacological Antimalarials (e.g., hydroxychloroquine) Maintenance For broad relief of constitutional symptoms For musculoskeletal/mucocutaneous manifestations Glucocorticoids For severe flares/often short-term use Immunosuppressives (e.g., azathioprine/methotrexate/rituximab) For severe flares Additional treatments Antibiotics for infections Thromboprophylaxis as required Antihypertensives if needed Analgesics (avoid NSAIDs if renal impairment and after 30 weeks gestation due to a concern about inducing premature closure of a PDA Abbreviations: NSAIDs = non-steroidal anti-inflammatory drugs; PDA = patent ductus arteriosus.

patients require regular follow-up. Many drugs used for SLE are the same as those that treat RA (Table 26.3). Treat musculoskeletal and skin complaints with antimalarial medication (plus analgesics) in patients with renal dysfunction, where NSAIDs are often considered inappropriate. Continuing hydroxychloroquine therapy during pregnancy is safer than stopping it; stopping it increases exacerbations and risks for the mother and fetus. Avoid sulfonamide-containing antibiotics as they are associated with SLE flares.45 Other drugs (e.g., hydralazine, procainamide, methyldopa), known to cause drug-induced SLE, are safe in the idiopathic form of the disease.

Obstetric Management Valuable Clinical Insights • Systemic lupus erythematosus parturients are at increased risk of PreE, with diagnostic difficulties in distinguishing from a nephritic lupus flare. • Unlike RA, SLE does not deteriorate postpartum. • Neonatal lupus, passively acquired from the transfer of maternal antibodies, can result in neonatal heart and skin problems.

As SLE pregnancies are high risk, patients should receive prepregnancy counseling. After baseline evaluation, discussion with the patient needs to center on individual risk stratification, increased maternal/fetal risk, in addition to suboptimal obstetric outcomes. Advise women to delay pregnancy until free of active disease for at least six months.46 Manage higherrisk patients at tertiary referral centers. Those with severe disease and comorbidities (e.g., pulmonary hypertension, severe interstitial lung disease, advanced renal failure) should consider avoiding pregnancy due to risks to themselves and their fetus.

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Close vigilance of the SLE parturient and her fetus is vital, as these patients are at high risk for associated conditions, in addition to specific organ deterioration. The additional physiological and metabolic demands imposed by the fetus may compromise already dysfunctional maternal organs. Therefore, it is necessary to have a multidisciplinary approach involving obstetricians, anesthesiologists, neonatologists, and rheumatologists to improve the care of SLE parturients. Assess the extent and activity of SLE using a combination of clinical history, examination, and serological studies. Initial investigations include CBC, platelet count, urea, electrolytes, LFTs, UA, autoantibody screen, urinary protein creatinine ratio, urinalysis, and 24-hour urine protein. Although anti-nuclear antibody (ANA) is a valuable diagnostic tool, titers do not change with disease activity. Baseline anti-double-stranded DNA antibodies (anti-dsDNA) and complement (C3/4) are important, as subsequent elevation in anti-dsDNA levels and reduction in C3/4 indicates SLE deterioration. Anti-RoSSA/lupus anticoagulant SSB predicts NL and is necessary as part of the baseline workup. A parturient who is positive for anti-RoSSA or anti-lupus anticoagulant SSB should have regular FHR auscultation from 16 weeks gestation and fetal echocardiography. Look for antiphospholipid antibodies; lupus anticoagulant is the most important due to its association with poor maternal outcome.47 Continuing hydroxychloroquine during pregnancy will reduce SLE flares,48 and the risk of congenital fetal heart block in NL.49 Azathioprine, tacrolimus, and glucocorticoids are considered relatively safe in pregnancy; however, discontinue mycophenolate mofetil, methotrexate, leflunomide, due to risk of congenital abnormalities. Start low-dose aspirin (75 mg/day) from 12 weeks gestation to reduce the risk of PreE.50 Vaginal delivery at term is preferred but will depend on maternal and fetal conditions. Increasing degrees of renal failure, hypertension (unresponsive to treatment), or fetal distress may necessitate earlier delivery. Patients on regular corticosteroid treatment often require corticosteroid supplementation during labor and

delivery. As a result of immunosuppression, one should closely watch for signs of infection and treat it promptly. Monitor the mother and neonate postpartum for flares and neonatal lupus, respectively.

Anesthetic Management Valuable Clinical Insights • Critical areas of anesthetic concern include cardiac abnormalities, renal dysfunction, hematological abnormalities, and neurological dysfunction. • Coagulation abnormalities (thrombocytopenia, clotting factor abnormalities) may preclude NA.

Complete evaluation of all associated organ disorders is essential (Table 26.6). Provision of obstetric analgesia and anesthesia depends on the predominant organ(s) affected51; discuss the risks and benefits of the options with the patient. SLE parturients have received general, epidural, and subarachnoid anesthesia.52–54 Although arthritis occurs in approximately 90% of patients with SLE, the spine and hips seldom are affected, and therefore intubation and positioning during labor and NA rarely present a technical challenge. Cardiac abnormalities occur in over 50% of SLE patients and include pericardial, myocardial, valvular, and coronary artery disease. Pericardial involvement is the most common cardiac manifestation,55 but usually follows a benign course. Occasionally, myocardial ischemia or infarction, resulting from coronary artery vasculitis or accelerated atherosclerosis, occurs in young women.56 Sixty percent of patients develop lupus nephritis resulting in significant morbidity. Adopt renal protective strategies, together with cautious use of nephrotoxic drugs, in pregnant patients with lupus nephritis.

Table 26.6  Clinical features and anesthetic implications of systemic lupus erythematosus

Organ

Disease problem

Anesthetic implication

Skin

Skin/mucous membrane lesions Typical “butterfly” facial rash (50%) Chronic discoid lesions

Minimal

CVS

Pericarditis (25%), myocarditis (5–10%) Valvular disease (10%) Increased risk if IHD Verrucous endocarditis (3–4%) Vasculitis

Depends on lesion May require endocarditis prophylaxis

RS

Pleuritis (35%), pneumonitis Interstitial lung disease Pulmonary hypertension (0.5–14%)

Respiratory insufficiency

Renal

Lupus nephritis (60%) Glomerulonephritis

Renal dysfunction Altered drug handling

CNS

Cognitive dysfunction (20–80%) Seizures (10–20%) Risk of stroke (< 15%) Peripheral neuropathy (10–15%) Psychiatric conditions/delirium

Consent issues Differentiate from preeclampsia Assessment of neurology prior to neuraxial block

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Autoimmune Disease

Table 26.6  (Cont.)

Organ

Disease problem

Anesthetic implication

Hematological

Anemia of chronic disease (40%) Leukopenia (50%) Autoimmune thrombocytopenia Antibodies in blood

Reduced oxygen-carrying capacity Risk of infection Risk of bleeding, risk in siting neuraxial block Problems in cross-matching blood

Musculoskeletal

Arthritis Osteoporosis (23%)

Care with positioning Increased fracture risk

Gastrointestinal

Esophagitis, intestinal pseudo-obstruction Lupus hepatitis Pancreatitis

Increased risk of aspiration

Eyes

Dry, irritated eyes with Sjorgen syndrome

Eye protection and artificial lubrication

Abbreviations: CNS = central nervous system; CVS = cardiovascular system; RS = respiratory system.

Neurological and psychiatric issues (e.g., anxiety, mood disorders, psychosis, cognitive dysfunction) occur in 37–95% of patients with SLE.51 Approximately 15% of SLE patients have peripheral neuropathy, with sensory rather than motor nerves likely affected. There are occasional reports of autonomic neuropathy. Document any neurological deficit before NA. Wu et  al.53 described a previously healthy patient who complained of bilateral motor weakness and sensory loss after CD under epidural anesthesia. The diagnosis of SLE was made after extensive investigations to exclude other causes of her neurological deficit. Seizures occur in 10–20 % of patients51 and may lead to a diagnosis of eclampsia. Interstitial pneumonitis, pulmonary hemorrhage, pulmonary hypertension, and pleural effusion are pulmonary complications of SLE. Evaluate these with radiological investigations of the chest. If pulmonary or cardiac involvement is suspected, perform arterial blood gas analysis. Pulmonary function tests in patients with SLE may show a restrictive pattern with decreased vital capacity and diffusion capacity. Pulmonary hypertension (Chapter 6) occurs in 0.5–14% of SLE patients51 and results from thromboembolism, pulmonary vasculitis, and fibrosis, secondary to interstitial lung disease. Consider this diagnosis in patients who complain of dyspnea, chest pain, and nonproductive cough. Parturients with pulmonary hypertension require good analgesia, adequate oxygenation, normocapnia, and avoidance of acidosis to prevent elevation of pulmonary vascular resistance (PVR). Maintaining adequate systemic vascular resistance, intravascular volume, and venous return is also necessary. Low-dose LEA is the preferred method of pain relief in labor; if instrumental delivery is necessary, extend the block slowly, carefully titrating the LA (or use a low dose CSE). Avoid a single-shot spinal as extreme hypotension and hypoxia can occur. Initially, treat hypotension by cautious administration of IV fluids and vasopressors, but this may worsen pulmonary hypertension. In one report, a parturient with SLE-restrictive lung disease and pulmonary hypertension successfully received a GA for an elective CD.52 Evaluate the SLE parturient hematologically as mild thrombocytopenia (platelet count 100–150 x 109/L) is commonly present; platelet counts of < 50 x 109/L (contraindicating NA) are rare. Antibodies to several clotting factors, including VIII, IX,

XII, and XIII are reported in SLE patients and may result in significant coagulopathy, precluding NA (Chapter 21). Atypical antibodies can make cross-matching and typing of blood difficult and time-consuming. Therefore, take note of patients at risk of significant bleeding and blood type or crossmatch early. Postpartum, monitor SLE patients carefully for signs of PreE. Those positive for antiphospholipid antibodies are at increased risk for thrombosis and should have additional prophylactic antithrombotic measures after delivery.

Polyarteritis Nodosa Valuable Clinical Insights • Polyarteritis nodosa (PAN) is a rare multisystem, autoimmune disease that causes necrotising vasculitis of primarily medium-sized muscular arteries. • Affected vessels increase the risk of ischemia and thrombosis to the organ supplied. • All organs can be affected, although there is pulmonary ­vessel sparing.

Polyarteritis nodosa, a rare multisystem, autoimmune disease, causes necrotizing vasculitis of primarily medium-sized muscular arteries and less commonly small-sized muscular arteries. The etiology and pathogenesis are poorly understood. Polyarteritis nodosa is not associated with antineutrophil cytoplasmic antibodies and does not affect veins, unlike other forms of vasculitis. Most cases are idiopathic, although there is a link with hepatitis B virus (HBV) and C (HCV) virus infection, HIV infection, and hairy cell leukemia. The prevalence is estimated at approximately 30 per million population and is possibly declining due to HBV vaccination.57 Parturients with PAN are rare, as men are affected more commonly than women (5 males:1 female) and peak age is 60 years.58 Polyarteritis nodosa is characterized by segmental transmural inflammation of the muscular arteries, causing narrowing of the affected vessels, ischemia and risk of thrombosis, in addition to weakening of the vessel wall with a risk of aneurysm. All organs are affected, but there is pulmonary vessel sparing.

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Table 26.7  Diagnosis of polyarteritis nodosa59 The American College of Rheumatology Classification Criteria> 3 of the following criteria in a patient with vasculitis - Livedo reticularis - Myalgia, weakness, tenderness of leg muscles - Mononeuropathy or polyneuropathy - New onset diastolic BP > 90 mmHg - Evidence of hepatitis B virus infection - Elevated levels of serum blood urea nitrogen (> 40 mg/dL or > 14.3 mmol/L) or Cr (> 1.5 mg/dL or > 132 micromol/L) - Unexplained weight loss > 4 kg - Testicular pain or tenderness - Characteristic arteriographic abnormalities - Biopsy of medium- or small-sized artery containing polymorphonuclear cells

Although possible to have lung involvement in PAN, its presence should prompt investigation of an alternate diagnosis. Common presenting symptoms include fatigue, weight loss, arthralgia, abdominal pain, fever, and signs such as skin lesions, hypertension, neurological deficit, and renal insufficiency. Diagnosis depends on the clinical picture59 (Table 26.7), exclusion of other causes of vasculitis, arteriographic abnormality (occluded vessels or aneurysms), and biopsy. The mainstays of therapy include corticosteroid and immunosuppressant drugs (cyclophosphamide, azathioprine). Mild disease without hepatitis is usually treated with glucocorticoid therapy alone, although many need an additional agent at some point. Antiviral therapy may be helpful in patients with HBV-related PAN to diminish the immunosuppressant enhanced viral replication. Otherwise, therapy aims to normalize any associated hypertension and to support treatment of affected organ dysfunction. Renal transplantation in PAN patients is associated with a lower renal survival than in patients with other causes of end-stage renal disease. The five-year survival with PAN patients is approximately eighty percent.60 Poor prognostic features include renal and GI involvement with mortality usually related to mesenteric, cerebral, or MI or renal failure.

Effect of Pregnancy on Disease Valuable Clinical Insights • Firm recommendations are difficult due to limited case reports of parturients with PAN. • Patients should be in sustained remission preconception for favorable pregnancy outcomes. • Polyarteritis nodosa results in an increased risk of miscarriage, premature rupture of membranes, and preterm delivery.

Due to the limited number of case reports of PAN in pregnancy, it is difficult to draw firm conclusions about the effects of pregnancy on PAN. Previous case series and reports included patients diagnosed as PAN but who, in fact, had non-PAN vasculitis.

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Disease onset during pregnancy is associated with poor outcomes. Ideally, patients should be in sustained remission prior to conception and on drugs compatible with pregnancy to maximize favorable maternal and fetal outcomes.61 The risk of vasculitis flares is less if the patient is in remission prior to pregnancy.62 Glucocorticoids, azathioprine, hydroxychloroquine, cyclosporine, and tacrolimus are compatible with pregnancy. A more detailed discussion of immunosuppressant therapy can be seen in the section on RA. Imaging of the vascular tree prior to pregnancy is useful, in addition to prepregnancy counseling to review medications, assess the risk of exacerbations and discuss potential adverse outcomes.63 Historical data (before 1982) indicated a high mortality rate in PAN parturients; however, evidence also showed favorable outcomes when pregnancy is conceived during remission and cutaneous PAN is present. Ross et al.63 published a literature review of 19 pregnancies, where 16% had a spontaneous miscarriage, and one had an IUFD associated with placental vasculitis. Premature rupture of membranes and preterm deliveries were common, as were low birth weight neonates. Damian et al.64 reported a case of a patient with a twin pregnancy who had an uneventful CD. Forty-eight hours postpartum, she developed tachycardia, fever, and abdominal pain, requiring a subtotal hysterectomy and, subsequently an adnexectomy. Ultimately, she was diagnosed with PAN. The authors noted that the lack of specific immunological tests and the presence of nonspecific ­biologic findings (e.g., pyrexia, leukocytosis, tachycardia) made the differential diagnosis from puerperal infection difficult. Low-dose aspirin (75  mg/day) should be started from 12 weeks gestation to reduce the risk of PreE.50 Priorities in maternal management include careful observation for the development of symptoms, treatment of any acute exacerbation, fetal growth assessment, and control of hypertension.

Anesthetic Management Valuable Clinical Insights • Neuraxial anesthesia is allowed unless there is extensive purpura or significant coagulation abnormalities. • Neurological evaluation and documentation are necessary before NA. • Avoid wide fluctuation of BP to avoid ischemia or vessel rupture.

There are no case reports which address the anesthetic management of PAN parturients. Clearly, it is crucial to involve other specialists, such as cardiologists, neurologists, and nephrologists depending on the clinical picture (Table 26.8). Neuraxial blocks are not contraindicated unless the patient presents with extensive purpura or significant abnormality of their coagulation profile. Careful documentation of any neurological deficit is required prior to any neuraxial technique. Avoid wide fluctuations of BP, as these patients may have multiple small aneurysms and areas of diminished blood flow, secondary to intimal fibrosis and occlusion, throughout the body. Look for signs and symptoms of myocardial ischemia, and fully evaluate all ­complaints of chest pain or dyspnea.

Autoimmune Disease

Table 26.8  Clinical features and anesthetic implications of polyarteritis nodosa

Organ

Disease problem

Anesthetic implication

NS

Mononeuropathy multiplex Asymmetric polyneuropathy Symmetric polyneuropathy (later stages) Risk of CVA, intracerebral hemorrhage

Neurological evaluation prior to neuraxial insertion Avoid cardiovascular instability Ameliorate pressor responses

CVS

Risk of IHD ischemic cardiomyopathy Hypertension

Depends on severity Differential diagnosis of preeclampsia

Renal

Glomerular ischemia Renal arterial aneurysms Multiple renal infarctions

Renal dysfunction Altered drug handling

GIT

Mesenteric vasculitis (abdominal pain) GIT hemorrhage

Risk of aspiration Anemia/shock

Skin

Livedo reticularis Purpura Bullous/Vesicular eruptions Erythematous nodules

Careful handling of patients Caution with neuraxial insertion

Muscle

Muscle weakness

Neurological evaluation prior to neuraxial insertion

Abbreviations: CVA = cerebral vascular accident; CVS = cardiovascular system; GIT = gastrointestinal tract; IHD = ischemic heart disease; NS = nervous system.

Supplementation of corticosteroids may be necessary during labor and delivery in those patients on regular corticosteroid treatment.

Systemic Sclerosis Valuable Clinical Insights • Systemic sclerosis (SSc) is a diverse, progressive multisystem disease characterized by vascular abnormalities, immune system activation, and disturbances in fibroblast function. • The incidence of parturients with SSc is increasing. • Base the diagnosis on the American College of Rheumatology/European League Against Rheumatism criteria. • Systemic sclerosis is classified into three main subgroups: limited cutaneous, diffuse cutaneous, and sine scleroderma. • A multifaceted approach to treating SSc is required, directed at the individual organs involved.

Systemic sclerosis is a diverse, progressive multisystem disease characterized by vascular abnormalities, immune system activation, and disturbances in fibroblast function. Clinical manifestations occur in the skin, musculoskeletal, nervous, cardiovascular, pulmonary, renal, and GI systems. Prevalence ranges from 4 to 489 cases per million individuals worldwide, with an annual incidence of 0.6–122 per million.65 There is a female-to-male preponderance of 9:1.66 Since the peak age of onset is in the fourth decade, SSc is relatively uncommon in pregnancy. However, the incidence of parturients with the ­disease is increasing as more women opt to have children later in life.

