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FANAROFF & MARTIN’S NEONATAL-PERINATAL MEDICINE  ISBN: 978-1-4557-5617-9

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Library of Congress Cataloging-in-Publication Data

Fanaroff and Martin’s neonatal-perinatal medicine : diseases of the fetus and infant / [edited by]
Richard J. Martin, Avroy A. Fanaroff, Michele C. Walsh.—10th edition.
   p. ; cm.
Neonatal-perinatal medicine
Includes bibliographical references and index.
ISBN 978-1-4557-5617-9 (2 v. set : hardcover : alk. paper)
I. Martin, Richard J. (Richard John), 1946-, editor. II. Fanaroff, Avroy A., editor. III. Walsh,
Michele C., editor. IV. Title: Neonatal-perinatal medicine.
[DNLM: 1. Fetal Diseases. 2. Infant, Newborn, Diseases. 3. Perinatal Care. 4. Pregnancy
Complications. WS 420]
RJ254
618.92’01–dc23
2014023366

Senior Content Strategist: Kate Dimock

Content Development Specialist: Kelly McGowan
Publishing Services Manager: Jeff Patterson
Senior Project Manager: Clay S. Broeker
Design Direction: Ellen Zanolle

Printed in China

Last digit is the print number: 9 8 7 6 5 4 3 2 1

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, and Mason Fanaroff;
Jodi, Peter, Austin, and Morgan Tucker;
and Amanda, Jason, Jackson, and Raya Hirsh

to the Walsh children

Sean and Ryan

with love, admiration, and deep appreciation

for their continued support and inspiration
 Contributors

Steven A. Abrams, MD A. Rebecca Ballard, MD

Professor, Pediatrics, Baylor College of Medicine, Assistant Clinical Professor, Pediatrics, Texas A&M
Houston, Texas Health Science Center, College of Medicine, McLane
Disorders of Calcium, Phosphorus, and Magnesium Children’s Hospital, Baylor Scott and White Health,
Metabolism in the Neonate Temple, Texas
Normal Mother-Infant Attachment; Attachment
Johan Agren, MD, PhD Challenges with Premature or Sick Infants
Faculty Member, Department of Women’s and
Children’s Health, Uppsala University; Attending Eduardo H. Bancalari, MD
Neonatologist, Division of Neonatology, University Professor, Pediatrics, Director, Division of Neonatology,
Children’s Hospital, Uppsala, Sweden University of Miami Miller School of Medicine;
The Thermal Environment of the Intensive Care Nursery Chief, Newborn Services, Holtz Children’s Hospital at
University of Miami/Jackson Memorial Medical
Sareea Al Remeithi, MBBS Center, Miami, Florida
Pediatric Endocrinologist, Department of Pediatrics, Bronchopulmonary Dysplasia in the Neonate
Sheikh Khalifa Medical City, Abu Dhabi, United Arab
Emirates Manish Bansal, MD
Disorders of Sex Development Assistant Professor of Pediatrics, Pediatric Cardiology,
Texas Children’s Hospital, Baylor College of
James E. Arnold, MD Medicine, Houston, Texas
The Julius W. McCall Professor, Program Director, Cardiovascular Problems of the Neonate
Otolaryngology and Head and Neck Surgery, Pediatric
Otolaryngology, Rainbow Babies and Children’s Nancy Bass, MD
Hospital, University Hospitals Case Medical Center; Associate Professor, Pediatrics and Neurology, Case
Professor, Otolaryngology, Case Western Reserve Western Reserve University, Rainbow Babies and
University School of Medicine, Cleveland, Ohio Children’s Hospital, Cleveland, Ohio
Upper Airway Lesions in the Neonate Hypotonia and Neuromuscular Disease in the Neonate

Ravi Ashwath, MD, FAAP Cynthia F. Bearer, MD, PhD

Assistant Professor of Pediatrics, Pediatric Cardiology, Mary Gray Cobey Endowed Professor of Neonatology,
Case Western Reserve University, Rainbow Babies and Associate Chair of Research, Chief, Division of
Children’s Hospital, Cleveland, Ohio Neonatology, Pediatrics, University of Maryland
Congenital Defects of the Cardiovascular System School of Medicine, Baltimore, Maryland
Adverse Exposures to the Fetus
Komal Bajaj, MD, FACOG
Reproductive Geneticist, North Bronx Healthcare William E. Benitz, MD
Network; Assistant Professor, Albert Einstein College Philip Sunshine Professor in Neonatology, Chief,
of Medicine, New York, New York Division of Neonatal and Developmental Medicine,
Genetic Aspects of Perinatal Disease and Prenatal Department of Pediatrics, Stanford University School
Diagnosis of Medicine, Stanford, California; Chief, Neonatology
Service, Lucile Packard Children’s Hospital, Palo Alto,
Jill E. Baley, MD California
Medical Director, Rainbow 4, University Hospitals Patent Ductus Arteriosus
Rainbow Babies and Children’s Hospital; Professor,
Pediatrics, Associate Professor, Obstetrics and John T. Benjamin, MD
Gynecology, Case Western Reserve University School Assistant Professor, Pediatrics, Division of Neonatology,
of Medicine, Cleveland, Ohio Vanderbilt University, Nashville, Tennessee
Perinatal Viral Infections; Schedule for Immunization of Developmental Immunology
Preterm Infants

v
 vi CONTRIBUTORS

Isaac Blickstein, MD Moira A. Crowley, MD

Professor, Obstetrics and Gynecology, Kaplan Medical Assistant Professor, Pediatrics, Case Western Reserve
Center, Rehovot, Israel; The Hadassah-Hebrew University School of Medicine; Co-Director, Neonatal
University School of Medicine, Jerusalem, Israel ECMO Program, Division of Neonatology, Rainbow
Diabetes Mellitus During Pregnancy; Fetal Effects of Babies and Children’s Hospital, Cleveland, Ohio
Autoimmune Disease; Obstetric Management of Multiple Neonatal Respiratory Disorders; Therapy for
Gestation and Birth; Post-Term Pregnancy Cardiorespiratory Failure in the Neonate

Kara L. Calkins, MD Joshua D. Dahlke, MD

Assistant Professor of Pediatrics, Pediatrics, Fellow, Maternal Fetal Medicine, Women and Infants
Neonatology, and Developmental Biology, David Hospital of Rhode Island, Warren Alpert Medical
Geffen School of Medicine at University of School of Brown University, Providence, Rhode Island
California—Los Angeles; Physician, Pediatrics, Mattel Immune and Nonimmune Hydrops Fetalis
Children’s Hospital, University of California—Los
Angeles, Los Angeles, California Peter Davis, MBBS, MD
Intrauterine Growth Restriction; Developmental Origins of Professor, Neonatology, University of Melbourne, Royal
Adult Health and Disease Women’s Hospital, Melbourne, Victoria, Australia
Role of Positive Pressure Ventilation in Neonatal
Bryan Cannon, MD Resuscitation
Associate Professor, Pediatrics, Pediatric Cardiology
Fellowship Program Director, Departments of Linda S. de Vries, MD, PhD
Cardiovascular Diseases, Children’s Center, and Professor, Neonatal Neonatology, Department of
Pediatric and Adolescent Medicine, Mayo Clinic, Neonatology, University Medical Center Utrecht,
Rochester, Minnesota Wilhelmina Children’s Hospital, Utrecht, The
Disorders of Cardiac Rhythm and Conduction in Netherlands
Newborns Intracranial Hemorrhage and Vascular Lesions in the
Neonate; Hypoxic-Ischemic Encephalopathy
Michael Caplan, MD
Chairman, Department of Pediatrics, NorthShore Katherine MacRae Dell, MD
University HealthSystem, Evanston, Illinois; Clinical Associate Professor, Pediatrics, Case Western Reserve
Professor, Pediatrics, University of Chicago, Pritzker University; Director, Clinical and Translational
School of Medicine, Chicago, Illinois Research, Pediatric Institute, Cleveland Clinic
Neonatal Necrotizing Enterocolitis Foundation, Cleveland, Ohio
Fluids, Electrolytes, and Acid-Base Homeostasis; The
Waldemar A. Carlo, MD Kidney and Urinary Tract of the Neonate
Edwin M. Dixon Professor of Pediatrics, University of
Alabama at Birmingham; Physician, Neonatology, Sherin U. Devaskar, MD
University of Alabama Hospital, Children’s of Distinguished Professor of Pediatrics, Pediatrics,
Alabama Hospital, Birmingham, Alabama Neonatology, and Developmental Biology, David
Assessment of Neonatal Pulmonary Function Geffen School of Medicine at University of
California—Los Angeles; Physician, Pediatrics, Mattel
Gisela Chemlinsky, MD Children’s Hospital, University of California—Los
Professor, Pediatrics, Medical College of Wisconsin, Angeles, Los Angeles, California
Milwaukee, Wisconsin Intrauterine Growth Restriction; Developmental Origins of
Disorders of Digestion in the Neonate Adult Health and Disease; Disorders of Carbohydrate
Metabolism in the Neonate
Janet Chuang, MD
Pediatric Endocrinologist, Nationwide Children’s Juliann M. Di Fiore, BSEE
Hospital, Columbus, Ohio Research Engineer, Department of Medicine, Case
Thyroid Disorders in the Neonate Western Reserve University; Research Engineer,
Division of Neonatology, Rainbow Babies and
Alan R. Cohen, MD, FACS, FAAP Children’s Hospital, Cleveland, Ohio
Neurosurgeon-in-Chief, Chairman, Department of Biomedical Engineering Aspects of Neonatal
Neurosurgery, Boston Children’s Hospital; Franc D. Cardiorespiratory Monitoring; Assessment of Neonatal
Ingraham Professor of Neurosurgery, Harvard Medical Pulmonary Function
School, Boston, Massachusetts
Disorders in Head Shape and Size; Myelomeningocele
and Related Neural Tube Defects
 CONTRIBUTORS vii

