Principles of Neonatology [1 ed.]

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Pediatric books 2024

Principles of Neonatology

Downloaded for mohamed salama ([email protected]) at University of Southern California from ClinicalKey.com by Elsevier on August 10, 2023. For personal use only. No other uses without permission. Copyright ©2023. Elsevier Inc. All rights reserved.

Downloaded for mohamed salama ([email protected]) at University of Southern California from ClinicalKey.com by Elsevier on August 10, 2023. For personal use only. No other uses without permission. Copyright ©2023. Elsevier Inc. All rights reserved.

Principles of Neonatology

Edited by

Akhil Maheshwari, MD, FAAP, FRCP (Edin) Professor (Clinical) of Pediatrics and of Molecular & Cellular Physiology Chief, Division of Neonatal Medicine Vice-Chair of Translational Research in Pediatrics Director, Fellowship Program of Neonatal-Perinatal Medicine Louisiana State University Health Sciences Center—Shreveport Shreveport, Louisiana Founding Chair, the Global Newborn Society Founding Editor-in-Chief, the journal Newborn CEO of the non-profit organization, GNS, LLC (publishing for public health) Managing Partner of the non-profit organization, CogniVantage, LLC (medical tools needed for public health) Member, Forum for Children’s Health, Louisiana

Section Editors:

Nitasha Bagga, Cynthia Bearer, John Benjamin, Shazia Bhombal, Renee Boss, Waldemar Carlo, Robert Christensen, Wendy Chung, David Cooke, Jonathan Davis, Sharon Groh-Wargo, David Hackam, Naveen Jain, Eric Jelin†, Sheela Magge, Frances Northington, Prabhu Parimi, Karen Puopolo, Michael Repka, Paul Sponseller, David Tunkel

Deceased

†

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List of Contributors Pankaj B. Agrawal, MD

Chief of Neonatology, University of Miami, Jackson Health System Professor of Pediatrics and Genetics, University of Miami Miami, Florida Chair, Project Newborn Visiting Professor Boston Children’s Hospital and Harvard Medical School Boston, Massachusetts

Yasmin Akhtar, DO, MPH

Clinical Associate of Pediatrics Division of Pediatric Endocrinology Johns Hopkins University School of Medicine Baltimore, Maryland

Jubara Alallah, MD, ABP, SBP

Neonatologist, Assistant Professor of Pediatrics King Abdulaziz Medical City-WR, Ministry of National Guard King Abdullah International Medical Research Centre King Saud bin Abdulaziz University for Health Sciences (KSAU-HS) Jeddah, Kingdom of Saudi Arabia

Ziad Alhassen, MD

Assistant Clinical Professor of Pediatrics Department of Pediatrics University of California Irvine Orange, California

Gabriel Altit, MDCM, MSc, FRCPC, FAAP Assistant Professor Department of Pediatrics McGill University Neonatologist Division of Neonatology Montreal Children’s Hospital Montreal, Quebec, Canada

Abbas AlZubaidi, PhD

Sigma Lambda Technologies Biomedical Prototyping Carleton, Gatineau, Quebec, Canada

Lahin M. Amlani, BS

Medical Student Johns Hopkins University School of Medicine Baltimore, Maryland

Martin Antelo, MD

Cardiac Surgeon Centro Cardiovascular, Hospital de Clínicas University of the Republic Montevideo, Uruguay

Gayatri Athalye-Jape, MD, FRACP, CCPU, PhD

Consultant Neonatologist Neonatal Paediatrics King Edward Memorial Hospital Clinical Lead, Neonatal Follow Up Program King Edward Memorial Hospital Clinical Senior Lecturer School of Medicine University of Western Australia Honorary Research Fellow Neonatal Paediatrics Telethon Kids Institute Perth, Western Australia, Australia

Jargalsaikhan Badarch, MD

Associate Professor Department of Obstetrics and Gynecology Mongolian National University of Medical Sciences Ulaanbataar, Mongolia

Gerri Baer, MD

US Food and Drug Administration Center for Drug Evaluation and Research, Office of New Drugs Silver Spring, Maryland

Stephanie M. Barr, MS, RDN, LD

Neonatal Dietitian Department of Pediatrics MetroHealth Medical Center Adjunct Lecturer Department of Nutrition Cass Western Reserve University School of Medicine Cleveland, Ohio

Andrew J. Bauer, MD

Director The Thyroid Center Division of Endocrinology & Diabetes The Children’s Hospital of Philadelphia Professor of Pediatrics The Perelman School of Medicine The University of Pennsylvania Philadelphia, Pennsylvania

Cynthia F. Bearer, MD, PhD, FAAP

Professor of Pediatrics Department of Pediatrics Rainbow Babies and Children’s Hospital Cleveland, Ohio

Ross M. Beckman, MD

Pediatric Surgery Fellow Baylor College of Medicine Texas Children’s Hospital Houston, Texas

Marc Beltempo, MD, FRCPC, MSc

Nitasha Bagga, MBBS, DNB, Fellowship in Neonatology Consultant Neonatologist Rainbow Children’s Hospital Hyderabad, India

Department of Pediatrics Montreal Children’s Hospital – McGill University Health Centre Montreal, Quebec, Canada

Timothy M. Bahr, MS, MD

Melania M. Bembea, MD, MPH, PhD

Yaniv Bar-Cohen, MD

Sheila Berlin, MD

Assistant Professor of Pediatrics Intermountain Healthcare University of Utah Salt Lake City, Utah Director, Electrophysiology Department of Pediatrics & Cardiology Children’s Hospital Los Angeles University of Southern California Los Angeles, California

Associate Professor Anesthesiology and Critical Care Medicine Johns Hopkins University School of Medicine Baltimore, Maryland Associate Professor and Vice Chair Department of Radiology University Hospitals of Cleveland Director of Pediatric CT Department of Radiology Rainbow Babies and Children’s Hospital Cleveland, Ohio

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List of Contributors   vii

Shandeigh N. Berry, PhD, RN

Assistant Professor of Nursing Saint Martin’s University Olympia, Washington

Vineet Bhandari, MD, DM

Professor of Pediatrics, Obstetrics & Gynecology, and Biomedical Sciences Cooper Medical School of Rowan University The Children’s Regional Hospital at Cooper Camden, New Jersey

Shaifali Bhatia, MD, MRCPCH

Metro Multispeciality Hospital Sector 11, NOIDA Uttar Pradesh, India

Shazia Bhombal, MD

Clinical Associate Professor of Pediatrics Division of Neonatal and Developmental Medicine Stanford University School of Medicine Palo Alto, California

Elaine O. Bigelow, MD

Resident Physician Department of Otolaryngology—Head and Neck Surgery Johns Hopkins University School of Medicine Baltimore, Maryland

Carley Blevins, BS

Laboratory Assistant Department of Thoracic Surgery Johns Hopkins University School of Medicine Baltimore, Maryland

Giuseppe Buonocore, MD

President, EURope Against Infant Brain Injury Secretary of the Union of European Neonatal and Perinatal Societies Siena, Italy

Jennifer Burnsed, MD, MS

Department of Pediatrics University of Virginia Charlottesville, Virginia

Andrew C. Calabria, MD

Clinical Director Division of Endocrinology & Diabetes The Children’s Hospital of Philadelphia Associate Professor of Clinical Pediatrics Department of Pediatrics Perelman University School of Medicine at the University of Pennsylvania Philadelphia, Pennsylvania

Melisa Carrasco, MD, PhD

Section of Pediatric Neurology Department of Neurology University of Wisconsin School of Medicine and Public Health Madison, Wisconsin

Brian S. Carter, MD

Professor of Pediatrics, Medical Humanities & Bioethics Pediatrics—Neonatology University of Missouri—Kansas City School of Medicine Bioethicist Bioethics Center Children’s Mercy Hospital Kansas City, Missouri

Praveen Chandrasekharan, MD, MS

Professor of Pediatrics & Microbiology University of Alabama at Birmingham Birmingham, Alabama

Associate Professor of Pediatrics Neonatologist, Oishei Children’s Hospital of Buffalo University of Buffalo Buffalo, New York

Renee Boss, MD, MHS

Raul Chavez-Valdez, MD

Suresh Boppana, MD

Associate Professor of Pediatrics Division of Pediatrics Johns Hopkins University School of Medicine Core Faculty Berman Institute of Bioethics Baltimore, Maryland

Sandra Brooks, MD, MPH, FAAP

Associate Medical Director—Neonatal Intensive Care Unit Department of Pediatrics Division of Neonatology Johns Hopkins All Children’s Hospital St. Petersburg, Florida

Department of Pediatrics—Division of Neonatology Laboratory of Neonatology Neuroscience Intensive Care Nursery Johns Hopkins University School of Medicine Baltimore, Maryland

Lauryn Choleva, MD, MSc

Instructor of Pediatrics Division of Pediatric Endocrinology Icahn School of Medicine at Mount Sinai New York, New York

Robert D. Christensen, MD

Professor of Pediatrics Department of Pediatrics University of Utah Salt Lake City, Utah

Wendy K. Chung, MD, PhD

Kennedy Family Professor of Pediatrics and Medicine Pediatrics, Division of Molecular Genetics Columbia University Irving Medical Center, New York New York, New York

Sarah A. Coggins, MD

Attending Neonatologist Division of Neonatology The Children’s Hospital of Philadelphia Philadelphia, Pennsylvania

David W. Cooke, MD

Associate Professor of Pediatrics Division of Pediatrics Johns Hopkins University School of Medicine Baltimore, Maryland

Laura Cummings, PharmD, BCPS, BCPPS Clinical Pharmacist MetroHealth Medical Center Cleveland, Ohio

Erin R. Currie, PhD, RN, CPLC

Assistant Professor School of Nursing University of Alabama at Birmingham Birmingham, Alabama

Joanne O. Davidson, PhD

Associated Professor Department of Physiology The University of Auckland Auckland, New Zealand

Jonathan M. Davis, MD

Vice-Chair of Pediatrics and Chief of Newborn Medicine Tufts Medical Center Boston, Massachusetts

Colby L. Day-Richardson, MD

Assistant Professor of Pediatrics Division of Neonatology University of Rochester Medical Center School of Medicine and Dentistry Rochester, New York

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viii 

List of Contributors

Diva D. De Leon, MD, MSCE

Professor of Pediatrics Division of Pediatrics The Children’s Hospital of Philadelphia/ Perelman School of Medicine at the University of Pennsylvania Chief Division of Endocrinology and Diabetes Department of Pediatrics Director Congenital Hyperinsulinism Center The Children’s Hospital of Philadelphia Philadelphia, Pennsylvania

Kavita Dedhia, MD

Assistant Professor Otolaryngology Head and Neck Surgery Division of Pediatric Otolaryngology University of Pennsylvania/Children’s Hospital of Philadelphia Philadelphia, Pennsylvania

Alvaro Dendi, MD

Neonatologist Department of Neonatology, Centro Hospitalario Pereira Rossell School of Medicine University of the Republic, Montevideo Montevideo, Uruguay

Anita Deshpande, MD

Assistant Professor of Pediatric Otolaryngology Emory University School of Medicine, Children’s Healthcare of Atlanta Atlanta, Georgia

Janis M. Dionne, MD

Clinical Associate Professor Division of Nephrology, Department of Pediatrics University of British Columbia Vancouver, British Columbia, Canada

Susan J. Dulkerian, MD

Associate Professor of Pediatrics Neonatology/Pediatrics University of Maryland School of Medicine Baltimore, Maryland

Vikramaditya Dumpa, MD

Associate Professor of Pediatrics University of Arkansas for Medical Sciences Arkansas Children’s Hospital Little Rock, Arkansas

Andrea F. Duncan, MD, MSClinRes

Associate Professor of Pediatrics, Division of Neonatology Associate Chief, Diversity, Equity and Inclusion, Division of Neonatology Associate Chair, Diversity and Equity, Department of Pediatrics Diversity Search Advisor, Department of Pediatrics University of Pennsylvania Perelman School of Medicine Medical Director, Neonatal Follow-up Program Children’s Hospital of Philadelphia Philadelphia, Pennsylvania

Alexandra M. Dunham, MD

Resident of Orthopaedic Surgery Johns Hopkins University School of Medicine Baltimore, Maryland

DiAnn Ecret, PhD, MSN, RN, MA cert Assistant Professor School of Nursing Ave Maria University Ave Maria, Florida

Kelstan Ellis, DO, MSCR, MBe

Assistant Professor of Pediatrics University of South Florida Tampa, Florida

Clinical Assistant Professor at the University of Missouri—Kansas City School of Medicine Department of Pediatrics, Division of Palliative Care at Children’s Mercy Hospital Kansas City, Missouri

Lee Donohue, MD, FAAP

Dina El-Metwally, MD, PhD

Keyur Donda, MBBS

Associate Clinical Professor Department of Pediatrics UC Davis Children’s Hospital Sacramento, California

Jefferson J. Doyle, MBBChir, PhD, MHS

Assistant Professor of Ophthalmology and Genetics Wilmer Eye Institute The Johns Hopkins Hospital Baltimore, Maryland

Chief Division of Neonatology Professor of Pediatrics Department of Pediatrics University of Maryland School of Medicine Baltimore, Maryland

Eric W. Etchill, MD, MPH

Resident of Cardiothoracic Surgery Johns Hopkins University School of Medicine Baltimore, Maryland

Yahya Ethawi, MD, CABPed, Neonatal Perinatal Fellowship Consultant and Head of NICU Department of Pediatrics Saudi German Hospital Ajman Ajman, United Arab Emirates

Allen D. Everett, MD

Professor of Pediatrics Department of Pediatrics & Cardiology Johns Hopkins University Baltimore, Maryland

Jorge Fabres, MD, MSPH

Associate Professor of Neonatology Department of Neonatology Pontificia Universidad Católica de Chile Santiago, Chile

Ryan J. Felling, MD, PhD

Associate Professor of Neurology Johns Hopkins University School of Medicine Baltimore, Maryland

Tanis R. Fenton, MHSc, PhD, RD, FDC Professor Cumming School of Medicine University of Calgary Calgary, Alberta, Canada

Dustin D. Flannery, DO, MSCE

Assistant Professor of Pediatrics Department of Pediatrics University of Pennsylvania Perelman School of Medicine Attending Physician Neonatology Children’s Hospital of Philadelphia Philadelphia, Pennsylvania

Joseph T. Flynn, MD, MS

Chief Division of Nephrology Seattle Children’s Hospital Professor of Pediatrics Department of Pediatrics University of Washington School of Medicine Seattle, Washington

Michaelene Fredenburg, LHD

President and CEO Institute of Reproductive Grief Care San Diego, California

John Fuqua, MD

Professor of Clinical Pediatrics Division of Pediatric Endocrinology Indiana University School of Medicine Indianapolis, Indiana

Alejandro V. Garcia, MD

Assistant Professor of Surgery Department of Surgery Johns Hopkins University School of Medicine Baltimore, Maryland

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List of Contributors   ix

Steven Garzon, MD

Assistant Professor of Clinical Pathology University of Illinois Chicago, Illinois

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

Marisa Gilstrop Thompson, MD

Mari L. Groves, MD

Assistant Professor of Neurosurgery Department of Neurosurgery Johns Hopkins University School of Medicine Baltimore, Maryland

Mireille Guillot, MD, MSc

Department of Pediatrics, Faculty of Medicine, CHU de Québec-Université Laval Quebec, Canada

Alistair J. Gunn, MBChB, PhD

Professor of Physiology and Paediatrics Department of Physiology University of Auckland Auckland, New Zealand

Arjun Gupta, BS

Maternal Fetal Medicine and Clinical Genetics Delaware Center for Maternal Fetal Medicine Newark, Delaware

Clinical Research Fellow Department of Orthopaedics Johns Hopkins University School of Medicine Baltimore, Maryland

Barton Goldenberg, BSc (Econ), MSc (Econ)

Chief of Pediatric Surgery Professor of Surgery Johns Hopkins University School of Medicine Pediatric Surgeon in Chief and Co-Director Johns Hopkins Children’s Center Baltimore, Maryland

President & Founder ISM/CRM Consultants, Inc. Bethesda, Maryland

Andres J. Gonzalez Salazar, MD General Surgery Resident Department of Surgery The Johns Hopkins Hospital Baltimore, Maryland

Julie E. Goodwin, MD

Associate Professor of Pediatrics (Nephrology) Department of Pediatrics, Section of Nephrology Yale University School of Medicine New Haven, Connecticut

Steven L. Goudy, MD

Professor of Pediatric Otolaryngology Division Chief of Pediatric Otolaryngology Emory University School of Medicine Children’s Healthcare of Atlanta Atlanta, Georgia

Ernest Graham, MD

Associate Professor of Gynecology & Obstetrics Johns Hopkins University School of Medicine Baltimore, Maryland

Kathryn Grauerholz, MSN, ANP-C, ACHPN Director of Healthcare Programs Healthcare Education Institute of Reproductive Grief Care San Diego, California

David J. Hackam, MD, PhD

Joaquin Hidalgo, MD

Neurosurgeon North Mississippi Health System Tupelo, Mississippi

Erin Honcharuk, MD

Assistant Professor of Orthopaedic Surgery Orthopaedic Surgery Johns Hopkins University School of Medicine Baltimore, Maryland

Zeyar Htun, MD

Fellow Pediatrics/Neonatology Rainbow Babies & Children’s Hospital Cleveland, Ohio

Mark L. Hudak, MD

Professor and Chair of Pediatrics Chief, Division of Neonatology University of Florida College of Medicine—Jacksonville Jacksonville, Florida

Colleen A. Hughes Driscoll, MD

Assistant Professor of Pediatrics Department of Pediatrics University of Maryland School of Medicine Baltimore, Maryland

Thierry A.G.M. Huisman, MD, PD, EDiNR, EDiPNR Radiologist-in-Chief and Edward B. Singleton Chair of Radiology Department of Radiology Texas Children’s Hospital and Baylor College of Medicine Houston, Texas

Mireille Jabroun, MD

Assistant Professor of Ophthalmology Department of Ophthalmology and Vision Science, University of Arizona College of Medicine Tucson, Arizona

Eric M. Jackson, MD

Associate Professor of Neurosurgery Pediatrics, and Plastic and Reconstructive Surgery Johns Hopkins University School of Medicine Baltimore, Maryland

Naveen Jain, MBBS, MD, DNB, DCH, DM Senior Consultant KIMSHEALTH Thiruvananthapuram Kerala, India

Rajesh Jain, MBBS, MD, PG Diploma Diabetes Chair Diabetology DiabetesAsia Jain Hospital and Research Centre Pvt Ltd Kanpur, Uttar Pradesh, India

Angie Jelin, MD

Associate Professor of Gynecology & Obstetrics Department of Gynecology & Obstetrics The Johns Hopkins Hospital Baltimore, Maryland

Eric Jelin, MD†

Associate Professor of Pediatric Surgery Surgery, Gynecology & Obstetrics Johns Hopkins University School of Medicine Baltimore, Maryland

Sandra E. Juul, MD, PhD, FAAP

Professor of Pediatrics and Neuroscience Co-Director, Intellectual and Developmental Disabilities Research Center University of Washington Seattle, Washington

David A. Kaufman, MD

Professor of Pediatrics Department of Pediatrics University of Virginia School of Medicine Charlottesville, Virginia Deceased

†

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List of Contributors

Haluk Kavus, MD

Medical Geneticist Postdoctoral Research Scientist Pediatrics Division of Molecular Genetics Columbia University New York, New York

Alison Kent, BMBS, FRACP, MD

Head of Unit, Neonatology, Women and Babies Division Women’s and Children’s Hospital Adelaide, South Australia, Australia Honorary Professor, Australian National University College of Health and Medicine Canberra, Australia Adjunct Professor of Pediatrics, Department of Pediatrics University of Rochester School of Medicine and Dentistry Golisano Children’s Hospital at URMC Rochester, New York

Sundos Khuder, MD, CABP

Arab Board of Pediatrics, Neonatal Intensive Care Fellowship Neonatologist/Head of Pediatric Department NICU Imam Zain El Abidine Hospital Karbala, Iraq Pediatrician/Head of NICU Department NICU Al Zahrawi Hospital Damascus, Syrian Arab Republic

Mark L. Kovler, MD

Surgical Resident Department of Surgery Johns Hopkins University School of Medicine Baltimore, Maryland

Courtney L. Kraus, MD

Assistant Professor of Ophthalmology Johns Hopkins Medical Center Baltimore, Maryland

Ganga Krishnamurthy, MBBS

Department of Pediatrics Columbia University Medical Center New York, New York

Stephanie K. Kukora, MD

Assistant Professor Division of Neonatal-Perinatal Medicine Department of Pediatrics University of Michigan CS Mott Children’s Hospital Ann Arbor, Michigan

Ashok Kumar, MD

Laura Lewallen, MD

Shaun M. Kunisaki, MD, MSc

Tamorah R. Lewis, MD, PhD

Professor and Head Department of Pediatrics Banaras Hindu University Varanasi, India Associate Professor of Surgery Pediatric Surgery Johns Hopkins Children’s Center Baltimore, Maryland

Margaret Kuper-Sassé, MD, FAAP

Assistant Professor of Pediatrics Orthopedic Surgery University of Chicago Chicago, Illinois Associate Professor of Pediatrics Department of Pediatrics University of Missouri—Kansas City School of Medicine Kansas City, Missouri

Assistant Professor of Pediatrics Department of Pediatrics-Neonatology Rainbow Babies and Children’s Hospital Cleveland, Ohio

Hillary B. Liken, MD

David M. Kwiatkowski, MD, MS

Arūnas Liubšys, MD, PhD

Associate Professor Department of Pediatric Cardiology Stanford University School of Medicine Palo Alto, California

Associate Professor Director of Neonatology Center Vilnius University Hospital Santaros Klinikos Vilnius, Lithuania

Satyan Lakshminrusimha, MBBS, MD, FAAP

Kei Lui, MB BS UNSW, MD UNSW, FRACP

Professor of Pediatrics Department of Pediatrics UC Davis Children’s Hospital Sacramento, California

Naomi T. Laventhal, MD, MA

Associate Professor Department of Pediatrics Division of Neonatal-Perinatal Medicine Center for Bioethics and Social Sciences in Medicine University of Michigan Ann Arbor, Michigan

Shelley M. Lawrence, MD, MS

Associate Professor of Pediatrics Department of Pediatrics Division of Neonatal-Perinatal Medicine University of Utah Salt Lake City, Utah

Angela E. Lee-Winn, PhD

Assistant Professor of Epidemiology Department of Epidemiology Colorado School of Public Health Aurora, Colorado

Steven Leuthner, MD, MA

Professor of Pediatrics and Bioethics Division of Neonatology and Palliative Care Medical College of Wisconsin Medical Director Palliative Care Children’s Wisconsin Wauwatosa, Wisconsin

Pediatric Cardiology Fellow University of Michigan Ann Arbor, Michigan

Senior Clinical Academic Neonatologist and Professor School of Clinical Medicine Discipline of Paediatrics and Child Health University of New South Wales Chair, Global Newborn Society Chair, Australian and New Zealand Neonatal Network Member, Board of Directors of the iNEO International Neonatal Network Sydney, Australia

Akhil Maheshwari, MD, FAAP, FRCP (Edin)

Professor (Clinical) of Pediatrics, and of Molecular & Cellular Physiology Louisiana State University Health Sciences Center—Shreveport Shreveport, Louisiana

Nathalie L. Maitre, MD, PhD

Professor Director of Early Development and Cerebral Palsy Research Division of Neonatology Department of Pediatrics Emory University School of Medicine Children’s Healthcare of Atlanta Atlanta, Georgia

Kartikeya Makker, MBBS

Division of Neonatal-Perinatal Medicine Assistant Professor of Pediatrics Johns Hopkins University School of Medicine Baltimore, Maryland

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List of Contributors   xi

Cherry Mammen, MD, FRCPC, MHSc

Pediatric Nephrologist Department of Pediatrics BC Children’s Hospital Vancouver, British Columbia, Canada

Richard J. Martin, MBBS

Professor Pediatrics, Reproductive Biology, and Physiology & Biophysics Case Western Reserve University School of Medicine Drusinsky-Fanaroff Chair in Neonatology Pediatrics/Neonatology Rainbow Babies & Children’s Hospital Cleveland, Ohio

María Mattos Castellano, MD

Neonatologist Centro Hospitalario Pereira Rossell Montevideo, Uruguay

Jessie R. Maxwell, MD

Rachel R. Milante, MD

Strabismus & Pediatric Ophthalmology Wilmer Eye Institute Baltimore, Maryland Strabismus & Pediatric Ophthalmology Legazpi Eye Center Albay, Legazpi City, Philippines

Jena L. Miller, MD

Assistant Professor of Gynecology & Obstetrics Division of Gynecology & Obstetrics Assistant Professor of Surgery Division of Surgery The Johns Hopkins Center for Fetal Therapy Baltimore, Maryland

Vinayak Mishra, MBBS

General Practice Registrar Blackpool Teach Hospitals NHS Foundation Trust Lancashire, United Kingdom

Sagori Mukhopadhyay, MD, MMSc

Shannon N. Nees, MD

Assistant Professor of Pediatrics Nemours Cardiac Center Nemours Children’s Health Wilmington, Delaware

Jessie Newville, BS

Neurosciences University of New Mexico School of Medicine Albuquerque, New Mexico

Mai Nguyen, MD

Assistant Professor John Peter Smith Hospital Burnett School of Medicine, Texas Christian University Fort Worth, Texas

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

Associate Professor of Pediatrics & Neurosciences Department of Pediatrics University of New Mexico Albuquerque, New Mexico

Assistant Professor of Pediatrics Department of Pediatric Medicine University of Pennsylvania Philadelphia, Pennsylvania

Renske McFarlane, BMBS, BA (Hons)

Assistant Professor of Pediatrics Division of Neonatology Assistant Professor of Internal Medicine Section of Palliative Care University of Texas Southwestern Dallas, Texas

Namrita J. Odackal, DO

Mimi L. Mynak, MD

Robin K. Ohls, MD

Department of Neonatology University Hospitals Sussex Brighton, United Kingdom

Gabrielle McLemore, PhD

Associate Professor of Biology Department of Biology, SCMNS Morgan State University Baltimore, Maryland

Kera M. McNelis, MD, MS

Assistant Professor of Pediatrics Department of Pediatrics Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine Cincinnati, Ohio

Christopher McPherson, PharmD

Clinical Pharmacy Specialist St. Louis Children’s Hospital Associate Professor of Pediatrics Department of Pediatrics Washington University School of Medicine St. Louis, Missouri

Ulrike Mietzsch, MD

Clinical Associate Professor of Pediatrics Department of Pediatrics Division of Neonatology University of Washington, Seattle Children’s Hospital Seattle, Washington

Sara Munoz-Blanco, MD

Department of Pediatrics Jigme Dorji Wangchuck National Referral Hospital Thimphu, Bhutan

Isam W. Nasr, MD

Assistant Professor of Surgery Johns Hopkins University School of Medicine Baltimore, Maryland

Assistant Professor of Pediatrics, Ohio State University Division of Neonatology, Nationwide Children’s Hospital Columbus, Ohio August L “Larry” Jung Presidential Endowed Chair Chief, Division of Neonatology Department of Pediatrics University of Utah Salt Lake City, Utah

Betsy E. Ostrander, MD

Associate Professor of Neurology Department of Neurology Division of Child Neurology University of Washington Seattle, Washington

Assistant Professor of Pediatrics Division of Pediatric Neurology University of Utah Salt Lake City, Utah Director, Fetal and Neonatal Neurology Program Primary Children’s Hospital Salt Lake City, Utah

Hema Navaneethan, MD

Mohan Pammi, MD, PhD, MRCPCH

Niranjana Natarajan, MD

Assistant Professor of Pediatrics Department of Pediatrics University of Nebraska Medical Center Omaha, Nebraska

Professor of Pediatrics Department of Pediatrics Baylor College of Medicine Houston, Texas

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xii 

List of Contributors

Prabhu S. Parimi, MD, MBA

Professor of Pediatrics Case Western Reserve University Division Chief of Neonatology Department of Pediatrics Metro Health Medical Center Cleveland, Ohio

Albert Park, MD

Professor Otolaryngology Head and Neck Surgery Division of Pediatric Otolaryngology University of Utah Salt Lake City, Utah

Monika S. Patil, MD

Mohammad M. Rahman, MBBS, DCH, FCPS (Neonatology)

Fellow of the Institute of Child and Mother Health and of the Institute of Education and Research Dhaka University Dhaka, Bangladesh

Kristina Reber, MD

Professor of Pediatrics Department of Pediatrics Baylor College of Medicine Division Chief of Neonatology Texas Children’s Hospital Houston, Texas

Assistant Professor of Pediatrics Department of Pediatrics Baylor College of Medicine Houston, Texas

Venkat Reddy Kallem, DrNB Neonatology

Elaine M. Pereira, MD

Michael X. Repka, MD, MBA

Muralidhar H. Premkumar, MBBS, DCH, DNB, MRCPCH, MS

Daniel S. Rhee, MD, MPH

Assistant Professor of Pediatrics Department of Pediatrics Columbia University Irving Medical Center/New York Presbyterian New York, New York

Associate Professor of Pediatrics & Neonatology Baylor College of Medicine Houston, Texas

Webra Price-Douglas, PhD, NNP-BC, IBCLC

The Johns Hopkins Hospital University of Maryland Medical Community Medical Groups Baltimore, Maryland

Karen M. Puopolo, MD, PhD

Professor of Pediatrics University of Pennsylvania Perelman School of Medicine Section Chief Newborn Medicine Pennsylvania Hospital Attending Physician Neonatology Children’s Hospital of Philadelphia Philadelphia, Pennsylvania

Heike Rabe, MD, PhD

Professor of Perinatal Medicine Academic Department of Paediatrics Brighton & Sussex Medical School University of Sussex Honorary Consultant Neonatologist Neonatology Brighton and Sussex University Hospitals Brighton, United Kingdom

Consultant Neonatologist Paramitha Children’s Hospital Hyderabad, Telangana, India

David L. Guyton MD and Feduniak Family Professor of Ophthalmology Professor of Pediatrics Johns Hopkins University School of Medicine Baltimore, Maryland Assistant Professor of Surgery Johns Hopkins University School of Medicine Baltimore, Maryland

Megan L. Ringle, MD, MPH

Assistant Professor of Neonatology Division of Neonatology Department of Pediatrics Wake Forest School of Medicine Winston Salem, North Carolina Clinical Medicine Fellow Division of Neonatal and Developmental Medicine Department of Pediatrics Stanford University Clinical Neonatal-Perinatal Medicine Fellow Neonatal and Perinatal Medicine Stanford University, School of Medicine Palo Alto, California

Marisa A. Ryan, MD, MPH

Pediatric Otolaryngologist—Head & Neck Surgeon Peak Pediatric Ear Nose & Throat Lehi, Utah

Maame E.S. Sampah, MD, PhD Research Fellow Department of Surgery The Johns Hopkins Hospital Baltimore, Maryland

Amarilis Sanchez-Valle, MD

Professor of Pediatrics University of South Florida Tampa, Florida

Guilherme M. Sant’Anna, MD, PhD, FRCPC Full Professor of Pediatrics Pediatrics—Neonatology Associate Member Department of Medicine—Division of Experimental Medicine McGill University Montreal, Quebec, Canada

Ola D. Saugstad, MD, PhD

Department of Pediatric Research University of Oslo and Oslo University Hospital Oslo, Norway Anne and Robert H. Lurie Children’s Hospital of Chicago, Feinberg School of Medicine, Northwestern University Chicago, Illinois

John P. Schacht, DO

Division of Clinical Genetics, Columbia University New York, New York

Robert L. Schelonka, MD

Professor and Chief Division of Neonatology Department of Pediatrics Oregon Health and Science University Portland, Oregon

Erin E. Schofield, MD

Allison Rohrer, MS, RD, LD

Neonatal Dietitian Department of Pediatrics Medical University of South Carolina Charleston, South Carolina

Assistant Professor Department of Pediatrics/Division of Neonatology University of Maryland School of Medicine Baltimore, Maryland

Christopher J. Romero, MD

David T. Selewski, MD, MSCR

Associate Professor of Pediatrics Division of Pediatric Endocrinology and Diabetes Icahn School of Medicine at Mount Sinai New York, New York

Associate Professor of Pediatrics Department of Pediatrics Medical University of South Carolina Charleston, South Carolina

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List of Contributors   xiii

Prakesh S. Shah, MD, MRCP, FRCPC, MSc

Paul D. Sponseller, MD, MBA

Professor of Pediatrics Division of Pediatrics Mount Sinai Hospital and University of Toronto Toronto, Ontario, Canada

Professor, Orthopaedic Surgery Chief, Division of Pediatric Orthopaedics Department of Orthopaedics Johns Hopkins University School of Medicine Baltimore, Maryland

Jessica G. Shih, MD

Carl E. Stafstrom, MD, PhD

Department of Plastic & Reconstructive Surgery Johns Hopkins University School of Medicine Baltimore, Maryland

Erica M.S. Sibinga, MD, MHS

Associate Professor of Pediatrics Division of Pediatrics Johns Hopkins University School of Medicine Baltimore, Maryland

Winnie Sigal, MD

Assistant Professor of Pediatrics Department of Pediatrics Division of Endocrinology and Diabetes The Children’s Hospital of Philadelphia/ Perelman School of Medicine at the University of Pennsylvania Philadelphia, Pennsylvania

Brian Sims, MD, PhD

Professor of Pediatrics Division of Neonatology UAB Women and Infant Center University of Alabama at Birmingham Birmingham, Alabama

Rachana Singh, MD, MS

Associate Chief, Newborn Medicine Department of Pediatrics Tufts Children’s Hospital Professor of Pediatrics Tufts University School of Medicine Boston, Massachusetts

Srijan Singh, MD, DM

Assistant Professor Department of Pediatrics Grant Government Medical College and Sir JJ Group of Hospitals Mumbai, Maharashtra, India

Donna Snyder, MD, MBE

US Food and Drug Administration Office of the Commissioner Office of Pediatric Therapeutics Silver Spring, Maryland

Helena Sobrero, MD

Adjunct Professor Neonatologist Department of Neonatology Centro Hospitalario Pereira Rossell School of Medicine, University of the Republic Montevideo, Uruguay

Director Division of Pediatric Neurology Department of Neurology Johns Hopkins University School of Medicine Baltimore, Maryland

Heidi J. Steflik, MD, MSCR

Assistant Professor of Pediatrics Department of Pediatrics Medical University of South Carolina Charleston, South Carolina

Lisa R. Sun, MD

Assistant Professor of Neurology Division of Neurology Johns Hopkins University School of Medicine Baltimore, Maryland

Sripriya Sundararajan, MBBS, MD

Rune Toms, MD, MSc

Associate Professor of Pediatrics Department of Pediatrics University of Alabama at Birmingham Birmingham, Alabama

Benjamin A. Torres, MD

Associate Professor of Pediatrics Department of Pediatrics University of South Florida Tampa, Florida

David E. Tunkel, MD

Professor of Otolaryngology-Head and Neck Surgery Johns Hopkins University School of Medicine Director of Pediatric Otolaryngology The Johns Hopkins Hospital Baltimore, Maryland

Christine H. Umandap, MD

Medical Geneticist DMG Children’s Rehabilitative Services Phoenix, Arizona

Associate Professor of Pediatrics Department of Pediatrics Division of Neonatology University of Maryland School of Medicine Baltimore, Maryland

Diana Vargas Chaves, MD

Sarah N. Taylor, MD, MSCR

Maximo Vento, MD, PhD

Professor of Pediatrics Section of Neonatal Perinatal Medicine Yale University School of Medicine New Haven, Connecticut

Norma Terrin, PhD

Tufts Clinical and Translational Science Institute and the Institute for Clinical Research and Health Policy Studies Tufts Medical Center Boston, Massachusetts

Prolima G. Thacker, MBBS, MS, DNB

Observer Pediatric Ophthalmology and Strabismus Wilmer Eye Institute Baltimore, Maryland

Bernard Thébaud, MD, PhD

Department of Pediatrics, Children’s Hospital of Eastern Ontario and CHEO Research Institute, Regenerative Medicine Program Ottawa Hospital Research Institute Department of Cellular and Molecular Medicine, University of Ottawa Ottawa, Ontario, Canada

Assistant Professor of Pediatrics Division of Neonatology Columbia University Medical Center New York, New York

Professor of Neonatology Division of Neonatology University & Polytechnic Hospital La Fe Professor Neonatal Research Group Health Research Institute La Fe Valencia, Spain

Jonathan Walsh, MD

Associate Professor of Otolaryngology-Head and Neck Surgery Department of Otolaryngology The Johns Hopkins Hospital Baltimore, Maryland

Jolan Walter, MD, PhD

Robert A. Good Endowed Chair, Division of Pediatric Allergy & Immunology Associate Professor, College of Molecular Medicine Associate Professor, College of Medicine Pediatrics Tampa, Florida

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xiv 

List of Contributors

Meaghann S. Weaver, MD, MPH, FAAP

Chief Division of Pediatric Palliative Care Pediatrics Children’s Hospital and Medical Center—Omaha Omaha, Nebraska

Kristin Weimer, MD, PhD, MHS

Assistant Professor of Pediatrics Department of Pediatrics Duke University Durham, North Carolina

Jennine Weller, MD, PhD

General Surgery Resident Department of Surgery The Johns Hopkins Hospital Baltimore, Maryland

Lindy W. Winter, MD

Medical and Quality Officer for Pediatric Services Medical Director Regional Neonatal Intensive Care Unit Medical Director Continuing Care Nursery Director of Neonatology Quality Improvement Department of Pediatrics University of Alabama, Birmingham Birmingham, Alabama

Mabel Yau, MD

Assistant Professor of Pediatrics Adrenal Steroid Disorders Program Mount Sinai School of Medicine New York, New York

Tai-Wei Wu, MD

Assistant 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

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Preface Newborn infants are a high-risk population with mortality rates similar to those in 58–60-year-olds. They can have many acute problems, which require timely management to ensure survival, and chronic issues that may have lifelong consequences. If appropriately treated, the practice is rewarding. If not, the consequences can be physically and emotionally devastating for both parents and care-providers. There is many a medical textbook focused on problems seen in newborn infants. But we still need one that (a) can cover the needs of both the East and the West, and so we requested help from more than 220 experts from all over the world; (b) is comprehensive, but the chapters are sized according to the likely needs of a practicing care-provider; and (c) contains enough useful information but is still

convenient to carry and is not so large that it becomes just a decorative piece in the office. We planned sections focused on the care of premature and critically-ill neonates; resuscitation and respiratory illness; feeding; nutrition; endocrine disorders; infections; cardiac defects and disorders; blood disorders; skin conditions; neurological disorders; immunology; sections on renal, eye, auditory, and orthopedic conditions; inborn errors and other genetic conditions; surgical issues; palliative care; follow-up; organization; and leadership. We have tried to size these sections based on the probability/frequency of need in clinical practice. Thinking further, we moved the section on skin conditions towards the end because of the higher likelihood of need during active patient care to facilitate quick access during clinical rounds.

