Avery's Diseases of the Newborn

Description

Completely revised and updated, Avery's Diseases of the Newborn, 11th Edition, remains your #1 choice for clinically focused, cutting-edge guidance on the evaluation, diagnosis, and treatment of diseases of the newborn. Drs. Christine A. Gleason, Taylor Sawyer, and a team of expert contributing authors provide comprehensive, up-to-date coverage of every key disease and condition affecting newborns, keeping you current in this fast-changing field. You’ll find the specific strategies you need to confidently provide care for this unique patient population, in a full-color, easy-to-use single volume that focuses on key areas of practice. Reflects the latest developments on all aspects of newborn evaluation and management, featuring new content, new chapters, new contributors, and fresh perspectives from a new co-editor.  Brings you the latest on current topics such as perinatal/neonatal COVID-19, genomics and precision medicine, acute and chronic neonatal respiratory disorders, brain injury and neuroprotection, necrotizing enterocolitis, probiotics, palliative care, prenatal drug exposure, retinopathy of prematurity, and more.  Provides clinically relevant, practical guidance in concise, focused chapters that include summary boxes, suggested readings, and more than 500 full-color illustrations, micrographs, and photographs.  Contains the 2020 American Academy of Pediatrics and American Heart Association neonatal resuscitation guidelines and the 2022 American Academy of Pediatrics guidelines on the management of hyperbilirubinemia.  Serves as a reliable quick reference for clinical questions and an excellent resource for board review.  An eBook version is included with purchase. The eBook allows you to access all of the text, figures and references, with the ability to search, customize your content, make notes and highlights, and have content read aloud.  cover Front Matter Title page Copyright Copyright Dedication Dedication Contributors Contributors​ Preface Preface​ Contents Contents I: Overview II: Fetal Growth and Development III: Maternal Conditions Affecting Pregnancy Outcomes IV: Labor and Delivery V: Essentials of Newborn Care VI: High-Risk Newborn Care VII: Genetics VIII: Metabolic Disorders of the Newborn IX: Immunology and Infections X: Respiratory System XI: Cardiovascular System XII: Neurologic System XIII: Gastrointestinal System and Nutrition XIV: Hematologic System and Disorders of Bilirubin Metabolism XV: Neoplasia XVI: Renal and Genitourinary System XVII: Endocrine Disorders XVIII: Craniofacial and Orthopedic Conditions XIX: Dermatologic Conditions XX: Eyes and Ears 1. Neonatal and Perinatal Epidemiology 1 Neonatal and Perinatal Epidemiology Introduction—Epidemiologic Approaches to the Perinatal and Neonatal Period Health Disorders of Pregnancy and the Perinatal Period Key Population Mortality Statistics Sources of Information on Mortality—Vital Data Time Trends in Mortality Rates of the Perinatal Period in the United States International Comparisons Health Disparities in the Perinatal Period Major Causes of Death Factors Affecting Perinatal Health Health States in Pregnancy Health Behaviors Perinatal Medical Care Epidemiologic Study Designs in the Perinatal Period Cohort Studies Beginning in Pregnancy or at Birth Case-Control Studies Randomized Controlled Trials Summary and Conclusions Acknowledgments References References Suggested Readings 2. Ethics, Data, and Policy in Newborn Intensive Care 2 Ethics, Data, and Policy in Newborn Intensive Care Background Getting Data Getting Data That Matters Policy Implications of Limited Data Public Policy: The Baby Doe Case Malpractice Cases Against Neonatologists Relationship Between Policy, Practice, and Outcomes Neonatal Resuscitation and Generational Conflict Implications of Increasingly Available Data Fetal Medicine Centers Expanded Newborn Screening Summary Acknowledgment References References Suggested Readings 3. Development, Function, and Pathology of the Placenta 3 Development, Function, and Pathology of the Placenta Development of the Placenta Trophoblast Lineage Allocation Trophoblast Differentiation Trophoblast Invasion Placental Functions Transport Metabolism Endocrine Function Steroid Hormones Progesterone Estrogens Glucocorticoids Pituitary-Like Hormones Human Chorionic Gonadotropin Human Chorionic Somatomammotropin Placental Growth Hormone Variant Insulin-Like Growth Factors Other Secreted Growth Factors Inhibin and Activin Proopiomelanocortin Hormones Hypothalamic-Like Hormones Gonadotropin-Releasing Hormone Corticotrophin-Releasing Hormone and Urocortins Thyrotropin-Releasing Hormone Growth Hormone-Releasing Hormone, Somatostatin, and Ghrelin Leptin Oxytocin Additional Placental Secreted Factors Vasoactive Peptides Endogenous Opioid Peptides Cytokines Eicosanoids Immunologic Function Regulation of Placental Function Evaluation of Placental Dysfunction Placental Histopathology Placental Imaging Serum Biomarkers of Placental Disease Serum Analytes Circulating Cell-Free Fetal DNA Extracellular Vesicles Summary References Suggested Readings REFERENCES 4. Abnormalities of Fetal Growth 4 Abnormalities of Fetal Growth Definitions Patterns of Altered Growth Fetal Causes of Growth Restriction Placental Causes of Growth Restriction Maternal Causes of Growth Restriction Smoking Short-Term Outcomes Developmental Outcomes: Early Childhood Long-Term Consequences: The Developmental Origins of Adult Disease Programming Epidemiology The Role of Catch-Up Growth Size at Birth, Insulin Secretion, and Insulin Action Epidemiologic Challenges Size at Birth Cannot Be Used as a Proxy for Fetal Growth Genetics versus Environment Cellular Mechanisms Molecular Mechanisms: Epigenetics Macrosomia Summary References Suggested Readings References 5. Multiple Gestations and Assisted Reproductive Technology 5 Multiple Gestations and Assisted Reproductive Technology Epidemiology of Multiples Diagnosing Zygosity and Chorionicity The Effect of Chorionicity Increase in Monozygotic Twins With Assisted Reproductive Technology Zona Pellucida Manipulation Blastocyst Transfer Ovulation Induction and Superovulation Neonatal Complications Associated With Multiples Fetal Complications Maternal Complications Psychosocial Factors Cost Decreasing the Risk of Multiples Multifetal Pregnancy Reduction Summary Acknowledgment References Suggested Readings References 6. Prematurity and Stillbirth- Causes and Prevention 6 Prematurity and Stillbirth: Causes and Prevention Preterm Birth and Stillbirth: Burden in the United States