Yaser Diab, MBBS Ross M. Fasano, MD

Director, Thrombosis Program, Children’s National Director, Chronic Transfusion Program, Hematology,
Medical Center; Assistant Professor, Pediatrics, George Children’s National Medical Center, Washington, DC
Washington University School of Medicine and Blood Component Therapy for the Neonate
Health Sciences, Washington, DC
Hematologic and Oncologic Problems in the Fetus and Smadar Friedman, MD, PhD
Neonate Senior Lecturer in Pediatrics, The Hebrew University
School of Medicine; Director, Neonatology Unit,
Katherine Dobbs, MD Hadassah University Medical Center, Jerusalem, Israel
Fellow, Pediatric Infectious Diseases and Rheumatology, Fetal Effects of Autoimmune Disease
Case Western Reserve University School of Medicine,
Cleveland, Ohio Meena Garg, MD
Postnatal Bacterial Infections Professor of Pediatrics, Pediatrics, Neonatology, and
Developmental Biology, David Geffen School of
Steven M. Donn, MD Medicine at University of California—Los Angeles;
Professor, Pediatrics, Division of Neonatal-Perinatal Physician, Pediatrics, Mattel Children’s Hospital,
Medicine, C. S. Mott Children’s Hospital, University University of California—Los Angeles, Los Angeles,
of Michigan Health System, Ann Arbor, Michigan California
Assisted Ventilation and Its Complications Disorders of Carbohydrate Metabolism in the Neonate

Elizabeth A. Dubil, MD Allison Gilmore, MD

LT MC USN Fellow, National Capital Consortium Assistant Professor, Pediatric Orthopaedics, Division of
Fellowship in Gynecologic Oncology, Walter Reed Pediatric Orthopaedics, Case Medical Center,
National Military Medical Center, Washington, Rainbow Babies and Children’s Hospital, Cleveland,
District of Columbia Ohio
Amniotic Fluid Volume Bone and Joint Infections in Neonates

Richard A. Ehrenkranz, MD Jay P. Goldsmith, MD

Professor, Pediatrics and Obstetrics, Gynecology and Elsie Schaefer Professor, Pediatrics, Chief, Section of
Reproductive Sciences, Interim Chief, Neonatal- Neonatology, Tulane University, New Orleans,
Perinatal Medicine, Section of Neonatal-Perinatal Louisiana
Medicine, Department of Pediatrics, Yale School of Overview and Initial Management of Delivery Room
Medicine; Interim Director, Neonatal Intensive Care Resuscitation; Chest Compression, Medications, and Special
Unit, Yale–New Haven Children’s Hospital, New Problems in Neonatal Resuscitation
Haven, Connecticut
Nutrient Requirements and Provision of Nutritional Blanca E. Gonzalez, MD
Support in the Premature Neonate Assistant Professor, Pediatrics, Center for Pediatric
Infectious Diseases, Cleveland Clinic Lerner College
Alison J. Falck, MD of Medicine, Case Western Reserve University,
Assistant Professor, Pediatrics, Division of Neonatology, Cleveland Clinic Children’s, Cleveland, Ohio
University of Maryland School of Medicine, Perinatal Viral Infections
Baltimore, Maryland
Adverse Exposures to the Fetus Jeffrey B. Gould, MD, MPH
Robert L. Hess Professor in Pediatrics, Director,
Avroy A. Fanaroff, MD, FRCPE, FRCPCH Perinatal Epidemiology and Health Outcomes
Emeritus Professor, Pediatrics and Reproductive Biology, Research Unit, Division of Neonatal and
Case Western Reserve University School of Medicine; Developmental Medicine, Stanford University School
Emeritus Eliza Henry Barnes Chair in Neonatology, of Medicine; Director, California Perinatal Quality
Rainbow Babies and Children’s Hospital, Cleveland, Care Collaborative, Stanford, California
Ohio Evaluating and Improving the Quality and Safety of
Epidemiology for Neonatologists; The Organization of Neonatal Intensive Care
Perinatal Services; Obstetric Management of Prematurity
Pierre Gressens, MD, PhD
Jonathan M. Fanaroff, MD, JD Professor of Foetal and Neonatal Neurology, Centre for
Associate Professor, Pediatrics, Case Western Reserve the Developing Brain and Department of Biomedical
University School of Medicine; Director, Rainbow Engineering, Division of Imaging Sciences, King’s
Center for Pediatric Ethics; Co-Director, Neonatal College London, The Rayne Institute, St Thomas’
Intensive Care Unit, Rainbow Babies and Children’s Hospital, London, United Kingdom; Director,
Hospital, Cleveland, Ohio Inserm–Université Paris Diderot, Département
Medical Ethics in Neonatal Care; Legal Issues in Hospitalo–Universitaire PROTECT, Hôpital Robert
Neonatal-Perinatal Medicine Debré, Paris, France
Normal and Abnormal Brain Development; White Matter
Damage and Encephalopathy of Prematurity
 viii CONTRIBUTORS

Florin Grigorian, MD Susan Hatters Friedman, MD, BA

Assistant Professor, Pediatric Ophthalmology, Case Associate Professor, Psychiatry and Pediatrics, Case
Western Reserve University, University Hospitals Case Western Reserve University School of Medicine,
Medical Center, Cleveland, Ohio Cleveland, Ohio; Associate Professor of Psychological
Examination and Common Problems of the Neonatal Eye Medicine, University of Auckland, Auckland,
New Zealand
Floris Groenendaal, MD, PhD Parental Mental Health Issues
Associate Professor of Neonatology, Department of
Neonatology, Wilhelmina Children’s Hospital, Yenon Hazan, MD
University Medical Center Utrecht, Utrecht, The Department of Obstetrics and Gynecology, Kaplan
Netherlands Medical Center, Rehovot, Israel
Hypoxic-Ischemic Encephalopathy Diabetes Mellitus During Pregnancy

Susan J. Gross, MD Anne Hellström, MD, PhD

Professor, Clinical Obstetrics and Gynecology and Professor, Pediatric Ophthalmology, Institute of
Women’s Health, Pediatrics, and Clinical Genetics, Neuroscience and Rehabilitation, Sahlgrenska
Chair, Department of Obstetrics and Gynecology and Academy, Gothenburg University, Gothenburg,
Women’s Health, North Bronx Healthcare Network, Sweden
Albert Einstein School of Medicine, Yeshiva Retinopathy of Prematurity
University, Bronx, New York
Genetic Aspects of Perinatal Disease and Prenatal Anna Maria Hibbs, MD, MSCE
Diagnosis Associate Professor, Pediatrics, Case Western Reserve
University; Attending Neonatologist, Rainbow Babies
Bhaskar Gurram, MD and Children’s Hospital, Cleveland, Ohio
Assistant Professor, Medical College of Wisconsin; Gastroesophageal Reflux and and Gastroesophageal Reflux
Pediatric Gastroenterologist, Children’s Hospital of Disease in the Neonate
Wisconsin, Milwaukee, Wisconsin
Disorders of Digestion in the Neonate James Adam Hill, MD, FAAP, FACC
Interventional Pediatric/Congenital Cardiologist,
Iris Gutmark-Little, MD Division of Pediatric Cardiology, Rainbow Babies and
Assistant Professor, Pediatric Endocrinology, Cincinnati Children’s Hospital, University Hospitals Case
Children’s Hospital Medical Center, Cincinnati, Ohio Medical Center; Assistant Professor, Pediatrics, Case
Thyroid Disorders in the Neonate Western Reserve University School of Medicine,
Cleveland, Ohio
David N. Hackney, MD, MS Principles of Medical and Surgical Management of the
Assistant Professor, Obstetrics and Gynecology, Neonate
University Hospitals Case Medical Center, Cleveland,
Ohio Susan R. Hintz, MD, MS Epi
Estimation of Fetal Well-Being Professor, Pediatrics, Division of Neonatal and
Developmental Medicine, Stanford University School
Louis P. Halamek, MD of Medicine; Medical Director, Center for Fetal and
Professor and Associate Chief, Education and Training, Maternal Health, Lucile Packard Children’s Hospital,
Division of Neonatal and Developmental Medicine, Palo Alto, California
Department of Pediatrics, Stanford University; Role of Imaging in Neurodevelopmental Outcomes of
Director, Center for Advanced Pediatric and Perinatal High-Risk Neonates
Education; Attending Neonatologist, Lucile Packard
Children’s Hospital at Stanford, Palo Alto, California Shinjiro Hirose, MD
Simulation in Neonatal-Perinatal Medicine Associate Professor of Clinical Surgery, Division of
Pediatric Surgery, Fetal Treatment Center, University
Aaron Hamvas, MD of California—San Francisco School of Medicine,
Raymond and Hazel Speck Barry Professor of San Francisco, California
Neonatology and Head, Division of Neonatology, Surgical Treatment of the Fetus
Ann and Robert H. Lurie Children’s Hospital of
Chicago, Northwestern University Feinberg School of Steven B. Hoath, MD
Medicine, Chicago, Illinois Professor Emeritus, Department of Pediatrics
Respiratory Distress Syndrome in the Neonate (Neonatology), University of Cincinnati; Attending
Neonatologist, Cincinnati Children’s Hospital
Medical Center, Cincinnati, Ohio
The Skin of the Neonate
 CONTRIBUTORS ix

