Fanaroff and Martin's Neonatal-Perinatal Medicine: Diseases of the Fetus and Infant [12 ed.] 0323932665, 9780323932752, 9780323932745

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Fanaroff and Martin’s

NEONATAL-PERINATAL MEDICINE Diseases of the Fetus and Infant TWELFTH EDITION

Richard J. Martin, MBBS, FRACP Professor, Pediatrics, Reproductive Biology, and Physiology and Biophysics Case Western Reserve University School of Medicine Drusinsky/Fanaroff Chair in Neonatology Rainbow Babies and Children’s Hospital Cleveland, Ohio

Avroy A. Fanaroff, MD, FRCPE, FRCPCH Emeritus Professor, Pediatrics and Reproductive Biology Case Western Reserve University School of Medicine Emeritus Eliza Henry Barnes Chair in Neonatology Rainbow Babies and Children’s Hospital Cleveland, Ohio Associate Editor

Michele C. Walsh, MD, MSE

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To our spouses Patricia Martin and Roslyn Fanaroff to the Martin children and grandchildren Scott, Molly, William, and Adelaide Martin; Sonya Martin; and Peter, Mateo, and Soren Graif to the Fanaroff children and grandchildren Jonathan, Kristy, Mason, Cole, and Brooke Fanaroff; Jodi, Peter, Austin, and Morgan Tucker; and Amanda, Jason, Jackson, and Raya Hirsh with love, admiration, and deep appreciation for their continued support and inspiration

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Contributors

Steven A. Abrams, MD Professor Department of Pediatrics Dell Medical School at the University of Texas at Austin Austin, Texas Disorders of Calcium, Phosphorus, and Magnesium Metabolism in the Neonate Johan Ågren, MD, PhD Associate Professor Department of Women’s and Children’s Health Uppsala University; Medical Director of Neonatal Intensive Care Neonatology Division University Children’s Hospital Uppsala, Sweden Thermal Environment of the Intensive Care Nursery Sanjay P. Ahuja, MD, MSc, MBA Professor Pediatric Hematology/Oncology Rainbow Babies and Children’s Hospital Cleveland, Ohio The Hemostatic System Red Blood Cell Disorders in the Fetus and Neonate White Blood Cells and Immune Disorders Hope Elizabeth Arnold, MD Assistant Professor Department of Pediatrics University of Alabama Birmingham, Alabama The Late Preterm Infant Janine Arruda, MD, FAAP, FACC Professor of Pediatrics and Medicine Director, Non-Invasive Imaging Pediatric Cardiology Rainbow Babies and Children’s Hospital Cleveland, Ohio Congenital Defects of the Cardiovascular System

Mohammad A. Attar, MD Associate Professor Department of Pediatrics University of Michigan Ann Arbor, Michigan Assisted Ventilation and Its Complications A. Rebecca Ballard, MD Medical Director Neonatal Intensive Care Unit Memorial Hermann the Woodlands Medical Center The Woodlands, Texas Support for the Family Eduardo H. Bancalari, MD Emeritus Professor Department of Pediatrics University of Miami Miami, Florida Bronchopulmonary Dysplasia in the Neonate Nancy Bass, MD Professor Medical College of Wisconsin Pediatric Neurologist Children’s Wisconsin Milwaukee, Wisconsin Hypotonia and Neuromuscular Disease in the Neonate Cynthia F. Bearer, MD, PhD Professor Department of Pediatrics Case Western Reserve University School of Medicine Division Chief of Neonatology William and Lois Briggs Chair of Neonatology Department of Pediatrics Rainbow Babies and Children’s Hospital Cleveland, Ohio Adverse Exposures to the Fetus William E. Benitz, MD Emeritus Philip Sunshine Professor in Neonatology Department of Pediatrics Division of Neonatal and Developmental Medicine Stanford University Stanford, California Patent Ductus Arteriosus vii

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John T. Benjamin, MD, MPH Associate Professor Department of Pediatrics Vanderbilt University Medical Center Nashville, Tennessee Developmental Immunology

Brian A. Boe, MD Medical Director Pediatric Cardiac Interventional Services Joe DiMaggio Children’s Hospital, Heart Institute Hollywood, Florida Neonatal Management of Congenital Heart Disease

Rachel Bensen, MD Clinical Associate Professor Department of Pediatrics - Gastroenterology Stanford Medicine Children’s Health, Stanford University Stanford, California Neonatal Jaundice and Liver Disease

Kara L. Calkins, MD, MSCR Associate Professor Department of Pediatrics David Geffen School of Medicine at UCLA; Physician Department of Pediatrics Mattel Children’s Hospital UCLA Los Angeles, California Fetal Growth Restriction: A Complex Interplay Between the Intrauterine and Maternal Environment

Sheila C. Berlin, MD Associate Professor and Vice Chair Department of Radiology University Hospitals Cleveland Medical Center Director of Pediatric CT Department of Radiology Rainbow Babies and Children’s Hospital Cleveland, Ohio Diagnostic Imaging of the Neonate Monika Bhola, MD Professor Department of Pediatrics Division of Neonatology Rainbow Babies and Children’s Hospital Cleveland, Ohio Importance of Simulation in Neonatology Shazia Bhombal, MD Clinical Associate Professor of Pediatrics Division of Neonatal and Developmental Medicine Stanford University School of Medicine Stanford, California Patent Ductus Arteriosus Tal Biron-Shental, MD Prof. Chairperson Department of Obstetrics and Gynecology Meir Medical Center Tel Aviv University Kfar Saba, Tel Aviv, Israel Fetal Effects of Autoimmune Disease Martin L. Bocks, MD Professor of Pediatrics Case Western Reserve University School of Medicine Director of Pediatric Interventional Cardiology The Congenital Heart Collaborative Rainbow Babies and Children’s Hospital Cleveland, Ohio Neonatal Management of Congenital Heart Disease

Bryan Cannon, MD Director, Pediatric Arrhythmia and Pacing Service Pediatric Cardiology; Chair of Education Department of Pediatrics Mayo Clinic Rochester, Minnesota Disorders of Cardiac Rhythm and Conduction in Newborns Waldemar A. Carlo, MD Edwin M. Dixon Professor of Pediatrics Department of Pediatrics Co-Director Division of Neonatology University of Alabama at Birmingham Birmingham, Alabama Perinatal and Neonatal Care in Developing Countries Assessment of Neonatal Pulmonary Function Cara Beth Carr, MD Assistant Professor Department of Pediatrics The University of North Carolina at Chapel Hill Chapel Hill, North Carolina Diagnostic Imaging of the Neonate Brian S. Carter, MD Professor of Pediatrics, Medical Humanities, and Bioethics Pediatrics - Neonatology University of Missouri-Kansas City, School of Medicine; Bioethicist Bioethics Center Children’s Mercy Hospital Kansas City, Missouri Perinatal Palliative Care

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Contributors

Janet Chuang, MD Assistant Professor Pediatric Endocrinology Cincinnati Children’s Hospital Medical Center Cincinnati, Ohio Thyroid Disorders in the Neonate Divyaswathi Citla-Sridhar, MD Assistant Professor Pediatric Hematology Oncology University of Arkansas for Medical Sciences Little Rock, Arkansas The Hemostatic System Mehmet N. Cizmeci, MD, PhD Neonatologist Division of Neonatology The Hospital for Sick Children Toronto, Ontario, Canada Intracranial Hemorrhage and Stroke in the Neonate Reese H. Clark, MD Vice President Clinical Research Clinical Services Pediatrix Marietta, South Carolina Big Data for the Smallest Patients—What We Can Learn From Neonatal Database Research Maged M. Costantine, MD Professor Department of Obstetrics and Gynecology Division of Maternal-Fetal Medicine The Ohio State University Columbus, Ohio Obstetric Management of Prematurity Moira A. Crowley, MD Associate Professor of Pediatrics Department of Pediatrics Case Western Reserve University School of Medicine Director, Neonatal ECMO Program Division of Neonatology Rainbow Babies and Children’s Hospital Co-Medical Director Neonatal Intensive Care Unit Rainbow Babies and Children’s Hospital Cleveland, Ohio Spectrum of Neonatal Respiratory Disorders Sean N. Curtis, MD Assistant Professor Department of Pediatrics Division of Neonatology Children’s Mercy Hospital Kansas City, Missouri Fluid, Electrolytes, and Acid-Base Homeostasis

Peter G. Davis, MBBS, MD Professor Obstetrics, Gynaecology and Newborn Health University of Melbourne; Professor Department of Neonatology The Royal Women’s Hospital Melbourne, Victoria, Australia Role of Positive Pressure Ventilation in Neonatal Resuscitation Diomel de la Cruz, MD Associate Professor Department of Pediatrics Division of Neonatology University of Florida College of Medicine Gainesville, Florida Neonatal Necrotizing Enterocolitis Linda S. de Vries, MD, PhD Emeritus Professor Department of Neonatology University Medical Center Utrecht, the Netherlands; Emeritus Professor Department of Neonatology Leiden University Medical Center Leiden, the Netherlands Intracranial Hemorrhage and Stroke in the Neonate Hypoxic-Ischemic Encephalopathy Ankita P. Desai, MD Associate Professor Division Chief Fellowship Program Director Medical Director of Antimicrobial Stewardship Division of Pediatric Infectious Disease Rainbow Babies and Children’s Hospital Cleveland, Ohio Viral Infections in the Neonate Sherin U. Devaskar, MD Distinguished Professor of Pediatrics Department of Pediatrics Division of Neonatology and Developmental Biology David Geffen School of Medicine at UCLA; Physician Department of Pediatrics Mattel Children’s Hospital UCLA Los Angeles, California Fetal Growth Restriction: A Complex Interplay Between the Intrauterine and Maternal Environment Developmental Origins of Health and Disease Disorders of Carbohydrate Metabolism in the Neonate

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Juliann M. Di Fiore, BS Research Engineer III Department of Pediatrics Case Western Reserve University School of Medicine Cleveland, Ohio Neonatal Cardiorespiratory Monitoring Assessment of Neonatal Pulmonary Function Hilda Ding, MD, MS Associate Professor Department of Pediatrics Division of Hematology-Oncology University of California San Diego Rady Children’s Hospital-San Diego San Diego, California The Hemostatic System Michael Dingeldein, MD, FACS, FAAP, FCCM Associate Professor of Surgery Case Western Reserve University School of Medicine Pediatric Surgery Rainbow Babies and Children’s Hospital Cleveland, Ohio Development of the Neonatal Gastrointestinal Tract Selected Gastrointestinal Anomalies in the Neonate Steven M. Donn, MD, FAAP, FAARC Professor Emeritus of Pediatrics Division of Neonatal-Perinatal Medicine C.S. Mott Children’s Hospital University of Michigan Health System Ann Arbor, Michigan Assisted Ventilation and Its Complications Rachel Egler, MD, MS Associate Professor Case Western Reserve University School of Medicine Department of Pediatrics Rainbow Babies and Children’s Hospital Cleveland, Ohio Neoplasms in the Neonate Danielle E.Y. Ehret, MD, MPH Associate Professor Department of Pediatrics Asfaw Yemiru Green and Gold Professor Global Health University of Vermont Larner College of Medicine; Chief Medical Officer Director of Global Health Vermont Oxford Network Burlington, Vermont Improving the Quality, Safety, and Equity of Neonatal Intensive Care for Infants and Families

Dina E. El-Metwally, MD, PhD Chief, Division of Neonatology Professor, Department of Pediatrics University of Maryland School of Medicine Baltimore, Maryland Adverse Exposures to the Fetus Kelstan Lynch Ellis, DO, MS-CR, MBe Assistant Professor Palliative Care Children’s Mercy Kansas City Kansas City, Missouri Perinatal Palliative Care Josephine M. Enciso, MD, MACM Clinical Professor Department of Pediatrics Division of Neonatology and Developmental Biology David Geffen School of Medicine at UCLA Los Angeles, California Developmental Origins of Health and Disease Mobolaji Famuyide, MD, MA Professor Pediatrics/Newborn Medicine University of Mississippi Medical Center Jackson, Mississippi Social and Economic Contributors to Neonatal Outcome in the United States Jonathan M. Fanaroff, MD, JD Professor of Pediatrics Department of Pediatrics Case Western Reserve University School of Medicine Director, Rainbow Center for Pediatric Ethics Rainbow Babies and Children’s Hospital Cleveland, Ohio Medical Ethics in Neonatal Care Stephanie M. Ford, MD Assistant Professor Department of Pediatrics Divisions of Neonatology and Pediatric Cardiology Case Western Reserve University School of Medicine Rainbow Babies and Children’s Hospital Cleveland, Ohio Cardiac Embryology Linda S. Franck, PhD, RN Professor Department of Family Health Care Nursing School of Nursing University of California, San Francisco San Francisco, California Improving the Quality, Safety, and Equity of Neonatal Intensive Care for Infants and Families

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Contributors

Smadar Eventov Friedman, MD, PhD Department Head Department of Neonatology Hadassah Medical Organization Faculty of Medicine Hebrew University of Jerusalem Jerusalem, Israel Multiple Gestation: Fetal and Maternal Considerations Susan Hatters Friedman, MD, DFAPA The Phillip Resnick Professor of Forensic Psychiatry Psychiatry Professor of Reproductive Biology and Pediatrics Reproductive Biology, Pediatrics Case Western Reserve University School of Medicine Cleveland, Ohio Support for the Family Meena Garg, MD Professor of Pediatrics Department of Pediatrics Division of Neonatology and Developmental Biology David Geffen School of Medicine at UCLA; Physician Department of Pediatrics Mattel Children’s Hospital UCLA Los Angeles, California Disorders of Carbohydrate Metabolism in the Neonate Ciprian P. Gheorghe, MD, PhD Assistant Professor of Obstetrics and Gynecology Department of Obstetrics and Gynecology Loma Linda University Loma Linda, California Genetic Aspects of Perinatal Disease and Prenatal Diagnosis Yuval Gielchinsky, MD, PhD Faculty of Medicine Tel Aviv University Tel Aviv, Israel; Director of the Fetal Medicine Center Department of Obstetrics and Gynecology Helen Schneider Hospital for Women Rabin Medical Center Petach Tikva, Israel Multiple Gestation: Fetal and Maternal Considerations Allison Gilmore, MD Associate Professor Case Western Reserve University School of Medicine Pediatric Orthopaedic Surgery Rainbow Babies and Children’s Hospital Cleveland, Ohio Bone and Joint Infections in Neonates

Michael P. Glotzbecker, MD Professor of Orthopaedics Case Western Reserve University School of Medicine Division Chief, Pediatric Orthopaedics Associate Surgeon in Chief George H Thompson Chair in Pediatric Orthopaedics University Hospitals, Rainbow Babies and Children’s Hospital Cleveland, Ohio Musculoskeletal Disorders in Neonates Jay P. Goldsmith, MD Clinical Professor Department of Pediatrics Tulane University New Orleans, Louisiana Overview and Initial Management of Delivery Room Resuscitation Blanca E. Gonzalez, MD Associate Professor of Pediatrics Center for Pediatric Infectious Diseases Cleveland Clinic Lerner College of Medicine of Case Western Reserve University Cleveland, Ohio Viral Infections in the Neonate Jeffrey B. Gould, MD, MPH Professor Department of Pediatrics Stanford University School of Medicine Palo Alto, California Improving the Quality, Safety, and Equity of Neonatal Intensive Care for Infants and Families Pierre Gressens, MD, PhD Professor U1141 National Institute of Health and Medical Research Paris, France Normal and Abnormal Brain Development Cerebral White Matter Damage and Encephalopathy of Prematurity Katherine Griswold, MD Associate Professor Department of Pediatrics Case Western Reserve University School of Medicine Cleveland, Ohio Physical Examination of the Healthy Newborn Floris Groenendaal, MD, PhD Associate Professor, Retired Department of Neonatology University Medical Center Utrecht Wilhelmina Children’s Hospital Utrecht, the Netherlands Hypoxic-Ischemic Encephalopathy

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Contributors

Susan J. Gross, MD Professor Department of Genetics and Genomic Sciences Icahn School of Medicine at Mount Sinai New York, New York; President The ObG Project Bronx, New York Genetic Aspects of Perinatal Disease and Prenatal Diagnosis Polina Gurevich, MD Senior Physician Neonatology Ziv Medical Center Safed, Israel Pregnancy Complicated by Diabetes Mellitus Iris Gutmark-Little, MD Assistant Professor Pediatric Endocrinology Cincinnati Children’s Hospital Medical Center Cincinnati, Ohio Thyroid Disorders in the Neonate David N. Hackney, MD, MS Associate Professor Case Western Reserve University School of Medicine Obstetrics and Gynecology University Hospitals Cleveland Medical Center Cleveland, Ohio Estimation of Fetal Well-Being Aaron Hamvas, MD Professor Pediatrics/Neonatology Ann and Robert H. Lurie Children’s Hospital/ Northwestern University Chicago, Illinois Respiratory Distress Syndrome in the Neonate Ryan Hanson, MD Assistant Professor Department of Anesthesiology Cleveland Clinic Lerner College of Medicine of Case Western Reserve University Cleveland, Ohio Anesthesia for Labor and Delivery Christina K. Hardesty, MD Associate Program Director Orthopaedic Surgery Case Western Reserve University School of Medicine Associate Professor Orthopaedic Surgery Rainbow Babies and Children’s Hospital Cleveland, Ohio Congenital Abnormalities of the Upper and Lower Extremities and Spine

Anantha Krishnan Harijith, MD, MRCP (UK) Associate Professor Department of Pediatrics Case Western Reserve University School of Medicine Cleveland, Ohio Unique Neonatal Cardiovascular Problems Marlyse F. Haward, MD Clinical Associate Professor Pediatrics Albert Einstein College of Medicine Children’s Hospital at Montefiore Bronx, New York Medical Ethics in Neonatal Care Ann Hellström, MD, PhD Professor Pediatric Ophthalmology Neuroscience and Physiology Goteborg, Sweden Retinopathy of Prematurity Calanit Hershkovich-Shporen, MD Director Department of Neonatology Kaplan Medical Center Rehovot, Israel Fetal Effects of Autoimmune Disease Anna Maria Hibbs, MD, MSCE Professor Department of Pediatrics Case Western Reserve University School of Medicine Vice Chair for Research Rainbow Babies and Children’s Hospital Cleveland, Ohio Gastrointestinal Reflux and Motility in the Neonate Thomas Alexander Hooven, MD Assistant Professor Department of Pediatrics University of Pittsburgh School of Medicine Pittsburgh, Pennsylvania Perinatal Infections and Chorioamnionitis Jeffrey D. Horbar, AB, MD Jerold F. Lucey Professor of Neonatal Medicine Department of Pediatrics University of Vermont; Chief Executive and Scientific Officer Vermont Oxford Network Burlington, Vermont Improving the Quality, Safety, and Equity of Neonatal Intensive Care for Infants and Families

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Contributors

Chi D. Hornik, PharmD, BCPS, CPP Assistant Professor Pediatrics Duke University School of Medicine; Director of Critical Care and Heart Center Research Pediatrics Duke Clinical Research Institute Durham, North Carolina Pharmacokinetics in Neonatal Medicine McCallum R. Hoyt, MD, MBA, FASA Director of Obstetric Anesthesia, Retired Anesthesiology Institute Cleveland Clinic Foundation; Professor of Anesthesiology Cleveland Clinic Lerner College of Medicine of Case Western Reserve University Cleveland, Ohio Anesthesia for Labor and Delivery Mark L. Hudak, MD Professor and Chair Department of Pediatrics Division Chief of Neonatology Associate Dean of Managed Care University of Florida College of Medicine-Jacksonville Jacksonville, Florida Infants of Substance-Using Mothers Petra S. Hüppi, MD Professor Department of Pediatrics University Children’s Hospital Geneva, Switzerland Normal and Abnormal Brain Development Cerebral White Matter Damage and Encephalopathy of Prematurity Terrie E. Inder, MBChB, MD Professor Department of Pediatrics University of California, Irvine Irvine, California; Director, Center for Neonatal Research Pediatrics Children’s Hospital of Orange County Orange, California Seizures in Neonates Cyril Jacquot, MD, PhD Associate Professor Departments of Pediatrics and Pathology George Washington University; Medical Director, Blood Donor Center and Hematology/Coagulation Laboratory Department of Laboratory Medicine Children’s National Hospital Washington, DC Blood Component Therapy for the Neonate

Lucky Jain, MD, MBA George W. Brumley, Jr. Professor and Chairman Department of Pediatrics Emory University School of Medicine; Pediatrician in Chief Children’s Healthcare of Atlanta Atlanta, Georgia The Late Preterm Infant Carla Janzen, MD, PhD Associate Professor Department of Obstetrics and Gynecology Division of Maternal-Fetal Medicine University of California, Los Angeles Los Angeles, California Fetal Growth Restriction: A Complex Interplay Between the Intrauterine and Maternal Environment Arun Jeyabalan, MD, MS Associate Professor Obstetrics, Gynecology, and Reproductive Sciences University of Pittsburgh School of Medicine Pittsburgh, Pennsylvania Hypertensive Disorders of Pregnancy Alan H. Jobe, MD, PhD Emeritus Professor of Pediatrics Pulmonary Biology, Neonatology Cincinnati Children’s Hospital Medical Center Cincinnati, Ohio Lung Development and Maturation Suhas G. Kallapur, MD Professor of Pediatrics Division of Neonatology and Developmental Biology David Geffen School of Medicine at UCLA Los Angeles, California Lung Development and Maturation Vishal Kapadia, MD, MSCS, FAAP Associate Professor Pediatrics University of Texas Southwestern Medical Center Dallas, Texas Chest Compression, Medications, and Special Problems in Neonatal Resuscitation Michael Kaplan, MBChB Professor of Pediatrics Faculty of Medicine Hebrew University; Emeritus Director Department of Neonatology Shaare Zedek Medical Center Jerusalem, Israel Neonatal Jaundice and Liver Disease

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Contributors

Anup C. Katheria, MD, FAAP Adjunct Associate Professor of Pediatrics Department of Pediatrics Loma Linda University; Director Neonatal Research Institute Sharp Mary Birch Hospital for Women and Newborns San Diego, California Role of Umbilical Cord Management in Neonatal Resuscitation David A. Kaufman, MD Professor Department of Pediatrics University of Virginia School of Medicine Charlottesville, Virginia Fungal and Protozoal Infections of the Neonate Simon Kayyal, MD Board Certified in Child Neurology Faculty Physician Pediatric Neurology Children’s Hospital of Orange County; Assistant Clinical Professor Department of Pediatrics UCI Health Orange, California Seizures in Neonates Ali Salar Khalili, MD Associate Professor Case Western Reserve University School of Medicine Pediatric Gastroenterology Pediatrics University Hospitals Cleveland Medical Center Rainbow Babies and Children’s Hospital Cleveland, Ohio Disorders of Digestion in the Neonate Laura L. Konczal, MD Assistant Professor of Medical and Biochemical Genetics Center for Human Genetics and Genomic Sciences University Hospitals Cleveland Medical Center; Assistant Professor of Pediatrics Department of Pediatrics University Hospitals Cleveland Medical Center Rainbow Babies and Children’s Hospital Cleveland, Ohio Inborn Errors of Metabolism Vasantha H.S. Kumar, MD Professor of Pediatrics Department of Pediatrics University at Buffalo Buffalo, New York; Professor of Pediatrics Department of Pediatrics University of Florida College of Medicine Jacksonville, Florida Postneonatal Respiratory Morbidity

Margaret Kuper-Sassé, MD, FAAP Assistant Professor Case Western Reserve University School of Medicine Department of Pediatrics Rainbow Babies and Children’s Hospital Cleveland, Ohio Adverse Exposures to the Fetus Satoshi Kusuda, MD, PhD Director Neonatal Research Network Neonatal Research Network of Japan Shinjuku, Tokyo, Japan; Neonatal Consultant Department of Pediatrics Kyorin University Mitaka, Tokyo, Japan Care of Periviable Micropreemies: The Japanese Perspective Megan Lagoski, MD Assistant Professor Department of Pediatrics Northwestern University Feinberg School of Medicine; Neonatologist Department of Pediatrics Lurie Children’s Hospital of Chicago Chicago, Illinois Respiratory Distress Syndrome in the Neonate Satyan Lakshminrusimha, MD, MBBS, FAAP Dennis and Nancy Marks Professor and Chair Department of Pediatrics University of California, Davis; Pediatrician-in-Chief UC Davis Children’s Hospital; Co-Chair Clinical Funds Flow Committee UC Davis Health Sacramento, California Postneonatal Respiratory Morbidity Naomi T. Laventhal, MD, MA, FAAP, HEC-C Professor, Associate Chair for Career Development Department of Pediatrics, Division of Neonatal-Perinatal Medicine Research Ethics Co-Chief Center for Bioethics and Social Sciences in Medicine University of Michigan Medical School Ann Arbor, Michigan Medical Ethics in Neonatal Care

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Contributors

Noam Lazebnik, MD Professor of Obstetrics & Gynecology and Radiology, Associate Professor of Genetics Department of Radiology Case Western Reserve University School of Medicine; Senior Physician Obstetrics and Gynecology, Maternal-Fetal Medicine University Hospitals Cleveland Medical Center Cleveland, Ohio Perinatal Ultrasound Roee S. Lazebnik, MD, PhD Global Head, Medical Affairs Global Medical Affairs Alcon Fort Worth, Texas Perinatal Ultrasound Hanmin Lee, MD Professor of Surgery Pediatric Surgery University of California, San Francisco San Francisco, California Surgical Treatment of the Fetus Liisa Lehtonen, MD, PhD Professor Department of Pediatrics Turku University; Head of the Division of Neonatology Department of Pediatrics Turku University Hospital Turku, Finland Optimization of the Neonatal Intensive Care Unit Environment John Letterio, MD Professor of Pediatrics Case Western Reserve University School of Medicine Department of Pediatrics Rainbow Babies and Children’s Hospital Cleveland, Ohio Red Blood Cell Disorders in the Fetus and Neonate White Blood Cells and Immune Disorders Neoplasms in the Neonate Peter Paul C. Lim, MD, FAAP Assistant Professor of Pediatrics University of South Dakota Sanford School of Medicine; Department of Pediatrics, Division of Infectious Diseases Avera McKennan University Health Center; Co-Investigator Avera Research Institute Sioux Falls, South Dakota Viral Infections in the Neonate

Raymond W. Liu, MD Victor M. Goldberg Professor Pediatric Orthopaedic Surgery Case Western Reserve University School of Medicine Rainbow Babies and Children’s Hospital Cleveland, Ohio Musculoskeletal Disorders in Neonates Everett F. Magann, MD Professor of Obstetrics and Gynecology Department of Obstetrics and Gynecology University of Arkansas for the Medical Sciences Little Rock, Arkansas Immune and Nonimmune Hydrops Fetalis Amniotic Fluid Volume Akhil Maheshwari, MD Professor (Clinical) of Pediatrics and Molecular & Cellular Physiology Louisiana State University Health Sciences Center Chief, Division of Neonatal Medicine Vice-Chair Translational Research in Pediatrics Director Fellowship Program of Neonatal-Perinatal Medicine Shreveport, Louisiana Developmental Immunology Henry H. Mangurten, MD Neonatologist Advocate Lutheran General Hospital Park Ridge, Illinois Birth Injuries Paolo Manzoni, MD, PhD University of Torino School of Medicine Division of Pediatrics and Neonatology Degli Infermi Hospital Torino, Italy Fungal and Protozoal Infections of the Neonate Camilia R. Martin, MD, MS Chief, Division of Neonatology Department of Pediatrics Weill Cornell Medicine, Alexandra Cohen Hospital for Women and Newborns New York, New York Nutritional Support for the Preterm Infant Kenichi Masumoto, MD, PhD Associate Professor Department of Neonatology Faculty of Medicine Toho University Tokyo, Japan Care of Periviable Micropreemies: The Japanese Perspective

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Contributors

Jacquelyn D. McClary, PharmD, BCPS Clinical Pharmacy Manager Department of Pharmacy Rainbow Babies and Children’s Hospital Cleveland, Ohio Principles of Drug Use in the Fetus and Neonate Principles of Drug Use During Lactation Therapeutic Agents R. Justin Mistovich, MD, MBA Associate Professor Pediatric Orthopaedic Surgery Case Western Reserve University School of Medicine Cleveland, Ohio Bone and Joint Infections in Neonates Anna L. Mitchell, MD, PhD Associate Professor Genetics and Pediatrics Case Western Reserve University School of Medicine Cleveland, Ohio Congenital Anomalies Yunchuan Delores Mo, MD Medical Director Department of Transfusion Medicine Children’s National Hospital Washington, DC Blood Component Therapy for the Neonate Eleanor J. Molloy, MB BCh BAO, PhD, FRCPI Chair and Professor of Paediatrics and Child Health Department of Paediatrics Trinity College, University of Dublin; Consultant Neonatologist Department of Paediatrics Coombe Hospital; Consultant Neonatologist and Paediatrician Neonatology and Developmental Paediatrics Children’s Health Ireland at Crumlin and Tallaght Dublin, Ireland Developmental Immunology Devashis Mukherjee, MD, MS Assistant Professor Department of Pediatrics Case Western Reserve University School of Medicine Cleveland, Ohio Postnatal Bacterial Infections