Genetic and environmental factors play a role in the etiology and pathogenesis of SSc. Although not fully understood, most theories suggest a complex interplay between immunological events and small vessel vasculopathy, resulting in the pathognomonic development of fibrosis within the skin and other target organs. To diagnose SSc, use the American College of Rheumatology/European League Against Rheumatism criteria to classify SSc67 (Table 26.9). The three main subgroups of SSc are limited cutaneous, diffuse cutaneous, and sine scleroderma. Raynaud phenomenon is a typical neurovascular complication in SSc. Skin manifestations include edema, hyperpigmentation, skin thickening and hardening, skin tightening followed by atrophy and contractures. Changes can be widespread but usually occur initially in the hands and face, with the back and buttocks spared. Dilated blood vessels (telangiectasia) commonly happen, particularly in the oral and nasal cavities. Cardiac disease results from fibrosis and sclerosis of the myocardial and conducting tissue and coronary vessels, in addition to indirect effects from pulmonary and systemic hypertension. Cardiopulmonary involvement accounts for most of the increased mortality in SSc and results from interstitial lung disease and the development of pulmonary artery hypertension (Chapter 6). Pulmonary artery hypertension affects approximately 10% of patients with SSc.68 Scleroderma renal crisis (SRC) may occur, consisting of a sudden onset of malignant hypertension, progressive renal insufficiency, and microangiopathic hemolysis. Peripheral and cranial neuropathy Table 26.9  American College of Rheumatology/European League Against Rheumatism systemic sclerosis classification for the diagnosis of systemic sclerosis

Systemic manifestations

Features

Score

Skin thickening of bilateral distal fingers extending to the metacarpophalangeal joints (sufficient criterion)

-

9

Skin thickening of the fingers

Puffy fingers Sclerodactyly of the fingers

2 4

Fingertip lesions

Distal finger ulcers Distal finger pitting scar

2 3

Telangiectasia

-

2

Abnormal nailfold capillaries

-

2

Evidence of pulmonary arterial hypertension and/or interstitial lung disease (maximum score: 2)

Pulmonary arterial hypertension Interstitial lung disease

2

Raynaud phenomenon

-

3

Evidence of SSc-related autoantibodies (maximum score: 3)

Anti-centromere Anti-topoisomerase I Anti-RNA polymerase III

3 3 3

2

Adapted from: van den Hoogen F, Kanna D, Fransen J, et al. Classification Criteria for Systemic Sclerosis: An American College of Rheumatology/ European League Against Rheumatism Collaborative Initiative. (2013)67 Total score is determined by adding the maximum score achieved in each category. ≥ 9 is classified as definite SSc.

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may result from compression of thickened adjacent connective tissue. Disease manifestations in the musculoskeletal system are due to edema, arthralgia, and myalgia. Use a multifaceted approach to treat the disease and direct symptomatic treatment at any involved organs. Immunomodulatory and antifibrotic methods do not conclusively alter long-term progression of the disease, although glucocorticoids and cyclophosphamide may be helpful in those patients with diffuse disease.69 Recombinant human relaxin (a heterodimer protein secreted by the corpus luteum and placenta during pregnancy) reduces skin thickening and improves motility in moderate to severe diffuse SSc.70 Calcium channel blockers, usually nifedipine, are first-line therapy for Raynaud phenomenon. Over time, improved management has led to more SSc patients surviving, and the 10-year survival is 66% after diagnosis.71 Poorer prognosis is associated with greater skin involvement, visceral disease (particularly cardiac, pulmonary, and renal), presence of anti-topoisomerase I (anti-Scl-70), anemia, and elevated erythrocyte sedimentation rate.72,73 Patients with the CREST variant (Calcinosis, Raynaud phenomenon, Esophageal dysmotility, Sclerodactyly, and Telangiectasia) have relatively benign disease and a better prognosis. In patients with SSc, there is an increased risk of cancer, particularly lung tumors.74

Effect of Pregnancy on Systemic Sclerosis The impact of pregnancy on SSc is difficult to quantify as many normal pregnancy symptoms are like those of the disease itself (e.g., GI reflux, edema, dyspnea). In a prospective series, maternal disease was stable in 60% of pregnancies, improved in 20%, and worsened in the remaining 20%.75 The most important determinants of adverse maternal and fetal outcomes in parturients with SSc are the extent and severity of organ involvement; pregnancy is safest in those patients without significant cardiac, pulmonary, or renal disease. Some suggest that those with early diffuse scleroderma avoid pregnancy until their disease stabilizes due to the risk of developing cardiopulmonary and renal problems early in the disease course. It is often problematic to distinguish SRC from PreE or HELLP, but pregnancy does not increase SRC risk. The incidence of SRC during pregnancy is around 2%, with a peak in the second trimester.76 Most consider angiotensin-converting enzyme (ACE) inhibitors contraindicated in pregnancy due to associated fetal risks (oligohydramnios, IUFD, renal atresia, and pulmonary hypoplasia when initiated beyond the second trimester). The benefits of these medications outweigh the risks in the treatment of SRC. Before the advent of ACE inhibitors, SRC was almost uniformly fatal.

Effect of Systemic Sclerosis on Pregnancy Most studies report that fertility is unaffected by SSc, although others disagree.77,78 Many studies report an increased risk of spontaneous abortion in parturients with SSc; higher rates of loss are seen in patients with diffuse rather than localized cutaneous disease.79 Various studies have observed that women with SSc have higher rates of miscarriage, IUGR, preterm deliveries,

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and SGA births than healthy controls. However, the influence of medications (particularly immunosuppressive agents) and other risk factors on these outcomes is unclear.80,81 Patients with hypertension or renal disease have a significantly increased risk of PreE, and frequent antenatal monitoring of BP is essential.82

Obstetric Management Valuable Clinical Insights • Maternal disease tends to be stable in 60% of pregnancies, improves in 20%, and worsens in the remaining 20%. • Systemic sclerosis is associated with higher rates of miscarriage, IUGR, preterm deliveries, and SGA births.

Fully evaluate SSc parturients throughout pregnancy with timely assessment and input from appropriate medical specialists, including the cardiology, respiratory, and renal teams. Additional investigations, including pulmonary function testing and echocardiography, may be indicated. Close fetal surveillance is also essential, with attention given to possible fetal effects of medications. Vaginal delivery is generally preferred, where possible. The interdisciplinary team will decide on management and type of delivery based on maternal and fetal disease and comorbidity. Ineffective uterine contractions or cervical dystocia during labor may result from uterine and cervical wall thickening. Augment labor with oxytocics cautiously as it may cause considerable hemodynamic changes. These changes may be detrimental in SSc patients with cardiac disease or pulmonary arterial hypertension. Carefully position SSc patients during delivery due to associated contractures and restrictive skin changes. Keep patients warm to reduce symptoms of Raynaud phenomenon. Monitor renal function in patients with renal insufficiency. There is a report of obstructive uropathy resulting from uterine enlargement within a noncompliant abdomen.83 Elective CD may be required when skin fibrosis involving the perineum and cervix prevents vaginal delivery.84 Wound healing may be problematic in patients with advanced disease or those on corticosteroids; a careful operative technique to promote healing is essential. Patients with significant cardiovascular, pulmonary, or renal compromise benefit from observation in a high dependency or critical care setting postpartum.

Anesthetic Management Valuable Clinical Insight An anesthetic review early in pregnancy is required to assess organ involvement and formulate anesthetic strategies, with particular attention to airway and venous access.

See Table 26.10. Patients should have an anesthetic review early in pregnancy to evaluate organ involvement and formulate anesthetic strategies. Venous access may be difficult due to cutaneous changes, and central venous catheterization may be

Autoimmune Disease

Table 26.10  Clinical features, anesthetic implications, and recommendations in systemic sclerosis

System

Involvement in systemic sclerosis

Anesthetic implications and recommendations

Airway

Microstomia Limited neck extension Oral and nasal telangiectasias

Difficult intubation – careful airway planning and positioning, consider AFOI where tracheal intubation required Bleeding risk if traumatized

Respiratory

Interstitial lung disease Pleural effusion Chest wall restriction Pulmonary arterial hypertension

Limited respiratory reserve Lung protective ventilation Avoid precipitants producing increased PVR (hypoxia, hypercapnia, acidosis, pain, hypothermia, high positive end expiratory pressure) Invasive cardiac monitoring and specialist intensive care involvement may be required – arterial line, TEE, PA catheter

Cardiovascular

Myocardial ischemia Chronic pericardial effusion Hypertension Conduction disturbances Raynaud phenomenon

Reduced cardiac reserve Risk of dysrhythmias Caution with uterotonics and hemodynamic effects Invasive cardiac monitoring and specialist intensive care involvement may be required – arterial line, TEE, PA catheter

Neurological

Peripheral/cranial neuropathy Autonomic instability

Possible prolonged sensory and motor neuraxial block – reduce dose of LA

Gastrointestinal

Dysmotility Reflux esophagitis Diarrhea/malabsorption

Risk of aspiration – consider fasting, rapid sequence induction, aspiration chemoprophylaxis Dehydration/malnutrition Coagulopathy (vitamin K deficiency)

Renal

Proteinuria Renal insufficiency Malignant hypertension Scleroderma renal crisis

Differential diagnosis of preeclampsia Altered drug handling Risk of end-organ damage

Skin

Non-pitting edema Hidebound skin Ischemic ulceration

Difficulty with cannulation Usually lumbar sparing – ease of NA is not affected

Musculoskeletal

Arthritis Myopathy Contractures

Adequate padding Careful patient positioning

Abbreviations: AFOI = awake fiberoptic intubation; PA = pulmonary artery; PVR = pulmonary vascular resistance; TEE = transesophageal echocardiography.

necessary. Patients with cardiorespiratory disease may require arterial cannulation, but it may induce vasospasm and distal necrosis. There may be less ischemic risk with brachial, rather than radial, arterial catheterization in patients with Raynaud phenomenon. Assess the airway; difficult mask ventilation and intubation occur from the limited mouth opening as temporomandibular joint fibrosis and skin thickening cause microstomia. Taut skin may diminish neck mobility and hardening of the tissue in the submental triangle may limit the ability to align the oral, pharyngeal, and laryngeal axes during laryngoscopy.85 In addition, note the presence of oral and nasal telangiectasias as they may bleed profusely if traumatized. Take extreme care during airway manipulation in these circumstances and consider awake fiberoptic intubation. The risk of aspiration in affected patients is more likely than normal parturients. Increased gastric hypomotility from SSc compounds the normal physiological GI changes of pregnancy; administer chemoprophylaxis. Rapid sequence induction may be problematic, despite the high risk of aspiration, due to the risk of difficult intubation and fibrosis of the esophagus, causing Sellick maneuver to be ineffective. Nerve blocks and NA can be successfully performed in parturients with SSc.86 Prolonged duration of sensory blocks can occur following nerve blocks and NA. This is a result

of diminished intravascular uptake due to disease-induced microvascular changes.87,88 Consider a reduced LA dose due to increased sensitivity to these agents.89 Some recommend providing NA incrementally with an epidural or intrathecal catheter as a high sensory block and severe hypotension requiring treatment have occurred in SSc parturients. The anesthesiologist can then titrate the dose of LA to effect.90,91 Early LEA for labor is advised, especially in patients with potentially difficult intubation, as this allows extension of the block if operative delivery is required. The skin of the lumbar region is frequently spared from cutaneous involvement, making needle insertion no more complex than one would expect in the obstetric population. General anesthesia has been used successfully for CD in patients with SSc.92–94 Ventilation may be difficult due to decreased pulmonary compliance, so use lung-protective ventilation strategies. Deciding whether to use NA or GA for CD will depend on the airway, the urgency of delivery, and the presence of a functioning epidural. In patients with a potentially difficult airway, one should make an early decision for a CD to enable adequate time for safe anesthesia. Take care with patient warming and positioning and protect pressure areas. As a result of decreased tear production in affected patients, use hydrating ointments and eye pads to protect against corneal damage.

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Maternal mortality in parturients with pulmonary arterial hypertension remains very high. In this group of patients, there is poor tolerance of the physiological changes of pregnancy and the peripartum period. These patients require close hemodynamic monitoring (possibly invasive) and thorough planning; referral to a specialist pulmonary arterial hypertension center may be necessary.95 Uterotonics often are contraindicated in parturients with cardiovascular disease. Patients with SSc have an increased risk of VTE, which may be particularly significant in the obstetric population.96

Antiphospholipid Syndrome Valuable Clinical Insights • Antiphospholipid syndrome (APS) is a multisystem autoimmune disorder characterized by antibodies directed against phospholipid-binding plasma proteins, together with the typical clinical manifestations of thromboembolic events and pregnancy morbidity. • Common clinical manifestations include DVT, thrombocytopenia, livedo reticularis, cerebrovascular accident, superficial thrombophlebitis, pulmonary embolism, fetal loss, transient ischemic attack, and hemolytic anemia.

Antiphospholipid syndrome (APS) is a multisystem autoimmune disorder characterized by antibodies directed against phospholipid-binding plasma proteins, together with the typical clinical manifestations of thromboembolic events and pregnancy morbidity.97 The three antiphospholipid antibodies (aPLs) associated with APS are anticardiolipin (aCLs), lupus anticoagulant and anti-β-2-glycoprotein-I antibodies.98 The diagnosis of APS requires the persistent presence of one or more of these aPLs, clinical evidence of vascular thrombosis, and increased pregnancy morbidity. Low titers of aPLs can be present in otherwise healthy individuals, particularly the elderly, who do not have APS. Certain infections, drugs, or malignancies may induce aPLs. Increased aPLs titers are also associated with SLE and other autoimmune diseases (e.g., RA, immune thrombocytopenic purpura). Approximately half of the patients with APS have primary disease. The other half have a concomitant systemic autoimmune disease, most commonly SLE.99 APS can be further classified according to clinical manifestation, thrombotic APS, APS associated with obstetric morbidity, or catastrophic APS. In thrombotic APS, there is venous, arterial, or microvascular thrombosis. Obstetric APS includes one or more unexplained deaths of a morphologically normal fetus, at or beyond the tenth week of gestation; one or more premature births of a morphologically normal neonate before the thirty-fourth week of pregnancy because of eclampsia or severe PreE, or recognized features of placental insufficiency; or three or more unexplained consecutive spontaneous abortions before the tenth week of gestation, with maternal anatomic or hormonal abnormalities and paternal and maternal chromosomic causes excluded.100 Catastrophic APS occurs in < 1% of all cases and represents a

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severe condition associated with multiorgan failure secondary to widespread thromboses predominantly affecting the small vessels. Due to variable organ involvement, possible clinical features are diverse (Table 26.11). In a series of 1000 patients with APS, the clinical manifestations reported were DVT (32%), thrombocytopenia (22%), livedo reticularis (20%), cerebrovascular accident (13%), superficial thrombophlebitis (9%), pulmonary embolism (9%), fetal loss (8%), transient ischemic attack (7%), and hemolytic anemia (7%).101 Both venous and arterial thrombosis occur, with venous thrombosis more frequent than arterial; these may be recurrent. Although thrombosis, infarction, and vasculopathy account for most clinical features, the exact etiology, and pathogenesis of APS remain unclear. Direct treatment of the primary and secondary prevention of thrombosis involves anticoagulants (heparin or warfarin), antiaggregants (aspirin or clopidogrel),

Table 26.11  Clinical features of antiphospholipid syndrome

Clinical feature Thrombosis - Venous - Arterial

Venous more than arterial Deep veins of lower extremities most common sites Other sites – pelvic, renal, pulmonary, hepatic, portal, axillary, subclavian, ocular, inferior vena cava, and cerebral sinuses Superficial veins Stroke/transient ischemic attack (cerebral arteries most common arterial site)

Obstetric morbidity

≥ 1 unexplained fetal death at or beyond 10 weeks gestation ≥ 1 premature birth due to severe PreE, eclampsia or consequences of placental insufficiency ≥ 3 unexplained consecutive spontaneous abortions before 10 weeks gestation

Skin

Livedo reticularis (reticular pattern of mottling over extremities or trunk) Splinter hemorrhages

Hematological

Autoimmune hemolytic anemia Thrombocytopenia Various thrombotic microangiopathic syndromes (TTP, HUS)

Renal

Nephropathy Thrombotic microangiopathy

Neurological

Stroke/transient ischemic attack Cognitive dysfunction Seizures

Cardiac

Intracardiac/coronary artery thrombosis Mitral/aortic regurgitation (due to thickened valves)

Pulmonary

Pulmonary thromboembolism Pulmonary arterial thrombosis Adult respiratory distress syndrome Diffuse alveolar hemorrhage Pulmonary artery hypertension

Gastrointestinal

Ischemic event

Ocular

Amaurosis fugax Retinal arterial/venous occlusion Anterior ischemic optic neuropathy

Autoimmune Disease

or by reducing antibodies (immunosuppressants: corticosteroids and cytotoxic agents). However, the mainstay of treatment is antithrombotic therapy, with immunosuppressive therapy reserved for those who are refractory to conventional treatment. There are insufficient data and no established guidelines to ­support treatment with direct oral anticoagulants in patients with APS. Although the prognosis varies, there is an increased risk of premature death in APS patients. Mortality is related to the increased propensity to TED and the increased rates of malignancy, ischemic heart disease, adverse effects of anticoagulant medication, and associated diseases (e.g., SLE). Patients with differing subclasses of aPLs may have varying degrees of disease risk. More than 50% of patients with APS who have experienced a thrombotic event will have a subsequent clinical thrombosis. In approximately 70%, the thrombosis will occur on the same side of the vascular tree.102 The development of catastrophic APS results in a grave prognosis. There is a 50% mortality rate; of the survivors, 20% have other recurrent thromboembolic events despite anticoagulation.103 Precipitating factors for catastrophic APS include surgery (even minor operative procedures), infection, and the withdrawal of anticoagulants.104

Effect of Pregnancy on Antiphospholipid Syndrome It is unknown whether pregnancy directly affects APS, but pregnancy compounds the already elevated risk of thrombosis in patients with APS.

Effect of Antiphospholipid Syndrome on Pregnancy Valuable Clinical Insight Antiphospholipid syndrome is associated with infertility, recurrent miscarriage, early severe PreE, eclampsia, HELLP syndrome, thrombocytopenia, prematurity, stillbirth, and IUGR.