Jeffrey D. Horbar, AB, MD Suhas G. Kallapur, MD

Jerold F. Lucey Professor of Neonatal Medicine, Professor, Pediatrics and Neonatology, University of
Pediatrics, University of Vermont; Chief Executive and Cincinnati, Cincinnati Children’s Hospital,
Scientific Officer, Vermont Oxford Network, Cincinnati, Ohio
Burlington, Vermont Lung Development and Maturation
Evaluating and Improving the Quality and Safety of
Neonatal Intensive Care Michael Kaplan, MB ChB
Emeritus Director of Neonatology, Shaare Zedek
McCallum R. Hoyt, MD, MBA Medical Center; Professor of Pediatrics, Faculty of
Director of Anesthesia, Hillcrest Hospital; Director of Medicine, Hebrew University, Jerusalem, Israel.
Obstetrical Anesthesia, Anesthesiology Institute, Neonatal Jaundice and Liver Diseases
Cleveland Clinic Foundation, Cleveland, Ohio
Anesthesia for Labor and Delivery David A. Kaufman, MD
Professor, Pediatrics, Division of Neonatology,
Mark L. Hudak, MD Department of Pediatrics, University of Virginia
Professor and Chairman, Pediatrics, University of Medical School; Physician, Neonatal Medicine,
Florida College of Medicine—Jacksonville, University of Virginia Children’s Hospital,
Jacksonville, Florida Charlottesville, Virginia
Infants with Antenatal Exposure to Drugs Perinatal Fungal and Protozoal Infections

Petra S. Hüppi, MD Kathleen A. Kennedy, MD, MPH

Professor, Pediatrics and Newborn Medicine, Division Professor, Pediatrics, Division of Neonatal-Perinatal
of Development and Growth, University of Geneva, Medicine, University of Texas Medical School at
Children’s Hospital, Geneva, Switzerland Houston, Houston, Texas
Normal and Abnormal Brain Development; White Matter Practicing Evidence-Based Neonatal-Perinatal Medicine
Damage and Encephalopathy of Prematurity
Peter C. Kouretas, MD, PhD
Corey W. Iqbal, MD, FAAP Associate Professor, Surgery and Pediatrics, Case
Chief, Section of Fetal Surgery, Children’s Mercy Western Reserve University; Chief, Division of
Hospital Fetal Health Center; Assistant Professor of Pediatric Cardiothoracic Surgery, Rainbow Babies and
Surgery, University of Missouri—Kansas City School Children’s Hospital, Cleveland, Ohio
of Medicine, Kansas City, Missouri Principles of Medical and Surgical Management of the
Surgical Treatment of the Fetus Neonate

Lucky Jain, MD, MBA Oleg Kovalenko, MD

Richard W. Blumberg Professor and Executive Vice Assistant Professor of Pediatrics, Pediatric Cardiology,
Chairman, Department of Pediatrics, Emory Director, Pediatric Electrophysiology, Women and
University; Executive Medical Director, Children’s Children’s Hospital of Buffalo, State University of
Healthcare of Atlanta Faculty Practices, Atlanta, New York at Buffalo, Buffalo, New York
Georgia Disorders of Cardiac Rhythm and Conduction in
The Late Preterm Infant Newborns

Arun Jeyabalan, MD, MS Catherine Larson-Nath, MD

Associate Professor, Maternal-Fetal Medicine, Instructor of Pediatrics, Pediatric Gastroenterology,
Department of Obstetrics, Gynecology, and Medical College of Wisconsin, Milwaukee, Wisconsin
Reproductive Sciences, University of Pittsburgh Disorders of Digestion in the Neonate
School of Medicine, Pittsburgh, Pennsylvania
Hypertensive Disorders of Pregnancy Noam Lazebnik, MD
Professor, OBGYN and Radiology, Associate Professor,
Alan H. Jobe, MD, PhD Genetics, Case Western Reserve University School of
Professor of Pediatrics, Pulmonary Biology and Medicine; Senior Physician, Obstetrics, Gynecology,
Neonatology, Cincinnati Children’s Hospital Medical and Maternal Fetal Medicine, University Hospitals
Center, Cincinnati, Ohio Case Medical Center, Cleveland, Ohio
Lung Development and Maturation Perinatal Imaging

Nancy E. Judge, MD
Associate Professor, Obstetrics, Gynecology, and
Women’s Health, Albert Einstein College of Medicine,
Yeshiva University, New York, New York
Perinatal Imaging
 x CONTRIBUTORS

Hanmin Lee, MD Naomi L. C. Luban, MD, FAAP

Michael R. Harrison Endowed Chair and Professor, Professor, Pediatrics and Pathology, Division of
Surgery, Pediatrics, Ob-Gyn and Reproductive Health Laboratory Medicine, Department of Pediatrics,
Services, Chief, Division of Pediatric Surgery, Director, George Washington University School of Medicine
Fetal Treatment Center, Surgeon-in-Chief, University and Health Sciences; Attending Hematologist,
of California—San Francisco Benioff Children’s Director of Transfusion Medicine, Chair of IRB,
Hospital; Vice-Chair, Department of Surgery, Children’s National Medical Center, Washington, DC
University of California—San Francisco School of Blood Component Therapy for the Neonate
Medicine, San Francisco, California
Surgical Treatment of the Fetus Lori Luchtman-Jones, MD
Hematologist, Center for Cancer and Blood Disorders,
Henry C. Lee, MD Children’s National Medical Center; Associate
Assistant Professor, Pediatrics, Division of Neonatal and Professor, Pediatrics, George Washington University
Developmental Medicine, Stanford University School Medical School, Washington, DC
of Medicine, Lucile Packard Children’s Hospital at Hematologic and Oncologic Problems in the Fetus and
Stanford; Director of Research, California Perinatal Neonate
Quality Care Collaborative, Stanford, California
Evaluating and Improving the Quality and Safety of Everett F. Magann, MD
Neonatal Intensive Care Professor, Obstetrics and Gynecology, University of
Arkansas for the Medical Sciences, Little Rock,
Liisa Lehtonen, MD, PhD Arkansas
Professor, Pediatrics, Turku University; Head, Division Immune and Nonimmume Hydrops Fetalis; Amniotic
of Neonatology, Department of Pediatrics, Turku Fluid Volume
University Hospital, Turku, Finland
Assessment and Optimization of Neurobehavioral Akhil Maheshwari, MD
Development in Preterm Infants Professor, Pediatrics and Molecular Medicine, Pamela
and Leslie Muma Chair in Neonatology, Chief,
Ethan G. Leonard, MD Division of Neonatology, Assistant Dean, Graduate
Associate Professor, Pediatrics, Pediatric Infectious Medical Education, University of South Florida
Diseases and Rheumatology, Case Western Reserve Health Morsani College of Medicine, Tampa, Florida
University School of Medicine; Chief Medical Officer Developmental Immunology
and Vice Chair for Quality, University Hospitals
Rainbow Babies and Children’s Hospital, Cleveland, Henry H. Mangurten, MD
Ohio Professor, Pediatrics, Rosalind Franklin University of
Postnatal Bacterial Infections Medicine and Science, The Chicago Medical School,
North Chicago, Illinois; Chairman Emeritus,
Tom Lissauer, MB, BChir, FRCPCH Pediatrics, Director, Pediatric Palliative Care,
Honorary Consultant Neonatologist, Imperial College Pediatrics, Advocate Children’s Hospital, Park Ridge,
Healthcare Trust; Consultant Paediatric Programme Illinois; Medical Director, Pediatrics, Journey Care for
Director in Global Health, Imperial College London, Children, Barrington, Illinois
London, Great Britain Birth Injuries
Physical Examination of the Newborn
Paolo Manzoni, MD
Raymond W. Liu, MD Associate Professor of Pediatrics and Neonatology,
Assistant Professor, Pediatric Orthopaedic Surgery, Case Neonatology and NICU, S. Anna Hospital, Torino,
Western Reserve University School of Medicine, Italy
Rainbow Babies and Children’s Hospitals, Cleveland, Perinatal Fungal and Protozoal Infections
Ohio
Musculoskeletal Disorders in Neonates Kara Beth Markham, MD
Associate Professor, Obstetrics, Gynecology, and
Suzanne M. Lopez, MD Maternal Fetal Medicine, Ohio State University,
Associate Professor, Pediatrics, Division of Neonatology, Columbus, Ohio
Director, Neonatal Perinatal Medicine Fellowship Obstetric Management of Pregnancy
Program, University of Texas Health Science Center at
Houston, Houston, Texas
Practicing Evidence-Based Neonatal-Perinatal Medicine

Timothy E. Lotze, MD
Associate Professor, Pediatrics and Neurology, Section
of Child Neurology, Texas Children’s Hospital, Baylor
College of Medicine, Houston, Texas
Hypotonia and Neuromuscular Disease in the Neonate
 CONTRIBUTORS xi

