Avery's Diseases of the Newborn [11 ed.] 032382823X, 9780323828239

Citation preview

AVERY’S DISEASES of the

NEWBORN

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Eleventh Edition

AVERY’S DISEASES of the

NEWBORN​

Christine A. Gleason, MD

Taylor Sawyer, DO, MBA, MEd

Professor Emerita of Pediatrics​ Division of Neonatology​ University of Washington School of Medicine​ Seattle, Washington​

Professor of Pediatrics​ Division of Neonatology​ University of Washington School of Medicine​ Seattle, Washington​

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ELSEVIER 1600 John F. Kennedy Blvd.​ Ste. 1600​ Philadelphia, PA 19103-2899​ AVERY’S DISEASES OF THE NEWBORN, ELEVENTH EDITION

ISBN: 978-0-323-82823-9

Copyright © 2024 by Elsevier Inc. All rights reserved.​ No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies, and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency can be found at our website: ​www.elsevier.com/permissions​. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein).​ Previous editions copyrighted 2018, 2012, 2005, 1998, 1991, 1984, 1977, 1971, 1965, 1960​ Notices​ Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. With respect to any drug or pharmaceutical products identified, readers are advised to check the most current information provided (i) on procedures featured or (ii) by the manufacturer of each product to be administered, to verify the recommended dose or formula, the method and duration of administration, and contraindications. It is the responsibility of practitioners, relying on their own experience and knowledge of their patients, to make diagnoses, to determine dosages and the best treatment for each individual patient, and to take all appropriate safety precautions. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein.​ The Publisher

Publisher: Sarah Barth​ Senior Content Development Manager: Meghan Andress​ Content Development Specialist: Erika Ninsin​ Publishing Services Manager: Catherine Jackson​ Senior Project Manager: John Casey​ Design Direction: Brian Salisbury​ Printed in India 9 8 7 6 5 4 3 2 1​

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To the babies—our patients—who humble and inspire us.​ To their families, who encourage us to keep moving our field forward.​ To neonatal caregivers everywhere, with gratitude for all you do.​

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Contributors​

Steven H.​Abman​, MD​ Professor of Pediatrics​ University of Colorado Health Sciences Center​ Director, Pediatric Heart Lung Center​ Children​’s Hospital Colorado​ Aurora​, ​Colorado​

David​Askenazi​, MD, MSPH​ Professor​ Department of Pediatrics​ Division of Nephrology​ University of Alabama at Birmingham​ Birmingham​, ​Alabama​

Noorjahan​Ali​, MD, MSc​ Associate Professor of Pediatrics ​ Division of Neonatal-Perinatal Medicine​ Department of Pediatrics​ UT Southwestern​ Dallas​, ​Texas​

Susan W.​ Aucott​, MD​ Associate Professor​ Department of Pediatrics​ Johns Hopkins University School of Medicine​ Baltimore, Maryland;​ Director, Neonatology​ Department of Pediatrics​ Greater Baltimore Medical Center​ Towson​, ​Maryland​

Karel​Allegaert​, MD, PhD​ Professor​ Department of Development and Regeneration ​ and Department of Pharmaceutical and Pharmacological Science​ KU Leuven​ Leuven, Belgium;​ Senior Consultant​ Department of Hospital Pharmacy​ Erasmus Medical Center​ Rotterdam​, ​Netherlands​ Jamie E.​Anderson​, MD, MPH​ Assistant Professor ​ Department of Surgery ​ Division of Pediatric Surgery ​ UC Davis Children​’s Hospital​ Sacramento​, ​California​ Deidra A.​Ansah​, MD​ Assistant Professor​ Section of Pediatric Cardiology​ Texas Children​’s Hospital​ Baylor College of Medicine​ Houston​, ​Texas​ Bhawna​ Arya​, MD​ Associate Professor​ Director of Fetal Cardiology ​ Department of Pediatrics ​ Seattle Children​’s Hospital ​ University of Washington School of Medicine ​ Seattle​, ​Washington​

Stephen A.​Back​, MD, PhD​ Clyde and Elda Munson Professor of Pediatric Research​ Departments of Pediatrics and Neurology​ Director, Neuroscience Section​ Papé Family Pediatric Research Institute​ Oregon Health & Science University​ Portland​, ​Oregon​ Gerri R.​Baer​, MD​ Medical Officer​ U.S. Food and Drug Administration ​ Silver Spring​, ​Maryland​ H. Scott​Baldwin​, MD​ Professor of Pediatrics​ Division of Pediatric Cardiology​ Vanderbilt University Medical Center​ Nashville​, ​Tennessee​ Jerasimos​Ballas​, MD, MPH​ Associate Clinical Professor​ Obstetrics, Gynecology and Reproductive Sciences​ University of California San Diego​ San Diego​, ​California​ Maneesh​Batra​, MD, MPH​ Professor​ Department of Pediatrics-Neonatology​ Adjunct Professor​ Department of Global Health​ University of Washington School of Medicine​ Seattle​, ​Washington​ vii

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Contributors

Cheryl​Bayart​, MD, MPH​ Assistant Professor​ Department of Pediatrics​ University of Cincinnati​ Cincinnati Children’s Hospital Medical Center​ Cincinnati​, ​Ohio​ Gary A.​Bellus​, MD, PhD​ Director, Clinical Genetics and Genomic Medicine​ Department of Pediatrics​ Geisinger Health System​ Danville​, ​Pennsylvania​ John T.​Benjamin​, MD, MPH​ Assistant Professor​ Department of Pediatrics​ Division of Neonatology​ Vanderbilt University Medical Center ​ Nashville​, ​Tennessee​ Gerard T.​ Berry​, MD​ Professor​ Department of Genetics​ Boston Children​’s Hospital ​ Harvard Medical School​ Boston​, ​Massachusetts​ Zeenia C.​Billimoria​, MD​ Associate Professor​ Department of Pediatrics​ University of Washington School of Medicine​ Seattle Children​’s Hospital​ Seattle​, ​Washington​ Gil​Binenbaum​, MD, MSCE​ Mabel Leslie Chair and Chief ​ Department of Ophthalmology​ The Children’s Hospital of Philadelphia​ Associate Professor​ Department of Ophthalmology​ University of Pennsylvania Perelman School of Medicine​ Philadelphia​, ​Pennsylvania​

Maryse L.​Bouchard​, MD, MSc​ Pediatric Orthopaedic Surgeon​ Division of Orthopaedic Surgery​ The Hospital for Sick Children​ Assistant Professor of Surgery​ University of Toronto​ Toronto​, ​Ontario​, ​Canada​ Heather A.​Brandling-Bennett​, MD​ Associate Professor​ Department of Pediatrics​ University of Washington​ Seattle Children​’s Hospital ​ Seattle​, ​Washington​ Colleen​ Brown​, WHNP-BC, MSN​ Nurse Practitioner​ Obstetrics and Gynecology​ Cayaba Care, LLC​ Philadelphia​, ​Pennsylvania​ Erin G.​Brown​, MD​ Associate Professor​ Division of Pediatric General, Thoracic, and Fetal Surgery​ UC Davis Medical Center​ Sacramento​, ​California​ Katherine H.​Campbell​, MD, MPH​ Associate Professor​ Department of Obstetrics, Gynecology & Reproductive Sciences​ Yale School of Medicine ​ New Haven​, ​Connecticut​ Katie​ Carlberg​, MD​ Clinical Assistant Professor​ Department of Pediatrics​ Department of Cancer and Blood Disorders​ Seattle Children’s Hospital ​ Seattle​, ​Washington​

Matthew S.​Blessing​, MD​ Associate Professor​ Department of Pediatrics​ University of Washington​ Craniofacial Center​ Seattle Children’s Hospital​ Seattle​, ​Washington​

Brian S.​Carter​, MD​ Professor of Pediatrics, Medical Humanities & Bioethics​ Department of Pediatrics–Neonatology​ University of Missouri–Kansas City School of Medicine ​ Bioethicist, Bioethics Center​ Children​’s Mercy Hospital ​ Kansas City​, ​Missouri​

Markus D.​Boos​, MD, PhD​ Associate Professor​ Department of Pediatrics and Dermatology​ University of Washington School of Medicine​ Seattle​, ​Washington​

Shilpi​ Chabra​, MD​ Professor of Pediatrics​ University of Washington School of Medicine​ Seattle Children’s Hospital​ Seattle​, ​Washington​

Brad​ Bosse​, MD​ MFM Fellow​ Department of Obstetrics and Gynecology ​ University of Wisconsin–Madison ​ School of Medicine and Public Health​ Madison​, ​Wisconsin​

Irene J.​Chang​, MD​ Assistant Professor​ Department of Pediatrics​ Division of Genetic Medicine​ University of Washington​ Seattle​, ​Washington​

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Contributors

Edith Y.​Cheng​, MD, MS​ Professor, Department of Obstetrics and Gynecology​ Division Chief, Maternal Fetal Medicine​ Medical Director, Perinatal Genetics and Fetal Therapy Program​ University of Washington​ Program Director, Fetal Care and Treatment Center​ Seattle Children​’s Hospital​ Seattle​, ​Washington​ Kai-wen​ Chiang​ Health Science Assistant Clinical Professor​ Department of Urology–Pediatric Urology​ UC Irvine​ Irvine​, ​California​ Robert D.​Christensen​, MD​ Professor of Pediatrics​ University of Utah​ Salt Lake City​, ​Utah​ Terrence​ Chun​, MD​ Associate Professor of Pediatrics​ University of Washington​​ Seattle​, ​Washington​

Benjamin​Dean​, MD, PhD​ Pediatric Neurology​ Mary Bridge Children’s Hospital​ Tacoma​, ​Washington​ Ellen​ Dees​, MD​ Assistant Professor of Pediatrics​ Division of Pediatric Cardiology​ Vanderbilt University Medical Center​ Nashville​, ​Tennessee​ Sara B.​DeMauro​, MD, MSCE​ Associate Professor of Pediatrics​ University of Pennsylvania Perelman School of Medicine ​ Program Director, Neonatal Follow-Up​ Children​’s Hospital of Philadelphia​ Philadelphia​, ​Pennsylvania​ Scott C.​Denne​, MD​ Professor of Pediatrics​ Indiana University​ Indianapolis​, ​Indiana​

Ronald I.​Clyman​, MD​ Professor Emeritus​ Department of Pediatrics​ UC San Francisco​ San Francisco​, ​California​

Emöke​Deschmann​, MD, MMSc, PhD​ Senior Attending Neonatologist, Postdoctoral Fellow ​ Department of Women​’s and Children​’s Health ​ Division of Neonatology​ Karolinska Institutet and Karolinska University Hospital​ Stockholm​, ​Sweden​

DonnaMaria E.​Cortezzo​, MD​ Associate Professor of Pediatrics and Anesthesia​ University of Cincinnati ​ Divisions of Neonatology and Pulmonary Biology, and ​ Pediatric Palliative Medicine​ Cincinnati Children​’s Hospital Medical Center​ Cincinnati​, ​Ohio​

Carolina Cecilia​Di Blasi​, MD​ Clinical Associate Professor​ Division of Endocrinology and Diabetes ​ University of Washington ​ Seattle Children’s Hospital​ Seattle​, ​Washington​

C.M.​Cotten​, MD, MHS​ Professor of Pediatrics​ Department of Pediatrics-Neonatology​ Duke University School of Medicine​​ Durham​, ​North Carolina​

Sara A.​DiVall​, MD​ Associate Professor​ Departments of Pediatrics and Pediatric Endocrinology​ University of Washington​​ Seattle​, ​Washington​

Sherry E.​Courtney​, MD, MS​ Professor of Pediatrics​ University of Arkansas for Medical Sciences​ Little Rock​, ​Arkansas​

Dan​Doherty​, MD, PhD​ Interim Chief, Developmental Medicine Professor of Pediatrics Divisions of Developmental Medicine and Genetic Medicine​ University of Washington Seattle Children’s Hospital​ Seattle​, ​Washington​

Jonathan M.​Davis​, MD​ Professor of Pediatrics​ Tufts University School of Medicine​ Vice-Chair of Pediatrics and Chief of Newborn Medicine​ Department of Pediatrics​ Tufts Medical Center​ Boston​, ​Massachusetts​ Alejandra G.​de Alba Campomanes​, MD, MPH​ Professor of Clinical Ophthalmology and Pediatrics ​ Department of Ophthalmology​ UC San Francisco​ San Francisco​, ​California​

David J.​Durand​, MD​ Division of Neonatology​ UCSF Benioff Children​’s Hospital Oakland​​ Oakland​, ​California​ Nicolle Fernández​Dyess​, MD, MEd​ Assistant Professor​ Department of Pediatrics​ University of Colorado School of Medicine​ Aurora​, ​Colorado​

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x

Contributors

Eric C.​Eichenwald​, MD​ Professor ​ Department of Pediatrics/Neonatology​ University of Pennsylvania Perelman School of Medicine ​ Chief, Division of Neonatology​ Department of Pediatrics​ Children​’s Hospital of Philadelphia​ Philadelphia​, ​Pennsylvania​ Kelsey B.​Eitel​, MD​ Fellow​ Department of Pediatrics ​ Division of Endocrinology and Diabetes​ University of Washington​ Seattle Children​’s Hospital​​ Seattle​, ​Washington​ Rachel M.​Engen​, MD, MS​ Assistant Professor​ Department of Pediatrics​ University of Wisconsin, Madison​ Madison​, ​Wisconsin​

Bobbi​ Fleiss​, PhD​ School of Health and Biomedical Sciences​ STEM College ​ Royal Melbourne Institute of Technology University​ Bundoora​, ​Victoria​, ​Australia​ Joseph​ Flynn​, Jr., ​MD, MS​ Professor of Pediatrics​ University of Washington School of Medicine​ Chief, Division of Nephrology​ Seattle Children’s Hospital​ Seattle​, ​Washington​ Katherine T.​Flynn-O’Brien​, MD, MPH​ Assistant Professor of Surgery​ Medical College of Wisconsin ​ Associate Trauma Medical Director​ Division of Pediatric Surgery​ Children​’s Wisconsin​ ​ Milwaukee​, ​Wisconsin​

Kelly N.​Evans​, MD​ Associate Professor​ Department of Pediatrics​ University of Washington​ Craniofacial Center​ Seattle Children​’s Hospital​ Seattle​, ​Washington​

G.​Kyle Fulton​, MD​ Assistant Professor​ Department of Pediatrics​ Louisiana State University Health Sciences Center ​ Medical Director​ Craniofacial Center​ Children​’s Hospital New Orleans​ New Orleans​, ​Louisiana​

Diana L.​Farmer​, MD, FACS, FRCS​ Distinguished Professor and Pearl Stamps Stewart Endowed Chair​ Department of Surgery​ UC Davis Medical Center​ Surgeon-in-Chief​ UC Davis Children’s Hospital​ Sacramento​, ​California​

Renata C.​Gallagher​, MD, PhD​ Professor of Clinical Pediatrics​ Department of Pediatrics​ UC San Francisco​ San Francisco​, ​California​

Emily​ Fay​, MD​ Assistant Professor​ Department of Obstetrics and Gynecology​ Division of Maternal Fetal Medicine​ University of Washington​ Seattle​, ​Washington​ Patricia Y.​ Fechner​, MD​ Professor of Pediatric Endocrinology​ University of Washington ​ Director, DSD Program ​ Director, CAH Center of Excellence ​ Co-Medical Director​ Turner Syndrome Clinic​ Seattle Children​’s Hospital​ Seattle​, ​Washington​ Rachel​ Fleishman​, MD​ Assistant Professor of Pediatrics​ Sidney Kimmel Medical College of Thomas Jefferson University ​ Attending Neonatologist​ Department of Pediatrics​ Albert Einstein Medical Center​ Philadelphia​, ​Pennsylvania​

Estelle B.​Gauda​, MD​ Professor of Pediatrics​ University of Toronto​ Head, Division of Neonatology​ Women’s Auxiliary Chair in Neonatology at SickKids​ Senior Associate Scientist, SickKids Research Institute​ Director, Toronto Centre for Neonatal Health​ The Hospital for Sick Children​ Toronto​, ​Ontario​, ​Canada​ W.​Christopher Golden​, MD​ Associate Professor of Pediatrics​ Johns Hopkins University School of Medicine​​ Baltimore​, ​Maryland​ Michelle M.​Gontasz​, MD​ Clinical Associate/Instructor​ Department of Neonatology ​ Department of Pediatrics​ Johns Hopkins University School of Medicine​ Associate Medical Director​ Neonatal Intensive Care Unit​ Johns Hopkins Bayview Medical Center​​ Baltimore​, ​Maryland​

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Contributors

Natasha González​Estévez​, MD​ Assistant Professor ​ Department of Pediatrics, Pediatric Cardiology Section​ University Pediatric Hospital​ University of Puerto Rico School of Medicine​ San Juan​, ​Puerto Rico​

Kara K.​Hoppe​, DO, MS​ Associate Professor​ Department of Obstetrics and Gynecology ​ University of Wisconsin–Madison ​ School of Medicine and Public Health​ Madison​, ​Wisconsin​

Sidney M.​Gospe​, Jr., ​​MD, PhD​ Herman and Faye Sarkowsky Endowed Chair of Child Neurology Emeritus​ Departments of Neurology and Pediatrics​ University of Washington ​ Seattle, Washington; ​ Adjunct Professor​ Department of Pediatrics​ Duke University​ Durham​, ​North Carolina​

Alyssa​ Huang​, MD​ Acting Assistant Professor​ Department of Pediatrics ​ Division of Endocrinology and Diabetes​ University of Washington ​ Seattle Children​’s Hospital​​ Seattle​, ​Washington​

Pierre​Gressens​, MD, PhD​ Professor ​ U1141 Inserm​ Paris​, ​France​ Deepti​ Gupta​, MD​ Associate Professor of Pediatrics ​ Division of Dermatology​ Seattle Children​’s Hospital ​ University of Washington​​ Seattle​, ​Washington​ Sangeeta​Hingorani​, MD, MPH​ Professor of Pediatrics​ University of Washington​ Seattle Children’s Hospital​ Division of Nephrology​ Associate Member​ Clinical Research Division​ Fred Hutchinson Cancer Research Center​ Seattle​, ​Washington​ Ashley P.​Hinson​, MD​ Clinical Associate Professor​ Wake Forest School of Medicine ​ Pediatric Hematology Oncology​ Levine Children​’s Hospital, Atrium Health​ Charlotte​, ​North Carolina​ Susan R.​Hintz​, MD, MS (Epi)​ Professor of Pediatrics​ Division of Neonatal and Developmental Medicine​ Stanford University School of Medicine ​ Director, Fetal and Pregnancy Health Program​ Lucile Packard Children​’s Hospital Stanford​ Palo Alto​, ​California​ W.​Alan Hodson​, MMSc, MD​ Professor Emeritus ​ Department of Pediatrics​ University of Washington​ Seattle​, ​Washington​

xi

Benjamin​ Huang​, MD​ Assistant Professor of Pediatrics​ UC San Francisco​ San Francisco​, ​California​ Kathy​Huen​, MD, MPH​ Assistant Clinical Professor​ Department of Urology​ David Geffen School of Medicine at UCLA​ Los Angeles​, ​California​ Katie A.​Huff​, MD, MS​ Assistant Professor of Pediatrics​ Indiana University School of Medicine​​ Indianapolis​, ​Indiana​ Cristian​ Ionita​, MD​ Associate Clinical Professor​ Department of Pediatrics and Neurology​ Yale School of Medicine​​ New Haven​, ​Connecticut​ J.​Craig Jackson​, MD, MHA​ Professor of Pediatrics​ University of Washington​ Neonatologist​ Fetal Care and Treatment Center​ Seattle Children​’s Hospital​ Seattle​, ​Washington​ Jordan E.​Jackson​, MD​ Pediatric and Fetal Surgery Research Fellow​ Division of Pediatric General, Thoracic, and Fetal Surgery​ UC Davis Medical Center​ Sacramento​, ​California​ Tom​Jaksic​, MD, PhD​ W. Hardy Hendren Professor of Surgery​ Harvard Medical School​ Vice-Chair Pediatric Surgery​ Surgical Director, Center for Advanced Intestinal Rehabilitation (CAIR)​ Boston Children’s Hospital​ Boston​, ​Massachusetts​

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Contributors

Patrick J.​Javid​, MD​ Professor of Surgery​ University of Washington School of Medicine ​ Pediatric Surgeon ​ Seattle Children​’s Hospital​ Seattle​, ​Washington​ Julia​Johnson​, MD, PhD​ Assistant Professor of Pediatrics​ Division of Neonatology​ Johns Hopkins University School of Medicine​ Assistant Professor of International Health​ Johns Hopkins Bloomberg School of Public Health​ Baltimore​, ​Maryland​ Cassandra D.​Josephson​, MD​ Department of Oncology​ Johns Hopkins University School of Medicine​ Director, Cancer and Blood Disorders Institute​ Director, Blood Bank and Transfusion Medicine​ Johns Hopkins All Children’s Hospital​ St. Petersburg​, ​Florida​ Emily S.​Jungheim​, MD, MSCI​ Edmond Confino MD Professor of Obstetrics and Gynecology​ Chief, Division of Reproductive Endocrinology and Infertility​ Department of Obstetrics and Gynecology​ Northwestern University Feinberg School of Medicine​ Chicago​, ​Illinois​ Sandra E.​Juul​, MD, PhD​ Professor of Pediatrics​ Department of Pediatrics, Division of Neonatology​ University of Washington School of Medicine​ Seattle Children​’s Hospital​​ Seattle​, ​Washington​ Mohammad Nasser​Kabbany​, MD​ Pediatric Gastroenterology, Hepatology, and Nutrition​ Cleveland Clinic Children’s Hospital​ Assistant Professor of Pediatrics ​ Cleveland Clinic Lerner College of Medicine ​ Case Western Reserve University​ Cleveland​, ​Ohio​ Heidi​ Karpen​, MD​ Associate Professor ​ Department of Pediatrics​ Emory University and Children’s Healthcare of Atlanta​ Atlanta​, ​Georgia​

Amaris M.​Keiser​, MD​ Assistant Professor​ Department of Pediatrics​ Johns Hopkins University School of Medicine​​ Baltimore​, ​Maryland​ Roberta L.​Keller​, MD​ Professor of Clinical Pediatrics​ Director of Neonatal Services​ Fetal Treatment Center​ UC San Francisco​ UCSF Benioff Children​’s Hospital​ San Francisco​, ​California​ Thomas F.​Kelly​, MD​ Clinical Professor and Chief, Division of Perinatal Medicine​ Obstetrics, Gynecology and Reproductive Sciences​ UC San Diego School of Medicine​ Director of Maternity Services​ UCSD Medical Center​ La Jolla​, ​California​ Kate​ Khorsand​, MD​ Staff Dermatologist​ North Idaho Dermatology​ Coeur D’Alene​, ​Idaho​ Grace​Kim​, MD, MS​ Associate Professor​ Division of Endocrinology and Diabetes ​ University of Washington ​ Seattle Children’s Hospital​ Seattle​, ​Washington​ John P.​Kinsella​, MD​ Professor of Pediatrics​ University of Colorado School of Medicine ​ Children​’s Hospital Colorado​ Aurora​, ​Colorado​ Allison S.​Komorowski​, MD​ Fellow Physician​ Division of Reproductive Endocrinology and Infertility​ Department of Obstetrics & Gynecology​ Northwestern University Feinberg School of Medicine​ ​ Chicago​, ​Illinois​

Gregory​ Keefe​, MD​ Research Fellow ​ Department of Surgery ​ Boston Children​’s Hospital​​ Boston​, ​Massachusetts​

Ildiko H.​Koves​, MD, FRACP​ Department of Pediatrics​ Division of Endocrinology and Diabetes​ University of Washington​ Seattle Children​’s Hospital​ Seattle​, ​Washington​

Jennifer C.​Keene​, MD, MS, MBA​ Assistant Clinical Professor​ Division of Pediatric Neurology​ University of Utah Health​ Salt Lake City​, ​Utah​

Joanne M.​Lagatta​, MD, MS​ Professor​ Department of Pediatrics​ Medical College of Wisconsin​​ Milwaukee​, ​Wisconsin​

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Contributors

Satyan​Lakshminrusimha​, MBBS, MD, FAAP​ Dennis & Nancy Marks Professor and Chair​ Department of Pediatrics​ UC Davis Medical Center ​ Pediatrician-in-Chief​ UC Davis Children​’s Hospital​ Sacramento​, ​California​ Christina​ Lam​, MD​ Associate Professor​ Department of Pediatrics​ University of Washington and Seattle Children​’s Research Center​ Seattle​, ​Washington​ John D.​Lantos​, MD​ JDL Consulting​ New York​, ​New York​ Janessa B.​Law​, MD​ Assistant Professor​ Department of Pediatrics – Neonatology​ University of Washington​ Seattle​, ​Washington​ Su Yeon​ Lee​, MD​ Pediatric and Fetal Surgery Research Fellow​ Division of Pediatric General, Thoracic, and Fetal Surgery​ UC Davis Medical Center​ Sacramento​, ​California​ Ofer​Levy​, MD, PhD​ Director, Precision Vaccines Program​ Division of Infectious Diseases​ Boston Children​’s Hospital ​ Professor of Pediatrics​ Harvard Medical School ​ Boston, Massachusetts;​ Associate Member​ Broad Institute of MT & Harvard​ Cambridge​, ​Massachusetts​ David B.​Lewis​, MD​ Professor ​ Chief, Division of Allergy, Immunology, and Rheumatology​ Department of Pediatrics​ Stanford University School of Medicine ​ Stanford, California;​ Attending Physician​ Lucile Salter Packard Children’s Hospital​​ Palo Alto​, ​California​ Philana Ling​Lin​, MD, MSc​ Associate Professor​ Department of Pediatrics​ Division of Pediatric Infectious Diseases​ UPMC Children​’s Hospital of Pittsburgh​ Pittsburgh​, ​Pennsylvania​

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Scott A.​Lorch​, MD, MSCE​ Kristine Sandberg Knisely Professor​ Department of Pediatrics​ University of Pennsylvania Perelman School of Medicine​ Attending Neonatologist​ Department of Pediatrics, Division of Neonatology​ Children’s Hospital of Philadelphia​ Philadelphia​, ​Pennsylvania​ Tiffany L.​Lucas​, MD​ Associate Physician​ Division of Pediatric Hematology/Oncology​ Kaiser Permanente Medical Group​ Oakland​, ​California​ Akhil​ Maheshwari​, MD​ Chair, Department of Neonatology​ Global Newborn Society​ Clarksville​, ​Maryland​ Emin​Maltepe​, MD, PhD​ Professor​ Department of Pediatrics, Biomedical Sciences, Developmental and Stem Cell Biology​ UC San Francisco​ San Francisco​, ​California​ Erica​ Mandell​, DO​ Associate Professor of Pediatrics ​ University of Colorado Health Science Center ​ Children​’s Hospital Colorado​ Aurora​, ​Colorado​ Winston M.​Manimtim​, MD​ Professor of Pediatrics​ University of Missouri–Kansas City ​ Neonatologist​ Department of Pediatrics​ Children​’s Mercy Kansas City​​ Kansas City​, ​Missouri​ Richard J.​Martin​, MBBS​ Professor​ Departments of Pediatrics, Reproductive Biology, and Physiology & Biophysics​ Case Western Reserve University School of Medicine​ Drusinsky/Fanaroff Professor​ Director, Neonatal Research​ Department of Pediatrics​ Rainbow Babies & Children​’s Hospital​ Cleveland​, ​Ohio​ Dennis E.​Mayock​, MD​ Professor of Pediatrics​ University of Washington​​ Seattle​, ​Washington​ Irene​McAleer​, MD, JD, MBA​ Health Sciences Clinical Professor (Ret)​ Department of Urology–Pediatric Urology​ UC Irvine​ Irvine​, ​California​

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Contributors

Patrick​ McQuillen​, MD​ Professor of Pediatrics and Neurology​ Department of Pediatrics​ UC San Francisco ​ UCSF Benioff Children​’s Hospital​ San Francisco​, ​California​ Ann J.​Melvin​, MD, MPH​ Professor​ Department of Pediatrics​ University of Washington ​ Pediatric Infectious Disease​ Seattle Children​’s Hospital​​ Seattle​, ​Washington​ Paul A.​Merguerian​, MD, MS​ Division Chief Urology​ Seattle Children’s Hospital​ Professor of Urology​ Michael Mitchell Chair Pediatric Urology​ University of Washington​ Seattle​, ​Washington​ Lina​ Merjaneh​, MD​ Associate Professor​ Departments of Pediatrics and Pediatric Endocrinology​ University of Washington​ Seattle​, ​Washington​ J.​Lawrence Merritt​, II, MD​ Clinical Professor​ Department of Pediatrics ​ University of Washington​ Seattle​, ​Washington​ Valerie​ Mezger​, PhD​ Director of Research CNRS​ Université Paris Cité ​ CNRS,Epigenetics and Cell Fate​​ Paris​, ​France​ Marian G.​Michaels​, MD, MPH​ Professor of Pediatrics and Surgery​ UPMC Children’s Hospital of Pittsburgh​ Division of Pediatric Infectious Diseases​ Pittsburgh​, ​Pennsylvania​ Ulrike​ Mietzsch​, MD​ Clinical Associate Professor of Pediatrics​ Department of Pediatrics, Division of Neonatology​ University of Washington School of Medicine​ Seattle Children​’s Hospital​ Seattle​, ​Washington​

Steven P.​Miller​, MDCM, MAS​ Professor and Head​ Department of Pediatrics​ University of British Columbia​ Chief, Pediatric Medicine​ Department of Pediatrics​ BC Children​’s Hospital​ Vancouver, British Columbia, Canada;​ Adjunct Senior Scientist​ Neuroscience & Mental Health​ SickKids Research Institute​ Chair in Pediatric Neuroscience​ Bloorview Children​’s Hospital​ Toronto​, ​Ontario​, ​Canada​ Thomas R.​Moore​, MD​ Professor Emeritus of Maternal Fetal Medicine​ Department of Obstetrics, Gynecology and Reproductive Sciences​ UC San Diego​ San Diego​, ​California​ Karen F.​Murray​, MD​ Chair, Pediatrics Institute​ Cleveland Clinic​ DeBartolo Family Endowed Chair in Pediatrics​ Physician-in-Chief, Cleveland Clinic Children’s Hospital​ President, Cleveland Clinic Children’s Hospital for Rehabilitation​ Professor and Chair, Department of Pediatrics​ Cleveland Clinic Lerner College of Medicine ​ Case Western Reserve University​ Cleveland​, ​Ohio​ Debika​ Nandi-Munshi​, MD​ Clinical Associate Professor​ Division of Endocrinology and Diabetes ​ University of Washington ​ Seattle Children’s Hospital​ Seattle​, ​Washington​ Niranjana​ Natarajan​, MD​ Associate Professor​ Department of Neurology​ Division of Child Neurology​ University of Washington​ Seattle​, ​Washington​ Kathryn D.​Ness​, MD, MSCI​ Clinical Professor​ Department of Pediatrics​ Division of Endocrinology and Diabetes​ University of Washington​ Seattle Children​’s Hospital​ Seattle​, ​Washington​ Josef​ Neu​, MD​ Professor of Pediatrics​ University of Florida​​ Gainesville​, ​Florida​

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Contributors

Shahab​Noori​, MD, MS, CBTI​ Professor of Pediatrics​ Fetal and Neonatal Institute ​ Division of Neonatology ​ Children’s Hospital Los Angeles ​ Department of Pediatrics​ Keck School of Medicine ​ University of Southern California​​ Los Angeles​, ​California​ Thomas Michael​ O​’Shea​, Jr., ​​MD, MPH​ Professor of Pediatrics​ University of North Carolina​ Chapel Hill​, ​North Carolina​ Julius T.​Oatts​, MD, MHS​ Assistant Professor​ Department of Ophthalmology​ UC San Francisco​​ San Francisco​, ​California​ Nigel​Paneth​, MD, MPH​ University Distinguished Professor Emeritus​ Department of Epidemiology and Biostatistics​ Michigan State University​ East Lansing​, ​Michigan​ Thomas A.​Parker​, MD​ Professor of Pediatrics​ University of Colorado School of Medicine​ Aurora​, ​Colorado​ Ravi Mangal​Patel​, MD, MSc​ Associate Professor ​ Department of Pediatrics​ Emory University School of Medicine​ Children​’s Healthcare of Atlanta​ Atlanta​, ​Georgia​ Simran​ Patel​, BS​ Eugene Applebaum College of Pharmacy and Health Sciences ​ Wayne State University​ Detroit​, ​Michigan​ Anna A.​Penn​, MD, PhD​ L. Stanley James Associate Professor of Pediatrics​ Director, Neonatology​ Department of Pediatrics​ Columbia University/ NYP Morgan Stanley Children​’s Hospital​ New York​, ​New York​ Christian M.​Pettker​, MD​ Professor​ Department of Obstetrics, Gynecology, & Reproductive Sciences​ Yale School of Medicine​ New Haven​, ​Connecticut​ Shabnam​Peyvandi​, MD, MAS​ Associate Professor of Clinical Pediatrics​ Department of Pediatric Cardiology​ UC San Francisco​ UCSF Benioff Children​’s Hospital​ San Francisco​, ​California​

Catherine​ Pihoker​, MD​ Professor​ Department of Pediatrics​ Division of Endocrinology and Diabetes​ University of Washington​ Seattle Children’s Hospital​ Seattle​, ​Washington​ Erin​ Plosa​, MD​ Assistant Professor​ Department of Pediatrics​ Mildred Stahlman Division of Neonatology​ Vanderbilt University School of Medicine​ Nashville​, ​Tennessee​ Brenda​Poindexter​, MD, MS​ Chief, Division of Neonatology​ Department of Pediatrics​ Emory University and Children​’s Healthcare of Atlanta​ ​ Atlanta​, ​Georgia​ Michael A.​Posencheg​, MD​ Associate Professor of Clinical Pediatrics​ Department of Pediatrics​ University of Pennsylvania Perelman School of Medicine ​ Medical Director, Intensive Care Nursery​ Neonatology and Newborn Services​ Hospital of the University of Pennsylvania​​ Philadelphia​, ​Pennsylvania​ Mihai​Puia-Dumitrescu​, MD, MPH​ Assistant Professor of Pediatrics​ University of Washington​​ Seattle​, ​Washington​ Vilmaris Quiñones​Cardona​, MD​ Assistant Professor of Pediatrics​ Drexel University College of Medicine​ Neonatologist, Department of Pediatrics​ St. Christopher​’s Hospital for Children​ Philadelphia​, ​Pennsylvania​ Samuel E.​Rice-Townsend​, MD​ Assistant Professor ​ Pediatric General and Thoracic Surgery​ Department of Surgery ​ University of Washington​​ Seattle​, ​Washington​ Art​Riddle​, MD, PhD​ Assistant Professor​ Department of Pediatrics​ Division of Pediatric Neurology​ Oregon Health & Science University​​ Portland​, ​Oregon​

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Contributors

Elizabeth​ Robbins​, MD​ Clinical Professor of Pediatrics​ UC San Francisco​ San Francisco​, ​California​ Mark D.​Rollins​, MD, PhD​ Professor​ Anesthesiology and Perioperative Medicine​ Mayo Clinic​​ Rochester​, ​Minnesota​ Mark A.​Rosen​, MD​ Professor Emeritus​ Department of Anesthesia and Perioperative Care​ Obstetrics, Gynecology, and Reproductive Sciences​ UC San Francisco​​ San Francisco​, ​California​ Courtney K.​Rowe​, MD​ Pediatric Urologist​ Department of Urology​ Connecticut Children​’s​ Hartford, Connecticut;​ Assistant Professor of Pediatrics​ University of Connecticut Medical School​ Farmington​, ​Connecticut​ Inderneel​ Sahai​, MD​ Chief Medical Officer​ New England Newborn Screening Program​ UMass Chan Medical School​ Worcester, Massachusetts;​ Attending Physician​ Department of Genetics and Metabolism​ Massachusetts General Hospital​ Boston​, ​Massachusetts​ Sulagna C.​Saitta​, MD, PhD​ Health Sciences Professor​ Division of Clinical Genetics​ Department of Pediatrics​ Director, Division of Reproductive Genetics​ Department of Obstetrics and Gynecology​ David Geffen School of Medicine at UCLA​ Los Angeles​, ​California​ Parisa​ Salehi​, MD​ Associate Professor ​ Department of Pediatrics​ Division of Endocrinology and Diabetes​ University of Washington​ Seattle Children​’s Hospital​ Seattle​, ​Washington​ Pablo J.​Sanchez​, MD​ Professor of Pediatrics​ Divisions of Neonatology and Pediatric Infectious Diseases​ Center for Perinatal Research​ Abigail Wexner Research Institute at Nationwide Children​’s Hospital​ Ohio State University College of Medicine​ Columbus​, ​Ohio​

Taylor​Sawyer​, DO, MBA, MEd​ Professor of Pediatrics ​ Division of Neonatology​ University of Washington School of Medicine ​ Seattle Children’s Hospital​ Seattle​, ​Washington​ Matthew A.​Saxonhouse​, MD​ Clinical Associate Professor​ Wake Forest School of Medicine ​ Levine Children​’s Hospital, Atrium Health ​ Division of Neonatology​​ Charlotte​, ​North Carolina​ Katherine M.​Schroeder​, MD, MS​ Assistant Professor​ Orthopaedic Surgery​ Seattle Children​’s Hospital​​ Seattle​, ​Washington​ David T.​Selewski​, MD, MSCR​ Associate Professor​ Department of Pediatrics​ Division of Nephrology​ Medical University of South Carolina​ Charleston​, ​South Carolina​ T.​Niroshi Senaratne​, PhD, FACMG​ Assistant Clinical Professor​ Department of Pathology and Laboratory Medicine​ David Geffen School of Medicine at UCLA​ Los Angeles​, ​California​ Istvan​Seri​, MD, PhD, HonD, HonP​ Professor​ First Department of Pediatrics ​ Semmelweis University ​ Budapest, Hungary;​ Adjunct Professor of Pediatrics ​ Department of Pediatrics and Neonatology​ Children​’s Hospital Los Angeles​ USC Keck School of Medicine​ Los Angeles​, ​California​ Emily E.​Sharpe​, MD​ Assistant Professor​ Department of Anesthesiology and Perioperative Medicine​ Mayo Clinic​​ Rochester​, ​Minnesota​ Sarah E.​Sheppard​, MD, PhD​ Tenure-Track Investigator​ Unit on Vascular Malformations, Division of Translational Medicine​ Division of Intramural Research​ Eunice Kennedy Shriver National Institute of Child Health and Human Development​ National Institutes of Health​ Bethesda​, ​Maryland​

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Contributors

Margarett​Shnorhavorian​, MD, MPH, FAAP, FACS​ Professor ​ Department of Urology ​ University of Washington School of Medicine ​ Pediatric Urologist ​ Seattle Children​’s Hospital​ Seattle​, ​Washington​

Caleb​Stokes​, MD, PhD​ Acting Assistant Professor​ Department of Pediatrics​ University of Washington ​ Pediatric Infectious Disease​ Seattle Children​’s Hospital​ Seattle​, ​Washington​

Robert​Sidbury​, MD, MPH​ Professor of Pediatrics ​ Chief, Division of Dermatology​ Seattle Children​’s Hospital ​ University of Washington School of Medicine​​ Seattle​, ​Washington​

Helen​Stolp​, BSc(Hons), PhD​ Perinatal Imaging and Health​ King​’s College London​ London​, ​United Kingdom​

LaVone​ Simmons​, MD​ Clinical Assistant Professor​ Department of Obstetrics and Gynecology ​ Division of Maternal Fetal Medicine ​ University of Washington​ Seattle​, ​Washington​ Rebecca A.​Simmons​, MD​ Hallam Hurt Professor of Pediatrics​ Department of Pediatrics​ Children​’s Hospital of Philadelphia​ Philadelphia​, ​Pennsylvania​ Rachana​Singh​, MD, MS​ Professor of Pediatrics​ Tufts University School of Medicine ​ Associate Chief, Newborn Medicine​ Department of Pediatrics​ Tufts Medical Center​​ Boston​, ​Massachusetts​ Martha C.​Sola-Visner​, MD​ Associate Professor ​ Department of Pediatrics​ Boston Children​’s Hospital ​ Harvard Medical School​​ Boston​, ​Massachusetts​ Lakshmi​Srinivasan​, MBBS, MTR​ Assistant Professor of Pediatrics​ Children​’s Hospital of Philadelphia​ Philadelphia​, ​Pennsylvania​ Heidi J.​Steflik​, MD, MSCR​ Assistant Professor​ Department of Pediatrics​ Division of Neonatal-Perinatal Medicine​ Medical University of South Carolina​ Charleston​, ​South Carolina​ Robin H.​Steinhorn​, MD​ Professor and Vice Dean​ Department of Pediatrics​ Rady Children​’s Hospital and UC San Diego​ San Diego​, ​California​

Jennifer​ Sucre​, MD​ Assistant Professor​ Department of Pediatrics ​ Mildred Stahlman Division of Neonatology​ Vanderbilt University School of Medicine​ Nashville​, ​Tennessee​ Angela​ Sun​, MD​ Physician​ Department of Pediatrics​ University of Washington​ Seattle​, ​Washington​ Dalal K.​ Taha​, DO​ Associate Professor of Clinical Pediatrics​ Department of Pediatrics ​ University of Pennsylvania Perelman School of Medicine​ Attending Neonatologist​ Department of Pediatrics, Division of Neonatology​ Jill and Mark Fishman Center for Lymphatic Disorders​ Children​’s Hospital of Philadelphia​ Philadelphia​, ​Pennsylvania​ Jessica​ Tenney​, MD​ Assistant Clinical Professor​ Department of Pediatrics​ Division of Medical Genetics​ UC San Francisco​​ San Francisco​, ​California​ Janet A.​ Thomas​, MD​ Professor of Pediatrics​ University of Colorado School of Medicine​ Aurora​, ​Colorado​ George E.​Tiller​, MD, PhD, FACMG​ Partner Emeritus ​ Department of Genetics​ Southern California Permanente Medical Group​​ Los Angeles​, ​California​ Benjamin A.​ Torres​, MD​ Associate Professor of Pediatrics​ University of South Florida​ Tampa​, ​Florida​

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Contributors

William E.​ Truog​, MD​ Center for Infant Pulmonary Disorders​ Children​’s Mercy Hospital​ Professor of Pediatrics​ University of Missouri Kansas City School of Medicine​ Kansas City​, ​Missouri​ Kirtikumar​ Upadhyay​, MD​ Clinical Associate Professor​ Department of Pediatrics​ University of Washington​​ Seattle​, ​Washington​ Gregory C.​Valentine​, MD, MEd​ Assistant Professor ​ Department of Pediatrics, Division of Neonatology​ University of Washington​ Seattle Children​’s Hospital ​ Seattle, Washington; ​ Adjunct Assistant Professor​ Department of Obstetrics and Gynecology​ Baylor College of Medicine​​ Houston​, ​Texas​ John N.​van den Anker​, MD, PhD​ Professor​ Division of Clinical Pharmacology​ Children​’s National Hospital​ Washington, DC;​ Intensive Care, Department of Pediatric Surgery​ Erasmus Medical Center–Sophia Children​’s Hospital​​ Rotterdam​, ​Netherlands​ Betty​ Vohr​, MD​ Department of Neonatology​ Women & Infants Hospital​ Professor of Pediatrics​ Alpert Medical School of Brown University​​ Providence​, ​Rhode Island​ Linda D.​ Wallen​, MD​ Clinical Professor ​ Department of Pediatrics​ University of Washington​ Associate Division Head for Clinical Operations​ Department of Neonatology​ Seattle Children​’s Hospital​ Seattle​, ​Washington​ Peter (Zhan Tao)​Wang​, MD, FRCSC​ Assistant Professor of Surgery​ Department of Surgery​ Division of Urology​ Western University​​ London​, ​Ontario​, ​Canada​

Bradley A.​ Warady​, MD​ Professor of Pediatrics​ University of Missouri–Kansas City School of Medicine ​ Director, Division of Pediatric Nephrology​ Director, Dialysis and Transplantation​ Department of Pediatrics​ Children​’s Mercy​ ​ Kansas City​, ​Missouri​ Robert M.​Ward​, MD, FACCP, DABCP​ Professor Emeritus, Pediatrics​ Division of Neonatology​ Adjunct Professor​ University of Utah​ Salt Lake City​, ​Utah​ Jon F.​ Watchko​, MD​ Professor Emeritus​ Department of Pediatrics​ University of Pittsburgh School of Medicine​ Pittsburgh​, ​Pennsylvania​ Elias​Wehbi​, MD, MSc, FRCSC​ Associate Clinical Professor​ Department of Urology​ Division of Pediatric Urology​ UC Irvine​ Orange​, ​California​ Joern-Hendrik​ Weitkamp​, MD​ Professor of Pediatrics​ Vanderbilt University Medical Center​ Nashville​, ​Tennessee​ David​ Werny​, MD, MPH​ Assistant Professor ​ Department of Pediatrics ​ Division of Endocrinology and Diabetes​ University of Washington ​ Seattle Children​’s Hospital​​ Seattle​, ​Washington​ Klane K.​White​, MD, MSc​ Professor​ Orthopedic Surgery and Sports Medicine​ University of Washington​ Director, Skeletal Health and Dysplasia Program​ Orthopedic Surgery and Sports Medicine​ Seattle Children​’s Hospital​​ Seattle​, ​Washington​ K.​ Taylor Wild​, MD​ Fellow Physician​ Department of Pediatrics ​ Division of Neonatology​ Division of Human Genetics​ Children​’s Hospital of Philadelphia​​ Philadelphia​, ​Pennsylvania​

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Contributors

Susan​ Wiley​, MD​ Professor of Pediatrics​ University of Cincinnati ​ Cincinnati Children​’s Hospital Center​​ Cincinnati​, ​Ohio​

Karyn​ Yonekawa​, MD​ Clinical Professor​ Department of Pediatrics​ Seattle Children​’s Hospital​ Seattle​, ​Washington​

Laurel​ Willig​, MD, MS​ Associate Professor of Pediatrics​ Children​’s Mercy​ Kansas City​, ​Missouri​

Elizabeth​ Yu​, MD​ Fellow​ Pediatric Nephrology​ Seattle Children​’s Hospital​ Seattle​, ​Washington​

George A.​Woodward​, MD, MBA​ Professor, Chief of Emergency Medicine​ Department of Pediatrics​ University of Washington School of Medicine​ Medical Director​ Emergency Department and Transport Medicine​ Seattle Children​’s Hospital​ Seattle​, ​Washington​

Elaine H.​Zackai​, MD​ Professor of Pediatrics​ University of Pennsylvania Perelman School of Medicine​ Director of Clinical Genetics Center​ Children​’s Hospital of Philadelphia​ Philadelphia​, ​Pennsylvania​

Clyde J.​ Wright​, MD​ Associate Professor​ Department of Pediatrics​ University of Colorado​ Aurora​, ​Colorado​

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xix

Preface​

“The neonatal period therefore represents the last frontier of medicine, territory which has just begun to be cleared of its forests and underbrush in preparation for its eagerly anticipated crops of saved lives.” From the Introduction to the 1st edition of ​Diseases of the Newborn

The History of Diseases of the Newborn Diseases of the Newborn was one of the first books dedicated to the diagnosis and treatment of problems of the neonate. The 1st edition was published in 1960 by Dr. Alexander Schaffer, a well-known Baltimore pediatrician who first coined the terms ​neonatology and​ neonatologist. He described neonatology as an emerging pediatric subspecialty concentrating on the “art and science of diagnosis and treatment of disorders of the newborn infant,” and a neonatologist as a “physician whose primary concern lay in that specialty.” Dr. Schaffer served as sole author for both the 1st and 2nd editions (1966) of the book. Dr. Mary Ellen Avery joined Dr. Schaffer as a co-author for the 3rd edition in 1971. Drs. Avery and Schaffer recognized that their book needed multiple contributors with subspecialty expertise as they developed the 4th edition in 1977, and they became co-editors, rather than co-authors. Dr. Schaffer died in 1981 and Dr. H. William Taeusch joined Dr. Avery in 1984 as co-editor for the 5th edition. Dr. Roberta Ballard joined Drs. Taeusch and Avery for the 6th edition in 1991, then titled, S​ chaffer & Avery's Diseases of the Newborn. The 7th edition, edited by Drs. Taeusch and Ballard, was published in 1998, and was entitled​ Avery's Diseases of the Newborn, in recognition of Dr. Avery’s diligent work on the book through four editions over 20 years. Dr. Christine Gleason joined Drs. Taeusch and Ballard in 2005 as editors for the 8th edition. In 2009, Drs. Avery, Taeusch, and Ballard retired from editing A ​ very's, and became “editors emeriti.” Sadly, Dr. Avery passed away in 2011. Her legacy lives on, however, in the title of this book. Dr. Sherin Devaskar joined Dr. Gleason in 2012 as co-editor for the 9th edition—the first edition with accompanying online content. For the 10th edition, Dr. Sandra “Sunny” Juul teamed with Dr. Gleason as co-editor, marking the first time since the 5​th edition that all editors were faculty at the same institution. For this new, 11th edition, Dr. Taylor Sawyer, also on the faculty at Dr. Gleason’s institution, joins as co-editor. This edition marks the fourth that Dr. Gleason has co-edited, making her the longest serving editor since Dr. Avery.​ The 1st edition of D ​ iseases of the Newborn was used mainly for diagnosis, but also included descriptions of early neonatal therapies that had led to a remarkable decrease in the infant mortality rate in the United States: from 47 deaths per 1000 live births in 1940 to 26 per 1000 in 1960. However, a pivotal year for the fledgling subspecialty of neonatology came in 1963, 3 years after

the first publication of D ​ iseases of the Newborn, with the birth of President John F. Kennedy​’s son, Patrick Bouvier Kennedy. Patrick was a preterm infant, born at 34-35 weeks​’ gestation, and his death at 3 days of age from complications of respiratory distress syndrome accelerated the development of infant ventilators, which, coupled with micro-blood gas analysis and the use of umbilical artery catheterization, led to the development of newborn intensive care in the late 1960s.​ Advances in neonatal surgery and cardiology, along with ongoing technological innovations, stimulated the development of neonatal intensive care units and regionalization of care for sick newborn infants over the next several decades. These developments were accompanied by an explosion of research that improved our understanding of the pathophysiology and genetic basis of diseases of the newborn. This in turn led to spectacular advances in neonatal diagnosis and therapeutics—particularly in the care of preterm infants. Combined, these advances have resulted in significant reductions in infant mortality worldwide: from 6.45% in 1990 to 2.82% in 2019. Current research efforts are focused on decreasing the unacceptable regional, ethnic, and global disparities in infant mortality, improving neonatal long-term outcomes, advancing neonatal therapeutics, preventing newborn diseases, and finally—teaming with our obstetrical colleagues—preventing prematurity. This edition tries—as all prior editions have—to translate the findings of ongoing research into practical advice for use at the bedside by neonatal caregivers.​

What's New and Improved About This Edition? Perhaps the most significant change to this edition is what was removed rather than what was added. We carefully reviewed the 10th edition’s table of contents, examining each chapter with a keen eye on keeping the book targeted on diseases of the newborn, bringing the content more in line with the original editions. Thus, several chapters that were not specifically disease-focused were archived, while chapters in some sections were subdivided into new chapters focused on disease-specific content.​ This book continues to be thoroughly (and sometimes painfully) revised and updated by some of the best clinicians and investigators in their fields—several of whom are new contributors. Some chapters required more extensive updates than others. For all chapters, however, we challenged authors to decrease the word count, use boxes, tables, and figures to break up dense text, and to do their best to make the content as disease-focused as appropriate. This resulted in a more concise, readable, and hopefully, clinically helpful text. We are so grateful to our authors for their contributions and hope readers appreciate their work.​ xxi

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Preface

Do We Still Need Textbooks? With the incredible amount of information immediately available on the internet, what​’s the value of a textbook? We believe that textbooks, such as A ​ very’s Diseases of the Newborn, will always be needed by clinicians striving to provide state-of-the-art neonatal care, by educators working to train the next generation of caregivers, and by investigators diligently advancing neonatal research and scholarship. A textbook​’s content is only as good as its contributors. This book, like in previous editions, has awesome contributors.​ The authors were chosen for their expertise and ability to integrate their knowledge into a comprehensive, readable, and useful chapter. They did this in the hope that their syntheses could, as Ethel Dunham wrote in the foreword to the 1st edition, “spread more widely what is already known … ​ ​and make it possible to apply these facts.”​ We are grateful that the online content of this textbook enjoys increasing popularity. However, we still find printed copies of this and other books lying dog-eared, coffee-stained, annotated, and broken-spined in places where neonatal caregivers congregate.​ With each subsequent edition, the authors of D ​ iseases of the Newborn help fulfill Dr. Schaffer’s vision of clearing the underbrush from the last frontier of medicine in preparation for its eagerly anticipated crops of saved neonatal lives. Textbooks connect us to the past, bring us up to date on the present, and prepare

and excite us for the future. We will always need them, in one form or another. To that end, we have challenged ourselves to meet, and hopefully exceed, that need—for our field, for our colleagues, and for the babies entrusted to our care.​

Acknowledgments and Gratitude We wish to thank some key staff at Elsevier— our Content Development Specialist, Erika Ninsin; our Senior Content Development Manager, Meghan Andress; our Publishing Services Manager, Catherine Jackson; our Senior Project Manager, John Casey; our Design Director, Brian Salisbury; and our Publisher, Sarah Barth. They demonstrated patience, guidance, and persistence; without them, we would still be hard at work, trying to make this book a reality! We also wish to thank our colleagues at our academic institution, the University of Washington, especially our Division Chief, Sunny Juul, and our Department Chair, Leslie Walker-Harding, whose leadership and unwavering support have meant so much to us both. We are deeply indebted to our chapter authors, who wrote the book and did so willingly, enthusiastically, and (for the most part) in a timely fashion—despite myriad other responsibilities in their lives, and a worldwide COVID-19 pandemic! Finally, we are extremely grateful for the support of our families throughout the long, and often challenging, editorial process.​ Christine Gleason and ​Taylor Sawyer

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Contents

PART I:  Overview

PART IV:  Labor and Delivery

1 Neonatal and Perinatal Epidemiology, 1

12 Assessment of Fetal Well-Being, 123

Nigel Paneth, Simran Patel, and Thomas Michael O’Shea Jr.

