Protocols for High-Risk Pregnancies: An Evidence-Based Approach [7 ed.] 1119635268, 2020024021, 2020024022, 9781119635260, 9781119635284, 9781119635291, 9781119635307

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Protocols for High‐Risk Pregnancies An Evidence‐Based Approach

Protocols for High‐Risk Pregnancies An Evidence‐Based Approach SEVENTH EDITION EDITED BY

John T. Queenan, MD Professor and Chair Emeritus Department of Obstetrics and Gynecology Georgetown University School of Medicine Washington, DC, USA

Catherine Y. Spong, MD Professor and Vice Chair Department of Obstetrics and Gynecology Chief, Division of Maternal-Fetal Medicine Gillette Professorship of Obstetrics and Gynecology University of Texas Southwestern Medical Center, Dallas, TX, USA

Charles J. Lockwood, MD, MHCM Senior Vice President, USF Health Dean of the Morsani College of Medicine Professor of Obstetrics and Gynecology, and Public Health University of South Florida, Tampa, FL, USA

This edition first published 2021 © 2021 John Wiley & Sons Ltd. Edition History John Wiley & Sons, Ltd (6e, 2015) All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, except as permitted by law. Advice on how to obtain permission to reuse material from this title is available at http://www.wiley.com/go/permissions. The right of John T. Queenan, Catherine Y. Spong and Charles J. Lockwood to be identified as the author(s) of the editorial material in this work has been asserted in accordance with law. Registered Office(s) John Wiley & Sons, Inc., 111 River Street, Hoboken, NJ 07030, USA John Wiley & Sons Ltd, The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, UK Editorial Office 9600 Garsington Road, Oxford, OX4 2DQ, UK For details of our global editorial offices, customer services, and more information about Wiley products visit us at www.wiley.com. Wiley also publishes its books in a variety of electronic formats and by print‐on‐demand. Some content that appears in standard print versions of this book may not be available in other formats. Limit of Liability/Disclaimer of Warranty The contents of this work are intended to further general scientific research, understanding, and discussion only and are not intended and should not be relied upon as recommending or promoting scientific method, diagnosis, or treatment by physicians for any particular patient. In view of ongoing research, equipment modifications, changes in governmental regulations, and the constant flow of information relating to the use of medicines, equipment, and devices, the reader is urged to review and evaluate the information provided in the package insert or instructions for each medicine, equipment, or device for, among other things, any changes in the instructions or indication of usage and for added warnings and precautions. While the publisher and authors have used their best efforts in preparing this work, they make no representations or warranties with respect to the accuracy or completeness of the contents of this work and specifically disclaim all warranties, including without limitation any implied warranties of merchantability or fitness for a particular purpose. No warranty may be created or extended by sales representatives, written sales materials or promotional statements for this work. The fact that an organization, website, or product is referred to in this work as a citation and/or potential source of further information does not mean that the publisher and authors endorse the information or services the organization, website, or product may provide or recommendations it may make. This work is sold with the understanding that the publisher is not engaged in rendering professional services. The advice and strategies contained herein may not be suitable for your situation. You should consult with a specialist where appropriate. Further, readers should be aware that websites listed in this work may have changed or disappeared between when this work was written and when it is read. Neither the publisher nor authors shall be liable for any loss of profit or any other commercial damages, including but not limited to special, incidental, consequential, or other damages. Library of Congress Cataloging‐in‐Publication Data Names: Queenan, John T., editor. | Spong, Catherine Y., editor. | Lockwood, Charles J., editor. Title: Protocols for high-risk pregnancies : an evidence-based approach / edited by John T. Queenan, Catherine Y. Spong, Charles J. Lockwood. Description: Seventh edition. | Hoboken, NJ : Wiley-Blackwell, 2021. | Includes bibliographical references and index. Identifiers: LCCN 2020024021 (print) | LCCN 2020024022 (ebook) | ISBN 9781119635260 (paperback) | ISBN 9781119635284 (adobe pdf) | ISBN 9781119635291 (epub) Subjects: MESH: Pregnancy, High-Risk | Pregnancy Complications | Evidence-Based Medicine Classification: LCC RG571 (print) | LCC RG571 (ebook) | NLM WQ 240 | DDC 618.3–dc23 LC record available at https://lccn.loc.gov/2020024021 LC ebook record available at https://lccn.loc.gov/2020024022 Cover Design: Wiley Cover Image: © Universal Images Group North America LLC/Alamy Stock Photo Set in 9.5/13pt Meridien by SPi Global, Pondicherry, India 10 9 8 7 6 5 4 3 2 1

Contents

Preface, ix List of Contributors, xi

Part 1  Concerns in Pregnancy 1 Alcohol Use in Pregnancy and Lactation, 3 Ruta M. Nonacs 2 Smoking, Vaping, and Nicotine Exposure, 9 John Byrne and George Saade 3 Opioid Use, Misuse, and Addiction in Pregnancy and Postpartum, 15 Mishka Terplan 4 Depression, 21 Kimberly Yonkers

Part 2  Antenatal Testing 5 Prenatal Testing for Chromosomal Abnormalities, 29 Mary E. Norton 6 Fetal Echocardiography, 41 Joshua A. Copel 7 Clinical Use of Doppler, 49 Henry L. Galan 8 Antepartum Testing, 61 Michael P. Nageotte 9 Fetal Blood Sampling and Transfusion, 69 Patricia Santiago‐Munoz 10 Preconception Genetic Screening, 77 Lauren Sayres and Jeffrey A. Kuller

Part 3  Maternal Disease 11 Maternal Anemia, 89 Elaine Duryea

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12 Hemoglobinopathies in Pregnancy, 97 Bradley Sipe and Judette Louis 13 Fetal and Neonatal Alloimmune Thrombocytopenia, 105 Russell Miller and Richard Berkowitz 14 Rheumatological Disorders, 113 Lisa R. Sammaritano and Bonnie L. Bermas 15 Antiphospholipid Syndrome, 125 Robert M. Silver 16 Inherited Thrombophilias, 131 Andra H. James and Jerome J. Federspiel 17 Valvular Heart Disease in Pregnancy, 141 Blake Zwerling and Afshan B. Hameed 18 Peripartum Cardiomyopathy, 165 Sarah Rae Easter and Carolyn M. Zelop 19 Thromboembolism, 181 Michael J. Paidas 20 Renal Disease, 201 Shivani Patel 21 Obesity, 209 Patrick S. Ramsey 22 Diabetes Mellitus, 219 Mark B. Landon and Steven G. Gabbe 23 Thyroid Disorders, 231 Elizabeth O. Buschur and Stephen F. Thung 24 Hepatitis in Pregnancy, 241 Andrew Myers, Asa Oxner, John Sinnott, and Christian Brechot 25 Asthma, 253 Michael Schatz 26 Epilepsy, 263 Thomas McElrath 27 Chronic Hypertension, 273 Michal Fishel Bartal and Baha M. Sibai 28 Cytomegalovirus, Genital Herpes, Rubella, and  Toxoplasmosis, 285 Kerry E. Drury and Brenna L. Hughes 29 Syphilis, 293 Emily H. Adhikari 30 Vector‐Borne Diseases in Pregnancy: Zika, West Nile, and Chagas Disease, 301 Karin Nielsen‐Saines and Tara Kerin

Contents  vii 31 Influenza, 317 Amanda C. Zofkie and Vanessa Rogers 32 Malaria, 323 Blair J. Wylie 33 Human Immunodeficiency Virus Infection, 333 Emily H. Adhikari 34 Parvovirus B19, 343 Kathy C. Matthews, Emilie L. Vander Haar, and Laura E. Riley 35 Group B Streptococcus, 351 Caitlin A. MacGregor, and Mara J. Dinsmoor, 36 Biliary, Liver, and Pancreatic Disease, 361 Vic Velanovich, Elizabeth Hoover, and Stephanie Ros

Part 4  Obstetric Problems 37 Cervical Insufficiency, 375 Rupsa C. Boelig and Vincenzo Berghella 38 Nausea and Vomiting, 387 Jared T. Roeckner and Haywood L. Brown 39 Fetal Death and Stillbirth, 397 Alexander M. Saucedo and Robert M. Silver 40 Abnormal Amniotic Fluid Volume, 407 Christina M. Ackerman, Thomas R. Moore, and Heather S. Lipkind 41 Fetal Growth Restriction, 421 Jodi S. Dashe and Anne M. Ambía 42 Rh and Other Blood Group Alloimmunizations, 431 Kenneth J. Moise Jr 43 Preterm Labor, 443 Hyagriv N. Simhan 44 Prevention of Preterm Birth, 449 Anna King and Sarah J.E. Stock 45 Premature Rupture of the Membranes, 461 Brian M. Mercer 46 Indicated Late‐Preterm and Early‐Term Deliveries, 475 Catherine Y. Spong 47 Chorioamnionitis, 481 Catalin S. Buhimschi and Irina A. Buhimschi 48 Third‐Trimester Bleeding, 493 Ilina D. Pluym and Christina S. Han, 49 Amniotic Fluid Embolism, 507 Irene A. Stafford and Michael A. Belfort

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50 Preeclampsia, 517 Michal Fishel Bartal and Baha M. Sibai

Part 5  Labor and Delivery 51 Elective Induction of Labor, 531 Rachel G. Sinkey 52 Electronic Fetal Heart Rate Monitoring, 539 David A. Miller 53 Breech Delivery, 555 G. Justus Hofmeyr, and Mercy‐Nkuba Nassali 54 Vaginal Birth After Cesarean, 563 James R. Scott 55 Placenta Accreta Spectrum, 571 Robert M. Silver and Deirdre J. Lyell 56 Shoulder Dystocia, 581 George A. Macones and Robert B. Gherman 57 Twins, Triplets, and Beyond, 587 Mary E. D’Alton 58 Postpartum Hemorrhage, 601 David B. Nelson Appendix A: Evaluation of Fetal Health and Defects, 613 Lynn L. Simpson Index, 629

Preface

The current acceleration in medical discoveries parallels Moore’s law for ­computer chips. In the 1950s, medical knowledge doubled every 50 years, by the 1980s it doubled every seven years, and now medical knowledge is estimated to double about every two months (Densen 2011). How can busy obstetricians keep pace? Through seven editions, Protocols for High‐Risk Pregnancies has helped address this exact challenge. Providing just‐in‐time content, its focus on protocols and guidelines helps organize medical thinking, avoid heuristic errors of omission and commission, and optimize maternal and fetal outcomes. As with the prior six editions, we have once again assembled some of the world’s top obstetrical and medical experts. Concomitantly, the seventh ­edition adds a number of new features including protocols on opioid use, misuse and addiction in pregnancy and postpartum, noninvasive prenatal diagnosis of aneuploidy, periconceptional genetic screening, and expanded protocols on maternal valvular heart disease and cardiomyopathies; we have also added protocols on arboviruses including Zika, and malaria, to reflect new technologies, changing clinical disease patterns, and emerging global pathogens. As in prior editions, our focus has been on conducting a comprehensive survey of recent relevant literature to extract the most current evidence‐ based practices and then presenting them with concise, focused text and crystal‐clear clinical paradigms. In areas where there are reasonable clinical alternatives, where no single compelling randomized clinical trial or a clear metaanalytical preference is available, we have again asked the authors to use their best judgment to make recommendations. We are deeply indebted to our common mentor, Dr John T. Queenan, who conceived of this text to help “clinicians in the trenches” and hope we have been faithful to his vision. We also appreciate the help of our editorial team at John Wiley & Sons, Deirdre Barry and Anupama Sreekanth. Catherine Y. Spong, MD Charles J. Lockwood, MD, MHCM

Reference Densen P. Challenges and opportunities facing medical education. Trans Am Clin Climatol Assoc 2011;122:48–58.

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List of Contributors

Christina M. Ackerman

Rupsa C. Boelig

Department of Obstetrics, Gynecology, and Reproductive Sciences, Division of Maternal Fetal Medicine, Yale School of Medicine, New Haven, CT, USA

Department of Obstetrics and Gynecology, Division of Maternal‐Fetal Medicine, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USA

Emily H. Adhikari

Christian Brechot

Department of Obstetrics and Gynecology, Division of Maternal‐Fetal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA

Department of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, USA

Haywood L. Brown Anne M. Ambía Department of Obstetrics and Gynecology, Division of Maternal‐Fetal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA

Michal Fishel Bartal Department of Obstetrics and Gynecology and Reproductive Sciences, The University of Texas Medical School at Houston, Houston, TX, USA

Michael A. Belfort Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, TX, USA

Department of Obstetrics and Gynecology, University of South Florida, Tampa, FL, USA

Catalin S. Buhimschi Department of Obstetrics and Gynecology, University of Illinois College of Medicine at Chicago, Chicago, IL, USA

Irina A. Buhimschi Department of Obstetrics and Gynecology, University of Illinois College of Medicine at Chicago, Chicago, IL, USA

Elizabeth O. Buschur Vincenzo Berghella Department of Obstetrics and Gynecology, Division of Maternal‐Fetal Medicine, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USA

Department of Internal Medicine, Division of Endocrinology, Metabolism, and Diabetes, The Ohio State University Wexner Medical Center, Columbus, OH, USA

John Byrne Richard Berkowitz Department of Obstetrics and Gynecology, Columbia University Medical Center, New York, USA

Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, TX, USA

Joshua A. Copel Bonnie L. Bermas Division of Rheumatic Diseases, University of Texas, Southwestern Medical Center, Dallas, TX, USA

Departments of Obstetrics, Gynecology and Reproductive Sciences, and Pediatrics, Yale School of Medicine, New Haven, CT, USA

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List of Contributors

Mary E. D’Alton

Robert B. Gherman

Department of Obstetrics and Gynecology, Columbia University College of Physicians and Surgeons, New York Presbyterian Hospital, New York, USA

Division of Maternal Fetal Medicine, WellSpan Health System, York, PA, USA

Jodi S. Dashe Department of Obstetrics and Gynecology, Division of Maternal‐Fetal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA

Mara J. Dinsmoor Department of Obstetrics and Gynecology, NorthShore University Health System, Evanston, IL, USA Department of Obstetrics and Gynecology, Pritzker School of Medicine, University of Chicago, Chicago, IL, USA

Kerry E. Drury Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC, USA

Afshan B. Hameed Division of Obstetrics and Gynecology, Irvine School of Medicine, University of California, Irvine, CA, USA

Christina S. Han Department of Obstetrics and Gynecology, Division of Maternal‐Fetal Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA Center for Fetal Medicine and Women’s Ultrasound, Los Angeles, CA, USA

G. Justus Hofmeyr Effective Care Research Unit, Universities of the Witwatersrand and Fort Hare, Bhisho, South Africa Department of Obstetrics and Gynecology, University of Botswana, Gaborone, Botswana

Elizabeth Hoover Elaine Duryea Maternal Fetal Medicine, Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, TX, USA

Department of Obstetrics and Gynecology, Morsani College of Medicine, University of South Florida, Tampa, FL, USA

Brenna L. Hughes Sarah Rae Easter Departments of Obstetrics and Gynecology, and Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

Jerome J. Federspiel Department of Obstetrics and Gynecology, Division of Maternal‐Fetal Medicine, Duke University Medical Center, Durham, NC, USA

Steven G. Gabbe Department of Obstetrics and Gynecology, The Ohio State University Wexner Medical Center, Columbus, OH, USA Department of Obstetrics and Gynecology, The Ohio State University College of Medicine, Columbus, OH, USA

Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC, USA

Andra H. James Department of Obstetrics and Gynecology, Division of Maternal‐Fetal Medicine, Duke University Medical Center, Durham, NC, USA

Tara Kerin Department of Pediatrics, David Geffen School of Medicine at UCLA/UCLA Mattel Children’s Hospital, Los Angeles, CA, USA

Anna King Department of Obstetrics and Gynaecology, Royal Infirmary of Edinburgh, Edinburgh, Scotland, UK

Henry L. Galan

Jeffrey A. Kuller

Department of Obstetrics and Gynecology, Division of Maternal‐Fetal Medicine, University of Colorado School of Medicine, Colorado Fetal Care Center, Aurora, CO, USA

Department of Obstetrics and Gynecology, Division of Maternal‐Fetal Medicine, Duke University School of Medicine, Durham, NC, USA

List of Contributors  xiii Mark B. Landon

Russell Miller

Department of Obstetrics and Gynecology, The Ohio State University College of Medicine, Columbus, OH, USA

Department of Obstetrics and Gynecology, Columbia University Medical Center, New York, USA

Heather S. Lipkind

Kenneth J. Moise Jr

Department of Obstetrics, Gynecology, and Reproductive Sciences, Division of Maternal Fetal Medicine, Yale School of Medicine, New Haven, CT, USA

Departments of Obstetrics, Gynecology and Reproductive Sciences, and Pediatric Surgery, McGovern School of Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA

Judette Louis Department of Obstetrics and Gynecology, Morsani College of Medicine, University of South Florida, Tampa, FL, USA

Deirdre J. Lyell Department of Obstetrics and Gynecology, Division of Maternal‐Fetal Medicine, Stanford University Medical Center, Stanford, CA, USA

Caitlin A. MacGregor Department of Obstetrics and Gynecology, NorthShore University Health System, Evanston, IL, USA Department of Obstetrics and Gynecology, Pritzker School of Medicine, University of Chicago, Chicago, IL, USA

Thomas R. Moore Department of Obstetrics, Gynecology and Reproductive Sciences, Division of Perinatal Medicine, University of California San Diego, San Diego, CA, USA

Andrew Myers Department of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, USA

Michael P. Nageotte Miller Children’s and Women’s Hospital, Long Beach, CA, USA Department of Obstetrics and Gynecology, University of California, Irvine, CA, USA

George A. Macones Division of Maternal Fetal Medicine, Dell Medical School‐University of Texas at Austin, Austin, TX, USA

Mercy‐Nkuba Nassali Department of Obstetrics and Gynecology, University of Botswana, Gaborone, Botswana

Kathy C. Matthews New York Presbyterian–Weill Cornell Medicine, New York, USA

Thomas McElrath Division of Maternal‐Fetal Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

Brian M. Mercer Department of Obstetrics and Gynecology, Case Western University–MetroHealth Medical Center, Cleveland, OH, USA

David B. Nelson Department of Maternal‐Fetal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA

Karin Nielsen‐Saines Department of Pediatrics, David Geffen School of Medicine at UCLA/UCLA Mattel Children’s Hospital, Los Angeles, CA, USA

Ruta M. Nonacs Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA

David A. Miller Department of Obstetrics, Gynecology and Pediatrics, Keck School of Medicine, University of Southern California, Children’s Hospital Los Angeles, Los Angeles, CA, USA

Mary E. Norton Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Francisco, CA, USA

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List of Contributors

Asa Oxner

Patricia Santiago‐Munoz

Department of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, USA

Department of Obstetrics and Gynecology, Division of Maternal‐Fetal Medicine, University of Texas Medical Center, Dallas, TX, USA

Michael J. Paidas

Alexander M. Saucedo

Department of Obstetrics, Gynecology and Reproductive Sciences, Miller School of Medicine, University of Miami, Miami, FL, USA

Department of Obstetrics and Gynecology, Division of Maternal‐Fetal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA

Shivani Patel Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, TX, USA

Lauren Sayres

Ilina D. Pluym

Michael Schatz

Department of Obstetrics and Gynecology, Division of Maternal‐Fetal Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA

Patrick S. Ramsey Department of Obstetrics and Gynecology, Center for Pregnancy and Newborn Research, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA

Laura E. Riley Department of Clinical Obstetrics and Gynecology, Weill Cornell Medicine, New York, USA

Jared T. Roeckner Department of Obstetrics and Gynecology, University of South Florida, Tampa, FL, USA

Vanessa Rogers Department of Obstetrics and Gynecology, Division of Maternal‐Fetal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA

Division of Maternal Fetal Medicine, University of Colorado, Aurora, CO, USA

Department of Allergy, Kaiser Permanente Medical Center, San Diego, CA, USA Department of Medicine, University of California San Diego School of Medicine, San Diego, CA, USA

James R. Scott Department of Obstetrics and Gynecology, University of Iowa Carver College of Medicine, Iowa City, IA, USA

Baha M. Sibai Department of Obstetrics and Gynecology and Reproductive Sciences, The University of Texas Medical School at Houston, Houston, TX, USA

Robert M. Silver Department of Obstetrics and Gynecology, Division of Maternal‐Fetal Medicine, University of Utah Health Sciences Center, Salt Lake City, UT, USA

Hyagriv N. Simhan

Department of Obstetrics and Gynecology, Morsani College of Medicine, University of South Florida, Tampla, FL, USA

Department of Obstetrics and Gynecology, Division of Maternal‐Fetal Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

George Saade

Lynn L. Simpson

Department of Obstetrics and Gynecology, Division of Maternal Fetal Medicine, University of Texas Medical Branch, Galveston, TX, USA

Department of Obstetrics and Gynecology, Columbia University Irving Medical Center, New York, USA

Lisa R. Sammaritano

Department of Obstetrics and Gynecology, Division of Maternal‐Fetal Medicine, University of Alabama at Birmingham, Birmingham, AL, USA

Stephanie Ros

Division of Rheumatology, Hospital for Special Surgery – Weill Cornell Medicine, New York, NY, USA

Rachel G. Sinkey

List of Contributors  xv John Sinnott

Emilie L. Vander Haar

Department of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, USA

New York Presbyterian–Weill Cornell Medicine, New York, USA

Vic Velanovich Bradley Sipe Department of Obstetrics and Gynecology, Morsani College of Medicine, University of South Florida, Tampa, FL, USA

Department of Surgery, Morsani College of Medicine, University of South Florida, Tampa, FL, USA

Blair J. Wylie Catherine Y. Spong Department of Obstetrics and Gynecology, Division of Maternal‐Fetal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA

Department of Obstetrics and Gynecology, Division of Maternal‐Fetal Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

Kimberly Yonkers Irene A. Stafford Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, TX, USA

Departments of Psychiatry, Obstetrics, Gynecology and Reproductive Sciences and School of Public Health, Yale University School of Medicine, New Haven, CT, USA

Sarah J.E. Stock

Carolyn M. Zelop

Department of Maternal and Fetal Medicine, Usher Institute, University of Edinburgh, Edinburgh, Scotland, UK

Department of Obstetrics and Gynecology, NYU School of Medicine, New York, USA

Amanda C. Zofkie Mishka Terplan Friends Research Institute, Adjunct Faculty, Clinical Consultation Center, University of California, San Francisco, CA, USA

Department of Obstetrics and Gynecology, Division of Maternal‐Fetal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA

Stephen F. Thung

Blake Zwerling

Department of Obstetrics and Gynecology, The Ohio State University College of Medicine, Columbus, OH, USA

Division of Obstetrics and Gynecology, Irvine School of Medicine, University of California, Irvine, CA, USA

PA R T 1

Concerns in Pregnancy

PROTOCOL 1

Alcohol Use in Pregnancy and Lactation Ruta M. Nonacs Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA

Overview According to data collected in the 2015–2017 Behavioral Risk Factor Surveillance System conducted by the Centers for Disease Control and Prevention (CDC), 11.5% of pregnant women in the United States reported consuming at least one alcoholic drink during the past 30 days, and 3.9% reported binge drinking (five or more drinks during one episode). Among pregnant women who reported binge drinking, the average frequency of binge drinking was 4.5 episodes during the past 30 days. The highest ­prevalence of alcohol use during pregnancy was observed in older (ages 35–44 years), college educated, and unmarried women. According to the same surveillance, the prevalence of any alcohol use was 53.6% among nonpregnant reproductive age women, indicating that pregnancy may be a time of increased motivation to decrease or stop drinking. Even among women with heavy alcohol use or patterns of use consistent with alcohol use disorder, 70–90% abstain from a­lcohol during pregnancy. Although many women achieve abstinence during pregnancy, studies have noted high rates of relapse during the postpartum period.

Alcohol use during pregnancy Alcohol use during pregnancy has been associated with an increased risk of fetal death in some, but not all, studies. For example, an increased risk of ­miscarriage was reported in women who consumed more than three drinks per week (adjusted odds ratio 2.3; 95% confidence interval [CI] 1.1–4.5), compared to women who reported no alcohol consumption. In a Danish study of nearly 90 000 pregnant women, a higher risk of fetal death after

Protocols for High-Risk Pregnancies: An Evidence-Based Approach, Seventh Edition. Edited by John T. Queenan, Catherine Y. Spong and Charles J. Lockwood. © 2021 John Wiley & Sons Ltd. Published 2021 by John Wiley & Sons Ltd.

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Protocol 1

22  weeks’ gestation (adjusted hazard ratio 2.20; 95% CI 1.73–2.80) was observed in pregnant women who reported either three or more drinks per week or two or more binge‐drinking episodes, compared to women who did not drink. Alcohol exposure during pregnancy also increases the risk of low birthweight and extreme preterm birth (10: Give buprenorphine/naloxone 4/1 mg 3 Repeat COWS in 1–2 hours and repeat administration of buprenorphine as above 4 Typical day 1 dose = 6–8 mg Day 2: 1 Administer COWS and total day 1 buprenorphine 2 Repeat COWS in 1–2 hours and administer additional buprenorphine as above 3 Typical day 2 dose = 8–16 mg Source: Based on Wesson DR, Ling W. The Clinical Opiate Withdrawal Scale (COWS). J Psychoactive Drugs 2003;35(2):253–9.

Opioid Use, Misuse, and Addiction in Pregnancy and Postpartum  19 opioid while receiving medication for opioid addiction, then a dose increase may be indicated. Medication for opioid addiction works. Recurrence rates for treated addiction are similar to other chronic conditions such as hypertension. Furthermore, much of the obstetric burden from substance use is from untreated rather than treated addiction. People with treated addiction have birth outcomes that are more like those without addiction than those with untreated disease.

Labor and delivery Upon presentation to labor and delivery units, medication for opioid use disorder should be continued. People with opioid addiction may have greater analgesic needs due to both tolerance and prior negative experiences with the healthcare system. Analgesia should be multimodal. People with addiction often experience discrimination from friends and family as well as from providers. It is therefore essential that all staff treat pregnant and parenting people with opioid addiction with dignity and respect.

Postpartum Neonatal abstinence syndrome is an expected and treatable outcome of in utero opioid exposure. Opioids are an essential but insufficient cause of NAS in part because maternal medication dose is not related to likelihood of developing NAS. Risk and protective factors for NAS are listed in Table 3.3. Postpartum, or the fourth trimester, is a period of increased vulnerability to addiction recurrence, compounded by insurance churn, noncontinuation of medication, maternal mood changes, and withdrawal of care from Table 3.3  Risks and protective factors for neonatal abstinence syndrome (NAS) Factors which increase likelihood, severity, and duration of NAS

Factors that decrease likelihood, severity, and duration of NAS

Maternal medications Gabapentin Benzodiazepines Selective serotonin reuptake inhibitors Maternal smoking Fetal methylation of the mu‐opioid receptor Neonatal intensive care unit admission

Smoking cessation Rooming‐in Breastfeeding Skin‐to‐skin contact Preservation of the maternal–infant dyad

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Protocol 3

prenatal care providers following delivery. For reasons that are unknown, people with opioid use disorder have almost four times the odds of death during the delivery hospitalization and overdose is one of the leading causes of maternal mortality in the US today.

Conclusion Although there has been an increase in the availability of addiction treatment in the past decade, there remains a large unmet treatment need, with only 30–70% of pregnant women with opioid addiction reporting any treatment during pregnancy. Universal assessment during prenatal care with early medication initiation with either methadone or buprenorphine are recommended. In general, women do well during pregnancy, but disease recurrence is common postpartum. Therefore, continuing care ­ postpartum is essential. Providers need to be sensitive to the discrimination that pregnant and parenting people with opioid addiction face.

Suggested reading Haight SC, Ko JY, Tong VT, Bohm MK, Callaghan WM. Opioid use disorder documented at delivery hospitalization – United States, 1999–2014. MMWR 2018;67:845–9. Kotelchuck M, Cheng ER, Belanoff C, et al. The prevalence and impact of substance use disorder and treatment on maternal obstetric experiences and birth outcomes among singleton deliveries in Massachusetts. Matern Child Health J 2017;21(4):893–902. Ondersma SJ, Chang G, Blake‐Lamb T, et  al. Accuracy of five self‐report screening instruments for substance use in pregnancy. Addiction 2019;114(9):1683–93. Schiff DM, Nielsen T, Terplan M, et al. Fatal and nonfatal overdose among pregnant and postpartum women in Massachusetts. Obstet Gynecol 2018;132(2):466–74. Substance Abuse and Mental Health Services Administration. Clinical Guidance for Treating Pregnant and Parenting Women With Opioid Use Disorder and Their Infants. HHS Publication No. (SMA) 18‐5054. Rockville, MD: Substance Abuse and Mental Health Services Administration, 2018. Terplan M. Women and the opioid crisis: historical context and public health solutions. Fertil Steril 2017;108(2):195–9. Terplan M, Kennedy‐Hendricks A, Chisolm MS. Prenatal substance use: exploring assumptions of maternal unfitness. Subst Abuse 2015;9(Suppl 2):1–4. Vowles KE, McEntee ML, Julnes PS, Frohe T, Ney JP, van der Goes DN. Rates of opioid misuse, abuse, and addiction in chronic pain: a systematic review and data synthesis. Pain 2015;156(4):569–76. Wachman EM, Hayes MJ, Lester BM, Terrin N, Brown MS, Davis JM. Epigenetic variation in the mu‐opioid receptor gene in infants with neonatal abstinence syndrome. J Pediatr 2014;165(3):472–8.

PROTOCOL 4

Depression Kimberly Yonkers Departments of Psychiatry, Obstetrics, Gynecology and Reproductive Sciences and School of Public Health, Yale University School of Medicine, New Haven, CT, USA

Clinical significance Approximately 20% of women suffer from a depressive disorder at some point in their lives. The risk of being depressed is greatest for women during their reproductive years and thus clinicians may encounter a pregnant woman with preexisting depression or a woman who becomes depressed during her pregnancy. The potentially devastating toll that a major depressive episode (MDE) has on a mother and the relatively low risk associated with treatment underscore the need to treat depressed pregnant women. Some women may experience improvement or remission with evidence‐ based psychotherapy. However, some women may require pharmacotherapy. This may lead to additional concerns because the antidepressants and anxiolytics, that are often used concurrently, are linked to adverse perinatal and fetal outcomes. Researchers note an increased risk of fetal malformations although the magnitude of this risk is small and largely centered on atrial and ventricular septal defects. Moreover, such risks are only associated with certain antidepressants (e.g., paroxetine). Other worrisome associations include delivery of an infant who is preterm or small for gestational age, as well as a very small increased likelihood of persistent pulmonary hypertension. The evidence for a number of these outcomes among women treated with antidepressants in pregnancy is mixed, with the strongest support for an increased risk of preterm birth. However, even the smallest risk can lead to apprehension on the part of patients and uneasiness for their prescribing physicians.

Pathophysiology As with many psychiatric disorders, the pathophysiology of a depressive disorder is unknown, although evidence suggests that underlying risk is determined by biology (e.g., genetic factors), stress, and trauma. Co‐occurring Protocols for High-Risk Pregnancies: An Evidence-Based Approach, Seventh Edition. Edited by John T. Queenan, Catherine Y. Spong and Charles J. Lockwood. © 2021 John Wiley & Sons Ltd. Published 2021 by John Wiley & Sons Ltd.

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general medical conditions and exposure to selected medications and other substances can also lead to development of depressive symptoms or an MDE. Brain imaging studies show that individuals with depression have changes in neurocircuitry and volume reductions in critical brain areas such as anterior cingulate cortex, amygdala, and hippocampus. These regions are also affected by elevations in glucocorticoids and there are long‐standing theories that implicate dysregulation of the hypothalamic–pituitary–adrenal axis in depression. For example, the introduction of stress leads to secretion of cortisol. The integrity of the feedback systems between cortisol, adrenocorticotrophic hormone, and corticotrophin‐releasing hormone (CRH) is compromised in many individuals, with depression leading to overexpression of these hormones. Ongoing exposure to these hormones can lead to anatomic and dynamic (signaling) changes in the aforementioned brain regions.

Diagnosis There are several mood disorders that fall under the category of “depression” and they are outlined in the Diagnostic and Statistical Manual (DSM) version 5 (American Psychiatric Association 2013). The prototypic depressive disorder is an MDE. There are nine candidate symptoms of an MDE: depressed mood, diminished interest, significant weight change, insomnia or hypersomnia, psychomotor retardation or agitation, fatigue, feelings of guilt or worthlessness, decreased concentration, and recurrent thoughts of death or suicide. An affected woman should have at least five of these symptoms, including either depressed mood and/or diminished interest, most of the time for two weeks. If a woman has a history of manic/hypomanic episodes as well as MDEs, she suffers from bipolar disorder but is presenting in the depressed phase. Mania is characterized by elevated/expansive/irritable mood, increased energy, grandiosity, decreased need for sleep, pressured speech, and increased participation in goal‐related or risky activities. If she has never had manic or hypomanic episodes, and she meets the above criteria, then her diagnosis is unipolar major depressive disorder.

Management The management of a pregnant woman with an MDE will vary depending upon whether she has unipolar or bipolar illness. In either case, she may benefit from psychotherapy although she should be monitored to ensure that this treatment is sufficient for response. If she requires pharmacotherapy, she should be apprised of the risks and benefits and this should be

Depression  23 documented in her medical chart. Along with her obstetrician, it may be prudent to have her evaluated and followed concurrently by a psychiatrist. If she experiences thoughts of self‐harm or suicide, she should be evaluated by a psychiatrist or clinical psychologist as soon as possible. Women with MDE who suffer from bipolar disorder will require treatment with a mood stabilizer and an antidepressant. Valproate and carbamazepine are effective mood stabilizers but also established teratogens and should not be used early in pregnancy. Lamotrigine is FDA approved for treatment of individuals with bipolar disorder and may be useful although it must be titrated up slowly and it is specifically useful for bipolar depression and not bipolar mania. Lithium is the gold standard treatment for bipolar disorder but has been associated with fetal cardiac defects. It may be best to avoid this agent early in pregnancy, although the absolute risk of lithium is now considered to be lower than it was after publication of results from the lithium registry. The risk of a major malformation, including a major heart anomaly, is about 70% higher than in those who are not exposed to lithium although some investigations find no increased risk for malformations. Moreover, many of the malformations are very rare so increased risk is difficult to establish, even in large cohorts. First‐ and second‐generation antipsychotics (e.g., olanzapine, risperidone) have good mood‐stabilizing properties and appear to have lower teratogenic risk than anticonvulsants. If mood improves, there is no need to add an antidepressant. Women with unipolar MDE who are not sufficiently treated with psychotherapy or women with bipolar disorder who did not respond to a mood stabilizer alone will need treatment with an antidepressant. The reproductive safety profile of the older tricyclic antidepressants is no better than for the newer, serotonin or serotonin‐norepinephrine reuptake inhibitors. However, older agents have more side effects. It is reasonable to start with either a selective serotonin reuptake inhibitor or bupropion. If a woman is struggling to avoid nicotine cigarettes, use of bupropion may help treat her nicotine addiction and her depression. Given data associating paroxetine use in pregnancy with malformations of the heart, many experts recommend that this agent not be prescribed to pregnant women in the first trimester. However, if a woman presents well into her first trimester of pregnancy on a particular agent, there may be little benefit to switching to a different agent since in utero exposure has already occurred. In any case, women should be counseled to minimize use of other harmful licit and illicit substances such as cigarettes, alcohol or recreational drugs. Use of such substances is more common in women with depression and patients may not realize that cigarettes, alcohol or other drugs are as harmful, if not more problematic, than antidepressant agents.

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Follow‐up It is ideal to see a woman a week after initiation of pharmacotherapy for MDE to determine the presence and magnitude of side effects to the medication and assess further deterioration in psychiatric status. Subsequently, she can be seen again after two weeks and then monthly. Some degree of mood improvement may be noticeable within a few weeks. However, it may take 6–8 weeks to see full response to treatment. The patient should be assessed for suicidal thoughts at each visit. While some clinicians have concerns that asking about suicidal thoughts will “suggest” this action to patients, this is not the case. Appropriate emergency medical care can be arranged if the patient endorses suicidal thoughts. If the obstetrician is unable to provide follow‐up care at these intervals, the patient may be referred to a psychiatrist who can communicate with the obstetrician regarding the patient’s progress. Once response has been obtained, the patient’s mood can be reevaluated at routine obstetrics visits.

Conclusion The risk period for an episode of MDE coincides with the period of women’s fertility. While some women benefit from psychotherapy and can avoid pharmacotherapy in pregnancy, this is not always the case. Women who have underlying bipolar disorder and those with severe recurrent major depressive disorder will likely require medication management. Antipsychotic agents have a lower risk profile than anticonvulsant mood stabilizers, which should be avoided early in pregnancy. Antidepressants are not major teratogens but clinicians need to apprise patients of potential risks and benefits of treatment, including perinatal complications such as preterm birth or transient neonatal distress.