Gilbert I. Martin, MD, FAAP Sandra M. Mooney, PhD

Clinical Professor of Pediatrics, Pediatrics and Associate Professor, Pediatrics, Division of Neonatology,
Neonatology, Loma Linda University Medical Center, University of Maryland School of Medicine,
Loma Linda, California; Clinical Professor of Baltimore, Maryland
Pediatrics, Pediatrics and Neonatology, University of Adverse Exposures to the Fetus
California (Irvine), Irvine, California; Director
Emeritus, Neonatology, Citrus Valley Medical Center, Colin J. Morley, MD, FRCPCH, FRACP
West Covina, California Retired Professor, Neonatal Medicine, Royal Women’s
Coding and Reimbursement: Principles and Practices Hospital, Melbourne, Victoria, Australia
Role of Positive Pressure Ventilation in Neonatal
Claudia Martinez-Rios, MD Resuscitation
Visiting Assistant Professor, Pediatric Radiology, Case
Western Reserve University School of Medicine; Stuart C. Morrison, MB, ChB, FRCP
Pediatric Radiologist, Rainbow Babies and Children’s Professor, Radiology, Cleveland Clinic Lerner College of
Hospital, Cleveland, Ohio Medicine of Case Western Reserve University,
Diagnostic Imaging of the Neonate Cleveland Clinic Children’s, Cleveland, Ohio
Perinatal Imaging
Matthew J. Maughan, PharmD
Director of Pharmacy Operations, Pharmacy, Sidra Anil Narang, MD, FIAP, FAMS, FNNF
Medical and Research Center, Doha, Qatar Former Senior Professor and Head, Pediatrics and
Enhancing Safe Prescribing in the Neonatal Intensive Neonatology, Advanced Pediatrics Centre,
Care Unit Postgraduate Institute of Medical Education and
Research, Chandigarh, India
Jacquelyn D. McClary, PharmD, BCPS Perinatal and Neonatal Care in Developing Countries
Clinical Pharmacist Specialist, Neonatal Intensive Care
Unit, Rainbow Babies and Children’s Hospital, Vivek Narendran, MD, MBA
Cleveland, Ohio Professor, Pediatrics, University of Cincinnati; Attending
Principles of Drug Use in the Fetus and Neonate; Neonatologist, Cincinnati Children’s Hospital
Principles of Drug Use During Lactation; Therapeutic Medical Center, Cincinnati, Ohio
Agents The Skin of the Neonate

Olachi J. Mezu-Ndubuisi, MD, OD Mary L. Nock, MD

Assistant Professor, Pediatrics and Ophthalmology, Associate Professor, Pediatrics, Case Western Reserve
Department of Pediatrics, Department of University School of Medicine; Director, Neonatal-
Ophthalmology and Visual Sciences, University of Perinatal Medicine Fellowship Program, Co-Director,
Wisconsin School of Medicine and Public Health, Neonatal Intensive Care Unit, Rainbow Babies and
Madison, Wisconsin Children’s Hospital, Cleveland, Ohio
Developmental Immunology Tables of Normal Values

Geoffrey Miller, MA, MB, BCh, MPhil, MD, FRCP, Faruk H. Örge, MD, FAAO, FAAP
FRACP William R. and Margaret E. Althans Chair and
Professor, Departments of Pediatrics and Neurology, Professor, Director, Center for Pediatric
Yale University School of Medicine; Co-Director, Ophthalmology and Adult Strabismus, Rainbow
Pediatric MDA Clinic, Yale–New Haven Hospital, Babies and Children’s Hospital; Vice Chair of Clinical
New Haven, Connecticut Affairs, Department of Ophthalmology and Visual
Hypotonia and Neuromuscular Disease in the Neonate Sciences, University Hospitals Eye Institute;
Fellowship Program Director and Associate Professor,
Anna L. Mitchell, MD, PhD Case Western Reserve University School of Medicine,
Assistant Professor, Genetics and Pediatrics, Center for Cleveland, Ohio
Human Genetics, Case Western Reserve University, Examination and Common Problems of the Neonatal Eye
Cleveland, Ohio
Congenital Anomalies; Genetic and Environmental Todd D. Otteson, MD, MPH
Contributions to Congenital Heart Disease Division Chief, Pediatric Otolaryngology, Case Medical
Center, University Hospitals Rainbow Babies and
Richard Molteni, MD, FAAP Children’s Hospital; Associate Professor,
Emeritus Professor of Pediatrics, University of Otolaryngology, Pediatrics, Case Western Reserve
Washington School of Medicine, Seattle, Washington; University School of Medicine, Cleveland, Ohio
Intermittent Consultant, Joint Commission Resources Upper Airway Lesions in the Neonate
and Joint Commission International, Oakbrook,
Illinois
Coding and Reimbursement: Principles and Practices
 xii CONTRIBUTORS

Louise Owen, MBChB, MRCPCH, FRACP, MD Brenda B. Poindexter, MD, MS

Neonatologist, Newborn Research, Royal Women’s Professor, Pediatrics, Section of Neonatal-Perinatal
Hospital, Melbourne, Victoria, Australia Medicine, Indiana University School of Medicine,
Role of Positive Pressure Ventilation in Neonatal Riley Hospital for Children at Indiana University
Resuscitation Health, Indianapolis, Indiana
Nutrient Requirements and Provision of Nutritional
Elaine Marie Pages-Arroyo, MD Support in the Premature Neonate
Obstetric Anesthesia Fellow, Department of Anesthesia,
Brigham and Women’s Hospital, Boston, Richard Polin, MD
Massachusetts William T. Speck Professor of Pediatrics, Department of
Anesthesia for Labor and Delivery Pediatrics, Columbia University College of Physicians
and Surgeons; Director, Division of Neonatology,
Aditi S. Parikh, MD Morgan Stanley Children’s Hospital, New York,
Clinical Assistant Professor, Genetics and Pediatrics, New York
Case Western Reserve University School of Medicine; Chorioamnionitis
Clinical Geneticist, Center for Human Genetics,
University Hospitals Case Medical Center, Cleveland, Preetha A. Prazad, MD
Ohio Attending Neonatologist, Director, NICU
Congenital Anomalies Developmental Follow-Up Clinic, Advocate
Children’s Hospital, Park Ridge, Illinois
Robert L. Parry, MD, FACS Birth Injuries
Associate Professor, Surgery, Northeast Ohio Medical
University, Rootstown, Ohio; Director, Division of Jochen Profit, MD, MPH
Pediatric Surgery, Akron Children’s Hospital, Akron, Assistant Professor, Pediatrics, Division of Neonatal and
Ohio Perinatal Medicine; Director, Perinatal Health Systems
Development of the Neonatal Gastrointestinal Tract; Research, Perinatal Epidemiology and Health
Selected Gastrointestinal Anomalies in the Neonate Outcomes Research Unit, Stanford University, Palo
Alto, California
Mary Elaine Patrinos, MD Evaluating and Improving the Quality and Safety of
Assistant Professor, Pediatrics, Medical Director, Neonatal Intensive Care
Neonatal Nurse Practitioner Program, Division of
Neonatology, University Hospitals Rainbow Babies Bhagya L. Puppala, MD
and Children’s Hospital, Cleveland, Ohio Assistant Professor of Pediatrics, Rosalind Franklin
Neonatal Apnea and the Foundation of Respiratory University of Medicine and Science, The Chicago
Control Medical School, North Chicago, Illinois; Adjunct
Professor of Pediatrics, Midwestern University,
Allison H. Payne, MD, MS Downer’s Grove, Illinois; Director, Neonatal Perinatal
Assistant Professor, Pediatrics, Department of Pediatrics, Medicine–Fellowship, Director, Neonatal Perinatal
Division of Neonatology, Case Western Reserve Medicine Research, Advocate Children’s Hospital,
University School of Medicine; Attending Park Ridge, Illinois
Neonatologist, Rainbow Babies and Children’s Birth Injuries
Hospital, Cleveland, Ohio
Early Childhood Neurodevelopmental Outcomes of Tonse N. K. Raju, MD, DCH
High-Risk Neonates Chief, Pregnancy and Perinatology Branch, Eunice
Kennedy Shriver National Institute of Child Health
Stephen A. Pearlman, MD, MSHQS and Human Development, National Institutes of
Attending Neonatologist, Neonatology, Christiana Care Health, Bethesda, Maryland
Health Center, Newark, Delaware; Clinical Professor Growth of Neonatal-Perinatal Medicine: A Historical
and Fellowship Director, Neonatology, Jefferson Perspective
Medical College, Philadelphia, Pennsylvania
Coding and Reimbursement: Principles and Practices Ashwin Ramachandrappa, MBBS, MPH
Neonatologist, Pedeatrix Medical Group; Attending
Sharon Perlman, MD Neonatologist, Phoenix Children’s Hospital, Phoenix,
Associate Professor, Pediatrics, Morsani College Of Arizona
Medicine, University of South Florida; Pediatric The Late Preterm Infant
Nephrologist, All Children’s Hospital, St. Petersburg,
Florida Tara M. Randis, MD
Diabetes Mellitus During Pregnancy Assistant Professor, Pediatrics, Columbia University
Medical Center; Assistant Attending Physician,
Division of Neonatology, New York Presbyterian
Morgan Stanley Children’s Hospital, New York,
New York
Chorioamnionitis
 CONTRIBUTORS xiii