The prevalence of aPLs in the general population ranges between 1% and 5%.105 This prevalence is much higher, with a range of 5–50% (mean 15%) in parturients with recurrent miscarriage.106 Additional pregnancy-associated complications of APS include infertility, recurrent miscarriage (> 10 weeks gestation), early severe PreE, eclampsia, HELLP syndrome, thrombocytopenia, prematurity, stillbirth, and IUGR.107 The precise mechanism for pregnancy morbidity in APS is unclear; however, some suggest that aPLs affect platelet and endothelial cell activation, promote coagulation, activate complement, and directly affect the human placental trophoblast. Paradoxically, APS may protect against recurrent fetal loss (< 10 weeks gestation). One possible explanation is that the trophoblast experiences reduced uteroplacental blood flow and low oxygen partial pressures in early normal pregnancy (< 10 weeks), i.e., conditions usually found in patients with APS. The presence of lupus anticoagulant,47 triple positivity (lupus anticoagulant, aCL, and anti-β-2-glycoprotein-I antibodies),108 and low complement levels are associated with a higher risk of adverse obstetric outcomes in parturients with APS.

Obstetric Management Treat pregnancies in women with APS as high-risk, with prevention of thrombosis being the most important therapeutic goal. The universal recommendation is to administer prophylactic low-dose aspirin and heparin. There is still a debate about the optimal treatment of parturients with APS as the scientific evidence is poor, largely due to flawed trial design and intertrial clinical heterogeneity.109 Benefits of low molecular weight heparin (LMWH), compared to unfractionated heparin (UFH), include better bioavailability, improved dosage regime, reduced risk of heparin-induced thrombocytopenia, and diminished risk of osteoporosis. In the final weeks of pregnancy, consider switching LMWH to UFH as it is easier to time the dosing and, if necessary, reverse it for delivery. Base the dose of LMWH on the patient’s risk factors; a prophylactic dose is usually used in patients with a lower risk, while patients with previous thrombosis or coexisting morbidity may receive an intermediate or full therapeutic dose. Consider converting women on longterm warfarin anticoagulation to therapeutic dose LMWH to avoid potential teratogenic risks. Warfarin can be resumed postpartum. There is no evidence to support corticosteroids or IVIG in affected parturients. However, there may be a role for hydroxychloroquine.110 Maternal and fetal status should determine monitoring and anticoagulation treatment during pregnancy. Due to the increased risk of developing PreE and placental insufficiency and the use of anticoagulation in parturients with APS, it is necessary to carefully plan the time of delivery to ensure maternal and fetal safety and the use of NA, if required.

Anesthetic Management Valuable Clinical Insights • Thrombosis prevention is the most important therapeutic goal in pregnancy. • Anesthetic assessment early in pregnancy is required; evaluate coexisting autoimmune disease (particularly SLE) and organ involvement. • Parturients may have significant thrombocytopenia, receive anticoagulant therapy, or rarely have antibodies to several clotting factors.

Assess parturients early in pregnancy for coexisting autoimmune disease (particularly SLE) and organ involvement. Patients with lupus anticoagulant have an artifactual in vitro prolongation of the PTT, despite normal or increased in vivo coagulation. Patients with APS may have significant thrombocytopenia, receive anticoagulant therapy, or rarely have antibodies to several clotting factors (including VIII, IX, XII, and XIII). If there is significant coagulopathy, it will preclude NA. Thrombocytopenia develops in a parturient with APS due to PreE, APS itself, or heparin induced. In patients receiving anticoagulation, NA is permitted four to six hours after UFH once the coagulation profile has normalized (remember that the PTT can be artificially prolonged in the presence of lupus anticoagulant). For those receiving LMWH, 12 hours should elapse after

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the last thromboprophylactic dose or after 24 hours for patients on a treatment dose. Weigh the advantages of NA in a particular patient against the small risk of spinal hematoma.111 Two series describe the anesthetic management of 20112 and 113 27 parturients with APS. Both authors emphasize the likelihood of patients requiring anesthetic involvement. Of the 47 cases, 28 received NA (22 epidurals, five spinals, one CSE), and 19 required CD. Despite antithrombotic treatment, five patients experienced thrombotic episodes (including transient ischemic attack, pulmonary embolus, bilateral renal vein thrombosis, and DVT) during pregnancy and the early postpartum period. Start prophylactic antithrombotic measures such as avoiding hypothermia, adequate hydration, early mobilization, and anti-embolic stockings as soon as feasible. Restart thromboprophylaxis or therapeutic anticoagulation (depending on the individual risk of thromboembolism) after delivery and continue for six weeks postpartum. Restart LMWH at least four hours after NA or removal of the epidural catheter and at least one hour before recommencing UFH. Consider long-term anticoagulation if thrombotic events are unrelated to the pregnant state. In addition to thromboembolism, parturients with APS are at risk of PPH, possibly due to anticoagulants, PreE, or thrombocytopenia. There are reports of peripartum hemorrhagic complications in patients with APS.114,115 The authors of a cohort trial of 264 pregnant women with APS suggested that an emergency CD was a significant risk factor for hemorrhage.116 Atypical antibodies can make cross-matching and blood-typing difficult and time consuming. Therefore, type and cross-match blood early in APS patients at risk of significant hemorrhage or those with residual anticoagulant effect. Administer surgical antibiotic prophylaxis to prevent infection. Infection, surgery, or pregnancy and the puerperium may trigger catastrophic APS. Several reports describe the problems associated with anesthetizing nonobstetric patients with catastrophic APS.117–120 The risks of opposing complications present an intraoperative challenge; the surgical stimulus may trigger a catastrophic exacerbation of the thrombotic tendency, and significant bleeding may result from the necessary anticoagulation.

Multiple Sclerosis

increased over the last few decades.121 The mean age of onset is around 30 years, with presentation usually between 15 and 45 years.122 The main pathological mechanisms in MS are inflammation, demyelination, and axonal degeneration, resulting in the characteristic presence of focal demyelinated plaques within the CNS, accompanied by variable degrees of inflammation and gliosis, with partial preservation of axons. The pathogenesis remains uncertain, but it likely begins as an acute inflammatory immune-mediated disorder characterized by autoreactive lymphocytes, followed by microglial activation and chronic neurodegeneration later in the disease.123 Genetic factors, geographical factors, low sun exposure, tobacco smoking, EpsteinBarr virus infection, and childhood obesity are associated with the development of MS.124 Demyelinated lesions may occur anywhere in the CNS, resulting in various clinical manifestations (Table 26.12). Classic presentations include unilateral optic neuritis (blurred vision with associated pain), partial myelitis (extremity and torso impaired sensation, weakness, and ataxia), focal sensory disturbance (limb paresthesia, abdominal or chest dysesthesia), or brainstem syndromes (intranuclear ophthalmoplegia, vertigo, hearing loss, facial sensory disturbance). Lhermitte sign, an electric shock-like sensation that runs down the back and limbs on neck flexion, is reported by patients with MS. Autonomic dysfunction may also occur, resulting in (orthostatic) hypotension and cardiac dysrhythmias. Multiple sclerosis presents as either relapsing-remitting or progressive types. There are four subtypes based on how it Table 26.12  Clinical manifestations of multiple sclerosis

Clinical manifestation Visual disturbance

Usually unilateral – optic neuritis, diplopia, or vision loss (partial/complete)

Sensory deficits

Paresthesia, anesthesia or neuralgia of the extremities or the trunk Impairment of facial sensation or trigeminal neuralgia

Cerebellar involvement

Tremor, ataxia, or nystagmus

Motor deficits

Paraparesis, paraplegia, muscular atrophy, spasticity, gait disturbance, or abnormal reflexes Hemifacial spasms or facial myokymia (fine unilateral involuntary rippling of facial muscles) Speech and swallowing difficulties

Bladder and bowel dysfunction

Bladder – urgency, frequency, hesitancy, retention, or incontinence Bowel – constipation or incontinence

Cognition

Cognitive dysfunction, depression, anxiety, dementia, fatigue, or seizures

Pain

Nociceptive, neuropathic, psychogenic, idiopathic or mixed types of pain Lhermitte sign

Sleep disorders

Obstructive sleep apnea, movement disorders, narcolepsy, or insomnia

Autonomic dysfunction

Orthostatic hypotension, bladder/bowel dysfunction, neurocardiogenic syncope or cardiac dysrhythmias

Valuable Clinical Insights • Multiple sclerosis (MS) is a chronic immune-mediated demyelinating disease of the CNS. • The main pathological mechanisms are inflammation, demyelination, and axonal degeneration; these give rise to focal demyelinated plaques occurring anywhere in the CNS, resulting in various clinical manifestations.

Multiple sclerosis is a chronic immune-mediated demyelinating disease of the CNS. The prevalence of MS varies worldwide but is 1–2 per 1000 people in Western countries. It has a strong female predominance with a female to male ratio of approximately 2–3 to 1. The prevalence and incidence, particularly in women, have

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Autoimmune Disease

Table 26.13  Types of multiple sclerosis

MS type

Characteristics

Clinically isolated syndrome

- represents the first attack of MS - usually presents with one or more clinically distinct symptoms with at least partial resolution

Relapsing-remitting

- clearly defined relapses with full or incomplete recovery - minimal progression between relapses - accounts for 85–90% of MS cases at onset

Secondary progressive

- characterized by an initial relapsing-remitting MS disease course followed by worsening with or without occasional relapses, minor remissions, or plateaus

Primary progressive

- disease progression from onset - accounts for approximately 10% of MS cases at onset

year and was significantly higher after delivery.129 Various studies have shown no overall adverse effect of pregnancy on the prognosis of long-term disability in MS.130 Gonadotropin-releasing hormone agonists in assisted conception are associated with an increased risk of relapse.131 Good disease control and the use of DMTs before pregnancy decrease postpartum relapse rates.132–134 Breastfeeding may lower postpartum relapse rates, although this remains uncertain.135,136 Breastfeeding is discouraged while the mother is receiving DMTs.

Effect of Multiple Sclerosis on Pregnancy Valuable Clinical Insight Multiple sclerosis does not seem to have any significant adverse maternal or neonatal effects during pregnancy.

presents over time rather than on specific symptoms or severity125 (Table 26.13). Make the diagnosis based on clinical findings, MRI, laboratory data, and the revised McDonald criteria.126 There are limited therapeutic options to prevent or slow disability in MS. Disease-modifying therapies (DMTs) suppress the inflammatory response, while symptomatic treatment, lifestyle modifications, psychological support, and rehabilitation interventions are part of the multifaceted approach to disease management. Neurological disability from MS and its progression is highly variable between patients. Relapsing-remitting MS has a better prognosis than progressive types, but eventually, it converts to a secondary progressive form in many patients. Life expectancy is reduced by 7 to 14 years in patients with MS compared to the general healthy population.127

Overall, MS does not seem to have any significant adverse maternal or neonatal effects during pregnancy.137 Some medications used to treat MS are known teratogens. Most others are FDA category C (“risk cannot be ruled out”) for use in pregnancy; discontinue these treatments at the recommended time before conception (drug dependent). An exception is glatiramer acetate, FDA category B (“no evidence of human risk in controlled studies”) so can continue on specialist advice if the benefits outweigh the risks.137 Some parturients require beta interferon, and less commonly natalizumab, during pregnancy following expert advice. While relapse rates decrease during pregnancy, some parturients will suffer severe relapses in pregnancy; treat these relapses with corticosteroids, IVIG, or plasma exchange may be required.

Effect of Pregnancy on Multiple Sclerosis

Obstetric Management

Valuable Clinical Insight The relapse rate significantly decreases during pregnancy compared to the preceding year and is significantly higher after delivery.

Multiple sclerosis affects women of childbearing age, but historically its significance was uncertain. The Pregnancy In Multiple Sclerosis (PRIMS) study in 1998, including 254 women during 269 pregnancies, was the first large prospective study to assess the influence of pregnancy and delivery on the clinical course of MS.128 They reported a reduction in the relapse rate during pregnancy (especially in the third trimester) compared to the year before pregnancy. A significant increase in the relapse rate occurred in the first three months postpartum, followed by a return to the prepregnancy rate. The relapse rate postpartum was 28%. Pregnancy did not influence disability progression. Relapse was most likely in women with more disease activity in the year before and during pregnancy.128 A meta-analysis and several other studies concluded that the relapse rate significantly decreases during pregnancy compared to the preceding

Multiple sclerosis does not usually influence obstetric management unless there is significant disability that may affect decision-making regarding mode of delivery. In general, there is no significant difference in CD or assisted vaginal delivery rates between parturients with MS and the general population, although some studies show a trend for increased CD or assisted vaginal delivery with increased MS disability.138 Women with spinal cord involvement or loss of sensation below T11 may not notice the onset of labor. Advise them to look for other symptoms, including increased spasticity, GI upset, flushing, and back pain.137 In parturients with severe spinal cord disease, consider autonomic dysreflexia in the differential diagnosis for PreE.

Anesthetic Management Valuable Clinical Insights • As part of the anesthetic assessment in pregnant MS patients, evaluate and document the extent of disease and neurological deficits, with particular attention to respiratory and autonomic dysfunction. • Both NA and GA have been used safely in MS parturients.

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An anesthesiologist should assess pregnant women with MS and document the extent of their disease and neurological deficits. Pay attention to respiratory problems and autonomic dysfunction. Discuss the risks and benefits of NA at this consultation as there are longstanding concerns about the safety of anesthesia in patients with MS. Historically all anesthetic techniques were implicated in exacerbating MS symptoms, mainly in case reports. Uncertainty surrounds the potential neurotoxic effects of LA administered during NA on demyelinated areas of nerves and its possible impact on the course of the disease. Local anesthetic administered via an epidural catheter theoretically poses less risk than a spinal technique because there is a lower concentration of LA in the CSF, leading many anesthesiologists to favor this technique. In 1998, the PRIMS study showed no significant increase in the rate of postpartum MS relapse among women who received LEA compared with those who did not.132 In 2006, a review of 592 UK anesthesiologists reported that most would perform NA for labor and CD in parturients with MS, provided the woman understood the relapse risks and gave full consent. An additional proviso was that these women would receive adequate follow-up.139 Further studies assessing the risks of NA in parturients with MS reported no effect on overall disability or relapse rates.140–142 In 2013, a retrospective cohort study of 431 deliveries to parturients with MS reported no increase in disability or relapse rate following 116 epidural and 82 spinal anesthetics.143 Multiparous women with MS were more likely to undergo epidural anesthesia compared to multiparous women in the general population. However, previous studies reported no increased rate of anesthesia in parturients with MS.143 A 2018 retrospective study of 70 deliveries to women with MS concluded that at six months postpartum, neither delivery mode nor type of obstetric anesthesia or analgesia had any impact on the course of MS .144 In 2019, a small retrospective case series of 18 deliveries to parturients with MS found no statistically significant link between NA and postpartum relapse.145 Further adding to the data supporting the safety of NA in parturients with MS, a 2021 retrospective cohort study of 118 deliveries in 104 parturients with MS reported no increase in postpartum relapse following neuraxial analgesia (n = 50) and neuraxial anesthesia (n = 46). Only disease activity before pregnancy was predictive of postpartum relapse.146 When indicated, there is no contraindication to GA with inhaled or intravenous anesthetic agents in parturients with MS, and most opioids are safe.147 However, be cautious with neuromuscular blocking agents (NMBAs). Depolarizing NMBAs may induce life-threatening hyperkalemia due to MS-induced denervation or misuse myopathy. Resistance to nondepolarizing NMBAs, possibly due to proliferation of extra junctional acetylcholine receptors produced by denervation, is possible with MS. Conversely, there could be increased sensitivity and prolonged effects due to decreased muscle mass when using non-depolarizing NMBAs in pregnant women with MS. The perioperative management of parturients with advanced disease affecting respiratory muscles and bulbar function is challenging. Lesions affecting the respiratory centers may cause obstructive sleep apnea, which may be problematic

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postoperatively.148 Patients affected by autonomic dysfunction have variable degrees of hemodynamic instability and marked hypotension with a reduced response to IV fluid or vasopressor therapy. Withhold disease-modifying treatments before conception and antenatally, however, continue symptomatic therapies such as analgesics and consider their effects on anesthetic management. Elevated body temperature is a trigger for the exacerbation of MS symptoms. Monitor and control body temperature peri­ operatively to minimize this risk; identify and treat any infection promptly. Additionally, stressful conditions, surgery, delivery, and fatigue may be associated with MS exacerbations or relapses.

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51. Ben-Menachem E. Systemic lupus erythematosus: a review for anesthesiologists. Anesthesia Analgesia 2010;111:665–676. 52. Cuenco J, Tzeng G, Wittels W. Anesthetic management of the parturient with systemic lupus erythematosus, pulmonary hypertension, and pulmonary edema. Anesthesiology 1999;91:568–570. 53. Wu L, Jiang X-Q, Xiong Y-Q, et al. Muscle weakness of the lower limbs after epidural anesthesia in a pregnant woman with undiscovered systemic lupus erythematosus. Anesth Analg 2020;135:621–622. 54. Vyas V, Shukla D, Patil S, et al. Caesarean section in a case of systemic lupus erythematosus. Indian J Anaesth 2014;58: 193–195. 55. Miner JJ, Kim AH. Cardiac manifestations of systemic lupus erythematosus. Rheum Dis Clin North Am 2014;40:51–60. 56. Ozaki M, Minami K, Shigematsu A. Myocardial ischemia during emergency anesthesia in a patient with systemic lupus erythematosus resulting from undiagnosed antiphospholipid syndrome. Anesth Analg 2002;95:255. 57. De Virgilio A, Greco A, Magliulo G, et al. Polyarteritis nodosa: a contemporary overview. Autoimmun Rev 2016;15:564–570. 58. Mahr A, Guillevin L Poissonnet M, et al. Prevalences of polyarteritis nodosa, microscopic polyangiitis, Wegener’s granulomatosis and Churg-Strauss syndrome in a French urban multi-ethnic population in 2000: a capture-recapture estimate. Arthritis Rheum 2004;51:92–99. 59. Lightfoot RW Jr, Michel BA, Bloch DA, et al. The American College of Rheumatology 1990 criteria for the classification of polyarteritis nodosa. Arthritis Rheum 1990;33:1088–1092. 60. Pagnoux C, Seror R, Henegar C, et al. Clinical features and outcomes in 348 patients with polyarteritis nodosa: a systematic retrospective study of patients diagnosed between 1963–2005 and entered into the French Vasculitis Study Group Database. Arthritis Rheum 2010;62:616–626. 61. Pagnoux C, Mahendira D, Laskin CA. Fertility and pregnancy in vasculitis. Best Pract Res Clin Rheumatology 2013;27:79–94. 62. Gatto M, Iaccarino L, Canova M, et al. Pregnancy and vasculitis: a systematic review. Autoimmuno Rev 2012;11:A447–A459. 63. Ross C, D’Souza R, Pagnoux C. Pregnancy outcomes in systemic vasculitides. Curr Rheumatol Rep 2020;22:63–76. 64. Damain L, Pamfil C, Fodor M. Polyarteritis nodosa in pregnancy. Ochsner Journal 2018;18:94–97. 65. Chifflot H, Fautrel B, Sordet C, et al. Incidence and prevalence of systemic sclerosis: a systematic literature review. Semin Arthritis Rheum 2008;73;223–235. 66. Meier FMP, Frommer KW, Dinser R, et al. Update on the profile of the EUSTAR cohort: an analysis of the EULAR Scleroderma Trials and Research group database. Ann Rheum Dis 2012;71;1355–1360. 67. van den Hoogen F, Khanna D, Fransen J, et al. 2013 classification criteria for systemic sclerosis: an American College of Rheumatology/European League against Rheumatism collaborative initiative. Arthritis Rheum 2013;65;2737–2747. 68. Avouac J, Airo P, Meune C, et al. Prevalence of pulmonary hypertension in systemic sclerosis in European Caucasians and metaanalysis of 5 studies. J Rheumatol 2010;37:2290–2298. 69. Valentini G, Paone C, La Montagna G, et al. Low-dose intravenous cyclophosphamide in systemic sclerosis: an open prospective efficacy study in patients with early diffuse disease. Scand J Rheumatol 2006;35:35–38.