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Acknowledgments I want to express gratitude to our section editors, Drs. Nitasha Bagga, Cynthia Bearer, Waldemar Carlo, Sharon Groh-Wargo, David Cooke, Sheela Magge, Karen Puopolo, Shazia Bhombal, Robert Christensen, Frances Northington, John Benjamin, Michael Repka, David Tunkel, Paul Sponseller, Wendy Chung, David Hackam, Renee Boss, Naveen Jain, Jonathan Davis, and Prabhu Parimi. Many authors participated in this book because of their commitment to the Global Newborn Society (https://www. globalnewbornsociety.org/), a rapidly-growing public service organization that is now active in 122 countries. There are other leaders

from the Rotary Club. I have learnt so much here—to each one, thank you! We want to take a moment of silence. We lost one of our dearest section editors, Dr. Eric Jelin, while this book was still in development. He will be missed but never forgotten. I wish to thank Sarah Barth, Priyadarshini Pandey, Daniel Fitzgerald and the entire Elsevier publishing team for making this book possible. I would also like to thank Drs. Sue Aucott and Tina Cheng at the Johns Hopkins University for supporting me in all times, good and bad.

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Contents List of Contributors, vi Preface, xv Acknowledgments, xvi

18 Possible Benefits and Risks of Using Probiotics in Neonates, 128 Mohan Pammi, Monika S. Patil, Kristina Reber, Akhil Maheshwari

Section 4: Nutrition

Section 1: Care of the Premature and Critically-Ill Neonate

19 Enteral Nutrition, 142



20 Parenteral Nutrition in Neonates, 156

1 Design of Neonatal Intensive Care Units, 2 Margaret Kuper-Sassé, Cynthia F. Bearer, Dina El-Metwally



2 NICU Environment for Parents and Staff, 7 Angela E. Lee-Winn, Dina El-Metwally, Erica M.S. Sibinga



3 Safe Use of Health Information Technology, 12 Yahya Ethawi, Abbas AlZubaidi, Akhil Maheshwari



4 Pharmacologic Management of Neonatal Pain and Agitation, 18 Christopher McPherson



5 Neonatal Transport, 27 Webra Price-Douglas, Susan J. Dulkerian



6 Radiation Safety in Premature and Critically-Ill Neonates, 33 Sheila Berlin

Section 2: Neonatal Resuscitation and Respiratory Care

7 Placental Transfusion in the Newborn, 38 Sripriya Sundararajan, Renske McFarlane, Heike Rabe



8 Neonatal Resuscitation, 44 Lee Donohue, Ziad Alhassen, Satyan Lakshminrusimha



9 Golden Hour and Thermoregulation, 57 Erin E. Schofield, Lindy W. Winter

10 Oxygen During Postnatal Stabilization, 62 Maximo Vento, Ola D. Saugstad

11 Respiratory Distress Syndrome, 66 Kartikeya Makker, Colby L. Day-Richardson, Mark L. Hudak

12 Invasive and Noninvasive Ventilation Strategies, 78 Vikramaditya Dumpa, Vineet Bhandari

13 Pulmonary Hypertension of the Newborn, 88 Praveen Chandrasekharan, Satyan Lakshminrusimha

14 Bronchopulmonary Dysplasia, 98 Mireille Guillot, Bernard Thébaud

15 Treatment of Apnea of Prematurity, 106 Zeyar Htun, Richard J. Martin

Section 3: Feeding 16 Human Milk, 112 Nitasha Bagga, Kei Lui, Arūnas Liubšys, Mohammad M. Rahman, Srijan Singh, Mimi L. Mynak, Akhil Maheshwari

17 Storage and Use of Human Milk in Neonatal Intensive Care Units, 120 Nitasha Bagga, Kei Lui, Arūnas Liubšys, Mohammad M. Rahman, Mimi L. Mynak, Akhil Maheshwari

Allison Rohrer, Sarah N. Taylor Stephanie M. Barr, Laura Cummings

21 Nutrition in Short Bowel Syndrome, 170 Muralidhar H. Premkumar, Alvaro Dendi, Akhil Maheshwari

22 Neonatal Nutrition Assessment, 178 Kera M. McNelis, Tanis R. Fenton

Section 5: Endocrine Disorders 23 Neonatal Hypoglycemia, 193 Winnie Sigal, Diva D. De Leon

24 Infants of Diabetic Mothers, 200 Vinayak Mishra, Kei Lui, Robert L. Schelonka, Akhil Maheshwari, Rajesh Jain

25 Evidence-Based Neonatology: Neonatal Pituitary Hormone Deficiencies, 207 Lauryn Choleva, Mabel Yau, Christopher J. Romero

26 Neonatal Thyroid Disease, 215 Andrew J. Bauer

27 Hypothalamic-Pituitary-Adrenal Axis in Neonates, 222 David W. Cooke, Yasmin Akhtar

28 Disorders of Neonatal Mineral Metabolism and Metabolic Bone Disease, 230 Andrew C. Calabria, Sarah A. Coggins

29 Disorders of Sex Development for Neonatologists, 241 John Fuqua

Section 6: Infections 30 Early-Onset Sepsis, 251 Karen M. Puopolo

31 Late-Onset Sepsis, 257 Dustin D. Flannery, Karen M. Puopolo

32 Neonatal Herpes Simplex Virus Infections, 261 Yahya Ethawi, Steven Garzon, Thierry A.G.M. Huisman, Suresh Boppana, Akhil Maheshwari

33 Postnatal Cytomegalovirus Infection Among Preterm Infants, 268 Sagori Mukhopadhyay, Kristin Weimer

34 Congenital Syphilis, 274 Alvaro Dendi, Helena Sobrero, María Mattos Castellano, Akhil Maheshwari

35 Invasive Fungal Infections in the NICU: Candida, Aspergillosis, and Mucormycosis, 279 David A. Kaufman, Namrita J. Odackal, Hillary B. Liken

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xviii Contents

Section 7: Cardiac Defects and Dysfunction 36 Congenital Heart Defects, 291

55 Treating Neonatal Abstinence Syndrome in the Newborn, 470 Jessie R. Maxwell, Sandra Brooks, Tamorah R. Lewis, Jessie Newville, Gabrielle McLemore, Estelle B. Gauda

Diana Vargas Chaves, Shazia Bhombal, Ganga Krishnamurthy

37 Cardiac Defects—Anatomy and Physiology, 299 Rune Toms, Rachana Singh

38 Medical and Surgical Management of Critical Congenital Heart Disease, 317 David M. Kwiatkowski

39 Neonatal Arrhythmia and Conduction Abnormalities, 326 Shazia Bhombal, Megan L. Ringle, Yaniv Bar-Cohen

40 Pulmonary Hypertension in Chronic Lung Disease, 336 Megan L. Ringle, Gabriel Altit

41 Hemodynamic Assessment and Management of a Critically Ill Infant, 344 Tai-Wei Wu, Shahab Noori

Section 10: Immunology 56 Neonatal Immunity, 484 Akhil Maheshwari, Sundos Khuder, Shelley M. Lawrence, Robert D. Christensen

57 Immunodeficiency Syndromes Seen During the Neonatal Period, 498 Keyur Donda, Benjamin A. Torres, Jolan Walter, Akhil Maheshwari

Section 11: Kidney 58 Neonatal Acute Kidney Injury, 508 Heidi J. Steflik, David T. Selewski, Alison Kent, Cherry Mammen

59 Renal Replacement Therapy, 519 Julie E. Goodwin, Ashok Kumar, Jorge Fabres, Akhil Maheshwari

Section 8: Jaundice, Blood Disorders, and Transfusions

60 Neonatal Hypertension, 525

42 A Practical Guide to Evaluating and Treating Severe Neonatal Indirect Hyperbilirubinemia, 351

61 Altered Development of the Kidneys and the Urinary Tract, 533

Timothy M. Bahr

43 Neonatal Anemia, 357 Robert D. Christensen

44 Evidence-Based Neonatal Transfusion Guidelines, 380 Robin K. Ohls

45 Neonatal Thrombocytopenia, 387 Akhil Maheshwari

Section 9: Neurological Disorders 46 Management of Hypoxic-Ischemic Encephalopathy Using Therapeutic Hypothermia, 400 Joanne O. Davidson, Alistair J. Gunn

47 Management of Hypoxic-Ischemic Encephalopathy Using Measures Other Than Therapeutic Hypothermia, 406 Jennifer Burnsed, Raul Chavez-Valdez

48 Management of Encephalopathy of Prematurity, 421 Sandra E. Juul, Niranjana Natarajan, Ulrike Mietzsch

49 Neonatal Seizures, 427 Melisa Carrasco, Carl E. Stafstrom

50 Stroke in Neonates, 438 Ryan J. Felling, Lisa R. Sun

51 Using Biomarkers for Management of Perinatal Brain Injury, 444 Allen D. Everett, Ernest Graham, Melania M. Bembea

52 Intraventricular Hemorrhage and Posthemorrhage Hydrocephalus, 447

Janis M. Dionne, Joseph T. Flynn Julie E. Goodwin, Akhil Maheshwari

Section 12: Eye Disorders 62 Retinopathy of Prematurity, 545 Prolima G. Thacker, Michael X. Repka

63 Developmental Anomalies of the Globe and Ocular Adnexa in Neonates, 552 Jefferson J. Doyle, Mireille Jabroun

64 Developmental Anomalies of the Cornea and Iris in Neonates, 560 Rachel R. Milante, Jefferson J. Doyle

65 Cataract and Glaucoma, 570 Rachel R. Milante, Courtney L. Kraus

Section 13: ENT and Auditory Conditions 66 Neonatal Tracheostomy, 577 Jonathan Walsh

67 Stridor and Laryngotracheal Airway Obstruction in Newborns, 582 Elaine O. Bigelow, David E. Tunkel

68 Pierre-Robin Sequence/Cleft Palate-Related Airway Obstruction Seen in Neonates, 592 Anita Deshpande, Mai Nguyen, Steven L. Goudy

69 Congenital Hearing Loss Seen in Neonates, 597 Kavita Dedhia, Albert Park

70 Nasal Obstruction in Newborn Infants, 607 Marisa A. Ryan, David E. Tunkel

Venkat Reddy Kallem, Akhil Maheshwari

53 Management of Neurotrauma, 456 Joaquin Hidalgo, Eric M. Jackson

54 Management of Myelomeningocele and Related Disorders of the Newborn, 462 Mari L. Groves, Jena L. Miller

Section 14: Orthopedic Conditions 71 Upper Extremity Conditions in the Neonate, 618 Jessica G. Shih, Lahin M. Amlani, Laura Lewallen

72 Newborn Spine Deformities, 624 Alexandra M. Dunham, Paul D. Sponseller

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Contents xix

73 Hip and Lower Extremity Deformities, 631 Erin Honcharuk

74 Fractures and Musculoskeletal Infections in the Neonate, 641 Arjun Gupta, Paul D. Sponseller

Section 15: Inborn Errors of Metabolism and Newborn Screening 75 Most Frequently Encountered Inborn Errors of Metabolism, 649 Jubara Alallah, Pankaj B. Agrawal, Alvaro Dendi, Akhil Maheshwari

76 Screening Programs for Early Detection of Inborn Errors of Metabolism in Neonates, 661 Amarilis Sanchez-Valle

89 Serious Communication in the Neonatal Intensive Care Unit: Evidence for Strategies and Training, 765 Stephanie K. Kukora, Naomi T. Laventhal

90 Pain and Symptom Management in Newborns Receiving Palliative and End-of-Life Care, 776 Kelstan Ellis, Brian S. Carter

91 Palliative Care Family Support in Neonatology, 783 Erin R. Currie, Hema Navaneethan, Meaghann S. Weaver

Section 19: Follow-Up 92 Early Diagnosis and Intervention in Neonatal Intensive Care Units, 791 Naveen Jain

Section 16: Genetic Conditions (Including Microarrays, Exome Sequencing)

93 Early Diagnosis and Intervention—On Neonatal Follow-Up, 797

77 An Overview of Genetic Testing, 671

94 Early Detection of Cerebral Palsy, 802

Wendy K. Chung, John P. Schacht, Haluk Kavus

78 Genetics of Common Birth Defects in Newborns, 677 Shannon N. Nees, Eric Jelin, Wendy K. Chung

79 Common Monogenetic Conditions in Newborns, 690 Christine H. Umandap, Elaine M. Pereira

80 Common Chromosomal Conditions in Newborns, 699 Marisa Gilstrop Thompson, Eric Jelin, Angie Jelin

Section 17: Neonatal Surgical Conditions 81 Necrotizing Enterocolitis, 707 Jennine Weller, Maame E.S. Sampah, Andres J. Gonzalez Salazar, David J. Hackam

82 Extracorporeal Membrane Oxygenation in Neonates, 715 Eric W. Etchill, Alejandro V. Garcia

83 Intestinal Surgery in the Newborn—Atresias, Volvulus, and Everything Else, 720 Ross M. Beckman, Daniel S. Rhee

84 Pulmonary Surgery in the Newborn, 727 Andres J. Gonzalez Salazar, Carley Blevins, Eric Jelin

85 Congenital Anorectal Malformations and Hirschsprung Disease in the Neonate, 738 Isam W. Nasr, Eric W. Etchill

86 Esophageal Surgery in Neonates: Esophageal Atresia, Gastroesophageal Reflux, and Other Congenital Anomalies, 745 Mark L. Kovler, Shaun M. Kunisaki

Section 18: Current State of Neonatal Palliative Care 87 Caring for Families Who Have Previously Endured Multiple Perinatal Losses, 754 Kathryn Grauerholz, Michaelene Fredenburg, Shandeigh N. Berry, DiAnn Ecret

Naveen Jain Betsy E. Ostrander, Nathalie L. Maitre, Andrea F. Duncan

95 Use of Neuroimaging to Predict Adverse Developmental Outcomes in High-Risk Infants, 812 Gayatri Athalye-Jape

96 Neurodevelopmental Impairment in Specific Neonatal Disorders, 823 Vinayak Mishra, Brian Sims, Margaret Kuper-Sassé, Akhil Maheshwari

Section 20: Designing Clinical Trials in Neonatology 97 Quality Improvement in Neonatal Care, 833 Colleen A. Hughes Driscoll

98 Neonatal Randomized Controlled Trials, 838 Gerri Baer, Norma Terrin, Donna Snyder, Jonathan M. Davis

99 Designing Clinical Trials in Neonatology—International Trials, 845 Marc Beltempo, Prakesh S. Shah

Section 21: Healthcare Leadership 100 Organization of Neonatal Intensive Care, 851 Prabhu S. Parimi, Guilherme M. Sant’Anna, Alvaro Dendi, Martin Antelo, Sundos Khuder, Jargalsaikhan Badarch, Mohammad M. Rahman, Ashok Kumar, Akhil Maheshwari

101 Leadership and Organizational Culture in Healthcare, 856 Prabhu S. Parimi, Jorge Fabres, Yahya Ethawi, Jubara Alallah, Michaelene Fredenburg, Rajesh Jain, Mohammad M. Rahman, Kei Lui, Arūnas Liubšys, Mimi L. Mynak, Barton Goldenberg, Giuseppe Buonocore, Akhil Maheshwari

Section 22: Neonatal Dermatology 102 Skin Disorders in Newborn Infants, 862 Shaifali Bhatia, Akhil Maheshwari

Index, 880

88 Current State of Perinatal Palliative Care: Clinical Practice, Training, and Research, 758 Renee Boss, Sara Munoz-Blanco, Steven Leuthner

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Section 1 CHAPTER

1

Design of Neonatal Intensive Care Units

Margaret Kuper-Sassé, Cynthia F. Bearer, Dina El-Metwally

KEY POINTS 1. Historically, neonatal intensive care units (NICUs) have been designed as open-bay units with multiple patient beds in a room. However, the trend has shifted toward designing units with single-patient or single-family rooms. 2. Single-family rooms have facilitated a reduction in auditory and noxious stimuli and improvement in positive stimuli to support appropriate development.

3. Parents and families have reported increased engagement in the care of their infants. 4. In NICUs with single-family rooms compared with open-bay NICUs, maternal feeding and infant growth seem to have improved. 5. Care in single-patient rooms was expected to reduce infection rates, but the evidence for such improvement is uncertain.

Introduction Historically, neonatal intensive care units (NICUs) have been designed as open-bay units with multiple patient beds in a room, a design that was introduced in the 1940s.1 The trend has shifted toward the inclusion of parents with neonatal care. Thus units consisting of single-patient or single-family rooms (SFRs; many of which include a reserved space for parents inside the patient room) required new construction. This configuration for neonatal care units was introduced as the ideal design in the 1990s.2 The new design reflected the general trend in healthcare toward patient and family satisfaction by emphasizing privacy and a feeling of individualized care, but by design, it neglects the elements that aid staff in caring for the patients, such as visibility, ease of access to patients, and efficiency of caring for multiple patients.1 The movement represented a change in focus away from the needs of staff and toward families’ needs, which in many cases are contradictory.3

Patient Safety Alarms are designed to alert staff members to patient status changes and allow for intervention as necessary. Caregiver alarm fatigue, caused by sensory overload and resultant decreased or delayed responsiveness to alarms, can have adverse effects on patient safety.4 Exposure of nurses and patients to alarm sounds was found to be 44% higher in the open-bay style NICU (Fig. 1.1) than in the SFR-style NICU (Figs. 1.2–1.4), potentially with effects on both patients and staff. Excessive alarm exposure may also cause nurses to increase upper alarm limits to decrease the frequency of alarms, resulting in patient oxygen saturations being outside of the recommended ranges. Infants experience greater than 80% of their noxious noise exposure from alarms, which can be harmful in many ways, including affecting patient cardiopulmonary stability and sleep-wake cycles.5,6

6. Single-family rooms have improved parent involvement but may have created new challenges for caregivers. The introduction of alarms may help by alerting staff members about changes in the clinical status of the patients and facilitating timely intervention.

Decrease Stressful Stimuli and Increase Positive Stimuli In the NICU environment, the needs of multiple parties must be balanced. Newborn and infant patients require minimal noxious stimuli (Figs. 1.5 and 1.6) and the presence of positive stimuli to support appropriate development. Parents want to be able to assist with the care of their infants and to have privacy while living in the unit with their infants (see Fig. 1.4). The staff needs to have the ability to care for patients in a low-stress and amicable working environment (see Fig. 1.6). 7 By the 1990s, preterm infants were increasingly found to be uniquely vulnerable to the effects of negative sensory stimuli, stress, and sleep-cycle disturbances.8 One negative sensory stimulus is noise, compared with sound. The goal for the sound environment in the NICU, especially when considering preterm infants whose auditory organs and neurologic pathways are still developing and maturing, should always be a minimization of noxious noise while maintaining exposure to positive sounds as would happen within the womb8a (see Fig. 1.5). The negative effects of noise, especially high-frequency noise,8b on preterm infants include short-term effects on the stability of cardiovascular and respiratory systems,8c,8d disruption of sleep patterns,8e and potential long-term harm to the auditory and nervous systems.8b,8f There has long been a recommendation to reduce sound exposure in the NICU so that it does not exceed a level greater than 45 dB for preterm infants and term infants who are ill.8a As was intended from the design, sound exposure is decreased in SFRs compared with open-bay NICUs.8g,8h An unintended consequence of the reduced sound environment appears to be delayed language development at 2 years of age in former preterm infants from SFRs compared with their open-bay counterparts.8a There is a positive correlation between preterm infants’ exposure to parental speech and their quantity and quality of vocalizations at postmenstrual ages of 32 and 36 weeks,8h indicating

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Chapter 1 |  Design of Neonatal Intensive Care Units   3

electroencephalogram.8k This study suggests that singing to preterm babies may have implications for their brain development. The SFR NICU plan reduces infants’ exposure to harmful noise. Future areas of study will need to examine how to provide positive auditory stimuli, more closely mimicking the environment in the womb, to the developing infant.

Infection

Fig. 1.1  An Open-Bay Newborn Intensive Care Unit With Eight Beds. Parents are provided comfortable chairs to spend time close to their infants. (2011, University of Maryland Hospital.)

that positive sound is beneficial to their development. Evidence shows enhanced development of the auditory cortex after exposure to recordings of maternal voice and heartbeat in infants born extremely prematurely, compared with routine NICU sound exposure.8i The modification of noise in the NICU environment has been shown to decrease transitory noise after the implementation of clinical mobility communication systems (CMCS) such as smartphones and the elimination of overhead pages. In one study, the percentage of sounds that exceeded the thresholds recommended by the Environmental Protection Agency and International Noise Council decreased from 31.2% to 0.2% after the implementation of CMCS.8j The benefit of music as a positive stimulus has also been explored. In one study, playing Brahms’ lullaby sung by a female vocalist to late preterm infants was noted to reduce sleep interruptions and increase brain maturation patterns measured by amplitude-integrated

Outcome studies comparing infection rates between open-bay and SFR NICUs are conflicting and controversial. No difference in hospital-acquired infections (HAI) was found in one study.8l In contrast, catheter-associated bloodstream infections were decreased from 10.1 per 1000 device-days to 3.3 per 1000 device-days over 9 months after the transition from an open-bay to an SFR-style layout in one US NICU.1 A systematic review and meta-analysis through August 2018 that included 13 separate patient populations (N = 4793) of preterm infants showed a reduction in rates of sepsis with no change in long-term neurodevelopmental outcome in the SFR design versus open bays.9 A retrospective review of medical records of infants admitted to open-bay versus single-family units, including 1823 infants and 55,166 patient-days, showed similar rates of methicillin-resistant Staphylococcus aureus (MRSA) colonization, late-onset sepsis, and mortality. Further analysis showed hand hygiene compliance was associated with decreased MRSA colonization, with hazard ratios of 0.83 and 0.72 per 1% higher compliance. The increased daily census was associated with increased MRSA colonization only in SFRs and not open-bay setups, with a hazard ratio of 1.31 (P = .039).10

Family-Centered Care and Improved Parent-Infant Interactions SFRs are an improvement in many aspects of family-centered care in the NICU (see Fig. 1.4). One of the most important attributes of

Fig. 1.2  Architectural Plan of the Single-Family-Room Newborn Intensive Care Unit at the University of Maryland Hospital. The single-family rooms allow the families to have some privacy. There is a family lounge where the parents can try to relax and at least transiently lower their anxiety levels from having a premature or critically ill infant with increased risk of mortality.

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4  Section 1  |  Care of the Premature and Critically-Ill Neonate

Fig. 1.3  Newborn Intensive Care Unit at the University of Maryland Hospital. Single-family rooms have community-based artwork, an attempt to create a pleasant environment.

Fig. 1.5  Newborn Intensive Care Unit at the University of Maryland Hospital. A noise meter (arrow) has been placed on the top of the isolette.

Fig. 1.4  A Single-Family Room in the Newborn Intensive Care Unit at the University of Maryland Hospital. The parents are provided with a recliner, breast pump, sleeping couch, and locker.

SFRs is parents’ ability to participate in decision-making and help with bedside caregiving.11 SFRs provide a feeling of increased privacy for families, as was shown in one NICU in the United States that conducted a survey during a 6-month period after moving from an open-bay style to an SFR style. Parents felt more involved in care and less like visitors and felt they had privacy to experience their emotions of happiness and distress with their infant.12 SFRs with space for families to stay have been shown in multiple studies to improve family satisfaction.13–15,15a Families are more involved in care, including spending more time in the patient’s room,16,16a maternal breastfeeding rates are higher,9,14 and the total length of stay is shortened,17 likely all because families feel more comfortable with a private, dedicated space within the patient room.3 Parents’ ability to be present and involved from admission to discharge likely also increases their confidence in caring for their infant long before discharge, contributing to the decreased length of stay.18 However, contrary to the expectation that spending more time at the bedside would reduce anxiety, maternal stress related to NICU admission was slightly increased in the SFR setting.19 To counter this difficulty, many centers have included family lounges within the NICUs to provide some space where parents can try to relax and at least transiently lower their anxiety levels from having a premature or critically ill infant who may be at increased risk of mortality (Fig. 1.7). Patient- and family-engaged care is defined as “care planned, delivered, managed, and continuously improved in active partnership with patients and their families (or care partners as defined by the

Fig. 1.6  Newborn Intensive Care Unit at the University of Maryland Hospital. The unit features spacious hallways, comfortable lighting, and rubber floors to minimize undue visual or auditory stimulation.

patient) to ensure integration of their health and healthcare goals, preferences, and values”20 and is considered the culture of care. There is a direct relationship between NICU design and the culture of care.21 The benefits of the SFR NICUs are owed to increased maternal and paternal involvement. The SFR setting provides the privacy and opportunity for maternal involvement; for example, increased rates of breastfeeding and human milk provision at 4 weeks was higher in SFR NICUs. Every 10 mL/kg/day increment of breast milk at 4 weeks was associated with increased cognitive, language, and motor Bayley scores (0.29, 0.34, and 0.24, respectively).24 The SFR provides a private space that promotes parental involvement, extensive presence, and skin-to-skin care that cannot be accomplished in a traditional and crowded open-bay unit.21

Staffing Patterns, Nursing Workload, and Communication The trend toward SFR structure in NICUs, despite solving some problems regarding parent involvement, creates a shift in challenges to caregivers, with inconsistent impressions among different groups. In

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Chapter 1 |  Design of Neonatal Intensive Care Units   5

SFR NICU group. In contrast, necrotizing enterocolitis rates were lower compared with the open-bay group (sepsis, 25.8 versus 17.9; necrotizing enterocolitis, 4.3 versus 10.6, respectively). Another published study compared two populations of infants with a gestational age of 28 to 32 weeks at birth in SFR versus open-bay NICUs that both used the same feeding protocols and found no significant differences in weight, length, or head circumference at 34 weeks’ postmenstrual age and 4 months’ chronologic age. Consistent with other studies, the SFR parents spent significantly more time with their babies and provided more skin-to-skin care than did the parents of babies in the open-bay unit, but developmental milestones achieved were not significantly different between the two.21

Neurodevelopment Outcome

Fig. 1.7  Family Lounge in a Newborn Intensive Care Unit at the University of Maryland Hospital.

a study of a group of 127 nurses conducted before and after the transition from open-bay to SFR NICUs, 70% of the nurses felt that they had an increased workload in the single-family layout owing to increased physical difficulty with more walking required and an inability to see all patients at once or from other patients’ bedsides.1 Nurses in single-family units found it troubling that there was not a centralized location from which all their patients could be seen, thus making it difficult to know the status of all their patients at all times.1,22 The reduced visibility of patients to their nurses and reliance on mechanical monitoring raises concerns about patient safety in an SFR-style unit.7 A study of 21 staff members conducted 1 year after transitioning from an open-bay to a single-family design found that the staff felt they had less interaction with one another and thus had fewer opportunities for assistance and learning from colleagues.22 In contrast, a survey of interdisciplinary staff conducted as quality improvement 1 year after the transition to an SFR structure found that staff had a perception of improved patient care, an improved environment for patients, families, and caregivers, and lower workplace stress.23 There may be other factors that influence caregivers’ impressions of workload and patient safety between sites, potentially including strategies (e.g., video monitors, communications systems, etc.) to adapt to these challenges.

Growth and Weight Gain Growth is improved in SFR NICUs compared with open-bay NICUs in preterm infants 35 weeks’ gestation, a 21% Fio2 should be used. The Fio2 should be titrated to achieve optimum preductal saturations7 (Table 9.3).

Table 9.3  Guidelines for Spo2 Values in First 10 Minutes of Lifea Minute of Life

Spo2, %

1

60–65

2

65–70

3

70–75

4

75–80

5

80–85

10

85–90

Neonatal Resuscitation Program recommendations.

a

Spo2, Oxygen saturation.

It is equally important for the resuscitation team to titrate the Fio2 down as goal oxygen saturations are achieved so as to avoid injury resulting from hyperoxia. Preterm infants are at particularly high risk for oxidative stress, which contributes to the development of bronchopulmonary dysplasia, retinopathy of prematurity, necrotizing enterocolitis, and intraventricular hemorrhage.16 If an infant needs positive pressure ventilation in the delivery room, it is important to use the minimal amount of pressure necessary to affect an adequate increase in heart rate and oxygen saturation. In preterm infants requiring resuscitations, most institutions start at a peak inspiratory pressure of 20 cm H2O and a positive end-expiratory pressure of 5 cm H2O. Again, NRP guidelines should be followed, and the peak inspiratory pressure and positive end-expiratory pressure should be adjusted as necessary to achieve the targeted rise in heart rate. Early nasal continuous positive airway pressure (nCPAP) in the delivery room, as opposed to prophylactic early intubation and surfactant administration, has been shown to reduce the rate of future intubations in the delivery room and the NICU, reduce the rate of postnatal corticosteroid use, and lead to a shorter duration of mechanical ventilation.17 When possible, early nCPAP should be initiated in the resuscitation of preterm infants. Compared with nCPAP, nasal intermittent positive pressure ventilation is more effective in decreasing rates of respiratory failure and the need for intubation in preterm infants with respiratory distress syndrome, but it can be harder to provide in the delivery room.18 Exogenous surfactant replacement therapy should be administered for a persistent Fio2 requirement >40% or per institutional guidelines.

Fluid Management and Prevention of Hypoglycemia During the Golden Hour Hypoglycemia in the newborn is common, and even transient hypoglycemia can lead to lasting neurodevelopmental impairments. These effects are especially pronounced in preterm infants as opposed to term infants.19,20 Preterm newborns are at high risk for hypoglycemia, particularly those who are growth restricted or large for gestational age or who have diabetic mothers. Like many other outcomes in the preterm neonate, the incidence of hypoglycemia is inversely related to gestational age.21 The initial blood glucose level should be measured within the Golden Hour, because blood glucose levels reach a physiologic nadir within approximately 60 minutes of postnatal life in the absence of exogenous supplementation. Intravenous (IV) access should be established as soon as possible after birth in the preterm neonate, either with a peripheral IV or umbilical venous catheter, and parenteral fluids containing dextrose and amino acids should be administered at maintenance levels. Early administration of such fluid has been demonstrated to improve growth outcomes and

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60  Section 2  |  Neonatal Resuscitation and Respiratory Care

decrease the incidence of hypoglycemia.22 Obtaining stable intravenous access by 1 hour of life should be incorporated into any Golden Hour protocol.

Prevention of Sepsis in the Golden Hour Neonatal sepsis is one of the most common causes of neonatal morbidity and mortality worldwide.23 Adult and pediatric critical care medicine have instituted their own Golden Hour protocols around the administration of antibiotics in patients at high risk for sepsis. This has been shown to significantly decrease mortality from sepsis in these patients.24,25 Risk factors for neonatal sepsis include prematurity, immunodeficiency, maternal Group B streptococcal colonization, and chorioamnionitis. Chorioamnionitis is a major risk factor for preterm birth and also independently increases the risk of early onset neonatal sepsis, development of cerebral palsy, and leukomalacia. Timely administration of appropriate antibiotics within the Golden Hour is critical in preventing early-onset sepsis and later sequelae of sepsis. Pharmacists should be included in the development of any Golden Hour protocol, because they can ensure that the NICU is stocked with the most common antibiotics used in the first days of a neonate's life. Having antibiotics, usually ampicillin and gentamicin, readily available for nurses to give negates the delay in having to order these medications from the pharmacy and have them approved prior to administration. It is important to note that overtreatment with antibiotics is also associated with poor outcomes, so once blood cultures show no growth after 36 to 48 hours, antibiotics should be discontinued. If a blood culture becomes positive, antibiotic therapy should be tailored to the most appropriate regimen for the specific organism.26

Optimizing Outcomes by Minimizing Interventions Neonatal intensive care is, by definition, intensive. It is our default, because intensive care practitioners want to know all that we can about our patients in order to help them. We need to balance our need for information with the potential harm that invasive procedures and laboratory tests can cause. Greater numbers of invasive (painful) procedures in neonates are associated with abnormal brain development.27 Infants who undergo more painful or invasive procedures have reduced white matter and subcortical gray matter on magnetic resonance spectroscopic imaging.28 These abnormalities in the white matter microstructure persist and are ultimately associated with a lower IQ in preterm neonates.29 Extremely preterm neonates typically have the highest rates of iatrogenic blood loss on the first day of life secondary to the routine laboratory studies done on admission to the NICU. These losses can be upward of 10 mL/kg, which is substantial considering that the average circulating red blood cell volume in a preterm neonate is just 90 to 100 mL/kg.30 Throughout a NICU admission, iatrogenic phlebotomy losses are one of the key contributors to neonatal anemia.31 Estimates for iatrogenic blood loss in the first 6 weeks of life in an ELBW infant range from 11 to 22 mL/kg/week, which represents 15% to 30% of circulating blood volume in an ELBW infant.31–33 Of all red blood cell transfusions during the NICU admission of an ELBW infant, 44% are given during the first 2 weeks of life and 70% during the first month of life.34 The amount of blood drawn for laboratory tests in the NICU is directly correlated with the number of blood transfusions in preterm

infants.33,35–37 Therefore, as providers, we can decrease the number of blood transfusions given to patients and the degree of anemia by judiciously ordering laboratory studies. Golden Hour protocols should have guidelines for decreasing iatrogenic phlebotomy losses in neonates. The initial “sticks” in the Golden Hour for laboratory blood draws can be reliably obtained from umbilical cord blood in the delivery room, provided that personnel have been properly trained in how to draw blood from the placenta via the umbilical cord. Multiple studies have demonstrated that laboratory tests such as complete blood cell count, blood culture, and blood type/antibody screens are equally reliable when drawn from the umbilical cord blood or directly from the infant.38–44 Umbilical cord blood samples can still be used for neonatal laboratory studies even if delayed cord clamping is done after birth, because a substantial portion of fetal cells remains even after delayed cord clamping is completed. The placenta and umbilical cord are rich reservoirs of fetal blood cells and should not simply be discarded after birth. To further decrease laboratory blood draws and “sticks” upon admission to the NICU, noninvasive monitors such as transcutaneous or end-tidal CO2 monitors should be considered.

Future Directions for the Golden Hour Standardization of care in the initial resuscitation and the first hour of life of high-risk neonates has improved long-term mortality and neurodevelopmental, respiratory, and ophthalmologic outcomes. Even after a standardized resuscitation and after the first hour of life, neonates are still at high risk for developing other morbidities. It stands to reason that these morbidities could potentially be mitigated with further standardization of care past the Golden Hour. ELBW infants have a 30% to 40% overall risk of developing an IVH during their NICU stay, with 90% of these hemorrhages occurring during the first 72 hours of life. Some factors leading to increased IVH risk in ELBW infants are the following45: • Capillary fragility • Mechanical ventilation • Sepsis • Episodes of hypotension or hypertension • Low Apgar scores • Hypernatremia • Hypothermia • Early blood transfusions Given these known risk factors, many centers have standardized multiple facets of neonatal care beyond the first 24 hours of life. One large academic medical center proposed a “Golden Week” for infants born at treat as above based on lab results

no

Differenal Diagnosis 1) Normal infant 2) Delayed rise in TSH (premature infant) 3) Non-thyroidal illness

Repeat Screen in 2, 6, 10 weeks -> treat as above based on lab results

Fig. 26.1  Screening Algorithm for Newborns With Potential Congenital Hypothyroidism. TSH, Thyroid-stimulating hormone.

permanent hypothyroidism.35,47 Fig. 26.1 reviews an algorithm for screening infants with potential congenital hypothyroidism.