Raymond W. Redline, MD Christopher S. Snyder, MD, FAAP

Professor, Pathology and Reproductive Biology, Case Key Bank-Meyer Family Chair, Pediatric Cardiology,
Western Reserve University, Cleveland, Ohio Associate Professor, Pediatrics, Case Western Reserve
Placental Pathology University, Cleveland, Ohio
Genetic and Environmental Contributions to Congenital
Orna Flidel Rimon, MD Heart Disease; Prenatal Diagnosis of Congenital Heart
Director of Neonatology, Kaplan Medical Center, Disease; Congenital Defects of the Cardiovascular System;
Rehovot, Israel Cardiovascular Problems of the Neonate; Disorders of
Post-Term Pregnancy Cardiac Rhythm and Conduction in Newborns

Shenandoah Robinson, MD, FAAP, FACS Jochen P. Son-Hing, MD, FRCSC

Associate Professor, Neurosurgery and Neurology, Division of Pediatric Orthopaedics, Rainbow Babies and
Boston Children’s Hospital, Harvard Medical School, Children’s Hospital; Assistant Professor, Orthopaedics
Boston, Massachusetts and Pediatrics, Case Western Reserve University,
Disorders in Head Shape and Size; Myelomeningocele Cleveland, Ohio
and Related Neural Tube Defects Congenital Abnormalities of the Upper and Lower
Extremities and Spine
Susan R. Rose, MD, Med
Professor, Pediatric Endocrinology, Cincinnati Robin H. Steinhorn, MD
Children’s Hospital Medical Center, University of Medical Director, Professor and Chair, Department of
Cincinnati, Cincinnati, Ohio Pediatrics, University of California—Davis Children’s
Thyroid Disorders in the Neonate Hospital, Sacramento, California
Pulmonary Vascular Development
Miriam Said, MD
Assistant Professor, Pediatrics, George Washington David K. Stevenson, MD
University School of Medicine and Health Sciences; Harold K. Faber Professor of Pediatrics, Division of
Attending Physician, Division of Neonatology, Neonatal and Developmental Medicine, Stanford
Children’s National Health System, Washington, DC University, Stanford, California
Blood Component Therapy for the Neonate Neonatal Jaundice and Liver Diseases

Mark S. Scher, MD Eileen K. Stork, MD

Professor, Pediatrics and Neurology, Case Western Professor of Pediatrics, Case Western Reserve University
Reserve University; Chief, Division of Pediatric School of Medicine; Director, Neonatal ECMO
Neurology, Pediatrics, Case Medical Center, Program, Case Medical Center, University Hospitals
Cleveland, Ohio Rainbow Babies and Children’s Hospital, Cleveland,
Seizures in Neonates Ohio
Therapy for Cardiorespiratory Failure in the Newborn
Eric S. Shinwell, MD
Professor, Neonatology, Ziv Medical Center, Tsfat, John E. Stork, MD
Bar-Ilan University, Tel Aviv, Israel Assistant Professor, Anesthesiology and Pediatrics,
Diabetes Mellitus During Pregnancy; Obstetric Departments of Anesthesiology and Pediatrics, Case
Management of Multiple Gestation and Birth Western Reserve University; Director, Comprehensive
Pediatric Pain Service; Pediatric Anesthesiologist,
Eric Sibley, MD, PhD Rainbow Babies and Children’s Hospital, Cleveland,
Associate Professor of Pediatrics (Gastroenterology), Ohio
Member, The Child Health Research Institute, Anesthesia in the Neonate
Assistant Dean for Academic Advising, Stanford
University School of Medicine, Palo Alto, California James Strainic, MD
Neonatal Jaundice and Liver Diseases Director of Pediatric Echo Lab, Rainbow Babies and
Children’s Hospital; Assistant Professor of Pediatrics,
Sunil K. Sinha MD, PhD, FRCP, FRCPCH Pediatric Cardiology, Case Western Reserve University,
Professor, Pediatrics and Neonatal Medicine, James Cleveland, Ohio
Cook University Hospital, University of Durham, Prenatal Diagnosis of Congenital Heart Disease
Middlesbrough, Great Britain
Assisted Ventilation and Its Complication Ye Sun, PhD
Fellow, Department of Ophthalmology, Harvard
Lois E. H. Smith, MD, PhD Medical School, Boston Children’s Hospital, Boston,
Professor of Ophthalmology, Department of Massachusetts
Ophthalmology, Harvard Medical School, Boston Retinopathy of Prematurity
Children’s Hospital, Boston, Massachusetts
Retinopathy of Prematurity
 xiv CONTRIBUTORS

Arjan B. te Pas, MD, PhD Dharmapuri Vidyasagar, MD, FAAP, FCCM

Associate Professor, Pediatrics, Neonatal Division, Professor Emeritus, Pediatrics, Division of Neonatology,
Leiden University Medical Center, Leiden, The University of Illinois of Chicago, Chicago, Illinois
Netherlands Perinatal and Neonatal Care in Developing Countries
Role of Positive Pressure Ventilation in Neonatal
Resuscitation Beth A. Vogt, MD
Associate Professor, Pediatrics, Division of Pediatric
George H. Thompson, MD Nephrology, Case Western Reserve University;
Director, Division of Pediatric Orthopedics, Rainbow Physician, Pediatric Nephrology, Rainbow Babies and
Babies and Children’s Hospital; Professor of Children’s Hospital, Case Medical Center, Cleveland,
Orthopedic Surgery and Pediatrics, Orthopedic Ohio
Surgery, Case Western Reserve University, Cleveland, The Kidney and Urinary Tract of the Neonate
Ohio
Musculoskeletal Disorders in Neonates; Bone and Joint Betty Vohr, MD
Infections in Neonates; Congenital Abnormalities of the Director of Neonatal Follow-Up, Neonatology, Women
Upper and Lower Extremities and Spine and Infants Hospital; Professor, Pediatrics, Alpert
Medical School of Brown University, Providence,
Frances Thomson-Salo, PhD Rhode Island
Honorary Principal Fellow, Department of Psychiatry, Hearing Loss in the Newborn Infant
University of Melbourne; Associate Researcher,
Murdoch Children’s Research Institute, Melbourne, Kelly C. Wade, MD, PhD, MSCE
Victoria, Australia Associate Professor, Clinical Pediatrics, Perelman School
Care of the Long-Stay Infant and Parents of Medicine, University of Pennsylvania, Children’s
Hospital of Philadelphia Newborn Care, Pennsylvania
Dov Tiosano, MD Hospital, Philadelphia, Pennsylvania
Associate Professor, Pediatrics, Director, Division of Pharmacokinetics in Neonatal Medicine
Pediatric Endocrinology, Rambam Health Care
Campus, The Bruce Rappaport Faculty of Medicine, Michele C. Walsh, MD, MSE
Technion–Israel Institute of Technology, Haifa, Israel Professor, Pediatrics, Case Western Reserve University
Disorders of Calcium, Phosphorus, and Magnesium School of Medicine; William and Lois Briggs Chair in
Metabolism in the Neonate Neonatology, Chief, Division of Neonatology,
Rainbow Babies and Children’s Hospital, Cleveland,
Chani Topf-Olivestone, MD Ohio
Department of Pediatrics, Kaplan Medical Center, Epidemiology for Neonatologists; The Organization of
Rehovot, Israel Perinatal Services; Design Considerations of the Intensive
Diabetes Mellitus During Pregnancy Care Nursery; Bronchopulmonary Dysplasia in the Neonate

Andrea N. Trembath, MD, MPH Jennifer A. Wambach, MD, MS

Assistant Professor, Department of Pediatrics, Case Assistant Professor, Pediatrics, Washington University
Western Reserve University, Division of Neonatology, School of Medicine, St. Louis, Missouri
Rainbow Babies and Children’s Hospital, Cleveland, Respiratory Distress Syndrome in the Neonate
Ohio
Epidemiology for Neonatologists Michiko Watanabe, PhD
Professor, Pediatrics, Case Western Reserve University
Robert Turbow, MD, JD School of Medicine, Cleveland, Ohio
Attending Neonatologist, Pediatrics, Marian Regional Cardiac Embryology
Medical Center; Chief Patient Safety Officer,
Administration, Dignity Health, Central Coast Service Dayna M. Weinert, MD
Area, Santa Maria, California Director, Pediatric Radiology, Rainbow Babies and
Legal Issues in Neonatal-Perinatal Medicine Children’s Hospital, University Hospitals of
Cleveland Case Medical Center, Cleveland, Ohio
Jon E. Tyson, MD, MPH Diagnostic Imaging of the Neonate
Michelle Bain Distinguished Professor, Department of
Pediatrics, University of Texas Health Science Center Diane Katherine Wherrett, MD, FRCPC
at Houston Medical School, Houston, Texas Associate Professor, Pediatrics, Hospital for Sick
Practicing Evidence-Based Neonatal-Perinatal Medicine Children; Associate Professor, Pediatrics, University of
Toronto, Toronto, Ontario, Canada
Maximo Vento, MD, PhD Disorders of Sex Development
Professor, Division of Neonatology, University and
Polytechnic Hospital La Fe, Neonatal Research Group,
Health Research Institute La Fe, Valencia, Spain
Oxygen Therapy in Neonatal Resuscitation
 CONTRIBUTORS xv