Karna Murthy, MD, MSc Professor Department of Pediatrics Northwestern University; Neonatology Department of Pediatrics Northwestern Memorial and Lurie Children’s Hospitals Chicago, Illinois; Chair Children’s Hospitals Neonatal Consortium Dover, Delaware Big Data for the Smallest Patients—What We Can Learn From Neonatal Database Research Santhosh M. Nadipuram, MD Assistant Professor-in-Residence Department of Pediatrics David Geffen School of Medicine at UCLA; Assistant Professor Department of Pediatrics Cedars-Sinai Medical Center Los Angeles, California Fungal and Protozoal Infections of the Neonate Hidehiko Nakanishi, MB Certified Neonatologist, Certified Pediatrician, Professor Department of Advanced Medicine Division of Neonatal Intensive Care Medicine Kitasato University School of Medicine Sagamihara, Kanagawa, Japan Care of Periviable Micropreemies: The Japanese Perspective Vivek Narendran, MD, MRCP (UK), MBA Professor of Pediatrics Perinatal Institute Cincinnati Children’s Hospital and Medical Center; Director, University of Cincinnati Medical Center Neonatal Intensive Care Unit University of Cincinnati Medical Center Cincinnati Children’s Hospital Medical Center Cincinnati, Ohio The Skin of the Neonate Josef Neu, MD Professor Department of Pediatrics University of Florida Gainesville, Florida Neonatal Necrotizing Enterocolitis Quang Nguyen, BBA, MBA, MD Resident Neurological Surgery University Hospitals Cleveland Medical Center Cleveland, Ohio Spinal Dysraphisms

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Contributors

Mary L. Nock, MD Professor Department of Pediatrics Case Western Reserve University School of Medicine Co-Director, Neonatal Intensive Care Unit Rainbow Babies and Children’s Hospital Cleveland, Ohio Tables of Normal Values Kimberly Novod, MPA Executive Director Saul’s Light Foundation New Orleans, Louisiana Improving the Quality, Safety, and Equity of Neonatal Intensive Care for Infants and Families Noa Ofek Shlomai, MD Faculty of Medicine Department of Neonatology Hadassah Medical Center Hebrew University of Jerusalem Tzur Hadassah, Israel Multiple Gestation: Fetal and Maternal Considerations Matilda Olajumoke Ogundare, MD, MPH Infectious Disease Fellow Case Western Reserve University School of Medicine; Infectious Disease Fellow Division of Pediatric Infectious Diseases University Hospitals Cleveland Medical Center Rainbow Babies and Children’s Hospital Cleveland, Ohio Viral Infections in the Neonate Shelley Ohliger, MD Assistant Professor Department of Anesthesiology Case Western Reserve University School of Medicine Rainbow Babies and Children’s Hospital Cleveland, Ohio Anesthesia in the Neonate Arielle L. Olicker, MD Assistant Professor Case Western Reserve University School of Medicine Department of Pediatrics Division of Neonatal-Perinatal Medicine Rainbow Babies and Children’s Hospital Cleveland, Ohio Tables of Normal Values Faruk H. Örge, MD, FAAO, FAAP William R. and Margaret E. Althans Professor and Director Center for Pediatric Ophthalmology and Adult Strabismus Department of Ophthalmology and Visual Sciences Cleveland, Ohio Examination and Common Problems in the Neonatal Eye

Todd D. Otteson, MD, MPH Professor Case Western Reserve University School of Medicine Chief Division of Pediatric Otolaryngology Rainbow Babies and Children’s Hospital Cleveland, Ohio Upper Airway Lesions in the Neonate Louise S. Owen, MBChB, MRCPCH, FRACP, MD Principal Researcher Obstetrics and Gynaecology University of Melbourne; Neonatologist Newborn Research Royal Women’s Hospital; Honorary Research Fellow Clinical Sciences Murdoch Children’s Research Institute Melbourne, Victoria, Australia Role of Positive Pressure Ventilation in Neonatal Resuscitation Amma Owusu-Ansah, MD Associate Professor Department of Pediatrics Case Western Reserve University School of Medicine Rainbow Babies and Children’s Hospital Cleveland, Ohio Red Blood Cell Disorders in the Fetus and Neonate Tulin Ozcan, MD Doctor Obstetrics and Gynecology Inova Fairfax Medical Campus Fairfax, Virginia Perinatal Ultrasound Kimberly V. Parsons, MD Assistant Professor Department of Pediatrics Emory University Atlanta, Georgia The Late Preterm Infant Irina Pateva, MD Associate Professor Department of Pediatrics Case Western Reserve University School of Medicine Pediatrics, Pediatric Hematology/Oncology Rainbow Babies and Children’s Hospital Cleveland, Ohio White Blood Cells and Immune Disorders

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Contributors

Mary Elaine Patrinos, MD Associate Professor Department of Pediatrics Case Western Reserve University School of Medicine Cleveland, Ohio Apnea, Bradycardia, Hypoxemia, and the Foundation of Respiratory Control Allison H. Payne, MD, MSCR Associate Professor Case Western Reserve University School of Medicine Neonatologist Division of Neonatology and Perinatal Medicine Rainbow Babies and Children’s Hospital Cleveland, Ohio Early Childhood Neurodevelopmental Outcomes of High-Risk Neonates David Peleg, MD Professor Obstetrics and Gynecology Ziv Medical Center Safed, Israel Post-Term Pregnancy Michelle-Marie Peña, MD Neonatology Division of Neonatology Children’s Hospital of Philadelphia Philadelphia, Pennsylvania Improving the Quality, Safety, and Equity of Neonatal Intensive Care for Infants and Families Brenda B. Poindexter, MD, MS Chief, Division of Neonatology Department of Pediatrics Emory University and Children’s Healthcare of Atlanta Atlanta, Georgia Nutritional Support for the Preterm Infant Richard Alan Polin, MD William T. Speck Professor of Pediatrics Executive Vice Chair, Department of Pediatrics Vagelos College of Physicians and Surgeons Columbia University; Executive Vice Chair Department of Pediatrics Columbia University; Executive Vice Chair Department of Pediatrics Morgan Stanley Children’s Hospital New York, New York Perinatal Infections and Chorioamnionitis

Preetha A. Prazad, MD Neonatologist Director, Neonatal Research Director, Neonatal Intensive Care Unit Follow-Up Clinic Department of Pediatrics Advocate Children’s Hospital - Park Ridge Park Ridge, Illinois Birth Injuries Jochen Profit, MD, MPH Professor Department of Pediatrics Stanford University Stanford, California Palo Alto, California Improving the Quality, Safety, and Equity of Neonatal Intensive Care for Infants and Families Thomas M. Raffay, MD Assistant Professor Department of Pediatrics Case Western Reserve University School of Medicine Attending Division of Neonatology Rainbow Babies and Children’s Hospital Cleveland, Ohio Neonatal Cardiorespiratory Monitoring Postneonatal Respiratory Morbidity Miriam Noble Rajpal, MD Neonatologist Department of Pediatrics Advocate Children’s Hospital - Park Ridge Park Ridge, Illinois Birth Injuries Tonse Narayana Krishna Raju, MD, DCH, FAAP Adjunct Professor Department of Pediatrics Uniformed Services University Gaithersburg, Maryland Growth of Neonatal-Perinatal Medicine—A Historical Perspective Tara M. Randis, MD, MS Associate Professor Departments of Pediatrics, Molecular Medicine, and Obstetrics & Gynecology USF Health Morsani College of Medicine Tampa, Florida Perinatal Infections and Chorioamnionitis

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Contributors

Raymond W. Redline, MD Professor Pathology and Reproductive Biology Case Western Reserve University School of Medicine Cleveland, Ohio Placental Pathology Nathaniel Robbins, MD Assistant Professor Department of Pediatrics Case Western Reserve University School of Medicine Physician Pediatrics-Cardiology Rainbow Babies and Children’s Hospital Cleveland, Ohio Congenital Defects of the Cardiovascular System Rita M. Ryan, MD Professor Case Western Reserve University School of Medicine Pediatrics Rainbow Babies and Children’s Hospital Cleveland, Ohio Postnatal Bacterial Infections Postneonatal Respiratory Morbidity Antonio Saad, MD Professor Maternal-Fetal Medicine The University of Texas Medical Branch Galveston, Texas Obstetric Management of Prematurity George Saade, MD Professor Obstetrics-Gynecology and Cell Biology The University of Texas Medical Branch Galveston, Texas Obstetric Management of Prematurity Zeina M. Salem, MD Fellow Ophthalmology University Hospitals Cleveland Medical Center Cleveland, Ohio Examination and Common Problems in the Neonatal Eye Renate D. Savich, MD Professor Department of Pediatrics University of New Mexico Albuquerque, New Mexico Social and Economic Contributors to Neonatal Outcome in the United States

Augusto F. Schmidt, MD, PhD Associate Professor Department of Pediatrics Division of Neonatology University of Miami Miller School of Medicine Miami, Florida Bronchopulmonary Dysplasia in the Neonate Marisa Eve Schwab, MD Department of Surgery University of California, San Francisco Medical Center San Francisco, California Surgical Treatment of the Fetus Thomas J. Sferra, MD Professor Department of Pediatrics Case Western Reserve University School of Medicine Chief, Pediatric Gastroenterology, Hepatology, and Nutrition Department of Pediatrics Rainbow Babies and Children’s Hospital Cleveland, Ohio Disorders of Digestion in the Neonate Jay Shah, MD Associate Professor Otolaryngology Case Western Reserve University School of Medicine Cleveland, Ohio Upper Airway Lesions in the Neonate Eric S. Shinwell, MD, FRCP Edin. Azrieli Faculty of Medicine Bar-Ilan University Safed, Israel; Professor of Neonatology Neonatology Ziv Medical Center Tsfat, Israel Pregnancy Complicated by Diabetes Mellitus Eric Sibley, MD, PhD Professor Department of Pediatrics - Gastroenterology Stanford University Stanford, California Neonatal Jaundice and Liver Disease Pamela M. Simmons, DO, MPH Maternal-Fetal Medicine Physician Maternal-Fetal Medicine Woman’s Hospital Baton Rouge, Louisiana Immune and Nonimmune Hydrops Fetalis Amniotic Fluid Volume

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xix

xx

Contributors

Yael Simpson-Lavy, MD Neonatologist Neonatal Intensive Care Unit Kaplan Medical Center Rehovot, Israel Post-Term Pregnancy Kothandam Sivakumar, MD, DM Head of Department and Senior Consultant Cardiologist Pediatric Cardiology Madras Medical Mission, Institute of Cardiovascular Diseases Chennai, Tamil Nadu, India Unique Neonatal Cardiovascular Problems Lois E.H. Smith, MD, PhD Professor of Ophthalmology Department of Ophthalmology Harvard Medical School, Boston Children’s Hospital Boston, Massachusetts Retinopathy of Prematurity Christopher S. Snyder, MD, FAAP Professor of Pediatrics Virginia Commonwealth University; Division Chief Pediatric Cardiology Children’s Hospital of Richmond Richmond, Virginia Disorders of Cardiac Rhythm and Conduction in Newborns Jochen P. Son-Hing, MD, FRCSC Associate Professor, Orthopaedics Associate Professor, Pediatrics Case Western Reserve University School of Medicine Attending Physician Rainbow Babies and Children’s Hospital Cleveland, Ohio Congenital Abnormalities of the Upper and Lower Extremities and Spine Ganga L. Srinivas, MBBS Associate Professor Department of Pediatrics Rainbow Babies and Children’s Hospital Cleveland, Ohio Physical Examination of the Healthy Newborn Robin H. Steinhorn, MD Professor and Vice Dean Department of Pediatrics Rady Children’s Hospital and University of California San Diego San Diego, California Pulmonary Vascular Development

Gretchen E. Stepanovich, MD Neonatal-Perinatal Medicine University of Michigan Ann Arbor, Michigan Assisted Ventilation and Its Complications David K. Stevenson, MD Harold K. Faber Professor of Pediatrics Division of Neonatal and Developmental Medicine Stanford University Stanford, California Neonatal Jaundice and Liver Disease James Strainic, MD Assistant Professor Pediatric Cardiology Case Western Reserve University School of Medicine Cleveland, Ohio Prenatal Diagnosis of Congenital Heart Disease Tara Sudhadevi, MSc, PhD Postdoctoral Research Scholar Pediatrics Case Western Reserve University School of Medicine Cleveland Heights, Ohio Unique Neonatal Cardiovascular Problems Ye Sun, MD, PhD Assistant Professor Department of Ophthalmology Boston Children’s Hospital, Harvard Medical School Boston, Massachusetts Retinopathy of Prematurity Kaitlyn Hebert Taylor, MD Resident Department of Obstetrics and Gynecology Louisiana State University Health Sciences Center Baton Rouge, Louisiana Immune and Nonimmune Hydrops Fetalis Amniotic Fluid Volume Shelby Thompson, MD, FRCPC Pediatric Endocrinologist Paediatric Endocrinology The Hospital for Sick Children Toronto, Ontario, Canada Disorders of Sex Development Frances Thomson-Salo, PhD Doctor of Psychiatry Murdoch Research Institute Parkville, Melbourne, Victoria, Australia Support for the Family

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Contributors

Dov Tiosano, Professor Pediatric Endocrinology Rambam Medical Center Haifa, Israel Disorders of Calcium, Phosphorus, and Magnesium Metabolism in the Neonate Veeral Nalin Tolia, MD Attending Neonatologist Research Director of the Neonatal Clinical Data Warehouse Pediatrix Sunrise, Florida; Faculty Pediatrics, Division of Neonatology Baylor University Medical Center Dallas, Texas Big Data for the Smallest Patients—What We Can Learn From Neonatal Database Research Krystal Tomei, MD, MPH Associate Professor Case Western Reserve University School of Medicine Neurological Surgery Rainbow Babies and Children’s Hospital Cleveland, Ohio Disorders in Head Shape and Size Spinal Dysraphisms Colm P. Travers, MD Assistant Professor Department of Pediatrics University of Alabama at Birmingham Birmingham, Alabama Assessment of Neonatal Pulmonary Function Andrea N. Trembath, MD, MPH Professor of Pediatrics Department of Pediatrics The University of North Carolina at Chapel Hill Chapel Hill, North Carolina Epidemiology for Neonatologists Verania Y. Huerta Urrutia, MD Assistant Professor Pediatric Hematology/Oncology Rainbow Babies and Children’s Hospital Cleveland, Ohio White Blood Cells and Immune Disorders Kristen VanHeyst, DO Assistant Professor Department of Pediatrics Case Western Reserve University School of Medicine Pediatric Oncologist Pediatric Hematology/Oncology Rainbow Babies and Children’s Hospital Cleveland, Ohio Neoplasms in the Neonate

Maximo Vento, MD, PhD Professor Division of Neonatology University and Polytechnic Hospital La Fe; Professor Neonatal Research Group Health Research Institute La Fe Valencia, Spain Oxygen Therapy in Neonatal Resuscitation Beth A. Vogt, MD Associate Professor Department of Pediatrics The Ohio State College of Medicine; Attending Physician Division of Nephrology Nationwide Children’s Hospital Columbus, Ohio The Kidney and Urinary Tract of the Neonate Betty R. Vohr, MD Professor of Pediatrics Department of Pediatrics Alpert Medical School of Brown University; Director of Neonatal Follow-Up Neonatology Women and Infants Hospital Providence, Rhode Island Hearing Loss in the Newborn Infant Kelly C. Wade, MD, PhD, MSCE Professor of Clinical Pediatrics Department of Pediatrics University of Pennsylvania, Children’s Hospital of Philadelphia Philadelphia, Pennsylvania Pharmacokinetics in Neonatal Medicine Jennifer A. Wambach, MD, MS Associate Professor Edward Mallinckrodt Department of Pediatrics Washington University School of Medicine St. Louis, Missouri Respiratory Distress Syndrome in the Neonate Michiko Watanabe, PhD Emeritus Professor Case Western Reserve University School of Medicine Cleveland, Ohio Cardiac Embryology Jennifer Webb, MD, MSCE Associate Professor Department of Pediatric Hematology Children’s National Hospital Washington, DC Blood Component Therapy for the Neonate

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xxi

xxii

Contributors

Maya Ram Weiner Lis Hospital for Women, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine Tel Aviv University Tel Aviv, Israel Pregnancy Complicated by Diabetes Mellitus

Ronald J. Wong, MD Senior Research Scientist Department of Pediatrics Stanford University School of Medicine Stanford, California Neonatal Jaundice and Liver Disease

Diane Katherine Wherrett, MD, FRCPC Professor Department of Pediatrics University of Toronto; Professor Department of Pediatrics The Hospital for Sick Children Toronto, Ontario, Canada Disorders of Sex Development

Myra H. Wyckoff, MD Professor Department of Pediatrics University of Texas Southwestern Medical Center; Director of Newborn Resuscitation Services Parkland Health and Hospital Systems Dallas, Texas Chest Compression, Medications, and Special Problems in Neonatal Resuscitation

Robert White, MD Medical Director Elkhart General Hospital’s Neonatology Solutions Elkhart, Indiana; Director, Regional Newborn Program Newborn Intensive Care Unit Beacon Children’s Hospital South Bend, Indiana Optimization of the Neonatal Intensive Care Unit Environment

Hilal Yildiz-Atar, MD Assistant Professor Department of Pediatrics University of Oklahoma Health Sciences Center Oklahoma City, Oklahoma Postneonatal Respiratory Morbidity

Travis J. Wilder, MD, MSc Assistant Professor Case Western Reserve University School of Medicine Congenital Heart Surgery Rainbow Babies and Children’s Hospital Cleveland, Ohio Neonatal Management of Congenital Heart Disease Deanne E. Wilson-Costello, MD Professor of Pediatrics Case Western Reserve University School of Medicine Division of Neonatology Rainbow Babies and Children’s Hospital Cleveland, Ohio Early Childhood Neurodevelopmental Outcomes of High-Risk Neonates

Yariv Yogev Professor Department of Obstetrics and Gynecology Lis Maternity and Women’s Hospital, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University Tel Aviv, Israel Pregnancy Complicated by Diabetes Mellitus Xiaofei Zhou, MD Assistant Professor Neurosurgery University Hospitals Cleveland Medical Center Cleveland, Ohio Disorders in Head Shape and Size

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Preface

HOW TO SUCCEED!

• SUCCESS IS NOT THE KEY TO HAPPINESS. • H  APPINESS IS THE KEY TO SUCCESS. • IF YOU LOVE WHAT YOU ARE DOING YOU WILL BE SUCCESSFUL. — DR. ALBERT SCHWEITZER

It is with a deep sense of satisfaction and great pride that we write this preface, which indicates that our task of revising the book has been completed. This twelfth edition represents the tenth time we have updated this textbook, originally published by the late Richard Behrman, MD, JD, who gifted it to us when he became the senior editor of the ­Nelson Textbook of Pediatrics. Each edition has presented special challenges as knowledge in the field of neonatal perinatal medicine has increased exponentially. Indeed, since the fifth edition we have been forced to present the material in two volumes. Having been on task now for 40 years, we are comfortable with the format of this text, commencing with the history of the subspecialty, followed by big data management; perinatal care; disorders of pregnancy and their impact on the fetus; delivery room care, including a special section on care of the cord; and disorders of the various organ systems. The importance of quality improvement and outcomes from multicentered organizations such as Pediatrix are highlighted. Japan has emerged with excellent outcomes for periviable babies, so we have added a special chapter on their approach to care in keeping with the international focus of this text and its contributors. As in prior editions, we have added new authors, experts in their respective fields, to about 25% of the chapters. Each chapter has been updated and carefully referenced with an attempt to retain only key references. The focus remains on evidence-based medicine as we search to move to personalized

medicine. Evidence-based medicine identifies what will happen to a group but not the individual. We deal with individuals, and the next steps to personalized medicine will be a huge leap forward, especially as we better understand the individual responses to pharmacologic agents. Once again, we express our gratitude to the multitude of contributors who not only give of their time and expertise, but do so graciously and in a timely manner. Their knowledge, writing skills, and diligence make our task so much simpler and more pleasant. The electronic submissions have all proceeded smoothly, enabling the publisher to complete the project on time. This project would not be possible without the assistance of our in-house editor, Bonnie Siner. We are eternally grateful to her. She is the ultimate professional and always calm in the storm. She reads and organizes every manuscript and is of great help to the contributing authors and us. We are extremely grateful to our former colleague, Michele Walsh, for her coeditor role in prior editions. We have also been blessed to have superb assistance and encouragement from Elsevier through Sarah Barth, Grace Onderlinde, and Kristine Feeherty.

PRIMUM NON NOCERE—FIRST DO NO HARM

• I T USUALLY REQUIRES CONSIDERABLE TIME TO DETERMINE WITH CERTAINTY THE VIRTUE OF A NEW METHOD OF TREATMENT AND • USUALLY STILL LONGER TO ASSESS THE HARMFUL EFFECTS. — DR. ALFRED BLALOCK

Richard J. Martin Avroy A. Fanaroff

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1

Growth of Neonatal-Perinatal Medicine—A Historical Perspective

TONSE NARAYANA KRISHNA RAJU

We trust we have been forgiven for coining the words, “neonatology” and “neonatologist.” We do not recall ever having seen them in print. The one designates the art and science of diagnosis and treatment of disorders of the newborn infant, the other the physician whose primary concern lies in the specialty. … We are not advocating now that a new subspecialty be lopped from pediatrics … yet such a subdivision … [has] as much merit as does pediatric hematology.

—A. J. Schaffer, 19601

I

n the preface to the first edition of his Diseases of the Newborn textbook, Alexander Schaffer christened a new specialty of pediatrics that he referred to as neonatology, and the practitioners of this field of medicine were neonatologists. He asked for readers’ forgiveness for introducing these terms.1 In retrospect, an apology was not needed, for he was immensely prophetic. In 1975, the American Board of Pediatrics offered the first examination in neonatal-perinatal medicine, certifying 355 individuals as “neonatologists.” By 2021, the Board had certified 5429 individuals under the age of 70, with an average of 104 neonatologists per state and 1.69 per county. These numbers parallel the growth in the fund of knowledge. A PubMed search using the terms “newborn,” “neonatal,” or “perinatal” yields more than 965,000 citations.2 Now, at the threshold of the second decade of the 21st century, neonatology stands tall and strong, carving out a unique niche that bridges obstetrics with pediatrics and intensive care with primary care. Although the subspecialty got its name only recently, the roots of systematic and organized neonatal care extend into the 19th century, when focused care for premature infants began in earnest, especially in France. This chapter provides an outline of the origin and growth of modern perinatal and neonatal medicine, with a brief perspective on its promises and failures. Numerous scholarly monographs and review articles are cited so readers can consult additional studies and research.3–8

Perinatal Pioneers For the sake of brevity, Fig. 1.1 identifies a handful of scientists who played strategic roles in developing the basic concepts in neonatal-perinatal medicine and inspired generations of future researchers around the world. Medicinal chemistry (later referred to as biochemistry) and classic physiology gained popularity toward the end of the 19th century. During the early decades of the 20th century, many leading scientists conducted basic science biochemical and physiological research in neonatal-perinatal medicine. Some of these pioneers included Sir Joseph Barcroft9,10 and his trainee Geoffrey Dawes in England (gas exchange and nutritional transfer across the placenta and oxygen carrying in fetal and adult hemoglobin); Arvo Ylppö in Finland (neonatal nutrition, jaundice, and thermoregulation); John Lind in Sweden (circulatory physiology); Clement Smith11 in Boston (fetal and neonatal respiratory physiology); Joseph DeLee12,13 in Chicago (incubators, high-risk obstetric topics, and first “incubator station” in the United States, which was located at the Chicago Lying-in Hospital); Richard Day in New York (temperature regulation, retinopathy of prematurity [ROP], and jaundice); and Harry Gordon14 in Denver (nutrition). Although no formal curriculum existed, they offered rigorous training in perinatal-neonatal physiology and clinical medicine, helping the trainees to establish their own training programs in their home cities. Clement Smith once said, “If you were interested in babies and liked Boston, I was the only wheel in town!”15 Table 1.1 highlights some of the milestones in perinatal medicine. 

The High-Risk Fetus and Perinatal Obstetrics Deaths during the newborn period and early infancy used to be so common that many cultures adopted remarkably innovative coping methods to deal with the tragedies.

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CHAPTER 1  Growth of Neonatal-Perinatal Medicine—A Historical Perspective

E

C

B

A

F

G

3

D

H

• Fig. 1.1  Pioneers in perinatal and neonatal physiology and medicine. (A) Joseph Barcroft. (B) Arvo Ylppö.

(C) John Lind. (D) William Liley. (E) Joseph DeLee. (F) Richard Day. (G) Clement Smith. (H) Harry Gordon. ([A] From Barcroft J. Research on Pre-natal Life. Vol. 1. Oxford: Blackwell Scientific; 1977, courtesy of Blackwell Scientific; [B–D and F–H] from Smith GF, Vidyasagar D, eds. Historical Review and Recent Advances in Neonatal and Perinatal Medicine: Neonatal Medicine. Vol. 1. Ann Arbor, MI: Mead Johnson Nutritional Division; 1983, pp. ix [B], xix [C], xxii [D], xvi [F], xii [G], and xiv [H], courtesy of Mead Johnson Nutritional Division; [E] Courtesy Mrs. Nancy DeLee Frank, Chicago, IL.)

According to a Jewish tradition, full, year-long mourning was not required for infants who died before 30 days of age.16 Among some Asian ethnic groups, naming ceremonies were not held until several months after the infant’s birth, until which time the infant would be referred to as “it.” In India, the first surviving infant after the death of a previous sibling was given an odd or a coarse-sounding meaningless name, such as “Kogga,” “Bukka,” or “Buddu,” to confuse the evil spirits lest they attack the current newborn. In A Distant Mirror: The Calamitous 14th Century, the author noted that infants were seldom depicted in medieval artworks.17 When they were (e.g., the infant Jesus), women were shown looking away, ostensibly displaying respect but also a fearful aloofness. Since antiquity, the care of pregnant women has been the purview of midwives, grandmothers, and experienced female elders in the community. Wet nurses helped to feed the infants if mothers were unavailable or unwilling to nurse their infants. Midwives helped during normal and uncomplicated labor and deliveries, but male physicians were summoned to manage complicated cases, although they could do little because many of them lacked expertise or an interest in treating women. Thus disasters during labor and delivery were unavoidable. Pregnant women dreaded the perinatal period, as this was the most dangerous phase of their lives.18

In the early 1900s, unexpected intrapartum complications accounted for 50% to 70% of all maternal deaths in England and Wales.19,20 Caregivers focused on tending to the new mother to save her life, and sick newborns received very little care, thus accounting for the high early neonatal death rate until the mid-20th century. Occasionally, happy outcomes of high-risk deliveries did occur. In one of the oldest works of art depicting labor and delivery (Fig. 1.2A), a bearded man and his assistant are standing behind a woman in labor, holding devices remarkably like the modern obstetric forceps. The midwife has delivered an evidently live infant. In Fig. 1.2B, three infants from a set of quadruplets, nicely swaddled, have been placed on the mother as the unwrapped fourth infant is being handed to her for nursing. A divine figure in the background can be seen blessing the newcomers. Cesarean sections were seldom performed on living women before the 13th century. Even subsequently, they were performed only as a final act of desperation, often to save a “precious fetus,” such as a royal offspring rather than the mother. Contrary to popular belief, Julius Caesar most likely was not delivered via a cesarean section. His mother was alive during his reign, but survival after a cesarean delivery was nearly impossible, so historians surmise that

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4 PA RT 1     The Field of Neonatal-Perinatal Medicine

TABLE 1.1    Selected Milestones in Perinatal Medicine

Category

Year(s)

Description

Antenatal aspects

1752

Queen Charlotte’s Hospital, the world’s first maternity hospital, is founded in London.85

1915–1924

Campbell introduces outlines of regular prenatal visits which become a standard.

1923–1925

Estrogen and progesterone are discovered.

1928

First pregnancy test is described, in which women’s urine is shown to cause changes in mouse ovaries.

1543

Vesalius observes fetal breathing movements in pigs.

1634

Paré teaches that absence of movement suggests a dead fetus.

1819, 1821

Laënnec introduces the stethoscope in 1819, and his friend Kergaradec shows that fetal heart sounds can be heard using it.

1866

Forceps are recommended when there is “weakening of the fetal heart rate.”

1903

Einthoven publishes his work on the electrocardiogram (ECG).

1906

The first recording of fetal heart ECG is made.

1908

The term fetal distress is introduced.

1948–1953

Developments are made in the external tocodynamometer.

1953

Apgar describes her scoring system.34

1957–1963

Systematic studies are conducted on fetal heart rate monitoring.

1970

Dawes reports studies on breathing movement in fetal lambs.

1980

Fetal Doppler studies begin.

1981

Nelson and Ellenberg report that Apgar scores are poor predictors of neurologic outcome.

ca. 1000–500 bc

In Ayurveda, the ancient Hindu natural system of medicine, physicians describe obstetric instruments.

98–138

Soranus develops the birthing stool and other instruments.

1500s

There are isolated reports of cesarean sections on living women.

1610

The first intentional cesarean section is documented.

1700s

Chamberlen forceps are kept as a family secret for three generations.

1921

Lower uterine segment cesarean section is reported.

1953

The modern vacuum extractor is introduced.

1900–1950

Barcroft, Dawes, Lind, Liley, and others study physiologic principles of placental gas exchange and fetal circulation.

Fetal assessment

Labor and delivery

Fetal physiology

See References 15, 18, 25, 36, 39, 64, 80, 81, 82, and 86.