and Global Estimates Pathophysiology of Preterm Birth and Stillbirth Demographic Factors and Disparities Environmental Factors Nutrition and Maternal Body Weight Infection and Microbiota SARS-CoV-2 Infection in Pregnancy Genetic Factors Placental and Pregnancy Factors Prevention of Preterm Birth Summary References Suggested Readings References 7. Nonimmune Hydrops 7 Nonimmune Hydrops Incidence Etiology Pathophysiology Normal Fluid Homeostasis Derangements in Fluid Homeostasis Elevated Central Venous Pressure Congenital Lymphatic Flow Disorders Decreased Oncotic Pressure Increased Capillary Leak Prenatal Diagnosis Prenatal Management Neonatal Evaluation Intensive Care of the Infant With Hydrops Fetalis Respiratory Management Fluid, Electrolyte, and Medical Management Cardiovascular Management Lymphatic Evaluation and Interventions Clinical Course and Outcome References Suggested Readings References 8. Maternal Diabetes 8 Maternal Diabetes Types of Diabetes Type 1 Diabetes Type 2 Diabetes Monogenic Diabetes Neonatal Consequences of MODY Gestational Diabetes Maternal Obesity Association Between Perinatal Outcomes and Periconception Glycemic Control Fetal Growth and Macrosomia Stillbirth and Perinatal Mortality Maternal Preeclampsia Obstetric Management of Diabetes in Pregnancy Preconception Care Medical Therapy for Diabetes in Pregnancy Antenatal Monitoring Delivery Planning Intrapartum Diabetes Management Neonatal Considerations Hypoglycemia Respiratory Distress Antenatal Corticosteroids for Reduction in Risk of Respiratory Distress Syndrome Hypertrophic Cardiomyopathy Hypocalcemia and Hypomagnesemia Polycythemia Hyperbilirubinemia Breastfeeding References Suggested Readings References 9. Maternal Medical Disorders of Fetal Significance 9 Maternal Medical Disorders of Fetal Significance General Principles in the Diagnosis and Management of Medical Complications During Pregnancy Diagnostic Imaging Surgery During Pregnancy Medication Usage Autoimmune Disorders Systemic Lupus Erythematosus Antiphospholipid Antibody Syndrome Neonatal Lupus Immune Thrombocytopenia Cardiovascular Disease Peripartum Cardiomyopathy Congenital Heart Disease Coronary Artery Disease Renal Disease Cancer Principles Chemotherapy Radiation Therapy Cervical Cancer Breast Cancer Ovarian Cancer Survivors of Childhood Cancer Maternal Seizure Disorders Perinatal Risk Fetal Hydantoin Syndrome Management Perinatal Mood and Anxiety Disorders Depression Postpartum Psychosis Schizophrenia References References Suggested Readings 10. Hypertensive Complications of Pregnancy 10 Hypertensive Complications of Pregnancy Classification of Hypertensive Disorders of Pregnancy Chronic Hypertension Antihypertensive Treatment of Chronic Hypertension in Pregnancy Antenatal Fetal Surveillance in Chronic or Gestational Hypertension Gestational Hypertension Preeclampsia-Eclampsia Etiology Prediction Prevention Antepartum Management Preeclampsia and Fetal Risk Intrapartum Management Eclampsia References Suggested Readings References 11. Intrauterine Drug Exposure-Fetal and Postnatal Effects 11 Intrauterine Drug Exposure: Fetal and Postnatal Effects Introduction Epidemiology of Perinatal Substance Exposure Health Policy Perinatal Exposure to Specific Substances Alcohol Introduction Diagnosis and Classification Pharmacology and Biologic Actions Fetal and Neonatal Effects Growth Restriction Dysmorphology Central Nervous System Abnormalities Long-Term Effects Cigarette Smoking, Electronic Cigarettes Introduction Pharmacology and Biological Actions Long-Term Effects of Perinatal Exposure to Cigarettes and Electronic Cigarettes Cannabis and/or Cannabidiol Introduction Pharmacology and Biological Actions Long-Term Effects of Perinatal Cannabis Exposure Opioids (Including Prescription Drugs) Introduction Pharmacology and Biologic Actions Fetal and Neonatal Effects Long-Term Effects of Perinatal Opioid Exposure Cocaine Introduction Pharmacology and Biologic Actions Fetal and Neonatal Effects Long-Term Effects of Prenatal Cocaine Exposure Amphetamines Introduction Pharmacology and Biologic Actions Obstetrical and Fetal Effects, Including Fetal Growth Restriction Neonatal and Infant Neurobehavioral Effects Long-Term Effects Prenatal Medication Exposures That May Be Associated With Neonatal Withdrawal Selective Serotonin Reuptake Inhibitors Benzodiazepines Gabapentin Stimulant Therapy for Attention Deficit Hyperactivity Disorder (ADHD) Screening Pregnant Persons for Substance Use Disorder Pregnancy Management Human Immunodeficiency Virus and Other Viral Infections Medication-Assisted Treatment for Opioid Use Disorder During Pregnancy Methadone Buprenorphine Buprenorphine Plus Naloxone Medically Supervised Withdrawal Neonatal Management After Gestational Substance Exposure Introduction Breastfeeding and Drug Exposure Neonatal Abstinence Syndrome Clinical Findings and Biomarkers Management Nonpharmocologic Treatment Pharmacologic Treatment Challenges With Polysubstance Exposure and Nonopioid Withdrawal Postdischarge Infant Follow-Up Conclusions References Suggested Readings References 12. Assessment of Fetal Well-Being 12 Assessment of Fetal Well-Being General Principles Principles of Testing Fetal Physiology and Behavior Technology Indications and Timing Fetal Assessment in Low-Risk Pregnancies Ultrasound: Pregnancy Dating Ultrasound: Second and Third Trimesters Fetal Movement Counting Fetal Assessment in High-Risk Pregnancies Cardiotocography Nonstress Test Contraction Stress Test Ultrasound Growth Assessment Amniotic Fluid Assessment Biophysical Profile Doppler Summary References Suggested Readings References 13. Complicated Deliveries 13 Complicated Deliveries Overview Vaginal Delivery Cesarean Section Operative Vaginal Delivery: Obstetric Forceps and Vacuum Extraction Description of the Obstetric Forceps Indications for Use of Obstetric Forceps Forceps and Potential Neonatal Morbidity Vacuum Delivery: Indications, Uses, and Comparison With Forceps Procedures Shoulder Dystocia Vaginal Breech Delivery Multifetal Delivery Twin Delivery Vertex–Vertex Vertex–Nonvertex Nonvertex–Nonvertex Monochorionic, Monoamniotic Twins Higher-Order Multiple Gestations Vaginal Birth After Cesarean: Neonatal Concerns Umbilical Cord Abnormalities References Suggested Readings References 14. Obstetric Analgesia and Anesthesia 14 Obstetric Analgesia and Anesthesia Anatomy of Labor Pain Changes in Maternal Physiology and the Implications Maternal Circulatory System Maternal Airway and Respiratory Systems Maternal Gastrointestinal System Uterine and Fetal Circulation Placental and Fetal