Suggested reading American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 5th edn. Washington, DC: American Psychiatric Association, 2013. Chambers C, Hernandez‐Diaz H, Marter LV, et al. Selective serotonin‐reuptake inhibitors and risk of persisitent pulmonary hypertension of the newborn. N Engl J Med 2006;354:579–87. Hermann A, Gorun A, Benudis A. Lithium use and non‐use for pregnant and postpartum women with bipolar disorder. Curr Psychiatry Rep 2019;21(11):114. Kallen B, Reis M. Neonatal complications after maternal concomitant use of SSRI and other central nervous system active drugs during the second or third trimester of pregnancy. J Clin Psychopharmacol 2012;32(5):608–14.

Depression  25 McKenna K, Koren G, Tetelbaum M, et al. Pregnancy outcome of women using atypical antipsychotic drugs: a prospective comparative study. J Clin Psychiatry 2005;66(4): 444–9; quiz 546. Ross LE, Grigoriadis S, Mamisashvili L, et al. Selected pregnancy and delivery outcomes after exposure to antidepressant medication: a systematic review and meta‐analysis. JAMA Psychiatry 2013;70(4):436–43. Yonkers K, Blackwell K, Glover J, Forray A. Antidepressant use in pregnant and postpartum women. Annu Rev Clin Psychol 2014;10:369–92. Yonkers KA, Norwitz ER, Smith MV, et al. Depression and serotonin reuptake inhibitor treatment as risk factors for preterm birth. Epidemiology 2012;23(5):677–85.

PA R T 2

Antenatal Testing

PROTOCOL 5

Prenatal Testing for Chromosomal Abnormalities Mary E. Norton Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Francisco, CA, USA

Overview Aneuploidy refers to an abnormal number of chromosomes, e.g., the presence of more or fewer than the usual diploid complement of 46. Presence of a single additional chromosome is known as trisomy and is an important cause of congenital malformations. The most common autosomal trisomies are Down syndrome (trisomy 21), Edward syndrome (trisomy 18), and Patau syndrome (trisomy 13). Sex chromosomal aneuploidies such as 47,XXY (Klinefelter syndrome) and 45,X (Turner syndrome) as well as an entire extra set of chromosomes (triploidy) can also be seen. In addition, deletions and duplications of portions of chromosomes also occur and can be associated with abnormalities such as DiGeorge syndrome, which results from a deletion on chromosome 22 (22q11.2), and Williams syndrome, which results from a deletion on chromosome 7 (7q11.23). Chromosomal microarray analysis can identify submicroscopic abnormalities that cannot be seen with conventional karyotyping, and these copy number variants can be associated with significant genetic diseases.

Pathophysiology The phenotype of trisomy 21 occurs when there is a triplication of dosage‐ sensitive genes on chromosome 21; these genes comprise the Down syndrome critical region. Nondisjunction of the chromosome 21 pair during meiosis of the germ cells accounts for 95% of cases of trisomy 21. In the vast majority of cases, the extra chromosome is maternal in origin, and there is a strong correlation between maternal age and the chances of fetal

Protocols for High-Risk Pregnancies: An Evidence-Based Approach, Seventh Edition. Edited by John T. Queenan, Catherine Y. Spong and Charles J. Lockwood. © 2021 John Wiley & Sons Ltd. Published 2021 by John Wiley & Sons Ltd.

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trisomy 21. In less than 5% of cases, the additional chromosome 21 material is a result of an unbalanced translocation, usually affecting chromosomes 14 and 21, but occasionally also involving chromosomes 15 or 22. About 50% of such cases occur as de novo translocations and 50% are inherited from a parent who carries a balanced translocation. Rarer cases of trisomy 21 are mosaic, in which some cell lines carry three copies of chromosome 21, while others are diploid and normal. Trisomies 13 and 18 also occur due to meiotic nondisjunction in approximately 85% of cases, while 10% of cases are mosaic and 5% are due to a translocation. Copy number variants (CNV) occur when the number of copies of a particular gene or genomic region varies from one individual to the next; these variants can be duplications or deletions. Large CNVs may be detectable by karyotype, but most require chromosomal microarray to be diagnosed. Although small when compared to trisomy of an entire chromosome, CNVs can be associated with significant medical and intellectual disabilities. Unlike the common trisomies, the rate of significant CNVs does not increase with maternal age and is estimated at about 0.5–1% of pregnancies in the mid‐trimester. Therefore, these are more common than Down syndrome and the common aneuploidies in women under age 35.

Diagnosis and screening protocols Prenatal screening and diagnostic testing for detection of chromosomal abnormalities should be offered to all pregnant women, regardless of maternal age. Prenatal diagnostic testing involves direct analysis of fetal tissue, with collection through chorionic villus sampling (CVS) and amniocentesis being the most commonly performed prenatal procedures for diagnostic genetic testing. In contrast, prenatal screening provides a risk of chromosomal abnormality, with the most common current approaches being combinations of first‐ and second‐trimester serum and sonographic screening, and cell‐free DNA (cfDNA) screening, also referred to as noninvasive prenatal testing (NIPT) or noninvasive prenatal screening (NIPS).

Prenatal diagnostic testing Prenatal diagnostic testing can be performed on fetal tissue collected by first‐ trimester CVS or second‐trimester amniocentesis. CVS is typically performed between 10 and 14 weeks of gestation, although a later placental biopsy is also possible and may be required under some clinical circumstances. Two approaches are commonly used to access the placenta under sonographic guidance; with the transabdominal approach, a 20 gauge spinal needle traverses the maternal abdominal and uterine walls, while with the transcervical approach, a plastic cannula or biopsy forceps traverses the vagina and cervix.

Prenatal Testing for Chromosomal Abnormalities  31 Both transabdominal and transcervical CVS are associated with an overall pregnancy loss rate of approximately 1 in 455 or 0.22%; this is not statistically different from the risk associated with amniocentesis. CVS performed prior to 10 weeks of gestation has been associated with a risk of fetal limb reduction defects and is not recommended; this risk is not increased with later procedures (10 weeks and later). Genetic amniocentesis is most commonly performed between 15 and 20 weeks of gestation, although can also be performed later. Sonographically directed placement of a 22 gauge spinal needle into the amniotic cavity is a very safe procedure, with a reported loss rate of 1 in 900 pregnancies, or 0.11%. Recent data indicate that when compared to patients with the same risk profile, the loss rate of CVS and amniocentesis is negligible. Fetal tissue obtained with CVS or amniocentesis can be cultured for ­karyotype analysis, or DNA can be extracted from chorionic villi, amniotic fluid, or cultured fetal cells for chromosomal microarray analysis (CMA) or other specialized genetic testing. When indicated, fluorescence in situ hybridization can be done on interphase cells for rapid aneuploidy testing or on metaphase cells for identification of microdeletions or duplications.

Cell‐free DNA screening In 2011, cell‐free DNA screening (also known as noninvasive prenatal testing or noninvasive prenatal screening) became clinically available as a screening test for aneuploidy. This screening test relies on the analysis of cell‐free DNA (cfDNA) fragments in the maternal circulation. After 10 weeks of gestation, approximately 10–15% of the cfDNA in the maternal serum is of placental origin and therefore reflects the fetal DNA. Clinical testing measures the chromosomal contribution of the cfDNA in the maternal circulation to determine whether there is over‐ or underrepresentation of targeted chromosomes. Different laboratories use different approaches, including massively parallel shotgun sequencing (MPSS), a targeted microarray approach, or targeted sequencing using single nucleotide polymorphisms (SNPs); performance for aneuploidy screening is generally comparable between platforms. Standard cfDNA screening tests for trisomies 13, 18, and 21, and can also assess the sex chromosomes to determine fetal sex and, in some cases, screen for sex chromosomal aneuploidy. The accurate performance of cfDNA screening depends on the presence of adequate fetal (placental) cfDNA, referred to as the “fetal fraction.” In some laboratories, a result is not provided when the fetal fraction falls below a prespecified level; this cut‐off is typically about 4%. Early gestational age, increasing maternal body mass index, and fetal aneuploidy are associated with a lower fetal fraction and increase the chances of a failed test. Studies of test performance for cfDNA screening report a >99% detection rate for fetal trisomy 21 and 98% detection for trisomy 18 with a combined

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false‐positive rate (FPR) of 0.13–0.25%. Because trisomy 13 is a rare ­disorder, data are far more limited but reported detection rates vary from 40% to 100% in individual studies. The detection rate of sex chromosome aneuploidy is also difficult to determine due to limited data. Importantly, these data were calculated for patients with a reported result, and as many as 3–4% of samples result in test failure. Test failure, particularly in the setting of low fetal fraction, is associated with an increased risk of aneuploidy and patients should be counseled accordingly and offered follow‐up testing. While cfDNA screening has excellent performance in detection of trisomy 21, both false‐positive and false‐negative results can occur, particularly with low fetal fraction. The presence of mosaicism or a vanishing twin may result in false‐positive cfDNA results. Standard cfDNA screening tests do not provide risk assessment for other chromosomal, genetic, or structural disorders. Some laboratories offer expanded cfDNA panels to test for chromosomal microdeletions, rare autosomal trisomies, or genome‐wide copy number variants. Such tests have not been clinically validated, performance characteristics are unknown, and these are generally not recommended at the present time.

First‐trimester combined screening The ability to provide an accurate, patient‐specific, risk assessment for fetal trisomy 21 during the first trimester is an established part of routine clinical practice. This allows patients the option of CVS to confirm or exclude fetal aneuploidy, and the possibility of pregnancy termination earlier in gestation. Such patient‐specific risk estimation is currently most commonly performed using a combination of maternal age, sonographic measurement of nuchal translucency (NT), and assay of two maternal serum markers – pregnancy‐associated plasma protein A (PAPP‐A) and either the free beta‐subunit (fβ) or the intact molecule of human chorionic gonadotrophin (hCG). Nuchal translucency sonography Nuchal translucency refers to the normal space that is visible between the spine and overlying skin at the back of the fetal neck during first‐trimester sonography (Figures 5.1 and 5.2). The larger this space, the higher the risk for trisomy 21, while the smaller the space, the lower the risk for trisomy 21. Measurement of the NT between 11 weeks and 3 days and 14 weeks and 2 days of gestation (45–84 mm) has been shown to be a useful sonographic marker for trisomy 21. Table  5.1 describes the components of a standardized NT sonographic protocol. Nuchal translucency sonography can be technically challenging to master and it requires considerable effort to maintain quality over time. Given

Prenatal Testing for Chromosomal Abnormalities  33

Figure 5.1  Nuchal translucency (NT) ultrasound measurement at 13 weeks’ gestation

in a chromosomally normal fetus, measuring 1.5 mm. Various features of good NT ultrasound technique are evident in this image: adequate image magnification, midsagittal plane, neutral neck position, inner to inner caliper placement perpendicular to the fetal body axis, and separate visualization of the overlying fetal skin and amnion. Source: Mary E. Norton, MD.

Figure 5.2  Increased nuchal translucency measurement at 13 weeks’ gestation in a fetus with Down syndrome. Source: Mary E. Norton, MD.

the importance of maintaining such accuracy, sonographers and physicians who provide this form of screening should be credentialed and enrolled in an ongoing quality assurance program. Examples of such QA programs include the Nuchal Translucency Quality Review (NTQR) managed by the Perinatal Quality Foundation in the US (www.ntqr.org) and the Fetal Medicine Foundation in Europe (www.fetalmedicine.org).

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Table 5.1  Nuchal translucency (NT) measurement criteria of the Nuchal Translucency

Quality Review (NTQR) Program 1 2 3 4 5 6 7 8 9 10

Fetal head, neck, and upper thorax should fill the majority of the image (>50%) Image should be optimized so the NT lines are thin and clear Fetus should be examined in a midsagittal plane Fetal neck should be in a neutral position Fetus should be observed away from the amnion The “+” calipers should be used Calipers should be placed on the echogenic inner borders of the nuchal membranes with none of the horizontal crossbars protruding into the translucent NT space Calipers should be placed perpendicular to the long axis of the fetal body At least three nuchal translucency measurements should be obtained and the maximum acceptable measurement should be used The ALARA (as low as reasonably achievable) criteria should be followed and the thermal index for bone (TIB) set with an output standardized display of ≤0.7

First‐trimester PAPP‐A and hCG [fo]Maternal serum levels of PAPP‐A are approximately 50% lower, and hCG levels (either total hCG or fβhCG) approximately twice as high, in trisomy 21 pregnancies compared with euploid pregnancies at 10–14 weeks of gestation, and these analytes can be used for assessment of trisomy 21 risk in the first trimester. The combination of maternal age, NT sonography, PAPP‐A, and hCG is referred to as first‐trimester combined screening and will detect about 85% of cases of trisomy 21, at a 5% false‐ positive rate, between 10 and 14 weeks of gestation. Secondary sonographic markers While measurement of the NT combined with serum markers has been the mainstay of general population screening for many years, other sonographic features of aneuploidy have also been reported in the first trimester. Cystic hygroma is reported in about 1 of every 300 first‐trimester pregnancies, and refers to a markedly enlarged NT, often extending along the entire length of the fetus, with septations clearly visible. While it is not clear that a cystic hygroma is distinct from a markedly enlarged NT, this finding is associated with a 50% risk for fetal aneuploidy and in the remaining euploid pregnancies, almost half will be found to have major structural fetal malformations, such as cardiac defects and skeletal anomalies. Less than 25% of all cases of first‐trimester septated cystic hygroma or markedly enlarged NT (e.g., ≥6.5 mm) will result in a normal liveborn infant. Therefore, this finding should prompt immediate referral for CVS, and pregnancies found to be euploid should be evaluated carefully for other malformations with a detailed fetal anomaly scan and fetal echocardiography at 18–22 weeks of gestation, or in the first trimester if such evaluation is available.

Prenatal Testing for Chromosomal Abnormalities  35

Figure 5.3  Nasal bone image of a euploid fetus at 13 weeks. Various features of good nasal bone technique are evident in this image: a good midsagittal plane, clear fetal profile, downward‐facing spine, slight neck flexion, and two echogenic lines, representing the overlying fetal skin and the nasal bone. The white arrow indicates the fetal nose bone, which loses its echogenicity distally. Source: Mary E. Norton, MD.

Other sonographic features that have been reported to be useful in detection of trisomy 21 at 11–14 weeks include an absent nasal bone (Figure 5.3), an abnormal Doppler blood flow pattern in the ductus venosus, and abnormal blood flow across the tricuspid valve with evidence of tricuspid regurgitation. However, studies suggesting a role for aneuploidy screening using these sonographic evaluations in the first trimester have been derived from select high‐risk populations, and likely overestimate the screening performance. At this time, while evaluation of the nasal bone can be useful for risk stratification in cases with enlarged nuchal translucency, first‐trimester evaluation of these other secondary markers is not recommended for general population screening.

Second‐trimester screening Risk assessment for fetal trisomy 21 for many years involved primarily second‐trimester serum screening with maternal serum assay of alphafetoprotein (AFP), hCG, unconjugated estriol (uE3), and inhibin‐A (quad marker screening). In some practices, ultrasound assessment of features of aneuploidy, such as characteristic malformations or minor findings or markers, was used to assess or modify risk. Second‐trimester serum screening is now less commonly used due to the higher detection of first‐trimester combined or cfDNA screening, as well as the benefits of earlier detection. However, there is still a role for quad marker screening in patients who do not present for care until the second trimester.

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Sonographic detection of major malformations The genetic sonogram is a term that has been used to describe second‐­ trimester sonographic assessment of the fetus for signs of aneuploidy. The detection of certain major structural malformations that are known to be associated with aneuploidy should prompt an offer of genetic amniocentesis. Table 5.2 summarizes the major structural malformations that are associated with the most common trisomies. Given the increasing popularity of first‐ trimester screening, many advanced obstetric ultrasound practitioners have attempted to bring the genetic sonogram forward in gestation so that an anomaly scan may also be performed toward the end of the first trimester. Relatively limited data are available to validate the accuracy of the genetic sonogram in the first trimester for general population screening, and therefore the optimal time remains at about 18–22 weeks of gestation. Table 5.2  Sonographic findings associated with trisomies 21, 18, and 13 Trisomy 21 Major structural malformations Cardiac defects: • Atrioventricular (AV) canal defect • Ventricular septal defect • Tetralogy of Fallot Duodenal atresia Cystic hygroma Hydrops fetalis

Minor sonographic markers Nuchal thickening Mild ventriculomegaly Short humerus or femur Echogenic bowel Renal pyelectasis Echogenic intracardiac focus Hypoplastic nasal bones Brachycephaly Clinodactyly Sandal gap toe Widened iliac angle Growth restriction

Trisomy 18

Trisomy 13

Cardiac defects: • Double outlet right ventricle • Ventricular septal defect • AV canal defect Meningomyelocele Agenesis of the corpus callosum Omphalocele Diaphragmatic hernia Esophageal atresia Clubbed or rocker‐bottom feet Renal abnormalities Orofacial clefting Cystic hygroma Hydrops fetalis

Holoprosencephaly Orofacial clefting

Nuchal thickening Mild ventriculomegaly Short humerus or femur Echogenic bowel Enlarged cisterna magna Choroid plexus cysts Micrognathia Strawberry‐shaped head Clenched or overlapping fingers Single umbilical artery Growth restriction

Cyclopia Proboscis Omphalocele Cardiac defects: • Ventricular septal defect • Hypoplastic left heart Polydactyly Clubbed or rocker‐bottom feet Echogenic kidneys Cystic hygroma Hydrops fetalis

Nuchal thickening Mild ventriculomegaly Echogenic bowel Enlarged cisterna magna Echogenic intracardiac focus Single umbilical artery Overlapping fingers Growth restriction

Prenatal Testing for Chromosomal Abnormalities  37 When a major structural malformation is found, such as an atrioventricular canal defect or a double‐bubble suggestive of duodenal atresia, the risk of trisomy 21 in that pregnancy is increased by approximately 20–30‐fold. For many patients, such an increase in their background risk for aneuploidy will be sufficiently high to justify genetic amniocentesis. Sonographic detection of minor features of aneuploidy Second‐trimester sonography can also detect a range of minor features or “markers” suggestive of aneuploidy. These are not structural abnormalities of the fetus per se but are associated with an increased probability that the fetus is aneuploid. These minor markers are typically much more common than structural abnormalities and likelihood ratios based on the presence or absence of these markers have been used to adjust each patient’s risk of having a fetus with trisomy 21. However, with improvements in aneuploidy screening, including serum and combined methods as well as cfDNA screening, these minor findings add little to the detection of chromosomal abnormalities. Rather, when screening results indicate a low risk of aneuploidy, these markers are most commonly normal variants. The one possible exception is a thickened nuchal fold, which is uncommon in euploid fetuses and therefore has a low false‐positive rate and relatively high specificity for Down syndrome. In cases in which multiple markers are seen, the risk of aneuploidy is higher and genetic counseling may be indicated. Table 5.2 also summarizes the minor sonographic markers that, when visualized, may increase the probability of an aneuploid fetus. Second‐trimester AFP, hCG, uE3, and inhibin‐A Maternal serum levels of AFP (MSAFP) and unconjugated estriol (uE3) are both approximately 25% lower, and levels of hCG and inhibin‐A approximately twice as high in pregnancies complicated by trisomy 21. MSAFP, uE3, and hCG all tend to be decreased in pregnancies complicated by ­trisomy 18. The combination of AFP, uE3, hCG and inhibin‐A, commonly known as the quad screen, can detect about 80% of cases of trisomy 21, at a 5% false‐positive rate. Quad marker screening has the additional advantage of also screening for neural tube defects given the inclusion of MSAFP. Performance of serum screening tests is optimized by accurate ascertainment of gestational age, and, wherever possible, sonographic dating should be used instead of menstrual dating.

Combined first‐ and second‐trimester screening In some programs, multiple markers in both the first and second trimesters are combined to optimize screening performance. The most common approaches include sequential screening, in which first‐trimester combined (serum and NT measurement) screening is performed and results provided. High‐risk patients are offered follow‐up with either cfDNA or diagnostic testing; patients at any risk level can also go on to have quad

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screening and be provided a final result including all serum analytes as well as the NT. This approach is associated with a 90–95% detection rate for trisomy 21 at a 5% false‐positive rate. It has the advantage of a high detection rate, the provision of a first‐trimester result, and the ability to screen for neural tube defects. Integrated screening involves the same two‐step screening protocol, but results are not released until all screening steps are completed. This results in a lower false‐positive rate but has the disadvantage of later provision of results. A serum integrated screening approach, including first and second trimester serum analytes, can also be used in patients who do not have access to NT measurement. Again, this has the advantage of a relatively high detection rate but provides a later result.

Conclusion A wide range of screening tests for fetal aneuploidy, in particular trisomy 21, is now available in both the first and second trimesters. Cell‐free DNA‐ based tests are more targeted and precise for the common aneuploidies, so are more appropriate for women at high risk for aneuploidy. Serum‐based tests have higher false‐positive rates but can detect risk for a broader array of abnormalities and therefore have some advantages for women at low risk for aneuploidy. No one approach is best, but concurrent use of serum and cfDNA screening can lead to confusion among patients and providers and should be avoided. All pregnant patients should be provided with pretest counseling to select the most appropriate screening or diagnostic test for their particular circumstances. Rapid developments in the field mean that test options and guidelines are constantly evolving.

Suggested reading American College of Obstetricians and Gynecologists. Noninvasive prenatal testing for fetal aneuploidy. Committee Opinion No. 545. Obstet Gynecol 2012;120:1532–34. American College of Obstetricians and Gynecologists. Practice Bulletin No. 162. Prenatal diagnostic testing for genetic disorders. Obstet Gynecol 2016;127:e108–22. Bianchi DW, Crombleholme TM, d’Alton ME, Malone FD. Fetology: Diagnosis and Management of the Fetal Patient, 2nd edn. New York: McGraw Hill, 2010. Gil MM, Accurti V, Santacruz B, Plana MN, Nicolaides KH. Analysis of cell‐free DNA in maternal blood in screening for aneuploidies: updated meta‐analysis. Ultrasound Obstet Gynecol 2017;50(3):302–14. Kaimal AJ, Norton ME, Kuppermann M. Prenatal testing in the genomic age: clinical outcomes, quality of life, and costs. Obstet Gynecol 2015;126(4):737–46. Malone FD, Canick JA, Ball RH, et al. A comparison of first trimester screening, second trimester screening, and the combination of both for evaluation of risk for Down syndrome. N Engl J Med 2005;353:2001–11.

Prenatal Testing for Chromosomal Abnormalities  39 Norton ME, Jacobsson B, Swamy GK, et  al. Cell‐free DNA analysis for noninvasive examination of trisomy. N Engl J Med 2015;372(17):1589–97. Nyberg DA, Souter VL. Chromosomal abnormalities. In: Nyberg DA, McGahan JP, Pretorius DH, Pilu G (eds) Diagnostic Imaging of Fetal Anomalies. Philadelphia: Lippincott Williams & Wilkins, 2003; pp. 861–906. Palomaki GE, Kloza EM, Lambert‐Messerlian GM, et  al. DNA sequencing of maternal plasma to detect Down syndrome: an international clinical validation study. Genet Med 2011;13:913–20. Salomon LJ, Sotiriadis A, Wulff CB, Odibo A, Akolekar R. Risk of miscarriage following amniocentesis or chorionic villus sampling: systematic review of literature and updated meta‐analysis. Ultrasound Obstet Gynecol 2019;54(4):442–51. Society for Maternal‐Fetal Medicine (SMFM), Norton ME, Biggio JR, Kuller JA, Blackwell SC. SMFM Consult Series #42: The role of ultrasound in women who undergo cell‐free DNA screening. Am J Obstet Gynecol 2017;216(3):B2–B7.

PROTOCOL 6

Fetal Echocardiography Joshua A. Copel Departments of Obstetrics, Gynecology and Reproductive Sciences, and Pediatrics, Yale School of Medicine, New Haven, CT, USA

Overview Congenital heart disease occurs in approximately eight of 1000 live births. Of these, approximately half are relatively minor ventricular septal defects or valve stenoses that are of little hemodynamic significance. Some of these can be identified prenatally with sensitive color Doppler flow mapping with little clinical impact, while many others are undetectable prenatally. The remainder are significant lesions that may benefit from prenatal detection, parental counseling, and obstetric‐pediatric planning for delivery and neonatal care.

Pathophysiology Most types of congenital heart disease are thought to be inherited in multifactorial fashion, with both genetic and environmental contributions. The indications used for fetal echocardiography, a prenatal ultrasound technique that can detect most significant congenital heart disease, reflect that etiological diversity. Many patients referred for fetal echocardiography have had prior affected children or other affected family members, and the recurrence risk for these families is about 2–3% if there has been a prior affected child, and 3–5% if one of the parents has congenital heart disease. The pathophysiology of congenital cardiac anomalies varies with the type of anatomical abnormality that is present. The underlying mechanisms include failures of cell migration leading to failure of a structure to form, or diminished flow, inhibiting the normal growth of a downstream structure (e.g., poor flow across the foramen ovale and mitral valve predisposing to a coarctation of the aorta).

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Structural heart disease Diagnosis and work‐up In patients without risk factors for congenital heart disease, full fetal echocardiography, which is generally more time‐consuming and expensive than general obstetric sonography, is not indicated unless cardiac anomalies are suspected. Many risk factors for congenital heart disease have been described (Table 6.1). The four‐chamber view of the heart has been suggested as an easy way of screening for congenital heart disease, although its sensitivity to significant cardiac anomalies has varied in the literature. Approximately one‐third of Table 6.1  Indications for fetal echocardiography Familial risk factors History of congenital heart disease (CHD) Previous sibling with CHD Paternal CHD Second‐degree relative to fetus with CHD Mendelian syndromes that include congenital heart disease (e.g., Noonan, tuberous sclerosis) Maternal risk factors Congenital heart disease Cardiac teratogen exposure: Lithium carbonate Phenytoin Valproic acid Trimethadione Carbamazepine Isotretinoin Paroxetine Maternal metabolic disorders: Diabetes mellitus Phenylketonuria In vitro fertilization Fetal risk factors Suspected cardiac anomaly Extracardiac anomalies Chromosomal Anatomical Fetal cardiac arrhythmia Irregular rhythm Tachycardia (greater than 200 bpm) in absence of chorioamnionitis Fixed bradycardia Nonimmune hydrops fetalis Lack of reassuring four‐chamber view during basic obstetric scan Monochorionic twins Increased nuchal translucency space at 11–14 weeks of gestation

Fetal Echocardiography  43 cases of major heart disease are detected on screening prenatal ultrasound, according to a review of the world’s literature. Our own experience suggests that it has a very high positive predictive value, with about half of patients referred for abnormal four‐chamber views actually having cardiac anomalies. Current recommendations from US medical societies, including the American College of Obstetricians and Gynecologists (ACOG), the American Institute of Ultrasound in Medicine (AIUM), and the International Society of Ultrasound in Obstetrics and Gynecology, all call for including outflow tract views in the standard (or so‐called “Level 1”) obstetric scan. Full fetal echocardiography includes obtaining all the views in the fetus routinely obtained in postnatal echocardiography (Table 6.2) using both real‐ time gray‐scale and color Doppler imaging. Additionally, spectral Doppler, cardiac biometry, and M‐mode data can be obtained as indicated. Fetal echocardiographers use these latter techniques variably. The two‐dimensional examination should be sufficient to exclude significant heart disease in the vast majority of affected individuals. The more sophisticated studies are especially useful in cases of suspected structural or functional abnormalities. In a recent Practice Parameter, the AIUM has described required and optional components of the detailed fetal echocardiographic examination, shown in Table 6.3. Table 6.2  Standard fetal echocardiographic views and what to see Four chamber Situs: check fetal position and stomach Axis of heart to the left Intact interventricular septum Atria approximately equal sizes Ventricles approximately equal sizes Free movement of mitral and tricuspid valves Heart occupies about one‐third of chest area Foramen ovale flap (atrial septum primum) visible in left atrium Long‐axis left ventricle Intact interventricular septum Continuity of the ascending aorta with mitral valve posteriorly Interventricular septum anteriorly Short axis of great vessels Vessel exiting the anterior (right) ventricle bifurcates, confirming it is the pulmonary artery Aortic arch Vessel exiting the posterior (left) ventricle arches and has three head vessels, confirming it is the aorta Pulmonary artery–ductus arteriosus Continuity of the ductus arteriosus with the descending aorta Venous connections Superior and inferior vena cavae enter right atrium Pulmonary veins entering left atrium from both right and left lungs

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Table 6.3  AIUM recommended components of detailed fetal echocardiographic exam A. Gray‐scale imaging • Four‐chamber view including pulmonary veins • Left ventricular outflow tract • Right ventricular outflow tract • Branch pulmonary artery bifurcation • Three‐vessel view (including view with PA bifurcation and more superior view with ductal arch) • Short‐axis views (“low” for ventricles, “high” for outflow tracts) • Long‐axis view (if clinically relevant) • Aortic arch • Ductal arch • Superior (SVC) and inferior vena cava (IVC) B. Color Doppler sonography • Systemic veins (including superior and inferior vena cava and ductus venosus) • Pulmonary veins (at least two, one right vein and one left vein) • Atrial septum and foramen ovale • Atrioventricular valves • Ventricular septum • Semilunar valves • Ductal arch • Aortic arch C. Pulsed Doppler sonography • Right and left atrioventricular valves • Right and left semilunar valves • Pulmonary veins (at least two; one right vein and one left vein) • Ductus venosus • Suspected structural or flow abnormality on color Doppler sonography D. Heart rate and rhythm assessment E. Cardiac biometry (z‐scores recommended) • Aortic and pulmonary valve annulus in systole (absolute size with comparison of left‐ to right‐sided valves) • Tricuspid and mitral valve annulus in diastole (absolute size with comparison of left‐ to right‐sided valves) F. Optional biometry • Right and left ventricular lengths • Aortic arch and isthmus diameter measurements from the sagittal arch view or three vessels and trachea view with comparison of aortic isthmus to ductus arteriosus • Main pulmonary artery and ductus arteriosus measurements • End‐diastolic ventricular diameter just inferior to the atrioventricular valve leaflets in the short or long axis view • Thickness of the ventricular free walls and interventricular septum in diastole just inferior to the atrioventricular valves • Additional measurements if clinically relevant, including: • systolic ventricular dimensions (short or long axis views) • transverse atrial dimensions • branch pulmonary artery diameters G. Cardiac function assessment (if clinically relevant) • Fractional shortening • Ventricular strain • Myocardial performance index

Fetal Echocardiography  45

Management When a cardiac anomaly is found, a full detailed fetal scan to detect any other extracardiac anomalies is mandatory. Many fetal syndromes include cardiac anomalies, and accurate counseling requires complete enumeration of associated anomalies. Fetal karyotype testing should be offered to the parents, as chromosome abnormalities are seen in a large segment of fetuses with congenital heart disease. Additional testing for a microdeletion of chromosome 22q11 can be helpful in fetuses with conotruncal malformations (e.g., tetralogy of Fallot, truncus arteriosus). As for all fetal anomalies, microarray testing for microdeletions and microduplications has also become routine. In selected cases specific gene sequencing or even whole exome or genome sequencing is indicated. Overall survival once a cardiac lesion is found depends on the nature of the cardiac problem, the presence of extracardiac anomalies, the karyotype, and the presence of fetal hydrops. Fetal hydrops in association with structural heart disease is virtually universally fatal. Aneuploid fetuses may have dismal prognoses even in the absence of heart disease; for example, fetal trisomy 18 may make repairing even a straightforward ventricular septal defect inadvisable. Lesions that can be repaired into a biventricular heart carry a better long‐ term prognosis than those that result in a univentricular heart. In general, infants known to have congenital heart disease prenatally do better than those whose cardiac defects are only found after birth.

Fetal arrhythmias Diagnosis and management The largest group of fetal arrhythmias are intermittent and due to atrial, junctional or ventricular extrasystoles. They carry a small risk of co‐existent structural abnormality. A greater risk exists of an unrecognized tachyarrhythmia, or the development of a tachyarrhythmia later in gestation. Atrial extrasystoles predispose the fetus to development of reentrant atrial tachycardia, which can lead to fetal hydrops. We recommend weekly auscultation of the fetal heart, along with avoidance of caffeine or other sympathomimetics, until resolution of the arrhythmia. Fetal tachycardias represent a management challenge, because determination of the precise electrophysiological cause of the arrhythmia is essential to any rational management strategy, but fetal electrocardiography is not yet clinically practical in the presence of intact membranes. The differential diagnoses of fetal tachycardias include reentrant atrial tachycardia, atrial flutter, and ventricular tachycardia. The treatment of these disorders differs significantly, and appropriate medications for one may be contraindicated for another. The correct diagnosis, which should be based on combinations of M‐mode, Doppler and color Doppler–M‐mode imaging, is essential to appropriate therapy.

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If there is a fetal bradycardia, the first step is to determine if there is a regular or an irregular atrial rate. If the atrial rate is regular and slow, that is, below 100 beats per minute, there may be sinus bradycardia, which should prompt a complete evaluation of fetal well‐being. The most common clinically important fetal bradycardia results from complete heart block, which will demonstrate a normal regular atrial rate with a slower ventricular rate whose beats do not occur in conjunction with atrial beats. In structurally normal hearts this is usually caused by maternal antibodies associated with lupus erythematosus and Sjögren syndrome, termed SSA/ Ro and SSB/La. A smaller group of patients, without maternal antibodies, may present with congenital complete heart block in a setting of complex congenital heart disease involving the central fibrous body of the heart (e.g., left atrial isomerism, corrected transposition of the great arteries). In these patients, the prognosis is directly related to the complexity of the heart disease and the association with congestive heart failure. A more benign cause of fetal bradycardia, which may be mistaken for 2:1 heart block, is blocked atrial bigeminy. In such cases the atrial rate is not regular, but rather demonstrates paired beating in which a premature atrial beat follows closely after a normal atrial beat with no ventricular response to the premature beat. This arrhythmia has no significance beyond that of isolated atrial extrasystoles.

Follow‐up The fetus with congenital heart disease should be carefully followed by ultrasound up to delivery. Structural lesions may evolve prenatally even as they do postnatally. It is particularly important to evaluate areas of potential obstruction, and the relationships of the great arteries to the ventricles. Fetuses with significant arrhythmias (including reentrant tachycardias, atrial flutter, and complete heart block) should also be followed at a center with experience in the prenatal medical management of fetal arrhythmias, by a team that includes perinatologists, pediatric cardiologists, and adult electrophysiologists. Delivery need not be by cesarean except in the presence of selected fetal arrhythmias that do not permit adequate fetal heart rate monitoring. For fetuses with lesions that are expected to render the neonate dependent on ductus arteriosus patency for systemic or pulmonary perfusion, prostaglandin E1 should be available in the nursery at the time of delivery to keep the ductus open.

Suggested reading American Institute of Ultrasound in Medicine. AIUM Practice Guideline for the Performance of Obstetric Ultrasound Examinations. www.aium.org/resources/guidelines/obstetric.pdf American Institute of Ultrasound in Medicine. AIUM Practice Parameter for the Performance of Fetal Echocardiography. https://doi.org/10.1002/jum.15188

Fetal Echocardiography  47 Bahtiyar MO, Dulay AT, Weeks BP, Friedman AH, Copel JA. Prenatal course of isolated muscular ventricular septal defects diagnosed only by color Doppler sonography: single‐institution experience. J Ultrasound Med 2008;27:715–20. Copel JA, Liang RI, Demasio K, Ozeren S, Kleinman CS. The clinical significance of the irregular fetal heart rhythm. Am J Obstet Gynecol 2000;182:813–17. Copel JA, Tan AS, Kleinman CS. Does a prenatal diagnosis of congenital heart disease alter short‐term outcome? Ultrasound Obstet Gynecol 1997;10:237–41. Donofrio MT, Moon‐Grady AJ, Hornberger LK, et al. Diagnosis and treatment of fetal cardiac disease: a scientific statement. Am Heart Assoc Circ 2014;129:2183–242. Kleinman CS, Copel JA. Electrophysiological principles and fetal antiarrhythmic therapy. Ultrasound Obstet Gynecol 1991;4:286–97. Miller A, Riehle‐Colarusso T, Alverson MS, et al. Congenital heart defects and major structural noncardiac anomalies, Atlanta, Georgia, 1968 to 2005. J Pediatr 2011;159:70–8. Pierpont ME, Brueckner M, Chung WK, et al. Genetic basis for congenital heart disease: revisited. A scientific statement from the American Heart Association. Circulation 2018:138:e653–e711. Silverman NH, Kleinman CS, Rudolph AM, et  al. Fetal atrioventricular valve insufficiency associated with nonimmune hydrops: a two‐dimensional echocardiographic and pulsed Doppler study. Circulation 1985;72:825–32. Todros T, Faggiano F, Chiappa E, Gaglioti P, Mitola B, Sciarrone A. Accuracy of routine ultrasonography in screening heart disease prenatally. Gruppo piemontese for prenatal screening of congenital heart disease. Prenatal Diag 1997;17:901–6.