Julius was born via the vaginal route. The term cesarean probably originated from lex caesarea, in turn from lex regia, or the “royal law,” prohibiting burial of corpses of pregnant women without removal of their fetuses.21,22 The procedure allowed for baptism (or a similar blessing) of the liveborn child or burial of the stillborn. Infants surviving the ordeal of cesarean birth were assumed to possess special powers, as supposedly did Shakespeare’s Macduff— “not of a woman born,” but of a corpse, and able to slay Macbeth.23

Soranus of Ephesus (circa 38–138 ad) influenced obstetric practice for 1400 years. His Gynecology is considered to be the first “textbook” of perinatal medicine. In 1956, The Johns Hopkins University Press published an English translation of the reconstructed Gynecology.24 Soranus described podalic version, obstructed labor, multiple gestations, fetal malformations, and other maternal and fetal disorders. In an age of belief in magic and the occult, he insisted that the midwife should be educated and free from superstitions. He forbade wet nurses from drinking alcohol lest it

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CHAPTER 1  Growth of Neonatal-Perinatal Medicine—A Historical Perspective

5

A

B • Fig. 1.2  High-risk deliveries. (A) Marble relief of uncertain date depicting a high-risk delivery. The physician

and his assistant in the background are holding devices similar to modern obstetric forceps. A midwife has just helped deliver a live infant while two people look through the window. (B) Delivery of quadruplets. (From Graham H. Eternal Eve: The History of Gynecology and Obstetrics. New York: Doubleday; 1951, pp. 68 [A] and 172 [B].)

render the infant “excessively sleepy.” His chapter entitled “How to Recognize the Newborn That Is Worth Rearing” is one of the earliest accounts on assessing the viability of sick newborns—a topic of concern and controversy even today. 

Midwives and Perinatal Care Although midwives were often objects of caricature (Fig. 1.3), good midwives were in great demand. Because male physicians disliked obstetrics and women preferred to not let male doctors care for them, only the midwives were left to attend labor and deliveries. Thus midwives held important social and political positions in many European courts.18,25,26 The emergence of man-midwives (Fig. 1.4) in England had a major effect on high-risk obstetric practice. Chamberlen the Elder (1575–1628) invented the modern obstetric forceps.18,25,27 Three generations of Chamberlens kept the details of the forceps a trade secret, but other inventors also developed similar implements. Because only male physicians were permitted to use devices such as the obstetric forceps that improved maternal outcomes, women began to associate good outcomes with the practices of male physicians, ultimately changing the dynamics of obstetric practice.18 Also, an increasing number of women began asserting their right to make choices for their care, thus accelerating the shift from female midwifery to male midwifery in 18th-century Europe.26 Currently, women are turning to midwives in greater numbers, particularly for home deliveries, underwater births, and even on-demand cesarean procedures. 

• Fig. 1.3  On call. “A Midwife Going to a Labour” is an 1811 caricature by Thomas Rowlandson. (Courtesy The British Museum, London.)

Neonatal Resuscitation: Tales of Heroism and Desperations Popular artworks and ancient medical writings provide accounts of miraculous revivals of apparently dead adults

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6 PA RT 1     The Field of Neonatal-Perinatal Medicine

• Fig. 1.5  US postage stamp featuring Virginia Apgar. (Courtesy the US Postal Service.)

•

Fig. 1.4  Man-midwife. (Courtesy Clements C. Fry Print Collections, Harvey Cushing/John Hay Whitney Medical Library, Yale University, New Haven, CT.)

and children.28 Such depictions, however, reflect only successes, for failures were buried and rarely reported. Attempts to “stimulate” and revive apparently dead newborns included beating, shaking, yelling, fumigating, dipping in ice-cold water, and dilating and blowing smoke into the anus, among the many more gruesome efforts.28–31 The practice of administering oxygen into the stomach using an orogastric tube persisted well into the mid-1950s, when James and Apgar showed that the therapy was utterly useless.32,33 

Apgar and the Language of Asphyxia Few scientists in the 20th century influenced the practice of neonatal resuscitation as much as Virginia Apgar (1909–1974). Trained as a surgeon, she practiced obstetric anesthesia. With the simple scoring system she devised, she inaugurated the modern era of assessing and reviving infants at birth.34 Right or wrong, the Apgar score became the language of asphyxia. It is often said that the first words a newborn infant hears are “What’s the Apgar score?” Over time, “giving an Apgar” became a ritual, and the scoring system has helped caregivers to formalize the process of observing, assessing, and communicating an infant’s status in a consistent manner. Eventually, a system of formal steps to resuscitate a newborn was developed based on the Apgar score. Apgar was also the first person to catheterize the umbilical artery in a newborn.35 A woman of enormous energy, talent, and compassion, Apgar was honored by being depicted on a 1994 US postage stamp (Fig. 1.5). 

Foundling Asylums and Infant Care In its early days, the Roman Empire experienced decreasing population growth. The emperors taxed bachelors and rewarded married couples to encourage procreation.36 In 315 ad, Emperor Constantine, hoping to curb infanticide and encourage the adoption of orphans, decreed that all “foundlings” would become slaves of those who adopted them. Similar humanitarian efforts by kings and the Council of the Roman Church led to the institutionalization of infant care by establishing foundling asylums for abandoned infants,36 also referred to as “Hospitals for the Innocent”— the first children’s hospitals. The parent of an unwanted infant deposited the infant in a revolving receptacle at the door of such an asylum, rang the doorbell, and disappeared into the night (Fig. 1.6). Sadly, such incidences occur even in modern times.37 Foundling asylums adopted pragmatic techniques for fundraising. In 18th-century France, lotteries were held, and souvenirs were sold. In May 1749, George Frideric Handel gave a concert to support London’s “Hospital for the Maintenance and Education of Exposed and Deserted Young Children.” The final item of the program was the playing of “The Foundling Hymn.”36 

Saving Infants to Man the Army During the French Revolution, France noticed a very high (more than 50%) infant mortality rate. Concerned about this appalling condition, in 1789, the Revolutionary Council enacted a decree proclaiming that working-class parents had a “… right to the nation’s succors at all times.”36 The

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CHAPTER 1  Growth of Neonatal-Perinatal Medicine—A Historical Perspective

A

7

B • Fig. 1.6  Foundling homes. (A) Le Tour—revolving receptacle. Mother ringing a bell to notify those within

that she is leaving her baby in the foundling home (watercolor by Herman Vogel, France, 1889). (B) Remorce (“Remorse”)—parents after placing their infant in a foundling home (engraving and etching by Alberto Maso Gilli, France, 1875). (Courtesy the Museum of the History of Medicine, Academy of Medicine, Toronto, Ontario, Canada; from Spaulding M, Welch P. Nurturing Yesterday’s Child: A Portrayal of the Drake Collection of Pediatric History. Philadelphia: Decker; 1991, pp. 110 [A] and 119 [B].)

post-revolutionary euphoria stimulated reforms and led to collecting and maintaining children’s vital statistics, thus enabling France to build the world’s first national database.36 Over the next century, France faced a decline in birth rates while infant mortality remained high. Fearing negative population growth and a shortage of soldiers to fight in their armies, military leaders established measures designed to increase the rates of childbirth and improve pregnancy and infant outcomes.3–5,36,38,39 Young parents were incentivized with money to have more children and encouraged to uphold their patriotism by helping to “man the future armies.” It is the irony of our times that the noble intention of saving a mother and her baby had to be motivated by a desire to build an army that could kill other humans, branded as “enemies.” 

An Ingenious Contrivance, the Couveuse, and Premature Baby Stations In 1878, an eminent French obstetrician, Stéphane Tarnier (1828–1897), paid a casual visit to the poultry section of the Paris Zoo. Seeing how eggs successfully hatched into chickens in the warm hatcheries, he requested Odile Martin, the zoo engineer, to construct similar “incubators” or couveuses3–5,38 to care for newborn infants. Martin devised a ventilated chamber heated by a “thermosyphon” method, such that the outside of the incubator was heated using an alcohol lamp. In 1880, at the Paris Maternity Hospital,

Tarnier installed the first of these couveuses, which were 1-m3, double-walled metal containers spacious enough to hold two premature infants. The effects on preterm infant survival rates were dramatic. Soon thereafter, Pierre-Constant Budin (1846–1907) and Paul Auvard (1855–1941), Tarnier’s students, institutionalized preterm infant care. They arranged the incubators side by side and placed groups of preterm infants together in a separate section of the hospital,3,4,40,41 thus establishing the fist “newborn baby care units.” They also improved the original couveuses by fitting them with glass sides rather than metal and improving the methods of heating. More technological innovations followed, and newer incubators were introduced into the markets in Europe, the United Kingdom, and the United States (Fig. 1.7 and Table 1.2). In 1884, Tarnier developed a small, flexible rubber tube that could be passed through the mouth into the stomach, and preterm infants could be fed by dripping milk directly into the stomach. He referred to this method as “gavage feeding.” More infants were living longer inside the warm incubators, and there was clearly a need for the long-term nutritional support that gavage feeding provided, which dramatically improved preterm infant survival rates.42,43 Tarnier recommended that a legal definition for viability should be 180 days of gestation, which was opposed by contemporary obstetricians, who thought that the concept was “therapeutic nihilism.”4 More than a century later, the definition of viability remains a highly emotional and contentious issue. 

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8 PA RT 1     The Field of Neonatal-Perinatal Medicine

A

B

Sponge

Bed

Hot-Water Tank

C

Air Exit

Air Entrance Filling Funnel Bunsen Burner

Glass Cover

•

Fig. 1.7 Early incubators. (A) Rotch incubator, circa 1893. (B) Holt incubator. (C) Schematics of the Holt incubator. ([A] From Cone TE Jr. History of American Pediatrics. Boston: Little Brown; 1979, pp. 57, 58, courtesy Little Brown. [B and C] From Holt LE. The Diseases of Infants and Children. New York: Appleton; 1897, pp. 12 [B] and 13 [C].)

Incubators, Baby Shows, and Origins of Neonatal Intensive Care Units About two decades after their debut in France, incubators appeared in the United States. In 1898, Joseph DeLee established the first “Premature Baby Incubator Station” for premature infants at the Chicago Lying-In Hospital. As academic obstetricians and pediatricians began organizing specialized care for premature infants, an interesting, if bizarre, set of events unfolded as “premature baby shows,” which began to appear in the last decade of the 19th century in Europe and continued through the 1940s in the United States.3,4,44 Martin Couney (1869–1950), a Budin associate of doubtful medical credentials, wanted to popularize the French incubator technology and show how it could “conserve” premature infants. (This account has been doubted.4)

Couney obtained six incubators, probably from the French inventor Alexandre Lion, for a technological exhibition. To add an element of drama, he took six premature infants from the Rudolf Virchow Hospital’s maternity unit in Berlin and exhibited them in the incubators at the 1896 Berlin Exposition. He coined a catchy phrase for the show—kinderbrutanstalt, or “child hatchery”—igniting the imagination of a public thirsty for sensational scientific breakthroughs. After his astounding success with the Berlin incubator exhibit, Couney took his show to Great Britain’s Victorian Era Exhibition in 1897. Again, the show was a hit, earning praise in an editorial in The Lancet,45 but later the journal warned of the “danger of making a public show of incubators for babies.”46 In 1898, Couney sailed to the United States and continued exhibiting premature infants at state fairs, traveling circuses, and science expositions. He settled in New York City and organized annual incubator baby shows at Coney Island and Atlantic City, where his final exhibition was held in 1940.44 Ever a showman, Couney organized “reunion” parties to which he invited “graduates” from his exhibitions for anniversary celebrations. In front of the invited news media, he awarded the infants with token gifts and certificates. The impact of these incubator baby shows on the growth of neonatal-perinatal medicine is difficult to assess, but Couney did indeed save hundreds of preterm infants. In addition to firing up the public’s imagination with regard to the hope that incubators offered, he also convinced the medical world that preterm infants could be saved and that most of them would be doing well on follow-up. In 1914, Julius Hess established a Premature Infant Station at the Sarah Morris Children’s Hospital at the Michael Reese Medical Center in Chicago. Due to their focused attention on environmental control, aseptic practices, and a regimental approach to feeding, Hess and his head nurse, Evelyn Lundeen (Fig. 1.8), achieved spectacular survival rates.47,48 Hess developed a double-walled metallic “cage” incubator that had warm water circulating between the walls. He used electric current for heating and devised a system to administer free-flow oxygen (Fig. 1.9). Only a few Hess incubators are known to have survived to this day. The development of incubators and their impact on pediatrics represent a tale of both technological success and unforeseen perils (such as the risk of ROP). In the heroic age of the mechanical revolution, the notion that machines could solve all human problems was all too appealing. The incubator stands as the most enduring symbol of the spectacular success of modern intensive care and (paradoxically) some of its failures.7,8 

Supportive Care and Oxygen Therapy In a single-page note in 1891, Bonnaire referred to Tarnier’s use of oxygen, 2 years earlier, to treat “debilitated” premature infants.49 This was the first published reference to the administration of supplemental oxygen in premature infants for a purpose other than resuscitation. The use of

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CHAPTER 1  Growth of Neonatal-Perinatal Medicine—A Historical Perspective

9

TABLE 1.2    Evolution of Incubators

Year(s)

Developer/Product

Comments

1835, ca. 1850

von Ruehl (1769–1846)

A physician to Czarina Feodorovna, wife of Czar Paul I, von Ruehl develops the first known incubator for the Imperial Foundling Hospital in St. Petersburg. About 40 of these “warming tubs” are installed in the Moscow Foundling Hospital in 1850.

1857

Denucé (1824–1889)

The first published account of introducing an incubator is a 400-word report by Denucé. This is a “double-walled” cradle.

1880–1883

Tarnier (1828–1897)

Tarnier incubator is developed by Martin and installed in 1880 at the PortRoyal Maternité.

1884

Credé (1819–1892)

Credé reports the results of 647 infants treated over 20 years using an incubator similar to that of Denucé.

1887

Bartlett (1816–1889)

Bartlett reads a paper on a “warming crib” based on Tarnier’s concept but uses a “thermosyphon.”

1893

Budin (1846–1907)

Budin popularizes the Tarnier incubator and establishes the world’s first “special care unit for premature infants” at Maternité and Clinique Tarnier in Paris.

1893

Rotch (1849–1914)

The first American incubator with a built-in scale, wheels, and fresh-air delivery system is developed; the equipment is very expensive and elaborate.

1897

Holt incubator

A simplified version of the Rotch incubator is developed. In this doublewalled wooden box, hot water circulates between the walls.

1897–1920s

Brown, Lyons, DeLee, and Allin

Many modifications are made to the early American and European incubators by physicians. These revised versions are referred to as baby tents, baby boxes, and warming beds, among other names.

1922

Hess

Hess introduces his famous incubator with an electric heating system. For transportation, he develops special boxes that can be plugged into the cigarette lighters in Chicago’s taxi cabs.

1930–1950s

Large-scale commercial incubators

There is worldwide distribution of Air-Shields and other commercial ventilators.

1970–1980

Modern incubators

Transport incubators with built-in ventilators and monitoring equipment are developed (i.e., mobile intensive care units).

See References 3, 4, 5, 7, 8, 38, 43, 44, 75, and 87 for primary citations.

oxygen in premature infants did not become routine, however, until the 1920s. Initially, a mixture of oxygen and carbon dioxide—instead of oxygen alone—was employed to treat asphyxia-induced narcosis. It was argued that oxygen relieved hypoxia, whereas carbon dioxide stimulated the respiratory center.50 Oxygen alone was reserved for “pure asphyxia” (whatever that meant). The advent of mobile oxygen tanks and their easy availability in the mid-1940s enabled the use of oxygen for resuscitation.7,51,52 The success of incubator care brought new and unexpected challenges.40,48 Methods had to be developed to feed the increasing number of premature infants surviving for longer periods. Their growth had to be monitored, and illnesses related to prematurity, such as sepsis, apnea, anemia, jaundice, and respiratory distress, had to be treated. An unexpected peril created by the use of incubator technology was an epidemic of blindness due to ROP, then referred to as retrolental fibroplasia, which is vividly described elsewhere.7,8 In retrospect, we can attribute the ROP epidemic

to the “leakproof ” incubator, which increased the inspired oxygen concentrations piped in free-flow manner into the incubators. As often happens, it was mistakenly believed that if a “little bit of oxygen” could save some lives, then “a lot of oxygen” could save even more. Due to the increasing number of preterm infants surviving, including those experiencing respiratory distress, providing longer term ventilatory assistance became an urgent necessity, giving rise to the development of techniques for prolonged ventilatory assistance. 

Ventilatory Care: “Extended Resuscitation” The first mechanical instrument used for intermittent positive-pressure ventilation in newborns was the aerophore pulmonaire, a simple device developed by the French obstetrician Gairal.28,53 It was a rubber bulb attached to a J-shaped tube, and by placing the bent end of the tube into the infant’s upper airway, one could pump air into the lungs.

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10 PA RT 1     The Field of Neonatal-Perinatal Medicine

•

Fig. 1.8 Hess and Lundeen medallions at the Michael Reese Hospital, Chicago, IL. (Courtesy Tonse N. K. Raju.)

•

Fig. 1.9 A Hess incubator on display at the Spertus Museum in Chicago, IL. (Courtesy the International Museum of Surgical Sciences, Chicago, IL.)

L. Emmett Holt recommended its use for resuscitation in his influential 1897 book, The Diseases of Infants and Children.54 Before beginning mechanical ventilation, one needed to cannulate the airway, a task nearly impossible without a laryngoscope and an endotracheal tube. James Blundell (1790–1878), a Scottish obstetrician, was the first to use a mechanical device for tracheal intubation in living newborns.55,56 Introducing two fingers of his left hand over the infant’s tongue, he could feel the epiglottis and then guide a silver pipe into the trachea with his right hand. His tracheal

pipe had a blunt distal end and two side holes. By blowing air into the tube about 30 times a minute until the heartbeat began, Blundell saved hundreds of infants with birth asphyxia and infants with laryngeal diphtheria. His method of tracheal intubation is still practiced in many countries today.57 In the late 19th century, a wide array of instruments evolved to provide longer periods of augmented or extended ventilation for infants who had been resuscitated in the labor room. Most of the early instruments were designed for use in adults, however, and only later were they used for newborns and infants, particularly to treat paralytic polio and laryngeal diphtheria.11,50,58,59 The iron lung (or “man-can”) was one of the earliest mechanical ventilatory devices (Fig. 1.10), and a US patent was issued for it in 1876.60–62 Other types of ventilatory equipment used varying methods for rhythmic inflation and deflation of the lungs for prolonged ventilation. Among those, the Fell-O’Dwyer apparatus used a unique foot-operated bellows system connected to an implement similar to the aerophore bulb.28,29,53 Between 1930 and 1950, there were sporadic but important reports of prolonged assisted ventilation being provided to newborns.50,63–65 Beginning in the late 1950s and continuing through the 1960s, more neonatal intensive care units (NICUs) began providing ventilatory assistance regularly (Table 1.3). Ventilatory care did not become reliably successful, however, until the early 1970s, when continuous positive pressure was incorporated into ventilatory devices.64–67 

Supportive Care: Intravenous Fluid and Blood Transfusions Blundell (of intubation fame) also made a major contribution to transfusion science. Believing that “only human blood should be employed for humans,” he developed instruments, syringes, and funnels for this purpose. In

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CHAPTER 1  Growth of Neonatal-Perinatal Medicine—A Historical Perspective

1818, Blundell carried out the first direct transfusion from a healthy donor into a recipient, and five of his first 10 patients survived. Human-to-human transfusions gradually became accepted, but physicians in the 19th century were puzzled about unexpected disasters that occurred among blood transfusion recipients. It took 15 years after Karl Landsteiner’s discovery of blood groups in 1901 to achieve general acceptance and understanding of the scientific basis for blood group incompatibility.68 Adult transfusions were rare, but newborn transfusions were rarer still. On March 8, 1908, a 4-day-old term infant who had hemorrhagic disease of the newborn made history. “As the child’s skin became waxen white

• Fig. 1.10  The Man-Can, circa 1873 to 1875. A handheld, negative-

pressure ventilatory device for which a patent was applied in 1876.60,61 (From DeBono E. Eureka! How and When the Greatest Inventions Were Made: An Illustrated History of Inventions from the Wheel to the Computer. New York: Holt, Rinehart & Winston; 1974, p. 159.)

11

and mucous membranes without color, it was decided to attempt transfusion of blood obtained from the infant’s father,” wrote Samuel Lambert from New York.69 Alexis Carrel, a surgeon from Rockefeller University Hospital, performed an end-to-end anastomosis of the right popliteal vein of the infant with the left radial artery of the father. No anesthetic was given to either patient. “The amount of blood transfused could not be measured, but enough blood was allowed to flow into the baby to change her color from pale transparent whiteness to brilliant red … [and] as soon as the wound was sutured, the infant fed ravenously and immediately went to sleep,” according to Lambert. Incidentally, Carrel was the first surgeon to develop innovative methods of suturing blood vessels—a contribution for which he received the 1912 Nobel Prize. Despite Lambert’s dramatic report, direct father-toinfant transfusion did not become routine. Often, blood transfusions led to unexpected reactions among the recipients, despite proper matching of the donors’ blood for major blood types. Why these happened remained a mystery until the discovery of Rh subtypes by Landsteiner and Alexander Wiener in 1940.68,70 The discovery of Rh blood types led to the conquest of erythroblastosis fetalis, which remains an unparalleled triumph in pediatric medicine. This is an example of an orderly progression of accumulating knowledge leading to the near eradication of a disease. Clinical descriptions of the disease (erythroblastosis) were followed by a revolutionary exchange transfusion therapy, which was

TABLE 1.3    Ventilatory Care, Respiratory Disorders, and Intensive Care

Category

Approximate Time Span

Procedures and Techniques

Resuscitation and oxygen

From antiquity to early 1970s

Mouth-to-mouth breathing (although it fell from favor in the late 18th century because many influential physicians declared it a “vulgar method” of revival)

1878

Tarnier uses oxygen in debilitated premature infants.

1900–1930s

The various methods of Schultz, Sylvester, and Laborde involved swinging infants (Schultz), traction of the tongue (Sylvester), and compression of the chest (Laborde).

1930–1960s

Oxygen administration to the oral cavity through a rubber catheter

1930s–1940s

Tight-fitting tracheal tube and direct tracheal oxygen administration

1913–1920s

Byrd-Dew method involved immersion in warm water, with alternate flexing and extending of the pelvis to help the “lungs open.”

1850–1930s

Dilation of the rectum

1930–1950s

Inhalation of oxygen and 7% CO2 mixture (for morphine-induced narcosis)

1940–1950s

Positive-pressure airlock (Bloxsom method)

1940 to late 1950s

Concept that “air in the digestive tract is good for survival” is used to promote the administration of oxygen to the stomach.

1950 to late 1960s

Hyperbaric oxygen in Vickers pressure chamber

1950–1960s

Mouth-to-mouth or mouth-to-endotracheal tube breathing Continued

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12 PA RT 1     The Field of Neonatal-Perinatal Medicine

TABLE 1.3    Ventilatory Care, Respiratory Disorders, and Intensive Care—cont’d

Category

Approximate Time Span

Procedures and Techniques

Assisted ventilation

1930s–1980s

Bell develops a negative-pressure jacket.

1930–1950

Negative-pressure ventilators and iron lungs, although used rarely in infants

1960s

Positive-pressure respirators are used for prolonged ventilatory support.

1971

Continuous positive airway pressure is introduced for use in newborns.

1973

Intermittent mandatory ventilator

1970–1980s

High-frequency ventilators and continuous monitoring of pulmonary function

1903

Hochheim reports “hyaline membranes” noted in the lungs of infants with respiratory distress syndrome.

1940–1950s

Clinical descriptions and pathology studied

1955–1956

Pattle discovers surfactant in pulmonary edema foam and lung extracts.

1959

Avery and Mead show an absence of surfactant in infants with hyaline membrane disease.88

1971

Gluck introduces the lecithin/sphingomyelin ratio.

1973

Liggins suggests that antenatal steroids help mature the pulmonary surfactant system.

1980

First effective clinical trial of postnatal surfactant (bovine) therapy

1989–1991

Commercial surfactants become available.

1995

Widespread antenatal steroid use leads to declines in rates for respiratory distress syndrome and improves survival rates for infants with birth weight 10 mm &/or TOD >25 mm Or

Any of the following clinical criteria HC growth >2 cm per week Separated sutures Bulging fontanelles Management: Consider LP 2–3 times Neurosurgical intervention including either temporizing measures or VP shunt MRI at Term Equivalent

Neurosurgical intervention when no stabilization occurs MRI at Term Equivalent Consider alterations in NIRS (i.e., decrease cerebral oxygenation) or Doppler US (i.e., Increase in Resistive Index) as additional information that may suggest impairment in cerebral perfusion and more urgent need for intervention.

• Fig. 55.6  A practical clinical tool to monitor commonly used ventricular measures and proposed risk stratification and management of infants with posthemorrhagic ventricular dilatation. Individual measures can be plotted in millimeters in the table as well as on the corresponding postmenstrual age in the graph to identify risk zone. AHW, Anterior horn width; cUS, cranial ultrasound; HC, head circumference; MRI, magnetic resonance imaging; NICU, neonatal intensive care unit; PMA, postmenstrual age; TOD, thalamo-occipital distance; VI, ventricular index. (From El-Dib M, Limbrick DD, Inder T, et al. Management of posthemorrhagic ventricular dilatation in the infant born preterm. J Pediatr. 2020;226:16–27.e3.) Downloaded for mohamed ahmed ([email protected]) at University of Southern California from ClinicalKey.com by Elsevier on April 05, 2024. For personal use only. No other uses without permission. Copyright ©2024. Elsevier Inc. All rights reserved.

CHAPTER 55  Intracranial Hemorrhage and Stroke in the Neonate

feeding intolerance, and apneas. In the long term, pressureinduced destruction of neuronal tissue can lead to motor and cognitive impairments.8 Short-term adverse effects on the developing brain have been confirmed using somatosensory and visual evoked potentials, Doppler estimates of cerebral blood flow velocity, and NIRS.46 In a study of nine infants with PHVD, NIRS was used, and a significant increase in cerebral blood flow was measured (15.6%) following a ventricular tap, but without a corresponding change in cerebral metabolic rate of oxygen (1.02 ± 0.41 mL O2/100 g/min).46 CSF levels of IL-8, interferon (IFN)-γ, and soluble Fas were noted to be raised in infants with PHVD and especially so in those with associated white matter injury.47 Other CSF biomarkers were found to be increased in infants with PHVD, including amyloid precursor protein (APP), soluble APP-α, and L1 cell adhesion molecule.48 Accumulating evidence shows that early drainage of CSF alters the natural history and outcome of PHVD. Brouwer et al.49 evaluated the differential impact of GMH-IVH and PHVD on the brain and CSF volumes and diffusion variables in preterm-born infants at TEA. The majority of the infants in this cohort were treated with early interventions. The authors showed that PHVD was independently associated with volumes of deep gray matter (β −1.4 cc; 95% CI −2.3 to −0.5), cerebellum (β −2.7 cc; 95% CI −3.8 to −1.6), ventricles (β +12.7 cc; 95% CI 7.9–17.4), and extracerebral CSF (β −11.2 cc; 95% CI −19.2 to −3.3), and with apparent diffusion constant (ADC) values in occipital, parietooccipital, and parietal white matter (β +0.066 to 0.119 × 10−3 mm2/s) on TEA-MRI (P < .05). No associations were found between GMH-IVH grades 2 and 3 and brain and CSF volumes or ADC values. In summary, PHVD was negatively related to deep gray matter and cerebellar volumes and positively to white matter ADC values on TEA-MRI, despite early intervention for PHVD in the majority of the infants. A recent observational study from Canada and the Netherlands showed results favoring earlier intervention for PHVD. In this study, outcomes were compared at 18 to 24 months between infants with and without intervention in preterm infants undergoing either an early approach in Dutch centers or a late approach in the Canadian center. It is important to note that the common practice in the Dutch centers was to intervene early based on the cUS measurements of the ventricles, whereas intervention decisions were based on the clinical findings of PHVD rather than the cUS measurements in the Canadian center. The study showed that infants undergoing earlier intervention for progressive PHVD, even when eventually requiring a ventriculoperitoneal shunt (VPS), had cognitive and motor outcomes similar to those without intervention, all being within the normal range. In contrast, later intervention was associated with an increased risk of adverse outcomes.50 The initial phase I trial of the drainage, irrigation, and fibrinolytic therapy (DRIFT) study showed a reduced need for VPS insertion of 26% compared with around 60% in previous multicenter studies. The authors concluded that reducing pressure, free iron, and pro-inflammatory and

1043

profibrotic cytokines may reduce periventricular brain damage and hydrocephalus.51 A subsequent randomized controlled trial randomly assigned 70 preterm infants with progressive PHVD who had GAs of 24 to 34 weeks to either (1) DRIFT or (2) tapping of CSF by the ventricular reservoir to control excessive expansion and signs of pressure (standard treatment). The composite outcome of death and VPS was not significantly different (44% vs. 50%, respectively). Of note, 12 (35%) of 34 infants who received DRIFT had secondary IVH compared with 3 (8%) of 36 in the standard group. Secondary IVH was associated with an increased risk for subsequent VPS surgery and more blood transfusions.52 However, when assessed at 2 years corrected age in a follow-up study, of 39 infants assigned to DRIFT, 21 (54%) died or were severely disabled versus 27 of 38 (71%) in the standard group (adjusted OR 0.25; 95% CI 0.08–0.82). Among the survivors, 11 of 35 (31%) in the DRIFT group had severe cognitive disability versus 19 of 32 (59%) in the standard group (adjusted OR 0.17; 95% CI 0.05–0.57). The authors concluded that despite an increase in secondary IVH, DRIFT reduced severe cognitive disability in survivors and overall death or severe disability.53 Recently, the DRIFT investigators further assessed if the cognitive advantage of DRIFT seen at 2 years persisted until 10 years of age. Among survivors, 28 in the DRIFT group and 24 in the standard treatment group were assessed, and the mean cognitive score was 69.3 ± 30.1 in the DRIFT group and 53.7 ± 35.7 in the standard treatment group (unadjusted P = .1; adjusted P = .01, after adjustment for the prespecified variables of gender, birth weight, and IVH grade). Survival without severe cognitive disability was 66% in the DRIFT group and 35% in the standard treatment group (unadjusted P = .019; adjusted P = .003).54 In summary, DRIFT was the first intervention for PHVD to objectively demonstrate sustained cognitive improvement in preterm infants with PHVD. Although LPs have not been shown to be effective in a meta-analysis to prevent PHVD, the treatment of PHVD interventions typically starts with LPs to decompress the ventricles as the initial step. It has been hypothesized that the physical removal of CSF that contains blood components and protein might mitigate the neuroinflammatory and neurotoxic reactions, decrease deposition of extracellular matrix proteins, and re-establish normal CSF drainage.55 Several retrospective studies in the past two decades have shown the various beneficial effects of intervening earlier based on cUS measurements.50 The ELVIS (Early versus Late Ventricular Intervention Study) trial56 was a multicenter study to address when and how best to intervene in preterm infants with progressive PHVD. In this prospective randomized controlled trial, a total of 126 preterm infants of less than 34 weeks’ GA with progressive PHVD were included between 2006 and 2016. Infants were eligible when they had a GMH-IVH grade 3, with or without PVHI. Recruited infants were randomly allocated to either low-threshold (LT) group (intervention when an increase in VI above the 97th percentile line showing an