Drug Transfer Analgesic Options for Labor and Vaginal Delivery Nonpharmacologic Analgesia Systemic Medications Inhaled Nitrous Oxide Neuraxial (Regional) Analgesia Neuraxial Local Anesthetics Neuraxial Opioids Neuraxial Techniques for Labor Analgesia Epidural Analgesia Effects on the Progress of Labor and Rate of Operative Delivery Spinal Analgesia Combined Spinal-Epidural Analgesia Dural Puncture Epidural Analgesia Contraindications and Complications of Neuraxial Techniques Paracervical and Pudendal Blocks Anesthesia for Cesarean Delivery Epidural Anesthesia for Cesarean Delivery Spinal Anesthesia for Cesarean Delivery General Anesthesia Induction Agents Nitrous Oxide Inhaled Halogenated Anesthetics Neuromuscular Blocking Agents Breastfeeding and Perioperative Medications Summary References Suggested Readings References 15. Perinatal Transition and Newborn Resuscitation 15 Perinatal Transition and Newborn Resuscitation Transition from Fetal to Extrauterine Life Birth Environment and Preparation for the Delivery Umbilical Cord Management Newborn Resuscitation Initial Steps Positive Pressure Ventilation Continuous Positive Airway Pressure (CPAP) Sustained Inflation Laryngeal Mask Airways Endotracheal Intubation Supplemental Oxygen Chest Compressions Epinephrine Volume Expanders Apgar Score Delivery Room Monitoring Exhaled CO2 Detector Pulse Oximetry Electrocardiography Respiratory Function Monitors Specific Problems Encountered During Resuscitation Neonatal Response to Maternal Anesthesia/Analgesia Conditions Complicating Resuscitation Limits of Viability Noninitiation and Discontinuing of Resuscitation Post-resuscitation Care Acknowledgment References Suggested Readings References 16. Care of the Newborn 16 Care of the Newborn Introduction Initial Newborn Evaluation The Initial Assessment The Newborn History Prenatal Ultrasound Findings Central Nervous System Findings Cardiac Findings Gastrointestinal Findings Urinary Tract Findings The Physical Examination Routine Management of the Newborn Prevention of Ophthalmia Neonatorum and Conjunctivitis Vitamin K Prophylaxis Universal Hepatitis B Immunization Newborn Feeding Breastfeeding Support of Breastfeeding Challenges With Breastfeeding Supplementation of Breastfeeding Contraindications to Breastfeeding Formula Feeding Umbilical Cord Care Circumcision Newborn Metabolic Screening Hearing Screening Screening for Critical Congenital Heart Disease Common Problems in Newborn Care Hypoglycemia Risk Factors Clinical Presentation Differential Diagnosis Initial Management Respiratory Distress Perinatal Risk Factors Clinical Presentation Differential Diagnosis Initial Management Cardiovascular Concerns Perinatal Risk Factors Clinical Presentation and Initial Management Early-Onset Sepsis Perinatal Risk Factors Clinical Presentation Initial Management Hyperbilirubinemia Risk Factors Initial Management Ineffective Thermoregulation Risk Factors Initial Management Abnormal Voiding Patterns Urination Stooling Discharge of the Newborn Anticipatory Guidance Safe Sleep Infant Car Seats Pediatrician Follow-Up Special Considerations for Late Preterm Infants Hospitalization Newborn Car Seat Challenge Follow-Up After Discharge Readmission to the Hospital Acknowledgments References Suggested Readings References 17. Temperature Regulation 17 Temperature Regulation Mechanisms of Heat Loss Evaporation Radiation Convection Conduction Mechanisms of Thermoregulation Nonshivering Thermogenesis Thermal Management Strategies Delivery Room Environment Care of the Extremely LBW Infant Warming Infants Incubators Versus Radiant Warmers Weaning to an Open Crib Skin-to-Skin Care Additional Considerations Transport Hypothermia Hyperthermia Bathing Summary References Suggested Readings References 18. Newborn Screening 18 Newborn Screening Screening Procedure Specimen Specimen Collection Procedure Timing of the Collection Screening Tests Secondary Tests Physician Contact for Abnormal Results Disorders Screened Metabolic Disorders Disorders With an Amino Acid or Acylcarnitines as the Primary Marker Biotinidase Deficiency Galactosemias Lysosomal Storage Disorders X-linked Adrenoleukodystrophy Endocrine Disorders Congenital Adrenal Hyperplasia Congenital Hypothyroidism Cystic Fibrosis Sickle Cell Disease Severe Combined Immunodeficiency Spinal Muscular Atrophy Critical Congenital Heart Disease Hearing Loss Specific Issues in Newborn Screening Criteria for Newborn Screening False-Positive Results Missed Cases Increased Detection of Cases The Future References Suggested Reading References 19. Neonatal Transport 19 Neonatal Transport Controversies Regionalization of Neonatal Care, Care in the Community, and Transfer Agreements Historical Perspective Care in the Community and Back Transport Transfer Agreements Transport Communication Medical Supervision Mode of Transport Transport Personnel, Education, and Team Composition Quality Improvement Transport Administration Transport Team Safety Training and Protocols Family-Centered Care Medical Legal Issues Patient Care During Transport Extreme Prematurity and the Limits of Viability Thermoregulation Surfactant Hypoxic Respiratory Failure Neurologic Issues Congenital Heart Disease Supplemental Oxygen Prostaglandin E1 Therapy Vascular Access Surgical Emergencies Congenital Diaphragmatic Hernia Abdominal Wall Defects Esophageal Atresia and Tracheoesophageal Fistula Midgut Volvulus Necrotizing Enterocolitis Meningomyelocele Future Directions References Suggested Readings References 20. Fluid, Electrolyte, and Acid-Base Balance 20 Fluid, Electrolyte, and Acid-Base Balance Fluid and Electrolyte Balance Developmental Changes Affecting Fluid and Electrolyte Balance in the Fetus and Neonate Developmental Changes in Body Composition and Fluid Compartments Changes During Intrauterine Development Changes During Labor and Delivery Effect of Timing of Cord Clamping Changes in the Postnatal Period Physiology of the Regulation of Body Composition and Fluid Compartments Regulation of the Intracellular Solute and Water Compartment Regulation of the Intracellular–Extracellular Interface: The Interstitial Compartment Regulation of the Extracellular Solute and Water Compartment Maturation of Organs Regulating Body Composition and Fluid Compartments Maturation of the Cardiovascular System Maturation of Renal Function Maturation of the Skin Maturation of End-Organ Responsiveness to Hormones Involved in the Regulation of Fluid and Electrolyte Balance Renin–Angiotensin–Aldosterone System. Vasopressin. Atrial Natriuretic Peptide. Brain (or B-Type) Natriuretic