Hyperthyroidism Neonates of mothers with GD are at increased risk for neonatal GD, but hypothyroidism can also occur. There are two types of TSH-receptor (TSHR) antibodies (TRAbs): TSHR-stimulating immunoglobulins, which cause overproduction of thyroid hormone (hyperthyroidism), and TSH-receptor inhibitory (blocking) immunoglobulins, which can cause hypothyroidism. Fetal thyroid hormone synthesis begins at approximately 10 to 12 weeks’ gestation, and the fetal TSH receptor starts responding to stimulation, including stimulation by thyroid-stimulating immunoglobulins, during the second trimester.48 TRAbs, which belong to the immunoglobulin G class, freely cross the placenta, similar to iodine, thyroxine (T4), and antithyroid drugs (ATDs) the mother may be taking for the treatment of GD. The balance of stimulatory and inhibitory TRAbs, as well as ATD dose, influence the thyroid status in the fetus and neonate, and the fluctuation of maternal antithyroid antibody titers may result in different risks to the fetus or neonate.49 In cases of transient neonatal GD, maternal TRAbs typically clear from the infant's circulation by 4 to 6 months of age, with resultant resolution of hyperthyroidism.48 As mentioned in the introduction, neonatal hyperthyroidism can also occur secondary to activating mutations in the TSH receptor or activating mutations in the alpha subunit of stimulatory G proteins

(GNAS) in McCune-Albright syndrome.17 This form of hyperthyroidism is permanent. Long-term antithyroid medical therapy is indicated until the child is old enough to safely complete definitive therapy to convert to hypothyroidism. Thyroidectomy is the treatment of choice, with some patients requiring radioactive iodine even after thyroidectomy if residual tissue is associated with persistent or recurrent hyperthyroidism.50–52

Clinical Features Fetuses of euthyroid women are protected from the effects of hypothyroidism by placental transfer of maternal thyroid hormone and because they commonly have some functioning thyroid tissue. Prenatal treatment of CH may be considered in rare cases of dyshormonogenesis that present with a large fetal goiter, which can cause polyhydramnios and airway compromise that may obstruct breathing after birth.53 The pattern and timing of dyshormonogenesis-associated goiter may vary based on the genetic etiology. Mutations in TG,54 TPO,55 and DUOXA256 have been reported as etiologies of fetal goiter. Infants with severe congenital hypothyroidism may present with hypothermia, bradycardia, poor feeding, hypotonia, large fontanelles, myxedema, macroglossia, and umbilical hernia. This presentation is most common when both fetal and maternal hypothyroidism are present, as in iodine deficiency or untreated maternal hypothyroidism. However,

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Chapter 26 |  Neonatal Thyroid Disease   219

many neonates manifest few or no symptoms even with significant hypothyroidism, making clinical diagnosis difficult in this age group. Implementation of universal newborn screening has nearly eradicated severe intellectual impairment due to CH in areas where screening is practiced, but CH remains a leading cause of preventable intellectual impairment in areas without newborn screening programs. Signs of hyperthyroidism can be detected in the fetus, and if present, are highly predictive of neonatal hyperthyroidism. Particularly in cases where maternal GD is poorly controlled, features concerning for fetal hyperthyroidism include fetal tachycardia (heart rate >160 beats/min), thyroid enlargement (goiter; fetal neck circumference >95%), intrauterine growth retardation, polyhydramnios or oligohydramnios, advanced bone age, craniosynostosis with microcephaly, and hydrops.57,58 Polyhydramnios is typically associated with a goiter with resultant esophageal and/or tracheal obstruction. Fetal bone age is assessed at the distal femur as the distal femoral epiphysis becomes detectable at about 32 weeks’ gestation.59 An advanced bone age is present if the femoral epiphysis is present prior to the 31st gestational week. For fetuses with severe thyrotoxicosis, there is an increased risk for premature delivery, and at the extreme, fetal death may occur.48 After delivery, a newborn may present with tachycardia, irritability with tremors, poor feeding, sweating, and difficulty sleeping secondary to thyrotoxicosis. Newborns may also have an emaciated appearance, proptosis with stare, and a goiter. Premature closure of cranial sutures (craniosynostosis) may be noted in severely affected infants. Other signs of neonatal hyperthyroidism, which may be confused with infection/ sepsis, include thrombocytopenia, hepatosplenomegaly, and jaundice.60 Fulminant liver failure and pulmonary hypertension secondary to neonatal hyperthyroidism may also be features of thyrotoxicosis.61–64

Evaluation Screening protocols vary but generally begin with measurement of TSH and/or T4 in a dried blood spot collected from the infant within a few days after delivery. The initial sample generally should be obtained at least 24 hours after delivery to avoid false-positive results due to the physiologic TSH surge.65,66 Prompt diagnosis and treatment of CH is critical to optimize developmental outcome, so any abnormal newborn screen result should prompt immediate confirmation of TSH and free T4 concentrations in a serum sample.67 If a repeat newborn screen is obtained after the first few days of life, whether to confirm an abnormal result or as standard practice in all or selected newborns, gestational age– and postnatal age–specific reference ranges must be used to avoid misinterpreting an elevated TSH as normal in the context of the higher TSH reference range that is applicable only to the first few days after birth.1 In preterm infants, the timing of thyroid hormone testing should be adjusted to surveil over the time required for HPT axis maturation and acute illness. In an effort to avoid missing appropriate treatment, serial thyroid hormone monitoring should be implemented. A standardized monitoring schedule should be considered, with two examples including testing at (1) 48 hours, 2 weeks, 6 weeks, 10 weeks, or until the infant is >1500 g,68 or (2) 72 to 120 hours, 1 week, 2 weeks, 4 weeks, and at term-corrected gestational age (see Fig. 26.1).47 There is no consensus on criteria for initiation of thyroid hormone replacement therapy, but treatment should be considered if the TSH is >10 μU/mL with a low T4.28 Levothyroxine (LT4) replacement should also be considered if the TSH is persistently between 5 and 10 μU/mL or if the TSH is >5 μU/mL with an upward trend on serially repeated thyroid function testing.

Determining the etiology of CH via radiologic imaging rarely alters initial management but may provide insight into prognosis. Ultrasound or thyroid scintigraphy (using 99mTc or 123I) can be used to assess the presence or absence of a normally located thyroid gland.69 Although hypothyroidism due to dysgenesis is usually permanent, about 35% of patients with a eutopic thyroid gland have transient disease and will not require lifelong therapy.70,71 Neonates considered to be at high risk for development of thyrotoxicosis include (1) infants born to mothers with GD, especially if the maternal TRAb level is greater than twice the upper limit of normal; (2) infants in whom intrauterine surveillance revealed fetal signs of hyperthyroidism; and (3) infants with a known family history of genetic causes of congenital hyperthyroidism including activating mutations in the TSH receptor. If possible, TRAbs should be measured in cord blood of infants at high risk for neonatal hyperthyroidism, because there is a strong correlation between maternal and neonatal TRAb levels. Cord blood TSH and free thyroxine (fT4) are less helpful in predicting the onset of neonatal hyperthyroidism. Maternal ATDs are usually metabolized and excreted by 5 days of life. Unless symptoms of hyperthyroidism develop earlier, thyroid function studies (TSH and fT4) should be sent between 3 and 5 days of life, when biochemical hyperthyroidism typically develops in neonates with hyperthyroidism secondary to maternal GD. Onset of signs and symptoms of thyrotoxicosis may be delayed for several days, either from the effect of maternal ATDs or due to a coexistent effect of blocking antibodies. Thyroid function studies should therefore be sent again at 10 to 14 days of life, as studies have shown that most cases of neonatal GD present within the first 2 weeks of life.72 However, there have been case reports of overt thyrotoxicosis secondary to neonatal GD occurring as late as 45 days of life.73 After 2 weeks of age, infants with no clinical or biochemical hyperthyroidism should continue close monthly follow-up with their primary care providers. Algorithms summarizing the evaluation and management of neonatal hyperthyroidism are available.17,72

Management Hypothyroidism In newborns whose screening whole blood TSH is ≥40 mIU/L, LT4 should be initiated as soon as the confirmatory serum sample is obtained, without awaiting the results. In infants with screening TSH 20 mIU/L or between 6 and 20 mIU/L with a low free T4 concentration (see Fig. 26.1).67 The management of infants with mild TSH elevation (serum TSH 6–20 mIU/L) and normal free T4 levels is controversial. Although such patients are frequently identified by more stringent newborn screening thresholds, the neurodevelopmental risks posed by untreated mild disease remain uncertain.74–77 Although there is a lack of consensus, if the TSH remains in the 6 to 20 mIU/L, beyond 21 days in a healthy, term neonate, LT4 replacement may be initiated with reevaluation for the need of continued therapy at 2 to 3 years of life.78 The initial dose of LT4 for CH is 10 to 15 micrograms (μg)/kg daily. For the majority of term infants, the typical starting dose is 37.5 mcg/day of LT4. For infants with marked elevation in TSH, >100 mIU/L, 50 mcg/day may be considered as a starting dose79,80 with close follow-up and dose reduction to avoid overtreatment that may be associated with altered neurodevelopmental outcome.81,82 Serum thyroid function testing is monitored every 1 to 2 weeks until normal, and then every 1 to 2 months during the first year of life and every 2 to 4 months during the 2nd and 3rd year of life with LT4.69 The target parameter for LT4 treatment is normalization of

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220  Section 5  |  Endocrine Disorders

TSH within the first weeks of initiation of therapy.80,83 LT4 dose is adjusted to maintain the serum TSH in the midnormal range and the serum free T4 in the mid- to upper half of the normal range. A subgroup of infants with CH displays variable degrees of thyroid hormone resistance with persistently elevated TSH levels despite high-normal or frankly elevated free T4 concentrations.84 For these patients, the addition of LT3 to LT4 therapy can facilitate normalization of the TSH, but whether this improves outcomes is unknown.85 To initiate combined therapy, the LT4 dose is typically decreased by 10% to 20% with addition of liothyronine (LT3) between 0.3 and 0.66 μg/kg/day, with the minimal reliable dose of 2.5 μg/day (1/2 tab) based on the smallest available tablet size (5 μg).85 In patients with suspected transient CH, based on the presence of a normal-appearing, eutopic thyroid gland on ultrasound and an initial borderline elevated TSH between 6 and 20 mIU/L, an LT4 dose of 4.7 μg/kg/day at 12 months or 24 months, respectively, are associated with an increased likelihood for permanent hypothyroidism.86 A trial off of LT4 is typically delayed until the child is 2 to 3 years of age, when the risk of potential hypothyroidism-related neurocognitive development is lower.78 In central hypothyroidism, the TSH is low or inappropriately normal despite low T4 levels, secondary to abnormalities in the hypothalamus (thyrotropin-releasing hormone, TRH) or pituitary gland (TSH). The goal of treatment in central hypothyroidism, in which, by definition, serum TSH does not reflect systemic thyroid status, is to maintain the serum free T4 level in the upper half of the reference range.87 However, before initiation of thyroid hormone replacement therapy in patients with suspected central hypothyroidism, assessment of the other anterior pituitary hormone axes must be completed to avoid inducing adrenal insufficiency secondary to thyroid hormone–associated increased clearance of cortisol.

LT4 tablets should be crushed, suspended in a small volume of water, breast milk, or non–soy-based infant formula, and administered via a syringe or teaspoon (not in a bottle). LT4 should not be administered with multivitamins containing calcium or iron. Limited data suggest that brand-name LT4 may be superior to generic in children with severe congenital hypothyroidism but not in those with equally severe acquired hypothyroidism.67,88 Compounded LT4 solutions do not provide reliable dosing and should not be used.89 Tirosint-SOL is a stable liquid form of levothyroxine that is available in Europe and the United States with reported unaltered absorption when administered with milk (and other breakfast beverages, in adults).90 With the potential of improved absorption, optimal dosing of liquid LT4 preparations in neonates may differ compared with tablet formulations.91,92 In patients that cannot tolerate LT4 by mouth or by nasogastric or gastrostomy tube, intravenous levothyroxine may be administered with a dose reduction of 25% based on a 70% to 80% absorption rate of oral levothyroxine in healthy subjects (thyroid hormone is absorbed in the jejunum and ileum).87 Prenatal treatment of CH may be considered in rare cases of dyshormonogenesis that present with a large fetal goiter, which can cause polyhydramnios as well as airway compromise that may obstruct breathing after birth. Intraamniotic injection of LT4 may help decrease fetal goiter size to prevent these complications. Although there is no consensus on intraamniotic LT4 dose or schedule, several reports have employed 150 to 500 μg/dose (or 10 μg/kg estimated fetal weight) every 2 weeks, with adjusted frequency based on fetal goiter response.19,93,94 Intrauterine demise and need for intubation at birth are potential complications in such cases.54

Hyperthyroidism In cases of suspected neonatal GD with biochemical hyperthyroidism, antithyroid drugs, (methimazole (MMI), and others) should be started

Fig. 26.2  Screening and Treatment Algorithm for Newborns at Risk for Neonatal Thyrotoxicosis. TSH, Thyroid-stimulating hormone.

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Chapter 26 |  Neonatal Thyroid Disease   221

at a dose of 0.2 to 0.5 mg/kg/day.17 Propranolol should be added at a dose of 2 mg/kg/day for signs of sympathetic hyperactivity including tachycardia and hypertension. Propylthiouracil (PTU) is not recommended in neonates and throughout childhood due to the increased risk for hepatotoxicity.95 In severe cases with hemodynamic compromise, Lugol's solution or potassium iodide may be given. Glucocorticoids may also be beneficial in the short term (Fig. 26.2). Because neonatal hyperthyroidism is more often transient and resolves with clearance of maternal TRAbs from the circulation, thyroid function tests should be monitored every 1 to 2 weeks after initiation of treatment to ensure appropriate MMI dose titration.72 In cases of nonautoimmune neonatal hyperthyroidism (activating mutations of the TSH receptor or McCune-Albright syndrome), MMI should be used for treatment similarly to cases of neonatal GD. Definitive therapy including thyroidectomy and/or radioiodine ablation will ultimately be required but can be delayed for months to years if the baby is responsive to medical therapy.96,97 Current guidelines note that breastfeeding is safe for mothers on antithyroid medications at moderate doses of MMI (20–30 mg/day) and PTU (less than 300 mg/day).98 Infants of mothers with GD who are breastfeeding should have periodic thyroid function screening to ensure they have not developed hypothyroidism.99

Conclusion Abundant basic and clinical research demonstrates that thyroid hormone signaling is required for both fetal and pediatric development. The identification of genes critical for thyroid hormone metabolism, transport, and receptor function has revealed that derangement of local thyroid hormone signaling can impact development, even in the absence of primary thyroid disease. The goal of thyroid hormone replacement in neonates is to optimize normal growth and development and reduce or eliminate hypothyroidism-related signs and symptoms. For many neonates, LT4 replacement is anticipated to be lifelong; however, there is potential to discontinue LT4 in patients with transient congenital hypothyroidism100,101 and drug-induced hypothyroidism (amiodarone33 and others). In neonates with hyperthyroidism, there are known short-term consequences of acute illness, a risk of craniosynostosis, and some evidence to suggest the potential for long-term adverse neurocognitive outcomes.102,103 Further clinical research is needed to understand the consequences of fetal and neonatal hypothyroxinemia and thyrotoxicosis, especially for preterm and/or critically ill infants, to better understand the potential benefits and risks of treatment.

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Chapter 26 |  Neonatal Thyroid Disease   221.e1

REFERENCES

1. Kilberg MJ, Rasooly IR, LaFranchi SH, Bauer AJ, Hawkes CP. Newborn screening in the US may miss mild persistent hypothyroidism. J Pediatr. 2018;192:204–208. 2. Hanley P, Lord K, Bauer AJ. Thyroid disorders in children and adolescents: a review. JAMA Pediatr. 2016;170(10):1008–1019. 3. Nilsson M, Fagman H. Development of the thyroid gland. Development. 2017;144(12):2123–2140. 4. Carre A, Stoupa A, Kariyawasam D, et al. Mutations in borealin cause thyroid dysgenesis. Hum Mol Genet. 2017;26(3):599–610. 5. Peters C, van Trotsenburg ASP, Schoenmakers N. Diagnosis of endocrine disease: congenital hypothyroidism: update and perspectives. Eur J Endocrinol/Eur Fed Endocr Soc. 2018;179(6):R297–R317. 6. van Tijn DA, de Vijlder JJ, Verbeeten B Jr, Verkerk PH, Vulsma T. Neonatal detection of congenital hypothyroidism of central origin. J Clin Endocrinol Metab. 2005;90(6):3350–3359. 7. Belfort MB, Pearce EN, Braverman LE, He X, Brown RS. Low iodine content in the diets of hospitalized preterm infants. J Clin Endocrinol Metab. 2012;97(4):E632–E636. 8. Markou K, Georgopoulos N, Kyriazopoulou V, Vagenakis AG. Iodineinduced hypothyroidism. Thyroid. 2001;11(5):501–510. 9. Pinsker JE, McBayne K, Edwards M, Jensen K, Crudo DF, Bauer AJ. Transient hypothyroidism in premature infants after short-term topical iodine exposure: an avoidable risk? Pediatr Neonatol. 2013;54(2):128–131. 10. Creo A, Anderson H, Cannon B, et al. Patterns of amiodarone-induced thyroid dysfunction in infants and children. Heart Rhythm. 2019. 11. Barr ML, Chiu HK, Li N, et al. Thyroid dysfunction in children exposed to iodinated contrast media. J Clin Endocrinol Metab. 2016;101(6):2366–2370. 12. Jick SS, Hedderson M, Xu F, Cheng Y, Palkowitsch P, Michel A. Iodinated contrast agents and risk of hypothyroidism in young children in the United States. Invest Radiol. 2019;54(5):296–301. 13. Farebrother J, Zimmermann MB, Andersson M. Excess iodine intake: sources, assessment, and effects on thyroid function. Ann NY Acad Sci. 2019;1446(1):44–65. 14. Brown RS, Alter CA, Sadeghi-Nejad A. Severe unsuspected maternal hypothyroidism discovered after the diagnosis of thyrotropin receptor-blocking antibody-induced congenital hypothyroidism in the neonate: failure to recognize and implications to the fetus. Horm Res Paediatr. 2015;83(2):132–135. 15. Haugen BR. Drugs that suppress TSH or cause central hypothyroidism. Best Pract Res Clin Endocrinol Metab. 2009;23(6):793–800. 16. Koulouri O, Moran C, Halsall D, Chatterjee K, Gurnell M. Pitfalls in the measurement and interpretation of thyroid function tests. Best Pract Res Clin Endocrinol Metab. 2013;27(6):745–762. 17. Samuels SL, Namoc SM, Bauer AJ. Neonatal thyrotoxicosis. Clin Perinatol. 2018;45(1):31–40. 18. Patel J, Landers K, Li H, Mortimer RH, Richard K. Delivery of maternal thyroid hormones to the fetus. Trends Endocrinol Metab. 2011;22(5):164–170. 19. Polak M, Luton D. Fetal thyroidology. Best Pract Res Clin Endocrinol Metab. 2014;28(2):161–173. 20. Lem AJ, de Rijke YB, van Toor H, de Ridder MA, Visser TJ, Hokken-­ Koelega AC. Serum thyroid hormone levels in healthy children from birth to adulthood and in short children born small for gestational age. J Clin Endocrinol Metab. 2012;97(9):3170–3178. 21. Alexander EK, Pearce EN, Brent GA, et al. 2017 Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and the postpartum. Thyroid. 2017;27(3):315–389. 22. Stenzel D, Huttner WB. Role of maternal thyroid hormones in the developing neocortex and during human evolution. Front Neuroanat. 2013;7:19. 23. Vulsma T, Gons MH, de Vijlder JJ. Maternal-fetal transfer of thyroxine in congenital hypothyroidism due to a total organification defect or thyroid agenesis. N Engl J Med. 1989;321(1):13–16. 24. Haddow JE, Palomaki GE, Allan WC, et al. Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of the child. N Engl J Med. 1999;341(8):549–555. 25. Pop VJ, Kuijpens JL, van Baar AL, et al. Low maternal free thyroxine concentrations during early pregnancy are associated with impaired psychomotor development in infancy. Clin Endocrinol (Oxf). 1999;50(2): 149–155.

26. Downing S, Halpern L, Carswell J, Brown RS. Severe maternal hypothyroidism corrected prior to the third trimester is associated with normal cognitive outcome in the offspring. Thyroid. 2012;22(6):625–630. 27. Segni M. Disorders of the thyroid gland in infancy, childhood and adolescence. In: Feingold KR, Anawalt B, Boyce A, et al, eds. Endotext. South Dartmouth (MA); 2000. 28. LaFranchi SH. Screening preterm infants for congenital hypothyroidism: better the second time around. J Pediatr. 2014;164(6):1259–1261. 29. Fisher DA, Nelson JC, Carlton EI, Wilcox RB. Maturation of human hypothalamic-pituitary-thyroid function and control. Thyroid. 2000;10(3):229–234. 30. Kratzsch J, Pulzer F. Thyroid gland development and defects. Best Pract Res Clin Endocrinol Metab. 2008;22(1):57–75. 31. Murphy N, Hume R, van Toor H, et al. The hypothalamic-pituitary-thyroid axis in preterm infants; changes in the first 24 hours of postnatal life. J Clin Endocrinol Metab. 2004;89(6):2824–2831. 32. Fisher DA. Thyroid system immaturities in very low birth weight premature infants. Semin Perinatol. 2008;32(6):387–397. 33. Barrett B, Hawkes CP, Isaza A, Bauer AJ. The effects of amiodarone on thyroid function in pediatric and young adult patients. J Clin Endocrinol Metab. 2019;104(11):5540–5546. 34. Chapman AK, Farmer ZJ, Mastrandrea LD, Matlock KA. Neonatal thyroid function and disorders. Clin Obstet Gynecol. 2019;62(2):373–387. 35. Vigone MC, Caiulo S, Di Frenna M, et al. Evolution of thyroid function in preterm infants detected by screening for congenital hypothyroidism. J Pediatr. 2014;164(6):1296–1302. 36. Williams FL, Ogston SA, van Toor H, Visser TJ, Hume R. Serum thyroid hormones in preterm infants: associations with postnatal illnesses and drug usage. J Clin Endocrinol Metab. 2005;90(11):5954–5963. 37. Warner MH, Beckett GJ. Mechanisms behind the non-thyroidal illness syndrome: an update. J Endocrinol. 2010;205(1):1–13. 38. Kaluarachchi DC, Allen DB, Eickhoff JC, Dawe SJ, Baker MW. Thyroidstimulating hormone reference ranges for preterm infants. Pediatrics. 2019;144(2). 39. Simpson J, Williams FL, Delahunty C, et al. Serum thyroid hormones in preterm infants and relationships to indices of severity of intercurrent illness. J Clin Endocrinol Metab. 2005;90(3):1271–1279. 40. Yoon SA, Chang YS, Ahn SY, Sung SI, Park WS. Incidence and severity of transient hypothyroxinaemia of prematurity associated with survival without composite morbidities in extremely low birth weight infants. Sci Rep. 2019;9(1):9628. 41. Delahunty C, Falconer S, Hume R, et al. Levels of neonatal thyroid hormone in preterm infants and neurodevelopmental outcome at 5 1/2 years: millennium cohort study. J Clin Endocrinol Metab. 2010;95(11):4898–4908. 42. La Gamma EF, van Wassenaer AG, Ares S, et al. Phase 1 trial of 4 thyroid hormone regimens for transient hypothyroxinemia in neonates of anterior

1 week

Necrosis with congestion and/or hemorrhage (size >1 cm)

Echolucent foci (“cysts”)

1–3 weeks

Cyst formation secondary to tissue dissolution (size >3 mm)

Ventricular enlargement, often with disappearance of “cysts”

≥2–3 months

Deficient myelin formation; gliosis, often associated with collapse of the cyst

From Neil JJ, Volpe JJ. Encephalopathy of prematurity: clinical-neurological features, diagnosis, imaging, prognosis, therapy. In: Volpe's Neurology of the Newborn. 6th ed. Philadelphia,: Elsevier; 2018.

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452  Section 9  |  Neurological Disorders

gaze and fixed pupils, flaccid quadriparesis, and bulging anterior fontanelle d. Systemic features noted are hypotension, bradycardia, temperature instability, and metabolic acidosis

Diagnosis Cranial ultrasound is the most reliable screening tool to detect and assess the severity of IVH. Advantages of ultrasound are its high resolution, portability, lack of radiation, and cost-effectiveness. The grading scale developed by Papile in 1978 and later modified by Volpe, with the addition of a grade IV, is used most frequently (see Fig. 52.5).3

Clinical Management Prevention of GM-IVH The following interventions may protect against IVH1,15,56–61: 1. Antenatal interventions: a. Antenatal glucocorticoids, particularly when given ≤48 hours prior to delivery. b. Antenatal magnesium sulfate may protect through antiinflammatory effects, not against IVH; may be considered in deliveries at 99% of cases with open NTDs, but false positives can occur in the setting of fetal abdominal wall defects, other major structural anomalies, congenital nephrosis, blood

Table 54.2  Etiologies of Spina Bifida Occulta Thickened filum terminale

Thickening of the filum terminale

Fatty filum

Some degree of fat causing thickening or infiltrating the filum terminale

Diastematomyelia

Split cord malformation where there is either a bony or fibrous attachment causing formation of two spinal cords

Lipomyelomeningocele

Fat attached to the surface of the spinal cord or nerve roots that may cause incomplete closure of the spinal cord and may be connected to the subcutaneous fat

Dermal sinus tract

A band of tissue extending from the cutaneous surface through the dura and attaching to the spinal cord

Meningocele

Skin-covered out-pouching of the dura with fluid without neuronal components

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464  Section 9  |  Neurological Disorders

A

B

C

D

E

Fig. 54.1  Prenatal Ultrasound and Magnetic Resonance Imaging (MRI) of a Lumbosacral Fetal Myelomeningocele. High-resolution ultrasound demonstrates the characteristic brain findings including (A) bitemporal indentation of the frontal bones (lemon sign) and the concave shape of the cerebellum (lemon sign), (B) ventriculomegaly, (C) sagittal views of the lumbosacral spine with the myelomeningocele sac, and (D) coronal view showing stretched neural elements extending to the surface of the lesion. (E) Corresponding MRI demonstrating evidence of the Chiari II malformation and myelomeningocele (MMC).

contamination, and impending miscarriage.18 Maternal serum screening for AFP performed at 16 to 18 weeks of gestation is the least sensitive as a primary screening tool. This test is only 75% sensitive for detecting an open NTD.19 False-positive results may occur in cases of underestimated gestational age, multiple pregnancies, or fetal abdominal wall defects. False-negative results may result from spina bifida occulta lesions such as myelocystoceles. Prenatal counseling aims to help parents understand the spectrum of outcomes possible for individuals with NTDs. Perinatal mortality is uncommon with proper treatment. Most mortalities within the first year of life are secondary to respiratory complications (poor effort or apnea) associated with symptomatic Chiari II malformation.20 In addition, morbidity may contribute significantly to a patient's quality of life. Ambulation, urinary and bowel continence, hydrocephalus, limitations of cognitive function, and spinal cord tethering remain significant challenges for these patients throughout the course of their lives. Up to 70% to 80% of patients with an open MMC have historically required a ventricular shunt, with up to 50% to 75% of shunts timed within the initial perinatal stay. Shunt malfunction rates have been reported as high as 30% to 40% within the first year, 60% within the first 5 years, and up to 85% at 10 years. Patients with hydrocephalus requiring shunt placement have been described as having a lower IQ. However, this may be related to underlying cortical dysplasias or serial shunt malfunctions, which are well documented to be associated with cognitive loss. In their series, Hunt and colleagues described that 89% of patients without a shunt had a high level of achievement, whereas only 69% of patients with a shunt but no revisions achieved the same level. This population dropped to 50% of those requiring shunt revisions before 2 years of age and 18% in those patients who required shunt revisions beyond 2 years of age.21 Despite the overwhelming majority of patients obtaining a normal intelligence quotient (IQ, 70%–75%), hydrocephalus may negatively impact both IQ and cognitive function22 and the ability to live independently.23 Ambulation and functional mobility of the lower extremities does correlate with the sensorimotor level, which can correlate with the

bony dehiscence. Patients with lesions higher than spinal level L3 are typically nonambulatory.24 The majority of preadolescent children are ambulatory, although the majority of patients in the series21 had a lumbosacral lesion. Ambulation does decline as patients age, however, partially due to the efficiency of wheelchair use but also to the children's inability to carry additional weight as they grow.25,26

Management Once the diagnosis is confirmed prenatally, referral to a tertiary care center is advised for multispecialty counseling and care coordination. The initial evaluation is aimed to determine the level of the lesion, which correlates with the degree of impairment as well as any associated anomalies, presence of a Chiari II malformation, and degree of ventriculomegaly. Assessment of fetal motor function can be performed to evaluate the potential for ambulation.27 Fetal magnetic resonance imaging is complementary to the ultrasound examination to assess for callosal or migrational disorders. Genetic counseling and amniocentesis should be offered to exclude chromosomal anomalies. Multidisciplinary, objective counseling and discussion of management options should be done by a team experienced with spina bifida and include specialists in maternal fetal medicine, neurosurgery, neonatology, developmental pediatrics, and social work. Management options include pregnancy continuation with postnatal repair, fetal surgical closure for selected cases, or termination of pregnancy.28 For continuing pregnancies planned for neonatal repair, ongoing prenatal care aims to provide parent education and support about the fetal condition with the goal to achieve a term delivery. Serial ultrasound surveillance is done to assess interval fetal growth and head size that may affect the mode of delivery.29 There has been substantial controversy about the optimal mode of delivery for fetal spina bifida. A recent meta-analysis demonstrated that cesarean delivery was not protective for neurologic function for unrepaired fetal spina bifida30; however, a substantial proportion of patients are delivered by cesarean section for obstetric indications such as breech presentation and macrocephaly.31 The American College of Obstetricians and Gynecologists

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Chapter 54 |  Management of Myelomeningocele and Related Disorders of the Newborn   465

recommends that decisions about delivery mode and timing be individualized based on the specific case characteristics.32 Maternal fetal surgery is reserved for cases of fetal spina bifida without any additional anomalies and a normal karyotype. The landmark Management of Myelomeningocele Study demonstrated that prenatal closure of the fetal lesion via maternal laparotomy and hysterotomy before 26 weeks’ gestation decreased the risk of death or need for shunt within the first year of life to 40% and improved the rate of independent ambulation at 30 months from 21% to 42%.33 However, prenatal surgery increases the risk for obstetric complications and the rate of preterm birth and maternal complications, primarily related to the uterine incision, in both the current and all future pregnancies.34 Accordingly, all women who undergo a hysterotomy for fetal surgery should be delivered by cesarean section expeditiously if there is concern for preterm labor or electively at 37 weeks due to the risk for uterine rupture.35 An alternative is the fetoscopic approach, which is minimally invasive to the uterus. It is performed using two to four small ports either completely percutaneously or with assistance of a maternal laparotomy. This aims to preserve the fetal benefits while avoiding the risks of a hysterotomy (Fig. 54.2). Although the optimal technique remains a matter of debate, an international registry cohort demonstrated similar outcomes for shunting within the first 12 months of life, allowing the option for vaginal delivery and avoiding the risk for uterine dehiscence at the surgical site.36 Regardless of whether the surgical closure is performed prenatally or planned after birth, delivery is recommended at a site where neonatal and neurosurgical services are available.37

Acute Perinatal Management for Open NTD After delivery, initial assessment should proceed to ensure that the infant is hemodynamically stable, breathing appropriately, and meeting baseline neonatal criteria for stabilization. When positioning a neonate with an open NTD, care should be taken to keep direct pressure off the open lesion. The patient should be placed in an infant warmer with the head of the bed level to keep the MMC defect level. This avoids additional gravitational pull of the CSF toward the lesion, which ultimately can leak out of the open defect. A sterile, salinesoaked gauze should be used to cover the defect. Larger lesions may be susceptible to significant loss of body heat and fluid and so electrolyte and fluid status should be monitored closely. Temperature regulation may require not only an infant warmer but even covering the patient in a plastic drape to help trap body heat. With active exposure of CSF to the unsterile environment, broad-spectrum intravenous antibiotics with CSF penetration

A

B

should be instituted early. This has been shown to significantly reduce the likelihood of ventriculitis until the lesion is closed. The most common contaminants are Escherichia coli, group B Streptococcus, or Staphylococcus.38 Some series have reported a high rate of shunt malfunction due to infection in infants who are concurrently shunted at the same time of their MMC closure.39 Initial newborn evaluation should examine whether there are other signs for a genetic or developmental syndrome because 15% will have clinically significant anomalies outside of the central nervous system.40,41 A thorough examination of other organ systems should be conducted, including the cardiovascular, gastrointestinal, pulmonary, and genitourinary systems. While most coexisting anomalies are not immediately life-threatening, severe anomalies may portend a poor prognosis. Parents of infants with a known underlying chromosomal anomaly may choose not to proceed with closure or have limited interventions. Adequate prenatal workup and diagnosis in conjunction with the neonatal team may help establish a birth and treatment plan to help ease the burden on families after delivery. Echocardiogram and renal ultrasound should be obtained to evaluate any physiologic dysfunction. If infants have had an adequate prenatal echocardiogram or do not manifest any clinical symptoms such as cyanosis or cardiac murmur, the echocardiogram may be delayed until after surgery. Most children with an MMC will have a neurogenic bladder, although this is rarely emergent in the immediate perinatal period and should not delay spinal closure. Additional preoperative considerations include hormonal and metabolic response to stress, adequate complete blood count, and nutrition. Preoperatively, enteral nutrition may be held, and if so, parenteral nutrition should be considered. Adequate enteral nutrition should be started as soon as possible but is dependent on several factors including hemodynamic and respiratory stability, extubation, gastrointestinal tract recovery from anesthesia, and in infants with a Chiari II malformation, aspiration risk or difficulty swallowing. Sensorimotor function should be assessed to help determine the physiologic lesion level. Lower-extremity contractures may signal muscle imbalance that can lead to fixed hip flexion, knee extension, or ankle dorsiflexion. Hydrocephalus may manifest as a full fontanelle with split cranial sutures. Over time, rapid increase in head circumference or limitation of upward movement of the eyes, or “sunsetting eyes,” may represent increased intracranial pressure. Brainstem dysfunction may manifest as bradycardia, apnea, swallowing deficits, weak cry, vocal cord palsies, and global hypotonia. Persistent brainstem dysfunction during the early perinatal period may represent symptomatic hydrocephalus as well as abnormal neuronal development within the brainstem itself.

C

Fig. 54.2  Maternal Fetal Surgery for Spina Bifida Closure Via Hysterotomy and Fetoscopy. After maternal laparotomy and hysterotomy, (A) the fetal lesion is initially exposed and then (B) a multilayer closure is performed. (C) For the laparotomy-assisted fetoscopic approach, two to four small ports are inserted into the uterus using ultrasound guidance to perform the fetal closure.

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466  Section 9  |  Neurological Disorders

Other routine preoperative preparation should include routine workup for neonates. Most neonatal infants have a high hematocrit and adequate intravascular volume. Routine monitoring of weight, blood pressure, and electrolyte status can help manage appropriate fluid and electrolyte management.42 Other perioperative considerations include hypothermia and hypoglycemia. Neonates may experience a quick drop in their normal core body temperature due to evaporative heat loss and exposed body surfaces. This can be combated by wrapping all exposed surfaces intraoperatively that are not included in the operative field and using warmed intravenous solutions and agents for inhalation. Historical series have looked at early versus late closure of MMCs. Unrepaired infants who are fed but denied antibiotics have a survival rate of 40% to 60%, albeit with significant impairment. With the addition of antibiotics, morbidity and mortality will fall for those infants repaired within the first 24 hours. Delaying the initial closure may have some benefit in families where there are significant underlying comorbidities in socially complex situations to allow for better surgical counseling. The current standard of care is for closure within 72 hours of birth to reduce the risk of complication. Infants with MMCs are at greater risk than the general population of developing latex allergies, most likely due to latex immunoglobulin E antibiotics that develop throughout multiple operations and exposures.43 Martinez and colleagues reported a prevalence of latex allergy in spina bifida patients ranging between 10% and 73%.44 Clinical allergic reactions may be as high as 20% to 30% and may manifest with urticaria, bronchospasm, laryngeal edema, and systemic anaphylaxis.1 Allergy may be related to age, the number of operations, and perhaps and underlying genetic predisposition. In our institution, all patients with MMC are listed as having a latex sensitivity, and procedures should be conducted in a latex-free environment.45

Operative Technique for Open NTD Infants with MMCs undergo administration of general endotracheal anesthesia. When placed in a supine position, the midline spinal

A

B

defect is generally protected by placing padding surrounding the lesion to alleviate any direct pressure or contact. Peripheral access is generally achieved without the need for central access. The infant is then placed in the prone position with bolsters or gel rolls under the chest and along the anterior iliac crest. Patients with a high lesion and contractures within the hips or knees may require additional padding or higher bolsters to allow for adequate tension-free positioning. Intravenous antibiotics should be initiated at birth with broad central nervous system coverage and are continued during the immediate perioperative period. The operative table should be placed in slight Trendelenburg position to avoid excessive drainage of CSF. The ambient room temperature should be elevated to minimize the difference with core temperature. In addition, a warming device should be placed underneath the infant to maximize surface area contact. Intravenous and irrigating fluids should be warmed as well to help maintain core body temperature. When preparing and sterilizing the skin, the neural placode should be avoided. Alcohol or iodine can be caustic to the neural tissue but may be applied up to the junctional zone to help cleanse the skin. Draping should be generous because rotational flaps or relaxing incisions may sometimes be necessary for skin closure. The placode is first sharply dissected along the junctional zone to separate the skin from the perimeter of the open neural placode to avoid any subsequent inclusion dermoids (Fig. 54.3). Vascular input to the neural placode is important, and any traversing small feeding arteries or draining veins should be preserved if possible. Once free, the anterior projecting nerve roots can be seen exiting the neural placode and will appear to be completely released and tension free (Fig. 54.4). The rostral extent of the spinal cord may be seen entering the spinal canal. The lateral edges of the placode should be approximated with the use of a fine suture to reconstitute the neural tube. Once the placode is closed, the dura can be reflected from the underlying fascia (see Fig. 54.3). In premature infants, or in cases where the dura is exceedingly thin, this may be reflected down to the paraspinal musculature and fatty plane. Dural grafts are rarely necessary, because the fascial incision can be done laterally enough to avoid strangulating the placode with a standard running suture.