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1044 PA RT 1 0    The Central Nervous System

increase toward the 97th percentile + 4 mm line, but before crossing the 97th percentile + 4 mm line; and an increase in AHW >6 mm and toward 10 mm and/or TOD >25 mm), or high-threshold (HT) group (intervention when the VI crossed the 97th percentile + 4 mm line and the AHW was >10 mm). Interventions started with lumbar punctures (LP) with a maximum number of 3, and if necessary, this was followed by tapping from a ventricular reservoir, aiming for VI less than 97th percentile line in both study arms within the next 7 to 10 days. Once or twice daily, 10 mL/kg were removed based on cUS measurements. Reservoir taps were continued until ventricular stabilization was documented. An infant with an ongoing requirement of reservoir taps when weight reached 2000 to 2500 g was challenged, and when ongoing punctures were needed, a VPS was inserted because of the requirement of permanent CSF diversion. The two noteworthy aspects of the ELVIS trial were that in both arms, interventions were solely based on cUS criteria and commenced while the infants were asymptomatic, and that the aim was to effectively reduce the ventricular size to less than 97th percentile in both study arms, whereas the prior studies focused on preventing further ventricular dilatation. Although no further reduction in the need for a VPS in the LT group was found, the need for VPS placement in both study arms was the lowest reported in the literature (19% and 23% in the LT and HT groups, respectively). In the LT group, the number of infants who received temporizing interventions with LPs or ventricular reservoirs was significantly higher than in the HT group. In a subsequent nested substudy, brain injury scores and brain volumes were compared between the groups on TEA-MRIs.57 Among the survivors, MRIs were obtained in 88 infants with an equal number of infants in each study arm. The most significant finding was the smaller ventricular volumes in the LT group. FOHR was lower in the LT group, and infants in the LT arm had lower global brain abnormality scores. After excluding infants with PVHI, the combination of the white matter and gray matter volumes was higher in the LT group, which shows the negative effect of enlarged ventricles on further brain injury. Infants in the HT group also more commonly demonstrated a delay in myelination and more often had thinning of the corpus callosum. Neurodevelopmental outcomes of the ELVIS trial at 2 years corrected age were also recently published.58 In 92% of the surviving infants, outcomes were assessed, and the composite adverse outcome was defined as death, CP, or cognitive/ motor score less than −2 SD on the Bayley Scales of Infant Development, second edition, or the Bayley Scales of Infant and Toddler Development, third edition. Although there was no difference between the LT (35%) and HT (51%) groups with respect to the composite outcome, in the post hoc analysis the LT intervention was associated with a decreased risk of an adverse outcome after correcting for GA, the severity of GMH-IVH, and CBH (adjusted OR 0.24; 95% CI 0.07–0.87; P = .03). These observations support the hypothesis that draining CSF earlier based on

cUS measurements may prevent further brain injury in preterm infants with progressive PHVD. LPs are followed by temporizing neurosurgical interventions if stabilization or regression of ventricular size does not occur. The American Academy of Neurological Surgeons reported that both a ventricular reservoir and ventriculosubgaleal shunt are acceptable options with similar complication rates. A recent meta-analysis by Lai et al.59 showed that a ventricular access device was the most commonly used temporizing neurosurgical intervention. The pooled rate for conversion to VPS was 60.5% (95% CI 54.9–65.8), moderate-severe NDI 34.8% (95% CI 27.4–42.9), infection 8.2% (95% CI 6.7–10.1), revision 14.6% (95% CI 10.4–20.1), and death 12.9% (95% CI 10.2–16.4). The investigators also found that older age at temporizing neurosurgical procedures was a predictor of conversion to VPS (P < .001) and moderate to severe NDI (P < .01). Neuroendoscopic lavage (NEL) is a surgical intervention that washes away hemorrhagic intraventricular CSF and removes remnants of blood clots. Irrigation is continued until anatomic landmarks are clearly visualized. This method seems to be more effective than intermittent punctures from a VAD to remove the hemorrhagic CSF.60 However, it is an invasive technique and requires considerable expertise. In a preliminary study, Park et al.61 performed a combination of ventricular drainage with intermittent administration of urokinase to actively dissolve blood clots via a single catheter (6000 IU/mL) for 14 days. Every day, 20 to 25 mL of hemorrhagic CSF was drained. The investigators started this intervention within 3 weeks of GMH-IVH onset and were able to show that this therapy was associated with fewer VPS placements (14%) and better neurodevelopmental outcomes, with no secondary hemorrhages following the procedure. In 2020, an international group of PHVD researchers published a medical progress article on the effective management of PHVD. The authors stated that combining the evidence from preclinical data showing the ability of early interventions to reverse brain injury, and from clinical data demonstrating improved neurodevelopmental outcomes in centers and trials using ventricular measurements as criteria for interventions, it appears prudent to adopt this evidence into clinical practice.42 Waiting for clinical signs can lead to late intervention and the potential for further brain injury. The investigators developed a practical tool to define risk zones based on the reference charts by Brouwer et al.44 to help the clinician plot ventricular measurements over time to assess risk progress. In this tool, the low-risk infants should be monitored closely and assessed by cUS at least twice weekly until the ventricles are stable for 2 weeks and then every 1 to 2 weeks until 34 weeks’ postmenstrual age. Infants in the moderate-risk group benefit from neurosurgical consultation and 2 to 3 LPs, aiming for the removal of 10 mL/kg of CSF. LPs can be started as soon as infants meet the criteria for measurements of ventricular size. cUS should be performed before and, preferably, also following the LP to assess the effect. Infants who reach the high-risk group

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CHAPTER 55  Intracranial Hemorrhage and Stroke in the Neonate

may also benefit from 2 to 3 LPs done acutely, while actively planning potential neurosurgical interventions. Temporizing neurosurgical interventions include ventricular reservoir or ventricular subgaleal shunt (likely after the infant’s weight is >700 g) based on center preference. Interventions might also include a VPS, based on such factors as center preferences, age, weight, clinical condition, CSF protein, and red cell count. The authors also recommended a TEA-MRI in all risk groups to better assess the extent of the injury and for better prognostication. 

Outcomes Mortality Several studies have shown the close association between mortality and the severity of GMH-IVH. In a large retrospective study on 147,823 preterm infants from the United States, mortality rates were 4%, 10%, 18%, and 40%, respectively, for GMH-IVH grades 1, 2, 3, and PVHI.62 In another large cohort study from the United States, extremely preterm infants were divided into two categories by their GAs: 23 to 25 weeks and 26 to 28 weeks. Of the 6638 infants included, 61.8% had no GMH-IVH, and 13.6% had severe GMH-IVH. Risk-adjusted odds of death or, NDI, and death were higher in the lower GA group. Lower GA also increased the odds of death before 30 days for infants with severe hemorrhage.63 In a recent study, one Dutch and two Canadian centers reported a mortality of 40% in infants with PVHI; however, the rate of redirection of care was also high at 78% in this study.13 

Neurodevelopmental Outcomes Data on long-term neurologic and developmental outcomes mostly focus on infants who had a large GMH-IVH with or without parenchymal involvement, and these follow-up data are mainly obtained from cUS examinations. However, associated white matter injury, especially the noncystic type, may have been missed using cUS. The severity of GMH-IVH, degree of prematurity, the timing of interventions, and requirement of a permanent VPS for progressive PHVD are the major determinants of NDI.1 

Outcomes of Low-Grade Germinal Matrix Hemorrhage-Intraventricular Hemorrhage In theory, a low-grade GMH-IVH may disrupt the neural and glial precursor cells in the germinal matrix region, cause neuroinflammation and neurotoxic effects on the white matter and impair myelination as well as axonal injury, and lead to cortical and thalamic dysmaturation in the developing brain. However, it remains unclear if infants with low-grade GMH-IVH (grades 1 and 2) will develop long-term sequelae, and it is important to note that several studies suggest similar neurodevelopmental outcomes in infants with low-grade GMH-IVH compared with controls without GMH-IVH. In a longitudinal observational study from 16 centers of the National Institute of Child Health and Human Development Neonatal Research Network, a total of 1472 preterm infants less than 27 weeks’ gestation

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were assessed, and low-grade GMH-IVH was not associated with significant differences in the unadjusted or adjusted risk of any adverse neurodevelopmental outcome compared with infants without hemorrhage.64 A more recent multicenter national collaborative study from the United States also found no difference in cognitive function, academic achievement, or behavior between children with low-grade GMH-IVH and those without at age 3, 8, and 18 years.65 In contrast, a regional cohort study of preterm infants born at 23 to 28 weeks’ gestation reported NDI at 2 to 3 years’ corrected age defined as developmental delay, CP, bilateral deafness, or bilateral blindness. Of the 1472 survivors, infants with high-grade GMH-IVH (grade 3 and/or PVHI) had higher rates of developmental delay (17.5%), CP (30%), deafness (8.6%), and blindness (2.2%). Infants with low-grade GMH-IVH (grades 1 and 2) also had increased rates of neurosensory impairment (22% vs. 12.1%), developmental delay (7.8% vs. 3.4%), CP (10.4% vs. 6.5%), and deafness (6% vs. 2.3%) compared with the no IVH group. The authors concluded that low-grade GMH-IVH, even with no documented white matter injury or other late cUS abnormalities, is associated with NDI in extremely preterm infants.66 Law et al.67 also reported an increasing CP rate of 6%, 16%, 33%, and 64% in infants with grades 1, 2, 3, and PVHI, respectively, in a prospectively recruited cohort. In a population-based cohort study, Hollebrandse et al.68 also reported the effect of severity of GMH-IVH on outcomes in a study of 499 extremely preterm infants at 8 years of age. In this study, CP was diagnosed in 8%, 15%, 18%, 26%, and 75% of infants with no GMH-IVH and grades 1, 2, 3, and PVHI, respectively. There was also a trend for increased motor dysfunction with increasing severity of GMH-IVH, from 24% with no hemorrhage, rising to 92% with PVHI. Children with grade 1 or 2 GMH-IVH were at higher risk of developing CP than those without (OR 2.24; 95% CI 1.21–4.16). Increased rates of impairment in intellectual ability and academic skills were observed with high-grade GMH-IVH but not for low-grade GMH-IVH. However, it is important to note that infants with cystic white matter injury were not excluded, and these additional lesions might have caused the motor impairments seen in infants with low-grade GMH-IVH in this cohort. A recent MRI study evaluated the effects of low-grade GMH-IVH on the white matter microstructure in preterm infants using diffusion tensor imaging (DTI). The authors found that white matter microstructural changes also occur in preterm infants with low-grade GMH-IVH and correlate with NDI at 24 months.9 

Outcomes of High-Grade Germinal Matrix Hemorrhage-Intraventricular Hemorrhage The neurologic deficits of PHVD have been linked to periventricular white matter injury. Using diffusion-based spectrum imaging, Isaacs et  al.69 assessed axonal and myelin integrity, fiber density, and extra-fiber pathologies of the white matter in 95 very preterm infants. The researchers showed reduced fiber fraction because of axonal and

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1046 PA RT 1 0    The Central Nervous System

myelin injury, increased cellular infiltration, vasogenic edema, and inflammation. These microstructural changes were seen in the corpus callosum, corticospinal tracts, and optic radiations. Larger ventricular size was associated with greater disruption, and postmortem immunohistochemistry confirmed the MRI findings. Similar findings were also observed in a recent retrospective study in extremely preterm infants using DTI.70 In this study, infants with PHVD showed lower fractional anisotropy values in their corpus callosum compared with controls reflecting the impaired microstructure of these commissural nerve fibers that are adjacent to the dilated ventricles. Impaired microstructure of the corpus callosum was shown to be associated with less favorable cognitive and motor scores at 2 years corrected age. Placement of a permanent VPS is regarded as a significant predictor of NDI as shown in a multicenter observational study that compared the outcomes of extremely low birth weight infants presenting with high-grade GMH-IVH with or without VPS. Of the 562 infants with a grade 3 hemorrhage, 103 (18%) needed a VPS, compared with 125 of the 436 (29%) with a grade 4 hemorrhage (=PVHI). Children with severe GMH-IVH and VPS had significantly lower scores on the neurodevelopmental tests compared with children with no GMH-IVH and children with GMH-IVH of the same grade and no VPS. A mental developmental index (MDI) less than 70 was found in 43% of infants with a grade 3 GMH-IVH without a VPS compared with 60% in those with a VPS. In those with PVHI without a shunt, 48% had an MDI less than 70, compared with 76% of those requiring a VPS. Infants with shunts were at increased risk for CP, and their head circumference was less than the 10th percentile at 18 months’ corrected age. It is important to emphasize that the timing of intervention for PHVD appears to be a more significant factor for the neurodevelopmental outcome than the presence of a VPS as supported by several retrospective observational studies as well as the ELVIS trial.58,71 Overall, infants with a grade 3 GMH-IVH without associated white matter involvement are more likely to do well, and those who have CP usually develop mild bilateral spastic CP affecting the lower extremities more severely than the upper extremities. Multiple studies have shown that the tissue destruction and related remote effects, the Wallerian degeneration, caused by the presence of PVHI is a major risk factor for NDI. Although both grade 3 and PVHI are regarded as high-grade GMH-IVH, neurodevelopmental outcomes of infants with PVHI are less favorable. Outcome data on PVHI show that these children are at risk of developing significant NDI, depending on the size and especially the site of the lesion. The most common handicap is unilateral spastic CP (=hemiplegia) contralateral to the side of the parenchymal hemorrhage. Bassan et  al.72 showed abnormal muscle tone in 60% of the survivors, visual field defects in 26%, developmental delays involving gross motor skills in 73%, fine motor skills in 59%, expressive language in 38%, and cognitive functioning

in 50% of surviving infants. Impairment in daily living and socialization was documented in 33% and 20%, respectively. Higher cUS-based PVHI severity scores predicted microcephaly and abnormalities in gross motor, visual receptive, and cognitive function. In the EPIPAGE study that reported outcomes at 5 years of age for 1812 infants born less than 33 weeks of gestation, CP was diagnosed in 8%, 11%, 19%, and 50% of survivors with grades 1, 2, 3, and PVHI, respectively.73 A recent multicenter study from the Netherlands and Canada did not show a decreasing trend in the incidence of PVHI in the current era; however, it reported slightly improved outcomes in survivors.13 In this study, the presence of PVHI was an independent risk factor for NDI that was observed in around one-third of surviving infants. The CP rate was 42%, which was slightly lower than reported in the literature, and 81% of the infants with CP were functioning at gross motor function classification system (GMFCS) level 1 or 2 and walking independently at 2 years of age. Of note, PVHI size and severity score were negatively associated with gross motor functioning, and infants with trigone involvement were more likely to develop CP. This finding demonstrates the relationship between the location of PVHI and the development of CP. It is also important to emphasize that, although PVHI lesions in the posterior frontal and parietal lobes can cause motor impairment and CP, anterior frontal lobe and temporal lobe involvements are usually associated with cognitive impairment, visual disturbances, and behavioral problems. Therefore efforts to define the anatomic location of PVHI in detail by using cUS are of paramount importance to predict outcome trajectories and introduce targeted rehabilitation programs early in infancy.16 Early prediction of development of hemiplegia is also possible using neonatal brain MRI. At term, myelination of the posterior limb of the internal capsule (PLIC) should be present in the posterior third (Fig. 55.7). In infants in whom hemiplegia subsequently developed, asymmetry and even a lack of myelination of the PLIC are noted (Fig. 55.8). Using DTI, visualization of the corticospinal tracts is also possible at an early stage and can be used as a predictor of hemiplegia. A small study evaluated preterm infants with PVHI at an early age (≤4 weeks after birth) and TEA-MRI. The involvement of corticospinal tracts was assessed by a visual assessment of the PLIC on DTI. Their PLIC was visually scored as asymmetrical in six and equivocal in one on the early DTI. Thirteen out of 16 infants with typical motor development had a symmetrical PLIC on early DTI; the remaining 3 were equivocal. All infants with hemiplegia had a fractional anisotropy asymmetry index greater than 0.05 (optimal cutoff value) on early DTI.74 

Outcomes of Cerebellar Hemorrhage Outcome data of preterm infants with a CBH are a reason for concern.75 Limperopoulos et  al.75 compared neurodevelopmental outcomes in three groups of premature infants (n = 86; 35 isolated CBH, 35 age-matched controls, and

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CHAPTER 55  Intracranial Hemorrhage and Stroke in the Neonate

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A

• Fig. 55.7  (A) Magnetic resonance image, T1-weighted sequence, at term age, in the same infant as in

Fig. 55.2. A symmetric high signal at the level of the posterior limb of the internal capsule is seen. (B) At a higher level, a small triangular area of high signal intensity is still seen as a sequel of the parenchymal hemorrhage.

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• Fig. 55.8  Magnetic resonance image, T1-weighted sequence, at term age, in the same infant as in Fig. 55.3. (A) There is no symmetric high signal at the level of the posterior limb of the internal capsule. (B) A fluidattenuated inversion recovery sequence at 18 months of age shows high signal intensity suggestive of gliosis adjacent to the porencephalic cyst and across the internal capsule.

16 CBH with supratentorial parenchymal injury). Neurologic abnormalities were present in two-thirds of the isolated CBH cases compared with 5% of the infants in the control group. Infants with isolated CBH versus controls had significantly lower scores on all tested measures, including severe motor disabilities (48% vs. 0%), delayed expressive language (42% vs. 0%), delayed receptive language (37% vs. 0%), and cognitive deficits (40% vs. 0%). Isolated CBH was also associated with severe functional limitations

in day-to-day activities. Significant differences were noted between cases of CBH versus controls on autism screening (37% vs. 0%) and internalizing behavioral problems (34% vs. 9%). Developmental, functional, and social-behavioral deficits were more common and severe in infants with vermis injury. However, the neurodevelopmental outcome of infants who had small and punctate lesions in the cerebellum, which can only be recognized with MRI, appears not to be abnormal, at least during the preschool period.

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1048 PA RT 1 0    The Central Nervous System

In infants with CBH, the neurodevelopmental outcome is closely related to the extent and location of CBH. A recent systematic review investigated infants with isolated CBH and showed high rates of delay in cognitive, motor, language, and behavioral outcomes in 38%, 39%, 41%, and 38%, respectively. Infants with vermis involvement and those with large lesions had the highest risk of adverse outcomes, and infants with punctate CBH had a better prognosis than infants with large CBH.76 A recent multicenter study on CBH in preterm infants, the CHOPIN study,19 assessed outcome data of 177/218 preterm infants at 2 years and showed NDI (defined as an abnormal neurologic exam or suboptimal score in neurodevelopmental tests or child behavior checklist) in 40% with punctate CBH, 51% with limited CBH, and 78% with massive CBH. No significant differences were found for the composite outcome between punctate and limited CBH (P = .42). The risk of an abnormal outcome increased with the increasing size of CBH, and infants with limited CBH showed a more favorable outcome than infants with massive CBH. A recent study assessed CBH total volume using volumetric MRI and assessed outcomes at 4.5 years. The investigators found that CBH size and location on preterm MRI (median 27.9 weeks) were associated with reduced preschool motor and visuomotor function and more externalizing behavior independent of supratentorial brain injury in a dose-dependent fashion. Thus the volumetric quantification and localization of CBH may provide an opportunity to improve motor and behavioral outcomes by providing targeted intervention.77 

Prevention Because treatment of GMH-IVH is mainly supportive once it has occurred, prevention of GMH-IVH is of paramount importance. Effective use of antenatal betamethasone before preterm deliveries and gentle care strategies in the neonatal intensive care unit, including minimal handling, minimizing environmental light and noise exposure, and maintaining glucose, pCO2, electrolytes, and body temperature within the optimal range, have been adopted by many centers caring for these infants.1 A multicenter cohort study from two Dutch tertiary centers showed a reduced risk of developing GMH-IVH in infants receiving nursing intervention bundles that consisted of maintaining the head in the midline, lifting the head of the incubator, avoiding flushing and rapid withdrawal of blood, and sudden elevation of the legs during infant care.78 Similarly, in a single-center quality improvement project from the United States, the investigators developed targeted interventions, including the development of potentially better practice guidelines, maintaining the head in the midline position in the first 72 hours, promoting early noninvasive ventilation, consistent use of rescue antenatal betamethasone, and risk-based indomethacin prophylaxis. The outcome measure was the rate of severe GMH-IVH. With the implementation of these measures, the rate of severe GMH-IVH decreased from

14% to 1.2%, with sustained improvement over 2.5 years. Mortality also decreased by 50% during the study period.79 Based on these recent data, these practical strategies seem to have significant potential to reduce the disease burden and should be further studied in large-scale prospective studies and implemented in daily practice. From a medication standpoint, antenatal steroids, magnesium sulfate, vitamin K, and phenobarbital administration have been hypothesized to be preventive against GMH-IVH in several studies. For the prevention of GMHIVH, the most effective prophylactic drug seems to be antenatal steroids. A 2020 meta-analysis assessed the effects of administering a course of corticosteroids to women before anticipated preterm birth on fetal and neonatal morbidity and concluded that the use of antenatal corticosteroids probably reduces the risk of GMH-IVH (RR 0.58, 95% CI 0.45–0.75; 8475 infants; 12 studies) with moderatecertainty evidence.3 A 2010 meta-analysis assessed the benefits and harms of giving phenobarbital to women at risk of imminent very preterm birth with the primary aim of preventing GMH-IVH. Analyses of all included trials showed a significant reduction in all grades of GMH-IVH (RR 0.65, 95% CI 0.50–0.83; 9 trials; 1591 women) and severe grades of GMH-IVH (RR 0.41, 95% CI 0.20–0.85; 8 trials; 1527 women) in infants whose mothers had been given prenatal phenobarbital. However, these results were influenced by low-quality trials, which contributed largely to the analysis. When only the two higher-quality trials were included, these beneficial effects disappeared for all grades of GMH-IVH (RR 0.90, 95% CI 0.75–1.08; 2 trials; 945 women) and severe grades of GMH-IVH (RR 1.05, 95% CI 0.60–1.83; 2 trials; 945 women).80 Studies of antenatal administration of magnesium sulfate yield different results. A systematic review published in 2009 involving 6145 fetuses substantially reduced the risk of CP (RR 0.69; 95% CI 0.54–0.87). The NNT to prevent one case of CP was 63 (95% CI 43–155). A significant reduction in the rate of gross motor impairment was also seen (RR 0.61; 95% CI 0.44–0.85; 4 trials; 5980 infants).81 In a multicenter randomized controlled trial from the United States, no significant reduction was found for the incidence of a large GMH-IVH (2.1% vs. 3.2%; RR 0.64; 95% CI 0.38–1.06). Moderate or severe CP occurred significantly less frequently in the magnesium sulfate group compared to the control group (1.9% vs. 3.5%; RR 0.55; 95% CI 0.32–0.95).82 Maternal vitamin K administration was also studied in a meta-analysis and seven trials were included, involving 607 women. Vitamin K administration, either parenterally or orally, to women at risk of imminent preterm birth was associated with a nonsignificant reduction in the overall rate of GMH-IVH (RR 0.76; 95% CI 0.54–1.06) and a significant reduction in severe GMH-IVH (RR 0.58; 95% CI 0.37–0.91). However, when the two quasi-randomized trials were excluded, antenatal vitamin K was associated with a nonsignificant reduction in all grades of GMH-IVH (RR 0.87; 95% CI 0.60–1.26) and a nonsignificant reduction in severe GMH-IVH (RR 0.82; 95% CI 0.49–1.36).83

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CHAPTER 55  Intracranial Hemorrhage and Stroke in the Neonate

Because persistent patent ductus arteriosus has also been associated with GMH-IVH in preterm infants, prostaglandin inhibitors such as indomethacin and ibuprofen have been studied in several clinical trials in the past two decades. The results of a meta-analysis involving 19 trials of 2872 infants showed a significant reduction in the incidence of high-grade GMH-IVH (pooled RR 0.66 95% CI 0.53– 0.82).84 The children of the original cohort were assessed at 8 years of age, and no effect of indomethacin was seen on long-term outcomes.85 Analysis of the original cohort by gender, however, showed that indomethacin halved the incidence of IVH, eliminated parenchymal hemorrhage, and was associated with higher verbal scores at 3 to 8 years in males.86 In a 2020 meta-analysis of ibuprofen, a possible decrease in the risk of high-grade GMH-IVH in infants receiving prophylactic ibuprofen was shown (RR 0.67; 95% CI 0.45–1.00; 7 trials; 925 infants) with moderate-quality evidence.87 

intracranial hemorrhage were delivered vaginally, with a prevalence of 26% in vaginal births. In this group, no association was seen with traumatic or assisted birth compared with those with uncomplicated vaginal births, and all cases were asymptomatic.88 Underlying mechanisms can be a tear of the dura, occipital diastasis, or rupture of bridging veins. A tear of the dura can occur after a precipitous delivery or from the use of instrumentation, both of which are not very common with preterm delivery. A dural tear results in extensive bleeding from the adjacent sinus. Occipital diastasis can occur during a vaginal breech delivery with an excessive extension of the neck of the infant, although vaginal breech deliveries are not commonly performed as a consequence of the results of multicenter, randomized studies. Rupture of the bridging veins is the most common etiology of a subdural hemorrhage and may be seen in association with a subarachnoid hemorrhage. Children are usually born at term and present with a full fontanelle, lethargy, apneas, or seizures. In case of a severe hemorrhage, a midline shift may be seen, and surgery needs to be considered. Bedside percutaneous needle aspiration of the extra-axial hematoma may be attempted, which was successful in a recent case series and may be recommended as the treatment of choice in infants who are critically ill and therefore not stable enough to be transferred to the operation room for neurosurgical decompression.89 The diagnosis in emergent cases usually is made using CT or MRI (Fig. 55.9). In these cases, hydrocephalus can develop from an outflow obstruction and may require temporary external drainage, sometimes followed by permanent drainage.

Other Hemorrhages Extra-axial hemorrhages in the neonate (e.g., subdural [see also Chapter 28] and subarachnoid hemorrhages) are probably underdiagnosed because they are difficult to recognize using cUS and the clinical signs may be subtle or absent. A significant subdural hemorrhage is most often related to birth trauma, and a small subdural hemorrhage is common when MRI is performed routinely. In a study looking at 88 neonates who had an MRI at a mean age of 21 days, 16 infants had a subdural hemorrhage, 2 subarachnoid hemorrhages, and 6 parenchymal hemorrhages. All neonates with

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• Fig. 55.9  (A) Magnetic resonance image, T1-weighted sequence, shows a large collection of blood in

the posterior fossa with blood along the tentorium bilaterally (black arrows). (B) At a higher level, extensive cortical highlighting is seen posteriorly and in the region of the sylvian fissure (white arrows). A posterior branch middle cerebral artery infarct is also seen on the right.

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1050 PA RT 1 0    The Central Nervous System

Small subarachnoid hemorrhages, which are usually asymptomatic, are sometimes seen in preterm infants at postmortem examination. Blood can leak into the subarachnoid space after a GMH-IVH by flowing through the aqueduct into the fourth ventricle and subsequently through the foramina of Luschka and Magendie into the subarachnoid space. Once again, the diagnosis is hard to make using cUS unless the lesion is large. In infants presenting with subarachnoid hemorrhage, hydrocephalus is less commonly seen than in children with a subdural hemorrhage. 

Potential Future Directions Mesenchymal stromal cell (MSC)-based therapy is emerging as a promising treatment option for neonatal neurologic disorders. In a series of studies, investigators from South Korea assessed whether intraventricular transplantation of human umbilical cord blood-derived MSCs prevents posthemorrhagic ventricular dilatation (PHVD) development in a rat model. It was shown that MSCs significantly reduced the rate of PHVD and brain injury caused by IVH.90 In two subsequent studies, it was shown that significant neuroprotection was demonstrated when MSCs were administered 2 days after the onset of IVH but not after 7 days, and both intraventricular and intravenous routes had similar therapeutic effects.91 The same investigators published the first phase I human trial of MSCs in PHVD, in which nine preterm infants received MSCs in incremental doses and no side effects were observed, confirming the safety and tolerability of MSCs.92 These promising findings resulted in a phase II human trial, which is completed and currently being analyzed (NCT02890953). There is also considerable basic research to find the ideal biomarker for the early detection of infants at risk of GMH-IVH and its most common complication, PHVD. Plasma, CSF, and urine biomarkers of GMH-IVH and impending PHVD can be used to optimize the timing of interventions in at-risk infants.47 Among them, interleukin (IL)-6, S100β protein, activin, chemokine ligand-18, and brain-type creatine kinase have been shown to be promising for the early detection of infants at risk of developing GMH-IVH. Transforming growth factors β1 and β2, matrix metalloproteinase, glial fibrillary acidic protein, and plasminogen activator inhibitor step forward as early biomarkers of an impending PHVD. The discovery and validation of neonatal biomarkers of hemorrhagic brain injury will be an important step in the evolution of neonatal neuroprotection.93 

Perinatal Stroke Perinatal stroke can be broadly classified into cerebral sinovenous thrombosis (CSVT) and arterial ischemic stroke (AIS). Both conditions can remain undiagnosed in the neonatal period because presenting symptoms may not always be clear and appropriate imaging is not always performed. Studies tend to exclude preterm infants, even though these also develop

perinatal stroke and, according to a recent population-based study, with a higher incidence than the full-term infant.94 Arteriovenous malformations are discussed in Chapter 77.