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70. Seibold JR, Korn JH, Simms R, et al. Recombinant human relaxin in the treatment of scleroderma. Ann Intern Med 2000;132;871– 879. 71. Steen VD, Medsger TA. Changes in causes of death in systemic sclerosis, 1972–2002. Ann Rheum Dis 2007;66:940–944. 72. Ferri C, Valentini G, Cozzi F, et al. Systemic sclerosis; demographic, clinical and serologic features and survival in 1,012 Italian patients. Medicine (Baltimore) 2002;81:139–153. 73. Scussel-Lonzetti L, Joyal F, Raynauld JP, et al. Predicting mortality in systemic sclerosis; analysis of a cohort of 309 French Canadian patients with emphasis on features at diagnosis as predictive factors for survival. Medicine (Baltimore) 2002;81:154–167. 74. Rothfield N, Kurtzman S, Vazquez-Abad D, et al. Association of anti-topoisomerase I with cancer. Arthritis Rheum 1992;35:724. 75. Steen VD. Pregnancy in women with systemic sclerosis. Obstet Gynecol 1999;94:15–20. 76. Clark K, Etomi O, Ong V. Systemic sclerosis in pregnancy. Obstet Med 2020;13:105–111. 77. Bernatsky S, Hudson M, Pope J, et al. Assessment of reproductive history in systemic sclerosis. Arthritis Rheum 2008;59:1661–1664. 78. Lidar M, Langevitz P. Pregnancy issues in scleroderma. Autoimmun Rev 2012;11:515–519. 79. Munira S, Christopher-Stine L. Pregnancy in myositis and scleroderma. Best Pract Res Clin Obstet Gynaecol 2020;64:59–67. 80. Blagojevic J, Al Odhaibi KA, Aly AM, et al. Pregnancy in systemic sclerosis: results of a systematic review and metaanalysis. J Rheumatol 2020;47:881–887. 81. Taraborelli M, Ramoni V, Brucato A, et al. Brief report: successful pregnancies but a higher risk of preterm births in patients with systemic sclerosis: an Italian multicenter study. Arthritis Rheum 2012;64;1970–1977. 82. Branch DW. Pregnancy in patients with rheumatic diseases: obstetric management and monitoring. Lupus 2004;13:696–698. 83. Moore M, Saffran JE, Baraf HS, et al. Systemic sclerosis and pregnancy complicated by obstructive uropathy. Am J Obstet Gynecol 1985;153;893–894. 84. Bellucci MJ, Coustan DR, Plotz RD. Cervical scleroderma; a case of soft tissue dystocia. Am J Obstet Gynecol 1984;150;891–892. 85. Thompson J, Conklin KA. Anesthetic management of a pregnant patient with scleroderma. Anesthesiology 1983;59;69–71. 86. Dempsey ZS, Rowell S, McRobert R. The role of regional and neuraxial anesthesia in patients with systemic sclerosis. Local Reg Anesth 2011;4:47–56. 87. Lewis GB. Prolonged regional analgesia in scleroderma. Can Anaesth Soc J 1974;21:495–497. 88. Neill RS. Progressive systemic sclerosis. Prolonged sensory blockade following regional anaesthesia in association with a reduced response to systemic analgesics. Br J Anaesth 1980;52:623–625. 89. Eisele JH, Reitan JA. Scleroderma, Raynaud’s phenomenon, and local anesthetics. Anesthesiology 1971;34:386–387. 90. Lee GY, Cho S. Spinal anesthesia for cesarean section in a patient with systemic sclerosis associated interstitial lung disease: a case report. Korean J Anesthesiol 2016;69:406–408. 91. Bailey AR, Wolmarans M, Rhodes S. Spinal anaesthesia for caesarean section in a patient with systemic sclerosis. Anaesthesia 1999;54:350–371. 92. Younker D, Harrison B. Scleroderma and pregnancy; anaesthetic considerations. Br J Anaesth 1985;57:1136–1139.

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  93. D’Angelo R, Miller R. Pregnancy complicated by severe preeclampsia and thrombocytopenia in a patient with scleroderma. Anesth. Analg 1997;85:839–841.   94. Hseu SS, Sung CS, Mao CC, et al. Anesthetic management in a parturient with progressive systemic sclerosis during caesarean section – a case report. Acta Anaesthesiol Sin 1997;35:161–166.   95. Moaveni D, Cohn J, Brodt K, et al. Scleroderma and pulmonary hypertension complicating two pregnancies: use of neuraxial anesthesia, general anesthesia, epoprostenol and a multidisciplinary approach for cesarean delivery. Int J Obstet Anesth 2015;24;375–382.   96. Zöller B, Li X, Sundquist J, et al. Risk of pulmonary embolism in patients with autoimmune disorders: a nationwide follow up study from Sweden. Lancet 2012;379:244–249.   97. Miyakis S, Lockhin MD, Atsumi T, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 2006;4:295–306.   98. Carp HJA. Antiphospholipid syndrome in pregnancy. Curr Opin Obstet Gynecol 2004;16:129–135.   99. Cervera R, Serrano R, Pons-Estel GJ, et al. Morbidity and mortality in antiphospholipid syndrome during a 10-year period: a multicentre prospective study of 1000 patients. Ann Rheum Dis 2015;74:1011–1018. 100. de Jesus GR, Agmon-Levin N, Andrade CA, et al. 14th International congress on antiphospholipid antibodies task force report on obstetric antiphospholipid syndrome. Autoimmun Rev 2014;13:795–813. 101. Cervera R, Piette JC, Font J, et al. Antiphospholipid syndrome: clinical and immunological manifestation and patterns of disease expression in a cohort of 1000 patients. Arthritis Rheum 2002;46:1019–1027. 102. Parke A. Short- and long-term maternal outcomes in patients with phospholipid antibodies. Lupus 2004;13:703–704. 103. Erkan D, Asherson RA, Espinosa G, et al. Long-term outcome of catastrophic syndrome survivors. Ann Rheum Dis 2003;62:530–533. 104. Asherson RA, Cervera R, Piette JC, et al. Catastrophic antiphospholipid syndrome: clinical and laboratory features of 50 patients. Medicine (Baltimore) 1998;77:195–207. 105. Kutteh WH. Antiphospholipid antibodies and reproduction. J Reprod Immunol 1997;35:151–171. 106. Vinatier D, Dufour P, Cosson M, et al. Antiphospholipid syndrome and recurrent miscarriages. Eur J Obstet Gynecol Reprod Biol 2001;96:37–50. 107. Derksen RH. Khamashta MA, Branch DW. Management of the obstetric antiphospholipid syndrome. Arthritis Rheum 2004;50:1028–1039. 108. Saccone G, Berghella V, Maruotti GM, et al. Antiphospholipid antibody profile based obstetric outcomes of primary antiphospholipid syndrome: the PREGNANTS study. Am J Obstet Gynecol 2017;216:525.e1–525.e12. 109. Arslan E, Branch DW, James R, et al. Antiphospholipid syndrome: diagnosis and management in the obstetric patient. Best Pract Res Clin Obstet Gynaecol 2020;64:31–40. 110. De Carolis S, Moresi S, Rizzo F, et al. Autoimmunity in obstetrics and autoimmune disease in pregnancy. Best Pract Res Clin Obstet Gynaecol 2019;60:66–76.

111. Rawat RS, Dehran M. Anaesthetic management of a pregnant patient with antiphospholipid antibody syndrome for emergency caesarean section. Int J Obstet Anesth 2003;12:311. 112. Ringrose DK. Anaesthesia and the antiphospholipid syndrome; a review of 20 obstetric patients. Int J Obstet Anesth 1997;6: 107–111. 113. Ralph CJ. Anaesthetic management of parturients with the antiphospholipid syndrome; a review of 27 cases. Int J Obstet Anesth 1999;8:249–252. 114. Shah S, Parasar K, Cohen S, et al. Haemorrhage during caesarean section for parturient with antiphospholipid syndrome. J Obstet Anaesth Crit Care 2015;5:93–94. 115. Bilal RM, Riaz A, Khan RAS. Ruptured ectopic pregnancy with APLA syndrome – a case report. Anaesth Pain & Intensive Care 2014;18:461–463. 116. Yelnik CM, Lambert M, Drumez E, et al. Bleeding complications and antithrombotic treatment in 264 pregnancies in antiphospholipid syndrome. Lupus 2018;27:1679–1686. 117. Ihle BU, Oziemski P. Multiorgan failure secondary to catastrophic anti-phospholipid syndrome. Anaesth Intensive Care 2002;30:82–85. 118. Dorman RIP. Acute postoperative biventricular failure associated with antiphospholipid antibody syndrome. Br J Anaesth 2004;92:748–754. 119. Ozaki M, Ogata M, Yokoyama T, et al. Prevention of thrombosis with prostaglandin E1 in a patient with catastrophic antiphospholipid syndrome. Can J Anesth 2005;52:143–147. 120. Batra Y. Anesthetic implications of the catastrophic antiphospholipid syndrome. Pediatric Anesth 2006;16:1090– 1093. 121. Sellner J, Kraus J, Awad A, et al. The increasing incidence and prevalence of female multiple sclerosis: a critical analysis of potential environmental factors. Autoimmun Rev 2011;10:495– 502. 122. Goodwin DS. The epidemiology of multiple sclerosis: insights to disease pathogenesis. Handb Clin Neurol 2014;122:231–266. 123. Compston A, Coles A. Multiple sclerosis. Lancet 2008;372:1502–1517. 124. McGinley MP, Goldschmidt CH, Rae-Grant AD. Diagnosis and treatment of multiple sclerosis: a review. JAMA 2021;325:765– 779. 125. Lublin FD, Reingold SC, Cohen JA, et al. Defining the clinical course of multiple sclerosis: the 2013 revisions. Neurology 2014;83:278–286. 126. Thompson AJ, Banwell BL, Barkhof F, et al. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald Criteria. Lancet Neurol 2018;17:162–173. 127. Scalfari A, Knappertz V, Cutter G, et al. Mortality in patients with multiple sclerosis. Neurology 2013;81:184–192. 128. Confavreux C, Hutchinson M, Hours MM, et al. Pregnancy in Multiple Sclerosis Group. Rate of pregnancy-related relapse in multiple sclerosis. N Engl J Med 1998;339:285–291. 129. Finkelsztejn A, Brooks JBB, Paschoal FM, et al. What can we really tell women with multiple sclerosis regarding pregnancy? A systematic review and meta-analysis of the literature. BJOG 2011;118:790–797. 130. Ferrero S, Pretta S, Ragni N. Multiple sclerosis: management issues during pregnancy. Eur J Obstet Gynecol Reprod Biol 2004;115:3–9.

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131. Michel L, Foucher Y, Vukusic S, et al. Increased risk of multiple sclerosis relapse after in vitro fertilisation. J Neurol Neurosurg Psychiatry 2012;83:796–802. 132. Vukusic S, Marignier R. Multiple sclerosis and pregnancy in the ‘treatment era’. Nat Rev Neurol 2015;11:280–289. 133. Dobson R, Jokubaitis VG, Giovannoni G. Change in pregnancyassociated multiple sclerosis relapse rates over time: a metaanalysis. Mult Scler Relat Disord 2020;44:102241. 134. Hughes SE, Spelman T, Gray OM, et al. Predictors and dynamics of postpartum relapses in women with multiple sclerosis. Mult Scler 2014;20:739. 135. Pakpoor J, Disanto G, Lacey MV, et al. Breastfeeding and multiple sclerosis relapses: a meta-analysis. J Neurol 2012;259:2246–2248. 136. Hellwig K, Rockhoff M, Herbstritt S, et al. Exclusive breastfeeding and the effect on postpartum multiple sclerosis relapses. JAMA Neurol 2015;72:1132–1138. 137. Dobson R, Dassan P, Roberts M, et al. UK consensus on pregnancy in multiple sclerosis: ‘Association of British Neurologists’ guidelines. Pract Neurol 2019;19:106–114. 138. Canibano B, Deleu D, Mesraoua B, et al. Pregnancy-related issues in women with multiple sclerosis: an evidence-based review with practical recommendations. J Drug Assess 2020;9:20–36. 139. Drake E, Drake M, Dird J, et al. Obstetric regional blocks for women with multiple sclerosis: a survey of UK experience. Int J Obstet Anesth 2006;15:115–123. 140. Pasto L, Portaccio E, Ghezzi A, et al. Epidural analgesia and caesarean delivery in multiple sclerosis post-partum

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relapses: the Italian cohort study. BMC Neurology 2012;12:7. https://doi.org/10.1186/1471-2377-12-165 141. Dalmas AF, Texier C, Ducloy-Bouthors AS, et al. Obstetrical analgesia and anaesthesia in multiple sclerosis. Annales Francaises D Anesthesie Et De Reanimation 2003;22:861–864. 142. Lavie C, Rollot F, Durand-Dubief F, et al. Neuraxial analgesia is not associated with an increased risk of post-partum relapse in MS. Mult Scler 2019;25:591–600. 143. Lu E, Zhao Y, Dahlgren L, et al. Obstetrical epidural and spinal anesthesia in multiple sclerosis. J Neurol 2013;260: 2620–2628. 144. Harazim H, Stourac P, Janku P, et al. Obstetric anesthesia/ analgesia does not affect disease course in multiple sclerosis: 10-year retrospective cohort study. Brain Behav 2018;8:e1082. https://doi.org/10.1002/brb3.1082 145. Perinpanayagam J, Powell J, Hammand S, et al. Regional anaesthesia and postpartum relapse for obstetric patients with multiple sclerosis: a case series. Int J Obstet Anesth 2019;39: 30–31. 146. Bouvet L, Chassard D, Fontana M, et al. Post-partum relapse in women with multiple sclerosis after neuraxial labour analgesia or neuraxial anaesthesia: a multicentre retrospective cohort study. Anaesth Crit Care Pain Med 2021;19:100834. https://doi .org/10.1016/j.accpm.2021.100834 147. Makris A, Piperopoulos A, Karmaniolou I. Multiple sclerosis: basic knowledge and new insights in perioperative management. J Anaesth 2014;28:267–278. 148. Caminero A, Bartolome M. Sleep disturbances in multiple sclerosis. J Neurol Sci 2011;309:86–91.

Chapter

27

Genetic Disorders David J. Combs and Vesela P. Kovacheva

Valuable Clinical Insights: Management of Genetic Disorders • Since genetic disorders commonly manifest early in life and affect multiple organ systems, obstetric anesthesiologists need a comprehensive approach to assess and care for the parturient and her fetus. • The physiologic changes associated with pregnancy are often less tolerated by patients with genetic disorders. • For many pregnant women with genetic disorders, recommendations include coordinating care by a multidisciplinary team and antepartum evaluation by an obstetric anesthesiologist.

Introduction Genetic disorders are of particular interest to obstetric care and reproductive health.1–3 Although there are many exceptions, genetic disorders frequently occur or progress in severity early in life, whereas disorders influenced by environmental exposures (e.g., smoking, diet) may require decades of exposure to develop. Thus, genetic disorders often markedly compromise the health of reproductive-age women, impacting their obstetric care. Furthermore, the advent of prenatal genetic screening and preimplantation genetic diagnosis means that patients who have or are carriers for certain genetic disorders may more frequently present for assisted reproductive technology or high-risk prenatal care at tertiary care centers. Finally, pregnancy may couple the biology of an unaffected mother with that of a fetus with a genetic disorder. The placenta is a fetal organ with fetal genetics, and fetal genetic disorders can disrupt placental biology adversely affecting maternal and fetal health.4 Certain fetal genetic disorders may also impact maternal care (e.g., mode of delivery) during pregnancy. This chapter will discuss key concepts in genetics. It will then describe the features and management of several genetic disorders, selected because they are relatively common, impact care in pregnancy, and are not already covered elsewhere in this text under their most relevant organ system. Table 27.1 lists many of the most common genetic disorders and their estimated prevalence.

Table 27.1  Common genetic disorders

Disease

Frequency

Chapter(s)

Achondroplasia

1:100–10,000

11

Alpha-1 antitrypsin deficiency

1:2500

27

Autosomal dominant polycystic kidney disease

1:400–1,000

19, 27

Charcot-Marie-Tooth disease

1:2500

27

Ehlers-Danlos syndrome

1:5000

13, 27

Factor V Leiden

3–8:100

Hereditary hemorrhagic telangiectasia

1:5,000–10,000

Hereditary spherocytosis

1:2,000

21

Loeys-Dietz syndrome

Unknown

27

Myotonic dystrophy

1:8,000

10

Neurofibromatosis

1:4,000

13

Osteogenesis imperfecta

1:20,000

13

Von Willebrand Disease

1:100–10,000

21

Cystic fibrosis

1:2,500–3,500

7

Hemochromatosis

1:200

18

Factor XI deficiency

1:1,000,000

21

Sickle cell disorder

1:500–1:5000

21

Spinal muscular atrophy

1:6,000–10,000

13

Alport syndrome

1:50,000

19

G6PDa deficiency

1:20–100

21, 27

Hemophilia

1:4,000–5,000

21

Down syndrome

1:700–1,000

27

Turner syndrome

1:2,500

27

1:4000c

10, 27

Autosomal dominant

Autosomal recessive disorders

X-linked disorders

Chromosomal disorders

Mitochondrial disorders MELAS/MERRF/LHONb a.