PROTOCOL 7

Clinical Use of Doppler Henry L. Galan Department of Obstetrics and Gynecology, Division of Maternal‐Fetal Medicine, University of Colorado School of Medicine, Colorado Fetal Care Center, Aurora, CO, USA

Overview Doppler ultrasound depends upon the ability of a pulsed ultrasound beam to be changed in frequency when encountering moving objects such as red blood cells (RBC). The change in frequency (Doppler shift) between the emitted reflected beams is proportional to the velocity of the RBC and dependent on the angle between the ultrasound beam and the vessel. Pulsed‐wave Doppler velocimetry provides a flow velocity waveform from which information can be obtained to determine three basic characteristics of blood flow that are useful in obstetrics: velocity, resistance indices, and volume blood flow. Doppler velocimetry is applied in a broad number of clinical circumstances in high‐risk pregnancies including diagnostic fetal echocardiography, fetal growth restriction (FGR), fetal anemia, adverse pregnancy outcome assessment, twin‐twin transfusion syndrome (TTTS), twin anemia polycythemia sequence (TAPS), and preterm labor (ductus arteriosus assessment for indomethacin tocolysis). Pulsed‐wave Doppler velocimetry is also used to evaluate the ductus venosus (DV) in first‐trimester risk assessment for Down syndrome but is not discussed in this protocol.

Pathophysiology Normal fetal circulation The umbilical vein is a conduit vessel bringing oxygen and nutrient‐rich blood from the placenta to the fetus. The umbilical vein enters the umbilicus, courses anteriorly along the abdominal wall prior to entering the liver, and becomes the hepatic portion of the umbilical vein. The umbilical vein eventually becomes the portal vein, but first gives off the left inferior

Protocols for High-Risk Pregnancies: An Evidence-Based Approach, Seventh Edition. Edited by John T. Queenan, Catherine Y. Spong and Charles J. Lockwood. © 2021 John Wiley & Sons Ltd. Published 2021 by John Wiley & Sons Ltd.

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and superior portal veins, the DV, and finally the right portal vein. Approximately 50% of umbilical vein blood is directed into the DV and then to an area under the diaphragm referred to as the subdiaphragmatic vestibulum. The subdiaphragmatic vestibulum also receives blood from the inferior vena cava and blood exiting the liver via the right, middle, and left hepatic veins. The process of preferential streaming begins in the subdiaphragmatic vestibulum with blood from the DV and the left and middle hepatic veins preferentially shunted across the foramen ovale into the left atrium and left ventricle so that the heart and head receive the most oxygenated and nutrient‐rich blood. In contrast, blood coming from the inferior vena cava and right hepatic vein are preferentially streamed into the right atrium and right ventricle. Then, after exiting through the pulmonary artery, this blood is shunted to the descending aorta via the ductus arteriosus. Blood leaves the fetus via two umbilical arteries ­arising from the hypogastric arteries which course around the lateral aspects of the bladder in an anterior and cephalad direction, exiting the umbilicus, returning oxygen‐reduced blood and waste products back to the placenta. There are three primary fetal circulatory shunts that require closure after delivery for normal newborn cardiopulmonary transition to occur and for the subsequent adult circulation to be established. As mentioned above, the DV shunts blood from the umbilical vein toward the heart. The ductus arteriosus shunts approximately 90% of the blood in the main pulmonary artery to the descending aorta, leaving only 10% of pulmonary artery blood to reach the fetal lungs. The third shunt is the foramen ovale, which is maintained in a patent state in utero to allow the process of preferential streaming to occur from the right atrium to the left. Failure of any one of these shunts to close properly may result in adverse cardiopulmonary transition in the newborn.

Fetal growth restriction Fetuses that fail to reach their genetically determined growth potential due to uteroplacental dysfunction may develop abnormal resistance to blood flow in the placenta. This abnormal resistance is due to numerous placental vascular abnormalities (poor villous capillarization, reduced number and branching of stem arteries, luminal reduction, and wall hypertrophy), which can be detected with Doppler velocimetry in the umbilical artery located upstream from the placenta. Progression of placental disease with concomitant worsening of blood flow resistance may lead to additional Doppler velocimetry changes in the central nervous system, and eventually in the precordial venous system or the heart. Once the fetus decompensates to that level of Doppler abnormality, acidemia is nearly always present.

Clinical Use of Doppler  51

Fetal anemia In Rh disease, a fetal RBC antigen enters the maternal bloodstream and stimulates antibody production against that RBC antigen. An amnestic response may occur in a subsequent pregnancy if the same RBC antigen is presented to the mother’s immune system and this may lead to a series of events that include fetal anemia, extramedullary hematopoiesis, hydrops fetalis, and fetal death. Historically, the degree of fetal anemia and need for fetal RBC transfusion involved an amniocentesis to determine the amniotic fluid ΔOD450 to assess the degree of RBC‐derived hemoglobin breakdown products and to estimate anemia. Isoimmunization with the Kell antibody also results in fetal anemia but does so through bone marrow suppression rather than hemolysis and thus, the ΔOD450 will not be abnormal. Fetal anemia can also result from infections such as parvovirus B19. Doppler velocimetry of the middle cerebral artery (MCA) is now used to determine the risk for moderate to severe anemia supplanting the previously used amniocentesis. If moderate to severe anemia is suspected, the fetus should undergo a fetal blood sampling and transfusion.

Preterm labor Although the pathophysiology of preterm labor is still largely unknown, tocolytic use is widespread. Use of agents that inhibit prostaglandin synthesis can result in premature closure of the ductus arteriosus and oligohydramnios. Doppler velocimetry is useful in assessment of ductus arteriosus closure by determining the peak systolic velocity as well as whether there is continuous flow throughout diastole.

Cardiac abnormalities Fetuses with known cardiac abnormalities including congenital or structural heart disease, arrhythmias and congestive failure may have intracardiac and outflow tract flow velocity abnormalities that can be detected with Doppler velocimetry. Depending on the nature of the abnormality, this can affect other flow velocity waveforms including the DV, hepatic veins, inferior vena cava, and umbilical vein.

Diagnosis Doppler techniques and measurements As mentioned in the overview, pulse‐wave Doppler velocimetry can be used to obtain the following information from a flow velocity waveform. • Velocity of the blood  –  requires an angle of insonation of zero degrees between the transducer and the vessel of interest (Figure 7.1). The angle correction function available on most ultrasound machines can be used but the actual angle between the vessel and the ultrasound beam should be less than 30°. For middle cerebral artery peak systolic velocity (MCA

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PSV), the sample volume should be placed in the proximal third of the MCA as it branches from the circle of Willis. • Resistance indices (systolic/diastolic or S/D ratio, resistance index, pulsatility index) – these are angle‐independent measurements such that the value obtained for any one of these indices is not dependent upon the angle between the transducer and the vessel being interrogated (Figure 7.2). • Volume blood flow (milliliters per minute) – this is determined by obtaining the velocity of the blood and multiplying it by the cross‐sectional area of the vessel (obtained by two‐dimensional ultrasound) times 60 seconds: Volume flow (mL/min) = velocity (cm/sec) × cross-sectional area (cm2) × 60 seconds Velocity

45°

0°

Figure 7.1  Schematic representing zero angle of insonation between the Doppler

transducer and the vessel of interest. Doppler indices of resistance

v cm/s

S D t S/D ratio

PI =

PI =

systrolic–diastolic mean velocity

systrolic–diastolic systolic

Easiest to calculate Most commonly used Requires mean height calculation; more resistant to FHR variation Only normally distributed index; maximum value attainable is one

Figure 7.2  Flow velocity waveform of the umbilical artery and definitions for the

­different Doppler indices of resistance.

Clinical Use of Doppler  53

Cardiac flow velocities Normal values and blood flow velocity patterns have been previously reported for cardiac Doppler velocities. More specifically, blood flow velocity values and patterns have been described for the pulmonary and aortic outflow tracts, ductus arteriosus, DV, pulmonary veins, tricuspid and mitral valve, and inferior vena cava. Any fetal structural cardiac abnormality or precordial or postcordial vascular abnormality can affect the blood flow velocity and waveform of the aforementioned vessels and valves. Further discussion of fetal echocardiography is found in Protocol 6.

Prediction of adverse pregnancy events There has been considerable effort over the past two decades with the application of maternal Doppler studies of the uterine arteries in the prediction of adverse pregnancy outcomes including preeclampsia, FGR, fetal demise, and preterm birth. The most distal branches of the uterine artery (spiral arteries) undergo a remarkable transition during the first half of pregnancy, from highly muscularized vessels with high resistance to remodeled vessels with low resistance. This is in response to differentiation of cytotrophoblast to noninvasive and invasive cytotrophoblast, with the latter literally invading and altering spiral artery muscular architecture. It is this change that leads to the enormous blood flow eventually seen in pregnancy (600–800 mL/min). There are many publications on the use of uterine artery Doppler for predicting adverse pregnancy outcomes in both low‐risk and high‐risk populations. In the low‐risk population, there does not seem to be a benefit of wide application of this Doppler test as a screening tool for adverse pregnancy events. There may be a role in uterine artery Doppler testing in high‐risk pregnancy as it may identify a subgroup of patients at a higher risk for adverse events, which may lead to useful additional monitoring during pregnancy or preventive strategies. In addition, the high negative predictive value for adverse pregnancy events can provide reassurance. However, before this test can be applied to the general or even the high‐risk pregnancy population, further evidence is needed to elucidate a clear predictive capability, the optimum gestational age for screening, standardization for study technique and abnormal test criteria, and an effective prevention therapy or strategy; this position has been supported by the Society for Maternal‐Fetal Medicine.

Fetal growth restriction Blood flow velocity waveforms obtained by pulsed‐wave Doppler velocimetry change in any given fetal vessel across gestation. In the umbilical artery of a normal pregnancy, there is a progressive increase in diastolic flow velocity across gestation, which reflects a decrease in the resistance within the

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­ lacenta. One characteristic of FGR due to uteroplacental insufficiency is an p increase in blood flow resistance within the placenta, which can be detected by Doppler velocimetry upstream in the umbilical arteries. Approximately 40% of cardiac output is directed toward the placenta via the umbilical artery. Thus, as placental disease progresses and blood flow resistance increases, fetal hypoxia may be reflected in the central nervous system (CNS) and the heart is subject to increased workload (afterload). Prior to significant cardiac dysfunction becoming apparent, abnormalities arise in the “prechordial” venous circulation (inferior vena cava, DV, and hepatic veins) in up to 70% of preterm, severely FGR fetuses. Further, recent data from a randomized clinical trial suggest that use of DV to manage early‐ onset FGR may reduce long‐term neurodevelopmental delay. Use of Doppler velocimetry in the management of FGR is further discussed in Protocol 41.

Rh sensitization As previously mentioned, fetal anemia resulting from maternal alloimmunization (except anti‐Kell) was historically detected by amniocentesis and assessment of the ΔOD450 and then confirmed by fetal blood sampling. Assessment of the MCA PSV has replaced the ΔOD450 as the gold standard test for fetal anemia. The MCA PSV has greater sensitivity for moderate to severe anemia than does the ΔOD450. Moreover, the ΔOD450 is not useful in Kell sensitization because fetal anemia in this condition is caused by bone marrow suppression rather than hemolysis and thus does not lead to RBC breakdown products in the amniotic fluid normally detected by the ΔOD450. One of the resultant pathophysiological features present in Rh disease is a reduction in the viscosity of the fetal blood, which is secondary to a lower hematocrit. This results in an increase in the velocity of blood flow, which can be detected by pulsed‐wave Doppler velocimetry. One of the vessels branching off the circle of Willis is the MCA, which lends itself to interrogation by Doppler because of its location and because the paired middle cerebral arteries carry 80% of the cerebral blood flow. The MCA is first identified with the use of color flow Doppler. With an angle of insonation of 0° (or less than 30° with angle correction), pulse‐wave Doppler velocimetry is used to obtain the flow velocity waveform. From the flow velocity waveform, one can determine the PSV across serial peaks of the systolic component of the flow velocity waveform profile and obtain a mean systolic peak velocity of the MCA flow waveform. Nomograms are available for PSV in the MCA across gestation. Web‐based MCA PSV multiples of the median (MoM) calculators for a given gestational age are also available at perinatology.com. When the MCA PSV surpasses the threshold of 1.55 MoM, there is a high risk of moderate to severe anemia in the fetus. The original report on this technique for assessing fetal anemia showed that a cut‐off 1.55 MoM has a

Clinical Use of Doppler  55 sensitivity of 100% and a negative predictive value of 100% for moderate to severe anemia. Subsequent studies have shown similar favorable performance characteristics of this screening test. Once this value is surpassed, the fetus can undergo blood sampling to determine the actual fetal hematocrit and determine if a transfusion is necessary. Using Doppler to assess the MCA PSV and identifying anemia in the fetus in this fashion avoids the standard invasive procedural risks of amniocentesis (needed for the ΔOD450) including exacerbation of the Rh sensitization. The MCA PSV measurement has also been used to guide management in cases of anemia due to infections such as parvovirus, loss of a co‐twin in monochorionic pregnancies, and in TAPS.

Management Congenital heart disease and arrhythmia Several clinical scenarios may warrant fetal echocardiography, which is discussed in more detail in Protocol 6. The ideal time to obtain a fetal echocardiogram is between 18 and 22 weeks of gestation; however, there are several specialized perinatal centers performing this in the first trimester. Counseling and management of the patient with a congenital heart defect involves a variety of steps that include defining the type and severity of cardiac lesion, consideration of the patient’s moral and religious disposition, genetic testing of the fetus (e.g., karyotype, chromosomal microarray, 22Q testing, etc.), and the presence of extracardiac abnormalities. In many instances, one of the most important things to determine in a fetus with congenital heart disease is whether the cardiac lesion will be ductal dependent and require newborn prostaglandin administration to maintain patency of the ductus arteriosus. This is an important step in the management of the pregnant patient, as it will determine whether she needs to be delivered in a hospital with a nursery capable of administering IV prostaglandin. Fetal arrhythmias are typically first detected incidentally by routine Doppler auscultation during a prenatal clinic visit or by external electronic fetal monitoring. Further identification of the specific type of arrhythmia requires the use of M‐mode cardiography and full assessment of the cardiac structure and flow velocities. Some patients with autoimmune conditions will be SSA/SSB antibody positive and require serial fetal echo for evaluation of P‐R intervals as one indicator of risk for developing complete heart block. Management of a patient with congenital heart disease should be a ­collaborative effort with a team consisting of a perinatologist, genetic counselor, pediatric cardiologist, neonatologist, pediatric cardiothoracic surgeon, and the primary obstetrical provider.

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Fetal growth restriction Once the fetus has been diagnosed by ultrasound to be growth restricted, a full ultrasound assessment of the fetus should be performed to exclude fetal anomalies, possible karyotypic abnormalities, and congenital infection. The dating criteria for the pregnancy should be reviewed and estimated date of confinement confirmed. Early‐onset structural abnormalities or symmetrical FGR should result in consideration of excluding karyotype abnormalities and congenital infection. Treatment options are limited in FGR and include avoidance of physically strenuous activities and work, increased fluid intake, and elimination of adverse social habits such as tobacco, alcohol or recreational drug use. Societal impact of bedrest is significant with an estimated 800 000 patients annually placed on bedrest leading to loss of work and wages. Bedrest should not be recommended as there is no evidence of benefit and there is risk of harm (thromboembolic disease). Avoidance or reduction of physically demanding work and exercise may be reasonable and the patient’s activity level can be labeled as “modified” rest and customized for the patient. In pregnant patients with a history of FGR due to preeclampsia in a previous pregnancy, a baby aspirin (81 mg) has been shown to have some benefit in reducing the risk of recurrence and should be started in the first half of pregnancy, preferably prior to 16 weeks of gestation. Surveillance of the growth‐restricted fetus includes the use of fetal activity count, serial assessment of fetal growth with ultrasound (every 3–4 weeks), nonstress test and/or biophysical profile, and Doppler velocimetry. Early‐ onset FGR fetuses who deteriorate in utero from an acid–base standpoint often demonstrate sequential Doppler changes in different vessels, while these changes occur far less frequently in late‐onset FGR. Use of Doppler in the management of the FGR fetus is further discussed in Protocol 41.

Fetal anemia The management of fetal anemia requires careful consideration of the etiological factors. The majority of cases will be due to RBC alloimmunization of the mother or parvovirus B19 infection. Rh sensitization begins with identification of an isoimmunized patient from routine blood type and Rh, and antibody screening tests. When the antibody screen shows the presence of an antibody that places the fetus(es) at risk for fetal anemia, the patient needs to undergo serial screening with antibody titers. An alternative to serial antibody titers that is now more commercially available is the use of cell‐free (cf) DNA to see if the fetus carries the RBC antigen in question. If the antigen is absent in the fetus, no further testing is needed. If the antigen is present, the patient should be followed with antibody titers. Once a critical threshold has been reached by a specific titer of a given RBC antigen antibody, the patient must undergo evaluation for fetal anemia. Most hospital laboratories use either a 1:16 or

Clinical Use of Doppler  57 1:32 threshold cut‐off and it is essential that each practitioner knows the threshold for their particular hospital or laboratory. Once the critical threshold has been reached, the patient needs to undergo either (i) an amniocentesis for assessment of ΔOD450 in the amniotic fluid or (ii) MCA PSV assessment using pulsed‐wave Doppler velocimetry. If the latter is available, it should receive priority over the amniocentesis simply because it avoids the risk associated with the amniocentesis and has very good performance characteristics as a screening test for moderate to severe anemia. If an amniocentesis is performed and the ΔOD450 is in the high zone 2 or zone 3 of the Liley or Queenan curve, then that fetus must undergo fetal blood sampling for documentation of the anemia and transfusion (see Protocol 42). Alternatively, if the MCA PSV is used to assess fetal anemia, a 1.55 multiple of the median (MoM) value should be used as a threshold above which fetal blood sampling and transfusion are needed. After one blood transfusion, the MCA PSV loses some accuracy and a different threshold for subsequent transfusion should be used (1.32 MoM has been suggested). The MCA PSV becomes increasingly less reliable for timing of subsequent transfusions and empiric intervals between transfusions are usually used: 7–10 days after the first transfusion, then two weeks until fetal bone marrow suppression is confirmed by Kleihauer–Betke stain and then three weeks thereafter. Administration of phenobarbital (30 mg PO TID) to enhance hepatic maturation can be considered at 34 weeks’ gestation or one week prior to delivery. Delivery of the anemic fetus receiving blood transfusion can generally be accomplished at between 36 and 37 weeks. If fetal blood sampling will be performed at a very preterm gestation, administration of betamethasone should be considered prior to the procedure.

Preterm labor Use of antiprostaglandin medications such as indomethacin for tocolysis results in inhibition of prostaglandin synthase activity and reduction in prostaglandin synthesis, which may constrict the ductus arteriosus. The effect on the ductus arteriosus is gestational age dependent and generally, indomethacin is not used beyond 32 weeks of gestation. A ductus arteriosus effect is not typically seen within the first 48 hours of treatment. Assessment of the velocity within the ductus arteriosus should be considered beyond that time if the patient continues prostaglandin synthase inhibitor therapy. Constriction is typically reversible with discontinuation of antiprostaglandin drugs.

Summary Color and pulsed‐wave Doppler velocimetry are useful ultrasound tools for the evaluation and management of fetuses with fetal anemia, growth restriction, congenital heart disease, and fetal arrhythmias. While Doppler

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ultrasound has been used in other fetal conditions, no study has demonstrated any clear clinical benefit for its use outside those stated above. Widespread use of the DV flow velocity waveforms in the diagnosis of Down syndrome in the first trimester has not yet occurred. Although this is a noninvasive tool to assess for Down syndrome, the emergence of maternal cell‐free fetal DNA screening is far more accurate with extremely high sensitivity for the detection of this chromosomal abnormality. While uterine artery Doppler evaluation of the high‐risk pregnancy might identify a subgroup of women who are at higher risk for adverse pregnancy outcome, the use of Doppler should not be considered a standard medical practice in the general population until further studies demonstrate benefit.

Suggested reading American College of Obstetricians and Gynecologists. Fetal Growth Restriction. Practice Bulletin. No 204. Obstet Gynecol 2019;133(2):e97–e109. Baschat AA, Genbruch U, Harman CR. The sequence of changes in Doppler and biophysical parameters as severe fetal growth restriction worsens. Ultrasound Obstet Gynecol 2001;18:571–7. Biggio JR Jr. Bed rest in pregnancy: time to put the issue to rest. Obstet Gynecol 2013;121(6):1158–1160. Ciscione AC, Hayes EJ. Uterine artery Doppler flow studies in obstetric practice. Am J Obstet Gynecol 2009;201(2):121–6. Committee on Practice Bulletins‐Obstetrics. Practice Bulletin No. 181: Prevention of Rh D Alloimmunization. Obstet Gynecol 2017;130(2):e57–e70. Ferrazzi E, Bellotti M, Bozzo M, et al. The temporal sequence of changes in fetal velocimetry indices for growth restricted fetuses. Ultrasound Obstet Gynecol 2002;19:140–6. Galan HL, Jozwik M, Rigano S, et al. Umbilical vein blood flow in the ovine fetus: comparison of Doppler and steady‐state techniques. Am J Obstet Gynecol 1999;181:1149–53. Hecher K, Bilardo CM, Stigter RH, et al. Monitoring of fetuses with intrauterine growth restriction: a longitudinal study. Ultrasound Obstet Gynecol 2001;18:564–70. Hecher K, Snijders R, Campbell S, Nicolaides K. Fetal venous, intracardiac, and arterial blood flow measurements in intrauterine growth retardation: relationship with fetal blood gases. Am J Obstet Gynecol 1995;173:10–15. Lees C, Marlow N, van Wassenaer‐Leemhuis A, et al. Perinatal morbidity and mortality in early‐onset fetal growth restriction: cohort outcomes of the trial of randomized umbilical and fetal flow in Europe (TRUFFLE). Lancet 2015;385:2162–72. Mari G. Middle cerebral artery peak systolic velocity for the diagnosis of fetal anemia: the untold story. Ultrasound Obstet Gynecol 2005;25:323–30. Mari G, Deter RL, Carpenter RL, et al. Collaborative group for doppler assessment of the blood velocity in anemic fetuses. Noninvasive diagnosis by Doppler ultrasonography of fetal anemia due to maternal red‐cell alloimmunization. N Engl J Med 2000;342:9–14. Mavrides E, Moscoso G, Carvalho JS, et  al. The anatomy of the umbilical, portal and hepatic venous systems in the human fetus at 14–19 weeks of gestation. Ultrasound Obstet Gynecol 2001;18(6):598–604. Moise KJ. The usefulness of middle cerebral artery Doppler assessment in the treatment of the fetus at risk for anemia. Am J Obstet Gynecol 2008;198:161.e1–161.e4.

Clinical Use of Doppler  59 Moise KJ, Huhta JC, Sharif DS, et al. Indomethacin in the treatment of premature labor: effects on the fetal ductus arteriosus. N Engl J Med 1998;319:327. Reed KL, Anderson CF, Shenker L. Changes in intracardiac Doppler blood flow velocities in fetuses with absent umbilical artery diastolic flow. Am J Obsetet Gynecol 1987;157:774. Rizzo G, Arduini D. Fetal cardiac function in intrauterine growth retardation. Am J Obstet Gynecol 1991;165:876–82. Scheier M, Hernandez‐Andrade E, Fonseca EB, Nicolaides KH. Prediction of severe fetal anemia in red blood cell alloimmunization after previous intrauterine transfusion. Am J Obstet Gynecol 2006;195:1550–6. Society for Maternal‐Fetal Medicine Publications Committee, Berkley E, Chauhan SP, Abuhamad A. Doppler assessment of the fetus with intrauterine growth restriction. Am J Obstet Gynecol 2012;206(4):300–8.

PROTOCOL 8

Antepartum Testing Michael P. Nageotte1,2 Miller Children’s and Women’s Hospital, Long Beach, CA, USA Department of Obstetrics and Gynecology, University of California, Irvine, CA, USA

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Antepartum fetal testing is utilized to assess fetal well‐being, especially in the complicated pregnancy. Several tests are utilized including the nonstress test (NST), the biophysical profile (BPP), the modified BPP, and the contraction stress test (CST).

Nonstress test The NST is currently the most common means of evaluation of fetal oxygenation status during the antepartum period. Less intensive than the CST in many regards, the NST evolved as an excellent means of fetal assessment following observations that the occurrence of two or more accelerations of the fetal heart during a CST most often predicted a negative CST while the absence of these accelerations of baseline fetal heart rate was associated with a positive test and poor perinatal outcome. The basic premise of the NST is that the fetal heart will accelerate its rate with fetal movement if the fetus is not acidotic or depressed neurologically. A reactive NST is defined by the presence of two or more accelerations of the fetal heart rate of at least 15 beats per minute lasting for at least 15 seconds within 20 minutes. Other definitions of reactivity have been proposed with a requirement of two or more accelerations in as little as 10 minutes before the test is considered reactive. If such accelerations are not elicited either spontaneously or with repeated vibroacoustic stimulation within 40 minutes of monitoring, the NST is interpreted as nonreactive. Options for further management include admission to hospital for delivery or extended monitoring or, more commonly, some form of backup test (e.g., a CST or BPP) is performed immediately. If the variable decelerations are repetitive or prolonged (lasting greater than one minute), the test is read as equivocal and a back‐up test is indicated at that time.

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The NST has a false‐negative rate of approximately 0.3% but this is influenced by indication for test and testing interval. Of note, most nonreactive NSTs have a normal back‐up test, which allows continuation of the pregnancy in most instances. The current recommendation is that the NST should be performed at least twice weekly.

Biophysical profile The fetal BPP is a frequently utilized method of antepartum fetal surveillance. The BPP score is a composite of four acute or short‐term variables (fetal tone, movement, breathing, and nonstress test) and one chronic or long‐term variable (amniotic fluid index). All four short‐term variables of the BPP are regulated by the fetal central nervous system (CNS). The fetal CNS is highly sensitive to decreases in the level of oxygenation and these biophysical variables are directly influenced by changes in the state of oxygenation of the fetus. In the presence of progressive hypoxemia, clinical studies have confirmed that reactivity is the first biophysical variable to disappear. This is followed by the loss of fetal breathing and subsequently the loss of fetal movement. Fetal tone is the last variable to be lost in the presence of ongoing in utero hypoxemia. Fetal urine production is the predominant source of amniotic fluid volume and is directly dependent upon renal perfusion. In response to sustained fetal hypoxemia, there is a long‐term adaptive response mediated by chemoreceptors located in the aortic arch and carotid arteries. This results in chemoreceptor‐mediated centralization of fetal blood flow by differential channeling of blood to vital organs in the fetus (brain, heart, adrenals), at the expense of nonessential organs (lung, kidney) by means of peripheral vasoconstriction. In cases of prolonged or repetitive episodes of fetal hypoxemia, there is a persistent decrease in blood flow to the lungs and kidneys resulting in a reduction in the amniotic fluid production leading to oligohydramnios. Amniotic fluid volume, therefore, is a reflection of chronic fetal condition. On average, it takes approximately 13 days for a fetus to progress from a normal to an abnormal amniotic fluid volume. The NST is first performed followed by the sonographic evaluation of fetal biophysical activities including fetal tone, movement, and breathing. Amniotic fluid volume is measured by holding the transducer perpendicular to the floor. The largest vertical pocket is selected in each quadrant. The composite of all four quadrants’ deepest vertical pockets is the amniotic fluid index (AFI). A total of 30 minutes is assigned for obtaining ultrasound variables. A normal variable is assigned a score of 2 and an abnormal variable a score of zero (see Table 8.1).

Antepartum Testing  63 Table 8.1  Fetal biophysical profile Biophysical variable

Normal (score = 2)

Abnormal (score = 0)

Nonstress test

Reactive: More than two accelerations of greater than 15 bpm for more than 15 seconds in 20 minutes More than one episode of more than 30 seconds in 30 minutes More than three discrete body/ limb movements in 30 minutes More than one active extension/ flexion of limb, trunk, or hand More than one pocket of fluid greater than 2 cm in two perpendicular planes

Nonreactive: Less than two accelerations of greater than 15 bpm for more than 15 seconds in 20 minutes Absence or less than 30 seconds in 30 minutes Fewer than two discrete body/ limb movements in 30 minutes Slow or absent fetal extension/ flexion No pocket greater than 1 cm in two perpendicular planes

Fetal breathing movements Gross body movements Fetal tone Amniotic fluid volume

Source: Based on Manning et al. (1980). Reproduced with permission of Elsevier.

A composite score of 8 or 10 is considered normal and correlates with the absence of fetal acidemia. A score of 6 is equivocal, and the test should be repeated in 24 hours, except in cases of oligohydramnios with intact membranes. In this particular instance, either delivery or close fetal surveillance is indicated depending on the gestational age. BPP scores of 4, 2 or 0 indicate fetal compromise and delivery should be strongly considered. The BPP score correlates linearly with fetal pH. A normal BPP score virtually rules out the possibility of fetal acidemia being present at the time of testing. A normal BPP result is highly reassuring, with a stillbirth (false‐negative) rate of 0.8 per 1000 within one week of the test. The positive predictive value of an abnormal BPP for evidence of fetal compromise (concerning fetal heart rate tracing in labor, acidemia, etc.) is approximately 50%, and a negative predictive value of 99.9% with a normal BPP. A BPP score of 6 has a positive predictive value of 25% while a score of 0 correlates with a compromised fetus in close to 100% of cases. Vibroacoustic stimulation (VAS) can be used as an adjunct in the assessment of BPP score without changing the predictive value of the test. Further, this may reduce unnecessary obstetric interventions. The BPP can either be used as a primary test for fetal well‐being in high‐ risk conditions or, more commonly, as a back‐up test for a nonreactive NST.

Modified biophysical profile Modified BPP is a commonly employed primary mode of fetal surveillance in many institutions. It takes into consideration the two most important predictors of fetal well‐being – fetal heart rate reactivity and amniotic fluid

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volume. The NST is an excellent predictor of normal fetal oxygenation when reactive. The amniotic fluid assessment is a means to evaluate the chronic uteroplacental function. The NST is performed in the usual manner and interpreted as previously defined. An amniotic fluid index is obtained as in the BPP and a value of greater than 5 is considered to represent a normal amount of amniotic fluid. The combination of the NST and ultrasonographic evaluation of amniotic fluid volume appears to be as reliable as BPP in acutely assessing fetal well‐being, with a very low incidence of false negativity. Indeed, the rate of stillbirth within one week of a normal modified BPP is the same as a normal BPP (0.8 per 1000). Consequently, the modified BPP is reliable, easy to perform and can be utilized as a primary means of surveillance. The testing frequency should be at least once per week. In a setting of an AFI of less than 8 but greater than 5, a repeat evaluation of the amniotic fluid is recommended within 3–4 days.

Contraction stress test The CST was historically the first method of fetal assessment using the noninvasive technique of fetal heart rate monitoring during the antepartum period. The test is based upon the fact that normal uterine contractions will restrict fetal oxygen delivery in a transient manner resulting from stasis of blood flow secondary to compression of maternal blood vessels in the uterine wall. Alterations in respiratory exchange in the maternal–fetal interface at the level of the placenta will result in differing responses of the fetus to interruption of maternal blood flow secondary to uterine contractions. If such contractions result in episodic fetal hypoxia, this will be demonstrated by the appearance of late decelerations of the fetal heart rate. The CST is performed over a period of 30–40 minutes with the patient in the lateral recumbent position while both the fetal heart rate and uterine contractions are simultaneously recorded utilizing an external fetal monitor. A frequency of at least three 40‐second or longer contractions in a 10‐minute period of monitoring is required and these contractions can be either spontaneous or induced with nipple stimulation or resulting from the intravenous infusion of oxytocin. The results of the CST are negative (no late or significant variable decelerations), positive (late decelerations following 50% or more of contractions), equivocal (intermittent late or significant variable decelerations or late decelerations following prolonged contractions of 90 seconds or more or with a contraction frequency of more than every two minutes), or unsatisfactory. A major problem associated with the CST is the high frequency of equivocal test results. Relative contraindications to the CST are those conditions associated with a significant increased risk of preterm labor, preterm rupture of

Antepartum Testing  65 membranes, placenta previa with bleeding or history of classic cesarean delivery or extensive uterine surgery. The CST has a remarkably low false‐negative rate of 0.04% (antepartum stillbirth within one week of a negative test) but up to 30% of positive tests when followed by induction of labor do not require intrapartum interventions for continued abnormalities of the fetal heart rate or adverse neonatal outcome. Because of the fact that the CST is more labor intensive, takes more time and has a high rate of equivocal test results, this test has generally been abandoned as the primary means of antepartum fetal surveillance. In some centers, the CST remains the primary test for women with type 1 diabetes. However, the CST remains a very reliable means of either primary or back‐up fetal surveillance for any number of high‐risk pregnancy conditions.

Umbilical Artery Doppler Velocimetry In pregnancies complicated with suspected intrauterine growth restriction in the third trimester, umbilical artery Doppler velocimetry has been used either as an adjunct to or in lieu of fetal heart rate testing. Doppler ultrasound ­testing is a noninvasive procedure which is used to assess the presence and severity of resistance within the umbilical artery. This resistance is typically reduced, absent or reversed during diastole in growth‐restricted fetuses in comparison to equal gestational age but normally growing fetuses. This end‐ diastolic flow is considered abnormal when it is either absent or reversed. The use of antepartum umbilical artery Doppler velocimetry has been shown to be of value but is limited to the management of pregnancies complicated with intrauterine growth restriction.

Indications for antepartum fetal surveillance In general, the American College of Obstetricians and Gynecologists has recommended antepartum testing for specific maternal and fetal conditions. Such testing is intended to reduce the risk of stillbirth and has been generally accepted. However, it should be noted that the benefit of fetal surveillance testing of whatever form is based solely on observational studies which allowed clinical intervention. These studies have consistently suggested that stillbirth rates in tested populations of at‐risk patients are significantly lower than those in either untested low‐risk patients or similarly risked pregnancies managed without fetal surveillance testing. There are a number of conditions associated with an increased risk of stillbirth for which fetal surveillance testing has been used routinely. Generally speaking, fetal surveillance testing is indicated in pregnancies complicated by conditions for which the stillbirth rate exceeds 0.8 per 1000

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(which is the false‐negative rate for either a normal biophysical profile or a normal modified biophysical profile) and which also have an increased relative risk for stillbirth of more than twofold when compared with pregnancies without such conditions. However, the mechanisms responsible for the increased risk of stillbirth for a specific abnormal pregnancy condition are generally unknown. Further, the lack of prospective studies establishing a benefit of reduced stillbirth with fetal testing in the management of such complicated pregnancies makes it challenging to establish a specific list of all indications for which antepartum testing is indicated. This also applies to the timing of testing initiation during pregnancy and frequency of testing. Newer examples of concerns for an increased risk of stillbirth but for which fetal surveillance testing has not previously been routinely recommended include conditions such as maternal obesity, advanced maternal age, pregnancy resulting from assisted reproductive techniques or pregnancies in women self‐reported as being black. While each of these conditions is a weak but potentially independent stillbirth risk factor, they are common and may present specific logistical, sociological, and systemic challenges if they are included as indications for antenatal fetal testing. Indeed, all indications for antepartum fetal testing should be considered as somewhat relative and may vary in significance among different providers. However, in general, the conditions for which fetal testing are recommended are listed below. • Maternal conditions: pregestational diabetes mellitus, hypertension, systemic lupus erythematosus, chronic renal disease, antiphospholipid syndrome, poorly controlled hyperthyroidism, hemoglobinopathy (such as sickle cell anemia, sickle‐hemoglobin C or sickle‐thalassemia disease), and cyanotic heart disease. • Pregnancy‐related conditions: preeclampsia, gestational hypertension, decreased fetal movement, oligohydramnios (deepest vertical pocket less than 2.0 cm), moderate or severe polyhydramnios (deepest vertical pocket 12.0 cm or greater or an AFI greater than 30.0 cm), intrauterine growth restriction, pregnancy at or beyond 41 completed weeks of ­gestation, ­isoimmunization, history of stillbirth, dichorionic twins with significant growth discrepancy or beyond 36 weeks’ gestation, monochorionic/­ diamniotic twins, premature rupture of membranes, and third‐trimester uterine bleeding. • Potential other indications: maternal age of 35 years or greater, obesity, ­maternal black race, suspected or confirmed fetal structural or genetic abnormalities, pregnancies conceived by in vitro fertilization, intrahepatic cholestasis of pregnancy, abnormal first‐ or second‐trimester serum analytes used in genetic risk assessment, abnormal umbilical cord findings such as vasa ­previa, single umbilical artery or velamentous cord insertion. The following general factors apply to testing. • Testing is generally initiated at 32–34 weeks for most patients; at 40 weeks for diet‐controlled gestational diabetics. However, it may begin as

Antepartum Testing  67 early as 26 weeks of gestation in pregnancies with multiple risk factors or when fetal compromise is suspected. The fetal heart rate reactivity may be diminished due to early gestational age and not necessarily reflect fetal compromise. Back‐up testing should be used whenever primary surveillance is of any concern. • Doppler velocimetry of the umbilical artery may be performed weekly in pregnancies complicated with suspected intrauterine growth restriction. This ultrasound procedure is generally performed in addition to biweekly nonstress testing. • A normal fetal surveillance heart rate test is typically  repeated on a twice‐weekly basis. • Test should be immediately repeated in the event of significant deterioration in the clinical status regardless of the time elapsed since the last test. Intervention with delivery is always a clinical decision and may be indicated with either normal or abnormal testing depending upon the clinical circumstances.