Sinovenous Thrombosis An incidence of 41 per 100,000 newborn infants with CSVT was found in the Canadian Pediatric Ischemic Stroke Registry but was higher in a population-based study performed in the Netherlands.95,96 Two-thirds of the cases come to medical attention within 48 hours of birth, although symptoms can also develop 10 to 14 days after delivery, sometimes associated with dehydration or infection.95,97 Almost half the children (43%) with CSVT in the Canadian registry were newborns.

Risk Factors During the birth process, molding of the skull and overriding of the sutures of the different parts of the skull may occur and affect the underlying sinus, resulting in the occurrence of CSVT. Perinatal asphyxia is a commonly associated risk factor, as reported in 24% of the cases in the Canadian Registry. The superior sagittal sinus and the transverse sinuses are most commonly involved, but in the study by Berfelo et al.,95 the straight sinus was most often affected, and an associated thalamic hemorrhage was common. Involvement of the vein of Galen and the internal cerebral vein has also been reported. The occurrence of associated IVH, especially a unilateral thalamic hemorrhage or periventricular congestion, may help clarify the diagnosis. Wu et al.98 noted that CSVT was significantly more common in full-term infants with IVH and unilateral thalamic hemorrhage (4 of 5) compared with newborns with IVH only (5 of 21). They strongly recommend the diagnosis of CSVT be considered in any full-term neonate presenting with IVH. Risk factors for CSVT during the first 28 days of life include dehydration, infection, maternal fever/chorioamnionitis, hypoxic–ischemic injury, and thrombophilia.95 In another study, risk factors were analyzed in 30 full-term infants with CSVT.99 They reported that 29% of these newborn infants had been on extracorporeal membrane oxygenation and that 23% had congenital heart disease. Another study also reported development of CSVT in 28% of infants following neonatal surgery for their congenital heart disease, with lower postmenstrual age and weight at time of surgery and use of internal jugular veins as potential risk factors.100 In the study by Wu et al.99 only seven infants were tested for a genetic thrombophilia, and four of these seven were found to be positive. Compression of the superior sagittal sinus has also been suggested to be a possible risk factor.101 

Diagnosis Seizures are the most common presenting symptoms and were reported in 70% of the infants in both the Dutch study as well as the Canadian Registry. Lethargy is also commonly present. The fontanelle may be full, and the scalp veins may be prominent. Diagnosis can be made using color Doppler

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CHAPTER 55  Intracranial Hemorrhage and Stroke in the Neonate

B

A

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C

• Fig. 55.10  Magnetic resonance imaging scans were obtained at age 12 days, after the development of

seizures on day 9. (A) Doppler ultrasound does not show any flow in the superior sagittal sinus. (B) On the midsagittal T2-weighted sequence, a large thrombus is seen at the level of the superior sagittal sinus. (C) Magnetic resonance venography image shows loss of flow at the level of the superior sagittal sinus and straight sinus.

flow ultrasonography, which may demonstrate absent or decreased flow in the affected sinus. Contrast-enhanced CT is no longer recommended, but it can show the so-called empty delta sign, the lack of contrast filling. The best modality is brain MR imaging, especially MR venography, which helps make a definitive diagnosis by demonstrating a reduction or absence of venous flow in the affected venous sinus (Fig. 55.10). 

Management Besides general management, including treatment of dehydration, seizures, and meningitis, there is no agreement on the use of antithrombotic therapy in this age group, even though recommendations in favor of its use have been made recently. Studies show that regional practices with regard to antithrombotic therapy show considerable variability.102 Different treatment policies were noted, with physicians in the United States being less likely to treat neonates with CSVT with antithrombotic medication compared with physicians at centers in other countries, 25% of these neonates being treated in the United States versus 69% in other countries.102 About 25% of the infants show propagation of the thrombus.97 Whether early anticoagulation therapy in those with involvement of the straight sinus may prevent the development of a thalamic hemorrhage still needs to be assessed, but data from a recent systematic review and meta-analysis suggested a reduction in propagation of the thrombus and no evidence of increased morbidity or mortality.103 The number of infants with CSVT is limited; therefore enrollment in many centers will be required to be able to conduct a randomized study to assess the effect of anticoagulation therapy. 

Outcome More than 90% of newborns with CSVT survive, with 48% to 61% of survivors having moderate to severe disabilities, and 9% experiencing a recurrence of cerebral or systemic thrombosis.95,97 In the retrospective study by Fitzgerald et al.104 who assessed 42 newborn infants, 57% presented

with seizures and 60% had associated parenchymal infarcts, which were mainly hemorrhagic. Of these 42 infants, 79% had any form of impairment, with 59% having cognitive impairment, 67% cerebral palsy, and 41% epilepsy. Infarction was associated with the presence of later impairment. In the subgroup of infants with an associated thalamic hemorrhage, it is common to see the development of electrical status epilepticus during sleep in early childhood, which has an adverse effect on cognitive outcomes.105 Finally, CSVT can also occur in the preterm infant, with the infant who tends to have no or only subtle symptoms, like irritability or unexplained thrombocytopenia. It is therefore often an incidental finding. Color Doppler US has been shown to have a high sensitivity in detecting neonatal CSVT and can help make the diagnosis.106 

Perinatal Arterial Ischemic Stroke Because of increased access to neonatal MRI, infarction of a major artery, or a branch arising from it, is better recognized. This condition is often referred to as neonatal arterial ischemic stroke, or perinatal arterial ischemic stroke (PAIS).107 Information about incidence is becoming available with the introduction of neonatal registries.94,107 Cerebral infarction in the neonate has been defined as severe disorganization or even complete disruption of both gray matter and white matter caused by embolic, thrombotic, or ischemic events. In infants dying in the acute stage of the condition, the hemisphere is swollen and deeply congested. There is involvement of both white matter and the cortex, with secondary hemorrhagic infarction in some cases. In infants who survive for longer, contraction of the affected area is seen with softening and cystic degeneration, giving a honeycomb appearance. It is recommended that a distinction be made between a unilateral parenchymal hemorrhage, which usually occurs in the preterm infant and evolves into a porencephalic cyst, and an infarct in the region of the middle cerebral artery, which usually occurs in a term newborn and evolves into an area of parenchymal cavitation. A porencephalic cyst occurring after parenchymal

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1052 PA RT 1 0    The Central Nervous System

hemorrhage of antenatal onset has, however, been referred to as fetal stroke, and small porencephalic cysts occurring after antenatal venous infarction have also been included within the spectrum of presumed perinatal stroke.108 Lesions involving the left hemisphere are three to four times more common than those of the right hemisphere. This may be the result of hemodynamic differences early after birth in association with the patent ductus arteriosus or a preferential flow across the left common carotid artery. Middle cerebral artery infarction occurs twice as often as the involvement of any other artery.109 A classification system based on the main artery involved can be used. Infarcts in the territory of the middle cerebral artery were further subdivided into the main branch, cortical branch, and lenticulostriate branch infarction.110 Perforator stroke is especially common in the preterm infants and is often an incidental finding.106

Incidence In recent population-based studies, the incidence of PAIS was as high as 20 to 30 per 100,000 newborn infants, which is much higher than reported previously.94,107 Neonatal stroke is the second most common cause of neonatal seizures. Data about focal infarction in preterm infants are scarce.106 In a recent German population-based study, the incidence was 32 per 100,000 preterm infants, higher than for full-term infants.94 

Risk Factors Newborn infants are susceptible to neonatal stroke because of a number of factors present around the time of delivery, such as the hypercoagulable state of the mother, mechanical stress during delivery, the transient right-to-left intracardiac shunt, and the risk of dehydration during the first few days after delivery, often associated with a high hematocrit and blood viscosity.109 Perinatal complications have been reported in more than 50% of newborn infants who had suffered a perinatal stroke.111,112 In a single-center cohort study, case-matched controls were used, and diverse etiologic factors were noted to be responsible for PAIS in term infants. Infertility, preeclampsia, prolonged rupture of membranes, chorioamnionitis, and hypoglycemia have been identified as independent maternal risk factors.111 In another study, male gender (OR 2.8), family history of seizures (OR 6.5) or neurologic diseases (OR 4.9), and 1 or greater (OR 5.8) and 2 or greater (OR 21.8) intrapartum complications were independently associated with neonatal stroke.112 Although intrapartum factors are common, they are not often severe enough to meet the selection criteria for hypothermia. Cardiac disease, extracorporeal membrane oxygenation, and portal vein thrombosis have all been reported as associated risk factors. Stroke was especially common (31%) among infants with transposition of the great arteries, and this was associated with balloon atrial septostomy.113 Maternal cocaine abuse has also been considered a cause of perinatal stroke. An underlying genetic prothrombotic disorder is no longer considered likely, and extensive investigations

should not be routinely performed. Stroke recurrence is very uncommon. Data on risk factors in preterm infants are scarce.114 Using 3:1 GA matched controls, etiologic factors responsible for perinatal arterial stroke in preterm infants were studied, and it was noted that these were different from those in infants born at term. Twin-twin transfusion syndrome (19% vs. 3%; OR 31.2; 95% CI 2.9–340; P = .005), fetal heart rate abnormality (58% vs. 26%; OR 5.2; 95% CI 1.5–17.6; P = .008), and hypoglycemia (42% vs. 18%; OR 3.9; 95% CI 1.2–12.6; P = .02) were identified as independent risk factors for preterm stroke.114 

Diagnosis Seizures are the most common presenting symptom of PAIS.115 When a newborn without an obvious history of perinatal asphyxia presents with focal seizures, care should be taken not to miss the diagnosis of PAIS. They are usually of the focal clonic variety, but multifocal tonic or subtle seizures also may be seen (see Chapter 57). Many of the infants show no major clinical neurologic abnormality between seizures. The largest population reported to date consisted of 248 infants, of whom 72% presented with seizures, which were focal in almost all cases, and 26% were admitted because of respiratory problems.115 Symptoms can be very subtle, especially in the preterm infant, and the diagnosis can be easily missed.114 Presentation with a hand preference later in infancy with an area of cavitation on CT or MRI may lead to a diagnosis of a perinatal or in utero AIS, which is now referred to as presumed perinatal ischemic stroke.108 

Neuro-Imaging The middle cerebral artery is most commonly involved, and the infarct occurs more often on the left than the right side.115 Arterial infarcts of the anterior and posterior cerebral artery are less often diagnosed, possibly because of the lack of clinical symptoms in the neonatal period (Fig. 55.11). Involvement of the smaller branches of the middle cerebral artery is more often seen in preterm infants, resulting in so-called perforator stroke.114 Infarcts can be hemorrhagic in 20% of cases, and bilateral infarcts can be seen in 10% to 15% (Fig. 55.12). In the absence of abnormalities on cUS, MRI is recommended to confirm or exclude the diagnosis. The diagnostic value of cUS in PAIS has been controversial, and cUS has not been considered reliable in making a diagnosis; this applies especially when the examination is made soon after the clinical presentation. By the end of the first week of postnatal life, a wedge-shaped area of echogenicity, often with a linear demarcation line, restricted to the territory of one of the main arteries, usually becomes apparent.116 Cystic evolution can take place over the next 4 to 6 weeks, often associated with ex-vacuo dilation of the ipsilateral lateral ventricle. Doppler cUS can show asymmetry of arterial pulsations. Decreased pulsations on the affected side can be seen in the acute phase, whereas an increase in size and number of visible vessels in the periphery of the infarct and increased mean blood flow velocity in vessels supplying or

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CHAPTER 55  Intracranial Hemorrhage and Stroke in the Neonate

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B

A

• Fig. 55.11  Preterm infant, gestational age 32 weeks. (A) Routine ultrasonography image obtained at 2

weeks shows an area of cystic evolution in the region of the left anterior cerebral artery. Mild ex vacuo dilation of the left ventricle is also present. (B) T2-weighted magnetic resonance imaging scan, spin-echo sequence, at age 7 years shows the parenchymal cavity in the same distribution.

A

B

•

Fig. 55.12 Full-term infant, magnetic resonance imaging (MRI) scans obtained at age 4 days. (A) T1-weighted sequence shows low signal intensity in the distribution of the right middle cerebral artery, suggestive of main branch involvement. (B) Diffusion-weighted imaging scan shows high signal intensity in the same area, as well as a smaller area of high signal intensity in the distribution of the left anterior cerebral artery.

draining the infarcted areas are often seen a few days later, and this is considered to result from luxury perfusion. The threshold for performing MRI should be low in infants presenting with neonatal seizures. If performed early after the clinical presentation, diffusion-weighted imaging (DWI) is very helpful. This technique reveals abnormalities, indicating cytotoxic edema, at a very early stage, preceding abnormalities seen on conventional MRI. This technique also enables visualization of acute involvement of the corticospinal tracts at the level of the midbrain.117 Several studies have shown that these findings predict Wallerian degeneration and the development of subsequent hemiplegia.117 A repeat scan can show asymmetry at the level of the mesencephalon, which can be seen as early as 4 to 6 weeks after the onset of the infarction and is referred to as Wallerian degeneration. MR angiography, which allows for investigation of the main vascular bed, can be used, and can sometimes show

dissection or occlusion of one of the main vessels. This may be rare, however, and this technique may also fail to show small vessel occlusion. EEG showing focal electrographic and electroclinical seizures with ipsilateral suppression of the background activity and focal sharp waves are strongly suggestive of the presence of perinatal stroke.118 Reorganization of the somatosensory cortex can be followed using a combination of transcranial magnetic stimulation and functional MRI.119 Staudt et al.120 showed that when a lesion abolishes the normal contralateral corticospinal control over the paretic hand, the contralesional hemisphere develops (or maintains) fast-conducting ipsilateral corticospinal pathways to the paretic hand. This reorganization with ipsilateral corticospinal tracts can mediate useful hand function. Normal hand function, however, seemed only possible with preserved crossed corticospinal projections from the contralateral hemisphere. Ipsilesional

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1054 PA RT 1 0    The Central Nervous System

reorganization is less effective in the restoration of good motor function as opposed to contralesional reorganization. 

Management Treatment is at present still mainly supportive, with treatment of hypoglycemia and controlling seizures with antiseizure medication, which can in most infants be discontinued before discharge. Symptoms tend to occur beyond the 6-hour window used for hypothermia. Neuroprotective trials are underway, and a safety study with mesenchymal stem cells administered intranasally has been performed in 10 infants.121 A multicenter study is enrolling infants at three sites, administering darbepoetin within a week after stroke onset, and a second dose 1 week later (NCT03171818). 

Outcome The overall prevalence of cerebral palsy is approximately 2 in every 1000 live births. On the basis of the estimated incidence of perinatal cerebral vascular infarction, it might be expected that this condition is the cause of the neurologic deficit in up to 20% of children with cerebral palsy. This is supported by data showing that 22% of 377 infants with cerebral palsy showed focal arterial infarction on head imaging.122 Neurodevelopmental outcome in most cases is relatively good. Spastic hemiplegia is the most important sequela, particularly after infarction of the main branch of the middle cerebral artery. There is an increased incidence among male infants. The majority of the infants achieve independent walking before 18 months, and those who develop hemiplegia show more involvement of the upper than lower limb with the majority classified as GMFCS I or II. Taking the lesion site and involvement of well-defined brain structures into account, a more precise prediction for

motor outcome as well as outcome for other domains can be made.110 Looking also at other domains (epilepsy, vision, behavior, and language), almost half (46%) of all infants surviving neonatal stroke were found to be doing well at a median age of 41 months in a large study of 161 infants.110 Deficits in higher-level cognitive skills may first become apparent at school age, and this is more common in males, involvement of the central gray nuclei, and not uncommonly associated with the development of epilepsy.123 Homonymous hemianopia may follow a posterior cerebral artery infarction.124 Outcome data depend very much on the threshold for performing MRI, on the artery involved, and on whether the main branch is involved or only a cortical branch or one of the lenticulostriate branches, the latter being especially common in the preterm inf ant.110,114,125 Post-neonatal epilepsy is a well-known complication and has been reported in 12% to 67% of affected infants.109 Lesions involving the cortex are more likely to be associated with epilepsy. Because epilepsy may first develop later in childhood, the rate of epilepsy will be higher when followup is longer. In a study with a mean follow-up of 8 years and 5 months, 16.4% of the patients developed post-neonatal epilepsy. The mean age at first post-neonatal seizure was 4 years and 2 months (range 1–10 years and 6 months).126 Even though the focus is often on motor outcomes, other outcome parameters are also important, and in a national cohort study, language was impaired in almost half (49%) of the children. Cerebral palsy, low academic skills, active epilepsy, and global intellectual disability were present in 32%, 28%, 11%, and 8%, respectively. Eventually, 59% of children were affected by at least one of the aforementioned conditions.127

Key Points • GMH-IVH is still a common problem in extremely preterm infants. • PHVD is an important complication of, especially, large GMH-IVH. • Data are accumulating to suggest that PHVD should be treated based on cranial ultrasound assessments of the ventricular size before the onset of clinical symptoms.

• Cerebral venous sinus thrombosis should be suspected when an IVH with or without a thalamic hemorrhage is seen in a full-term infant. • PAIS occurs in about 20 to 30 per 100,000 full-term infants and usually presents with focal clonic seizures.

References

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45. Radhakrishnan R, Brown BP, Kralik SF, et al. Frontal occipital and frontal temporal horn ratios: comparison and validation of head ultrasound-derived indexes with MRI and ventricular volumes in infantile ventriculomegaly. AJR Am J Roentgenol. 2019;213(4):925–931. 46. McLachlan PJ, Kishimoto J, Diop M, et  al. Investigating the effects of cerebrospinal fluid removal on cerebral blood flow and oxidative metabolism in infants with post-hemorrhagic ventricular dilatation. Pediatr Res. 2017;82(4):634–641. 47. Schmitz T, Felderhoff-Mueser U, Sifringer M, et al. Expression of soluble Fas in the cerebrospinal fluid of preterm infants with posthemorrhagic hydrocephalus and cystic white matter damage. J Perinat Med. 2011;39(1):83–88. 48. Morales DM, Silver SA, Morgan CD, et  al. Lumbar cerebrospinal fluid biomarkers of posthemorrhagic hydrocephalus of prematurity: amyloid precursor protein, soluble amyloid precursor protein alpha, and L1 cell adhesion molecule. Neurosurgery. 2017;80(1):82–90. 49. Brouwer MJ, de Vries LS, Kersbergen KJ, et al. Effects of posthemorrhagic ventricular dilatation in the preterm infant on brain volumes and white matter diffusion variables at termequivalent age. J Pediatr. 2016;168:41–49.e41. 50. Leijser LM, Miller SP, van Wezel-Meijler G, et al. Posthemorrhagic ventricular dilatation in preterm infants: when best to intervene? Neurology. 2018;90(8):e698–e706. 51. Whitelaw A, Pople I, Cherian S, et al. Phase 1 trial of prevention of hydrocephalus after intraventricular hemorrhage in newborn infants by drainage, irrigation, and fibrinolytic therapy. Pediatrics. 2003;111(4 Pt 1):759–765. 52. Whitelaw A, Evans D, Carter M, et al. Randomized clinical trial of prevention of hydrocephalus after intraventricular hemorrhage in preterm infants: brain-washing versus tapping fluid. Pediatrics. 2007;119(5):e1071–1078. 53. Whitelaw A, Jary S, Kmita G, et al. Randomized trial of drainage, irrigation and fibrinolytic therapy for premature infants with posthemorrhagic ventricular dilatation: developmental outcome at 2 years. Pediatrics. 2010;125(4):e852–858. 54. Luyt K, Jary SL, Lea CL, et al. Drainage, irrigation and fibrinolytic therapy (DRIFT) for posthaemorrhagic ventricular dilatation: 10-year follow-up of a randomised controlled trial. Arch Dis Child Fetal Neonatal Ed. 2020;105(5):466–473. 55. Whitelaw A, Lee-Kelland R. Repeated lumbar or ventricular punctures in newborns with intraventricular haemorrhage. Cochrane Database Syst Rev. 2017;4:CD000216. 56. de Vries LS, Groenendaal F, Liem KD, et al. Treatment thresholds for intervention in posthaemorrhagic ventricular dilation: a randomised controlled trial. Arch Dis Child Fetal Neonatal Ed. 2019;104(1):F70–F75. 57. Cizmeci MN, Khalili N, Claessens NHP, et al. Assessment of brain injury and brain volumes after posthemorrhagic ventricular dilatation: a nested substudy of the randomized controlled ELVIS Trial. J Pediatr. 2019;208:191–197.e192. 58. Cizmeci MN, Groenendaal F, Liem KD, et  al. Randomized controlled early versus late ventricular intervention study in posthemorrhagic ventricular dilatation: outcome at 2 years. J Pediatr. 2020;226:28–35.e23. 59. Lai GY, Chu-Kwan W, Westcott AB, et al. Timing of temporizing neurosurgical treatment in relation to shunting and neurodevelopmental outcomes in posthemorrhagic ventricular dilatation of prematurity: a meta-analysis. J Pediatr. 2021;234:54–64 e20. 60. Schaumann A, Buhrer C, Schulz M, Thomale UW. Neuroendoscopic surgery in neonates - indication and results over a 10-year practice. Childs Nerv Syst. 2021;37(11):3541–3548.

61. Park YS, Kotani Y, Kim TK, et  al. Efficacy and safety of intraventricular fibrinolytic therapy for post-intraventricular hemorrhagic hydrocephalus in extreme low birth weight infants: a preliminary clinical study. Childs Nerv Syst. 2021;37(1):69–79. 62. Christian EA, Jin DL, Attenello F, et al. Trends in hospitalization of preterm infants with intraventricular hemorrhage and hydrocephalus in the United States, 2000-2010. J Neurosurg Pediatr. 2016;17(3):260–269. 63. Goldstein RF, Cotten CM, Shankaran S, et al. Influence of gestational age on death and neurodevelopmental outcome in premature infants with severe intracranial hemorrhage. J Perinatol. 2013;33(1):25–32. 64. Payne AH, Hintz SR, Hibbs AM, et  al. Neurodevelopmental outcomes of extremely low-gestational-age neonates with lowgrade periventricular-intraventricular hemorrhage. JAMA Pediatr. 2013;167(5):451–459. 65. Ann Wy P, Rettiganti M, Li J, et al. Impact of intraventricular hemorrhage on cognitive and behavioral outcomes at 18 years of age in low birth weight preterm infants. J Perinatol. 2015;35(7):511–515. 66. Bolisetty S, Dhawan A, Abdel-Latif M, et  al. Intraventricular hemorrhage and neurodevelopmental outcomes in extreme preterm infants. Pediatrics. 2014;133(1):55–62. 67. Law JB, Wood TR, Gogcu S, et al. Intracranial hemorrhage and 2-year neurodevelopmental outcomes in infants born extremely preterm. J Pediatr. 2021;238:124–134.e110. 68. Hollebrandse NL, Spittle AJ, Burnett AC, et  al. School-age outcomes following intraventricular haemorrhage in infants born extremely preterm. Arch Dis Child Fetal Neonatal Ed. 2021;106(1):4–8. 69. Isaacs AM, Neil JJ, McAllister JP, et  al. Microstructural periventricular white matter injury in post-hemorrhagic ventricular dilatation. Neurology. 2021;98(4):e364–e375. 70. Nieuwets A, Cizmeci MN, Groenendaal F, et al. Post-hemorrhagic ventricular dilatation affects white matter maturation in extremely preterm infants. Pediatr Res. 2022;92(1):225–232. 71. Brouwer A, Groenendaal F, van Haastert IL, et al. Neurodevelopmental outcome of preterm infants with severe intraventricular hemorrhage and therapy for post-hemorrhagic ventricular dilatation. J Pediatr. 2008;152(5):648–654. 72. Bassan H, Limperopoulos C, Visconti K, et al. Neurodevelopmental outcome in survivors of periventricular hemorrhagic infarction. Pediatrics. 2007;120(4):785–792. 73. Beaino G, Khoshnood B, Kaminski M, et  al. Predictors of cerebral palsy in very preterm infants: the EPIPAGE prospective population-based cohort study. Dev Med Child Neurol. 2010;52(6):e119–125. 74. Roze E, Benders MJ, Kersbergen KJ, et  al. Neonatal DTI early after birth predicts motor outcome in preterm infants with periventricular hemorrhagic infarction. Pediatr Res. 2015;78(3):298–303. 75. Limperopoulos C, Bassan H, Gauvreau K, et al. Does cerebellar injury in premature infants contribute to the high prevalence of long-term cognitive, learning, and behavioral disability in survivors? Pediatrics. 2007;120(3):584–593. 76. Hortensius LM, Dijkshoorn ABC, Ecury-Goossen GM, et al. Neurodevelopmental consequences of preterm isolated cerebellar hemorrhage: a systematic review. Pediatrics. 2018; 142(5):e20180609. 77. Garfinkle J, Guo T, Synnes A, et al. Location and size of preterm cerebellar hemorrhage and childhood development. Ann Neurol. 2020;88(6):1095–1108.

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CHAPTER 55  Intracranial Hemorrhage and Stroke in the Neonate

78. de Bijl-Marcus K, Brouwer AJ, De Vries LS, et  al. Neonatal care bundles are associated with a reduction in the incidence of intraventricular haemorrhage in preterm infants: a multicentre cohort study. Arch Dis Child Fetal Neonatal Ed. 2020;105(4):419–424. 79. Kramer KP, Minot K, Butler C, et al. Reduction of severe intraventricular hemorrhage in preterm infants: a quality improvement project. Pediatrics. 2022;149(3):e2021050652. 80. Crowther CA, Crosby DD, Henderson-Smart DJ. Phenobarbital prior to preterm birth for preventing neonatal periventricular haemorrhage. Cochrane Database Syst Rev. 2010;1:CD000164. 81. Doyle LW, Crowther CA, Middleton P, Marret S. Antenatal magnesium sulfate and neurologic outcome in preterm infants: a systematic review. Obstet Gynecol. 2009;113(6):1327–1333. 82. Rouse DJ, Hirtz DG, Thom E, et al. A randomized, controlled trial of magnesium sulfate for the prevention of cerebral palsy. N Engl J Med. 2008;359(9):895–905. 83. Crowther CA, Crosby DD, Henderson-Smart DJ. Vitamin K prior to preterm birth for preventing neonatal periventricular haemorrhage. Cochrane Database Syst Rev. 2010;1:CD000229. 84. Fowlie PW, Davis PG, McGuire W. Prophylactic intravenous indomethacin for preventing mortality and morbidity in preterm infants. Cochrane Database Syst Rev. 2010;(7):CD000174. 85. Vohr BR, Allan WC, Westerveld M, et al. School-age outcomes of very low birth weight infants in the indomethacin intraventricular hemorrhage prevention trial. Pediatrics. 2003;111(4 Pt 1):e340–346. 86. Ment LR, Vohr BR, Makuch RW, et al. Prevention of intraventricular hemorrhage by indomethacin in male preterm infants. J Pediatr. 2004;145(6):832–834. 87. Ohlsson A, Shah SS. Ibuprofen for the prevention of patent ductus arteriosus in preterm and/or low birth weight infants. Cochrane Database Syst Rev. 2020;1:CD004213. 88. Looney CB, Smith JK, Merck LH, et  al. Intracranial hemorrhage in asymptomatic neonates: prevalence on MR images and relationship to obstetric and neonatal risk factors. Radiology. 2007;242(2):535–541. 89. Cizmeci MN, Thewissen L, Zecic A, et al. Bedside ultrasoundguided percutaneous needle aspiration of intra- and extraaxial intracranial hemorrhage in neonates. Neuropediatrics. 2018;49(4):238–245. 90. Ahn SY, Chang YS, Sung DK, et  al. Mesenchymal stem cells prevent hydrocephalus after severe intraventricular hemorrhage. Stroke. 2013;44(2):497–504. 91. Park WS, Sung SI, Ahn SY, et al. Optimal timing of mesenchymal stem cell therapy for neonatal intraventricular hemorrhage. Cell Transplant. 2016;25(6):1131–1144. 92. Ahn SY, Chang YS, Sung SI, Park WS. Mesenchymal stem cells for severe intraventricular hemorrhage in preterm infants: phase I dose-escalation clinical trial. Stem Cells Transl Med. 2018;7(12):847–856. 93. Douglas-Escobar M, Weiss MD. Biomarkers of brain injury in the premature infant. Front Neurol. 2012;3:185. 94. Sorg AL, von Kries R, Klemme M, et  al. Incidence estimates of perinatal arterial ischemic stroke in preterm- and term-born infants: a national capture-recapture calculation corrected surveillance study. Neonatology. 2021;118(6):727–733. 95. Berfelo FJ, Kersbergen KJ, van Ommen CH, et  al. Neonatal cerebral sinovenous thrombosis from symptom to outcome. Stroke. 2010;41(7):1382–1388. 96. deVeber G, Andrew M, Adams C, et  al. Cerebral sinovenous thrombosis in children. N Engl J Med. 2001;345(6):417–423.