Robert D. White, MD Ronald J. Wong, MD

Director, Regional Newborn Program, Memorial Senior Research Scientist, Pediatrics, Stanford University
Hospital; Medical Director, Pediatrix Medical Group; School of Medicine, Stanford, California
Adjunct Professor, Psychology, University of Notre Neonatal Jaundice and Liver Diseases
Dame; Clinical Assistant Professor, Pediatrics, Indiana
University School of Medicine, South Bend, Indiana Myra Wyckoff, MD
The Sensory Environment of the Intensive Care Nursery; Associate Professor, Pediatrics, University of Texas
Design Considerations of the Intensive Care Nursery Southwestern Medical Center; Director, Newborn
Resuscitation Services, Parkland Health and Hospital
Jamie Wikenheiser, PhD Systems, Dallas, Texas
Assistant Professor, Anatomy and Neurobiology, Chest Compression, Medications, and Special Problems in
Director of Gross Anatomy, Director of Surgical Neonatal Resuscitation
Anatomy, University of California—Irvine School of
Medicine, Irvine, California Arthur B. Zinn, MD, PhD
Cardiac Embryology Associate Professor, Genetics and Pediatrics, Case
Western Reserve University; Attending Physician,
Deanne E. Wilson-Costello, MD Center for Human Genetics, University Hospitals
Professor, Pediatrics, Rainbow Babies and Children’s Case Medical Center, Cleveland, Ohio
Hospital, Cleveland, Ohio Inborn Errors of Metabolism
Early Childhood Neurodevelopmental Outcomes of
High-Risk Neonates
 Preface

The foundation for successful outcomes in neonatal-peri- reached its tenth edition. With the combination of print
natal medicine has been the ability to apply knowledge and electronic journals, the effort to stay current in a
of the fundamental pathophysiology of the various neo- single subspecialty remains a daunting task. To facilitate
natal disorders to safe interventions. Molecular, biologic, this, Elsevier, our publisher, has migrated the existing
and technologic advances have facilitated the diagnosis, Web-based Student Consult and Expert Consult plat-
monitoring, and therapy of these complex disorders. forms to a new platform hosted by Inkling.com. Inkling
Advances at the bench have been translated to the bedside, is a pioneer in interactive cloud publishing and reimaging
and survival statistics reveal slow but steady improve- of books, including medical texts. The combination of an
ments. Nonetheless, although the survival rates may give extensive library of expert content with their ability to
reason to rejoice, the high early morbidity and persistent truly bring that content alive paves an exciting path
neurodevelopmental problems remain cause for concern. forward for the distribution of medical knowledge.
Such problems include bronchopulmonary dysplasia, Owners of the book will enjoy easy searches, a consistent
nosocomial infections, necrotizing enterocolitis, hypoxic- structure, rich media, social and community features, and
ischemic encephalopathy, cerebral palsy, and the inability seamless electronic access from any device.
to sustain the intrauterine rate of growth when infants are For this tenth edition, we have added several new
born prematurely. These problems need to be solved in sections and authors, notably expanding our interna-
addition to the complex, ever-expanding genetic disor- tional contributors and hence providing a truly global
ders and birth defects that now loom as the major prob- perspective. Many sections have been completely reorga-
lems in the neonatal intensive care unit and as the leading nized, and a large number of chapters have been rewrit-
causes of neonatal mortality. ten or updated. Our accomplished authors and careful
The field of neonatal-perinatal medicine has transi- editing continue to focus on the biologic basis of devel-
tioned from anecdotal medicine to evidence-based medi- opmental disorders and the evidence basis for their
cine. The problem is that evidence-based medicine management.
predicts outcomes for groups but not individuals. The This book would not exist without the remarkable
next frontier, individualized or personalized medicine, clinical and intellectual environment that constitutes
requires application of the human genome project to the Rainbow Babies and Children’s Hospital in Cleveland.
individual patient. That frontier is rapidly approaching On a daily basis, we gain knowledge from our faculty
with the acquisition and application of new knowledge colleagues and fellows and wisdom from our nursing
and technology. The translation of bench research to staff, who are so committed to their young patients. Once
bedside innovation is proceeding smoothly, as is the again, we have been blessed with an in-house editor,
understanding of the underlying mechanisms of many Bonnie Siner, to whom we cannot adequately express
disorders. Advances in genetics have provided insight into our thanks. She is the glue behind the binding in the
the etiology of many disorders, and many previously book and has worked tirelessly with Elsevier staff
mysterious diseases can now be attributed to single gene members to bring this project to fruition. Elsevier has
defects or mitochondrial disorders accompanied by cel- once again provided the resources to accomplish this
lular energy failure. We have addressed and incorporated mammoth task.
these advances into the body of the text.
Presenting the current status of the field of neonatal- Richard J. Martin
perinatal medicine, even in a two-volume textbook, has
become extremely challenging. It is a tribute to the con- Avroy A. Fanaroff
tributors to Neonatal-Perinatal Medicine that this text has Michele C. Walsh

xvii
 1 Growth Of Neonatal-Perinatal
Medicine: A Historical Perspective
TONSE N. K. 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, 196074

The terms neonatology and neonatologist were not in general Medicinal chemistry (later called biochemistry) and
use 50 years ago. In the preface to the first edition of his classic physiology gained popularity and acceptance
monograph Diseases of the Newborn, Dr. Alexander Schaf- toward the end of the nineteenth century, inaugurating
fer christened the new specialty and its practitioners, studies on biochemical and physiologic problems in the
asking our “forgiveness” for doing so. An apology was not fetus and newborn. Some leading scientists in the early
needed because time has proved him to be immensely twentieth century making fundamental contributions
prophetic. In 1975, the first Neonatal-Perinatal Medicine and training scores of scientists from around world
subspecialty examination was offered by the American included Barcroft8,34 and his mentee Dawes in England
Board of Pediatrics, and 355 were certified as the country’s (gas exchange and nutritional transfer across the placenta
first neonatologists. After the 2012 certifying examina- and oxygen carrying in fetal and adult hemoglobin);
tion, 5552 individuals have been certified by the Board Ylppö in Finland (neonatal nutrition, jaundice, and ther-
as neonatologists. This phenomenal growth has been moregulation); Lind in Sweden (circulatory physiology);
matched by an increasing fund of knowledge. Today a Smith in Boston81 (fetal and neonatal respiratory physiol-
cursory search using the subject heading “newborn” in ogy); DeLee in Chicago26,27 (leading researcher on incu-
the National Library of Medicine’s PubMed database yields bators and in high-risk obstetric topics, he also founded
nearly 60,000 citations.59 Thus, at the beginning of the the first US “incubator station” at the Chicago Lying-in
twenty-first century, neonatology stands tall and strong as Hospital); Day in New York (temperature regulation, reti-
a specialty, carving a unique niche, bridging obstetrics nopathy of prematurity, and jaundice); and Gordon38
with pediatrics and intensive care with primary care. in Denver (nutrition). Although no formal curriculum
Although the formal naming of our specialty appears existed, all these centers offered rigorous training in peri-
to be recent, its roots extend into the nineteenth century, natal physiology and clinical medicine Smith once said,
when systematic and organized care for premature infants “If you were interested in babies and liked Boston, I was
began in earnest. This chapter traces the origins and the only wheel in town!”60 Table 1-1 highlights some
growth of modern perinatal and neonatal medicine, with milestones in perinatal medicine.
a brief perspective on its promises and failures. The reader
may consult scholarly monographs and review articles on
specific topics for in-depth analyses.6,7,24,31,78,79 The High-Risk Fetus and
Perinatal Obstetrics
Perinatal Pioneers Because so many deaths occurred in early infancy in times
Many scientists played strategic roles in developing the past, many cultures adopted remarkably innovative
basic concepts in neonatal-perinatal medicine that helped methods to deal with such tragedies. According to a
to formalize the scientific basis for neonatal clinical care. Jewish tradition, full, year-long mourning is not required
Their work and teachings inspired generations of further for infants who die before 30 days of age.40 In some Asian
researchers advancing the field. For brevity’s sake, only a ethnic groups, infant-naming ceremonies are held only
few are shown in Figure 1-1. after several months, until which time the infant is simply
2
 1 • Growth Of Neonatal-Perinatal Medicine: A Historical Perspective 3

A B C D

E F G H
Figure 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, 1977, Blackwell
Scientific, courtesy of Blackwell Scientific; B-D, F-H, From Smith GF, Vidyasagar D, editors: Historical review and recent advances in neonatal and perinatal
medicine: neonatal medicine, vol 1, Evansville, IN, 1984, Ross Publication, pp ix [B], xix [C], xxii [D], xvi [F], xii [G], xiv [H], courtesy of Mead Johnson
Nutritional; E, Courtesy of Mrs. Nancy DeLee Frank, Chicago.)