Peptide. Prostaglandins. Prolactin. Management of Fluid and Electrolyte Homeostasis General Principles of Fluid and Electrolyte Management Assessment of Fluid and Electrolyte Status Water Homeostasis and Management Water Losses Management of Water Requirements Treatment of Fluid Overload Treatment of Dehydration Sodium Homeostasis and Management Hyponatremia Hypernatremia Treatment of Hypernatremia. Hypokalemia. Treatment of Hypokalemia. Hyperkalemia. Treatment of Hyperkalemia. Potassium Homeostasis and Management Clinical Conditions Associated With Fluid and Electrolyte Disturbances Extreme Prematurity Transient Tachypnea of the Newborn Bronchopulmonary Dysplasia Patent Ductus Arteriosus and Treatment With Indomethacin/Ibuprofen Syndrome of Inappropriate Antidiuretic Hormone Secretion Surgical Conditions Acid-Base Balance Physiology of Acid-Base Balance Regulation Disturbances of Acid-Base Balance in the Newborn General Principles Transitional Physiology After Birth Metabolic Acidosis Respiratory Acidosis Metabolic Alkalosis Respiratory Alkalosis References Suggested Readings References 21. Neonatal Pharmacology 21 Neonatal Pharmacology Principles of Neonatal Therapeutics Diagnosis Absorption Distribution Metabolism Elimination Pharmacogenetics and Pharmacogenomics Pharmacokinetic Principles Compartment First-Order Kinetics Half-Life Multicompartment First-Order Kinetics Apparent Single-Compartment First-Order Kinetics Zero-Order Kinetics Noncompartmental Analysis Advanced Mathematical Approaches: Population- and Physiology-Based Pharmacokinetic Models Target Drug Concentration Strategy Therapeutic Drug Monitoring (TDM) Pharmacokinetic-Based Dosing Repetitive Dosing and the “Plateau Principle” Clearance Modeling and Simulations Clinical Applications of Pharmacokinetics How to Estimate Dose Adjustments Gentamicin Phenobarbital Adverse Drug Reactions Illustrations of Adverse Drug Reactions in Neonates Reduction and Prevention of Medication Errors in Newborn Care Drug Elimination in Breast Milk Neonatal Drug Development Remains an Obvious and Shared Need Summary References Suggested Readings References 22. Neonatal Pain and Stress 22 Neonatal Pain and Stress Background Taxonomy Ontogeny and Development of Pain and Stress Responses Recognizing and Treating Pain Infant Pain Scores Bedside Noninvasive Neurophysiologic Measures to Evaluate Pain and Stress Long-Term Consequences of Neonatal Pain and Stress Clinical Pain and Stress Management Strategies Fetal Interventions Postoperative Pain Management Strategies Mechanical Ventilation Procedures Blood Sampling and Monitoring Tracheal Intubation Circumcision Other Invasive Procedures Pharmacologic Analgesia Nonopioid Analgesics Nonsteroidal Antiinflammatory Drugs (Indomethacin, Ibuprofen, Ketorolac) Acetaminophen Opioid Analgesics Morphine Fentanyl Enterally Dosed Opioids Long-Term Effects of Neonatal Opioid Exposure Experimental Animal Studies Clinical Studies Topical and Local Anesthetics Sedatives Benzodiazepines Dexmedetomidine and Clonidine Gabapentin Nonpharmacologic Analgesia Summary References Suggested Readings References 23. Palliative Care 23 Palliative Care What Is Palliative Care? Paradigms of Palliative Care Scope of the Problem Which Patients Benefit From Neonatal-Perinatal Palliative Care? Timing of the News Early Prenatal Diagnosis Late Prenatal Diagnosis Postnatal Diagnosis Components of Neonatal-Perinatal Palliative Care in the Neonatal Intensive Care Unit Neonatal End-of-Life Care Memory-making, Legacy Building, and Grief and Bereavement Support Ethical Concerns Barriers to Palliative Care in the Neonatal Intensive Care Unit Training in Neonatal–Perinatal Palliative Care Research Opportunities/Future Directions References Suggested Readings References 24. Risk Assessment a­nd N­eu­ro­de­ve­lop­mental Outcomes 24 Risk Assessment a­nd N­eu­ro­de­ve­lop­mental Outcomes Outcome Assessment in High-Risk Infants Who Is the “High-Risk” Infant? What Is Meant by “Outcomes”? Early Neurodevelopmental Outcome Assessments Motor Function Cognitive Assessment Hearing and Vision Outcomes Neurodevelopmental Impairment—Difficulties and Realities of a Composite Outcome Limitations and Challenges to Interpreting Early Neurodevelopmental Outcomes Studies Focus on Functional and Adaptive Outcomes Outcomes of Preterm Infants Across the Life Spectrum Early Neurodevelopmental Outcomes of Extremely Preterm Infants The Victoria Infant Collaborative Study Group EPICure 2 Extremely Preterm Infants in Sweden Study Japan Neonatal Research Network Eunice Kennedy Shriver NICHD Neonatal Research Network Follow-Up Study Group Canadian Neonatal Follow-Up Network (CNFUN) School-Age Outcomes After Prematurity Adolescent and Adult Outcomes After Prematurity Risk Factors for Adverse Outcomes in Preterm Infants Brain Injury Cranial Ultrasound Magnetic Resonance Imaging Bronchopulmonary Dysplasia Retinopathy of Prematurity Infection Necrotizing Enterocolitis Growth and Nutrition Socioeconomic Status Other Infants at High Risk for Adverse Outcomes Hypoxic–Ischemic Encephalopathy Congenital Heart Disease Extracorporeal Membrane Oxygenation Postdischarge Management of the High-Risk Infant Discharge Planning for the High-Risk Infant Referral for Early Intervention Services What Is Multidisciplinary Follow-Up Care for the High-Risk Infant? Challenges of the Current State Goals for the Future State Challenges to and Importance of Follow-Up References Suggested Readings References 25. The Human Genome and Neonatal Care 25 The Human Genome and Neonatal Care The Human Genome Project and the Big Picture of Genomic Medicine The Genome and Genomics Mitochondrial Deoxyribonucleic Acid Variations in the Human Genome Single Nucleotide Polymorphisms Copy Number Variants Variant Counts in Individuals Linking Genes and Diseases Making a Diagnosis in the Post Human Genome Era Clinical Application of Next-Generation Sequencing Incidental Findings Genomics of Common Complex Diseases Associated With Prematurity Retinopathy of Prematurity Necrotizing Enterocolitis Intraventricular Hemorrhage Bronchopulmonary Dysplasia Conclusion References Suggested Readings References 26. Prenatal Diagnosis and Counseling 26 Prenatal Diagnosis and Counseling Background Principles of Prenatal Screening and Diagnosis Invasive Prenatal Diagnostic Procedures Midtrimester Genetic Amniocentesis Chorionic Villus Sampling Percutaneous Umbilical Cord Blood Sampling Genetic Testing of the Fetus Microarray Technology Whole Exome Sequencing Noninvasive Prenatal Screening Maternal Serum Screening Cell-Free DNA (Noninvasive Prenatal