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97. Moharir MD, Shroff M, Stephens D, et al. Anticoagulants in pediatric cerebral sinovenous thrombosis: a safety and outcome study. Ann Neurol. 2010;67(5):590–599. 98. Wu YW, Hamrick SE, Miller SP, et al. Intraventricular hemorrhage in term neonates caused by sinovenous thrombosis. Ann Neurol. 2003;54(1):123–126. 99. Wu YW, Miller SP, Chin K, et al. Multiple risk factors in neonatal sinovenous thrombosis. Neurology. 2002;59(3):438–440. 100. Claessens NHP, Noorlag L, Weeke LC, et al. Amplitude-integrated electroencephalography for early recognition of brain injury in neonates with critical congenital heart disease. J Pediatr. 2018;202:199–205.e191. 101. Tan MA, Miller E, Shroff MM, et  al. Alleviation of neonatal sinovenous compression to enhance cerebral venous blood flow. J Child Neurol. 2013;28(5):583–588. 102. Jordan LC, Rafay MF, Smith SE, et al. Antithrombotic treatment in neonatal cerebral sinovenous thrombosis: results of the International Pediatric Stroke Study. J Pediatr. 2010;156(5):704– 710, 710.e1–710.e2. 103. Bhatt MD, Chan AK. Venous thrombosis in neonates. Fac Rev. 2021;10:20. 104. Fitzgerald KC, Williams LS, Garg BP, et al. Cerebral sinovenous thrombosis in the neonate. Arch Neurol. 2006;63(3):405–409. 105. van den Munckhof B, Zwart AF, Weeke LC, et  al. Perinatal thalamic injury: MRI predictors of electrical status epilepticus in sleep and long-term neurodevelopment. Neuroimage Clin. 2020;26:102227. 106. Steggerda SJ, de Vries LS. Neonatal stroke in premature neonates. Semin Perinatol. 2021;45(7):151471. 107. Dunbar M, Mineyko A, Hill M, et al. Population based birth prevalence of disease-specific perinatal stroke. Pediatrics. 2020;146(5):e2020013201. 108. Kirton A, Deveber G, Pontigon AM, et al. Presumed perinatal ischemic stroke: vascular classification predicts outcomes. Ann Neurol. 2008;63(4):436–443. 109. Dunbar M, Kirton A. Perinatal stroke: mechanisms, management, and outcomes of early cerebrovascular brain injury. Lancet Child Adolesc Health. 2018;2(9):666–676. 110. Wagenaar N, Martinez-Biarge M, van der Aa NE, et al. Neurodevelopment after perinatal arterial ischemic stroke. Pediatrics. 2018;142(3):e20174164. 111. Harteman JC, Groenendaal F, Kwee A, et al. Risk factors for perinatal arterial ischaemic stroke in full-term infants: a case-control study. Arch Dis Child Fetal Neonatal Ed. 2012;97(6):F411–416. 112. Martinez-Biarge M, Cheong JL, Diez-Sebastian J, et  al. Risk factors for neonatal arterial ischemic stroke: the importance of the intrapartum period. J Pediatr. 2016;173:62–68.e61. 113. Miller SP, McQuillen PS, Hamrick S, et  al. Abnormal brain development in newborns with congenital heart disease. N Engl J Med. 2007;357(19):1928–1938. 114. Benders MJ, Groenendaal F, Uiterwaal CS, et al. Maternal and infant characteristics associated with perinatal arterial stroke in the preterm infant. Stroke. 2007;38(6):1759–1765. 115. Kirton A, Armstrong-Wells J, Chang T, et al. Symptomatic neonatal arterial ischemic stroke: the International Pediatric Stroke Study. Pediatrics. 2011;128(6):e1402–1410. 116. Olive G, Agut T, Echeverria-Palacio CM, Arca G, Garcia-Alix A. Usefulness of cranial ultrasound for detecting neonatal middle cerebral artery stroke. Ultrasound Med Biol. 2019;45(3):885– 890. 117. Kirton A, Shroff M, Visvanathan T, deVeber G. Quantified corticospinal tract diffusion restriction predicts neonatal stroke outcome. Stroke. 2007;38(3):974–980.

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118. Low E, Mathieson SR, Stevenson NJ, et al. Early postnatal EEG features of perinatal arterial ischaemic stroke with seizures. PLoS One. 2014;9(7):e100973. 119. Kirton A, Metzler MJ, Craig BT, et al. Perinatal stroke: mapping and modulating developmental plasticity. Nat Rev Neurol. 2021;17(7):415–432. 120. Staudt M, Gerloff C, Grodd W, et al. Reorganization in congenital hemiparesis acquired at different gestational ages. Ann Neurol. 2004;56(6):854–863. 121. Baak LM, Wagenaar N, van der Aa NE, et al. Feasibility and safety of intranasally administered mesenchymal stromal cells after perinatal arterial ischaemic stroke in the Netherlands (PASSIoN): a first-in-human, open-label intervention study. Lancet Neurol. 2022;21(6):528–536. 122. Wu YW, Croen LA, Shah SJ, et  al. Cerebral palsy in a term population: risk factors and neuroimaging findings. Pediatrics. 2006;118(2):690–697.

123. Murias K, Brooks B, Kirton A, Iaria G. A review of cognitive outcomes in children following perinatal stroke. Dev Neuropsychol. 2014;39(2):131–157. 124. van der Aa NE, Dudink J, Benders MJ, et al. Neonatal posterior cerebral artery stroke: clinical presentation, MRI findings, and outcome. Dev Med Child Neurol. 2013;55(3):283–290. 125. Ecury-Goossen GM, Raets MM, Lequin M, et al. Risk factors, clinical presentation, and neuroimaging findings of neonatal perforator stroke. Stroke. 2013;44(8):2115–2120. 126. Suppiej A, Mastrangelo M, Mastella L, et al. Pediatric epilepsy following neonatal seizures symptomatic of stroke. Brain Dev. 2016;38(1):27–31. 127. Chabrier S, Peyric E, Drutel L, et al. Multimodal outcome at 7 years of age after neonatal arterial ischemic stroke. J Pediatr. 2016;172:156–161.e153.

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56

Hypoxic-Ischemic Encephalopathy

FLORIS GRO ENENDAAL AND LINDA S. DE VRIES

Summary Hypoxic-ischemic encephalopathy (HIE) following severe perinatal asphyxia (also described in the literature as perinatal hypoxia-ischemia or asphyxia neonatorum) has an incidence of 1 to 2 per 1000 live births in the Western world and is far more common in developing countries (see Chapter 7). Although metabolic disorders may mimic perinatal asphyxia, and genetic and placental factors may contribute to the clinical picture, brain imaging techniques have demonstrated acute changes in the term neonatal brain following perinatal asphyxia. The risk of irreversible damage or death following severe perinatal asphyxia is high, up to 65% of patients enrolled in trials of neuroprotective strategies. Therapeutic hypothermia is neuroprotective as has been demonstrated in several trials and is standard therapy for (near-) term neonates with severe perinatal asphyxia and encephalopathy in high-income countries.1 Ongoing studies will aim at additive strategies to augment the neuroprotection of hypothermia. Experiments in animals have demonstrated that the immature brain is more resistant to hypoxia-ischemia than the brain of the term neonate. The several reasons to explain this difference are a lower cerebral metabolic rate; lower sensitivity to neurotransmitters with potential neurotoxicity; and the greater plasticity of the immature central nervous system. Nevertheless, in the fetus and preterm neonate, cerebral hypoxia-ischemia is a major cause of acute mortality and morbidity in survivors. However, the neuropathology will be different from that of the full-term neonate (see Chapter 54). 

used, and some suggest that the term neonatal encephalopathy be best used, because the cause of encephalopathy is not always obvious. This has also been suggested by the American College of Obstetricians and Gynecologists’ Task Force on Neonatal Encephalopathy, and was reaffirmed in 2019.2 The severity of HIE can be defined as mild, moderate, or severe depending on clinical findings as described by Sarnat et al.3; this classification is widely used and is summarized in Table 56.1. The Sarnat score has been modified so it can be used within the 6-hour time window when a decision is made to start hypothermia.4 Other clinical scoring systems have been developed to assess the severity of HIE, and are used to select infants for therapeutic hypothermia (Table 56.2).5 

Hypoxia or Anoxia This denotes a partial (hypoxia) or complete (anoxia) lack of oxygen supply to the brain or blood. Hypoxemia denotes lack of oxygen in the blood. 

Ischemia This is reduction (partial) or cessation (total) of blood flow to an organ (e.g., the brain) that compromises both oxygen and substrate delivery such as glucose to the tissue. Global ischemia may result following reduced cardiac output, as in circulatory failure. Focal brain ischemia, or ischemic stroke, has been demonstrated more commonly during the last decade in both term and preterm neonates with the increased use of cranial MRI, which is a sensitive technique to demonstrate stroke. 

Definitions

Perinatal Asphyxia

Hypoxic-Ischemic Encephalopathy

The term asphyxia, from the Greek word for absence of pulse, is used to describe the interrupted supply of oxygen through the placenta and umbilical cord to the fetus. This will lead to a combined hypoxemia and hypercapnia. In the case of total interruption of oxygen, within minutes

This term describes abnormal neurologic behavior in the neonatal period following perinatal hypoxia-ischemia. Previously, the term post-asphyxial encephalopathy has been

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1060 PA RT 1 0    The Central Nervous System

TABLE 56.1   Clinical Grading Scale for Neonatal Encephalopathy

Clinical Feature

Stage 1

Stage 2

Stage 3

Level of consciousness

Hyperalert

Lethargic or obtunded

Stuporous

Spontaneous movement

Frequent symmetrical

Decreased

Absent

Autonomic system

Generalized sympathetic

Generalized parasympathetic

Both systems depressed

 Pupils

Mydriasis

Miosis

Variable; poor light reflex

  Heart rate

Tachycardia

Bradycardia

Variable (loss of heart rate variability)

  Gastrointestinal motility

Normal or decreased

Increased; passing meconium

Variable

 Suck

Weak

Weak or absent

Absent

 Moro

Strong

Weak; incomplete

Absent

  Tonic neck

Slight

Strong

Absent

Olfactory response

Strong

Weak

Absent

Myotendon stretch reflex

Brisk

Brisk

Absent

  Muscle tone

Normal

Mild hypotonia

Flaccid

 Posture

Normal or mild distal flexion

Strong distal flexion

Intermittent decerebration, fisting, thumb adduction

  Central tone

Normal

Decreased

Flaccid

Primitive reflexes

Neuromuscular control

Modified from Sarnat HB, Flores-Sarnat L, Fajardo C, et al. Sarnat grading scale for neonatal encephalopathy after 45 years: an update proposal. Pediatr Neurol. 2020;113:75–79.

TABLE 56.2   Thompson Score Score

Sign

0

1

2

3

Tone

Normal

Hypertonic

Hypotonic

Flaccid

Level of consciousness

Normal

Hyper alert stare

Lethargic

Comatose

Fits

None

Infrequent < 3/day

Frequent > 2/day

Posture

Normal

Fisting, cycling

Strong distal flexion

Moro

Normal

Partial

Absent

Grasp

Normal

Poor

Absent

Suck

Normal

Poor

Absent ± bites

Respiration

Normal

Hyperventilation

Brief apnea

Fontanelle

Normal

Full, not tense

Tense

Day 1

Day 2

Day 3

Decerebrate

IPPV (apnea)

Total score per day IPPV, Intermittent positive-pressure ventilation. From Thompson CM, Puterman AS, Linley LL, et al. The value of a scoring system for hypoxic ischaemic encephalopathy in predicting neurodevelopmental outcome. Acta Paediatr. 1997;86:757–761.

anaerobic glycolysis will occur and a lactic acidosis, and thereby metabolic acidosis, will be produced. This can be measured by blood gas analysis. In addition, a (fetal) bradycardia will develop, which will add ischemia to the process and augment cerebral hypoxia and hypercapnia. 

Pathophysiology Systemic Adaptation to Hypoxic-Ischemic Insult Severe fetal hypoxic-ischemic injury affects the entire organism, and these effects have been well studied in animal

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CHAPTER 56  Hypoxic-Ischemic Encephalopathy

• BOX 56.1 Causes of Fetal Hypoxic-Ischemic Insult

Maternal • • • • •

 ardiac arrest C Asphyxiation Severe anaphylactoid reaction Status epilepticus Hypovolemic shock 

Uteroplacental • • • •

 lacental abruption P Cord prolapse Uterine rupture Hyperstimulation with oxytocic agents 

25

5

5 mm in diameter or >2.5 cm from anal verge), infantile hemangioma less than 2.5 cm, and hypertrichosis. Low-risk cutaneous findings include simple dimple, hyper- or hypopigmentation, melanocytic nevi, teratomas, port-wine stain, or telangiectasias (Table 60.2). Based on the risk category, certain imaging modalities are recommended. MRI is recommended for all high-risk cutaneous findings. For intermediate-risk cutaneous finding, ultrasound is recommended for those less than 6 months and MRI for those greater than 6 months. Lastly, most cases of low-risk cutaneous stigmata do not require imaging; if overly concerned, an ultrasound can be performed.3 

Imaging The two major imaging modalities used to confirm and characterize spinal dysraphisms are spinal ultrasonography and MRI. Ultrasound is possible in newborns and in early infancy before 6 months of age because of the lack of ossification of the predominantly cartilaginous posterior elements of the spine. Spinal ultrasound can sometimes be performed after 6 months if a persistent posterior

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CHAPTER 60  Spinal Dysraphisms

1149

TABLE 60.2    Common Neurocutaneous Stigmata Separated Into Risk Category

High Risk

Intermediate Risk

Low Risk

• • • • • • •

• A  typical dimple • Infantile hemangioma 2.5 cm >2 Cutaneous stigmata

spinal defect is present. However, as the posterior elements ossify, the quality of ultrasound images decreases. MRI is extremely useful in the evaluation of pediatric spinal anomalies. Given the resolution provided by MRI of the soft tissues, it allows for improved diagnosis of spinal dysraphisms and has enhanced the possibility of earlier and case-tailored treatment, especially in the case of complex dysraphisms where there may be rotation of the neural elements. Thus MRI is the gold standard for imaging spinal dysraphisms.13 Ultrasonography is widely used today for prenatal screening for spinal dysraphism. It represents a cost-effective imaging modality for diagnosing and treating spinal anomalies in utero. High-resolution ultrasonography offered today can accurately localize the site of osseous and soft tissue defects. This has made it possible to accurately diagnose conditions such as myelomeningocele, lipomyelomeningocele, and diastematomyelia in utero. During the second trimester fetal anatomic survey, it is important to visualize the longitudinal, sagittal, coronal, and axial images of the spine. This allows for a complete view of the spine to analyze for spinal anomalies. If the transabdominal scan is not optimal, transvaginal scans are done to evaluate the spine. In addition to localization of the conus medullaris and spinal defects, it is important to measure any visualized sacs, especially if in utero repair is planned, because larger defects may require tissue matrix for closure.14 The components of any visualized sac are analyzed to determine the presence of neural elements, which appear as linear echogenic areas surrounded by anechoic cerebrospinal fluid. The neural placode of the myelomeningocele can also be visualized and appears as a hypoechoic, ovoid region within the sac.15 The wall of the myelomeningocele is also assessed on the ultrasound and characterized as thin or thick. The accuracy of ultrasonography varies greatly and depends on operator experience, maternal obesity, fetal movement, and fetal positioning. Nevertheless, correct identification of spinal anomalies and associated CNS and non-CNS abnormalities has been reported to have a sensitivity rate of 97% and a specificity rate of 100%.16,17 MRI is a useful adjunct imaging modality in the fetus, infants, and children for detecting and further characterizing spinal anomalies. The high resolution of the soft tissues offered by this imaging modality can provide

 imple dimple S Hyper-or hypopigmentation Melanocytic nevi Teratomas Port-wine stain or telangiectases

better visualization and more understanding of patientspecific pathology before surgical intervention. It is useful in detecting the degree of hindbrain herniation before repair and evaluating both brain and spinal cord anatomy when ultrasound is limited. Fetal MRI is important to obtain when in utero repair of spinal dysraphism is being considered. If good-quality images are able to be obtained prenatally, it may eliminate the need for postnatal images, which often require sedation to obtain a quality image.18–20 

Overall Management Spinal NTDs can cause a wide variety of presentations and neurologic deficits. Thus it is of the utmost importance to properly manage these patients to improve their neurologic outcome and prevent infection in open spinal defects. The urgency and timing of intervention differ greatly between open and closed spinal dysraphism. Open spinal dysraphism requires more urgent management and intervention because the neural tissue and cerebrospinal fluid are directly exposed to the outside environment, predisposing these children to infections such as meningitis. Myelomeningocele is one of the most morbid and debilitating of the open spinal NTDs. It can cause severe neurologic deficit, hydrocephalus, and meningitis in the postnatal period. Although some centers repair myelomeningoceles in utero during the prenatal period (see also Chapter 12), postnatal repair of myelomeningoceles remains the standard of care. Nevertheless, no specific guidelines exist regarding the management of these conditions. Although each institution may differ in how they manage myelomeningocele, the overall premise of management remains the same.21 When myelomeningocele is diagnosed in utero, the first issue that arises is the mode of delivery. Many institutions advocate for cesarean section before labor when compared with vaginal delivery or cesarean section after labor. Some studies have shown improved motor function at 2 years of age in patients delivered via cesarean section before labor when compared with any mode of delivery after labor. Other studies have shown that once labor commences, there is no change in outcome based on mode of delivery. Given the impact upon the mother, if a cesarean section is recommended, this is often a discussion between the obstetrician

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1150 PA RT 1 0    The Central Nervous System

and the neurosurgeon in the prenatal period that takes into consideration the presence or absence of hydrocephalus, which may preclude a vaginal delivery if the head size is too large. After the fetus is delivered, focus turns to prevention of infection, including prophylactic antibiotics, maintaining the sterility of the open dysraphism with sterile coverings, and timing of intervention.22,23 After delivery of the fetus, the size and location of the lesion should be noted. The lesion should also be assessed for leaking of cerebrospinal fluid. When assessing the lesion, sterile, nonlatex gloves are recommended to minimize the risk of latex sensitization.24,25 The defect should be covered with a sterile, saline-soaked dressing. Larger defects should be covered by a plastic wrap to prevent heat loss. The infant should also be placed in a prone or lateral position to avoid prolonged pressure on the lesion.26 A thorough neurologic examination should also be performed with the objective of defining the baseline neuropathology of the patient, paying attention to the observation of spontaneous activity, extent of muscle weakness, leg posture and paralysis, response to sensation, deep tendon reflexes, and anocutaneous reflex for assessment of spinal cord function. The functional level of the lesion is as important as the anatomic level, because there may not be an exact correlation depending on the functionality of the exposed neural tissue (Table 60.3). The newborn should also be evaluated for club feet and flexion or extension of the hips, knees, or ankles because this helps to define the level of the lesion. In addition, one should evaluate for signs of hydrocephalus, including a measurement of head circumference, assessment of the fontanelle and sutures for signs of splaying or fullness, and signs of brainstem compression from a Chiari II malformation. Concerning signs of apnea or bradycardia, lower brainstem dysfunction may be an indication to treat the hydrocephalus, and persistence of symptoms after treatment is a poor prognostic sign (Table 60.4). The spinal column may demonstrate kyphosis, and assessment should include evaluation for other congenital anomalies involving the heart, airway, kidneys, or GI tract.

Although there is no consensus for the specific type of prophylactic antibiotic used in these patients, the agents often used are ampicillin in addition to either gentamycin or cefotaxime. This provides coverage for group B streptococcus and gram-negative bacteria. Antibiotics should be started within 1 hour of birth and continued for at least 48 hours after repair. Prophylactic antibiotics and wound sterility greatly reduce the risk of early CNS infection, but timely repair of the defect also significantly reduces the risk of CNS infection.27 Postnatal repair should be performed within 48 to 72 hours after birth.1,21,28 However, most would advocate closure within 24 to 48 hours. Postoperatively, patients should remain in the prone or lateral position to avoid pressure on the incision and allow for wound healing. Close attention should also be placed to prevent urine or feces from entering the wound, and bumpers with drapes are often used between the wound and diaper to prevent diaper contents from affecting the wound and causing an infection. Given the high risk of hydrocephalus in this patient population, the infant should be monitored for signs and symptoms of hydrocephalus and at the very least get daily head circumference measurements and weekly head ultrasounds.21 Closed spinal dysraphism management is less urgent than open spinal dysraphisms. This is because the defect is covered TABLE   Signs and Symptoms of Hydrocephalus 60.4  and Symptomatic Chiari II Malformation

Hydrocephalus

Chiari II Malformation

• B  ulging anterior fontanelle • Increasing head circumference • Sunsetting eyes • Dilated scalp veins • Weakness • Irritability, vomiting • Hemodynamic instability (Cushing triad)

• • • • • • •

 ystagmus N Apnea Gagging Swallowing difficulties Syncope Weakness Hemodynamic instability (lower brainstem)

TABLE   Corresponding Motor and Sensory Levels for Assessment of the Functional Level of a Patient With 60.3  Myelomeningocele

Level

Motor Function

Sensory Level

T10

Rectus

Umbilicus

L1

Hip flexion

Anterolateral thigh

L2

Hip adduction

Anteromedial thigh

L3

Knee extension

Knee and shin

L4

Dorsiflexion

Dorsum of foot

L5

Extensor hallucis longus

First to second toe interspace

S1

Plantar flexion

Plantar foot

Note: In general, hip flexion indicates higher lumbar, knee extension indicates mid-lumbar, and isolated club feet indicate a low-lumbar lesion.

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CHAPTER 60  Spinal Dysraphisms

by skin and not directly exposed to the outside environment. Thus prophylactic antibiotics are not needed for these conditions, with the potential exception being dermal sinus tracts that have direct extension into the thecal sac and an opening at the skin. Nevertheless, thorough neurologic examination should be performed in these patients to assess for any neurologic deficit given the close association with tethered spinal cord. A thorough cutaneous examination should also be performed to look for cutaneous stigmata for a subcutaneous fatty mass as in the case of lipomyelomeningocele. MRI of the entire spine is recommended for patients who have two or more cutaneous lumbosacral spine lesions, a subcutaneous back mass, or neurologic symptoms concerning tethered cord syndrome. MRI or ultrasound is also recommended for patients with isolated midline cutaneous lumbosacral spine lesions. Patients with radiographically confirmed closed spinal dysraphism should be referred to neurosurgery for an evaluation. Surgery in these cases is nonurgent and is usually performed more urgently in patients with neurologic deficits in the setting of a tethered cord. Conservative management with observation is reasonable for patients who are asymptomatic from a closed spinal dysraphism, although surgery may be considered as a prophylactic means of treatment because of the high risk of neurologic deterioration and potential for irreversible neurologic injury.2,6 

Surgical Treatment Open spinal dysraphisms require timely surgical intervention to reduce the risk of early CNS infection and further neurologic decline. Myelomeningocele, the most common open spinal dysraphism, can be treated either pre- or postnatally, although postnatal treatment still represents the standard of care. The Management of Myelomeningocele Study (MOMS) was a randomized study of 183 patients at several pediatric centers across the United States comparing prenatal to postnatal repair of myelomeningocele and published in 2011. Patients were randomly assigned to undergo either prenatal repair of the myelomeningocele before 26 weeks’ gestation or standard postnatal repair. The primary endpoints of the study included fetal or neonatal death, need for shunt at 12 months, as well as mental development and motor function at 30 months. Of the 183 patients enrolled, 158 patients were evaluated at 12 months, and results showed that only 40% of patients required a shunt after prenatal repair compared with 82% in the postnatal group. The study also showed that the prenatal group had improved mental and motor development at 30 months when compared with the postnatal group. Secondary outcomes, such as hindbrain herniation and ambulation at 30 months, were also improved in the prenatal group.29 Although the study offered promising results, enrollment was stopped because of efficacy secondary to increased risk of preterm delivery and uterine dehiscence at delivery. In addition, the population of mothers who were able to enroll in the study because of the location restrictions associated with fetal repair narrowed the applicable population of both

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appropriate maternal candidates and size and location of lesion. The follow-up to MOMS, MOMS II, followed the prenatal versus postnatal surgery groups into school age with the primary outcome measure of Vineland composite score between the groups. The study found no significant difference between the two groups at school age regarding their Vineland Composite Score or adaptive behavior. However, the follow-up study found that parents in the prenatal group reported reduced negative social and family impact in addition to the continued benefits found in MOMS, such as improvement in motor and neurologic outcomes.30 Since the trials, other centers have started performing fetoscopic repair; however, these results are not widespread yet. Given the risks of prenatal repair as well as that these interventions are occurring at limited centers, postnatal repair still represents the standard of care for treatment. Repair is usually performed in a timely manner, between 24 and 48 hours, and involves approximation of the lateral edges of the open neural plate in the midline to form a neural tube, closure of a meningeal sac, and closure of the skin over the open defect. Although there is no evidence to support neural tube closure, it is thought that reforming the neural tube reduces the incidence of tethered spinal cord by reducing the raw edge at risk of scarring. The most common condition to develop after repair is hydrocephalus, and infants must be monitored closely with head circumferences and head ultrasounds. Upward of 60% to 80% of infants with myelomeningocele develop hydrocephalus and require placement of shunt.31 Other conditions that require monitoring and possible treatment in this patient population include Chiari II malformation, tethered cord, shunt malfunction, neurogenic bladder and bowel, and several orthopedic deformities.1 Closed spinal dysraphism is amenable to a delay in surgical intervention when compared with the open dysraphism, because the defect is not exposed to the external environment. Surgical treatment is often required for infants with tethered cord syndrome with a neurologic deficit, because some patients can be asymptomatic from their closed spinal dysraphism. Surgical treatment involves removal of the subcutaneous mass (if any), identification of the defect and release of the tethered, possible release of the filum terminale, preservation of neural elements, and prevention of retethering of the spinal cord. Given the complexity of the surgery for NTDs, surgery is not without significant risks. Common risks of surgical intervention include neurologic decline from tethered cord or secondary to nerve injury during the surgery, incomplete wound healing or wound dehiscence, infection, and meningitis. Patients with lipomyelomeningocele have a complication rate between 10% and 30%, a 5.8% risk of worse neurologic function after surgery, and between a 10% and 20% risk of retethering postoperatively.6

Fetal Repair of Myelomeningocele Surgically treating myelomeningocele postnatally is still considered the standard of care. However, with studies

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1152 PA RT 1 0    The Central Nervous System

showing the benefits of intrauterine closure of myelomeningocele and advances in surgical techniques, prenatal surgical treatment is worth a more thorough discussion. The benefit of intrauterine repair of myelomeningocele begins with the idea of the two-hit theory. The two-hit theory suggests that the first neurological injury occurs immediately at the time of failure of neural tube closure, and the second hit occurs because of the neural tissue being in contact with intrauterine contents, hydrodynamic pressures, or even direct trauma.32 As a result of the two-hit theory, intrauterine repair of myelomeningocele can reduce the second “hit” and improve neurological outcomes.30 In general, two surgical techniques are used for intrauterine repair of myelomeningocele: open and endoscopic. The open technique begins with an incision from the pubis to just above the umbilicus. The fetus and placenta are then localized using sonography, and a 6- to 8-cm hysterotomy is created. The neural placode, or malformed spinal cord, is then sharply incised to allow the neural elements to fall into the spinal canal. The dura is then closed in a watertight fashion, or synthetic dura can be used for help with closure. The last step is then tensionless closure of the skin.33 Endoscope repair has been forced to evolve over the years because of its difficulty with visualization along with a small working field. Endoscope repair began in the early 2000s by laying a synthetic patch over the defect to protect the neural

elements, then doing a formal skin closure in the postnatal setting. Recent advances in techniques have included both laying on the synthetic patch and attempting a single-layer skin closure through endoscopy.33 Both techniques have risk regarding both the fetus and the mother. The effectiveness of one versus the other is dictated not only by the surgical equipment used but also by the experience and expertise of the surgeon. Pediatric neurosurgeons are constantly modifying the techniques in the hope of reducing limitations and complications for both the mother and the patient. 

Conclusion Spinal NTDs are a diverse group of congenital spinal anomalies and can result in severe neurologic outcomes. These conditions range from open spinal dysraphisms, which require prompt delivery, ICU management, and surgical intervention, to closed spinal dysraphism, which may initially be asymptomatic, and can be treated in a delayed fashion. These infants may have other severe conditions that can require complex management in the neonatal ICU. Thus it is paramount for clinicians to understand the embryology, pathogenesis, physical examination findings, management, and treatment to provide the optimal care for these patients in the ICU.

Key Points • Spinal dysraphisms include both open and closed defects with varying degrees of neurologic impairment. •  Open defects include meningocele and myelomeningocele, which may be repaired prenatally but more commonly are repaired postnatally and warrant urgent surgical repair and perinatal antibiotic prophylaxis to prevent meningitis. • Monitoring for signs of infection, hydrocephalus, and symptoms of a Chiari II malformation is critical in the perinatal period.

• Closed spinal dysraphisms may be amenable to delayed treatment to prevent neurologic decline from a tethered spinal cord. • Fetal repair of myelomeningocele has been proven to be beneficial but is limited in its practice because of the high maternal risk as well as a steep learning curve and limited availability.

References

7. Singh I, Rohilla S, Kumar P, Sharma S. Spinal dorsal dermal sinus tract: an experience of 21 cases. Surg Neurol Int. 2015;6(suppl 17):S429–S434. 8. Dhawan V, Kapoor K, Singh B, et al. Split notochord syndrome: a rare variant. J Pediatr Neurosci. 2017;12(2):177–179. 9. Srivastava P, Gangopadhyay AN, Gupta DK, Sharma SP. Split notochord syndrome associated with dorsal neuroenteric fistula: a rare entity. J Pediatr Neurosci. 2010;5(2):135–137. 10. Krantz DA, Hallahan TW, Carmichael JB. Screening for open neural tube defects. Clin Lab Med. 2016;36(2):401–406. 11. Wilson RD, Sogc Genetics C, Special C. Prenatal screening, diagnosis, and pregnancy management of fetal neural tube defects. J Obstet Gynaecol Can. 2014;36(10):927–939. 12. Kibar Z, Capra V, Gros P. Toward understanding the genetic basis of neural tube defects. Clin Genet. 2007;71(4):295–310. 13. Dhingani DD, Boruah DK, Dutta HK, Gogoi RK. Ultrasonography and magnetic resonance imaging evaluation of pediatric spinal anomalies. J Pediatr Neurosci. 2016;11(3):206–212.