TABLE 1-1 Selected Milestones in Perinatal Medicine

Category Year(s) Description
Antenatal 1752 Queen Charlotte’s Hospital, the world’s first maternity hospital, is founded in London57
aspects 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
Fetal assessment 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 ECG
1906 The first recording of fetal heart ECG is made
1908 The term fetal distress is introduced
1948-1953 There are developments in the external tocodynamometer
1953 Apgar describes her scoring system3
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
Labor and ca. 1000–500 BC In Ayurveda, the ancient Hindu medical system, physicians describe obstetric instruments
delivery 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 The 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
Fetal physiology 1900-1950 Barcroft, Dawes, Lind, Liley, and others study physiologic principles of placental gas exchange and fetal
circulation

ECG, Electrocardiogram.
See references 2, 41, 43, 61, 82 for primary citations.
 4 PART 1 • THE FIELD OF NEONATAL-PERINATAL MEDICINE

called “it.” In India, an odd or coarse-sounding name is fourth infant is being handed to her for nursing. A divine
given to the first surviving infant after the death of a previ- figure in the background is blessing the newcomers.
ous sibling; this is aimed at deflecting evil spirits. In her Cesarean sections were seldom performed on living
book on the history of the Middle Ages, Tuchman notes women before the thirteenth century. Even subsequently,
that infants were seldom depicted in medieval artworks.89 the procedure was performed only as a final act of des-
When they were drawn (e.g., the infant Jesus), women in peration. Contrary to popular belief, Julius Caesar’s birth
the pictures looked away from the infant, ostensibly con- was not likely by cesarean section. Because Caesar’s
veying respect, but perhaps because of fearful aloofness. mother was alive during his reign, historians believe that
Since antiquity, the care of pregnant women has been she probably delivered him vaginally. The term cesarean
the purview of midwives, grandmothers, and experienced probably originated from lex caesarea, in turn from lex
female elders in the community. Wet nurses helped when regia, the “royal law” prohibiting burial of corpses of
mothers were unavailable or unwilling to nurse their pregnant women without removal of their fetuses.11,94 The
infants. Little or no assistance was needed for normal or procedure allowed for baptism (or a similar blessing) if
uncomplicated labor and delivery. For complicated deliv- the child was alive or burial otherwise. Infants surviving
eries, male physicians had to be summoned, but they the ordeal of cesarean birth were assumed to possess
could do little because many of them lacked expertise or special powers, as supposedly did Shakespeare’s Macduff—
interest in treating women. Disasters during labor and “not of a woman born,” but of a corpse, and able to slay
delivery were common, rendering this phase in their lives Macbeth.54
the most dreaded for women.43 In the early 1900s, unex- Soranus of Ephesus (circa 38-138 AD) influenced
pected intrapartum complications accounted for 50% to obstetric practice for 1400 years. His Gynecology can be
70% of all maternal deaths in England and Wales.17,56 regarded as the first formal “textbook” of perinatal medi-
Because the immediate concern during most high-risk cine. Initially extant, it was rediscovered in 1870 and
deliveries was to save the mother, sick newborns were not translated into English for the first time in 1956.88 Soranus
given substantial attention; their death rates remained wrote superbly about podalic version, obstructed labor,
very high. multiple gestations, fetal malformations, and numerous
Occasionally, happy outcomes of high-risk deliveries other maternal and fetal disorders. In an age of belief in
did occur. In one of the oldest works of art depicting labor magic and the occult, he insisted that midwives should
and delivery (Figure 1-2, A), a bearded man and his assis- be educated and free from superstitions. He forbade wet
tant are standing behind a woman in labor, holding devices nurses from drinking alcohol lest it render the infant
remarkably similar to the modern obstetric forceps. The “excessively sleepy.” His chapter, “How to Recognize the
midwife has delivered an evidently live infant. In Figure Newborn That Is Worth Rearing,” remains one of the
1-2, B, three infants from a set of quadruplets, nicely swad- earliest accounts on assessing viability of sick newborns—
dled, have been placed on the mother, as the unwrapped a topic of great concern even today.

B
Figure 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 are looking through the
window. B, Delivery of quadruplets. (From Graham H. Eternal Eve: the history of gynecology and obstetrics, New York, 1951, Doubleday, pp 68, 172.)
 1 • Growth Of Neonatal-Perinatal Medicine: A Historical Perspective 5

Figure 1-3 On call. “A Midwife Going to a Labour,” caricature by

Thomas Rowlandson, 1811. (Courtesy of The British Museum, London.)

Figure 1-4 Man-midwife. (Courtesy of Clements C. Fry Print Collec-

Midwives and Perinatal Care tions, Harvey Cushing/John Hay Whitney Medical Library, Yale University,
New Haven, CT.)
Although occasionally caricatured (Figure 1-3), midwives
were responsible for delivering obstetric care for thou- adults and children.66 These are tales of successes only,
sands of years. Men disliked obstetrics, and women were for the failures were buried and rarely reported. Attempts
shy to let male physicians handle them. Good midwives to “stimulate” and revive apparently dead newborns
were always in great demand, and many of them held included beating, shaking, yelling, fumigating, dipping in
important social and political positions in European ice-cold water, and dilating and blowing smoke into the
courts.43,61,91 rectum.25,30,66 Oxygen administration through an orogas-
The emergence of man-midwives (Figure 1-4) in tric tube to revive asphyxiated infants persisted well into
England had a major effect on high-risk obstetric prac- the mid-1950s, when James and Apgar showed conclu-
tice. Chamberlen the Elder (1575-1628) is usually cred- sively that the therapy was useless.1,52
ited for inventing the modern obstetric forceps.43,61,63 For
150 years, through three generations of Chamberlens, the
instrument remained a trade secret. By then, others had Apgar and the Language
developed similar devices, and patients began associat-
ing good obstetric outcomes with male physicians—a
of Asphyxia
strategic factor in transforming midwifery to a male- Few scientists in the twentieth century influenced the
dominated craft.43 The shift from women-midwifery to practice of neonatal resuscitation as profoundly as Apgar
men-midwifery might also have been caused by changing (1909-1974). A surgeon, she chose obstetric anesthesia
social values and gender relationships in which women for her career. Her simple scoring system inaugurated the
voluntarily began making choices about their bodies.91 modern era of assessing infants at birth on the basis of
Today’s increasing roles for female midwives and the simple clinical examination.3 Right or wrong, the Apgar
higher proportion of women choosing specific birth score became the language of asphyxia. It is often said
practices (e.g., home versus hospital delivery, “under- that the first words heard by a newborn infant are “What’s
water births,” cesarean delivery on request) offer inter- the Apgar score?” Although “giving an Apgar” has become
esting contrasts and perspectives to eighteenth century a ritual, its profound effect has been on formalizing the
obstetrics. process of observing, assessing, and communicating the
infant status at birth in a consistent and uniform manner.
This process eventually led to the formal steps of resusci-
Neonatal Resuscitation: Tales tation at birth using the score. Few people know that it
of Heroism and Desperation was also Apgar who was the first to catheterize the umbili-
cal artery in a newborn.16 A woman of enormous energy,
Popular artworks and ancient medical writings provide talent, and compassion, Apgar was honored with her
accounts of miraculous revivals of apparently dead depiction on a 1994 US postage stamp (Figure 1-5).
 6 PART 1 • THE FIELD OF NEONATAL-PERINATAL MEDICINE

and rewarded married couples to encourage procre-

Foundling Asylums ation.82 In 315 AD, Emperor Constantine, hoping to curb
and Infant Care infanticide and encourage the adoption of orphans,
decreed that all “foundlings” would become slaves of
In its early days, the Roman Empire experienced decreas- those who adopted them. Similar humanitarian efforts
ing population growth. The emperors taxed bachelors by kings and the Council of the Roman Church led to the
institutionalization of infant care by establishing found-
ling asylums for abandoned infants,82 also called “Hospi-
tals for the Innocent”—the first children’s hospitals.
Parents of unwanted infants “dropped off” their infants
in a revolving receptacle at the door of such asylums, rang
the doorbells, and disappeared into the night (Figure
1-6). Such accounts are poignant reminders of the con-
temporary problem of child abandonment, because of
which many states have programs to save such “dumpster
babies” or abandoned infants.72
Foundling asylums adopted pragmatic techniques for
fundraising. In eighteenth century France, lotteries were
held, and souvenirs were sold. In May 1749, Handel gave
a concert to support London’s “Hospital for the Mainte-
nance and Education of Exposed and Deserted Young
Children.” The final item of the program was the playing
of “The Foundling Hymn.”82

Saving Infants to Man the Army

During the French Revolution, France faced appalling
rates of infant mortality. With rates greater than 50%, the
Revolutionary Council in 1789 enacted a decree pro-
claiming that working-class parents “have a right to the
nation’s succors at all times.”82 The postrevolutionary
Figure 1-5 Virginia Apgar, US postage stamp. (Courtesy of the US euphoria about equality and fraternity among men stim-
Postal Service.) ulated reforms, heralding an idealistic welfare state,

A B
Figure 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 (engrav-
ing and etching by Alberto Maso Gilli, France, 1875). (A and B, Courtesy of 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, 1991, Decker,
p 110 [A] and p 119 [B].)
 1 • Growth Of Neonatal-Perinatal Medicine: A Historical Perspective 7

leading to collecting and maintaining valid statistics

about children. The world’s first national databases began
in France in the late eighteenth century.82
Over the next century, France faced a population
problem similar to that of ancient Rome—a negative
population growth. The birth rate had declined, and
infant mortality remained high. Fearing future shortages
of troops, the military leaders, deeply engaged in battles
with Prussia, were naturally alarmed. Commissions were
set up to study the depopulation problem and develop
remedial actions. A series of measures began to improve
maternal and neonatal care.6,7,22,24,82 Young parents were
encouraged to uphold their patriotism and bear more A
children to “man the future armies.” It is the irony of
our times that such noble intentions as saving infants
were motivated by brutal needs for enhancing military
might.