C

Fig. 54.3  Dorsal Nonannotated (A) and Annotated (B) View of the Neuroplacode at the Time of Operative Closure. The neuroplacode is seen as part of a fluid-filled sac containing cerebrospinal fluid. The sac is formed dorsally by the pia and disorganized neural tissue, which are fused to the epidermis at the zona epitheliosa. Following transection of this (C), the deeper layers of the dura are encountered, and these can be reflected to recreate the dural sac (*). Disorganized paraspinal muscles with investing fascia may be seen laterally, which can be incised to reflect additional closure.

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Chapter 54 |  Management of Myelomeningocele and Related Disorders of the Newborn   467

Fig. 54.4  Ventral Exiting Nerve Roots Through the Neuroforamina (*).

The lumbodorsal fascia may then be reflected over to create a myofascial flap closure over the dural closure to further reduce the incidence of CSF leak. Varying types of skin closures have been described, including vertical, horizontal, and a Z-plasty closure.46 A vertical closure most closely mimics traditional midline spinal incisions and minimizes wound complications if future surgery is necessary. Care should be taken to avoid undermining the skin too laterally to avoid compromising the perforating vascular supply to the skin from the underlying fascia. If aggressively undermined, the skin may become necrotic due to loss of these perforators and could cause further wound complications. Initial treatment of hydrocephalus is typically considered in a delayed fashion for several days to ensure there is no underlying infection. However, patients with considerable hydrocephalus evident at birth may require daily fontanelle taps to minimize wound leakage from the lumbar wound. CSF diversion at the time of repair has some advantages including avoiding a future procedure with intubating and decreasing the potential for CSF leakage. Miller and colleagues showed that placement of a ventriculoperitoneal shunt at the time of MMC closure compared with shunting in a delayed fashion reduced wound complications and spinal fluid leakage from 17% to 0%.47 However, with simultaneous placement there was a higher percentage of patients who developed a shunt malfunction (19%, compared with 8% in the delayed shunt treatment group).

Postoperative Management for Open NTD Postoperatively, infants are observed in the neonatal intensive care unit and should continue to follow routine best practices for critically ill newborns. Consideration for prior concerns including thermoregulation, cardiorespiratory monitoring, stress response, and fluid and electrolyte management should be maintained for all critically ill newborns. Specific postoperative concerns including pain management and nutritional status will be addressed in more detail. Infants will need to be monitored daily for the development of worsening hydrocephalus, infection, or concern for wound healing. Nutritional status can be challenging in some infants with MMC due to prolonged intubation or multiple procedures that may delay or

interrupt enteral feeding. Gastrointestinal function should be monitored to assess for paresis or delayed emptying due to anesthesia or pain medication by monitoring for abdominal distension or the passage of stool. In addition, brainstem dysfunction may manifest with swallowing difficulty or poor latch and/or suck reflexes, signaling a risk for aspiration. Babies might be noted to choke on liquids or have significant nasal regurgitation or vomiting. If there is a concern, a nasogastric tube can be inserted for gavage feeding, and this can be done in conjunction with a nutritionist and gastroenterologist. In infants who have ongoing surgical procedures for which gavage feeding may not be possible, parenteral nutrition should be considered. Postoperative positioning should avoid pressure points over any tenuous areas of closure over the spine. Some closures may necessitate a prolonged period of time in the prone position, and this would include nursing in a manner that reduces pressure overlying the skin closure. Wound infections may manifest with erythema, swelling, tenderness at the site, or purulent drainage. In such cases, wound debridement may be necessary with initiation of systemic broad-spectrum antibiotics.48 In their series, Charney and colleagues describe only 1% of infants receiving preoperative prophylactic antibiotics developing ventriculitis, compared with 19% of infants who did not receive antibiotics.38 Ventriculitis may relate to wound breakdown or CSF fistulation at the site of closure.48 Care should be taken to keep the operative site clean after repair, because infants with a neurogenic bladder and bowel may have a high rate of contamination of an incision that lies within the diaper itself.

Long-Term Outcomes Long term care for infants with MMC are best managed with a multidisciplinary clinic that can address the myriad of medical concerns that will surround this patient population. Neurosurgery, orthopedic, urologic, physical therapy, occupational therapy, and neurocognitive specialists may be helpful. The long-term prognosis of children with spina bifida varies widely based on the level of lesion and presence of associated anomalies. In general, more than 90% of infants will survive beyond infancy.25 Mortality within the first year is most commonly related to the Chiari malformation and underlying brainstem dysfunction as well as shunt malfunction or infections. Overall mortality has a significant range between 24% and 60%, typically highest within the first 5 years at 15% to 34% and decreasing to 9% to 26% after the 5-year mark.49,50

Neurosurgical Hydrocephalus Hydrocephalus and rates of ventricular shunting are somewhat variable throughout the literature, with rates ranging from 80% to 90% in some series to only 60% to 70%.51 There may be geographic variability as well as an increased tolerance for ventriculomegaly in more contemporary series. In addition, the advent of endoscopic third ventriculostomy as an alternative to shunting has been introduced during the past few decades and has shifted treatment paradigms for hydrocephalus. Success rates for patients with MMC may reach as high as 70% among eligible patients who meet the following criteria: evidence of noncommunicating hydrocephalus, minimal or no discernible subarachnoid space, and a third ventricle at least 4 mm in width.52 Shunted patients experience a shunt failure rate at 40%, 60%, and 85% at 1, 5, and 10 years after shunting, respectively. Shunt infection rates have fallen during the past three decades, but patients shunted before 6 months of age have a higher likelihood of

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468  Section 9  |  Neurological Disorders

malfunction and complication. Any neurologic clinical deterioration that is seen in children with MMC with shunted hydrocephalus may be attributed to the shunt. Therefore, evaluation of the neuraxis should always begin with a full assessment of the shunt. Characteristic cognitive strengths and weaknesses in children with open spina bifida are highly variable. Neurocognitive difficulties may stem from anomalies within the corpus callosum that typically are associated with reduced interhemispheric communication and difficulties integrating information in language, reading, and social domains. In general, procedural learning and attention functions involving sustained attention and persistence are generally preserved.53 General deficits in timing, attention, and movement can be seen as early as 6 months of age and can continue to affect infants over the course of their lifetime. Assembled processes, such as learning to construct and assimilate information, can be challenging. In contrast, children often have greater strengths with associative processing, such as associative and procedural learning.54 The severity of the malformation and hydrocephalus can lead to significant variability within these findings.

Chiari II Malformation Up to 70% to 80% of infants with MMC will have a radiographic Chiari II malformation, with herniation of the cerebellar vermis, brainstem, and fourth ventricle. Typically infants will present with lower cranial neuropathies, disordered eye movements, swallowing dysfunction, or disordered breathing compared with the more commonly seen Chiari I malformation that may manifest with occipital, exertional headaches.55 Although Chiari malformation is commonly seen radiographically, most children are asymptomatic and only one-third of patients will require surgical intervention due to progressive symptoms.55–59 In patients who present with progressive failure to thrive, clinicians should have a low threshold to evaluate for swallowing dysfunction. Other concerning signs may include disordered breathing, central or obstructive apnea as seen on a sleep study, inspiratory stridor, vocal cord paralysis, and a hoarse, weak, or high-pitched cry. Patients who have stridor and apnea at the time of delivery have a poorer outcome and higher overall mortality rate than patients who develop these symptoms in a more delayed fashion.60 Older children may present with such signs as spasticity or weakness of the extremities, headaches and neck pain, cerebellar dysfunction, oculomotor dysfunction, and scoliosis.57 In patients in whom there is concern for a symptomatic Chiari malformation, care should first assess whether there is any underlying hydrocephalus or shunt malfunction. If there is any concern, shunt insertion or revision should be considered prior to decompression of the Chiari malformation. Additional workup should include a formal swallowing study, direct laryngoscopy to evaluate vocal cord paresis, and pulmonary studies such as a sleep study to evaluate the degree of dysfunction of apnea. Treatment hinges on the severity and on the age of presentation. Some series argue against treatment of a Chiari malformation in infants due to a historically high mortality rate that is no better than the natural history of the underlying disease process.57,61 However, other studies have shown improvement in outcomes for infants treated early and aggressively. In general, newborns with underlying brainstem dysfunction often may require tracheostomy and gastrostomy with Nissen fundoplication. Neonates with less brainstem involvement and older children have a lower rate of surgical morbidity and mortality as well as improved overall outcomes.62,63

Tethered Cord Syndrome Clinical neurologic deterioration has been described in children with MMC, with up to one-third of patients requiring surgical untethering in childhood.64 Tethering is thought to cause symptoms due to

ongoing stretching of the spinal cord that leads to an overall decreased blood flow. This then shifts to anaerobic metabolism with reduced glucose metabolism and mitochondrial failure that can lead to progressive neuronal loss with time. Increased pull occurs during periods of rapid growth, and this can lead to additional stretch of an already compromised spinal cord.65,66 Releasing this tension can result in stability and some improvement in neurologic function, urologic function, and orthopedic deformities. All patients with an MMC have some degree of radiographic tethering. Therefore, tethered cord syndrome is based on the development or progression of clinical symptoms. Patients may manifest with axial back pain, radicular pain, motor deterioration or worsening spasticity, sensory changes, worsening bowel or bladder function, and progressive orthopedic deformities such as pes cavus, equinovarus, hip dislocations, or scoliosis.

Urologic Urologic anomalies are ubiquitous with spina bifida and do not always correlate with the level of spinal involvement. Typical urodynamic findings include decreased bladder capacity, decreased compliance, detrusor overactivity, detrusor-sphincter dyssynergia, bladder outlet obstruction, and complete denervation. Goals of management include ensuring safe bladder storage pressures and adequate bladder emptying at low pressures. Early recognition and management are critical to preventing progressive deterioration; however, the timing and interpretation of urodynamic studies or initiation of clean intermittent catheterization are controversial.67 A thorough urologic evaluation includes a renal and bladder ultrasound, voiding cystourethrography, functional imaging such as a radionuclide scan, and urodynamics, once feasible. These help establish a baseline appearance and function of the upper and lower urinary tracts for future comparison. Infants should undergo evaluation with renal and bladder ultrasonography early to determine the postvoid residual urine. This additionally will help detect early signs of upper tract deterioration to help prevent additional renal damage. Renal and bladder ultrasound can help identify any worrisome findings such as hydronephrosis, ureteral dilation, renal size discrepancy, or bladder wall thickening and can help determine the need for antibiotic prophylaxis. Early management is controversial. Some centers perform expectant management, where patients are monitored clinically and interventions such as catheterization are only performed if there is evidence of clinical deterioration. Other centers follow a more proactive approach and initiate catheterization early. Outcomes have been largely mixed in the literature, and there is no clear consensus. Lifetime goals include preserving renal function and achieving continence. This may require a combination of catheterization, anticholinergics, intradetrusor botulinum toxin A injections, bladder neck bulking agents, or reconstruction with bladder augmentation and/ or a bladder neck procedure. As children grow, preventing bladder perforation, chronic renal disease, and kidney stone disease are important clinical factors.68 Neurogenic bowel dysfunction is also a common comorbidity and has been associated with a significant decrease in quality-of-life measures. Psychosocial metrics such as depression, discrimination of peers, decreased school attendance, and lower rates of employment have all been linked to poor management of neurogenic bowel incontinence.69–71 Up to 80% of patients with MMC will require a bowel management program for constipation or fecal continence.72 Interventions to help achieve some degree of control include oral medications, digital rectal stimulation through suppositories or enemas, large-volume enemas, Peristeen, antegrade enemas, or pouched fecal

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Chapter 54 |  Management of Myelomeningocele and Related Disorders of the Newborn   469

diversion. Overall fecal continence remains low at 30% to 65% despite interventions73 but remains an important goal given the hope to maintain healthy self-esteem and improved quality of life.

Orthopedic Scoliosis, or a curvature of the spine, may be seen in up to 90% of children with MMC and is more prevalent in patients with thoracic or upper lumbar lesions.74–76 In neuromuscular cases of scoliosis, paravertebral muscle weakness as well as sensorimotor imbalance and muscle contractures may all contribute to spinal deformity progression. In patients with midlumbar-level lesions, with a curvature less than 45 degrees, curve stabilization may be obtained through untethering the spinal cord. Curvatures that present at 45 or 55 degrees are less likely to respond to untethering, and spinal deformity correction should be considered to obtain the best possible stabilization. Patients with spinal deformities beyond 80 or 90 degrees may develop pulmonary or cardiac compromise, and surgical morbidity is less in more modest spinal curvatures. Other orthopedic concerns include hip or pelvic and severe foot deformities. Hip deformities or instability may be the result of muscle imbalance and paralysis around the hip joint. Approximately up to 50% of infants may develop instability or dislocation by 1 year of age. This results from unopposed action of the flexor and adductor muscles given paralysis of hip extensor and abductor muscles. Ultrasound can be used to evaluate the infant hip because the acetabulum and femoral head are cartilaginous. After 1 year of age, this can be

followed with x-rays. Hip anomalies can be further exacerbated by hip contractures and subluxation and dislocation. If left untreated, pelvic obliquity can result and can drive sitting imbalance and scoliosis formation. Knee, tibia, and fibula deformities can lead to rotational issues that may make fitting of orthotics more challenging. These should be assessed with x-rays or magnetic resonance imaging when indicated. Congenital and acquired foot deformities are common, occurring in 80% to 95% of infants. Intrauterine paralysis is the major cause of congenital deformities, with malposition and intrauterine pressure leading to additional abnormalities. Talipes equinovarus, or club foot, is also commonly seen due to muscle paralysis or structural anomalies. Initial treatment consists of serial casting as early as possible, and surgical correction can be performed after a year of life if indicated. In conclusion, NTDs remain the most common congenital birth defect of the central nervous system that results in lifelong morbidity from local nerve damage and the secondary effects of hydrocephalus from the Chiari II malformation. Due to the multisystem impacts of the condition, multidisciplinary care beginning during pregnancy allows for prenatal characterization of the lesion, assessment of ventriculomegaly, consideration of maternal fetal surgery for selected cases, and initial pediatric consultations. Postnatal management involves early surgical closure for children unrepaired at birth and management of associated hydrocephalus and urologic and orthopedic sequelae. Goals of treatment are targeted to optimize baseline function and enhance quality of life.

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Chapter 54 |  Management of Myelomeningocele and Related Disorders of the Newborn   469.e1

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25. McLone DG. Continuing concepts in the management of spina bifida. Pediatr Neurosurg. 1992;18(5–6):254–256. 26. Lullo B, Mueske N, Diamant C, Van Speybroeck A, Ryan D, Wren T. Predictors of walking activity in children and adolescents with myelomeningocele. Arch Phys Med Rehabil. 2020;101(3):450–456. 27. Carreras E, Maroto A, Illescas T, et al. Prenatal ultrasound evaluation of segmental level of neurological lesion in fetuses with myelomeningocele: development of a new technique. Ultrasound Obstet Gynecol. 2016; 47(2):162–167. 28. American College of Obstetricians and Gynecologists. ACOG committee opinion no. 550: maternal-fetal surgery for myelomeningocele. Obstet Gynecol. 2013;121(1):218–219. 29. Gotha L, Pruthi V, Abbasi N, et al. Fetal spina bifida: what we tell the parents. Prenat Diagn. 2020;40(12):1499–1507. 30. Tolcher MC, Shazly SA, Shamshirsaz AA, et al. Neurological outcomes by mode of delivery for fetuses with open neural tube defects: a systematic review and meta-analysis. BJOG. 2019;126(3):322–327. 31. Benjamin RH, Lopez A, Mitchell LE, et al. Mortality by mode of delivery among infants with spina bifida in Texas. Birth Defects Res. 2019;111(19): 1543–1550. 32. Practice bulletin no. 187: neural tube defects. Obstet Gynecol. 2017;130(6):e279–e290. 33. Adzick NS, Thom EA, Spong CY, et al. MOMS Investigators. A randomized trial of prenatal versus postnatal repair of myelomeningocele. N Engl J Med. 2011;364(11):993–1004. 34. Johnson MP, Bennett KA, Rand L, et al. Management of Myelomeningocele Study Investigators. The Management of Myelomeningocele Study: obstetrical outcomes and risk factors for obstetrical complications following prenatal surgery. Am J Obstet Gynecol. 2016;215(6):778.e1–778.e9. 35. Goodnight WH, Bahtiyar O, Bennett KA, et al. fMMC consortium sponsored by NAFTNet. Subsequent pregnancy outcomes after open maternal-fetal surgery for myelomeningocele. Am J Obstet Gynecol. 2019;220(5):494.e1–494.e7. 36. Sanz Cortes M, Chmait RH, Lapa DA, et al. Experience of 300 cases of prenatal fetoscopic open spina bifida repair: report of the international fetoscopic neural tube defect repair consortium. Am J Obstet Gynecol. 2021; S0002-9378(21):00612–00618. 37. American College of Obstetricians and Gynecologists. ACOG committee opinion no. 550: maternal-fetal surgery for myelomeningocele. Obstet Gynecol. 2013;121(1):218–219. 38. Charney EB, Melchionni JB, Antonucci DL. Ventriculitis in newborns with myelomeningocele. Am J Dis Child. 1991;145(3):287–290. 39. Arslan M, Eseoglu M, Gudu BO, et al. Comparison of simultaneous shunting to delayed shunting in infants with myelomeningocele in terms of shunt infection rate. Turk Neurosurg. 2011;21:397–402. 40. Luthy DA, Wardinsky T, Shurtleff DB, et al. Cesarean section before the onset of labor and subsequent motor function in infants with meningomyelocele diagnosed antenatally. N Engl J Med. 1991;324(10):662–666. 41. Nyberg DA, Mack LA, Hirsch J, Pagon RO, Shepard TH. Fetal hydrocephalus: sonographic detection and clinical significance of associated anomalies. Radiology. 1987;163(1):187–191. 42. Katz AL, Wolfson P. General surgical considerations. In: Spitzer AR, ed. Intensive Care of the Fetus and Neonatae. Philadelphia: Elsevier Mosby; 2005:1353–1368. 43. Rendelli C, Nucera E, Ausili E, et al. Latex sensitization and allergy in children with myelomeningocele. Childs Nerv Syst. 2006;22(1):28–32. 44. Martinez JF, Molto MA, Pagan JA. Latex allergy in patients with spina bifida and treatment. Neurocirugia. 2001;12(1):36–42. 45. Meneses V, Parenti S, Burns H, Adams R. Latex allergy guidelines for people with spina bifida. J Pediatr Rehabil Med. 2020;13(4):601–609. 46. Lien SC1, Maher CO, Garton HJ, Kasten SJ, Muraszko KM, Buchman SR. Local and regional flap closure in myelomeningocele repair: a 15-year review. Childs Nerv Syst. 2010;26(8):1091–1095. 47. Miller PD, Pollack IF, Pang D, Albright AL. Comparison of simultaneous versus delayed ventriculoperitoneal shunt insertion in children undergoing myelomeningocele repair. J Child Neurol. 1996;11(5):370–372. 48. Punt J. Surgical management of neural tube defects. In: Levene MI, Chervenak FA, Whittle MJ, eds. Fetal and Neonatal Neurology and Neurosurgery. New York: Churchill Livingstone; 2001:753–773.

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469.e2  Section 9  |  Neurological Disorders 49. Oakeshott P, Hunt GM, Poulton A, Reid F. Expectation of life and unexpected death in open spina bifida: a 40-year complete, non-selective, longitudinal cohort study. Dev Med Child Neurol. 2010;52(8):749–753. 50. Bowman RM, McLone DG, Grant JA, Tomita T, Ito JA. Spina bifida outcome: a 25-year prospective. Pediatr Neurosurg. 2001;34(3):114–120. 51. Swank M, Dias L. Myelomeningocele: a review of the orthopaedic aspects of 206 patients treated from birth with no selection criteria. Dev Med Child Neurol. 1992;34:1047–1052. 52. Teo C, Jones R. Management of hydrocephalus by endoscopic third ventriculostomy in patients with myelomeningocele. Pediatr Neurosurg. 1996;25:57–63, discussion 63. 53. Treble-Barna A, Kulesz PA, Dennis M, Fletcher JM. Covert orienting in three etiologies of congenital hydrocephalus: the effect of midbrain and posterior fossa dysmorphology. J Int Neuropsychol Soc. 2014;20(3): 268–277. 54. Taylor HB, Barnes MA, Landry SH, Swank P, Fletcher JM, Huang F. Motor contingency learning and infants with spina bifida. J Int Neuropsychol Soc. 2013;19(2):206–215. 55. Pollack IF, Pang D, Kocoshis S, Putnam P. Neurogenic dysphagia resulting from Chiari malformations. Neurosurgery. 1992;30:709–719. 56. Dyste GN, Menezes AH, VanGilder JC. Symptomatic Chiari malformations. An analysis of presentation, management, and long-term outcome. J Neurosurg. 1989;71:159–168. 57. Hoffman HJ, Hendrick EB, Humphreys RP. Manifestations and management of Arnold-Chiari malformation in patients with myelomeningocele. Childs Brain. 1975;1:255–259. 58. Park TS, Hoffman HJ, Hendrick EB, Humphreys RP. Experience with surgical decompression of the Arnold-Chiari malformation in young infants with myelomeningocele. Neurosurgery. 1983;13:147–152. 59. Holinger PC, Holinger LD, Reichert TJ, Holinger PH. Respiratory obstruction and apnea in infants with bilateral abductor vocal cord paralysis, meningomyelocele, hydrocephalus, and Arnold-Chiari malformation. J Pediatr. 1978;92:368–373. 60. Ocal E, Irwin B, Cochrane D, Singhal A, Steinbok P. Stridor at birth predicts poor outcome in neonates with myelomeningocele. Childs Nerv Syst. 2012;28:265–271. 61. Bell WO, Charney EB, Bruce DA, Sutton LN, Schut L. Symptomatic ArnoldChiari malformation: review of experience with 22 cases. J Neurosurg. 1987;66:812–816. 62. Pollack IF, Pang D, Albright AL, Krieger D. Outcome following hindbrain decompression of symptomatic Chiari malformations in children

previously treated with myelomeningocele closure and shunts. J Neurosurg. 1992;77:881–888. 63. Pollack IF, Kinnunen D, Albright AL. The effect of early craniocervical decompression on functional outcome in neonates and young infants with myelodysplasia and symptomatic Chiari II malformations: results from a prospective series. Neurosurgery. 1996;38:703–710, discussion 710. 64. Bowman RM, Mohan A, Ito J, Seibly JM, McLone DG. Tethered cord release: a long-term study in 114 patients. J Neurosurg Pediatr. 2009;3:181–187. 65. Yamada S, Zinke DE, Sanders D. Pathophysiology of “tethered cord syndrome.” J Neurosurg. 1981;54:494–503. 66. Yamada S, Iacono RP, Yamada BS. Pathophysiology of the tethered spinal cord. In: Yamada S, ed. Tethered Cord Syndrome. Park Ridge, IL: American Association of Neurological Surgeons; 1996:29–48. 67. Cardona-Grau D, Chiang G. Evaluation and lifetime management of the urinary tract in patients with myelomeningocele. Urol Clin North Am. 2017;44(3):391–401. 68. Le HK, Cardona Grau D, Chiang G. Evaluation and long term management of neurogenic bladder in spinal dysraphism. Neoreviews. 2019;20(12):e711– e724. doi:10.1542/neo.20-12-e711. 69. Krogh K, Christensen P, Sabroe S, Lauberg S. Neurogenic bowel dysfunction score. Spinal Cord. 2006;44(10):625–631. 70. Szymanski KM, Cain MP, Whittam B, Kaefer M, Rink RC, Misseri R. All incontinence is not created equal: impact of urinary and fecal incontinence on quality of life in adults with spina bifida. J Urol. 2017;197(3 Pt 2):885–891. 71. Wiener JS, Suson KD, Castillo J, et al. Bowel management and continence in adults with spina bifida: results from the national spina bifida patient registry 2009–15. J Pediatr Rehabil Med. 2017;10(3–4):335–343. 72. Kelly MS, Wiener JS, Liu T, et al. Neurogenic bowel treatments and continence outcomes in children and adults with myelomeningocele. J Pediatr Rehabil Med. 2020;13(4):685–693. 73. Sawin KJ, Liu T, Ward E, et al. The national spina bifida patient registry: profile of a large cohort of participants from the first 10 clinics. J Pediatr. 2015;166(2):444–450.e1. 74. Piggott H. The natural history of scoliosis in myelodysplasia. J Bone Joint Surg Br. 1980;62(B):54–58. 75. Shurtleff DB, Goiney R, Gordon LH, Livermore N. Myelodysplasia: the natural history of kyphosis and scoliosis. A preliminary report. Dev Med Child Neurol Suppl. 1976;37:126–133. 76. Reigel DH, Tchernoukha K, Bazmi B, Kortyna R, Rotenstein D. Change in spinal curvature following release of tethered spinal cord associated with spina bifida. Pediatr Neurosurg. 1994;20:30–42.

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Section 9 CHAPTER

55

Treating Neonatal Abstinence Syndrome in the Newborn

Jessie R. Maxwell, Sandra Brooks, Tamorah R. Lewis, Jessie Newville, Gabrielle McLemore, Estelle B. Gauda

KEY POINTS 1. In the United States an infant is born every 15 minutes who will develop symptoms of neonatal abstinence syndrome (NAS); each year, about 32,000 infants are estimated to develop NAS. 2. The exposure of the developing fetus to stimulants, alcohol, cannabinoids, and antidepressant medication can all have a negative impact. To refer specifically to

the impact of opioids, the term neonatal opioid withdrawal syndrome (NOWS) is preferred. 3. We have summarized the information on the impact of transplacentally transferred opiates on the developing fetus. Various therapeutic options that are currently available for the management of NOWS or are under evaluation have been discussed.

Introduction In the United States an infant is born with neonatal abstinence syndrome (NAS) every 15 minutes, with an estimated 32,000 babies with NAS born every year.1 This estimates only the infants with symptomatic withdrawal after prenatal opioid exposure. Additional use of substances during pregnancy, such as stimulants, alcohol, cannabinoids, and antidepressant medication, can all result in negatively impacting the developing fetus. Thus it is paramount to understand the mechanism of how each substance can result in exposure to the fetus and if any known therapies are effective to mitigate these changes.

Opioids Opioids are a class of drugs that are usually used to reduce pain. This can include prescription medication, such as oxycodone, hydrocodone, fentanyl, morphine, and methadone, as well as illicit substances such as heroin. Use of these drugs by pregnant women can result in adverse outcomes such as stillbirth or preterm birth, NAS, and birth defects. From 1999 to 2014, across the United States, the rates of opioid use disorder at the time of delivery more than quadrupled.2 Infants exposed to opioids throughout pregnancy develop a dependence on the drug, with a resultant withdrawal once the drug is no longer present.3 The withdrawal was previously referred to as NAS, which is now more specifically termed neonatal opioid withdrawal syndrome (NOWS).4 Opioids can cross the placenta, thus resulting in exposure to the fetus. The following describes placental transport of opioids, the resultant symptoms in infants after birth, current therapeutic options, and the resultant impact on development.

Mechanism of In Utero Exposure One puzzling aspect of neonatal opiate withdrawal is the lack of association between the maternal opiate dose during pregnancy and the incidence or severity of NOWS. A recent systematic review confirms the results of many smaller studies, namely that there is no currently known relationship between the maternal dose of methadone and the

4. The effects of transplacentally transferred pharmacologic stimulants such as cocaine, methamphetamine, and prescription drugs; herbal stimulants such as kratom tea; alcohol; cannabinoids; and antidepressant medications have been described in separate sections.

incidence or severity of NOWS.5 This lack of association is likely because the current thinking on the maternal–fetal–neonatal transfer and effect of opiate medications is oversimplified and does not account for the potential impact of drug metabolism and drug target variability. This drug metabolism and drug target variability is influenced by maternal and fetal genetics as well as the stage of gestation and fetal development. There have been some important efforts to understand the pathogenesis of NOWS (Fig. 55.1), but we still do not have all the answers. Many factors can affect the amount of free drug in the maternal circulation available for transplacental fetal transfer at any given time. It is known that maternal drug metabolism changes through different trimesters and that environmental factors such as maternal comedication and cigarette use can alter rates of drug metabolism and placental transport.6,7 In addition, there is known genetic variation in opiate metabolism.8–10 The efficiency of placental metabolizing enzymes and placental opiate transport proteins such as multidrug resistant protein 1 (MDR1) and breast cancer resistance protein can dictate how much drug reaches the fetus for any specific mother-infant pair.11–13 MDR1 is a known placental transporter for methadone. Using a single layer of placental cells in a dual perfusion model, Nanovskaya et al. showed that methadone transfer to the fetal circuit was increased by 30% by different MDR1 inhibitors.12 The authors concluded based on this experiment that the concentration of methadone in the fetal circulation is likely affected by the expression and activity of placental MDR1. Data from experiments in an ex vivo placental model provides evidence that buprenorphine transport across the placenta is not mediated by MDR114 but rather via passive diffusion. Buprenorphine crosses placental cells into the fetal circuit to a lesser degree than methadone, with less than 10% of initial maternal concentrations detected on the fetal side of the circuit after a 4-hour equilibration.13 This decreased transfer of buprenorphine is thought to be secondary to its highly lipophilic nature and significant tissue accumulation within the placenta compared with both the maternal and fetal compartments. The fetal and neonatal blood-brain barrier also contribute to the risk of developing NOWS. On postmortem samples from gestational age 20 weeks to postmenstrual age 3 months, it was found that p-glycoprotein expression is very limited in the fetal and neonatal period compared with older infants and adults.15 This is important

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Chapter 55 |  Treating Neonatal Abstinence Syndrome in the Newborn   471

A Dopamine  Hyperirritability Anxiety Delivery  Absent transmission of opioids via placenta  Adenyl cyclase activated  cAMP  Transcription factors  Release of neurotransmitters

Noradrenaline Hyperthermia Hypertension Tremors Tachycardia





Serotonin  Sleep deprivation Sleep fragmentation

Prenatal exposure to drugs + other risk factors

B

Physiologic and/or behavioral dysregulation

Acetylcholine  Diarrhoea Vomiting Yawning Sneezing Sweating

Corticotrophin  Hyperphagia

State control/Attention

Autonomic control

Motor and tone control

CNS Hyperirritability

GI Dysfunction

Sensory processing

Respiratory symptoms

Autonomic Instability

Fig. 55.1  Pathophysiology of Neonatal Abstinence Syndrome (NAS), Which May Be More Appropriately Termed Neonatal Opiate Withdrawal Syndrome (NOWS). (A) At a mechanistic level, the clinical manifestations can be understood in terms of altered levels of different neurotransmitters; (B) in clinical assessment, NOWS is marked by dysregulation in four domains of functioning. (B, Reproduced with modifications from Jansson and Patrick. Pediatric Clinics of North America. 2019;66:353–367.)

because p-glycoprotein plays a critical role in efflux of opiates from the central nervous system (CNS) back into the systemic circulation. There are currently no studies in humans to elucidate the extent of methadone or buprenorphine accumulation in the CNS.

Neonatal Opioid Withdrawal Syndrome Symptoms Chronic in utero opiate exposure leads to activation of the fetal brain μ-opioid receptor. This leads to intracellular adaptations, including decreased adenylyl cyclase activity and decreased cyclic adenosine 3ʹ,5ʹ-cyclic monophosphate (cAMP) and release of excitatory neurotransmitters. After umbilical cord ligation at birth, there is an abrupt cessation to opiate exposure, which, as the newborn metabolizes and clears the maternal opiate, leads to an abrupt increase in adenylyl cyclase activity and downstream effects (Fig. 55.2).3 This leads to a large increase in central sympathetic outflow, resulting in the symptoms of newborn opiate withdrawal. These symptoms include autonomic signs such as diarrhea, emesis, yawning, sneezing, and sweating. They also include CNS excitatory signs such as hyperirritability, tremors, hyperthermia, tachycardia, and poor sleep (Fig. 55.3). In extreme and untreated cases of newborn opiate withdrawal, the neuroexcitatory neurotransmitter milieu of epinephrine and norepinephrine can lead to clinical seizures. The duration of opiate withdrawal symptoms is highly variable and depends in part on which drugs were part of in utero exposure (Table 55.1).3 NOWS as a result of methadone or buprenorphine tends to last longer than heroin or short-acting prescription drugs, but polypharmacy and multiple in utero exposures are common, and the way these modify NOWS severity and duration are poorly understood. The treatment of NOWS symptoms includes opiate replacement and slow weaning of postnatal treatment, providing the deranged CNS pathways time to reset and return to normal. Current research about optimal NOWS therapy seeks to find a balance between control of symptoms and avoiding prolonged and excessive opiate exposure.

Treatment of Neonatal Opioid Withdrawal Syndrome

the particular clinical unit and the local patient population (Fig. 55.4). There is universal agreement that nonpharmacologic treatments should be implemented prior to use of medications to alleviate NOWS. A simple yet critically important first step is to maintain the mother-infant dyad if possible. Many infants are moved to a newborn intensive care unit, which will then separate the pair. A meta-analysis of 6 studies and 549 patients showed a decrease in hospitalization by 10 days when rooming-in, or maintaining the mother-infant dyad, occurred.16 These infants had a reduction in the use of pharmacotherapy by 63%.16 Additional environmental measures such as minimizing stimulation through dim lighting and optimizing comfort through swaddling should be considered standard treatment for this patient population. Observing the infant’s response to environmental stimuli is critical to determine the best interventions to minimize overstimulation. Various signs of stress in the infant can be used to identify a stimulus as stressful, such as hiccups, color change (mottling, perioral cyanosis), excess gas, and even changes in breathing patterns.17 If a woman is prescribed methadone or buprenorphine, the levels measured in breast milk have been observed to be low.18 This does not seem to be impacted by the maternal dose, and thus breastfeeding is considered safe.18 It has also been observed that breastfeeding can result in a shorter hospital stay and decreased need for pharmacologic treatment. Breastfeeding should be encouraged, although a recent review found that many women on opioid maintenance therapy did not breastfeed.19 There is discussion that it may be related to schedule demands on the woman; however, societal stigma may result in a lack of patient support, even in hospitals with the Baby-Friendly designation.19

Mechanism of Action for Pharmacologic Treatments Opiates are the mainstay of pharmacologic therapy for NOWS, although other nonopiate drugs such as clonidine show great promise as either monotherapy or adjunct therapy. Pharmacologic therapy is indicated for infants who fail nonpharmacologic interventions and display significant and persistent signs of opiate withdrawal, as quantified by a validated NOWS scoring tool.

Nonpharmacologic Treatments

Morphine and Methadone

The most optimum treatment of NOWS is still a matter of debate. However, most clinicians agree on the need for adopting one standardized protocol and following this with close follow-up to optimize it for

Morphine and methadone are the most commonly used opiate to treat NOWS, but there are increasing data about buprenorphine as a primary modality.20 Morphine is a short-acting μ-opiate receptor

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472  Section 9  |  Neurological Disorders

A

B

Fig. 55.2  (A) A schematic illustration of cellular signaling in an opioid-sensitive neuron under normal conditions that are altered under conditions of opioid dependence and withdrawal. Chronically stimulated μ-opioid receptors lead to reduced responsiveness to opioid agonists and a g-protein–regulated decrease in calcium ion concentration. Importantly, chronic stimulation results in overactivation of g-protein–coupled receptors, suppression of adenylyl cyclase activity, and ultimately, reduced cyclic adenosine monophosphate (cAMP) concentrations. These opioid-induced effects produce an adaptive up-regulation of adenylyl cyclase machinery and superactivation of adenylyl cyclase under conditions of withdrawal, leading to elevated cAMP and phospho-cAMP-response element binding protein (CREB). (B) Step-by-step summary of molecular events that lead to altered production and release of various neurotransmitters responsible for the acute symptoms of opioid withdrawal. (Adapted from Kocherlakota P. Neonatal abstinence syndrome. Pediatrics. 2014;134:e547–e561.)