Suggested reading American College of Obstetricians and Gynecologists. Antepartum Fetal Surveillance. Practice Bulletin Number 145. Obstet Gynecol 2014;124:182–92. Baschat AA, Gembruch U, Harman CR. The sequence of changes in Doppler and biophysical parameters as severe growth restriction worsens. Ultrasound Obstet Gynecol 2001;18:571. Burgess JL, Unal ER, Nietert PJ, Newman RB. Risk of late‐preterm stillbirth and neonatal morbidity for monochorionic and dichorionic twins. Am J Obstet Gynecol 2014;210(6):578. Evertson LR, Gauthier RJ, Schifrin BS, Paul RH. Antepartum fetal heart rate testing. I. Evolution of the nonstress test. Am J Obstet Gynecol 1979;133:29. Freeman RK, Anderson G, Dorchester W. A prospective multi‐institutional study of antepartum fetal heart rate monitoring. I. Risk of perinatal mortality and morbidity according to antepartum fetal heart rate test results. Am J Obstet Gynecol 1982;143:771. Lagrew DC, Pircin RA, Towers CV, Dorchester W, Freeman RK. Antepartum fetal surveillance in patients with diabetes: when to start? Am J Obstet Gynecol 1993;168:1820. Manning FA, Platt LW, Sipos L. Antepartum fetal evaluation: development of a biophysical profile. Am J Obstet Gynecol 1980;136:787. Miller DA, Rabello YA, Paul RH. The modified biophysical profile: antepartum testing in the 1990s. Am J Obstet Gynecol 1996;174:812. Nageotte MP, Towers CV, Asrat T, Freeman RK. Perinatal outcomes with the modified biophysical profile. Am J Obstet Gynecol 1994;170:1672. Signore C, Freeman RK, Spong CY. Antenatal testing – a reevaluation. Executive summary of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Workshop. Obstet Gynecol 2009;113:687. Stillbirth Collaborative Research Network Writing Group. Association between stillbirth and risk factors known at pregnancy confirmation. JAMA 2011;306(22):2469.

PROTOCOL 9

Fetal Blood Sampling and Transfusion Patricia Santiago‐Munoz Department of Obstetrics and Gynecology, Division of Maternal‐Fetal Medicine, University of Texas Medical Center, Dallas, TX, USA

Clinical significance Fetal blood sampling or cordocentesis is a straightforward procedure where fetal blood is typically accessed at the site of the umbilical vein, using a long, small‐gauge spinal needle. Access to fetal blood via the hepatic vein or heart (cardiocentesis) has also been described. Fetal blood sampling is performed for various indications such as cytogenetic diagnosis, congenital infection, and fetal anemia. It is rarely performed for the evaluation of fetal coagulopathies and platelet disorders, given the potential risk for fetal hemorrhage secondary to the pathologies suspected. Most of the time cordocentesis is performed as the precursor to fetal transfusion.

Cytogenetic diagnosis As earlier and earlier identification of fetal anomalies with ultrasound ­ iagnostic has become more common, most patients who choose invasive d testing typically rely on chorionic villus sampling or amniocentesis, which can yield earlier results than cordocentesis would. In addition, the advent of noninvasive prenatal testing (NIPT) has also decreased patient requests for invasive testing overall, especially in the setting of normal sonographic findings. Cytogenetic analysis via fetal blood sampling is usually reserved for cases where quick turnaround of results is required, such as when a patient is nearing the gestational age for legal termination of pregnancy or when the results might affect delivery planning and neonatal management of a fetus with an anatomical abnormality.

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Fetal infection Cordocentesis is rarely used to evaluate or treat a fetus with congenital infection. Most diagnoses are suspected based on maternal serologies and ultrasound findings, and confirmed through polymerase chain reaction (PCR) in amniotic fluid. The one exception to this rule would be the evaluation and treatment of fetal parvovirus B19 infection, which causes fetal anemia via bone marrow failure.

Fetal anemia Given current technologies and diagnostic tools, most cordocenteses are done in the evaluation of the fetus suspected to be anemic, the overwhelming majority typically due to maternal severe red blood cell alloimmunization. Fetuses at risk of anemia are identified by serial Doppler interrogation of the middle cerebral artery to measure peak systolic velocity. A distant second indication for cordocentesis is parvovirus B19 infection. The literature reports other potential indications for fetal transfusion, including fetomaternal hemorrhage, twin anemia polycythemia sequence, and alpha‐thalassemia, as well as placental and fetal tumors, but because these indications are so rare, none of them has sufficient data to show that fetal transfusion leads to improved outcomes.

Procedure‐related risks Over the last 15 years, reported survival rates for intrauterine fetal transfusion for red cell alloimmunization have improved to over 90% in expert hands. Survival rates for parvovirus infection are lower, in the 70–80% range, likely related to late diagnosis in many cases. In the largest series to date of fetal intravascular transfusion, procedure‐related complications have decreased over time, from 9.8% to 3.3% per fetus. The two most common complications of fetal transfusion in this series were fetal demise and fetal distress leading to emergency cesarean delivery. Fetal distress may occur due to cord trauma or volume overload related to the procedure itself. Delayed complications include chorioamnionitis, premature rupture of membranes, and preterm labor but these are extremely rare. Needling of a free loop of cord, inadvertent arterial puncture, and failure to use fetal paralysis are all associated with higher rates of procedural complications. Nonetheless, procedure‐related fetal demise decreased over time in this large series of 1678 transfusions, from 1.6% to 0.6% per procedure. Associated risk factors for fetal loss include presence of fetal hydrops, early gestational age at first transfusion, and limited operator experience.

Fetal Blood Sampling and Transfusion  71

Long‐term effects There is evidence to suggest long‐lasting effects of fetal anemia seen in ­survivors of fetal blood transfusion. Studies done in these patients and in their nonanemic siblings show that the subjects who underwent transfusion were born at earlier gestation, and as adults have smaller left ventricular volumes, increased left ventricular wall thickness, and decreased myocardial perfusion at rest. This is important information that shows that cardiovascular development is altered in fetuses who survive anemia, which may have implications for adult cardiovascular health. Reassuringly, neurodevelopmental outcomes appear to be good, and at least one large study of over 1284 fetal transfusions performed in 451 fetuses in a 20‐year period showed that over 95% of the survivors had normal neurodevelopment.

Technique Fetal blood sampling Fetal blood sampling can be done in the outpatient setting and requires minimal preparation, especially in a previable pregnancy. As shown in Figure  9.1, a sterile field, a 22 gauge needle, heparinized syringes, and ultrasound guidance are typically all that is required for diagnostic cordocentesis. Color Doppler can help to identify umbilical cord vessels at their insertion into the placenta. Accessing the fetal umbilical vein at its placental insertion is preferred; this is the most stable point and the least likely to

Figure 9.1  A typical procedure tray set‐up for cordocentesis, with 22 gauge spinal needles

of varying lengths, 10 cc and 20 cc syringes to collect amniotic fluid samples, if needed, and heparinized syringes to collect a fetal blood sample. Sterile gel and ultrasound transducer probe cover are also shown in the image.

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allow the needle to dislodge. When this approach is technically difficult, the second choice should be the intrahepatic part of the umbilical vein. Alternatively, a free loop of cord can be used, which will prove more challenging and is also associated with a higher procedural loss rate. Placement into the lumen of the umbilical vein is immediately confirmed by observing either backflow of blood or turbulent flow in the cord when a saline flush is utilized and further documented by assessing putative fetal versus known maternal red blood cell (RBC) mean corpuscular volume (MCV) values. Fetal samples are drawn into heparinized syringes and sent for testing. Some streaming is expected from the cord once the needle is withdrawn.

Fetal blood transfusion Though diagnostic cordocentesis may be done in the outpatient setting, most fetal transfusions are performed in or near an operating room, particularly if a fetus is viable and a failed procedure might prompt delivery. The patient would be evaluated preoperatively by the obstetric anesthesia providers, as well as the NICU team, depending on gestational age. Anesthesia options for the mother range from regional block to sedation and local anesthetic. The NICU team will want to discuss with the patient the neonatal management of anemia in a newborn. Steroids for fetal lung maturation should also be considered preprocedurally depending on gestational age, though they are not used routinely in some major centers. It is a critical part of preparation for fetal blood transfusion to communicate with your blood bank/transfusion services, so they are aware of the request for a specially prepared unit. These units require a maternal “type and cross” for ½ to 1 unit of O negative, washed, leukoreduced, irradiated, cytomegalovirus (CMV)‐negative packed red blood cells (PRBC), with a hematocrit (Hct) of at least 75%. If there is suspicion of fetal thrombocytopenia (for instance, in cases of parvovirus) you may also need to order an aliquot of platelets for fetal transfusion. Preoperative testing of the mother should include complete blood count (CBC). You will need the maternal MCV to compare to the fetal MCV to ensure you have sampled the fetal blood, since fetal RBCs are larger than maternal RBCs. Labs to be drawn at the time of fetal blood sampling (fetal Hgb/Hct, MCV, blood type/Rh, and platelets) should be preordered in the medical record so results are processed in the most expeditious manner, since total transfusion volume will depend on those initial results. In anticipation of the fetal transfusion, you will want to make all calculations for transfusion volume ahead of time based on most recent estimated fetal weight. The original formula described by Rodeck and colleagues in 1984 is: Estimated fetal blood volume (mL) × [desired final Hct – initial fetal Hct] Hct of donor blood

Fetal Blood Sampling and Transfusion  73 Estimated fetal blood volume varies with gestational age but a good rule of thumb is 100 mL per kg. A helpful webpage for quicker calculations is www.perinatology.com/protocols/rhc.htm. As an example, assuming a Hct of 75% for the transfusion unit, and a 1600 g fetus with a starting Hct of 20% and an end Hct goal of 35%, you will need to transfuse 35 mL of blood. You will want to have worked out the possibilities for several starting hematocrits and chart them on a table so you don’t have to do math in your head while holding a needle inside the cord of a fetus! Generally, you might suspect a low Hct hematocrit based on sonographic findings (hydrops, for example) or other signs of fetal compromise. The goal at the first transfusion in such cases is to reach a closing Hct of 30–35%. Overtransfusion might put the fetus at risk of heart failure. The compromised fetus might need follow‐up transfusion within a week of the initial one with a goal of closing Hct 40–45%. Thereafter transfusions are scheduled depending on the diagnosis and severity of disease. The preferred route of fetal transfusion is intravascular, via the umbilical vein. On occasion, related to fetal position or posterior placenta, it might be technically impossible to access the umbilical vein at the cord, making it necessary to access the intrahepatic portion of the umbilical vein. In the very premature or hydropic fetus, intraperitoneal transfusion may also be performed by injecting donor blood directly into the fetal peritoneal cavity, where blood would be absorbed through lymphatics. Absorption of the transfused blood may not be optimal in these situations. A typical set‐up for fetal transfusion is shown in Figure  9.2. Your OR table should be readied with prepared syringes with paralytics and sedative for the fetus. The appropriate doses are based on estimated fetal weight: the usual dose for vecuronium is 0.1 mg/kg, and typical dose for fentanyl is 10 μg/kg. Though these may not be needed, especially in the case of an anterior placenta with easy access to the placental cord insertion site, use of paralytics has been associated with lower rates of procedure‐related fetal loss. You will also need heparinized syringes to draw fetal blood samples for testing. These can be prepared by drawing heparin into 1 cc syringes. Caution is required when using heparinized syringes: you will need to waste the heparin from each syringe immediately prior to drawing a fetal sample. IV tubing for your transfusion circuit, sterile probe and ultrasound covers, and spinal needles should be placed on the procedure table as well. Once your OR table set‐up is complete, follow sterile technique to prep and drape the maternal abdomen. Most large studies conclude that routine antibiotic prophylaxis is not necessary. Your ultrasound machine should ideally have a clear plastic sterile cover over the control panel, so you can continue to manipulate your image settings even after you are gowned up in sterile fashion. A sterile probe cover is part of the usual prep of equipment as well. Prior to your initial attempt at sampling of the cord, prime the transfusion circuit. The specifics of a transfusion circuit may vary, but typically consist

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Figure 9.2  A typical OR procedure table set‐up for fetal blood transfusion. Left to right,

top: Labeled syringe with fetal dose of fentanyl; labeled syringes with fetal dose of vecuronium; labeled syringes with saline to flush the transfusion circuit as needed; marker; three‐way stopcock with attached 10 or 20 cc syringe in the middle port to serve as blood reservoir, as well as IV tubing, one lateral port leading to the donor blood unit and the other port leading to the fetus; 4 × 4 OR sponges. Left to right, bottom: Syringes with heparin to collect fetal blood samples; 20 or 22 gauge spinal needles of varying length; sterile ultrasound probe cover; sterile ultrasound gel; OR drape.

of simple IV tubing connecting the donor blood unit to the lateral port of a three‐way stopcock, and another piece of simple IV tubing extending from the other lateral port, to connect to the spinal needle that accesses the fetal intravascular space. This fetal side of the circuit remains closed while a 10 or 20 cc syringe attached to the middle port is used to draw blood into it to use as a reservoir. Make sure that you and your assistant are familiar with the on/off twisting of the three‐way stopcock and how it changes direction of flow prior to starting the procedure. Accessing the cord is the same as in a diagnostic cordocentesis: using your 22 gauge needle and under continuous ultrasound guidance, you will puncture the fetal umbilical vein and direct the tip of the needle to its lumen. When you think you are in the cord, connect your transfusion circuit to the spinal needle. Maintaining the circuit closed to the donor blood, the middle port of the three‐way stopcock is used to confirm needle placement with a saline flush; you should see turbulent flow within the cord as the fluid is pushed through. Once placement is confirmed, use a heparinized syringe to obtain a fetal blood sample. That initial sample is sent to the OR or STAT lab for processing, and you may start transfusion (at a rate of 3–5 mL/min) while you wait for results. To transfuse, you will pull blood from the donor unit into the reservoir and then push it towards the fetus from the reservoir, opening and closing the ports of the three‐way stopcock as needed to guide the flow of blood in

Fetal Blood Sampling and Transfusion  75 the right direction. As you transfuse, continue to watch for movement of the blood within the cord, which will appear as echogenic turbulent flow, and keep an eye on the fetal heart rate to make sure the fetus is tolerating the procedure. After you have transfused the necessary blood volume, you will want a closing sample to confirm that you have reached your goal Hct. Once you have removed the needle from the cord, you might observe streaming of blood from the puncture site, which is expected.

Postprocedure care The patient post fetal transfusion will need fetal monitoring to ascertain a reassuring fetal status, and to evaluate for preterm labor. There are no data to suggest a particular length of monitoring post procedure, but if contractions are noted on tocometry, a 24‐hour observation period on Labor and Delivery would be reasonable. Most centers perform fetal transfusion up to 35 weeks of gestation with delivery anticipated at 37–38 weeks. However, every fetal transfusion carries the risk of a procedure‐related loss, especially in the already compromised fetus, so every decision for repeat transfusion should be individualized. Once discharged from the hospital, the patient should return for follow‐ up sonographic evaluation within a week. Doppler of the fetal middle ­cerebral artery and other sonographic findings will still guide timing of next procedure.

Future directions The largest volume of cordocenteses and fetal transfusions is done for the evaluation and treatment of fetuses with suspected anemia, usually due to red cell alloimmunization. Besides fetal transfusion, other interventions have been tested to prevent or decrease the severity of fetal anemia in cases of early and severe maternal red cell alloimmunization. These include treatment with either plasmapheresis or IVIG alone or in combination for an attempt at immunomodulation of the disease. There is currently ongoing research into the development of a human IgG1 monoclonal antibody targeting FcRn, the receptor responsible for mediating transfer of IgG across the placenta into the fetal circulation. If these interventions prove successful, they may delay or perhaps eliminate the need for fetal transfusion in some situations.

Suggested reading Deka D, Dadhwal V, Sharma AK, et al. Perinatal survival and procedure‐related complications after intrauterine transfusion for red cell alloimmunization. Arch Gynecol Obstet 2016;293(5):967–73.

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Dodd JM, Windrim RC, van Kamp I. Techniques of intrauterine fetal transfusion for women with red‐cell alloimmunization for improving health outcomes. Cochrane Database Syst Rev 2012;(9):CD007096. Hellmund A, Geipel A, Berg C, et al. Early intrauterine transfusion in fetuses with severe anemia caused by parvovirus B19 infection. Fetal Diagn Ther 2018;43(2):129–37. Lindenburg ITM, Smits‐Wintjens VE, van Klink JM, et  al. Long‐term neuro‐developmental outcome after intrauterine transfusion for hemolytic disease of the fetus/newborn: the LOTUS study. Am J Obstet Gynecol 2012;206:141.e1–148.e8. Lindenburg ITM, van Kamp I, Oepkes D. Intrauterine blood transfusion: current indications and associated risks. Fetal Diagn Ther 2014;36:263–71. Ruma MS, Moise KJ Jr, Kim E, et al. Combined plasmapheresis and intravenous immune globulin for the treatment of severe maternal red cell alloimmunization. Am J Obstet Gynecol 2007;196;138.e1–138.e6. Wallace AH, Dalziel SR, Cowan BR, et al. Long‐term cardiovascular outcome following fetal anaemia and intrauterine transfusion: a cohort study. Arch Dis Child 2017;102(1):40–5. Zwiers C, Lindenburg ITM, Klumper FJ, et al. Complications of intrauterine intravascular blood transfusion: lessons learned after 1678 procedures. Ultrasound Obstet Gynecol 2017;50:180–6. Zwiers C, van der Bom JG, van Kamp I, et al. Postponing Early Intrauterine Transfusion with Intravenous immunoglobulin Treatment: the PETIT study on severe hemolytic disease of the fetus and newborn. Am J Obstet Gynecol 2018;219:291.e1–9. Zwiers C, van Kamp I, Oepkes D, Lopriore E. Intrauterine transfusion and non‐invasive treatment options for hemolytic disease of the fetus and newborn – review on current management and outcome. Exp Rev Hematol 2017;10(4):337–44.

PROTOCOL 10

Preconception Genetic Screening Lauren Sayres1 and Jeffrey A. Kuller2 Division of Maternal Fetal Medicine, University of Colorado, Aurora, CO, USA Department of Obstetrics and Gynecology, Division of Maternal‐Fetal Medicine, Duke University School of Medicine, Durham, NC, USA 1

2 

Overview Carrier screening is defined as testing performed on individuals to assess whether they carry one allele for a genetic condition for which they do not have the phenotype. The American College of Obstetricians and Gynecologists (ACOG) recommends that all pregnant women be provided information about carrier screening. Ideally, this carrier screening is performed prior to conception to maximize reproductive options and facilitate decision making. Ethnic, panethnic, and expanded carrier screening are all acceptable strategies for carrier screening. ACOG recommends that each obstetrician‐gynecologist or healthcare provider should establish a standard approach to screening. Historically, screening has been offered based on the individual’s pretest risk of carrier status as determined by her racial or ethnic background or her family history. However, in an increasingly multiethnic society, such targeted strategies are being supplanted by panethnic screening algorithms. With the advent of lower cost, high‐throughput genotyping technology, expanded carrier screening panels that evaluate for hundreds of conditions are being introduced. ACOG has recommended the following screening criteria for disorders that should be included in expanded panels. Carrier frequency should be 1 in 100 or greater, corresponding to a disease incidence of 1 in 40 000. The phenotype associated with the condition should be well defined, occur early in life, and cause significant physical or cognitive impairment or affect quality of life. The condition will ideally be amenable to prenatal diagnosis, changes to antenatal or delivery management, and parental education about coordination of care after delivery. In contrast to diseases for which newborn screening is mandated, carrier screening is offered for lethal conditions such as Tay–Sachs disease that do not necessarily have postnatal intervention strategies. Protocols for High-Risk Pregnancies: An Evidence-Based Approach, Seventh Edition. Edited by John T. Queenan, Catherine Y. Spong and Charles J. Lockwood. © 2021 John Wiley & Sons Ltd. Published 2021 by John Wiley & Sons Ltd.

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The purpose of this chapter is to review specific genetic conditions for which carrier screening is most commonly offered. We review the clinical significance, cause, and screening recommendations for each condition.

Cystic fibrosis Clinical significance Cystic fibrosis is a progressive disease that has severe effects on the pulmonary, pancreatic, hepatic, and gastrointestinal systems. The majority of males with cystic fibrosis also have primary infertility due to absence of the bilateral vas deferens. The median predicted survival is 42 years of age. The incidence is 1 in 2500 among Caucasian individuals but significantly lower in other populations. The carrier rates are approximately 1 in 25 for Ashkenazi Jewish and Caucasian populations, 1 in 60 for Hispanics and African Americans, and 1 in 94 for those of Asian ancestry.

Genetic etiology Cystic fibrosis is caused by autosomal recessive inheritance of a mutation of the CFTR gene. CFTR is responsible for production of proteins that aid in transmembrane transport of chloride and regulate the activity of other ion channels. Greater than 2000 CFTR mutations have been identified, although most of the mutations are exceptionally rare. Individuals with cystic fibrosis can be homozygotes or compound heterozygotes. Genotype can provide some insight into phenotype due to variable effects of these mutations on the chloride channel proteins.

Screening Screening for cystic fibrosis should be offered to all women who are considering pregnancy or are currently pregnant. The sensitivity of screening varies significantly among individuals of different races and ethnicities given the variable carrier rate of different mutations. Detection rates range from 49% to 94% depending on the population being screened. Individuals should be counseled that a negative screen cannot completely rule out ­carrier status. The American College of Medical Genetics and Genomics (ACMG) recommends use of a panel that screens for the most common 23 or greater CFTR mutations. Expanded panels may minimally improve detection rate of carriers, particularly among those of Caucasian backgrounds. Additionally, CFTR sequencing may be useful for individuals with a family history of cystic fibrosis who have negative screening panels, although it is not recommended for routine carrier screening because ­variants of uncertain significance may be discovered and thus preclude practitioners’ ability to provide meaningful counseling.

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Spinal muscular atrophy Clinical significance Spinal muscular atrophy is a disease that results in diffuse and progressive muscle atrophy. Its effects range widely from onset of severe muscle weakness in infancy and early death from respiratory failure to mild muscle weakness in adults with otherwise normal survival. There are several types of spinal muscular atrophy which are based on age at onset of symptoms. The phenotypes are characterized in order of severity from type 1 (most severe) to type 4 (least severe). Of genetic disorders, spinal muscular atrophy is relatively common, with an incidence of 1 in 8000 live births and a carrier rate of 1 in 35 to 1 in 117, depending on ethnicity. It is the most common cause of infant death by a monogenic etiology.

Genetic etiology The SMN1 gene and, to a lesser extent, the SMN2 gene are responsible for the production of survival motor neuron proteins, which inhibit degradation of anterior horn cells and motor nuclei. Most cases of spinal muscular atrophy are caused by a deletion or mutation in SMN1, found on chromosome 5, resulting in deficient protein production. In a noncarrier, there is typically one copy of SMN1 per chromosome, although rarely two copies can be present on the same chromosome. The number of ­copies of SMN2 per chromosome ranges from zero to three. In affected individuals, SMN2 copy number modifies the overall production of the protein, with a greater copy number corresponding to milder clinical phenotypes (types 3 and 4).

Screening Screening for spinal muscular atrophy should be offered to all women who are considering pregnancy or are currently pregnant. Screening entails evaluation of the number of copies of SMN1, which is two in nonaffected noncarriers of spinal muscular atrophy. It is important to note that some individuals will have a chromosome with two copies and a chromosome with zero copies, which will be detected as a normal overall SMN1 copy number of two; these individuals are unaffected but can transmit a chromosome with zero copies of SMN1 to their offspring, who will thus be affected. Therefore, individuals should be counseled regarding the residual risk of carrier status despite a normal screening result. There is also a relatively high 2% de novo mutation rate of SMN1 that limits the ability to completely determine risk of spinal muscular atrophy. Copy number of SMN2 is generally not tested as part of carrier screening (and therefore, carrier screening cannot predict phenotype) but is used for prognostic purposes in the setting of diagnostic testing.

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For individuals with a family history of spinal muscular atrophy, reports of genetic testing of the affected individual and carrier testing of the parent should be reviewed to determine residual risk in the setting of a negative screen. If reports are unavailable, testing should instead be offered to the low‐risk partner.

Hemoglobinopathies Clinical significance Hemoglobinopathies can be divided into sickle cell disorders and thalassemias. Sickle cell disorders lead to vasoocclusion, pain, and infarcts in vital organs including the spleen, kidneys, heart, lungs, and brain. Hemoglobin S, the most common variant hemoglobin leading to sickle cell disease, is carried by approximately 1 in 10 African Americans but fewer than 1 in 100 Hispanics or non‐Hispanic whites or Asians. Alpha‐thalassemia minor causes mild anemia, hemoglobin H disease causes hemolytic anemia with splenomegaly and iron overload, and alpha‐thalassemia major (hemoglobin Bart disease) causes hydrops fetalis with intrauterine fetal demise. Alpha‐thalassemia is more common among individuals of African, Mediterranean, Middle Eastern, and Southeast Asian backgrounds, with carrier status among these groups ranging from 1 in 3 to 1 in 30. Beta‐thalassemia minor causes mild anemia, while beta‐thalassemia major causes severe anemia and poor growth, resulting in childhood death in the absence of treatment. Beta‐thalassemia is more common among those with Mediterranean, Middle Eastern, Asian, and Indian ancestry and has a carrier frequency as low as 1 in 8 among certain populations.

Genetic etiology Hemoglobin A, the normal adult form of hemoglobin, is comprised of two alpha and two beta globin chains. Sickle cell disorders are due to an abnormal combination of hemoglobin structural variants including S, C, or E, or one of these variants coupled with a thalassemic mutation. Such variant sickle cell hemoglobins are produced by single nucleotide alterations in the beta globin chain. Alpha‐thalassemia is due to deletion of two (alpha‐thalassemia minor), three (hemoglobin H disease), or four (alpha‐thalassemia major or hemoglobin Barts) of the four copies of the alpha globin gene which results in decreased or absent production. Notably, a cis‐mutation of alpha globin, defined as deletion of both alpha globin copies on the same chromosome, is more common among those of Southeast Asian background and is more likely to result in hemoglobin H disease or alpha‐thalassemia major. In contrast, a transmutation where a single deletion is found on each chromosome (more common among those of African American race) is less

Preconception Genetic Screening  81 likely to result in a fetus with alpha‐thalassemia major. Beta‐thalassemia minor occurs among heterozygotes with a beta globin gene mutation resulting in deficient production; beta‐thalassemia major is due to homozygosity or compound heterozygosity of a mutated beta globin gene that causes decreased to absent production. When the production of alpha or beta globin is impaired, increasing quantities of variant hemoglobin, such as hemoglobin F or A2, are produced relative to the production of normal hemoglobin A, causing the variation in disease states described above.

Screening The American College of Obstetricians and Gynecologists recommends initial screening of all populations with a complete blood count. This should be followed by reflex to hemoglobin electrophoresis in the presence of a microcytosis (low mean corpuscular hemoglobin or low mean corpuscular volume) and among individuals of African, Mediterranean, Middle Eastern, Southeast Asian, or Indian descent. Hemoglobin electrophoresis is the gold standard for diagnosis of sickle cell disorders and thalassemias. Solubility tests, isoelectric focusing, and high‐performance liquid chromatography can fail to identify certain hemoglobinopathy traits that can have important reproductive consequences and therefore are generally not used for primary screening. Beta‐thalassemia will be detected through a hemoglobin constitution of greater than 3.5% hemoglobin A2 and a variably elevated hemoglobin F because beta globin is not present in either of these hemoglobin variants. Alpha‐thalassemia trait may result in a normal hemoglobin electrophoresis and therefore requires diagnosis with DNA‐based testing, which should be pursued in the setting of a low mean corpuscular volume only after iron deficiency anemia and beta‐thalassemia have been excluded and usually after the patient’s partner is also found to be a thalassemia carrier.

Fragile X syndrome Clinical significance Fragile X syndrome causes intellectual disability that ranges from mild to severe. It can be associated with autism spectrum disorder and physical anomalies. Affected males tend to have a much more severe phenotype, but females can be affected as well. Premature ovarian failure and fragile X‐associated tremor/ataxia, which causes late onset of Parkinsonism, can affect female and male carriers of fragile X premutation but not intermediate expansion (defined below) respectively. The incidence is 1 in 3600 males and 1 in 5000 females. The carrier frequency depends on family history of developmental delay and ranges from 1 in 86 to 1 in 257.

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Genetic etiology Most cases of fragile X syndrome are caused by an expansion in the number of CGG repeats in the FMR1 gene. The normal range of repeats is between 5 and 44. Repeat size of 45 to 54 is considered to be of intermediate expansion; 55 to 200 repeats is a premutation; and greater than 200 repeats represents a full mutation. With any number of repeats beyond 44, the region becomes unstable and can lead to expansion during gene replication in oogenesis but generally not spermatogenesis. Hence, a female carrier of CGG repeat number in the premutation range can transmit a full mutation to her offspring. A female carrier of an intermediate expansion, however, can transmit only a premutation but not a full mutation (therefore, risk is assumed by her grandchildren rather than children). A chromosome with a full mutation results in hypermethylation of the DNA, impaired transcription of the downstream FMRP protein, and impaired prenatal and postnatal brain development.

Screening Women with a family history of intellectual disability that is confirmed or suspected to be due to fragile X syndrome are recommended to undergo carrier screening. Although neither ACOG nor ACMG recommends universal screening, guidelines state that it is reasonable to offer carrier screening to any individual requesting screening after appropriate counseling. If a woman is found to carry a premutation or full mutation, diagnostic testing should be offered. Chorionic villus sampling can determine number of CGG repeats but is limited in its ability to determine FMR1 gene methylation; amniocentesis can more reliably determine both repeat number and methylation status.

Tay–Sachs disease and other disorders more prevalent in individuals of Ashkenazi Jewish descent Clinical significance Due to founder effects, a number of diseases are more common among individuals of Ashkenazi (Eastern and Central European) Jewish descent. These include Tay–Sachs disease, Canavan disease, familial dysautonomia, Gaucher disease, Fanconi anemia, and a number of other rare disorders. While the clinical manifestations of each of these diseases vary, they have in common severe metabolic, neurologic, or other consequences that lead to early morbidity and mortality. The carrier rates range from 1 in 15 to 1 in 168 for those of Ashkenazi Jewish descent but are typically much rarer in other populations. Tay–Sachs disease specifically is carried by 1 in 30 individuals with Ashkenazi Jewish backgrounds and 1 in 50 individuals of French Canadian, Cajun, and Irish descent.

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Genetic etiology These conditions are inherited in an autosomal recessive manner. Most are caused by mutations that have been clearly characterized among individuals of Ashkenazi Jewish background but are often uncertain among other populations.

Screening The American College of Obstetricians and Gynecologists recommends that carrier screening for Tay–Sachs disease, Canavan disease, familial dysautonomia, and cystic fibrosis be offered to those of Ashkenazi Jewish ancestry, while the ACMG recommends screening for a panel of nine genetic conditions (see Table 10.1). Expanded screening panels that cover these conditions as well as a broader range of conditions more commonly carried by the Ashkenazi Jewish population are also available. Tay–Sachs screening is also recommended for individuals of French Canadian, Cajun, and Amish backgrounds or those with a family history. For a couple where one partner is Ashkenazi Jewish, the person of Ashkenazi Jewish background should be tested first. Counseling regarding residual risk should be performed, particularly whenever screening an individual without Ashkenazi Jewish ancestry, due to the potential to be a carrier of a rare mutation. In the case of screening for Tay–Sachs disease, DNA‐based mutation analysis is highly effective for those in high‐risk populations. However, the serum or leukocyte hexosaminidase enzymatic activity (the enzyme that is deficient in those affected by Tay–Sachs disease) can be used to distinguish carriers from noncarriers in a manner that is not specific to ethnic background. Because it is not mutation specific, biochemical analysis is more sensitive and therefore preferred for screening for Tay–Sachs disease among individuals of nonhigh‐risk ancestry. Table 10.1  Recommended carrier screening for individuals of Ashkenazi Jewish

backgrounds American College of Obstetricians and Gynecologists

American College of Medical Genetics and Genomics

Cystic fibrosis Tay–Sachs disease Familial dysautonomia Canavan disease

Cystic fibrosis Tay–Sachs disease Familial dysautonomia Canavan disease Fanconi anemia (group C) Niemann–Pick disease (type A) Bloom syndrome Mucolipidosis IV Gaucher disease

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Management and follow‐up Carrier screening is optional. It is critical that patient counseling be performed and consent be obtained prior to screening. In the context of expanded panels, for which all conditions cannot be specifically addressed, this education should include a description of the general types of conditions being screened and their common clinical features. Patients should be informed of the potential benefits of acquiring information and the availability of preimplantation genetic diagnosis, donor gametes, prenatal diagnosis and management, coordination of postnatal care, pregnancy termination, and adoption services. There should be a clear process for post‐test counseling and offering of screening to the patient’s reproductive partner or diagnostic testing of the pregnancy in the setting of a positive result. The limitations of carrier screening, including the concept of residual risk and the evolving landscape of expanded panels, should be explained in advance of screening. Efforts should be made to ensure confidentiality of genetic screening results. It is important to note that carrier screening can complement, but does not replace, state‐ mandated newborn screening.

Conclusion Preconception carrier screening is being offered for an increasing number of genetic conditions and to a broadening population of patients. It is incumbent on providers to stay abreast of the types of screening offered through clinical and commercial laboratories. We must educate pregnant women and those considering pregnancy on the availability of screening. As screening expands, so must our pretest and post‐test counseling surrounding the potential benefits and risks of this screening and the implications and follow‐up for both positive and negative results. Professional guidelines should continue to be updated to reflect scientific developments and the changing role of carrier screening.

Suggested reading American College of Obstetricians and Gynecologists. Carrier screening for genetic conditions. Committee Opinion 691. Obstet Gynecol 2017;129:e41–55. American College of Obstetricians and Gynecologists. Family history as a risk assessment tool. Committee Opinion 478. Obstet Gynecol 2011;117:747–50. American College of Obstetricians and Gynecologists. Carrier screening in the age of genomic medicine. Committee Opinion 690. Obstet Gynecol 2017;129:e35–40. Brennan ML, Schrijver I. Cystic fibrosis: a review of associated phenotypes, use of molecular diagnostic approaches, genetic characteristics, progress, and dilemmas. J Mol Diagn 2016;18:3–14.

Preconception Genetic Screening  85 Edwards J, Feldman G, Goldberg J, et  al. Expanded carrier screening in reproductive medicine – points to consider. A joint statement of the American College of Medical Genetics and Genomics, American College of Obstetricians and Gynecologists, National Society of Genetic Counselors, Perinatal Quality Foundation, and Society for Maternal‐ Fetal Medicine. Obstet Gynecol 2015;125:653–62. Hoffman JD, Park JJ, Schreiber‐Agus N, et al. The Ashkenazi Jewish carrier screening panel: evolution, status quo, and disparities. Prenat Diagn 2014;34:1161–7. Hussein N, Weng SF, Kai J, Kleijnen J, Qureshi N. Preconception risk assessment for thalassemia, sickle cell disease, cystic fibrosis, and Tay–Sachs disease. Cochrane Database Syst Rev 2015;(8):CD010849. Kraft SA, Duenas D, Wilifond BS, Goddard KAB. The evolving landscape of expanded carrier screening: challenges and opportunities. Genet Med 2019;21:790–7. MacDonald WK, Hamilton D, Kuhle S. SMA carrier testing: a meta‐analysis of differences in test performance by ethnic group. Prenat Diagn 2014;34:1219–26. Nolin SL, Brown WT, Glicksman A, et  al. Expansion of the fragile X CGG repeat in females with permutation or intermediate alleles. Am J Hum Genet 2003;72:454–64. Vrettou C, Kakourou G, Mamas T, Traeger‐Synodinos J. Prenatal and preimplantation diagnosis of hemoglobinopathies. Int J Lab Hematol 2018;40:74–82.