  

1. Copp AJ, Greene ND. Neural tube defects—disorders of neurulation and related embryonic processes. Wiley Interdiscip Rev Dev Biol. 2013;2(2):213–227. 2. Copp AJ, Stanier P, Greene ND. Neural tube defects: recent advances, unsolved questions, and controversies. Lancet Neurol. 2013;12(8):799–810. 3. Sewell MJ, Chiu YE, Drolet BA. Neural tube dysraphism: review of cutaneous markers and imaging. Pediatr Dermatol. 2015;32(2):161–170. 4. McComb JG. A practical clinical classification of spinal neural tube defects. Childs Nerv Syst. 2015;31(10):1641–1657. 5. Pang D. Surgical management of complex spinal cord lipomas: how, why, and when to operate. A review. J Neurosurg Pediatr. 2019;23(5):537–556. 6. Sarris CE, Tomei KL, Carmel PW, Gandhi CD. Lipomyelomeningocele: pathology, treatment, and outcomes. Neurosurg Focus. 2012;33(4):E3.

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CHAPTER 60  Spinal Dysraphisms

14. Meller C, Aiello H, Otano L. Sonographic detection of open spina bifida in the first trimester: review of the literature. Childs Nerv Syst. 2017;33(7):1101–1106. 15. Bulas D. Fetal evaluation of spine dysraphism. Pediatr Radiol. 2010;40(6):1029–1037. 16. 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. 17. Coleman BG, Langer JE, Horii SC. The diagnostic features of spina bifida: the role of ultrasound. Fetal Diagn Ther. 2015;37(3):179–196. 18. Badve CA, Khanna PC, Phillips GS, et al. MRI of closed spinal dysraphisms. Pediatr Radiol. 2011;41(10):1308–1320. 19. Nagaraj UD, Bierbrauer KS, Peiro JL, Kline-Fath BM. Differentiating closed versus open spinal dysraphisms on fetal MRI. AJR Am J Roentgenol. 2016;207(6):1316–1323. 20. Egloff A, Bulas D. Magnetic resonance imaging evaluation of fetal neural tube defects. Semin Ultrasound CT MR. 2015;36(6):487– 500. 21. Cavalheiro S, da Costa MDS, Moron AF, Leonard J. Comparison of prenatal and postnatal management of patients with myelomeningocele. Neurosurg Clin N Am. 2017;28(3):439–448. 22. Brown SD, Feudtner C, Truog RD. Prenatal decision-making for myelomeningocele: can we minimize bias and variability? Pediatrics. 2015;136(3):409–411. 23. Greene S, Lee PS, Deibert CP, et al. The impact of mode of delivery on infant neurologic outcomes in myelomeningocele. Am J Obstet Gynecol. 2016;215(4): 495.e491–495.e411.

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24. Cremer R, Kleine-Diepenbruck U, Hoppe A, Blaker F. Latex allergy in spina bifida patients--prevention by primary prophylaxis. Allergy. 1998;53(7):709–711. 25. Rendeli C, Nucera E, Ausili E, et  al. Latex sensitisation and allergy in children with myelomeningocele. Childs Nerv Syst. 2006;22(1):28–32. 26. McLone DG. Care of the neonate with a myelomeningocele. Neurosurg Clin N Am. 1998;9(1):111–120. 27. Charney EB, Melchionni JB, Antonucci DL. Ventriculitis in newborns with myelomeningocele. Am J Dis Child. 1991;145(3):287–290. 28. Burke R, Liptak GS; Council on Children with Disabilities. Providing a primary care medical home for children and youth with spina bifida. Pediatrics. 2011;128(6):e1645–1657. 29. Adzick NS, Thom EA, Spong CY, et  al. A randomized trial of prenatal versus postnatal repair of myelomeningocele. N Engl J Med. 2011;364(11):993–1004. 30. Houtrow AJ, Thom EA, Fletcher JM, et  al. Prenatal repair of myelomeningocele and school-age functional outcomes. Pediatrics. 2020;145(2). 31. Talamonti G, D’Aliberti G, Collice M. Myelomeningocele: longterm neurosurgical treatment and follow-up in 202 patients. J Neurosurg. 2007;107(suppl 5):368–386. 32. Hutchins GM, Meuli M, Meuli-Simmen C, et al. Acquired spinal cord injury in human fetuses with myelomeningocele. Pediatr Pathol Lab Med. 1996;16(5):701–712. 33. Dewan MC, Wellons JC. Fetal surgery for spina bifida. J Neurosurg Pediatr. 2019;24(2):105–114.

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61

Hearing Loss in the Newborn Infant

BETTY R. VOHR

Background Tremendous progress has been made during the past 25 years in the identification of hearing loss (HL) in newborns. The National Institutes of Health issued a “Consensus Statement on Early Identification of Hearing Impairment in Infants and Young Children” in 1993 that concluded that all infants admitted to the neonatal intensive care unit (NICU) should be screened for HL before hospital discharge and that universal hearing screening should be implemented for all infants within the first 3 months of life.1 The percentage of infants screened for HL in the United States increased from 46% in 1999 to 98.4% in 2014. The percentage of infants who fail the screening process is about 1.6%, and the rates of permanent HL subsequently diagnosed by comprehensive audiology testing range from one to three per 1000, making congenital HL the most common birth defect diagnosed as a result of the newborn screening process (https://www.cdc.gov/ncbddd/ hearingloss/2019-data/01-data-summary.html#data-item). A report to assess the impact of universal hearing screening in a large cohort of infants identified a prevalence of deafness by school age of 3.65/1000 compared to a neonatal rate of 1.79/1000.2 The prevalence of deafness by 3 to 17 years of age as reported by the Centers for Disease Control and Prevention (CDC) National Health Interview Survey for the years 1997 to 2005 was 5/1000 (https://www.cdc.gov/ncbd dd/hearingloss/data.html). It is important to recognize that the neonatal screen does not identify all HL and is least sensitive to mild impairments. Undetected, HL in young infants and children negatively affects communication development, academic achievement, literacy, and social and emotional development,3,4 whereas early identification and intervention, particularly within the first 6 months of life, clearly provide benefit for communication development in infants.3,5–9 There is accumulating evidence that the brain may be optimally responsive to language input early in life.10–13 Based on these findings, the 2007 Joint Committee on Infant Hearing (JCIH) Position Statement published

the 1-3-6 recommendation to maximize the outcomes of infants with all degrees of HL14: (1) All infants in the NICU and well-baby nursery should be screened for HL at no later than 1 month of age. (2) Infants who do not pass the screen should have a comprehensive evaluation by an audiologist skilled in assessing infants and children no later than 3 months of age, for confirmation of hearing status. When a diagnosis of permanent HL has been made, timely referral for assistive technology for enhancing access to language is indicated.13–15 (3) Infants with confirmed HL should receive appropriate intervention no later than 6 months of age from professionals with expertise in HL and deafness in infants and young children.16 

Normal/Typical Hearing and Hearing Loss The ear consists of outer, middle, and inner components. The external ear includes the pinna and the outer ear canal. Sound waves travel through the air and are conducted through the outer ear canal to the tympanic membrane, where vibrations enter the middle ear and are amplified and transmitted through the ossicles to the fluid within the cochlea (inner ear). Sound waves in the inner ear are transmitted through the fluid and stimulate both the outer and inner hair cells of the cochlea. The outer hair cells respond to sound energy by producing an echo of sounds referred to as otoacoustic emissions (OAEs), and the inner hair cells act by converting mechanical energy into electrical energy transmitted to the cochlear branch of the eighth cranial nerve, the brainstem, and finally the auditory cortex for perception of the meaning of sounds. In normal hearing individuals, all components of the pathway are intact and functioning. Blockage of sound conduction in the outer or middle ear may result in either transient (fluid or debris) or permanent (anatomic abnormality such as atresia or microtia) conductive HL. Failure of sound transmission within the cochlea, outer and inner hair cells, and eighth cranial nerve is a manifestation of sensorineural HL, whereas pathology of the inner hair cells and eighth cranial nerve with intact outer

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CHAPTER 61  Hearing Loss in the Newborn Infant

hair cells is characteristic of neural HL, also referred to as auditory neuropathy or auditory dyssynchrony.17–19 HL can be classified as bilateral or unilateral and as slight, mild, moderate, severe, or profound. HL severity is defined by measuring the hearing threshold in decibels (dB) across frequencies (Table 61.1). Normal hearing has a threshold of 10 to 15 dB. It is important to recognize that the presence of even slight or mild HL can affect language development in young children and may be progressive. For children with bilateral HL, the severity of loss is based on the better-functioning ear.20 The types of transient and permanent HL that can be identified at birth with newborn screening include sensorineural, neural, and conductive (Table 61.2). Transient conductive HL may also be present, especially in infants who have been hospitalized in a NICU. Mixed HL is a combination of permanent HL and transient conductive HL. Neonatal hearing screening programs in the United States are conducted under the guidance of an audiologist. An audiologist experienced in assessing infants and young children is responsible for completing the comprehensive diagnostic assessment necessary to confirm the diagnosis of HL. Increasing numbers of NICUs are completing the diagnostic assessment prior to discharge to avoid a delay in the diagnosis for the most medically high-risk infants. 

Tests for Hearing Loss Screening and diagnostic hearing tests are shown in Table 61.3. Physiologic tests include those that measure electrical activity or reflexes and include otoacoustic emissions (OAEs) and auditory brainstem response (ABR) testing. These tests do not require an active response from the infant and can be performed when the infant is asleep or quiet and awake. OAE screen measurements are obtained using a sensitive microphone within a probe inserted into the ear canal that records the sound produced by the outer hair cells of a normal cochlea in response to a sound stimulus. Abnormal outer and middle ear function caused by blockage or background noise may interfere with recording OAEs. The automated auditory brainstem response (AABR) for screening and ABR for diagnostic testing are obtained from surface electrodes that record neural activity in the cochlea, outer and inner hair cells, auditory nerve, and brainstem in response to a click stimulus. In AABR, a predetermined algorithm provides an automated pass-or-fail response to the presence or absence of wave 5 on the ABR. Both OAE and ABR detect sensorineural and conductive HL. A false-positive fail screen for permanent HL may result from outer or middle ear dysfunction, including the presence of a transient conductive HL (fluid or debris) or noise interference. OAEs cannot be used to screen for neural HL, because pathology in this disorder involves the inner hair cells, eighth cranial nerve, and brainstem with intact outer hair cells. Infants with neural HL will therefore fail ABR but pass OAE. The 2007 JCIH stated that infants cared for in the NICU for greater than 5 days are at highest risk

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TABLE 61.1    Definitions of Degrees of Hearing Loss No hearing loss

10–15 dB

Slight

16–25 dB

Mild

26–40 dB

Moderate

41–55 dB

Moderately severe

56–70 dB

Severe

71–90 dB

Profound

≥91 dB

TABLE 61.2    Types of Hearing Loss

Type

Characteristics

Sensorineural

Pathology involving cranial nerve VIII and outer hair cells and inner hair cells of the cochlea that impairs neuroconduction of sound energy to the brainstem

Permanent conductive

Anatomic obstruction of the outer ear (atresia) or middle ear (fusion of ossicles) that blocks transmission of sound

Neural or auditory neuropathy or auditory dyssynchrony

Pathology of the myelinated fibers of cranial nerve VIII or the inner hair cells that impair neuroconduction of sound energy to the brainstem; the function of the outer hair cells remains intact

Transient conductive

Debris in the ear canal or fluid in the middle ear that blocks the passage of sound waves to the inner ear

Mixed hearing loss

A combination of sensorineural or neural hearing loss with transient or permanent conductive hearing loss

for neural HL and therefore should be screened only with AABR.14,21 Some hospitals use a two-step screen with both AABR and OAE. Screening time with OAE is quicker and more cost effective; therefore OAE is considered an acceptable screen in the well-baby nursery. Because OAE will not

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1156 PA RT 1 0    The Central Nervous System

TABLE 61.3    Tests for Hearing Screening and Diagnosis

Test

Mechanism

Type of Hearing Loss

Otoacoustic emissions (OAE) screen

OAE tests evaluate the response of the outer hair cells in the cochlea to a sound stimulus; the hair cells produce echolike responses that can be detected and recorded with a high-sensitivity microphone. Automated equipment is available.

Sensorineural Conductive

Automated auditory brainstem response (AABR) screen

AABR screen tests based on threshold algorithms have become standard for screening.

Sensorineural Conductive Neural

The following physiologic and behavioral tests are used as part of a diagnostic battery: Auditory brainstem response (ABR) diagnostic

ABR potentials are a reflection of electrical activity in cranial nerve VIII and auditory brainstem pathway that can be detected with scalp electrodes to produce an ABR.

Sensorineural Conductive Neural

Tympanometry battery

This measure of middle ear function is part of the battery for all children. For infants younger than 6 months, a high-frequency probe tone of 1000 Hz is indicated.

Conductive

Vision reinforcement audiometry (>6 months of age) Conditioned audiometry response (>2.5 years of age)

Observations of the infant’s behavioral responses to sounds

Sensorineural Conductive Neural

Standard audiometry (>4.5 years of age)

Observation of the child’s behavioral responses to a task in response to sounds

Sensorineural Conductive Neural

identify auditory neuropathy, it is not recommended for screening in the NICU. Tympanometry (immittance) testing is used to assess the peripheral auditory system, including the function, intactness, and mobility of the tympanic membrane; the pressure in the middle ear; and the mobility of the middle ear ossicles. A probe is placed into the external ear canal, and air pressure is changed to assess the movement of the tympanic membrane. The tympanogram shows the tympanic membrane response to the pressure stimulus: A type A curve is considered a normal response, but a completely flat response may be reflective of fluid in the middle ear or perforation of the tympanic membrane. Tympanometry is not used for screening. Behavioral tests include vision reinforcement audiometry (VRA), which is appropriate for rested alert infants with a developmental age of at least 6 months. The infant must have the functional capability of turning to sounds. For the administration of VRA, the infant sits on the mother’s lap in a sound booth, earphones are inserted, and the infant is conditioned to turn to sounds that are paired to animated toys that appear on either the right or left side. Traditional behavioral testing is used for toddlers at least 2.5 years of age. Children respond by placing a block in a box each time they hear a sound. For confirmation of an infant’s hearing status, a test battery is required to cross-check results of both the physiologic measures and the behavioral measures.22 The purposes of the audiologic test battery are to assess the integrity of the

auditory system, estimate hearing sensitivity across the frequency range, and determine the type of loss. Infants who fail a newborn screen should have a diagnostic assessment as soon as possible after the newborn screen and not later than 3 months of age. Primary care physicians and health centers are beginning to implement routine surveillance and hearing screening of children with OAE and tympanometry during well-child visits.23–26 This would appear to be an important adjunct to newborn screening because of the known rate of late-onset HL by school age, which is equivalent to the rate identified in newborn screening. However, NICU infants who fail the newborn screen should never be screened in the medical home but should be referred to an audiologist. In addition, children who do not pass the OAE screen in the medical home need to be referred to audiology for further diagnostic testing. 

Early Intervention Services There is a body of evidence supporting the importance of enrollment in early intervention services to improve the outcomes of children with HL. Before universal hearing screening, children with severe to profound HL were identified at 24 to 30 months of age and subsequently demonstrated significant delays in communication, language, and literacy. The Colorado Newborn Hearing Screening Project first reported that children with HL who received intervention services before 6 months of age had speaking, sign, or

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CHAPTER 61  Hearing Loss in the Newborn Infant

total communication language scores comparable with hearing children at 3 years of age.3,13,27 A second report demonstrated that at 12 to 16 months, children with HL who were enrolled in early intervention at 3 months or younger had significantly higher scores for number of words understood, words produced, early gestures, later gestures, and total gestures compared with children enrolled after 3 months of age.7 The 2007 JCIH recommended that infants with all degrees of unilateral or bilateral HL should be referred to early intervention services at the time of diagnosis and receive services no later than 6 months of age. These services should be provided by professionals who have expertise in HL, including educators of the deaf, speech-language pathologists, and audiologists. The 2013 Supplement to the 2007 JCIH Position Statement provides comprehensive guidelines for early intervention after confirmation that the child is deaf or hard of hearing.28 The 12 best-practice goals and guidelines recommended provide an evidence-based framework for family-centered culturally competent, individualized early intervention services to meet the diverse needs of children and families regardless of type and degree

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of HL and modality of communication (Table 61.4). Recent longitudinal data from the Colorado Newborn Hearing Screening Project confirm the strong association between the amount of child-directed parent talk in the first 4 years and language outcomes at 7 years of age.13 

Etiology of Hearing Loss It is estimated that at least 50% of congenital HL is hereditary. Nearly 400 syndromes and hundreds of genes associated with HL have been identified.29–32 Genetic HL is about 30% syndromic and 70% nonsyndromic. Among children with nonsyndromic HL, 75% to 85% of cases are autosomal recessive (DFNB, deafness, neurosensory, autosomal recessive), 15% to 24% are autosomal dominant (DFNA, deafness, neurosensory, autosomal dominant), and 1% to 2% are X-linked (DFN). Therefore most infants with HL have nonsyndromic autosomal recessive HL and are born to hearing parents. A single gene, GJB2, which encodes connexin 26, a gap-junction protein expressed in the connective tissues of the cochlea, accounts for up to 50% of all cases

TABLE 61.4    Best-Practice Guidelines for Early Intervention Services for Children Who Are Deaf or Hard of Hearing Goal 1

Access to timely and coordinated entry into early intervention programs supported by a data management system capable of tracking

Goal 2

Timely access to coordinators with specialized knowledge and skills related to working with children and adults who are deaf or hard of hearing

Goal 3

• E  arly intervention providers who have the professional qualifications and core knowledge and skills to optimize the child’s development and child/family well-being • Early intervention services to teach American Sign Language provided by professionals who have native or fluent skills and are trained to teach parents/families and young children • Early intervention services to develop listening and spoken language skills provided by professionals who have specialized skills and knowledge

Goal 4

Children with additional disabilities have access to specialists with the qualifications and specialized skills to support optimal outcomes.

Goal 5

Children from culturally diverse backgrounds and/or non–English-speaking homes have access to culturally competent services of the same quality and quantity as provided to majority culture families.

Goal 6

All children have progress monitored every 6–36 months, with standardized, norm-referenced developmental assessments for language (spoken and/or signed), the modality of communication (auditory, visual, and/or augmentative), and social-emotional, cognitive, and motor skills.

Goal 7

Children with all degrees of hearing loss, including unilateral or slight hearing loss, auditory neuropathy, and progressive or fluctuating hearing loss, receive appropriate monitoring and immediate referral to early intervention services as needed.

Goal 8

Families are participants in the development and implementation of EHDI systems at the state/territory and local level.

Goal 9

Families have access to other families who have children who are D/HH and are trained to provide culturally and linguistically sensitive support and guidance.

Goal 10

Individuals who are D/HH are active participants in the development and implementation of EHDI systems at the national, state/territory, and local levels.

Goal 11

Children who are D/HH and their families have access to support, mentorship, and guidance from individuals who are D/HH.

Goal 12

All children who are D/HH and their families are ensured of fidelity in the implementation of early intervention.

D/HH, Deaf or hard of hearing; EHDI, early hearing detection and intervention.

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1158 PA RT 1 0    The Central Nervous System

of profound nonsyndromic HL. More than 100 mutations of GJB2 have been identified. A single GJB2 mutation, 35delG, accounts for up to 70% of the mutations. The etiology of HL will be reviewed relative to the risk factors for HL published by the JCIH in 2007 and 2019 (Box 61.1). Several mitochondrial DNA mutations of the 12S rRNA gene are associated with aminoglycoside-induced nonsyndromic HL. This is potentially important for NICU infants, because aminoglycosides remain one of the most common medications administered in the NICU.33 Studies have examined the frequency of these genes in NICU populations and identified a rate of ∼1% to 1.8%,34,35 but neither of them identified an association in neonates between the presence of the genetic marker in conjunction with aminoglycoside administration and HL. Neonatal genetic screening with rapid turnaround is steadily becoming more available. A concern with the current reports, however, is that mitochondrial HL has a variable age of onset and may not be identified in the newborn period. In addition, it has been suggested that there may be a modifier gene effect that is protective.35 

Risk Factors The first two risk factors in Box 61.1 are obtained by parent report. Parents may not be aware of a family history • BOX 61.1 Risk Factors Associated With

Permanent Congenital, DelayedOnset, or Progressive Hearing Loss

1. Caregiver concernsa regarding hearing, speech, language, or developmental delay 2. Family history of permanent HLa 3. Neonatal intensive care for greater than 5 days and hyperbilirubinemia requiring exchange transfusion regardless of length of stay 4. In utero infections, such as cytomegalovirus,a Zika virus, herpes virus, rubella, syphilis, and toxoplasmosis 5. Craniofacial anomalies, including atresia, microtia, and temporal bone anomalies 6. Physical findings, such as white forelock, that are associated with syndromes known to include a sensorineural or permanent conductive HL 7. Syndromes associated with HL or progressive or lateonset HL,a such as neurofibromatosis, osteopetrosis, and Usher syndrome; other frequently identified syndromes include Waardenburg, Alport, Pendred, and Jervell and Lange-Nielsen 8. Neurodegenerative disordersa such as Hunter syndrome or sensory motor neuropathies such as Friedreich ataxia or Charcot-Marie-Tooth disease 9. Culture-positive postnatal infectionsa associated with sensorineural HL, including confirmed bacterial and viral (especially herpesviruses and varicella) meningitis 10. Head trauma, especially basal skull or temporal bone fracture that requires hospitalization 11. Chemotherapya HL, Hearing loss. factors that are greater for delayed-onset or progressive HL.

aRisk

of HL (risk factor 2) or of syndromes associated with HL until discussing the possibility with relatives. If a family history of HL is reported for an infant who passes the screen, ongoing surveillance is indicated with at least one follow-up audiologic assessment by 24 to 30 months of age. All families with an infant with HL, regardless of family history of HL, will benefit from a genetics consultation. Risk factor 1, caregiver concern regarding hearing, speech, language, or developmental delay in the first 2 to 3 years of life,36 has also been shown to be associated with an increased risk for lateonset or progressive HL not detected in a newborn screen. It is important to remember that the rate of HL doubles between birth and school age from one to three per 1000 in newborns to about three to four per 1000 at school age22; therefore caregiver concern should prompt a referral for further evaluation. Medical complications are associated with 40% of childhood permanent HL. Risk factor 3 includes infants requiring NICU care for greater than 5 days and any of the following exposures regardless of length of stay: extracorporeal membrane oxygenation, assisted ventilation, exposure to ototoxic medications (gentamicin and tobramycin) or loop diuretics (furosemide or lasix), and hyperbilirubinemia requiring exchange transfusion.37–39 Risk factor 4 includes in utero infections such as cytomegalovirus (CMV), herpes, rubella, syphilis, toxoplasmosis, and Zika virus.40 CMV remains the most common medical cause of both early- and delayed-onset HL in infants and children.41–43 Most infants with congenital CMV infection have no clinical findings at birth, and the diagnosis goes unrecognized. Treatment of children with positive CMV, but without clinical findings or HL, with valgancyclovir remains controversial because of an increased risk of side effects.44,45 Zika virus is also a neurotropic virus that has emerged and is associated with early and possibly delayed-onset HL. It may occur in association with abnormalities of the central nervous system, and the type of HL is either sensorineural or auditory neuropathy.46,47 Because of the association with CNS abnormalities, these infants should be screened with AABR. Risk factors 5 to 8 are all associated with congenital abnormalities or syndromes. Risk factor 5 includes craniofacial anomalies, such as those involving the pinna or ear canal, ear pits, and temporal bone anomalies.48 These defects are common in both the well-baby nursery and the NICU. Many of these findings reflect abnormalities in the embryologic development of the ear. The external ear, middle ear, and Eustachian tube develop from the branchial apparatus beginning at the fourth week of gestation. The pinna arises from the coalescence of the first and second arch tissues of the first branchial cleft, which will become the external auditory canal. The Eustachian tube and middle ear space develop from the first pharyngeal pouch, and the ossicles from the mesoderm of the first and second arches. The inner ear develops from surface ectoderm and neuroectoderm beginning in the third week of gestation, with the cochlea, semicircular canals, utricle, and saccule formed by 15 weeks. The inner ear reaches adult size by 23 weeks. Risk

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CHAPTER 61  Hearing Loss in the Newborn Infant

factor 6 includes visible physical findings such as white forelock, which is associated with Waardenburg syndrome. Risk factor 7 includes syndromes associated with neonatal, progressive, or late-onset HL such as neurofibromatosis, osteopetrosis, and Usher syndrome. Usher syndrome is the most common cause of autosomal recessive syndromic HL (4%–6% of children with HL). Affected individuals develop vestibular problems secondary to progressive retinitis pigmentosa and become blind with increasing age. Subtypes are associated with either mild to severe or severe to profound HL. Early diagnosis is critical, because a visual means of communication is not an option for a child who will become blind with increasing age. Other frequently identified syndromes include Waardenburg, Pendred, Jervell and Lange-Nielsen, branchio-otorenal, and Alport syndromes.29,30,49 The most common autosomal dominant syndrome is Waardenburg syndrome. It occurs in 1% to 4% of children with HL. Children have sensorineural or permanent conductive HL and associated heterochromia iridis. Pendred syndrome is the second most common autosomal recessive cause of syndromic HL. It is characterized by severe to profound HL and euthyroid goiter, which presents during adolescence or later. An abnormality called Mondini dysplasia or dilated vestibular aqueduct, which is diagnosed by computed tomography examination of the temporal bones, is associated with Pendred syndrome. Jervell and Lange-Nielsen syndrome is characterized by prolongation of the QT segment on electrocardiogram and is associated with sudden infant death and syncope. Children with QT prolongation should be seen in consultation by cardiology for management. Branchio-otorenal syndrome is autosomal dominant and occurs in 2% of HL. It is characterized by preauricular pits, malformed pinnae, branchial fistulas, and renal anomalies. Alport syndrome is X-linked or autosomal recessive, occurs in 1% of children with HL, and is associated with progressive HL. Risk factor 8 consists of neurodegenerative disorders such as Hunter syndrome or sensory motor neuropathies such as Friedreich ataxia and Charcot-Marie-Tooth syndrome.49 Risk factor 9 is culture-positive postnatal infections and includes confirmed bacterial and viral (especially herpesviruses and varicella virus) meningitis. Meningitis is associated with an increased incidence of sensorineural HL.50,51 Children with cochlear implants may be at increased risk of meningitis.52,53 Risk factors 10 and 11 are risk factors encountered after discharge. Serious head trauma, especially basal skull or temporal bone fractures requiring hospitalization, is a risk factor for HL in childhood.54,55 Although rare in children, chemotherapy for leukemia or cancer remains a risk factor, which in some cases is reversible.56 Box 61.1 specifically identifies the risk factors associated with delayed-onset HL. Although all children with a risk factor should have ongoing surveillance in the medical home and at least one follow-up visit with an audiologist, children with increased risk for delayed-onset HL may benefit from more frequent assessments. 

1159

Medical Workup for Hearing Loss and Care Coordination An initial physician visit is beneficial after a newborn hearing screen is failed. At that time, parents are informed of the risk of HL and the importance of follow-up with an audiologist. A second physician visit should be scheduled with the family as soon as a diagnosis of HL is made to discuss the audiologist’s report, provide information on community resources, and offer support for the family during a stressful time. During the postdiagnosis appointment, the physician reviews the pregnancy, neonatal, and family history for HL; re-examines the child for evidence of any craniofacial abnormalities or a syndrome associated with HL; and discusses the benefits of early intervention services and amplification. The primary care physician therefore needs to be aware of community resources and support the family’s choice of early intervention program and mode of communication. Ongoing communication of the primary provider with the family is necessary to answer questions and provide support. Sharing evidence of significantly improved outcomes as a result of early diagnosis and early intervention provides some reassurance and comfort to the family. During this time of transition, some families derive benefit from meeting other families with young children with HL who are further along in the process. Successful care coordination of the child with HL requires the partnering of the primary care provider, audiologist, otolaryngologist, early intervention provider, developmental pediatrician, geneticist, and, most importantly, the family. Every infant with confirmed HL should be evaluated by an otolaryngologist with knowledge of pediatric HL. The otolaryngologist conducts a comprehensive assessment to determine the etiology of HL and provides recommendations and information to the family, audiologist, and primary care provider on candidacy for amplification, assistive devices, and surgical intervention, including reconstruction, bone-anchored hearing aids, and cochlear implantation. Because of the prevalence of hereditary HL, all families of children with confirmed HL should be offered a genetics evaluation and counseling. This evaluation can provide families with information on etiology, prognosis, associated disorders, and the likelihood of HL in future offspring. The geneticist will review the family history for specific genetic disorders or syndromes, examine the child, and complete genetic testing for syndromes or gene mutations for nonsyndromic HL such as GJB2 (connexin 26).30,57,58 Additional referrals may be made at that time for a developmental assessment or other indicated specialty evaluation. Because 30% to 40% of children with confirmed HL have comorbidities or other disabilities, the primary care physician should closely monitor developmental milestones and initiate referrals for suspected disabilities as needed.25 Because of the association of HL with vision impairments and the importance of vision for children with HL, it is recommended that each child with a permanent HL have at least one examination to assess visual acuity by an ophthalmologist experienced in evaluating infants. 