2 Ethics, Data, and Policy in Newborn Intensive Care, 13 Joanne M. Lagatta and John D. Lantos

PART II:  Fetal Growth and Development 3 Development, Function, and Pathology of the Placenta, 19 Emin Maltepe and Anna A. Penn

4 Abnormalities of Fetal Growth, 33 Rebecca A. Simmons

5 Multiple Gestations and Assisted Reproductive Technology, 42 Allison S. Komorowski and Emily S. Jungheim

6 Prematurity and Stillbirth: Causes and Prevention, 50 Julia Johnson and Maneesh Batra

7 Nonimmune Hydrops, 58 Dalal K. Taha and Scott A. Lorch

PART III: Maternal Conditions Affecting Pregnancy Outcomes 8 Maternal Diabetes, 67 Emily Fay, LaVone Simmons, and Colleen Brown

9 Maternal Medical Disorders of Fetal Significance, 82 Jerasimos Ballas and Thomas F. Kelly

10 Hypertensive Complications of Pregnancy, 99 Thomas R. Moore

11 Intrauterine Drug Exposure: Fetal and Postnatal Effects, 106 Gerri R. Baer, Rachana Singh, and Jonathan M. Davis

Christian M. Pettker and Katherine H. Campbell

13 Complicated Deliveries, 135 Kara K. Hoppe and Brad Bosse

14 Obstetric Analgesia and Anesthesia, 147 Emily E. Sharpe, Mark A. Rosen, and Mark D. Rollins

15 Perinatal Transition and Newborn Resuscitation, 159 Noorjahan Ali and Taylor Sawyer

PART V:  Essentials of Newborn Care 16 Care of the Newborn, 173 Michelle M. Gontasz, Amaris M. Keiser, and Susan W. Aucott

17 Temperature Regulation 192 Janessa B. Law and W. Alan Hodson

18 Newborn Screening, 199 Inderneel Sahai

PART VI:  High-Risk Newborn Care 19 Neonatal Transport, 217 Zeenia C. Billimoria and George A. Woodward

20 Fluid, Electrolyte, and Acid-Base Balance, 231 Clyde J. Wright, Michael A. Posencheg, and Istvan Seri

21 Neonatal Pharmacology, 253 Karel Allegaert, Robert M. Ward, and John N. van den Anker

22 Neonatal Pain and Stress, 266 Vilmaris Quiñones Cardona, Dennis E. Mayock, and Rachel Fleishman

23 Palliative Care, 279 DonnaMaria E. Cortezzo and Brian S. Carter

24 Risk Assessment a­nd N­eu­ro­de­ve­lop­mental Outcomes, 287 Sara B. DeMauro and Susan R. Hintz xxiii

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Contents

PART VII:  Genetics 25 The Human Genome and Neonatal Care, 309

39 Neonatal Pulmonary Physiology, 548 William E. Truog and Winston M. Manimtim

40 Neonatal Respiratory Therapy, 559

C.M. Cotten

26 Prenatal Diagnosis and Counseling, 322 Edith Y. Cheng and J. Craig Jackson

27 The Dysmorphic Infant, 335 K. Taylor Wild, Sarah E. Sheppard, and Elaine H. Zackai

28 Chromosome Disorders, 347 T. Niroshi Senaratne, Elaine H. Zackai, and Sulagna C. Saitta

PART VIII: Metabolic Disorders of the Newborn 29 Inborn Errors of Carbohydrate, Ammonia, Amino Acid, and Organic Acid Metabolism, 363 J. Lawrence Merritt II and Renata C. Gallagher

30 Lysosomal Storage Disorders Presenting in the Neonate, 386 Irene J. Chang, Angela Sun, and Gerard T. Berry

31 Congenital Disorders of Glycosylation, Peroxisomal Disorders, and Smith-­Lemli-Opitz Syndrome, 396 Janet A. Thomas and Christina Lam

PART IX:  Immunology and Infections 32 Immunology of the Fetus and Newborn, 409 Joern-Hendrik Weitkamp, David B. Lewis, and Ofer Levy

33 Neonatal Bacterial Sepsis and Meningitis, 439 Gregory C. Valentine and Linda D. Wallen

34 Viral Infections of the Fetus and Newborn, 450 Caleb Stokes and Ann J. Melvin

35 Congenital Toxoplasmosis, Syphilis, Malaria, and Tuberculosis, 487 Marian G. Michaels, Pablo J. Sánchez, and Philana Ling Lin

36 Fungal Infections in the Neonatal Intensive Care Unit, 512 Kirtikumar Upadhyay and Mihai Puia-Dumitrescu

37 Healthcare-Associated Infections, 519 Lakshmi Srinivasan

PART X:  Respiratory System 38 Lung Development, 535 Erin Plosa and Jennifer Sucre

David J. Durand and Sherry E. Courtney

41 Control of Breathing, 580 Estelle B. Gauda and Richard J. Martin

42 Acute Neonatal Respiratory Disorders, 594 Nicolle Fernández Dyess, John P. Kinsella, and Thomas A. Parker

43 Chronic Neonatal Respiratory Disorders, 614 Roberta L. Keller and Robin H. Steinhorn

44 Anatomic Disorders of the Chest and  Airways, 626 Su Yeon Lee, Jordan E. Jackson, Satyan Lakshiminrusimha, Erin G. Brown, and Diana L. Farmer

PART XI:  Cardiovascular System 45 Developmental Biology of the Heart, 659 Ellen Dees and H. Scott Baldwin

46 Cardiovascular Compromise in the Newborn Infant, 675 Shahab Noori and Istvan Seri

47 Persistent Pulmonary Hypertension, 703 Erica Mandell, Robin H. Steinhorn, and Steven H. Abman

48 Patent Ductus Arteriosus in the Preterm Infant, 716 Ronald I. Clyman

49 Perinatal Arrhythmias, 727 Terrence Chun and Bhawna Arya

50 Congenital Heart Disease, 743 Natasha González Estévez and Deidra A. Ansah

51 Long-Term Neurologic Outcomes in Children With Congenital Heart Disease, 772 Shabnam Peyvandi and Patrick McQuillen

PART XII:  Neurologic System 52 Central Nervous System Development, 781 Bobbi Fleiss, Helen Stolp, Valerie Mezger, and Pierre Gressens

53 Congenital Malformations of the Central Nervous System, 787 Benjamin Dean and Dan Doherty

54 Brain Injury in the Preterm Infant, 809 Art Riddle, Steven P. Miller, and Stephen A. Back

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Contents

55 Neonatal Encephalopathy, 827 Ulrike Mietzsch and Sandra E. Juul

56 Neonatal Neurovascular Disorders, 843 Mihai Puia-Dumitrescu and Sandra E. Juul

57 Neonatal Neuromuscular Disorders, 854

xxv

71 Neonatal Leukocyte Physiology and Disorders, 1033 John T. Benjamin, Benjamin A. Torres, and Akhil Maheshwari

72 Neonatal Hyperbilirubinemia and Kernicterus, 1045 W. Christopher Golden and Jon F. Watchko

Niranjana Natarajan and Cristian Ionita

58 Neonatal Seizures, 862 Jennifer C. Keene, Niranjana Natarajan, and Sidney M. Gospe Jr.

PART XV:  Neoplasia 73 Congenital Malignant Disorders, 1067 Tiffany L. Lucas, Benjamin Huang, and Elizabeth Robbins

PART XIII: Gastrointestinal System and Nutrition

PART XVI:  Renal and Genitourinary System

59 Enteral Nutrition, 871

74 Renal Development, 1087

Heidi Karpen and Brenda Poindexter

60 Parenteral Nutrition for the High-Risk Neonate, 888 Katie A. Huff and Scott C. Denne

61 Structural Anomalies of the Gastrointestinal Tract, 897 Katherine T. Flynn-O’Brien and Samuel E. Rice-Townsend

62 Abdominal Wall Defects, 913 Shilpi Chabra, Jamie E. Anderson, and Patrick J. Javid

63 Neonatal Gastroesophageal Reflux, 925 Eric C. Eichenwald

64 Necrotizing Enterocolitis and Short Bowel Syndrome, 930 Gregory Keefe, Tom Jaksic, and Josef Neu

65 Disorders of the Liver, 940 Mohammad Nasser Kabbany and Karen F. Murray

PART XIV: Hematologic System and Disorders of Bilirubin Metabolism 66 Developmental Hematology, 957 Sandra E. Juul and Robert D. Christensen

67 Neonatal Bleeding and Thrombotic Disorders, 965 Matthew A. Saxonhouse and Ashley P. Hinson

68 Neonatal Platelet Disorders, 982 Emöke Deschmann and Martha Sola-Visner

69 Neonatal Erythrocyte Disorders, 996 Katie Carlberg

70 Neonatal Transfusion, 1025 Ravi Mangal Patel and Cassandra D. Josephson

Irene McAleer and Kai-wen Chiang

75 Developmental Abnormalities of the Kidneys, 1100 Rachel M. Engen and Sangeeta Hingorani

76 Developmental Abnormalities of the Genitourinary System, 1111 Courtney K. Rowe and Paul A. Merguerian

77 Acute Kidney Injury, 1125 Heidi J. Steflik, David Askenazi, and David T. Selewski

78 Chronic Kidney Disease, 1139 Laurel Willig and Bradley A. Warady

79 G­lo­merulonephropathies and Disorders of Tubular Function, 1148 Elizabeth Yu and Karyn Yonekawa

80 Urinary Tract Infections and Vesicoureteral Reflux, 1155 Kathy Huen, Peter (Zhan Tao) Wang, and Elias Wehbi

81 Systemic Hypertension, 1163 Joseph T. Flynn Jr.

PART XVII:  Endocrine Disorders 82 Developmental Endocrinology, 1173 Sara A. DiVall and Lina Merjaneh

83 Disorders of Calcium and Phosphorus Metabolism, 1182 Kelsey B. Eitel, Ildiko H. Koves, Kathryn D. Ness, and Parisa Salehi

84 Disorders of the Adrenal Gland, 1201 Patricia Y. Fechner

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xxvi

Contents

85 Differences in Sex Development, 1215 Margarett Shnorhavorian and Patricia Y. Fechner

86 Disorders of the Thyroid Gland, 1238 Grace Kim, Debika Nandi-Munshi, and Carolina Cecilia Di Blasi

87 Neonatal Hypoglycemia and Hyperglycemia, 1254 David Werny, Alyssa Huang, Jessica Tenney, and Catherine Pihoker

PART XVIII: Craniofacial and Orthopedic Conditions 88 Craniofacial Conditions, 1269 G. Kyle Fulton, Matthew S. Blessing, and Kelly N. Evans

89 Common Neonatal Orthopedic Conditions, 1294 Katherine M. Schroeder, Maryse L. Bouchard, and Klane K. White

90 Skeletal Dysplasias and Heritable Connective Tissue Disorders, 1306 George E. Tiller and Gary A. Bellus

PART XIX:  Dermatologic Conditions

92 Congenital and Hereditary Disorders of  the Skin, 1332 Cheryl Bayart and Heather A. Brandling-Bennett

93 Infections of the Skin, 1347 Markus D. Boos and Robert Sidbury

94 Common Newborn Dermatoses, 1356 Kate Khorsand and Robert Sidbury

95 Vascular Anomalies and Other Cutaneous Congenital Defects, 1366 Deepti Gupta and Robert Sidbury

PART XX:  Eyes and Ears 96 Eye and Vision Disorders, 1391 Julius T. Oatts, Alejandra G. de Alba Campomanes, and Gil Binenbaum

97 Ear and Hearing Disorders, 1414 Betty Vohr and Susan Wiley

Index, 1423

91 Newborn Skin Development: Structure and Function, 1325 Robert Sidbury

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PA RT I Overview

1

Neonatal and Perinatal Epidemiology

NIGEL PANETH, SIMRAN PATEL, AND THOMAS MICHAEL O’SHEA JR.

KEY POINTS • Maternal and child health in the population have traditionally been assessed by monitoring two key statistics—the maternal mortality ratio and the infant mortality rate. The infant mortality rate is the sum of the neonatal mortality and post-neonatal mortality rates. • Due to improvements in income, housing, birth spacing, and nutrition, along with public health interventions to produce cleaner food and water, improve maternal and infant nutrition, and immunize mothers and infants against infectious diseases, maternal mortality and infant mortality declined steadily through the 20th century. By 2000, neonatal mortality had declined by 90% from its 1915 value, postneonatal mortality by 93%, and maternal mortality by 98%. • In high-income countries, the leading causes of neonatal mortality are preterm birth and congenital anomalies. The leading cause of postneonatal mortality is sudden infant death syndrome. • Health disparities are especially prominent in the perinatal period. Even as rates of infant mortality decline in both Black and White babies, infant mortality among Black babies remains about twice that of White infant mortality in the United States. • Despite comparable, or lower, birthweight-specific infant mortality rates, the United States has one of the highest infant mortality rates among high-income countries. This surprising phenomenon is due to the striking excess of preterm births in the United States, as compared with other high-income countries. • Notable improvements in health outcomes resulting from epidemiologic research include reductions in neural tube defects (reduced by prenatal folate), sudden infant death syndrome (reduced by supine infant sleeping), and cerebral palsy among preterm infants (reduced by maternal magnesium sulfate).

Introduction—Epidemiologic Approaches to the Perinatal and Neonatal Period The period surrounding the time of birth, the perinatal period, is a critical window in human development, as the infant makes the transition from its dependence upon maternal and placental support—oxidative, nutritional, and endocrinologic—to establishing independent life. That this transition is not always successful is signaled by an annualized mortality rate in the neonatal period that is not exceeded until age 85 and older,1 and risks for damage to organ systems, most notably the brain, that can be lifelong. However, years must pass before the effects on

higher cortical functions of insults and injuries occurring during the perinatal period can reliably be detected. Epidemiologic approaches to the perinatal period must therefore be bidirectional—looking backward to examine the causes of adverse health conditions that arise during the perinatal period and looking forward to seeing how these conditions shape disorders of health found later in life. Traditionally the perinatal period was described as extending from 28 weeks of gestation until 1 week of life, but in 2004 the World Health Organization (WHO) antedated the onset of the perinatal period to 22 weeks.2 For the purposes of this discussion we will define perinatal more expansively, as including the second half of gestation (by which time most organogenesis has occurred, but growth and maturation of many systems has yet to occur) and the first month of life. The neonatal period, usually considered as the first month of life, is thus included in the term perinatal, reflecting the view that addressing the problems of the neonate requires an understanding of intrauterine phenomena.

Health Disorders of Pregnancy and the Perinatal Period Key Population Mortality Statistics Maternal and child health in the population have traditionally been assessed by monitoring two key statistics—the maternal mortality ratio and the infant mortality rate. A maternal death is defined by the WHO as the death of a woman during pregnancy or within 42 days of pregnancy.3 Because maternal deaths are not part of the denominator of births, the resulting fraction is referred to as the maternal mortality ratio. When the cause of death is attributed to a pregnancy-related cause, it is described as direct. When pregnancy has aggravated an underlying health disorder present before pregnancy, the death is termed an indirect maternal death. The WHO recommends that both direct and total (direct plus indirect) maternal mortality rates be monitored. Typically, the ratio is indexed to 100,000 births. Because pregnancy can contribute to deaths beyond 42 days, the term “late maternal death” has been used to describe the death of a woman from direct or indirect obstetric causes more than 42 days but less than 1 year after termination of pregnancy.

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PA RT I Overview

These later deaths are not usually included in tabulations of ­maternal mortality in vital data,4,5 although they are included in “pregnancy-associated mortality” as defined by the Centers for Disease Control and Prevention (CDC).6 Deaths unrelated to pregnancy, but occurring within 42 days of pregnancy, are termed incidental maternal deaths and are not included in maternal mortality.7 However, even incidental deaths may bear a relation to pregnancy; for example, homicide and suicide are more common in pregnancy and shortly thereafter and might not be entirely incidental to it.8,9 In most geographic entities, infant mortality is defined as all deaths occurring from birth to 365 days of age. The infant mortality rate is the number of infant deaths in a calendar year divided by the number of births occurring in the same year. This approach makes for imprecision because some deaths in the examined year occurred to the previous year’s birth cohort, and some births in the examined year will die as infants in the following year. In recent years, birth-death linkage has permitted vital registration areas in the United States to provide infant mortality rates that avoid this imprecision. The standard infant mortality rate reported by the National Center for Health Statistics (NCHS) links deaths for the index year to all births to whom the death occurred, including births that took place the previous year. This form of infant mortality is termed period infant mortality. An alternative procedure is to take births for the index year and link them to infant deaths, including those taking place the following year. This is referred to as birth cohort infant mortality and is not used for regular annual comparisons because it cannot be completed in as timely a fashion as can period infant mortality.10 The denominator for all forms of infant mortality is 1000 live births. Infant deaths are conventionally divided into deaths in the first 28 days of life (neonatal deaths) and deaths later in the first year (postneonatal deaths). Neonatal deaths, which are largely related to preterm birth and birth defects, tend to reflect the circumstances of pregnancy and birth; postneonatal deaths, when high, are largely from infection, often in the setting of poor nutrition. In highincome countries (HICs), neonatal deaths have for many years made up a larger proportion of infant mortality than postneonatal deaths. This has been true of the United States since 1921, and in recent years the ratio of neonatal to postneonatal deaths in the United States has consistently been approximately 2 to 1. Until quite recently, postnatal deaths outnumbered neonatal deaths in low- and middle-income countries (LMICs), but in 2019, infant mortality was 28.2/1000 live births in LMICs while neonatal mortality was 17.9/1000 live births, indicating that infant mortality in LMICs is beginning to resemble patterns seen in HICs.11 Perinatal mortality is a term used for a rate that combines stillbirths and neonatal deaths in some fashion.2 Stillbirth reporting prior to 28 weeks is probably incomplete, even in the United States, where such births are required to be reported in every state.12 Nonetheless, stillbirths continue to be reported at a level not much lower than that of neonatal deaths, and our understanding of the causes of stillbirth remains very uncertain.13

Sources of Information on Mortality—Vital Data All US mortality data depend upon the collection of information about all births and deaths. Routinely collected vital data are the nation’s key resource for monitoring progress in caring for mothers and children. Annual counts of births and deaths collected by the 52 vital registration areas of the United States (50 states, District of Columbia [DC], and NYC) are assembled into national data

sets by the NCHS and described under the heading of National Vital Statistics Reports (NVSRs).14 Unlike data collected in hospitals or clinics, or even from nationally representative surveys, birth and death certificates are required by law to be completed for each birth and death. Birth and death registration have been virtually 100% complete for all parts of the United States since the 1950s. The universality of this process renders many findings from vital data analyses stable and generalizable, although formatting changes recommended in 2003, affecting both the birth and death certificates, have created some difficulties in interpretation because the NCHS can only recommend format revisions in vital data certificates; each state is free to adopt them or not. The 2003 revision of the birth certificate emphasized recording of data from medical records rather than maternal interview and recommended the reformatting of some elements, such as date of first prenatal visit, in ways that produced differences in findings compared to an earlier revision made in 1989. To complicate matters further, states adopted the 2003 revision at different times, and for much of the next decade, both versions of the birth certificate—1989 and 2003 revisions—were in use, leading to the NCHS deciding not to issue national data for several years for the prevalence of gestational diabetes, gestational hypertension, and gestational age at initiation of prenatal care. This problem has now been resolved because, as of 2016, all 50 states, the DC, Puerto Rico, Guam, Commonwealth of the Northern Marianas, and US Virgin Islands reported data based on the 2003 US Certificate of Live Birth. American Samoa continues to report based on the earlier 1989 birth certificate revision.15 In 2003, the NCHS also recommended revisions to the US Standard Certificate of Death,16 including a special checkbox for identifying whether the decedent, if female, was pregnant or had been pregnant in the previous 42 days. As with the birth certificate, this revision was variably followed by states, and it has been found that the number of deaths recognized as maternal in states that adopted the checkbox is higher than in those that did not (Fig. 1.1).17 The limitations of vital data are well known. Causes of death are subject to certifier variability and, perhaps more importantly, to professional trends in diagnostic categorization. The accuracy of recording of conditions and measures on birth certificates is often uncertain and variable from state to state and hospital to hospital. Yet the frequencies of births and deaths in subgroups defined objectively and recorded consistently, such as birthweight and mode of delivery, are likely to be valid.

Time Trends in Mortality Rates of the Perinatal Period in the United States Maternal mortality and infant mortality declined steadily through the 20th century; by 2000, neonatal mortality had declined by 90% from its 1915 value, postneonatal mortality by 93%, and maternal mortality by 98%. These extraordinary and unprecedented changes are the product of a variety of complex social factors including improvements in income, housing, birth spacing, and nutrition, as well as ecological-level public health interventions that produced cleaner food and water.18 Public health action at the individual level, including targeted maternal and infant nutrition programs and immunization programs have made a lesser, but still notable contribution. Medical care per se was, until recently, less critically involved in these declines, with the exception of the decline in maternal mortality, which was very sensitive to the developments in blood banking and antibiotics that began in the 1930s.

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MOTHER

29a. DATE OF FIRST PRENATAL CARE VISIT ______ /________/ __________ No Prenatal Care MM DD YYYY

Neonatal and Perinatal Epidemiology

30. TOTAL NUMBER OF PRENATAL VISITS FOR THIS PREGNANCY _________________________ (If none, enter A0".)

31. MOTHER’S HEIGHT _______ (feet/inches)

32. MOTHER’S PREPREGNANCY WEIGHT 33. MOTHER’S WEIGHT AT DELIVERY 34. DID MOTHER GET WIC FOOD FOR HERSELF _________ (pounds) _________ (pounds) Yes No DURING THIS PREGNANCY?

35. NUMBER OF PREVIOUS LIVE BIRTHS (Do not include this child)

37. CIGARETTE SMOKING BEFORE AND DURING PREGNANCY 38. PRINCIPAL SOURCE OF 36. NUMBER OF OTHER For each time period, enter either the number of cigarettes or the PAYMENT FOR THIS PREGNANCY OUTCOMES number of packs of cigarettes smoked. IF NONE, ENTER A0". DELIVERY (spontaneous or induced losses or ectopic pregnancies) Average number of cigarettes or packs of cigarettes smoked per day. Private Insurance 36a. Other Outcomes # of cigarettes # of packs Medicaid Three Months Before Pregnancy _________ OR ________ Number _____ Self-pay First Three Months of Pregnancy _________ OR ________ Other Second Three Months of Pregnancy _________ OR ________ None (Specify) _______________ Third Trimester of Pregnancy _________ OR ________

35a. Now Living

35b. Now Dead

Number _____

Number _____

None

None

35c. DATE OF LAST LIVE BIRTH _______/________ MM YYYY

MEDICAL AND HEALTH INFORMATION

29b. DATE OF LAST PRENATAL CARE VISIT ______ /________/ __________ MM DD YYYY

 

CHAPTER 1

36b. DATE OF LAST OTHER PREGNANCY OUTCOME _______/________ MM YYYY

39. DATE LAST NORMAL MENSES BEGAN ______ /________/ __________ MM DD YYYY

43. OBSTETRIC PROCEDURES (Check all that apply)

41. RISK FACTORS IN THIS PREGNANCY (Check all that apply) Diabetes Prepregnancy (Diagnosis prior to this pregnancy) Gestational (Diagnosis in this pregnancy)

46. METHOD OF DELIVERY A. Was delivery with forceps attempted but unsuccessful? Yes No

Cervical cerclage Tocolysis External cephalic version: Successful Failed

Hypertension Prepregnancy (Chronic) Gestational (PIH, preeclampsia) Eclampsia

B. Was delivery with vacuum extraction attempted but unsuccessful? Yes No

None of the above

Previous preterm birth

44. ONSET OF LABOR (Check all that apply)

Other previous poor pregnancy outcome (Includes perinatal death, small-for-gestational age/intrauterine growth restricted birth)



Premature Rupture of the Membranes (prolonged, 12 hrs.)



Precipitous Labor (38°C (100.4°F) Moderate/heavy meconium staining of the amniotic fluid Fetal intolerance of labor such that one or more of the following actions was taken: in-utero resuscitative measures, further fetal assessment, or operative delivery Epidural or spinal anesthesia during labor None of the above

47. MATERNAL MORBIDITY (Check all that apply) (Complications associated with labor and delivery) Maternal transfusion Third or fourth degree perineal laceration Ruptured uterus Unplanned hysterectomy Admission to intensive care unit Unplanned operating room procedure following delivery None of the above

NEWBORN INFORMATION

NEWBORN

48. NEWBORN MEDICAL RECORD NUMBER 49. BIRTHWEIGHT (grams preferred, specify unit) ______________________  grams  lb/oz 50. OBSTETRIC ESTIMATE OF GESTATION:

Mother’s Medical Record No. ____________________

Mother’s Name ________________

(completed weeks)

51. APGAR SCORE: Score at 5 minutes:________________________ If 5 minute score is less than 6, Score at 10 minutes: _______________________ 52. PLURALITY - Single, Twin, Triplet, etc. (Specify)________________________ 53. IF NOT SINGLE BIRTH - Born First, Second, Third, etc. (Specify) ________________

54. ABNORMAL CONDITIONS OF THE NEWBORN (Check all that apply) Assisted ventilation required immediately following delivery Assisted ventilation required for more than six hours NICU admission Newborn given surfactant replacement therapy Antibiotics received by the newborn for suspected neonatal sepsis Seizure or serious neurologic dysfunction Significant birth injury (skeletal fracture(s), peripheral nerve injury, and/or soft tissue/solid organ hemorrhage which requires intervention)

55. CONGENITAL ANOMALIES OF THE NEWBORN (Check all that apply) Anencephaly Meningomyelocele/Spina bifida Cyanotic congenital heart disease Congenital diaphragmatic hernia Omphalocele Gastroschisis Limb reduction defect (excluding congenital amputation and dwarfing syndromes) Cleft Lip with or without Cleft Palate Cleft Palate alone Down Syndrome Karyotype confirmed Karyotype pending Suspected chromosomal disorder Karyotype confirmed Karyotype pending Hypospadias None of the anomalies listed above

 None of the above

56. WAS INFANT TRANSFERRED WITHIN 24 HOURS OF DELIVERY?  Yes  No IF YES, NAME OF FACILITY INFANT TRANSFERRED TO:______________________________________________________

58. IS THE INFANT BEING 57. IS INFANT LIVING AT TIME OF REPORT? BREASTFED AT DISCHARGE? Yes No Infant transferred, status unknown Yes No

• Fig. 1.1  US Birth and Death Certificates. (A) US national standard birth certificate, 2003 version. (B) US national standard death certificate, 2003 version.

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3

4



PA RT I Overview

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CHAPTER 1

Neonatal and Perinatal Epidemiology

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5

6



PA RT I Overview

Maternal mortality remains a major public health problem in much of the world, and such manageable complications as hemorrhage and infection continue to account for a large fraction of the world’s maternal deaths.19 A notable feature of the last half of the 20th century was the sharp decline in all three mortality rates beginning in the 1960s, following a period of stagnation in the 1950s. The decline began with maternal mortality, followed by postneonatal and then neonatal. The contribution of medical care of the neonate was most clearly seen in national statistics in the 1970s, a decade that witnessed a larger proportional decline in neonatal mortality than in any previous decade of the century. All of the change in neonatal mortality between 1950 and 1975 was in mortality for a given birthweight; no improvement was seen in the birthweight distribution.20 This finding suggested the effectiveness of newborn intensive care, whose impact on mortality in very small babies has been striking. In 1960, shortly before the development of newborn intensive care, survival of an infant with birthweight of 1000 g was no more than 5%. Forty years later, survival at that birthweight was 95%.21 In retrospect, several factors seem to have played critical roles in the rapid development of the newborn intensive care programs that largely accounted for this rapid decline in birthweight-specific neonatal mortality. Perhaps the most important was the provision of more than nursing care to marginal populations such as the premature infant. Although the death of the mildly premature son of President Kennedy in 1963 provided a stimulus to the development of newborn intensive care,22 it should be noted that the decline in infant mortality that began in the 1970s was paralleled by a similar decline in mortality for the extremely old,23 perhaps an indicator that the availability of federal funding through Medicare and Medicaid enabled previously underserved populations at the extremes of age to receive greater medical attention than before. The Medicaid program, adopted in 1965, may have made it feasible for the first time to pay for the intensive care of premature newborns, among whom the medically indigent are overrepresented. While financial support for newborn intensive care may have been a necessary ingredient in its development, finances would not have been sufficient to improve neonatal mortality had not new medical technologies, especially those supporting ventilation of the immature newborn lung, been developed at about the same time.24 Advances in newborn care have ameliorated the impact of premature birth and birth defects on mortality. Progress has come from improved medical care of the high-risk pregnancy and the sick infant, rather than through understanding and prevention of the disorders themselves. Unfortunately, the frequencies of underlying disorders that drive perinatal mortality have shown less improvement. With the very important exception of neural tube defects, the prevalence of which has declined with folate fortification of flour in the United States and programs to encourage intake of folate in women of child-bearing age,25 prevalence rates of the major causes of death—preterm birth and birth defects—have not declined. The incidence of cerebral palsy, the major neurodevelopmental disorder that can be of perinatal origin, was remarkably stable for decades,26 notwithstanding advances in obstetric and neonatal care. However, there are now suggestions from some parts of the world that the birth prevalence of this disorder is on the decline.27 The pace of decline in infant, neonatal, and postneonatal mortality in the United States began to slow in 1995 and changed little in the following decade. However, a decline of nearly 20% in both neonatal and postneonatal mortality has been seen since 2005 (Table 1.1).

For infants weighing 501 to 1500 g at birth, data from the Vermont Oxford Neonatal Network encompassing more than a quarter of a million newborns from hundreds of largely North American neonatal units showed a decline in mortality of 12.2% in the final decade of the 20th century28 and a further decline of 13.3% from 2000 to 2009.29 For infants at the threshold of viability (born at 22 to 24 weeks), the large multicenter National Institute of Child Health and Human Development (NICHD) neonatal network has reported that mortality declined by 12.6% between 2000 and 2011.30 These declines are more modest than in the early days of newborn intensive care. From 1960 to 1985, a greater than 50% decline in mortality for infants weighing 501 to 1500 g at birth was recorded in national data,31,32 even though much of the first decade of that interval preceded the use of newborn intensive care technology in all but a few pioneering centers. The pace of advances in newborn medicine and the expansion of newborn intensive care to populations previously underserved, factors that have exerted a constant downward pressure on infant mortality since the 1960 s, have lessened in the past two decades or so. Reported maternal mortality has actually climbed substantially in recent years, but this almost certainly reflects the effect of improved reporting. The CDC has a special unit dedicated to the problem of maternal mortality, the Pregnancy Mortality Surveillance System (PMSS).33 Established in 1987, its counts of “pregnancy-related” deaths, based on more in-depth exploration than is possible from a vital registration system alone, have provided consistently higher estimates of maternal mortality than data reported by the HCHS, as shown in Fig. 1.2, in part because the CDC count includes deaths occurring up to 1 year after delivery. The major reason for the increase in reported maternal mortality was the recommendation by the NCHS in 2003 that all death certificates to females include a checkbox indicating whether the decedent had been pregnant in the prior year. This recommendation was initially adopted by some states and not others, producing considerable variability across states’ reported maternal mortality ratios. The inconsistency led the NCHS to not report on maternal mortality ratios in the United States from 2008 to 2017, as seen in Fig. 1.2.34 Inasmuch as use of the checkbox has now been adopted by all states, the NCHS resumed reporting maternal mortality ratios in 2018 and has provided a detailed overview of issues in defining this important health parameter in vital data.35 The checkbox on the death certificate has proven to be a mixed blessing. While it uncovers many otherwise unknown maternal deaths, it also produces a small number of false positives. For example, in 2013, seven births were reported to women in their 60s, yet 53 death certificates for women of that age had indicated a recent pregnancy. The careful assessments by NCHS of the procedures for recording maternal deaths may account for a welcome convergence of estimates of maternal mortality from the two systems. PMSS estimated the maternal mortality ratio at 17.3/100,000 in 2017, and the NCHS estimated it at 17.4 in 2018. However, the NCHS reported an increase in the maternal mortality ratio to 20.1/100,000 in 2019, although with continued cautions about data quality.36 The risk of preterm birth (85) at 1 year (72% vs. 41%) were observed.219 A larger phase II clinical trial was planned but stopped early due to poor enrollment. The results showed no difference in mortality between groups (5.9% in the intervention vs. 5.6% in the placebo group), but an improved neurodevelopmental outcome at 22 to 26 months, with 72% of participants having a Bayley III score of greater than 85 in the cognitive, language, and motor domain compared to 40% in the placebo group, was present (clinicaltrials.gov: NCT02612155). Other stem cell types such as embryonic stem cells, neural stem cells, induced pluripotent stem cells, bone marrow-derived mesenchymal stem cells, and amniotic fluid-derived stem cells all have a potential benefit but ethical problems in obtaining those cells (e.g., embryonic or fetal tissue), time constraints in finding, preparing, and administering matching cells, as well as immunologic concerns as the source is most often not autologous, have made these cell types less feasible for neonates with HIE. However, neural stem cells derived from reprogrammed induced pluripotent stem cells could offer autologous use. The timing of administration of stem cells will need to be studied, as hypothermia may diminish their effect.

Cannabinoids The activation of the endocannabinoid system decreases glutamate excitotoxicity, attenuates microglia activation, and reduces cell death.220 Systemic cannabinoid administration in piglets with HIE improved oxygenation and EEG features.221 At this time, however, no clinical studies in humans are ongoing. Allopurinol Allopurinol is a xanthine oxidase inhibitor, which decreases free radical and superoxide formation. Neuroprotective effects of allopurinol have been shown when given shortly after the ischemic insult in an HIE rat model.222 In small clinical trials, the effect of allopurinol given within 4 hours of birth to neonates with moderate to severe HIE was equivocal, but trends towards improvement, particularly in neonates with moderate HIE, were seen.223 Allopurinol might be more effective when given prior to reperfusion injury,224 which is currently being evaluated in a phase III clinical trial (clinicaltrials.gov: NCT03162653).

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CHAPTER 55

Azithromycin Azithromycin has anti-inflammatory neuroprotective effects through its immune-modulatory properties.225 Pre-clinical trials in a rat model of HIE showed a dose-dependent reduction in brain injury and improvement in sensorimotor function.226 Clinical trials to study the neuroprotective effects of azithromycin in neonates with moderate to severe HIE alone or in conjunction with therapeutic hypothermia are in the early phases. Further ongoing research is targeting the inflammatory response, autophagy, and mitochondrial function. Optimal neuroprotection will likely include multiple targeted approaches at different times.

Other Causes of Neonatal Encephalopathy Neurovascular disorders including perinatal stroke and cerebral sinus thrombosis are discussed in detail elsewhere (see Chapter 56).

Metabolic Causes of Neonatal Encephalopathy Neonatal Hypoglycemia Symptomatic hypoglycemia is a well-known cause of neurologic injury, but the exact glucose concentration or duration of hypoglycemia that will result in injury remains unclear. Blood glucose values in the fetus are 70% of maternal levels and rapidly fall in the first hour after birth to as low as 25 mg/dL, with a gradual increase over the next hours and days.227 Glucose concentration in the brain is approximately 30% of the systemic blood concentration, and this level is tightly controlled via glucose transporter type 1 (GLUT1) since the intact blood-brain barrier prevents the free diffusion of glucose.228 Hypoglycemia in the newborn can be transient and physiologic or secondary to an underlying metabolic or endocrine disorder. Risk factors for prolonged and/or symptomatic hypoglycemia include small or large for gestational age, maternal diabetes, perinatal asphyxia, respiratory distress, sepsis, metabolic disorders, and congenital abnormalities, particularly midline defects. Hypoglycemia may be asymptomatic or can manifest as cyanosis, tremors, apnea, seizures, change in consciousness, irritability, high-pitched cry, altered muscle tone, and feeding problems. The proposed mechanism of hypoglycemia-induced injury is hypoglycemia-induced neuronal depolarization and subsequent increase in presynaptic glutamate, which leads to excessive NMDA receptor activation. This activation induces increased intracellular sodium and calcium concentrations. Increased calcium influx into cells alters mitochondrial function and generates free radicals. ATP production is hampered, which leads to apoptosis and neuronal necrosis.229 Hypoglycemia may result in brain swelling, necrosis, and white matter demyelination, especially in areas rich with NMDA receptors. On MRI, brain regions affected include the cerebral cortex, dominantly in the parieto-occipital region, corpus callosum, basal ganglia, thalamus, and posterior limb of the internal capsule.230,231 The degree of injury is likely directly related to the depth and duration of hypoglycemia and the presence of any comorbidities, especially HIE. Long-term sequelae associated with hypoglycemia include visual impairment, epilepsy, and cognitive deficits. While neurocognitive outcomes at 2 years of age between hypoglycemic and non-hypoglycemic neonates remain similar,232,233 differences

Neonatal Encephalopathy

837

become more apparent during mid-childhood with odds of 3.62 for an abnormal neurodevelopmental outcome in hypoglycemic neonates.232

Inborn Errors of Metabolism Most inborn errors of metabolism that manifest in the immediate neonatal period are accompanied by systemic symptoms including neurologic findings. Encephalopathy is commonly seen in affected infants due to the primary or secondary toxic effects of the involved metabolites (e.g., ammonia) or as a symptom of ongoing energy depletion in organs with high energy demand such as the brain and the heart in the case of mitochondrial disorders, respiratory chain disorders, or pyruvate dehydrogenase deficiency.234

Metabolic Encephalopathies due to Toxic Metabolite Accumulation This extensive category includes a variety of metabolic disorders and can affect an array of metabolic pathways. Fetal development is rarely affected since the placenta clears most of the toxic substrates. Thus, malformations are uncommon, and the pregnancy appears uncomplicated. The newborn often appears well at birth, only to deteriorate over the initial days to weeks. Symptoms can be triggered by catabolic states, initiation of protein intake, or acute illness, depending on the underlying defect. Clinical symptoms are often rapidly progressive in the newborn period and are related to the accumulation of toxic metabolites. While many of the metabolic disorders in this category are now somewhat treatable, massive metabolite accumulation in the presenting stage can impact survival and can impair neurodevelopmental outcomes in survivors. Therefore, rapid removal of the toxic product before it causes permanent damage is crucial. Evaluation of plasma and urine amino acids, urine organic acid profile, and assessment of acylcarnitines can be diagnostic. Some of the more common disorders presenting with neonatal encephalopathy are described below.

Urea Cycle Disorders Urea cycle disorders (UCDs) are loss of function defects of any of the urea cycle enzymes. The dominant source for ammonia detoxification is via the urea cycle, which converts excess ammonia into excretable urea and produces arginine. Urea cycle disorders are autosomal recessive disorders with the exception of ornithine transcarbamylase (OTC) deficiency, which is X-linked. An estimated 1:35,000 newborns are affected by UCD235 and 27% become symptomatic in the neonatal period.236 Neonates with absent urea cycle enzyme activity typically present after the first 24 hours of life with feeding difficulties and progressive lethargy or even coma, which is caused by the rapid accumulation of ammonia and subsequent development of cytotoxic edema and seizure. Hyperammonemia leads to metabolic acidosis, which initially is often attempted to compensate for by the newborn clinically visible as tachypnea, and on blood gas as hyperventilation. Blood glucose levels are often normal. Diagnosis is made by obtaining plasma amino acids which often show an increase in glutamine and alanine and a decrease in citrulline and arginine. Subsequent targeted genetic testing allows to identify the individual enzyme defect. Outcomes are strongly related to the duration and extent of hyperammonemia. Therefore, the initial treatment has to focus on quickly and effectively decreasing ammonia levels (pharmacological and/or dialysis) and the prevention of further accumulation

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838

PA RT XI I

Neurologic System

(cessation of an exogenous protein supply, and provide a high energy supply to avoid endogenous protein catabolism). Seizures can also be present as ammonia has an epileptogenic effect, and therefore, EEG monitoring is recommended. On MRI, cerebral edema is the most common acute finding but changes in the white matter involving the deep sulci of the insular and peri-rolandic watershed territories can be seen. MR spectroscopy allows direct measurement of metabolites. The mortality of UCD is approximately 24% and neurocognitive morbidities vary among the defects. Global developmental delay and abnormal gross motor function are not uncommon.236

Methylmalonic Acidemia Methylmalonic acidemia (MMA) is a deficiency of the mitochondrial enzyme methyl-malonyl–coenzyme A mutase (MCM), a deficiency of its cofactor adenosyl-cobalamin (cblA or cblBMMA), or deficiency of the enzyme methylmalonyl-coenzyme A epimerase. The absence of one of the enzymes results in the accumulation of methylmalonic acid. MMA can present in the newborn who was healthy for the first day to weeks of life, with a presenting history of poor feeding, vomiting, progressive lethargy, and decreased muscle tone. The incidence is about 2:100,000 live births, and approximately 50% of patients become symptomatic in the neonatal period. Typical laboratory findings include significant metabolic acidosis, hyperammonemia, and plasma and urine ketones with or without hypoglycemia. Abnormal acyl-carnitines (C3-carnitine) and unspecific amino acid elevations, most commonly glycine and alanine, can be found in blood specimens. Urine organic acids demonstrate large amounts of methylmalonic acid, 2-methylcitrate, propionic acid, 3-hydroxy propionic acid, and triglycine. Definite diagnosis is made by mutation testing for the five genes associated with MMA: MMUT (encodes MCM), MMAA (encodes cobalamin A—cblA), MMAB (encodes cblB). MRI scans typically demonstrate bilateral involvement of basal ganglia and white matter lesions, with the globus pallidus being selectively affected.236a Therapy focuses on the elimination of ammonia, establishing a catabolic state, restricting dietary precursor amino acids, and promoting urinary excretion of MMA by providing adequate hydration. Mortality during early infancy is ~30% and survivors often show neurocognitive disabilities. A liver transplant can significantly reduce episodes of hyperammonemia237 and thereby improve outcome. Molybdenum Cofactor Deficiency Molybdenum cofactor deficiency (MCOD) is a disorder of the sulfur amino acid metabolism that occurs in 0.5 to 1:100,000 live births.238 There are three types described: MCOD type A results from molybdenum cofactor synthesis (MOCS) 1 gene mutation, MCOD type B is the result of MOCS 2 mutations, and type C is associated with gephyrin (GPHN) mutations. The absence of molybdenum cofactor results in functional deficiencies of molybdenum cofactor-dependent enzymes (sulfite oxidase, xanthine dehydrogenase, aldehyde oxidase, and mitochondrial amidoxime reducing component) which leads to an accumulation of their metabolites sulfite, taurine, S-sulfocysteine, and thiosulfate, which produces the severe neurologic symptoms seen in the affected patient. Newborns become symptomatic soon after birth and ­present with intractable seizures and an encephalopathic picture often so fast and profound that their clinical appearance is indistinguishable from a newborn with HIE. On MRI, diffusion restriction in the cortex and subcortical necrosis can be seen and in later stages, multicystic white matter lesions and atrophy are seen

(Fig. 55.3). Diagnosis is made by targeted genetic testing of the affected genes. Serum uric acid is commonly elevated, and urine studies reveal an elevated uric acid, S-sulfocysteine, xanthine, and hypoxanthine. While therapy for MOCD type B and C is supportive and death occurs typically in early infancy,238 a treatment for MOCD type A has recently become available. Cyclic pyranopterin monophosphate (cPMP), when applied shortly after birth, has shown significant improvement in an otherwise fatal disease.239

Nonketotic Hyperglycinemia Classic nonketotic hyperglycinemia (NKH) occurs in 1:76,000 live births and is caused by a mutation in the GLDC and/or AMT gene, which encode protein components of the glycine cleavage enzyme system and results in absent or significantly decreased activity.240 Glycine accumulates in the body, particularly in the brain and causes overstimulation of the NMDA receptors. Patients usually present in the immediate neonatal period with progressive encephalopathy and intractable seizures. Frequent hiccupping is common and is often present prenatally. Diagnostic testing includes amino acid profiles, which show elevation of glycine in plasma, CSF, and urine samples. CSF glycine is highly suggestive of NKH. Confirmatory testing is done via sequencing of the GLDC (affected in 80% of patients) and AMT genes. MRS can show high glycine peaks, and on occasion, nonspecific brain anomalies such as abnormal corpus callosum, hydrocephalus, and cerebellar hypoplasia are present. The outcome is universally poor for patients with classic NKH, with up to 30% mortality in the neonatal period and significant developmental delay and intractable seizures in survivors. The treatment is largely symptomatic and supportive and focuses on the elimination of glycine and NMDAreceptor blockage.

Energy Deficiency Disorders This group of metabolic disorders is characterized by insufficient energy supply, either caused by defects in production or transportation. In contrast to metabolic disorders accumulating toxic metabolites, metabolic disorders affecting the energy metabolism can become symptomatic during fetal development and affected organs are those of high energy demand such as the brain, liver, and heart. Therefore, abnormal development of the brain and cardiovascular system are the most common prenatal findings. Neonates with energy deficiency disorders often do not experience a symptom-free period and can present with encephalopathy at the time of birth. Since the neonatal brain consumes about 30% of the body’s energy, it is not surprising that disorders affecting the energy supply frequently present with neurologic symptoms, in particular hypotonia and seizures. Brain imaging can reveal abnormal development of various structures, such as cerebral dysgenesis, thinning of the corpus callosum, and cerebral and/or cerebellar heterotopia.241 Other common presenting clinical features include cardiomyopathy, liver failure, and adrenal insufficiency.

Mitochondrial Disorders Mitochondrial disorders are the most severe forms of energy deficiency disorders. This group consists of defects in aerobic glucose oxidation, mitochondrial respiratory chain disorders (including the respiratory chain, mitochondrial energy transporter molecules, or coenzyme Q10 biosynthesis), and fatty oxidation defects.242 They are caused by mutations in mitochondrial protein-encoding genes, found on either mitochondrial DNA or nuclear DNA, and lead to defects in the mitochondrial electron transport chain and/

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A

B

C

D

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• Fig. 55.3 

A Term Female Neonate With Molybdenum Cofactor Deficiency. (A) Axial diffusion-weighted image (DWI) obtained on day of life 2 shows widespread diffusion restriction predominantly in the subcortical white matter (arrowheads) and basal ganglia (arrows) with relative sparing of the thalami (asterisks). (B) The corresponding axial T2-weighted image shows normal white matter and basal ganglia signal at day of life 2. (C) Axial DWI image obtained on day of life 12 shows persistent and new areas of DWI signal abnormality. (D) The corresponding axial-T2 weighted image at day of life 12 demonstrates evolution of the injury with new abnormal signal hyperintensity in the basal ganglia (arrows) and subcortical white matter (arrowheads) indicating early cystic changes. (Images courtesy of Dr. Francisco Perez, Seattle Children’s Hospital, Seattle, WA.)

or oxidative phosphorylation. The dysfunctional mitochondria are unable to produce and supply enough energy to maintain adequate organ function. Brain, muscle, liver, heart, and adrenal glands are often significantly affected. Therefore, the most common presenting findings are symptoms of encephalopathy, including hypotonia, feeding difficulties, seizures, cardiomyopathy, liver dysfunction, and adrenal insufficiency. Laboratory evaluation

commonly reveals lactic acidosis and hypoglycemia, ketones can be normal or elevated, and liver dysfunction and secondary hyperammonemia might be present. Therapy remains symptomatic, and to date only very few defects can be improved with pharmacological intervention. Prognosis is in general poor, and survivors of the neonatal period often experience life-altering disabilities and epilepsy.

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Genetic Causes of Neonatal Encephalopathy

Neuronal Migration Defects—Lissencephaly

Genetic syndromes and disorders often also affect brain development. Genetic epilepsies (covered in Chapter 58) present within the first few days to weeks of life with symptoms resembling neonatal encephalopathy. Brain malformation presenting in the immediate neonatal period is often suspected during pregnancy, but alterations might go unrecognized until the newborn presents with neurologic symptoms after birth.

Lissencephaly is the description of a smooth brain appearance on MRI as a result of a simplified gyration pattern (pachygyria). Classic lissencephaly is commonly related to abnormalities in the LIS1 gene, which affects microtubular functioning and intracellular transport, but a variety of copy number variants and mutations in other genes (TUBA1A, TUBB2B, ACTB, ACTG1, DCX among others) have also been associated with classic lissencephaly.246 Depending on the degree of abnormal structures, patients may present in the neonatal period with seizures, hypotonia, and feeding difficulties.

Holoprosencephaly Holoprosencephaly is a divergence in brain development that results from an abnormal cleavage of the prosencephalon into the two hemispheres. The incidence is 1:16,000 live births. The three forms of holoprosencephaly are alobar, semilobar, and lobar holoprosencephaly. Alobar holoprosencephaly is the most severe form with a single common central ventricle and complete absence of hemispheric separation. The cortical structure is frequently malformed which results in intractable seizures. Semilobar holoprosencephaly is characterized by partial separation of the frontal and parietal lobes and partial separation of the deep gray matter nuclei. Lobar holoprosencephaly is the least severe form with incomplete separation of the frontal lobe and complete separation of the deep gray matter nuclei.243 Chromosomal abnormalities account for up to 50% of cases, and the prevalence is with 70% highest in trisomy 13 but is also relatively common seen in trisomy 18 and triploidy.243 Copy number variants include multiple described deletion and duplication syndromes often involving genes associated with holoprosencephaly and account for approximately 25% of cases. Mutations in the SHH (sonic hedgehog) gene and ZIC2 (encodes zinc finger protein 2) gene are the most common ­single-gene mutations described and account for approximately 10% of cases with holoprosencephaly,244 but multiple other genes have been associated with holoprosencephaly, and with the ability of advances in genetic testing, the list is constantly growing. Neonates with holoprosencephaly commonly present with distinguishing facial features such as cyclopia, single nares, and cleft palate. The severity of facial deformity correlates with the degree of holoprosencephaly. Heterotopias and abnormal cortical development often cause intractable seizures and other neurologic symptoms such as hypotonia and irritability. Furthermore, the development of the pituitary gland can be absent or incomplete, and structural defects of the thalamus can be seen, both of which may result in significant endocrinopathies, such as panhypopituitarism.243 The prognosis depends on the severity and form of holoprosencephaly. While newborns with isolated alobar holoprosencephaly often do not survive the first year of life, patients with milder forms can reach early adulthood. In cases of association with cytogenetic abnormalities, as few as 2% survive the first year of life.245

Neuronal Proliferation Defects Cortical dysplasia spectrum, including focal cortical dysplasia and hemimegalencephaly. Patients with significant involvement can present during the neonatal period, most commonly with intractable seizures and feeding difficulties. Since seizures are often refractory to pharmacological treatment, surgical options, including hemispherectomy can be offered.246

Postmigrational Development Defects— Polymicrogyria Polymicrogyria occurs at the end of neuronal migration and during cortical development and results in abnormal cortical folding and cortical disorganization which predisposes affected patients to seizures. The occurrence can be associated with congenital infections (cytomegalovirus), vascular anomalies, genetic syndromes (e.g., Zellweger syndrome, 22q11.2, or 1p36 deletion syndromes), and single-gene mutations.247 Clinical presentation depends on the extent and location, and affected neonates commonly present with seizures, abnormal tone, and feeding difficulties.

1p36 Deletion Syndrome This deletion syndrome is one of the most common deletion syndromes and affects 1:5000 newborns.248 This syndrome is characterized by terminal and interstitial deletions throughout the 30 Mb of DNA constituting the 1p36 region. The phenotype varies widely depending on the size and location of the deletion and involved genes. Multiple of the involved genes have a role in brain development, seizures, and congenital heart defects. Commonly seen clinical features include seizures, fetal akinesia, hypotonia, neurodevelopmental impairment, neuropsychiatric anomalies, brain anomalies (cortical development, hippocampal development, delayed myelination), ventriculomegaly, microcephaly, intellectual disability, developmental delay, vision problems, hearing loss, congenital heart defects, noncompaction cardiomyopathy, orofacial clefting, retrognathia, renal anomalies, and short stature.248–250 The majority of fetuses affected by this deletion syndrome have signs of perinatal distress, 59% of term-born infants need some form of resuscitation, and 18% present with cardiac arrest.251 The clinical presentation is consistent with neonatal encephalopathy in many cases and can even mimic HIE.