Screening—NIPS) Prenatal Fetal Imaging Preimplantation Genetic Diagnosis/Screening Preimplantation Genetics Building a Prenatal Diagnosis Center The People The Infrastructure A Practical Guide to Prenatal Counseling The Role of a Neonatologist in Prenatal Diagnosis Clinic Summary References Suggested Readings References 27. The Dysmorphic Infant 27 The Dysmorphic Infant When and Why to Consider a Genetic Evaluation Patterns of Anomalies Genetics Evaluation History Prenatal Birth Medical Pedigree Analysis and Family History Specialized Clinical Evaluations Physical Examination for Dysmorphology Adjunct Studies Literature Review Specialized Laboratory Tests Diagnosis Example Evaluations for Common Neonatal Anomalies Summary Suggested Online Resources References Suggested Readings References 28. Chromosome Disorders 28 Chromosome Disorders Human Karyotype Fluorescence in situ hybridization (FISH) Chromosomal Microarray Analysis (CMA) Trisomies Down Syndrome (Trisomy 21) Clinical Features Genetic Counseling Trisomy 18 (Edwards Syndrome) Clinical Features Genetic Counseling Trisomy 13 (Patau Syndrome) Clinical Features Genetic Counseling 45,X (Turner Syndrome) Clinical Features Triploidy (69,XXX or 69,XXY) Deletion Syndromes Chromosome 1p Deletion Syndrome (1p–) Wolf–Hirschhorn Syndrome (4p–) Cri du Chat Syndrome (5p–) Segmental Duplications and Microdeletion/Microduplication Syndromes Williams–Beuren Syndrome (7q11.2 Deletion) 22q11.2 Deletion Syndrome Additional Microdeletion and Microduplication Syndromes Disorders of Imprinted Chromosomes Prader–Willi Syndrome Angelman Syndrome Beckwith–Wiedemann Syndrome Russell–Silver Syndrome Future Directions: Characterization of Structural Variation by Genome Sequencing Summary References Suggested Readings References 29. Inborn Errors of Carbohydrate, Ammonia, Amino Acid, and Organic Acid Metabolism 29 Inborn Errors of Carbohydrate, Ammonia, Amino Acid, and Organic Acid Metabolism Carbohydrate Metabolism Disorders Galactosemia Epimerase Deficiency Galactosemia Galactokinase Deficiency Glycogen Storage Diseases Hepatic Glycogen Storage Diseases Muscular Glycogen Storage Diseases Fructose Metabolism Urea Cycle Disorders Transient Hyperammonemia of the Newborn Amino Acid Metabolism Disorders Maple Syrup Urine Disease Tyrosinemia Type 1 Nonketotic Hyperglycinemia Hyperhomocysteinemias: Cystathionine β-Synthase Deficiency and Remethylation Disorders Phenylketonuria Organic Acidemias Methylmalonic Acidemia Propionic Acidemia Isovaleric Acidemia Multiple Carboxylase Deficiency Glutaric Aciduria Type 1 Fatty Acid Oxidation Disorders Medium-Chain Acyl-CoA Dehydrogenase Deficiency Very Long-Chain Acyl-CoA Dehydrogenase Deficiency Short-Chain Acyl-CoA Dehydrogenase Deficiency Long-Chain 3-Hydroxy Acyl-CoA Dehydrogenase Deficiency and Trifunctional Protein Deficiency Primary Carnitine Transporter Deficiency Carnitine Palmitoyltransferase Type I Deficiency Carnitine Acylcarnitine Translocase Deficiency Carnitine Palmitoyltransferase Type II Deficiency Multiple Acyl-CoA Dehydrogenase Deficiency Ketone Metabolism Disorders Mitochondrial Disorders Primary Lactic Acidosis Pyruvate Dehydrogenase Complex Deficiency Pyruvate Carboxylase Deficiency Electron Transport Chain Defects Leigh Disease: Subacute Necrotizing Encephalomyelopathy Pearson Syndrome Barth Syndrome Early Lethal Lactic Acidosis References Suggested Readings References 30. Lysosomal Storage Disorders Presenting in the Neonate 30 Lysosomal Storage Disorders Presenting in the Neonate​ Introduction Clinical Presentations Acid Sphingomyelinase Deficiency (Niemann–Pick Disease Types A and B) Etiology Clinical Features Niemann-Pick Disease Type C Etiology Clinical Features Gaucher Disease Type 2 (Acute Neuronopathic) Etiology Clinical Features Krabbe Disease (Globoid Cell Leukodystrophy) Etiology Clinical Features GM1 Gangliosidosis Etiology Clinical Features Mucopolysaccharidosis Type I Etiology Clinical Features Mucopolysaccharidosis Type VII (Sly Disease) Etiology Clinical Features Wolman Disease Etiology Clinical Features Farber Lipogranulomatosis Etiology Clinical Features Sialidosis Etiology Clinical Features Galactosialidosis Etiology Clinical Features Infantile Sialic Acid Storage Disease Etiology Clinical Features I-Cell Disease Etiology Clinical Features Mucolipidosis Type IV Etiology Clinical Features Diagnosis, Management, and Prognosis of Lysosomal Storage Diseases References Suggested Readings References 31. Congenital Disorders of Glycosylation, Peroxisomal Disorders, and Smith-­Lemli-Opitz Syndrome 31 Congenital Disorders of Glycosylation, Peroxisomal Disorders, and Smith-­Lemli-Opitz Syndrome Congenital Disorders of Glycosylation Epidemiology of Congenital Disorders of Glycosylation Clinical Presentation of Congenital Disorders of Glycosylation N-Linked Protein Glycosylation Defects Etiology Clinical Features O-Linked Protein Glycosylation Defects Etiology Clinical Features Combined Glycosylation Defects Etiology Clinical Features Glycosylphosphatidylinositol Anchor Glycosylation Defects Etiology Clinical Features Lipid Glycosylation Defects Diagnosis of Congenital Disorders of Glycosylation Management of Congenital Disorders of Glycosylation Peroxisomal Disorders Epidemiology of Peroxisomal Disorders Clinical Presentation of Peroxisomal Disorders Disorders of Peroxisomal Biogenesis Zellweger Syndrome Neonatal Adrenoleukodystrophy Infantile Refsum Disease Rhizomelic Chondrodysplasia Punctata Peroxisomal Fission Defects Single Peroxisomal Enzyme Defects D-Bifunctional Protein Deficiency Acyl-Coenzyme A Oxidase Deficiency 2-Methylacyl-Coenzyme A Racemase Deficiency X-Linked Adrenoleukodystrophy Diagnosis of Peroxisomal Disorders Management of Peroxisomal Disorders Outcomes of Peroxisomal Disorders Smith-Lemli-Opitz Syndrome Etiology of Smith-Lemli-Opitz Syndrome Clinical Features of Smith-Lemli-Opitz Syndrome Diagnosis of Smith-Lemli-Opitz Syndrome Management of Smith-Lemli-Opitz Syndrome References Suggested Readings References 32. Immunology of the Fetus and Newborn 32 Immunology of the Fetus and Newborn Maternal and Placental Immunology Role of Regulatory T Cells in Pregnancy Role of the Microbiome Effect of Chorioamnionitis on the Developing Fetal Immune System Developmental Fetal–Neonatal Immunology Innate Immunity Complement Antimicrobial Proteins and Peptides Innate Lymphoid Cells, Including Natural Killer Cells Polymorphonuclear Neutrophils Monocytes, Macrophages, and Dendritic Cells Adaptive Immunity T Lymphocytes Recent Thymic Emigrants and the Naïve T-Cell Compartment Naïve CD4 T-Cell Activation