PA R T 3

Maternal Disease

PROTOCOL 11

Maternal Anemia Elaine Duryea Maternal Fetal Medicine, Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, TX, USA

A comprehensive review of all causes of anemia may be intimidating, and many available algorithms are not high yield when evaluating pregnant women. The protocol presented here provides an algorithm for the initial evaluation of anemia in pregnancy, with treatment algorithms for the most common causes in pregnancy. Women who do not meet one of the definitions provided below are best managed in consultation with a hematologist.

Definition During a singleton gestation, plasma volume doubles (increasing approximately 1000 mL) and red blood cell (RBC) volume increases by 25% (300 mL), with RBC production lagging slightly behind plasma expansion. This results in a physiological dilutional anemia of pregnancy, which reaches a nadir during the late second to early third trimester (Table 11.1). The Centers for Disease Control and Prevention (CDC) define anemia as a hemoglobin (Hb) below the fifth centile for a healthy, iron‐supplemented population. This translates to a threshold of Hb less than 11 g/dL in the first and third trimesters, and less than 10.5 g/dL during the second trimester. Rates of anemia in pregnancy vary widely between different populations and socioeconomic classes.

Consequences In developed countries, maternal anemia has been associated with increased risk of preterm birth and low‐birthweight infants, as well as neonatal and perinatal death. In addition, maternal complications associated

Protocols for High-Risk Pregnancies: An Evidence-Based Approach, Seventh Edition. Edited by John T. Queenan, Catherine Y. Spong and Charles J. Lockwood. © 2021 John Wiley & Sons Ltd. Published 2021 by John Wiley & Sons Ltd.

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Table 11.1  Changes in laboratory values in pregnancy

Hemoglobin (g/dL) Hematocrit RBC count (× 106/mL) MCV (fL) MCHC Reticulocytes (× 109/L) Ferritin (ng/mL) RDW (red cell distribution width)

Nonpregnant women

Pregnant women

12–16 36–46% 4.8 80–100 31–36% 50–150 >25 11–15%

11–14 33–44% 4.0 = = = >20 =

=

 , unchanged. Source: Based on ACOG Practice Bulletin No. 107, 2009.

with anemia include preeclampsia, cesarean delivery, postpartum depression, and an increased likelihood for transfusion either intrapartum or postpartum despite equivalent blood loss. Women with anemia are asymptomatic or describe vague symptoms such as fatigue and palpitations; therefore, screening for anemia during pregnancy is recommended regardless of symptoms.

Diagnostic work‐up and treatment Causes of anemia may be classified by pathophysiology, such as comparing acquired versus inherited causes, or mechanisms of anemia such as decreased RBC production versus increased destruction. In clinical practice, more often the evaluation of maternal anemia starts with the mean corpuscular volume (MCV), based on which anemias are defined as microcytic (less than 80 fL), normocytic (80–100 fL) or macrocytic (greater than 100 fL) (Figure 11.1).

Macrocytic anemia Figure 11.1 shows the appropriate work‐up for the search of causes in the presence of macrocytic anemia. Vitamin B12 deficiency is rare, as most healthy individuals have 2–3 years’ storage available in the liver. However, vitamin B12 deficiency can be encountered in individuals who have undergone bariatric surgery with partial gastric resection and are noncompliant with recommended vitamin B12 supplementation (350 μg/day sublingually plus 1000 μg IM every three months if needed), in individuals with pernicious anemia (an extremely uncommon autoimmune disease in women of reproductive

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Macrocytic (MCV >100 fL) Microcytic (MCV 95%. • Mode of delivery according to normal maternal/fetal indications. • Alert pediatric team if neonate is at risk for hemoglobinopathy.

Postpartum management • Continue to ensure adequate analgesia and hydration. • Maintain oxygen saturations >95%. • Contraception counseling including consideration of immediate postpar­ tum long‐acting reversible contraception (LARC). All forms of contracep­ tion are safe in SCD (category 1 or 2 according to CDC Medical Eligibility Criteria). • Avoid hydroxyurea if breastfeeding. If not breastfeeding, can consider restarting hydroxyurea in consultation with SCD provider/hematologist.

Pregnancy management of thalassemias Management of thalassemias in pregnancy does not differ significantly from management of low‐risk pregnancies. Patients who are affected or are car­ riers of either alpha‐thalassemia or beta‐thalassemia should be referred for genetic counseling and partner testing to assess risk for an affected fetus. Should they be at risk of an affected fetus, diagnostic prenatal testing should be discussed and offered in conjunction with a maternal‐fetal medicine consultation. Patients with alpha‐thalassemia trait and HbH overall have favorable pregnancy outcomes affected by mild to moderate anemia and their care should not differ significantly from routine prenatal care. Patients with beta‐thalassemia minor will often have only a mild asymptomatic anemia.

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There have been reports of higher rates of fetal growth restriction with beta‐thalassemia minor and therefore a third‐trimester growth ultrasound should be considered. In all patients with any form of thalassemia, regular monitoring for anemia should be performed. Iron supplementation should not exceed normal prophylactic doses of iron unless laboratory evidence of iron deficiency is noted. Pregnancies in women with beta‐thalassemia major were rare prior to the introduction of hypertransfusion and iron chelation therapy. Reports since that time have shown overall favorable outcomes. Per the American College of Obstetricians and Gynecologists, pregnancy in women with beta‐thalassemia is only recommended for those with normal cardiac function and who have undergone prolonged hypertransfusion therapy with iron chelation. These patients are at risk of fetal growth restriction and should be monitored with serial growth ultrasounds. During pregnancy, the goal for these patients is to maintain hemoglobin levels around 10 g/dL with serial transfusions as neces­ sary. Iron chelation therapy is typically deferred during pregnancy given the paucity of data on its safety in pregnancy.

Suggested reading American College of Obstetricians and Gynecologists. ACOG Practice Bulletin No. 78: hemoglobinopathies in pregnancy. Obstet Gynecol 2007;109(1):229–37. Boafor TK, Olayemi E, Galadanci N, et al. Pregnancy outcomes in women with sickle‐cell disease in low and high income countries: a systematic review and meta‐analysis. Br J Obstet Gynaecol 2016;123(5):691–8. Brown JA, Sinkey RG, Steffensen TS, Louis‐Jacques AF, Louis JM. Neonatal abstinence syndrome among infants born to mothers with sickle cell hemoglobinopathies. Am J Perinatol 2020;37:326–32. Curtis KM, Tepper NK, Jatlaoui TC, et al. U.S. medical eligibility criteria for contraceptive use, 2016. MMWR Recommend Rep 2016;65(3):1–103. Howard J, Oteng‐Ntim E. The obstetric management of sickle cell disease. Best Pract Res Clin Obstet Gynaecol 2012;26(1):25–36. Kim DK, Hunter P. Advisory Committee on Immunization Practices recommended immunization schedule for adults aged 19 years or older – United States, 2019. MMWR 2019;68(5):115–18. National Institutes of Health. Evidence‐Based Management of Sickle Cell Disease, Expert Panel Report 2014. www.nhlbi.nih.gov/health‐topics/evidence‐based‐management‐ sickle‐cell‐disease Okusanya BO, Oladapo OT. Prophylactic versus selective blood transfusion for sickle cell disease in pregnancy. Cochrane Database Syst Rev 2016;12:CD010378. Oteng‐Ntim E, Meeks D, Seed PT, et  al. Adverse maternal and perinatal outcomes in pregnant women with sickle cell disease: systematic review and meta‐analysis. Blood 2015;125(21):3316–25. Ware RE, de Montalembert M, Tshilolo L, Abboud MR. Sickle cell disease. Lancet 2017;390(10091):311–23.

PROTOCOL 13

Fetal and Neonatal Alloimmune Thrombocytopenia Russell Miller and Richard Berkowitz Department of Obstetrics and Gynecology, Columbia University Medical Center, New York, USA

Introduction Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a maternal alloimmune condition in which specific maternal antibodies target paternally derived human platelet antigen (HPA) expressed on fetal platelets, resulting in potentially severe fetal and neonatal thrombocytopenia. Disease incidence has been estimated as 1 out of every 1000 live births, varying by ethnicity. Fetal and neonatal alloimmune thrombocytopenia requires that a phenotypic incompatibility exists between the biological mother and father for a disease‐causing HPA antigen, and that the fetus inherits a paternally derived antigen that the mother does not possess, resulting in sensitization. The most common antigen implicated in disease is the HPA‐1a antigen, which is responsible for about 80% of confirmed cases. Common antigens implicated in FNAIT pathogenesis include HPA 1, 2, 3, 5, and 15 systems, and these together are believed to account for over 95% of cases.

Diagnosis The diagnosis of FNAIT is first suspected based upon a qualifying history of a fetus or neonate with suspected or confirmed thrombocytopenia. This presentation can vary widely, ranging from asymptomatic mild thrombocytopenia to spontaneous intracranial hemorrhage (ICH) in the setting of profound thrombocytopenia. The detection of newborn petechiae or ecchymoses in the early hours after birth can be a first sign of thrombocytopenia and should prompt a neonatal platelet count and further investigation if abnormal. ICH is the most severe complication of FNAIT, occurring in about 10–20% of cases. The majority of ICH presentations

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have a prenatal origin and can result in perinatal death or survival with permanent neurological disability. A suspected FNAIT diagnosis requires evaluation by parental blood testing, which includes HPA genotyping of both parents. Should a platelet antigen incompatibility be determined within a tested couple, further maternal testing for the presence of antigen‐specific anti‐HPA antibodies is performed to secure a FNAIT diagnosis. Paternal genotyping is also important to determine recurrence risk in a subsequent pregnancy for the same couple, which can be either 50% (paternal heterozygosity) or 100% (paternal homozygosity) for a given disease‐causing HPA antigen, depending on paternal zygosity status. In cases involving paternal heterozygosity, amniocentesis can be performed to determine if the pregnancy is at risk. Chorionic villus sampling (CVS) is discouraged in pregnancies at risk for FNAIT, as it may exacerbate alloimmunization and increase risk for fetal loss. Cell‐free fetal DNA is a promising approach for the noninvasive determination of fetal HPA‐1a status, with limited data supporting clinical accuracy. However, in the United States access to this technology for that indication remains limited, and further validation may be required. It should be noted that an inability to detect platelet‐specific antibodies does not entirely exclude a FNAIT diagnosis. One example includes cases in which months have elapsed after an affected delivery. For these patients, repeat maternal antibody screening may be considered on an every‐trimester basis in a subsequent at‐risk pregnancy. Fetal and neonatal alloimmune thrombocytopenia testing is recommended if a patient has an obstetric history diagnostic or suggestive of FNAIT, such as a fetal or neonatal ICH or evidence of neonatal thrombocytopenia 1:80 Within each domain only the highest‐ weighted criterion is counted toward the total score. Must have at least one clinical criterion and score of >10 points

Hematological: Leukopenia Thrombocytopenia Autoimmune hemolysis Neuropsychiatric: Delirium Psychosis Seizure Mucocutaneous: Nonscarring alopecia Oral ulcers Subacute cutaneous or discoid lupus Acute cutaneous lupus Serosal: Pleural/pericardial effusion Acute pericarditis Musculoskeletal: Joint involvement Renal: Proteinuria >0.5 g/24 h Renal biopsy class II or V lupus nephritis Renal biopsy class III or IV lupus nephritis

 

Complement proteins: Low C3 or C4 Low C3 and C4

  3 4

2

3 4 4   2 3 5

SLE specific antibodies:   anti‐dsDNA antibody or   anti‐Smith antibody 6

  2 2 4   6   5 6   6   4 8   10

ANA, antinuclear antibodies; SLE, systemic lupus erythematosus.

g­estational age (SGA) neonates. Predictors of poor outcome included ­presence of lupus anticoagulant (LA), antihypertensive use, active disease, and low platelet count. Non‐Hispanic white race was protective. A metaanalysis by Smyth et al. of 37 studies conducted between 1980 and 2009 and involving 1842 SLE patients with 2751 pregnancies reported rates of lupus flare of 25.6%, hypertension 16.3%, nephritis 16.1%, preeclampsia

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7.6%, and eclampsia 0.8%. The rate of spontaneous abortion was 16.0%, stillbirth 3.6%, neonatal death 2.5%, and IUGR 12.7%. The preterm birth rate was 39.4%.

Evaluation The following laboratory studies should be obtained at the first visit and, generally, in each trimester. • aPL screen with LA, anticardiolipin antibody (aCL), and anti‐beta‐2 glycoprotein I (aβ2GPI) antibodies, once prior to or early in pregnancy. • Urine protein evaluation (spot urine protein/creatinine level or 24‐hour collection). • Complete blood count and comprehensive metabolic panel, to rule out autoimmune hemolysis, thrombocytopenia, superimposed preeclampsia or HELLP syndrome. • Anti‐Ro/SSA and anti‐La/SSB antibodies, once prior to or early in pregnancy. Neonatal lupus occurs in 15–20%, and CHB in 2%, in offspring of antibody‐positive mothers. • Anti‐ds DNA antibodies and complement (CH50, or C3 and C4) levels: these are relatively sensitive markers for flare. Fetal surveillance should include the following. • Baseline dating ultrasound scan. • Anatomy scan at 20 weeks. • Serial fetal echocardiograms between weeks 16 and 26 at regular intervals to assess for CHB, only in women positive for anti‐Ro/SSA and/or anti‐La/SSB antibodies. In women with a prior infant with CHB, weekly echocardiograms are suggested and patients should be co‐managed with a pediatric cardiologist. • Monthly growth scans and assessment of amniotic fluid volume. • Nonstress tests and/or biophysical profiles, weekly beginning at 36 weeks in uncomplicated cases or at 28 weeks and beyond given the presence of IUGR, aPL, lupus flare, worsening renal function, or hypertension.

Treatment • The most important tenet of treatment is for patients to have quiescent disease on medications compatible with pregnancy for several months prior to conception. Contraindicated medications such as angiotensin converting enzyme (ACE) inhibitors, mycophenolate mofetil, cyclophosphamide, methotrexate, and leflunomide should be discontinued prior to pregnancy. • Continuing hydroxychloroquine (HCQ) during pregnancy reduces the risk of disease flare and improves pregnancy outcome, and data suggest HCQ may reduce risk of CHB in women with anti‐Ro/SSA and anti‐La/ SSB antibodies. All lupus patients should be encouraged to take HCQ during pregnancy unless contraindicated.

Rheumatological Disorders  117 • In women who require immunosuppressive therapy for disease control, transitioning to a pregnancy‐compatible immunosuppressive agent such as azathioprine, cyclosporine or tacrolimus should be done prior to conception and patients should be observed for several months to make sure that their disease is stable. • For disease flares, nonfluorinated glucocorticoids such as prednisone can be used at the lowest dose possible to control disease. Prednisone is associated with pregnancy‐induced hypertension, diabetes, IUGR, and preterm birth. Azathioprine, tacrolimus, and cyclosporine can be used for pregnancy flares and renal disease during pregnancy to avoid long‐ term high‐dose corticosteroid use. • Since low‐dose aspirin reduces the occurrence of preeclampsia and SLE patients are at increased risk for preeclampsia, they should receive low‐ dose aspirin, as endorsed by the American College of Obstetricians and Gynecologists. • Low molecular weight heparin (LMWH) should be used in SLE patients with APS in prophylactic or therapeutic dosage as indicated (see Protocol 15).

Antepartum SLE flare (Table 14.2) Management of an SLE flare during pregnancy is dependent on organ system involvement. Mild flares such as skin rash, mild arthritis, serositis, and cytopenias can be managed with nonfluorinated glucocorticoids at the lowest dose possible. Tapering should occur once symptoms are controlled. More severe symptoms that require higher dose or more protracted glucocorticoids should be managed with immunosuppressive agents compatible with pregnancy such as azathioprine, cyclosporine or tacrolimus. In cases

Table 14.2  Differentiating a lupus flare from preeclampsia Lupus flare

Superimposed PIH

Any gestational age Diffuse SLE symptoms Increased anti‐DNA titer Low complement levels Low white blood cell count Stable platelets (if no immune thrombocytopenia or APA) Normal AST, ALT Normal plasma fibronectin Exacerbation postpartum Low uric acid

Third trimester Preeclampsia symptoms (headache, etc.) Stable anti‐DNA titer Normal or high complement levels Normal or high white blood cell count Thrombocytopenia Elevations in AST, ALT Increased plasma fibronectin Resolution postpartum Elevated uric acid

ALT, alanine aminotransferase; APA, alkaline phosphatase activity; AST, aspartate aminotransferase; PIH, pregnancy‐induced hypertension; SLE, systemic lupus erythematosus.

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of severe flare such as lupus nephritis, intravenous methylprednisolone (1 g/day for three days) may permit rapid control, followed by a tapering steroid course. Therapy with azathioprine and/or tacrolimus should be ­initiated. Given the osteopenic effects of glucocorticoids, patients should receive calcium supplementation; they should also undergo repeated ­glucose screens. In patients treated with >5 mg/day of prednisone (or its equivalent) for more than three weeks during the pregnancy who are undergoing cesarean delivery (or who have a protracted or complicated vaginal delivery), stress dose steroids should be given. Individuals who are managed with the biologic medications rituximab, belimumab or abatacept in the preconception period can continue these medications through to the time of conception. Rituximab may be continued for organ‐ or life‐threatening disease during pregnancy. Cyclophosphamide should be limited to maternal life‐threatening conditions in the late second or third trimester.

Timing of delivery Uncomplicated SLE In patients with SLE, in the absence of lupus nephritis or hypertension, fetal growth restriction, oligohydramnios, or superimposed preeclampsia, delivery can be delayed until 40 weeks provided that fetal testing is reassuring. In the presence of deteriorating maternal or fetal health Beyond 34 weeks of gestation Patients beyond 34 weeks with worsening renal, liver, or CNS function, hypertension, IUGR with oligohydramnios, absent or reversal of diastolic Doppler flow, cessation of fetal growth, or nonreassuring fetal testing should be promptly delivered. Cesarean delivery is reserved for usual obstetric indications. Intravenous magnesium sulfate prophylaxis should be used in the presence of superimposed preeclampsia. At 28–34 weeks of gestation Patients between 28 and 34 weeks with worsening renal or liver function, development of or exacerbation of hypertension, CNS symptoms, or uteroplacental vascular compromise should be immediately hospitalized and given appropriate medical therapy (e.g., prednisone, antihypertensives) as well as a course of betamethasone to enhance fetal lung maturity, and daily fetal heart rate testing or biophysical profiles. In life‐threatening situations, initiation of rituximab or cyclophosphamide can be considered. Delivery is indicated for uncontrolled maternal hypertension, the development of severe preeclampsia, or fetal distress. The cessation of fetal growth (evaluated every two weeks) may be an indication for delivery after 28 weeks in the presence of severe oligohydramnios, persistent reverse diastolic Doppler flow, or both. Cesarean delivery is reserved for usual obstetric indications.

Rheumatological Disorders  119 Intravenous magnesium sulfate prophylaxis should be used as indicated in the presence of suspected preeclampsia or for neonatal neuroprotection. At 24–28 weeks of gestation Patients between 24 and 28 weeks with deteriorating maternal or fetal health should be immediately hospitalized with daily fetal testing using nonstress testing or biophysical profile, treated with prednisone and antihypertensives if indicated, and given antenatal steroids to enhance fetal lung maturity. In life‐threatening situations, initiation of rituximab or cyclophosphamide can be considered. Delivery is indicated for deteriorating maternal renal, cardiac, liver, or CNS function unresponsive to therapy, the development of severe preeclampsia, or for fetal distress. Again, attempts at a vaginal delivery are indicated in the absence of acute fetal distress. Intravenous magnesium sulfate prophylaxis can be used as needed. At less than 24 weeks of gestation Patients at less than 24 weeks with a rapidly deteriorating maternal or fetal condition that is refractory to medical therapy and bedrest should be given the option of pregnancy termination since the prognosis is poor in this setting. Patients should be cautioned, however, that the maternal condition may not improve after pregnancy termination. Postpartum care Because some experts believe a lupus flare after delivery may be more likely, patients require careful monitoring during the puerperium. Patients should be counseled to promptly report any concerning symptoms. Estrogen‐containing contraceptives are contraindicated in the presence of aPL as they may contribute to thrombosis risk; long‐term progestin‐only contraceptives are excellent alternatives.

Rheumatoid arthritis Overview Rheumatoid arthritis (RA) is the most common autoimmune disease in women of childbearing age, with a prevalence of 1 in 2000 pregnancies. Its peak incidence is at 35–40 years of age.

Pathophysiology Rheumatoid arthritis is thought to result from a combination of genetic and environmental interactions. The human leukocyte antigen (HLA) major histocompatibility (MHC) genes are important in determining risk (HLA‐DR4). Repeated activation of innate immunity from protein m ­ odification (such as citrullination) leads to production of autoantibodies. Recruitment of

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l­ ymphocytes and monocytes, production of multiple cytokines, complement activation, and angiogenesis all contribute to a transformed phenotype of synovial lining cells that leads to proteolytic degradation of cartilage and bone. Rheumatoid factor (RF) and/or anticitrullinated peptide/protein antibodies are present in most, but not all, patients.

Diagnosis The diagnosis of RA requires most or all of the following clinical features. • Inflammatory arthritis (three or more joints). • Duration of symptoms greater than six weeks. • Positive rheumatoid factor (RF) and/or anticyclic citrullinated peptide (CCP). • Elevated C‐reactive protein or erythrocyte sedimentation rate. • Exclusion of other diseases involving joints. Additional features may include the following. • Rheumatoid nodules: 1–4 cm subcutaneous nodules over the elbows, pressure points, or in lungs and heart valves. • Symmetrical involvement simultaneously in similar joint areas. • Characteristic radiographic findings, especially on posteroanterior hand and wrist radiographs. • Rare features: Felty syndrome (a rare complication seen in long‐standing RA, associated with splenomegaly and granulocytopenia), rheumatoid vasculitis, pleuritis, or pericarditis.

Effect of pregnancy on RA Using objective scoring of disease activity based on 28 joint counts (DAS 28), about 50% of RA patients improve during pregnancy; remission is almost always followed by postpartum exacerbation.

Effect of RA on pregnancy Pregnancy outcomes in well‐controlled RA patients are comparable to the general population. However, women with active RA during pregnancy are at increased risk for small for gestational age (SGA) infants and preterm birth. While measurable, the magnitude of the adverse outcomes associated with active RA in pregnancy is lower than that seen with SLE and APS patients.

Management Methotrexate and leflunomide are commonly used RA medications that are teratogenic and should be discontinued prior to pregnancy. Some RA medications may be continued through part or all of pregnancy, including tissue necrosis factor (TNF)‐alpha inhibitors, sulfasalazine, ­ and hydroxychloroquine. Data are inadequate for other medications. As with any rheumatological disorder, RA patients should be on ­pregnancy‐ compatible medications with well‐controlled disease prior to pregnancy.

Rheumatological Disorders  121 If they do flare once pregnant, options include intraarticular steroid i­ njections (for monoarticular or oligoarticular flare), or a course of low‐dose prednisone. If prolonged therapy or doses greater than 20 mg prednisone/day are required, the addition of a new or additional disease‐modifying antirheumatic drug (DMARD) should be considered. The utility and/or safety of RA drugs are listed below. • Acetaminophen is the analgesic of choice but will not reduce joint swelling or disease activity. • Nonsteroidal antiinflammatory agents (NSAIDs) may be used sparingly in the first or second trimesters, but not in the third trimester due to risk of premature closure of the ductus arteriosus. • Hydroxychloroquine and sulfasalazine may be effective for mild RA and are compatible with both pregnancy and breastfeeding. • Azathioprine is rarely used for RA but is compatible with pregnancy and breastfeeding and may be added if other agents are inadequate. • TNF inhibitor therapy may be continued at least until the end of the first trimester and through the second or even third trimesters. It is recommended they be stopped, if possible, at the start of the third trimester due to high transplacental passage. Inflammatory bowel disease patients who required TNF inhibitor therapy throughout pregnancy showed no increase in adverse pregnancy outcomes or infections in infants up to one year. Most experts recommend holding live vaccines for the first six months of life. Different TNF inhibitors do not have equivalent transplacental passage: certolizumab has little or no passage, and etanercept has moderate passage compared to the high passage observed with adalimumab and infliximab. • Non‐TNF biologic medications for RA such as tocilizumab, abatacept, rituximab, and anakinra are generally stopped at the time of pregnancy diagnosis; they may be resumed during breastfeeding. • If patients have been treated with leflunomide within two years of conception, a cholestyramine washout protocol is necessary due to the long drug half‐life (8 g TID × 11 days with subsequent documentation of negative metabolite levels). • Novel small molecule therapies for RA, including tofacitinib, baracitinib and others, are not well studied in pregnancy and are thought likely to pass through the placenta due to their low molecular weight. They are not suggested for use in pregnancy or breastfeeding. Other points to bear in mind include the following. • Evaluate cervical spine stability and hip range of motion before delivery • Consider prophylactic antibiotics for total joint replacements, and stress dose steroid for cesarean delivery if prior steroid use. • Many patients are able to stop their RA medications during pregnancy: one should have a medication plan in place for the anticipated postpartum flare.

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Scleroderma Overview Scleroderma is a rare autoimmune disease associated with progressive fibrosis and vasculopathy that primarily affects the skin; it is classified into diffuse and limited cutaneous forms. When there are systemic manifestations, it is called systemic sclerosis. CREST syndrome is the most common limited form (calcinosis, Raynaud, esophageal dysmotility, sclerodactyly, and telangiectasias). Patients may have positive ANA, anti‐scl‐70, anti‐ RNA polymerase III or anticentromere antibodies.

Pathophysiology Scleroderma is characterized by an autoimmune reaction causing fibroblast stimulation and overproduction, deposition and remodeling of collagen and other extracellular matrix proteins. Excess collagen causes thickening of the skin and other organs. Important features include early microvascular damage, mononuclear cell infiltrates, and slowly developing fibrosis. Later stages include densely packed collagen in the dermis, loss of cells and atrophy. Clinical manifestations include the following. • Raynaud phenomenon (seen in almost all patients). • Cutaneous manifestations, primarily sclerodactyly: skin involvement is a near universal feature; it may be limited to the hands or be more extensive. Other cutaneous manifestations are telangiectasia and calcinosis. • Pulmonary involvement occurs in >70% patients, either interstitial lung disease (ILD) or pulmonary arterial hypertension (PAH). • Dysphagia and gastrointestinal motility disorders occur in 90% patients • Renal disease includes scleroderma renal crisis which occurs most commonly in early systemic disease and is associated with poor prognosis • Cardiac disease, including cardiomyopathy and cardiac conduction abnormalities.

Effect of pregnancy on scleroderma There does not appear to be a clear effect of pregnancy on disease activity. Raynaud symptoms tend to improve due to increased blood flow and gastrointestinal reflux often worsens due to pregnancy‐related changes in lower esophageal sphincter tone and progressive compression of the stomach by the expanding uterus. Maternal prognosis is worsened by the presence of pulmonary and malignant systemic hypertension, and such patients are discouraged from attempting pregnancy. The most serious complication occurring during pregnancy is scleroderma renal crisis, although it is rare. While use of ACE inhibitors is generally contraindicated in pregnancy, they are the cornerstone of therapy

Rheumatological Disorders  123 for renal crisis; the risk to the fetus is felt to be outweighed by the risk of maternal death and renal failure. Many treatments for scleroderma are contraindicated in pregnancy, including prostaglandin analogues for Raynaud and the endothelin receptor antagonist bosentan for pulmonary hypertension and digital ulcers. Mycophenolate, used for ILD, and methotrexate, used for arthritis, are also contraindicated.

Effect of scleroderma on pregnancy Earlier reports suggested that scleroderma was associated with high rates of perinatal mortality due to preeclampsia (35%), preterm birth (30%), and stillbirth (30%). However, ascertainment bias may have inflated these rates and perinatal mortality appears to have lessened with the advent of improved fetal surveillance and neonatal intensive care. There does not appear to be a higher incidence of spontaneous abortion, but there are modestly higher risks of preterm birth, IUGR, and cesarean delivery, particularly in the setting of renal disease and hypertension.

Management Patients with active renal disease, PAH or significant cardiac compromise should avoid pregnancy due to high maternal risk and those with early diffuse disease should defer pregnancy due to higher risk of scleroderma renal crisis. Patients should be followed for evidence of deteriorating renal function and worsening hypertension. Presence of co‐existing aPL and anti‐Ro/SSA and/or La/SSB antibodies should be assessed and, if detected, managed as described for SLE. Fetal surveillance should follow the paradigm outlined for SLE above. The cornerstones of scleroderma management in pregnancy include the following. • Avoidance of medications known to be teratogenic or for which data are inconclusive. • Baseline and serial assessment of 24‐hour urine collection for creatinine clearance and total protein, and serial assessment of serum creatinine. • Frequent monitoring of blood pressure, with antihypertensive therapy as needed (calcium channel blockers); avoid ACE inhibitors unless confirmed scleroderma renal crisis. • Low‐dose prednisone for concomitant myositis. • Antacids and other pregnancy‐compatible medications for reflux esophagitis. • Physiotherapy for hand or other contractures. • Fetal surveillance as described for patients with SLE, including early dating ultrasonography, serial scans for growth, and nonstress tests and/or

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­ iophysical profiles weekly beginning at 36 weeks in uncomplicated cases b or 28 weeks and beyond given the presence of IUGR, worsening renal function, or hypertension.

Suggested reading Systemic lupus erythematosus Aringer M, Costenbader K, Daikh D, et al. 2018 European League Against Rheumatism/ American College of Rheumatology Classification criteria for systemic lupus erythematosus. Arthritis Rheumatol 2019;71:1400–12. Buyon J, Kim M, Gurerra M, et al. Predictors of pregnancy outcomes in patients with lupus: a cohort study. Ann Intern Med 2015;163:153–63. Chakravarty E, Colon I, Langen E, et al. Factors that predict prematurity and preeclampsia in pregnancies that are complicated by systemic lupus erythematosus. Am J Obstet Gynecol 2005;192:1897–904. Petri M. The Hopkins Lupus Pregnancy Center: ten key issues in management. Rheum Dis Clin North Am 2007;33(2):227–35. Smyth A, Oliveira GH, Lahr BD, Bailey KR, Norby SM, Garovic VD. A systematic review and meta‐analysis of pregnancy outcomes in patients with systemic lupus erythematosus and lupus nephritis. Clin J Am Soc Nephrol 2010;5(11):2060–8. Tedeschi SK, Guan H, Fine A, Costenbader KH, Bermas B. Organ‐specific systemic lupus erythematosus activity during pregnancy is associated with adverse pregnancy outcomes. Clin Rheumatol 2016;35:1725–32.

Rheumatoid arthritis Bharti B, Lee SJ, Lindsay SP, et al. Disease severity and pregnancy outcomes in women with rheumatoid arthritis: results from the organization of teratology information specialists autoimmune diseases in pregnancy project. J Rheumatol 2015;42(8):1376–82. De Man YA, Dolhain RJ, van de Geijn FE, Willemsen SP, Hazes JM. Disease activity of rheumatoid arthritis during pregnancy: results from a nationwide prospective study. Arthritis Care Res 2008;59(9):1241–8. Krause ML, Makol A. Management of rheumatoid arthritis during pregnancy: challenges and solutions. Open Access Rheumatol Res Rev 2016;8:23. Mahadevan U, Martin CF, Dubinsky M, Kane SV, Sands BE, Sandborn W. 960 exposure to anti‐TNFα therapy in the third trimester of pregnancy is not associated with increased adverse outcomes: results from the PIANO registry. Gastroenterology 2014;146(5):S‐170.

Scleroderma Betelli M, Breda S, Ramoni V, et al. Pregnancy in systemic sclerosis. J Scleroderma Relat Disord 2018;3(1):21–9. 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(6):1970–7.

PROTOCOL 15

Antiphospholipid Syndrome Robert M. Silver Department of Obstetrics and Gynecology, Division of Maternal‐Fetal Medicine, University of Utah Health Sciences Center, Salt Lake City, UT, USA

Overview The major acquired thrombophilia is antiphospholipid syndrome (APS). Antiphospholipid antibodies (aPL) are autoantibodies directed against p ­ roteins bound to negatively charged phospholipids. They are present in up to 20% of individuals with venous thromboembolism (VTE), and affected patients have a 5% risk of VTE during pregnancy and the puerperium despite treatment. However, antiphospholipid antibody (APA)‐related thrombosis can occur in any tissue or organ and can be either venous or arterial. In addition, APS is linked to placental insufficiency and higher rates of associated complications such as preeclampsia, abruption, fetal growth restriction, and fetal loss. Pregnancy is a hypercoagulable state by virtue of hormone‐induced increases in vitamin K‐dependent clotting factor levels, reduced levels of the anticoagulant co‐factor, free protein S, and decreased fibrinolysis, coupled with venous stasis of the lower extremities and vascular injury due to placentation. Thus, the risk of VTE increases at least fivefold in pregnancy compared to age‐matched nonpregnant women. In the United States, VTE complicates about 1 per 1600 pregnancies, roughly divided between deep venous thrombosis (75%) and acute pulmonary embolism (25%); the latter accounts for about 10% of maternal deaths. Accordingly, the risk of VTE during pregnancy is especially high in women with APS.

Pathophysiology There are several pathological mechanisms by which aPL induce VTE and adverse pregnancy outcomes. These potentially include complement activation; impairment of endothelial annexin V, thrombomodulin and activated protein C‐mediated anticoagulation; aberrant induction of endothelial tissue

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factor expression; impairment of fibrinolysis; and increased platelet activation. These effects occur in vascular endothelium and the placenta, leading to thrombosis and pregnancy complications. Thus, treatments focus on reducing inflammation and anticoagulation.

Diagnosis The diagnosis of APS requires meeting at least one of the following clinical and laboratory criteria. • Thrombosis diagnosed by diagnostic imaging or histology involving one or more venous, arterial, or small vessels but not including superficial venous thrombosis; or • Adverse pregnancy outcome including one or more unexplained fetal death at 10 weeks of gestation or more of a morphologically normal fetus, or one or more preterm birth(s) prior to 34 weeks due to preeclampsia or placental insufficiency, or three or more unexplained embryonic losses at less than 10 weeks gestation; and • At least one of the following laboratory criteria on two or more occasions at least 12 weeks apart and no more than five years prior to clinical manifestations. ○○ IgG and/or IgM anticardiolipin antibodies (aCL) (greater than 40 GPL or MPL units or more than 99th percentile for the testing laboratory); or ○○ Antibodies to beta‐2‐glycoprotein‐1 of IgG or IgM more than 99th percentile for the testing laboratory; or ○○ Lupus anticoagulant (LA) activity detected according to published guidelines.

Effect on pregnancy The LA activity and high aCL IgG levels present the highest risk of adverse pregnancy outcomes. LA poses the highest risk for pregnancy loss which is up to 80% in untreated women. Although aPL are present in up to 20% of women with recurrent early pregnancy loss, most have low titers of doubtful clinical relevance. Most losses in women with APS occur after fetal cardiac activity is noted and aPL are not associated with worse outcomes in women undergoing in vitro fertilization. Also, aPL are present in approximately 2% of the general obstetric population. Women with APS have high rates of placenta‐mediated obstetric complications. In addition to fetal death, about a third have fetal growth restriction, a third have preeclampsia, and a third have medically indicated preterm birth owing to these disorders. These problems may occur even with treatment. Thus, antenatal surveillance is warranted.

Antiphospholipid Syndrome  127

Antepartum management Baseline information • Assessment of serum creatinine and urine protein:creatinine (UPC) ratio. • Platelet count since APS is associated with autoimmune thrombocytopenia. • Assessment of aPL including LA, IgG, and IgM anticardiolipin antibodies (aCL), and IgG and IgM antibodies to beta‐2‐glycoprotein‐1 if the diagnosis is uncertain. There is no benefit to serial assessment of antibodies during pregnancy once a diagnosis is made. • Early sonogram for accurate determination of gestational age.