An Ingenious Contrivance,
the Couveuse, and Premature
Baby Stations
A popular story of the origin of modern incubator tech-
B
nology is that upon seeing the poultry section during a
casual visit to the Paris Zoo in 1878, Tarnier (1828-1897),
a renowned obstetrician, conceived the idea of “incuba-
Air Exit
tors” similar to the “brooding hen” or couveuse.6,7,22,24 He Glass Cover
asked an instrument maker, Martin, to construct similar
Sponge
equipment for infants. With a “thermo-syphon” method Bed
Air Entrance
to heat the outside with an alcohol lamp, Martin devised Filling
a sufficiently ventilated, 1 m3 double-walled metal cage, Funnel
spacious enough to hold two premature infants. The first

Bunsen Burner
Hot-Water Tank
couveuses were installed at the Paris Maternity Hospital in
1880. Tarnier’s efforts led to dramatic improvements in
survival rates for preterm infants.
Although a few others had developed incubators C
before Tarnier,7 it was he and his students, Budin (1846-
1907) and Auvard, who are largely responsible for insti- Figure 1-7 Early incubators. A, Rotch incubator, circa 1893. B, Holt
incubator. C, Schematics of the Holt incubator. (A, From Cone TE Jr.
tutionalizing preterm infant care. They placed several
History of American pediatrics, Boston, 1979, Little Brown, pp 57 and 58,
incubators side by side, promoting the concept of caring courtesy of Little Brown; B and C, From Holt LE. The diseases of infants
for groups of sick preterm infants in geographically sepa- and children, New York, 1897, Appleton, pp 12 and 13, courtesy of
rate regions within their hospital.6,7,86 Budin and Auvard Appleton.)
improved the original couveuse by replacing its walls with
glass and using simpler methods for heating. Their efforts
greatly influenced incubator technology during the first
half of the twentieth century in Europe and the United
Incubators, Baby Shows, and
States (Figure 1-7 and Table 1-2). Origins of Neonatal Intensive
In 1884, Tarnier made another important contribu-
tion; he invented a small, flexible rubber tube for intro-
Care Units
duction through the mouth into the stomach of preterm Almost two decades after its debut in France, incubator
infants. With this tube, he could drip milk directly into technology appeared in the United States, heralding orga-
the stomach. This method of nutritional support he nized newborn intensive care. As in France, it was an
called “gavage feeding.” Gavage feeding plus keeping obstetrician who spearheaded the movement. In 1898,
infants in relatively constant and warm temperatures had DeLee established the first “Premature Baby Incubator
a dramatic impact on improving survival rates.15,21 Tarnier Station” at the Sara Morris Hospital in Chicago. During
also recommended that the legal definition of viability the early 1900s, as academic obstetricians and pediatri-
should be 180 days of gestation, which was opposed by cians were organizing specialized care for premature
contemporary obstetricians, who thought that the concept infants, an interesting, if bizarre, set of events led to the
was “therapeutic nihilism.”7 Defining viability remains a era of “premature baby shows,” which began in Europe
highly emotional and contentious issue in contemporary and continued in the United States, lasting well into the
neonatal-perinatal practice. 1940s.6,7,78
 8 PART 1 • THE FIELD OF NEONATAL-PERINATAL MEDICINE

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 Port-Royal
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 Bartlett reads a paper on a “warming-crib” based on Tarnier’s concept, but uses a
“thermo-syphon”
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 double-walled
wooden box, hot water circulates between the walls
1897-1920s Brown, Lyons, DeLee, Allin Many modifications are made to the early American and European incubators by
physicians. These are called baby-tents, baby boxes, warming beds, and 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 taxicabs
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—mobile intensive care units

See references 6, 7, 22-24, 77-79 for primary citations.

Couney, a Budin associate of doubtful medical creden- a regimental approach to feeding, Hess and his head
tials, wished to popularize the French technology abroad nurse, Evelyn Lundeen (Figure 1-8), achieved spectacular
and show the value of “conserving” premature infants. survival rates.47,67 Hess also developed an incubator built
(This account has been doubted.7) Couney obtained six on the concept of a double-walled metallic “cage” with
incubators, probably from the French innovator Lion. warm water circulating between the walls. He used elec-
Initially, Couney wanted to exhibit only the incubators tric current for heating and devised a system to administer
as a technology of hope for saving infants. To add drama, free-flow oxygen (Figure 1-9). Only a few Hess incubators
however, he brought six preterm infants from Virchow’s are known to have survived to this day. Hess’s premature
maternity unit in Berlin and exhibited them inside the unit outlasted the DeLee Premature Station. In December
incubators at the 1896 Berlin Exposition. He coined a 2008, the Michael Reese Medical Center closed, however,
catchy phrase for the show—kinderbrutanstalt or “child declaring bankruptcy.
hatchery”—igniting the imagination of a public thirsty The story of development of incubators and their
for sensational scientific breakthroughs. impact on pediatrics is a tale of the success of technology
Couney’s Berlin exhibit was an astounding success. and that of the perils technology might beget (see later
One such show was at Great Britain’s Victorian Era section on relationship of improved incubator care and
Exhibition in 1897. The show was praised by Lancet in the retinopathy of prematurity [ROP] epidemic). In the
an editorial that recommended that large “incubator heroic age of the mechanical revolution, the notion that
stations” be established similar to fire stations, where machines could solve all human problems was all too
parents could borrow incubators.36 This was the origin of appealing. The incubator stands as the most enduring
the phrase “premature baby incubator stations,” which symbol of the spectacular success of modern intensive
became part of the medical lexicon. In a later editorial, care and (paradoxically) some of its failures.79,80
Lancet also criticized the “danger of making a public show
of incubator for babies.”37 Couney sailed to the United
States and, beginning in 1898, started premature infant Supportive Care and
exhibitions at many state fairs, traveling circuses, and
science expositions, and finally settled in New York City
Oxygen Therapy
to organize annual incubator baby shows in Coney In a single-page note in 1891, Bonnaire referred to Tar-
Island. The last infant show was held during the 1939- nier’s use of oxygen in treating “debilitated” premature
1940 season in Atlantic City.78 infants 2 years earlier14—this was the first published refer-
In 1914, Hess of Chicago started a Premature Infant ence to the administration of supplemental oxygen in
Station at the Sarah Morris Children’s Hospital (of premature infants for a purpose other than resuscitation.
the Michael Reese Medical Center). With great attention The use of oxygen in premature infants did not become
to environmental control and aseptic practices and routine, however, until the 1920s. Initially, a mixture of
 1 • Growth Of Neonatal-Perinatal Medicine: A Historical Perspective 9

Figure 1-8 Hess and Lundeen medallions at the Michael Reese Hospital, Chicago. (Photo courtesy of Tonse N. K. Raju.)

who were surviving for longer periods than ever before.

Their growth needed to be monitored, and illnesses
related to prematurity, such as sepsis, apnea, anemia,
jaundice, and respiratory distress, had to be studied and
treated. Another completely unexpected peril from
“improved” incubator technology was the epidemic of
blindness from ROP (then called retrolental fibroplasia),
documented in vivid detail elsewhere.79,80 The apparent
culprit in cases of ROP was the “leakproof” incubator that
led to a great increase in the inspired oxygen concentra-
tions (piped in free-flow manner), coupled with the
belief that oxygen was innocuous and that if a little bit
could save lives, a lot could save even more lives. Because
more and more sick and small preterm infants began to
survive with incubator care, providing ventilatory assis-
tance became an urgent necessity.

Ventilatory Care:
“Extended Resuscitation”
The first mechanical instrument used for intermittent
positive pressure ventilation in newborns was the aero-
phore pulmonaire, a simple device developed by the French
obstetrician Gairal.65,66 It was a rubber bulb attached to a
J-shaped tube. By placing the bent end of the tube into
Figure 1-9 A Hess incubator on display at the Spertus Museum in
the infant’s upper airway, one could pump air into the
Chicago. (From the International Museum of Surgical Sciences, Chicago.)
lungs. Holt recommended its use for resuscitation in his
influential 1897 book.48
oxygen and carbon dioxide—instead of oxygen alone— Before starting mechanical ventilation, one needed to
was employed to treat asphyxia-induced narcosis. It was cannulate the airway, a task nearly impossible without a
argued that oxygen relieved hypoxia, whereas carbon laryngoscope and an endotracheal tube. Blundell (1790-
dioxide stimulated the respiratory center.85 Oxygen alone 1878), a Scottish obstetrician, was the first to use a
was reserved for “pure asphyxia” (whatever that meant). mechanical device for tracheal intubation in living new-
The advent of mobile oxygen tanks and their easy avail- borns.13,32 Introducing two fingers of his left hand over
ability in the mid-1940s enabled the use of oxygen for the infant’s tongue, he would feel the epiglottis and
resuscitation.51,53,79 then guide a silver pipe into the trachea with his right
The success of incubator care brought new and unex- hand. His tracheal pipe had a blunt distal end and
pected challenges.68 Innovative methods had to be devel- two side holes. By blowing air into the tube about 30
oped to feed the increasing number of premature infants times a minute until the heartbeat began, Blundell saved