Sensory Processing Hypersensitivity/hyposensitivity Visual Auditory Touch Movement

Motor and Tone Control Hypertonicity Tremors Increased movements Poorly controlled movements Seizures

State Control and Attention Rapid/abrupt state transition Poor state definition Absence of states Irritability Gaze aversion/staring

Autonomic Control Patterns of respiration Hiccups Gagging Skin color changes Bowel movements/gas Vomiting/spitting up Fever

Fig. 55.3  Signs of Neonatal Opiate Withdrawal Syndrome Expression in the Four Major Domains of Functioning. Each domain can influence expression in other domains. (Reproduced with modifications from Jansson and Patrick. Pediatric Clinics of North America. 2019;66:353–367.)

agonist. Because of the short half-life of morphine, the best outcomes have been demonstrated when morphine doses are given no longer than 4 hours apart (generally with feedings). Methadone is a long-acting μ-opiate receptor agonist. The longer half-life of methadone provides less of a flux between peak and trough levels while also providing ease of administration at less frequent intervals. However, the long half-life necessitates waiting 48 to 72 hours to see the full effect of dosing changes; thus there is concern that it is less “easily titratable” than short-acting morphine. Multiple studies have evaluated the differences in treating with morphine or methadone in an attempt to determine superiority. One such meta-analysis reviewed five studies and found no significant difference in opioid treatment days, length of hospital stay, and duration of treatment between morphine or methadone.21

Buprenorphine Buprenorphine is emerging as a safer and more efficient drug for adult detoxification and maintenance programs and has been studied during pregnancy as an alternative to methadone. Overall, it is showing great promise as a therapeutic agent for the treatment of NAS. Buprenorphine is a long-acting partial μ-opioid receptor agonist. At the molecular level, there are three well-described opioid receptors (μ-opioid receptor, δ-opioid receptor, and κ-opioid receptor). Morphine and methadone are among the opioids that act as agonists

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Chapter 55 |  Treating Neonatal Abstinence Syndrome in the Newborn   473

Table 55.1  The Onset of Withdrawal Symptoms, Frequency of Withdrawal Occurrence After Exposure, and Duration of Withdrawal Caused by Various Substances Onset, Duration, and Frequency of NAS Opioids

Stimulants Depressants SSRIs

Onset (h)

Frequency (%)

Duration (d)

Heroin

24–48

40–80

8–10

Methadone

48–72

13–94

Up to 30+

Buprenorphine

36–60

22–67

Up to 28+

Prescription medication

36–72

5–20

10–30

Kratom tea (high dose)

6–33

Unknown

5–12+

Methamphetamine

24

2–49

7–10

Cocaine

48–72

6

Up to 7

THC

24–72

Unknown

7–30

Alcohol

3–12

2–5

Up to 3

Prescription medication

24–48

20–30

2–6

NAS, Neonatal abstinence syndrome; SSRI, selective serotonin reuptake inhibitor; THC, Δ9-tetrahydrocannabinol. Adapted from Kocherlakota P. Neonatal abstinence syndrome. Pediatrics. 2014;134:e547–e561.

at each of these receptors, but buprenorphine differs because it has an antagonistic effect at the κ-opioid receptor.22 This molecular characteristic is thought to allow for less sedation and less respiratory depression among buprenorphine users. The effect on neonates of the maternal use of buprenorphine during pregnancy has been well studied. A double-blind, double-dummy, flexible dosing, randomized controlled trial found that infants exposed to prenatal buprenorphine versus methadone had required significantly less morphine therapy (mean dose, 1.1 mg versus 10.4 mg; P < .0091), had a significantly shorter hospital stay (10.0 days versus 17.5 days; P < .0091), and had a significantly shorter duration of treatment for NAS (4.1 days versus 9.9 days; P < .003125) with no difference in neonatal or maternal adverse outcomes.23 A recent retrospective study showed similar results with less use of phenobarbital as adjunct therapy in infants exposed to buprenorphine prenatally.24 The first published use of buprenorphine for the treatment of NAS dates back to 2008 when Kraft and

colleagues randomized 13 infants to receive sublingual buprenorphine (initial dose of 13.2 mcg/kg/day divided in three doses) and compared them to the same number of infants who were managed with their standard-of-care oral opium solution. There were no adverse effects noted in the buprenorphine-treated group. The mean length of treatment and the overall mean length of hospital stay were shorter in this group as well (mean length of treatment of 22 days compared with 32 days and overall mean length of hospital stay of 38 days compared with 27 days).25 Additional studies have compared buprenorphine with other commonly used drugs in the treatment of NAS. A single-site, randomized, open-label trial was published in 2011 and compared buprenorphine at a dose of 15.9 mcg/kg/day given in three divided doses to morphine at a dose of 0.4 mg/kg/day in six divided doses. There were 12 infants in each arm, and again the results were in favor of treatment with buprenorphine. Infants had a 40% reduction in length of treatment (23 days versus 38 days) and a 24%

Monitor clinical manifestations of NOWS every 3 hours “Eat, Sleep, Console”

“Yes” to any ESC item or 3 for Consoling Support Needed

Is this the 2nd “Yes” in a row for the same ESC item or the 2nd “3” in a row for consoling support needed

No Formal Parent/Caregiver Huddle Indicated Continue to optimize non-pharmacological interventions Continue ESC assessment

Responses to ESC are “no” or Consoling Support 75%) present with bilateral disease, although the severity may be asymmetric.30 About 15% of cases present with a classical triad of photophobia, epiphora (tearing), and blepharospasm (frequent blinking). More frequently, the condition is seen as a hazy or cloudy cornea and buphthalmos (see Fig. 65.2). “Buphthalmos,” or eye enlargement, is derived from the Greek word bous (ox or cow) due to the resemblance of eyes in infants with high IOP to large bovine eyes. CYP1B1 mutation in the GLC3A locus and LTBP2 mutation in the GLC3C locus have been linked to PCG.31 Secondary glaucoma with anterior segment dysgenesis can occur in up to 50% of those with aniridia, Axenfeld-Rieger syndrome, and Peters’ anomaly and 15% of those with posterior polymorphous dystrophy.28 Glaucoma has been linked with abnormalities in many genes, including PITX2, PITX3, FOXC1, FOXE3, PAX6, LMX1B, and MAF.31 Aniridia refers to bilateral congenital hypoplasia of the iris and can present with high IOP in infants (Fig. 65.3). Many infants may also have microcornea, cataracts, angle abnormalities,32 and foveal and optic nerve hypoplasia.33 Careful systemic and genetic evaluation is necessary even in sporadic cases; there are known associations with PAX6 mutations and Wilms tumor, genitourinary abnormalities, and mental retardation (WAGR syndrome).34

RENAL

Postoperative Management After surgery, an eye patch and/or shield is placed over the operated eye for 24 hours, and close monitoring is needed. The infant needs to wear corrective lenses and adhere to amblyopia therapy to lower the risk of later strabismus.20,21 Please see the online version for details.

Complications and Long-Term Prognosis Posterior capsular opacification, glaucoma, intraocular hemorrhage, inflammation, infectious endophthalmitis, and retinal detachment can occur after cataract surgery. Please see the online version for details.5,11,12,22–27

MUSCULOSKELETAL

DERMATOLOGIC

OTHER

CHROMOSOMAL ABNORMALITIES

Trisomy 13

Cataracts, glaucoma

Trisomy 18

Cataracts

Trisomy 21

Cataracts

Turner syndrome

Glaucoma

PSC, Posterior subcapsular cataract.

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Chapter 65 |  Cataract and Glaucoma   573

A

B

C

Fig. 65.2  (A and B) Bilateral congenital glaucoma in an infant with enlarged corneal diameters (>12 mm), corneal haze (bluish coloration of iris), and haab striae. (C) Peter’s anomaly featuring congenital glaucoma and cloudy cornea.

Fig. 65.3  Aniridia. Eye has undergone cataract extraction and is aphakic.

Axenfeld-Rieger syndrome is a spectrum of developmental anomalies35 in the anterior segment of the eye involving the cornea (posterior embryotoxon), angle (iridotrabecular and iridocorneal processes), iris (corectopia), and lens. Systemic associations include dental anomalies (oligodontia, anodontia), skeletal and skull dysplasia, and umbilical abnormalities.

A

Peters’ anomaly is a congenital defect in the Descemet membrane in the cornea, which causes opacities with variable lens involvement and iris adhesions. It can occur as an isolated ocular disorder or with associated congenital abnormalities such as colobomatous microphthalmia, persistent fetal vasculature, and retinal detachment.36,37 Peters’ plus syndrome can be associated with developmental delay, short stature, facial dysmorphism, cleft lip/palate, external ear abnormalities, congenital heart disease, and genitourinary and neurologic structural defects.37 Glaucoma management is complicated by a limited view through the opacity. Successful long-term outcome is also limited by inherent challenges of corneal transplantation in children. Posterior polymorphous dystrophy is an AD condition involving the Descemet membrane and endothelium causing vesicular changes in the cornea. Infrequently, iridocorneal adhesions are present.38 The IOP may rise during early infancy due to anterior chamber malformations or later in childhood due to elevated episcleral venous pressure.39 Regular IOP measurements and fundus examinations can help monitor for choroidal hemangiomas that may be seen in up to 40% of cases and can cause macular edema and exudative retinal detachment (Fig. 65.4).28 Table 65.1 summarizes various systemic diseases associated with glaucoma. Glaucoma is the most common ocular morbidity (30%– 70%) in Sturge-Weber syndrome. Childhood glaucoma can also

B

Fig. 65.4  (A) Affected right eye demonstrating reddish hue consistent with diffuse choroidal hemangioma in a patient with right-sided port-wine stain. Cupping of the optic nerve consistent with glaucoma can be seen. (B) Left eye uninvolved.

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574  Section 12  |  Eye Disorders

Table 65.2  Differential Diagnoses in Addition to Congenital Glaucoma Based on Specified Clinical Findings44 Clinical Finding

Possible Condition

High IOP

Poor cooperation (squeezing/straining) Lid speculum Elevated intrathoracic pressure from endotracheal tube Thick corneas (i.e., aphakia, pseudophakia, aniridia)

Globe enlargement

Megalocornea without glaucoma Corneal ectasia High myopia Proptosis Lid retraction or contralateral ptosis

Descemet tears/ bands

Birth injury secondary to forceps Corneal ectasia Hypotony Endothelial infection (i.e., rubella, syphilis)

Corneal haze/ scarring

Congenital hereditary endothelial dystrophy Corneal dystrophy Mucopolysaccharides and other storage disease

Optic nerve cupping

Physiologic cupping in large optic nerve heads Papillorenal syndrome Optic nerve hypoplasia in periventricular leukomalacia

IOP, Intraocular pressure.

develop in association with other eye diseases such as retinoblastoma, inflammatory conditions such as antinuclear antibody-associated uveitis, steroid use, lens pathology (angle closure induced by lens subluxation in Weill-Marchesani syndrome or Marfan syndrome), neovascularization (sickle retinopathy), or retinopathy of prematurity.28,40 Glaucoma can occur after cataract surgery in about 30% of infants by 5 years of age; the risk is higher if there is associated microphthalmia and/or after congenital cataract surgery at 0.3 and/or marked asymmetry between the two eyes are indicative of glaucoma.43 However, these signs are not specific and can be seen in other conditions that may be mistaken as childhood glaucoma (Table 65.2).44 IOP measurements can help in the diagnosis and management of glaucoma. The average IOP in infants ranges from 8 to 15 mm Hg and is lower than in adults.45 The use of anesthesia may be helpful in uncooperative infants who need measurements of IOPs, corneal

Fig. 65.5  Ocular Findings. Measuring the horizontal corneal diameter in an uncooperative child can be performed by taking a photo with a ruler as shown. This toddler’s horizontal corneal diameters are 11 mm on both eyes.

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Chapter 65 |  Cataract and Glaucoma   575

Table 65.3  Ocular and Systemic Adverse Effects of Pediatric Glaucoma Drugs59 Class

Drugs

Ocular Adverse Effects

Systemic Adverse Effects

Beta blockers

Timolol, betaxolol, carteolol

Burning, pain, itching, erythema, dry eyes, allergic reaction, occasional corneal disorders

Hypotension, bradycardia, bronchospasm, apnea, light-headedness, depression, masked hypoglycemia in diabetics

Carbonic anhydrase inhibitors (topical)

Dorzolamide, brinzolamide

Burning, stinging, itching, blurred vision, lacrimation, conjunctivitis, superficial punctate keratitis, eyelid inflammation, anterior uveitis, corneal edema

Metabolic acidosis

Carbonic anhydrase inhibitors (oral)

Acetazolamide

Transient myopia

Headache, dizziness, paresthesia, asthenia, sinusitis, rhinitis, nausea, hypersensitivity reaction, bitter taste, epistaxis, urolithiasis, growth suppression

Alpha-2 agonists

Brimonidine (apraclonidine)

Frequent hyperemia, burning, stinging, blurring, pruritus

Central nervous system toxicity, somnolence, respiratory depression, apnea, and coma

Prostaglandin analogs

Latanoprost, travoprost, bimatoprost

Transient conjunctival redness, blepharitis, brown pigmentation of the iris, ocular irritation, transient punctate epithelial erosion, skin rash and darkening, thickening and lengthening of eyelashes

Uncommon dyspnea and asthma exacerbation, sleep disturbance, and sweating

tomography can be used for sequential measurement of the optic nerve head retinal fiber layer thickness.49,50 Unlike in adults, perimetry testing cannot be used in infants with glaucoma for quantifying visual fields.51

Treatment Options Medications and Special Considerations Medical management of infantile glaucoma is often a temporizing measure until surgical intervention. Many IOP-lowering drugs are not approved by the US Food and Drug Administration for use in children, and the dosing needs to be customized based on the child’s age and general health, the type of glaucoma, and the known efficacy and safety profiles of each medication.52 Beta-blockers, carbonic anhydrase inhibitors, alpha-adrenergic agonists, parasympathomimetics, and prostaglandin analogs can be useful in infants (Table 65.3). Monotherapy with beta-blockers such as timolol and prostaglandin analogs such as latanoprost can be useful but may need to be avoided in heart failure, high-degree atrioventricular block, sinus bradycardia, and bronchospasm.53,54 Alpha-adrenergic

agonists such as brimonidine are avoided in infants due to frequent side effects. Combination preparations, most commonly timolol-dorzolamide, are preferred to simplify the treatment regimen. Oral acetazolamide (10–20 mg/kg/day in divided doses) lowers IOP more than topical forms. Systemic side effects including loss of appetite, sleepiness/listlessness, nausea, and a need for metabolic monitoring reduce its use for refractory cases.28

Surgical Approaches Angle surgery may help some patients with PCG.55–57 The details are provided online.58

Long-Term Management After treatment for the acute increase in IOP, repeated EUAs are needed to monitor for disease progression. Amblyopia therapy with patching or penalization is required. Subsequently, refractive correction of significant myopia and astigmatism may be needed. In addition to optic neuropathy, corneal opacity, refractive error, and strabismus, amblyopia is one of the most common reasons for permanent visual loss in glaucoma.42

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Chapter 65 |  Cataract and Glaucoma   575.e1

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1. McGavin D. The global initiative for the elimination of avoidable blindness—vision 2020: the right to sight. Commun Eye Heal. 1999;12(13): 615–619. 2. SanGIovanni J, Chew E, Reed G. Infantile cataract in the collaborative perinatal project: prevalence and risk factors. Arch Ophthalmol. 2002;120:1559–1565. 3. Holmes J, Leske D, Burke J, Hodge D. Birth prevalence of visually signifiant infantile cataract in a defined U.S. population. Ophthalmic Epidemiol. 2003;10(2):67–74. 4. Trivedi RH, Wilson ME. Pediatric cataract: preoperative issues and considerations. In: Pediatric Ophthalmology: Current Thought and a Practical Guide. Berlin, Heidelberg: Springer-Verlag; 2009:311–323. 5. Repka MX, Dean TW, Lazar EL, et al. Cataract surgery in children from birth to less than 13 years of age: baseline characteristics of the cohort. Ophthalmology. 2016;123(12):2462–2473. 6. Chung DC, Traboulsi EI. An overview of the diagnosis and management of childhood cataracts. Contemp Ophthalmol. 2004;3(4):1–10. 7. Davitt B, Christiansen SP, Hardy R, Tung B, Good W. Incidence of cataract development by 6 months’ corrected age in the Early Treatment for Retinopathy of Prematurity study. J AAPOS. 2013;17(1):49–53. 8. Lim Z, Rubab S, Chan YH, Levin AV. Pediatric cataract: the toronto experience-etiology. Am J Ophthalmol [Internet]. 2010;149(6):887–892. http:// dx.doi.org/10.1016/j.ajo.2010.01.012. 9. Johar S, Savalia N, Vasavada A, Gupta P. Epidemiology based etiological study of pediatric cataract in western India. Indian J Med Sci. 2004;58:115– 121. 10. Musleh M, Hall G, Lloyd IC, et al. Diagnosing the cause of bilateral paediatric cataracts: comparison of standard testing with a next-generation sequencing approach. Eye [Internet]. 2016;30(9):1175–1181. http:// dx.doi.org/10.1038/eye.2016.105. 11. Vishwanath M, Cheong-Leen R, Taylor D. Is early surgery for congenitlal cataract a risk factor for glaucoma? Br J Ophthalmol. 2004;88: 905–910. 12. Lambert SR, Purohit A, Superak HM, Lynn MJ, Beck AD. Long-term risk of glaucoma after congenital cataract surgery. Am J Ophthalmol. 2013;156(2):355–361. 13. Lambert SR. The timing of surgery for congenital cataracts. J Am Assoc Pediatr Ophthalmol Strabismus. 2016;20(3):191–192. 14. Freedman SF, Kraker RT, Repka MX, et al. Glaucoma or glaucoma suspect in the first year after pediatric lensectomy. JAMA Ophthalmol. 2019; In-Press. 15. Vasavada V. Paradigms for pediatric cataract surgery. Asia-Pacific J Ophthalmol. 2017;7(2):123–127. 16. Khokhar S, Pillay G, Agarwal E. Pediatric cataract—importance of early detection and management. Indian J Pediatr. 2018;85(3):209–216. 17. Sachdeva V, Katukuri S, Kekunnaya R, Fernandes M, Ali M. Validation of guidelines for undercorrection of intraocular lens power in children. Am J Ophthalmol. 2017;174:17–22. 18. Infant Aphakia Treatment Study Group, Lambert SR, Lynn MJ, Hartmann EE, et al. Comparison of contact lens and intraocular lens correction of monocular aphakia during infancy: a randomized clinical trial of HOTV optotype acuity at age 4.5 years and clinical findings at age 5 years. JAMA Ophthalmol [Internet]. 2014;132(6):676–682. https://www.ncbi.nlm.nih. gov/pmc/articles/PMC4138810/. 19. Bothun E, Wilson M, Traboulsi EI, et al. Outcomes of unilateral cataracts in infants and toddlers 7 to 24 months of age: Toddler Aphakia and Pseudophakia Study Group (TAPS). Ophthalmology. 2019;126(8):1189–1195. 20. Bothun ED, Lynn MJ, Christiansen SP, et al. Sensorimotor outcomes by age 5 years after monocular cataract surgery in the Infant Aphakia Treatment Study (IATS). J AAPOS [Internet]. 2016;20(1):49–53. http://dx.doi. org/10.1016/j.jaapos.2015.11.002. 21. Celano M, Hartmann EE, Dubois LG, Drews-Botsch C. Motor skills of children with unilateral visual impairment in the Infant Aphakia Treatment Study. Dev Med Child Neurol. 2016;58(2):154–159. 22. Whitman MC, Vanderveen DK. Complications of pediatric cataract surgery. Semin Ophthalmol. 2014;19(5–6):414–420. 23. Kuhli-Hattenbach C, Luchtenberg M, Kohnen T, Hattenbach L. Risk factors for complications after congenital cataract surgery without intraocular

lens implantation in the first 18 months of life. Am J Ophthalmol. 2008;146(1):1–7. 24. Good W, HIng S, Irvine A. Postoperative endophthalmitis in children following cataract surgery. J Pediatr Ophthalmol Strabismus. 1990;27(6):283–285. 25. Wheeler D, Stager DR, Weakley DR. Endophthalmitis following pediatric intraocular surgery for congenital cataracts and congenital glaucoma. J Pediatr Ophthalmol Strabismus. 1992;29(3):139–141. 26. Rabiah P, Du H, Hahn E. Frequency and predictors of retinal detachment after pediatric cataract surgery without primary intraocular lens implantation. J AAPOS. 2005;9(2):152–159. 27. Haargaard B, Andersen EW, Oudin A, et al. Risk of retinal detachment after pediatric cataract surgery. Investig Ophthalmol Vis Sci. 2014;55(5):2947–2951. 28. Freedman SF, Johnston SC. Glaucoma in infancy and early childhood. In: Trivedi RH, Wilson ME, Saunders RA, eds. Pediatric Ophthalmology: Current Thought and A Practical Guide: Heidelberg; Springer Berlin Heidelberg; 2009:347–369. 29. Papadopoulos M, Cable N, Rahi J, Khaw P. The British Infantile and Childhood Glaucoma (BIG) eye study. Investig Ophthalmol Vis Sci. 2007;48:4100–4106. 30. Dominguez A, Banos M, Alvare M, Contra G, Quintla F. Primary infantile glaucoma (congenital glaucoma). Surv Ophthalmol. 1983;78:110–116. 31. Liu Y, Allingham RR. Molecular genetics in glaucoma. Exp Eye Res. 2011;93(4):331–339. 32. Grant W, Walton DS. Progressive changes in the angle in congenital aniridia, with development of glaucoma. Trans Am Ophthalmol Soc. 1974;72:207–228. 33. McCulley T, Mayer K, Dahr S, Simpson J, Holland E. Aniridia and optic nerve hypoplasia. Eye. 2005;19(7):762–764. 34. Mochon M, Blanc J, Plauchu H, Philip T. WAGR syndrome, Wilms’ tumor, aniridia, gonadoblastoma, mental retardation: a review apropos of 2 cases. Pediatrie. 1987;42(4):249–252. 35. Shields M, Buckley EG, Klintworth G, Thresher R. Axenfeld-Rieger syndrome. A spectrum of developmental disorders. Surv Ophthalmol. 1985;29:387. 36. Traboulsi EI, Maumanee I. Peters’ anomaly and associated congenital malformations. Arch Ophthalmol. 1992;110(12):1739–1742. 37. Heon E, Barsoum-Homsy M, Cevrette L, et al. Peters’ anomaly. The spectrum of associated ocular and systemic malformations. Ophthalmic Paediatr Genet. 1992;13(2):137–143. 38. Strachan I, Maclean H. Posterior polymorphous dystrophy of the cornea. Br J Ophthalmol. 1968;52:270. 39. Mantelli F, Bruscolimi A, Cava LM, Abdolrahimzadeh S, Lambiase A. Ocular manifestations of Sturge–weber syndrome: pathogenesis, diagnosis, and management. Clin Ophthalmol. 2016;10:871–878. 40. Emanuel ME, Gedde SJ. Indications for a systemic work-up in glaucoma. Can J Ophthalmol [Internet]. 2014;49(6):506–511. http://dx.doi.org/10.1016/j. jcjo.2014.10.001. 41. Egbert JE, Wright MM, Dahlhauser KF, Keithahn MAZ, Letson RD, Summers CG. A prospective study of ocular hypertension and glaucoma after pediatric cataract surgery. Ophthalmology [Internet]. 1995;102(7):1098–1101. http://dx.doi.org/10.1016/S0161-6420(95)30906-2. 42. Kipp MA. Childhood glaucoma. Pediatr Clin North Am [Internet]. 2003;50(1):89–104. http://www.ncbi.nlm.nih.gov/pubmed/12713106. 43. Shaffer R, Heatherington J. Glaucomatous disc in infants: a suggested hypothesis for disc cupping. Trans Am Acad Ophthalmol Otolaryngol. 1969;73:929–935. 44. Khan AO. Conditions that can be mistaken as early childhood glaucoma. Ophthalmic Genet. 2011;32(3):129–137. 45. Duckman RH, Fitzgerald DE. Evaluation of intraocular pressure in a pediatric population. Optom Vis Sci. 1992;69(9):705–709. 46. Dominguez A, Banos M, Alvare M, Contra G, Quintela F. Intraocular pressure measurements in infants under general anesthesia. Am J Ophthalmol. 1974;78:110–116. 47. Karaman T, Dogru S, Karaman S, et al. Intraocular pressure changes: the McGrath video laryngoscope vs the Macintosh laryngoscope; a randomized trial. J Clin Anesth. 2016;34:358–364.

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575.e2  Section 12  |  Eye Disorders 48. Ehlers N, Sorensen T, Bramsen T, Poulsen E. Central corneal thickness in newborns and children. Acta Ophthalmol. 1976;53:285–290. 49. Lee H, Proudlock FA, Gottlob I. Pediatric optical coherence tomography in clinical practice-recent progress. Investig Ophthalmol Vis Sci. 2016;57(9):OCT69–OCT79. 50. El-Dairi MA, Asrani SG, Enyedi LB, Freedman SF. Optical coherence tomography in the eyes of normal children. Arch Ophthalmol. 2009;127(1):50–58. 51. Patel DE, Cumberland PM, Walters BC, et al. Study of optimal perimetric testing in children (OPTIC): feasibility, reliability and repeatability of perimetry in children. PLoS One. 2015;10(6):1–12. 52. Samant M, Medsinge A, Nischal KK. Pediatric glaucoma: pharmacotherapeutic options. Pediatr Drugs. 2016;18(3):209–219. 53. Collignon P. Cardiovascular and pulmonary effects of beta-blocking agents: implications for their use in ophthalmology. Surv Ophthalmol. 1989;33(Suppl):455–456.

54. Zimmerman TJ. Topical ophthalmic beta blockers: a comparative review. J Ocul Pharmacol. 1993;9(4):373–384. 55. Yu Chan JY, Choy BNK, Ng ALK, Shum JWH. Review on the management of primary congenital glaucoma. J Curr Glaucoma Pract. 2015;9(3):92–99. 56. O’Malley Schotthoefer E, Yanovitch TL, Freedman SF. Aqueous drainage device surgery in refractory pediatric glaucomas: I. Long-term outcomes. J AAPOS. 2008;12(1):33–39. 57. O’Malley Schotthoefer E, Yanovitch TL, Freedman SF. Aqueous drainage device surgery in refractory pediatric glaucoma: II. Ocular motility consequences. J AAPOS. 2008;12(1):40–45. 58. Kirwan J, Shah P, Khaw P. Diode laser cyclophotocoagulation: role in management of refractory pediatric glaucomas. Ophthalmology. 2002;109:316–323. 59. Coppens G, Stalmans I, Zeyen T. Casteels I. The safety and efficacy of glaucoma medication in the pediatric population. J Pediatr Ophthalmol Strabismus. 2009;46(1):12–18.

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Section 13

Neonatal Tracheostomy

CHAPTER

66

Jonathan Walsh

KEY POINTS 1. Chronic cardiopulmonary and neurologic disorders are the most common indications for neonatal tracheostomy, overtaking upper airway obstruction. 2. Noninvasive ventilation of neonates is likely reducing indications and the need for tracheostomy.

3. Neonatal tracheostomy is associated with high overall mortality and morbidity and lower quality of life. 4. Postoperative and long-term care is necessary to help mitigate and manage the increased risks associated with neonatal tracheostomy.

Introduction Tracheostomy has played a critical role in the care of infants since the early 1900s. Prior to the 1800s, tracheostomies were viewed with skepticism and criticism because these procedures were performed for acute airway obstruction and associated with high mortality rates. The relative success of tracheostomy in the treatment of children with diphtheria helped increase acceptance of the procedure.1–5 Holinger published a 30-year review of infant tracheostomy in 1965, demonstrating more acceptance of the procedure, improved technology of tracheostomy tubes, and an increasing list of indications, primarily for airway obstruction.6 Unfortunately, the mortality changed very little during that time period, with mortality rates approximately 30% for these infants.6–10 The mid 1900s heralded great advances in neonatal resuscitation and ventilation. In 1953 Donald and Lord published a description of an infant mechanical ventilation device.2,7 In 1965, McDonald and Stocks demonstrated success in longer-term intubation and ventilation in neonates.3,8 Continuous positive pressure ventilation for respiratory distress of newborns was published in 1971.4 The 1960s also saw the establishment of the first neonatal intensive care units, and more infants were surviving conditions that in decades past were considered fatal. The history of neonatal tracheostomy has been an evolving story of changing indications, technological advancements, and improvements in survival. An understanding of the history of neonatal tracheostomy and neonatal care provides insight into the current evidence-based management of neonatal tracheostomy and the challenges now faced. The landscape of neonatal tracheostomy is changing. Very low birth weight preterm infants are now surviving, and noninvasive methods of respiratory support for these infants are reducing morbidity. Young children with severe chronic cardiopulmonary or neurologic disorders are managed with ventilators both in the neonatal intensive care unit (NICU) and out of the hospital. Some of the questions we now face for neonatal tracheostomy center on appropriate timing for tracheostomy, improving postoperative care pathways, decreasing morbidity of the procedure and subsequent care, facilitating adaptive neurodevelopment and communication, and improving quality of life after tracheostomy.

Pathophysiology Multiple factors impact the pathophysiology and indications of neonatal tracheostomy. Unique neonatal anatomy, physiology, and

5. Tracheostomies have impact in all domains of neurodevelopment.

medical conditions associated with prematurity influence tracheostomy decisions in the neonatal period. The infant and neonatal airway diameter and length will vary by gestational age. The narrowest portion of the infant airway is at the glottis and subglottis, and these locations are the most common sites of postintubation stenosis. For a newborn, the subglottis has a 3.5- to 4-mm inner diameter. The tracheal length from glottis to carina is about 40 mm. Premature infants may have a subglottic airway of less than 3 mm.5 Airflow and effective ventilation in these small airways are influenced by Bernoulli’s and Poiseuille’s equations. Small changes in airway size will have significant effects on airway pressure, dynamic collapse, and resistance to flow. The clinical implication for many preterm infants is that airway edema or stenosis changes at the 1-mm level or less can destabilize effective ventilation, requiring increased support or tracheostomy. Subglottic stenosis occurred in 12% to 20% of infants with prolonged intubation in the 1960s. With contemporary neonatal respiratory care, rates of stenosis are typically around 1%.11,12 Tracheostomy can be used to bypass levels of stenosis or decrease the need for respiratory support by removing upper airway resistance. Typical indications for neonatal tracheostomy are prolonged ventilation, facilitation of ventilator weaning, upper airway obstruction, subglottic stenosis, or infectious etiologies.13–24 Although Holinger demonstrated infectious etiologies and airway obstruction as the most common indication for neonates in the 1960s, chronic cardiopulmonary and neurologic disorders are now the primary indications for tracheostomy. Multiple studies have described this shift from infectious indications for tracheostomy to cardiopulmonary and neurologic indications in neonates who have comorbid conditions.6,15,16,22,24,25

Clinical Features and Indications When tracheostomy is required, the decisions of timing and patient selection are critical to reduce morbidity. However, a limiting factor is the size of the neonatal airway in relation to the smallest available tracheostomy tube outer diameter (OD). The inner diameter of a fullterm neonatal trachea is approximately 3.5 to 4 mm. Extremely premature infants may have an inner diameter of 2 mm or smaller. Currently the smallest OD tracheostomy tube is the 2.5 Tracoe with an OD of 3.6 mm or a 2.5 NEO Bivona TTS cuffed trach with an OD of 4.0 mm. Tracheal length also may be a factor in being able to accommodate the 30 mm of length of the tracheostomy tubes. These anatomic constraints are critical when considering airway interventions 577

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578  Section 13  |  ENT and Auditory Conditions

prenatally. Since the 1990s, ex utero intrapartum treatment procedures created the possibility of prenatal airway management for cases of congenital high airway obstruction (CHAOS), airway tumors, laryngeal and tracheal stenosis, and lymphatic malformations.26 In addition to tracheal size and gestational age, patient weight is a consideration. Studies of other procedures have shown increased morbidity and mortality in procedures performed in neonates weighing less than 2.5 kg.27–29 There is no established weight requirement for a tracheostomy procedure.16–18 Tracheostomy performed in infants with weights between 2.0 and 2.5 kg is common. Rawal et al. did not find increased morbidity when comparing infants 2.5 kg in an American College of Surgeons National Surgical Quality Improvement Program–Pediatric (ACS NSQIP-P) Database study.30 The data regarding appropriate timing of tracheostomy in infants is based on retrospective studies.31 It appears that the timing of tracheostomy does not decrease the duration of mechanical ventilation in the majority of infants.31–33 Advances in noninvasive ventilation of newborns have improved morbidity and mortality through decreasing intubations and related iatrogenic lung and laryngotracheal injury. Systematic reviews have demonstrated the efficacy and safety of these methods compared with traditional orotracheal intubation.34–38 The implications of these advances for neonates requiring tracheostomy are varied. The total number of infants requiring tracheostomy may be decreasing, along with the aforementioned decrease in subglottic stenosis rates.11,12 However, tracheostomy rates may be increasing in certain subpopulations of very low birth weight premature infants with more severe cardiopulmonary disease.18,39 In some of these critical ill neonates, the risk of tracheostomy may be unacceptable. Highly unstable pulmonary hypertension or cardiopulmonary disease can be relative contraindications.23 If the neonate is unable to be transported safely to the operating room, be manipulated and positioned for surgery, and tolerate exchange of the endotracheal tube to a tracheostomy tube, then surgery should be delayed or deferred. Table 66.1 lists common indications and relative contraindications for neonatal tracheostomy.

Management Discussion of management can be organized into preoperative planning, intraoperative procedure, postoperative care, and long-term care.

Preoperative Preoperative planning is crucial for neonates with complex and critical medical status who require a tracheostomy. The workup for tracheostomy should be tailored to the indications and status of the

infant. Neurologic evaluation, magnetic resonance and computed tomography imaging, echocardiography, chest x-ray, laryngoscopy, bronchoscopy, and laboratory studies may all be used for preoperative workup. Coordination with a multidisciplinary team of neonatologists, pulmonologists, cardiologists, surgeons, social workers, and family can expedite care and improve quality of care.33 For infants with critical congenital cardiac disease that requires repair, tracheostomy may be deferred to reduce wound infections and morbidity.40,41 Early family integration in the decision, planning, and timing of the tracheostomy helps counseling of both short- and long-term implications of a neonatal tracheostomy on family care. Estimated 2-year healthcare costs associated with infants receiving tracheostomy range from $1643 to $112,608, with costs for the care of some children much higher.42 In addition to cost, there is a social and personal burden and decreased quality of life for families and caregivers.43–45 Family counseling and tracheostomy care education are important in the success and safety of neonatal tracheostomies. Families should be prepared for routine and emergency care of infants with tracheostomy, with early guidance to assist with expectations and to avoid misconceptions before the surgery is performed.46,47 Families and caregivers may experience a significant burden in quality-of-life, financial, social, and relational domains. Quality of life is lower in families of neonates with tracheostomy compared with neonates without tracheostomy. Neonates with tracheostomy are more likely to have readmissions, outpatient visits, and fewer parents with full-time employment.43–45,48

Procedure49 In a standard neonatal tracheostomy, the patient is positioned with a small shoulder roll and extended neck position. The critical landmarks of the sternal notch, trachea, cricoid, and thyroid cartilage are palpated and marked. Careful palpation deep to the sternal notch is performed to identify any abnormally high location of large vessels. The proposed incision is injected with lidocaine and epinephrine with a dose as appropriate for weight. The patient is then prepped and draped in a sterile fashion but should be draped in a manner to allow access to the endotracheal tube for removal at the time of tracheostomy tube placement. Typically, a 1.5-cm horizontal incision is made just below the cricoid in the midline. Subcutaneous fat is removed to expose the cervical fascia and strap muscles. The midline raphe is identified to separate the strap muscles vertically, being careful to remain in midline. The cricoid cartilage and thyroid gland isthmus are identified and the isthmus is divided. Tracheal rings 2 through 4 are isolated and identified using the cricoid cartilage as a landmark (Fig. 66.1). The endotracheal tube cuff is deflated to

Table 66.1  List of Common Indications and Relative Contraindications for Neonatal Tracheostomy Indications

Contraindications (Relative)

Chronic cardiopulmonary disease (bronchopulmonary dysplasia, pulmonary hypertension, etc.)

Critically ill and unable to tolerate general anesthesia or transportation to the operating room

Neurologic disorders, congenital and acquired

Critical mid to low tracheal stenosis or agenesis

Acquired or congenital glottic, subglottic, or tracheal stenosis

Craniofacial and cervical dysmorphia that prevents surgical access

Craniofacial syndromes and disorders (Robin sequence, Treacher Collins, Goldenhar, etc.)

Congenital cardiac disease requiring sternotomy, which may be contaminated by presence of tracheostomy

CHAOS (congenital high airway obstruction syndrome)a Vascular malformations or tumors Via ex utero intrapartum treatment (EXIT) procedure.

a

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Chapter 66 |  Neonatal Tracheostomy   579

Fig. 66.2  The Tracheostomy Tube Is Secured With Ties, and Skin-Protecting Dressing Can Be Applied to the Neck, Chin, and Chest to Limit Skin Breakdown During the Healing Process.

Fig. 66.1  In the Tracheostomy Surgical Procedure, a Vertical Incision Is Made Through Tracheal Rings 2 Through 4. (From: Chapter 1, authored through Elsevier. Clinics in Perinatology: Diagnosis and Management of Pediatric ENT Conditions. Dec 2018.)

avoid inadvertent cuff puncture, and tracheal retraction sutures are placed through 2 tracheal rings oriented vertically with 3-0 Prolene “stay” sutures. They are labeled with “left” and “right” identifiers. These stay sutures are placed to facilitate tube reinsertion should accidental decannulation occur postoperatively. Using 5-0 chromic sutures, the skin edges can be tacked to the superior and inferior edges of the trachea to help mature50 the tracheostomy stoma. Next, a vertical incision is made through tracheal rings 2 through 4 in the midline between the two retraction sutures. Simultaneously, the endotracheal tube is pulled back just above the tracheostomy site. A tracheostomy tube is then placed into the incision, and confirmation of correct placement is made with auscultation of lung fields, end tidal CO2 measurement, and visualization through the tracheostomy tube lumen using a small fiberoptic scope. The tracheostomy tube is then secured with ties, and skin-protecting dressing (DuoDERM, Mepilex) to limit skin breakdown during the healing process can be applied to the neck, chin, and chest (Fig. 66.2).

Tracheostomy Tube Sizes Neonatal tracheostomy tube choices vary by diameter size and length. The principal manufacturers in the United States are Smiths Medical Bivona, Shiley, and TRACOE. These manufacturers offer both cuffed and uncuffed options (Fig. 66.3). The decision for type and style of tracheostomy may depend on ventilation pressure requirements and the size of the trachea for a given infant. The numeric sizes of the tracheostomy tubes are in reference to their inner diameter. Additionally, designations of NEO (neonatal) versus PEDs

Fig. 66.3  Neonatal Tracheostomy Tubes Are Available From Several Manufacturers, With Both Cuffed and Uncuffed Options.