Hypophosphatasia Hypophosphatasia is a rare disease of defective mineralization, caused by mutations in the APLP gene, which encodes the enzyme tissue-nonspecific alkaline phosphatase (TNSALP). Inheritance, particularly in severe forms, is most commonly autosomal recessive but dominant forms have also been described.252 Two forms are present in the prenatal or perinatal period: the severe form and the benign form. The severe form is characterized by minimal to no bone mineralization, resulting skeletal deformities, lung hypoplasia, and seizures. The benign form is characterized by poor feeding, hypotonia, irritability, and seizures. Skeletal deformations

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are not consistently present in the benign form. The incidence of the severe form is estimated to be 0.2 to 1:100,000 live births and 1 to 5:10,000 live births for milder forms.252 Affected patients can present in the immediate neonatal period with symptoms of neonatal encephalopathy, resembling HIE.253 Seizures in affected patients occur secondary to disruption of pyridoxal-5′-phosphate (PLP) conversion to pyridoxal (PL) by TNSALP in neuronal cells. PL is able to cross the cell membrane and is intracellularly rephosphorylated to PLP, a cofactor in inhibiting excitatory neurotransmitter activity. Therefore, decreased central nervous system (CNS) PLP results in an increase in excitatory neurotransmitter activity and decreased seizure threshold. The seizures are commonly pyridoxine responsive, but the exact mechanism by which pyridoxine mitigates the intracellular PLP deficiency is incompletely understood. Diagnosis can be suspected when plasma PLP levels are elevated, alkaline phosphatase levels are decreased, and hypocalcemia is observed. Definitive diagnosis is made via molecular genetic testing. While the severe form was historically lethal in the neonatal period, enzyme replacement therapy with asfotase alfa is now available which can restore TNSALP levels and improve survival from 42–95% at 1 year and decrease ventilator dependence to 25% among survivors.254

Central Nervous System Infections and Neonatal Encephalopathy Bacterial Meningitis Bacterial meningitis is a serious infection of the CNS affecting the meninges surrounding the brain and spinal cord. Neonates are at greater risk of meningitis than other age groups because of the inefficiency of the alternative complement pathway, deficient migration and phagocytosis of neutrophils, and decreased T-cell and B-cell activity, leaving them at risk for infections with encapsulated bacteria.255 Streptococcus agalactiae, group B streptococcus (GBS), is responsible for 50% of meningoencephalitis in the term newborn period, followed by Escherichia coli (30–40%) and Listeria monocytogenes (5–7%).256 The incidence of bacterial meningitis is 0.3:1000 live births.257,258 Neurologic injury can result primarily from the direct insult of the pathogen or its toxin, or secondary to the inflammatory reaction associated with the acute infection, leading to impaired cerebral autoregulation, vasculitis including microthrombi, and oxidative injury. The blood-brain barrier becomes permeable which contributes further to the development of cytotoxic edema and compromise of cerebral perfusion.258 Clinical symptoms include temperature instability, apnea or bradycardia, hypotension, feeding difficulty, hepatic dysfunction, irritability alternating with lethargy, and seizures. Any neonate with signs of sepsis or unexplained neurologic symptoms should have a lumbar puncture to examine the CSF. Up to one-third of infants with negative blood cultures have positive CSF cultures, suggesting that cases of meningitis may be missed if lumbar punctures are not performed.259,260 No single CSF parameter can reliably exclude the presence of meningitis in a neonate.261 Real-time polymerase chain reaction (RT-PCR) technique allows for increased diagnostic accuracy compared to conventional culture,262,263 particularly after antibiotic treatment has already been initiated by identifying the DNA of bacterial components. Seizures occur in up to 40% of newborns with meningitis and therefore, monitoring with EEG is indicated.256 Cerebral abscesses

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develop in 13% of neonates with meningitis and should be considered with new seizures, signs of elevated intracranial pressure, or new focal neurologic signs, and brain imaging with contrast is essential for making the definitive diagnosis.264 Ventriculitis occurs in as many as 20% of neonates with meningitis and results in sequestration of infection to areas that are poorly accessible to systemic antimicrobial drugs.265 Inflammation of the ependymal lining of ventricles often obstructs CSF flow and can lead to hydrocephalus in up to 24% of infants. Imaging can give information about complications of meningitis. The choice of an antibiotic regimen should be based on the likely pathogen, ability to penetrate the blood-brain barrier, and the local patterns of antimicrobial drug sensitivities. Treatment duration is usually 14 to 21 days but depends on the identified organism and extent of infection (e.g., abscess formation). Most experts suggest a repeat lumbar puncture 2 to 3 days into treatment. Survivors of neonatal meningitis are at significant risk for white matter injury and neurodevelopmental sequelae. The most common sequelae of neonatal meningitis are motor deficits, including cerebral palsy, epilepsy, deafness, and neurodevelopmental impairment. In a prospective sample of more than 1500 neonates surviving to the age of 5 years, 55% had a normal outcome, 29% had mild neurodevelopmental impairment, and 16% had moderate to severe neurodevelopmental impairment. Among survivors of meningitis, motor disabilities (including cerebral palsy) were present in 8.1%, learning disability in 7.5%, epilepsy in 7.3%, speech and language problems in 15.6%, behavioral problems in 11.9%, vision problems in 13.7%, and hearing problems in 25.8%.266

Human Parechovirus In recent decades with the increased diagnostic ability of PCR techniques, human parechovirus (HPeV) meningoencephalitis, particularly type 3, has emerged as a newer virus identified in neonates presenting with seizures, poor feeding, irritability, and sepsis-like symptoms within the first weeks of life. CSF studies often show no to mild pleocytosis. HPeV RNA induces the release of inflammatory substances which compromise preoligodendrocytes and axons.109 In addition, inflammatory changes particularly in the periventricular white matter are characteristic findings.267 On MRI, diffuse abnormalities in the supratentorial white matter tracts with thalamic involvement268 and later evolution into cystic encephalomalacia have been described.269 Affected patients are at high-risk for impaired neurodevelopmental outcomes, including cerebral palsy, vision deficits, and developmental delay.269

Cytomegalovirus Cytomegalovirus (CMV) is the most common congenital viral infection, with an incidence of 6 to 7.5:1000 live births in the United States.270 Primary infection of the mother or reactivation of a latent infection at any gestational age can result in transmission of the virus to the fetus. Congenital infections may result in intrauterine growth restriction, thrombocytopenia, hydrops, jaundice, hepatosplenomegaly, microcephaly, periventricular calcification, seizures, and sensorineural hearing loss. About 40–58% of newborns who are symptomatic at birth go on to develop sequelae, including sensorineural hearing loss, intellectual disability, seizure disorder, cerebral palsy, visual deficits, or developmental delay.271,272 The diagnosis of CMV in the neonate can be made by PCR of urine, blood, or saliva.273 Antibody titers cannot reliably

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indicate the diagnosis, as maternal CMV immunoglobulin G crosses the placenta, and neonates mount weak immunoglobulin M responses. Audiologic assessment should be performed on all infants with congenital CMV infection, as sensorineural hearing loss (SNHL) affects greater than 70% of symptomatic newborns; 80% of those show SNHL early on but may be absent at birth and evolve over time.274 Therefore, frequent assessments throughout childhood are necessary to detect later onset hearing deterioration.275 SNHL can be ameliorated by early treatment with ganciclovir. One randomized study indicated that 84% of ganciclovir recipients either had improved hearing or maintained normal hearing between baseline and 6 months. In contrast, only 59% of control patients had improved or stable hearing.276 Results were even more encouraging when the study and control groups were compared for subsequent maintenance of normal hearing, as none of the ganciclovir recipients had a worsening in hearing between baseline and 6-month follow-up, compared with 41% of control patients. Furthermore, neonates treated with ganciclovir show fewer developmental delays at 6 and 12 months compared with untreated infants.277

Zika Virus The World Health Organization declared the rapidly spreading epidemic of Zika virus (ZIKV), an arbovirus (mosquito-borne) member of the Flaviviridae family, a “Public Health Emergency of International Concern” on February 1, 2016, based on emerging evidence that the virus might cause severe fetal brain injury,278 specifically severe microcephaly much more pronounced than in other congenital viral infections. While many different cell lines can be infected with ZIKV, neural progenitor cells (NPCs) are a direct target of ZIKV.279 Normal brain development is highly dependent on NPC differentiation, migration, and maturation. ZIKV-infected NPCs had increased cell death, downregulated proliferation, and altered neurosphere production.279–281 leading to microcephaly and congenital contractures.282 Children born with congenital Zika syndrome have significant long-term morbidities, including epilepsy in ~50%, hearing loss, blindness, hypotonia, and significant global neurodevelopmental delay.282

Toxoplasmosis The incidence of congenital toxoplasmosis is 0.1 to 1:1000 live births and is caused by Toxoplasma gondii.273 Human infection occurs via ingestion of contaminated meat or soil and can disseminate via the placenta to the fetus. Pregnant women are cautioned to avoid exposure to uncooked meat and cat feces. The immune response resulting from placental and fetal infection as

well as direct impact of the parasite causes leptomeningeal and cerebral necrosis, which can lead to dystrophic calcifications in the basal ganglia and periventricular region, white matter lesions, and subsequent development of hydrocephalus.283 Neonates can present with neurologic symptoms, including microcephaly, seizures, and feeding difficulties, in addition to clinical findings of systemic involvement, such as jaundice, hepatosplenomegaly, chorioretinitis, petechiae or purpura, and intrauterine growth restriction.284 Congenital toxoplasmosis treatment consists of pyrimethamine, sulfadiazine, and leucovorin for up to 1 year285 and is most effective in reducing CNS involvement and serious neurologic sequelae when initiated prenatally. Vision impairment due to macular involvement is the most common long-term ­ consequence in ­addition to cognitive and motor impairment.

Suggested Readings Douglas-Escobar M, Weiss MD. Hypoxic-ischemic encephalopathy: a review for the clinician. JAMA Pediatr. 2015;169(4):397–403. Glass HC. Hypoxic-Ischemic Encephalopathy and Other Neonatal Encephalopathies. Continuum (Minneap Minn). 2018;24(1, Child Neurology):57–71. Glass HC, Glidden D, Jeremy RJ, Barkovich AJ, Ferriero DM, Miller SP. Clinical Neonatal Seizures are Independently Associated with Outcome in Infants at Risk for Hypoxic-Ischemic Brain Injury. J Pediatr. 2009;155(3):318–323. Gunn AJ, Thoresen M. Hypothermic Neuroprotection. NeuroRx. 2006; 3(2):154–169. Hagberg H, Mallard C, Ferriero DM, et al. The role of inflammation in perinatal brain injury. Nat Rev Neurol. 2015;11(4):192–208. Kharoshankaya L, Stevenson NJ, Livingstone V, et  al. Seizure burden and neurodevelopmental outcome in neonates with hypoxic-ischemic encephalopathy. Dev Med Child Neurol. 2016;58(12):1242–1248. Kwon JM. Testing for Inborn Errors of Metabolism. Continuum (Minneap Minn). 2018;24(1, Child Neurology):37–56. Mitra S, Bale G, Meek J, Tachtsidis I, Robertson NJ. Cerebral Near Infrared Spectroscopy Monitoring in Term Infants With Hypoxic Ischemic Encephalopathy-A Systematic Review. Front Neurol. 2020; 11:393. Ostrander B, Bale JF. Congenital and perinatal infections. Handb Clin Neurol. 2019;162:133–153. Wassink G, Davidson JO, Lear CA, et al. A working model for hypothermic neuroprotection. J Physiol. 2018 Wassink G, Gunn ER, Drury PP, Bennet L, Gunn AJ. The mechanisms and treatment of asphyxial encephalopathy. Front Neurosci. 2014;8:40. Wood T, Thoresen M. Physiological responses to hypothermia. Semin Fetal Neonatal Med. 2015;20(2):87–96.

References The complete reference list is available at Elsevier eBooks+.

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268. Sarma A, Hanzlik E, Krishnasarma R, Pagano L, Pruthi S. Human Parechovirus Meningoencephalitis: Neuroimaging in the Era of Polymerase Chain Reaction-Based Testing. AJNR Am J Neuroradiol. 2019;40(8):1418–1421. 269. Verboon-Maciolek MA, Groenendaal F, Hahn CD, et al. Human parechovirus causes encephalitis with white matter injury in neonates. Ann Neurol. 2008;64(3):266–273. 270. Swanson EC, Schleiss MR. Congenital cytomegalovirus infection: new prospects for prevention and therapy. Pediatr Clin North Am. 2013;60(2):335–349. 271. Boppana SB, Pass RF, Britt WJ, Stagno S, Alford CA. Symptomatic congenital cytomegalovirus infection: neonatal morbidity and mortality. Pediatr Infect Dis J. 1992;11(2):93–99. 272. Dollard SC, Grosse SD, Ross DS. New estimates of the prevalence of neurological and sensory sequelae and mortality associated with congenital cytomegalovirus infection. Rev Med Virol. 2007;17(5): 355–363. 273. Ostrander B, Bale JF. Congenital and perinatal infections. Handb Clin Neurol. 2019;162:133–153. 274. Lanzieri TM, Leung J, Caviness AC, et al. Long-term outcomes of children with symptomatic congenital cytomegalovirus disease. J Perinatol. 2017;37(7):875–880. 275. Dahle AJ, Fowler KB, Wright JD, Boppana SB, Britt WJ, Pass RF. Longitudinal investigation of hearing disorders in children with congenital cytomegalovirus. J Am Acad Audiol. 2000;11(5): 283–290. 276. Kimberlin DW, Lin CY, Sanchez PJ, et  al. Effect of ganciclovir therapy on hearing in symptomatic congenital cytomegalovirus disease involving the central nervous system: a randomized, controlled trial. J Pediatr. 2003;143(1):16–25. 277. Oliver SE, Cloud GA, Sanchez PJ, et al. Neurodevelopmental outcomes following ganciclovir therapy in symptomatic congenital cytomegalovirus infections involving the central nervous system. J Clin Virol. 2009;46(Suppl 4):S22–26. 278. Gulland A. Zika virus is a global public health emergency, declares WHO. BMJ. 2016;352:i657. 279. Tang H, Hammack C, Ogden SC, et al. Zika Virus Infects Human Cortical Neural Progenitors and Attenuates Their Growth. Cell Stem Cell. 2016;18(5):587–590. 280. Li C, Xu D, Ye Q, et al. Zika Virus Disrupts Neural Progenitor Development and Leads to Microcephaly in Mice. Cell Stem Cell. 2016;19(5):672. 281. Garcez PP, Loiola EC, Madeiro da Costa R, et  al. Zika virus impairs growth in human neurospheres and brain organoids. Science. 2016;352(6287):816–818. 282. Vhp L, Aragao MM, Pinho RS, et  al. Congenital Zika Virus Infection: a Review with Emphasis on the Spectrum of Brain Abnormalities. Curr Neurol Neurosci Rep. 2020;20(11):49. 283. Frenkel LD, Gomez F, Sabahi F. The pathogenesis of microcephaly resulting from congenital infections: why is my baby’s head so small? Eur J Clin Microbiol Infect Dis. 2018;37(2):209–226. 284. Swisher CN, Boyer K, McLeod R. Congenital toxoplasmosis. The Toxoplasmosis Study Group. Semin Pediatr Neurol. 1994;1(1):4–25. 285. Pediatrics AAo Red Book: 2021-2024 Report of the Committee on Infectious Diseases. 32nd ed : American Academy of Pediatrics; 2021.

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MIHAI PUIA-DUMITRESCU AND SANDRA E. JUUL

from studies presenting associations rather than causation. Most cases lack definitive causes.

KEY POINTS • Perinatal stroke is a vascular event causing focal interruption of blood supply and can be categorized based on the vascular distribution of stroke (arterial or venous), age at the time of stroke, and age at presentation. • When a stroke is suspected in a neonate, neuroimaging is required for confirmation of diagnosis, followed by risk factor assessment and creation of a specific treatment plan. • In infants and neonates, cerebral sinus venous thrombosis usually presents with seizures and/or encephalopathy, and treatment varies from conservative neuromonitoring to anticoagulation. • Subdural and subarachnoid hemorrhages are both associated with vacuum/forceps-assisted deliveries and coagulopathy. Evaluation includes neuroimaging and monitoring, and outcomes vary based on location and size. • Vein of Galen malformation is the most common arteriovenous malformation of the newborn, often presenting with cardiac and/or neurologic complications. The clinical picture depends on the age at presentation.

Perinatal Stroke Epidemiology Ischemic perinatal strokes (IPS) are focal or multifocal arterial or venous infarctions occurring between 20 weeks’ gestation and 28 days’ postnatal life and are confirmed by neuroimaging or neuropathologic studies.1,2 The reported incidence varies between 1 in 1600 and 1 in 5000 live births,3,4 with likely higher incidence given that most of the studies were retrospective and magnetic resonance imaging (MRI) was not routinely used. The IPS is responsible for one-third of term and late-preterm children affected with hemiplegic cerebral palsy (CP).5 IPS is slightly more common in males and non-Hispanic black ethnicity when compared to whites and occurs most often in the left middle cerebral artery (MCA) distribution, with the most affected region being the left cerebral hemisphere. Risk factors for perinatal stroke include maternal primiparity, preeclampsia, prolonged rupture of membranes, chorioamnionitis, and cord anomalies.6 Presence of more than one of these risk factors can increase the probability of perinatal stroke to 1 in 200.3 Complicated deliveries involving emergency cesarean section or instrumentation have also been associated with IPS. Table 56.1 includes multiple proposed risk factors for perinatal stroke, mostly

Pathophysiology Ischemic perinatal stroke is pathological or neuroradiological evidence of focal arterial or venous infarction that occurred in the perinatal period. The pathogenesis of IPS is not well understood. Physiologic changes in the mother during pregnancy may cause a hypercoagulable and prothrombotic state. Fetuses are also at increased risk for developing clots as physiologic polycythemia leads to hyperviscosity, and there is a depressing anticoagulant activity present. These factors, coupled with the placenta having areas of reduced blood flow, increase the proclivity for thrombotic generation on the fetal side of the placenta. These thrombi will travel via the umbilical vein and are poised to pass through the patent foramen ovale to enter the systemic and, most importantly, the cerebral arteries. Other fetal conditions leading to increased risk of perinatal stroke include twin pregnancies, twin-to-twin transfusion, arteriovenous malformations, prolonged neck traction, and cardiac defects.7,8 Perinatal arterial stroke (PAS) lesions are usually singular (70%), involving the anterior circulation (71%), posterior circulation (7%), or both (20%).9 Strokes are most commonly left-sided (51% of all strokes, 73% of all anterior strokes), with 9% occurring on the right and 20% showing bilateral distribution.9 Classification of perinatal strokes can be categorized based on the vascular distribution of stroke (arterial or venous), age at the time of stroke, and age at presentation, with multiple authors using different terms to describe the IPS (Table 56.2).3,10–17 Because the timing of the vascular event leading to IPS is almost always unknown, it has been suggested that the classification of IPS be based on the gestational or postnatal age at diagnosis.

Clinical Presentation Diagnosing an infant with perinatal stroke is challenging in the newborn period. Most infants with PAS are asymptomatic at birth, and signs of acute illness are only seen in 25% of cases.9 Diffuse neurologic signs and symptoms are more common than focal signs, with the abnormal tone, apnea, and depressed level of consciousness more common than hemiparesis, which is usually absent or subtle in the neonate.18 Nonspecific symptoms include breathing and feeding difficulty. In the week following 843

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TABLE 56.1 Risk Factors for Perinatal Stroke

Maternal/Placental

Fetal/Neonatal

History of infertility Primiparity Pre-eclampsia Maternal diabetes Autoimmune disorders (e.g., systemic lupus erythematous) Maternal prothrombotic disorders Maternal antiphospholipid antibodies Coagulation disorders Anticardiolipin antibodies Drug use (cocaine, smoking) Maternal infection (chorioamnionitis) Maternal fever Trauma Placental abnormalities (e.g., thrombotic vasculopathy, emboli, inflammatory mediators)

Growth restriction Multiple gestation Twin to twin transfusion syndrome Trauma to great arteries at birth Intrapartum asphyxia Congenital heart disease Vascular anomalies Col4a1 and 2 mutations Infection (e.g., central nervous system, systemic) Thrombophilia Antiphospholipid antibodies Hypoglycemia Extracorporeal membrane oxygenation (ECMO) Other central catheterization

(From Dr. Catherine Amlie-Lefond and Dr. Nina Natarajan, Seattle Children’s Hospital, Seattle.)

birth, most newborns with perinatal arterial ischemic stroke (PAIS) become symptomatic, with the most prevalent symptom being seizures (large range, up to 70% to 90%). Approximately 12% of infants with PAS present with recurrent focal seizures with typical onset at 12 to 48 hours of age.4,13,19–21 Typical presentation for different forms of perinatal stroke is presented in Table 56.2.

Evaluation Assessment of the neonate with perinatal stroke includes neuroimaging (cranial ultrasound [CUS], head computed tomography [CT], brain MRI), electroencephalography, and echocardiogram to evaluate for congenital heart disease or intracardiac thrombus. Risk factors include a maternal history of autoimmune disorders, recurrent pregnancy loss, or thrombosis, and placental pathological examination and toxicology screens may also provide helpful information. Given that the most common presenting symptom is seizures, the work-up should begin with ruling out other etiologies of seizure such as hypoglycemia, hypocalcemia, electrolyte disorders, infection, and metabolic syndromes. In nonhemorrhagic stroke, MRI is considerably more sensitive than CUS or CT,

TABLE 56.2 Ischemic Perinatal Stroke Classification ARTERIAL DISTRIBUTION

Age at Diagnosis

Terminology

Description

Typical Presentation

Fetal

Fetal Arterial Stroke

Arterial ischemic stroke found on prenatal imaging.

Incidental finding of diffusion restriction on fetal MRI.

Preterm

Perinatal/Neonatal Arterial Ischemic Stroke (P/NAIS)

Arterial ischemic stroke in infants PT

Variable

Subdural

5–25

Between dura and arachnoid

FT > PT

Benign

Subarachnoid

1–2 FT 10 PT

Between arachnoid and pia

PT > FT

Benign

Cerebellar

0.1 FT 0.2 5 PT

Cerebellar hemispheres and/or vermis

PT > FT

Serious

Intraventricular

0.2 FT 15 PT

Within ventricles or including periventricular hemorrhagic infarction

PT > FT

Serious

Parenchymal

0.1 FT 2–4 PT

Cerebral parenchyma

FT > PT

Variable

FT, Full term; PT, preterm.

TABLE 56.4 Characteristics of Subdural and Subarachnoid Hemorrhages in Newborns

Subarachnoid Hemorrhage

Subdural Hemorrhage Epidemiology

25% (8%–45%) of all intracranial bleeds. Rate: between 2.9/10,000 for spontaneous deliveries to 21.3/10,000 when both vacuum and forceps are used in delivery65

Rate: 1.3 per 10,000 spontaneous vaginal deliveries, with a higher prevalence in vacuum and/or forcepsassisted deliveries65

Location

Below the dura mater and superior to the subarachnoid villi

Below the arachnoid mater, in the subarachnoid space

Pathophysiology

Trauma/tearing of veins and venous sinuses

Trauma to the veins of the subarachnoid villi

Risk factors

Vacuum- or forceps-assisted delivery; coagulopathy

Clinical presentation

Posterior fossa (infratentorial): severe hemorrhage with acute signs: stupor, lateral eye deviation, unequal pupils, nuchal rigidity, opisthotonos, bradycardia, respiratory compromise, apnea, or death. Insidious onset: may be clinically silent for days, followed by lethargy, full fontanel, irritability, respiratory abnormalities, apnea, bradycardia, and eye deviation. Hemorrhage over convexities: may have minimal or no symptoms; severe hemorrhage with acute signs: seizures, lateral eye deviation, nonreactive dilated pupil on the side of the hematoma, hemiparesis; insidious onset: may be clinically silent for months with initial presentation of increased head circumference (may occur if chronic subdural effusion)

Rarely of clinical significance and often asymptomatic May have early onset refractory seizures (usually on the second postnatal day) due to meningeal and cortical irritation or secondary hydrocephalus69

Outcomes

Less severe hemorrhages have variable prognoses: • ~80%–90% will have normal outcomes • ~10%–15% may have serious sequelae, including hydrocephalus requiring shunt placement • ~5% mortality Severe infratentorial hemorrhage has an extremely poor prognosis.

Very good prognosis in general. Frontal lobe or multiple hemorrhages are associated with higher rates of disability.63

68,69

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compares subdural and subarachnoid hemorrhages. Incidence, location, risk factors, presentation, and outcomes are presented side by side. Note that subdural hemorrhage is more frequent, and risk factors for both types are related to delivery mode, instrumentation, and the presence of coagulopathy.

Pathophysiology Subdural hemorrhages occur when bridging veins that carry blood through the dura mater to the arachnoid mater of the meninges are torn. This bleeding results in blood collecting below the dura and superior to the subarachnoid villi. Subarachnoid hemorrhage occurs when the veins of the subarachnoid villi are torn, resulting in a collection of blood in the subarachnoid space.

Clinical Presentation Subdural and subarachnoid hemorrhages often occur with no injury to the scalp or head to suggest intracranial injury. Thus, the hemorrhages may go unrecognized. Most neonates with subdural hemorrhage remain asymptomatic, and the lesion resolves without consequence. Clinical signs of subdural hemorrhage arise when there is a large-volume hemorrhage or if bleeding slowly continues over hours or even days, as in cases of bleeding disorders. Symptomatic subdural hemorrhages often present 24 to 48 hours after birth with nonspecific signs, including apnea, respiratory distress, altered neurologic state, or seizures. The most common clinical presentation of subarachnoid hemorrhage is seizures, as the blood from the hemorrhage can irritate the meninges and adjacent cortex. In some cases, a large subarachnoid hemorrhage irritates the meninges and causes a secondary impairment of cerebrospinal fluid (CSF) resorption resulting in hydrocephalus.

Evaluation The three primary brain imaging modalities—CUS, CT, and MRI—have different sensitivities for detecting hemorrhage. CUS is not the modality of choice for all forms of hemorrhage: it lacks the sensitivity of MRI and CT for identifying intracranial injury and hemorrhage (other than intraventricular) and is particularly limited for the detection of extra-axial hemorrhage (subdural, subarachnoid, and extradural).70,71 CUS also lacks sensitivity in detecting subarachnoid hemorrhage because of the normal increase in echogenicity around the periphery of the brain.72 CT was recommended in the 2002 American Academy of Neurology practice parameters for neonates with birth trauma and a low hematocrit or coagulopathy73 based on data from two small studies reporting on CT diagnoses of ICH leading to interventions.74,75 However, given the risks of radiation exposure associated with CT imaging, we suggest using MRI, when available, as the preferred method of evaluation. The use of MRI has the added benefit of better sensitivity for detecting parenchymal injury than CT. The development of more rapid MRI sequences to allow for shorter studies to detect cerebral hemorrhage should enhance physician comfort with this as a first-line technique. MRI is more effective than CT in the delineation of posterior fossa subdural hemorrhage. Detection of subdural hematoma by ultrasound scanning, although reported, generally is difficult and requires imaging through the mastoid fontanelle in addition to the anterior fontanelle. Moreover, even when these hematomas are detected, the extent and distribution of supratentorial lesions are

• Fig. 56.4  Tentorial Subdural Hemorrhage With Blood Layering Along

Both Leaves of the Tentorium and Posterior Falx. (Adapted from Castillo M, Fordham LA. MR of neurologically symptomatic newborns after vacuum extraction delivery. AJNR Am J Neuroradiol. 1995;16:816–818.)

usually demonstrated far better by MRI or CT, and infratentorial lesions are detected better by MRI. In addition, the vast majority of subdural hematomas are infratentorial, where ultrasound has even greater challenges in accurate diagnosis (Fig. 56.4). Similarly, the diagnosis of primary subarachnoid hemorrhage is usually made by MRI or CT and, on rare occasions, by ultrasound.71 On CT, the distinction between the normal, slightly increased attenuation in the regions of the falx and major venous sinuses and the increased attenuation caused by subarachnoid hemorrhage may be difficult. Sometimes, the possibility of primary subarachnoid hemorrhage is raised initially by the findings of an elevated number of red blood cells and an elevated protein content in the CSF, usually obtained for another purpose (e.g., to rule out meningitis). Exclusion of the relatively common (e.g., extension from subdural, cerebellar, or IVH) and uncommon (e.g., tumor, vascular lesions) causes of blood in the subarachnoid space is best done by MRI.

Management Most neonates with subdural hemorrhage can be managed symptomatically. Serial hematocrits and vital signs should be monitored frequently. In most cases, the blood collection will gradually resorb over weeks to months. In rare cases of large subdural hemorrhage that cause increased intracranial pressure or mass effect, neurosurgical drainage may be required. Seizures are treated with antiseizure medications. Neonates with subarachnoid hemorrhage should receive serial head circumference measurements and serial head ultrasounds to screen for hydrocephalus.

Outcomes The outcomes of neonates with subdural and subarachnoid hemorrhage are generally good. An estimated 80% of infants with

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subdural hemorrhages will have no disability. The location and extent of the subarachnoid hemorrhage can impact outcomes. Hemorrhages in the frontal lobe or in multiple areas of the brain are associated with higher rates of disability.

Vascular Malformations Arteriovenous malformations (AVM) are fast-flow vascular defects consisting of connections between the arterial and venous vessels through a fistula or a nidus.76 Intracranial AVM is the most common type of AVM, affecting 1/10,000 people.77 They represent 27% to 44% of the vascular malformations causing ICH.78,79 Up to 80% hemorrhagic presentation in children with AVMs has been reported.80 There is a wide range of vascular malformations; some are only found in children, and the lesion included here for discussion is the vein of Galen malformation.

Vein of Galen Malformation Epidemiology The vein of Galen aneurysmal malformation (VGAM) is a rare congenital vascular malformation that constitutes about one-third of the pediatric vascular and about 1% of all pediatric congenital anomalies.80–83 It is the most common arteriovenous malformation of the newborn, and the majority (approximately 60% of all pediatric cases of VGAM) are identified during the neonatal period.84 The overall incidence of VGAM is estimated to be 1 in 10,000 to 1 in 25,000 births.85

Pathophysiology The main feature of VGAM is the dilation of the vein of Galen (Fig. 56.5). Vein of Galen malformations arise because of direct arteriovenous communication between the arterial network and the median prosencephalic vein. During neurovascular development in fetal life, between 6 and 10 weeks of gestation, the choroid plexus is responsible for fluid circulation. During this period, the median prosencephalic vein of Markowski develops and is responsible for venous drainage. After the 10th week, the venous drainage from the choroid plexus is the role of the newly developed paired internal cerebral veins. They terminate in the posterior portion of the Markowski vein, which normally disappears by the 11th week, and remnants of it form the vein of Galen.86–88 The

A

B

Neonatal Neurovascular Disorders

851

formation of the VGAM is then promoted by the enlargement of the median prosencephalic vein of Markowski, and this is consistent with the variation in drainage through either a normal sinus or a persistent falcine sinus, a normally transient fetal vessel.89 The arterial supply to the dilated vein of Galen is the posterior choroidal artery, the anterior cerebral (pericallosal) artery, the middle cerebral artery, the anterior choroidal artery, and the posterior cerebral artery.84,87,90 There are two classification systems that are used in clinical practice, proposed by Lasjaunias and Yasargil (Table 56.5). The Lasjaunias system includes two types of aneurysmal malformations: a primary (true) vein of Galen malformation that could be mural or choroidal form, and a secondary type resulting from a deep AVM that drains into the vein of Galen.91 A different classification proposed by Yasargil et al. is based on the arterial feeder patterns of drainage into the vein of Galen and is divided into four types.92 Type I includes direct fistulas between the pericallosal and posterior cerebral arteries and the vein of Galen, type II is made up of numerous fistulas between the thalamoperforators and the vein of Galen, type III consists of multiple fistulous connections from different vessels having characteristics of type I and II malformations, and type IV has adjacent AVMs that drain into the vein of Galen and cause a secondary aneurysmal venous dilatation. Distinguishing between true VGAM (where the vein of Markowski is the pathological vessel) and AVMs that can cause aneurysmal dilatation of the vein of Galen is extremely important in order to describe the features, natural history, and treatment options of VGAMs.93 Based on the two classifications used in clinical practice, true VGAMs are represented by the primary malformation (Lasjaunias classification) and types I to III malformations (Yasargil classification). In contrast, the secondary vein of Galen malformations (Lasjaunias classification) and type IV malformations (Yasargil classification) are parenchymal AVMs that generate secondary dilatation of the vein of Galen (Table 56.5). The pathological findings observed with VGAM consist of a variety of ischemic, hemorrhagic, and mass effects of the malformation.86,87,94,95

Cardiovascular Findings The arteriovenous connection present in the VGAM is a highflow, low resistance system that causes an increase in cardiac output and high-output heart failure. Heart failure is usually present shortly after birth after the loss of the low-resistance

C

• Fig. 56.5  Images From a Term Newborn With Vein of Galen Malformation. (A, B) Note large flow void on the T2-weighted images. (C) Corresponding angiogram. (Images courtesy Dr. Bob McKinstry.)

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TABLE 56.5 Classification of Vein of Galen Aneurysmal Malformation

Classification

True VGAM

Lasjaunias91

Primary malformation Mural type: • Fistulae in the subarachnoid space in the wall of the median prosencephalic vein • Presents later (infant) with hydrocephalus

Yasargil92

Secondary Aneurysmal Dilation of Vein of Galen Due to Parenchymal Arteriovenous Malformations (AVM)

Choroidal type: • Multiple feeders, including: thalamoperforating, choroidal and pericallosal arteries are located in the subarachnoid space in the choroidal fissure • Presents earlier (neonate) with more severe shunts

Type I: fistulas between the anterior and posterior pericallosal and posterior cerebral arteries and the vein of Galen Type II: multiple fistulas between the thalamoperforator network that lies between the arterial feeders and the vein of Galen

Secondary malformation: deep AVM that drains into the vein of Galen

Type IV: adjacent AVMs of the mesencephalon that drain into the vein of Galen and cause a secondary aneurysmal venous dilatation

Type III: high-flow type I or II malformations with multiple fistulous connections from different vessels VGAM, Vein of Galen aneurysmal malformation

placental circulation. After birth, blood flow increases significantly through the VGAM.96 As much as 80% of the left ventricular output may be supplied to the brain in severe cases.97 The high cardiac output, low diastolic pressure, increased intraventricular pressure, and impaired coronary blood flow contribute to myocardial ischemia, making the cardiac failure multifactorial and challenging to manage. The intracranial “steal” caused by the absent or reversed diastolic cerebral blood flow and congestive heart failure result in cerebral ischemia.97–99 The increased venous return and left to right shunts through the patent foramen ovale and the patent ductus arteriosus can lead to and worsen pulmonary hypertension.100,101

Neurologic Findings The neuropathological findings in the VGAM include impaired cortical development, cerebral atrophy, hemorrhagic lesions (thrombosis of the dilated vein of Galen with hemorrhagic infarction and or intracerebral hemorrhage, vascular rupture, and massive hemorrhage), or hydrocephalus (from compression and obstruction of the cerebral aqueduct or from the high venous pressure in the medullary veins that prevents reabsorption of cerebrospinal fluid due to venous hypertension).90,95,99,101–105

Clinical Presentation The clinical picture of patients with VGAM depends on the age at presentation and is commonly characterized by cardiac and neurologic complications. About 44% of the cases are detected in the neonatal period, and the presentation varies with the size of the malformation. The vast majority of the neonates with VGAM present with high-output cardiac failure, pulmonary hypertension, and, in more severe cases, multiorgan system failure.82,84,88,100,106–110 The timing of presentation and symptoms are dependent on the size of the aneurysm (the greater the size, the larger the degree of shunting through the lesion, and the earlier the presentation). Neonates tend to present clinical signs and symptoms in the first

few hours of age that may worsen over the first 3 days of life. Some of the features present with the VGAM are the bounding carotid pulses with or without prominent peripheral pulses and the continuous cranial bruit over the posterior fontanelle and cranium. Cyanosis may be a presenting sign seen in these patients, and a diagnosis of congenital cyanotic heart disease is often in the differential. Due to congestive heart failure and diastolic flow reversal in the descending aorta, some infants may present with hepatic or renal insufficiency and prerenal azotemia.96,99 The clinical presentation differs in infants and older children. Infants present most commonly with hydrocephalus (about 15% of the overall presentation for VGAM), and children present most commonly with neurologic signs and symptoms like headaches, focal neurologic deficits, and syncope.

Evaluation The antepartum diagnosis for VGAM can be made during the routine prenatal screening ultrasound or with the fetal MRI, which is increasingly used for more detailed characterization prenatally. When a dilated structure is visualized posterior to the third ventricle, pulsatile flow within it helps differentiate VGAMs from other midline cystic lesions.111–114 However, based on prenatal imaging, the clinical course in neonates with VGAM has been difficult to predict. Every neonate with prenatally suspected or diagnosed VGAM should be admitted to the neonatal intensive care unit for complete evaluation and management, including weight and head circumference. Cardiac evaluation, including echocardiography, renal and liver function tests, and head imaging, should be part of the initial evaluation. When there is no prenatal data or suspicion, the diagnosis of VGAM should be considered in any neonates with high-output congestive heart failure, unexplained intracranial hemorrhage, or hydrocephalus. In this scenario, the initial evaluation is performed using cranial ultrasonography with a Doppler.115,116 The use of ultrasound adds important value to the follow-up of patients after treatment to assess the status of the shunt and the presence of thrombosis.

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Another useful imaging method to detect a mass, mostly in older infants, is CT.117 When used in combination with angiography, a better understanding of the vascular structures can be mapped. CT angiography can be part of the planning process for intervention. MRI can be used to demonstrate the location, and the vascular components, including the status of venous drainage. The location and detection of major arterial vessels feeding the fistula are better identified on MRI than CT. Angiography remains the gold standard imaging modality to evaluate and define the architecture of the VGAM, including size, location, arterial feeders, and the dynamic aspect of venous drainage, which helps with decisions regarding intervention.

Management The management of the patient with significant VGAM manifesting in the neonatal period remains a big challenge. Timing and approach to treatment depend on the patient’s age, the severity of congestive heart failure, and the architecture of the lesion at the time of diagnosis.118 Overall, the management approach, when indicated, is divided into medical, endovascular, or neurosurgical interventions. The main therapy goal is to minimize congestive heart failure using different therapeutic approaches that may include combinations between systemic vasodilators and low-dose dopamine.119 Embolization (transvenous or transarterial approach) results in better survival compared to surgical techniques and are thus the preferred approach for intervention.120 For many years, to evaluate the risks and benefits of interventions, clinicians used the Bicêtre neonatal evaluation score.93 A Bicêtre score of less than 8 out of 21 is historically associated with a near-fatal prognosis. Hence, these neonates are not considered good candidates for emergent embolization. A score between 8 and 12 characterizes neonates who are most likely to benefit from emergent embolization. A score greater than 12 suggests the infant can be managed medically and does not require embolization. In recent years, many centers have moved away from using Bicêtre score cutoffs as it is possible for some neonates with scores less than 8 to have good outcomes from embolization. Embolization is considered the main approach to treatment and can be performed by an arterial transarterial approach using liquid adhesive agents or micro coils or by a transvenous approach typically using the umbilical or femoral veins.89,93,96,102,120,121 Even though microsurgery is no longer a primary treatment strategy, neurosurgical intervention plays an important role in persistent hydrocephalus, intracranial bleeds, hematomas, or when embolization fails.90,122,123

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mortality remain high.90,106,108,124,125 As the treatment evolves and becomes more centralized, the spectrum of impairments for survivors with poor outcomes has to be better characterized. One of the largest, most recent cohorts from the UK (n = 85) reported that more than one‐third of newborns with a vein of Galen malformation did not survive and that outcome was good in about half of the survivors.124 Two other meta‐analyses described poor clinical outcomes or death in almost one‐half of neonates with VGAM.126,127 Prognosis depends on the size of the malformation, age at diagnosis, the severity of congestive heart failure, the degree of brain injury, and the success of embolization. Neonates with untreated VGAM that survive the neonatal period with medically managed congestive cardiac failure are at increased risk for developmental delays. Later presentations include failure to thrive, seizures, focal neurological deficits, intracranial bleeds, and progressive hydrocephalus.90,99,101,102,128,129

Acknowledgment The authors would like to acknowledge Dr. Ryan McAdams, Christopher Traudt, Jeffery Neil, and Terrie Inder for their work on this topic in the previous edition of this textbook. We would also like to acknowledge Dr. Catherine Amlie-Lefond and Dr. Nina Natarajan for their assistance with this chapter.

Suggested Readings Arko L, et al. Fetal and neonatal MRI predictors of aggressive early clinical course in vein of Galen malformation. AJNR Am J Neuroradiol. 2020;41(6):1105–1111. Berfelo FJ, et al. Neonatal cerebral sinovenous thrombosis from symptom to outcome. Stroke. 2010;41(7):1382–1388. Gailloud P, et al. Diagnosis and management of vein of Galen aneurysmal malformations. J Perinatol. 2005;25(8):542–551. Raju TN, Nelson KB, Ferriero D, Lynch JK. Participants N-NPSW. Ischemic perinatal stroke: summary of a workshop sponsored by the National Institute of Child Health and Human Development and the National Institute of Neurological Disorders and Stroke. Pediatrics. 2007;120(3):609–616. Roach ES, Golomb MR, Adams R, et  al. Management of stroke in infants and children: a scientific statement from a Special Writing Group of the American Heart Association Stroke Council and the Council on Cardiovascular Disease in the Young. Stroke. 2008;39(9): 2644–2691. Siddiq I, Armstrong D, Surmava A-M, et  al. Utility of neurovascular imaging in acute neonatal arterial ischemic stroke. J Pediatr. 2017; 188:110–114.

Outcomes The development and implementation of endovascular interventions have been critical in improving outcomes in patients with VGAM, and despite therapeutic techniques, morbidity and

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References The complete reference list is available at Elsevier eBooks+.

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References 1. Raju TN, et al. Ischemic perinatal stroke: summary of a workshop sponsored by the National Institute of Child Health and Human Development and the National Institute of Neurological Disorders and Stroke. Pediatrics. 2007;120(3):609–616. 2. van der Aa NE, et al. Neonatal stroke: a review of the current evidence on epidemiology, pathogenesis, diagnostics and therapeutic options. Acta Paediatr. 2014;103(4):356–364. 3. Lee J, et al. Maternal and infant characteristics associated with perinatal arterial stroke in the infant. JAMA. 2005;293(6):723–729. 4. Laugesaar R, et al. Acutely and retrospectively diagnosed perinatal stroke: a population-based study. Stroke. 2007;38(8):2234–2240. 5. Wu YW, et al. Neuroimaging abnormalities in infants with congenital hemiparesis. Pediatr Neurol. 2006;35(3):191–196. 6. Harteman JC, et  al. Risk factors for perinatal arterial ischaemic stroke in full-term infants: a case-control study. Arch Dis Child Fetal Neonatal Ed. 2012;97(6):F411–F416. 7. Golomb MR, Williams LS, Garg BP. Perinatal stroke in twins without co-twin demise. Pediatr Neurol. 2006;35(1):75–77. 8. Benders MJ, et  al. Maternal and infant characteristics associated with perinatal arterial stroke in the preterm infant. Stroke. 2007; 38(6):1759–1765. 9. Kirton A, et  al. Symptomatic neonatal arterial ischemic stroke: the International Pediatric Stroke Study. Pediatrics. 2011;128(6): e1402–e1410. 10. Chabrier S, et al. New insights (and new interrogations) in perinatal arterial ischemic stroke. Thromb Res. 2011;127(1):13–22. 11. Ramaswamy V, et al. Perinatal stroke in term infants with neonatal encephalopathy. Neurology. 2004;62(11):2088–2091. 12. Lynch JK, et  al. Report of the National Institute of Neurological Disorders and Stroke workshop on perinatal and childhood stroke. Pediatrics. 2002;109(1):116–123. 13. Lee J, et al. Predictors of outcome in perinatal arterial stroke: a population-based study. Ann Neurol. 2005;58(2):303–308. 14. Golomb MR. The contribution of prothrombotic disorders to peri- and neonatal ischemic stroke. Semin Thromb Hemost. 2003;29(4):415–424. 15. Cowan FM, de Vries LS. The internal capsule in neonatal imaging. Semin Fetal Neonatal Med. 2005;10(5):461–474. 16. Ozduman K, et al. Fetal stroke. Pediatr Neurol. 2004;30(3):151–162. 17. Golomb MR, et  al. Presumed pre- or perinatal arterial isch emic stroke: risk factors and outcomes. Ann Neurol. 2001;50(2): 163–168. 18. Trauner DA, et al. Neurologic profiles of infants and children after perinatal stroke. Pediatr Neurol. 1993;9(5):383–386. 19. Sreenan C, Bhargava R, Robertson CM. Cerebral infarction in the term newborn: clinical presentation and long-term outcome. J Pediatr. 2000;137(3):351–355. 20. Lee C-C, et  al. Clinical manifestations, outcomes, and etiologies of perinatal stroke in Taiwan: comparisons between ischemic, and hemorrhagic stroke based on 10-year experience in a single institute. Pediatr Neonatol. 2017;58(3):270–277. 21. Ferriero DM. Neonatal brain injury. N Engl J Med. 2004;351(19): 1985–1995. 22. Lee S, et al. Pathways for neuroimaging of neonatal stroke. Pediatr Neurol. 2017;69:37–48. 23. Siddiq I, et  al. Utility of neurovascular imaging in acute neonatal arterial ischemic stroke. J Pediatr. 2017;188:110–114. 24. Govaert P, Smith L, Dudink J. Diagnostic management of neonatal stroke. Semin Fetal Neonatal Med. 2009;14(5):323–328. 25. Estan J, Hope P. Unilateral neonatal cerebral infarction in full term infants. Arch Dis Child Fetal Neonatal Ed. 1997;76(2):F88–F93. 26. Kenet G, et  al. Impact of thrombophilia on risk of arterial ischemic stroke or cerebral sinovenous thrombosis in neonates and children: a systematic review and meta-analysis of observational studies. Circulation. 2010;121(16):1838–1847.

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27. Monagle P, et al. Antithrombotic therapy in neonates and children: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008;133(6 Suppl): 887S–968S. 28. Roach ES, et  al. Management of stroke in infants and children: a scientific statement from a Special Writing Group of the American Heart Association Stroke Council and the Council on Cardiovascular Disease in the Young. Stroke. 2008;39(9):2644–2691. 29. Cnossen MH, van Ommen CH, Appel IM. Etiology and treatment of perinatal stroke: a role for prothrombotic coagulation factors? Semin Fetal Neonatal Med. 2009;14(5):311–317. 30. Arrigoni F, et  al. Deep medullary vein involvement in neonates with brain damage: an MR imaging study. AJNR Am J Neuroradiol. 2011;32(11):2030–2036. 31. Clancy R, et al. Focal motor seizures heralding stroke in full-term neonates. Am J Dis Child. 1985;139(6):601–606. 32. Golomb MR. Outcomes of perinatal arterial ischemic stroke and cerebral sinovenous thrombosis. Semin Fetal Neonatal Med. 2009;14(5):318–322. 33. Kurnik K, et al. Recurrent thromboembolism in infants and children suffering from symptomatic neonatal arterial stroke: a prospective follow-up study. Stroke. 2003;34(12):2887–2892. 34. Osborne JP, et al. The underlying etiology of infantile spasms (West syndrome): information from the United Kingdom Infantile Spasms Study (UKISS) on contemporary causes and their classification. Epilepsia. 2010;51(10):2168–2174. 35. Golomb MR, Garg BP, Williams LS. Outcomes of children with infantile spasms after perinatal stroke. Pediatr Neurol. 2006;34(4): 291–295. 36. Fox CK, et al. Neonatal seizures triple the risk of a remote seizure after perinatal ischemic stroke. Neurology. 2016;86(23):2179–2186. 37. Fox CK, et al. Prolonged or recurrent acute seizures after pediatric arterial ischemic stroke are associated with increasing epilepsy risk. Dev Med Child Neurol. 2017;59(1):38–44. 38. Ricci D, et al. Cognitive outcome at early school age in term-born children with perinatally acquired middle cerebral artery territory infarction. Stroke. 2008;39(2):403–410. 39. Mercuri E, et al. Neonatal cerebral infarction and neuromotor outcome at school age. Pediatrics. 2004;113(1 Pt 1):95–100. 40. Kirton A, et al. Quantified corticospinal tract diffusion restriction predicts neonatal stroke outcome. Stroke. 2007;38(3):974–980. 41. van der Aa NE, et al. Neonatal neuroimaging predicts recruitment of contralesional corticospinal tracts following perinatal brain injury. Dev Med Child Neurol. 2013;55(8):707–712. 42. Kirton A, et al. Presumed perinatal ischemic stroke: vascular classification predicts outcomes. Ann Neurol. 2008;63(4):436–443. 43. Kirton A, et  al. Risk factors and presentations of periventricular venous infarction vs arterial presumed perinatal ischemic stroke. Arch Neurol. 2010;67(7):842–848. 44. Chabrier S, et al. Multimodal outcome at 7 years of age after neonatal arterial ischemic stroke. J Pediatr. 2016;172:156–161. e3. 45. deVeber G, et  al. Cerebral sinovenous thrombosis in children. N Engl J Med. 2001;345(6):417–423. 46. Berfelo FJ, et  al. Neonatal cerebral sinovenous thrombosis from symptom to outcome. Stroke. 2010;41(7):1382–1388. 47. Devasagayam S, et al. Cerebral venous sinus thrombosis incidence is higher than previously thought: a retrospective population-based study. Stroke. 2016;47(9):2180–2182. 48. Suppiej A, et al. Paediatric arterial ischaemic stroke and cerebral sinovenous thrombosis. First report from the Italian Registry of Pediatric Thrombosis (R. I. T. I., Registro Italiano Trombosi Infantili). Thromb Haemost. 2015;113(6):1270–1277. 49. Sirachainan N, et al. Incidences, risk factors and outcomes of neonatal thromboembolism. J Matern Fetal Neonatal Med. 2018;31(3): 347–351. 50. Sébire G, et al. Cerebral venous sinus thrombosis in children: risk factors, presentation, diagnosis and outcome. Brain. 2005;128(Pt 3): 477–489.

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51. Schaller B, Graf R. Cerebral venous infarction: the pathophysiological concept. Cerebrovasc Dis. 2004;18(3):179–188. 52. Moharir MD, et al. A prospective outcome study of neonatal cerebral sinovenous thrombosis. J Child Neurol. 2011;26(9):1137–1144. 53. Miller E, et al. Color Doppler US of normal cerebral venous sinuses in neonates: a comparison with MR venography. Pediatr Radiol. 2012;42(9):1070–1079. 54. Wu YW, et al. Intraventricular hemorrhage in term neonates caused by sinovenous thrombosis. Ann Neurol. 2003;54(1):123–126. 55. Nwosu ME, et  al. Neonatal sinovenous thrombosis: presentation and association with imaging. Pediatr Neurol. 2008;39(3):155–161. 56. Moharir MD, et al. Anticoagulants in pediatric cerebral sinovenous thrombosis: a safety and outcome study. Ann Neurol. 2010;67(5): 590–599. 57. Lebas A, et  al. EPNS/SFNP guideline on the anticoagulant treatment of cerebral sinovenous thrombosis in children and neonates. Eur J Paediatr Neurol. 2012;16(3):219–228. 58. von Vajna E, Alam R, So TY. Current clinical trials on the use of direct oral anticoagulants in the pediatric population. Cardiol Ther. 2016;5(1):19–41. 59. Capecchi M, Abbattista M, Martinelli I. Cerebral venous sinus thrombosis. J Thromb Haemost. 2018;16(10):1918–1931. 60. Wasay M, et  al. Cerebral venous sinus thrombosis in children: a multicenter cohort from the United States. J Child Neurol. 2008; 23(1):26–31. 61. Kenet G, et al. Risk factors for recurrent venous thromboembolism in the European collaborative paediatric database on cerebral venous thrombosis: a multicentre cohort study. Lancet Neurol. 2007;6(7):595–603. 62. Arauz A, et al. Time to recanalisation in patients with cerebral venous thrombosis under anticoagulation therapy. J Neurol Neurosurg Psychiatry. 2016;87(3):247–251. 63. Gupta SN, Kechli AM, Kanamalla US. Intracranial hemorrhage in term newborns: management and outcomes. Pediatr Neurol. 2009;40(1):1–12. 64. Hanigan WC, et al. Symptomatic intracranial hemorrhage in fullterm infants. Childs Nerv Syst. 1995;11(12):698–707. 65. Towner D, et al. Effect of mode of delivery in nulliparous women on neonatal intracranial injury. N Engl J Med. 1999;341(23):1709–1714. 66. Whitby EH, et al. Frequency and natural history of subdural haemorrhages in babies and relation to obstetric factors. Lancet. 2004; 363(9412):846–851. 67. Rooks VJ, et  al. Prevalence and evolution of intracranial hemorrhage in asymptomatic term infants. AJNR Am J Neuroradiol. 2008; 29(6):1082–1089. 68. Looney CB, et  al. Intracranial hemorrhage in asymptomatic neonates: prevalence on MR images and relationship to obstetric and neonatal risk factors. Radiology. 2007;242(2):535–541. 69. Barker S. Subdural and primary subarachnoid hemorrhages: a case study. Neonatal Netw. 2007;26(3):143–151. 70. Pfister RH, et  al. The Vermont Oxford Neonatal Encephalopathy Registry: rationale, methods, and initial results. BMC Pediatr. 2012;12:84. 71. Barnette AR, et  al. Neuroimaging in the evaluation of neonatal encephalopathy. Pediatrics. 2014;133(6):e1508–e1517. 72. Shackelford GD, Volpe JJ. Cranial ultrasonography in the evaluation of neonatal intracranial hemorrhage and its complications. J Perinat Med. 1985;13(6):293–304. 73. Ment LR, et al. Practice parameter: neuroimaging of the neonate: report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology. 2002;58(12):1726–1738. 74. Odita JC, Hebi S. CT and MRI characteristics of intracranial hemorrhage complicating breech and vacuum delivery. Pediatr Radiol. 1996;26(11):782–785. 75. Perrin RG, et  al. Management and outcomes of posterior fossa subdural hematomas in neonates. Neurosurgery. 1997;40(6):1190– 1199. discussion 1199-200.

76. Couto JA, et  al. Somatic MAP2K1 mutations are associated with extracranial arteriovenous malformation. Am J Hum Genet. 2017; 100(3):546–554. 77. Berman MF, et al. The epidemiology of brain arteriovenous malformations. Neurosurgery. 2000;47(2):389–396. discussion 397. 78. Griffiths PD, Beveridge CJ, Gholkar A. Angiography in non traumatic brain haematoma. An analysis of 100 cases. Acta Radiol. 1997;38(5):797–802. 79. Kumar R, Shukla D, Mahapatra AK. Spontaneous intracranial hemorrhage in children. Pediatr Neurosurg. 2009;45(1):37–45. 80. Kondziolka D, et al. Arteriovenous malformations of the brain in children: a forty year experience. Can J Neurol Sci. 1992;19(1): 40–45. 81. Casasco A, et  al. Percutaneous transvenous catheterization and embolization of vein of galen aneurysms. Neurosurgery. 1991;28(2): 260–266. 82. Gold A, Ransohoff J, Carter S. Vein of galen malformation. Acta Neurol Scand Suppl. 1964;40(SUPPL 11):1–31. 83. Lasjaunias P, et al. Dilatation of the vein of Galen. Anatomoclinical forms and endovascular treatment apropos of 14 cases explored and/ or treated between 1983 and 1986. Neurochirurgie. 1987;33(4): 315–333. 84. Hoffman HJ, et al. Aneurysms of the vein of Galen. Experience at The Hospital for Sick Children, Toronto. J Neurosurg. 1982;57(3): 316–322. 85. Li A-H, Armstrong D, terBrugge KG. Endovascular treatment of vein of Galen aneurysmal malformation: management strategy and 21-year experience in Toronto. J Neurosurg Pediatr. 2011;7(1): 3–10. 86. Lasjaunias P, et al. Vein of Galen malformation. Endovascular management of 43 cases. Childs Nerv Syst. 1991;7(7):360–367. 87. Raybaud CA, Strother CM, Hald JK. Aneurysms of the vein of Galen: embryonic considerations and anatomical features relating to the pathogenesis of the malformation. Neuroradiology. 1989; 31(2):109–128. 88. Horowitz MB, et al. Vein of Galen aneurysms: a review and current perspective. AJNR Am J Neuroradiol. 1994;15(8):1486–1496. 89. Pearl M, et  al. Endovascular management of vein of Galen aneurysmal malformations. Influence of the normal venous drainage on the choice of a treatment strategy. Childs Nerv Syst. 2010;26(10): 1367–1379. 90. Gailloud P, et al. Diagnosis and management of vein of galen aneurysmal malformations. J Perinatol. 2005;25(8):542–551. 91. Lasjaunias P, et al. Treatment of vein of Galen aneurysmal malformation. J Neurosurg. 1989;70(5):746–750. 92. Yasargil MG, et al. Arteriovenous malformations of vein of Galen: microsurgical treatment. Surg Neurol. 1976;3:195–200. 93. Lasjaunias PL, et  al. The management of vein of Galen aneurysmal malformations. Neurosurgery. 2006;59(5 Suppl 3):S184–S194. ­discussion S3-13. 94. Recinos PF, et al. Vein of Galen malformations: epidemiology, clinical presentations, management. Neurosurg Clin N Am. 2012;23(1): 165–177. 95. Norman MG, Becker LE. Cerebral damage in neonates resulting from arteriovenous malformation of the vein of Galen. J Neurol Neurosurg Psychiatry. 1974;37(3):252–258. 96. Hoang S, et al. Vein of Galen malformation. Neurosurg Focus. 2009; 27(5):E8. 97. King WA, et al. Management of vein of Galen aneurysms. Combined surgical and endovascular approach. Childs Nerv Syst. 1989;5(4): 208–211. 98. Pellegrino PA, et al. Congestive heart failure secondary to cerebral arterio-venous fistula. Childs Nerv Syst. 1987;3(3):141–144. 99. Krings T, Geibprasert S, Terbrugge K. Classification and endovascular management of pediatric cerebral vascular malformations. Neurosurg Clin N Am. 2010;21(3):463–482.