Glucose-6-phosphate dehydrogenase.

Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), myoclonic epilepsy with ragged red fibers (MERRF), Leber hereditary optic neuropathy (LHON). b.

c.

Collective frequency of all three mitochondrial disorders.

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David J. Combs and Vesela P. Kovacheva

Inheritance A trait is a characteristic of an organism, determined by genetics, environmental factors, or both. Hair color, height, and diabetes are all examples of traits. Trait is sometimes used interchangeably with phenotype, although phenotype can also refer to a collection of traits. The influence of single genes strongly determines certain traits; these monogenic or simple traits include many well-known genetic disorders (e.g., cystic fibrosis, sickle cell disease) that show characteristic inheritance patterns. Other disorders show more complex patterns of inheritance. For these complex traits (e.g., cardiovascular disease, diabetes mellitus), multiple genes and multiple environmental factors each exert a minor influence on the development of the disorder. Certain monogenic disorders show Mendelian patterns of inheritance, named after Gregor Mendel, who conducted pioneering studies of inherited traits in plants in the nineteenth century.5 Although he did not know the molecular details, Mendel recognized that genes could determine traits; and that genes exist as pairs of alleles, one inherited from each parent. He proposed that alleles separate from each other during gamete formation (now known as meiosis) and that alleles for a given gene separate into gametes independently from the alleles for other genes (no longer valid for linked genes). He also described three inheritance patterns for traits: dominant traits, where one allele (a heterozygote) is sufficient to produce the trait; recessive traits, where both alleles (homozygotes) are needed to produce the trait; and codominant traits, where both alleles may equally contribute to the phenotype with heterozygotes showing an intermediate phenotype. When observed over two or more generations, Mendelian disorders – generally rare, monogenic ­disorders – follow these rules, showing inheritance patterns such as autosomal dominant or X-linked depending on the trait.6 Since only one allele is enough to confer disease, many autosomal dominant disorders occur de novo (not inherited). Autosomal dominant traits may result from a gain of function, haploinsufficiency, or dominant-negative mechanisms. In ­contrast, autosomal recessive traits typically stem from a loss of function mechanisms. There are many cases where disorders show familial inheritance, but the pattern does not appear to follow strict Mendelian predictions.7,8 Disorders can vary in their penetrance, defined as the fraction of carriers of the disease genotype who show evidence of the disease, and penetrance can be variable for a given disorder in different populations. Among those for whom the disorder is penetrant, there can also be variation in the severity or nature of that phenotype; a phenomenon termed variable expressivity. Variation in penetrance and expressivity may stem from variation in disease-causing alleles or genes, other modifier genes, or environmental factors. NonMendelian inheritance is responsible for traits with significant mosaicism: two different genetic populations of cells arising from a single fertilized oocyte. Mosaicism can occur when a disease-causing variant arises very early in development such that only a fraction of an individual’s cells inherit the variant. X-inactivation (inactivation of one copy of the X chromosome in females) can create a similar state of effective mosaicism,

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yielding female penetrance in X-linked autosomal recessive disorders. However, this is strictly an epigenetic rather than a genotypic form of variation. Certain traits show mitochondrial inheritance, including myoclonic epilepsy with ragged red fibers (MERRF) and mitochondrial encephalomyopathy, lactic acidosis, and stroke (MELAS).9 Mitochondrial DNA is inherited only from the oocyte; thus, affected fathers cannot pass these diseases to their offspring. Disorders like myotonic dystrophy can show more severe disease in successive generations, a phenomenon known as anticipation.10 Expression of some traits can also vary depending on which parent contributed the gene variant. Known as imprinting, epigenetic silencing of alleles during gametogenesis results in the expression of the allele from the other parent.11 Certain genetic disorders arise from alterations in the number or structure of chromosomes rather than allelic variation in individual genes. Changes in the number of chromosomes, known as aneuploidy, often result from nondisjunction of chromosomes during meiosis rather than true parental inheritance.12 This can result in disorders like Down syndrome (Trisomy 21) or Turner syndrome (45XO). Chromosomal translocations, deletions, and inversions also result in genetic disorders, some of which show Mendelian inheritance. Finally, in contrast to Mendelian disorders, in which variations in one gene lead to disease, complex traits or polygenic disorders are due to variants in many genes. The contribution of each of those variants to the disease is relatively small; thus, the overall phenotype is determined by a combination of multiple variants in multiple genes, often in concert with environmental factors.13 The total effect of these genes is defined as polygenic risk score (PRS), determined using complex mathematical models. For example, people with the highest PRS for coronary heart disease are at high risk for MI and may benefit from statin therapy.14 While the PRS predicts the risk of developing a disease based on genotype, the individual risk also depends on many environmental factors and lifestyle modifications. Thus, a PRS is included as part of multivariate models for disease prediction and the associated environmental and lifestyle factors. The genetic variants associated with these disorders are located mainly in non-coding regions (e.g., introns, regulatory regions) of the genome and affect the processing or expression of genes rather than the amino acid sequence of expressed proteins.

Autosomal Dominant Disorders Alpha-1 Antitrypsin Deficiency Alpha-1 antitrypsin deficiency (A1AD) has a prevalence in the United States of approximately 1:2000–5000 individuals.15,16 These patients are susceptible (80% penetrant) to developing obstructive lung disease with symptoms similar to chronic obstructive pulmonary disease; those with specific risk alleles may develop liver or skin disease. In A1AD patients, the emphysematous/bullous changes are typically basilar, and patients can develop pneumothorax or bronchiectasis. Of note, lung disease does not develop among all patients with A1AD, even those with severe deficiencies. Smoking strongly influences the risk and age of onset of lung disease in these patients. In general, pulmonary disease is uncommon in patients with A1AD in the first four decades of life,

Genetic Disorders

but in smokers, one can see pulmonary changes and even COPD in the third decade of life. In contrast, liver disease can develop in childhood or early adulthood and progress to hepatitis, hepatocellular carcinoma, or cirrhosis in patients with risk alleles. Finally, panniculitis, red, hot, painful plaques or nodules on the thighs or buttocks, rarely occurs in patients with A1AD. Alpha-1 antitrypsin (AAT) is an acute phase reactant and serine protease inhibitor produced primarily by the liver.17,18 In addition to inhibitory activity against various neutrophils, mast cells, pancreatic, and secretory proteases, AAT is the primary neutrophil elastase inhibitor. In A1AD, unopposed neutrophil elastase activity triggered by smoking or infection causes damage to the lung, a so-called toxic loss of function mechanism. In contrast, patients who develop liver symptoms have allelic variants (including the Z variant) that cause polymerization and accumulation of AAT in hepatocytes, a toxic gain of function mechanism. Thus, null homozygotes develop lung disease but not liver disease. (A null allele is a nonfunctional allele caused by a genetic mutation. These mutations can cause a complete lack of production of the associated gene product or a product that does not function properly – either way the allele is nonfunctional). AAT expression is codominant, meaning that both alleles contribute to plasma levels. The M allele is the normal allele; MM homozygotes are considered wild type and make up about 95% of the United States’ population. The Z allele is the most common deficient allele found in most patients with A1AD. A1AD is often associated with a ZZ genotype, commonly denoted as PiZZ (protease inhibitor ZZ). Alpha-1 antitrypsin levels increase four- to six-fold during normal pregnancy, returning to normal postpartum.19 Reduced AAT levels are associated with several obstetric conditions, including PreE, recurrent pregnancy loss, and preterm premature rupture of membranes, but the significance of these associations is unclear. This raises questions about whether the disease of pregnant patients with A1AD worsens due to a decrease in their AAT level during pregnancy or whether they are at increased risk for certain obstetric complications. Descriptions of A1AD in pregnancy are limited to several case reports. These reports describe significant drops in the forced expiratory volume over 1 second (FEV1) during pregnancy, pulmonary infections requiring inpatient admission, pregnancy complications of IUGR, PreE, preterm delivery, miscarriage, pneumothorax requiring chest tube, and panniculitis episodes.19–26 Counsel patients with A1AD to completely abstain from tobacco inhalants. Genetic counseling is appropriate, but while prenatal testing is available, it is not often used, given the complex relationship between genotype and phenotype. Other management recommendations mirror those for patients with other forms of obstructive lung disease. In addition to smoking cessation and reducing second-hand smoke exposure, other strategies include avoidance of triggering exposures, supplemental oxygen when needed, pulmonary rehabilitation, and vaccination. Therapy includes long-acting beta-agonists, anticholinergics, and corticosteroids. As worsening pulmonary disease is associated with adverse pregnancy outcomes, these women should continue their regular medications.

Augmentation therapy, or the administration of exogenous AAT, is indicated for patients with PFT showing fixed, moderate airflow obstruction, a rapid decline in FEV1, a CT scan demonstrating emphysema, or those with panniculitis. Augmentation therapy has been used in pregnancy and has no known safety concerns (class C).19 AAT is detectable in breast milk; however, the impact of exogenous AAT on AAT levels in breast milk is unknown. AAT hypersensitivity or absolute IgA deficiency are considered contraindications to augmentation therapy.

Anesthesia for Alpha-1 Antitrypsin Deficiency The peer-reviewed literature provides little guidance for the anesthetic management of patients with A1AD in pregnancy. However, one can adapt the recommendations for patients with other forms of obstructive lung disease or liver disease. Diaz et al. present an algorithm for managing pulmonary and hepatic disease, specifically in patients with A1AD.27 They emphasize the importance of chest imaging and PFT in evaluating the extent of pulmonary disease. They also point out that the rate of decline of FEV1 is the most sensitive metric to assess the adequacy of medical management and perform risk stratification. Evaluate all A1AD patients for liver disease, including a thorough history and physical examination, laboratory testing (platelet count, coagulation testing), and hepatic imaging as indicated. In patients with hepatic disease and thrombocytopenia or coagulopathy, balance the risks and benefits before possible NA.28 Generally, patients with obstructive pulmonary disease are at increased risk of morbidity and mortality from perioperative pulmonary complications.29 Patients with abnormal physical examination findings like wheezing or prolonged expiration may benefit from aggressive bronchodilator treatment or systemic steroid administration. Treat those with evidence of upper respiratory tract infections (fever, productive cough), postpone surgery if possible, and counsel patients to cease smoking. Peripheral nerve blocks and NA may reduce the risk of perioperative pulmonary complications. With GA, patients with severe disease are at particular risk for air trapping with positive pressure ventilation and inadequate expiratory times. Air trapping can lead to hemodynamic instability as rising intrathoracic pressures impair venous return and increase right heart afterload. Minimize extubation failure by ensuring complete reversal of neuromuscular blockade, restoring the patient’s baseline PaCO2, bronchodilator treatment, and potentially extubating onto noninvasive ventilation. Finally, asthma, another obstructive pulmonary disease, is a relative contraindication to receiving carboprost in the setting of uterine atony30; it is unclear whether patients with A1AD merit similar concerns.

Autosomal Dominant Polycystic Kidney Disease Autosomal dominant polycystic kidney disease (ADPKD) affects roughly 1:1000 individuals.31 Prevalence is equal among men and women, and about one-third of the cases are asymptomatic. Most patients (~ 80%) carry a mutation in the PKD1 locus on chromosome 14, whereas 14% have a mutation in PKD2 on chromosome 4, and still smaller numbers carry mutations in other genes. Compared with PKD1, those with mutations at the PKD2 locus

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tend to have less severe disease and present at an older age. PKD1 and PKD2 encode polycystins, channel proteins involved in regulating cellular calcium and expressed in primary cilia in renal, pancreatic, and hepatic tissue. Mutations in PKD1 and PKD2 in ADPKD lead to cyst formation and organ dysfunction.31 The clinical presentation of patients with ADPKD includes renal insufficiency, hypertension, hematuria, proteinuria, and flank pain, the latter arising from renal stones, hemorrhage, or infection.32 Most patients retain normal renal function until their fourth decade of life, and ADPKD accounts for about 5% of patients who initiate dialysis in the United States. Risk factors associated with chronic kidney disease (CKD) progression include early age of onset, certain professions, kidney size, male sex, hypertension, proteinuria, high urine sodium, and specific mutant alleles. Although males show various reproductive abnormalities, fertility in female patients with ADPKD appears normal.33 Extrarenal manifestations of ADPKD include intracranial aneurysms, cardiac disease, pancreatic cysts, and polycystic liver disease. Patients with ADPKD have a four-fold higher incidence of intracranial aneurysms than the general population, with a family history of aneurysms the most significant risk factor.34 Women, particularly multiparous women, are more likely to develop large liver cysts, possibly due to the impact of sex hormones on cyst growth.35 Hepatic cysts are often asymptomatic but can cause pain, become infected, and, particularly within the context of pregnancy, cause IVC compression (as can large renal cysts), leading to secondary hypotension and thrombosis. Cardiac disease in ADPKD includes coronary aneurysms and dissections, mitral valve prolapse, aortic regurgitation, and pericardial effusions. Patient risk for CKD progression determines ADPKD management. All patients, regardless of risk, need hypertension controlled, with either an angiotensin-converting enzyme inhibitor (ACEI) or an angiotensin receptor blocker (ARB) (discontinue them in pregnancy). All ADPKD patients should restrict sodium intake to < 2 grams/day and increase fluids to at least three liters. For those at high risk of progression, administer the vasopressin V2 receptor tolvaptan to slow the decline in renal function.36,37 Consider renal transplantation or hemodialysis in patients who progress to end-stage kidney disease; peritoneal dialysis is used less frequently because of concern about the tolerance of large peritoneal volumes in patients with very large kidneys. Chronic kidney disease, including that which arises from ADPKD, is associated with adverse pregnancy outcomes; the severity of CKD, and concomitant proteinuria or hypertension, worsens the incidence and severity of those outcomes.38,39 Women with CKD, including stage 1 disease, have higher rates of induction of labor and CD, greater risk of worsening renal function, and a higher incidence of gestational hypertension and PreE. Fetal risks include increased rates of small for gestational age, IUGR, and prematurity.40 Fetal malformations are more common in patients with more severe CKD, and multiple gestations increase the risk of both maternal and fetal complications.41 Genetic testing and preimplantation genetic diagnosis are possible for patients with ADPKD. A multidisciplinary care team, including a nephrologist with expertise in high-risk pregnancy, should care for these women during pregnancy. Monitor

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BP, renal function, degree of proteinuria, and bacteriuria regularly with frequency of monitoring determined by patient risk.42 Recommendations for managing pregnant patients with ADPKD include a third trimester fetal US, uterine artery Dopplers, amniotic fluid assessment and aspirin prophylaxis, given the high risk of hypertensive disorders of pregnancy. In pregnant patients with chronic hypertension, discontinue ACEI/ARB drugs and initiate alternative agents for BP control. There is an increased rate of UTI in all pregnant women, and this risk is greater in pregnant women with ADPKD. Treat asymptomatic bacteriuria, consider antibiotic prophylaxis in appropriate patients, and assess patients carefully for evidence of cyst infection.

Anesthesia for Autosomal Dominant Polycystic Kidney Disease Case reports describe anesthetic management of patients with ADPKD, including for CD.43,44 When evaluating patients for the degree of renal impairment, remember the expected physiologic reduction in serum creatinine levels during pregnancy. Carefully assess serum electrolytes, acid-base status, volume status (particularly in dialysis-dependent patients), and adequacy of BP control. Advanced renal disease can lead to anemia and uremiarelated quantitative and qualitative platelet defects. Use NSAIDs cautiously in parturients with ADPKD with CKD, as well as drugs with significant renal metabolism, including certain analgesics (e.g., morphine, meperidine), antibiotics (e.g., aminoglycosides), and muscle relaxants (e.g., vecuronium). Patients with advanced renal disease require judicious fluid management, avoiding both over- and under-resuscitation and carefully protecting any arteriovenous fistula. Neuraxial anesthesia and peripheral nerve blocks can be used safely in ADPKD with advanced CKD. However, patients must be evaluated for coagulopathy (including dialysis-related heparin administration), acidemia (can impact thresholds for LA toxicity), and hypovolemia. In addition to renal disease, assess patients with ADPKD for extrarenal disease. Chronic pain, secondary to renal capsular distension or other factors, is common in patients with ADPKD.45 Patients on chronic opioid analgesics may benefit from a consultation with a pain medicine specialist; opioid down-titration may lessen the incidence or severity of neonatal abstinence syndrome. Polycystic liver disease is the most common extrarenal manifestation of ADPKD, and rates may be exceptionally high in pregnant women.46 Patients should be evaluated for any associated liver function defect, particularly before NA. However, reassuringly most patients with polycystic liver disease are asymptomatic.47 Screen for intracranial aneurysms in patients with a family history of aneurysm or subarachnoid hemorrhage, those who are smokers or have uncontrolled hypertension, those requiring anticoagulation or having major surgery, and those in high-risk occupations.48 If there is a known aneurysm, neurosurgical consultation is warranted. Hemodynamic and hormonal changes of pregnancy can influence aneurysm growth, but reports are inconclusive regarding whether pregnancy carries an increased risk of rupture.42 It is essential to control BP during pregnancy, labor, and delivery and for the multidisciplinary team to discuss how best to manage hemodynamic stress during delivery. There is inadequate data to definitively support CD over a vaginal delivery with adequate analgesia and limitation of the second stage.