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1160 PA RT 1 0    The Central Nervous System

Middle Ear Disease Otitis media with effusion (OME) is highly prevalent among young children, and about 90% of children have an episode of OME before starting school.59 Middle ear status should be monitored closely in children with permanent HL, because the presence of middle ear effusion can further compromise hearing. Recommendations related to diagnosis of OME include examination with a pneumatic otoscope and documentation of laterality, duration of effusion, and severity of symptoms. Although about 40% to 50% of children with OME do not have symptoms,60 some children, including those with unilateral HL, may have associated balance problems.61,62 Medical management of OME in children with permanent HL may include hearing testing, amplification adjustment, and tympanostomy tubes.60 Most OME is self-limited, and 75% to 90% of cases spontaneously resolve in 3 months. Therefore a 3-month period of observation is recommended. Evidence suggests that no benefit is derived from the use of antihistamines or decongestants in children. Children with persistent OME (≥4 months’ duration) with associated persistent HL or structural injury to the tympanic membrane or middle ear become candidates for surgical intervention with tympanostomy, which has been shown to be associated with decreases in middle ear effusion and improved hearing. 

Communication Options One of the important decisions that the family needs to make for the child is the communication mode that will work optimally for the child and family.59 There are five options. Auditory oral communication encourages the use of residual hearing and amplification with visual support (speech reading), and the goal is spoken language. Auditory verbal communication is based on listening skills alone, and the goal is spoken language. Cued speech uses a visual communication system that combines listening with eight hand shapes in four placements near the face and supports spoken language. Total communication combines all means of communication and encourages simultaneous use of speech and sign. Deaf children learn American Sign Language, and English is learned as a second language when American Sign Language has been mastered. The choice of communication option for the family may change over time depending on the progress of the child and the degree of HL. For example, for an infant born with a profound HL, the family may initially choose total communication, but, after a cochlear implant at 12 months of age, they may use predominantly auditory verbal or auditory oral communication. 

Audiologic Devices

the first month of life. The main components are the microphone that picks up sounds and the amplifier. The audiologist uses computer programming to adjust the sound for an individual child’s needs. If the child has different degrees of HL at different frequencies, the audiologist adjusts the gain (loudness) by frequency. Normal speech range is from 500 to 2000 Hz. Ear molds are made from an impression of the child’s ear. As a young infant grows, the ear molds may have to be replaced every 6 to 8 weeks. 

Frequency-Modulated Systems Frequency-modulated (FM) systems were developed for individuals with HL to hear better in noisy environments. An FM system consists of a microphone and a receiver. A small radio transmitter is attached to a microphone and a small radio receiver. A parent or teacher wears the FM transmitter and microphone while the child wears the FM receiver. The FM transmitter sends a low-power radio signal to the FM receiver, which must be within 50 feet of the transmitter. The FM receiver gets the signal from the microphone and sends it to a personal hearing aid or cochlear implant. Listening to the FM signal is similar to listening to speech only inches away. FM systems can be used in a variety of situations, including in the home, while shopping, or at school. 

Cochlear Implants Children and adults who are deaf or severely hard of hearing can be fitted for cochlear implants. According to the US Food and Drug Administration (FDA), as of December 2019, approximately 736,000 people worldwide have received implants. In the United States, roughly 118,000 adults and 65,000 children have received them.63 Candidacy age criteria for pediatric cochlear implantation has continued to decrease from ≥2 years in 1990 to 18 months in 1998, 12 months in 2000, and 9 months in 2020.64 There are increasing reports demonstrating the beneficial effects on speech and language for infants with bilateral profound HL implanted before 12 months of age and with greater cumulative wear time.65–69 In cases of deafness caused by meningitis, implants may be placed early in the first year of life. Children up to 7 years of age appear to derive the greatest benefit from a cochlear implant for the development of speech.12,62 Because of an increased risk for bacterial meningitis, it is recommended that physicians monitor all patients with cochlear implants52,53 for middle ear and other infections.70 Streptococcus pneumoniae is the most common pathogen causing meningitis in cochlear implant recipients.53 All children with cochlear implants should be vaccinated according to the American Academy of Pediatrics (AAP) high-risk schedule. 

Hearing Aids

Continued Surveillance

Hearing aids are compact and worn either in-the-ear (ITE) or behind-the-ear (BTE). They can be fitted on an infant in

The 2007 and 2019 JCIH Position Statements have recommendations for ongoing surveillance in the medical home

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CHAPTER 61  Hearing Loss in the Newborn Infant

for all infants with and without risk factors for HL.14,15,72 Regular surveillance of developmental milestones, auditory skills, parental concerns, and middle ear status should be performed in the medical home, consistent with the AAP periodicity schedule. All infants should have an objective standardized screen of global development with a validated screening tool at 9, 18, and 24 to 30 months of age or at any time if the health care professional or family has concerns. Language screens that can be used in the primary care setting include the Early Language Milestone Scale,73 the MacArthur Communicative Development Inventory,74 the Language Development Survey,75 and Ages and Stages.76 Infants who do not pass the speech-language portion of a global screening or for whom there is a concern regarding hearing or language should be referred for speech-language evaluation and audiology assessment. This recommendation was implemented because of the known increase in the number of children identified with HL between the newborn screen and school age. This is related to three factors: (1) mild HL is missed with newborn screening tools, (2) some children experience delayed-onset or progressive HL such as that associated with CMV, and (3) some children experience late-onset HL secondary to meningitis, trauma, or chemotherapy. Infants with OME may have transient HL and associated language delays. Further management and evaluation of hearing skills and HL have been outlined by Cunningham et al.77 in an AAP Clinical Report. In addition to risk factors for HL, the report specifically addresses the need for continued surveillance of speech and language milestones in the first 36 months of life.25,77 

Stress and Impact on the Family Parents perceive varying degrees of stress when they are informed that their infant has failed a newborn hearing screen. Although the screen result may be either a falsepositive or a true fail, most parents will have some increase in worry until their infant is rescreened. NICU infants have higher false-positive rates and higher fail rates than wellbaby nursery infants. In one study of well-baby nursery infants, parents reported increased “worry” at 2 to 8 weeks

1161

of age when they returned for the rescreen.78 Mothers who were more informed about hearing screening experienced decreased worry. Physicians who understand the screening process can support the family whose infant fails the screen, encourage the family to return for the rescreen, and follow up with the family about the rescreen results. A second study reported that mothers of infants with a false-positive screen did not report increased levels of stress or impact at 12 to 16 months or at 18 to 24 months.78 In addition, greater family resources were protective against persistent stress, whereas NICU stays contributed to prolonged stress.79 There is a continuum of stress for families whose infants are identified with HL that increases as they progress through the hearing screen fail, rescreen fail, diagnostic fail, and intervention process.80 Perception of stress at the time of diagnosis varies significantly among parents. Parents who are culturally deaf may have anticipated the diagnosis and be totally comfortable with it. Hearing parents of children diagnosed with an HL perceive greater stress, which is, in part, related to the fear of disability.79,81 About 95% of children with congenital HL are born to hearing parents. Prompt sharing of diagnostic test results with the family and physician and referral to early intervention services by the audiologist on the day of diagnosis may provide needed information and support to parents to mitigate stress. If the physicians become aware of financial difficulties experienced by the family, the case manager from Part C Early Intervention should be alerted to assist the family to identify resources such as a hearing aid loaner program, Social Security benefit, Katie Beckett Program, or eligibility for Medicaid. The physician may also facilitate referrals to parent support groups such as Hands and Voices and Family Voices. Because half of the children identified with congenital HL have been in a NICU and because about 40% of children with permanent HL have other disabilities, these children may require the resources of a number of different medical and educational disciplines, adding to both financial and emotional burdens.72,82,83 In summary, infants born in 2024 with congenital HL who have early identification, amplification, and intervention have enhanced opportunities for successful communication and academic achievement.

Key Points • Neonates requiring care in the neonatal intensive care unit are at increased risk of auditory neuropathy and should always be screened with automated auditory brainstem response. • Hearing loss (HL) is found in association with genetic mutations, over 400 congenital syndromes, and medical risk factors such as extreme prematurity and cytomegalovirus infection. • Undetected HL in infants and children negatively affects communication development, academic achievement, literacy, and social-emotional development.

• Early amplification and increased daily use of hearing aids are associated with improved speech and developmental outcomes. • Provision of early intervention services no later than 6 months of age is associated with improved speech and American Sign Language communication skills. • Newborn hearing screening does not identify all HL, and ongoing surveillance of hearing skills and language skills in the medical home to identify progressive and lateonset HL is indicated.

  

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References 1. NIH Consensus Statement. Early identification of hearing impairment in infants and young children. Medscape. 1993;11(1):1–24. 2. Watkin P, Baldwin M. The longitudinal follow up of a universal neonatal hearing screen: the implications for confirming deafness in childhood. Int J Audiol. 2012;51(7):519–528. 3. Yoshinaga-Itano C. Early intervention after universal neonatal hearing screening: impact on outcomes. Ment Retard Dev Disabil Res Rev. 2003;9(4):252–266. 4. Yoshinaga-Itano C, Coulter D, Thomson V. Developmental outcomes of children with hearing loss born in Colorado hospitals with and without universal newborn hearing screening programs. Semin Neonatol. 2001;6(6):521–529. 5. Nelson HD, Bougatsos C, Nygren P. Universal newborn hearing screening: systematic review to update the 2001 US Preventive Services Task Force Recommendation. Pediatrics. 2008;122(1):e266–e276 (Force USPST). 6. Tomblin JB, Harrison M, Ambrose SE, et al. Language outcomes in young children with mild to severe hearing loss. Ear Hear. 2015;36(suppl 1):76S–91S. 7. Vohr B, Jodoin-Krauzyk J, Tucker R, et al. Early language outcomes of early-identified infants with permanent hearing loss at 12 to 16 months of age. Pediatrics. 2008;122(3):535–544. 8. Vohr B, Jodoin-Krauzyk J, Tucker R, et al. Expressive vocabulary of children with hearing loss in the first 2 years of life: impact of early intervention. J Perinatol. 2011;31(4):274–280. 9. Vohr B, Topol D, Girard N, et al. Language outcomes and service provision of preschool children with congenital hearing loss. Early Hum Dev. 2012;88(7):493–498. 10. Cardon G, Campbell J, Sharma A. Plasticity in the developing auditory cortex: evidence from children with sensorineural hearing loss and auditory neuropathy spectrum disorder. J Am Acad Audiol. 2012;23(6):396–411; quiz 495. 11. Cardon G, Sharma A. Central auditory maturation and behavioral outcome in children with auditory neuropathy spectrum disorder who use cochlear implants. Int J Audiol. 2013;52(9):577–586. 12. Gilley PM, Sharma A, Mitchell TV, Dorman MF. The influence of a sensitive period for auditory-visual integration in children with cochlear implants. Restor Neurol Neurosci. 2010;28(2):207–218. 13. Yoshinaga-Itano C, Sedey AL, Mason CA, et al. Early intervention, parent talk, and pragmatic language in children with hearing loss. Pediatrics. 2020;146(suppl 3):S270–S277. 14. American Academy of Pediatrics, Joint Committee on Infant Hearing. Position statement: principles and guidelines for early hearing detection and intervention programs. Pediatrics. 2007;120(4):898–921. 15. Joint Committee on Infant Hearing. Year 2019 position statement: principles and guidelines for early hearing detection and intervention programs. J Early Hear Detect Interv. 2019;4(2):1– 44. 16. Yoshinaga-Itano C. Principles and guidelines for early intervention after confirmation that a child is deaf or hard of hearing. J Deaf Stud Deaf Educ. 2014;19(2):143–175. 17. Roush P, Frymark T, Venediktov R, Wang B. Audiologic management of auditory neuropathy spectrum disorder in children: a systematic review of the literature. Am J Audiol. 2011;20(2):159–170. 18. Starr A, Rance G. Auditory neuropathy. Handb Clin Neurol. 2015;129:495–508.

19. Wake M, Poulakis Z. Slight and mild hearing loss in primary school children. J Paediatr Child Health. 2004;40(1–2):11–13. 20. American Speech-Language-Hearing Association. Type, Degree, and Configuration of Hearing Loss; 2017. Accessed July 17, 2023. https://hearingspecialistsofmichigan.com/wp-content/ uploads/2014/09/AIS-Hearing-Loss-Types-Degree-Configuration.pdf 21. Norrix LW, Velenovsky DS. Auditory neuropathy spectrum disorder: a review. J Speech Lang Hear Res. 2014;57(4):1564–1576. 22. Watkin PM, Baldwin M. Identifying deafness in early childhood: requirements after the newborn hearing screen. Arch Dis Child. 2011;96(1):62–66. 23. American Academy of Pediatrics. Universal Newborn Hearing Screening, Diagnosis, and Intervention: Guidelines for Pediatric Medical home Providers. Elk Grove Village, IL: American Academy of Pediatrics; 2010. http://www.medicalhomeinfo.org/ downloads/pdfs/Algorithm1_2010.pdf 24. American Academy of Pediatrics. Guidelines for Rescreening in the Medical Home Following a “Do Not Pass” Newborn Hearing Screening. https://www.aap.org/en-us/advocacy-and-policy/aaphealth-initiatives/PEHDIC/Documents/NBHSRescreening1%2 00414.pdf 25. Harlor Jr AD, Bower C, Committee on Practice and Ambulatory Medicine, Section on Otolaryngology–Head and Neck Surgery. Hearing assessment in infants and children: recommendations beyond neonatal screening. Pediatrics. 2009;124(4): 1252–1263. 26. Ross DS, Visser SN. Pediatric primary care physicians’ practices regarding newborn hearing screening. J Prim Care Community Health. 2012;3(4):256–263. 27. Yoshinaga-Itano C. Levels of evidence: universal newborn hearing screening (UNHS) and early hearing detection and intervention systems (EHDI). J Commun Disord. 2004;37(5):451–465. 28. Joint Committee on Infant Hearing of the American Academy of Pediatrics, Muse C, Harrison J, et al. Supplement to the JCIH 2007 position statement: principles and guidelines for early intervention after confirmation that a child is deaf or hard of hearing. Pediatrics. 2013;131(4):e1324–e1349. 29. Alford RL, Arnos KS, Fox M, et  al. American College of Medical Genetics and Genomics guideline for the clinical evaluation and etiologic diagnosis of hearing loss. Genet Med. 2014;16(4):347–355. 30. Carey JC, Palumbos JC. Advances in the understanding of the genetic causes of hearing loss in children inform a rational approach to evaluation. Indian J Pediatr. 2016;83(10):1150–1156. 31. Nance WE, Kearsey MJ. Relevance of connexin deafness (DFNB1) to human evolution. Am J Hum Genet. 2004;74(6):1081–1087. 32. Smith EE, du Souich C, Dragojlovic N, et al. Genetic counseling considerations with rapid genome-wide sequencing in a neonatal intensive care unit. J Genet Couns. 2019;28(2):263–272. 33. Clark RH, Bloom BT, Spitzer AR, Gerstmann DR. Reported medication use in the neonatal intensive care unit: data from a large national data set. Pediatrics. 2006;117(6):1979–1987. 34. Ealy M, Lynch KA, Meyer NC, Smith RJ. The prevalence of mitochondrial mutations associated with aminoglycoside-induced sensorineural hearing loss in an NICU population. Laryngoscope. 2011;121(6):1184–1186. 35. Johnson RF, Cohen AP, Guo Y, et  al. Genetic mutations and aminoglycoside-induced ototoxicity in neonates. Otolaryngol Head Neck Surg. 2010;142(5):704–707.  

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CHAPTER 61  Hearing Loss in the Newborn Infant

36. Dedhia K, Kitsko D, Sabo D, Chi DH. Children with sensorineural hearing loss after passing the newborn hearing screen. JAMA Otolaryngol Head Neck Surg. 2013;139(2):119–123. 37. Fligor BJ, Neault MW, Mullen CH, et al. Factors associated with sensorineural hearing loss among survivors of extracorporeal membrane oxygenation therapy. Pediatrics. 2005;115(6):1519–1528. 38. Robertson CM, Howarth TM, Bork DL, Dinu IA. Permanent bilateral sensory and neural hearing loss of children after neonatal intensive care because of extreme prematurity: a thirty-year study. Pediatrics. 2009;123(5):e797–e807. 39. Wickremasinghe AC, Risley RJ, Kuzniewicz MW, et al. Risk of sensorineural hearing loss and bilirubin exchange transfusion thresholds. Pediatrics. 2015;136(3):505–512. 40. Dumanch KA, Holte L, O’Hollearn T, et  al. High risk factors associated with early childhood hearing loss: a 3-year review. Am J Audiol. 2017;26(2):129–142. 41. Boppana SB, Fowler KB, Pass RF, et al. Congenital cytomegalovirus infection: association between virus burden in infancy and hearing loss. J Pediatr. 2005;146(6):817–823. 42. Fowler KB, Boppana SB. Congenital cytomegalovirus (CMV) infection and hearing deficit. J Clin Virol. 2006;35(2):226–231. 43. Rawlinson WD, Palasanthiran P, Hall B, et  al. Neonates with congenital cytomegalovirus and hearing loss identified via the universal newborn hearing screening program. J Clin Virol. 2018;102:110–115. 44. Cannon MJ, Griffiths PD, Aston V, Rawlinson WD. Universal newborn screening for congenital CMV infection: what is the evidence of potential benefit? Rev Med Virol. 2014;24(5):291–307. 45. Kimberlin DW, Jester PM, Sanchez PJ, et al. Valganciclovir for symptomatic congenital cytomegalovirus disease. N Engl J Med. 2015;372(10):933–943. 46. de Fatima Vasco Aragao M, van der Linden V, Brainer-Lima AM, et al. Clinical features and neuroimaging (CT and MRI) findings in presumed Zika virus related congenital infection and microcephaly: retrospective case series study. BMJ. 2016;353:i1901. 47. Leal MC, Muniz LF, Ferreira TS, et al. Hearing loss in infants with microcephaly and evidence of congenital Zika virus infection - Brazil, November 2015-May 2016. MMWR Morb Mortal Wkly Rep. 2016;65(34):917–919. 48. Swibel Rosenthal LH, Caballero N, Drake AF. Otolaryngologic manifestations of craniofacial syndromes. Otolaryngol Clin North Am. 2012;45(3):557–577, vii. 49. Nance WE. The genetics of deafness. Ment Retard Dev Disabil Res Rev. 2003;9(2):109–119. 50. Adachi N, Ito K, Sakata H. Risk factors for hearing loss after pediatric meningitis in Japan. Ann Otol Rhinol Laryngol. 2010;119(5):294–296. 51. Cohen BE, Durstenfeld A, Roehm PC. Viral causes of hearing loss: a review for hearing health professionals. Trends Hear. 2014;18. 52. Biernath KR, Reefhuis J, Whitney CG, et al. Bacterial meningitis among children with cochlear implants beyond 24 months after implantation. Pediatrics. 2006;117(2):284–289. 53. Reefhuis J, Honein MA, Whitney CG, et  al. Risk of bacterial meningitis in children with cochlear implants. N Engl J Med. 2003;349(5):435–445. 54. Bergemalm PO. Progressive hearing loss after closed head injury: a predictable outcome? Acta Otolaryngol. 2003;123(7):836–845. 55. Lew HL, Lee EH, Miyoshi Y, et  al. Brainstem auditoryevoked potentials as an objective tool for evaluating hearing dysfunction in traumatic brain injury. Am J Phys Med Rehabil. 2004;83(3):210–215.

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56. Gruss I, Handzel O, Ingber S, Beiser M. [Hearing loss due to chemotherapy and radiation therapy in young children]. Harefuah. 2012;151(1):24–28. 62. 57. Santos RL, Aulchenko YS, Huygen PL, et  al. Hearing impairment in Dutch patients with connexin 26 (GJB2) and connexin 30 (GJB6) mutations. Int J Pediatr Otorhinolaryngol. 2005;69(2):165–174. 58. Seligman KL, Shearer AE, Frees K, et al. Genetic causes of hearing loss in a large cohort of cochlear implant recipients. Otolaryngol Head Neck Surg. 2021:1945998211021308. 59. Meinzen-Derr J, Sheldon RM, Henry S, et  al. Enhancing language in children who are deaf/hard-of-hearing using augmentative and alternative communication technology strategies. Int J Pediatr Otorhinolaryngol. 2019;125:23–31. 60. Rosenfeld RM, Schwartz SR, Pynnonen MA, et  al. Clinical practice guideline: tympanostomy tubes in children. Otolaryngol Head Neck Surg. 2013;149(suppl 1):S1–S35. 61. Engel-Yeger B, Golz A, Parush S. Impact of middle ear effusion on balance performance in children. Disabil Rehabil. 2004;26(2):97–102. 62. Sokolov M, Gordon KA, Polonenko M, et al. Vestibular and balance function is often impaired in children with profound unilateral sensorineural hearing loss. Hear Res. 2019;372:52–61. 63. National Institute on Deafness and Other Communication Disorders. Cochlear Implants. Accessed July 17, 2023. http://www. nidcd.nih.gov/health/hearing/pages/coch.aspx 64. Warner-Czyz AD, Roland Jr JT, Thomas D, Uhler K, Zombek L. American Cochlear Implant Alliance Task Force guidelines for determining cochlear implant candidacy in children. Ear Hear. 2022;43(2):268–282. 65. Gagnon EB, Eskridge H, Brown KD, Park LR. The impact of cumulative cochlear implant wear time on spoken language outcomes at age 3 Years. J Speech Lang Hear Res. 2021;64(4):1369–1375. 66. Leigh J, Dettman S, Dowell R, Briggs R. Communication development in children who receive a cochlear implant by 12 months of age. Otol Neurotol. 2013;34(3):443–450. 67. Mitchell RM, Christianson E, Ramirez R, et al. Auditory comprehension outcomes in children who receive a cochlear implant before 12 months of age. Laryngoscope. 2020;130(3):776–781. 68. Miyamoto RT, Hay-McCutcheon MJ, Kirk KI, et al. Language skills of profoundly deaf children who received cochlear implants under 12 months of age: a preliminary study. Acta Otolaryngol. 2008;128(4):373–377. 69. Yoshinaga-Itano C, Baca RL, Sedey AL. Describing the trajectory of language development in the presence of severe-to-profound hearing loss: a closer look at children with cochlear implants versus hearing aids. Otol Neurotol. 2010;31(8):1268–1274. 70. Moon PK, Qian ZJ, Ahmad IN, et  al. Infectious complications following cochlear implant: risk factors, natural history, and management patterns. Otolaryngol Head Neck Surg. 2022:1945998221082530. 71. Deleted in review. 72.  Committee on Practice and Ambulatory MedicineBright Futures Periodicity Schedule Workgroup. 2021 recommendations for preventive pediatric health care. Pediatrics. 2021;147(3):e2020049776. https://doi.org/10.1542/peds.2020049776. PMID: 33593848. 73. Coplan J. Early Language Milestone Scale. 2nd ed. Austin, TX: Pro-ed; 1993. 74. Fenson L, Dale PS, Resnick JS, et al. The MacArthur Communicative Development Inventories: User’s Guide and Technical Manual. San Diego, CA: Singular Publishing; 1993.

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75. Rescoria L. The language development survey: a screening tool for delayed language in toddlers. J Speech Hear Disord. 1989;54:587–599. 76. Bricker D, Squires J. Ages and Stages Questionnaires: A ParentCompleted, Child-Monitoring System. Baltimore, MD: Paul H. Brookes Publishing Co; 1999. 77. Cunningham M, Cox EO. Committee on Practice and Ambulatory Medicine and the Section on Otolaryngology and Bronchoesophagology. Hearing assessment in infants and children: recommendations beyond neonatal screening. Pediatrics. 2003;111(2):436–440. 78. Vohr BR, Letourneau KS, McDermott C. Maternal worry about neonatal hearing screening. J Perinatol. 2001;21(1):15–20. 79. Vohr BR, Jodoin-Krauzyk J, Tucker R, et al. Results of newborn screening for hearing loss: effects on the family in the first

2 years of life. Arch Pediatr Adolesc Med. 2008;162(3):205– 211. 80. Stuart A, Moretz M, Yang EYK. An investigation of maternal stress after neonatal hearing screening. Am J Audiol. 2000;9:135–141. 81. Quittner AL, Barker DH, Cruz I, et  al. Parenting stress among parents of deaf and hearing children: associations with language delays and behavior problems. Parent Sci Pract. 2010;10(2):136–155. 82. Mitchell RE. National profile of deaf and hard of hearing students in special education from weighted survey results. Am Ann Deaf. 2004;149(4):336–349. 83. Mohr PE, Feldman JJ, Dunbar JL. The societal costs of severe to profound hearing loss in the United States. Policy Anal Brief H Ser. 2000;2(1):1–4.

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62

Early Childhood Neurodevelopmental Outcomes of High-Risk Neonates

DEANNE E. WILSON-COSTELLO AND ALLISON H. PAYNE

dependence on gastrostomy feeds, necessitating multiple special outpatient services for more than half of the surviving infants.4 Infants at highest risk for later neurodevelopmental problems resulting from perinatal sequelae include those who had severe asphyxia, severe intracranial hemorrhage, infarction or periventricular leukomalacia, meningitis, seizures, respiratory failure resulting from pneumonia, persistent fetal circulation, bronchopulmonary dysplasia (BPD), and multisystem congenital malformations, as well as children born with extremely low birth weight or at extremely early gestational age (Boxes 62.1 and 62.2). The rates of health problems and neurodevelopmental sequelae are inversely proportional to both birth weight and gestational age, with children born at less than 27 weeks’ gestation experiencing the greatest risk of moderate to severe impairments (Fig. 62.1 and Table 62.1). • BOX 62.1 Factors Affecting Outcome of the

A

dvances in obstetric and neonatal care, which have been responsible for the improved survival of highrisk neonates, have not resulted in decreased morbidity. Because perinatal interventions can alter later growth and development, long-term follow-up is essential to ensure that therapies such as oxygen administration and postnatal steroids, which demonstrate dramatic and immediate positive effects, are not associated with adverse long-term outcomes. The earliest follow-up studies of preterm infants after the introduction of modern methods of neonatal intensive care in the 1960s described a decrease in adverse neurodevelopmental sequelae compared with that of the preceding era. During the 1980s and 1990s, there was a continued decrease in mortality, and thus the absolute number of both healthy and neurologically impaired survivors increased.1 Furthermore, the survival of increasing numbers of extremely immature infants with low birth weight resulted in a relatively high disability rate in the subpopulation of infants born weighing less than 750 g or born at less than 26 weeks’ gestation.2 Since 2000, mortality rates for infants above 25 weeks’ gestation have leveled off, but there continues to be increasing survival rates for those born at 23 to 24 weeks’ gestation, which have now reached 49% and 70%, respectively.3 As the survivors of neonatal intensive care have reached young adulthood, myriad more subtle neurodevelopmental issues, such as visuomotor problems, learning disabilities, autism, or developmental coordination disability, have flooded the literature and demonstrated the need for assessments of functional outcomes. Additionally, the survival of increasingly immature infants along with improvements in managed care systems have resulted in early discharge of infants with unresolved medical or surgical issues such as oxygen dependence, need for assisted ventilation, maintenance of external medical devices, or

Infant With Very Low Birth Weight

• B  irth weight less than 750 g or less than 25 weeks’ gestation • Periventricular hemorrhage (grades III and IV) or infarction • Periventricular leukomalacia • Persistent ventricular dilation • Neonatal seizures • Chronic lung disease • Neonatal meningitis • Subnormal head circumference at discharge • Parental drug abuse • Poverty and parental deprivation • Coexisting congenital malformation • Adverse childhood experiences (ACEs)

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1166 PA RT 1 0    The Central Nervous System

Although most survivors of prematurity are not significantly impaired, there are a variety of medical and neurodevelopmental sequelae that necessitate scrutiny. Therefore follow-up programs should be an integral extension of every neonatal intensive care unit (NICU). The goals of effective follow-up programs include early identification of neurosensory or developmental disability, parental counseling, identification and treatment of medical complications, identification of risk factors for impairment, evaluation of the impact of therapeutic interventions, and provision of feedback for perinatal and pediatric caregivers. In particular, specialized follow-up care must consider problems of growth, development, behavior, and chronic disease. If

possible, follow-up care should initially involve the coordinated and complementary effort of the neonatologist and the primary care pediatrician in conjunction with physical and occupational therapy, nutritional therapy, and social work. If there are concerns for developmental or neurologic problems, the child should also be referred to a subspecialist or a child development center. Recently, comprehensive NICU follow-up programs, working in tandem with community early intervention services, have enhanced medical and developmental evaluations and support programs for NICU graduates with complex needs. The initial continuity of care by the neonatologist is important to reassure the family that the same personnel

• BOX 62.2 Factors Affecting Outcome of the Term

TABLE   Health Outcomes by Birth Weight at 8 62.1  Years



Infant

• • • •

Birth Weight (kg)

 irth depression or asphyxia B Persistent pulmonary hypertension Meningitis Intrauterine growth failure Intrauterine infection Symmetric growth restriction (microcephaly) Major congenital malformations Neonatal seizures Extracorporeal membrane oxygenation (ECMO) and nitric oxide therapy Persistent hypoglycemia Severe hyperbilirubinemia Parental substance abuse Adverse childhood experiences (ACEs)

1 activities of daily living because of health (%)

46

34

27

17

Data from Hack M, et al. Long-term developmental outcomes of low birth weight infants. Future Child. 1995;5:176–196.

40 35 30 Percentage of children

• • • • • • • • •

25 20 15 10 5 0

Any moderate/severe Moderate/severe deficiency cognitive deficit

Moderate/severe cerebral palsy