into Effector Th1, Th2, Th17, and Follicular Helper T cells Circulating Cord Blood CD4 T Cells with Th1, Th2, and Th17 Memory Phenotypes Naïve CD8 T-Cell Activation into Cytolytic Effector Cells Antigen-Specific Memory T-Cell Responses Regulatory T Cells γδ T Cells Natural Killer T Cells Mucosal-Associated Invariant T Cells Tissue Resident Memory (TRM) CD4 and CD8 T Cells B Lymphocytes B-Cell Development B-Cell Preimmune Selection and Maturation Fetal and Neonatal B-Cell Development and Surface Phenotype B-Cell Activation, Somatic Hypermutation, and Isotype Switching Immunoglobulins Immunoglobulin G Immunoglobulin M Immunoglobulin A Immunoglobulin E Immunoglobulin D Specific Immunologic Deficiencies of the Newborn Severe Combined Immunodeficiency Syndrome Epidemiology Pathophysiology Clinical Presentation Evaluation Management Outcome DiGeorge Syndrome (22q11.2 Deletion Syndrome) Epidemiology Pathophysiology Clinical Presentation Evaluation Management Outcome Combined Immune Disorders Involving T Cells and B Cells B-Cell Immunodeficiencies Innate Immune Deficiency Disorders Implications of Studies of Immune Ontogeny for Enhancing Neonatal Immunization Acknowledgments References Suggested Readings References 33. Neonatal Bacterial Sepsis and Meningitis 33 Neonatal Bacterial Sepsis and Meningitis Early-Onset Neonatal Bacterial Infections Pathogenesis of Early-Onset Neonatal Bacterial Infections Epidemiology of Early-Onset Bacterial Infections Bacterial Pathogens in Early-Onset Infections Group B Streptococcal Infections Transmission of GBS to Infants and the Role of Intrapartum Antibiotic Prophylaxis Group B Streptococcal Virulence Factors GBS Sepsis Escherichia Coli Infections Listeria Monocytogenes Infections Miscellaneous Bacterial Pathogens Clinical Signs of Early-Onset Bacterial Infections Evaluation of Early-Onset Bacterial Infections Laboratory Testing Blood Culture Urine Culture Cerebrospinal Fluid White Blood Cell Count and Neutrophil Indices Platelet Counts Acute-Phase Reactants Bacterial Polymerase Chain Reaction (PCR) Diagnostic Approach to Neonates with Suspected Sepsis Diagnostic Approach for Neonates at Risk for GBS Early-Onset Disease (GBS-EOD) Treatment of Early-Onset Bacterial Infections Antimicrobial Therapy Experimental Immunologic Adjuvant Therapies Late-Onset Neonatal Bacterial Infections Pathogenesis and Epidemiology of Late-Onset Neonatal Bacterial Infections Late-Onset Bacterial Pathogens Coagulase-Negative Staphylococci Gram-Negative Bacteria Bacterial Pathogens Causing Both EOS and LOS: GBS and L. monocytogenes Prevention Strategies for Late-Onset Neonatal Bacterial Infections Evaluation of a Neonate with Potential Late-Onset Bacterial Sepsis Treatment of Late-Onset Neonatal Bacterial Infections Neonatal Bacterial Meningitis Pathology and Clinical Manifestations of Neonatal Bacterial Meningitis Diagnosis of Neonatal Bacterial Meningitis Treatment of Neonatal Bacterial Meningitis Outcomes of Neonatal Bacterial Meningitis References Suggested Readings References 34. Viral Infections of the Fetus and Newborn 34 Viral Infections of the Fetus and Newborn Introduction General Diagnostic Concepts Cytomegalovirus Epidemiology Postnatal Acquisition of Cytomegalovirus: Implications for the Premature Infant Pathophysiology Clinical Presentation Diagnosis Prenatal Diagnosis Postnatal Diagnosis Management Prevention Rubella Epidemiology Pathogenesis Clinical Presentation Evaluation Management Outcomes Prevention Human Parvovirus B19 Epidemiology Pathophysiology Clinical Presentation Evaluation Management Outcomes Prevention Zika Virus Epidemiology Pathophysiology Clinical Presentation Evaluation Management Outcomes Lymphocytic Choriomeningitis Virus Epidemiology Pathophysiology Clinical Presentation Evaluation Management Prevention Outcomes Herpes Simplex Viruses Epidemiology Pathophysiology Clinical Presentation Evaluation Management Prevention Outcomes Varicella-Zoster Virus Epidemiology Pathophysiology Clinical Presentation Congenital Neonatal Evaluation Congenital Neonatal Management Prevention Outcomes Human Immunodeficiency Virus Epidemiology Prevention Antepartum Intrapartum Postpartum Management Management of the HIV-Exposed Infant Management of the HIV-Infected Infant Hepatitis Viruses Hepatitis B Virus Epidemiology Pathophysiology Clinical Presentation Evaluation Prevention Management Outcomes Hepatitis C Virus Epidemiology Pathophysiology Clinical Presentation Evaluation Management Prevention Outcomes Enteroviruses and Parechoviruses Epidemiology Pathophysiology Clinical Presentation Evaluation Management Prevention Outcomes Respiratory Viruses Respiratory Syncytial Virus Epidemiology Clinical Presentation Evaluation Prevention Influenza SARS-CoV-2 Adenoviruses Epidemiology Clinical Presentation Management Prevention Gastroenteritis Viruses Rotavirus Norovirus Human Herpesviruses 6, 7, and 8 Human Herpesvirus 6 and 7 Human Herpesvirus 8 Epstein-Barr Virus References Suggested Readings References 35. Congenital Toxoplasmosis, Syphilis, Malaria, and Tuberculosis 35 Congenital Toxoplasmosis, Syphilis, Malaria, and Tuberculosis Congenital Toxoplasmosis Epidemiology Pathogenesis Clinical Presentation Evaluation Management Outcomes Prevention Congenital Syphilis Epidemiology Pathogenesis Clinical Presentation Evaluation Management Prevention Congenital Malaria Epidemiology Pathogenesis Clinical Presentation Evaluation Management Outcomes Prevention Congenital Tuberculosis Epidemiology Pathogenesis Clinical Presentation Evaluation Management Outcomes Prevention References Suggested Readings References 36. Fungal Infections in the Neonatal Intensive Care Unit 36 Fungal Infections in the Neonatal Intensive Care Unit Epidemiology Pathophysiology Infections Caused by Candida Species Congenital Candidiasis Local Infections With Candida Species Diaper Dermatitis Funisitis Urinary Tract Infection Peritonitis Systemic Infection Candidemia Associated With Central Venous Catheters Disseminated Candidiasis Antifungal Therapy for Systemic Infection Antifungal Prophylaxis Infections Ascribable to Other Fungi Invasive Fungal Dermatitis Line Infections Caused by Lipophilic Organisms Miscellaneous Fungal Infections Aspergillus Species Trichosporon beigelii References Suggested Readings References 37. Healthcare-Associated Infections 37 Healthcare-Associated Infections Defining Neonatal Healthcare-Associated Infection Diagnosing Neonatal Healthcare-Associated Infection Diagnosis of Central Line–Associated Bloodstream Infection Diagnosis of Ventilator-Associated Pneumonia Diagnosis of Urinary