Genetic Disorders

Charcot-Marie-Tooth Disease

Anesthetic Implications

Charcot-Marie-Tooth disease (CMTD) is the most common inherited neurologic disorder in the United States. The incidence of CMTD is 1:1200, and life expectancy is average.49 Classified into subtypes based on the mode of inheritance and nerve conduction velocity, types 1 and 2 have an autosomal dominant inheritance; the other types have autosomal recessive or X-linked inheritance. As a result of mutations in genes associated with myelin production or axonal formation, most commonly the PMP22 or the MPZ gene, the patients develop variable degrees of peripheral motor and sensory neuropathy, accompanied by atrophy of the peroneal muscles and motorsensory disorders in the extremities. Many patients develop characteristic loss of sensation in the extremities in the glove and stocking distribution. As the disease progresses, the neuropathy may involve the phrenic nerve, resulting in diaphragmatic weakness and respiratory compromise.50 During pregnancy, the gravid uterus may further compromise respiratory function resulting in dyspnea and orthopnea.51 Patients with severe scoliosis may develop restrictive lung disease and decreased exercise tolerance. Chronic hypoxemia may cause cor pulmonale, pulmonary hypertension, and right ventricular hypertrophy. The development of autonomic neuropathy results in impaired thermoregulation and BP lability. Despite the sensory loss, some patients experience severe, debilitating pain. In most patients, pregnancy does not impact the course of the disease, but symptoms like diminished sensation, pain, and fatigue may transiently worsen.52 There is a higher incidence of placenta previa and abnormal presentations but no increased risk for PPH.

Neuraxial anesthesia is safe,53 and there are multiple reports of its successful use during obstetric54,55 and orthopedic procedures.56,57 Due to the higher incidence of spine deformities such as scoliosis and difficulty with positioning, the procedure may be technically challenging. There is a report of a prolonged sensory block,56 but no other reported complications.53 Demyelination of the sensory and motor fibers may mandate lower doses or concentrations of LA.56 In case GA is needed, the effects of neuromuscular blockers in patients with CMTD are highly variable. Succinylcholine is safe in most patients58 but use it cautiously in those with an acute exacerbation associated with muscle weakness due to the risk of hyperkalemia. There is a report of malignant hyperthermia,59 but the overall risk for CMTD patients is likely low.53,58

Ehlers-Danlos Syndrome Ehlers-Danlos syndrome (EDS) is a group of clinically heterogeneous monogenic connective tissue disorders with variable manifestations, characterized mainly by joint hypermobility and instability, skin texture anomalies, and vascular and soft tissue fragility. The incidence can be 1:500 or even higher due to increased awareness and new methods of molecular diagnosis.60 There are multiple forms of EDS due to defects in different genes, and the most common forms involve defects in collagen production or modification (Table 27.2). The underlying molecular defect can manifest itself in many tissues and organs with varying degrees of severity; this has widespread implications for anesthesia and perioperative management.

Table 27.2  Classification of Ehlers-Danlos syndrome (modified from Malfait et al.)61

Clinical subtype

Mode of Inheritance

Gene

Protein

Selected Clinical Symptoms

Classical EDS

AD

COL5A1, COL5A1, COL1A1

Type V collagen, Type I collagen

Skin hyperextensibility, joint hypermobility, easy bruising

Classical-like EDS

AR

TNXB

Tenascin XB

Generalized joint hypermobility, smooth, velvety skin

Cardiac-valvular

AR

COL1A2

Type I collagen

Severe progressive cardiac-valvular problems, joint hypermobility

Vascular EDS

AD

COL3A1, COL1A1

Type III and Type I collagen

Arterial/intestinal/uterine fragility or rupture; extensive bruising, characteristic facial appearance

Hypermobile EDS

AD

Unknown

Unknown

Generalized joint, hypermobility, unusually soft or velvety skin

Arthrochalasia EDS

AD

COL1A1, COL1A2

Type I collagen

Generalized joint hypermobility with recurrent subluxations, tissue fragility, including atrophic scars

Dermatosparaxis EDS

AR

ADAMTS2

ADAMTS-2

Severe skin fragility, premature rupture of fetal membranes

Kyphoscoliotic EDS

AR

PLOD1, FKBP14

LH1, FKBP22

Congenital hypotonia, congenital and progressive scoliosis, arterial rupture

Brittle cornea syndrome

AR

ZNF469, PRDM5

ZNF469, PRDM5

Thin cornea, blue sclerae, early onset progressive keratoglobus

Spondylodysplastic EDS

AR

B4GALT7, B3GALT6, SLC39A13

b4GalT7, b3GalT6, ZIP13

Short stature, muscle hypotonia, delayed cognitive development

Musculocontractural EDS

AR

CHST14, DSE

D4ST1, DSE

Congenital multiple contractures, characteristic craniofacial features

Myopathic EDS

AD or AR

COL12A1

Type XII collagen

Congenital muscle hypotonia, proximal joint contractures

Periodontal EDS

AD

C1 R, C1S

C1 r, C1S

Severe and intractable periodontitis of early-onset, lack of attached gingiva

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The most common of the 13 subtypes of EDS are classic, hypermobility, vascular, kyphoscoliosis, arthrochalasis, and dermatosparaxis. All subtypes exhibit varying degrees of joint hypermobility, skin hyperextensibility, and connective tissue fragility; the diagnosis is derived from a combination of major and minor criteria.61 The highest risk for complications occurs with the vascular type EDS. This type is predominantly due to mutations in the COL3A1 gene affecting type III procollagen, which is essential for maintaining the structural integrity of vessel and organ walls. These patients are prone to vascular and hollow organ rupture, fistulae formation, and easy bruising.

Obstetric and Anesthetic Implications Pregnant patients with EDS are at higher risk for obstetric complications, with the best outcomes achieved with preconception planning. There is no agreement on the best mode of delivery as uterine rupture, hemorrhage, delayed wound healing, and dehiscence may complicate both vaginal and CD. Elective CD may be best for patients with vascular-type EDS and those at high risk for complications. In patients with vascular-type EDS, life-threatening complications include arterial dissection/ rupture (9.2%), uterine rupture (2.6%), and surgical complications (2.6%).62 Due to the higher morbidity and mortality, patients with aortic dilatation > 40 mm should undergo elective repair, ideally preconception.63 In patients with vascular EDS, the maternal death rate is 6.5%. However, survival data show that pregnancy does not affect overall mortality and life expectancy.62 In addition, patients with vascular EDS have a heightened risk of premature delivery and third- and fourth-degree lacerations.62 Due to limited evidence, the mode of delivery can be decided after carefully weighing the risks and benefits for each patient. Patients with aortic pathology present a particular challenge; these patients should deliver at a tertiary care center with a multidisciplinary team, including cardiothoracic surgery. Use serial echocardiography to monitor pregnant patients with all types of EDS for aortic dilation as the risk increases during pregnancy.64 During labor, patients with aortic pathology require frequent hemodynamic monitoring and avoidance of sudden elevations of HR and BP. The risk for rupture remains heightened postpartum so extend vascular surveillance for at least six months postpartum.63 Pregnancy can exacerbate joint hypermobility and pain, especially pelvic pain.64 EDS, particularly the hypermobility type, is associated with postural orthostatic tachycardia syndrome (POTS), so consider prophylaxis with IV fluids and vasopressors, especially for NA.65 Some patients with EDS have a higher risk for PPH due to tissue fragility, defective hemostasis, and uterine atony, so some use prophylactic desmopressin and tranexamic acid.66–68 The topic of NA in patients with EDS is controversial. The prevailing evidence is that it is generally safe;68 however, EDS patients are at higher risk for dural ectasias, PDPH, vascular malformations, and hematoma. There is a higher incidence of Tarlov cysts in the lower spine, which may be a risk for ineffective NA or ADP,68 but detailed studies are lacking. The majority of patients are good candidates for NA and, despite a few reports

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for LA resistance,69 spinal and epidural anesthesia generally work well.66 Some recommend using a CSE for CD with lower doses of LA in the spinal portion, so there is less risk of a sudden onset of sympathetic block, especially in patients with POTS. The epidural catheter will allow additional top-ups if needed.66 When using NA, take extra care to prevent injury, especially hip or knee dislocation in patients with joint hypermobility.68 Weigh the risks of pneumothorax when considering nitrous oxide for labor analgesia. If GA is required, pregnant patients with a history of temporomandibular joint dislocation may be at higher risk for difficult intubation than the general population.68 In addition, premature spondylosis or occipital atlantoaxial instability may contribute to the risk of difficult intubation and neurological damage.70 In those cases, an awake, fiberoptic intubation may be the safest approach.

Loeys-Dietz Syndrome Loeys-Dietz syndrome (LDS) is a rare, recently described autosomal dominant connective tissue disease. What is known is based on case reports and registries, but the incidence is currently unknown.71 It is caused by mutations in components of the transforming growth factor β signaling pathway, most commonly the transforming growth factor receptors 1/2 (TGFBR1/2),71 as well as the decapentaplegic homolog 2/3 (SMAD2/3) and transforming growth factor ligand 2/3 (TGFB2/3).72 Characterized by variable phenotypic expression, LDS may present with cardiovascular, craniofacial, neurocognitive, and skeletal abnormalities. Most commonly, there is a variable combination of hypertelorism, a bifid uvula, cleft palate, generalized arterial tortuosity with widespread vascular aneurysms, and risk of dissection. Affected patients have a high risk of aortic rupture at an early age which can occur independently of aortic dilatation. The most common cause of death is aortic aneurysm dissection, especially involving the thoracic aorta, and the median age of survival is 37 years.73 Surgical intervention is generally successful.73

Obstetric and Anesthetic Implications Based on case series, LDS patients are at high risk for aortic dissection, uterine rupture, and bleeding due to vascular tortuosity. The rate of aortic dissection during pregnancy increases due to hormonal and hemodynamic changes to as high as 1.6%.74 Reports of rupture are documented in patients with aortic root diameters of 31–35  mm, suggesting the need for continuous vigilance.74 Ideally, diagnosis of this syndrome is made preconception to allow for proper optimization and counseling. Complete aortic evaluation by MRI or CT imaging is recommended at diagnosis and every six months after that to look for enlargement.63 Surgery may be warranted if the aortic diameter is > 40  mm.63 These patients respond well to ACE inhibitors and beta-blockers before pregnancy. In addition, as there may be dural ectasia or vascular abnormalities of multiple organs, annual MRI of the cerebrovascular circulation to the pelvis is recommended.63 A multidisciplinary team should manage the care of the pregnant patient with LDS and the delivery planned for a specialized tertiary center with cardiothoracic surgery available. It

Genetic Disorders

is crucial to monitor the BP regularly and maintain a low normal BP and HR during pregnancy. Beta-blockers are used to avoid sudden hemodynamic stress. Monitor the ascending aortic dimensions with monthly echocardiograms until delivery.63 The mode of delivery is controversial, but generally, if the aortic diameter is > 40–45 mm, a CD is recommended.75 For both vaginal and CD, NA is the optimal choice to maintain hemodynamic stability and avoid sudden surges in HR or BP due to pain or pushing in the second stage. When NA is contraindicated, avoid acute tachycardia and hypertension during induction of GA. Patients with LDS are at higher risk of bleeding due to uterine rupture or uterine vascular tortuosities. If uterotonics are needed, administer oxytocin as an infusion rather than bolus and avoid methylergonovine to maintain hemodynamic stability. As there is a heightened risk of aortic dissection for up to six months postpartum, surveillance via imaging and avoidance of hypertension are vital.63

X-linked Disorders Glucose-6-phosphate Dehydrogenase Deficiency Glucose-6-phosphate dehydrogenase deficiency (G6PD) is the most common human enzyme deficiency, with approximately 400 million people worldwide carrying mutant alleles.76 The enzyme G6PD catalyzes the first step in the pentose phosphate pathway, providing a source of reducing power in NADPH to combat oxidative stress. Red blood cells lack mitochondria, and in these cells, the pentose phosphate pathway is the only source of NADPH and protection against oxidative damage. Pregnancy alters the trafficking of G6PD in neutrophils, a factor that may influence susceptibility to infections and other inflammatory conditions in pregnancy.77 Remarkably, G6PD deficiency prevalence is highest in regions where malaria is endemic, and the disorder may provide resistance against malaria. Glucose-6-phosphate dehydrogenase deficiency is an X-linked disorder. Females, having two copies of the X chromosome, are typically heterozygous for mutant G6PD alleles, although homozygosity is not rare in specific populations. As a result of mosaicism from X inactivation, heterozygotes can have tissues with G6PD deficiency; female heterozygotes have less severe symptoms than males with G6PD deficiency, although hemolytic anemia can occur. Approximately 140 different mutations in G6PD exist.78 The clinical presentation is acute hemolysis, typically triggered when RBCs experience oxidative stress by a triggering agent, like infection, certain drugs, or fava bean ingestion. Symptoms of jaundice, fatigue, and back pain are typical. Laboratory findings include increased unconjugated bilirubin and lactate dehydrogenase levels and an elevated reticulocyte count. However, most people with G6PD deficiency are asymptomatic and unaware of their diagnosis. A subset of patients with G6PD deficiency carrying certain variants might develop congenital nonspherocytic hemolytic anemia, a state of chronic hemolysis. Several drugs induce acute hemolysis in patients with G6PD deficiency. Variation in pharmacokinetics, the G6PD defect, comorbid conditions, and co-administered agents in individual

patients often complicate establishing the causal role for particular drugs. Symptoms typically appear within 24–72 hours of drug administration. Strong associations exist between G6PD deficiency and the following agents: primaquine, pamaquine, dapsone, certain sulfonamides (e.g., sulfamethoxazole, sulfacetamide), nitrofurantoin, and phenazopyridine. There is evidence that maternal drug administration can provoke reactions in neonates.79 Infections, including pneumonia, hepatitis A and B virus, cytomegalovirus, and typhoid, are the most common cause of hemolysis in patients with G6PD deficiency. Hemolysis triggered by fava bean (favism) can show marked variation among and within patients with G6PD but is most common after eating fresh beans.78 Breastfed infants with G6PD deficiency whose mothers eat fava beans are at risk for hemolysis.80 It is possible that triggering medications that pass into breast milk could be transferred to a breastfeeding infant, a particular concern for male infants. Limited evidence exists to guide the management of pregnant patients with G6PD deficiency.81,82 Patients with known G6PD deficiency should avoid triggering agents. Transfuse RBCs in those G6PD patients who develop severe anemia from hemolytic episodes. Although prenatal diagnosis of G6PD deficiency is possible,83 it is of questionable value given the generally low morbidity and mortality of this disorder in the general population.

Anesthesia for Glucose-6-phosphate Dehydrogenase Deficiency Females with mutant G6PD alleles are likely to be heterozygotes and unlikely to have clinical disease. As such, most are suitable for usual care. For those with a known history of hemolysis, a chief concern will be triggering medications. Although some anesthetic drugs can affect G6PD enzyme activity in vitro, this does not appear to have meaningful clinical significance. Historically, there were concerns about certain analgesics, including NSAIDs, being triggering agents. However, NSAIDs are now considered to be safe for most patients with G6PD deficiency.76 Indeed, in a study of ten male infants, all with severe G6PD deficiency, the administration of NSAIDs did not trigger hemolytic episodes.84 Patients with G6PD deficiency may be at greater risk for developing methemoglobinemia given their limited reducing capacity in RBCs. Cautiously use agents that cause methemoglobinemia in these patients.85

Chromosomal Disorders Down Syndrome Down syndrome (DS) or trisomy 21 is the most common chromosomal disorder, occurring in 1:700 infants yearly.86 In 95% of individuals, DS is due to an extra copy of chromosome 21; in 3%, it is due to translocation of parts of chromosome 21, and the remainder 2% have tissue mosaicism. Patients with DS have multiple congenital anomalies, including heart disease, congenital diaphragmatic hernia, and GI malformations, such as duodenal atresia, annular pancreas, and Hirschsprung disease. Other clinical features associated with DS include polydactyly, cleft palate, and cataracts. The median age of survival is 53 years,87 and the majority of the patients reach reproductive age

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due to improved medical care. Most complex congenital comorbidities persist into adulthood and may worsen with age. Female patients with DS can reproduce but have decreased fertility. Cardiopulmonary conditions are the leading cause of morbidity for adults with DS and account for up to 60% of all mortality.88 Almost 50% of DS patients have congenital heart disease, most commonly atrioventricular septal defects, atrial septum defects, ventricular septum defects, and tetralogy of Fallot.88 Most of these are surgically repaired by adulthood. Those with a previously repaired atrioventricular septal defect are most likely to have complications involving left ventricular outflow obstruction and Eisenmenger syndrome.89 Even patients without congenital heart disease are at higher risk for valvular disease, dysrhythmias, especially atrial fibrillation, and dilated cardiomyopathy.90 In addition, there is a higher incidence of cerebrovascular events even in patients with minimal risk factors.90 There is a high incidence of pulmonary hypoplasia and decreased immunity leading to frequent respiratory infections. Pulmonary hypertension is also likely due to coexisting conditions such as obstructive sleep apnea, pulmonary hypoplasia, and recurrent pneumonias.91 Musculoskeletal and facial features include midface hypoplasia, macroglossia, micrognathia, and a small upper airway. In addition, ligamentous laxity can predispose to atlantoaxial instability, potentially leading to spinal canal stenosis and spinal cord compression. There is a higher incidence of hip and other joint dislocations, scoliosis, and degenerative disk disease.92,93 The GI features in adulthood include a higher incidence of gastro­ esophageal reflux disease and dysphagia, which can predispose to aspiration.94 Endocrine disorders most commonly seen are hypothyroidism and type 1 diabetes mellitus. There is a higher prevalence of obesity compared to the general population.90,95 Neuropsychiatric symptoms include intellectual disability, cognitive impairment, and a higher incidence of depression, anxiety, and obsessive-compulsive disorder.96 There is also a higher incidence of seizures and epilepsy.97

Anesthetic Implications Patients with DS can present with multisystem comorbidities during pregnancy, necessitating a multidisciplinary team approach. As cardiac disease is a significant risk for mortality and morbidity, evaluation with an ECG and echocardiogram is indicated even in the absence of congenital heart disease. Patients with adult congenital heart disease should have their condition optimized. Anesthetic management, ultimately, depends on the lesion, the type of repair, the long-term complications, progression of corrected or uncorrected defects, and other comorbidities. The use of NA has been described and is safe, assuming no contraindications exist.98 There is a case report of cardiac arrest after spinal anesthesia,99 however, there is insufficient evidence to generalize this complication. Pregnancy and relaxin may exacerbate ligamentous laxity. Routine cervical imaging for asymptomatic individuals is not needed, but cervical spine positioning precautions with in-line stabilization may be appropriate during intubation.100 If there are symptoms from cervical spine degenerative disease, consider flexion and extension X-rays and a neurologic evaluation. If GA is necessary, balance

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the risks of difficult airway and aspiration with the urgency of the situation.