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100. Chevret L, et al. Severe cardiac failure in newborns with VGAM. Prognosis significance of hemodynamic parameters in neonates presenting with severe heart failure owing to vein of Galen arteriovenous malformation. Intensive Care Med. 2002;28(8):1126–1130. 101. Alvarez H, et  al. Vein of galen aneurysmal malformations. Neuroimaging Clin N Am. 2007;17(2):189–206. 102. Khullar D, Andeejani AM, Bulsara KR. Evolution of treatment options for vein of Galen malformations. J Neurosurg Pediatr. 2010;6(5):444–451. 103. Zerah M, et al. Hydrodynamics in vein of Galen malformations. Childs Nerv Syst. 1992;8(3):111–117. discussion 117. 104. Yamashita Y, et al. Neuroradiological and pathological studies on neonatal aneurysmal dilation of the vein of Galen. J Child Neurol. 1990;5(1):45–48. 105. Wong FY, et  al. Hemodynamic disturbances associated with ­endovascular embolization in newborn infants with vein of Galen malformation. J Perinatol. 2006;26(5):273–278. 106. Lylyk P, et al. Therapeutic alternatives for vein of Galen vascular malformations. J Neurosurg. 1993;78(3):438–445. 107. Garcia-Monaco R, et al. Congestive cardiac manifestations from cerebrocranial arteriovenous shunts. Endovascular management in 30 children. Childs Nerv Syst. 1991;7(1):48–52. 108. Friedman DM, et  al. Recent improvement in outcome using transcatheter embolization techniques for neonatal aneurysmal malformations of the vein of Galen. Pediatrics. 1993;91(3): 583–586. 109. Lasjaunias P, et  al. Vein of Galen aneurysmal malformations. Report of 36 cases managed between 1982 and 1988. Acta Neurochir (Wien). 1989;99(1-2):26–37. 110. Kassem MW, et al. Imaging characteristics of dural arteriovenous fistulas involving the vein of Galen: a comprehensive review. Cureus. 2018;10(2):e2180. 111. Gupta AK, Varma DR. Vein of Galen malformations: review. Neurol India. 2004;52(1):43–53. 112. Nuutila M, Saisto T. Prenatal diagnosis of vein of Galen malformation: a multidisciplinary challenge. Am J Perinatol. 2008;25(4): 225–227. 113. Vintzileos AM, et al. Prenatal ultrasonic diagnosis of arteriovenous malformation of the vein of Galen. Am J Perinatol. 1986;3(3): 209–211. 114. Arko L, et  al. Fetal and neonatal MRI predictors of aggressive early clinical course in vein of Galen malformation. AJNR Am J Neuroradiol. 2020;41(6):1105–1111.

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115. Tessler FN, et  al. Cranial arteriovenous malformations in neonates: color Doppler imaging with angiographic correlation. AJR Am J Roentgenol. 1989;153(5):1027–1030. 116. Cubberley DA, Jaffe RB, Nixon GW. Sonographic demonstration of Galenic arteriovenous malformations in the neonate. AJNR Am J Neuroradiol. 1982;3(4):435–439. 117. Schum TR, et al. Neonatal intraventricular hemorrhage due to an intracranial arteriovenous malformation: a case report. Pediatrics. 1979;64(2):242–244. 118. Yan J, et al. The natural progression of VGAMs and the need for urgent medical attention: a systematic review and meta-analysis. J Neurointerv Surg. 2017;9(6):564–570. 119. Frawley GP, et  al. Clinical course and medical management of neonates with severe cardiac failure related to vein of Galen malformation. Arch Dis Child Fetal Neonatal Ed. 2002;87(2): F144–F149. 120. Kim DJ, et  al. Adjuvant coil assisted glue embolization of vein of Galen aneurysmal malformation in pediatric patients. Neurointervention. 2018;13(1):41–47. 121. McSweeney N, et al. Management and outcome of vein of Galen malformation. Arch Dis Child. 2010;95(11):903–909. 122. Moriarity Jr. JL, Steinberg GK. Surgical obliteration for vein of Galen malformation: a case report. Surg Neurol. 1995;44(4): 365–369. discussion 369-70. 123. Hernesniemi J. Arteriovenous malformations of the vein of Galen: report of three microsurgically treated cases. Surg Neurol. 1991; 36(6):465–469. 124. Lecce F, et al. Cross-sectional study of a United Kingdom cohort of neonatal vein of galen malformation. Ann Neurol. 2018; 84(4):547–555. 125. Rodesch G, et al. Prognosis of antenatally diagnosed vein of Galen aneurysmal malformations. Childs Nerv Syst. 1994;10(2):79–83. 126. Yan J, et al. Outcome and complications of endovascular embolization for vein of Galen malformations: a systematic review and meta-analysis. J Neurosurg. 2015;123(4):872–890. 127. Brinjikji W, et al. Endovascular treatment of vein of Galen malformations: a systematic review and meta-analysis. AJNR Am J Neuroradiol. 2017;38(12):2308–2314. 128. Gupta AK, et al. Evaluation, management, and long-term follow up of vein of Galen malformations. J Neurosurg. 2006;105(1):26–33. 129. Fullerton HJ, et  al. Neurodevelopmental outcome after endovascular treatment of vein of Galen malformations. Neurology. 2003;61(10):1386–1390.

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57

Neonatal Neuromuscular Disorders NIRANJANA NATARAJAN AND CRISTIAN IONITA

KEY POINTS • Evaluation of neonatal hypotonia includes neuromuscular conditions, and the diagnostic work-up should be approached in a stepwise manner. • A normal creatine phosphokinase does not completely rule out muscle disease. • Electromyography is useful in the diagnostic evaluation of hypotonia and weakness. • Spinal muscular atrophy (SMA) can present in the neonatal period and has time-sensitive treatments. Genetic testing for the commonly found gene deletion in SMA is increasingly available as newborn screen testing in the United States. • The search for a genetic diagnosis is crucial in patients with neuromuscular disease.

Neonatal Neuromuscular Disorders Neuromuscular disorders comprise diseases of the muscle (congenital myopathies and muscular dystrophies), neuromuscular junction (myasthenia gravis and congenital myasthenic syndromes), nerves (neuropathies), and anterior horn motor neurons (spinal muscular atrophies). They present in the neonatal period as floppy infant syndrome with or without contractures. Respiratory insufficiency and swallowing difficulties can be in the forefront of the clinical picture and are frequently associated with significant hypotonia and weakness. This chapter reviews our current knowledge of neuromuscular disorders with neonatal onset and their clinical details alongside pathologic, genetic, and radiologic aspects as applicable. Finally, an approach to the diagnostic evaluation of neonates when a neuromuscular disorder is suspected is discussed.

Primary Muscle Disorders Historically, neonatal muscle disorders were divided based on histopathologic criteria into (1) congenital muscular dystrophies (CMDs), (2) congenital myopathies (CMs), (3) congenital myotonic dystrophy, and (4) metabolic myopathies. CMDs demonstrate dystrophic changes on muscle biopsy, with disruption of the muscle fiber and its architecture. Congenital myopathies have more subtle changes with preservation of the muscle fiber architecture. While histopathologically and genetically distinct, their phenotypes are often indistinguishable and characterized by congenital onset of muscle weakness and hypotonia. Some distinguishing features of various disorders are apparent at birth, while

others become apparent later. Muscle weakness tends to be progressive with CMDs and relatively static in CMs. Improvement in strength has been reported with some congenital myopathies. Involvement of the central nervous system is seen more often with CMDs and congenital myotonic dystrophy and less so with CMs. Creatine phosphokinase (CPK) tends to be elevated with CMDs and normal or mildly elevated with CMs. Many entities are sporadic or inherited in autosomal recessive fashion with few notable exceptions. Congenital myotonic dystrophy type 1 is inherited in autosomal dominant pattern and shows anticipation. Collagen VI- and RYR1-related disorders can have both autosomal-dominant and autosomal-recessive inheritance. The genetic advancements of the last decade promised a better understanding of this heterogeneous group of disorders. Instead, it became clear that a pure genetic ­classification remains impractical for the practicing physician. There are numerous situations where one gene leads to multiple phenotypes and the same phenotype is caused by numerous genes. Recent attempts to classification are based on genetic but also pathologic and clinical data. In the end, a classification that follows a mechanistic approach will likely prove to be most helpful.

Congenital Muscular Dystrophies CMDs comprise a heterogeneous group of disorders characterized by a dystrophic process on muscle biopsy. Classification schemas alongside diagnostic approaches have been proposed that take into account the recent expansion of knowledge.1–3 Given the numerous genes discovered, CMDs have most recently been separated into seven subtypes of disorders: merosin-deficient congenital muscular dystrophy, α-dystroglycanopathies, collagen VI-related disorders, LMNA-related congenital muscular dystrophy, SEPN1-related myopathy, RYR1-related myopathies, and CMD without a genetic diagnosis.2 SEPN1 and RYR1, which are typically considered myopathies, are in this classification scheme secondary to the varying phenotype at presentation.

LAMA2-Related Congenital Muscular Dystrophy (Merosin-Deficient Congenital Muscular Dystrophies; MDC1A) LAMA2-related CMD is due to autosomal recessive mutations of LAMA2 gene known to encode the α2 subunit of merosin. Merosin is an essential component of the extracellular matrix. In the UK, MDC1A was the most common form of congenital

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muscular dystrophy, followed, as a group, by dystroglycanopathies and collagen VI myopathies.4 Clinically, MDC1A often presents at birth or early infancy with severe hypotonia and diffuse weakness. A weak cry, poor suck and swallow, and respiratory failure are common. Contractures may be present at birth in the more severe cases or develop in time. As opposed to dystroglycanopathies, neonates with MDC1A typically have no encephalopathy, and cognitive as well as speech development is normal. On brain MRI, white matter T2 and FLAIR signal abnormalities become apparent in the second half of the first year5,6 and approximately 20% of patients develop seizures. A mild demyelinating neuropathy is often present, generally not at the forefront of clinical picture. CPK levels in neonatal period and infancy are elevated four to five times above normal limits.7 Muscle biopsy demonstrates decreased or absent laminin α2 immunostaining aside from dystrophic features. Care for patients with LAMA2 mutations is supportive in nature.

Dystroglycanopathies Dystroglycan complex includes α- and β-dystroglycan and represents one of the transmembrane complexes that link cytoskeleton with extracellular matrix as part of the larger dystrophin-glycoprotein complex. α-Dystroglycan, the extracellular component of the complex, through its heavily glycosylated segment, interacts with several extracellular matrix proteins such as laminin α2 and agrin. As a receptor for several extracellular matrix proteins, dystroglycan plays a major role in the maintenance of muscle cell structural integrity and synaptogenesis. In the central nervous system, dystroglycan plays an important role in forebrain development, specifically neuronal migration as well as synaptic plasticity and blood-brain barrier integrity.8,9 Dystroglycan plays important roles in other tissues such as eye and secreting tissues. Dystroglycanopathies are a phenotypically heterogenous group of disorders that share a common pathophysiologic theme: abnormal interaction of dystroglycan complex with extracellular matrix proteins because of defective α-dystroglycan O-glycosylation. Their phenotype ranges from severe neonatal muscle weakness with early lethality as well as abnormal brain and eye development to asymptomatic hyperCKemia discovered in adult years. The modern classification of these disorders is based on their genotype and pathophysiology instead of severity. In this classification, dystroglycanopathies are subdivided into primary (due to mutations in DAG1 gene which encodes the two dystroglycans), secondary (due to mutations in genes known to encode enzymes involved in O-glycosylation of the α-dystroglycan), and tertiary (due to mutations in genes known to encode enzymes and other factors implicated in production of the oligosaccharide building blocks). Primary dystroglycanopathies are the most recent addition to the group and includes a handful of cases, all found in consanguineous families. Their phenotype parallels the more common secondary dystroglycanopathies and includes severe as well as mild forms.10 Secondary dystroglycanopathies are due to malfunction of various enzymes involved in α-dystroglycan O-glycosylation at the endoplasmic reticulum and Golgi apparatus levels. The number of enzymes involved and their encoding genes have seen significant expansion over the last two decades. Severe forms, classically labeled as Walker Warburg syndrome” or “Muscle Eye Brain disease”, present at birth with severe muscle weakness and hypotonia, as well as often severe brain and eye malformations. Although hypotonia and muscle weakness are severe,

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the clinical picture is dominated by encephalopathy, brain and eye malformation, and sometimes seizures. CPK is generally elevated. Brain involvement includes one or a combination of the following findings: agyria, lissencephaly (type 2, “cobblestone”), focal pachygyria or polymicrogyria, heterotopia, complete or partial agenesis of corpus callosum, cerebellum abnormalities, brainstem abnormalities including a “kinked” appearance, posterior fossa cyst, occipital encephalocele microcephaly, hydrocephalus, and white matter changes.11 Eye abnormalities are quite variable as well and can include cataracts, abnormalities of the anterior chamber, abnormalities of the posterior chamber, microphthalmia, microcornea, small lens, retinal abnormalities, optic nerve hypoplasia, coloboma, and glaucoma. Many of these patients have significantly shortened life span and show little psychomotor developmental progress. Milder phenotypes present at birth or soon after with hypotonia and muscle weakness. MRI might show white matter abnormalities starting in the second half of the first year and cognitive disability which first becomes obvious as various degrees of global developmental delay. Yet, milder forms exist with onset as late as adult years. Tertiary dystroglycanopathies is another emerging group which phenotypically is indistinguishable from other dystroglycanopathies.

Collagen VI-Related Disorders Collagen VI-related disorders are caused by mutations in the genes that encode one of the three subunits of collagen VI (COL6A1, COL6A2, COL6A3) and are classically divided into Ullrich CMD and Bethlem myopathy. Overlaps between the two phenotypes are common though, and the reader is encouraged to think about this group of disorders as a continuum between the two entities.12 In collagen VI-related disorders there is often a combination of joint laxity and joint contractures in addition to hypotonia and weakness. While Ullrich CMD has a more severe phenotype and onset in utero, often with congenital contractures, Bethlem myopathy tends to be milder and has more variable onset starting in utero and extending into adult life. Ullrich CMD presents at birth with severe muscle weakness, hypotonia, and a combination of marked joint laxity (involving the distal joints) and joint contractures (involving the proximal joints, kyphoscoliosis, and torticollis). Weakness is slowly progressive and respiratory insufficiency is either present at birth or develops later. When it presents in utero or at birth, Bethlem myopathy tends to have a milder phenotype and behaves more like a congenital myopathy. Other useful distinguishing features for collagen VI-related disorders include a prominent calcaneus, hyperkeratosis pilaris on the extensor surfaces, keloid formation, and sometimes congenital hip dislocation. CPK is normal or moderately elevated and muscle biopsy can show both myopathic and dystrophic features. Diagnosis is generally suspected based on clinical grounds and confirmed by targeted genetic testing.

LMNA-Related Congenital Muscular Dystrophy The LMNA gene, which is associated with autosomal dominant form of Emery–Dreifuss syndrome in older children or adults, has been found mutated in neonates and children with CMD.13–16 LMNA encodes for lamin A/C, which is a nuclear envelope protein. The syndrome is classically described as reduced fetal movements, severe hypotonia, and weakness with a “dropped head” appearance because of involvement of the neck muscles.15

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SEPN1-Related Myopathies SEPN1-related myopathies straddle the demarcation line between CMDs and CMs, and encodes for selenoprotein N. SEPN1 is an endoplasmic reticulum glycoprotein preferentially expressed early in the development, and with roles in redox signaling and Ca homeostasis.17 Most patients with SEPN1-related myopathies present at birth or within the first 2 years of life with predominantly axial hypotonia, poor head control, and feeding difficulties. The distinguishing features of SEPN1-related myopathies, including spine rigidity, amyotrophy, and respiratory impairment, became apparent in childhood.17 Despite a relatively well-defined phenotype, the pathologic findings are variable and include dystrophic features, multi-minicore lesions, fiber size disproportion, and desmin inclusions.

Congenital Myopathies The term congenital myopathies (CMs) refers to muscle disorders that present in neonatal period or early infancy and lack dystrophic changes on muscle biopsy. CMs tend to have a slowly progressive or nonprogressive course. The severity spectrum is wide, starting with severe illnesses often fatal in the first years of life (MTM1 and severe ACTA1 disorders), to mild muscle weakness leading to mild gross motor developmental delay. Muscle biopsy shows structural changes at the myofiber level in absence of dystrophic features. The type of structural abnormalities defines the various types of congenital myopathies. Electron microscopy is often very helpful and should always be included when CM is suspected. As with CMDs, genetic advances expanded our understanding of congenital myopathies. We now know that certain genotype might lead to several different histopathologic and clinical phenotypes.18 The best recognized congenital myopathies are core myopathy, nemaline myopathy, centronuclear myopathy, fiber-type disproportion myopathy, and myosin storage myopathy. In a population study, core myopathies were the most common, representing approximately half of all CMs cases, followed by nemaline and centronuclear myopathies each representing approximately 15% of all CMs cases.19 Typical neonates present with hypotonia, and weakness. More severe cases have respiratory insufficiency and swallowing difficulties. Elongated and weak face, high-arched palate, and mild ptosis are seen in some of the CMs (nemaline and centronuclear myopathies). Skeletal abnormalities such as hip dislocation, club feet, and pectus excavatum are common. As opposed to congenital muscular dystrophies, CPK may be normal or mildly elevated. Typically, electromyography (EMG) shows myopathic change. EMG can also be normal and even show neurogenic features. Aside from nonspecific myopathic features, muscle biopsy often reveals specific structural abnormalities that define each group of disorders. Genetic testing is often employed first nowadays.

Core Myopathies Central core and multi-minicore disease together comprise the “core myopathies” and are the most common form of congenital myopathies.20 Histopathologically, focal myofibrillar disruption with absence of mitochondria leads to formation of single or multiple cores visible on oxidative stains such as Gomori trichrome. The majority of cases are due to autosomal recessive or autosomal dominant mutations in the RYR1 gene. Clinically, patients with

RYR1-related central core or multicore myopathies tend to have a milder phenotype with hypotonia and muscle weakness, and often lack facial involvement.20 The more severe cases, often autosomal recessive, present at birth with contractures, arthrogryposis, and respiratory insufficiency.21 Serum CPK is often normal or mildly elevated. The RYR1 gene encodes the ryanodine receptor, a sarcoplasmic reticulum calcium channel with role in excitationcontraction coupling.22 Mutations in RYR1 can lead to various phenotypes (nemaline myopathy, congenital myasthenic syndrome),23 as well as malignant hyperthermia. Malignant hyperthermia precautions are needed every time RYR1 mutations are a possibility. Multi-minicore disease is rare in the neonatal period and, when present, is notable for marked axial weakness, myopathic facies, and respiratory failure. Patients may present with arthrogryposis. The two genes most often associated with multi-minicore myopathy are SEPN1 and RYR1. SEPN1, discussed previously, accounts for the majority of patients.24 There is significant phenotypic overlap with rigid spine syndrome.

Nemaline Myopathy Nemaline myopathy derives its name from “nema,” the Greek word for thread. The muscle biopsy shows threadlike rods. The rods stain red on Gomori trichrome, giving its characteristic appearance. Newborns may present with hypotonia with weakness including bulbar involvement. The facial and axial muscles are often involved. Neonates may require respiratory support because of weak respiratory muscles, frequent suctioning, and nutritional support often via gastrostomy tube due to swallowing difficulties. In more severe forms, reduced fetal movements and polyhydramnios occur, and the neonate has severe respiratory failure and feeding difficulties in addition to arthrogryposis.25 The most severe cases of nemaline myopathy, often caused by ACTA1 mutations, have poor prognosis with rare survival past the first year of life. Those with the milder presentation may show improvement and, some achieve independent ambulation. However, many may still require respiratory assistance because of nocturnal hypoventilation and may have failure to thrive or scoliosis. More than 10 genes are associated with nemaline myopathy with NEB causing most autosomal recessive cases, and ACTA1 most autosomal dominant cases.26

Centronuclear Myopathy Centronuclear myopathy is a rare cause of neonatal weakness. The name comes from the histopathologic appearance of centrally located nuclei.27 Both X-linked as well as autosomal dominant and recessive forms exist as mutations in more than 10 genes, which are associated with this phenotype. The X-linked form caused by mutations in MTM1 gene is the most common form and often associated with a severe phenotype. Presentation in neonates is notable for severe hypotonia and weakness, associated with bulbar and extraocular muscle involvement, and myopathic facies. Respiratory compromise and need for ventilation are common.27 Neonates are often macrocephalic, with long, narrow face and may have undescended testes. The MTM1 gene, encoding for myotubularin, is located on the X chromosome at Xq28, thus resulting in the male predilection for this disease. However, secondary to random X-inactivation, females may be affected.28

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Autosomal dominant DNM2 mutations, as well as autosomal recessive RYR1, TTN mutations, may also lead to neonatal disease.23

Congenital Fiber-Type Size Disproportion Myopathy Congenital fiber-type size disproportion myopathies are characterized by type 1 fibers that are significantly and uniformly smaller than the type 2 fibers. So far, over 10 genes are associated with this pathologic phenotype inherited in both autosomal dominant and recessive fashion. Clinically they share often neonatal onset, with hypotonia, muscle weakness, and variable facial, bulbar, extraocular, and respiratory muscle involvement.

Myosin Storage Myopathy In addition to several muscle disorders and cardiomyopathy, MYH7 mutations are also responsible for myosin storage myopathy, also known as hyaline body myopathy. Onset is neonatal with hypotonia and weakness. On muscle biopsy, hyaline bodies are noted predominantly in type 1 muscle fibers on H&E and myosin ATPase stains, and defined as granular material on electron microscopy.

Congenital Myotonic Dystrophy Myotonic dystrophy is a multisystem, triple repeats disease with wide phenotypic variation dependent, in great part, on the number of cytosine–thymine–guanine (CTG) repeats in the DMPK gene. The transcribed CUG RNA repeat has negative impact on expression of DMPK as well as other genes such as SIX5 and splicing of mRNA of the ClC1 gene. The congenital form is the most severe and is generally associated with CTG repeats higher than 1000.29 In these cases, pregnancy is usually remarkable for polyhydramnios and reduced fetal movements. Newborns with congenital myotonic dystrophy are often delivered prematurely. At birth, there is marked hypotonia and paucity of movements. Breathing, sucking, and swallowing difficulties are often present and persistent, often leading to gastrostomy tube placement and tracheostomy. Talipes equinovarus is often present. Facial features include facial diplegia with a “carp” mouth appearance and bilateral ptosis. Clinical examination demonstrates hyporeflexia or areflexia and diffuse weakness more severe in distal muscles than proximal ones. Grip and percussion myotonia are not present at this age and develop in childhood. There may be pulmonary hypoplasia. These factors lead to high morbidity in the neonatal period and infancy. The duration and severity of the respiratory muscle weakness and pulmonary hypoplasia are key determinants of outcome. Prolonged mechanical ventilation, defined as greater than 4 weeks in duration, is a negative prognostic factor in these neonates.30 Some neonates with severe myotonic dystrophy require tracheostomy placement; however, it is not uncommon for older infants or children to be decannulated. The diagnosis of congenital myotonic dystrophy should be considered when there is a positive family history. The disease is transmitted by mother and shows anticipation. A detailed history and examination of the mother often, but not always, reveals characteristic facial features associated with classical myotonic dystrophy,

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including frontal balding, ptosis, facial diplegia, temporal wasting, or cataracts. In addition, examination of the mother typically reveals grip myotonia. These symptoms are often subtle, such that the mother is unaware of her diagnosis. Laboratory evaluation reveals normal to mildly elevated CPK. Muscle biopsy is often remarkable for markedly increased number of internal nuclei. Electrographic or clinical myotonia is absent in the neonatal period. The diagnosis is often suspected on the clinical basis and confirmed by genetic studies. The DMPK gene, located at chromosome 19q13.3, contains a CTG trinucleotide repeat in the 3′ noncoding region.31 Unaffected individuals have between 5 and 27 repeats, while patients with a classical (not congenital) presentation have 50 to 1000 repeats. Just like other triple repeats diseases, myotonic dystrophy exhibits anticipation, resulting in earlier and more severe presentation. Neonates who survive the neonatal period typically require ongoing respiratory support and can survive into adulthood with close respiratory and cardiac monitoring and with therapy; however, cognitive impairment is frequent and can be severe.32

Metabolic Myopathies Neonatal presentation is not typical for metabolic myopathies except acid maltase deficiency. Other glycogen storage disorders rarely present at this age and when they do, myopathy is associated with other systemic features such as cardiomyopathy and liver involvement. Infantile form of acid maltase disease, also known as Pompe disease, can present at birth with severe and progressive muscle weakness and hypotonia. The majority of patients have cardiac disease, respiratory insufficiency, and a fatal course unless enzyme replacement therapy is initiated early. CPK is usually elevated, and EMG is myopathic with frequent myotonic and complex repetitive discharges. Muscle biopsy shows vacuoles which stain positive with acid phosphatase.

Motor Neuron Disorders Motor neuron disorders comprise a group of genetic disorders that share involvement of the anterior horn motor neurons. This group is dominated by 5q spinal muscular atrophy (SMA), the most common inherited motor neuron disorder. A substantial number of other rare forms of motor neuron disease are characterized; the more common ones will be mentioned below.

5q Spinal Muscular Atrophy 5q SMA is an autosomal recessive disorder with an incidence of approximately 1 in 10,000 live births, and is the most common form of SMA.33 Onset and severity fall along a wide spectrum, from very severe cases with intrauterine onset, to mild cases with onset in adult years and mild disability.34 Given the wide variability, SMA categorized by age of onset and anticipated motor outcome, classically as types 1 to 4, though some recognize “type 0”, reserved for those cases with in utero onset.35 The majority of patients have a homozygous deletion of the SMN1 gene, survivor motor neuron 1. This gene is expressed in all cell types, and severity of disease is modified by the SMN2 gene, survivor motor neuron gene 2. The SMN2 gene is nearly identical to SMN1 and produces principally a truncated, nonfunctional protein as well as

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a small amount of functional protein. Increased copies of SMN2 modify the severity of disease, with greater copies correlating with the milder phenotype.36 Historically, patients undergo a course that includes a decline phase followed by a plateau phase. The decline phase occurs in utero for SMA type 0 newborns affected at birth. For infants whose onset is after birth, a period of normal development is followed by a decline phase that usually lasts for weeks to months. SMA type 0 neonates have onset of weakness in utero and present with arthrogryposis at birth. Respiratory distress and facial weakness can be present in addition to profound hypotonia and limb muscle weakness. Most of these patients die in the first weeks of life. SMA type 1 or Werdnig–Hoffmann disease presents between birth and 6 months of age. Some of these neonates become symptomatic soon after birth, while others come to medical attention at several months of age in the setting of respiratory or feeding difficulties. Typical patients have profound hypotonia and severe weakness affecting legs more than arms, and proximal more than distal muscles. Usually there are no antigravity movements of the more proximal limb muscles with some movements distally at the level of ankles/wrists or fingers/toes. Deep tendon reflexes are absent, and facial muscles are unaffected. In fact, these infants tend to have a very bright facial expression, however bulbar weakness with dysphagia and poor feeding are often present, as are tongue fasciculations. Various degrees of respiratory insufficiency are present at the time of diagnosis. Because of the disproportionate involvement of the intercostal muscles and relative sparing of the diaphragm, a “bell-shaped” chest conformation is noted. Contractures are not part of the typical initial presentation of SMA, although they can develop after prolonged immobilization. Typically, respiratory function declines over time, with historic cohorts requiring respiratory support by BiPAP or invasive ventilation in the first year of life.34 Diagnostic evaluation is often broad initially, beginning with CPK testing, which can be normal to mildly elevated (up to 500 IU/L), however genetic testing is imperative, with testing of SMN1 and SMN2 copy number variants. Most cases of 5q SMA are secondary to a homozygous deletion of the SMN1 gene, and as noted, the copy number of SMN2 modifies phenotype. In cases where genetic testing is unrevealing, EMG and/or muscle biopsy can be considered to aid in localization and subsequent targeted genetic testing of less common causes of SMA. Until 2016, treatment for SMA was supportive, without therapeutic options; now, there are three Food and Drug Administration (FDA) approved drugs for the most common cause of SMA, which has altered the landscape for clinical degree of concern, testing, treatment, and outcomes.37–39 With the advent of therapeutic options as discussed below, there are moves toward universal newborn screening, given the recognition that early treatment augments outcome. In the United States, SMA is one of the disorders nationally recommended to be on the newborn screen, however implementation is at the state level, with nearly three-fourths of states screening as of May 2021.40 Any infant with positive newborn screen for SMA should undergo confirmatory genetic testing of SMN1 and SMN2 copy numbers, alongside consultation of neurology. Involvement of the neurologist and pulmonologist can aid in next steps on potential treatment. Consensus guidelines are available for

management of the neonate with positive newborn screen findings for SMA.41,42 There are currently three FDA-approved medications for SMA: nusinersen (brand name Spinraza), onasemnogene abeparvovec (brand name Zolgensma), and risdiplam (brand name Evrysdi). Nusinersen is an mRNA antisense oligonucleotide, while risdiplam is an mRNA splicing modifier, both acting to increase survival motor neuron protein via the SMN2 gene. Nusinersen is administered intrathecally, while risdiplam is administered orally. In the sentinel Phase 3 clinical trial, 37 of 73 SMA type I patients who received intrathecal nusinersen gained motor milestones compared to 0 of 37 patients who received sham injections.43 Providing more hope for presymptomatic treatment was a Phase 2 trial of 25 asymptomatic newborns predicted to have type I or II SMA phenotype based on absence of SMN1 and copy numbers of SMN2, where 22 of 25 patients achieved independent ambulation during the 2.9 years of follow up.44 Onasemnogene abeparvovec (AVXS-101) utilizes adenoassociated virus, serotype 9 (AAV9) vector to delivery SMN1 gene. In the sentinel study, 15 patients with SMA type I treated with onasemnogene abeparvovec survived, were event free, defined as not requiring respiratory support for greater than 16 hours continuously for 14 days in the absence of an acute reversible illness or perioperative state at 20 months of life, and gained motor milestones after a single intravenous dose.45 Onasemnogene abeparvovec is currently approved for those under 2 years of age.38 Risdiplam is the most recently approved medication (August 2020) for SMA, and is the only approved oral medication.39 Like nusinersen, risdiplam is a small molecule, however, it is noted to affect expression of SMN protein in peripheral tissues in addition to the CNS/motor neuron. Based on two open-label studies (ClinicalTrials ID NCT02913482, NCT02908685) FDA approval was given due to clinical improvement. Currently, part 1 outcomes are available, which demonstrated increased SMN protein concentration in the blood.46

Non-5q Spinal Muscular Atrophies Non-5q SMAs comprise a genetically and phenotypically heterogeneous group of disorders that share motor neuron involvement. Different classifications are used, including mode of inheritance and pattern of muscle involvement. Some of these disorders are important entities for neonatologists, while others are not seen in newborns. Although rare, two etiologies that may present in the neonatal period are addressed below.

Spinal Muscular Atrophy With Respiratory Distress Spinal muscular atrophy with respiratory distress (SMARD) represents a group of motor neuron disorders that present at birth but are notable by a rather sudden and severe respiratory insufficiency that leads to a requirement for ventilatory support as well as predominantly distal weakness and distal contractures. Respiratory insufficiency is less common at birth, but more often noted between 6 weeks and 6 months of life. Diaphragmatic weakness leading to diaphragmatic eventration is characteristic. Clinically, SMARD can be distinguished from 5q SMA by diaphragmatic weakness and eventration with resultant normal thoracic appearance and lack of the “bell-shaped” chest. Distal weakness with contractures can be present, versus the proximal predilection

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of 5q SMA. Several genes have been identified, most notably IDHMBP2 (immunoglobulin μ-binding protein 2), which results in SMARD, type 1.47 Current management for SMARD is supportive. Restrictive lung disease is the main cause of morbidity and mortality. Swallowing difficulties, aspirations, and poor caloric intake are also common, leading to gastrostomy tube placement. Cognitive development is believed to be normal. Palliative care is often offered for the more severe cases, while milder cases may benefit from aggressive respiratory and gastrointestinal management. Late-onset forms with a milder phenotype have also been described.

Pontocerebellar Hypoplasia Plus Spinal Muscular Atrophy Pontocerebellar hypoplasia is a heterogeneous group of inherited disorders that share hypoplasia or atrophy of the cerebellum and pons, with or without other brain or eye abnormalities.48 Pontocerebellar hypoplasia type 1 can present with features of SMA, with pathologic studies demonstrating anterior horn cell degeneration. Several genes have been implicated, most commonly EXOSC3, with increasing knowledge of the genotypic-phenotypic variation in presentation.49–52 All are inherited in an autosomal recessive pattern. Although the severity and age of onset varies, neonatal presentation includes hypotonia and weakness, contractures, and respiratory distress as well as encephalopathy given pontocerebellar findings. Management is supportive.

Neonatal Neuromuscular Junction Disorders Transient Neonatal Myasthenia Gravis Maternal myasthenia gravis is an autoimmune disorder caused by antibodies to acetylcholine receptor (AChR) or to the muscle-specific tyrosine kinase (MuSK). In a subset of mothers with myasthenia gravis, neonates develop transient weakness, often initially presenting as feeding difficulty or bulbar weakness, but can progress to respiratory failure requiring ventilatory support. Most commonly, this is in the setting of AChR receptor antibodies, however there are case reports of involvement in the setting of MuSK antibodies, which can present more severely.53,54 Interestingly, neonatal disease does not appear to be related to antibody level in the mother, thus requiring all neonates born to mothers with disease to be monitored closely. While neonatal symptoms can occur immediately after birth, they may not develop until a few days after birth. Therefore, newborns of mothers with myasthenia gravis should be observed between 2 and 4 days post birth.55,56 Affected newborns should receive supportive care such as nasogastric feeds or ventilatory support. Pyridostigmine is indicated in those with maternal AChR antibodies, and intravenous immunoglobulin can be considered in severe cases.56

Congenital Myasthenic Syndromes Congenital myasthenic syndromes (CMS) include a growing number of heterogeneous disorders that are all characterized by the failure of neuromuscular transmission secondary to a genetic defect. A significant proportion of CMS cases present in the

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neonatal period or early infancy; however, presentation can be subtle, and diagnosis may be delayed by years. The general clinical characteristics include fatigable muscle weakness involving the extraocular, bulbar, respiratory, and limb muscle systems in different combinations.57 Certain patterns are unusual enough to deserve special mention. Dok7 CMS patients can present in the neonatal period with stridor due to bilateral vocal cord paralysis, respiratory distress, and feeding difficulties. Intubation and ventilator support are necessary for some patients.58 Choline acetyltransferase mutations lead to hypotonia with marked bulbar symptoms and respiratory insufficiency in the neonatal period followed by life-threatening episodes of apnea later in infancy.59 In a retrospective review of CMS cases presenting in early infancy, 8 out of 11 patients presented at birth in general with severe respiratory distress in addition to hypotonia, weakness, and contractures.60 Laboratory evaluation for CMS is usually unremarkable, with normal CPK. Muscle biopsy is either unremarkable or shows mild nonspecific findings. Guidance to diagnosis comes from EMG with repetitive nerve stimulation, which historically has been paramount in the establishment of a neuromuscular junction defect. Increased availability of genetic testing has reduced the necessity of electrophysiologic testing and should be considered in the setting of phenotypic variability in presentation. Pyridostigmine is the most commonly used medical treatment for CMS. Although a good number of CMS patients respond partially to pyridostigmine, patients with certain types of CMS may worsen. Close observation is needed when pyridostigmine is administered, especially if the exact type of CMS is not known. Other medical treatments may be available, depending on the specific CMS identified; for example, patients with Dok7 mutations may respond to oral albuterol.61 Respiratory support remains important though. Noninvasive ventilation is preferred as some patients improve with age. Nutritional support with a gastrostomy tube should be considered.

Peripheral Neuropathies Hereditary peripheral neuropathies are a rare cause of floppy infant syndrome in the neonatal period. The presentations in the neonatal period can vary from severe hypotonia and weakness with respiratory difficulties, to milder with feet deformities.62 Electrophysiologic studies will confirm the neuropathy and orient the genetic testing by subdividing them into axonal versus demyelinating. Management is supportive.

Approach to the Hypotonic Newborn The field of pediatric neuromuscular disorders has exploded following the genetic advances of the last two decades. While the old clinicopathologic classification remains useful, advances in genetics have elucidated the degree of genotypic-phenotypic variability and have implications in the approach to diagnostic evaluation. Hypotonia in the newborn can occur from many reasons, including neurologic, systemic (such as sepsis), and genetic such as trisomy 21 or Prader-Willi syndrome. Neurologic etiologies can originate across the neuroaxis, from central to peripheral (neuromuscular) etiologies. Central causes constitute the majority of cases, accounting for between 60% and 80% of hypotonic newborn.63,64

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Initial efforts to evaluate hypotonia start with history and physical examination, including a neurologic examination. Historical features include quality of reported fetal movements and complications such as polyhydramnios or previous pregnancy losses. Polyhydramnios suggests poor swallowing ability in utero. Three generations of family history can identify other affected family members, recognizing limitations given intrafamilial variability of neuromuscular conditions. Examination of the neonate’s mother for grip myotonia and querying maternal history of easy tripping or muscle stiffness such as hand cramping will help point the clinician toward congenital myotonic dystrophy. This is something that should be done each time a newborn is evaluated for hypotonia; grip myotonia can be tested by asking the mother to squeeze her hand tight and quickly let go, or by testing for percussion myotonia at the thenar eminence or brachioradialis. Examination of the floppy newborn should include delineation of hypotonia (axial vs. proximal vs. distal vs. diffuse) as well as degree of weakness. Hypotonia is when the tone of the muscle is decreased, whereas weakness refers to decreased muscle strength. Weakness equal to or greater than hypotonia is suggestive of a peripheral etiology and can be further classified as primarily proximal or distal, while weakness that is minor as compared to hypotonia is more suggestive of a central etiology. Weakness can be noted by a newborn’s ability to generate strength, even if hypotonic. The presence or absence of deep tendon reflexes, the resting position, and the frequency of spontaneous movements are important. Central hypotonia is more common than neuromuscular causes, with 60% to 80% of neonatal hypotonia in this category.63,64 Signs and symptoms suggestive of CNS involvement include, but are not limited to, microcephaly or macrocephaly, hyperreflexia, encephalopathy, seizures, dysmorphic features, history suggestive of hypoxic-ischemic injury, severe hypotonia in a setting of mild weakness, and metabolic derangements. A history of hypoxic-ischemic injury is not mutually exclusive for a neuromuscular condition, as many of these conditions place the newborn at risk for hypoxic-ischemic injury in and of themselves, and thus detailed prenatal and perinatal history obtained in those presenting with presumed hypoxic-ischemic injury should still assess for signs of hypotonia prior to delivery. MRI of the brain should be obtained in newborns with hypotonia. In most neuromuscular conditions, these studies are normal. Pontine and cerebellar hypoplasia will point in the direction of SMA with PCH. Some forms of CMD can often present with significant brain malformations, as mentioned above. The white matter changes described in merosin-deficient CMD are not apparent in the neonatal period. In addition to the history and physical examination, the tools available to the clinician include the following: 1. CPK 2. EMG with nerve conduction studies 3. Muscle biopsy 4. Genetic testing Few gestalt diagnoses exist. Congenital myotonic dystrophy presents with typical facial features. If this is combined with maternal myopathic facial appearance and grip myotonia, one may go straight to genetic confirmation. The presentation of SMA in the neonatal period is another situation when gestalt diagnosis is possible for the experienced neonatologist and is increasingly available on newborn screen.

Creatine Phosphokinase CPK is a rapid test that should be performed when a neuromuscular condition is first suspected. Significantly elevated values (more than five times normal) will point toward a muscle disorder, more likely a CMD. Normal or mildly elevated values can be seen in congenital myopathies and SMA.

Electromyography Seen as a difficult test to perform in newborns, when performed by experienced electrophysiologists, EMG can be of immense help. The main advantage of EMG is a rapid, on the spot, diagnosis of a neurogenic process versus myopathic process versus neuromuscular junction defect. Given increasing availability of genetic testing, pragmatically, EMG is now often reserved when genetic testing options are limited, or targeted genetic testing is required.

Muscle Biopsy Despite advances in genetic diagnosis, muscle biopsy remains an important tool in the diagnosis of neuromuscular disorders. Its main utility consists in identification of particular types of congenital myopathy or CMD and, as a consequence, directing the genetic testing toward smaller panels of genes. As the pricing of genetic testing is decreasing, it is becoming feasible to start the work-up with genetic testing and employ muscle biopsy only if the first round of genetic tests fails to reveal a genetic abnormality.

Genetic Testing The availability of genetic testing has increased exponentially in the last decade. A clinicopathologic diagnosis is no longer sufficient, and every effort should be made for genetic confirmation. Single genes as well as panels of genes are now commercially available from multiple commercial laboratories. In newborns with multiple congenital abnormalities in addition to hypotonia, genetic testing should begin with karyotype and chromosomal microarray (CMA). Microarray may also detect Prader-Willi syndrome, as can methylation testing. Increasingly, whole exome sequencing is available, and is noted to provide diagnoses in 25% to 49% of cases in concerns for pediatric neuromuscular disorders or neurologic disorders.65–69 Notably, whole exome sequencing has limitations: secondary to technical limitations, it cannot assess for trinucleotide repeats, and thus will not detect disorders with anticipation, such as congenital myotonic dystrophy. Additionally, it may not detect copy number variants, or certain single gene deletions secondary to probe size. Concomitant chromosomal microarray may aid in this detection. There is increasing interest and availability of whole genome sequencing as well, which has been used to evaluate critically ill neonates using trio technique (e.g., testing the patient, as well as biologic mother and father).70,71 Limitations currently include availability of this testing, and challenges in interpretations of variants in noncoding regions. A suggested approach to evaluating neonatal hypotonia is presented in Fig. 57.1.

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CHAPTER 57

Approach to Neonatal Hypotonia

Neonatal Neuromuscular Disorders

861

History and Physical

Findings suggestive of central hypotonia

Findings suggestive of neuromuscular weakness CPK

Seizures, encephalopathy Yes

Findings suggestive of hypotonia etiology

Normal or mildly elevated

No

MRI Brain

No

SMA testing

CMA, consider methylation testing for Prader-Willi

Significantly elevated >5-10x normal

Genetic testing for congenital myopathies and CMSs

Yes

Congenital Muscular Dystrophy

Genetic testing for congenital muscular dystrophies by expanded clinical panel

Muscle biopsy and EMG if genetic testing negative or inconclusive

Workup as indicated

• Fig. 57.1  Diagnostic approach to neonatal hypotonia. CMA, Chromosomal microarray; CMS, congenital myasthenic syndrome; CPK, Creatine ­phosphokinase; EMG, electromyography; SMA, spinal muscular atrophy.

Suggested Readings Baets J, Deconinck T, De Vriendt E, et al. Genetic spectrum of hereditary neuropathies with onset in the first year of life. Brain. 2011;134(Pt 9): 2664–2676. Bönnemann CG, Wang CH, Quijano-Roy S, et al. Diagnostic approach to the congenital muscular dystrophies. Neuromuscul Disord. 2014; 24(4):289–311. Claeys KG. Congenital myopathies: an update. Dev Med Child Neurol. 2020;62(3):297. De Vivo DC, Bertini E, Swoboda KJ, et  al. Nusinersen initiated in infants during the presymptomatic stage of spinal muscular atrophy: Interim efficacy and safety results from the Phase 2 NURTURE study. Neuromuscul Disord. 2019;29(11):842–856. Engel AG. Congenital myasthenic syndromes in 2018. Curr Neurol ­Neurosci Rep. 2018;18(8). 46–46. Glascock J, Sampson J, Connolly AM, et al. Revised recommendations for the treatment of infants diagnosed with spinal muscular atrophy via

newborn screening who have 4 copies of SMN2. J Neuromuscul Dis. 2020;7(2):97–100. Mendell JR, Al-Zaidy S, Shell R, et  al. Single-dose gene-replacement therapy for spinal muscular atrophy. N Engl J Med. 2017;377(18): 1713–1722. Mercuri E, Muntoni F. The ever-expanding spectrum of congenital muscular dystrophies. Ann Neurol. 2012;72(1):9–17. Norwood F, Dhanjal M, Hill M, et  al. Myasthenia in pregnancy: best practice guidelines from a U.K. multispecialty working group. J Neurol Neurosurg Psychiatry. 2014;85(5):538–543. Peredo DE, Hannibal MC. The floppy infant: evaluation of hypotonia. Pediatr Rev. 2009;30(9):e66–e76.

References The complete reference list is available at Elsevier eBooks+.

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CHAPTER 57

References 1. Muntoni F, Voit T. The congenital muscular dystrophies in 2004: a ­century of exciting progress. Neuromuscul Disord. Oct 2004;14(10): 635–649. https://doi.org/10.1016/j.nmd.2004.06.009. 2. Bonnemann CG, Wang CH, Quijano-Roy S, et al. Diagnostic approach to the congenital muscular dystrophies. Neuromuscul Disord. Apr 2014; 24(4):289–311. https://doi.org/10.1016/j.nmd.2013.12.011. 3. Mercuri E, Muntoni F. The ever-expanding spectrum of congenital muscular dystrophies. Ann Neurol. Jul 2012;72(1):9–17. https://doi. org/10.1002/ana.23548. 4. Sframeli M, Sarkozy A, Bertoli M, et al. Congenital muscular dystrophies in the UK population: clinical and molecular spectrum of a large cohort diagnosed over a 12-year period. Neuromuscul Disord. Sep 2017;27(9):793–803. https://doi.org/10.1016/j.nmd.2017.06.008. 5. Ibrahim Abdulla JK, Vattoth S, Al Tawari AA, Pandey T, Abubacker S, Brain MRI. features of merosin-negative congenital muscular dystrophy. Australas Radiol. Dec 2007;51(Suppl):B221–B223. https:// doi.org/10.1111/j.1440-1673.2007.01852.x. 6. Kumar S, Aroor S, Mundkur S, Kumar M. Merosin-deficient congenital muscular dystrophy with cerebral white matter changes: a clue to its diagnosis beyond infancy. BMJ Case Rep. Mar 6 2014;2014 https://doi.org/10.1136/bcr-2013-202684. 7. Oliveira J, Santos R, Soares-Silva I, et  al. LAMA2 gene analysis in a cohort of 26 congenital muscular dystrophy patients. Clin Genet. Dec 2008;74(6):502–512. https://doi.org/10.1111/j.13990004.2008.01068.x. 8. Satz JS, Ostendorf AP, Hou S, et  al. Distinct functions of glial and neuronal dystroglycan in the developing and adult mouse brain. J Neurosci. Oct 27 2010;30(43):14560–14572. https://doi. org/10.1523/JNEUROSCI.3247-10.2010. 9. Noell S, Wolburg-Buchholz K, Mack AF, et al. Evidence for a role of dystroglycan regulating the membrane architecture of astroglial endfeet. Eur J Neurosci. Jun 2011;33(12):2179–2186. https://doi. org/10.1111/j.1460-9568.2011.07688.x. 10. Brancaccio A. A molecular overview of the primary dystroglycanopathies. J Cell Mol Med. May 2019;23(5):3058–3062. https://doi. org/10.1111/jcmm.14218. 11. Dobyns WB, Pagon RA, Armstrong D, et  al. Diagnostic criteria for Walker-Warburg syndrome. Am J Med Genet. Feb 1989;32(2): 195–210. https://doi.org/10.1002/ajmg.1320320213. 12. Bönnemann CG. The collagen VI-related myopathies: muscle meets its matrix. Nat Rev Neurol. 2011;7(7):379–390. 13. Mercuri E, Poppe M, Quinlivan R, et  al. Extreme variability of phenotype in patients with an identical missense mutation in the lamin A/C gene—From congenital onset with severe phenotype to milder classic Emery-Dreifuss variant. Archives of Neurology. May 2004;61(5):690–694. https://doi.org/10.1001/archneur.61.5.690. 14. D’Amico A, Benedetti S, Petrini S, et  al. Major myofibrillar changes in early onset myopathy due to de novo heterozygous missense mutation in lamin A/C gene. Neuromuscular Disorders. Dec 2005;15(12):847–850. https://doi.org/10.1016/j.nmd.2005. 09.007. 15. Quijano-Roy S, Mbieleu B, Bonnemann CG, et  al. De novo LMNA mutations cause a new form of congenital muscular dystrophy. Annals of Neurology. Aug 2008;64(2):177–186. https://doi. org/10.1002/ana.21417. 16. Benedetti S, Bertini E, Iannaccone S, et al. Dominant LMNA mutations can cause combined muscular dystrophy and peripheral neuropathy. J Neurol Neurosurg Psychiatry. Jul 2005;76(7):1019–1021. https://doi.org/10.1136/jnnp.2004.046110. 17. Arbogast S, Ferreiro A. Selenoproteins and Protection against Oxidative Stress: Selenoprotein N as a Novel Player at the Crossroads of Redox Signaling and Calcium Homeostasis. Antioxid Redox Sign. Apr 2010;12(7):893–904. https://doi.org/10.1089/ars.2009.2890. 18. Claeys KG. Congenital myopathies: an update. Dev Med Child Neurol. Mar 2020;62(3):297. https://doi.org/10.1111/dmcn.14365.

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19. Maggi L, Scoto M, Cirak S, et  al. Congenital myopathies— Clinical features and frequency of individual subtypes diagnosed over a 5-year period in the United Kingdom. Neuromuscul Disord. Mar 2013;23(3):195–205. https://doi.org/10.1016/j.nmd.2013. 01.004. 20. Jungbluth H, Sewry CA, Muntoni F. Core myopathies. Semin Pediatr Neurol. Dec 2011;18(4):239–249. https://doi.org/10.1016/j.spen. 2011.10.005. 21. Romero NB, Monnier N, Viollet L, et  al. Dominant and recessive central core disease associated with RYR1 mutations and fetal akinesia. Brain. Nov 2003;126(Pt 11):2341–2349. https://doi. org/10.1093/brain/awg244. 22. Ferreiro A, Monnier N, Romero NB, et al. A recessive form of central core disease, transiently presenting as multi-minicore disease, is associated with a homozygous mutation in the ryanodine receptor type 1 gene. Ann Neurol. Jun 2002;51(6):750–759. https://doi. org/10.1002/ana.10231. 23. Snoeck M, van Engelen BG, Kusters B, et al. RYR1-related myopathies: a wide spectrum of phenotypes throughout life. Eur J Neurol. Jul 2015;22(7):1094–1112. https://doi.org/10.1111/ene.12713. 24. Ferreiro A, Quijano-Roy S, Pichereau C, et  al. Mutations of the selenoprotein N gene, which is implicated in rigid spine muscular dystrophy, cause the classical phenotype of multiminicore disease: reassessing the nosology of early-onset myopathies. Am J Hum Genet. Oct 2002;71(4):739–749. https://doi.org/10.1086/342719. 25. Romero NB, Clarke NF. Congenital myopathies. Hand Clinic. 2013;113:1321–1336. 26. Wallgren-Pettersson C, Pelin K, Nowak KJ, et al. Genotype-phenotype correlations in nemaline myopathy caused by mutations in the genes for nebulin and skeletal muscle alpha-actin. Neuromuscul Disord. Sep 2004;14(8-9):461–470. https://doi.org/10.1016/j.nmd.2004. 03.006. 27. Heckmatt JZ, Sewry CA, Hodes D, Dubowitz V. Congenital centronuclear (myotubular) myopathy. A clinical, pathological and genetic study in eight children. Brain. Dec 1985;108(Pt 4): 941–964. https://doi.org/10.1093/brain/108.4.941. 28. Dahl N, Hu LJ, Chery M, et  al. Myotubular myopathy in a girl with a deletion at Xq27-q28 and unbalanced X inactivation assigns the MTM1 gene to a 600-kb region. Am J Hum Genet. May 1995; 56(5):1108–1115. 29. Tsilfidis C, MacKenzie AE, Mettler G, Barcelo J, Korneluk RG. Correlation between CTG trinucleotide repeat length and frequency of severe congenital myotonic dystrophy. Nat Genet. Jun 1992;1(3):192–195. https://doi.org/10.1038/ng0692-192. 30. Rutherford MA, Heckmatt JZ, Dubowitz V. Congenital myotonic dystrophy: respiratory function at birth determines survival. Archives of Disease in Childhood. 1989;64(2):191–195. https://doi. org/10.1136/adc.64.2.191. 31. Mahadevan M, Tsilfidis C, Sabourin L, et al. Myotonic-dystrophy mutation: an unstable CTG repeat in the 3’ untranslated region of the gene. Science. Mar 6 1992;255(5049):1253–1255. https://doi. org/10.1126/science.1546325. 32. Echenne B, Rideau A, Roubertie A, Sebire G, Rivier F, Lemieux B. Myotonic dystrophy type I in childhood. Long-term evolution in patients surviving the neonatal period. Eur J Paediatr Neuro. May 2008;12(3):210–223. https://doi.org/10.1016/j.ejpn.2007.07.014. 33. Verhaart IEC, Robertson A, Wilson IJ, et al. Prevalence, incidence and carrier frequency of 5q-linked spinal muscular atrophy—a literature review. Orphanet J Rare Dis. 2017;12(1). https://doi. org/10.1186/s13023-017-0671-8. 124-124. 34. Prior T.W., Leach M.E., Finanger E. Spinal Muscular Atrophy. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. 1993. 35. MacLeod MJ, Taylor JE, Lunt PW, Mathew CG, Robb SA. Prenatal onset spinal muscular atrophy. Eur J Paediatr Neurol. 1999;3(2): 65–72. https://doi.org/10.1053/ejpn.1999.0184. 36. Prior TW, Krainer AR, Hua Y, et  al. A positive modifier of spinal muscular atrophy in the SMN2 gene. Am J Hum Genet. Sep 2009;85(3):408–413. https://doi.org/10.1016/j.ajhg.2009.08.002.