Tract Infection Healthcare-Associated Infection Surveillance and Data Sources Epidemiology of Healthcare-Associated Infection Healthcare-Associated Infection in the Newborn Nursery Healthcare-Associated Infection in the Neonatal Intensive Care Unit Risk Factors for Development of Healthcare-Associated Infection Risk Factors for Central Line–Associated Bloodstream Infection Risk Factors for Ventilator-Associated Pneumonia Risk Factors for Urinary Tract Infection Healthcare-Associated Infection: Distribution by Pathogen Microbial Resistance Gram-Positive Bacteria Coagulase-Negative Staphylococci Staphylococcus aureus Enterococcus Group B Streptococcus Gram-Negative Bacteria Fungi Viruses Respiratory Syncytial Virus Influenza Rotavirus Enterovirus Prevention of Healthcare-Associated Infection Quality Improvement Efforts Overall Approach to Infection Control Guidelines for Hand Hygiene Practices Guidelines for Gloves and Gowns Care of the Patient Environment Human Milk Feedings Skin Care Surveillance for Resistant Pathogens and Control Measures Additional Strategies in Limited Resource Settings Prevention of Central Line–Associated Bloodstream Infection Catheter Removal Following Central Line–Associated Bloodstream Infection Prevention of Healthcare-Associated Pneumonia Antibiotic and Adjunctive Therapies Adverse Outcomes Related to Healthcare-Associated Infection Conclusion References Suggested Readings References 38. Lung Development 38 Lung Development Key Events in Lung Development Development of Airways and Gas Exchange Surfaces Composition of Airways and Alveoli Proximal Airways Distal Airways Alveolar Epithelium Surfactant Development of the Pulmonary Vasculature Development of Pulmonary Host Defense Development of Detoxification Systems Mechanisms of Lung Development Branching Morphogenesis Stretch and Mechanotransduction Static Stretch: Fetal Lung Fluid Production Cyclic Stretch: Fetal Breathing Movements Alveolarization Interdependence of Alveolar and Vascular Development Molecular Basis for Lung Development Growth Factors in Lung Development Transcription Factors in Lung Development Disorders of Lung Development Novel Concepts in Lung Development Stem/Progenitor Cells in the Lung Epigenetic Regulation of Lung Development and Maturation Summary References Suggested Readings References 39. Neonatal Pulmonary Physiology 39 Neonatal Pulmonary Physiology Lung Volumes and Lung Mechanics Respiratory System Compliance Airway Resistance Inertance Dynamic Interaction Work of Breathing Time Constants Measurements of Respiratory System Mechanics Pulmonary Gas Exchange Overview Tools Available for Assessing Pulmonary Gas Exchange Principles of Ventilation Perfusion Matching Some Specific Conditions Impacting VA/Q Matching Positive Pressure Ventilation and Gas Exchange Acknowledgment References Suggested Readings References 40. Neonatal Respiratory Therapy 40 Neonatal Respiratory Therapy KEY POINTS Respiratory Support Supplemental Oxygen Target Ranges of O2 and CO2 Target Ranges for PaO2 and SPO2 PCO2 and pH Target Ranges Types of Noninvasive Respiratory Support Head Box or Tent O2 Administration Nasal Cannula O2 Administration High-Flow Nasal Canula Nasal Continuous Positive Airway Pressure Bi-Level NCPAP Noninvasive Ventilation Noninvasive Ventilation and Neurally Adjusted Ventilatory Assist Noninvasive High-Frequency Ventilation Nasal Interface Complications of Noninvasive Support Choice of Noninvasive Support Weaning From Noninvasive Support Invasive Mechanical Ventilation Intubation Conventional Ventilation Time-Cycled Pressure-Limited Intermittent Mandatory Ventilation Synchronized Intermittent Mandatory Ventilation Assist/Control Ventilation Pressure Support Ventilation Volume-Targeted Ventilation Choice of Conventional Ventilator Modes High-Frequency Ventilation Types of High-Frequency Ventilation High-Frequency Oscillatory Ventilation High-Frequency Jet Ventilation High-Frequency Percussive Ventilation Clinical Use of High-Frequency Ventilation When to Initiate Invasive Mechanical Ventilation Weaning From Mechanical Ventilation Weaning From High-Frequency Ventilation Weaning From Conventional Ventilation Extubation Failure Inspired Gas Conditioning Other Respiratory Gases Nitric Oxide Nitrogen Heliox Pulmonary Drug Delivery Surfactant Aerosol Drug Delivery Bronchodilators Steroids Mucolytics Veno-Arterial Extracorporeal Membrane Oxygenation Veno-Venous Extracorporeal Membrane Oxygenation Extracorporeal Membrane Oxygenation Types of Extracorporeal Membrane Oxygenation Liquid Ventilation Monitoring Respiratory Status Physical Exam Chest Radiograph Respiratory and Heart Rate Monitors Graphics Monitoring During Conventional Ventilation Blood Gas Measurement Arterial Catheters Arterial Puncture Capillary Blood Gas Venous Blood Gas Mixed Venous Saturation Errors in Blood Gas Measurement Noninvasive Estimation of Blood Gases Pulse Oximetry Transcutaneous Blood Gas Monitoring End-Tidal Carbon Dioxide Monitoring Near-Infrared Spectroscopy Acknowledgment References Suggested Readings References 41. Control of Breathing 41 Control of Breathing Animal Models of Control of Breathing Respiratory Muscles Brainstem Rhythmogenesis Neurochemical Control of Respiration Genetic Mutations Affecting Respiratory Control Bronchopulmonary Reflexes That Modulate the Central Respiratory Network Slowly Adapting Stretch Receptors: Major Modulators of Respiratory Timing Rapidly Adapting Receptors: Cough, Augmented Breaths C-Fiber Receptors: Apnea, Bronchoconstriction, Rapid Shallow Breathing Laryngeal Reflexes Maturation of CO2/H+ Sensitivity of Central Chemoreceptors Maturation of O2 Sensitivity of Peripheral Arterial Chemoreceptors Hypoxic Ventilatory Depression: Consequences for the Neonate Effect of Sleep State on Breathing Apnea of Prematurity Therapeutic Approaches Continuous Positive Airway Pressure Methylxanthines Gastroesophageal Reflux and Apnea of Prematurity Resolution and Consequences of Neonatal Apnea References Suggested Readings References 42. Acute Neonatal Respiratory Disorders 42 Acute Neonatal Respiratory Disorders Evaluation of the Newborn With Hypoxemia/Respiratory Distress History Physical Examination Response to Supplemental Oxygen Interpretation of Pulse Oximetry Measurements Laboratory and Radiologic Evaluation Echocardiography Persistent Pulmonary Hypertension of the Newborn Specific Pulmonary Conditions Causing Respiratory Distress in the Newborn Respiratory Distress Syndrome Risk Factors Pathophysiology Surfactant Physiology Clinical Signs Laboratory Features Radiographic Features Treatment