Turner Syndrome Turner syndrome (TS) is a chromosomal disorder affecting one in every 2500–3000 females.101 It may arise from several distinct genotypes involving total or partial absence of an X chromosome, with 45XO being the most common (45% prevalence) karyotype. About half of the patients have mosaicism (e.g., 45X/46XX, 45X/47XY), which may not be equally present in all body tissues. Features of TS vary and may involve multiple organ systems. Short stature affects 95–100% of patients with TS, and other musculoskeletal features include head and neck changes (webbed neck, short neck, micrognathia) and kyphoscoliosis. Cardiovascular disease is common, including hypertension (in 50–60%), aortic dilatation, aortic coarctation (7–18%), bicuspid aortic valve (15–30%), aortic stenosis, coronary artery disease, and vasculopathy.102 Other features include congenital renal anomalies, elevated hepatic enzymes (50–80%), glucose intolerance or diabetes mellitus, Hashimoto thyroiditis or other thyroid diseases, gastroesophageal reflux, and neurocognitive changes. Primary ovarian insufficiency affects 95% of patients with TS, and only 5–20% of girls experience menarche.103,104 Spontaneous pregnancy is rare (0.5%) in those with a 45X monosomy but occurs more frequently in patients with mosaicism,105 with rates across all TS patients ranging from 1.8% to 7.6%. Most pregnancies in TS patients result from assisted reproductive technology (ART). In most cases, this involves using donor oocytes, but IVF with cryopreserved oocytes is possible for some patients. Single embryo transfer is mandatory given the increased risk of multiple gestation pregnancy. The American Society for Reproductive Medicine considers TS a relative contraindication for pregnancy and an absolute contraindication if there is cardiac disease (Table 27.3).106 Prior aortic dissection or aortic surgery is a contraindication for pregnancy. Turner syndrome patients should have a comprehensive cardiovascular evaluation, including transthoracic echocardiography (TTE) and cardiac MRI, within two years before pregnancy or ART.101,107 For TS patients, pregnancy and the early postpartum period carry an increased risk of aortic dissection or rupture. Avoid ART or pregnancy in patients with an aortic size index (ASI, aortic diameter indexed to body surface area) > 2.5 cm/m2 or those with an ASI between 2.5 and 2.0 cm/m2 who have risk factors for aortic dilatation, including bicuspid aortic valve, elongation of the transverse aorta, coarctation, or uncontrolled hypertension. Patients with TS should have their ART and pregnancy care coordinated by a multidisciplinary team in a tertiary care center. Miscarriage is more common in pregnant women with TS, perhaps due to uterine hypoplasia, bicornuate uteri, or a thinner endometrial lining. Pregnancy in TS is also associated with a high risk of hypertensive disease, including gestational hypertension (35–67% of singleton pregnancies, 100% with multiple gestation) and PreE (18–44% singleton, 75–100% multiple gestation). Turner syndrome patients should receive aspirin

Genetic Disorders

Table 27.3  Pregnancy in patients with Turner syndrome (adapted from Bouet et al.)103

Risks Fetal risks (frequency)

Maternal risks (frequency)

Miscarriage (29%)

Thyroid dysfunction (22%)

Small for gestational age (18–28%)

Gestational diabetes (4–9%)

Prematurity (12%)

Preeclampsia (21%) Cesarean delivery (82%) Worsening congenital heart disease (1%) Heart failure (1%) Aortic dissection (1–2%) Maternal death (2%)

Pregnancy contraindications Absolute

Relative

History of aortic surgery

Turner syndromea

History of aortic dissection

Poorly controlled diabetes

Aortic dilatation with aortic size index (ASI) > 2 cm/m2

Bicuspid aortic valve

Coarctation of the aorta

Portal hypertension with esophageal varices

Resistant hypertension

Poor uterine development

a

Recommended monitoring Multidisciplinary follow-up Prenatal diagnosis for autologous oocytes Blood pressure monitoring at each visit Cardiology consultation and echocardiography each trimester Increased monitoring frequency in third trimester (possible thoracic MRI) Proteinuria screening Gestational diabetes screening Nutrition counseling and weight gain monitoring Liver function testing in first trimester, repeat if abnormal Multidisciplinary planning for mode of delivery and cardiovascular monitoring a  From the American Society for Reproductive Medicine.

prophylaxis from 12 weeks until delivery, and careful BP control, with a goal pressure < 135/85 mmHg and at least monthly BP screenings. Preferred antihypertensives are the same as those for patients without TS. In patients with TS do at least one TTE at 20 weeks.107 If the ASI exceeds 2.0 in the presence of risk factors, perform TTEs every four weeks through the first postpartum month. If TTE images are of poor quality, cardiac MRI may offer better evaluation of increases in aortic diameter. Counsel patients to seek immediate care for acute and severe chest pain. Although cardiac complications are the most dangerous, liver disease, diabetes, and thyroid dysfunction can complicate pregnancy in TS patients. Pregnancy in TS also carries a higher risk of IUGR, so perform regular US screenings. Turner syndrome patients should deliver in a facility with access to cardiothoracic surgery. Cesarean delivery is

recommended for an ASI > 2.5 mm/m2 or in patients with a rapidly increasing ASI.101 Otherwise, vaginal delivery is preferred if there are no maternal or fetal indications. Rates of CD range from 82% to 100% in some series.104,105 If significant aortic dilatation occurs before fetal viability, surgical repair is warranted, but delivery should occur first if the fetus is viable.

Anesthetic Implications Peer-reviewed literature on the anesthetic management of TS patients in pregnancy is limited to case reports.108–112 When caring for TS patients presenting for ART, with antepartum complications, or in the peripartum period, a careful preoperative assessment, with attention to cardiovascular disease, is critical. The physiologic changes to the cardiovascular system during pregnancy lead to increasing wall tension and intimal shear forces with each trimester. Short stature and kyphoscoliosis and a more pronounced lumbar lordosis, may make NA more challenging. Hypotension or bradycardia from high neuraxial blockade will limit aortic wall stress, but the former often is poorly tolerated in patients with aortic stenosis. Most patients with prior aortic valve repair will be anticoagulated, so it is essential to time NA based on anticoagulant dosing. The facial features of TS patients (webbed neck, short neck, micrognathia) can make airway management, already challenging in the parturient, still more difficult. There are reports of unintended endobronchial intubation in patients with TS, attributed to their short stature and short neck.110,112 For GA, pay careful attention to hemodynamic stability at induction and emergence to minimize tachycardia and hypertension, both of which put significant stress on aortic lesions.

Mitochondrial Disorders Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like Episodes Syndrome Mitochondrial diseases are very heterogeneous. Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes syndrome (MELAS) is a rare maternally inherited mitochondrial disorder. The symptoms are associated with severe multiorgan pathology and stress-induced episodes of metabolic decompensation and lactic acidosis. The prevalence of symptomatic disease is 1:10,000; additionally, 1:6000 children and adults younger than retirement age are at risk for developing mitochondrial disease.113 There are more than 30 mitochondrial DNA gene mutations, and the most common is a point mutation (m.3243A>G) in the mitochondrially encoded transfer RNA leucine 1 (MT-TL1) gene. As a result of the impaired mitochondrial function, the main features of the disease are due to cellular energy supply and demand mismatch in the CNS and musculoskeletal system. The symptoms include headaches associated with vomiting, seizures, hemiplegia, blindness, focal radiologic supratentorial lesions, and elevated lactate concentration. Mitochondrial diseases have variable clinical presentations due to heteroplasmy, a condition in which the mutant DNA may be expressed only in a portion of the cellular mitochondria. Pregnancy, a period of increased energy demands,

451 https://doi.org/10.1017/9781009070256.028 Published online by Cambridge University Press

David J. Combs and Vesela P. Kovacheva

may exacerbate the disease. Most of the recommendations come from a few published case reports114 and the Newcastle Mitochondrial Disease Guidelines.115

Obstetric and Anesthetic Implications Refer patients with known or suspected mitochondrial disease considering pregnancy for preconception planning and consultation with a mitochondrial disease geneticist. These patients are at elevated risk for gestational diabetes, and if they need medication for glycemic control, avoid metformin due to the heightened risk for lactic acidosis. Patients are at an increased risk for PreE,116 and, if indicated, initiate aspirin prophylaxis in subsequent pregnancies. Magnesium sulfate treatment may be associated with toxicity even at normal therapeutic levels, so monitor these patients frequently.117 Perioperatively, patients with mitochondrial disease are at higher risk for complications. The key to managing them is adequate hydration, avoiding prolonged starvation, and administering all scheduled medications as indicated.115 Neuraxial anesthesia and analgesia are considered safe.115 If GA is needed, avoid prolonged propofol infusions. Specific risks arise based on the systems involved. Some patients present with a significant myopathy and compromised respiratory function, both made worse by pregnancy.116 These patients have a higher risk for cardiac dysrhythmias and peripartum cardiomyopathy, so assess cardiac function with an ECG and echocardiogram. There is a risk of paralytic ileus and dysmotility of the GI system. Patients with mitochondrial disease are at higher risk for aortic dilation and dissection.114 In these patients, include imaging the aorta using CT in the preconception evaluation and refer for surgery if the diameter is > 45 mm. During pregnancy, continue monthly surveillance with an echocardiogram and, if signs of dilation, especially > 45 mm, do a CD. Overall, NA is recommended in patients with aortic disease, as is careful hemodynamic control with avoidance of BP and HR lability.63

Cleidocranial Dysplasia This rare skeletal disorder is mainly inherited as an autosomal dominant genetic trait. It has a wide range of symptoms (variable expression), including short stature, distinct facial appearance, narrow sloping shoulders, premature closure of the fontanelles, and other skeletal and dental abnormalities. The gene for cleidocranial dysplasia is designated CBFA1 and found on chromosome 6p21. Further information is found at rarediseases.org (National Organization of Rare Disorders – NORD). The anesthetic issues for pregnant women with this condition are described in two cases reports.118,119

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46. Wu M, Wang D, Zand L, et al. Pregnancy outcomes in autosomal dominant polycystic kidney disease: a case-control study. J Matern Fetal Neonatal Med 2016;29:807–812. 47. D’Agnolo HMA, Drenth JPH. Risk factors for progressive polycystic liver disease: where do we stand? Nephrol Dial Transplant 2016;31:857–859. 48. Lee VW, Dexter MAJ, Mai J, et al. KHA-CARI autosomal dominant polycystic kidney disease guideline: management of intracranial aneurysms. Semin Nephrol 2015;35:612–617.e20. 49. Braathen GJ. Genetic epidemiology of Charcot-Marie-Tooth disease. Acta Neurol Scand 2012;193:iv–22. https://doi .org/10.1111/ane.12013 50. Laroche CM, Carroll N, Moxham J, et al. Diaphragm weakness in Charcot-Marie-Tooth disease. Thorax 1988;43:478–479. 51. Reah G, Lyons GR. Wilson RC. Anaesthesia for caesarean section in a patient with Charcot-Marie-Tooth disease. Anaesthesia 1988;53:586–588. 52. Pisciotta C, Calabrese D, Santoro L, et al. Pregnancy in CharcotMarie-Tooth disease: data from the Italian CMT national registry. Neurology 2020;95:e3180–e3189. 53. Rudnik-Schoneborn S, Thiele S, Walter MC, et al. Pregnancy outcome in Charcot-Marie-Tooth disease: results of the CMTNET cohort study in Germany. Eur J Neurol 2020;27:1390–1396. 54. Scull T, Weeks S. Epidural analgesia for labour in a patient with Charcot-Marie-Tooth disease. Can J Anaesth 1996;43:1150–1152. 55. Tanaka S, Tsuchida H, Namiki A. Epidural anesthesia for a patient with Charcot-Marie-Tooth disease, mitral valve prolapse syndrome and IInd degree AV block. Masui 1994;43:931–933. 56. Schmitt HJ, Muenster T, Schmidt J. Central neural blockade in Charcot-Marie-Tooth disease. Can J Anaesth 2004;51:1049–1050. 57. Zanjani AP, Ghorbani A, Eslami B, et al. Epidural anesthesia combined with light general anesthesia for a juvenile with Charcot-Marie-Tooth disease undergoing corrective spine surgery: a case report. Anesth Pain Med 2017;7:e14189. 58. Antognini JF. Anaesthesia for Charcot-Marie-Tooth disease: a review of 86 cases. Can J Anaesth 1992;39:398–400. 59. Ducart A, Adnet P, Renaud B, et al. Malignant hyperthermia during sevoflurane administration. Anesth Analg 1995;80:609– 611. 60. Demmler JC, Atkinson MD, Reinhold EJ, et al. Diagnosed prevalence of Ehlers-Danlos syndrome and hypermobility spectrum disorder in Wales, UK: a national electronic cohort study and case-control comparison. BMJ Open 2019;9:e031365. 61. Malfait F, Francomano C, Byers P, et al. The 2017 international classification of the Ehlers-Danlos syndromes. Am J Med Genet C Semin Med Genet 2017;175:8–26. 62. Murray ML, Pepin M, Peterson S, et al. Pregnancy-related deaths and complications in women with vascular Ehlers-Danlos syndrome. Genet Med 2014;16:874–880. 63. Hiratzka LF, Bakris GL, Beckman JA, et al. 2010 ACCF/AHA/ AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM Guidelines for the diagnosis and management of patients with thoracic aortic disease: Executive summary: A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, American Association for Thoracic Surgery, American College of Radiology, American Stroke Association, Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Society of Thoracic Surgeons, and Society for Vascular Medicine. Anesth Analg 2010;111:279–315.

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64. Lind J, Wallenburg HC. Pregnancy and the Ehlers-Danlos syndrome: a retrospective study in a Dutch population. Acta Obstet Gynecol Scand 2002;81:293–300. 65. Grigoriou E, Boris JR, Dormans JP. Postural orthostatic tachycardia syndrome (POTS): association with Ehlers-Danlos syndrome and orthopaedic considerations. Clin Orthop Relat Res 2015;473:722–728. 66. Karthikeyan A, Venkat-Raman N. Hypermobile Ehlers-Danlos syndrome and pregnancy. Obstet Med 2018;11:104–109. 67. Mast KJ, Nunes ME, Ruymann FB, et al. Desmopressin responsiveness in children with Ehlers-Danlos syndrome associated bleeding symptoms. Br J Haematol 2009;144:230–233. 68. Wiesmann T, Castori M, Malfait F, et al. Recommendations for anesthesia and perioperative management in patients with EhlersDanlos syndrome(s). Orphanet J Rare Dis 2014;9:109. https://doi .org/10.1186/s13023-014-0109-5 69. Hakim AJ, Grahame R, Norris P, et al. Local anaesthetic failure in joint hypermobility syndrome. J R Soc Med 2005;98:84–85. 70. Halko GJ, Cobb R, Abeles M. Patients with type IV Ehlers-Danlos syndrome may be predisposed to atlantoaxial subluxation. J Rheumatol 1995;22:2152–2155. 71. Loeys BL, Chen J, Neptune ER, et al. A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2. Nat Genet 2005;37:275–281. 72. Schepers D, Tortora G, Morisaki H, et al. A mutation update on the LDS-associated genes TGFB2/3 and SMAD2/3. Hum Mutat 2018;39:621–634. 73. Loeys BL, Schwarze U, Holm T, et al. Aneurysm syndromes caused by mutations in the TGF-beta receptor. N Engl J Med 2006;355:788–798. 74. Jondeau G, Ropers J, Regalado E, et al. International Registry of Patients Carrying TGFBR1 or TGFBR2 Mutations: Results of the MAC (Montalcino Aortic Consortium). Circ Cardiovasc Genet 2016;9:548–558. 75. Regitz-Zagrosek V, Roos-Hesselink JW, Bauersachs J, et al. 2018 ESC guidelines for the management of cardiovascular diseases during pregnancy. Eur Heart J 2018;39:3165–3241. 76. Cappellini MD, Fiorelli G. Glucose-6-phosphate dehydrogenase deficiency. Lancet 2008;371:64–74. 77. Kindzelskii AL, Huang J-B, Chaiworapongsa T, et al. Pregnancy alters glucose-6-phosphate dehydrogenase trafficking, cell metabolism, and oxidant release of maternal neutrophils. J Clin Invest 2002;110:1801–1811. 78. Bulliamy T, Luzzatto L, Hirono A, et al. Hematologically important mutations: glucose-6-phosphate dehydrogenase. Blood Cells Mol Dis 1997;23:302–313. 79. Perkins RP. Hydrops fetalis and stillbirth in a male glucose-6phosphate dehydrogenase-deficient fetus possibly due to maternal ingestion of sulfisoxazole; a case report. Am J Obstet Gynecol 1971;111:379–381. 80. Schiliro G, Russo A, Curreri R, et al. Glucose-6-phosphate dehydrogenase deficiency in Sicily. Incidence, biochemical characteristics and clinical implications. Clin Genet 1979;15:183– 188. 81. Perkins RP. The significance of glucose-6-phosphate dehydrogenase deficiency in pregnancy. Am J Obstet Gynecol 1976;125:215–223. 82. Chintapatla R, Melinscak H, Varma M. Significance of low levels of glucose-6-phosphate dehydrogenase levels in pregnancy. Blood 2012;120:5165.

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103. Bouet P-E, Godbout A, El Hachem H, et al. Fertility and pregnancy in Turner syndrome. J Obstet Gynaecol Can 2016;38:712–718. 104. Calanchini M, Aye CYL, Orchard E, et al. Fertility issues and pregnancy outcomes in Turner syndrome. Fertil Steril 2020;114:144–154. 105. Bernard V, Donadille B, Zenaty D, et al. Spontaneous fertility and pregnancy outcomes amongst 480 women with Turner syndrome. Hum Reprod 2016;31:782–788. 106. Practice Committee of the American Society for Reproductive Medicine. Increased maternal cardiovascular mortality associated with pregnancy in women with Turner syndrome. Fertil Steril 2012;97:282–284. 107. Donadille B, Bernard V, Christin-Maitre S. How can we make pregnancy safe for women with Turner syndrome? Am J Med Genet C Semin Med Genet 2019;181: 100–107. 108. Mashour GA, Sunder N, Acquadro MA. Anesthetic management of Turner syndrome: a systematic approach. J Clin Anesth 2005;17:128–130. 109. Kalopita K, Michala L, Theofanakis C, et al. Anesthetic management of mosaic Turner’s syndrome posted for elective cesarean delivery after spontaneous pregnancy. Int J Obstet Anesth 2018;34:102–105. 110. Liu WC, Hwang CB, Cheng RK, et al. Unexpected left endobronchial intubation in a case of Turner’s syndrome. Acta Anaesthesiol Sin 1997;35:253–256. 111. Maranhão MVM. Turner syndrome and anesthesia. Rev Bras Anestesiol 2008;58:84–89.