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55. Kochhar PK, Schumacher RE, Sarkar S. Transient neonatal myasthenia gravis: refining risk estimate for infants born to women with myasthenia gravis. J Perinatol. 2021 https://doi.org/10.1038/ s41372-021-00970-6. 56. Norwood F, Dhanjal M, Hill M, et  al. Myasthenia in pregnancy: best practice guidelines from a U.K. multispecialty working group. J Neurol Neurosurg Psychiatry. May 2014;85(5):538–543. https:// doi.org/10.1136/jnnp-2013-305572. 57. Engel AG. Congenital Myasthenic Syndromes in 2018. Curr Neurol Neurosci Rep. 2018;18(8). https://doi.org/10.1007/s11910-0180852-4. 46-46. 58. Jephson CG, Mills NA, Pitt MC, et al. Congenital stridor with feeding difficulty as a presenting symptom of Dok7 congenital myasthenic syndrome. Int J Pediatr Otorhinolaryngol. 2010;74(9):991–994. https://doi.org/10.1016/j.ijporl.2010.05.022. 59. Ohno K, Tsujino A, Brengman JM, et  al. Choline acetyltransferase mutations cause myasthenic syndrome associated with episodic apnea in humans. Proceedings of the National Academy of Sciences of the United States of America. 2001;98(4):2017–2022. https://doi. org/10.1073/pnas.98.4.2017. 60. Zafeiriou DI, Pitt M, de Sousa C. Clinical and neurophysiological characteristics of congenital myasthenic syndromes presenting in early infancy. Brain Dev. 2004;26(1):47–52. https://doi. org/10.1016/s0387-7604(03)00096-2. 61. Tsao C-Y. Effective treatment with albuterol in DOK7 congenital myasthenic syndrome in children. Pediatr Neurol. 2016;54:85–87. https://doi.org/10.1016/j.pediatrneurol.2015.09.019. 62. Baets J, Deconinck T, De Vriendt E, et  al. Genetic spectrum of hereditary neuropathies with onset in the first year of life. Brain. 2011 https://doi.org/10.1093/brain/awr184. 63. Peredo DE, Hannibal MC. The floppy infant: evaluation of hypotonia. Pediatr Rev. 2009;30(9):e66–e76. https://doi.org/10.1542/ pir.30-9-e66. 64. Richer LP, Shevell MI, Miller SP. Diagnostic profile of neonatal hypotonia: an 11-year study. Pediatr Neurol. 2001;25(1):32–37. https://doi.org/10.1016/s0887-8994(01)00277-6. 65. Kuperberg M, Lev D, Blumkin L, et  al. Utility of whole exome sequencing for genetic diagnosis of previously undiagnosed pediatric neurology patients. J Child Neurol. Dec 2016;31(14):1534–1539. https://doi.org/10.1177/0883073816664836. 66. Nolan D, Carlson M. Whole exome sequencing in pediatric neurology patients: clinical implications and estimated cost analysis. J Child Neurol. Jun 2016;31(7):887–894. https://doi. org/10.1177/0883073815627880. 67. Tsang MHY, Chiu ATG, Kwong BMH, et al. Diagnostic value of whole-exome sequencing in Chinese pediatric-onset neuromuscular patients. Mol Genet Genomic Med. May 2020;8(5):e1205. https:// doi.org/10.1002/mgg3.1205. 68. Vissers LELM, van Nimwegen KJM, Schieving JH, et al. A clinical utility study of exome sequencing versus conventional genetic testing in pediatric neurology. Genet Med. 2017;19(9):1055–1063. 69. Waldrop MA, Pastore M, Schrader R, et  al. Diagnostic utility of whole  exome sequencing in the neuromuscular clinic. Neuropediatrics. Apr 2019;50(2):96–102. https://doi.org/10.105 5/s-0039-1677734. 70. Dimmock DP, Clark MM, Gaughran M, et  al. RCIGM Investi­ gators. An RCT of rapid genomic sequencing among seriously ill infants results in high clinical utility, changes in management, and low perceived harm. Am J Hum Genet. 2020;107(5):942–952. 71. Kingsmore SF, Cakici JA, Clark MM, et al. RCIGM Investigators. A randomized, controlled trial of the analytic and diagnostic performance of singleton and trio, rapid genome and exome sequencing in ill infants. Am J Hum Genet. 2019;105(4):719–733.

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58

Neonatal Seizures JENNIFER C. KEENE, NIRANJANA NATARAJAN, AND SIDNEY M. GOSPE JR.

KEY POINTS • Neonatal seizures are common. • Clinical assessment alone is insufficient for diagnosis, and EEG evaluation is necessary. • Seizures are often symptomatic of an underlying cause requiring investigation. • Confirmed seizures should be treated with antiseizure medications.

Neonatal Seizures Seizures in the neonate occur in 2 to 4 per 1000 live births and are a cause of neonatal morbidity and mortality.1–3 Frequently, this onset is a neurologic emergency, requiring prompt and thorough diagnostic investigations and therapeutic interventions. Seizures in the newborn may be transient due to electrolyte abnormalities, the harbinger of underlying brain injury or developmental abnormalities, or the initial presentation of an underlying epilepsy. The clinical appearance of seizures in the neonate differs from that seen in older infants and children. Seizures themselves may be subtle, or without clinical manifestations, and challenging to differentiate from other involuntary movements in the neonate. There are ongoing efforts to determine how aggressively to treat seizures, which medications to use, how long to treat, and the impact of neonatal seizures on neurodevelopmental outcomes. This chapter discusses the diagnosis, neurophysiologic criteria, etiologic considerations, treatment, and prognosis of neonatal seizures. For the purposes of this chapter, the term seizure refers to an epileptic event: that is, an event with an electrographic correlate.

Classification of Neonatal Seizures Seizures in the neonate often are often difficult to clinically differentiate from nonepileptic movements and may present differently than seizures in older infants or children. In 2021, the International League Against Epilepsy (ILAE) published a new framework for the classification of neonatal seizures.4 The updated classification system emphasizes the need to incorporate electroencephalography (EEG) evaluation (Fig. 58.1), as fewer than 50% of paroxysmal clinical events are correctly identified as seizure versus non-seizure, with poor inter-observer agreement, regardless of the observer’s specialty.5 The ILAE classification system recognizes that approximately 50% to 80% of neonatal

seizures are electrographic only and categorizes electroclinical seizures as either (1) motor seizures characterized by abnormal movements, (2) nonmotor seizures characterized by autonomic changes or behavioral arrest, or (3) sequential seizures or unclassified (Table 58.1).6–9

Motor Seizure Automatisms Neonatal seizures with automatisms are typically manifested as oral–buccal–lingual movements, often with impairment of consciousness. They may be seen in conjunction with other seizure types, such as clonic or sequential seizures. These seizures often appear voluntary and are notoriously difficult to determine clinically. Seizures may have associated vital sign changes, including otherwise unexplained fluctuations in heart rate, blood pressure, or oxygen saturation. As more benign movements may mimic the motor features of these seizures, confirmation with EEG is mandatory. Clonic Seizures Clonic seizures are characterized by rhythmic movements with a rapid flexor phase followed by a slower extension phase persisting despite flexion of the affected limb. Movements may be symmetric or asymmetric. Clonic seizures can be mistaken for nonepileptic phenomena such as tremor or jitteriness and may be differentiated by the rhythmicity of the event and its ability to be suppressed or altered by changes in positioning. Focal clonic or hemiclonic seizures can be seen in neonates with injury localized to a specific site, such as a perinatal stroke or another cerebrovascular event.10–13 Multifocal seizures—clonic seizures that arise, at times, from multiple locations—can be seen in neonates with multifocal or generalized brain abnormalities, such as hypoxic-ischemic encephalopathy. Myoclonic Seizures Myoclonic movements are rapid, lightning fast (72 hours) or markedly abnormal EEG pattern is associated with poor outcome in this setting.98,99

Cerebrovascular Lesions Ischemic or hemorrhagic lesions of either arterial or venous origin are associated with a high risk of seizure in the newborn.70–74 In term neonates with perinatal arterial stroke, seizure is the most common clinical presentation, accounting for between 70% and 90%, followed by hypotonia or feeding difficulties.75,76 Neonates with cerebral infarction often are otherwise healthy in appearance, with reassuring presentation, not consistent with asphyxia. The use of neuroimaging with magnetic resonance imaging is necessary to demonstrate the focal lesion.77,78 In preterm infants, intraventricular hemorrhage is the most common cause of seizures79,80 and is the etiology of seizures in as many as 45% of EEG-confirmed seizures. Seizures in preterm newborns are thought to be underestimated, as studies prospectively assessing seizure frequency in high-risk preterm neonates find a higher incidence than in those where EEG is obtained in response to a clinical event.53,79,81 Cerebral venous infarction may also result in neonatal seizures.74 This may occur in the setting of systemic infection, dehydration, or poor feeding leading to cerebral venous sinus thrombosis. In preterm infants, venous thrombosis may result in periventricular hemorrhagic infarction within the deep white matter, which may be complicated by seizures.81 Infants requiring congenital heart defect repair, with persistent pulmonary hypertension of the newborn, or requiring extracorporeal membrane oxygenation have an increased risk of seizures caused by recurrent hypoxia hypotensive injury and embolic infarction. EEG monitoring following cardiac surgery demonstrates approximately 10% of neonates experience clinical or subclinical seizures82–86 and in children undergoing extracorporeal membrane oxygenation up to 30% demonstrate seizures.86,87 The anticoagulation necessary for extracorporeal membrane oxygenation circuit use may convert an ischemic injury to a hemorrhagic one, with a risk of edema or herniation. The presence of seizures is associated with increased inpatient mortality and worsened neurodevelopmental outcomes.82–84

Metabolic Derangements Hypoglycemia, along with electrolyte disturbances such as hypocalcemia, hypomagnesemia, hyponatremia, or hypernatremia may result in seizures. Repletion of glucose and correction of electrolyte levels is imperative for treatment.

Hypoglycemia Hypoglycemia is generally accepted as a glucose level less than 47 mg/dL, although the definition remains controversial.100,101 Hypoglycemia may coexist with hypoxic-ischemic injury or with hypocalcemia, both of which may also result in seizures. Jitteriness, tremors, and abnormal tone may be present in neonates with hypoglycemia, mimicking seizures. Persistent or profound hypoglycemia may result in cerebral injury, classically described as white matter injury or occipital injury.102,103 Seizures should first be treated by correction of hypoglycemia. Particularly if cerebral injury occurs, seizures may persist despite correction and require treatment with ASMs. Infants with hypoglycemia and cerebral injury may later develop occipital lobe epilepsy, although the severity of the epilepsy varies.104

Hypocalcemia Hypocalcemia is defined as a total calcium level of less than 8.0 mg/dL (2 mmol/L) in term neonates and less than 7.0 mg/ dL (1.75 mmol/dL) in preterm neonates or an ionized calcium of less than 4.8 mg/dL (1.2 mmol/L) in term infants and less than 4.0 mg/dL (1 mmol/L) in premature infants.105 Neonates with hypocalcemia may present with seizures secondary to increased excitability of the cell membrane,106 thus resulting in exaggerated startles, jitteriness, myoclonic jerks, or seizures.107,108 Hypocalcemic seizures should be treated with calcium repletion. Hyponatremia and Hypernatremia Hyponatremia is a cause of seizures across the life span106; however, it is a relatively rare cause in neonates. When present, this may reflect iatrogenic causes, renal failure, a transient or constitutional defect in the mineralocorticoid pathway, or an inappropriate secretion of antidiuretic hormone.109 Hypernatremic seizures are also rare in neonates but may be secondary to inadequate breastfeeding110 or iatrogenic from the administration of intravenous solutions with high sodium concentrations.111

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Drug Withdrawal and Intoxication Newborns of mothers with prenatal substance use may be at an increased risk of seizures in the neonatal period. Prenatal exposure to opiates can result in neonatal abstinence syndrome, which, in severe cases, can result in seizures.112 Similarly, perinatal exposure to alcohol intoxication is associated with withdrawal seizures.113 Cocaine can produce seizures in neonates either secondary to intoxication, from withdrawal,114,115 or from neonatal stroke, which in turn increases the risk of seizures. Exposure to other stimulants, such as methamphetamine, may be associated with a withdrawal syndrome accompanied by jitteriness, tremor, and exaggerated startle, but seizures have not been typically reported.116 Maternal use of SSRIs such as fluoxetine, paroxetine, and sertraline may also result in withdrawal symptoms including tremors, jitteriness, vomiting, diarrhea, and sleep disturbance. In some cases, convulsions may be present as a component of the withdrawal syndrome.117 EEG remains imperative in diagnosis, however, as many abnormal movements noted may have an EEG correlate.

Congenital Brain Malformations Approximately 9% of neonates presenting with seizures are found to have brain malformations.80 These disorders are caused by alterations in stages of induction, segmentation, proliferation, migration, synaptogenesis, and myelination and are discussed in greater detail elsewhere in this text. Encephalopathy is typically present and may coexist or be mistaken for birth asphyxia. Many brain dysgenesis disorders lack specific physical examination findings, but magnetic resonance neuroimaging is appropriate to evaluate for underlying brain malformations. Neonates with brain dysgenesis and seizures in the neonatal period have an exceptionally high likelihood of subsequently developing epilepsy and requiring prolonged use of ASMs.118

Inborn Errors of Metabolism Genetic biochemical abnormalities are rare causes of neonatal seizures, accounting for between 1% and 4% of cases.119 Although uncommon, consideration of this etiology is imperative, as specific treatments may be available for some causes, based on the enzymatic defect uncovered. In cases where treatment is not available, prognostic implications remain essential. Inborn errors of metabolism causing seizures may be placed in three categories: defects in neurotransmission; disorders of energy production; and metabolic disorders resulting in brain malformation, destruction, or dysfunction.120 Examples of each are given below, although an extensive review of inborn errors is beyond the scope of this chapter. Signs suggestive of an inborn error of metabolism include seizures that start prenatally, refractory seizures requiring multiple ASMs, progressive clinical worsening, or deterioration of the EEG.121 Some neonates may have an initial presentation consistent with HIE, thus a high level of clinical suspicion is necessary in neonates with refractory seizures. Specific neuroimaging may demonstrate characteristic lesions supporting a metabolic etiology.122 Defects in neurotransmission include glycine encephalopathy and pyridoxine-dependent epilepsy. Glycine encephalopathy, also known as nonketotic hyperglycinemia, is due to deficiencies in the ability to cleave glycine. Glycine has both inhibitory and excitatory neurotransmitter activities, and glycine encephalopathy presents with apnea, myoclonic seizures, and burst suppression on EEG. In retrospect, mothers will often note that significant

hiccups were present in utero, representing fetal myoclonic seizures. Seizures may initially respond to benzodiazepines, but, long term, patients develop early myoclonic encephalopathy, or Ohtahara syndrome.20,21 Pyridoxine-dependent epilepsy is an uncommon but treatable cause of neonatal seizures, caused by deficiency of α-aminoadipic semialdehyde dehydrogenase, an enzyme involved in the lysine catabolic pathway. In retrospect, mothers may report paroxysmal in utero movements representing seizures, and newborns may present with seizures, encephalopathy, and hypotonia in the first few days of life.123,124 In some patients with pyridoxine-dependent epilepsy, lactic acidosis and other biochemical abnormalities may be present, mimicking features of neonatal encephalopathy secondary to hypoxia or ischemia. It is an autosomal recessive condition, caused by a genetic mutation in ALDH7A1, and affected patients have elevated levels of α-aminoadipic semialdehyde (AASA) in blood and urine,123,124 which is the standard screening laboratory evaluation. Recommended treatment and evaluation of neonates with refractory status epilepticus include an empiric trial of intravenous pyridoxine while carefully monitoring EEG for treatment response. Examples of disorders of energy production and utilization include urea cycle defects and glucose transporter type 1 (GLUT1) deficiency. Urea cycle defects may present with encephalopathy and seizures in the setting of hyperammonemia as toxic breakdown products accumulate. Treatment includes dialysis or exchange transfusion while determining the enzymatic defect. Glucose transport to the brain is mediated by GLUT1. Reduced glucose transport through the blood-brain barrier results in hypoglycorrhachia (cerebrospinal fluid glucose levels less than 45 mg/ dL or a ratio of cerebrospinal fluid glucose to serum glucose of 6 months) α-tocopherol supplementation in extremely low birth weight (ELBW) infants may increase the performance intelligence quotient.56

Vitamin K In the United States, 0.5 to 1.0 mg phytonadione (vitamin K) is routinely administered at birth by intramuscular injection to prevent hemorrhagic disease of the newborn. There are oral dosing regimens reported in the literature, but there is a lack of evidence to support routine alternative use.57 Genetic polymorphisms in the vitamin K–dependent coagulation system may cause some preterm infants to be at higher risk of developing intraventricular hemorrhage.58 Proteins induced by vitamin K absence are the most sensitive indicators of vitamin K status, but prothrombin time and coagulation studies are commonly used.

Options for Enteral Nutrition When clinicians are considering enteral feeding in neonates, there are several basic choices that they must make. First and foremost is the choice of base diet for the infant, with three

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options commonly used: maternal milk, donor human milk, or preterm formula. Once this decision has been made, clinicians must decide (1) when to initiate enteral feeding, (2) concomitant medical conditions that may affect feeding, (3) how to advance the feeding volumes, and (4) how to feed the infant, for example, by mouth, by gravity bolus via a nasogastric (NO)/orogastric (OG) tube, or by timed or continuous infusion via NG/ OG tube. Because of the specific nutritional needs of preterm infants (primarily the requirement for higher protein and mineral intake than that provided by human milk alone) and critically ill late-preterm/term infants (increased caloric and protein requirements), there is an additional decision to be made, and that is determining when human milk fortification will be initiated, what to fortify the milk with, and how to manage ongoing milk fortification.

Human Milk Exclusive breastfeeding is recommended for all infants through 6 months of age. Continued breastfeeding for 12 months or beyond is advocated by the World Health Organization (WHO) and the AAP. Not all those who give birth and lactate are female or identify themselves as female. It is therefore appropriate to ask parents what pronouns they prefer when addressing issues surrounding lactation and breastfeeding. Some suggested terms include “lactating person/parent,” “mother’s own milk,” “parent’s milk,” and “father’s milk.”59 The term “mother’s own milk” in this chapter refers to any parent’s milk belonging to that infant.

Benefits of Human Milk Human milk (HM) is considered the ideal source of nutrition for all infants.60 HM feeding has been associated with a greatly reduced incidence of gastroenteritis, otitis media, respiratory illnesses,61 and allergic and autoimmune disease,62 and is recommended as the exclusive diet for infants less than 6 months of age.60 In premature infants, a HM diet has been associated with a decreased incidence of late-onset sepsis, increased intestinal motility and gastric emptying, improved feeding tolerance, and general antiinflammatory effects.63,64 Most notably, breast milk has been associated with a 6- to 10-fold decrease in the risk of developing NEC than those fed formula).65–67 Human milk diets have also been associated with a reduction in bronchopulmonary dysplasia with proportionate decrease based on percentage of MBM.68 Furthermore, HM diets are associated with decreased time to full enteral feeds, decreased hospital length of stay (LOS),64,68–70 and decreased rates of rehospitalization in preterm infants.71 These beneficial effects on time to full enteral feeds, LOS, and time on parenteral nutrition have also been shown in late preterm/term infants with surgical intestinal disorders.72 Neurodevelopmental Outcome Effects Longer duration of breastfeeding and greater exclusivity of breastfeeding are associated with better receptive language at age 3 years and with higher verbal and nonverbal IQ (intelligence quotient) at age 7 years,73 as well as enhanced white matter development in exclusively breastfed infants.74 In ELBW preterm infants, maternal milk was associated with higher motor, cognitive, and behavioral scores on BSD-II at 18-month and 30-month neurodevelopmental follow-up. This was a dose-dependent response with an estimated increase of 0.5 in IQ for every 10 mL/kg increase in breast milk in the diet.71 Similarly, there was a dose-dependent increase in hippocampal and gray matter volume, as well as overall

intracranial volume for each day VLBW infants were fed greater than 50% mother’s own milk (MOM).75

Human Milk Nutrient Content Protein

Human milk is comprised of approximately 70% whey proteins and 30% casein compared to bovine milk, which is predominantly casein with less than 20% whey. The percentage of whey:casein in human milk varies by the stage of lactation, and wanes to 50:50 late in lactation.76 The inverted ratio of whey:casein in human milk, as compared to bovine milk, lends to a very different amino acid profile. Glutamine is the most abundant free amino acid in human milk and has several key functions, including providing ketoglutaric acid for the Krebs cycle, a key energy source for intestinal epithelial cells and perhaps providing a substrate for neurotransmitters.77 Glutamine levels rise over 20-fold from colostrum to mature milk. Whey proteins in HM include α-lactalbumin, β-lactoglobulin, serum albumin, immunoglobulins, lactoferrin and peptide hormones such as growth hormone and insulin-like growth factors, epidermal growth factor, b-cellulin, TGF-α and platelet-derived growth factor. Other proteins include lysozyme, casein, lipase and amylase, bifidus factor, folate-binding protein, α1-antitrypsin, antichymotrypsin, and haptocorrin.78 The most abundant protein in HM is α-lactalbumin, which functions both as a nutritional protein source for the infant as well as an essential component for lactose synthesis in the mammary gland itself. Several proteins, such as lactoferrin, lysozyme, and immunoglobulins, play a role in innate host defense and are particularly resistant to acid hydrolysis in the GI tract. Protein content of preterm human milk is higher than that of term milk (2.2 g/dL vs. 1.2 g/dL) and both show a significant decrease in the first month and continued decline over the course of lactation, both leveling out around 0.9 to 1.0 g/dL by 3 months of lactation (Table 59.2).79

Colostrum

The protein content of colostrum is very high due in part to the passage of larger bioactive proteins and trophic factors, such as IgA and growth factors, through the mammary epithelium than found in mature milk. Colostrum is also high in cellular content, human milk oligosaccharides (HMOs), lactobacillus, and antioxidant compounds, all of which provide a trophic environment for the newly colonizing neonatal intestine. In the animal model, colostrum and colostrum protein concentrate have been shown to stimulate mucosal growth and increased tight junctions in the epithelium.

Carbohydrate

The two main sources of carbohydrates in human milk are lactose and HMOs. Lactose is a disaccharide comprised of galactose and glucose monosaccharides produced in the mammary gland by the enzyme system lactose synthase, a complex of galactosyltransferase and α-lactalbumin. The transcription of α-lactalbumin, which is essential to human milk synthesis, is regulated by the hormone prolactin, and is only active in the mammary gland during pregnancy and lactation. Unlike protein and fat, lactose content is not influenced by maternal diet, nor does it vary or decline during lactation, and is similar between preterm and term human milk.80

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CHAPTER 59

Enteral Nutrition

877

TABLE 59.2 Composition of Preterm and Term Human Milk

Energy (kcal/dL)

Protein (g/dL)

Fat (g/dL)

Lactose (kcal/dL)

Oligosaccharides (g/dL)

Week 1

60 (45–75)

2.2 (0.3–4.1)

2.6) (0.5–4.7)

5.7 (3.9–7.5)

2.1 (1.3–2.9)

Week 2

71 (49–94)

1.5 (0.8–2.3)

3.5 (1.2–5.7)

5.7 (4.1–7.3)

2.1 (1.1–3.1)

Weeks 3–4

77 (61–92)

1.4 (0.6–2.2)

3.5 (1.6–5.5)

6.0 (5–7)

1.7 (1.1–2.3)

Weeks 10–12

66 (39–94)

1.0 (0.6–1.4)

3.7 (0.8–6.5)

6.8 (6.2–7.2)

NA

Week 1

60 (44–77)

1.8 (0.4–3.2)

2.2 (0.7–3.7)

5.8 (4.2–7.4)

1.9 (1.1–2.7)

Week 2

67 (47–86)

1.3 (0.8–1.8)

3.0 (1.2–4.8)

6.2 (5–7.3)

1.9 (1.1–2.7)

Weeks 3–4

66 (48–85)

1.2 (0.8–1.6)

3.3 (1.6–5.1)

6.7 (5.3–8.1)

1.6 (1–2.2)

Weeks 10–12

68 (50–86)

0.9 (0.6–1.2)

3.4 (1.6–5.2)

6.7 (5.3–8.1)

NA

Preterm

Term

Values are given as the mean ± 2 standard deviations. NA, Not available. Modified from Gidrewicz DA, Fenton TR. A systematic review and meta-analysis of the nutrient content of preterm and term breast milk. BMC Pediatr. 2014;14:216.

Human Milk Oligosaccharides HMOs are complex sugar molecules found in human milk which are unique to each mother. HMOs are comprised of five monosaccharide building blocks: galactose (Gal), glucose (Glc), N-acetylglucosamine (GlcNAc), fucose (Fuc), and the sialic acid (Sia) derivative N-acetylneuraminic acid (Neu5Ac). All HMOs consist of a lactose backbone (Galb1–4Glc) at the reducing end, which can then be elongated/branched by the addition of a variety of disaccharides. These elongated/branched chains can then be fucosylated or sialylated. HMOs are often classified by the presence or absence of Neu5Ac, which results in either a sialylated (acidic) or nonsialylated (neutral) HMO, both of which can be fucosylated.81 The presence of fucosylated HMOs is genetically determined by the mother’s secretor (expression of Se gene) and Lewis blood group status. One particular HMO, disialyllacto-Ntetraose (DSLNT), seems to confer particular protection against NEC. Although the exact mechanism of this protection remains to be elucidated, it suggests a very structure-specific and potentially host receptor-mediated effect.81 HMOs in bovine milk are not structurally similar to those found in human milk; hence, formula is not a source of HMOs for the infant. Colostrum HMO content is higher than in mature milk and can reach up to 20 to 25 g/L. As the milk matures, this concentration declines to 5 to 20 g/L, which still exceeds the total milk protein concentration. HMOs are generally resistant to the stomach’s acidic environment and degradation from pancreatic enzymes and arrive at the colon intact.82 Roles of Human Milk Oligosaccharides Prebiotics: Promote the growth of certain but not all Bifidobacterium, such as B. infantis, which may keep potentially harmful bacteria in check as they compete for limited nutrient supply.83 Antiadhesive antimicrobials: HMOs resemble intestinal cellsurface glycan molecules and act as decoy receptors to prevent viral, bacterial, and protozoan pathogen binding.

Modulators of intestinal epithelial cell responses: HMOs may also directly modulate host intestinal epithelial cell responses by altering expression of sialylated cell surface glycans which many pathogenic bacteria such as Escherichia coli use to adhere to the host’s intestinal epithelial cells. Immune modulators: In addition to local effects of HMOs on mucosa-associated lymphoid tissue, HMOs may also act to modulate the systemic immune response as approximately 1% of HMOs are absorbed into the systemic circulation. Here they have been postulated to influence lymphocyte maturation and enhance the shift towards a more balanced Th1/Th2 cytokine response and decrease production of IL-4 which may contribute toward food allergy prevention (Fig. 59.1).82

Fat Fat provides 50% of the energy in human milk. The lipid system in human milk is structured in a way that facilitates fat digestion and absorption. In human milk, fat exists as organized fat globules containing an outer protein coat and an inner lipid core. The type of fatty acids (high palmitic 16:0, oleic 18:1, linoleic 18:2ω-6, and linoleic 18:3ω-3), their distribution on the triglyceride molecule (16:0 at the 2-position of the molecule), and the presence of bile salt–stimulated lipase are important components of the lipid system in human milk. Fat content of preterm milk is higher than that of term milk in the first 2 weeks (2.2 to 3.5 g/dL in preterm milk vs. 1.8 to 3.0 g/dL in term milk) (see Table 59.2).9 Fat content of human milk differs among women, changes during the day, rises slightly during lactation, and increases dramatically within a single milk expression. The variability in total fat content is unrelated to maternal dietary fat intake. Because it is not homogenized, the fat separates out of human milk on standing. The separated fat may adhere to collection containers, feeding tubes, and syringes and thus may not be delivered to the infant, compromising energy intake. The variability in the fat content of human milk may be used to advantage in the premature infant. Most milk transfer during

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PA RT XI I I

A

Gastrointestinal System and Nutrition

B

Prebiotics – HMO

C

Antiadhesive Antimicrobials

+ HMO

+ HMO

– HMO

Intestinal Epithelial Cell Modulators – HMO

+ HMO

altered proliferation, differentiation, apoptosis

D

altered glycan expression

Immune Modulators – HMO

+ HMO

T cell

differential gene expression

T cell

Th1

Th2

Th1

Th2

F

Brain Development Nutrients – HMO

E

?

Modulators of Leukocyte Rolling and Adhesion – HMO Rolling

Achesion

Cell cycle shifts

+ HMO

!

+ HMO Leucocyte

Migration

EC Subendothelial tissue

EC

subendothelial tissue

EC

• Fig. 59.1  Postulated Human Milk Oligosaccharides (HMO) Effects. HMOs may benefit the breast-fed

infant in multiple different ways. (A) HMOs are prebiotics that serve as metabolic substrates for beneficial bacteria (green) and provide them with a growth advantage over potential pathogens (purple). (B) HMOs are antiadhesive antimicrobials that serve as soluble glycan receptor decoys and prevent pathogen attachment. (C) HMOs directly affect intestinal epithelial cells and modulate their gene expression, which leads to changes in cell surface glycans and other cell responses. (D) HMOs modulate lymphocyte cytokine production, potentially leading to a more balanced Th1/Th2 response. (E) HMOs reduce selectin-mediated cell–cell interactions in the immune system and decrease leukocyte rolling on activated endothelial cells, potentially leading to reduced mucosal leukocyte infiltration and activation. (F) HMOs provide sialic acid as potentially essential nutrients for brain development and cognition. (Bode L. Human milk oligosaccharides: every baby needs a sugar mama. Glycobiology. 2012;22[9]:1147–1162.)

a feeding occurs in 10 to 15 minutes, but continued milk expression yields a milk with a progressively higher fat content. Thus, the “hindmilk” has a higher fat content than the earlier “foremilk.” The fat content of hindmilk may be 1.5- to 3-fold greater than that of foremilk. The use of hindmilk in selected cases may provide the infant with additional energy. Hindmilk and foremilk contain similar concentrations of nitrogen, calcium, phosphorus, sodium, and potassium. Copper and zinc concentrations decline by approximately 5% from foremilk to hindmilk. The differences between foremilk and hindmilk should also be considered in terms of the distribution of calories. Fat and protein account for 42% and 12%, respectively, of the calories in foremilk and 55% and 9% of the calories in hindmilk. The long-term feeding of hindmilk thus could have a negative effect on protein status. A greater proportion of protein calories (10% to 12%) is recommended for premature infants.

Essential Fatty Acids The essential fatty acids, linoleic and linolenic acids, are present in ample quantities in human milk and commercial formula. Without an adequate intake of these fatty acids, essential fatty acid deficiency (thrombocytopenia, dermatitis, increased infections, and delayed growth) can develop in as little as 1 week. Only 0.5 g/ kg/day of essential fatty acids (~4% of total energy intake) will prevent the deficiency. α-Linolenic acid is an important precursor for synthesis of both eicosapentaenoic acid and docosahexaenoic acid (DHA). The very long chain polyunsaturated fatty acids arachidonic acid (AA) (20:4ω-6) and DHA (22:6ω-3) are found in human milk but not bovine milk and are components of phospholipids found in brain, retina, and red blood cell membranes. AA and DHA functionally have been associated with body growth, vision, and cognition. In addition, the fatty acids are integral parts of prostaglandin metabolism. When their diet was supplemented

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CHAPTER 59

with polyunsaturated fatty acids, formula-fed premature infants had red blood cell concentrations of DHA paralleling those of similar infants fed human milk. Follow-up studies of such supplemented infants suggest improvements in visual acuity compared with infants that received no supplementation but of similar magnitude to that in infants fed human milk.84 Improvement in cognitive measures during the first year of life has also been shown. Both AA and DHA are now added to premature formula. The recommended intakes for DHA and AA are 11 to 27 mg/100 kcal and 16 to 39 mg/100 kcal, respectively.85–87

Carnitine Carnitine is synthesized from lysine and methionine and serves as an important effector of fatty acid oxidation in the mitochondria. The provision of carnitine in the diet results in improved fatty acid oxidation. Human milk contains abundant carnitine, and all infant formulas are supplemented with carnitine.

Human Milk Enzymes Human milk contains enzymes that aid the infant in nutrient digestion. α-Amylase, the enzyme responsible for most of polysaccharide digestion, is not fully developed at birth, even in term infants, who have only 0.2% to 0.5% of adult activity. Mammary amylase is active at the pH of both the stomach and the duodenum and can aid in the digestion of glucose polymers and starches. Although human milk does not contain substrate for α-amylase, this enzyme may aid in digestion of feedings, including infant formula or HMFs that contain complex carbohydrates. Lipases (similar to pancreatic lipase) are present in human milk and aid in digestion of triglycerides such that a significant fraction are broken down into free fatty acids and glycerol before digestion in the small intestine. Bile salt–stimulated lipase, a lipase present in human milk, is highly active because of its wide substrate specificity: it hydrolyzes monoacylglycerols, diacylglycerols, and triacylglycerols, as well as cholesterol esters. This enzyme is also stable in the duodenum and resistant to the low pH of the stomach.76

Vitamins and Minerals Some vitamins and minerals such as thiamine, riboflavin, vitamin B6, vitamin B12, choline, vitamin A, vitamin C, vitamin D, selenium, zinc, and iodine appear to be rapidly secreted into milk. Maternal dietary intake and states of depletion can substantially affect concentrations of these components in the breast milk. Maternal intake, however, has little effect on concentrations of calcium, magnesium, and iron secreted into breast milk.80 The vitamin and mineral content of preterm MOM multicomponent human milk fortifiers are shown in Table 59.3.

Preterm Milk Recent studies of preterm milk analysis show a similar decline in protein content of mother’s own milk from ~1.6 to 2.2 g/dL on the first day after delivery to 1.2 to 1.6 g/dL by day 28. This decline was more pronounced in white mothers compared to black mothers.88 Of note, maternal factors including parity, mode of delivery, prepregnancy body mass index (BMI), previous breastfeeding status, and maternal diet, as well as neonatal factors such as umbilical artery Doppler flows, neonatal AGA or SGA status, gestation, and weight at birth appear to have no impact on the macro- and

Enteral Nutrition

879

micro-nutrient content of the breastmilk.79 Micronutrients such as vitamin D, zinc, calcium, and phosphorus also decline over the first month post-partum and highlight the need for multi-nutrient fortification for preterm infants. Sodium content was significantly lower in milk of mothers of infants born less than 28 weeks’ gestation compared to those born greater than 28 weeks’ gestation, which can be particularly problematic as the sodium losses for those infants in urine and stool are greater and this can contribute to growth failure.88

Special Issues/Contraindications to Mother’s Own Milk Contraindications to breastfeeding and the use of mother’s own milk vary throughout the world depending on the risks/benefits to the infant to not breastfeed/receive mother’s own milk. In the United States, the following sets of guidelines are generally endorsed (Table 59.4).

Breastfeeding and Substances of Abuse In addition to the direct risks of contamination of breastmilk by alcohol or drugs, substance use disorders often expose the infant to associated behaviors or conditions that place them independently at higher risk. Although substance use crosses all socioeconomic boundaries, low socioeconomic status, low levels of education, poor prenatal care, food insecurity, and poor nutrition also play a role. Polysubstance abuse is common (drugs, alcohol, tobacco), and adulterants to the drugs, infectious diseases, and mental illness add to the burden of risk to the breastfeeding infant. Despite these multifaceted risks, the proven benefits of human milk and breastfeeding must be carefully considered and weighed.89 Studies evaluating the outcomes of these risks/exposures are inherently flawed as the infant has already likely been exposed to these circumstances in utero. Cocaine and phencyclidine hydrochloride (PCP) have both been detected in high concentrations in human milk and have been reported to cause infant intoxication.90 Other than the drugs discussed below, there is little to no data on other drugs of abuse, as ethical considerations preclude controlled studies.

Opioids Short courses of most low-dose prescription opioids can be safely used for episodic pain by a breastfeeding mother. Codeine, however, should be used with caution as CYP2D6 ultra-rapid metabolizers may experience high morphine (metabolite) blood levels, potentially placing the infant at increased risk. Information is lacking on the safety of breastfeeding with the use of moderate to high doses of opioids for longer periods of time, nor is there data available for transitioning mothers from short-acting opioids to opioid maintenance therapy while breastfeeding.

Methadone As the concentration of methadone excreted in human milk is low, women on stable methadone maintenance regimens should be encouraged to breastfeed regardless of their methadone replacement dose. Despite this low excretion rate, provision of breastmilk and breastfeeding have been shown to reduce the severity and duration of neonatal opioid withdrawal syndrome (NOWS)

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TABLE 59.3 Comparison of Nutrient Content of Preterm Mother's Own Milk + Multicomponent Fortifiers

Per 100 kcal

Similac HMF Hydrolyzed Proteina

Enfamil HMF High Proteinb

Enfamil HMF Standard Proteinc

Prolact +4 H2MFd

Protein (g)

3.58

4

3.4

3

Fat (g)

4.98

6

6

5.7

Carbohydrate (g)

10.4

7.9

8.7

9.2

Vitamin A (IU)

1238

1240

1240

93.2

Vitamin D (IU)

149

200

200

10

Vitamin E (IU)

5.3

6.2

6.2

0.5

Vitamin K (μg)

10.3

7.9

7.9

0.2

Thiamin (vitamin B1) (μg)

224

200

200

10.1

Riboflavin (vitamin B2) (μg)

362

300

300

30.8

Vitamin B6 (μg)

226

150

150

6.1

Vitamin B12 (μg)

0.6

0.68

0.68

0

Niacin (μg)

4279

4000

4000

223.4

Folic acid (μg)

32.9

35

35

6.1

Pantothenic acid (μg)

1489

1190

1190

264.7

Biotin (μg)

24.8

4.1

4.1

0.5

Vitamin C (ascorbic acid) (mg)

43.7

20

20

4.2

Sodium (mg)

47

57

57

70.8

Potassium (mg)

148

98

98

108.3

Chloride (mg)

113

88

88

83.5

Calcium (mg)

152

145

145

139.4

Phosphorus (mg)

85

80

80

78.5

Magnesium (mg)

12.1

5.3

5.3

10.3

Iron (mg)

0.59

1.9

1.9

0.1

Zinc (mg)

1.66

1.37

1.37

1.1

Copper (μg)

131

101

101

112.4

Manganese (μg)

9.9

10.7

10.7

112.4

Osmolality (mOsm)

450

350

330

360

http://abbottnutrition.com/brands/products/similac-human-milk-fortifier-hydrolyzed-protein-concentrated-liquid. https://www.hcp.meadjohnson.com/s/product/a4R4J000000PpQRUA0/enfamil-liquid-human-milk-fortifier-high-protein. c https://www.hcp.meadjohnson.com/s/product/a4R4J000000PpQmUAK/enfamil-liquid-human-milk-fortifier-standard-protein. d http://www.prolacta.com/Data/Sites/14/media/PDF/mkt-180-prolact-hmf-nutrition-labels.pdf. HMF, Human milk fortifier; IU, international unit. a

b

treatment.91 Similar results and recommendations apply for buprenorphine treatment for maternal opioid use disorder.

Marijuana Marijuana is a particularly difficult substance to establish breastfeeding policy for given the differences in legality across state lines, although it currently remains illegal at the federal level. It is also difficult to assess the risk/benefit balance across levels of use from occasional use to heavy use. Δ9-Tetrahydrocannabinol (THC),

the psychoactive component found in marijuana, is concentrated up to eight times that found in maternal serum.92 Once ingested or inhaled, it is rapidly distributed to fat tissues such as adipose and brain, where it may be stored for weeks to months. Because of this long half-life, metabolites may be found in neonatal urine and feces for several weeks, making it extremely difficult to differentiate the occasional versus chronic user, although number of daily uses and time to last use correlate with levels of Δ9-THC in the milk.93 Also concerning is the increase in potency of marijuana from approximately 3% in the 1980s to 12% in 2012. These

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Enteral Nutrition

881

TABLE 59.4 Contraindications to Breastfeeding and the Use of Human Milk

Contraindications to Breastfeeding and Use of Expressed Breast Milk Infant is diagnosed with classic galactosemia. Mother is infected with the human immunodeficiency virus.a Mother is using an illicit street drug, such as PCP (phencyclidine) or cocaine. (Narcotic-dependent mothers who are enrolled in a supervised methadone program and have a negative screening for human immunodeficiency virus (HIV) infection and other illicit drugs should be encouraged to breastfeed.) Mother has suspected or confirmed Ebola virus disease.

Temporary Restrictions on Breastfeeding and Use of Expressed Breast Milk Mother is infected with untreated brucellosis. Mother is taking certain medications.b Mother is undergoing diagnostic imaging or treatment with radiopharmaceuticals. Mother has an active herpes simplex virus (HSV) infection. (Can breastfeed directly from the unaffected breast if lesions on the affected breast are covered completely to avoid transmission.)

Temporary Restrictions on Breastfeeding, but May Use Expressed Breast Milk Mother has active, untreated tuberculosis. (The mother may resume breastfeeding once she has been treated appropriately for 2 weeks and is documented to be no longer contagious.) Mother has active varicella (chicken pox) infection that developed within 5 days prior to delivery to 2 days following delivery. See section on HIV/undetectable viral load for additional considerations. For the most up-to-date information available on medications and lactation, refer to LactMed. https://www.cdc.gov/breastfeeding/breastfeeding-special-circumstances/contraindications-to-breastfeeding.html.

a

b

issues complicate long-term neurodevelopmental studies. In utero exposure during periods of brain development can have profound effects on brain maturation, leading to long-lasting changes in cognitive function and behavior. Given the long-term neurobehavioral concerns, a mother wishing to breastfeed should be counseled to eliminate or reduce their use/exposure to marijuana.

Alcohol Alcohol use during pregnancy has been well-documented to be associated with fetal alcohol syndrome, birth defects, preterm birth, spontaneous abortions, and immune dysregulation. Despite the fact that many women reduce or completely eliminate alcohol use during pregnancy, more than half of women in the United States return to consuming alcohol at least occasionally while breastfeeding.94 Levels of alcohol in human milk parallel those found in maternal serum and effects on the neonate range from somnolence to poor feeding to concern for effects on psychomotor development. Typical recommendations for consumption of alcohol and breastfeeding involve the 2/2/2 rule: no more than 2 (4 oz) glasses of wine or 2 beers, followed by at least a 2-hour waiting period before resuming breastfeeding. A more detailed nomogram based on maternal weight and amount of alcohol consumed has been published and is available online at the Canadian Motherisk program.95,96

Human Immunodeficiency Virus/Undetectable Viral Load in Human Immunodeficiency Virus Breastfeeding in high-income countries (HICs) by women living with human immunodeficiency virus (HIV) remains a contentious issue. There is a dichotomy of advice regarding infant feeding and HIV in the US. The WHO advocates that all new

mothers should breastfeed regardless of their status, while the AAP, American College of Obstetricians and Gynecologists, and Centers for Disease Control and Prevention (CDC) continue to recommend formula feeding by mothers living with HIV to eliminate the risk of postnatal transmission. Approximately 8700 HIV-infected women give birth in the United States in 2006. With current interventions, mother-tochild HIV transmission during pregnancy and labor is very low: under 1%. In the absence of antiretroviral prophylaxis, postnatal infection risk appears to be highest in the first 4 to 6 weeks of life, ranging from 0.7% to 1% per week. The risk continues for the duration of breastfeeding. Two large studies showed that late postnatal transmission risk, after 4 to 6 weeks of age, was 8.9 infections per 100 child-years of breastfeeding (approximately 0.17%/ week) and was constant throughout this period. Breastfeeding transmission rates with antiretroviral prophylaxis administered to either the infant or the mother, although low, are still 1% to 5%, and transmission can occur despite undetectable maternal plasma RNA concentrations. Factors associated with increased risk of HIV transmission via human milk include high maternal plasma and human milk viral load, low maternal CD4+ cell count, longer breastfeeding duration, breast abnormalities (e.g., mastitis, nipple abnormalities), oral lesions in the infant, mixed breastfeeding and formula feeding in the first few months of life (compared with exclusive breastfeeding), and abrupt weaning. Antiretroviral drugs taken by the mother have differential penetration into human milk, with some drugs achieving concentrations much higher or lower than maternal plasma concentrations. The decision to breastfeed with an undetectable HIV viral load is a multifaceted one and requires a thoughtful discussion between the clinician and parent on medication compliance, duration of zero viral load, commitment to

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exclusive breastfeeding, and the overall risks/benefits to the infant and mother.

COVID-19 COVID-19 was declared a public health emergency of international concern by the WHO in early 2020 and spread into a worldwide pandemic soon thereafter. Concern for possible transmission of the virus via breast milk led to initial restrictions on breastfeeding and use of MOM. To date, live, replicatable virus has not been isolated from colostrum or breast milk of mothers positive for SARS-CoV-2 and there has been no convincing evidence for infant infection from breastmilk.97 The risk of SARS-CoV-2 transmission to the neonate is primarily via contact with infectious respiratory secretions from the mother, caregiver, or other person with SARS-CoV-2 infection. Breastfeeding and provision of breastmilk should continue to be encouraged as the benefits to both the infant and mother outweigh the risks. The CDC has published guidance on safe breastfeeding and handling of breastmilk with COVID-19. Donor milk banks perform extensive screening of their donor mothers for travel and illnesses, including viruses such as COVID-19. In addition, the milk is then pasteurized under conditions which have been shown to kill other viruses such as influenza and SARS-CoV, as cold storage alone is insufficient to kill these viruses.98,99

COVID Vaccination Women receiving SARS-CoV-2 mRNA vaccines have shown robust secretion of IgA, IgM, and IgG antibodies against the virus in their breastmilk for 6 weeks after vaccination.100,101 The second dose of vaccine further increased levels of IgG in the breastmilk, while IgA remained constant. These antibodies showed neutralizing effects against SARS-CoV-2, providing passive immune transfer to neonates through breastmilk, which may indicate a potential protective effect against infection in the infant. This suggests a critical role for breastmilk IgG in neonatal immunity against SARS-CoV-2 which is similar to the mechanism of protection from several other viral pathogens such as HIV, respiratory syncytial virus, and influenza. The difference in antibody isotype transfer in breastmilk (IgG in vaccine, IgA in natural infection) likely reflects differences in antibody profile programming between naturally acquired SARS-CoV-2 infection (mucosal) versus vaccination (intramuscular).100 Whether breastmilk IgG or IgA will provide greater neonatal protection remains unclear.

Donor Human Milk Although MOM is the ideal source of nutrition for at-risk infants, especially the VLBW infant, access to sufficient MOM is often problematic. Admission to an intensive care unit has been shown to impact initiation of pumping, volume of milk pumped per day, and rates of breastfeeding at discharge. A recent study from Children’s Hospital of Philadelphia examined these issues in their cardiac ICU. Rates of initiation of pumping were higher among mothers whose babies were inborn (96%) versus mothers who were separated from their infant after birth because of transport to a tertiary care center (67%).102 Factors that affect provision of maternal milk include separation of mother and infant after delivery, stress of having a critically ill infant, lack of lactation support, and clinician opinion. There is now general consensus from multiple expert panels that pasteurized donor human milk should be provided to VLBW infants as a supplement or alternative to MOM when

maternal milk is insufficient in supply.103,104 Newer data on the advantages of donor milk as a supplement/alternative for MOM in late preterm and term infants with high level of ­disease severity (CHD, CDH, surgical intestinal disorders) is also evolving. The majority of donor human milk currently used in NICUs in North America is processed and dispensed from the 31 member banks of the nonprofit Human Milk Banking Association of North America (HMBANA). With expanded criteria for donor milk usage, and the availability for families to buy milk directly from these milk banks for home use, there has been an exponential increase in the amount of milk processed over the past 20 years, from less than 500,000 oz in 2000 to over 7.4 million ounces of milk dispensed in 2019. Human milk processed and dispensed by HMBANA is obtained from healthy donors, most of whom delivered term infants and who undergo extensive screening by HMBANA milk banks, both verbally and in written questionnaires. Donor screenings include detailed inquiries regarding international travel as well as recent illness history including family members in the home. They also require a medical release form to be completed by each donor’s licensed healthcare provider. Serologic testing of donors includes human immunodeficiency virus, human T-lymphotropic virus 1 and 2, hepatitis B, hepatitis C, and syphilis. Pooled milk is then processed by a Holder pasteurization, where the milk is heated to 62°C for 30 minutes, allowed to cool, then aliquoted and frozen for shipping. Samples of each batch of pasteurized milk undergo bacteriologic screening. Holder pasteurization is not only highly effective in eliminating all bacterial contamination but eliminates all viruses as well, including members of the SARS (severe acute respiratory syndrome) and MERS (Middle East respiratory syndrome) families. Since the inception of these screening practices in 1985, there has never been an incident of disease transmission or a negative outcome in an infant due to the processing or distribution of pasteurized donor human milk by an HMBANA member bank. There are several for-profit companies that also supply donor human milk to NICUs and families. Prolacta Bioscience (City of Industry, CA) uses a process similar to Holder pasteurization to process the donated milk. Their screening process is more extensive and, in addition to serologic testing of the mother, the milk is DNA fingerprinted against the mother and tested for drugs of abuse and adulteration. Prolacta is currently the only source of human milk-based fortifiers for both preterm and term infants. Medolac Laboratories (Lake Oswego, OR) and Ni-Q (Wilsonville, OR) both use a proprietary version of retort processing which exposes the milk to sterilization by heating to 121°C for 5 min, with added pressure of 15 pounds per square inch above atmospheric pressure. This shelf-stable milk does not require refrigeration until after opening and has a shelf life or 1 to 2 years. This milk is an alternative for NICUs that may not have the storage space or volume of usage for a dedicated -80°C freezer and is an option for families who wish to supplement their own milk supply without the use of informal milk sharing.

Differences Between Maternal and Donor Human Milk Donor human milk has several major differences when compared to mother’s own milk. Most milk is donated by mothers of term infants and generally obtained later in the course of lactation. Consequently, donor milk is less calorically dense and contains less protein than mother’s own milk from term and preterm infants. Analysis of 415 sequential milk samples from 273 donors showed marked reduction in both energy content and protein. Fat content

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CHAPTER 59

was the most variable, leading to a mean energy content of 19 kcal/oz, while 25% of samples were less than 17 kcal/oz and 65% were less than 20 kcal/oz. Processing, container changes, and tube feeding also lead to further decreases in fat content, as human milk fats adhere to the plastics typically used to manufacture these products.105 Protein content was decreased from estimates of ~1.4 g/dL in mother’s own milk to 0.9 to 1.1 g/dL, with over a third of the samples having a protein content of less than 1 g/dL.106 A recent metaanalysis by Perrin et al. showed substantial differences between the AAP and American Dietetic and Nutrition published nutritional content values for DHM (donor human milk) and published results from 14 studies. Protein and fat content, as well as total energy, were the most variable between samples, and lower than published norms, and may reflect donor pools and methodological differences in measurements.107 Micronutrients such as vitamin D, zinc, calcium, and phosphorus also decline over the first month postpartum and highlight the need for multinutrient fortification for preterm infants. Sodium content was significantly lower in milk of mothers of infants born less than 28 weeks’ gestation compared to those born greater than 28 weeks’ gestation, which can be particularly problematic as the sodium losses for those infants in urine and stool are greater, and this can contribute to growth failure.88 Commercial suppliers of DHM have proprietary processes for balancing macro- and micro-nutrient content between batches and label their products with nutritional content information. Some HMBANA milk banks have pools specifically from mothers who deliver preterm to deliver higher protein content to the smallest infants. Many milk banks also label their pasteurized DHM (PDHM) with total energy and/or nutritional content information. There are also substantial effects of the pasteurization and sterilization methods on the growth factors and immune components of donor human milk. In both methods, Lactobacillus and lymphocytes including B and T cells are destroyed. There is also marked reduction in lactoferrin, erythropoietin, IL-10, IL-1β and IFN-γ. Notably, there is little to no change in electrolytes, vitamins, and iron, as well as lysozyme and HMO integrity, although the composition will be very different to each baby than their MOM. The impact of these differences is highlighted in a recent study by de Halleux et al., in which babies were fed diets of raw MOM, pasteurized MOM (P-MOM), and PDHM and individually fortified, giving equal caloric, protein, and fat content among the groups. The groups fed MOM and P-MOM had substantial increases in weight gain and length and most of that increase was attributable to the raw MOM.108 These findings raise interesting questions about the effects of noncaloric/macronutrient components of human milk on growth and development.

Donor Milk as a Bridge to Breastfeeding for Term and Late-Preterm Infants Late preterm infants (LPIs), born between 34 and 36 6/7 weeks. gestational age, are at increased risk of morbidity and mortality, much of which is related to feeding difficulties. They have immature sleep-wake cycles that interfere with their feeding cues, weaker sucks, and early fatigue which lead to poor milk transfer and poor thermoregulation, all of which contribute to hypoglycemia, hyperbilirubinemia, and excessive weight loss that prompts readmission to the hospital and breastfeeding failure. Hospital policies often delineate formula as the only option to supplement breastfeeding and exclude LPIs from receipt of PDHM.109

Enteral Nutrition

883

A recent study from Mannel et al.110 examined the type of milk supplementation with LOS and breastfeeding status at discharge in LPIs supplemented with PDHM versus formula. Breastfed infants supplemented with expressed human milk and/or PDHM had a similar LOS to exclusively breastfed infants who required no supplementation. Exclusively formula-fed infants had significant longer LOS. In addition, formula supplementation of breastfed infants led to a 16% decrease in likelihood of breastfeeding at discharge compared to those that received PDHM supplementation. Supplementation with PDHM must be accompanied by robust lactation support in order to produce the desired effect of exclusive breastfeeding success, and policies must evolve to address both of these issues.111 Meeting the increased demand for PDHM to include this growing population of infants may stress an already limited resource and will need consideration.

Informal Milk Sharing Wet nursing and cross nursing have existed for thousands of years, being referenced in the Babylonian Code of Hammurabi and ancient Greco-Roman texts. Between the 11th and 18th centuries, the majority of aristocratic infants were fed by wet nurses, as breastfeeding was deemed “indecent.” The use of wet nurses declined in the 19th to 20th centuries, as did breastfeeding overall, with the advent of alternate milk sources and formula. With the renewed emphasis on the benefits of breastfeeding for the infant and the mother’s health, many families are again exploring the issue of milk sharing through direct wet nursing or cross nursing or attaining donor milk through informal sources such as the Internet or community-based milk sharing groups. Several studies have documented that milk sold for profit on Internet-based sites can pose greater risk than other milk sharing sites. Issues such as milk adulteration (mixing with other substances such as cow’s milk to extend the volume), improper storage/freezing methods, bacterial contamination, and lack of transparency of the donor’s health, medication, and social histories can greatly increase the risk to the infant.112,113 The 2017 Academy of Breastfeeding Medicine Position Statement addresses these concerns and offers recommendations for healthcare providers and families on the strategies to reduce the risk in obtaining milk from informal sources, as well as instructions for home pasteurization. Some HMBANA milk banks and for-profit companies now offer families the opportunity to purchase pasteurized/sterilized donor milk for home use.

Human Milk Fortification For the term infant, mother’s own milk will likely provide adequate protein and energy intake as long as feeding volumes are not restricted and the infant can consume approximately 180 to 200 mL/kg/day. Preterm infants, especially the very low birthweight (VLBW, 200 mg/dL) in an infant G) has been reported to cause TNDM in some individuals and PNDM in others, even within the same family. The reason for this variability is unknown.

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CHAPTER 87

Homozygous pathogenic variants in the gene SLC2A2, encoding the GLUT2 transporter, which transports glucose into the beta cell, have been reported in 4 unrelated patients with TNDM; parents were first cousins in 3 of these patients.107,109 Three of the patients presented with apparently isolated diabetes, but eventually, all four demonstrated findings associated with FanconiBickel syndrome (FBS). Biallelic pathogenic variants in SLC2A2 are known to cause FBS, whose features include renal Fanconi syndrome, poor growth, hepatomegaly, and impaired utilization of glucose and galactose.110 However, over 95% of patients with biallelic SLC2A2 pathogenic variants present with symptoms of FBS without evidence of neonatal diabetes, but the reason for this variable expressivity is unknown.