(pediatric) tracheostomy reflect differences in overall length of the tracheostomy tube. Even small changes in diameter from 2.5 mm to 3.0 mm will have a dramatic effect on airflow resistance according to Poiseuille’s law. Length also affects resistance but to a lesser degree. Table 66.2 lists neonatal tracheostomy tube options.

Postoperative Complications Neonatal tracheostomies have high intermediate- and long-term morbidity and overall mortality. Mortality of infants and children with tracheostomies is reported between 1.5% and 8.9%. 42,51–53 However, tracheostomy-specific mortality is lower, reported to be 0.7%. 51 Intraoperative complications such as decannulation,

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580  Section 13  |  ENT and Auditory Conditions

Table 66.2  List of Neonatal Tracheostomy Tube Options Tracheostomy Tube

ID (mm)

OD (mm)

Distal Length (mm)

Cuff Option

Material

Suction Size

2.5

2.5

4

30

Y

Silicone

6 Fr

3

3

4.7

32

Y

Silicone

6–8 Fr

3.5

3.5

5.3

34

Y

Silicone

8 Fr

4

4

6

36

Y

Silicone

8 Fr

2.5

2.5

4.2

28

Y

PVC

6 Fr

3

3

4.8

30

Y

PVC

6–8 Fr

3.5

3.5

5.4

32

Y

PVC

8 Fr

4

4

6.0

34

Y

PVC

8 Fr

4.5

4.5

6.7

36

Y

PVC

8 Fr

2.5

2.5

3.6

30

Y

Silicone/PVCa

6 Fr

3

3

4.3

32

Y

Silicone/PVC

6–8 Fr

3.5

3.5

5.0

34

Y

Silicone/PVC

8 Fr

4

4

5.6

36

Y

Silicone/PVC

8 Fr

BIVONA (NEONATAL)

SHILEY (NEONATAL)

TRACOE

Both soft silicone and PVC options are available.

a

ID, Inner diameter; OD, outer diameter.

pneumothorax, bleeding, laryngeal injury, and skin burns have been reported to be approximately 3%.42,51–54 Short-term postoperative complications include skin pressure ulceration, accidental false tracking and accidental decannulation, mucous plugging, neck infection, bleeding, or tracheal or carinal ulceration. Analysis of the ACS NSQIP database in 2016 and 2019 described major and minor complications.30,53 The highest major complications were a 7.55% rate of sepsis and a 6.45% rate of reoperation. Death occurred in 4.24% of infants.30 Minor complications included a 1.66% rate of skin infection.30 Skin infection and ulceration can occur due to unintended pressure by the ventilator tubing, tracheostomy tube and flanges, or trach ties.55 To prevent accidental decannulation and false tracking, the tracheostomy tube must be well secured during the early healing period. This vigilance may also create conditions where skin breakdown can occur. Meticulous perioperative care from the surgical, nursing, and respiratory therapy team is needed to prevent such morbidity. Protective dressings and standardized postoperative care can reduce morbidities of accidental decannulation and pressure ulcers.55–57 When considering long-term complications and associated comorbidities, the overall morbidity associated with an infant through the first years after placement is high, reported to be between 19.9% and 63%.42,51–53 Reported long-term complications can be stoma bleeding or granulomas, accidental decannulation, tracheostomy mucous plugging, tracheomalacia, pneumonia, tracheitis, trachea-esophageal fistula, trachea-innominate fistula, or respiratory failure leading to death.42,51–53 Infants with significant congenital cardiac disease in addition to tracheostomy had increased morbidity and complications compared with infants without cardiac disease.40,41,53 These infants likely have lower cardiopulmonary reserve to tolerate morbidities when they occur, and long-term care should be delivered with vigilance due to their higher risk. An improperly sized tracheostomy tube or overly aggressive tracheal suctioning can lead to granulation of tracheal tissue, ulceration, and erosion. Chronic infections, tracheitis, and suprastomal

granulomas can occur. Tracheostomy tubes, as indwelling foreign bodies, are prone to biofilm and bacterial colonization and tracheitis.58,59 Chronic infection of the tracheal cartilage can be a risk factor for secondary tracheal stenosis. With growth of an infant, the initial tracheostomy tube size and length may be inadequate for the neck anatomy, leading to accidental decannulations or pressure with the tracheal wall. Severe erosion through the tracheal wall can lead to a tracheo-innominate artery fistula or a tracheoesophageal fistula, especially with long-term tracheostomy or concomitant tracheal and/ or thoracic pathology. Long-term routine tracheostomy care and follow-up are needed to help prevent these complications.46,47,60

Postoperative Care Important considerations in postoperative tracheostomy care are the frequency/method of suctioning, maintenance of secure tracheostomy ties, and timing of the first trach change. There are no comprehensive, universally accepted guidelines for tracheostomy care, but many institutions have created protocols and care pathways to reduced morbidity. The American Academy of Otolaryngology published a clinical consensus statement on tracheostomy care for both pediatric and adult patients. Statements addressed the timing of the first tracheostomy tube change within the first 5 to 7 days postoperatively as well as decannulation pathways.61 Specific protocols for routine care and tracheostomy maintenance should be modified for each patient’s needs to limit mucous plugging, pressure ulceration, accidental decannulation, false tracking, and long-term complications.51,52,61 Saline installation and suctioning is performed to a predetermined appropriate depth based on the length and position of the tracheostomy tube, and this is done for pulmonary toilet and to prevent mucous plugging. Daily wound and peristomal/neck skin examinations should be performed and protective dressings should be used to minimize risk for and severity of skin ulcerations (see Fig. 66.2).55–57 Timing of the first tracheostomy tube change may depend on patient

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Chapter 66 |  Neonatal Tracheostomy   581

anatomy, medical and ventilator status, and surgical site healing. The first tracheostomy tube change can occur between postoperative day 2 and day 7.62,63 Timing of the first change seeks to balance the goals of adequate surgical site healing for safe tube exchange with reducing patient immobilization and decreasing skin ulceration risk. Even before the first tracheostomy tube change, families and caregivers can begin structured training for tracheostomy care.46,47

Long-Term Outcomes With the complex medical comorbidities of neonates with tracheostomy, longer-term mortality has been shown to be 8.9% in a study following such children in a Medicaid population during a 2-year period.42 When looking at tracheostomy-specific long-term outcomes in children, there are adverse effects on speech, language, feeding, neurodevelopment, Eustachian tube function, quality of life, financial burden, and caregiver burden.64–71 Speech and language development can be significantly affected by tracheostomy in children.65–67 Between 40% and 80% of children with tracheostomy, even without neurologic disorders, may have such delays.65–67 Adaptive communication technologies, integrative speech and language therapy, and early use of speaking valves may help mitigate some risk.72,73 In some infants, a speaking valve may be able to be used in the first months of life.72 Speaking valve tolerance can be increased by drilling side holes in the valve.74 This technique has been described to decrease subglottic pressure for infants who do not have an adequate airway for a standard speaking valve. It requires an “off-label” modification of a device, which may compromise vocalization with the device. Education and care should be taken if device modification is to be performed. Although the presence of a tracheostomy in and of itself does not preclude oral feeding in neonates, dysphagia is a significant comorbidity in infants with tracheostomy tube placement. One study showed that only 43% of infants with a tracheostomy tube had an oral diet at discharge, and 57% required nasogastric or gastrostomy tube feeding.64 In another study, 70% of infants had demonstrated problems with the oral or pharyngeal phase of swallowing and 43% showed aspiration.75

A large multicenter study evaluating neurodevelopment impairment outcomes in 8683 preterm infants found increased impairment associated with patients who received a tracheostomy (odds ratio, 4.0).65 Neurodevelopmental impairment was present in 81% of preterm infants receiving a tracheostomy compared with 36% without a tracheostomy. Additionally, in the same cohort of preterm infants, those with tracheostomy had higher rates of cognitive delay (77%), motor delay (68%), visual impairment (4%), and hearing impairment (8%).65 However, in a cohort of preterm infants with severe bronchopulmonary dysplasia, infants who received tracheostomy had improved growth and increased participation in physical therapy activities.76 The family and financial burdens associated with the care of infants with tracheostomy cannot be overlooked. Families of infants with tracheostomies had lower quality of life, increased social isolation, and financial burden.43,44,48,70 Nursing support, educational programs, and caregiver intervention can help provide the needed support and resources for these families.77–82

Summary The indications for tracheostomy in young infants have changed, and the rates of tracheostomy in newborns are decreasing.15,16,19,22 Neonatal care has had significant advances in noninvasive methods of respiratory support, and more extremely preterm and very low birth weight infants are surviving NICU care. Management of severe chronic cardiopulmonary or neurologic disorders both in the NICU and at home has become more common, and neonates with tracheostomy have highly complex needs. As a result, neonatal tracheostomy has high mortality rates and substantial morbidities. Due to these high morbidities, the ACS NSQIP data analysis has demonstrated neonatal tracheostomy as a surgical procedure that would benefit from increased outcomes research and quality improvement.53,54 To mitigate these risks and improve outcomes, multidisciplinary care pathways, teaching and training protocols, and improved long-term outpatient resources and support for families and caregivers will likely have the greatest impact.

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Chapter 66 |  Neonatal Tracheostomy   581.e1

REFERENCES

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29. Kalfa D, Krishnamurthy G, Levasseur S, et al. Norwood stage I palliation in patients less than or equal to 2.5 kg: outcomes and risk analysis. Ann Thorac Surg. 2015;100:167–173. 30. Rawal RB, Farquhar DR, Kilpatrick LA, Drake AF, Zdanski CJ. Considering a weight criterion for neonatal tracheostomy: an analysis of the ACS NSQIP-P. Laryngoscope. 2019;129(2):500–505. doi:10.1002/ lary.27272. 31. Cheng J, Lioy J, Sobol S. Effect of tracheostomy timing in premature infants. Int J Pediatr Otorhinolaryngol. 2013;77:1873e6. 32. Overman AE, Liu M, Kurachek SC, et al. Tracheostomy for infants requiring prolonged mechanical ventilation: 10 years’ experience. Pediatrics. 2013;131:e1491e6. 33. Abman SH, Collaco JM, Shepherd EG, et al., Bronchopulmonary Dysplasia Collaborative. Interdisciplinary care of children with severe bronchopulmonary dysplasia. J Pediatr. 2017;181:12–28.e1. 34. Isayama T, Iwami H, McDonald S, Beyene J. Association of noninvasive ventilation strategies with mortality and bronchopulmonary dysplasia among preterm infants: a systematic review and meta-analysis. JAMA. 2016;316(6):611–624. 35. Schmölzer GM, Kumar M, Pichler G, Aziz K, O’Reilly M, Cheung P. Non-invasive versus invasive respiratory support in preterm infants at birth: systematic review and meta-analysis. BMJ. 2013;347:f5980. 36. Subramaniam P, Ho JJ, Davis PG. Prophylactic nasal continuous positive airway pressure for preventing morbidity and mortality in very preterm infants. Cochrane Database Syst Rev. 2016(6):CD001243. 37. Lemyre B, Laughon M, Bose C, Davis PG. Early nasal intermittent positive pressure ventilation (NIPPV) versus early nasal continuous positive airway pressure (NCPAP) for preterm infants. Cochrane Database Syst Rev. 2016;12:CD005384. 38. Wilkinson D, Andersen C, O’Donnell CP, De Paoli AG, Manley BJ. High flow nasal cannula for respiratory support in preterm infants. Cochrane Database Syst Rev. 2016;22(2):CD006405. 39. Wang CS, Kou YF, Shah GB, Mitchell RB, Johnson RF. Tracheostomy in extremely preterm neonates in the United States: a cross-sectional analysis. Laryngoscope. 2020;130(8):2056–2062. 40. Ortmann LA, Manimtim WM, Lachica CI. Outcomes of tracheostomy in children requiring surgery for congenital heart disease. Pediatr Cardiol. 2017;38(2):296–301. 41. Toeg H, French D, Gilbert S, Rubens F. Incidence of sternal wound infection after tracheostomy in patients undergoing cardiac surgery: a systematic review and meta-analysis. J Thorac Cardiovasc Surg. 2017;153(6): 1394–1400.e7. 42. Watters K, O’Neill M, Zhu H, Graham RJ, Hall M, Berry J. Two-year mortality, complications, and healthcare use in children with medicaid following tracheostomy. Laryngoscope. 2016;126(11):2611–2617. 43. Hartnick CJ, Bissell C, Parsons SK. The impact of pediatric tracheotomy on parental caregiver burden and health status. Arch Otolaryngol Head Neck Surg. 2003;129(10):1065–1069. 44. Hartnick C, Diercks G, De Guzman V, Hartnick E, Van Cleave J, Callans K. A quality study of family-centered care coordination to improve care for children undergoing tracheostomy and the quality of life for their caregivers. Int J Pediatr Otorhinolaryngol. 2017;99:107–110. 45. McAndrew S, Acharya K, Westerdahl J, et al. A prospective study of parent health-related quality of life before and after discharge from the neonatal intensive care unit. J Pediatr. 2019;213:38–45.e3. 46. Boykova M. Transition from hospital to home in preterm infants and their families. J Perinat Neonatal Nurs. 2016;30(3):270–272. 47. Joseph RA. Tracheostomy in infants: parent education for home care. Neonatal Netw. 2011;30(4):231–242. 48. Nassel D, Chartrand C, Doré-Bergeron MJ, et al. On behalf of the Canadian Neonatal Network and the Canadian Neonatal Follow-Up Network. Very preterm infants with technological dependence at home: impact on resource use and family. Neonatology. 2019;115(4):363–370. 49. Walsh J, Rastatter J. Neonatal tracheostomy. Clin Perinatol. 2018;45(4):805–816. 50. Colman KL, Mandell DL, Simons JP. Impact of stoma maturation on pediatric tracheostomy-related complications. Arch Otolaryngol Head Neck Surg. 2010;136(5):471–474.

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581.e2  Section 13  |  ENT and Auditory Conditions 51. Carr MM, Poje CP, Kingston L, Kielma D, Heard C. Complications in pediatric tracheostomies. Laryngoscope. 2001;111(11):1925–1928. 52. D’Souza JN, Levi JR, Park D, Shah UK. Complications following pediatric tracheotomy. JAMA Otolaryngol Head Neck Surg. 2016;142(5):484–488. 53. Mahida JB, Asti L, Boss EF, et al. Tracheostomy placement in children younger than 2 years: 30-day outcomes using the national surgical quality improvement program pediatric. JAMA Otolaryngol Head Neck Surg. 2016;142(3):241–246. 54. Shah RK, Stey AM, Jatana KR, Rangel SJ, Boss EF. Identification of opportunities for quality improvement and outcome measurement in pediatric otolaryngology. JAMA Otolaryngol Head Neck Surg. 2014;140(11):1019–1026. 55. Hart CK, Tawfik KO, Meinzen-Derr J, et al. A randomized controlled trial of velcro versus standard twill ties following pediatric tracheotomy. Laryngoscope. 2017;127(9):1996–2001. 56. Lippert D, Hoffman MR, Dang P, McMurray JS, Heatley D, Kille T. Care of pediatric tracheostomy in the immediate postoperative period and timing of first tube change. Int J Pediatr Otorhinolaryngol. 2014;78(12):2281–2285. 57. Kuo CY, Wootten CT, Tylor DA, Werkhaven JA, Huffman KF, Goudy SL. Prevention of pressure ulcers after pediatric tracheotomy using a Mepilex Ag dressing. Laryngoscope. 2013;123(12):3201–3205. 58. Sanders CD, Guimbellot JS, Muhlebach MS, Lin FC, Gilligan P, Esther CR Jr. Tracheostomy in children: epidemiology and clinical outcomes. Pediatr Pulmonol. 2018;53(9):1269–1275. 59. McCaleb R, Warren RH, Willis D, Maples HD, Bai S, O’Brien CE. Description of respiratory microbiology of children with long-term tracheostomies. Respir Care. 2016;61(4):447–452. 60. Gergin O, Adil E, Kawai K, Watters K, Moritz E, Rahbar R. Routine airway surveillance in pediatric tracheostomy patients. Int J Pediatr Otorhinolaryngol. 2017;97:1–4. 61. Mitchell RB, Hussey HM, Setzen G, et al. Clinical consensus statement: tracheostomy care. Otolaryngol Head Neck Surg. 2013;148:6e20. 62. Woods R, Geyer L, Mehanna R, Russell J. Pediatric tracheostomy first tube change: when is it safe? Int J Pediatr Otorhinolaryngol. 2019;120:78–81. 63. Van Buren NC, Narasimhan ER, Curtis JL, Muntz HR, Meier JD. Pediatric tracheostomy: timing of the first tube change. Ann Otol Rhinol Laryngol. 2015;124(5):374–377. 64. Joseph RA, Evitts P, Bayley EW, Tulenko C. Oral feeding outcome in infants with a tracheostomy. J Pediatr Nurs. 2017;33:70–75. 65. DeMauro SB, D’Agostino JA, Bann C, et al. Developmental outcomes of very preterm infants with tracheostomies. J Pediatr. 2014;164(6):1310.e2. 66. Hill BP, Singer LT. Speech and language development after infant tracheostomy. J Speech Hear Disord. 1990;55(1):15–20. 67. Jiang D, Morrison GAJ. The influence of long-term tracheostomy on speech and language development in children. Int J Pediatr Otorhinolaryngol. 2003;67:S220.

68. Palmisano JM, Moler FW, Revesz SM, Custer JR, Koopmann C. Chronic otitis media requiring ventilation tubes in tracheotomized ventilator dependent children. Int J Pediatr Otorhinolaryngol. 1994;30(3): 177–182. 69. Norman V, Louw B, Kritzinger A. Incidence and description of dysphagia in infants and toddlers with tracheostomies; a retrospective review. Int J Pediatr Otorhinolaryngol. 2007;71:1087–1092. 70. Flynn AP, Carter B, Bray L, Donne AJ. Parents’ experiences and views of caring for a child with a tracheostomy: a literature review. Int J Pediatr Otorhinolaryngol. 2013;77:1630–1634. 71. Edwards JD, Kun SS, Keens TG. Outcomes and causes of death of children on home mechanical ventilation via tracheostomy: an institutional and literature review. J Pediatr. 2010;157:955–959.e2. 72. Engleman S, Turnage-Carrier C. Tolerance of the Passy-Muir speaking valve in infants and children less than 2 years of age. Pediatr Nurs. 1997;23(6):571. 73. Zabih W, Holler T, Syed F, Russell L, Allegro J, Amin R. The use of speaking valves in children with tracheostomy tubes. Respir Care. 2017;62(12):1594–1601. 74. Buckland A, Jackson L, Ilich T, Lipscombe J, Jones G, Vijayasekaran S. Drilling speaking valves to promote phonation in tracheostomy-dependent children. Laryngoscope. 2012;122(10):2316–2322. 75. Streppel M, Veder LL, Pullens B, Joosten KFM. Swallowing problems in children with a tracheostomy tube. Int J Pediatr Otorhinolaryngol. 2019;124:30–33. 76. Luo J, Shepard S, Nilan K, et al. Improved growth and developmental activity post tracheostomy in preterm infants with severe BPD. Pediatr Pulmonol. 2018;53(9):1237–1244. 77. Kirk S, Glendinning C. Supporting ‘expert’ parents–professionals support and families caring for a child with complex health care needs in the community. Int J Nurs Stud. 2002;39:625–635. 78. Montagnino BA, Maurio RV. The child with a tracheostomy and gastrostomy: parental stress and coping in the home—a pilot study. Pediatr Nurs. 2004;30(5):P373–P401. 79. Hopkins C, Whetstone S, Foster T, Blaney G, Morrison G. Impact of paediatric tracheostomy on both the patient and the parent. Int J Pediatr Otorhinolarngol. 2008;73:15–20. 80. Fiske E. Effective strategies to prepare infants and families for home care tracheostomy. Adv Neonatal Care. 2004;4:42–53. 81. Hettige R, Arora A, Ifecho S, Narula A. Improving tracheostomy management through design, implementation and prospective care bundle; how we do it. Clin Otolaryngol. 2008;33:474–494. 82. Day T, Iles N, Griffiths P. Effect of performance feedback on tracheal suctioning knowledge and skills: randomized controlled trial. J Adv Nurs. 2009;65:1423–1431.

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Section 13 CHAPTER

67

Stridor and Laryngotracheal Airway Obstruction in Newborns

Elaine O. Bigelow, David E. Tunkel

KEY POINTS 1. Stridor is a sound caused by obstruction of the upper airway, usually from abnormalities within one or more of the subsites of the larynx (supraglottis, glottis, and subglottis) or in the trachea. 2. Stridor is a physical sign and not a diagnosis. It can be characterized by its presence during inspiration or expiration (or both), by its pitch and loudness, and by its change with activity or position.

3. Laryngomalacia is the most common cause of neonatal stridor, and most cases will improve over the first 12 to 18 months of life. 4. The second most common cause of neonatal stridor is vocal cord paralysis, but it is the likely diagnosis when stridor is observed immediately after delivery.

Introduction Stridor describes the sound caused by turbulent airflow within the large airways during respiration. Stridor is typically highpitched, although the sound can vary with changes in shape and caliber of the airway and with respiratory effort. Stridor can be inspiratory, expiratory, or biphasic, and this quality can indicate the likely site of obstruction. Inspiratory stridor is associated with extrathoracic airway obstruction, typically at the level of the vocal cords or above. Expiratory stridor may be seen with intrathoracic obstruction within the middle or distal trachea. Biphasic stridor indicates obstruction at the level of the vocal cords, subglottis, or upper trachea and is characterized by noise during both inspiration and expiration, although the inspiratory component often predominates. Stridor must be differentiated from stertor: a lowpitched, gurgly, inspiratory or expiratory sound caused by reverberation of redundant soft-tissue or secretions within the oropharynx, nose, or nasopharynx. Stridor and stertor may coexist or be present in isolation. Stridor in neonates is most commonly caused by laryngomalacia. The other likely causes of stridor in newborns are vocal cord paralysis and subglottic stenosis. Stridor may present immediately at birth or within days to months. Stridor is a sign, not a diagnosis, and persistent stridor in a neonate necessitates formal diagnostic evaluation. Although laryngomalacia, the most common cause of neonatal stridor, typically has a favorable course and requires little intervention, stridor may signal a potentially progressive airway lesion that mandates urgent action. However, with proper evaluation and management, most infants with neonatal stridor have a good prognosis.

Pathophysiology and Clinical Features Stridor can emanate from obstruction at any level of the larger airways. It can be explained using the Bernoulli principle: when

5. Subglottic stenosis presents with stridor and airway obstruction and can be either congenital or acquired from prior endotracheal intubation. 6. Subglottic hemangiomas should be suspected when stridor develops in infants 1 to 2 months of age, especially when cutaneous hemangiomas are also seen.

airway diameter decreases at the level of an obstruction, air flow velocity increases exponentially, resulting in negative pressure and airway collapse behind it. Therefore typical laminar flow is disrupted and the turbulent flow results, vibrating the surrounding upper airway soft tissues with resultant stridor.1 The larynx has three subsites: the supraglottis, glottis, and subglottis (Fig. 67.1). The supraglottis includes the cartilaginous structures above the true vocal cords, including the epiglottis and arytenoid cartilages and the false vocal folds. The glottis includes the true vocal cords. The subglottis is the area just below the true vocal cords and includes the cricoid cartilage. Stridor may also be a result of narrowing of the trachea, which is composed of C-shaped cartilaginous rings with a muscular membrane posteriorly. Clinical features of a newborn with stridor often suggest the site of obstruction and likely pathology (Table 67.1). A careful clinical assessment will allow appropriate timing and selection of diagnostic studies.

Supraglottic Larynx The presence of inspiratory stridor most often portends supraglottic obstruction. The supraglottis is involved with respiration and with airway protection during swallowing and as such has several moving parts. Laryngomalacia is the inspiratory collapse of supraglottic soft tissues and accounts for most cases of neonatal stridor (Fig. 67.2). Multiple etiologic theories have been proposed, with roles for supraglottic anatomic abnormalities, immature supraglottic cartilages, neuromotor abnormalities, or gastroesophageal reflux disease (GERD).2 One prospective study of 201 infants with laryngomalacia supports abnormal sensorimotor integrative function as an etiologic theory, with laryngeal tone and sensorimotor integrative function found to be altered and correlated with disease severity.3

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Chapter 67 |  Stridor and Laryngotracheal Airway Obstruction in Newborns   583

Stridor • Inspiratory – Supraglottic/epiglottic – Vocal cords/glottic • Biphasic – Glottic – Subglottic • Expiratory – Tracheal – Bronchial

Fig. 67.1  Depiction of Laryngotracheal Anatomic Sites Related to Stridor.

Laryngomalacia is characterized by high-pitched, inspiratory stridor that manifests within the first 2 weeks of birth. Stridor is exacerbated with agitation or exertion and typically worsens while supine and improves when prone or upright. Stridor may be associated with feeding difficulties (including coughing, choking, and

regurgitation). Laryngomalacia often coexists with gastroesophageal reflux. One systematic review examining the relationship between laryngomalacia and gastroesophageal reflux found an overall reflux prevalence of 59% among infants with laryngomalacia, with three studies finding increased prevalence of reflux among infants with more severe laryngomalacia.4 However, a causal relationship with GERD and laryngomalacia cannot be inferred, at least with existing studies. Laryngomalacia may also coexist with other comorbidities including neurologic disease (such as seizure disorders, cerebral palsy, microcephaly, and Chiari malformation), synchronous secondary airway lesions (such as tracheomalacia or subglottic stenosis), congenital heart disease, or genetic disorders (commonly Down syndrome).5 Laryngomalacia is characterized as mild, moderate, or severe based on the degree of airway obstruction and of feeding impairment. Most infants with laryngomalacia have mild disease, consisting of stridor without signs of respiratory difficulties (such as retractions, nasal flaring, tachypnea, etc.) and no major feeding symptoms. In the majority of infants with mild laryngomalacia, it resolves by age 12 to 18 months. Infants with moderate laryngomalacia have stridor that is associated with frequent feeding-related symptoms, including coughing, choking, and transient periods of respiratory distress. Infants with moderate laryngomalacia typically improve with acid suppression therapy and feeding modification strategies, including upright positioning or thickened feeds. Infants with severe

Table 67.1  Clinical Features Condition

Clinical Presentation

Symptom Onset, Severity, and Progression

Key Diagnostic Procedure and Additional Tests to Consider

SUPRAGLOTTIS Laryngomalacia

• High-pitched, inspiratory stridor, worse with agitation or when supine, better at rest or when prone • Feeding problems/GERD • May be associated with OSA, FTT, ALTEs, or neuromotor disease

Onset: first 2 weeks of life Severity: most commonly mild, but can be severe Progression: may initially worsen; typically resolved in 6–18 months

Fiberoptic laryngoscopy • Swallowing evaluation (VFSS/FEES) • Polysomnography • Imaging or direct laryngoscopy/ bronchoscopy to rule out second airway lesions

Cysts (saccular, ductal, vallecular)

• Inspiratory stridor (may mimic laryngomalacia by causing supraglottic obstruction or epiglottis prolapse into airway) • May have associated abnormal cry/ feeding difficulties

Onset: at birth Severity: variable with size/location of mass Progression: stable

Fiberoptic laryngoscopy • Imaging or direct laryngoscopy/ bronchoscopy to rule out second airway lesions

Vocal cord paralysis

• Unilateral: mild high-pitched inspiratory stridor, hoarse or weak cry • Bilateral: inspiratory stridor from birth (may be severe), respiratory distress; typically a normal cry • May be associated with neck or chest/cardiac surgery or CNS abnormalities (e.g., Chiari malformation, hydrocephalus)

Onset: congenital paralysis manifests at birth; acquired paralysis may present after extubation or after neck/chest procedure Severity and progression: variable; many cases resolve over time

Fiberoptic laryngoscopy • Unilateral paralysis may warrant echocardiogram or other tests of cardiac anatomy • Congenital bilateral paralysis warrants CNS imaging

Glottic web

• Abnormal cry (high-pitched or weak) • Biphasic stridor and airway obstruction, worse with larger webs • May be associated with 22q11 deletions (VCFS, DiGeorge)

Onset: at birth Severity: variable Progression: stable

Fiberoptic laryngoscopy • Genetic testing • Tests of cardiac anatomy if VCFS is suspected • Laryngoscopy/bronchoscopy to look for SGS

Iatrogenic vocal cord injury

• Inspiratory or biphasic stridor, abnormal/hoarse cry • Associated with airway manipulation

Onset: within hours to days of extubation Severity and progression: variable

Fiberoptic laryngoscopy

GLOTTIS

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584  Section 13  |  ENT and Auditory Conditions

Table 67.1  Clinical Features—Cont’d Clinical Presentation

Symptom Onset, Severity, and Progression

Key Diagnostic Procedure and Additional Tests to Consider

Subglottic stenosis and subglottic cyst

• Inspiratory or biphasic stridor • Barky cough or repeated croup-like illnesses • Acquired SGS or cysts associated with history of intubation or extubation failure

Onset: congenital SGS may manifest at birth or later; acquired SGS or cysts may present within hours to days of laryngeal manipulation or extubation Severity and progression: variable

Laryngoscopy and bronchoscopy in operating room

Subglottic hemangioma

• Inspiratory or biphasic stridor • Barky cough or recurrent croup-like illnesses • May be associated with cutaneous hemangioma or PHACES

Onset: 4–6 weeks after birth Severity and progression: rapidly progressive within several months of diagnosis if not treated

Laryngoscopy and bronchoscopy in operating room

Tracheomalacia

• Expiratory stridor, wheezing, apneic events if severe • Feeding difficulties, possible recurrent respiratory infections • Extubation failure • May be associated with cardiovascular anomalies

Onset: at birth if severe; may be within weeks to months Severity and progression: variable

Flexible tracheobronchoscopy during spontaneous respiration • PFTs • Consider airway fluoroscopy • Chest imaging if suspicious of cardiothoracic abnormalities

Vascular rings

• Expiratory stridor, respiratory distress, apneic spells • Feeding difficulties • May be associated with genetic disease or cardiovascular anomalies

Onset: at birth Severity: may be severe Progression: typically stable

CT or MR angiography • Laryngoscopy and bronchoscopy in operating room • Echocardiogram

Tracheal stenosis

• Expiratory or biphasic stridor • Respiratory distress, apneas dependent on degree of obstruction • Often associated with cardiovascular abnormalities, bronchial anatomic abnormalities, genetic conditions

Onset: at birth Severity and progression: variable

Laryngoscopy and bronchoscopy in operating room • Chest CT

Condition

SUBGLOTTIS

TRACHEA

ALTE, Apparent life-threatening event; CNS, central nervous system; CT, computed tomography; GERD, gastroesophageal reflux disease; FEES, fiberoptic endoscopic evaluation of swallow; FTT, failure to thrive; MR, magnetic resonance; OSA, obstructive sleep apnea; PFT, pulmonary function test; PHACES, posterior fossa malformations–hemangiomas–arterial anomalies–cardiac defects–eye abnormalities–sternal cleft and supraumbilical raphe; SGS, subglottic stenosis; VCFS, velocardiofacial syndrome; VFSS, video fluoroscopic swallow study.

Fig. 67.2  Laryngomalacia. Note the curled, omega-shaped epiglottis seen in a patient intubated for surgery.

laryngomalacia are those who have stridor associated with severe respiratory and feeding symptoms, including apneic spells, aspiration, recurrent cyanosis, and failure to thrive. Infants within this category often require surgical intervention.2 Congenital laryngeal cysts are a rarer cause of supraglottic obstruction, with an estimated incidence of 1.8 to 3.5 per 100,000 live births. They may be saccular or ductal.6 Saccular cysts arise within the laryngeal saccule just above the vocal cords and may result from atresia or obstruction of the laryngeal ventricular opening. They may be contained to the larynx or may extend to extralaryngeal tissues.7 Ductal cysts result from obstruction of submucosal salivary ducts, leading to mucous-retention cysts. Vallecular cysts are a type of ductal cyst that arise within the space at the base of the tongue that marks the boundary between the pharynx and larynx. Vallecular cysts originate outside the supraglottis, but they can cause supraglottic obstruction by posterior displacement of the epiglottis (Fig. 67.3). Histologic analysis of laryngeal cysts may reveal either squamous or respiratory epithelium. Infants with congenital laryngeal cysts may present with inspiratory stridor and respiratory distress soon after birth. Infants with smaller cysts may not have significant stridor and may instead present later with feeding difficulties or incidentally.6,7

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Chapter 67 |  Stridor and Laryngotracheal Airway Obstruction in Newborns   585

Fig. 67.4  Congenital Anterior Glottic Web.

Fig. 67.3  Vallecular Cyst Causing Posterior Displacement of the Epiglottis.

Glottic Larynx Vocal cord paralysis is the second most common cause of neonatal stridor. Vocal cord paralysis can be unilateral or bilateral, and it can be congenital or acquired. Congenital vocal cord paralysis may be related to anomalies of the central nervous system that cause dysfunction of the vagus nerve (such as Chiari malformation, hydrocephalus, or cerebral palsy)8 or idiopathic. Unilateral vocal cord paralysis is more likely to be acquired and may be associated with birth difficulties such as difficult forceps delivery or nuchal umbilical cord.9 Unilateral vocal cord paralysis can be seen after cardiothoracic surgery or treatment with extracorporeal membrane oxygenation therapy (ECMO), because these procedures can cause recurrent laryngeal nerve injury in the neck or the chest.10,11 Bilateral and unilateral vocal cord paralysis have also been seen after periods of endotracheal intubation. Infants with bilateral vocal cord paralysis may present with severe inspiratory or biphasic stridor and even respiratory distress. The cry is typically normal because the vocal cords usually can oppose, but they do not abduct for adequate respiration. Infants with unilateral paralysis rarely are distressed and they present with a hoarse cry. Anterior glottic webs are a less common cause of neonatal stridor at the glottic level, accounting for approximately 5% of congenital laryngeal abnormalities (Fig. 67.4).12 Glottic webs occur when the laryngeal lumen fails to recanalize during embryologic development, a process that occurs between weeks 8 and 10.13 Glottic webs range from mild (0.40 for a lengthy period. The approach to treatment in the newborn population is similar to that for older patients. Opioid medications remain the mainstay of treatment for dyspnea in the dying newborn. In addition to the opioid medications already discussed here, intranasal fentanyl offers quick onset and does not require IV access. Sublingual morphine can also be used for dyspnea, but there are some concerns for adequate absorption, and the time to absorption can be greater than 2 hours. Prompt relief of air hunger is desirable and should be pursued. Like most facets of symptom management at the end of a newborn's life, additional research would be beneficial.

Sialorrhea Secretions can be problematic and cause a “death rattle” that is distressing to families and loved ones of a dying neonate. Deep suctioning can be traumatic to patients, but alleviation of some secretions through clinician or parental oral and pharyngeal suctioning is acceptable. In older pediatric patients, atropine drops administered sublingually have been shown to effectively decrease secretions,32 and transdermal scopolamine is frequently used in the adult hospice population.33 However, neither of these has been studied in the newborn population, and therefore they have not been accepted into common practice.

Myoclonus Myoclonic jerking may occur in the neonate as a result of hypoxic ischemic brain damage or an immature central nervous system or as a side effect from another medication that is being used in the treatment of agitation or pain—frequently opioids, most classically morphine. Myoclonus can be a distressing symptom, particularly to family members of infants at the EOL. Management should be focused on reversing the underlying cause if possible, i.e., stopping medications that may contribute to myoclonic jerking. If the jerking is not determined to be the side effect of a medication, discussion with the family and reassurance may be helpful. Avoid using neuromuscular blocking agents simply to mask myoclonus, because this only introduces additional concerns, including a need for complete ventilator support (and again, this may make some clinicians uneasy because this class of agents has been used in euthanasia).

Seizures If a patient is known to have an underlying seizure disorder, any established anticonvulsant medications should be continued. Hypoxia at the EOL may result in seizures, and maintaining a route to easily administer additional anticonvulsant medications may be desirable. Although any uncontrolled symptom can be difficult to witness in a dying child, seizures are particularly distressing for families. This is likely due to the physical manifestations of convulsing as visible evidence of suffering. As previously mentioned, some benzodiazepines including lorazepam and midazolam are frequently used as pain adjuncts and anxiolytics at the EOL. These conceivably may also aid in seizure control, because both have been used for refractory seizures in the critically ill neonate. Midazolam has also been studied in the palliative care setting.34

Nonpharmacologic Interventions Although medical management is extremely valuable in the relief of symptoms, nonpharmacologic interventions for pain and anxiolysis

are effective and convenient and may be considered primary interventions from which to start. They are safe and often allow for less “technical” interventions—allowing family caregivers to contribute to the care and management of their loved one at the EOL. Interventions that have been studied and shown to reduce pain in neonates in the ICU include facilitated tuck/swaddling, skin to skin (also called kangaroo care), holding, sucrose administration, massage, breastfeeding, and nonnutritive sucking.35,36 A recent study demonstrated decreased pain scores in infants exposed to the diffused odor of their mother's breast milk.37 The majority of these interventions have been studied in procedural pain, and extensive literature in the palliative care context does not exist. However, because of the high potential for benefit with minimal to no risk, it may be reasonable to recommend any or all of these to aid in comfort at a neonate's EOL. Studies have demonstrated that parents recognize the environment as an important component of the EOL experience, both positive and negative.38 Having family rooms, spaces for parents to sleep, etc. were shown to be positive associations. Bright lights, noise, and technology were suggested to be negative associations. Parents of a dying infant should be allowed and encouraged to hold their child, skin to skin or swaddled as desired, and incorporate comforting touch, soothing sounds, and suckling. Notably, parents also express that the location of death was not as important as the people who were present for the death of their child.