112. Divekar VM, Kothari MD, Kamdar BM. Anaesthesia in Turner’s syndrome. Can Anaesth Soc J 1983;30:417–418. 113. Schaefer AM, McFarland R, Blakely EL, et al. Prevalence of mitochondrial DNA disease in adults. Ann Neurol 2008;63:35– 39. 114. Balachandran Nair D, Bloomfield M, Parasuraman R, et al. Mitochondrial encephalomyopathy, lactic acidosis and strokelike episodes (MELAS) syndrome in pregnancy. BMJ Case Rep 2021;14:e235111. https://doi.org/10.1136/bcr-2020-235111 115. Group TGD. Newcastle Mitochondrial Disease Guidelines. 2013. Available from: www.newcastle-mitochondria.com/ wp-content/uploads/2016/03/Pregnancy-Guidelines.pdf [last accessed October 4, 2022]. 116. de Laat P, Fleuren LH, Bekker MN, et al. Obstetric complications in carriers of the m.3243A>G mutation, a retrospective cohort study on maternal and fetal outcome. Mitochondrion 2015;25:98–103. 117. Moriarty KT, McFarland R, Whittake R, et al. Pre-eclampsia and magnesium toxicity with therapeutic plasma level in a woman with m.3243A>G melas mutation. J Obstet Gynaecol 2008;28:349. 118. Ioscovich A, Barth D, Samueloff A, et al. Anesthetic management of a patient with cleidocranial dysplasia undergoing various obstetric procedures. Int J Obstet Anesth 2010;19:106–108. 119. Nishio Y, Hiraki T, Taniguchi H, et al. Anesthetic management during a cesarean section in a patient with cleidocranial dysplasia: a case report. JA Clin Rep 2018;4:2. https://doi .org/10.1186/s40981-017-0141-2

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Chapter

28

Anesthesia for Rare Fetal and Placental Conditions Marla B. Ferschl and Mark D. Rollins

Introduction Anesthesia for fetal surgery is a relatively novel subspecialty in anesthesiology. With advances in imaging technologies and improvements in surgical instrumentation and technique, lesions that were previously fatal or caused significant morbidity are now treated prenatally. Fetal procedures require a multidisciplinary team approach, whereby one must consider the health of two patients, the mother and the fetus. Although most fetal lesions are not amenable to prenatal intervention, an increasing number of fetal lesions are now considered appropriate for prenatal treatment (Table 28.1). Anesthetic management strategy varies based on procedure type and indication. Valuable Clinical Insights • Most fetal anomalies are not appropriate for in utero intervention. • Fetal surgery is used for lesions that would otherwise result in significant ongoing harm before adequate fetal maturity for delivery and postnatal intervention.

• Fetal therapy should only occur when there is a reasonable probability of long-term benefit and minimal maternal risk. • Multidisciplinary planning and a careful preoperative history and physical are essential for any pregnant patient before a fetal intervention.

Conditions Amenable to Intrauterine Intervention Twin-to-Twin Transfusion Syndrome Unequally shared placental blood vessels in monochorionic twins lead to twin-to-twin transfusion syndrome (TTTS). Under normal circumstances, umbilical arteries pair with returning venous blood vessels in each placenta cotyledon. Imbalanced or unidirectional vascular connections between the two fetuses are present in TTTS, resulting in arteriovenous anastomoses between the two twins (Figure 28.1). One twin

Table 28.1  Indications for fetal intervention

Fetal condition

Rationale

Type

Intervention

Anemia or thrombocytopenia

Prevention of fetal hydrops

FIGS-IT

Intrauterine blood transfusion

Twin-to-twin transfusion syndrome

Prevention of fetal hydrops

Fetoscopy

Laser photocoagulation of placental vessels

Twin reversed arterial perfusion

Prevention of high-output cardiac failure

Fetoscopy

Ablation or ligation of umbilical cord of acardiac twin

Lower urinary tract obstruction

Bladder decompression to improve renal and pulmonary function

FIGS-IT or fetoscopy

Percutaneous vesicoamniotic shunting or fetoscopic posterior urethral valve ablation

Aortic stenosis, pulmonary atresia, or intact atrial septum with hypoplastic left heart syndrome

Improve fetal cardiac function, reduce ventricular hypoplasia

FIGS-IT

Percutaneous fetal valvuloplasty or septostomy

Congenital diaphragmatic hernia

Improve pulmonary development

Fetoscopy

Fetal tracheal balloon occlusion

Myelomeningocele

Reduce spinal cord damage to improve neurologic function and reduce hydrocephalus

Open or fetoscopy

Closure of fetal myelomeningocele

Sacrococcygeal teratoma

Prevention of hydrops fetalis

FIGS-IT or open

Ablation of tumor vasculature or open resection

Congenital pulmonary airway malformation

Improve pulmonary development and prevent hydrops fetalis

FIGS-IT or open

Thoracoamniotic shunt or open fetal resection

Abbreviation: FIGS-IT = fetal image-guided surgery for intervention or therapy. Modified from Partridge EA, Flake AW. Maternal–fetal surgery for structural malformations. Best Pract Res Clin Obstet Gynaecol 2012;26:669–682.

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Anesthesia for Rare Fetal and Placental Conditions

serves as the “donor” twin and has reduced blood flow resulting in growth restriction, oligohydramnios, hypovolemia, and increased risk of renal dysfunction. The “recipient” twin develops polyhydramnios, polyuria, polycythemia and is at risk for hypertrophic cardiomyopathy. Both twins are at risk for impaired neurodevelopment, cardiac failure, hydrops fetalis, and demise.1 The clinical diagnosis of TTTS requires a monochorionic, diamniotic pregnancy and differing amniotic fluid volumes in the donor and recipient, with maximal vertical fluid pockets < 2 cm and > 8 cm, respectively. The Quintero staging system grades the severity of the TTTS2 (Table 28.2). Untreated advanced TTTS can cause fetal mortality up to 80%3; surviving infants are at risk for severe neurologic disability.4 In utero treatment of stages II–IV TTTS includes amnio­ reduction and selective fetoscopic laser photocoagulation (SFLP). Intervention with SFLP occurs during the second Table 28.2  Stages of twin-to-twin transfusion syndrome

Stage

Ultrasound findings

1

Oligohydramnios in the donor twin amniotic sac with MVP < 2 cm and polyhydramnios in the recipient twin amniotic sac with MVP > 8 cm

2

Stage 1 criteria AND no bladder visible in the donor twin during 1 hour of continuous US evaluation

3

Stage 2 criteria AND (1) Absent or reversed umbilical artery enddiastolic blood flow, (2) Ductus venous a-wave flow reversal, or (3) Pulsatile flow in the umbilical vein

4

Fetal hydrops in either twin plus stage 1 or stage 2 criteria

5

Fetal demise in one or both twins

Abbreviation: MVP = maximum vertical pocket. Staging data based on criteria from Quintero RA, Morales WJ, Allen MH, et al. Staging of twin-twin transfusion syndrome. J Perinatol 1999;19:550–555.2

trimester of pregnancy.5 In this technique, a small trocar is inserted into the amniotic sac of the recipient twin. Under US guidance, the operator photocoagulates placental surface vessels that cross the membrane between the two amniotic sacs6 (Figure 28.1). In 2004, a multicenter, randomized trial demonstrated the efficacy of SFLP for treatment of severe TTTS, with better survival and neurologic outcomes in the laser treated group, compared to twins who underwent amnioreduction.7 Current outcomes of advanced TTTS from centers routinely performing midgestation SFLP are approximately 70% dual twin survival and > 90% survival of at least one twin.8 More recent work suggests intervention for stage I TTTS may not be necessary. However, as many of these pregnancies evolve into advanced TTTS with further gestation, periodic surveillance is required throughout the pregnancy.9,10 Risks to the fetus and pregnancy associated with the SFLP procedure include preterm premature rupture of the membranes (PPROM), placental abruption, chorioamnionitis, and fetal limb entrapment and ischemia.1,5

Twin Reversed Arterial Perfusion Sequence Twin reversed arterial perfusion sequence (TRAP) occurs in approximately 1% of monozygotic twin pregnancies when one twin lacks a connection to the placenta and has an absent or nonfunctioning heart. This twin receives retrograde flow from the normal or “pump” twin through arterial-arterial anastomoses. Ultrasound confirmation of this retrograde umbilical artery flow is diagnostic of TRAP. The pump twin is at risk of high output cardiac failure, hydrops fetalis, polyhydramnios, and preterm delivery. Untreated pump twins have a survival rate of 45–65% and an average gestational age of 29 weeks.11,12 Fetal intervention for TRAP terminates blood flow to the acardiac nonviable twin by US-guided radiofrequency ablation of Figure 28.1  Twin-to-twin transfusion syndrome. Twin-to-twin transfusion syndrome is seen in monozygotic, diamniotic twins. One twin serves as the donor twin, shunting blood to the recipient twin. The donor twin exhibits growth restriction and oligohydramnios while the recipient develops polyhydramnios. For in utero laser ablation, a fetoscope is inserted under US guidance and intertwin vessels are ablated under direct visualization. (See color plate section).

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Marla B. Ferschl and Mark D. Rollins

its umbilical cord or laser coagulation of the umbilical artery or vascular anastomoses.13,14 These interventions can be done as early as the first trimester of pregnancy. Treated pregnancies have favorable outcomes, with the pump twin survival approximately 80% and most pregnancies progressing to near term.13,15,16

Obstructive Uropathy Fetal lower urinary tract obstruction (LUTO) affects approximately one in 5000 live births and can occur at the level of the urethra, the ureterovesical junction, or the ureteropelvic junction. The most common causes include posterior urethral valves (typically male fetuses) or urethral atresia.17 Urethral or bilateral obstruction is 90% fatal, with survivors often having significant renal impairment.18 Presence of LUTO can be suspected in the case of severe oligohydramnios due to decreased or absent urine output or dilation of the urinary tract on prenatal US, with further confirmation by either fetal US or MRI.19 Two in utero surgical treatment options for LUTO exist. Percutaneous placement of a US guided vesico-amniotic shunt (VAS) decompresses the fetal urinary tract into the amniotic cavity. These shunts are typically valveless and have a double-coiled or double basket design.17 Unfortunately, the shunts can malfunction or migrate in up to 60% of cases.20 A 2015 meta-analysis determined an improved survival rate (p < 0.01) with VAS placement (57%) versus conservative care (39%).21 A second intervention is fetal cystoscopy, with laser ablation of posterior urethral valves. Fetal cystoscopy has the advantage of direct visualization and correction of the lesion. However, it can be technically challenging and is not always successful. A 2020 meta-analysis examined the efficacy of fetal interventions for LUTO. Findings included overall six-month survival being higher in fetuses treated with either VAS or cystoscopy compared to no in utero intervention.22 Additionally, improvement in early renal function was seen in fetuses treated in utero with VAS or fetal cystoscopy. Complications from these procedures include fetal trauma

or abdominal wall injury, amnioperitoneal fluid leak, PPROM, infection, and preterm labor and delivery.

Congenital Diaphragmatic Hernia Congenital diaphragmatic hernia (CDH) results from incomplete closure of the diaphragm in the first trimester of gestation and affects approximately one in 3000 live births. Abdominal contents herniate through the defect, restricting lung development and causing a mediastinal shift, pulmonary hypoplasia, pulmonary hypertension, and pulmonary insufficiency.23 Though neonatal outcomes have improved at specialized centers, fetuses with a low (less than 25%) observed-to-expected lung-to-head ratios (O/E LHR) and/or a herniated liver are at risk for severe morbidity and mortality.24 Fetal endoscopic tracheal occlusion (FETO) improves lung development and function. During a FETO procedure, a tiny detachable balloon is placed percutaneously under fetoscopic and US guidance into the fetal trachea (Figure 28.2). By plugging the trachea and preventing the normal egress of fetal pulmonary fluid, lung growth and development can occur.25 Before delivery, a second percutaneous procedure removes the balloon, allowing a vaginal delivery. A multi-institutional randomized trial recently established the current efficacy of this procedure in babies with O/E LHR 2L of IV fluids. Excess fluids combined with nitroglycerin and/or magnesium may cause pulmonary edema.77 Volatile anesthetic agents are titrated for uterine relaxation. In the rare instances where there is a contraindication to volatile anesthetic agents (e.g., malignant hyperthermia), one can achieve uterine relaxation with nitroglycerin (up to 20 µg/kg/min).78 Throughout the case, every effort should be made to maintain maternal hemodynamics (BP and HR) within 10% of their preinduction baseline values in order to maximize uterine and placental perfusion. Prophylactic use of a maternal phenylephrine infusion with additional ephedrine and glycopyrrolate is often required. In addition, maintain uterine displacement throughout the case if possible. Intraoperative FHR monitoring is critical to acutely determining fetal distress. Intermittent fetal echocardiography assesses not only FHR, but also ventricular function, and ductal patency. During open fetal surgery, moderate to severe ventricular dysfunction commonly occurs.79 Additionally, maternal indomethacin and volatile anesthetic agents may contribute to the abnormal ductus arteriosus flow and constriction occasionally observed during open fetal procedures.80 One can use umbilical artery Doppler to monitor for absent or reversed end-diastolic flow as a potential indication of inadequate uteroplacental or fetal perfusion.81 These advanced fetal monitoring

techniques not only alert the perioperative team to acute fetal distress but also allow a better understanding of expected physiologic and hemodynamic changes during specific parts of each type of case. Once verification of uterine relaxation and US confirmation of the placental location have occurred, the surgeon creates a small hysterotomy away from the fetus and placenta. Before fetal incision, administer an opioid to the fetus intramuscularly using either transuterine US guidance prior to hysterotomy or under direct vision following uterine hysterotomy. Using a stapling devise, the surgeon places absorbable lactomer staples to extend the initial hysterotomy and seal the amniotic membranes to the endometrium. At this time, uterine blood loss can be significant and difficult to quantify, especially in the case of a stapler misfire.57 Once the hysterotomy is complete, the surgeon carefully positions the fetus to expose the operative site. Amniotic fluid is replaced with warmed crystalloid irrigation to assist with positioning and prevent umbilical cord compression or kinking. As the fetus cannot thermoregulate, careful attention to fetal temperature is required as hypothermia may increase fetal systemic resistance and bradycardia. If planning resection of a fetal mass (e.g., cases of CPAM or SCT), establish fetal IV access for resuscitation and volume replacement prior to surgical resection. A plan for emergent delivery should be in place should prolonged fetal bradycardia occur. Preterm labor and delivery pose a significant challenge following open fetal procedures.57 Typically, magnesium sulfate is used for tocolysis, with a bolus dose of 4–6 grams, followed by an infusion of 1–2 grams/hour. Some fetal centers administer magnesium at the beginning of the procedure, while others wait until uterine closure or near the end of the case.82,83 During surgical closure, the epidural catheter is activated following a negative test dose as volatile anesthetic doses are decreasing. At the conclusion of surgery, the mother is extubated once fully awake. The epidural catheter provides postoperative maternal analgesia. Uterine activity and FHR are frequently monitored in the first postoperative days as ongoing tocolysis is frequently necessary. Valuable Clinical Insights • Open fetal procedures are typically performed under GA. • Uterine relaxation is paramount to optimize fetal perfusion and prevent uterine contraction and placental abruption. • During open fetal procedures, the risk of maternal hemorrhage is significant due to the high uterine blood flow and profound uterine relaxation. • Adequate IV access, careful maternal monitoring, and readily available maternal blood are essential. • Fetal instability is a risk during fetal intervention. P ­ eriodic intraoperative fetal assessment should be performed to assure fetal wellbeing. • Prior to the start of open fetal procedures, fetal resuscitation medications are typically prepared in unit doses. • If the fetus is considered viable, have a plan in place for emergent delivery. • Preterm rupture of membranes and preterm labor following open fetal procedures remain a significant cause of morbidity.

463 https://doi.org/10.1017/9781009070256.029 Published online by Cambridge University Press

Marla B. Ferschl and Mark D. Rollins

The Ex-Utero Intrapartum Treatment Procedure The ex-utero intrapartum treatment (EXIT) procedure involves partial delivery of the fetus while maintaining placental circulatory support by delaying placental separation. The procedure allows for controlled stabilization of the fetus while maintaining adequate oxygenation and perfusion. Originally designed to safely remove the tracheal occlusive device used for the fetal treatment of CDH, there now are more indications for the EXIT procedure (Table 28.4). Its most common use is to establish a definitive airway before delivery in cases where large fetal neck masses or airway lesions may make airway management difficult (Figure 28.5). Other uses of the EXIT procedure include intrathoracic mass excision or as a transition to extracorporeal membrane oxygenation (ECMO), allowing continued oxygenation during these challenging and potentially morbid procedures.84 Similar to open fetal procedures, the EXIT procedure requires profound uterine relaxation until fetal delivery. These procedures require significant multidisciplinary planning and coordination, and immediate availability of maternal, fetal, and neonatal resuscitation supplies. A sterile breathing circuit is required to confirm ventilation before delivery and discontinuation of placental circulation. A sterile pulse oximeter probe is frequently placed on the fetal hand during the procedure to monitor FHR and oxygen saturation.49 Usually, these patients receive GA with high-dose volatile agent for uterine relaxation and placement of an epidural catheter for postoperative analgesia.85 If necessary, nitroglycerin can supplement uterine ­relaxation with bolus doses (100–400 µg) or via infusion (1–10 µg/kg/minute). Similar to open fetal procedures, fetal intramuscular administration of opioids and muscle relaxants is required to optimize surgical or procedural conditions. In some cases

where postnatal spontaneous ventilation is desirable, supplementation of volatile anesthetic with IV remifentanil (0.3 µg/ kg/minute) can provide fetal analgesia and obviate the need for fetal muscle relaxation.86 The anesthesia team should prepare for possible maternal blood loss, and maintain maternal hemodynamics near baseline. The EXIT procedure length can vary depending on the indication, but typical anesthetic regimens can provide successful conditions for several hours.87 Following the delivery of the fetus, uterine relaxation is no longer required, so rapid reversal with oxytocin is required, and if necessary, administration of additional uterotonic agents. To prevent uterine atony, decrease volatile anesthetic agents to