Nonsyndromic Causes of Permanent Neonatal Diabetes Mellitus Infants with neonatal diabetes without evidence of remission in the first year or two of life are classified as having PNDM. The most common cause of PNDM is heterozygous, activating pathogenic variants in the potassium channel subunit genes KCNJ11 and ABCC8 (more commonly KCNJ11), accounting for almost half of all patients with PNDM.111,112 These pathogenic variants decrease the potassium channel’s sensitivity to the cellular ATP concentration, keeping the channel inappropriately open and inhibiting insulin secretion. 20% of individuals with PNDM due to KCNJ11 pathogenic variants will also have developmental delay, epilepsy, and neonatal diabetes (DEND) syndrome.113 There are clear genotype-phenotype correlations within the KCNJ11 gene, with some pathogenic variants being associated with DEND syndrome and others with only PNDM. Patients with PNDM due to pathogenic variants in KCNJ11 and ABCC8 typically respond well to sulfonylureas.114 Interestingly, some neurologic features of DEND have also been reported to respond to sulfonylureas, highlighting the importance of the potassium channel in neuronal cells.115 Pathogenic variants within the INS are also a common cause of PNDM, found in approximately 10% of patients with PNDM. INS gene pathogenic variants can be homozygous (more common among offspring of consanguineous relationships) or heterozygous, but in both cases, the pathogenic variants lead to inadequate production of insulin protein.98,108,116 Rarer genetic causes of nonsyndromic PNDM include biallelic inactivating pathogenic variants in glucokinase (GCK), and the transcription factor PDX1.117,118 GCK serves as the “glucose sensor” of the beta cell, converting glucose into glucose 6-phosphate. PDX1 is a transcription factor necessary for the formation of the pancreas in utero. Heterozygous pathogenic variants in GCK are a relatively common cause of MODY, accounting for 20% to 50% of MODY patients. Therefore, GCK should be strongly considered in patients with PNDM who have a positive family history of MODY, mild fasting hyperglycemia, or gestational diabetes in a nonobese mother. Some patients with homozygous pathogenic variants of PDX1 have pancreatic agenesis, producing exocrine insufficiency in addition to PNDM, while in others, a pancreatic exocrine function is intact.118 Syndromic Causes of Neonatal Diabetes Mellitus In addition to the genes described above, there are multiple other known genetic causes of NDM, which are typically considered “syndromic” because they are often associated with other nonendocrine features. Although some syndromic forms of NDM present with other features (e.g., congenital heart defects), diabetes

Neonatal Hypoglycemia and Hyperglycemia

1267

is often the initial presentation, making early genetic diagnosis helpful as it can guide management and necessary screening. For example, patients with biallelic pathogenic variants in EIF2AK3 have Wolcott-Rallison syndrome, which usually presents with neonatal diabetes, while other features (skeletal dysplasia, developmental delays, and liver dysfunction) may not manifest until later. A quarter of NDM patients whose parents are consanguineous have Wolcott-Rallison syndrome, making it the most common cause of PNDM among this group of patients. The remaining syndromic causes of neonatal diabetes are listed in Table 87.3. Because of the considerable number of genetic causes of neonatal diabetes, sequencing multiple genes in parallel is typically the most efficient diagnostic approach. TABLE 87.3 Syndromic Causes of Neonatal Diabetes

Gene

Syndrome

Reference

EIF2AK3

Wolcott-Rallison syndrome

122,123

FOXP3

IPEX syndrome: severe diarrhea, type 1 DM, dermatitis, X-linked

124,125

GATA4

Neonatal and childhood onset DM, may have pancreatic hypoplasia, cardiac malformations, and neurocognitive defects

126

GATA6

Pancreatic agenesis, ± congenital heart defects

127

GLIS3

NDM with congenital hypothyroidism

128,129

HNF1B

Renal cysts and diabetes (RCAD), neonatal diabetes (NDM)

130

IER3IP1

NDM with microcephaly, lissencephaly, and epileptic encephalopathy

131,132

MNX1

NDM with neurologic features, Currarino syndrome (sacral agenesis, imperforate anus)

133,134

NEUROD1

NDM with cerebellar hypoplasia, sensorineural hearing loss, visual impairment

135

NEUROG3

NDM with congenital malabsorptive diarrhea

136,137

NKX2-2

NDM with developmental delays, hypotonia, short stature and hearing loss

134

PTF1A

NDM with pancreatic and cerebellar agenesis

138

RFX6

NDM with pancreatic hypoplasia, intestinal atresia, gall bladder hypoplasia (MitchellRiley syndrome)

139,140

SLC19A2

NDM with deafness and thiamine-responsive megaloblastic anemia (Rogers syndrome)

141

SLC2A2

NDM with renal dysfunction (Fanconi Bickel syndrome)

142

WFS1

Wolfram syndrome, DIDMOAD, low frequency sensorineural hearing loss, optic atrophy

143

PAX6

Neonatal diabetes with brain malformations, microcephaly, and microphthalmia

144

LRBA

Common variable immunodeficiency with autoimmunity

145

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Management of Neonatal Hyperglycemia

Suggested Readings

Management of hyperglycemia in the neonatal period is dictated by the clinical scenario and the results of genetic testing. Transient hyperglycemia is best managed by treating the underlying cause (e.g., sepsis). In addition to close monitoring of glucose, exogenous glucose administration can be decreased to approximately 3 mg/kg/min. If necessary, insulin treatment can commence, starting with a low-dose insulin infusion (e.g., 0.03 units/kg/h). Treatment of neonatal diabetes requires insulin, at least until a genetic diagnosis is made. For those with a genetic aberration at 6q24, insulin requirements usually drop quite quickly, and treatment is often discontinued by 12 weeks of age.119 Hyperglycemia may recur with intercurrent illness and then recurs in over half of children, generally at the time of puberty. Infants with an identified pathogenic variant in KCNJ11 or ABCC8 can be treated with sulfonylureas. Generally, it is best to gradually decrease insulin dosing as sulfonylurea treatment is initiated. Sulfonylurea dosing tends to be higher than typically used in adults. While over 90% of those with a KCNJ11 or ABCC8 pathogenic variant can successfully transition from insulin to sulfonylurea and maintain near normal glycemic control, the factors associated with sulfonylurea failure are the specific genetic variant and longer duration of diabetes.120 Treatment with sulfonylureas is not only effective in achieving euglycemia but also has led to improvements in neurological status for patients with DEND syndrome; this appears to be secondary to improved cerebellar perfusion.121

Adamkin DH. Neonatal hypoglycemia. Curr Opin Pediatr. 2016;28: 150–155. De Leon DD, Thornton PS, Stanley CA, Sperling MA. Hypoglycemia in the Newborn and Infant. Pediatric Endocrinology. Philadelphia: Elsevier; 2014. Lemelman MR, Letourneau L, Greeley SA. Neonatal diabetes mellitus: an update on diagnosis and management. Clin Perinatol. 2018;45: 41–59. Menon RK, Sperling MA. Carbohydrate metabolism. Semin Perinatol. 1988;12:157–162. Rubio-Cabezas O, Hattersley AT, Njolstad PR, et  al. Pediatric International Society for Adolescent Diabetes. 2014. ISPAD Clinical Practice Consensus Guidelines. The diagnosis and management of monogenic diabetes in children and adolescents. Pediatr Diabetes. 2014;15(Suppl 20):47–64. Stanley CA. Perspective on the genetics and diagnosis of congenital hyperinsulinism disorders. J Clin Endocrinol Metab. 2016;101: 815–826. Stanley CA, Rozance PJ, Thornton PS, et al. Re-evaluating “transitional neonatal hypoglycemia”: mechanism and implications for management. J Pediatr. 2015;166:1520. Stanley CA, Anday EK, Baker L, Delivoria-Papadopolous M. Metabolic fuel and hormone responses to fasting in newborn infants. Pediatrics. 1979;64:613–619. Thornton PS, Stanley CA, De Leon DD, et  al. Pediatric Endocrine Society. Recommendations from the Pediatric Endocrine Society for evaluation and management of persistent hypoglycemia in neonates, infants, and children. J Pediatr. 2015;67:238–245.

Acknowledgments We would like to thank the authors of the 9th edition of this chapter—Vandana Jain, Ming Chen, and Ram K. Menon— whose work was the starting point for our chapter.

References The complete reference list is available at Elsevier eBooks+.

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122. Julier C, Nicolino M. Wolcott-Rallison syndrome. Orphanet J Rare Dis. 2010;5:29. https://doi.org/10.1186/1750-1172-5-29. 123. Rubio-Cabezas O, et  al. Wolcott-Rallison syndrome is the most common genetic cause of permanent neonatal diabetes in consanguineous families. J Clin Endocrinol Metab. 2009;94:4162–4170. https://doi.org/10.1210/jc.2009-1137. 124. Tan QKG, Louie RJ, Sleasman JW. In GeneReviews (eds M. P. Adam et al.) (1993). 125. Letourneau LR, Greeley SAW. Congenital diabetes: comprehensive genetic testing allows for improved diagnosis and treatment of diabetes and other associated features. Curr Diab Rep. 2018;18:46. https://doi.org/10.1007/s11892-018-1016-2. 126. Shaw-Smith C, et al. GATA4 mutations are a cause of neonatal and childhood-onset. diabetes. Diabetes. 2014;63:2888–2894. https:// doi.org/10.2337/db14-0061. 127. De Franco E, et al. GATA6 mutations cause a broad phenotypic spectrum of diabetes from pancreatic agenesis to adult-onset diabetes without exocrine insufficiency. Diabetes. 2013;62:993–997. https://doi.org/10.2337/db12-0885. 128. Senee V, et al. Mutations in GLIS3 are responsible for a rare syndrome with neonatal diabetes mellitus and congenital hypothyroidism. Nat Genet. 2006;38:682–687. https://doi.org/10.1038/ ng1802. 129. Dimitri P, et al. Novel GLIS3 mutations demonstrate an extended multisystem phenotype. Eur J Endocrinol. 2011;164:437–443. https://doi.org/10.1530/EJE-10-0893. 130. Yorifuji T, et al. Neonatal diabetes mellitus and neonatal polycystic, dysplastic kidneys: Phenotypically discordant recurrence of a mutation in the hepatocyte nuclear factor-1beta gene due to germline mosaicism. J Clin Endocrinol Metab. 2004;89:2905–2908. https://doi.org/10.1210/jc.2003-031828. 131. Abdel-Salam GM, et  al. A homozygous IER3IP1 mutation causes microcephaly with simplified gyral pattern, epilepsy, and permanent neonatal diabetes syndrome (MEDS). Am J Med Genet A. 2012;158A:2788–2796. https://doi.org/10.1002/ajmg.a. 35583. 132. Shalev SA, et  al. Microcephaly, epilepsy, and neonatal diabetes due to compound heterozygous mutations in IER3IP1: insights into the natural history of a rare disorder. Pediatr Diabetes. 2014;15:252–256. https://doi.org/10.1111/pedi.12086. 133. Bonnefond A, et  al. Transcription factor gene MNX1 is a novel cause of permanent neonatal diabetes in a consanguineous family. Diabetes Metab. 2013;39:276–280. https://doi.org/10.1016/j. diabet.2013.02.007.

134. Flanagan SE, et al. Analysis of transcription factors key for mouse pancreatic development establishes NKX2-2 and MNX1 mutations as causes of neonatal diabetes in man. Cell Metab. 2014;19:146– 154. https://doi.org/10.1016/j.cmet.2013.11.021. 135. Rubio-Cabezas O, et al. Homozygous mutations in NEUROD1 are responsible for a novel syndrome of permanent neonatal diabetes and neurological abnormalities. Diabetes. 2010;59:2326–2331. https://doi.org/10.2337/db10-0011. 136. Pinney SE, et  al. Neonatal diabetes and congenital malabsorptive diarrhea attributable to a novel mutation in the human neurogenin-3 gene coding sequence. J Clin Endocrinol Metab. 2011;96:1960–1965. https://doi.org/10.1210/jc.2011-0029. 137. Rubio-Cabezas O, et  al. Permanent neonatal diabetes and enteric anendocrinosis associated with biallelic mutations in NEUROG3. Diabetes. 2011;60:1349–1353. https://doi.org/10.2337/db10-1008. 138. Sellick GS, et al. Mutations in PTF1A cause pancreatic and cerebellar agenesis. Nat Genet. 2004;36:1301–1305. https://doi.org/10.1038/ ng1475. 139. Smith SB, et al. Rfx6 directs islet formation and insulin production in mice and humans. Nature. 2010;463:775–780. https://doi. org/10.1038/nature08748. 140. Sansbury FH, et  al. Biallelic RFX6 mutations can cause childhood as well as neonatal onset diabetes mellitus. Eur J Hum Genet. 2015;23:1750. https://doi.org/10.1038/ejhg.2015.208. 141. Shaw-Smith C, et  al. Recessive SLC19A2 mutations are a cause of neonatal diabetes mellitus in thiamine-responsive megaloblastic anaemia. Pediatr Diabetes. 2012;13:314–321. https://doi. org/10.1111/j.1399-5448.2012.00855.x. 142. Sansbury FH, et al. SLC2A2 mutations can cause neonatal diabetes, suggesting GLUT2 may have a role in human insulin secretion. Diabetologia. 2012;55:2381–2385. https://doi.org/10.1007/ s00125-012-2595-0. 143. Rohayem J, et al. Diabetes and neurodegeneration in Wolfram syndrome: a multicenter study of phenotype and genotype. Diabetes Care. 2011;34:1503–1510. https://doi.org/10.2337/dc10-1937. 144. Johnson MB, et  al. Recessively inherited LRBA mutations cause autoimmunity presenting as neonatal diabetes. Diabetes. 2017;66:2316–2322. https://doi.org/10.2337/db17-0040. 145. Solomon BD, et  al. Compound heterozygosity for mutations in PAX6 in a patient with complex brain anomaly, neonatal diabetes mellitus, and microophthalmia. Am J Med Genet A. 2009;149A:2543–2546. https://doi.org/10.1002/ajmg.a.33081.

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Craniofacial Conditions

G. KYLE FULTON, MATTHEW S. BLESSING, AND KELLY N. EVANS

KEY POINTS • Craniofacial malformations can impact swallowing, breathing, hearing, vision, speech, and development and for some neonates can result in life-threatening airway compromise. • Early recognition and assessment of craniofacial conditions that include appropriate diagnostic studies, identification of associated health concerns, and family education can have a positive impact on the care and outcome of affected newborns. • Timely referral to or consultation with a multidisciplinary craniofacial team in a newborn with a craniofacial condition is an important step in the provision of coordinated medical and surgical management. Key members of the craniofacial team are shown in Box 88.1. A list of teams accredited by the American Cleft Palate-Craniofacial Association (ACPA) can be found on the ACPA website: https://acpa-cpf.org/acpa-familyservices/find-a-team/.

diagnosis. Approximately one-quarter of infants with cleft palate (CP) were found to have RS in a population-based, case-control study.1 RS is an etiologically and phenotypically heterogeneous disorder. In a large cohort study of 191 children with RS, 38% had isolated RS, 9% had a chromosome anomaly, 29% had a Mendelian disorder, and 24% had no detectable cause. Twentytwo Mendelian disorders were diagnosed, of which Stickler syndrome was the most frequent.2 The tremendous heterogeneity and lack of uniformly accepted diagnostic criteria for, or definitions of, RS make it challenging to know the true prevalence. In a review of 42 international studies, the estimated birth prevalence for RS ranged between 1:3900 and 1:122,400 (0.8 to 32.0 per 100,000), with a mean prevalence of 1:24,500.3

Phenotype

Micrognathia/Robin Sequence

While there is great variation in severity, RS is characterized by the following phenotypic features: micrognathia, g­lossoptosis, and resultant base of tongue-level upper airway obstruction (Fig.  88.1A, B).4 Cleft palate is a common additional feature, occurring in approximately 90%.5 A wide, U-shaped cleft is classic in RS and should prompt the provider to evaluate for any signs of micrognathia or airway obstruction, while the narrow, V-shaped cleft palate is more typical in infants without RS. Micrognathia, or a small and symmetrically receded mandible, is a subjective diagnosis, although assessing the maxillomandibular discrepancy ­(distance between the maxillary and mandibular alveolar ridges in the midline) can help with recognition. Glossoptosis is dynamic and defined as displacement of the tongue base into the oropharynx and hypopharynx. Tongue size varies across the spectrum of RS, and the severity of glossoptosis does not always correlate with the degree of micrognathia. Intraoral examination of the infant with glossoptosis may reveal a posteriorly positioned tongue, occasionally pulled up into a palatal cleft. Upper airway obstruction (often presenting with stertor, increased effort, or obstructive apnea) in infants with RS can be associated with feeding difficulties and challenges gaining weight. Clinical judgment can be made about whether the patient represents “isolated RS,” “RS plus (RS with other anomalies)” or a syndromic form of RS.

Diagnosis and Etiology

Intensive Care Unit Concerns

The triad of micrognathia, glossoptosis, and airway obstruction is known as Robin sequence (RS) or Pierre Robin sequence. Cleft palate is a common feature of RS, although not obligatory to the

Upper airway obstruction in RS is a result of tongue displacement toward the posterior pharyngeal wall or up into the cleft. The tongue can act as a ball valve, leading to inspiratory obstruction.

The neonatal care provider is often the first point of contact for a child born with a craniofacial malformation. Abnormalities of the face and head can be distressing to a new parent, who is immediately wondering, “Is my child going to look, feel, and develop ­normally?” Having a basic understanding of the relationship between craniofacial abnormalities and feeding, breathing, hearing, vision, speech, and overall development will help care providers to begin to counsel a family. Airway compromise is well described in multiple craniofacial syndromes, and early identification can be lifesaving. Prompt recognition of a constellation of anomalies pointing toward a syndrome or diagnosis will result in better-targeted evaluations and therapies for that patient. Tables 88.1 and 88.2 contain a concise presentation of potential ­intensive care unit (ICU) issues that may be encountered with craniofacial malformations and syndromes. This chapter highlights the most relevant craniofacial conditions that neonatal care providers will encounter. We describe here the diagnosis, etiology, phenotype, and potential ICU issues as well as basic management and screening recommendations to help guide neonatal practitioners in caring for an infant with craniofacial malformations.

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TABLE 88.1 Craniofacial Syndromes Commonly Associated With Cleft Lip and/or Cleft Palate

Syndrome

Phenotype

ICU Issues

OMIM

Robin sequencea

Micrognathia, glossoptosis with upper airway obstruction, cleft palate

Airway obstruction, feeding difficulties

261800

Stickler syndromea

Cleft palate, micrognathia, glossoptosis (Robin sequence), high myopia, risk of retinal detachment and blindness, midface hypoplasia, hearing impairment, arthropathy, pectus, short fourth and fifth metacarpals

Airway obstruction, feeding difficulties

180300, 604841, 184840, 614134, 614284, 609508

22q11.2 deletion syndrome (velocardiofacial syndrome, DiGeorge syndrome)a

Cleft palate and submucous cleft palate, small mouth, myopathic facies, retrognathia, prominent nose with squared-off nasal tip, hypoplastic nasal alae, short stature, slender tapering digits

Cardiac anomalies, airway obstruction, feeding difficulties, aspiration

192430, 188400, 611867

Opitz oculogenitolaryngeal syndrome (Opitz BBB/G syndrome)a

Hypertelorism, telecanthus, cleft lip and/or palate, dysphagia, esophageal dysmotility, laryngotracheoesophageal cleft (aspiration), hypospadias, bifid scrotum, cryptorchidism, agenesis of the corpus callosum, congenital heart disease, intellectual disability

Laryngotracheoesophageal clefting (stridor, feeding difficulties, choking, aspiration)

145410, 300000

Pallister–Hall syndromea

Cleft palate, flat nasal bridge, short nose, multiple buccal frenula, microglossia, micrognathia, malformed ears, hypothalamic hamartoblastoma, hypopituitarism, postaxial polydactyly with short arms, imperforate anus, genitourinary anomalies, intrauterine growth restriction

Laryngotracheoesophageal clefting (stridor, feeding difficulties, choking, aspiration), panhypopituitarism

146510

IRF6-related disorders (including Van der Woude and popliteal pterygium syndrome)

Cleft lip with or without cleft palate, cleft palate only, lower lip pits or cysts, ankyloglossia; popliteal pterygium syndrome will also have popliteal pterygia, bifid scrotum, cryptorchidism, finger and/or toe syndactyly, abnormalities of the skin around the nails, syngnathia and ankyloblepharon

Not anticipated

119300, 119500

CHARGE syndromea

Coloboma of the eye, heart malformations, choanal atresia, growth retardation, genital anomalies, ear abnormalities and/or deafness, facial palsy, cleft palate, dysphagia

Airway obstruction, bilateral choanal atresia, cardiac anomalies, feeding difficulties, aspiration

214800

Smith–Lemli–Opitz syndromea

Cleft palate, micrognathia, short nose, ptosis, high square forehead, microcephaly, hypospadias, cryptorchidism, ventricular septal defect, tetralogy of Fallot, hypotonia, intellectual disability, postaxial polydactyly, 2–3 toe syndactyly, defect in cholesterol biosynthesis

Cardiac anomalies, airway hypotonia, and airway obstruction

270400

Ectrodactyly, ectodermal dysplasia, and clefting syndrome

Cleft lip and/or palate, split-hand/split-foot, ectodermal dysplasia (sparse hair, dysplastic nails, hypohidrosis, hypodontia), genitourinary anomalies

Not anticipated

129900, 604292, 129400

Ankyloblepharon, ectodermal dysplasia, and clefting syndrome

Cleft lip with or without cleft palate, cleft palate only, intraoral alveolar bands, maxillary hypoplasia, ankyloblepharon (eyelid fusion), ectodermal dysplasia (sparse hair, dysplastic nails, hypohidrosis, anodontia)

Not anticipated

106260

Orofaciodigital syndrome

Median cleft of upper lip, cleft palate, accessory oral frenula, lobulated tongue with hamartomas, broad nasal root, small nostrils, syndactyly, brachydactyly, postaxial polydactyly, polycystic renal disease, agenesis of the corpus callosum

Not anticipated

311200

Kabuki syndromea

Cleft palate, arched eyebrow, long palpebral fissures, eversion of lateral third of lower eyelid, brachydactyly, short fifth metacarpal, cardiac anomalies, postnatal growth deficiency/dwarfism, intellectual disability

Cardiac anomalies

147920, 300867

Fryns syndromea

Cleft lip with or without cleft palate, micrognathia, coarse facies, diaphragmatic hernia, distal limb hypoplasia, malformations of the cardiovascular, gastrointestinal, genitourinary, and central nervous systems

Congenital diaphragmatic hernia, pulmonary hypoplasia; cardiac anomalies

229850

Miller syndrome (postaxial acrofacial dysostosis)a

Cleft palate (more than cleft lip), malar and mandibular hypoplasia, downslanting palpebral fissures, lower eyelid coloboma, microtia/atresia, conductive hearing loss, postaxial limb deficiency, absent fifth digit

Airway obstruction

263750

Continued

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TABLE 88.1 Craniofacial Syndromes Commonly Associated With Cleft Lip and/or Cleft Palate—cont’d

Syndrome

Phenotype

ICU Issues

OMIM

Treacher Collins syndrome (mandibulofacial dysostosis)a

Cleft palate, malar and mandibular hypoplasia, downslanting palpebral fissures, lower eyelid coloboma (missing medial lower eyelid lashes), microtia/atresia, conductive hearing loss

Airway obstruction

154500, 613717, 613715, 248390, 618939

Aarskog syndrome (faciodigitogenital syndrome)

Hypertelorism, widow’s peak, ptosis, downslanting palpebral fissures, strabismus, maxillary hypoplasia, broad nasal bridge with anteverted nostrils, occasional cleft lip and/or palate, floppy ears, brachydactyly, clinodactyly, joint laxity, shawl scrotum

Not anticipated

100050, 305400

Wolf–Hirschhorn syndrome (4p deletion syndrome)a

Cleft lip and palate, coloboma, hypertelorism, growth deficiency, microcephaly, intellectual disability, cardiac septal defects

Congenital diaphragmatic hernia, cardiac anomalies, seizures, airway hypotonia/obstruction

194190

Amnion rupture sequencea

Cleft lip and palate, oblique facial clefts, focal areas of scalp aplasia, constriction bands with terminal limb amputations and syndactylies, occasional anencephaly, encephalocele, and ectopia cordis

Encephalocele, oropharyngeal/ airway deformation

217100

Potential ICU issues. ICU, Intensive care unit; OMIM, online mendelian inheritance in man.

a

TABLE 88.2 Craniosynostosis Syndromes and Potential Airway Compromise

Syndrome

Key Features

Apert syndromea

Craniosynostosis (coronal > lambdoid > sagittal), acrobrachycephaly (steep, wide forehead and flat occiput), proptosis, hypertelorism, exotropia, trapezoid-shaped mouth, prognathism, invariable symmetric syndactyly of hands and feet, variable elbow fusion, cognitive impairment, narrow palate with lateral palatal swellings, widely patent sagittal suture connecting anterior and posterior fontanels

Crouzon syndromea

Tracheal Abnormalities

Midface Hypoplasia

OMIM

Tracheoesophageal fistula, tracheal cartilaginous sleeve less common

Significant maxillary hypoplasia, obstructive sleep apnea syndrome

101200

Craniosynostosis (coronal > lambdoid > sagittal), brachycephaly, prognathism, exophthalmos, papilledema, hypermetropia, divergent strabismus, atresia of auditory canals, Chiari type 1 malformation and hydrocephalus

Solid cartilaginous trachea or tracheal cartilaginous sleeve

Significant maxillary hypoplasia, obstructive sleep apnea syndrome

123500, 612247

Pfeiffer syndrome types I, II, and IIIa

Craniosynostosis (coronal > sagittal > lambdoid), brachycephaly, hypertelorism, proptosis, broad first digits with radial deviation, variable syndactyly and elbow fusion, cloverleaf skull

Solid cartilaginous trachea or tracheal cartilaginous sleeve

Significant maxillary hypoplasia, obstructive sleep apnea syndrome

101600

Muenke syndrome

Unilateral or bilateral coronal craniosynostosis, brachydactyly, downslanting palpebral fissures, thimble-like middle phalanges, coned epiphysis, carpal and tarsal fusions, sensorineural hearing loss, KlippelFeil anomaly

Mild maxillary hypoplasia, no airway compromise anticipated

602849

SaethreChotzen syndromea

Unilateral or bilateral coronal craniosynostosis, acrocephaly, brachycephaly, low frontal hairline, hypertelorism, facial asymmetry, ptosis, characteristic ear (small pinna with a prominent crus), fifth finger clinodactyly, partial 2–3 syndactyly of the fingers, duplicated halluces

Maxillary hypoplasia

101400

Carpenter syndrome

Craniosynostosis (coronal > lambdoid > sagittal), hypertelorism, proptosis, brachycephaly, brachydactyly, preaxial polysyndactyly, intellectual disability

Maxillary hypoplasia

201000

Jackson–Weiss syndrome

Craniosynostosis (coronal), acrocephaly, hypertelorism, proptosis, midface hypoplasia, radiographic abnormalities of the foot including fusion of the tarsal and metatarsal bones, 2–3 syndactyly, broad short first metatarsals and broad proximal phalanges

Maxillary hypoplasia

123150

Significant risk of airway morbidity. OMIM, Online mendelian inheritance in man.

a

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A

B

• Fig. 88.1  (A) Infant with Robin sequence and signifiC The principal physiologic sequelae of RS are the inability to effectively feed and breathe due to airway obstruction. In the immediate neonatal period, patients with RS may have increased inspiratory work of breathing, cyanosis, and apnea. Rising CO2 levels may be a signal of worsening airway obstruction and often precedes hypoxemia in the neonate with RS.6 Obstruction is more common in the supine position and can be exacerbated during feeding and in sleep or in any state where there is loss of pharyngeal tone. Chronic obstruction can lead to failure to thrive, carbon dioxide retention, pulmonary hypertension, and eventually right-sided heart failure (cor pulmonale). Airway exposure is often compromised in the infant with RS, which impacts the ability to safely intubate the neonate with RS.7 Airway obstruction is the main cause of feeding and growth issues in infants with RS. Feeding problems can also be related to abnormal coordination, primary swallowing dysfunction, pharyngeal hypotonia, and suction mechanics are complicated by the presence of a cleft palate. Increased energy expenditures because of the increased work of breathing may lead to failure to thrive if the infant is not receiving adequate caloric intake. Gastroesophageal reflux is common in infants with RS, as it is in other infants who have increased work of breathing, and may contribute to episodes of distress and aspiration or apnea.

Management First and foremost, the airway must be addressed. Placement of a nasopharyngeal (NP) airway or endotracheal tube may be required in an emergency, and it is important to realize that severe, life-threatening airway obstruction can present in the delivery room. RS features are not commonly noted before birth; however, if microgathia or maternal polyhydramnios is a prenatal concern, there should be heightened suspicion for worse airway

cant micrognathia. (B) U-shaped cleft palate. (C) Infant with Robin sequence and a nasopharyngeal tube in place.

• Box 88.1 K  ey Members of a Multidisciplinary Craniofacial Team These are the core members of the craniofacial team that follow a neonate through early adulthood. Each team has slightly different core and ancillary members, and frequently includes other specialists guided by patient-specific needs.

Typical Core Disciplines • Audiology • Dentistry • Feeding and Nutrition Specialist • Genetics • Neurosurgery • Nursing • Oral Surgery

• • • •

Orthodontics Otolaryngology Pediatrics Plastics and Craniofacial Surgery • Social Services • Speech and Language Pathology

Other ancillary but important disciplines that are frequently consulted depending on specific patient needs: Child Life, Cardiology, Gastroenterology, Neurodevelopmental Medicine, Ophthalmology, Psychology, Pulmonology, and Sleep Medicine

obstruction. Although uncommon, a prenatal diagnosis of micrognathia allows the involvement of neonatologists and otolaryngologists before and during delivery. Key members of the craniofacial team are shown in Box 88.1. Treatment protocols differ across institutions,8 and an example of the initial evaluation and clinical team discussion for the neonate with tongue-based airway obstruction is provided in Box  88.2. While the threshold for intervention and the management options differ substantially, most neonates with RS can be treated nonsurgically. A number of therapeutic maneuvers can be used to stabilize

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CHAPTER 88

• Box 88.2 E  valuation and Decision Making for Neonates With Tongue-Based Airway Obstruction Initial Evaluation in the Neonatal ICU • Physical examination (supine vs. prone): attention to craniofacial features, respiratory status, cardiac and limb differences • Evaluation for presence of glossoptosis, stertor, obstructive apnea, and work of breathing • Capillary blood gas and total CO2 level • Oxygen saturation monitoring • Growth parameters • Dysmorphology evaluation • Craniofacial and otolaryngology consultations • Consider genetics evaluation if there are multiple anomalies or a concerning family history (micrognathia, cleft palate, childhood hearing loss/myopia/joint problems) • Consider airway endoscopy (guided by airway severity and response to interventions) • Consider airway imaging (guided by airway severity and response to interventions)

Multidisciplinary Team Treatment Discussions May Address • Does the patient need escalation in care to treat airway obstruction? • Have appropriate subspecialty consults and evaluations been obtained? (Varies by institution, but can include specialists with expertise in neonatal intensive care, craniofacial and pediatric care, airway evaluations, airway surgery, jaw surgery, parent/family support) • Should the patient undergo CT imaging to assess the craniofacial bony anatomy, level(s) of airway obstruction, and candidacy for MDO (if so, when and how to proceed safely)? • Has the distal part of the airway been evaluated to look for other levels of airway obstruction? • Does the patient need a tracheostomy tube, or is he/she a candidate for mandibular distraction? • What is the family and social context? • What will the disposition be once airway has been stabilized? CT, Computed tomography; ICU, intensive care unit; MDO, mandibular distraction osteogenesis.

the upper airway in RS, ranging from positioning to surgery. Placing the baby in the prone or lateral decubitus position can improve airway patency to some degree, and has the potential to decrease work of breathing.9 When prone positioning fails to stabilize the airway, alternative approaches include the use of an NP airway, intraoral device such as the Tubingen palatal plate (TPP) or orthodontic airway plate (OAP), noninvasive positive pressure, treatment with tongue–lip adhesion (TLA), and mandibular advancement through distraction osteogenesis. An NP airway provides a temporary way to bypass the infant’s airway obstruction (see Fig. 88.1C). An endotracheal tube can be modified so that it can be passed through the nares into the hypopharynx above the epiglottis, bypassing the obstruction at the base of the tongue.10 The NP airway can be both diagnostic of isolated base of tongue level airway obstruction, and therapeutic, and in some institutions, the infant is discharged home with an NP airway in place.11 Infants are monitored with oximetry, and parents are taught NP airway suctioning and replacement. The TPP or OAP is a newer therapy in the United States but well established in Europe. This intraoral device can bring the tongue forward to improve airway patency in neonates and infants, allow for full oral feeding, and safe discharge home. Airway compromise and stability are assessed by physical examination, CO2 levels, oxygenation, overnight sleep studies, and growth, monitored over time.12,13 While trending oxygen and CO2 levels is considered the minimum assessments for RS,14 some

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centers recommend sleep studies routinely to aid in decision making and to assess the success of interventions.15 Improved infant normative sleep data, access to quality sleep studies, and understanding long-term outcomes will impact approaches to neonates at risk for early obstructive sleep apnea. The infant’s clinical status, a perceived need for long-term respiratory support, and failure of less invasive interventions will determine whether invasive surgery is recommended.16 Tracheotomy is considered a gold standard to bypass severe tongue-based airway obstruction, and the preferred option for infants who are not candidates for less invasive treatments, for example, those with multilevel airway obstruction and those who need longer-term mechanical ventilation. However, other surgical interventions may avoid a tracheostomy tube. Children with isolated airway obstruction at the base of the tongue without other medical comorbidities may be considered for mandibular distraction osteogenesis (MDO).17,18 The surgery consists of surgical osteotomy and placement of a distraction device to slowly increase mandibular length and bring the base of the tongue forward, thereby increasing the airway space. This procedure will not achieve respiratory stabilization in patients with concomitant airway anomalies, lung disease, central apnea, or the need for positive pressure ventilation. In some institutions, TLA may be a temporizing measure to reduce base of tonguelevel obstruction while allowing for mandibular growth.19 Airway endoscopy helps to delineate the level of obstruction, and computed tomography (CT) of the facial skeleton provides optimal understanding of jaw anatomy and tooth bud position before MDO. For many infants with RS needing an ICU, the patterns of obstruction are more complex. In addition to glossoptosis, other mechanisms may contribute to airway obstruction in individuals with RS, such as pharyngeal hypotonia and/or compromised airway clearance in the infant with a concomitant neurological disorder. Recognition of other causes of respiratory compromise, for example, poor secretion handling, laryngotracheomalacia, or ventilatory muscle weakness, affects treatment decisions. Children with RS associated with syndromes, skeletal dysplasia, or neurologic conditions may have multiple causes of respiratory compromise such that a tracheostomy may be the best approach to alleviate respiratory compromise. Thus infants with RS who have airway obstruction unresponsive to positional techniques for whom surgical options are being considered should have a comprehensive airway evaluation as well as a diagnostic evaluation for an underlying syndrome or associated malformations that might impact respiratory status and response to therapies. The multidisciplinary approach and considerations of all therapeutic options and potential outcomes should be considered for the neonate with RS requiring airway escalation. Nutrition can be maintained with a fortified breast milk or formula given by side-lying feeding using a cleft feeder, or via a feeding tube; placement of a surgical gastrostomy tube is more common among infants with a syndromic form of RS.20 Oral feeding can and should be introduced when the airway is stable, and consultation with a feeding therapist is crucial. As tone and tongue position improve, and growth ensues, swallow coordination and safe feeding can also improve. A formal swallow evaluation may be helpful for the infant with persistent feeding challenges. Close observation for symptoms of gastroesophageal reflux with proactive treatment to prevent reflux and aspiration should also be considered. Genetics consultation is recommended, as identification of an associated syndrome will have implications for treatment decisions and additional screening.

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Screening and Surveillance Syndrome diagnoses may become more apparent over time, and reassessments investigating a unifying diagnosis should be continued as the child with RS grows.21 Associated anomalies can impact respiratory function, including skeletal dysplasias. CNS anomalies and hypotonia will impact care needs and prognosis. Congenital heart defects are present in up to 25% of babies with RS who die in early infancy.22 It has been reported that a portion of individuals with RS experience developmental delay, cognitive impairment, and poorer school achievement.23 Overall morbidity and mortality are higher in syndromic RS, RS plus, and RS with associated neurological anomalies compared with isolated RS.24 Diagnostic work-up should include investigation of common associated anomalies and syndromes.25,26 Specific genetic and syndrome diagnosis will guide surveillance protocols, but for all infants and children with RS, we recommend: • An eye exam in the first 6 months of life to evaluate for ocular features of Stickler syndrome • Hearing assessment annually, more frequently if hearing loss is detected • Close monitoring of development and referral to early intervention services for developmental assessment, monitoring, and support • Monitoring for obstructive sleep apnea, with a low threshold for a sleep study referral

• Monitoring dental eruption, occlusion and facial growth over time; most children will benefit from orthodontic management, and some will be candidates for mandibular or bimaxillary advancement surgery in adolescence

Stickler Syndrome The most common syndrome associated with RS is Stickler syndrome (SS). Approximately one-third of individuals with RS will have Stickler syndrome.21 Stickler syndrome is most commonly an autosomal dominant (with variable expressivity) connective tissue disorder with ophthalmic, orofacial, auditory, and articular manifestations.27 SS may present with a wide range of findings, including RS, cleft palate without RS, hearing loss, or early onset osteoarthritis. Ocular forms of SS can present with congenital high myopia, cataracts, and risk for retinal detachment. Midface hypoplasia in SS can produce a flat and occasionally concave facial profile, and other facial features can include a depressed nasal bridge, short nose, anteverted nares, micrognathia, telecanthus, and epicanthal folds (Fig. 88.2). Hearing loss can be sensorineural with increasing prevalence with age (most common) with or without conductive hearing loss. Skeletal features associated with some forms of SS include early-onset arthritis, joint hypermobility, scoliosis, and kyphosis.24,28 The diagnosis of Stickler syndrome should be considered in any neonate with RS or a cleft palate, especially when associated with myopia or hearing loss. Spondyloepiphyseal dysplasia is not usually apparent in the newborn period. Mutations affecting multiple collagen genes have been associated with Stickler syndrome, and clinical molecular testing by sequence analysis is sensitive and available. More than 90% of individuals with Stickler syndrome are found to have a mutation in either COL2A1 or COL11A1.27 The diagnosis should also be considered in any newborn with a family history of RS or SS features. In addition to appropriate management of feeding, breathing, and growth (as described for RS), management of Stickler syndrome includes active detection of the ocular features of the syndrome, as the associated risk of retinal detachment and blindness are preventable. An initial ophthalmologic evaluation is recommended for all children with RS aged between 6 and 12 months or at the time of a definitive molecular diagnosis of Stickler syndrome and then routine surveillance thereafter.

Orofacial Clefts

• Fig. 88.2  Infant with Stickler syndrome, showing a flat face, depressed nasal bridge, and epicanthal folds. This infant also has Robin sequence and required tracheostomy.

Orofacial clefts of the primary and secondary palate are among the most common congenital anomalies. Classified as either cleft lip with or without cleft palate (CL±P) or cleft palate only (CPO), these two phenotypes are thought to be distinct in origin. On an average day in the United States, 17 infants are born with an orofacial cleft,29 and prevalence varies by phenotype (Table 88.3).

TABLE 88.3 Orofacial Clefting Prevalence and Relative Risk for Recurrence

Phenotype

Prevalence29

Babies Affected per Year in the United States29

Relative Risk for Recurrence for Offspring (%)40

Relative Risk for Recurrence for a Subsequent Sibling (%)40

Cleft lip with cleft palate

1 in every 1563 births

2518

4.1

4.6

Cleft lip without cleft palate

1 in every 2807 births

1402

3.5

2.2

Cleft palate

1 in every 1687 births

2333

4.2

3.3

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Diagnosis and Etiology

Anatomy

Cleft lip and palate is the most common type of orofacial clefting, followed by cleft lip, then CPO. Less prevalent are atypical clefts (macrostomia or lateral cleft, Tessier or oblique, and midline clefts). Unilateral CL±P is more common than bilateral involvement.1 A bifid uvula can be a normal variant, found in 2% to 4% of births, but can also be a sign of an associated submucous cleft palate, which can have the same functional impact as an overt CP.30 The causes of most orofacial clefts are unknown and are nonsyndromic (isolated) in 70% to 75% of infants with CL±P and approximately 55% of those with CPO.31,32 Neonates with orofacial clefting who are born prematurely or have low birth weight may have a higher incidence of associated congenital malformations.33 Racial and ethnic variation in the prevalence of clefts has been described. In the US, rates are closest to those of the area from which the population originated34 with the highest prevalence of CL±P found in Native Americans, followed by whites and Hispanics, and the lowest overall prevalence of CL±P demonstrated in African Americans.35 The cause of nonsyndromic clefts is complex and multifactorial, likely resulting from an interaction between environmental and genetic factors. Known environmental risk factors include maternal tobacco and alcohol use, anticonvulsant treatment, and nutritional status.34,36 There is some evidence showing a protective association with preconception folate supplementation in preventing nonsyndromic orofacial clefts.37–39 Although many candidate genes have been described, in the absence of a family history of cleft or lip pits, routine clinical genetic testing for a child with isolated CL±P is not recommended. Recurrence risk information for the parents of a child with CL±P or for the affected individual depends upon either the specific syndrome/genetic diagnosis or the empiric risks for those with nonsyndromic clefts. Recurrence risk for nonsyndromic clefts differs based on the cleft phenotype and the number of affected individuals in a family (see Table 88.3).40

Embryologic development of the primary palate begins early in gestation, and the upper lip and primary palate have usually fused by the seventh week of gestation. A failure of fusion of the medial and lateral nasal processes with the maxillary process produces CL±P. Clefts can affect the primary palate (lip, alveolus, or anterior portion of the hard palate that extends to the incisive foramen) and secondary palate (posterior hard palate and soft palate). Clefts of the primary and secondary palate can be unilateral or bilateral and complete or incomplete. A complete cleft of the primary palate leaves no residual tissue between the alar base and the lip, whereas an incomplete cleft does not extend through the floor of the nose (Fig. 88.3A–C, F). A submucous cleft palate is a defect in the musculature of the palate with intact overlying mucosa.

Phenotype The cleft of the primary and secondary palate affects facial shape and growth (see Fig. 88.3A–C). Children with cleft palate (CP) are at increased risk of eustachian tube dysfunction, recurrent otitis media, acquired hearing loss, as well as speech issues in childhood. Feeding difficulties, nasal regurgitation of feeds, and difficulty gaining weight may also occur in infants with a CP (submucous and overt clefts of the palate). Associated dental findings include hypodontia and natal teeth. Lateral facial clefting or macrostomia is pathogenically distinct from isolated CL±P and is often associated with syndromes, including craniofacial microsomia and Treacher Collins syndrome. Amniotic rupture sequence can be associated with oblique facial clefts and may be associated with underlying central nervous system (CNS) malformations and transverse limb anomalies. A true median cleft of the upper lip is the rarest type of facial cleft (see Fig. 88.3D). Midline clefts can be associated with other congenital defects as can be seen in orofaciodigital syndrome and frontonasal dysplasia, and CNS malformations are common in

A

B

C

D

E

F

• Fig. 88.3  (A) Infant with a unilateral incomplete cleft lip. (B, C) Infant with bilateral complete cleft lip and palate. (D) Infant with midline cleft and hypertelorism. He also has a frontonasal encephalocele. (E) Infant with premaxillary agenesis and holoprosencephaly. (F) Infant with Van der Woude syndrome with unilateral complete cleft lip and a lip pit (arrow).

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children with midline clefts. Some midline clefts are not true clefts but represent hypoplasia or agenesis of the primary palate or premaxillary agenesis, which can be associated with holoprosencephaly (HPE) sequence (see Fig. 88.3E). Infants with HPE often have a depressed nasal tip and a short columella and appear hypoteloric (compared with FND or frontonasal encephalocele, where a midline cleft may be present, but the infant has a broad nasal tip, wide columella and hypertelorism). Orofacial clefts are rarely associated with clefting of airway structures, such as cleft larynx or extension of clefting into the trachea. Opitz G/BBB syndrome is a multiple congenital anomaly syndrome characterized by facial anomalies (100% are hyperteloric and 50% have CL±P), genitourinary abnormalities (90% have hypospadias), and laryngotracheoesophageal (LTE) defects (present in 70%).41 Autosomal dominant and X-linked recessive forms of Opitz G/BBB syndrome are recognized. Pallister–Hall syndrome (PHS) is characterized by a constellation of findings that include hypothalamic hamartoma (resulting in seizures and pituitary dysfunction), polydactyly, airway clefting, and other anomalies (genitourinary, renal, pulmonary, and imperforate anus). Bifid epiglottis is the most common airway manifestation in PHS, although LTE clefts have been reported. LTE defects may range from LTE dysmotility in mild forms to laryngeal or tracheoesophageal clefts in more severe forms.

Syndromes Associated With Cleft Lip and/or Palate It is estimated that there are more than 400 syndromes associated with orofacial clefts.22 Associated malformations occur in about 30% of children with CL±P.42 In considering a diagnosis of a syndrome, one should categorize the type of cleft (CL±P, U-shaped or V-shaped cleft palate, or more atypical orofacial cleft) and look for any other malformations. Table 88.1 describes the syndromes most commonly associated with clefting, their key features, and potential ICU issues. A referral to a clinical geneticist is recommended when an underlying diagnosis is suspected.

Intensive Care Unit Concerns Most infants with CL±P do not require ICU care. Thus an infant with an apparently isolated cleft who develops significant respiratory or electrolyte abnormalities requiring ICU care should be considered syndromic until proven otherwise. In these infants, a genetics consultation should be pursued. The newborn with a midline cleft or premaxillary agenesis is at risk of serious underlying CNS anomalies, including HPE. In the presence of HPE, the detection of associated medical issues is essential. Endocrine abnormalities can arise because the midline malformation affects the development of the hypothalamus and the pituitary gland. Clinical manifestations include growth hormone deficiency, adrenal hypoplasia, hypogonadism, diabetes insipidus, and thyroid deficiency. Neurologic manifestations warrant close attention, including seizures, hypotonia, spasticity, autonomic dysfunction, and developmental delays. With an LTE cleft, there is communication between the airway and the esophagus, allowing tracheal aspiration of oral contents, including saliva and feeds. Clefting of the larynx may result in stridor, a hoarse cry, respiratory distress, swallowing dysfunction, feeding difficulties, regurgitation, aspiration, hypoxia, recurrent pneumonias, and eventually severe respiratory compromise if unrecognized. An infant boy with hypertelorism, hypospadias,

orofacial clefting, and symptoms of airway obstruction or aspiration should be evaluated for Opitz syndrome. Infants with PHS may also have respiratory distress due to airway clefting, as well as other potentially life-threatening clinical manifestations such as seizures and severe panhypopituitarism. Genetic evaluation and consideration of molecular testing for Opitz syndrome and PHS can be coordinated through a geneticist.

Management The specifics of management of orofacial clefting are centerspecific. Because of the potential impact of the orofacial cleft on breathing, eating, hearing, speech, facial growth, and dental health, it is recommended that infants and children with clefts be referred to a multidisciplinary care team for long-term management. Infants cared for with a multidisciplinary cleft or craniofacial team have better long-term functional and aesthetic outcomes.42 The nearest cleft team may be found through the American Cleft Palate-Craniofacial Association (ACPA) team listings. Overviews of recommended team care for patients with cleft lip/palate can be accessed electronically.43,44 On the initial assessment, the provider should assess the cleft and examine the infant for dysmorphic features and other anomalies. Hearing should be evaluated by evoked otoacoustic emissions or by brainstem auditory evoked response if the newborn does not pass the initial hearing screen.45 Although this finding is often attributed to middle ear effusion because of the high prevalence of middle ear disease in children with CP, the incidences of sensorineural hearing loss, conductive hearing loss, and mixed hearing loss are higher in children with clefts.46 A neonate with a complete cleft lip should be evaluated by a craniofacial or cleft team in the first 2 weeks of life, and some centers offer taping or presurgical molding (such as nasoalveolar molding) that can be initiated in early infancy. Many mothers will be able to breastfeed an infant born with an isolated cleft lip. Breastfeeding a baby with CP (with or without cleft lip) will prove extremely challenging because the open palate will not generate the negative pressure needed for sucking. Thus the mother of infants with CP with or without cleft lip should be encouraged to provide expressed breast milk with the use of a specialized cleft feeder. Lactation counselor support should be offered to all mothers to discuss feeding at the breast or pumping to provide expressed breast milk to the infant. A variety of cleft nipples/bottles exist to allow oral feeding (http:// www.cleftline.org/who-we-are/what-we-do/feeding-your-baby/). There are assisted milk delivery systems such as the Medela special needs feeder (formerly known as the Haberman) and the Mead Johnson squeeze bottle. There are also infant-driven systems, such as the Dr. Brown’s specialty feeding system (with valve and varied nipple sizes allowing flow variation) and the Pigeon system. Infants with CP tend to swallow more air during feedings and should feed in an upright position, as gravity will help prevent nasal regurgitation. If the child is still having difficulty feeding safely or efficiently, a feeding therapist should be consulted. If a feeding specialist is not available, a lactation counselor or the nearest ACPA Cleft/Craniofacial team’s nurse coordinator can be an additional helpful resource for feeding support. Adequate weight gain is important for overall health, development, and readiness for the surgical procedures that occur in the first year of life. Newborns with clefts are considered nutritionally high risk, but a child with an isolated orofacial cleft should be expected to follow typical growth charts. Infants with suboptimal weight gain may require additional nutrition support from a

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CHAPTER 88

dietitian to help determine caloric needs and to closely monitor growth. Surgical timelines and approach differ between teams but often span from infancy into early adulthood. In general, surgery to repair the cleft lip and associated nasal deformity occurs within the first 6 months of life. Palatoplasty typically occurs between 9 and 12 months of age with the primary goal to normalize palate muscle function to facilitate normal speech development. Newborns with orofacial clefting should have a follow-up with their primary care pediatrician and be evaluated by a cleft/craniofacial specialist as soon as possible after discharge from the birth and NICU hospitalization, ideally within 1 week from discharge.

Screening and Surveillance Routine screening laboratory and imaging studies are not typically recommended in the neonate with an isolated cleft. For children with syndromes, surveillance is guided by syndrome-specific protocols, with some special considerations noted here: • Although rare, airway or laryngeal clefts can cause respiratory distress, coughing, choking, stridor, recurrent croup, and recurrent aspiration. Recommended evaluations include a clinical swallow evaluation, videofluoroscopy, functional endoscopic evaluation of swallow, and the gold standard for diagnosis is microlaryngoscopy and bronchoscopy. Given the risk of gastrointestinal manifestations such as gastroesophageal reflux, dysmotility, and aspiration, anti-reflux precautions should be initiated in infants with suspected or confirmed LTE defects. Early diagnosis and proper repair of the laryngeal cleft are essential to prevent injury to the lungs. Significant LTE defects will need to be managed surgically,47 and tracheostomy may be necessary initially to ensure airway stability and safety. • In the presence of a midline cleft, it is important to evaluate the neonate for underlying CNS malformations such as HPE. In any child with a midline cleft or facial features consistent with premaxillary agenesis/hypoplasia, CNS imaging (CT or MRI) is recommended. Consultation with a geneticist or genetic counselor may provide insight into the genetics, molecular testing options, and recurrence risk of HPE. Treatment of HPE is supportive and based on symptoms. The outcome depends on the severity of HPE and the associated medical and neurologic manifestations.

22q11.2 Deletion Syndrome Diagnosis and Etiology 22q11.2 deletion syndrome (22q11.2DS) is the most common microdeletion syndrome, with an estimated prevalence of 1 in 4000 births, in which affected individuals are missing a region (typically 3 Mb, encompassing approximately 40 genes) on one copy of chromosome 22.48,49 22q11.2DS is associated with more than 180 clinical features, and phenotypic variation is a hallmark of this genetic condition.49 In some cases, this condition is diagnosed prenatally. Testing may occur as part of the evaluation for fetuses with congenital heart disease or because of a parental history of 22q11.2DS. The clinical indications for genetic testing for this condition in neonates include congenital heart malformations (particularly conotruncal anomalies), hypocalcemia, dysphagia, CP, other palatal dysfunction (e.g., submucous CP, velopharyngeal insufficiency with intact palate), and immunodeficiency identified on newborn screening or by noting thymic hypo-/aplasia, such

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1277

as during heart surgery.50 Overt CP is less common than submucous CP and velopharyngeal insufficiency; genetic testing is more definitively indicated for CP when other features associated with 22q11.2DS are also observed.

Phenotype 22q11.2DS commonly presents with multiorgan system involvement, including cardiac and palatal abnormalities, immune differences, endocrine and gastrointestinal problems, developmental delay, and later-onset conditions across the life span, including variable cognitive deficits and psychiatric illness. Several craniofacial features have been observed in individuals with 22q11.2DS; however, many of these are subtle and may not be apparent in the newborn period. Common features identified include small ears with overfolded helices, a long face, tubular conformation of the nose, nasal alar hypoplasia, and hooded eyelids.50 In neonates, some of the most indicative findings include dysphagia and/or nasal regurgitation (including in the absence of an overt CP, due to palatal dysfunction), congenital heart disease, and hypocalcemia.