Medical therapy (anticoagulation and immunosuppressive therapy) Low‐dose aspirin plus: • (if prior VTE) therapeutic doses of unfractionated or low molecular weight heparin (e.g., enoxaparin 1  mg/kg subcutaneously every 12 hours, adjusted to achieve anti‐factor Xa level at 0.6–1 U/mL 4 h after an injection). It is noteworthy that activated partial thromboplastin time (aPTT) is unreliable for assessment of anticoagulation in women with LA • (if no prior VTE) prophylactic doses of unfractionated or low molecular weight heparin (e.g., enoxaparin 30–40 mg subcutaneously every 12 hours). If low molecular weight heparin (LMWH) is used in the antepartum period, one may consider switching to unfractionated heparin (10 000 units subcutaneously every 12 hours for prophylaxis) at 36 weeks or earlier if preterm delivery is expected since it has a shorter half‐life than LMWH. If the aPTT for patients on unfractionated heparin is normal or vaginal or cesarean delivery occurs more than 12 hours after the last dose of unfractionated LMWH, patients should not experience anticoagulation‐related problems with delivery. Protamine may fully reverse the anticoagulant effects of unfractionated heparin. Many cases (up to 30%) are refractory to standard treatment. Although of unproven efficacy, additional immunosuppressive therapy using hydroxychloroquine may be considered. Women with SLE (up to 40% of women with APS) may need additional therapy as appropriate.

Pregnancy monitoring • Level II ultrasonography at 18 weeks. • Fetal growth should be monitored every 4–8 weeks beginning at 20 weeks for any patient on anticoagulation; ultrasonographic assessment should be more frequent if fetal growth restriction is suspected or documented; in such a case, Doppler studies may be useful in determining the optimal timing of delivery.

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• Office visits as often as every two weeks beginning at 20 weeks to screen for preeclampsia. • Nonstress tests (NST) and/or biophysical profiles (BPP) weekly beginning at 36 weeks in uncomplicated cases or earlier as clinically indicated.

Timing of delivery If the pregnancy is complicated by fetal growth restriction or preeclampsia, antenatal testing and maternal status will guide the timing of delivery. If the pregnancy is uncomplicated, delivery can be delayed until 39 completed weeks provided that antenatal surveillance (NST/BPP) is reassuring.

Postpartum management Pneumatic compression boots should be used during labor and delivery or at cesarean delivery. Either unfractionated heparin or LMWH can be restarted six hours after vaginal delivery or 12 hours after cesarean delivery. This should be continued until at least six weeks postpartum. If the patient has a history of VTE, long‐term prophylaxis is required as there is as high as a 30% recurrence risk for VTE in an aPL‐positive patient with a prior VTE. In this case, warfarin is to be started on day 2, and both heparin and warfarin are to be continued for five days and until the INR is therapeutic (2–3) for two consecutive days. Rarely, patients may develop catastrophic APS (CAPS), defined as multiple thromboses, usually involving small vessels, resulting in multiorgan failure. Pregnancy is a recognized trigger and many cases present postpartum. Treatment includes therapeutic anticoagulation, supportive care and immunosuppression, often with steroids and immune globulin or plasma exchange.

Conclusion The combination of VTE, obstetric complications, and aPL defines the antiphospholipid syndrome. The three aPLs most commonly associated with clinical problems are lupus anticoagulant, IgG anticardiolipin antibodies, and IgG anti‐beta‐2‐glycoprotein‐I antibodies. These antibodies, especially LA, are associated with an elevated risk of thromboembolism (venous and arterial) and obstetric complications including fetal loss, abruption, severe preeclampsia, and fetal growth restriction. Treatment includes low‐dose aspirin and heparin.

Suggested reading American College of Obstetricians and Gynecologists Committee on Practice Bulletins‐ Obstetrics. ACOG Practice Bulletin No. 118: Antiphospholipid Syndrome. Obstet Gynecol 2011;117:192–9.

Antiphospholipid Syndrome  129 Arslan E, Branch DW. Antiphospholipid syndrome: diagnosis and management in the obstetric patient. Best Pract Res Clin Obstet Gynaecol 2020;64:31–40. Lockshin MD, Laskin CA, Guerra M, et al. Lupus anticoagulant, but not anticardiolipin antibody, predicts adverse pregnancy outcome in patients with antiphospholipid antibodies. Arthritis Rheum 2012;64:2311–18. Miyakis S, Lockshin 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(2):295–306.

PROTOCOL 16

Inherited Thrombophilias Andra H. James and Jerome J. Federspiel Department of Obstetrics and Gynecology, Division of Maternal‐Fetal Medicine, Duke University Medical Center, Durham, NC, USA

Overview Thrombophilia is a term that can refer to almost any risk factor (such as the postoperative state) which could predispose to thrombosis. More specifically, the term has been used to describe a hemostatic factor that predisposes to thrombosis. Given pregnancy itself increases thrombosis risk four‐ to fivefold, the addition of a thrombophilia superimposed on pregnancy has implications for both mother and fetus. The purpose of this protocol is to review the inherited thrombophilias (versus acquired thrombophilias such as the antiphospholipid syndrome, which are reviewed separately), their association with thrombosis and adverse pregnancy outcomes, and their evaluation and treatment in pregnancy.

Mechanisms of hemostasis The physiological response to blood vessel injury is formation of clot. Platelets adhere to damaged endothelium at the site of injury via von Willebrand factor, and in the process are activated, aggregate, and form an initial platelet plug. The aggregated platelets are enmeshed by fibrin, which has been converted from soluble fibrinogen by the enzyme thrombin, to form a more stable clot. Factor XIII, also activated by thrombin, cross‐links the fibrin monomers, further stabilizing the evolving clot. Thrombin is converted from its precursor, prothrombin, in the presence of activated factor X (FXa) and its co‐factor, activated factor V (FVa). Both factor X and factor IX are activated by factor VII, which has been activated by tissue factor exposed at the time of blood vessel injury. Factor X can also be activated by activated factor IX and its co‐factor, activated factor VIII (FVIIIa), which is also activated by thrombin.

Protocols for High-Risk Pregnancies: An Evidence-Based Approach, Seventh Edition. Edited by John T. Queenan, Catherine Y. Spong and Charles J. Lockwood. © 2021 John Wiley & Sons Ltd. Published 2021 by John Wiley & Sons Ltd.

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The natural anticoagulants protein C, protein S, antithrombin, and tissue factor pathway inhibitor regulate clot formation and localize the clot to the site of injury. During hemostasis, excess thrombin binds to thrombomodulin and the thrombin–thrombomodulin complex activates protein C. Activated protein C and its co‐factor, protein S, inactivate FVIIIa and FVa. Antithrombin inactivates thrombin, FXa, and activated factor IX (FIXa). (Heparin potentiates antithrombin at least 1000‐fold.) In normal hemostasis, a clot is temporary and undergoes fibrinolysis or degradation rather than propagation. Plasmin, which is converted from plasminogen in the presence of fibrin, is responsible for fibrin degradation. The process is upregulated by tissue plasminogen activator and downregulated by thrombin‐activatable fibrinolysis pathway inhibitor (TAFI) and plasminogen activator inhibitor type‐1 (PAI‐1).

Mechanisms of thrombosis Thrombosis (a pathological clot) can occur in the arterial or venous circulation, but the mechanisms and major risks factors, while overlapping, are different. The major risk factor for arterial thromboembolism (e.g., myocardial infarction and stroke) is endothelial damage most commonly due to atherosclerosis. Endothelial damage alters blood flow, causing turbulence and platelet activation. In contrast, the primary mechanism in venous thromboembolism (VTE), which accounts for 80% of the thromboembolic events in pregnant women, is activation of coagulation factors.

Genetic risk factors for thrombosis Inherited changes resulting in increased levels of coagulation factors, decreased levels of the natural anticoagulants, decreased levels of fibrinolytic factors, or increased levels of fibrinolytic inhibitors can each increase the risk of thrombosis. The factor V Leiden (FVL) mutation is a single nucleotide polymorphism (SNP) in the factor V gene (G1691A). The consequence of this SNP is a single amino acid difference that eliminates one of the cleavage sites of FVa. Absence of this cleavage site confers resistance to activated protein C with prolonged procoagulant activity compared to that of normal FVa. Similarly, another SNP, in the untranslated portion of the prothrombin (FII) gene (G20210A), is also associated with an increased risk of thrombosis. In contrast to these discrete, SNP‐based genotypes, there are several mutations each associated with protein C deficiency, protein S deficiency, and antithrombin deficiency. As there is no one mutation for these conditions, deficiencies of these natural

Inherited Thrombophilias  133 a­ nticoagulants are diagnosed by decreased anticoagulant activity rather than genetic testing. Venous thromboembolism is a multifactorial condition potentially involving multiple environmental and genetic factors. Occurrence of VTE is contingent upon an individual’s combined risk factors at the time. The various genetic risk factors have different risk profiles (Table 16.1). Deficiencies of the natural anticoagulants (antithrombin, protein C, and protein S) are relatively rare and manifest as high‐ or moderate‐risk thrombophilias (relative risk for heterozygotes about 10). There is an activity cut‐off below which the condition is thought to be present, but there is a spectrum in the degree of deficiency. A recent study documented that even mild deficiencies of antithrombin confer an increased risk of VTE (three‐ to fourfold for levels less than 70% of normal and two‐ to threefold for levels between 70% and 80% of normal). FVL and FII G20210A are more common and confer a moderate risk (fivefold for FVL and twofold to threefold for FII G20210A). Multiple other SNPs have been discovered in genes for coagulation factors, the natural anticoagulants, the fibrinolytic factors and the fibrinolytic inhibitors associated with an increased risk of VTE, but all would be considered weak risk factors. The methylenetetrahydrofolate reductase SNPs C677T and A1298C, previously thought to be associated with an increased risk for thrombosis, no longer are considered to be prothrombotic mutations. There are other genetic risk factors for thrombosis that are not classically regarded as inherited thrombophilias, but nonetheless increase the risk of Table 16.1  Inherited thrombophilia and the risk of venous thromboembolism (VTE) Thrombophilia

Increased risk of VTE

Prevalence

Approximate prevalence among VTE patients

Antithrombin Protein C Protein S Factor V Leiden (FVL)

0.02% 4 cm should be advised against pregnancy. CHF, congestive heart failure; CO, cardiac output; HR, heart rate; HTN, hypertension; LV, left ventricle; PVR, pulmonary vascular resistance; RV, right ventricle; SVR, systemic vascular resistance; VSD, ventricular septal defect.

a

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main pulmonary artery. As such, severe stenosis may result in symptomatic right heart failure, particularly in the setting of right ventricular systolic dys­ function. Balloon valvotomy or surgical intervention (depending on the anatomy of the lesion) may be indicated for asymptomatic patients with a domed pulmonic valve and peak instantaneous gradient >60 mmHg or symp­ tomatic patients with a peak instantaneous gradient >50 mmHg. Mitral stenosis Rheumatic heart disease is the most common cause of mitral stenosis (MS) worldwide, whereas congenital MS is a larger contributing factor in devel­ oped countries. Increased cardiac output in pregnancy along with decreased filling time due to the increased heart rate may lead to elevated left atrial pressure. In turn, this may result in a higher propensity for atrial fibrilla­ tion and/or pulmonary edema. About one‐third of patients with signifi­ cant MS (valve area 40 mm Hg or symp­ tomatic patients) may quickly decompensate due to the hemodynamic changes of pregnancy. Complications most often arise in those patients with severe AS due to increased left ventricular end‐diastolic pressure and include heart failure, pulmonary edema, and atrial and ventricular arrhyth­ mias. That being said, arrhythmias, aortic dissection, and maternal deaths are rare with appropriate management. For asymptomatic AS patients, heart failure is also relatively rare (10.0 cm2 vena contracta width >0.70 cm, or patients with heart failure regardless of other parameters) prior to preg­ nancy. (Regurgitation is visualized by color flow Doppler as a jet of flow from right ventricle to right atrium in diastole; the jet area corresponds to the severity of regurgitation. Vena contracta is the narrowest central flow region of the regurgitation jet by color flow Doppler just below the valve that corresponds to the severity of valve regurgitation.) Pulmonic regurgitation In patients of childbearing age, pulmonic regurgitation (PR) most often arises from CHD or may be iatrogenic after surgical intervention for right ventricular outflow obstruction. PR can lead to right ventricular volume overload. Cardiac output decreases for those with right ventricular dysfunc­ tion, with compensatory increase in heart rate and oxygen requirement. Therefore, any increase in oxygen demand may be poorly tolerated. In severe cases, PR may be associated with right ventricular dilation with para­ doxical septal motion or systolic dysfunction, which in turn can precipitate right‐sided heart failure as well as atrial or ventricular tachyarrhythmias. Surgical valve replacement is indicated for symptomatic patients with severe PR or for asymptomatic patients with two of the following criteria:

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mild to moderate right ventricular (RV) or left ventricular (LV) systolic dysfunction, severe RV dilation (RV end‐diastolic volume index ≥160 mL/ m2, RV end‐systolic volume index ≥80 mL/m2, or RV end‐diastolic volume ≥two times LV end‐diastolic volume), RV systolic pressure ≥2/3 systemic pressure, or progressive reduction in objective exercise tolerance. Mitral regurgitation Mitral valve regurgitation (MR) may arise from rheumatic heart disease, mitral valve prolapse, or other CHD. Generally well tolerated, the presence of LV systolic dysfunction or pulmonary hypertension will determine pregnancy risk. Heart failure occurs in 20–25% of women with moderate or severe rheumatic MR (central jet MR >40% of left atrium or holosystolic eccentric jet MR, vena contracta ≥0.7 cm, regurgitant volume ≥60 mL, regurgitant frac­ tion ≥50%, effective regurgitant orifice ≥0.40 cm2, angiographic grade 3–4+). In addition, persistent worsening of regurgitation may occur. Surgery is rec­ ommended for symptomatic patients with chronic severe disease and LV ejec­ tion fraction >30% or for asymptomatic patients with LV dysfunction (LV ejection fraction 30–60%). Generally, repair is preferred to replacement when feasible. Transcatheter repair may also be considered. There are also fetal risks for patients with MR. Five to ten percent of fetuses born to mothers with moderate or severe MR will have growth restriction. Aortic regurgitation Like aortic stenosis, aortic regurgitation (AR) often results from bicuspid aor­ tic valves or less commonly is due to aortopathy, endocarditis, or rheumatic heart disease. Asymptomatic women generally tolerate pregnancy well. However, those with secondary left ventricular systolic dysfunction or pul­ monary hypertension are more prone to heart failure from volume over­ load. Particularly at risk are women with a left ventricular ejection fraction 140 mmHg. Increased systemic blood pressure increases regurgitation in diastole as the aortic valve is not com­ pletely closed due to incompetence. Dihydropyridine calcium channel blockers are preferred. Other preferred options for nonpregnant individu­ als such as angiotensin‐converting enzyme inhibitors and angiotensin receptor blockers are teratogenic and therefore avoided in pregnant patients or those seeking pregnancy. For patients with Marfan syndrome, the risk of aortic dissection may be minimized with use of beta‐blockers. Valve replacement is indicated for patients with severe AR (jet width ≥65% of the LV outflow tract, vena contracta >0.6 cm, holodiastolic flow reversal in the proximal abdominal aorta, regurgitant volume ≥60 mL/beat, regurgitant

Valvular Heart Disease in Pregnancy  155 fraction ≥50%, effective regurgitant orifice ≥0.3 cm2 or angiography grade 3–4+) regardless of LV functional status. Patients with asymptomatic disease and LV dysfunction (LV ejection fraction 65 mm), or those undergoing cardiac surgery for other indications are also candidates.

Mixed anomalies Data are lacking on the prognosis and optimal management of patients with mixed VHD. The most hemodynamically significant valvular lesion predominantly determines risk stratification and approach to care.

Artificial valves For women considering valve replacement, the limited durability and higher potential for valvular structural deterioration during pregnancy of bioprosthetic valves must be weighed against the risk of pregnancy‐related thromboembolic complications, the increased risk of major cardiac events, and anticoagulation with mechanical valves. Pregnancy outcomes appear to be similar. Women with bioprosthetic valves who are hemodynamically stable and do not require anticoagulation tend to tolerate pregnancy well. The risk of maternal cardiovascular complications is low for patients with no or lim­ ited valve dysfunction and normal ventricular function. However, biopros­ theses have a more limited life span than mechanical valves; depending on the position of the graft and the age of the recipient, 30–35% of hetero­ graft and 10–20% of homograft prostheses fail within 10–15 years. Therefore, many patients of childbearing age who have a bioprosthesis placed will require further surgery during their lifetime. That being said, pregnancy does not seem to accelerate need for replacement. Mechanical valves confer a high risk of both maternal and fetal risks (WHO risk classification III). Valve thrombosis and, conversely, the risk of hemorrhagic complications with necessary anticoagulation confer the highest maternal risk. In the international prospective observational Registry of Pregnancy and Cardiac Disease, women with mechanical valves had a 58% chance of an event‐free pregnancy, compared to 79% women with bioprosthetic valves and 78% of women without valve prostheses. Mechanical valve thrombosis complicated the pregnancy of 4.7% of patients, and hemorrhagic events occurred in 23.1% of patients. Of 212 women, maternal mortality was significantly increased compared to those without a prosthetic valve (1.4% vs 0.2%) (Regitz‐Zagrosek et al. 2018).

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Mechanical valves require anticoagulation, which are associated with an increased risk of miscarriage, bleeding complications, and embryopathy (for a more complete discussion, see the section on Anticoagulation below). Overall, women with older mechanical valves (e.g., ball‐and‐cage, single tilting disk), mitral mechanical valves, multiple mechanical valves, arrhyth­ mias, or a history of thromboembolic events are at the highest risk of valve thrombosis. Therefore, those patients requiring valve replacement and desiring future fertility should avoid mechanical valves where possible.

Cardiac surgery in pregnancy For patients with an appropriate indication, surgery prior to pregnancy can reduce pregnancy risk. Surgical intervention not only improves the patient’s ability to tolerate pregnancy, but also increases fertility and decreases fetal risks for patients with cyanotic heart disease. These women should discuss surgical and transcatheter interventions for VHD, including risks and benefits of mechanical prostheses, bioprostheses, and valve repair. Particular attention should be paid to the risks of anticoagulation during pregnancy with mechanical valves compared to the limited life span of bioprostheses and technical feasibility of valve repair. If possible, cardiac surgery should be avoided during pregnancy. In par­ ticular, urgent surgery with cardiopulmonary bypass poses an increased risk of maternal mortality, as well as fetal complications due to nonpulsatile blood flow and reduced uteroplacental flow. For those undergoing bypass, maintenance of a mean arterial blood pressure above 70 mmHg is recom­ mended to optimize placental perfusion. If surgery can be safely delayed until after viability, a concomitant cesarean delivery may be performed.

Preconception and early pregnancy counseling Ideally, a thorough evaluation of a patient with preexisting VHD must be initiated before pregnancy to allow for shared decision making regarding individual risks and advisability of pregnancy. When possible, VHD should be fully characterized before conception or as early in the pregnancy as pos­ sible to facilitate a comprehensive therapeutic plan. The evaluation begins with a thorough history and physical examination to characterize the patient’s functional status (Table 17.9). Factors that increase the risk of car­ diovascular complications should be fully assessed, for example a history of heart failure, the presence of prosthetic valve, or a history of thromboem­ bolism. Counseling should be provided by both a high‐risk obstetrician and cardiologist with expertise in managing VHD in pregnancy.

Valvular Heart Disease in Pregnancy  157 Table 17.9  New York Heart Association (NYHA) risk stratification NYHA class

Classification

I

No limitations on physical activity. Ordinary physical activity does not result in undue symptomsa Slight limitations on physical activity. Comfortable at rest. Ordinary physical activity results in mild symptoms Marked limitations on physical activity. Comfortable at rest. Less than ordinary physical activity results in symptoms Unable to carry out any physical activity without discomfort. Symptoms may be present even at rest. Discomfort increases with any physical activity

II III IV

 Symptoms include fatigue, palpitations, dyspnea, or anginal pain. Source: Based on Dolgin (1994).

a

Preconception counseling includes a discussion of the patient’s cardiac anomaly and baseline functional status, opportunities for optimizing her cardiac status by medical or surgical means, and any additional risk factors. In addition, if the mother has a CHD her risk of having a child affected by a cardiac lesion needs mentioning. Normal physiological changes of preg­ nancy and their anticipated (sometimes permanent) effects on VHD should also be discussed and medications reviewed and revised to avoid terato­ gens (e.g., ACE inhibitors and angiotensin II receptor blockers). Perhaps the most psychosocially difficult counseling point may be the patient’s physical ability to care for a child and her life expectancy. The NYHA classification system (see Table  17.9) delineates patients by functional status and can help predict pregnancy risk. While women with NYHA class I/II generally tolerate pregnancy well, those with class III or IV disease are at increased risk of adverse maternal and fetal outcomes. Women with class III or IV functional status should reconsider pregnancy. When patients present with severe symptomatic disease early in preg­ nancy, termination of pregnancy should be offered. Counseling for these women may include a discussion of alternative means of family formation, including surrogacy and adoption. Basic diagnostic testing includes a 12‐lead electrocardiogram, tran­ sthoracic echocardiogram, and/or exercise testing. An echocardiogram helps determine the type and severity of valvular lesions, concomitant ventricular dysfunction, and the presence of pulmonary hypertension or other associated cardiac defects. Exercise testing can objectively describe functional capacity – an important predictor of pregnancy outcome, par­ ticularly in CHD. Some high‐risk women may require intervention prior to pregnancy. See the sections on artificial valves (above) and anticoag­ ulation (below).

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Antepartum management Key principles in the antepartum management of VHD focus on minimizing cardiac work while optimizing perfusion of the tissues, including the utero­ placental circulation. Any factors that may potentially increase cardiac work, such as anxiety, anemia, infection, arrhythmia, or nonphysiological edema, should be identified and eliminated or minimized. The patient’s functional status should be closely monitored as pregnancy progresses. Any diminution in cardiac function or worsening of maternal functional class should prompt further evaluation and consideration for hospitalization. Oxygen, diuretics, and inotropes such as digitalis can be used as necessary to optimize cardiac function. Women with cardiac disease should consult with their cardiologist before attempting strenuous activity during pregnancy. Patients who are functional class III or IV will need to significantly limit their physical activity and have specified daily rest periods. Fetal growth should be monitored closely, and a fetal echocardiogram performed between 18 and 22 weeks of gestation if the mother has a CHD. Depending on the maternal functional class and fetal status, weekly or biweekly evaluation of fetal well‐being should be considered beginning in the third trimester.

Anticoagulation Pregnancy is a hypercoagulable state, and pregnant women with mechani­ cal heart valves or cardiac failure are at especially high risk of thrombo­ embolism. The American College of Cardiology and American Heart Association (AHA) recommend that all women with mechanical heart valves undergo therapeutic anticoagulation during pregnancy (Nishimura et al. 2014). However, anticoagulation management is challenging as no therapy is devoid of maternal and fetal risk, therefore an individualized treatment plan should be formulated with the patient using a joint deci­ sion‐making model. • Warfarin: although warfarin is the most effective therapy in preventing thrombosis associated with mechanical valves, it readily crosses the pla­ centa and has adverse fetal effects throughout pregnancy. If used in the first trimester, it increases the risk of early pregnancy loss or may result in warfarin embryopathy, which includes abnormal cartilage formation and a hypoplastic midface. If used in the second or third trimesters, warfarin increases the risk of pregnancy loss, growth restriction, and abnormalities caused by vascular disruption like cerebral bleeding or limb reduction defects. There are some data suggesting that these complications are less likely if the daily dose is 5 mg or less per day, therefore the AHA

Valvular Heart Disease in Pregnancy  159 r­ ecommends continuation of warfarin therapy for these patients. For these patients, the goal should be to maintain an international normalized ratio (INR) of 2.5–3.5. Many women will elect to discontinue warfarin when attempting pregnancy or immediately after conception and receive unfractionated heparin (UFH) or low molecular weight heparin (LMWH) until 12 weeks’ gestation. The various forms of heparin do not cross the placenta and are therefore safe for the fetus, but are not completely effective in preventing thrombosis. However, reports indicate a 12–30% incidence of thromboembolic complications and a 4–15% incidence of mortality for pregnant women with mechanical valves taking heparin. • LMWH: patients electing for LMWH often require greater than weight‐ based dosing twice daily to achieve a target anti‐Xa level of 0.8–1.2 U/mL measured four hours after administration of the third dose, and a trough level prior to the next dose of 0.6–0.8 U/mL. Subcutaneous UFH is not recommended due to the difficulty of attaining stable therapeutic levels. However, if the patient chooses UFH, it should be given as a continuous infusion in pregnancy. In addition to anticoagulation, all women with mechanical valves should receive antiplatelet therapy in the form of low‐dose aspirin (70–100 mg/day). Patients on anticoagulation need a coordinated delivery plan. Patients on warfarin should be switched to UFH infusion in hospital at least one week prior to delivery to avoid persistent neonatal warfarin effect, which includes increased risk of intracranial hemorrhage during vaginal delivery. The timing of delivery should be individualized. Ideally, patients are switched to therapeutic UFH at 35–36 weeks. As UFH has a short half‐life (1.5 hours), its effects can be rapidly reversed with protamine sulfate, and an aPTT can rapidly confirm that its effects have resolved. Patients should be instructed to withhold UFH at the onset of labor or 8–12 hours prior to a planned induction of labor or cesarean, primarily so they can receive neuraxial anesthesia (see section on Anesthesia). Should urgent delivery occur while the patient is still fully anticoagu­ lated, those on UFH or LMWH should be reversed with protamine sulfate. Of note, the half‐life of LMWH is longer than UFH, so repeated dosing or an infusion may be required. Patients on warfarin should receive four‐factor prothrombin complex concentrate with a goal INR of ≤1.5 as it is more effective than fresh frozen plasma. The dose of four‐factor prothrombin complex is weight and pretreatment INR based. Vitamin K may also be administered orally or intravenously but may take 8–12 hours to achieve efficacy. The dose varies from 1 mg to 10 mg based on the level of INR and severity of bleeding. The effect of vitamin K persists and can make antico­ agulation after delivery more of a challenge. Of note, the neonate may also remain anticoagulated for 8–10 days and may also require fresh frozen plasma as well as vitamin K.

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Postpartum, therapeutic heparin (either UFH or LMWH) and warfarin should be restarted 4–6 hours after vaginal delivery or 6–12 hours after cesarean delivery, as long as the patient has no significant bleeding. The tim­ ing of warfarin initiation is variable, but 48 hours is reasonable. It is crucial to maintain therapeutic doses of UFH or LMWH until the INR is in the thera­ peutic range for two successive days, which is usually at least five days.

Delivery planning Generally, women with low‐risk VHD can deliver at their local hospital, but those with moderate‐ and high‐risk disease (including those with prosthetic valves) should deliver at regional centers with expertise in maternal VHD. All patients with VHD should be evaluated by the obstetric (OB) and/or cardiac anesthesia team prior to delivery when possible and have a person­ alized plan of care prepared in conjunction with high‐risk OB and cardiol­ ogy. VHD patients with moderate‐ and high‐risk disease require special attention during labor and delivery. Heart rate, stroke volume, cardiac out­ put, and mean arterial pressure all increase during labor and in the imme­ diate postpartum period. Lateral positioning and adequate pain control can reduce maternal tachycardia and increase cardiac output. Fluid balance and pulse oximetry readings should be carefully reviewed. Women with high‐risk VHD may require continuous telemetry. There is no consensus on intrapartum invasive hemodynamic monitoring, but intraarterial blood pressure monitoring may benefit women with NYHA class III or IV disease, particularly for those with severe aortic stenosis. Timing of delivery is controversial and should be individualized based on the patient’s cardiac lesion, functional status, and any other maternal or fetal complications of the pregnancy. Generally, induction of labor should be con­ sidered at or after 39 weeks. In patients without cardiac disease, scheduling induction of labor at this time reduces the risk of emergency cesarean deliv­ ery by 12% and the risk of stillbirth by 50%. The benefits for patients with VHD may be greater still. From a practical perspective, when possible deliv­ ery timing should be optimized to have the adult CHD team available. However, planned delivery prior to 39 weeks of gestation must weigh poten­ tial maternal benefit with the increased risk of fetal lung immaturity.

Medications on L&D Providers need to be aware that many cardiac medications have obstetric implications (Table 17.10). In addition, lactation should be considered to optimize medications for breastfeeding as inappropriate advice can lead patients to unnecessarily discontinue breastfeeding.

Valvular Heart Disease in Pregnancy  161 Table 17.10  Select obstetric medications with cardiac implications Medication

Cardiovascular side effects

VHD conditions adversely affected

Corticosteroids Ketorolac

Fluid retention, hypertension Tachycardia, hypertension, bleeding, syncope

Magnesium sulfate

Vasodilation, hypotension

Methylergonovine

Coronary artery vasospasm, hypertension, arrhythmias Arrhythmias, hypotension

Heart failure, hypertension Pulmonary edema, patients on active anticoagulation, patients sensitive to tachycardia, e.g., severe aortic stenosis Stenotic valvular lesions, particularly aortic stenosis Aortopathies

Oxytocin

Terbutaline

Tachycardia, hypotension, arrhythmias

Tranexamic acid

Theoretical increased risk of thrombosis

Patients at risk of arrhythmias or ischemia; stenotic valvular lesions, particularly mitral stenosis Patients at risk of arrhythmias or ischemia; stenotic valvular lesions, particularly mitral stenosis Those at increased risk of VTE, including mechanical valves

VTE, venous thromboembolism. Source: Based on American College of Obstetricians and Gynecologists (2018a).

Delivery and the immediate postpartum period Vaginal delivery with anesthesia and limited Valsalva (e.g., an assisted second stage of labor) is generally preferred for patients with VHD. ­ Operative assistance with forceps or vacuum with the second stage of labor may decrease maternal cardiac work. Cesarean delivery results in increased blood loss (on average twice that associated with vaginal delivery), greater hemodynamic fluctuations, as well as increased risks of infection, throm­ boembolism, and postoperative complications. Generally, elective cesarean delivery confers no maternal benefit and results in earlier delivery and lower birthweight. However, women with certain severe cardiac condi­ tions may benefit from elective cesarean delivery. These include women with severe congestive heart failure or recent myocardial infarction, severe aortic stenosis, dilated aortic root (>4 cm), pulmonary hypertension, warfarin use within two weeks of delivery (due to risk of fetal intracranial hemor­ rhage during delivery), and those who require valve replacement immedi­ ately after delivery. The immediate postpartum period is critical for the patient with VHD. Blood loss must be minimized and blood pressure maintained, on one hand, and attention must be paid to avoid congestive failure from fluid overload, on the other. Postpartum, high‐risk patients may require further monitoring in the cardiac intensive care unit.

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Prophylactic antibiotics Women with a history of acute rheumatic fever and endocarditis who are taking penicillin prophylaxis should continue throughout pregnancy. Whether women with other types of VHD should receive antibiotic prophy­ laxis during pregnancy is controversial. The American College of Cardiology and the American Heart Association Task Force on Practice Guidelines have stated that, in general, intrapartum antibiotics are not necessary for women undergoing vaginal or cesarean delivery unless bacteremia is suspected or there is an active infection. This is because most cases of endocarditis are attributed to random bacteremia from routine daily activities rather than invasive procedures, so prophylactic antibiotics would prevent only a small subset of endocarditis cases. Therefore, the risk of antibiotic‐associated adverse events outweighs the potential benefit. However, prophylactic anti­ biotics should be considered at the time of membrane rupture or prior to delivery for certain high‐risk patients. These special populations are listed in Table 17.11 with preferred antibiotic regimens summarized in Table 17.12.

Anesthesia Conduction anesthesia is the preferred method of intrapartum pain control for patients with VHD. However, it is important to avoid hypotension when establishing regional anesthesia. Careful administration of intravenous crystalloid before placement of the catheter, close monitoring of fluid status, and slow administration of the anesthetic agent help to prevent this com­ plication. Ephedrine is generally the agent of choice for the treatment of hypotension associated with regional anesthesia because it does not con­ Table 17.11  Special populations requiring antibiotic prophylaxis during labor

and delivery Women with prosthetic heart valves or prosthetic material used for valve repair Heart defects repaired with prosthetic material (within six months of the procedure) Heart defects repaired with prosthetic material with residual defects adjacent to the prosthetic material (any time after the procedure) History of endocarditis Unrepaired or palliated cyanotic heart defect (including those with a surgically constructed shunt or conduit) Cardiac transplant patients with valve regurgitation due to a structurally abnormal valve Sources: American College of Obstetricians and Gynecologists (2018b) and Nishimura et al. (2014).

Valvular Heart Disease in Pregnancy  163 Table 17.12  Infective endocarditis prophylactic antibiotic regimens in pregnancya Name

Standard IV regimen

Allergy to penicillin/ampicillin

Regimen IV

PO

Ampicillin 2 g or Cefazolin 2 g or Ceftriaxone 1 g Cefazolinb 2 g or Ceftriaxone 1 g or Clindamycin 600 mg

Amoxicillin 2 g

Clindamycin 600 mg IVc

 Ideally should be given 30–60 minutes prior to delivery.  Do not use cephalosporins in patients with a history of immediate‐type hypersensitivity reactions to penicillins. c  Use vancomycin if enterococcus is a concern. IV, intravenous; PO, by mouth (per os). Source: American College of Obstetricians and Gynecologists (2018b). a

b

strict the placental vessels. However, as ephedrine increases the maternal heart rate, phenylephrine may be more appropriate for patients in whom tachycardia and increased myocardial work must be avoided (e.g., those with mitral and aortic stenosis). A single‐dose spinal technique is relatively contraindicated in patients with significant cardiac disease because hypo­ tension frequently occurs during establishment of the spinal block. A nar­ cotic epidural is an excellent alternative method and may be particularly effective for patients in whom systemic hypotension must be avoided (e.g., those with pulmonary hypertension, etc.). Anesthesia for patients on anticoagulation therapy can be a challenge. Patients should stop anticoagulation at the onset of labor. Ideally, patients are transitioned from warfarin at least one week prior to planned proce­ dures and LMWH should be stopped 36 hours before. Those patients on UFH should hold it 8–12 hours prior to a planned induction of labor or cesarean, primarily so they can receive neuraxial anesthesia. Regional anesthesia should only be administered during labor after clotting studies return to normal to avoid spinal or epidural hematomas. Epidural anesthesia is generally considered safe for patients with a nor­ mal aPTT and platelet count. However, anesthesia guidelines often recom­ mend stopping aspirin 7–10 days prior to neuraxial anesthesia for patients on joint anticoagulation therapy; both the risks and benefits must be weighed for pregnant patients with mechanical valves. Therefore, it may be reasonable to continue aspirin therapy, but the choice of anesthesia should be decided in conjunction with an anesthesiologist.

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Follow‐up Most of the cardiovascular changes of pregnancy will have resolved approx­ imately 4–6 weeks after delivery and so the patient should be reevaluated by a cardiologist. However, the hemodynamic changes of pregnancy may not fully resolve for six months. Therefore, additional follow‐up visits at 4–6 months may be warranted to further evaluate and adjust medications. Based on the outcome of the pregnancy and the results of the cardiac reevaluation, the patient should be counseled regarding the risks for subse­ quent pregnancy and provided with appropriate contraception if desired.

Suggested reading American College of Obstricians and Gynecologists. ACOG Committee Opinion No. 756: Optimizing Support for Breastfeeding as Part of Obstetric Practice. Obstet Gynecol 2018a;132(4):e187–e196. American College of Obstricians and Gynecologists. ACOG Practice Bulletin No. 199: Use of Prophylactic Antibiotics in Labor and Delivery. Obstet Gynecol 2018b;132(3):e103–e119. Boudoulas KD, Borer JS, Boudoulas H. Etiology of valvular heart disease in the 21st century. Cardiology 2013;126(3):139–152. Canobbio MM, Warnes CA, Aboulhosn J, et al. Management of pregnancy in patients with complex congenital heart disease: a scientific statement for healthcare profession­ als from the American Heart Association. Circulation 2017;135(8):e50–e87. Centers for Disease Control and Prevention. Pregnancy Mortality Surveillance System | Maternal and Infant Health. Bethesda: CDC; 2019. www.cdc.gov/reproductivehealth/ maternalinfanthealth/pregnancy‐mortality‐surveillance‐system.htm Dolgin M (ed.). Nomenclature and Criteria for Diagnosis of Diseases of the Heart and Great Vessels, 9th edn. Boston: Little, Brown & Co; 1994. Drenthen W, Boersma E, Balci A, et al. Predictors of pregnancy complications in women with congenital heart disease. Eur Heart J 2010;31(17):2124–32. Nanna M, Stergiopoulos K. Pregnancy complicated by valvular heart disease: an update. J Am Heart Assoc 2014;3(3):e000712. Nishimura RA, Otto CM, Bonow RO, et al. 2014 AHA/ACC guideline for the manage­ ment of patients with valvular heart disease: executive summary. Circulation 2014;129(23):2440–92. Regitz‐Zagrosek V, Roos‐Hesselink JW, Bauersachs J, et al. 2018 ESC guidelines for the man­ agement of cardiovascular diseases during pregnancy. Eur Heart J 2018;39(34):3165–241. Samiei N, Amirsardari M, Rezaei Y, et al. Echocardiographic evaluation of hemodynamic changes in left‐sided heart valves in pregnant women with valvular heart disease. Am J Cardiol 2016;118(7):1046–52. Sanghavi M, Rutherford JD. Cardiovascular physiology of pregnancy. Circulation 2014;130(12):1003–8. Silversides CK, Colman JM, Sermer M, Siu SC. Cardiac risk in pregnant women with rheumatic mitral stenosis. Am J Cardiol 2003;91(11):1382–5. Siu SC, Sermer M, Colman JM, et al. Prospective multicenter study of pregnancy out­ comes in women with heart disease. Circulation 2001;104(5):515–21. Thorne S, MacGregor A, Nelson‐Piercy C. Risk of contraception and pregnancy in heart disease. Heart 2006;92(10):1520–5.