Symptom Management in the Actively Dying Neonate The circumstances surrounding the actively dying infant require special consideration. There should be efforts made, ideally prior to the final days or hours of a child's life, to determine the family's goals, hopes, and wishes for the dying process. Helping families achieve these goals may require a skilled interdisciplinary team. Healthcare professionals who work in the NICU typically have experience and some training in EOL management. However, when there are symptoms that are difficult to control, when there is distress among the medical team and/or family, or when additional support is needed, subspecialty consultation can be beneficial. For example, if medications that are considered the standard of care for management of newborn distress are insufficient for pain/symptom control and additional agents are being considered, pain management or palliative care teams may be helpful. Some families may desire religious rituals to be performed, photographs taken, and many other important experiences. Medical management and adequate symptom control play an important role in creating a peaceful environment for the EOL. To help facilitate the appropriate environment for the dying process, unnecessary procedures and interventions such as lab draws and monitoring of vital signs should be reduced. These can cause additional patient pain, exacerbate symptoms, and contribute to caregiver distress (both parents and staff). Additional considerations should include the location of death (in the NICU or a rooming-in room, on a hospital ward, in a palliative care suite, or at home), understanding that there may be specific circumstances, logistics, or safety concerns that affect each of these choices. It is typically very comforting for both the baby and family to allow patient holding, but this too may require special or unique considerations to respect safety and minimize any associated decompensation during the process. As the EOL approaches, it is the responsibility of the healthcare team to provide continual assessment and management of the

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782  Section 18  |  Current State of Neonatal Palliative Care

patient's and family's needs. Informed clinicians should strive for open communication and can both lead and partner with parents in advocating for adequate symptom management. Additionally, these clinicians can provide anticipatory guidance about the dying process, including decreasing tone, perfusion, and temperature; changes in color; waning responsiveness; and changes in the respiratory pattern. The progression to death may also be impacted by the need to withdraw life-supporting medical technology. Clinicians should be prepared to counsel families on how each step of procedures and removal of medical equipment and devices will impact the patient and any expected changes that may be observed.

Conclusion The death of a neonate is always a tragedy. Similarly distressing are uncontrolled symptoms, particularly in this exceptionally vulnerable population. It is the goal of the medical team, including NICU staff and subspecialty teams, to provide care to these patients even through their deaths by minimizing suffering and maximizing comfort. This chapter has laid out a variety of pharmacologic and nonpharmacologic interventions that should be considered and used in the NICU when a patient is receiving palliative care and particularly in the period surrounding the EOL.

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Chapter 90 |  Pain and Symptom Management in Newborns Receiving Palliative and End-of-Life Care  782.e1

REFERENCES

1. Carter BS, Brunkhorst J. Neonatal pain management. Semin Perinatol. 2017;41(2):111–116. 2. Anand KJ. Pain and its effects in the human neonate and fetus. N Engl J Med. 1987;317(21):1321–1329. 3. Carbajal R, Rousset A, Danan C, et al. Epidemiology and treatment of painful procedures in neonates in intensive care units. JAMA. 2008;300(1):60. 4. Chan JD, Treece PD, Engelberg RA, et al. Narcotic and benzodiazepine use after withdrawal of life support. Chest. 2004;126(1):286–293. 5. Zimmerman KO, Hornik CP, Ku L, et al. Sedatives and analgesics given to infants in neonatal intensive care units at the end of life. J Pediatr. 2015;167(2):299–304.e3. 6. Carter BS, Jones PM. Evidence-based comfort care for neonates towards the end of life. Semin Fetal Neonatal Med. 2013;18(2):88–92. 7. Harlos MS, Stenekes S, Lambert D, Hohl C, Chochinov HM. Intranasal fentanyl in the palliative care of newborns and infants. J Pain Symptom Manage. 2013;46(2):265–274. 8. Fahnenstich H, Steffan J, Kau N. Fentanyl-induced chest wall rigidity and laryngospasm in preterm and term infants. Crit Care Med. 2000;28(3): 836–839. 9. Vaughn PR, Townsend SF, Thilo EH, McKenzie S, Moreland S, Denver KK. Comparison of continuous infusion of fentanyl to bolus dosing in neonates after surgery. J Pediatr Surg. 1996;31(12):1616–1623. 10. McClain BC, Probst LA, Pinter E, Hartmannsgruber M. Intravenous clonidine use in a neonate experiencing opioid-induced myoclonus. Anesthesiology. 2001;95(2):549–550. 11. Agthe AG, Kim GR, Mathias KB, et al. Clonidine as an adjunct therapy to opioids for neonatal abstinence syndrome: a randomized, controlled trial. Pediatrics. 2009;123(5):e849–e856. 12. Provoost V, Cools F, Bilsen J, et al. The use of drugs with a life-shortening effect in end-of-life care in neonates and infants. Intensive Care Med. 2006;32(1):133–139. 13. Partridge JC, Wall SN. Analgesia for dying infants whose life support is withdrawn or withheld. Pediatrics. 1997;99(1):76–79. 14. Sulmasy DP, Pellegrino ED. The rule of double effect. Arch Intern Med. 1999;159(6):545. 15. Irikura M, Minami E, Ishitsuka Y, Kawase A, Kondo Y, Irie T. Abnormal movements of Japanese infants following treatment with midazolam in a neonatal intensive care unit: incidence and risk factors. ISRN Pharmacol. 2012;2012:1–5. 16. O'Connell C, Ziniel S, Hartwell L, Connor J. Management of opioid and sedative weaning in pediatric congenital heart disease patients: assessing the state of practice. Dimens Crit Care Nurs. 2017;36(2):116–124. 17. Lam F, Bhutta AT, Tobias JD, Gossett JM, Morales L, Gupta P. Hemodynamic effects of dexmedetomidine in critically Ill neonates and infants with heart disease. Pediatr Cardiol. 2012;33(7):1069–1077. 18. Edwards L, DeMeo S, Hornik CD, et al. Gabapentin use in the neonatal intensive care unit. J Pediatr. 2016;169:310–312. 19. de Leeuw TG, Mangiarini L, Lundin R, et al. Gabapentin as add-on to morphine for severe neuropathic or mixed pain in children from age 3 months to 18 years—evaluation of the safety, pharmacokinetics, and efficacy of a new gabapentin liquid formulation: study protocol for a randomized controlled trial. Trials. 2019;20(1):49. 20. Harma A, Aikio O, Hallman M, Saarela T. Intravenous paracetamol decreases requirements of morphine in very preterm infants. J Pediatr. 2016;168:36–40.

21. Reynolds SL, Bryant KK, Studnek JR, et al. Randomized controlled feasibility trial of intranasal ketamine compared to intranasal fentanyl for analgesia in children with suspected extremity fractures. Acad Emerg Med. 2017;24(12):1430–1440. 22. Singh V, Gillespie TW, Harvey RD. Intranasal Ketamine and its potential role in cancer-related pain. Pharmacotherapy: J Human Pharmacology Drug Ther. 2018;38(3):390–401. 23. Yanay O, Brogan TV, Martin LD. Continuous pentobarbital infusion in children is associated with high rates of complications. J Crit Care. 2004;19(3):174–178. 24. Tobias JD. Tolerance, withdrawal, and physical dependency after longterm sedation and analgesia of children in the pediatric intensive care unit. Crit Care Med. 2000;28(6):2122–2132. 25. Traube C, Silver G, Kearney J, et  al. Cornell Assessment of Pediatric Delirium: a valid, rapid, observational tool for screening delirium in the PICU. Crit Care Med. 2014;42(3):656–663. 26. Harris J, Ramelet AS, van Dijk M, et al. Clinical recommendations for pain, sedation, withdrawal and delirium assessment in critically ill infants and children: an ESPNIC position statement for healthcare professionals. Intensive Care Med. 2016;42(6):972–986. 27. Brahmbhatt K, Whitgob E. Diagnosis and management of delirium in critically Ill infants: case report and review. Pediatrics. 2016; 137(3):e20151940. 28. Edwards LE, Hutchison LB, Hornik CD, Smith PB, Cotten CM, Bidegain M. A case of infant delirium in the neonatal intensive care unit. J Neonatal Perinatal Med. 2017;10(1):119–123. 29. Groves A, Traube C, Silver G. Detection and management of delirium in the neonatal unit: a case series. Pediatrics. 2016;137(3):e20153369. 30. Patel AK, Biagas KV, Clarke EC, et al. Delirium in children after cardiac bypass surgery. Pediatr Crit Care Med. 2017;18(2):165–171. 31. Omayma K, Simone S, Lardieri AB, Graciano AL, Tumulty J, Edwards S. Antipsychotic treatment of delirium in critically Ill children: a retrospective matched cohort study. Pediatr Pharmacol Ther. 2019; 24(3):204–213. 32. Kintzel PE, Chase SL, Thomas W, Vancamp DM, Clements EA. Anticholinergic medications for managing noisy respirations in adult hospice patients. Am J Health Syst Pharm. 2009;66(5):458–464. 33. Norderyd J, Graf J, Marcusson A, et  al. Sublingual administration of atropine eyedrops in children with excessive drooling—a pilot study. Int J Paediatr Dent. 2017;27(1):22–29. 34. Zaporowska-Stachowiak I, Szymański K, Oduah M-T, Stachowi ak-Szymczak K, Łuczak J, Sopata M. Midazolam: safety of use in palliative care: a systematic critical review. Biomed Pharmacother. 2019; 114:108838. 35. Harrison D, Reszel J, Bueno M, et al. Breastfeeding for procedural pain in infants beyond the neonatal period. Cochrane Database Syst Rev. 2016;10:CD011248. 36. Johnston C, Campbell-Yeo M, Disher T, et  al. Skin-to-skin care for procedural pain in neonates. Cochrane Database Syst Rev. 2017; 2:CD008435. 37. Baudesson de Chanvill AB-M, V, Garbi A, Tosello B, et al. Analgesic effect of maternal human milk odor on premature neonates: a randomized controlled trial. J Hum Lact. 2017;33(2):300–308. 38. Brosig CL, Pierucci RL, Kupst MJ, Leuthner SR. Infant end-of-life care: the parents’ perspective. J Perinatol. 2007;27(8):510–516.

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Section 18 CHAPTER

91

Palliative Care Family Support in Neonatology Erin R. Currie, Hema Navaneethan, Meaghann S. Weaver

KEY POINTS maintaining hope and managing uncertainty related to their infant’s prognosis. 3. Palliative care requires interdisciplinary specialty groups who seek to work with seriously ill infants and their families to provide comprehensive treatment of suffering. 4. Families’ spiritual needs to be considered. End-of-life care is extremely important to bereaved

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Core palliave care services for paent (comfort care, sibling support) and for families (spiritual care, counseling, nursing teams)

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Cynthia is a 26-year-old woman from Mississippi who is pregnant with her third child. Cynthia and the child’s father are no longer together; the father of the baby is involved but lives in another city 45 minutes away. Cynthia currently lives in a small town and travels nearly 2 hours to the nearest tertiary care hospital for the majority of her medical care. Cynthia arrives at her 20-week ultrasound appointment. During the ultrasound, Cynthia can tell something is wrong. Her worries are confirmed when she and her mother are unexpectedly asked to meet with a

Specialist services for comfort care for infant

pd

Clinical Case Report

maternal-fetal medicine specialist after the ultrasound. Cynthia is heartbroken as she learns her baby, a boy, has multiple congenital malformations. Although the maternal-fetal medicine specialist states that additional testing is needed, she explains to Cynthia that she will likely have difficult decisions to make soon. The specialist predicts the fetus may survive until delivery, but it is unclear how long he may survive after birth. If he

ou

Prenatal Phase

NICU parents as they cling to the limited memories of their deceased infant. 5. Family bereavement supports may include individual/family counseling, spiritual support, efforts to encourage verbal and/or nonverbal expression in parent groups, family camps, longitudinal staff remembrances, and follow-up meetings.

Gr

In this chapter we will describe the evidence for palliative care family support beginning in the prenatal period and extending to acute and chronic neonatal intensive care unit (NICU) care and finally to bereavement. Neonatal providers have the unique opportunity to improve family-centered care for patients and families experiencing serious illness in the NICU and to make a long-term impact on NICU families’ lives (Fig. 91.1). For infants who do not survive, neonatal providers may improve the care leading up to death and affect parent grief experiences by facilitating an interdisciplinary palliative approach and supporting families to create meaningful and positive memories despite the limitations of an intensive care unit (ICU) environment. However, there are challenges to implementing this palliative approach and providing care that is concordant with family wishes (Fig. 91.2). Perinatal palliative care (PPC) as an additional layer of family support is often delayed until death is imminent, preventing families from experiencing the full range of this layer of support. Beginning with a fetal diagnosis, families require intensive support given the extremely difficult decisions they must make in the event of a life-limiting or life-threatening diagnosis. During a NICU hospitalization, the infant’s state of clinical uncertainty and unknown survival makes decision-making very difficult for families, and they require intensive support to balance their new identity as a “NICU parent” with life and other demands outside of the hospital. Medical advancements have decreased the number of perinatal and infant deaths over time; however, there are now more infants surviving with chronic critical illness, and families continue to require support as their goals of care shift.

Gr o

1. Neonatal intensive care unit (NICU) admission rates have increased over time, with a consequent increase in the number of extremely premature and critically ill infants who are at risk of chronic illness and mortality. 2. The death of an infant is one of the most devastating and difficult experiences in life. Parents of seriously ill infants bear many roles such as caregiver, advocate, and decision-maker while

Assigned care-provider for coordinaon

Fig. 91.1  Care of Critically Ill Infants and Their Families. Support for patients and families should be integrated with ongoing medical care.

Life-prolonging/curative therapy Palliative care

D E A T H

Bereavement

Time Diagnosis Fig. 91.2  Current Accepted Model for Care of Infants at Serious Risk of Mortality. (Reproduced with permission and modifications from Natbony. Palliative care. In: Harriet Lane Handbook, ch. 23, 566–573.e1.)

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784  Section 18  |  Current State of Neonatal Palliative Care

survives, the specialist worries he will never breathe on his own and will have severe delays in development. The specialist shares with Cynthia that there are multiple care pathways to consider at this time, but given the severity of the anomalies, she encourages Cynthia to think about termination of the pregnancy. Cynthia is overcome with sadness and grief. Cynthia has a strong faith tradition and fears judgment for even considering termination of the pregnancy. She is torn because she also worries her child will not have the quality of life she would want for him. Cynthia is left feeling completely overwhelmed and is unsure how to proceed.

Epidemiology of Perinatal Death and Parent Outcomes With advancements in perinatal medicine, perinatal mortality has steadily declined during the past several decades, although it has begun to plateau in more recent years.1,2 In 2016, the perinatal mortality rate in the United States was 6.0 deaths per 1000 live births.2 Although there have been overall declines in perinatal mortality rates, a large disparity remains in outcomes related to race and geography. The mortality rate of infants born to non-Hispanic Black women is more than twice that of non-Hispanic White women, and the southern states of Mississippi and Alabama have consistently had worse outcomes than the rest of the country.2 It is important to recognize that perinatal loss is a traumatic event with long-lasting parental effects. Gold et al.3 found that after a perinatal loss, bereaved mothers had four times higher odds of depressive symptoms and seven times higher odds of posttraumatic stress disorder symptoms. Although no differences in symptom levels were noted among races, disparities in treatment were noted. African American mothers who screened positive for posttraumatic stress disorder or depression were much less likely to receive treatment.3 Perinatal loss also affects the marital dyad. Couples who had stillbirths were at higher risk of dissolution of their relationship in the decade following the death compared with those who did not have a fetal loss.3 In 2017, congenital malformations were the most common cause of infant mortality in the United States.4 Many advancements in perinatal medicine have led to earlier and more accurate fetal diagnoses. Although these early forms of screening can provide families and clinicians with beneficial information regarding the health of the mother and fetus, parents are often not prepared for a potentially life-threatening or life-limiting diagnosis for their child.6

Role of Perinatal Palliative Care Parents who have received news of a life-limiting or life-threatening fetal diagnosis describe “grieving multiple losses,” including the loss of their healthy baby, the loss of a normal pregnancy, and the loss of future parenting.7 After the diagnosis of a life-limiting or life-threatening fetal diagnosis, the American College of Obstetricians and Gynecologists committee on ethics and the American Academy of Pediatrics committee on bioethics recommend that the “full range of options, including fetal intervention, postnatal therapy, palliative care or pregnancy termination” be discussed with families.8 Early PPC, introduced at the time of diagnosis, may help develop a trusting relationship and can guide decision-making and support parental needs during this complex time. PPC brings the interdisciplinary approach into the prenatal period and the immediate postnatal period (see Fig. 91.1). An interdisciplinary approach is vital to palliative care principles and should be integrated throughout the care of the patient and family.5,6 For example, social workers often work with the PPC team to identify financial or counseling resources, child life specialists can assist with

preparing siblings for the birth and possibly death of a newborn, and lactation specialists may assist the mothers with either weaning off of breast milk or donating their breast milk.

Spiritual and Cultural Considerations A family’s spiritual needs and wishes should be considered at all points in care. Parents may struggle with existential questions after the diagnosis of a life-limiting condition. In a study evaluating values applied to parental decision-making in delivery room resuscitations, family decision-making was largely steered by religion, spirituality, and hope as opposed to the medical information presented.7 Wishes for spiritual or cultural rituals should be coordinated whenever possible. The care team should be aware of any culture-specific customs or practices and honor them whenever able.7,8

Communication After news of a life-limiting or life-threatening diagnosis, parents are often forced to make difficult and often time-sensitive decisions regarding multiple aspects of care for their child. Communication and information delivery during this prenatal time is crucial. In a study of 19 families given the prenatal diagnosis of trisomy 18, the majority of parents felt they were not appropriately informed about the potential diagnosis during the screening process and believed ultrasound findings were poorly communicated.9 From the same study, empathic communication was found to be essential in parents’ overall satisfaction with care.9 It is important to recognize that a family’s communication needs may vary. Whereas some families may choose to seek out additional information regarding the diagnosis, others may avoid it as a method of coping.10 Dialogue with parents about their preferred communication styles and approach to receiving information is important in making sure parental needs are being met. Prenatal consultation with neonatologists provides parents with the opportunity to discuss care and talk through decisions specific to their child and family. Miquel-Verges et al. conducted interviews with 22 women after a diagnosis of congenital anomalies and discovered parents valued five major themes in prenatal consultation.11 Parents valued the opportunity to feel prepared, have a knowledgeable physician, have a caring physician, have the opportunity to allow hope, and spend time with the physician. Parents also felt touring the NICU beforehand equipped them with additional knowledge and helped them feel more prepared for a transition to NICU care.12

Prenatal Decisions: Termination, Imaging, Monitoring After a discussion of possible options, some parents face the difficult decision of continuation or termination of the pregnancy. In a study by Breeze et al., the median time for parents to decide on termination or continuation of pregnancy was 1.5 days (range, 0–8 days), illustrating the urgent nature in which this decision must sometimes be made.12 Parents’ decision to continue or terminate a pregnancy may be multifactorial. In a study by Guon et al. of 332 parents who chose continuation of pregnancy in the setting of a trisomy 13 or trisomy 18 diagnosis, themes of moral beliefs and child-centered reasons such as love for their child, the value of their child, and uncertain outcomes affected their decision to continue the pregnancy.13 Families who choose continuation of pregnancy often hear messaging to terminate the pregnancy or face feeling unsupported by their medical team.14 Ongoing maternal and fetal care, including potential interventions and monitoring, should be discussed and individualized to facilitate plans

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Chapter 91 |  Palliative Care Family Support in Neonatology  785

matching parental goals.15 Offering families routine fetal surveillance may provide reassurance and add a sense of normalcy to the pregnancy.15 Routine surveillance and standardized testing such as ultrasounds can also promote memory-making and bonding. In a qualitative study, seven parents were interviewed who received life-threatening fetal diagnoses, and all parents expressed their desire to hear the fetal heartbeat and see ultrasound images as a chance to “get to know their baby.”16

Delivery Decisions: Location, Mode, and Infant Care Parental preferences surrounding intrapartum care should be discussed in conjunction with the obstetrician and neonatologist or pediatrician (see Fig. 91.2). Parents who reported struggling for control over prenatal and delivery options were reported to have lower levels of satisfaction with care.9 The location of delivery is one component that should be reviewed. Based on parental goals, some families may choose to deliver within their community to be closer to home and familiar supports. Some families may plan for delivery in a larger, tertiary care center with additional access to neonatology and potential life-sustaining measures.9 The mode of delivery is another key component to be evaluated. Although vaginal delivery has been previously considered the recommended mode of delivery in the setting of a lethal diagnosis, a cesarean section may be considered in some situations. Women may request a cesarean section with the goal of delivering a live infant.14,15 Parents were noted to be dissatisfied with care in situations where physicians declined to perform a cesarean section when requested at the time of delivery.9 Reviewing steps of resuscitation with the family and determining how these potential actions and interventions fit with their goals should be completed prenatally whenever possible. For families planning on a focus on comfort after delivery, it is important to discuss anticipated symptom management needs.8,15 Plans for memory-making activities such as photographs, hand and foot prints, and molds may also be coordinated prior to delivery when possible. Communication of intrapartum plans should be shared with all members of the care team who may participate in the delivery and provide ongoing care to ensure parental wishes are met.15

Ongoing Decisions: The Unexpected and the Uncertain Recognizing the limitations of prognostication that remain despite technological advancements, preparing families for unexpected outcomes is an important step (Table 91.1). Introducing families to potential decisional points they may face in the future allows parents the opportunity to consider these complex choices in a more controlled setting. This may include reviewing potential ongoing interventions or familial wishes for discharge with hospice support if feasible.18,19 Diagnosis of a life-limiting or life-threatening prenatal diagnosis forces parents to make complex and often unexpected choices regarding the care of their child. Palliative care provides longitudinal and interdisciplinary support to families and individualized guidance centered on goals of care throughout the decision-making process.9,11,15,18,19

Acute Neonatal Intensive Care Phase Continuation of Clinical Case Report Cynthia decides to maintain her pregnancy and delivers her baby boy, named Jacob, at 28 weeks’ gestation. Upon birth, Jacob’s multiple congenital anomalies are confirmed, and he is intubated, stabilized, and

Table 91.1  Prenatal Diagnoses in Which Palliative Care Should Be Considered 1. Genetic abnormalities a. Trisomy 13, 15, or 18 b. Triploidy c. Thanatophoric dwarfism or lethal forms of osteogenesis imperfecta d. Some inborn errors of metabolism 2. Renal abnormalities a. Potter’s syndrome/renal agenesis with severe lung hypoplasia b. Some cases of polycystic kidney disease or renal failure requiring dialysis 3. Central nervous system abnormalities a. Anencephaly/acrania b. Holoprosencephaly c. Some complex or severe cases of meningomyelocele or large encephalocele d. Hydranencephaly e. Congenital severe hydrocephalus with absent/minimal brain growth f. Neurodegenerative diseases requiring ventilation 4. Heart defects a. Acardia b. Inoperable cardiac anomalies c. Hypoplastic left heart syndrome d. Ectopia cordis 5. Structural anomalies a. Some cases of giant omphalocele b. Severe congenital diaphragmatic hernia with lung hypoplasia c. Inoperable conjoined twins From Catlin A, Carter B. Creation of a neonatal end-of-life palliative care protocol. J Perinatol. 2002;22(3):184.

transferred 2 hours away to the only specialized children’s hospital in the state. During Jacob’s first week of life, he is extubated and placed on nasal continuous positive airway pressure, and feedings are started via nasogastric tube. Cynthia is still recovering from childbirth and is relieved that Jacob is stable. However, she is struggling to care for herself, Jacob, and her other two children, who are temporarily staying with her mother 2 hours away. She is on the waiting list for a room at the Ronald McDonald house and is currently residing in the NICU at the bedside. The palliative care team is now involved and is starting to talk to her about her goals of care given Jacob’s life-limiting prognosis and the likely need for chronic feeding and respiratory support. On day of life 8, Jacob develops a distended abdomen, and a necrotizing enterocolitis diagnosis is confirmed. His congenital anomalies are now complicated by surgical resection of the bowel and short-gut syndrome. Cynthia was just beginning to accept the reality of a complex, chronic illness and was hopeful to have time at home with Jacob and her family. Now, she is struggling to make decisions given the sudden change in Jacob’s clinical course.

NICU Hospitalizations and Infant Death in the United States NICU admission rates have steadily increased over time.17 In 2012, there were 77.9 NICU admissions per 1000 live births and a substantial increase in admissions for infants born weighing at least 2500 g. Therefore more and more parents are experiencing the stress of a NICU hospitalization. In 2017 more than 22,000 infants died in the United States, with the majority of infant deaths occurring in an intensive care setting.18 As with perinatal mortality, there are known racial disparities within infant mortality. Parents of non-Hispanic Black infants were twice as likely to suffer from infant mortality (11.4 per 1000 births) than were parents of non-Hispanic White infants (4.9 per 1000 births).19 These significant disparities must be addressed in the provision of culturally appropriate palliative and end-of-life care for families in the NICU. Clearly, NICU parents are a growing group within NICU family-centered care who require intensive support throughout a NICU admission.

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786  Section 18  |  Current State of Neonatal Palliative Care

Parent Experiences and Needs in an Uncertain NICU Environment NICU patients commonly oscillate between periods of stability and then intense periods of uncertain survival. During the ups and downs of NICU illness trajectories, parents of seriously ill infants bear many roles such as caregiver, advocate, and decision-maker, while maintaining hope and managing uncertainty related to their infant’s prognosis.20,21 Parents of infants in the NICU are heavily burdened psychologically, psychosocially, financially, spiritually, and physically because of the heavy demands associated with caring for a seriously ill infant and maintaining life outside of the NICU.20 These demands place parents of infants in the NICU at a higher risk for and prevalence of anxiety, depression, stress, acute stress disorder, and posttraumatic stress disorder.22 Therefore, it is critical to understand how neonatal healthcare providers may better support parents of seriously ill infants, and in particular, those infants and parents who receive end-of-life care.

Parent Support Needs Parents of seriously ill NICU patients experience unique needs in order to develop their identity as a parent and meaningful memories as a family.23 Because of the inherent uncertainty in NICU patient survival and discharge to a home setting, NICU providers should optimize the quality of time and provide opportunities for memory making regardless of prognosis. For infants who die in the NICU, these patients and families experience life together within the intensive or acute care setting.18,24 This presents limitations for parents who wish to involve other children and extended family members in their infant’s care, because there are often NICU policies preventing young children or numerous family members from visiting the NICU. Privacy is a priority for parents as they anticipate the death of their infant and wish to make the most of the limited time they have together.25 If the NICU is an open unit with multiple bed spaces in one room, transferring the patient to a private room where the restrictions on visitors are not as rigid may be an appropriate alternative for inpatient end-of-life care. Developing and maintaining the parent role in an unnatural setting such as the NICU requires careful consideration and communication from the neonatal medical team.23 Providing “normal” parenting opportunities through end-of-life care, such as holding the infant and providing hands-on care,is extremely important to bereaved NICU parents as they cling to the limited memories of their infant after death.20,23 Parents of seriously ill infants prefer communication from healthcare providers that is compassionate, sensitive, kind, sincere, nonjudgmental, and sympathetic to the stresses parents must manage while their infant is hospitalized in the ICU.25–30 Parents of infants in the NICU also reported the need for healthcare providers to take care of parents during the NICU admission by giving “permission” to leave the bedside and engage in self-care without feeling like a bad parent.20,28 Outside of the neonatal medical team, bereaved parents have reported friends, family, and religious or community groups as supportive.20 However, other NICU parents are seen as especially supportive because of the ability to express empathy and seek support from those who “know their road.”20

Cultural Differences in Parent End-of-Life Experiences Because of the known racial disparities in perinatal and infant mortality,4 it is critical to understand cultural preferences in the NICU. Brooten et al.27 found racial differences in what parents did not find helpful from healthcare providers near their child’s death. White and Hispanic parents reported insensitive and nonsupportive staff as the

most unhelpful characteristics, whereas Black parents reported conflict between providers and parents as the least helpful.27 Davies et  al.31 explored the palliative care experiences of Mexican and Chinese American parents and found less optimal patterns of communication, including no information or basic information regarding prognosis of the child’s health status. This resulted in parent frustration, anger, and sadness.31 If interpretation is required, the interpreter must be trained to provide accurate information to the families, even if it is “bad news.” Providing honest, compassionate communication to families is essential to build trust between the medical team and the family. Lack of accurate interpretation could result in the perpetuation of cultural barriers and make the already tragic experience worse for these vulnerable parents.

Decision-Making: Central Role for Parents in the NICU Decision-making is often shared between the parents and neonatal medical team. High-quality communication from the medical team is critical for parents to join in informed, goal-concordant decisions. Parents of infants hospitalized in a NICU preferred straightforward information that was presented in a positive way due to parental beliefs of medical miracles and the importance of maintaining hope in the decision-making process.30,32 However, the fast-paced clinical changes and urgent nature of decisions make this a difficult process for clinicians and parents. Parents often receive updates and prognostic information in clinician-parent conferences. During these conferences, parents are presented with complex clinical information and sometimes uncertain prognoses.33

Conflicts Between the Healthcare Team and Parents Parents often have different opinions and beliefs about survival of preterm infants than their neonatal providers do. Boulais et  al.34 conducted a study comparing concern for infant mortality among perinatal and neonatal physicians and parents of infants who were discharged alive from the NICU. Physicians believed that parental concern for mortality increased with decreased gestational age.34 However, parents were just as worried for their infants no matter the gestational age of their infant. 34 Parental concern for mortality was, however, associated with infant length of stay and the documentation of at least one discussion regarding infant mortality with physicians.34 It is clear that conversations with clinicians have an impact on family understanding; thus the first step to getting families and clinicians on the same page about mortality is to talk about it. Determining prognostic information in the neonatal population is difficult for providers because they must forecast survival and quality of life without reliable data. However, neonatal providers are tasked with delivering prognostic information to families and predicting the infant’s prognosis, short- and long-term outcomes, and quality-of-life issues.35 Boss et al.35 recorded and analyzed 16 parent-clinician conferences that discussed “difficult news” (e.g., severe intracranial hemorrhage, cardiopulmonary resuscitation decisions, or genetic diagnoses). Prognostic information was shared in most care conferences, and prognosis discussions were initiated by the provider. However, this prognostic information was delivered broadly rather than as detailed information related to the prognosis. Without detailed information, broad statements may be subject to different interpretations. Also, clinicians in this study explained that less than 25% of the cases discussed had a chance of surviving without serious complications; however, clinicians were twice as likely to be optimistic versus pessimistic when explaining the prognosis to parents. Parents and clinicians often walked away from these

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Chapter 91 |  Palliative Care Family Support in Neonatology  787

care conferences with different interpretations of the infant’s prognosis and quality of life, with parents having more of an optimistic view of their infant’s survival and quality of life.

Decision-Making at the End-of-Life Parents describe an infant’s death as the most devastating and difficult experience they have faced.36 Parents may see their infant suffering from invasive procedures that are deemed futile and decide to limit medical treatment, withdraw life-sustaining technology (e.g., compassionate extubation), or use home hospice services. After infant death, parents must decide to see or hold their infant, donate organs, agree to an autopsy, and make funeral arrangements. These end-oflife decisions are particularly stressful, partly because they are often made in a NICU environment with unfamiliar people and noises, little privacy, and impending loss of their identity as a parent and the parent caretaking role.25 Neonatologists may support parents by offering to discuss the autopsy and organ donation processes with them before a precipitous decision must be made. Parents often struggle with the “what-ifs” after infant death. That is, parents may report feeling at peace with the death but continue to wonder what the outcome would have been if different interventions were attempted at different times.20 Brooten et al.37 explored parents’ retrospective reflections on what they had wished was done or not done during their child’s death in the NICU or pediatric intensive care unit. Mothers wished to have spent more time with the child, held the child more, and selected a different treatment course. Fathers wished to have spent more time with their child and monitored their child more closely.37 These regrets emphasize the importance of providing high-quality, supportive communication surrounding decision-making, recognizing the importance of the parent role, and creating meaningful opportunities for parents to develop memories with their infant in the NICU. Neonatologists may also support parents by providing a postdeath conference and discussing autopsy reports and the events leading up to their infant’s death to clarify any questions and provide an element of clarity to the parents’ grief process.25,28,38,39

Sources of Support for Parents During End-of-Life Decision Making Use of a Question Prompt List to Empower Parents The use of a question prompt list (QPL) in the processes of information gathering and informed decision-making is one strategy to engage parents in informed decision-making and provide goal-concordant care. A QPL is a suggested list of questions for the patient or caregiver that guides communication with the healthcare team. Lemmon et al.40 developed a QPL for NICU families to use in preparation for clinician-parent care conferences. This QPL was developed using audio-recorded NICU care conferences with parents of infants treated for therapeutic hypothermia and was universally accepted by NICU clinicians and parents.40 An example QPL item on being a NICU parent is the following: “What is the best way for me to participate when the team makes the plan for the day (rounds)?”40 Parents who used a QPL found that it was useful and facilitated more prepared answers from their neonatology team.41 Implementing decision-making supports such as a QPL may empower parents to ask questions that are most important to them during a time when they may be too overwhelmed to develop a list of questions on their own.

Perinatal Palliative Care as an Added Layer of Support in the NICU Palliative care is an interdisciplinary specialty that aims to provide the best possible quality of life for seriously ill infants and their

families and involves comprehensive treatment of suffering.42 By definition, serious illness is “a health condition that carries a high risk of mortality and either negatively impacts a person’s daily function or quality of life, or excessively strains their caregivers.”43 There are three general categories of patients who receive PPC in the NICU: (1) newborns born at the threshold of viability, (2) newborns or infants born with birth anomalies that may threaten vital functions, and (3) newborns or infants who are receiving intensive care but become burdened with interventions that no longer seem beneficial and are instead only prolonging the infant’s dying or causing suffering.44 For infants and their parents to receive the maximum benefit, PPC should be initiated at the time of diagnosis and provided concurrently with curative efforts.42,45 Early integration of PPC is a great opportunity to build trust with the medical team, and PPC support may assist parents with eliciting goals of care and planning questions and discussions with the neonatal medical team during care conferences. Palliative providers specialize in eliciting care preferences by using excellent communication skills, supporting the decision-making process, managing distressing symptoms, helping to increase the continuity of care, providing family support, and enhancing quality of life in all realms of suffering including physical, spiritual, psychological, and psychosocial suffering.46 PPC may facilitate the opportunities for parents to make memories with their infant by coordinating resources, eliciting parent preferences for care, aligning care with their preferences, and facilitating cultural rituals that are important to families. However, PPC is commonly avoided in the NICU or integrated only near the end of life when death is imminent. One common explanation for the avoidance of PPC in the NICU is the misconception that palliative care means giving up on aggressive treatment and transitioning to exclusive end-of-life or comfort care.20 However, bereaved parents have reported positive experiences with PPC teams before infant death in the NICU. For example, parents wished they had involved the PPC team earlier and more often because the palliative care team acted as a sounding board for their questions and concerns and orchestrated meaningful opportunities for them to create memories with their infant when survival was uncertain.20 For NICU patients who did receive PPC, PPC teams were most often consulted for communication needs or aligning care with the goals of care and wishes of the family.47 Neonatologists have reported the value of communication expertise that palliative care providers brought to their complex clinical cases.

Chronic Critical Illness Phase Continuation of Clinical Case Report Cynthia has returned to work part-time. She and Baby Jacob’s siblings faithfully visit the NICU every weekend because of work schedules and financial hardships associated with the 2-hour commute to the hospital. Baby Jacob is recovering from acute necrotizing enterocolitis. His feeds are through a gastrostomy tube. Due to having undergone multiple bowel surgeries and a subsequent short gut, he receives calories through total parental nutrition in a central line despite multiple attempts to advance to full feeds. Cynthia expresses disappointment that he isn’t able to “enjoy eating” or “receive comfort from either breastfeeding or even a bottle.” He depends on a tracheostomy with a back-up ventilator rate for respiratory support. Due to the home health nursing shortage in his community, Baby Jacob remains in the hospital setting for his first 11 months of life. Cynthia is struggling with the reality that he may reach his first birthday never having been home. His siblings continue to ask, “When will Baby Jacob come home?”

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788  Section 18  |  Current State of Neonatal Palliative Care

Table 91.2  Neonatal/Pediatric Chronic Critical Illness (CCI) Prolonged hospitalization

Prolonged dependence on technology

Hospitalization in an intensive care unit (ICU) for >28 days after term corrected age. In some hospitals, many such infants may be transferred to pediatric intensive care units (PICU) and if so, the hospitalization would be considered prolonged with PICU stays >14 consecutive days. CCI is defined as a history of prolonged ICU stay and/or 2 or more acute care or ICU admissions within 12 months. Dependence on one or more support systems, including respiratory support with tracheostomy, mechanical ventilation, non-invasive positive-pressure ventilation, or continuous positive airway pressure; feeding assistance through a gastrostomy/jejunostomy; renal replacement therapy; or support for other vital organs.