Intensive Care Unit Concerns About two thirds of patients with 22q11.2DS have congenital heart disease, sometimes severe, which often leads to prolonged ­neonatal hospital stays. If a seizure occurs in the neonatal period, especially in the setting of known congenital heart disease, 22q11.2DS and hypocalcemia should be strongly suspected. Hypocalcemia is most common in the newborn period and is triggered by physiologic stressors (e.g., peripartum period, surgery, infection). Importantly, hypocalcemia and neonatal seizures caused by it have been linked with worse intellectual outcomes for patients.51 Feeding challenges can be due to cleft palate, palatal dysfunction, and dysphagia. Rarely, severe immunodeficiency can be present, increasing the risk for serious infections. It can be identified on newborn screening for T-cell receptor excision circles (TRECs).52 About one-third of patients with 22q11.2DS have structural urinary tract abnormalities. Cervical spine anomalies can occur; routine screening in infancy is not recommended, but neonates should be monitored for symptoms of cord compression and cervical spine instability.48 In addition, infants with 22q11.2DS often have airway obstruction, most commonly due to tracheomalacia, subglottic stenosis, laryngomalacia, glottic web, and bronchomalacia; this is most commonly observed in patients who also have congenital heart disease.53

Management Chest x-ray, EKG, echocardiogram, and cardiology consultation should be pursued in suspected and confirmed cases of this condition, and 22q11.2 deletion testing should be considered in cases of confirmed congenital heart disease.54 Calcium and parathyroid levels should be checked, as the neonatal period is the most common time for hypoparathyroidism to present itself.48,51 A complete blood count, screening for leukopenia and thrombocytopenia, and flow cytometry for T and B cells should be obtained. An immunologist should be consulted if any concern arises for abnormalities in these studies, newborn screening, or clinical suspicion of hypo- or athymia. Renal ultrasonography should be obtained for all suspected and confirmed cases.48 Newborns should have a palatal examination to evaluate for overt or submucous CP, as

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well as a diagnostic hearing test. Infants with evidence of dysphagia, regardless of the presence/absence of CP, benefit from an evaluation by a feeding therapist to determine if a swallow study is needed and/or if other feeding interventions, such as the introduction of a specialized cleft feeder, would be helpful. Families of infants diagnosed with 22q11.2DS should receive genetic counseling. Ophthalmology evaluation is warranted for all confirmed diagnoses, as well. Thyroid function should be assessed with newborn screening.

when it does not fit a classic pattern of anomalies. Advances in high-throughput DNA sequencing have led to the identification of causative variants and genetic pathways in these relatively common congenital anomalies.60,61 Our understanding of the genetic causes of craniosynostosis is increasing, and for the growing proportion of syndromic forms, identification of the primary genetic cause is possible with the use of clinically available genetic tests.

Screening and Surveillance

There is a concern that children with untreated single suture synostosis are at risk for elevated ICP, local brain injury, and later developmental delays. For this reason, early recognition and referral are thought to be key to devising optimal treatment plans to protect the developing brain.62 Sagittal synostosis is the most common single suture synostosis (approximately 60%).63 Known risk factors include male sex, intrauterine head constraint, twin gestation, maternal thyroid hormone dysregulation, and maternal smoking. Uncommon but reported associated anomalies include congenital heart defects and genitourinary tract malformations. Syndromes with synostosis involving only the sagittal suture are rare. Premature union of the sagittal suture hinders normal calvarial expansion, leading to scaphocephaly, an elongated, narrow calvarium, decreased biparietal width, frontal bossing, and occipital elongation (Fig. 88.4). Premature fusion of the suture before birth leads to abnormal head shape in the newborn period. A breech-positioned neonate can have dolichocephaly that may mimic sagittal synostosis. However, in sagittal synostosis, frontal bossing and biparietal narrowing progress, whereas the head shape in a breech-positioned infant will begin to normalize in the first months of life. Metopic synostosis has become increasingly common, representing approximately 20% to 30% of single suture synostosis. Risk factors include male sex, twin gestation, and in-utero exposure to valproate.64 Syndromes, associated anomalies, and chromosomal abnormalities occur in approximately one-quarter of individuals with metopic synostosis.65,66 Premature fusion of the metopic suture results in a triangular head shape, or trigonocephaly, and additional features including a midline forehead ridge, frontotemporal narrowing, pterion constriction, hypotelorism, and an increased biparietal diameter (see Fig.  88.4). Isolated metopic ridging is common in infancy, does not distort forehead shape, and is not associated with metopic synostosis. Coronal synostosis represents about 10% to 20% of single suture synostosis and presents with anterior plagiocephaly. Recognizable skull differences in unicoronal craniosynostosis include a flat supraorbital rim and orbit that appears higher on the affected side, with a frontal bulge on the contralateral side (see Fig. 88.4). In addition to orbital and frontal asymmetry, the nose often twists away from the coronal fusion. Genetic syndromes are more frequently seen in individuals with coronal synostosis, including Saethre-Chotzen syndrome, Muenke syndrome, and craniofrontonasal dysplasia. All families of children with coronal synostosis should be offered genetic consultation and/or genetic testing to include FGFR2, FGFR3, TWIST1, TCF12, and EFNB1 on the basis of clinical examination. Lambdoid synostosis (1% to 3% of single suture craniosynostosis) is the least common form of single suture synostosis. It is characterized by flattening of the ipsilateral occiput, posterior– inferior displacement of the ear, bulge of the mastoid process on the fused side, a skull base tilted downward on the affected side, and may exhibit facial scoliosis or asymmetry. This head shape is

Long term, children with 22q11.2DS benefit from a multi-disciplinary team, often including pediatrics, cardiology, immunology, behavioral health, psychiatry, feeding therapy, speech, social work, nursing, audiology, and endocrinology. In addition, other subspecialties may need to be involved, depending on which chronic issues are present, such as constipation, urologic abnormalities, cervical spine instability, and scoliosis. Some children’s hospitals and academic health centers include dedicated 22q11.2DS clinics. Many infants and toddlers with 22q11.2DS have persistent dysphagia and swallowing problems, and it is not uncommon for them to depend on supplemental tube feedings for months or years. As they get older, medical issues often stabilize, and the focus shifts to understanding and supporting learning differences, behavioral health, and mental health. Older children and young adults are at an increased risk for psychiatric disorders, including depression, anxiety, ADHD, and schizophrenia.

Craniosynostosis Diagnosis and Etiology Craniosynostosis refers to the premature fusion of one or more cranial sutures (metopic, sagittal, right or left coronal, right or left lambdoid) that normally separate the bony plates of the cranium. The birth prevalence of all craniosynostoses has been estimated at 1 in 2500 live births, with shifting epidemiology and a more recent study estimating an increase of prevalence to 1 in 1400 live births.55,56 Typically, patent sutures allow the calvaria to expand as the brain grows, producing a normal head shape and size. If one or more sutures fuse prematurely, this typically happens prenatally, and there is restricted growth perpendicular to the fused sutures and compensatory growth in the patent sutures, producing a progressively abnormal head shape.57 Physical exam by an experienced craniofacial provider can be sufficient for the diagnosis, and a CT scan is typically needed to confirm the extent of synostosis and for surgical planning. Plain skull radiographs in neonates are unreliable and not helpful.58 Craniosynostosis is a heterogeneous disorder with health consequences that range from an abnormal head shape and increased intracranial pressure (ICP) to secondary visual and intellectual impairments. The causes of craniosynostosis are heterogeneous, with mono­­ genic, chromosomal, polygenic, and environmental/teratogenic factors all playing key roles. A genetic diagnosis can currently be identified in 25% of individuals with craniosynostosis. Nonsyndromic single suture craniosynostosis accounts for 65% of patients.59 Syndromic craniosynostosis may involve single or multiple fused sutures, additional anomalies (such as limb, cardiac, CNS, and tracheal malformations), and developmental delay. Multiple suture involvement is usually considered hereditary even

Single Suture Synostosis

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• Fig. 88.4  Head shapes in single suture synostosis. From left to right: normal head shape, sagittal synostosis, right coronal synostosis, and metopic synostosis.

often confused with positional deformational plagiocephaly, but skull base tilt and vertical ear displacement should not be present in positional plagiocephaly.

Multiple Suture Synostosis Multiple suture (or multisuture) synostosis describes patients who have two or more fused sutures. Although children with multisuture synostosis are more likely to have a known syndromic form of craniosynostosis such as Apert, Crouzon, Pfeiffer, or Muenke syndromes, some have chromosome aberrations or patterns of craniosynostosis with associated anomalies not previously described. With 20 known hereditary forms of craniosynostosis, genetic consultation and counseling are of critical importance in the management of these conditions.60,61,67 Discussed in this section are select major syndromes with craniosynostosis that may have medical issues in the newborn period. See Table 88.2 for a description of key phenotypic features and potential airway compromise. Apert syndrome was initially described as acrocephaly with four-limb syndactyly. The symmetric hand and foot involvement with syndactyly and symphalangism is an important clue to the diagnosis (Fig.  88.5). Inheritance is autosomal dominant and Apert is associated with advanced paternal age. Neurocognitive outcomes vary, but a moderate to severe degree of cognitive impairment is most common. Multiple mutations in FGFR2 causing Apert syndrome have been identified.68 Crouzon syndrome is an autosomal dominant condition that demonstrates wide phenotypic variability. Shallow orbits with proptosis are an important diagnostic finding, although this feature may be subtler in the newborn (Fig.  88.6). Significant abnormalities involving the CNS include the frequent presence of a Chiari type 1 malformation, with progressive hydrocephalus and risk for intracranial hypertension. Compared with Apert syndrome, Crouzon syndrome is associated with more extensive suture involvement, smaller cranial volume, and more severe intracranial constraint; however, cognitive development is usually normal. Like Apert syndrome, Crouzon syndrome is caused by mutations in FGFR2. A less common form of Crouzon syndrome

with acanthosis nigricans skin findings developing in the first 2 years of life is caused by a transmembrane mutation in FGFR3. Pfeiffer syndrome is a hereditary craniosynostosis that shares significant overlap, both phenotypically and genetically, with Crouzon syndrome. It is an autosomal dominant disorder with craniosynostosis accompanied by proptosis, broad and deviated thumbs, and large first toes (Fig.  88.7). Mutations in FGFR1 and FGFR2 cause Pfeiffer syndrome. Type 1 Pfeiffer syndrome involves mild manifestations including brachycephaly, midface hypoplasia, and digital malformations. Type 2 consists of cloverleaf skull, extreme proptosis, digital malformations, elbow ankylosis, developmental delay, and neurologic complications. Type 3 is similar to type 2 but without a cloverleaf skull. CNS and spine anomalies are common in Pfeiffer syndrome.69 Muenke syndrome is an autosomal dominant syndrome caused by a single P250R mutation in the FGFR3 gene. Like Apert syndrome, Muenke syndrome is associated with advanced paternal age. Individuals with Muenke syndrome may have coronal craniosynostosis (unilateral or bilateral), macrocephaly, variable degrees of proptosis, a high prevalence of sensorineural hearing loss, and do not typically have significant midface hypoplasia (Fig. 88.8). Saethre-Chotzen syndrome is caused by a mutation in the TWIST1 gene on chromosome 7. The inheritance is autosomal dominant, and many children with Saethre-Chotzen syndrome will have an affected parent. In addition to craniosynostosis, affected individuals commonly have a low frontal hairline, ptosis, 2 to 3 syndactyly of the fingers, cervical spine anomalies, and duplicated halluces. Although learning difficulties may be noted, cognitive impairment is not typical of Saethre-Chotzen syndrome caused by intragenic mutations. Children with deletions rather than point mutations often demonstrate significant developmental delays. ERF-related craniosynostosis is a recently recognized syndromic form of craniosynostosis caused by variants in the ERF gene.70 The multisutural involvement varies, including pansynostosis and a pattern involving the sagittal and lambdoid sutures (Mercedes-Benz pattern), and can be postnatal in onset with insidious and progressive effects on head shape and unsuspected

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B

A

C • Fig. 88.5  (A)

Infant with Apert syndrome, a high and full forehead, proptosis and exotropia, midface hypoplasia, and a trapezoid-shaped mouth. (B, C) Hands and feet in Apert syndrome. Note the syndactyly symmetrically affecting hands and feet. All five digits may be webbed, or a single toe, finger, or thumb may be free.

A

B • Fig.  88.6  (A)

Infant with Crouzon syndrome with acro brachycephaly. (B) Proptosis and midface retrusion are seen in the lateral view.

A

B

C

• Fig. 88.7  (A, B) Infant with Pfeiffer syndrome, brachycephaly, a high forehead, midface hypoplasia, pro-

ptosis, and ocular hypertelorism. (C) An older child with Pfeiffer syndrome and the typical broad thumbs with radial deviation.

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A

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C

• Fig. 88.8  (A,

B) Infant with Muenke syndrome, acrobrachycephaly due to bicoronal synostosis, and absence of proptosis. (C) Sibling of the infant in (A, B) also with Muenke syndrome; note the downslanting palpebral fissures.

intracranial hypertension. Facial features include hypertelorism, mild exorbitism, and malar hypoplasia. Chiari malformation and developmental concerns are common. Cloverleaf skull can result from any form of multisuture craniosynostosis. The skull forms a trilobular appearance, as the cerebrum bulges through the sagittal and squamosal sutures, because of craniosynostosis affecting the coronal, metopic, and lambdoid sutures. Cloverleaf skull is most commonly associated with a syndrome, and it is estimated that up to 20% of cases represent Pfeiffer syndrome.

Intensive Care Unit Concerns The most significant concerns for the newborn with craniosynostosis are airway compromise due to upper airway obstruction and intracranial hypertension. Midface hypoplasia and tracheal anomalies that may be present in syndromic craniosynostosis can lead to significant airway compromise (see Table 88.2). With midface hypoplasia, there is decreased nasal and oropharyngeal space because of a small maxilla, narrowing at the level of the posterior choanae, and posterior displacement of bony and soft tissue structures, leading to breathing problems, obstructive sleep apnea, asphyxia, and even death (Fig. 88.9). Obstructive sleep apnea is common in Apert, Pfeiffer, and Crouzon syndromes. Cartilaginous tracheal abnormalities can be present in multisuture craniosynostosis syndromes. Vertically fused tracheal cartilage (also referred to as tracheal cartilaginous sleeve, solid cartilaginous trachea, and stovepipe trachea) in Crouzon and Pfeiffer syndromes may produce a rigid trachea resulting in upper airway stenosis, inability to clear secretions, and increased risk of injury because of decreased distensibility. Characteristic tracheal cartilaginous rings are fused to form a continuous sleeve of cartilage, which may extend from below the subglottis to the carina or bronchus; rarely, the cartilaginous sleeve can begin more proximally, at the level of the cricoid cartilage. Infants with congenital tracheal anomalies may have stridor, increased work of breathing, and distress, particularly with respiratory illnesses. Neurologic abnormalities such as hydrocephalus and increased ICP may arise, especially in multisuture craniosynostosis. Increased ICP due to constraint of the growing brain within a restricted calvarium is usually chronic, causing symptomatic intracranial hypertension when brain growth is rapid during the first 2 years of life. ICP issues in the neonate are not usually life threatening, given the open fontanel and compensatory splaying of normal

sutures or erosion of the calvarium, but brain injury and encephalomalacia may result if cranial expansion is not performed. Hydrocephalus, which is more common in Crouzon and Pfeiffer syndromes compared with other multisuture synostosis syndromes, can occur as a result of obstruction of cerebrospinal fluid at the basal cistern, aqueductal stenosis, or impeded venous flow or when there is an associated Chiari malformation. Hydrocephalus is extremely common in cloverleaf skull. Individuals with multisuture craniosynostosis (particularly Apert syndrome) more commonly have nonprogressive distortion ventriculomegaly or compensated hydrocephalus, which does not require shunting.71 Abnormalities of the corpus callosum and septum pellucidum have been described in Apert syndrome, and neuroimaging and genetic advances will illustrate links between brain architecture, phenotype, and genotype.72 Seizures presenting in multisuture craniosynostosis syndromes are more commonly due to encephalopathy rather than increased ICP. Chiari malformation is frequently diagnosed in syndromic craniosynostosis. Cerebellar tonsillar herniation, especially in the setting of cord compression, can affect control of breathing and lead to central sleep apnea, ranging from mild to profound. Treatment of airway obstruction can unmask central apnea and continued monitoring for apnea over time is necessary in syndromic craniosynostosis.

Management The evaluation of the patient with craniosynostosis includes recognizing and confirming the type of suture fusion, clinical syndrome identification, evaluation for associated anomalies, and preparedness for surgical repair. A detailed physical examination should be performed as part of the initial evaluation, looking for any other anomalies, with specific attention to cleft palate, limb defects, heart defects, and ear anomalies. The assessment of cranial and face shape, the fontanelles, presence of sutural ridging, skull base symmetry, and ear position is important. Proptosis and exorbitism due to shallow orbits are important to recognize as exposure keratopathy is the major etiology of corneal pathology encountered in multisuture craniosynostosis, and ophthalmology involvement early can be vision sparing. If proptosis is present, as can occur in Apert, Crouzon, and Pfeiffer syndromes, ocular lubricants help to prevent exposure keratopathy. Although rare, severe proptosis can lead to globe luxation and may need surgical intervention such as tarsorrhaphy, in addition to eye surface lubrication,

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A

B

C

D • Fig. 88.9  (A, B) Three-dimensional reconstruction of a child with Apert syndrome with significant mid-

face hypoplasia, leading to upper airway obstruction. Also notable is acrobrachycephaly due to bicoronal synostosis and the typical pattern of sagittal suture patency. (C) CT scan axial slice at the level of the skull base in a newborn with Apert syndrome. The arrow pointing to the airway illustrates significant airway obstruction. (D) CT scan of a newborn illustrating a normal airway (arrow).

to preserve eye health. During the neonatal period and as a child grows, an ophthalmologist with experience in craniosynostosis is recommended.73 CT with three-dimensional reconstruction will ultimately confirm the diagnosis of craniosynostosis, delineate the degree of suture involvement, and help with preoperative planning. Although the specific timing of the surgical treatment may differ between teams, it is generally accepted that individuals with synostosis should undergo cranial surgery in the first year of life. Cranioplasty involves the release of fused sutures and repositioning and reconstruction of the calvaria to expand the skull to prevent increased ICP and progressive abnormal craniofacial development. Several techniques, including endoscopic strip craniectomy, calvarial distraction, and traditional cranioplasty, are currently used. Consultation with a craniofacial team should be initiated when craniosynostosis is suspected, as the timing of some surgical interventions are performed in the first few days or weeks of life. A comprehensive guideline has been recently updated by Mathijssen in 2021.74

Attention to facial shape, especially the degree of maxillary hypoplasia, is important in determining the risk of airway compromise due to midface hypoplasia. If concerning airway symptoms are present, such as snoring, stridor, or apnea, consultation with a sleep specialist and polysomnography may help to quantify the presence and severity of early obstructive sleep apnea, and identify perhaps more subtle central apnea and the need for positive pressure ventilation. Awareness of potential airway compromise and proactive airway management are crucial in many craniosynostosis syndromes. Temporizing measures to bypass airway obstruction include placement of nasal stents, endotracheal intubation, and tracheotomy. Specific airway management in syndromic craniosynostosis will depend on the level and severity of obstruction. Consultation with an otolaryngologist and airway endoscopy to identify the types and degree of airway narrowing is essential in infants with multisuture craniosynostosis and airway obstruction. Particular attention to the presence of tracheal malformations, such as vertically fused tracheal cartilage, is crucial in craniosynostosis syndrome as early recognition of tracheal malformations

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can be lifesaving.75 With the increased awareness of this condition, the diagnosis of tracheal malformations is increasingly made on direct laryngoscopy/bronchoscopy or with MRI, and ultrasound is an emerging tool.76 Infants with tracheal anomalies benefit from skilled complex airway management that may include airway surgery or even tracheotomy with custom airways to achieve airway patency and prevent mortality in infancy.77 Serious caution must be exercised in the placement and care of tracheostomies in patients with tracheal cartilaginous sleeves because of unique airway shape, abnormal tissue healing, and granulation tissue formation. Midface advancement surgery may be necessary for some children who have nasal level airway obstruction, swallowing, feeding, and dental malocclusion. This is usually performed later in childhood. The family and prenatal history, including documentation of affected family members, teratogen exposure, maternal thyroid disease, and in utero constraint (oligohydramnios, twins, fetal movement), and the birth history should be ascertained, specifically looking for risk factors. For all individuals with craniosynostosis, we recommend the early involvement of a craniofacial team including members specializing in pediatrics, genetics, neurosurgery, ophthalmology, oral surgery, orthodontics, otolaryngology, nursing, nutrition, plastic surgery, and social work.78 Prenatal involvement of craniofacial and airway specialists is especially critical for planning the safe delivery and post-partum care when multisuture craniosynostosis is anticipated.

Screening and Surveillance Many genetic causes of craniosynostosis require screening for additional health characteristics as well as complications. Accurate and prompt diagnosis requires a combination of careful clinical evaluation and correctly targeted diagnostic testing, proceeding to exome/whole genome sequencing if necessary.59 The role of the geneticist in understanding the causes of single suture craniosynostosis is evolving. The families of children with multisuture synostosis with the presence or absence of associated syndrome should be offered appropriate genetic consultation, molecular testing, genetic counseling, and surveillance monitoring guided by the unique genotype.79 Below are some important considerations: • CNS: In all children with craniosynostosis, and particularly in those with multisuture involvement, it is important to monitor for any signs or symptoms of increased ICP. Evaluation for hydrocephalus should be a part of the initial assessment of all children with multisuture craniosynostosis. Ventriculomegaly may be identified by the initial diagnostic head CT, and followup imaging should be pursued if any acceleration in OFC or bulging fontanelle is noted. MRI of the brain may be helpful in defining any associated CNS anomalies, and screening for Chiari malformation is recommended for children with multisuture craniosynostosis, or craniosynostosis with Chiari symptoms. • Spine: In coronal synostosis and syndromes including Apert, Crouzon, Pfeiffer, and Saethre-Chotzen, associated vertebral anomalies, including fusions and instability, may be present, detected on spine radiographs, and more accurately visualized with CT C-spine imaging that can be coordinated with CT head imaging in the young infant. • Eyes: Early ophthalmology consultation and ongoing surveillance are valuable in the management of proptosis, monitoring for optic neuropathy, vision and eye alignment given the high risk for strabismus.

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• Hearing: Conductive and mixed hearing loss, most commonly due to middle ear disease, ossicular abnormalities, and external auditory canal stenosis or atresia, can be present in syndromic craniosynostosis. Early amplification (for example with a bone conduction sound processor on a soft band in the setting of canal atresia) may be indicated to support communication. Sensorineural hearing loss has been described in Saethre–Chotzen syndrome and Muenke syndrome. Timely hearing screening is recommended for all children with craniosynostosis, and continued monitoring for progressive hearing loss is indicated for children with coronal and multisuture craniosynostosis. • Development: Developmental monitoring and referral to early intervention services is recommended for all infants with single and multi-suture craniosynostosis, especially those with craniosynostosis syndromes. Although school-age children with repaired single suture craniosynostosis have been found to have evidence of mild developmental delays, the pathogenesis and direct relationship to synostosis have not been determined.80 • Sleep: Monitoring for sleep apnea in infants and children with multisuture craniosynostosis and syndromes is recommended, with a low threshold for referral for a sleep study. • Heart: In Apert syndrome, a cardiac and genitourinary evaluation is recommended. • GI: Low threshold to obtain imaging to rule out malrotation in the infant with emesis and multisuture craniosynostosis, given the association with intestinal abnormalities.81 • Limbs: If any limb abnormalities are seen, as in Apert, Jackson– Weiss, Pfeiffer, and Saethre–Chotzen syndromes, radiographs with orthopedic or hand specialist consultation should be obtained.

Disorders of the First and Second Branchial Arches Craniofacial Microsomia Craniofacial microsomia (CFM), a congenital malformation in which there is asymmetric deficiency in skeletal and soft tissue on one or both sides of the face, is the most frequently encountered form of facial asymmetry. CFM affects approximately 1 in 3000 to 1 in 5600 births.82,83

Diagnosis and Etiology Individuals with features of CFM have been classified under a variety of different diagnoses (hemifacial microsomia, oculoauriculovertebral spectrum, facioauriculovertebral syndrome, first and second branchial arch syndrome, otomandibular dysostosis, Goldenhar syndrome, lateral facial dysplasia) attesting to the phenotypic variability. There are no accepted diagnostic criteria, but the presence of ipsilateral mandibular and ear defects is most common. Infants with CFM are often born small for their gestational age, and the perinatal history may include polyhydramnios due to fetal swallowing dysfunction. Various causes, both environmental and heritable, have been studied, and for most, the cause is thought to be multifactorial. Most often CFM is a sporadic condition with a recurrence risk of approximately 2% for future pregnancies unless there is a known family history of microtia or CFM.84

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Phenotype CFM is primarily a condition of the first or second branchial arches, resulting in the underdevelopment of the ear, temporomandibular joint, mandibular ramus and body, and mastication muscles. Asymmetric bilateral facial involvement is common (Fig.  88.10A). The affected external ear can be underdeveloped and small (microtia) or malformed, may be lower in position compared with the ear on the contralateral side (see Fig. 88.10B), can present with no external ear (anotia), and may be accompanied by preauricular tags. Hearing loss may result from maldevelopment of the ossicular chain and a stenotic or atretic external auditory canal and can affect one or both sides. Second branchial arch defects can involve the facial nerve and muscles of facial expression, which can be difficult to appreciate in a newborn. A common classification system for CFM is the OMENS system, which characterizes the degree of involvement of facial structures: orbital distortion, mandibular hypoplasia, ear anomaly, nerve involvement, and soft tissue deficiency.85,86 Isolated microtia may represent a forme fruste of CFM. Other craniofacial features include external auditory canal stenosis or atresia, unilateral macrostomia (transverse facial cleft leading to lateral displacement of the oral commissure and the most common form of orofacial clefting in CFM), cleft lip and/or palate, temporomandibular joint ankylosis, ankyloglossia, preauricular or facial pits (most common in the distribution of the facial nerve), midface hypoplasia and malocclusion, epibulbar lipodermoids (see Fig. 88.10C), microphthalmia, eyelid and ocular colobomas, facial nerve palsy or paresis, and other cranial nerve palsies. There can be extreme variability of phenotypic expression, and the severity of mandible, ear, and facial involvement varies from mild to more impacted (see Fig.  88.10D). Goldenhar syndrome has historically been described as a subgroup variant of CFM characterized by vertebral anomalies and epibulbar dermoids in addition to the ear and jaw findings. Extracraniofacial anomalies are common in CFM, with one large study describing a prevalence of 47%, and higher among those with bilateral CFM or more severe bony and soft tissue involvement. Extracraniofacial anomalies can include vertebral (28%; scoliosis, block vertebrae, hemivertebrae), cardiac (21%; septal defects, valve anomalies, tetralogy of Fallot), CNS (11%; hydrocephalus, ventriculomegaly, intracranial cyst), urogenital tract (11%; renal aplasia, undescended testicle, hydronephrosis), GI tract (9%; inguinal hernia, imperforate anus, esophageal atresia), and respiratory tract (3%; laryngomalacia).87 In CFM, deficient growth of the hypoplastic mandible and the compensatory growth of the contralateral maxilla and zygoma contribute to facial asymmetry that progresses with growth.

Conversely, facial and skull asymmetry caused by deformation (intrauterine or postnatally with plagiocephaly and torticollis) will improve with time, repositioning, and treatment of torticollis.

Branchial Arch Malformation Syndromes While multiple syndromes can be associated with malformations of the first and second branchial arches, presented in this chapter are two syndromes with particular relevance to the neonatologist.

Moebius Syndrome Moebius syndrome is a rare congenital condition affecting approximately 2000 people worldwide.88 The sixth and seventh cranial nerves are universally affected. Sixth nerve palsy leads to an inability to abduct the eyes beyond the midline. This is usually bilateral but may be unilateral or asymmetric. Paralysis of facial muscles results from the seventh nerve palsy. While newborns may have a “masklike facies,” the presentation is challenging to recognize in the newborn period.89 Feeding difficulties may result from problems with swallowing and sucking, aspiration, and palatal weakness related to more widespread cranial nerve involvement. Both abnormalities of cranial nerve nuclei and neural connection issues are hypothesized to cause Moebius syndrome. Many associated features have been described, and hypotonia is common, also impacting swallowing and breathing in infancy.90 Associations with chest wall abnormalities, including the absence of the pectoralis muscle, suggest a pathogenic relationship with the Poland anomaly. Exposure conjunctivitis and keratopathy can occur in children with facial paralysis and lagophthalmos and should be prevented with ocular lubricants. Limb defects occur in more than half of children with Moebius syndrome, most commonly talipes deformity; however, transverse limb anomalies are also seen. Individuals with hypoglossia-hypodactylia or Hanhart syndrome can have severe limb deformities, ankyloglossia, and temporomandibular joint ankylosis, in addition to Moebius syndrome–like features and micrognathia. As a consequence, they are at risk of significant swallowing dysfunction and airway compromise.91

Treacher Collins Syndrome Treacher Collins syndrome (TCS) is a disorder of craniofacial development that affects approximately 1 in 50,000 live births.92 As in CFM, the tissues affected in TCS arise from the first and second branchial arches. The major clinical features of TCS include hypoplasia of facial bones (mandible and zygoma), microtia,

• Fig. 88.10  (A,

B) Infant with craniofacial microsomia, mandibular asymmetry, and left-sided microtia. (C) Child with an epibulbar lipodermoid and craniofacial microsomia. (D) Infant with more severe mandible hypoplasia, airway obstruction, and an associated tracheostomy tube.

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external auditory canal atresia, bilateral conductive hearing loss, downward sloping palpebral fissures, and lower eyelid colobomas, as well as risk of exposure keratitis (Fig. 88.11A, B).93 Cleft palate may occur and hearing loss is present in up to 50% of individuals with TCS.94 In severe cases, the zygomatic arch may be absent. Extracraniofacial features are rare in TCS, and limb anomalies can distinguish other forms of mandibulofacial dysostoses from TCS: for example, Miller syndrome with craniofacial features similar to TCS plus postaxial limb anomalies affecting the fifth digital ray of all four limbs, and Nagar syndrome with craniofacial features similar to TCS plus preaxial limb anomalies, hypoplastic/absent thumbs and or radii. Mutations in one of four genes (TCOF1, POLR1B, POLR1C, POLR1D) are causative of TCS and mutations in the TCOF1 gene account for 71% to 93% of affected individuals. The diagnosis of TCS is usually made clinically and can be confirmed with genetic testing.95 In newborns with TCS, airway management may be required to address narrowing of the airway or extreme shortening of the mandible (see Fig. 88.11C). When compared with that in CFM, the mandibular hypoplasia in TCS is usually bilateral and symmetric, leading to an even higher

A

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risk of upper airway obstruction. In addition to glossoptosis and mandible involvement similar to RS, choanal stenosis or atresia can be present in neonates with TCS predisposing to multilevel airway involvement not effectively resolved with neonatal mandible advancement.96,97 Among infants with TCS and significant airway compromise, there is an increased need for tracheostomy, and risk of death in the neonatal period.

Intensive Care Unit Concerns Mandibular hypoplasia in CFM can lead to upper airway obstruction that may be obvious on physical examination, presenting with stertor or stridor and increased work of breathing, or may be more subtle, with noisy breathing occurring with sleep or feeding. Bilateral severe mandibular and maxillary involvement in TCS leads to airway obstruction at the level of the nasopharynx and base of the tongue and substantial respiratory compromise. As multilevel airway obstruction is common in TCS, airway endoscopy to help target treatment options should be pursued for any neonate with TCS or CFM and signs of airway obstruction.

B

C • Fig. 88.11  (A) Infant with Treacher Collins syndrome (TCS), microtia, severe mandibular and zygomatic

hypoplasia, and airway obstruction requiring tracheostomy. (B) An older child with TCS, downslanting palpebral fissures, eyelid colobomas, and bilateral microtia wearing a hearing augmentation device. (C) Threedimensional reconstruction of TCS. Note the severe mandibular hypoplasia, which may lead to significant airway compromise. Also notable are zygoma hypoplasia and orbital defects seen in TCS.

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Infants with CFM may have feeding difficulties that may be related to macrostomia affecting lip seal; among infants with CFM and TCS, swallow coordination issues and dysphagia are attributed to both palate dysfunction and more commonly hypoglossal dysfunction and muscular and bony underdevelopment. Infants with Moebius syndrome may have cranial nerve palsies that affect swallow and oral coordination and are consequently at high risk of aspiration. Close monitoring and support of feeding, swallowing, and growth is recommended in all of the branchial arch conditions.

Management In newborns with suspected CFM, an evaluation for associated anomalies should be undertaken. All children with external ear anomalies or any evidence of first or second branchial arch abnormalities should undergo diagnostic hearing testing in the newborn period, with follow-up audiometry in the first year of life. If there is any hearing loss, ongoing monitoring of hearing is routine. It is also important to monitor ear health and eustachian tube function in the patent/hearing ear. CT imaging to assess middle and inner ear anatomy is not recommended in the neonatal period. Consultation to discuss ear reconstruction and atresia repair typically occur by 4 years of age, although consultation for hearing amplification should occur as soon as possible in infants with hearing loss, and infants diagnosed with hearing loss should receive intervention services as soon as possible, but no later than 6 months of age (https://www.cdc.gov/ncbddd/hearingloss/treatment.html). Additionally, aural habilitation support is helpful. Mild airway obstruction in CFM and TCS may be reduced with prone positioning. However, infants with severe unilateral or bilateral mandibular hypoplasia or multilevel airway obstruction may have significant airway compromise and require tracheostomy placement. In cases with airway compromise or signs of obstructive sleep apnea, early referral to a craniofacial center to determine optimal and safe airway management should be pursued.98 The timing of surgery to address mandibular underdevelopment is typically in later childhood and depends on the degree of mandibular hypoplasia, mandibular growth, occlusion, and airway involvement.99 For children with severe hypoplasia of the mandible, bone grafting may be necessary for jaw reconstruction before mandible distraction. Oral feeding should be introduced when the airway is stable. Given the risk of feeding difficulty and aspiration in infants with malformations of the first and second branchial arches, early consultations with a dietitian and a feeding therapist are helpful.

Screening and Surveillance for Craniofacial Microsomia • Diagnostic hearing test in infancy and regular assessments of hearing guided by initial audiologic assessment and hearing loss risk • CT to assess middle and inner ear anatomy and guide atresia repair options at 4 years of age. • Renal ultrasound in infancy to evaluate for structural malformations • Cardiac examination (echocardiogram) in infancy if any clinical concerns or murmur • Ophthalmology consultation to manage epibulbar lipodermoids, colobomas (if present), and prevent exposure keratopathy • Cervical spine screening radiographs to identify vertebral anomalies (defects in segmentation). If the newborn has no

symptoms of cervical spine abnormality, screening four-view cervical spine radiographs can be deferred until the child is 2 to 3 years old, when vertebrae are more reliably imaged. Appropriate cervical spine imaging is recommended in children undergoing surgery before 2 years of age and children with head tilt or signs of vertebral anomalies. • Spine monitoring for progressive scoliosis • Monitoring for obstructive sleep apnea, with a low threshold for referral for a sleep study • Dental and occlusal monitoring through childhood

CHARGE Syndrome Diagnosis and Etiology The term CHARGE (coloboma, heart defect, atresia choanae, growth retardation, genital hypoplasia, ear anomalies/deafness) was first coined by Pagon, given the observation that the associated malformations occurred more frequently together than one would expect on the basis of chance.100 Over time, the facial features and associated malformations were better characterized as a syndrome, with mutations in at least one major gene described. This multiple malformation condition has a prevalence of approximately 1 in 10,000 births.101 Mutations in the CHD7 gene account for most cases, but CHARGE syndrome remains a clinical diagnosis, with some individuals meeting the classic criteria without a CHD7 abnormality.102 Molecular testing for mutations in the CHD7 gene is especially useful in atypical cases where the diagnosis is being considered but can also be performed to confirm the diagnosis and assist in counseling for the parents and the patient. For children in whom CHD7 gene testing results are normal, further genetic testing is warranted.103 The clinical diagnosis of CHARGE syndrome is summarized in Table 88.4. Additional findings include renal, spinal, hand, neck, and shoulder anomalies.101,103 With improving diagnostics, the

TABLE 88.4 Clinical Diagnosis of CHARGE Syndrome

Major Criteria

Minor Criteria

Coloboma (80%–90%)

Cardiovascular malformations (conotruncal and aortic arch most common)

Choanal atresia/stenosis (50%–60%)

Genital hypoplasia

Cranial nerve dysfunction (especially I, VII, VIII, IX, X) (40%–90%)

Cleft lip and/or palate

Characteristic CHARGE ear findings (inner, middle, outer) (90%–100%)

Tracheoesophageal fistula

Distinctive CHARGE facies Growth deficiency Developmental delay CHARGE syndrome strongly suspected if all major criteria or 3 major and 3 minor criteria are present.

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B

A • Fig. 88.12  (A) Child with CHARGE syndrome with (B) classic ear malformation—hypoplastic lobes, cupped and low set.

phenotype is expanding, and gastrointestinal problems, immunodeficiency, and neuromuscular problems are also described.103 Polyhydramnios is commonly present prenatally, secondary to upper airway obstruction and/or swallowing dysfunction.

Phenotype Distinctive ear anomalies (hypoplastic lobes, cupped/lop, low-set, and posteriorly rotated) occur in most cases (Fig. 88.12). Facial features include a square face with malar flattening, broad forehead, facial asymmetry, pinched nostrils, full nasal tip, and long philtrum. Ocular colobomas can range from iris involvement to anophthalmia. A minority of cases have cleft lip and/or palate. A heart murmur may indicate congenital heart disease. Limited neck range of motion may indicate cervical spine anomalies. In the neonatal period, breathing and feeding difficulties are often the most prominent features, as the characteristic facial and ear features may not be as pronounced.

Intensive Care Unit Concerns The most important potential postnatal emergency in CHARGE syndrome is bilateral posterior choanal atresia.104 Neonates with bilateral choanal atresia will have breathing difficulty and cyanosis within the first hour of life. Crying relieves the cyanosis by allowing the obligate nose breather to take in air through the mouth; feeding exacerbates respiratory distress. Left untreated, asphyxiation and death can occur. Symptoms of bilateral choanal stenosis or unilateral atresia may not present until after the newborn period with chronic rhinorrhea and nasal airway obstruction exacerbated by respiratory infections. Feeding difficulties and sialorrhea are significant causes of morbidity. These issues, and secondary growth problems, are common in early infancy and may be attributed to swallowing dysfunction, pharyngeal incoordination, gastroesophageal reflux, and aspiration. Cranial nerve palsies (specifically of V, IX, and X) may contribute to swallowing dysfunction, and tracheoesophageal fistula (TEF), if present, contributes to aspiration risk.

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Swallowing dysfunction and gastroesophageal reflux can cause descending and ascending aspiration and lower respiratory tract disease, leading to chronic respiratory distress. Infants with CHARGE may also have micrognathia and glossoptosis, putting them at risk of airway obstruction at the level of the pharynx/ hypopharynx. Infants with CHARGE syndrome may require multiple surgical procedures during the first year of life and are at increased risk of postoperative airway events.104,105 Cyanotic heart disease may present in the immediate newborn period because of tetralogy of Fallot, outflow tract anomalies, and interrupted aortic arch. There should be a very low threshold to obtain an echocardiogram and involve cardiology in a neonate with possible CHARGE syndrome. Although it is well described that infants with CHARGE syndrome who survive the newborn period are more likely to survive childhood, the risk of death in infancy remains. Bilateral choanal atresia, TEF, cyanotic heart disease, atrioventricular septal defects, CNS malformations, and ventriculomegaly have all been associated with reduced life expectancy in individuals with CHARGE syndrome.104,106 A study of 77 individuals with CHARGE syndrome found mortality to be 13%; the ages at the time of death range from less than 1 week old to 9 years old.106

Management Many children with CHARGE syndrome will require intensive medical management and undergo multiple surgical interventions in infancy and early childhood. Early management targets airway stabilization and circulatory support. Neonates suspected to have CHARGE syndrome require immediate evaluation of their airway and cardiac structure and function. An oral airway should be placed if bilateral choanal atresia is suspected. Once the airway has been secured, a confirmatory CT scan of the nasal passages can be obtained; a CT of the temporal bones should be included and may reveal the characteristic inner ear findings of CHARGE syndrome (Mondini malformation of the cochlea and/or absent or hypoplastic semicircular canals). If the oral airway does not allow adequate air entry, endotracheal intubation may be required. In consultation with a pediatric otolaryngologist, trans-nasal stents may be placed to keep the nasal passages patent in choanal stenosis (and postoperatively after choanal atresia repair). Given the significant risk of cyanotic heart defects, an echocardiogram should be obtained as soon as feasible. If heart surgery is needed, documentation of the presence/absence/removal of the thymus should be reported. Infants with confirmed or suspected CHARGE syndrome should have audiologic and ophthalmologic evaluations in the neonatal period and should be referred to early intervention services. While there is no consensus on immune screening in CHARGE, given the emerging data and implications, a full blood count with a lymphocyte differential and calcium level (because of the connection between immunodeficiency and abnormalities of the parathyroid glands observed in CHARGE syndrome, not unlike 22q11.2DS) should be considered in the neonatal period in CHARGE syndrome.107 Consultation with an immunologist should occur for the individual with CHARGE syndrome and recurrent infections.108 Underdevelopment of the genitals and genitourinary anomalies may be present. If there is a concern for hypogonadism, the pituitary-gonadal axis can be evaluated in infancy and will help determine the option for sex steroid therapy. Screening renal ultrasonography should also be performed in all suspected cases.109

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Consultations with a feeding specialist and a dietitian are recommended in the newborn period. If the clinical bedside feeding evaluation or video fluoroscopic swallow study are concerning for swallowing dysfunction or aspiration, supplemental tube feeding should be initiated. With prolonged feeding issues, gastrostomy tube feeding is often necessary. Infants with severe gastroesophageal reflux and/or aspiration risk may benefit from post-pyloric feeding with a nasoduodenal or more secure gastrojejunal feeding tube.

Screening and Surveillance CHARGE syndrome has potential impacts on nearly all body systems, and it is difficult to summarize them here. Trider et al. (2017) provides an exceptional summary of health supervision for these patients. Some important highlights include: • Gonadotropins screening at 3 months of age • Screening for lymphopenia and hypocalcemia due to overlap in phenotype with 22q11.2 deletion syndrome • Referral to deaf-blind resources • Assessment for potential cochlear implants • Treatment of GI motility issues • Holistic neurodevelopmental and early intervention services.

Some features suggestive of BWS may present prenatally, including polyhydramnios (due to swallowing dysfunction), preeclampsia, fetal macrosomia, and a large placenta. Prematurity is also associated with BWS.112

Intensive Care Unit Concerns Hypoglycemia due to hyperinsulinemia occurs in 30% to 60% of neonates with BWS, usually within the first days of life.116 Polycythemia can occur and is a potential marker of a congenital Wilms tumor.117 Upper airway obstructive symptoms typically present in later infancy, although they may present in the newborn period if macroglossia is severe. The enlarged tongue can occlude the upper airway, leading to respiratory distress, apnea, and hypoxia. Macroglossia can also contribute to feeding issues, dysphagia, and aspiration. Mortality among infants with BWS has been reported to be as high as 21% and is related to complications of prematurity and macroglossia.111 Congenital heart disease is present in 13% to 20% of neonates with BWS and can include cardiomegaly, cardiomyopathy, patent ductus arteriosus, patent foramen ovale, atrial and ventricular septal defects, long QT syndrome, and more severe defects.112

Management

Macroglossia/Beckwith-Wiedemann Syndrome Diagnosis and Etiology Beckwith-Wiedemann syndrome (BWS) has been estimated to affect 1 in 10,340 live births.110 The genetics of BWS is complex and variable. Most cases are sporadic and may result from chromosomal rearrangement, mutations, or epigenetic effects (DNA methylation changes) affecting imprinted genes on chromosome band 11p15.5. Approximately 80% of individuals with features of BWS are found to have an 11p15.5 abnormality by clinically available testing.111 An international group of experts has developed consensus criteria for classical BWS, which require a score ≥4 in Table 88.5 for clinical diagnosis.112 As children with BWS are at risk of neoplasms in early childhood, recognition and diagnosis of BWS are consequential. Infants conceived by in vitro fertilization may be at higher risk of BWS.113 Although genetic testing can provide confirmation of diagnosis in 80% of individuals, clinical suspicion alone should initiate medical management and tumor surveillance studies. At this time, initiation of screening studies and consultation with genetics are recommended.112

Phenotype Most clinical features outlined in Table 88.5 can present in the neonatal period. Macroglossia (Fig.  88.13) is the most frequent and most obvious manifestation of BWS, present 85% to 95% of the time.112 It is defined as a tongue that protrudes beyond the alveoli at rest.114 Other craniofacial features include capillary nevus flammeus, large fontanelle, mandibular prognathism, prominent eyes, infraorbital creases, anterior earlobe linear creases, and posterior helical pits. Additional findings in BWS include renal and cardiac defects; cleft palate is also described, albeit less often.115 The risk of embryonal tumors (Wilms tumor, hepatoblastoma, neuroblastoma, rhabdomyosarcoma) in childhood is estimated to be 7.5%, of which 95% present in the first 8 years of life.112

Neonatal hypoglycemia should be managed according to standard protocols. If it persists or is refractory to therapy, additional biochemical testing and consultation with an endocrinologist are helpful to guide treatment.116,118 In severe cases, subtotal pancreatectomy may be a treatment option.112,116 If present, polycythemia may need to be treated and could have implications for TABLE Clinical Diagnosis of Beckwith-Wiedemann 88.5 Syndrome

Cardinal Features (2 Points Each)

Suggestive Features (1 Point Each)

Macroglossia

Birth weight >2 standard deviations above mean

Omphalocele

Facial nevus simplex

Lateralized overgrowth

Polyhydramnios and/or placentomegaly

Multifocal and/or bilateral Wilms tumor or nephroblastomatosis

Ear creases and/or pits

Hyperinsulinism beyond 1 week of age and needing escalated treatment

Neonatal hypoglycemia lasting 4.5 cm in a term neonate) • Broadening of the nasal root • Midline facial cleft affecting the nose, lip, or palate • Unilateral or bilateral clefting of the alae nasi • Hypoplastic nasal tip • Anterior cranium bifidum • V-shaped frontal hairline FND is a diverse and genetically heterogeneous condition found in isolation without other concerns, or can be associated with a pattern of other malformations,122 or as a spectrum of syndromes with known genetic changes123 such as craniofrontonasal syndrome.124 In addition to hypertelorism, eye anomalies, including epibulbar dermoids, colobomas, ptosis, nystagmus, or cataracts, may be present in FND and are associated with a more severe phenotype and an increased incidence of CNS abnormalities. Associated CNS manifestations include encephalocele or meningocele (most commonly frontonasal location), agenesis of the corpus callosum, and abnormal neuronal migration. When FND is associated with CNS anomalies, there is an increased association with cognitive impairment.122 Craniofrontonasal syndrome is an X-linked condition in a subset of patients with frontonasal malformations who also present with coronal craniosynostosis and variable skeletal and ectodermal defects. Similar to FND, facial features include hypertelorism, frontal bossing, broad nasal bridge, and a bifid nasal tip. Children with CFNS often have significant facial asymmetry due to unicoronal synostosis. In this X-linked condition, females are more severely affected (and typically have hypertelorism and grooved nails), and mutations are detected in the EFNB1 gene. Affected individuals usually have normal intelligence.124

• Fig. 88.14  MRI of an infant with frontonasal dysplasia and a midline cleft

lip. The scan reveals a moderate-sized meningocele extending into the posterior nasopharynx. The white arrow points to midbrain meningocele coming through the cribriform plate; the black arrow points to the intraoral meningocele.

Intensive Care Unit Concerns Intracranial abnormalities associated with FND may put the infant at risk of CNS manifestations such as hydrocephalus or seizures. If the pituitary gland is involved or deficient, as can be seen with HPE sequence, there can be serious endocrine abnormalities (as discussed in Orofacial Clefts). Also, frontonasal encephalocele may contribute to upper airway compromise at the level of the nasopharynx (Fig. 88.14). Management In any infant with hypertelorism or features that raise suspicion for FND, awareness of potential underlying malformations is critical, and cranial imaging by CT scan or MRI should be considered. Instrumentation of the nose and mouth, including placement of a nasogastric tube or suction catheter, should be avoided or used with caution until the CNS anatomy has been delineated. Because infants with FND have a high incidence of frontonasal encephalocele or meningocele, placement of these catheters could lead to brain injury. If an infant with FND needs urgent or emergent endotracheal intubation, intraoral structures should be examined carefully to prevent injury to potential herniating CNS structures. Management of seizures or any electrolyte derangements should be managed as per the neonatal ICU standard protocol. Consultation with a craniofacial team, including ophthalmology, can clarify the work-up and management (including potential surgical interventions) for individuals with FND.

Congenital Nasal Pyriform Aperture Stenosis Diagnosis and Etiology Congenital nasal pyriform aperture stenosis (CNPAS) is a rare but notable cause of nasal obstruction in the neonate. The pyriform aperture (PA) is the pear-shaped maxillary nasal inlet and is

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B • Fig. 88.15  (A) 3D reconstruction of CT scan with congenital nasal pyriform aperture stenosis (CNPAS). (B) CT scan axial slice with arrow showing CNPAS measuring 4mm.

the narrowest portion of the nasal airway (Fig. 88.15). CNPAS is caused by a bony overgrowth of the maxilla at the pyriform aperture during embryogenesis. Any decrease in the cross-sectional area leads to a significant increase in nasal airway resistance. The true prevalence of CNPAS is unknown due to varying degrees of clinical presentation and stenosis but has been estimated at 1 in 25,000 births.125 First described in the medical literature in 1989, case reports and publications have more than doubled in recent years. Age and symptoms at presentation often depend on the degree of narrowing. CNPAS may not be diagnosed immediately due to its rare occurrence and nonspecific presentation as other types of nasal obstruction, most frequently mistaken as neonatal rhinitis or choanal atresia or stenosis. Most infants have symptoms shortly after birth or in the first few weeks of life. Presentation can be mild with intermittent noisy breathing, constant congestion, and stertor, and for some infants, nasal airway obstruction presents with difficulties feeding, cyanosis with feeds, or failure to thrive. More severe obstruction may present with obstructive apneas and occasionally, infants may have life-threatening respiratory distress. When suspected clinically, the diagnosis of CNPAS is confirmed with nasal endoscopy and imaging. Respiratory distress or cyanosis with feeding, constant congestion that improves with crying, or difficulty/inability to pass a 5 to 6 French catheter or NG through the PA should prompt further investigation into nasal airway obstruction. Anterior rhinoscopy will reveal a narrow anterior nasal valve passage, typically effecting both nares. Otolaryngology may have difficulty passing a flexible fiberoptic scope through the PA to visualize the rest of the nasal cavity. A definitive diagnosis is made by measuring the width of the PA at the level of the inferior meatus on axial cuts of a maxillofacial computed tomography scan. In a term infant, the PA averages 16.9 mm (depending on the study); with CNPAS being defined as a PA that measures less than 11 mm in a term neonate.126

Phenotype Physical exam findings in the infant with CNPAS can include microcephaly, midface hypoplasia, absent maxillary labial frenulum, and prominent central incisor; with the last two findings being relatively unique to CNPAS.127 CNPAS can occur as an isolated condition or in combination with other midline defects, most commonly a solitary median maxillary central incisor (60%). It is considered a microform of the holoprosencephaly spectrum and can have CNS anomalies: pituitary anomalies, corpus callosum abnormalities, Arnold-Chiari I malformation, optic nerve hypoplasia, olfactory bulb agenesis, hydrocephalus, and a shallow sella turcica. Up to 40% of patients manifest endocrine dysfunction due to agenesis or hypoplasia of the hypothalamus and anterior or posterior pituitary gland.128 CNPAS has been associated with multiple chromosomal abnormalities and syndromes in the literature including Apert and Crouzon syndromes; tuberous sclerosis; craniosynostosis; RHYNS; VACTERL; deletion of Xp22.2, 22q11,128 18p, 13q, 5q129; and ring 18.125 Intensive Care Unit Concerns Most infants with CNPAS are admitted to the NICU for respiratory distress or cyanosis with feeding. Use of an oral airway, supplemental oxygen, or CPAP are common initial first steps to stabilize the airway in the neonate with CNPAS and respiratory distress. A complete metabolic panel can assess an infant’s glucose, electrolytes, and bilirubin levels. Hypoglycemia and conjugated hyperbilirubinemia are highly predictive of pituitary dysfunction.130 For any infant suspected or confirmed to have CNPAS, an endocrinology consult and evaluation is recommended to monitor for a disorder of the hypothalamic-pituitary axis that can include diabetes insipidus, adrenal insufficiency, hypothyroidism, growth hormone deficiency, and hypogonadism. Early diagnosis and appropriate hormonal replacement are crucial as morbidity

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and mortality are risks among the cohort of neonates that have respiratory distress and may need surgery.130 Recurrent hypoglycemic seizures, electrolyte imbalance, and subsequent cardiac arrest have been reported in infants with CNPAS.131 Nutrition can be supported with supplemental nasogastric or orogastric feeds, and continued oral trials are appropriate as respiratory status allows. Working with a feeding therapist is key to developing a safe feeding plan, including pacing, preventing overexertion, and providing a positive feeding experience for the neonate.