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Peripartum Cardiomyopathy Sarah Rae Easter1 and Carolyn M. Zelop2 Departments of Obstetrics and Gynecology, and Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA 2 Department of Obstetrics and Gynecology, NYU School of Medicine, New York, USA 1

Peripartum cardiomyopathy and the obstetric care provider Peripartum cardiomyopathy (PPCM) is a clinical diagnosis of exclusion defined as heart failure with a reduced ejection fraction towards the end of pregnancy or in the immediate postpartum period. This seemingly simple definition is challenged by the complexities of caring for patients in the third trimester of pregnancy and postpartum. Physiological dyspnea coupled with the other hallmark cardiovascular adaptations of pregnancy can confound the clinical presentation, and the overlap of PPCM with other obstetric and cardiovascular diagnoses further complicate the diagnostic dilemma. Despite these challenges, the increasing contribution of both cardiovascular disease and cardiomyopathy to maternal mortality highlights the importance of a framework for diagnosis and management of the disease. The goals of the obstetric care provider responsible for the care of a patient with PPCM are threefold. First, the provider must entertain this condition in the patient with the appropriate clinical presentation and pursue appropriate work‐up to establish the diagnosis. The provider is then challenged to stabilize the patient while awaiting the input of consulting colleagues with expertise in the management. Finally, the obstetric care provider must be familiar enough with the short‐ and long‐term management to provide input about treatment options while balancing the goals of care for the patient and her fetus or neonate.

Clinical presentation and diagnosis Clinical symptoms that may suggest PPCM include dyspnea, orthopnea, edema, chest pain, palpitations, dizziness, or fatigue. The obvious overlap between symptoms of this life‐threatening condition and a normal Protocols for High-Risk Pregnancies: An Evidence-Based Approach, Seventh Edition. Edited by John T. Queenan, Catherine Y. Spong and Charles J. Lockwood. © 2021 John Wiley & Sons Ltd. Published 2021 by John Wiley & Sons Ltd.

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uncomplicated pregnancy challenges even the most astute historian. Reassuringly, physical exam can help distinguish normal pregnancy physiology from pathological conditions warranting further investigation. Patients with cardiomyopathy typically demonstrate vital sign abnormalities including hypoxia, tachypnea, hypo‐ or hypertension, and tachycardia. Other more specific exam findings such as crackles or rales, systolic or diastolic murmur, or extra heart sounds such as an S3 or S4 heighten concerns for PPCM. Evaluation includes a chest x‐ray to evaluate for pulmonary edema and an electrocardiogram (ECG) to evaluate for ischemia or arrhythmias to suggest a cardiovascular etiology of the clinical presentation. Abnormalities in these studies clearly warrant follow‐up, but a normal chest x‐ray or ECG in the face of an atypical history or physical exam may also warrant further investigation (Figure 18.1). The most recent guidelines from the European Society of Cardiology outline a diagnosis of PPCM based on three features. • Heart failure secondary to left ventricular systolic dysfunction with left ventricular ejection fraction (LVEF) 300 can aid in distinguishing cardiovascular pathology from other diagnoses. Ultimately, PPCM is a diagnosis of exclusion that warrants an understanding of other causes of heart failure with reduced ejection fraction (HFrEF).

Differential diagnosis As with many other diseases, a useful framework for the differential diagnosis of the pregnant or newly postpartum patients with HFrEF is to consider conditions exacerbated by the physiological changes of pregnancy, diseases unique to pregnancy, and diseases unrelated to the pregnant state (Figure 18.2). The diagnosis is made from clinical features with transthoracic echocardiogram (TTE) and ECG. An ECG is mandatory to evaluate for HFrEF in the setting of pregnancy‐ associated myocardial infarction or heart failure as a downstream consequence of arrhythmias. For patients with co‐morbid arrhythmias, one must consider whether this is a consequence of the disease or related to its pathophysiology as in cases of arrhythmogenic cardiomyopathies such as arrhythmogenic right ventricular cardiomyopathy (ARVC). Once concern for HFrEF is raised, a targeted personal and family history and labs (chemistry, thyroid stimulating hormone [TSH] and assessment of urine protein) guide the provider towards the etiology and appropriate follow‐up testing.

Peripartum Cardiomyopathy  167

History and Physical Exam

Suggests Normal Pregnancy or Noncardiovascular Etiology

Suggests Cardiovascular Etiology

CXR, ECG, NT-proBNP Normal

CXR Suggests Pulmonary Edema, ECG Abnormal, or NT-proBNP Elevated

Transthoracic Echo (TTE) with Preserved Ejection Fraction

Evaluate for Preeclampsia: CBC Chemistry Urine Protein

Evaluate for Extracardiac Etiologies: CBC with Differential Chemistry and Thyroid Studies Arterial Blood Gas Viral Serologies Blood and Respiratory Cultures

Transthoracic Echo (TTE) with Reduced Ejection Fraction

Evaluate for Preeclampsia: CBC Chemistry Urine Protein Obstetrical Ultrasound

Consider Preexisting Cardiac Disease: Detailed History Discuss Family History Review of TTE Consideration of Chest CT

Figure 18.1  Diagnostic approach to the patient presenting with cardiopulmonary c­ omplaints. CBC, complete blood count; CXR, chest x‐ray; ECG, electrocardiogram; NT‐proBNP, N‐terminal pro‐brain natriuretic peptide.

Echocardiography can demonstrate the presence of known or newly diagnosed medical co‐morbidities exacerbated by pregnancy such as congenital heart disease or valvular heart disease. The echocardiographic features in cases with reduced ejection fraction can further narrow the differential. In some cases, transesophageal echocardiography (TEE) or cardiac magnetic resonance imaging (MRI) may be useful adjuncts for better visualization of valvular structures (via TEE) or characterization of the myocardium (via MRI). Cardiomyopathy is classically subdivided into dilated, restrictive, and hypertrophic types. Additional unclassified variants of note include stress cardiomyopathy, ARVC, and left ventricular noncompaction. Patient demographics and clinical presentation can suggest clues to the underlying diagnosis, but echocardiographic features are central to diagnostic criteria (Table 18.1).

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Unaffected by Pregnancy: • Myocarditis or Infectious • Metabolic Disorders • Inflammatory Disorders • Medication or Toxin Exposure

Affected by Pregnancy: • Congenital Heart Disease • Valvular Heart Disease • Myocardial Infarction • Dilated Cardiomyopathy • Stress-Induced Cardiomyopathy

Unique to Pregnancy: • Preeclampsia • Peripartum Cardiomyopathy • Amniotic Fluid Embolism • Mirror Syndrome

Figure 18.2  Differential diagnosis for heart failure with reduced ejection fraction in

pregnancy.

Etiopathogenesis of peripartum and other cardiomyopathies Dilated cardiomyopathy Dilated cardiomyopathy, of which peripartum cardiomyopathy is a subtype, is the most frequently encountered type of cardiomyopathy. The echocardiographic features include dilation of the left ventricle with reduced systolic function most commonly expressed as reduced ejection fraction. Therefore, the clinical presentation of PPCM is most often that of decompensated left‐sided heart failure though right‐sided dysfunction can be present. Distinguishing PPCM from other forms of dilated cardiomyopathy is a diagnostic dilemma but a targeted history looking for infectious etiologies (such as viral, HIV, Lyme disease), toxic etiologies (alcohol, cocaine, medications like anthracycline derivatives), or chronic medical conditions (renal disease, sarcoidosis, lupus) can be instructive. Without historical or laboratory clues to suggest another cause of dilated cardiomyopathy, a diagnosis of PPCM is often assumed. Understanding PPCM is complex due to the multifactorial pathogenesis and overlap with other clinical syndromes. PPCM has often been conceptualized as

Table 18.1  Clinical and echocardiographic features of variants of cardiomyopathy Cardiomyopathy

Clinical and physiological features

Echocardiographic features

Etiologies

Dilated cardiomyopathy

Dilation and impaired contraction of one or both ventricles Heart failure Arrhythmias

Hypertrophic cardiomyopathy

LVOT obstruction (often dynamic) Diastolic dysfunction Myocardial ischemia Mitral regurgitation Systolic dysfunction (end stage)

Infectious Medications Toxic Inflammatory Genetic mutations Peripartum Genetic mutations in sarcomere genes

Restrictive cardiomyopathy

Pulmonary and systemic congestion History of co‐morbid diagnosis

LV spherical dilation Normal or reduced WT Reduced systolic indicesa Four‐chamber enlargement± Reduced TAPSEb ± RWM abnormalitiesc Hypertrophied LV Nondilated LV Asymmetrical septal hypertrophy Septal WT ≥15 mm ± LVOT Obstruction ± SAM of MV Biatrial enlargement No RV/LV hypertrophy No RV/LV dilation

Arrhythmogenic right ventricular cardiomyopathy (ARVC)

Ventricular arrhythmias Sudden cardiac death

Abnormal RV function Regional RV akinesis

Familial Infiltrative Storage diseases Endomyocardial fibrosis Genetic Desmosomal gene mutations (continued)

Table 18.1  (Continued) Cardiomyopathy

Clinical and physiological features

Echocardiographic features

Etiologies

Stress cardiomyopathy

Acute substernal chest pain History of emotional or physical stress LVOT obstruction Mimics acute coronary syndrome Heart failure Thromboembolism Ventricular arrhythmias

LV systolic dysfunction Apical LV ballooning Hyperkinesis of basal walls ± LVOT obstruction Prominent LV trabeculae Continuity between LV cavity and deep intertrabecular recesses

Associated with excess catecholamines Must exclude evidence of coronary artery disease, typically with angiography

Left ventricular noncompaction

Due to intrauterine arrest of compaction of loose interwoven meshwork

 Systolic indices include LV fractional shortening, fractional area change, and ejection fraction.  Reduced tricuspid annular plane systolic excursion (TAPSE) is a marker of right ventricular dysfunction. Reduced TAPSE not necessary to make the diagnosis but TAPSE 30 years, African descent, multiple gestation, and a history of hypertension or preeclampsia. More rare but notable risk factors include long‐term tocolytic therapy with beta‐adrenergic agonists such as terbutaline, maternal cocaine abuse, and nutritional deficiencies (such as selenium). These risk factors have a synergistic as opposed to simply additive effect on the odds of developing PPCM. In an epidemiological study, the presence of one risk factor conferred a twofold increase in the odds of PPCM whereas the presence of two risk factors conferred an 11‐fold increase. Development of PPCM may be mediated through a variety of pathways related to a genetic predisposition, antiangiogenic factors from the placenta, endothelial damage, and the excretion of prolactin in conjunction with oxidative stress (Figure  18.3). The presence of a genetic predisposition is ­suggested by both pedigrees and the wide variation in incidence globally, ranging from a reported 1 in 100 patients in Zaria, Nigeria, to 1 in 20 000 live births in Japan. In a landmark prospective study, researchers sequenced 43 genes associated with dilated cardiomyopathy and identified variants in 15% of patients with PPCM. The rate of genetic abnormalities in this cohort

Prolactin Cleaved by Cathepsin D to 16 kDa Fragment Causing Endothelial Apoptosis Genetic Mutations in Sarcomere Proteins

Placental Release of sFLT-1 to Inhibit VEGF

Release of Cathepsin D by Damaged Myocyte

Endothelial Dysfunction Leading to Release of miRNA-146A

Injury to Cardiac Myocyte

Figure 18.3  Contemporary understanding of the pathophysiology of peripartum

cardiomyopathy.

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parallels the 17% prevalence of variants in patients with idiopathic dilated cardiomyopathy, suggesting a common genetic basis for this condition. Moreover, specific genetic variants such as truncating mutations in TTN – the gene encoding the sarcomeric protein titin – were associated with lower odds of recovery of cardiac function. An underlying genetic predisposition may explain part of the pathology but additional mediators of endothelial damage and oxidative stress leading to damage of cardiac myocytes play an important role in the pathogenesis of the disease. Basic science studies have revealed a role for both prolactin and the placenta in the mechanism of the disease. In times of increased oxidative stress, the enzyme cathepsin D cleaves prolactin released from the anterior pituitary to a 16 kDa fragment that causes endothelial apoptosis. The expression of soluble fms‐like tyrosine kinase receptor 1 (sFlt‐1) is an antiangiogenic protein that sequesters circulating vascular endothelial growth factor leading to endothelial dysfunction in a similar manner to preeclampsia. Endothelial dysfunction leads to increased expression of microRNA MiR‐146a which blocks several important pathways leading to cardiac myocyte death. Apoptosis of myocytes leads to additional stress and release of cathepsin D, providing a positive feedback loop for cardiac damage. These mechanisms of injury underscore the challenges of distinguishing PPCM from other diseases with an overlapping clinical presentation, including dilated cardiomyopathy and preeclampsia.

Hypertrophic cardiomyopathy In contrast to PPCM, other cardiomyopathies typically present with preserved ejection fraction except for those with end‐stage disease. For example, hypertrophic cardiomyopathy is characterized by a hypertrophied left ventricle without dilation. Although chronic diseases like hypertension or valvular heart disease in the setting of aortic stenosis can lead to hypertrophy of the left ventricle, hypertrophic cardiomyopathy classically refers to asymmetrical septal hypertrophy due to mutations in the genes encoding the sarcomere proteins in the contractile apparatus. This asymmetrical septal hypertrophy can lead to a dynamic left ventricular outflow tract (LVOT) obstruction characterized by systolic anterior motion (SAM) of the mitral valve. This finding reflects movement of the mitral valve to the hypertrophied intraventricular septum leading to obstruction of the LVOT and reduced stroke volume. The dynamic nature of this obstruction is a hallmark of the disease and is worsened with decreased LV filling, which can be exacerbated by decreases in the systemic vascular resistance or tachycardia. The thickened hypertrophied ventricle can also predispose the patient to ischemia, ventricular arrhythmias, and cardiac death. Understanding this hallmark physiology helps anticipate the adaptation to pregnancy and inform the treatment needs for pregnant women with this co‐morbidity.

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Restrictive cardiomyopathy Like hypertrophic cardiomyopathy, restrictive cardiomyopathy typically presents with diastolic dysfunction and preserved LV systolic function. The clinical presentation often includes pulmonary congestion manifest as ­pulmonary edema as well as systemic congestion with associated hepatosplenomegaly and ascites. Atrial arrhythmias can be common due to the increased burden of work with atrial contraction to force blood into a stiff and noncompliant ventricle. Echocardiographic features include a nondilated ventricle with normal wall thickness with impaired relaxation and diastolic filling from stiff noncompliant ventricles. Biatrial enlargement is often seen and excluding evidence of constructive pericarditis is essential. Restrictive cardiomyopathies are rare and can be caused by familial syndromes, infiltrative disorders (amyloidosis, sarcoidosis), glycogen storage diseases, or endomyocardial fibrosis. The clinical history can give insight into possible etiologies of the disease, but MRI can be necessary to make the diagnosis.

Stress cardiomyopathy Though other rare cardiomyopathy variants exist, a relevant unclassified disorder that should be on the differential diagnosis for a pregnant or postpartum patient presenting with evidence of HFrEF is stress cardiomyopathy. Stress cardiomyopathy is a catecholamine‐associated phenomenon that can present with evidence of acute coronary syndrome (ACS) including substernal chest pain, ST segment elevations, and elevated troponins. The hallmark echocardiographic finding is ballooning of the apex of the left ventricle which informed the initial name of the disease – takotsubo cardiomyopathy – taken from the Japanese name for octopus trap with a similar appearance of the left ventricle. Interrogation of the coronary arteries to exclude coronary artery disease may be required in cases with clinical presentation overlapping with ACS. Distinguishing this entity from PPCM is clinically relevant as the management of stress cardiomyopathy and dilated cardiomyopathy, particularly in cases of decompensated heart failure, is vastly different. As with the other cardiomyopathies, an understanding of the echocardiographic features and pathophysiology is of critical importance, both to guide acute treatment and provide anticipatory guidance about prognosis and recurrence risk.

Stabilization and treatment Immediate management of PPCM mirrors that of acute heart failure: ­optimization of preload typically with diuretics, afterload reduction, and supportive care. Frequent hemodynamic monitoring including cardiac

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telemetry, continuous fetal monitoring, and close urine output monitoring with the placement of a urethral catheter are warranted. In addition to assessment of heart rate, blood pressure, and respiratory status, other components of the clinical exam should be considered, including evidence of tissue hypoperfusion such as oliguria, cold skin either centrally or peripherally, an elevated lactate, or a depressed mixed or central venous oxygen saturation for those rare patients in whom invasive hemodynamic monitoring is warranted. The obstetric care provider should understand and explain maternal‐fetal physiology to the multidisciplinary team, and counsel the patient and her family about goals of care.

Stabilization of acute heart failure Supplemental oxygen may be necessary with a target of an SpO2 >95% for pregnant patients and SpO2 >90% for postpartum patients. Supplemental oxygen in the absence of hypoxemia is not warranted and may reduce cardiac output via vasoconstriction. For patients with refractory hypoxia, noninvasive mechanical ventilation (NIV) reduces the need for intubation in those with cardiogenic pulmonary edema likely due to the hemodynamic impact of positive pressure ventilation in addition to the respiratory support. The use of continuous positive airway pressure (CPAP) or bilevel positive airway pressure (BiPAP) provides additional hemodynamic support through the increase in intrathoracic pressure and reduction of preload and LV afterload. Optimization of preload is an essential stabilizing measure for patients presenting with heart failure. For most patients with PPCM and other HFrEF, this typically means diuresis though volume overload should not be assumed. Patient positioning in left lateral tilt 30–90° may help to mitigate the effect of aortocaval compression upon cardiac output when uterine size is greater than or equal to 20 weeks’ gestation. Clinical exam such as assessment of the jugular venous pulsation (JVP) or lower extremities for evidence of systemic congestion is essential. Additional maneuvers such as the passive leg raise or point‐of‐care TTE to assess left ventricular filling and for evidence of collapsibility of the inferior vena cava can aid in this assessment. For patients presenting with evidence of volume overload, the use of furosemide or other loop diuretics should be initiated at a low dose and quickly escalated until a clinical response is achieved. For diuretic‐naïve individuals, beginning with 10 mg IV furosemide and doubling this dose in 30‐minute intervals would be a favored approach. Afterload reduction is the other critical component of hemodynamic optimization for patients with PPCM and is classically achieved with the use of nitrates to target a systolic blood pressure of 95% (or >90% if Postpartum) with NIV Preferred to Intubation

>37 Weeks Delivery When Maternal Hemodynamics Optimized

Figure 18.4  Framework and clinical pearls for stabilization and ongoing management of the pregnant patient with peripartum cardiomyopathy from the standpoint of the obstetric care provider. ACE‐I, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blocker; ECMO, venoarterial extracorporeal membrane oxygenation; IABP, intraaortic balloon pump; MCS, mechanical circulatory support; NIV, noninvasive ventilation; SBP, systolic blood pressure; SpO2, oxygen saturation; VA‐VAD, ventricular assist device.

Peripartum Cardiomyopathy  177 pathophysiology of the patient, and requires shared decision making among the patient, her family, and her extended care team. Patients at an early preterm gestation who stabilize with medical management can continue with expectant management. The obstetrician can be helpful in educating colleagues about anticipated neonatal outcomes at a given gestational age category and to help weigh the maternal risks of ongoing pregnancy against potential fetal benefit. Delaying delivery to allow for optimization of maternal hemodynamics is warranted independent of gestational age. An attempted vaginal delivery is recommended for patients without an obstetric contraindication, with consideration of cesarean delivery for causes of acute decompensated heart failure. Neuraxial analgesia is the preferred mode of anesthesia to avoid the hemodynamic shifts with induction of a general anesthetic. These decisions should be individualized and should consider the hemodynamic status of the patient, obstetric co‐ morbidities, and future fertility goals. Outlining a delivery plan for patients requires multidisciplinary input with an overarching goal of prioritizing maternal stability to improve both maternal and fetal outcomes. Contingency plans in the event of fetal distress or maternal decompensation should be discussed specifically with an emphasis on the role of delivery in cases of maternal cardiac arrest.

Chronic therapy and long‐term follow‐up After initial stabilization and delivery, chronic heart failure therapy mirrors that of the general population and includes beta‐blockers, angiotensin converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB), and diuretics. Prophylactic or even therapeutic anticoagulation may be recommended for those with a persistently depressed ejection fraction less than 30–35% to avoid thromboembolic complications. Patients with a depressed ejection fraction 50% at six months, though 2–7% may require ventricular assist device placement as a bridge to either transplant or recovery of ventricular function. LVEF >30% or LV end‐diastolic diameter 100‐fold risk of thromboembolic disease. Well‐conducted prospective studies suggest that lower‐risk inherited thrombophilias, including FVL, have a weaker association with maternal thrombosis than that reported by prior retrospective

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Table 19.1  Inherited thrombophilia, personal history of VTE and pregnancy VTE risk Thrombophilia

Prevalence in general population (%)

VTE risk per pregnancy (no Hx) (%)

VTE risk per pregnancy (previous VTE) (%)

Percentage of all VTE

FVL heterozyg FVL homozyg PGM heterozyg PGM homozyg FVL/PGM double heterozyg AT deficiency PC deficiency PS deficiency

1–15 17 >20

40 2 17 0.5 1–3

0.02 0.2–0.4 0.03–0.13

0.2–11.6 0.1–1.7 0.3–6.6

40 4–17 0–22

1 14 3

Source: ACOG (2018a). Reproduced with permission of Wolters Kluwer Health, Inc.

studies. In fact, in one study, 4885 low‐risk women were screened in the first trimester for thrombophilias and 134 (2.7%) carried the factor V Leiden mutation, but none had a thromboembolic event during pregnancy or the puerperium (95% confidence interval [CI] 0–2.7%). Another two studies screening for factor V Leiden in early pregnancy found no thrombotic episodes in women found to carry heterozygous mutations. Prothrombin gene mutation (prothrombin G20210A) has been found to increase circulating prothrombin levels and, hence, the risk of both thrombosis and pregnancy complications. In women with a history of VTE during pregnancy, prothrombin G20210A was found in 17% of patients compared with 1% of age‐matched controls, and the factor V Leiden mutation was found in nearly 45% of patients. Homozygosity for prothrombin G20210A confers an equivalent risk of VTE to that of factor V Leiden homozygosity. The pregnancy‐associated VTE risk in women without any prior history of VTE due to deficiencies of the natural anticoagulants, protein S, protein C, and antithrombin account for 0.3–6.6%, 0.1–1.7% and 0.2–11.6% respectively. Antithrombin deficiency is the rarest and most thrombogenic of the inherited thrombophilic conditions (Table 19.1).

Acquired thrombophilia Antiphospholipid antibody syndrome (APS) is defined by the combination of VTE, obstetric complications, and antiphospholipid antibodies (APA). Venous thrombotic events associated with APA include DVT with or without acute pulmonary embolus. The most common arterial events include cerebral vascular accidents and transient ischemic attacks. At least half of

Thromboembolism  187 patients with APA have systemic lupus erythematosus. Anticardiolipin antibodies are associated with an odds ratio (OR) of 2.17 (1.51–3.11; 14 studies) for any thrombosis, 2.50 (1.51–4.14) for DVT and PE, and 3.91 (1.14–13.38) for recurrent VTE. Patients with systemic lupus erythematosus (SLE) and lupus anticoagulants are at a sixfold greater risk of VTE compared with SLE patients without lupus anticoagulants, while SLE patients with anticardiolipin antibodies have a twofold greater risk of VTE compared with SLE patients without these antibodies. The lifetime prevalence of arterial or venous thrombosis in affected patients with antiphospholipid antibodies is about 30%, with an event rate of 1% per year. These antibodies are present in up to 20% of individuals with VTE. A review of 25 prospective, cohort and case–control studies involving more than 7000 patients observed an  OR range for arterial and venous thromboses in patients with lupus anticoagulants of 8.65–10.84 and 4.09–16.2, respectively, and 1.0–18.0 and 1.0–2.51 for anticardiolipin antibodies. There is a 5% risk of VTE during pregnancy and the puerperium among patients with APA despite treatment. Recurrence risks of up to 30% have been reported in APA‐positive patients with a prior VTE; thus, long‐term prophylaxis is required in patients with APS and a prior VTE. A severe form of APS is termed catastrophic APS, or CAPS, which is defined as a potentially life‐threatening variant with multiple vessel thromboses leading to multiorgan failure. Potential mechanism(s) by which APA induce arterial and venous thrombosis as well as adverse pregnancy outcomes include APA‐mediated impairment of endothelial thrombomodulin and APC‐mediated anticoagulation; induction of endothelial tissue factor expression; impairment of fibrinolysis and antithrombin activity; augmented platelet activation and/ or adhesion; impairment of the anticoagulant effects of the anionic phospholipid binding proteins β2‐glycoprotein‐1 and annexin V. APA induction of complement activation has been suggested to play a role in fetal loss, with heparin preventing such aberrant activation. Antiphospholipid antibody‐related thrombosis can occur in any tissue or organ except superficial veins, while accepted associated obstetric complications include at least one fetal death at or beyond the 10th week of gestation, or at least one premature birth at or before the 34th week, or at least three consecutive spontaneous abortions before the 10th week. All other causes of pregnancy morbidity must be excluded. APAs must be present on two or more occasions at least 12 weeks apart. A positive test occurs with detection of IgG and/or IgM of one of three APAs. Positive test results are as follows: anticardiolipin antibodies IgG or IgM greater than 40 GPL (1 GPL unit is 1 μg of IgG antibody or 40 MPL (1 MPL unit is 1 μg of IgM antibody, or greater than the 99th percentile), anti‐β2‐glycoprotein‐I (IgG or IgM greater than the 99th percentile), or lupus anticoagulant.

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Diagnosis and management of venous thromboembolism associated with pregnancy Deep venous thrombosis In pregnancy, the diagnosis of VTE is based on history, physical examination, and diagnostic studies. The typically cited signs and symptoms of DVT include erythema, warmth, pain, edema, tenderness, and a positive Homan sign. However, among patients with these signs and symptoms, the diagnosis of DVT is confirmed in only one‐third when reliable objective tests are performed. Venous ultrasound with or without color Doppler is the primary diagnostic modality for evaluating patients at risk of DVT. The most accurate ultrasonic criterion for diagnosing venous thrombosis is noncompressibility of the venous lumen in a transverse plane under gentle probe pressure using duplex and color flow Doppler. The sensitivity and specificity of venous ultrasound is generally reported to be 90–100% for proximal vein thromboses but is thought to be lower with calf vein thrombosis. Two other imaging modalities include magnetic resonance imaging (MRI) and impedance plethysmography. The published literature suggests that the range of sensitivity and specificity for MRI in the diagnosis of DVT is 80–100% and 90–100%, respectively, with median published rates of 100% for both. For isolated iliac DVT, MRI is the “gold standard” although an alternative strategy is negative serial compression ultrasonography (CUS) with imaging of the iliac veins. Impedance plethysmography utilizes two sets of electrodes placed around the patient’s calf and an oversized blood pressure cuff around the thigh. Published sensitivities and specificities for diagnosing proximal DVT range from 65% to 98% and 83% to 97% respectively. It is expensive, and the test is insensitive (20 breaths/min) and tachycardia (>100 beats/min) are present in 90% of patients with PE but are nonspecific indices of risk. Symptoms such as dyspnea and pleuritic chest pain are present in up to 90% of patients with PE, while presyncope and syncope are rarer and indicative of massive emboli. Electrocardiographic changes may be present in 87% of patients with proven PE who are without underlying cardiopulmonary disease; however, these findings are nonspecific. The Urokinase Pulmonary Embolism Trial found that 26–32% of those with massive PE

Thromboembolism  189 had electrocardiogram (ECG) manifestations of acute cor pulmonale (S1 Q3 T3 pattern, right bundle branch block, P‐wave pulmonale, or right axis deviation). Assessments of arterial blood gases and oxygen saturation are also of limited value in PE; pO2 values of >80 mmHg are found in 29% of PE patients less than 40 years of age. More than 80% of patients with PE display sonographic imaging or Doppler abnormalities of right ventricular size or function, including a dilated and hypokinetic right ventricle, tricuspid regurgitation, and absence of preexisting pulmonary arterial or left heart pathology. Laboratory assessment with D‐dimer to determine a pregnant woman’s risk for PE is generally not recommended as it has a lower sensitivity in pregnant patients with PE and thus is not helpful as a test for ruling out disease. Pregnant patients with imaging‐confirmed PE have been found to have negative D‐dimer testing. One study reported a 73% and 15% sensitivity and specificity, respectively, for D‐dimer in testing in pregnant patients with clinically suspected PE. However, a 2019 study from Leiden University Medical Center Netherlands evaluating three criteria from the YEARS algorithm (clinical signs of DVT, hemoptysis, and pulmonary embolism as the most likely diagnosis) and D‐dimer level measured in 494 women suspected to have pulmonary embolism in pregnancy found that acute PE was safely ruled out in all cases. No patient was found to have a PE and CT pulmonary angiography was avoided in 65% of patients who began the study in the first trimester and in 32% who began the study in the third trimester (Figure  19.5). This promising study suggests that the imaging risks associated with pulmonary embolism evaluation may be significantly reduced if this algorithm is adopted. In the USA, the existing algorithm in place for evaluating hemodynamically stable patients with suspicion for PE is based upon the guideline developed by the American Thoracic Society, Society of Thoracic Radiology, and ACOG (Figure 19.6). This algorithm considers the possibility of lower extremity DVT and the results of the chest radiograph prior to moving to other imaging modalities. Chest radiographs may be abnormal in up to 84% of patients with PE, with common findings including pleural effusions, pulmonary infiltrates, atelectasis, and elevated hemidiaphragm. Despite this, a chest radiograph cannot be used to rule out a pulmonary embolism. Chest radiography should be performed when assessment of the lower extremities for DVT is negative or when no lower extremity signs or symptoms exist. A normal chest radiograph should then prompt screening with a V/Q scan. V/Q scanning is performed by imaging both the pulmonary vascular bed and the airspace. Perfusion scanning is accomplished by injecting isotopically labeled (e.g., technetium‐99) human albumin macroaggregates into the bloodstream where they are deposited in the pulmonary capillary bed.

Suspected acute pulmonary embolism in a pregnant patient

Order D-dimer test and assess presence of the three YEARS criteria: 1. Clinical signs of deep-vein thrombosis 2. Hemoptysis 3. Pulmonary embolism as the most likely diagnosis

Clinical signs of deep-vein thrombosis

Compression ultrasonography of symptomatic leg

Normal compression ultrasonography

No YEARS criteria and D-dimer 250–500 >250–500 >220–440

>400 >800 >320 200 > 500 > 500 >440

Source: GINA (2019).

Table 25.3  Recommendations for preferred step therapy for asthma during pregnancy Step one Step two Step three Step four Step fivea Step six

No controller Low‐dose inhaled corticosteroids Low‐dose inhaled corticosteroid plus long‐acting beta‐agonist or medium‐dose inhaled corticosteroids Medium‐dose inhaled corticosteroids plus long‐acting beta‐agonist High‐dose inhaled corticosteroids plus long‐acting beta‐agonist High‐dose inhaled corticosteroids plus long‐acting beta‐agonist plus oral corticosteroids at lowest effective dose

 Based on data in nonpregnant patients, alternative Step five therapy includes tiotropium and asthma biologics (see text). Source: National Asthma Education and Prevention Program (2004, 2007).

a

to alternatives; and leukotriene receptor antagonists, due to a paucity of published human gestational data for these drugs. Although oral corticosteroids have been associated with possible increased risks during pregnancy (oral clefts, prematurity, lower birthweight), if needed during pregnancy, they should be used because these risks are less than the potential risks of severe uncontrolled asthma (which include maternal or fetal mortality). Since the original recommendations in Table 25.3 in the 6th edition of this book were published, two types of newer medications have become available for use in Step 5 care. First, tiotropium (see Table 25.1) has been shown to be effective in nonpregnant patients uncontrolled by inhaled corticosteroids and long‐acting beta‐agonists (ICS/LABA) combination drugs. Although no human pregnancy safety data have been published for tiotropium, animal studies have been reassuring, and it would be reasonable to add tiotropium in pregnant women whose asthma is not controlled by ICS/LABA. Second, five biologic drugs are now available for the treatment of moderate to severe asthma not controlled by conventional therapy (Table 25.5). Human data only exist for omalizumab, but animal

Asthma  259 Table 25.4  Classification of asthma control during pregnancya Variable

Well‐controlled asthma

Asthma not well controlled

Very poorly controlled asthma

Frequency of symptoms

2 or fewer days/ week 2 or fewer times/ month None

More than 2 days/ week 1–3 times/week

Throughout the day 4 or more times/ week Extreme

2 or fewer days/ week Greater than 80%b 0–1 in past 12 months

2 or more days/ week 60–80%b 2 or more in past 12 months

Frequency of night‐time awakening Interference with normal activity Use of short‐acting beta‐ agonist for symptom control FEV1 or peak flow Exacerbations requiring use of systemic corticosteroid (no.)

Some

Several times per day Less than 60%b

 The level of control is based on the most severe category. The frequency and effect of symptoms should be assessed according to the patient’s recall of the previous 2–4 weeks. b  Percentage of the predicted or personal best value. Source: Schatz and Dombrowski (2009). © 2009. Reproduced with permission of Massachusetts Medical Society. a

studies are reassuring for all of the biologics. Their use during pregnancy could be considered in women who are candidates for the drugs, considering the risks of uncontrolled asthma, asthma exacerbations, and oral corticosteroids.

Acute asthma A major goal of chronic asthma management is the prevention of acute asthmatic episodes. When acute asthma does not respond to home therapy, expeditious acute management is necessary for the health of both mother and fetus. Due to progesterone‐induced hyperventilation, normal blood gases during pregnancy reveal a higher PO2 (100–106 mmHg) and a lower PCO2 (28– 30 mmHg) than in the nonpregnant state. The changes in blood gases that occur secondary to acute asthma during pregnancy will be superimposed on the “normal” hyperventilation of pregnancy. Thus, a PCO2 of 35 or greater or a PO2 of 70 or lower associated with acute asthma represent more severe compromise during pregnancy than will similar blood gases in the nongravid state. The recommended pharmacological therapy of acute asthma during pregnancy is summarized in Table 25.6. Intensive fetal monitoring as well as maternal monitoring is essential. In addition to pharmacological therapy, supplemental oxygen (initially 3–4 L/min by nasal cannula) should be administered, adjusting FiO2 to maintain at PO2 70 or greater and/or O2 saturation by pulse oximetry 95% or greater. Intravenous fluids (containing glucose if the patient is not hyperglycemic) should also be administered, initially at a rate of at least 100 mL/h.

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Table 25.5  Asthma biologics Drug

Action

Indication

Benralizumab Anti‐IL‐5R Add‐on maintenance treatment in patients with severe asthma and an eosinophilic phenotype (≥300 cells/μL) Anti‐IL‐4R Add‐on maintenance Dupilumab treatment in patients with moderate‐severe asthma with an eosinophilic phenotype or oral corticosteroid‐ dependent asthma Mepolizumab Anti‐IL‐5 Maintenance treatment of severe asthma in patients with an eosinophilic phenotype (≥150–300 cells/μL) Omalizumab Anti‐IgE Moderate‐severe asthma uncontrolled by ICS with positive allergy testing Reslizumab Anti‐IL‐5 Add‐on maintenance treatment in patients with severe asthma and an eosinophilic phenotype (≥400 cells/μL)

Dose

Pregnancy data

30 mg SC every 4 weeks × 3, then every 8 weeks

Animal studies reassuring

200 or 300 mg SC every 2 weeks

Animal studies reassuring

100 mg SC every 4 weeks

Animal studies reassuring

0.016 mg/kg/IU of IgE SC every 2–4 weeks 3 mg/kg IV every 4 weeks

Reassuring data in 250 exposed women Animal studies reassuring

Sources: McGregor et al. (2019), Namazy et al. (2020).