Epidemiology and Definition of Chronic Critical Illness Advances in medicine and development of biomedical technology have dramatically shifted the epidemiology of pediatric outcomes in the past 2 to 3 decades.48 Life-prolonging interventions have resulted in the survival of infants with previously terminal medical conditions. Infants are now surviving with chronic critical illness, often through the support of multiple advanced medical technologies and extended hospitalizations to include intensive-care stays (Table 91.2).51 Although less than 1% of the United States pediatric population consists of children with medical complexity, this population accounts for as much as one-third of total pediatric healthcare spending and almost half of pediatric hospital charges.49,50 Children with medical complexity are noted to be lifelong high users of healthcare, warranting service coordination among multiple subspecialists and interdisciplinary team members. In a recent study quantifying the time invested by multidisciplinary care team members to perform nonreimbursable care coordination activities for children with medical complexity, the median time spent in nonreimbursed care coordination was 2.3 hours (interquartile range, 0.8–6.8 hours) per child per month.52 This translates into the need for case managers in NICU settings and the need to proactively help families with discharge planning and preparatory care coordination even in a busy NICU setting. The location of care for children with complex, chronic medical conditions is often limited to inpatient hospital settings or skilled nursing facilities due to gaps in home service provisions. The longitudinal relationships and developmental stimulation deserved by children is often beyond that which is currently offered in biomedical-focused critical care settings.53 Enabling factors and barriers to the empowerment of home as a feasible care location are listed in Table 91.3. The concept of home as a feasible, viable, and livable location requires “intentional care models.”54 Lack of home-care nursing was recognized as the most frequent cause of discharge delay for technology-dependent children in hospital settings, “directly accounting for an average length of stay increase of 53.9 days (range: 4–204) and 35.7 days (3–63) for new and existing patients, respectively.” 55 Respiratory technology, younger age of the child, and lack of insurance plan coverage are consistently cited as reasons for discharge delays.55,56 NICU providers and interdisciplinary team members need to prepare families of children with chronic critical illness for potential loss of parental employment due to lack of access to home nursing and long-term hands-on medical needs for children.

Table 91.3  Facilitators and Barriers to Home as a Feasible Care Setting for Children With Chronic, Critical Illness Facilitators

Barriers

Communication and coordination of healthcare teams across care settings

Gaps in pediatric home health nursing

Early and longitudinal family education and inclusion

Lack of coverage for home-based durable medical supplies and equipment for children

State-supported case management with tangible transition models

Inconsistent family support

Home-based interdisciplinary care services

Care model centralization to inpatient hospital services

Empowerment of general pediatric medical homes

Minimal reimbursement for home-based services

Table 91.4  Model of Exploring Medical Technology’s Decisional Impact on Lived Experience Medical Technology

Lived Experience Inquiries

Central line

1. F amily access to a sterile environment for dressing changes 2. Impact on the bathing routine or water play 3. Risk of infection and change in urgency level with fevers when an outpatient

Gastrostomy tube

1. C  ultural or familial interpretation of nutrition 2. Implications of the role of food for pleasure and social interaction versus for caloric intake

Tracheostomy with ventilator

1. E scalation of care may shift the child’s ability to discharge to a home setting 2. Meaning of the expansion of medical technologies to sustain or maintain life

Early and longitudinal palliative care integration for babies with complex health needs is noted to be formative in decision-making and family support. For a baby such as Jacob, the palliative care team could help the NICU providers with decisional assessment for each escalation of care technology to include informational case management and translation of each decision into the family’s “lived experience.” Palliative care teams can help extend family-centered care to address sibling, paternal, and grandparent factors.57,58 An example of a model for decisional impact of escalation of medical technologies is provided as Table 91.4.

Bereavement Phase Continuation of Clinical Case Report Baby Jacob is noted to have increased secretions and work of breathing. Cynthia is tearful at his bedside, recognizing Baby Jacob is less alert to her voice and touch. Despite maximal medical management, Baby Jacob continues to worsen, requires more hemodynamic and respiratory support, and is steadily less responsive to provider interventions and to maternal presence. He undergoes a code event. Cynthia, the baby’s father, Steven, and Cynthia’s mother meet with the palliative care team and decide to compassionately discontinue artificial technologies and allow natural death. Jacob is held by his mother, who is comforted by his grandmother’s singing in his hospital room at the time of death. Baby Jacob has never been in his home nursery, so the family brings his nursery bedding to the intensive care unit and his home lamp to surround him with physical reminders of comfort. After Jacob’s death, Cynthia struggles to make decisions about an autopsy

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Chapter 91 |  Palliative Care Family Support in Neonatology  789

and the disposition of Jacob’s body. She is now planning Jacob’s funeral with financial assistance from the hospital pastoral care department. Cynthia is struggling with talking to her surviving children about Jacob’s death and adjusting to a new family routine without Jacob.

Bereaved Parent Health Epidemiology Bereaved parents describe their child’s death as a life-changing event.36 The complex grief process bereaved parents endure places them at risk for poor health. Bereaved parents are at an increased risk for mortality,59 psychiatric hospitalizations,60 and morbidity including cancer61,62 and type 2 diabetes63 compared with parents who have not lost a child. Parents who lost their only child were at the highest risk for psychiatric hospitalizations.62 Specifically, parents report frequent acute illness episodes and hospitalization in the first 13 months following an infant/child death in the NICU or pediatric intensive care unit.64,65 It is critical to acknowledge the grief experiences of bereaved parents of NICU infants and develop effective support to facilitate healthy coping and grief outcomes in this population.

Parent Grief Experiences Memories from the ICU remain with parents for years after their infants’ death66 and may affect their grief experiences.67 Thus it is critical to facilitate families’ preferences for the sometimes brief moments they have with their infants. Currie et al.36 conducted a qualitative study exploring parent grief and coping experiences after infant death in the NICU. Parents reported changing levels of grief over time, with grief symptoms waxing and waning in the first year of life and eventually decreasing over time. However, the grief never completely dissipated; rather, the type of emotions and intensity of grief symptoms shifted. Personal growth was also reported and was manifested by new insights that brought positive meaning to their lives. Some parents suffered from spiritual or existential distress but also reported spiritual growth over time, becoming “closer to God.”36 These parents’ coping styles also evolved over time. Some of the barriers parents reported to coping with grief were different coping styles between the mother and father, lack of accessible grief counseling, and hurtful communication from friends, family, and community members.36 In contrast, helpful coping strategies were remembering their infant through traditions or physical keepsakes, developing a support network with other parents who could emphasize with their grief and experiences, spending time making sense of the loss through researching their infant’s medical condition, and cognitive distraction by staying busy with new hobbies.36

Grief as a Shared Family Experience Grief for families of children with serious illness begins at the moment of diagnosis (including fetal diagnosis), fluctuates with remissions and exacerbations of the illness, escalates at the time of death (although feelings of relief and guilt may interplay), and continues at varying levels for years afterward. Parental impact from infant death is notably prolonged and not easily measured by calendar chronology. Families never “get over” the death of their child and move on; instead, they learn to move through and with the experience as they integrate the memories of their child into a “new normal” of family life. The goal of the grief trajectory, if adequately supported, is to eventually enter into a season of posttraumatic growth. The loss of a child impacts not only parents but also siblings, grandparents, and the community at large.

Sibling bereavement needs to include clear communication in a developmentally relevant format.68 Child life specialists may serve as resources to help families understand how and when children grieve, include siblings in remembering their sibling, and validate inclusion of siblings in the end-of-life and bereavement process.69 Depending on their developmental stage, siblings may appreciate being offered memory-making ideas such as making artwork to remember their sibling, receiving footprints and handprints of their sibling, or putting special mementos in a memory box to honor their sibling’s life.70 Grandparent bereavement is unique in that grandparents are often “double-grievers” in mourning the loss for their adult child and mourning the loss of their grandchild.71 Grandparents have been termed “forgotten grievers” despite their “cumulative pain,” because they are often positioned to care for their adult children’s grief while also grieving their own loss.72 The roles of grandparents in a family structure and even the amount of access a grandparent has been granted to medical information by their adult child impacts the grandparent experience.73 Historically, the NICU and palliative care literature focused on maternal grief in a way that has not fully acknowledged the paternal experience of neonatal life or loss.74 Qualitative literature on the grief experience for fathers after the death of a child has highlighted themes of grief denial, lonely grief, bottled feelings, and an abrupt return to work or activity to distract and cope.75 Grief patterns may not coincide in chronology, in intensity, or in expression.76 How a dad experiences infant life and loss is highly related to how a dad defines his father role,74,77 warranting interdisciplinary father-specific grief attentiveness rather than a “one size fits all” grief model for parents. Grief support is ideally individualized to parent identity and parents’ perception of their role. Family bereavement supports may include the following: 1. Individual or family counseling78,79 2. Moderated parent support group 80,81 3. Bibliotherapy resources82 4. Chaplain/spiritual ministry83 5. Art therapy or legacy-intervention such as digital storytelling74 6. Family camps84 7. Child life inclusion or sibling legacy experiences85,86 8. Longitudinal staff remembrances in the form of cards or personalized contact87 9. Offering a follow-up meeting with the infant’s medical team to discuss autopsy results and events leading up to infant death88

Staff Remembering Whether in the form of attendance at a memorial service, a personalized sympathy card about their child, a remembrance card for their child, or a coordinated grief counseling phone call, bereaved families have described feeling supported by commemorative events and supportive gestures by staff.89 Individual staff members may feel at a loss for what to say or how to say it to a bereaved family, warranting a team approach to coordinated bereavement.90 Although the death of a child is always tragic, professional meaning can be derived from knowing the child’s comfort and function were maximized throughout his or her lifetime because of palliative interventions; that the family’s grief and distress were lessened; and that a peaceful death, if it occurs, was achieved. A family-centered palliative care approach supports families experiencing serious illness in the NICU and loss from the time of diagnosis through the time of discharge or bereavement.91

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1. Mathews TJ, Driscoll AK. Trends in infant mortality in the United States, 2005–2014. NCHS Data Brief. 2017(279):1–8. 2. Gregory ECW, Drake P, Martin JA. Lack of change in perinatal mortality in the United States, 2014–2016. NCHS Data Brief. 2018(316):1–8. 3. Gold KJ, Leon I, Boggs ME, Sen A. Depression and posttraumatic stress symptoms after perinatal loss in a population-based sample. J Women’s Health. 2015;25(3):263–269. 4. Centers for Disease Control and Prevention. Infant Mortality. 2019. https:// www.cdc.gov/reproductivehealth/maternalinfanthealth/infantmortality. htm 5. Longmore M. Neonatal nursing: palliative care guidelines. Nurs NZ. 2016;22(4):36. 6. Marc-Aurele KL, English NK. Primary palliative care in neonatal intensive care. Semin Perinatol. 2017;41(2):133–139. 7. Boss RD, Hutton N, Sulpar LJ, West AM, Donohue PK. Values parents apply to decision-making regarding delivery room resuscitation for highrisk newborns. Pediatrics. 2008;122(3):583–589. 8. Catlin A, Carter B. Creation of a neonatal end-of-life palliative care protocol. J Perinatol. 2002;22(3):184–195. 9. Walker LV, Miller VJ, Dalton VK. The health-care experiences of families given the prenatal diagnosis of trisomy 18. J Perinatol. 2008;28(1):12–19. 10. Lalor JG, Begley CM, Galavan E. A grounded theory study of information preference and coping styles following antenatal diagnosis of foetal abnormality. J Adv Nurs. 2008;64(2):185–194. 11. Miquel-Verges F, Woods SL, Aucott SW, Boss RD, Sulpar LJ, Donohue PK. Prenatal consultation with a neonatologist for congenital anomalies: parental perceptions. Pediatrics. 2009;124(4):e573–e579. 12. Breeze AC, Lees CC, Kumar A, Missfelder-Lobos HH, Murdoch EM. Palliative care for prenatally diagnosed lethal fetal abnormality. Arch Dis Child Fetal Neonatal Ed. 2007;92(1):F56–F58. 13. Guon J, Wilfond BS, Farlow B, Brazg T, Janvier A. Our children are not a diagnosis: the experience of parents who continue their pregnancy after a prenatal diagnosis of trisomy 13 or 18. Am J Med Genet. 2014;164(2):308–318. 14. Janvier A, Farlow B, Barrington KJ. Parental hopes, interventions, and survival of neonates with trisomy 13 and trisomy 18. Am J Med Genet C Semin Med Genet. 2016;172(3):279–287. 15. Munson D, Leuthner SR. Palliative care for the family carrying a fetus with a life-limiting diagnosis. Pediatr Clin North Am. 2007;54(5):787–798, xii. 16. Cote-Arsenault D, Denney-Koelsch E. “My baby is a person”: parents’ experiences with life-threatening fetal diagnosis. J Palliat Med. 2011;14(12):1302–1308. 17. Harrison W, Goodman D. Epidemiologic trends in neonatal intensive care, 2007-2012. JAMA Pediatrics. 2015;169(9):855–862. 18. Brandon D, Docherty SL, Thorpe J. Infant and child deaths in acute care settings: implications for palliative care. J Palliat Med. 2007;10(4):910–918. 19. Centers for Disease Control and Prevention, National Center for Health Statistics, Infant Health. 2021. https://www.cdc.gov/nchs/fastats/infanthealth.htm. Accessed March 20, 2023. 20. Currie ER, Christian BJ, Hinds PS, et al. Parent perspectives of neonatal intensive care at the end-of-life. J Pediatr Nurs. 2016;31(5):478–489. 21. Hill DL, Nathanson PG, Carroll KW, Schall TE, Miller VA, Feudtner C. Changes in parental hopes for seriously ill children. Pediatrics. 2018;141(4):e20173549. 22. Roque ATF, Lasiuk GC, Radunz V, Hegadoren K. Scoping review of the mental health of parents of infants in the NICU. J Obstet Gynecol Neonatal Nurs. 2017;46(4):576–587. 23. Abraham A, Hendriks MJ. “You can only give warmth to your baby when it’s too late”: parents’ bonding with their extremely preterm and dying child. Qual Health Res. 2017;27(14):2100–2115. 24. Trowbridge A, Walter JK, McConathey E, Morrison W, Feudtner C. Modes of death within a children’s hospital. Pediatrics. 2018;142(4): e20174182. 25. Meert KL, Briller SH, Schim SM, Thurston C, Kabel A. Examining the needs of bereaved parents in the pediatric intensive care unit: a qualitative study. Death Studies. 2009;33:712–740. 26. Brinchmann BS, Nortvedt RF. What matters to parents? A qualitative study of parents’ experiences with life-and-death decisions concerning their premature infants. Nursing Ethics. 2002;9(4):388–404.

27. Brooten D, Youngblut JM, Seagrave L, Caicdeo C, Hawthorne D, Roche R. Parent’s perceptions of health care providers actions around child ICU death: what helped, what did not. Am J Hosp Palliat Care. 2012;30(1):40–49. 28. Brosig CL, Pierucci R, Kupst MJ, Leuthner SR. Infant end-of-life care: the parents perspective. J Perinatol. 2007;27:510–516. 29. Caeymaex L, Speranza M, Vasilescu C, et al. Living with a crucial decision: a qualitative study of parental narratives three years after the loss of their newborn in the NICU. PloS One. 2011;6(12):e28633. 30. Pector EA. Views of bereaved multiple-birth parents on life support decisions, the dying process, and decisions surrounding death. J Perinatol. 2004;24(4):4–10. 31. Davies B, Contro N, Larson J, Widger K. Culturally-sensitive information-sharing in pediatric palliative care. Pediatrics. 2010;125(4): 859–865. 32. Boss RD, Hutton N, Sulpar LJ, West AM, Donohue PK. Values parents apply to decision-making regarding delivery room resuscitation for highrisk newborns. Pediatrics. 2008;122:583–589. 33. Davies B, Sehring SA, Partridge JC, et al. Barriers to palliative care for children: perceptions of pediatric healthcare providers. Pediatrics. 2008;121(2):282–288. 34. Boulais J, Vente T, Daley M, Ramesh S, McGuirl J, Arzuaga B. Concern for mortality in the neonatal intensive care unit (NICU): parent and physician perspectives. J Perinatol. 2018;38(6):718–727. 35. Boss RD, Lemmon ME, Arnold RM, Donohue PK. Communicating prognosis with parents of critically ill infants: direct observation of clinician behaviors. J Perinatol. 2017;37(11):1224–1229. 36. Currie ER, Christian BJ, Hinds PS, et al. Life after loss: parent bereavement and coping experiences after infant death in the neonatal intensive care unit. Death Stud. 2018:1–10. 37. Brooten D, Youngblut JM, Caicedo C, Dankanich J. Parents: wish I had done, wish I had not done, and coping after child NICU/PICU death. J Am Assoc Nurse Pract. 2019;31(3):175–183. 38. Meert KL, Eggly S, Pollock M, et  al. Parents’ perspectives regarding a physician-parent conference after their child’s death in the pediatric intensive care unit. J Pediatr. 2007;151(1):50–55. 39. Raingruber B, Milstein J. Searching for circles of meaning and using spiritual experiences to help parents of infants with life-threatening illness cope. J Holist Nurs. 2007;25:39–49. 40. Lemmon ME, Donohue PK, Williams EP, Brandon D, Ubel PA, Boss RD. No question too small: development of a question prompt list for parents of critically ill infants. J Perinatol. 2018;38(4):386–391. 41. Lemmon ME, Huffstetler HE, Donohue P, et al. Neurodevelopmental risk: a tool to enhance conversations with families of infants. J Child Neurol. 2019;34(11):653–659. 42. National Institute of Nursing Research. Palliative care: conversations matter. 2017. https://www.ninr.nih.gov/newsandinformation/conversationsmatter/conversations-matter-newportal. 43. Kelley AS, Bollens-Lund E. Identifying the population with serious illness: the “denominator” challenge. J Palliat Med. 2018;21(S2):S7–S16. 44. Carter BS. Pediatric palliative care in infants and neonates. Children (Basel, Switzerland). 2018;5(2):21. 45. National Association of Neonatal Nurses Board of Directors. Palliative and end-of-life care for newborns and infants: Position statement #3063; 2015. 46. Center to Advance Palliative Care. What is pediatric palliative care? 2017. https://www.capc.org/about/palliative-care/ 47. Richards CA, Starks H, O’Connor MR, et al. When and why do neonatal and pediatric critical care physicians consult palliative care? Am J Hosp Palliat Care. 2018;35(6):840–846. 48. Burns KH, Casey PH, Lyle RE, Bird TM, Fussell JJ, Robbins JM. Increasing prevalence of medically complex children in US hospitals. Pediatrics. 2010;126(4):638–646. 49. Berry JG, Hall M, Neff J, et al. Children with medical complexity and Medicaid: spending and cost savings. Health Aff (Millwood). 2014;33(12):2199–2206. 50. Simon TD, Berry J, Feudtner C, et  al. Children with complex chronic conditions in inpatient hospital settings in the United States. Pediatrics. 2010;126(4):647–655.

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789.e2  Section 18  |  Current State of Neonatal Palliative Care 51. Shapiro MC, Henderson CM, Hutton N, Boss RD. Defining pediatric chronic critical illness for clinical care, research, and policy. Hosp Pediatr. 2017;7(4):236–244. 52. Ronis SD, Grossberg R, Allen R, Hertz A, Kleinman LC. Estimated nonreimbursed costs for care coordination for children with medical complexity. Pediatrics. 2019;143(1):e20173562. 53. Henderson CM, Williams EP, Shapiro MC, et al. “Stuck in the ICU”: caring for children with chronic critical illness. Pediatr Crit Care Med. 2017;18(11):e561–e568. 54. Boss RD, Williams EP, Henderson CM, et al. Pediatric chronic critical illness: reducing excess hospitalizations. Hosp Pediatr. 2017 hpeds.2016-0185. 55. Maynard R, Christensen E, Cady R, et al. Home health care availability and discharge delays in children with medical complexity. Pediatrics. 2019;143(1):e20181951. 56. Weaver MS, Wichman B, Bace S, et al. Measuring the impact of the home health nursing shortage on family caregivers of children receiving palliative care. J Hosp Palliat Nurs. 2018;20(3):260–265. 57. Nicholas DB, Beaune L, Barrera M, Blumberg J, Belletrutti M. Examining the experiences of fathers of children with a life-limiting illness. J Soc Work End Life Palliat Care. 2016;12(1-2):126–144. 58. Pulgaron ER, Marchante AN, Agosto Y, Lebron CN, Delamater AM. Grandparent involvement and children’s health outcomes: the current state of the literature. Fam Syst Health. 2016;34(3):260–269. 59. Li J, Precht DH, Mortensen PB, Olsen J. Mortality in parents after death of a child in Denmark: a nationwide follow-up study. Lancet. 2003;361(9355):363–367. 60. Serwint JR, Nellis ME. Deaths of pediatric patients: relevance to their medical home, an urban primary care clinic. Pediatrics. 2005;115(1):57–63. 61. Li J, Johansen C, Hansen D, Olsen J. Cancer incidence in parents who lost a child: a nationwide study in Denmark. Cancer. 2002;95(10):2237–2242. 62. Fang F, Fall K, Sparen P, et al. Risk of infection-related cancers after the loss of a child: a follow-up study in Sweden. Cancer Res. 2011;71(1):116–122. 63. Olsen J, Li J, Precht DH. Hospitalization because of diabetes and bereavement: a national cohort study of parents who lost a child. Diabet Med. 2005;22(10):1338–1342. 64. Brooten D, Youngblut JM, Caicedo C, Del Moral T, Cantwell GP, Totapally B. Parents’ acute illnesses, hospitalizations, and medication changes during the difficult first year after infant or child NICU/PICU death. Am J Hosp Palliat Care. 2018;35(1):75–82. 65. Youngblut JM, Brooten D, Cantwell P, Del Moral T, Totapally B. Parent health and functioning 13 months after infant or child NICU/PICU death. Pediatrics. 2013;132(5):e1295–e1301. 66. Meert KL, Briller SH, Schim SM, Thurston CS. Exploring parents’ environmental needs at the time of a child’s death in the pediatric intensive care unit. Pediatr Crit Care Med. 2008;9(6):623–628. 67. van der Geest IM, Darlington AS, Streng IC, Michiels EM, Pieters R, van den Heuvel-Eibrink MM. Parents’ experiences of pediatric palliative care and the impact on long-term parental grief. J Pain Symptom Manage. 2014;47(6):1043–1053. 68. Duncan J, Joselow M, Hilden JM. Program interventions for children at the end of life and their siblings. Child Adolesc Psychiatr Clin N Am. 2006;15(3):739–758. 69. Packman W, Horsley H, Davies B, Kramer R. Sibling bereavement and continuing bonds. Death Stud. 2006;30(9):817–841. 70. Potts S, Farrell M, O’Toole J. Treasure weekend: supporting bereaved siblings. Palliat Med. 1999;13(1):51–56.

71. Tatterton MJ, Walshe C. How grandparents experience the death of a grandchild with a life-limiting condition. J Fam Nurs. 2018;25(1):109–127. 72. Gilrane-McGarry U, O Grady T. Forgotten grievers: an exploration of the grief experiences of bereaved grandparents (part 2). Int J Palliat Nurs. 2012;18(4):179–187. 73. Tatterton MJ, Walshe C. Understanding the bereavement experience of grandparents following the death of a grandchild from a life-limiting condition: a meta-ethnography. J Adv Nurs. 2018;75(7):1406–1417. 74. Akard TF, Duffy M, Hord A, et al. Bereaved mothers’ and fathers’ perceptions of a legacy intervention for parents of infants in the NICU. J Neonatal Perinatal Med. 2018;11(1):21–28. 75. Aho AL, Tarkka MT, Astedt-Kurki P, Kaunonen M. Fathers’ grief after the death of a child. Issues Ment Health Nurs. 2006;27(6):647–663. 76. Youngblut JM, Brooten D, Glaze J, Promise T, Yoo C. Parent grief 1–13 months after death in neonatal and pediatric intensive care units. J Loss Trauma. 2017;22(1):77–96. 77. Wallerstedt C, Higgins P. Facilitating perinatal grieving between the mother and the father. J Obstet Gynecol Neonatal Nurs. 1996;25(5): 389–394. 78. Flenady V, Boyle F, Koopmans L, Wilson T, Stones W, Cacciatore J. Meeting the needs of parents after a stillbirth or neonatal death. BJOG. 2014;121(suppl 4):137–140. 79. Woodward S, Pope A, Robson WJ, Hagan O. Bereavement counselling after sudden infant death. Br Med J (Clin Res Ed). 1985;290(6465): 363–365. 80. Suttle ML, Jenkins TL, Tamburro RF. End-of-life and bereavement care in pediatric intensive care units. Pediatr Clin North Am. 2017;64(5):1167–1183. 81. Kang T, Hoehn KS, Licht DJ, et al. Pediatric palliative, end-of-life, and bereavement care. Pediatr Clin North Am. 2005;52(4):1029–1046, viii. 82. Arruda-Colli MNF, Weaver MS, Wiener L. Communication about dying, death, and bereavement: a systematic review of children’s literature. J Palliat Med. 2017;20(5):548–559. 83. McClung E, Grossoehme DH, Jacobson AF. Collaborating with chaplains to meet spiritual needs. Medsurg Nurs. 2006;15(3):147–156. 84. Summers KH. Camp Sunrise: supporting bereaved children. Am J Hosp Palliat Care. 1993;10(3):24–27. 85. Fletcher J, Mailick M, Song J, Wolfe B. A sibling death in the family: common and consequential. Demography. 2013;50(3):803–826. 86. Krell R, Rabkin L. The effects of sibling death on the surviving child: a family perspective. Fam Process. 1979;18(4):471–477. 87. Snaman JM, Kaye EC, Torres C, Gibson DV, Baker JN. Helping parents live with the hole in their heart: the role of health care providers and institutions in the bereaved parents’ grief journeys. Cancer. 2016;122(17):2757–2765. 88. October T, Dryden-Palmer K, Copnell B, Meert KL. Caring for parents after the death of a child. Pediatr Crit Care Med. 2018;19(8S suppl 2):S61–S68. 89. Macdonald ME, Liben S, Carnevale FA, et al. Parental perspectives on hospital staff members’ acts of kindness and commemoration after a child’s death. Pediatrics. 2005;116(4):884–890. 90. Wiener L, Rosenberg AR, Lichtenthal WG, Tager J, Weaver MS. Personalized and yet standardized: an informed approach to the integration of bereavement care in pediatric oncology settings. Palliat Support Care. 2018;16(6):706–711. 91. Kenner C, Press J, Ryan D. Recommendations for palliative and bereavement care in the NICU: a family-centered integrative approach. J Perinatol. 2015;35(suppl 1):S19–S23.

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Section 19

Early Diagnosis and Intervention in Neonatal Intensive Care Units

CHAPTER

92

Naveen Jain

KEY POINTS 1. Most infants who develop neurodevelopmental disability (NDD) are normal on examination at birth. 2. Surveillance for NDD must start with neurologic examination in the neonatal intensive care unit and continue through childhood, because early diagnosis and intervention may be beneficial. 3. A tailored care plan should guide healthcare professionals and parents to best practices

that support intact outcomes from birth to childhood. 4. Estimation of the risk of NDD is based on the severity of perinatal factors; promotion of early and guided parent participation; optimization of nutrition, such as with the use of mother’s own milk (such interventions should be evaluated with anthropometric follow-up, with head growth interpreted in the context of weight

Except for a small proportion of babies with genetic disorders, preterm babies (or other sick babies) are born “normal.” Most neurodevelopmental disorders (NDDs) seem to be acquired due to severe medical morbidities that necessitate intensive care, an experience that, despite best efforts, is quite unlike the in-utero environment. Providing a child the opportunity to achieve full potential is the prime responsibility of perinatal healthcare professionals. Now that neonatal care has grown “beyond survival,” the priorities have moved to the intactness and quality of survival (good neurodevelopment outcome). Neonatal intensive care unit (NICU) graduates have high rates of NDDs, and many of these disorders (poor scholastic performance, behavioral issues, and adaptation to society) are more frequent than cerebral palsy, blindness, and deafness put together (disabilities that are measured in our current protocols). Efforts to improve the disruptive NICU environment with developmentally supportive care (DSC), combined with continued surveillance for NDDs through childhood, would be logical. Early detection of suboptimal neurodevelopmental performance deviating toward an NDD, and timely institution of DSC, will very likely improve outcomes. The pursuit for a perfect diagnostic tool to predict NDDs in the early neonatal period may not be the best approach. The aim of early detection is to identify at-risk infants who may benefit from early intervention, to prevent rather than confirm the presence of NDDs. Early referral and scientifically appropriate therapies with good interprofessional coordination must be offered as a seamless care plan to parents before discharging the infants from the NICU. The search for suboptimal behaviors starts at birth and continues even after discharge from the NICU; this is collectively called as “follow-up of NICU graduates.”1 The earlier an at-risk infant can be identified, the greater the likelihood of a good outcome without an NDD may be.2 In the NICU, the care providers are constantly focused on preventing mortality in an infant being cared for with multiple life-support systems. The availability of well-organized, validated algorithms for management of respiratory supports, circulation, fluid and electrolytes, nutrition, jaundice, and infection control ensure minimum errors. Now, we need to develop similar, meticulously developed care bundles for early detection, referral, and intervention to optimize neurodevelopment. To optimize DSC practices and surveillance alongside medical care, we have developed a checklist model in our NICU that we call the “blue book,” which begins on

and length centiles); infrastructure changes and training of staff, including physicians, nurses, and therapists (occupational, physical, and speech) to promote developmentally sensitive care; early screening for retinopathy of prematurity, hearing, hypothyroidism, and neurosonographical abnormalities; and standardization of a protocol-based discharge planning process.

the first postnatal day and continues through discharge (Fig. 92.1). The “follow-up” after discharge into childhood will be discussed in the next chapter. In the following sections, we propose a simple process map, as a time-line checklist, that will help care-providers to incorporate neurodevelopment follow-up with medical care.

Days 1 to 3 of Life Step 1: Assign Risk of NDD Based on Perinatal Factor Severity The severity of a perinatal risk factor has a greater association with NDDs than its mere presence. The lowest gestations (1000 g

≤1000 g

Days 3 to 7 of Life in the NICU

Fetal growth

>10th centile

≤10th centile for gestation

Step 4: Track Head Circumference

Antenatal risk factors

Abruptio placenta Death of MC twin A/R EDF Severe eclampsia

Resuscitation at birth

Chest compression, medications Moderate/severe HIE

Perfusion

Shock requiring inotropes PDA requiring medical/surgical treatment

Head circumference measurement should be started at 2 to 3 days of life. A weekly plot of head circumference must continue until discharge from the NICU and at every visit thereafter until 2 years age. Look for slow head growth (risk of an NDD) or rapid head growth (points to hydrocephalus). Head circumference is best interpreted in relation to length and weight centiles. Serial measurements have greater prognostic value than does a single point measure. Population studies from Canada have shown that poor head growth between birth and discharge from the NICU was associated with poor motor and cognitive outcomes in preterm babies (24 hours Seizures

A/R EDF, Absence/reversal of end-diastolic flow; HIE, hypoxic ischemic encephalopathy; MC, monochorionic twins; NDD, neurodevelopmental disability; NICU, neonatal intensive care unit; PDA, patent ductus arteriosus.

infants proved that the presence of parents mitigates the negative influences of pain associated with diagnostic and therapeutic procedures and stressful environments. Also, parents and families who were allowed FIC experienced less strain. Parents are traditionally involved in care only after babies are medically stable, often a few days before discharge from the NICU. This obviously is too late! A recently published randomized controlled trial from India demonstrated that parent involvement very early (from day 1) is safe and beneficial.7 Preterm babies (born between 28 and 33 weeks) had lesser events of physiologic instability (apnea, feed intolerance) if they were cared for by parents early. Breast milk feeding rates were also higher in the early parent participation group. In a similar study from Hong Kong, decreases in severe retinopathy of prematurity (ROP) rates were demonstrated. COVID 19 significantly restricted the number of parents in NICUs and posed new challenges. There has been a temporary setback to FIC. Evidence supports breastfeeding and benefits of avoiding separation of the mother and baby, despite COVID.8

Step 5: Compliance With Core Elements of Developmentally Supportive Care14 1. Engineering/infrastructure optimization to provide a DSC environment. 2. Staff awareness of DSC. 3. Attention to the position in which the baby is nursed, synchronizing care with optimal behavioral states, ensuring protected sleep, and minimizing negative sensations such as pain, noise, and excess light. 4. Parent education: Parents must be supported throughout the NICU stay by a structured transfer of knowledge and skills through printed leaflets, group teaching, and videos or online classes. 5. Various early intervention programs are practiced across NICUs. A recent systematic review found the Newborn Individualized Developmental Care and Assessment Program was proven to be beneficial.15

Step 3: Mother’s Own Milk

Step 6: Role of Neonatal Therapy in the NICU

Efforts to maximize feeding with mother’s own milk should start with antenatal counseling.9 Immediately after delivery, the mother is advised to express breast milk frequently, either manually or using a breast pump. Pain relief must be combined with minimizing emotional stress by honest updates on the baby’s health and opportunities to touch the baby. Galactagogues may be required if mother’s own

Neonatal therapy is provided by occupational therapists, physical therapists, and speech therapists. Their role in the NICU includes positioning of babies, passive stretch, hand function, neck control, sensory integrations, oral stimulation, and much more; they also help families to cope better. The need for full-time services of each type of therapist has been defined by recent recommendations.16

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794  Section 19  |  Follow-Up

A

B

C

Fig. 92.2  Bonding Opportunities With Parents Are Important in Developmental Care. (A) Infant interacting with the mother. Mutual reciprocity is promoted during massage and social engagement opportunities. (B) Dad and daughter engaged in skin-to-skin care. (C) The infant’s response to maternal affection is evident in the intent gaze. Parent-infant interaction can promote individualized developmental care for high-risk newborns in the neonatal intensive care unit. (A and B were reproduced with permission and minor modifications from Ricciardi and Blatz. Developmental care—understanding and applying the science. In: Klaus and Fanaroff’s Care of the High-Risk Neonate, 8, 171–189.e7; C was reproduced with permission from Vandenberg KA. Early Hum Dev. 2007;83:433–442.)

Step 7: Screening Screening for congenital hypothyroidism must be initiated at day 3 to 7 of life and then followed by a repeat test in preterm infants at 2 to 4 weeks and 6 to 8 weeks of life, nearing an estimated term age.17

Days 7 to 14 Neurosonograms: Most NICUs recommend at least 2 neurosonograms, the first at 7 to 14 days of life and the second at 36 to 40 weeks of life.

Third to Fourth Week 1. ROP screening must be initiated and continued as per protocol. 2. Repeat a thyroid function test. 3. Hearing screening must include automated brainstem evoked audiometry (screening by otoacoustic emissions (OAE) alone will miss sensorineural impairment). 4. A neurosonogram done at 36 to 40 weeks’ postmenstrual age has higher predictive ability than an early scan. 5. Routine use of magnetic resonance imaging at estimated term age is not recommended.

Prior to Discharge From the NICU Step 8: Neurologic Examination Classify the baby’s behavior as optimal or suboptimal after a neurologic examination. Suboptimal behavior is associated with a higher risk of NDDs; these babies will benefit from closer follow-up and a more intense intervention program. The negative predictive value of neurologic examination is good; a normal report indicates that the baby is at a low risk of NDDs and can be followed up with a community facility. The positive predictive values are fortunately low, so most babies, despite suboptimal neurologic findings, will eventually be normal. Neonates have well-organized brain structure and function from very early life.18 As early as 23 weeks’ gestation, preterm neonates have consistent responses to most stimuli, and neurologic

examination uses these to classify babies’ behavior as optimal or suboptimal. The General Movement Assessment tool is a very reliable tool but requires training and experience to interpret, limiting its widespread use. The Hammersmith Neonatal Neurological Examination (HNNE) is easy to perform and requires no additional training. The shorter version of the HNNE takes less than 10 minutes to complete. The HNNE assesses orientation of the baby to vision and hearing; the ease with which one can arouse and console are a measure of higher functions. The baby’s tone is assessed systematically as head and neck, trunk, upper limbs, and lower limbs. Spontaneous movements, reflexes, and abnormal signs are elicited. The HNNE has been found to have reasonable predictive ability, compared with magnetic resonance imaging, in predicting outcomes.19 The HNNE has recently been evaluated for use earlier than term gestation (Fig. 92.3).20 The HNNE performed early (HNNE PE) was used before discharge of the preterm baby from birth admission, at a median gestation of 36 weeks. The diagnostic accuracy was similar to that of an HNNE performed at estimated term age. Besides the greater benefit of early detection of neonates at higher risk, the neurologic examination was easier to perform on a baby still admitted to the hospital than on an outpatient basis. The Premie-Neuro tool evaluated neurobehavior of preterm infants even earlier, at 30 weeks’ postmenstrual age, and found it to predict reliably adverse neurobehavior at later ages.21 Reliable evaluation of neurobehavior in preterm infants may be performed by the NICU Network Neurobehavioral Scale, Neurobehavioral Assessment of the Preterm Infant, and Assessment of Preterm Infants’ Behavior.22,23

Step 9: Discharge Planning24 Discharge planning starts with admission; the medical care team must inform the family about a tentative date of discharge (this date may be revised as the health condition evolves). Family-centered care throughout the NICU stay facilitates a smooth transition to home. The discharge planning meeting must happen at least a few days prior to discharge, allowing sufficient time to the family. Standardization reduces inadvertent misses. The cost of care and hospital stay are also reduced.

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Chapter 92 |  Early Diagnosis and Intervention in Neonatal Intensive Care Units  795

Warning signs

POSTURE

arms & legs extended or very slightly flexed

Warning signs legs slightly flexed

leg well-flexed but not adducted

leg well-flexed & adducted near abdomen

abnormal posture: a) opistotonus b) arm flexed, leg extended

For 25-27 weekers only arms flex slightly or some resistance felt

arms flex well till shoulder lifts, then straighten

arms flex at approx 100° & mantained as shoulder lifts

flexion of arms