Management and Screening Once diagnosed, treatment of CNPAS can be conservative or surgical, depending on the degree of obstruction and severity of associated symptoms. Initial medical management consists of saline irrigation, intranasal steroids, and topical decongestants with the timing of medications optimized for feeds. Conservative management should be attempted for up to 2 weeks before considering surgery.129 During this time, it is paramount to evaluate the neonate for endocrine dysfunction, electrolyte abnormalities, CNS anomalies, or any other associated issues. Brain MRI is recommended for all infants with CNPAS. An ectopic posterior pituitary, anterior pituitary aplasia/hypoplasia, and a pituitary stalk abnormality (in descending order of specificity) on MRI is highly suggestive of pituitary dysfunction, and a structurally normal pituitary does not rule out pituitary dysfunction. Endocrine follow-up through at least 1 year of life is recommended for all infants with CNPAS, and low or plateaued linear growth at 1  year is a predictor of long-term pituitary dysfunction.130 Given the rarity of CNPAS and potential concomitant clinical abnormalities and syndromes that would affect management, genetic consultation is warranted. Failure of medical management is determined by persistence of symptoms: stertor, wheezing, increased work of breathing, inability to wean from respiratory or airway support, sleep apnea, inability to feed, or failure to thrive.125 In these cases, before performing surgery, an alternative procedure has emerged using dilation of the anterior nasal opening. This technique uses a balloon or dilators to provide slight concentric pressure on the bone/cartilage tissue that has natural plasticity due to the presence of circulating maternal estrogens.132 Ultimately, surgical intervention may be needed for infants with persistent symptoms. The mean PA width in neonates needing surgical intervention varied from 4.8 mm to 6.6 mm.133 The most common technique is a sublabial approach where the excessive bony growth around the PA is removed to widen the bony nasal entry. It is considered sufficient to open each side so that at least a 3.5-mm endotracheal tube can be passed without difficulty. Postoperatively, nasal stents are generally left in place for 2 to 4 weeks; however, there is no standardization of technique or timeline for stent usage. Some otolaryngologists may recommend topical or parenteral steroids after surgery. Newer techniques are emerging using endoscopic repairs or using silicon splints along the nasal septum. As with any nasal surgery, postoperative nasal irrigation with saline solution is important to clean the nasal passages and maintain the patency of a stent or other surgically placed foreign body.125 Infants who have surgical treatment are found to have good long-term success, with few needing subsequent nasal airway surgery.133

Prenatal Screening for Fetal Face Anomalies The American College of Obstetricians and Gynecologists recommend routine surveillance of pregnancy with an ultrasound at 18 to 22 weeks’ gestation and have included essential elements to a standardized examination of fetal anatomy that now includes visualization of the upper lip.134 Most studies estimating the incidence of prenatal recognition and diagnosis of orofacial clefting focus on this anatomic examination. Adequate evaluation of the facial structures with ultrasonography can be achieved by 16 to 17 weeks’ gestation. However, the accuracy of this evaluation is impacted by multiple factors such as fetal size, position, limb positioning, and movement; maternal factors such as maternal abdominal scars and maternal body habitus; and other factors including oligohydramnios, type or technology of ultrasound machine, and experience of the ultrasonographer.134,135 Ideally, many facial features can be visualized with routine two-dimensional ultrasonography at 18 weeks’ gestation with standard 3-plane facial views: orbital size and position, eye size (including microphthalmia and anophthalmia), shape of nose, nasal hypoplasia, length of the philtrum, clefts of the upper lip, frontal bossing, retrognathia, micrognathia, macroglossia, and soft tissue abnormalities.136 Cleft lip with or without cleft palate can be detected by prenatal ultrasonography, whereas cleft palate only (CPO) without lip and alveolar involvement may be obscured by the tongue, thus making a prenatal diagnosis of CPO more difficult using traditional 2D ultrasound. A systematic review evaluating the diagnostic accuracy of orofacial clefts detected by second-trimester anatomy scans showed that with 2D ultrasound, detection of CL±P was 9% to 100%, and only 0% to 22% in cases of CPO. Using 3D and 4D ultrasounds, detection was 86% to 90% for CL±P and 0% to 89% of cases of CPO.137 Advances in ultrasound technology and techniques allow ultrasonographers to provide a more detailed, comprehensive, and systematic evaluation of fetal anatomy and should improve detection rates of all craniofacial conditions.138 Among high-risk pregnancies, fetal MRI has higher accuracy in confirming and diagnosing anomalies of the head, face, and neck135,139 and extracraniofacial anomalies otherwise not detected on ultrasound.140 Some centers have started using fetal MRI to predict the need for immediate neonate airway intervention due to airway compromise caused by glossoptosis in Robin sequence,141 micrognathia, or craniofacial masses.142 When fetal airway compromise is anticipated based on prenatal imaging with polyhydramnios, severe micrognathia, mass induced in utero neck extension, neck vessel compression,142 tracheal compression/ deviation, or a solid neck mass,143 delivery may be coordinated at a tertiary care center with obstetric, neonatology, pediatric otolaryngology, and pediatric anesthesia cooperation to perform an ex utero intrapartum treatment (EXIT) procedure. EXIT procedure allows controlled treatment of fetal airway obstruction while maternal-fetal circulation is maintained as a bridge to a secure airway, resection of obstructing lesion, or onto ECMO for severe cardiac anomalies or congenital diaphragmatic hernias.142 Improvement in fetal imaging modalities has shifted the diagnosis of craniofacial anomalies from detection at birth to prenatal diagnosis, and this facilitates parental counseling and planning of delivery and postnatal treatment.135 Prenatal counseling with a craniofacial team has been shown to decrease negative parental perceptions of orofacial clefting144 and reduce rates of postpartum

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depression.145 Families who meet members of an experienced craniofacial team before delivery have the opportunity to build trust with their baby’s providers, to know what to expect after their child’s birth, and to be armed with knowledge, tools, and partners to help their child receive the best care possible.

Acknowledgment Thank you to our mentors and authors of the previous version of this important craniofacial chapter: Michael L. Cunningham MD, PhD, and Anne V. Hing, MD.

Suggested Reading Aljerian A, Gilardino MS. Treacher Collins syndrome. Clin Plast Surg. 2019; 46(2):197–205. Birgfeld C, Heike C. Craniofacial microsomia. Clin Plast Surg. 2019; 46(2):207–221. Breugem CC, Evans KN, Poets CF, et al. Best practices for the diagnosis and evaluation of infants with Robin sequence: a clinical consensus report. JAMA Pediatr. 2016;170(9):894–902. Brioude F, Kalish JM, Mussa A, et al. Expert consensus document: clinical and molecular diagnosis, screening and management of BeckwithWiedemann syndrome: an international consensus statement. Nat Rev Endocrinol. 2018;14(4):229–249.

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Cielo CM, Montalva FM, Taylor JA. Craniofacial disorders associated with airway obstruction in the neonate. Semin Fetal Neonatal Med. 2016;21(4):254–262. https://doi.org/10.1016/j.siny.2016.03.001. Dias MS, Samson T, Rizk EB, Governale LS, Richtsmeier JT. Section on Neurologic Surgery, Section on Plastic and Reconstructive Surgery. Identifying the misshapen head: craniosynostosis and related disorders. Pediatrics. 2020;146(3):e2020015511. Galluzzi F, Garavello W, Dalfino G, Castelnuovo P, Turri-Zanoni M. Congenital bony nasal cavity stenosis: a review of current trends in diagnosis and treatment. Int J Pediatr Otorhinolaryngol. 2021;144:110670. Hudson A, Trider CL, Blake K. CHARGE syndrome. Pediatr Rev. 2017;38(1):56–59. Lewis CW, Jacob LS, Lehmann CU. AAP Section on Oral Health. The primary care pediatrician and the care of children with cleft lip and/or cleft palate. Pediatrics. 2017;139(5):e20170628. Martha VV, Vontela S, Calder AN, Martha RR, Sataloff RT. Laryngeal cleft: a literature review. Am J Otolaryngol. 2021;42(6):103072. McCarthy JG, Warren SM, Bernstein J, et al. Parameters of care for craniosynostosis. Cleft Palate Craniofac J. 2012;49(Suppl):1S–24S. McDonald-McGinn DM, Sullivan KE, Marino B, et  al. 22q11.2 deletion syndrome. Nat Rev Dis Primers. 2015;1:15071. Published 2015 Nov 19.

References The complete reference list is available at Elsevier eBooks+.

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18. Paes EC, Mink van der Molen AB, Muradin MS, et al. A systematic review on the outcome of mandibular distraction osteogenesis in infants suffering Robin sequence. Clin Oral Investig. 2013;17(8):1807– 1820. https://doi.org/10.1007/s00784-013-0998-z. 19. Camacho M, Noller MW, Zaghi S, et al. Tongue-lip adhesion and tongue repositioning for obstructive sleep apnoea in Pierre Robin sequence: a systematic review and meta-analysis. J Laryngol Otol. 2017;131(5):378–383. https://doi.org/10.1017/S002221511700 0056. 20. El Ghoul K, Calabrese CE, Koudstaal MJ, Resnick CM. A comparison of airway interventions and gastrostomy tube placement in infants with Robin sequence. Int J Oral Maxillofac Surg. 2020 Jun;49(6):734–738. https://doi.org/10.1016/j.ijom.2019.10.013. 21. Izumi K, Konczal LL, Mitchell AL, Jones MC. Underlying genetic ­diagnosis of Pierre Robin sequence: retrospective chart review at two children’s hospitals and a systematic literature review. J Pediatr. 2012; 160(4):645–650. e2. https://doi.org/10.1016/j.jpeds.2011.09.021. 22. Hennekam RCM, Krantz ID, Allanson JE. Chapter 21: Orofacial clefting syndromes: general aspects. Gorlin’s Syndromes of the Head and Neck. 5th ed. New York, NY: Oxford University Press; 2010: 943–971. 23. Persson M, Sandy J, Kilpatrick N, Becker M, Svensson H. Educational achievements in Pierre Robin sequence. J Plast Surg Hand Surg. 2013;47(1):36–39. https://doi.org/10.3109/2000656X.2012.729216. 24. Logjes RJH, Haasnoot M, Lemmers PMA, et al. Mortality in Robin sequence: identification of risk factors. Eur J Pediatr. 2018;177(5): 781–789. https://doi.org/10.1007/s00431-018-3111-4. 25. Gomez-Ospina N, Bernstein JAClinical. cytogenetic, and molecular outcomes in a series of 66 patients with Pierre Robin sequence and literature review: 22q11.2 deletion is less common than other chromosomal anomalies. Am J Med Genet A. 2016;170A(4):870–880. https://doi.org/10.1002/ajmg.a.37538. 26. Tan TY, Kilpatrick N, Farlie PG. Developmental and genetic perspectives on Pierre Robin sequence. Am J Med Genet C Semin Med Genet. 2013;163C(4):295–305. https://doi.org/10.1002/ajmg.c. 31374. 27. Robin NH, Moran RT, Ala-Kokko L. Stickler syndrome. 2000 Jun 9 [Updated 2021 May 6]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2021. Available from: https://www.ncbi. nlm.nih.gov/books/NBK1302/. 28. Boothe M, Morris R, Robin N. Stickler syndrome: a review of clinical manifestations and the genetics evaluation. J Pers Med. 2020; 10(3):105. Published 2020 Aug 27. https://doi.org/10.3390/jpm 10030105. 29. Mai CT, Isenburg JL, Canfield MA, et al. National population-based estimates for major birth defects. 2010–2014. Birth Defects Res. 2019; 111(18):1420–1435. https://doi.org/10.1002/bdr2.1589. 30. McBride WA, McIntyre GT, Carroll K, Mossey PA. Subphenotyping and classification of orofacial clefts: need for orofacial cleft subphenotyping calls for revised classification. Cleft Palate Craniofac J. 2016; 53(5):539–549. https://doi.org/10.1597/15-029. 31. Calzolari E, Bianchi F, Rubini M, Ritvanen A, Neville AJ. EUROCAT Working Group. Epidemiology of cleft palate in Europe: implications for genetic research. Cleft Palate Craniofac J. 2004; 41(3):244–249. https://doi.org/10.1597/02-074.1. 32. Leslie EJ, Marazita ML. Genetics of cleft lip and cleft palate. Am J Med Genet C Semin Med Genet. 2013;163C(4):246–258. https://doi. org/10.1002/ajmg.c.31381. 33. Milerad J, Larson O, Hagberg C, Ideberg M. Associated malformations in infants with cleft lip and palate: a prospective, populationbased study. Pediatrics. 1997;100(2 Pt 1):180–186. https://doi. org/10.1542/peds.100.2.180. 34. Mossey PA, Little J, Munger RG, Dixon MJ, Shaw WC. Cleft lip and palate. Lancet. 2009;374(9703):1773–1785. https://doi.org/ 10.1016/S0140-6736(09)60695-4. 35. Croen LA, Shaw GM, Wasserman CR, Tolarová MM. Racial and ethnic variations in the prevalence of orofacial clefts in California,

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123. Farlie PG, Baker NL, Yap P, Tan TY. Frontonasal dysplasia: towards an understanding of molecular and developmental aetiology. Mol Syndromol. 2016;7(6):312–321. https://doi.org/10. 1159/000450533. 124. van den Elzen ME, Twigg SR, Goos JA, et al. Phenotypes of craniofrontonasal syndrome in patients with a pathogenic mutation in EFNB1. Eur J Hum Genet. 2014;22(8):995–1001. https://doi. org/10.1038/ejhg.2013.273. 125. Galluzzi F, Garavello W, Dalfino G, Castelnuovo P, Turri-Zanoni M. Congenital bony nasal cavity stenosis: a review of current trends in diagnosis and treatment. Int J Pediatr Otorhinolaryngol. 2021;144:110670. https://doi.org/10.1016/j.ijporl.2021.110670. 126. Wormald R, Hinton-Bayre A, Bumbak P, Vijayasekaran S. Congenital nasal pyriform aperture stenosis 5.7 mm or less is associated with surgical intervention: a pooled case series. Int J Pediatr Otorhinolaryngol. 2015;79(11):1802–1805. https://doi.org/10. 1016/j.ijporl.2015.07.026. 127. Patel VA, Carr MM. Congenital nasal obstruction in infants: a retrospective study and literature review. Int J Pediatr Otorhinolaryngol. 2017;99:78–84. https://doi.org/10.1016/j.ijporl.2017.05.023. 128. Ruda J, Grischkan J, Allarakhia Z. Radiologic, genetic, and endocrine findings in isolated congenital nasal pyriform aperture stenosis patients. Int J Pediatr Otorhinolaryngol. 2020;128:109705. https://doi.org/10.1016/j.ijporl.2019.109705. 129. Visvanathan V, Wynne DM. Congenital nasal pyriform aperture stenosis: a report of 10 cases and literature review. Int J Pediatr Otorhinolaryngol. 2012;76(1):28–30. https://doi.org/10.1016/j. ijporl.2011.09.016. 130. Chen SC, McDevitt H, Clement WA, et al. Early identification of pituitary dysfunction in congenital nasal pyriform aperture stenosis: recommendations based on experience in a single centre. Horm Res Paediatr. 2015;83(5):302–310. https://doi.org/10.1159/000369805. 131. Hui Y, Friedberg J, Crysdale WS. Congenital nasal pyriform aperture stenosis as a presenting feature of holoprosencephaly. Int J Pediatr Otorhinolaryngol. 1995;31(2-3):263–274. https://doi.org/10.1016/ 0165-5876(94)01096-g. 132. Gungor AA, Reiersen DA. Balloon dilatation for congenital nasal piriform aperture stenosis (CNPAS): a novel conservative technique. Am J Otolaryngol. 2014;35(3):439–442. https://doi. org/10.1016/j.amjoto.2013.12.016. 133. Moreddu E, Le Treut-Gay C, Triglia JM, Nicollas R. Congenital nasal pyriform aperture stenosis: elaboration of a management algorithm from 25 years of experience. Int J Pediatr Otorhinolaryngol. 2016;83:7–11. https://doi.org/10.1016/j.ijporl.2016.01.011. 134. Committee on Practice Bulletins—Obstetrics and the American Institute of Ultrasound in Medicine. Practice Bulletin No. 175: ultrasound in pregnancy. Obstet Gynecol. 2016;128(6):e241–e256. https://doi.org/10.1097/AOG.0000000000001815. 135. Zemet R, Amdur-Zilberfarb I, Shapira M, et al. Prenatal diagnosis of congenital head, face, and neck malformations—is complementary fetal MRI of value. Prenat Diagn. 2020;40(1):142–150. https://doi.org/10.1002/pd.5593. 136. Mak ASL, Leung KY. Prenatal ultrasonography of craniofacial abnormalities. Ultrasonography. 2019;38(1):13–24. https://doi. org/10.14366/usg.18031. 137. Maarse W, Bergé SJ, Pistorius L, et  al. Diagnostic accuracy of transabdominal ultrasound in detecting prenatal cleft lip and palate: a systematic review. Ultrasound Obstet Gynecol. 2010;35(4): 495–502. https://doi.org/10.1002/uog.7472. 138. Faure JM, Mousty E, Bigorre M, et al. Prenatal ultrasound diagnosis of cleft palate without cleft lip, the new ultrasound semiology. Prenat Diagn. 2020;40(11):1447–1458. https://doi.org/10.1002/ pd.5794. 139. Rubio EI. Imaging of the fetal oral cavity, airway and neck. Pediatr Radiol. 2021;51(7):1122–1133. https://doi.org/10.1007/ s00247-020-04851-6.

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140. Laifer-Narin S, Schlechtweg K, Lee J, et al. A comparison of early versus late prenatal magnetic resonance imaging in the diagnosis of cleft palate. Ann Plast Surg. 2019;82(4S Suppl 3):S242–S246. https://doi.org/10.1097/SAP.0000000000001881. 141. Resnick CM, Kooiman TD, Calabrese CE, et  al. An algorithm for predicting Robin sequence from fetal MRI. Prenat Diagn. 2018;38(5):357–364. https://doi.org/10.1002/pd.5239. 142. Cash H, Bly R, Masco V, et  al. Prenatal imaging findings predict obstructive fetal airways requiring EXIT. Laryngoscope. 2021;131(4):E1357–E1362. https://doi.org/10.1002/lary.28959. 143. Jiang S, Yang C, Bent J, et al. Ex utero intrapartum treatment (EXIT) for fetal neck masses: a tertiary center experience and literature

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review. Int J Pediatr Otorhinolaryngol. 2019;127:109642. https:// doi.org/10.1016/j.ijporl.2019.109642. 144. Maarse W, Boonacker CWB, Swanenburg de Veye HFN, Kon M, Breugem CC, Mink van der Molen AB, van Delden JJM. Parental attitude toward the prenatal diagnosis of oral cleft: a prospective cohort study. Cleft Palate Craniofac J. 2018 Jan 1:1055665618763337. https://doi.org/10.1177/1055665618763337. 1 45. Johns AL, Hershfield JA, Seifu NM, Haynes KA. Postpartum depression in mothers of infants with cleft lip and/or palate. J Craniofac Surg. 2018;29(4):e354–e358. https://doi.org/10.1097/ SCS.0000000000004319.

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89

Common Neonatal Orthopedic Conditions KATHERINE M. SCHROEDER, MARYSE L. BOUCHARD, AND KLANE K. WHITE

KEY POINTS • Developmental dysplasia of the hip represents a spectrum of diseases. All infants should be screened by physical examination; selective imaging based on risk factors is recommended. • Most cases of congenital muscular torticollis resolve spontaneously. Physical therapy and surgery are reserved for recalcitrant cases. • A variety of foot deformities are common and can be encountered in the neonate. Stretching, casting, or surgery may be required for resolution. • Torsional and angular deformities of the lower extremities must be differentiated from physiologic variants. Asymmetry and rapid progression are the hallmarks of pathologic variants. • Congenital vertebral anomalies result from failures of formation or segmentation of spinal elements. Spinal deformities such as scoliosis or kyphosis may ensue. • Although orthopedic afflictions of the newborn are generally not life threatening, they do have the potential to significantly impair functional performance, even when diagnosed and treated early. This chapter discusses the most commonly encountered of these orthopedic problems.

Developmental Dysplasia of the Hip The term developmental dysplasia of the hip (DDH) encompasses a spectrum of diseases from acetabular dysplasia to hips that are located but unstable (femoral head can be moved in and out of the confines of the acetabulum), to frankly dislocated hips in which there is a complete loss of contact between the femoral head and acetabulum. Although geographic and racial variations have been reported, DDH occurs in 11.5 of 1000 infants, with frank dislocations occurring in 1 to 2 per 1000.1 Studies have suggested that breech positioning, family history of DDH, limited hip abduction, talipes, female sex, swaddling, large birth size, and first-born infants have all been associated with a higher probability of finding DDH.2 The left hip alone is affected in 60% of infants, the right hip alone is affected in 20% of infants, and both hips are affected in 20% of infants.3 With regards to dislocated hips, they can be divided into two groups: syndromic and typical. Syndromic dislocations are most frequently associated with neuromuscular conditions such as myelodysplasia and arthrogryposis or with syndromes such as Larsen syndrome. Syndromic dislocations probably occur between

week 12 and week 18 of gestation.1 Typical dislocations occur in otherwise healthy infants in the third-trimester prenatal period or postnatally. Congruent reduction and stability of the femoral head are necessary for normal growth and development of the hip joint. The natural history of untreated DDH is controversial as newborn hip instability may resolve or progress to painless dislocation. In cases that progress to subluxation, individuals have significantly increased risk of developing precocious arthritis with moderate to severe hip pain as young adults.4,5 This pain can be debilitating and the reconstruction difficult. Early detection and treatment of DDH are thus important in avoiding the devastating sequelae of a late diagnosis. While the physical exam of an infant hip is paramount to the diagnosis of DDH, there are no pathognomonic signs of a dislocated hip. The physical examination requires patience on the part of the examiner and may be facilitated by having the baby feed from a bottle or swaddling the arms. Communication between providers is encouraged if the practitioner examining the newborn in the hospital is different from the 2-week follow-up examiner. The presence of asymmetric hip abduction is suggestive of a unilateral dislocation. Limitation of hip abduction in babies older than 12 weeks is the most reliable examination finding suggestive of DDH. Hip abduction of 75 degrees should be possible in most newborns. The Galeazzi sign is elicited with the baby placed supine on an examining table so that the pelvis is level, with the hips and knees flexed to 90 degrees. With the baby’s hips in neutral abduction, the examiner determines if the knees are at the same height. If one femur appears shorter than the other, the hip may be dislocated posteriorly (Fig. 89.1). Each of these signs, individually or in combination, may serve to increase the index of suspicion of the examiner and lower the threshold for further diagnostic studies or referral to a pediatric orthopedist. A unilateral dislocated hip may result in asymmetric thigh folds; however, extra thigh folds are a normal variant and do not necessarily indicate hip dislocation. It is important to note that in an infant with bilateral hip dislocations, the Galeazzi sign will be negative and the hip abduction symmetric. There are two common methods of assessing hip stability in the newborn (Fig. 89.2). The Ortolani test aims to reduce a dislocated hip. This is performed on one leg at a time, with the infant supine on the examining table. The index and middle fingers of the examiner are placed along the greater trochanter, while the thumb is placed on the medial aspect of the thigh. The pelvis is stabilized

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by the placing of the thumb and ring or long finger of the opposite hand on top of both anterior iliac crests simultaneously. The hip is flexed to 90 degrees and gently abducted while the leg is lifted with the hip in neutral external/internal rotation. A palpable clunk is felt as the dislocated femoral head reduces into the acetabulum. This finding is reported as the Ortolani sign (positive result on the Ortolani test). The Barlow test is an attempt to dislocate or subluxate a located but unstable hip. The thigh is held, and the pelvis stabilized in the same manner as for the Ortolani test. With the hip

• Fig. 89.1  Presence of Galeazzi Sign.

A

Ortolani sign

B

Barlow sign

 

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in neutral external/internal rotation and at 90 degrees of flexion, the leg is then gently adducted with a mild posteriorly directed pressure applied to the knee. A palpable clunk or sensation of posterior movement constitutes a positive result (i.e., the Barlow sign). High-pitched clicks are frequently elicited with hip range of motion. These sounds are most frequently attributed to snapping of the iliotibial band over the greater trochanter and are not associated with dysplasia.6 With progressive soft tissue contractures and loss of ligamentous laxity, both the Ortolani test and the Barlow test become unreliable after approximately 3 months of age. Imaging of the immature hip can be a valuable adjunct to the physical examination. An anteroposterior (AP) radiograph of the pelvis can be difficult to interpret before the age of 4 to 5 months as the femoral head is composed entirely of cartilage until the secondary center of ossification appears. Before the appearance of the secondary center, ultrasound examination is the method of choice for visualizing the cartilaginous femoral head and acetabulum. Static ultrasound images allow visualization of acetabular and femoral head anatomy, while the complementary dynamic images give information on the stability of the hip joint.7,8 The primary limitation of hip ultrasonography is that the results are dependent on the experience and skill of the operator, especially when performed within the first 3 weeks after birth.9 For these reasons, ultrasonography is recommended as an adjunct to clinical evaluation rather than as an independent screening tool.1 Studies conducted before 6 weeks after birth may be useful for confirming equivocal physical examination findings and for monitoring treatment of hips with known dislocations. Clinicians must be aware, however, that ultrasound images in this age group often reveal minor degrees of dysplasia (physiologic immaturity) that usually resolve spontaneously and may lead to overtreatment of physiologic hip variations. Ultrasonography is the technique of choice for assessment of infants at high risk of DDH after 4 to 6 weeks of age and again is useful in following up the results of

“clunk”

“clunk”

• Fig. 89.2  Assessing Hip Stability. (A) Ortolani-positive hips are those where the dislocated hip can be relocated. (B) Barlow-positive hips are reduced but can be dislocated.

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intervention. After 6 months of age, the gold standard remains the AP radiograph of the pelvis. All newborns should be screened for DDH by a properly trained healthcare provider by physical examination. Risk factors for DDH should be determined by the treating physician. A Cochrane review found that neither universal nor targeted ultrasound screening strategies have been demonstrated to improve clinical outcomes, including the incidence of late-diagnosed DDH and need for surgery.10 Adding further confusion to the debate over the approaches to optimal DDH screening procedure is a report by the US Preventive Services Task Force, which found “insufficient evidence” to recommend any routine DDH screening, including physical examination.11 This recommendation was based on the lack of clear evidence for the efficacy of infant screening to reduce the incidence of late-presenting DDH. In response to these findings, the American Academy of Orthopedic Surgeons (endorsed by the American Academy of Pediatrics, the Pediatric Society of North America, and the Society for Pediatric Radiology) has published a revised clinical practice guideline to aid in the early diagnosis of and initiation of appropriate intervention for DDH.12 These recommendations are summarized as follows: 1. Universal ultrasound screening. Moderate evidence supports not performing universal ultrasound screening of newborn infants. 2. Evaluation of infants with risk factors for DDH. Moderate evidence supports performing an imaging study before 6 months of age in infants with one or more of the following risk factors: breech presentation, family history, or history of clinical instability. 3. Imaging of the unstable hip. Limited evidence supports that the practitioner might obtain an ultrasound image in infants younger than 6 weeks of age with positive instability examination findings to guide the decision to initiate brace treatment. 4. Imaging of the infant hip. Limited evidence supports the use of an AP radiograph of the pelvis instead of an ultrasound image to assess DDH in infants beginning at 4 months of age. 5. Surveillance after normal findings from an infant hip examination. Limited evidence supports that a practitioner reexamine infants previously screened as having normal hip examination findings on subsequent visits before 6 months of age. 6. Stable hip with ultrasound imaging abnormalities. Limited evidence supports observation without a brace for infants with a clinically stable hip with morphologic ultrasound imaging abnormalities. 7. Treatment of clinical instability. Limited evidence supports either immediate or delayed (2 to 9 weeks) brace treatment for hips with positive instability examination findings. 8. Type of brace for the unstable hip. Limited evidence supports use of the von Rosen splint over Pavlik, Craig, or Frejka splints for initial treatment of an unstable hip. 9. Monitoring of patients during brace treatment. Limited evidence supports that the practitioner perform serial physical examinations and periodic imaging assessments (ultrasound or radiograph depending on age) during management for unstable infant hips. If there are no risk factors, then serial examinations are recommended according to a standard periodicity schedule until the child is 6 months old. If during these periodic visits physical findings raise suspicion of DDH, or if a parental concern suggests hip disease, confirmation is recommended by an expert physical examination, by referral to a pediatric orthopedist (or other practitioner with expertise in medical and surgical management of newborn hip

disease), or by age-appropriate imaging. When a positive Ortolani or Barlow test is present at birth and persists beyond the usual age of spontaneous resolution (2 to 9 weeks), the infant should be referred to an orthopedist for management. However, if the positive Ortolani or Barlow test disappears, then age-appropriate imaging (ultrasonography at 6 weeks or radiograph by 6 months) is warranted. If the infant has positive risk factors, such as breech positioning at birth or a family history but stable hip examination findings, then age-appropriate imaging is recommended (ultrasonography at 6 weeks or radiograph at 6 months). Treatment of DDH is dependent on the age at presentation. Although previously recommended, double diapering is not an accepted form of treatment in DDH. For children aged 0 to 6 months, a reducible hip is treated in a Pavlik harness or another appropriate orthosis. The Pavlik harness is a dynamic orthosis that allows the infant to actively move the hips through a sphere of motion that encourages deepening and stabilization of the acetabulum (Fig. 89.3). The harness is applied as soon as possible after the diagnosis of DDH is made. The length of treatment is dependent on the age at presentation and severity of dysplasia. Progress

• Fig. 89.3  The Pavlik Harness. Lightweight orthotic, useful in treatment

of neonatal developmental dysplasia of the hip (DDH). The device holds the hip in flexion and abduction, promoting optimal positioning of the femoral head in the acetabulum. Excessive flexion and abduction should be avoided.

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is judged by serial physical examinations and ultrasonography. In the case of a frankly dislocated hip, treatment is abandoned if the hip is not reduced within 4 weeks of harness application. The success of Pavlik harness treatment is variable and correlates with the severity of the hip dysplasia. Treatment is successful in nearly 100% of stable hips, greater than 90% of dislocatable (Barlowpositive) hips, 61% to 93% of dislocated but reducible (Ortolanipositive) hips, and only 40% of irreducible dislocations.13–17 For a persistently irreducible dislocation, or a child that presents late with a dislocated hip (after 6 months of age), either closed or open reduction of the hip under general anesthesia, with subsequent spica casting, is often required.18

Foot Deformities Congenital deformities of the foot are relatively common but often overlooked in newborns. Consequently, the true incidence of the milder, self-limited deformities is unknown. For identification purposes, congenital foot abnormalities can be divided into those that result in the toes pointing upward (calcaneovalgus, congenital vertical talus), those that result in the toes pointing inward (metatarsus adductus, clubfoot), and those with too many toes or toes stuck together (polydactyly, syndactyly). Calcaneovalgus is thought to be a postural deformity secondary to intrauterine positioning in which the dorsum of the foot is, or can be, directly opposed to the anterior aspect of the leg (Fig. 89.4). Plantar flexion of the foot is often limited from contracture of the anterior ankle and lateral soft tissues. The estimated incidence of calcaneovalgus is 0.4 to 1 per 1000 live births.19,20 It appears to be more common in girls and after breech deliveries.20 There may be an increased association with hip dysplasia, so a thorough hip examination is warranted, as outlined in Developmental Dysplasia of the Hip.21 Complete resolution with gentle stretching exercises conducted by the parents can be achieved, although generally occurs spontaneously by 3 to 6 months of age. In the more severe calcaneovalgus feet where the ankle cannot be plantar flexed past the neutral position, serial casting to facilitate correction is often required. Calcaneovalgus may be seen in conjunction with external rotation of the tibia and posteromedial bowing of the tibia. A deformity that fails to resolve mandates referral to a pediatric orthopedist. Calcaneovalgus should be differentiated from congenital vertical talus (CVT), a rarer condition that is frequently associated with neuromuscular conditions and syndromes such as arthrogryposis and spina bifida.22 In CVT the hindfoot is fixed in equinus (plantar flexion), giving the sole of the foot a characteristic “rocker bottom” appearance because of dorsal dislocation of the midfoot though the talonavicular joint (Fig. 89.5). Treatment during infancy consists of serial casting to stretch dorsal soft tissues and reduce the midfoot, followed by limited surgical release if needed, pinning of the talonavicular joint, and Achilles tenotomy.23 Most children require surgery between 6 and 12 months of age, and best outcomes are achieved when surgery is performed before age 2 years.24 When casting fails to reduce the midfoot, more extensive surgical releases are required. The two common neonatal foot deformities resulting in medial deviation of the toes are metatarsus adductus and talipes equinovarus (clubfoot). Metatarsus adductus is present at birth but frequently diagnosed later during the first year of life. It has been estimated to occur in 1 in 100 births25 and is thought to result from intrauterine crowding.

 

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Characteristic features include a concave medial border of the foot with a curved lateral border, a “bean-shaped” sole of the foot, a higher-than-normal-appearing arch, and a neutral heel (Fig. 89.6).26 Metatarsus adductus can be classified into cases that undergo passive correction and those that do not. Feet which passively correct are best left alone and will improve spontaneously. Feet in which passive correction is not possible (the curved lateral border cannot be straightened) should be treated with manipulation and serial casting by age 6 to 9 months. The corrections can then be maintained with reverse or straight last shoes if necessary. Operative treatment should be considered only in children older than 3 years who have a rigid deformity and have failed to respond to a casting program.27

• Fig. 89.4  Calcaneovalgus

Foot. (From Pediatric Pes Planus JAAOS Oct. 2015, Bouchard M, Mosca VS. Flatfoot deformity in children and adolescents: surgical indications and management. J Am Acad Orthop Surg. 2014;22:623–632.)

• Fig. 89.5  Congenital Vertical Talus. (From Pediatric Pes Planus JAAOS

Oct. 2015, Bouchard M, Mosca VS. Flatfoot deformity in children and adolescents: surgical indications and management. J Am Acad Orthop Surg. 2014;22:623–632.)

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The term clubfoot describes a foot with hindfoot equinus, heel varus, and adduction and supination of the forefoot (Fig. 89.7). Clubfoot deformities range from mild to severe and occur in 1 in 1000 to 2 in 1000 live births.28 A risk factor for clubfoot is early amniocentesis (11 to 13 weeks’ gestation), which is hypothesized to cause decreased fetal movement during a critical phase of foot development.29 Although the cause of clubfoot remains unproven, there appears to be dysplasia of all osseous, muscular, tendinous, cartilaginous, skin, and neurovascular tissues distal to the knee in the affected limb. The mild, “postural” clubfoot appears to represent a packaging problem due to intrauterine positioning. This deformity is passively correctible, demonstrates minimal or no calf atrophy, and resolves spontaneously or responds quickly to a stretching and casting regimen. At the opposite end of the spectrum is the arthrogrypotic or neuromuscular clubfoot that demonstrates severe rigidity. Between these two extremes lies the classic, idiopathic clubfoot deformity. Idiopathic clubfeet demonstrate a deep, single medial skin crease, curved lateral border with a high arch, and rigid varus and equinus of the heel with a deep, single, posterior skin crease.30 This gives the foot its “down and in” position and toes pointing to the midline. In unilateral cases the affected limb has a smaller foot and calf circumference (see Fig. 89.7).

All clubfoot deformities should be referred to a pediatric orthopedist for treatment. Initial treatment for all cases of congenital clubfoot is nonoperative. Untreated clubfoot has a poor natural history, with development of early degenerative changes in the foot joints. Historically, clubfeet were treated with early and extensive surgical correction. The long-term results, however, are poor, with high recurrence rates.27 Consequently, this approach was abandoned, and surgeons began advocating nonoperative methods of clubfoot correction.31–33 Although many forms of nonoperative clubfoot treatment exist, the Ponseti method of cast correction has achieved preeminence in this regard. Studies show excellent mid-term to long-term results with decreased stiffness.34 The Ponseti method uses a specific set of manipulations and serial corrective long-leg casts, followed by a prolonged period of bracing. Treatment is ideally commenced within the first few weeks after birth, but successful treatment is commonly achieved when treatment is initiated up to 1 year of age.35 We prefer to initiate treatment 1 to 2 weeks after discharge from the hospital to allow parental adjustment for the new infant at home. Every 5 to 7 days, manipulation of the foot is performed with passive stretching, and the correction is maintained with a new long-leg cast, with an average of four to five casts in the idiopathic clubfoot.23 This is followed by percutaneous Achilles tenotomy in most patients and a further 3 weeks of casting. Children are then placed into a foot abduction orthosis full-time for a period of 3 months and then part-time, while sleeping, until approximately age 4 years. The “French functional method” has also been successfully duplicated in at least one US hospital with good results.28,36 This method necessitates daily manipulations by a trained physical therapist for 8 weeks, with the addition of continuous passive motion during the first 4 weeks. This is followed by strapping and continued bracing. The Ponseti and the French “nonoperative” methods both frequently use Achilles tenotomy and, at times, tendon transfers to attain the ultimate desired result. Recurrences of deformity are common (16% to 37%), requiring further casting. A smaller percentage of patients (8% to 16%) require surgical release of the hindfoot to various degrees.36,37

Torticollis • Fig. 89.6  The

Appearance of the Foot with Metatarsus Adductus. (Courtesy Dr. Vincent S. Mosca, Seattle Children’s Hospital, Seattle.)

• Fig. 89.7 The

Appearance of an Untreated Newborn Clubfoot. (Courtesy Dr. Vincent S. Mosca, Seattle Children’s Hospital, Seattle.)

Congenital muscular torticollis (CMT) manifests itself at birth or soon, thereafter, and is the most frequent cause of wryneck. However, other conditions, some more serious, may cause torticollis. 1. Bony anomalies of the vertebra and skull (e.g., Klippel Feil syndrome, hemivertebrae, basilar invagination, craniosynostosis)38–40 2. Abnormalities of the central nervous system (e.g., syringomyelia, tumors)41 3. Chiari malformations42 4. Ocular abnormalities43 5. Pharyngeal abscess 6. Gastroesophageal reflux (e.g., Sandifer syndrome).44 Patients with CMT can be divided into those who demonstrate a sternocleidomastoid muscle (SCM) “pseudotumor,” those with tightness or fibrosis of the SCM without pseudotumor (termed muscular torticollis), and those with all the characteristic features of congenital torticollis without evidence of contracture or fibrosis of muscle (termed postural torticollis).45

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CMT has been estimated to occur in 0.3% to 2.0% of live births.45 It is usually discovered between 6 and 8 weeks after birth. Infants present with a cock robin appearance, with the head tilted toward and the chin rotated away from the affected SCM. 20-30% of patients will have a palpable pseudotumor present in the middle to inferior aspect of the affected SCM, which spontaneously regresses with time, leaving a fibrous band.46 More than half will have facial asymmetry or plagiocephaly. The left and right SCMs are affected in equal proportions. CMT probably results from ischemia within the SCM, leading to fibrosis.47 The cause of the ischemia is unknown, but intrauterine crowding may play a role, in as much as some authors have reported an association of torticollis with other deformations, such as DDH and metatarsus adductus.48,49 Excellent results with a manual stretching program can be attained in children first seen before 1 year of age.48,50 Initially, the parents are instructed in the technique of stretching the contracted SCM by rotating the infant’s chin toward the affected SCM while simultaneously tilting the head away from it. This is completed 10 times each session and held for a count of 10 and done at least 10 times per day. Unfortunately, adherence may be an issue. If the child fails to improve substantially within 3 to 4 weeks, a physical therapist is enlisted to see the child two or three times weekly to supervise the program and reinforce the home therapy. Additionally, parents are instructed to configure the infant’s crib and toys in such a manner as to encourage active rotation toward the involved side. Surgery is not warranted in any child younger than 1 year or in any child who has not completed a minimum of 6 months of therapy.45,48 In a prospective study of 821 children with muscular torticollis, only 8% of patients with a history of a pseudotumor, and 3% of those without, required surgical intervention following a well-structured stretching program.45 Because of the difficulty of monitoring exercise programs, because parental adherence is always in question, and because surgical intervention is infrequent, it is possible that in many patients the resolution is spontaneous. No patients with postural torticollis require surgery. Risk factors for surgery include late initial presentation, presence of a pseudotumor, and rotation deficit of greater than 15 degrees. The timing of surgical intervention remains controversial. In patients with significant plagiocephaly and facial asymmetry, surgery should be considered just before 2 years of age to maximize the chance for complete remodeling. For those with either no or mild facial asymmetry, good to excellent results can be expected with surgery up to 6 years of age.51 Acceptable results are reported as late as 12 years of age, but the ability to remodel facial asymmetry appears diminished.52 More recent literature suggests good surgical outcomes in neglected CMT even after 15 years of age.53 Surgery entails bipolar release or lengthening of the SCM through cosmetically pleasing incisions.54 The use of a molded helmet to promote facial and skull remodeling is common. Prospective studies that establish the effectiveness of helmets are lacking, and in at least one study was found to be possibly detrimental.55 A less frequent cause of congenital torticollis is osseous fusion between bones in the cervical spine. These fusions may be between the skull and C1 and/or C2 or in the lower cervical spine. They result from failure of the bones to properly segment during embryogenesis. These abnormalities, in combination with a low posterior hairline and a short, webbed neck with limited range of motion and head tilt, constitute the triad referred to as KlippelFeil syndrome (KFS).56 These congenital bone fusions can range from involvement of two segments to involvement of the entire

 

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cervical spine. Colloquially, KFS has come to refer to any congenital malformation in the cervical spine with or without other elements of the triad. Most cases of KFS do not have a genetic etiology, however additional forms of KFS include autosomal recessive KFS2 caused by mutation in the MEOX1 gene, autosomal dominant KFS3 caused by mutation in the GDF3 gene, and autosomal recessive KFS4 caused by mutation in the MYO18B gene. In infants and young children, the neck may remain quite flexible despite the bone abnormalities. In a newborn with torticollis who does not improve with passive stretching exercises, radiologic evaluation is mandatory. Cervical spine radiographs are not recommended in all patients initially presenting with neonatal torticollis, as these radiographs are quite difficult to interpret in this age group because of the predominance of cartilage in the bones of the neck. Furthermore, many neonates would be subjected to unnecessary ionizing radiation. The natural history of KFS in most cases is quite favorable, requiring nothing more than periodic observation. In patients with severe involvement, however, the consequences of this disorder can include early spondylosis with the development of pain or stenosis, the development of progressive torticollis and scoliosis, and the occurrence of neurologic compromise and sudden death secondary to even minimal trauma.46 Despite these potentially devastating sequelae, the greatest advantage of early detection of KFS is in being alerted to commonly associated disorders, including congenital heart disease (14% to 29%), renal anomalies (25% to 35%), scoliosis (60%), audiologic anomalies (80%), including deafness (15% to 35%), synkinesis (15% to 20%), and less commonly, posterior fossa desmoid tumors.46,57 The recognition of a Klippel-Feil anomaly should prompt a thorough evaluation for these associations. Treatment of KFS most often involves periodic observation with activity modification. In the face of progression of deformity or severe deformity, surgical intervention may be warranted. Sandifer syndrome (gastroesophageal reflux) can also cause a torticollis. With this syndrome the torticollis is intermittent and may change direction, and there is no tightness of the SCM, with normal findings on radiographs.44 Hemiatlas, or the failure of formation of a portion of the first cervical vertebra, is also a rare cause of torticollis.39 In an infant the neck may be quite flexible and the torticollis passively correctable. An open-mouth (odontoid view) cervical spine radiograph reveals this deformity. If the torticollis is progressive or severe, gradual correction of the deformity with a halo vest followed by posterior occiput to cervical spine fusion is necessary. Other potential causes of torticollis in the neonate include central nervous system tumors and syringomyelia. If radiographs appear normal, a thorough neurologic examination and referral to a neurologist are recommended.

Torsional and Angular Deformities of the Lower Extremities Torsional and angular deformities of the legs constitute the most frequent nontraumatic reason for referral to a children’s orthopedist. Torsional deformities of the lower extremities rarely come to the attention of the physician before the child reaches walking age. Neonates often demonstrate bowing of the legs, or genu varum, but are rarely concerning to parents prior to walking age. Internal tibial torsion imparts an appearance of bowing to the tibia,58 which is often concerning to both the parent and the physician. The true

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incidence of genu varum is unknown, but in our experience, it is extremely common. Both genu varum and internal tibial torsion are nearly universal in neonates. Both should spontaneously resolve between 2 and 3 years of age, with a small minority of affected children manifesting a pathologic condition. Genu varum is physiologic up to the age of 2 years. In 1975, Salenius and Vankka59 documented the tibiofemoral angles both clinically and radiographically in 979 children based on 1408 examinations between birth and 16 years of age. They noted that newborns demonstrate a mean varus alignment of 15 degrees, which increases and becomes maximal at 6 months of age and then decreases to neutral at approximately 18 months. The maximum valgus (knock knees) of 12 degrees is then achieved by 3 to 4 years. By age 7 years, normal adult valgus alignment is achieved (Fig. 89.8). Natural history studies have demonstrated that physiologic genu varum is a self-limited process, and even with an angulation greater than 30 degrees has been shown to undergo correction spontaneously with growth.60 Management of physiologic genu varum and tibial torsion consists of serial observation, parental reassurance and education. Treatment with an orthosis is not recommended. Physical examination should include evaluation of the torsional profile,61 which includes measurements of internal and external rotation of the hips, the thigh–foot angle, and the patient’s foot progression angle when walking. Measurement of the thigh–foot angle is performed with the child in the prone position comparing the axes of the sole of the foot with the thigh and is an indicator of tibial torsion. It is important to note whether onset of the varus of the lower extremities is gradual or abrupt, and if the deformity can be localized to the distal part of the femur, the proximal part of the tibia,

or the midportion of the tibia. Radiographs are indicated only with asymmetric deformities, with short stature, persistent varus past 2 years of age, or in infants with progressive deformities. The examiner should also look for evidence of rhizomelic shortening and genu varum, which may herald a diagnosis of achondroplasia or other skeletal dysplasia. Considerations in the differential diagnosis of genu varum include focal fibrocartilage dysplasia, skeletal dysplasias, posttraumatic physeal growth arrests, osteogenesis imperfecta (OI), and metabolic bone disease such as vitamin D–resistant rickets, renal osteodystrophy, and tibia vara (infantile Blount disease). Blount disease is bilateral in 80% of affected children and does not occur before walking age. Most clinicians agree that this diagnosis cannot be made before 2 years of age. Tibial bowing can also occur in the sagittal plane. There are two major types of bowing distinguished by the direction of the apex of the bow. Posteromedial bowing has been previously described in conjunction with calcaneovalgus foot position in the neonate. Its cause is unknown, but numerous hypotheses have been proffered, including intrauterine fracture with malunion and in utero malpositioning with subsequent growth retardation and soft tissue contractures.62 The deformity is unilateral and evident at birth. Other features include shortening of the tibia and a smaller calf circumference and smaller foot relative to the contralateral side. Frequently there is a skin dimple at the apex of the deformity. Radiographic examination of the entire extremity from hip to ankle should be performed. Radiographs demonstrate the degree of bowing and in some cases thickening and sclerosis of the diaphyseal cortices on the compression side of the deformity with obliteration of the intramedullary canal. There is no increased fracture risk associated with the deformity.

+20°

Development of the tibiofemoral angle during growth Varus Valgus

Varus

+15°

+ –

+10°

+5°

Age

1 2 3 4 5 6 7 8 9 10 11 12 13 years years years years years years years years years years years years years

0°

Valgus

–5°

–10°

±0 – 11

±0 – 12

±0 – 10

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±0 – 14

±0 – 10

±0 – 11

+4 – 17

+13 – 19

+20 – 20

+21 – 13

+34 ± 0

Extreme values

–15° ±0 – 11

1300

• Fig. 89.8  Development of the Tibiofemoral Angle During Growth. (Data from Salenius P, Vankka E. The development of the tibiofemoral angle in children. J Bone Joint Surg Am. 1975;57:259–261.)

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Posteromedial bowing tends to resolve with growth, such that much of the deformity resolves by 2 years of age, with continued gradual correction beyond that. The shortening of the tibia and fibula persists, however, and progressively worsens during growth. Leg length inequality at skeletal maturity averages 4.1 cm.63 Early referral to and serial follow-up assessments by a pediatric orthopedist are necessary to appropriately time epiphysiodesis surgery of the normal longer leg to allow equal leg lengths at skeletal maturity. The second and more serious type of tibial bowing is anterolateral. It is usually identified at the newborn examination. It is unilateral and can be associated with congenital pseudoarthrosis of the tibia. Although its cause is unknown, congenital pseudoarthrosis of the tibia is associated with neurofibromatosis type 1 (NF1) in 40% to 80% of cases.62,64,65 It is arguably the most challenging congenital malformation to treat in orthopedics. It is estimated to occur in 1 in 140,000 live births.66 Cutaneous signs of NF1 may be evident. Early referred to pediatric orthopedics and genetics are recommended. If fracture has occurred, motion at the pseudoarthrosis site will be apparent. The foot may be normal or slightly small. The ankle may be in slight valgus to compensate for the bowing. The natural history of congenital pseudoarthrosis of the tibia is that of fracture with nonunion and repeated surgical attempts at obtaining union. In the perambulatory child, a total-contact (clamshell) ankle– foot orthosis should be fabricated and worn full-time except for bathing, to diminish the chance of fracture. Bracing is continued until skeletal maturity is attained. Although definite proof that long-term bracing affects the natural history of this condition is lacking, most orthopedists consider that bracing is warranted. Many treatment options exist once a documented pseudoarthrosis occurs. Long-term immobilization, external fixation, internal fixation, bone transport, bone grafting, microvascular bone transfer, and electric stimulation have been attempted.66 High failure rates are commonly reported. Amputation has been advocated as a salvage procedure after failed attempts at union and typically has good outcomes.67,68 Herring et al.68 reported that children who underwent Syme amputation had better psychologic and orthopedic functioning than those children who underwent numerous corrective surgical procedures. A more recent cross-union technique has been described with the goal of producing a synostosis between the tibia and fibula and has shown excellent union rates.69 Tibial bowing in the anteromedial direction rarely occurs and is typically seen in children with fibular hemimelia, a condition with multiple lower limb anomalies. In addition to a deficient or absent fibula, there is a strong association with absent lateral rays of the foot, a bowed tibia, knee deformities, a short femur, hip dysplasia, and leg length discrepancy. Orthopedic referral is indicated. Tibial bowing may also be confused with a congenital knee dislocation. This is a rare condition, noted at birth, with a reported incidence of 0.017 per 1000.70 The cause is unknown but most likely related to contracture of the quadriceps muscle. Congenital knee dislocations can be associated with clubfoot, arthrogryposis, myelodysplasia, and Larsen syndrome, with ipsilateral hip dysplasia occurring in 70% to 100% of cases.71 The knee can be hyperextended so severely that the foot might even reach the child’s face, and the knee cannot be flexed. Nonsurgical treatment, consisting of manipulation and serial casting, should be started promptly after radiographic diagnosis. Surgery is reserved for children who do not respond to nonsurgical treatment and is best performed at the age of approximately 6 months (Fig. 89.9).72

 

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Congenital Vertebral Malformations Congenital vertebral malformations occur in 0.5 in 1000 to 1 in 1000 live births. Although a minority of cases may be due to genetic inheritance, there are no established gene defects that solely account for these disorders. The syndromes associated with them include Klippel-Feil syndrome (KFS), Goldenhar syndrome, VATER (VACTERL) sequence, and spondylocostal dysostosis. Likewise, many congenital vertebral malformations occur in isolation and may be due to intrauterine exposures such as maternal hyperglycemia, exposure to carbon monoxide, or exposure to antiepileptic drugs. The ultimate concern with congenital vertebral anomalies is their potential to result in significant spinal deformity; namely, scoliosis or kyphosis, or a combination of the two. Many, however, remain asymptomatic throughout life. Defects can be attributed to a failure of formation, a failure of segmentation, or both.73 Failures of formation result from asymmetric vertebral body formation and ensuing development of a hemivertebra. Hemivertebrae can be incomplete, with partial retention of the affected side, or complete. When partial retention of the pedicle occurs, a wedge vertebra develops. Complete hemivertebra can be further categorized. Radiographically, the presence of open disk spaces signifies the presence of growth plates and therefore growth potential. Unsegmented hemivertebrae, in which the segment is fused to one vertebra or both adjacent vertebrae, have less growth potential and therefore less deformity potential. Fully segmented hemivertebrae retain full growth potential from both the cranial end and the caudal end and consequently demonstrate a much greater propensity to result in significant deformity. Failures of segmentation are characterized by bony fusions (bars) between adjacent vertebrae. Bilateral bars result in “block vertebrae” that, because of their symmetry, have minimal potential for deformity. The propensity to result in a clinically significant deformity depends on the location of the defect, the type of defect, and the age of the patient.74 Curves at the lumbosacral and cervicothoracic junctions may result in more clinically apparent deformities. Prediction of progression is largely driven by the presence of unbalanced defects.73 In order of severity, the risk of progression in congenital spinal deformities is associated with the following

• Fig. 89.9  Congenital Knee Dislocation.

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defects: unilateral bar with contralateral hemivertebra, unilateral bar, hemivertebra, wedge vertebra, and block vertebra (Fig. 89.10). Additionally, the presence of multiple anomalies at multiple levels (e.g., multiple hemivertebra) can result in additional risk of progression when they are on the ipsilateral side or, conversely, may result in balanced growth when they are on contralateral sides of the spine. All patients with known congenital spinal deformities should be evaluated for associated cardiac and renal anomalies. Cardiac anomalies are found in approximately 15% of these children and are usually evident on physical examination. Routine screening with an echocardiogram is not recommended unless clinical findings are suggestive.75 Renal anomalies, on the other hand, are often clinically silent and have been reported in up to 37% of children with known congenital spinal anomalies.76 Thus, routine sonography of the urinary tract system is recommended for all children with congenital spinal malformations. Occult intraspinal anomalies are found in up to 30% of children with congenital spinal malformations. These include Chiari malformations, syringomyelia, tethered cord, reduced spinal cord diameter, and diastematomyelia. Associated physical examination findings are those consistent with occult dysraphism, such as dimpling of the skin, pigmentation changes, or the presence of hairy patches or skin tags in the lower back or intergluteal cleft. Changes to the lower extremities such as atrophy, foot deformities, and asymmetric or pathologic reflexes are also suggestive of intraspinal defects. Infants with congenital spine anomalies should initially be evaluated with dedicated plain radiographs of the whole spine. Coned-down views of affected parts of the spine may offer additional information about the anatomy of interest. Rib anomalies should be noted, because they are commonly associated with thoracic spine malformations and may have significant long-term implications with regard to restrictive lung disease.77 The position of the scapula should also be evaluated, because Sprengel deformity is found in up to 50% of children with congenital cervical spine anomalies.38 The use of magnetic resonance imaging (MRI) is reserved for those children preparing to undergo surgical intervention or those with clinical evidence of neurologic abnormality.74 Cutaneous anomalies of the lumbar spine in the newborn may be evaluated by ultrasonography. This is a particularly effective method for determining the level of the conus medullaris and thus the presence of tethered cord. Computed tomography is typically not indicated in the newborn owing to concerns of unneeded radiation exposure, but if done for other reasons, it can give additional detail on spinal anatomy.

Obstetric Trauma Birth trauma can be divided into two categories: fractures and neurologic injuries. Birth fractures most commonly involve the clavicle, with clavicular fractures occurring in 2 to 3 per 1000 births.78 Birth fractures may also occur in the proximal part of the humerus79,80 the femur (0.13 per 1000 births),81 and even the thoracic spine. It is important to note that clavicular fracture can be seen in combination with a proximal humeral physeal separation or in combination with a brachial plexus injury. Reported risk factors for upper extremity birth fractures include: 1. Large size of the baby 2. Limited experience of the obstetrician 3. Midforceps delivery78,82 Risk factors for femoral fracture include: 1. Twin gestation 2. Breech presentation 3. Prematurity 4. Osteoporosis81 Nadas et al. have reported an association of long-bone fractures with cesarean delivery, breech delivery with assistance, and low birth weight.83 The natural history of isolated birth fractures to the extremities is that of uneventful rapid healing without untoward sequelae. Clavicle fractures may be difficult to diagnose, because the neonate may be asymptomatic. Newborns with either a clavicle fracture or a proximal humeral physeal separation often have pseudoparalysis of the upper extremity. Considerations in the differential diagnosis include an obstetric brachial plexus palsy and hematogenous metaphyseal osteomyelitis of the humerus with septic glenohumeral arthritis. Pain with direct palpation of the clavicle may be present with obvious deformity. Pain with motion of the shoulder joint and with palpation of the proximal part of the humerus may be caused by either fracture or infection. Elicitation of neonatal reflexes such as the Moro reflex and asymmetric tonic neck reflex (ATNR) may be helpful in evaluating active upper extremity muscle function.84 Radiographs should be obtained. Ultrasound evaluation of the proximal part of the humerus may be helpful because the proximal humeral epiphysis is entirely cartilaginous at birth and thus radiolucent. Ultrasound examination can detect proximal physeal separation, metaphyseal osteomyelitis, and septic shoulder arthritis.79,80 Asymptomatic birth fractures of the clavicle and humerus in neonates may be observed. The fracture will unite in short order, with remodeling of bone occurring with growth. Symptomatic fractures in which the child exhibits pseudoparalysis of the upper

Type of congenital anomaly Site of curvature

Block vertebra

Wedge vertebra

Upper thoracic