Table 25.6  Pharmacological management of acute asthma during pregnancy 1  Beta‐2‐agonist bronchodilator (nebulized or metered‐dose inhaler) • up to 3 doses in first 60–90 minutes • every 1–2 hours thereafter until adequate response 2 Nebulized ipratropium (may be repeated every 6 hours) 3 Systemic corticosteroids with initial therapy in patients on regular corticosteroids and in patients with severe exacerbations (peak expiratory flow rate less than 40% predicted or personal best) and for those with incomplete response to initial therapy • 40–80 mg/day in 1 or 2 divided doses until peak expiratory flow rate reaches 70% of predicted or personal best • may be given orally; IV for severe exacerbation • taper as patient improves 4 Consider intravenous magnesium sulfate (2 g) for women with life‐threatening exacerbations (peak expiratory flow rate less than 25% predicted or personal best) and for those whose exacerbations remain in the severe category after 1 hour of intensive conventional therapy

Asthma  261 Systemic corticosteroids (40–80 mg/day in one or two divided doses) are recommended for patients who do not respond well (FEV1 or peak expiratory flow rate [PEF] less than 70% predicted) to the first beta‐agonist treatment as well as for patients who have recently taken systemic steroids and for those who present with severe exacerbations (FEV1 or PEF less than 40% of predicted). Patients with good responses to emergency therapy (FEV1 or PEF 70% or greater of predicted) can be discharged home, generally on a course of oral corticosteroids. Inhaled corticosteroids should also be continued or initiated upon discharge until review at medical follow‐up. Hospitalization should be considered for patients with an incomplete response (FEV1 or PEF 40% or greater but 70% or less than predicted). Admission to an intensive care unit should be considered for patients with persistent FEV1 or PEF 40% or less of predicted, PCO2 42 or greater or sensorium changes. Intubation and mechanical ventilation may be required for patients whose condition deteriorates or fails to improve associated with decreasing PO2, increasing PCO2, progressive respiratory acidosis, declining mental status or increasing fatigue.

Follow‐up Careful follow‐up by physicians experienced in managing asthma is an essential aspect of optimal gestational asthma management. Asthmatic women requiring regular medication should be evaluated at least monthly. In addition to symptomatic and auscultatory assessment, objective measures of respiratory status (optimally spirometry, minimally PEF) should be obtained on every clinic visit. In addition, patients with more severe or labile asthma should be considered for home PEF monitoring. All pregnant patients should have a written action plan for increased symptoms and facilitated access to their physician for uncontrolled symptoms.

Conclusion Asthma is a common medical problem during pregnancy. Optimal diagnosis and management of asthma during pregnancy should maximize maternal and fetal health.

Suggested reading American College of Obstetricians and Gynecologists. ACOG Practice Bulletin No. 90. Asthma in Pregnancy. Obstet Gynecol 2008;111:457–64. Bonham CA, Patterson KC, Strek ME. Asthma outcomes and management during pregnancy. Chest 2018;153:515–27. Global Initiative for Asthma (GINA). Global Strategy for Asthma Management and Prevention. https://ginasthma.org/wp‐content/uploads/2019/06/GINA‐2019‐main‐ report‐June‐2019‐wms.pdf

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McGregor MC, Krings JG, Nair P, Castro M. Role of biologics in asthma. Am J Respir Crit Care Med 2019;199:433–45. Murphy VE, Namazy JA, Powell H, et al. A meta‐analysis of adverse perinatal outcomes in women with asthma. Br J Obstet Gynaecol 2011;118:1314–23. Namazy J, Schatz M. Management of asthma during pregnancy: optimizing outcomes and minimizing risk. Semin Respir Crit Care Med 2018;39:29–35. Namazy JA, Murphy VE, Powell H, et al. Effects of asthma severity, exacerbations, and oral corticosteroids on perinatal outcomes. Eur Respir J 2013;41:1082–90. Namazy JA, Blais L, Andrews EB, et  al. Pregnancy outcome in the omalizumab pregnancy registry and a disease‐matched comparison comparator cohort. J Allergy Clin Immunol 2020;145:528–36. National Asthma Education and Prevention Program. Expert Panel Report Managing Asthma During Pregnancy: Recommendations for Pharmacologic Treatment – Update 2004. J Allergy Clin Immunol 2005;115:34–46. National Asthma Education and Prevention Program. Expert Panel Report 3: Guidelines for the diagnosis and management of asthma. J Allergy Clin Immunol 2007;120:S93–138. Racusin DA, Fox KA, Ramin SM. Severe acute asthma. Semin Perinatol 2013;37:234–45. Schatz M, Dombrowski MP. Asthma in pregnancy. N Engl J Med 2009;360:1862–9.

PROTOCOL 26

Epilepsy Thomas McElrath Division of Maternal‐Fetal Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

Overview Obstetrics has developed tremendously since earlier times when women with epilepsy were counseled not to get pregnant or were even encouraged to undergo sterilization. Epilepsy is a common condition among reproductive‐ aged women with a prevalence of 1.2% of the general population. The average obstetrician‐gynecologist in community practice will regularly encounter women with epilepsy seeking preconceptual advice or care during a pregnancy. While over 90% of these women will have uncomplicated pregnancies and uneventful deliveries, as a group, women with epilepsy are at increased risk of ante‐, intra‐, and postpartum complications. Managing these risks implies the modification of standard obstetrical care with additional counseling, more frequent follow‐up, and multidisciplinary coordination.

Pathophysiology and risks Inheritance The child of an epileptic parent has an approximate 4% risk of developing a seizure disorder. The risk is, however, heavily influenced by the type of epilepsy in the parent. Parents with seizures secondary to traumatic injury would have a lower risk than would parents with an epileptic syndrome.

Seizure threshold Pregnant women with epilepsy have an increased risk of seizure during pregnancy compared with nonpregnant epilepsy patients. The risk increases with the progression of pregnancy with an increase in seizure rates in the intrapartum and postpartum periods. There are likely several reasons for this increase including decreased quality and quantity of sleep,

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increased emotional lability, and increased stress. However, beyond these, one of the primary reasons for the increase in the risk of seizure during pregnancy is an associated decrease in antiepileptic drug (AED) plasma concentrations. AED levels decrease in response to increased hepatic and renal clearance as well as an overall increased volume of distribution during pregnancy.

Fetal risks There appears to be a small increase in the risk of intrauterine demise among women with epilepsy. While statistically significant, the absolute risk is relatively limited at an approximate 20% increase beyond that of the baseline population. Exposure to maternal seizure activity also represents a potential source of fetal harm that is independent of the risk associated with AEDs (discussed below). Maternal seizure activity has been associated with evidence of fetal hypoxia. Paradoxically, the risk of hypoxic injury to the fetus increases with advancing gestation. The risk of fetal injury secondary to maternal trauma during a seizure or the possibility of placental abruption also represent indirect mechanisms associating seizure activity and fetal injury. The potential for prematurity represents an additional fetal risk. Pregnancies of women with epilepsy are at increased risk of preterm birth with the risk of both preeclampsia (60% increase) and spontaneous preterm birth (50% increase) compared to the baseline population. Additionally, fetuses of women with epilepsy have a 70% increased risk of intrauterine growth restriction.

Maternal risks Recent work has suggested that pregnant women with epilepsy are at a 10‐fold increased risk of maternal mortality when compared to women without epilepsy. This finding has been replicated in studies from three separate, developed countries, thereby lending credibility to the observation. However, the mechanism remains unclear. It may include a risk of seizure‐related complications exacerbated by the charged physiology of pregnancy and/or may represent an increased incidence of the entity known as sudden unexpected death in epilepsy (SUDEP). This remains a topic of investigation.

Antiepileptic drugs Antiepileptic drugs represent one of the few cases where known or suspected teratogens are prescribed to pregnant patients on a regular basis. Except for insulin, no other class of medications used during pregnancy has such a high potential for harm if not managed carefully.

Epilepsy  265

Teratogenicity A teratogen is an agent that alters the morphology or future function of a developing fetus. This is typically considered either a birth defect or developmental limitation. Baseline risk of birth defect in humans is 2–4%. To be considered a teratogen, a medication or exposure must increase the rate of malformation beyond this level. For over 50 years, AEDs have been suspected of or associated with birth defects. Typical defects are midline and involve morphological maldevelopment of the heart, mouth, penis, and neural tube. The type of malformation risk varies between different AEDs. • Cardiac most common with carbamazepine, lamotrigine, barbiturates, and phenytoin. • Neural tube defects with valproate. Valproate is associated with the highest rate of major malformations; phenytoin and phenobarbital with relatively high rates; carbamazepine, topiramate, and zonisamide with intermediate rates while lamotrigine, levetiracetam, and oxcarbazepine appear to have low rates similar to those found in nonmedicated women.

Risks associated with specific medications This list is presented in order from most to the least concerning. • Trimethadione is associated with an unacceptably high rate of fetal loss and major malformation (>80%). It should be considered as contraindicated for use during pregnancy. • Valproate as a monotherapy is associated with neural tube defects in 2% of exposed fetuses. Exposure is also associated with oral clefts, cardiac and urogenital malformations. It should be considered as highly teratogenic. Additionally, prolonged intrauterine exposure is associated with developmental delay (valproate syndrome), suggesting that damage to the developing fetus can be cumulative and beyond that of early morphological maldevelopment. A dose response does exists with higher doses representing greater risk. However, as is the case with alcohol exposure, a minimal safe threshold has not been identified. Recent work also suggests an association with in utero valproate exposure and the development of disorders on the autism spectrum. • Phenytoin is associated with orofacial, cardiac and urogenital defects. Up to 6% of exposed fetuses can exhibit a major malformation. • Phenobarbital is similarly associated with an increase in orofacial, cardiac, and urogenital malformations. Major malformations occur at a rate of 6% in fetuses exposed to phenobarbital. • Carbamazepine exposure is associated with a moderate increase in the rate of fetal malformation when compared to the unexposed population. While some sources have recorded modestly increased rates of malformation in orofacial, cardiac, and urogenital structures, carbamazepine

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has not consistently been associated with an increase in fetal abnormalities. There does, however, appear to be an increase in the risk of neural tube defects in older studies with a frequency of up to 1% of exposed fetuses. • Topiramate has been associated with an increased risk of orofacial clefts although this may only be at the higher dose ranges. Similarly, the risks may increase when topiramate is used as a component of polytherapy. Topiramate has also been associated with a risk of small for gestational age birth. • Lamotrigine appears not to have a risk of congenital malformation greater than that of the background population. Individual studies have suggested that at higher doses, there may be an increased risk of major malformation. These have not been consistently confirmed, however, in other studies. • Levetiracetam, in several large registry studies, is not associated with an increase in the risk of major congenital malformation beyond the standard background risk. Additionally, the pediatric follow‐up data available do not suggest an association between levetiracetam and neurodevelopmental outcomes. • Oxcarbazepine, while one of the less frequently used agents, has not been associated with an increased risk of major congenital malformation beyond that of the background population. • Zonisamide does not appear to have an increased rate of major congenital malformation although limited evidence has suggested an association with small for gestational age births. An important emerging concept is that exposure to multiple medications simultaneously may interact in a fashion that increases the risk of adverse fetal effects. These effects can be both an increased risk of major birth defect or an increased risk of delayed neurological development. The effect is most marked and best documented for combinations that include valproate as one of the AEDs. Polytherapy with valproate represents an increased risk of delayed neurological development and decreased IQ. Polytherapy should be reduced to single‐agent therapy prior to conception if this can be done safely.

Pregnancy management The care of a pregnant patient with epilepsy requires a multidisciplinary team. In addition to the obstetrician, a maternal‐fetal medicine specialist should be involved for counseling if not supervisory management, with a neurologist subspecialized in epilepsy management and, ideally, interested in/familiar with the physiological and neurological changes of pregnancy. A plan between the providers should be worked out in advance as to how

Epilepsy  267 seizure activity will be managed. The team might also include a consulting pharmacist as many of the standard AEDs differ slightly in their concentrations between manufacturers.

Pre‐pregnancy Ideally, the pregnancy is planned and counseling can occur pre‐pregnancy. The patient should meet with both her neurologist and a maternal‐fetal medicine specialist for general counseling. To some degree, the counseling of the two specialties will overlap and the plan of care presented here is intended more as a suggestion of what should be covered rather than who should cover it. The neurologist should review the patient’s epilepsy diagnosis and clarify pertinent details in her history. The specifics of her auras and triggers should be noted. She should also discuss the optimization of her medical regime with the possibility of planning a trial of alternative AED so as to minimize potential fetal risk. This consultation should also discuss the plan for medication plasma level monitoring per trimester and postpartum. The patient should meet with a maternal‐fetal medicine specialist to review the risks of teratogenicity and how these will be evaluated. The course of her prenatal care and plan for AED plasma level testing will also need to be reviewed. The unique aspects of the labor and delivery process should be discussed. The patient should also be reminded that the benefits of an optimized AED regime, even if it requires delaying pregnancy, will almost always supersede the risks of additional maternal age. • If patient has been seizure free for a sufficient interval, trial off medication may be considered. To ensure stability, pregnancy should be deferred for a minimum of 6‐12 months after medication discontinuation. • Alteration of AED. ○○ A pre‐pregnancy interval of stability of a least three months prior to conception. ○○ Use of delayed‐release preparations or divided dose medications should be considered to blunt peak levels. ○○ Polytherapy should be avoided unless absolutely necessary to maintain seizure control. ○○ Valproate should be used only if seizure control cannot be obtained with another agent. • Folic acid supplementation should be initiated at least three months prior to conception as low serum folate levels are associated with fetal malformation and delayed neurological development, particularly in women with epilepsy. ○○ 1 mg per day begun prior to and continued through pregnancy. ○○ Increase this to 4 mg per day for cases of a prior neural tube defect, patients on valproate or on carbamazepine. • Begin standard prenatal vitamins.

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First trimester The patient should be seen by her neurologist approximately once every trimester and by the obstetrical care provider per the recommended care prenatal care schedule. • The first visit should be between 7 and 10 weeks gestation. • AED levels should be drawn with first visit prenatal labs. Levels adjusted as needed. • Monthly plasma AED levels should be planned for the remainder of the pregnancy. • Aneuploidy screening should be per age appropriate protocol. • Pregnancy‐associated emesis is a particular concern in the first trimester. ○○ The patient should be instructed to retake her medications if she vomits within one hour of taking the dose. ○○ If emesis occurs more than one hour later, then she has likely absorbed a sufficient quantity of the medication. ○○ The patient should be discouraged from looking for the pill in the emesis as an indication of the need to redose or not to redose. ○○ If emesis becomes a ongoing problem and there is a question if potentially several lost doses, then she should contact her obstetrician for means to treat the nausea.

Second trimester By the second trimester, typically the concerns for pregnancy‐associated emesis are reduced. If they persist, they should be managed as noted above. • A level three ultrasound should be obtained. The patient’s epilepsy and medications should be made known to the sonologist. • A prescription for prophylactic lorazepam should be provided. ○○ 1 mg PO for the occurrence of an aura. ○○ 2 mg for a seizure. • The patient and her family should be instructed to call the care team in case of seizure.

Third trimester Care in this trimester is characterized by more visits and surveillance than would be the case for patients who do not have epilepsy. • Monthly ultrasounds for fetal growth to rule out intrauterine growth restriction. • Continue monthly plasma AED measurements. • Induction should be considered in the 39th week given the ongoing risk of fetal and maternal harm due to seizure and that the fetus has optimally developed by this stage of gestation.

Epilepsy  269 • A predelivery consultation with the obstetrical anesthesia department is ideal. • Obtaining adequate sleep can be a troubling issue for all pregnant women, but it is particularly concerning for patients with epilepsy. Evidence exists that all pregnant patients lose one REM cycle on average. Clinically, patients frequently note that they awaken early from sleep and cannot fall back to sleep. • Patients should attempt to obtain a minimum of four consecutive hours of sleep and may consider napping in the daytime if work permits so as to maximize the total hours of sleep.

First seizure during pregnancy In the rare event that a patient develops new‐onset seizures while pregnant, the management is largely similar to that of a new‐onset seizure while not pregnant. • The possibility of eclampsia, intracerebral mass effect, hemorrhage or thrombosis must be excluded. • Consultation with an epilepsy specialist. • Neuroimaging should be considered. ○○ MRI can be safely performed regardless of trimester but gadolinium should not be administered. ○○ CT can be considered with contrast. Given the diagnostic benefits of this imaging modality, it should not be deferred over concerns for fetal ionizing radiation exposure. The dose of ionizing radiation to the maternal pelvis during a head CT is minimal and typically only involves reflection off internal skeletal stru Appropriate shielding should be employed. ○○ Full serum toxin screen, electrolytes, and metabolic studies should be ordered immediately. ○○ Electroencephalography per neurological recommendation. • The initial AED should be chosen with regard to the stage of pregnancy and fetal safety. ○○ Lamotrigine may be problematic to initiate during pregnancy given the risk of rash and difficulty obtaining a therapeutic level given enhanced clearance. ○○ Valproate and trimethadione should be avoided given the risks discussed above.

Intrapartum The mode of delivery should be determined entirely by obstetrical indication. Barring an atypical neuroanatomical anomaly, there is no indication for a cesarean delivery purely for the indication of maternal epilepsy. Given the often‐marked variation in concentration between different manufacturers of the same AED, the patient should bring her own AED

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preparation and be allowed to take it at her standard interval while hospitalized. • Neuraxial analgesia is recommended given the association with decreased pain and stress as well as increased opportunities to sleep. • A minimum of four hours of intrapartum sleep should be sought. • Intravenous access should be obtained even if neuraxial analgesia is deferred. • Lorazepam both oral and intravenous preparations should be on hand in case of aura or seizure: 1 mg for occurrence of aura, 2 mg for seizure activity. • Pediatrics should be present for delivery if lorazepam has been administered given the risk of respiratory suppression in the newborn.

Postpartum The postpartum care of the epileptic patient is similar to that of most postpartum patients but a premium should be placed on allowing the patient to obtain sleep. • Epileptic patients should be allowed to room out their infant such that they can obtain a minimum of four hours sleep. • Postpartum staff may have to be educated that this recommendation is not a matter of convenience but instead sleep is recommended as prophylactic “medication.” • AED dosing should be tapered to pre‐pregnancy dosing. • Tapering should not begin prior to three days postpartum unless the patient exhibits symptoms of overdosing. • Consultation with an epilepsy specialist should be sought to determine an appropriate dosing taper. • Breastfeeding should be strongly encouraged. While many of the AEDs will penetrate into breast milk, the levels in infant plasma will typically only be a fraction of that in maternal blood. The developmental and infectious benefits of breastfeeding outweigh the largely unproven and theoretical risks of this minimal exposure. • Parents will need to organize patterns of infant care and feeding that allow sufficient maternal sleep. • Parents also should not engage in co‐sleeping. • Bathing of the infant should always be supervised by a parent not diagnosed with epilepsy.

Suggested reading Hernández‐Díaz S, Smith CR, Shen A, et al. Comparative safety of antiepileptic drugs during pregnancy. Neurology 2012;78;1692–1699. Hernández‐Díaz S, Mittendorf R, Smith CR, Hauser WA, Yerby M, Holmes LB,; North American Antiepileptic Drug Pregnancy Registry. Association between topiramate and zonisamide use during pregnancy and low birth weight. Obstet Gynecol 2014;123(1): 21–8.

Epilepsy  271 MacDonald, S. C., Bateman, B. T., McElrath, T.F,. & Hernández‐Díaz, S. Mortality and morbidity during delivery hospitalization among pregnant women with epilepsy in the United States. JAMA Neurol 2015;72:981–8. Management Issues for Women with Epilepsy  –  Focus on Pregnancy (An Evidence‐ Based Review): Report of the Quality Standards Subcommittee and the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and the American Epilepsy Society. I. Obstetrical complications and change in seizure frequency. Epilepsia 2009;50(5):1229–36. II. Teratogenesis and perinatal outcomes. Epilepsia 2009;50(5):1237–46. III. Vitamin K, folic acid, blood levels, and breast‐feeding. Epilepsia 2009;50(5):1247–55. Meador KJ, Baker G, Browning N, et al. Cognitive function at 3 years of age after fetal exposure to antiepilepticdrugs. N Engl J Med 2009;360(16):1597–605. Pennell PB. Antiepileptic drug pharmacokinetics during pregnancy and lactation. Neurology 2003;61:S35–S42. Pennell P, McElrath T. Management of epilepsy during preconception, pregnancy, and the postpartum period. www.uptodate.com/contents/management‐of‐epilepsy‐during‐ preconception‐pregnancy‐and‐the‐postpartum‐period Pennell P, McElrath T. Risks associated with epilepsy during pregnancy and postpartum period. www.uptodate.com/contents/risks‐associated‐with‐epilepsy‐during‐pregnancy‐ and‐postpartum‐period/print Tomson T, Landmark C, Battino D. Antiepileptic drug treatment in pregnancy: changes in drug disposition and their clinical implications. Epilepsia 2013;54(3):405–14.

PROTOCOL 27

Chronic Hypertension Michal Fishel Bartal and Baha M. Sibai Department of Obstetrics and Gynecology and Reproductive Sciences, The University of Texas Medical School at Houston, Houston, TX, USA

According to data derived from the National Health and Nutrition Examination Survey, 2015–2016, the prevalence of chronic hypertension among women of childbearing age (18–39 years) is 7.5%. Hypertension prevalence was higher among non‐Hispanic black than non‐Hispanic white, non‐Hispanic Asian or Hispanic adults. Recent data suggest that chronic hypertension will complicate 0.9–1.5% of all pregnancies. The rate is expected to increase secondary to increased obesity and increased maternal age.

Definition and diagnosis In pregnant women, chronic hypertension is defined as elevated blood pressure that is present and documented before pregnancy. In women whose pre‐pregnancy blood pressure is unknown, the diagnosis is assumed to be present based on the presence of sustained hypertension before 20 weeks of gestation. Traditionally, hypertension in pregnancy was defined as either systolic blood pressure of at least 140 mm Hg or diastolic blood pressure of at least 90 mmHg on at least two occasions measured at least four hours apart. The American College of Cardiology (ACC) and the American Heart Association (AHA) had recently published a new classification of blood pressure that added a new definition of stage 1 hypertension defined as systolic blood pressure of 130–139 mmHg or diastolic blood pressure of 80–89 mmHg. Importantly, the recommendation now suggests beginning treatment in stage 1 hypertension for nonpregnant adults with risk factors for cardiovascular disease. The effect of the new ACC/AHA definition and treatment for stage 1 hypertension in pregnancy is unknown but a recent secondary analysis of 164 women with stage 1 hypertension found that women with stage

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1 hypertension had increased risk for preeclampsia, gestational diabetes, and preterm delivery compared to normotensive women. Hypertension during pregnancy also is classified as severe if at or above cut‐off points of 160 mmHg for systolic blood pressure and/or 110 mmHg for diastolic blood pressure on at least two occasions measured at least four hours apart. Up to 20–50% of women with chronic hypertension may develop superimposed preeclampsia. The chronic hypertension ACOG Practice Bulletin emphasizes the difficulty with diagnosis of superimposed preeclampsia with no strict definition; a sudden increase in baseline hypertension or a sudden increase in proteinuria (above the threshold for normal or a clear change from baseline) should prompt assessment for a possible diagnosis of superimposed preeclampsia and consideration for subspecialty (e.g., maternal–fetal medicine) referral. However, it is often difficult to distinguish between worsening of chronic hypertension and chronic hypertension with superimposed preeclampsia. The ACOG Hypertension in Pregnancy Task Force recommended that superimposed preeclampsia be stratified into two groups to guide management. 1 Superimposed preeclampsia defined as: • a sudden increase in blood pressure that was previously well controlled or escalation of antihypertensive medications to control blood pressure, or • new‐onset proteinuria (300  mg or more/24‐hour collection or a protein:creatinine ratio of 0.3 or more) or sudden increase in proteinuria in a woman with known proteinuria before or early in pregnancy. 2 Superimposed preeclampsia with severe features should be assumed in the presence of any of the following. • Severe range BP (systolic blood pressure of at least 160 mmHg or/and diastolic blood pressure of at least 110 mmHg) despite escalation of antihypertensive therapy. • Persistent cerebral (headaches) or visual disturbances. • Significant increase in liver enzymes (two times the upper limit of normal concentration for a particular laboratory). • Thrombocytopenia (platelet count less than 100 000/microliter). • New‐onset and worsening renal insufficiency. • Pulmonary edema.

Etiology and classification The etiology and severity of chronic hypertension is an important consideration in the management of pregnancy. Chronic hypertension is subdivided into primary (essential) and secondary. Primary hypertension is by

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Evaluation preconception or before 20 weeks

Assess etiology and severity Assess presence of other medical conditions or target organ damage Assess prior obstetric history

• Uncomplicated essential hypertension • No previous perinatal loss • Systolic pressure less than 160 mmHg and diastolic less than 110 mmHg

Low risk

• • • •

Secondary hypertension Target organ damage* Previous perinatal loss Systolic pressure ≥160 mmHg or diastolic >110 mmHg

• Systolic ≥160 or diastolic ≥110 • Preeclampsia

High risk

* Left ventricular dysfunction, rentinopathy, dyslipidemia, maternal age above 40 years, microvascular disease, stroke.

Figure 27.1  Initial evaluation of women with chronic hypertension.

far the most common cause of chronic hypertension seen during ­pregnancy (90%). In 10% of cases, chronic hypertension is secondary to one or more underlying disorders such as renal disease (glomerulonephritis, interstitial nephritis, polycystic kidneys, renal artery stenosis), collagen vascular ­disease (lupus, scleroderma), endocrine disorders (diabetes mellitus with vascular involvement, pheochromocytoma, thyrotoxicosis, Cushing disease, hyperaldosteronism), or coarctation of the aorta. For management and counseling purposes, chronic hypertension in pregnancy is also categorized as either low risk or high risk as described in Figure 27.1. The patient is considered to be at low risk when she has mild essential hypertension without any organ involvement.

Maternal–perinatal risks Pregnancies complicated by chronic hypertension are at increased risk for superimposed preeclampsia, gestational diabetes, placental abruption, fetal growth restriction, preterm delivery, and adverse maternal outcomes. Although uncommon, women with chronic hypertension have increased maternal mortality and increased risk for cerebrovascular accidents, pulmonary edema or renal failure compared to normotensive

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women. Up to 20–50% of women with chronic hypertension may develop superimposed preeclampsia. Sibai and associates studied the rate of superimposed preeclampsia among 763 women with chronic hypertension followed prospectively at several medical centers in the United States. The overall rate of superimposed preeclampsia was 25%. The rate was not affected by maternal age, race, or presence of proteinuria early in pregnancy. However, the rate was significantly greater in women who had hypertension for at least four years (31% vs 22%), in those who had had preeclampsia during a previous pregnancy (32% vs 23%), and in those whose diastolic blood pressure was 100–110 mmHg compared with those whose diastolic blood pressure was below 100 mmHg at baseline (42% vs 24%). Panaitescu et  al. studied the rate of adverse pregnancy outcome in a recent large prospective study of 1417 women with chronic hypertension. Chronic hypertension was associated with increased risk of stillbirth (odds ratio [OR] 2.38; 95% confidence interval [CI] 1.51–3.75), preeclampsia (OR 5.76; 95% CI 4.93–6.73), small for gestational age (OR 2.06; 95% CI 1.79–2.39), gestational diabetes (OR 1.61; 95% CI 1.27–2.05), iatrogenic preterm birth 3 SD below the mean for gestational age and gender); (ii) brain abnormalities (subcortical calcifications, ventriculomegaly, cortical thinning, gyral pattern anomalies, hypoplasia of the cerebellum, or corpus callosum anomalies); (iii) ocular findings; (iv) congenital contractures, also known as arthrogryposis; and (v) neurological impairment. Microcephaly rates in the few prospective studies conducted during the epidemic ranged from 3% to 7% among infants with in utero ZIKV exposure. The most common CNS abnormalities include cerebral calcifications, cortical developmental malformations (lissencephaly, pachygyria, agyria), ventriculomegaly due to brain atrophy, posterior fossa alterations including brainstem or cerebellar hypoplasia, corpus callosum abnormalities, enlarged extraaxial cerebrospinal fluid spaces, and enlarged cisterna magna. Ophthalmological and sensorineural hearing loss have been reported in 7% and 12% of infants, respectively, followed since the time of maternal acute infection. Hearing deficits and eye abnormalities are more frequently identified in children with additional CNS findings but they can also be isolated findings. Eye manifestations of ZIKV in utero infection include retinal pigment epithelium of the macula, optic nerve hypoplasia, chorioretinal atrophy; unusual manifestations include colobomas and microphthalmia. Affected children with abnormal eye exams generally have abnormal visual function in early infancy. Eye abnormalities following ZIKV in utero infection do not tend to progress. Interestingly, 10% of children with confirmed maternal in utero ZIKV exposure were found to have congenital heart defects. Studies evaluating longer term outcomes of infants with in utero ZIKV exposure have shown that approximately 14.5% will have severe neurodevelopmental problems and sensorineural abnormalities by 3 years of age. While not all children with abnormalities at birth have later neurodevelopmental repercussions, infants exposed to ZIKV in utero and found to be normal at birth might have abnormal developmental outcomes years later. Prospective studies demonstrated that 31.5% of in utero exposed children have below average neurodevelopment or abnormal eye or hearing findings, with 29% of children scoring below average in Bayley IIII neurodevelopmental assessments in the third year of life. Secondary microcephaly, microcephaly that develops after birth, and a higher rate of autism spectrum disorder have been identified in children exposed to ZIKV in utero, underscoring the need for long‐term follow‐up.

Pathophysiology Individuals with ZIKV infection have a short window period of viremia and viruria, usually no longer than 14 days in most cases. Following primary infection, the virus infects CD14+ blood monocytes, an ideal target as these

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cells can be used as a “Trojan horse” to infiltrate immune‐sheltered tissues such as the placenta, testes, and brain. During the period of acute maternal viremia, ZIKV can cross the placenta, infecting placental macrophages. The virus is exceedingly neurotropic and has been shown to disrupt neural progenitor cell development, leading to the occurrence of microcephaly in animal models. Worse fetal outcomes are associated with maternal infection earlier in pregnancy, with CNS malformations most common with first‐ and second‐trimester infections. Late fetal demise has been shown to occur as well, due to placental vascular involvement leading to a focal necrotic vasculitis and placental failure. For this reason, adverse outcomes following ZIKV infection have been noted in all stages of pregnancy. Epidemiological studies suggest a link with spontaneous abortions and prospective series have found high rates of fetal growth restriction. The virus has also been found to induce CNS calcifications and bone fusion, with craniosynostosis being another feature of congenital ZIKV infection. Because the virus can persist for extended periods of time in the semen, pregnant women could potentially be at risk for infection weeks to months following their partner’s travel to an endemic area.

Diagnosis and management The diagnosis of ZIKV infection during pregnancy can be difficult. ZIKV identification in blood and urine by PCR has a narrow diagnostic window, generally not exceeding 14 days from the time of acute infection in adults and children postnatally infected. Since most individuals have asymptomatic infection and most who do have symptoms have only mild findings, it is very easy to miss the diagnosis of acute ZIKV infection, particularly in nonepidemic settings where awareness is diminished. Serological diagnosis is fraught because of the cross‐reactivity of ZIKV serological assays with preexisting dengue (DENV) antibodies. There is significant cross‐reactivity between ZIKV NS1 and DENV NS1 antibodies, as well as cross‐reactivity with E (envelope) protein‐based antibodies. For confirmatory serological diagnosis of ZIKV infection, plaque reduction neutralization assays (PRNT) are optimally performed but these assays are cumbersome, generally unavailable except through health departments and the CDC, as well as time‐consuming, so immediate results are not feasible. Zika IgM can be used for diagnostic purposes in some settings, such as travelers to endemic areas. However, IgM responses to ZIKV are short‐ lived, making retrospective diagnosis of ZIKV even more difficult. There are different approaches to diagnosis for pregnant and nonpregnant women. CDC guidelines recommend that when there is suspicion of ZIKV infection during pregnancy, i.e., a positive exposure history from the patient or her partner, symptoms consistent with ZIKV infection, and/or ultrasound findings suggestive of ZIKV infection, the following algorithm should be followed (see Figures 30.1 and 30.2). Prenatal ultrasonagraphy to evaluate for fetal abnormalities consistent with CZS is recommended for

Approach to diagnostic testing for dengue and Zika virus infection in symptomatic pregnant women with risk for infection with both viruses Specimen collected ≤12 weeks postsymptom onset Perform dengue and Zika virus NAATs (blood and urine) and dengue and Zika virus IgM serology

Positive dengue virus NAAT

Positive Zika virus NAAT

Negative dengue and Zika virus NAATs and positive dengue or Zika virus IgM

Negative dengue and Zika virus NAATs and negative dengue or Zika virus IgM

Perform dengue and Zika virus PRNTs

Acute dengue virus infection

Acute Zika virus infection

Dengue virus PRNT ≥10 and Zika virus PRNT 15 000 cells/mm3 in the absence of corticosteroids. • Purulent fluid (cloudy or yellowish thick discharge confirmed visually on speculum exam) coming from the cervical canal. Triple I is “confirmed” when biochemical (glucose, lactate dehydrogenase [LDH], WBC count, leukocyte esterase activity) and/or microbiological (cultures, gram stain) test results are consistent with microbial invasion and/or inflammation of the AF. Overall, the accuracy of clinical signs and symptoms in detecting intraamniotic infection is not high, with only 10–50% of patients with clinically suspected Triple I actually having a confirmed diagnosis. These numbers further vary based on the presence or absence of preterm prelabor rupture of the fetal membranes (PPROM). The accuracy of each clinical risk factor in predicting Triple I is 51.1% for maternal tachycardia, 57.8% for fetal

Chorioamnionitis  483 tachycardia, and 55.6% for maternal leukocytosis. Remarkably, direct microbiological analysis of the AF, although perceived as the “gold standard” diagnostic test for infection, is not always accurate as to the presence or absence of AF bacteria since uncultivable bacteria are frequently responsible for triggering an inflammatory response. Where transabdominal amniocentesis is performed to confirm or exclude Triple I, the AF laboratory tests used for clinical management are glucose levels, LDH activity, WBC count, leukocyte esterase activity, gram stain, and bacterial cultures. Some patients who present with preterm labor or PPROM may have clinical symptoms strongly suggestive of Triple I. In subjects with preterm labor or PPROM who do not exhibit any of the above classic signs or symptoms, physicians should remain vigilant for a subclinical intrauterine infection. For women in preterm labor, with intact membranes, Triple I is common among those failing first‐line tocolytic therapy, displaying advanced cervical dilation (>3 cm), or when amniotic fluid “sludge” is visualized by transvaginal ultrasound.

Isolated maternal fever Isolated maternal fever is defined as any maternal temperature between 38.0 °C (100.4 °F) and 38.9 °C (102.1 °F) with no additional risk factors present, and with or without persistent temperature elevation (Figure 47.1). Differential diagnosis includes but is not limited to fever secondary to ­epidural anesthesia, prostaglandin use, dehydration, hyperthyroidism, and excess ambient heat. When a laboring patient has fever and the Group B streptococcus (GBS) status is unknown at ≥37 weeks of gestation, intrapartum prophylaxis should be initiated as per ACOG guidelines. Standardization of fever evaluation at term should consider that maternal temperature ≥39.0 °C or 102.2 °F on one reading constitutes a fever which by ACOG recommendation is suggestive of Triple I. If the temperature is ≥38.0 °C (100.4 °F) but less than 39.0 °C (102.2 °F), the temperature should be retaken in 30 minutes for confirmation. A repeat temperature ≥38.0 °C or 100.4 °F constitutes a documented fever. For the diagnosis of fever, temperature should be measured orally.

Isolated maternal fever • Temp ≥38.0°C (100.4°F) to 38.9°C (102.1°F) with no additional risk factors present, and with or without persistent temperature elevation • If Temp ≥38.0°C (100.4°F) but 160 b/m) • Maternal tachycardia (>100 b/m) • Maternal WBC >15,000 cells/mm3 • Uterine purulent fluid • AF glucose, LDH, cultures, Gram stain GA: >37 weeks Membrane status • Intact: delivery indicated • PROM: delivery indicated Intrapartum • Ampicillin 2 gr IV every 6 hours • Gentamicin 1.5 mg/kg every 8 hours Postpartum Cesarean delivery • Ampicillin 2 gr IV X1 • Gentamicin 1.5 mg/kg x 1 Add:

Steroids Intrapartum • Ampicillin 2 gr IV every 6 hours • Gentamicin 1.5 mg/kg every 8 hours Postpartum Cesarean delivery • Ampicillin 2 gr IV X1 • Gentamicin 1.5 mg/kg x 1

• Clindamycin (900 mg IV) x 1 OR • Metronidazole (500 mg IV) x 1

Add: • Clindamycin (900 mg IV) x 1 OR • Metronidazole (500 mg IV) x 1

Vaginal delivery • No antibiotics necessary

Vaginal delivery • No antibiotics necessary

Figure 47.2  Diagnosis of triple I.

GA: >23 to 34 to