Antenatal Steroids Continuous Positive Airway Pressure Exogenous Surfactant Historical Summary Types of Surfactants Available for Clinical Use Surfactant Selection Timing and Method of Surfactant Administration Number of Surfactant Doses and Dosing Intervals Clinical Care After Dosing Pulmonary Hemorrhage Incidence and Clinical Signs Etiology Treatment Pulmonary Hypoplasia Etiology and Incidence Prenatal Diagnosis Prenatal Treatment Pathology Clinical and Radiographic Signs Treatment Pneumonia Incidence and Etiology Clinical, Laboratory, and Radiographic Signs Treatment Air Leak Syndromes Etiology and Incidence Clinical, Laboratory, and Radiographic Signs Treatment Transient Tachypnea of the Newborn Definition and Etiology Diagnosis Treatment Prognosis Aspiration Syndromes Definition and Etiology Prevention Clinical and Radiographic Signs Treatment Congenital Diaphragmatic Hernia Surfactant Protein Deficiency Overview Surfactant-Associated Protein B Deficiency Surfactant-Associated Protein C Deficiency Adenosine Triphosphate–Binding Cassette Subfamily A Member 3 Deficiency Thyroid Transcription Factor 1 Gene Mutation Surfactant-Associated Proteins A and D Other Interstitial Lung Diseases Alveolar Capillary Dysplasia/Misalignment of Pulmonary Veins Pulmonary Interstitial Glycogenosis Summary Acknowledgment References Suggested Readings References 43. Chronic Neonatal Respiratory Disorders 43 Chronic Neonatal Respiratory Disorders KEY POINTS Introduction Epidemiology of Bronchopulmonary Dysplasia and the Vulnerable Preterm Lung Additional Risks to the Developing Lung Pharmacological Prevention of Bronchopulmonary Dysplasia Persistent Respiratory Morbidity in Former Preterm Newborns Composite Respiratory Morbidity Outcomes Antecedents and Covariates for Persistent Respiratory Morbidity Wheeze, Asthma, and Lung Function in Former Preterm Newborns Conclusions References Suggested Readings References 44. Anatomic Disorders of the Chest and Airways 44 Anatomic Disorders of the Chest and Airways Anomalies of the Airways Nasopharyngeal Obstructive Disorders Congenital Choanal Atresia Congenital Nasal Pyriform Aperture Stenosis Pierre Robin Syndrome (Robin Sequence) Glossoptosis–Apnea Syndrome Pharyngeal Incoordination Laryngeal Deformities Laryngomalacia (Congenital Laryngeal Stridor) Vocal Cord Paralysis Laryngeal Atresia Congenital Subglottic Stenosis Congenital Subglottic Hemangioma Laryngotracheoesophageal Cleft (Congenital Laryngeal Cleft) Tracheal Deformities and Other Tracheal Disorders Tracheal Agenesis Congenital Tracheal Stenosis Tracheobronchomalacia (Tracheomalacia) Tracheal Compression by Vascular Rings Tracheal Compression by Extrinsic Masses Congenital High Airway Obstruction Syndrome (CHAOS) and the Ex-Utero (3HD) Intrapartum Treatment (EXIT) Procedure Disorders of the Mediastinum Thymus Congenital Mediastinal Teratoma Congenital Bronchogenic Cysts Neurenteric Cysts Congenital Thoracic Neuroblastoma Disorders of the Chest Wall Skeletal Disorders Defects of Sternal Fusion Pectus Excavatum Poland Syndrome Thoracic Dystrophies Asphyxiating Thoracic Dystrophy (Jeune Syndrome) Other Thoracic Dystrophies Neuromuscular Disorders Disorders of the Pleural Cavity Congenital Chylothorax Management of Chylothorax Congenital Thoracic Masses and Cysts Congenital Pulmonary Airway Malformation of the Lung Congenital Pulmonary Airway Malformation Types Fetal Diagnosis and Natural History Prenatal Management Postnatal Management Bronchopulmonary Sequestration Other Cystic Lesions Congenital Lobar Emphysema Pleuropulmonary Blastoma Postinfectious Pneumatoceles Hyperinflation and Emphysema in Chronic Lung Disease Miscellaneous Cysts Disorders of the Diaphragm Congenital Diaphragmatic Hernia Prenatal Diagnosis and Management Postnatal Diagnosis and Management Long-Term Morbidity Hepatopulmonary Fusion Congenital Eventration of the Diaphragm Diaphragmatic Paresis Neonatal Scimitar Syndrome Acknowledgments References Suggested Readings References 45. Developmental Biology of the Heart 45 Developmental Biology of the Heart Overview of Cardiac Developmental Anatomy Cell Types Within the Heart and Their Origins Gastrulation and the Cardiac Crescent Genetic Control of Gastrulation Looping and Laterality of the Heart Tube Genetic Control of the Secondary Heart Field and Cardiac Looping Clinical Abnormalities in Cardiac Looping and Laterality Ventricular Inlet Septation: Endocardial Cushions Clinical Abnormalities of the AV Canal Ventricular Outflow Tract Septation: Endocardial Cushions and Neural Crest Clinical Conotruncal Defects and DiGeorge Syndrome Separation of Aorta and Pulmonary Artery Cardiac Valve Formation Clinical Valve Abnormalities and Noonan Syndrome Development of the Ventricles and Ventricular Septum Development of the Atria and Atrial Septum Systemic and Pulmonary Vein Development Aortic Arch Development Coronary Arteries Conduction System Conclusion References Suggested Readings References 46. Cardiovascular Compromise in the Newborn Infant 46 Cardiovascular Compromise in the Newborn Infant Principles of Developmental Cardiovascular Physiology and Pathophysiology, Phases, and Etiology of Neonatal Shock Principles of Oxygen Delivery Developmental Regulation of Cardiac Output and Its Determinants Preload Contractility Afterload Changes in Preload, Contractility, and Afterload During Transition Developmental Regulation of Systemic Blood Pressure Developmental Regulation of Organ Blood Flow and Its Autoregulation and Vital Organ Assignment Cerebral Blood Flow Autoregulation Vital Organ Assignment Developmental Regulation of Cerebral Oxygen Demand-Delivery Coupling Phases of Shock Pathogenesis of Neonatal Shock Etiologic Factors Hypovolemia Myocardial Dysfunction Abnormal Peripheral Vasoregulation Clinical Presentations of Shock in Neonates Associated With Multiple Etiologic Factors Transitional Circulatory Compromise of the Very Preterm Neonate Low Preload and Immediate Umbilical Cord Clamping Myocardial Dysfunction and High Afterload Patent Ductus Arteriosus Respiratory Support and Hemodynamics Ischemia-Reperfusion Vital Organ Assignment Vasopressor-Resistant Hypotension Sepsis Diagnosis of Circulatory Compromise Heart Rate and Blood Pressure Capillary Refill Time (CRT) Core-Peripheral Temperature Difference Low Urine Output and Hyperkalemia Lactic Acid, pH, and Base Excess Organ Blood Flow Near-Infrared Spectroscopy (NIRS) Echocardiographic Systemic Blood Flow Measures Measurement of Systemic Blood Flow Using Electrical Impedance Velocimetry Treatment of Neonatal Shock Association Between Systemic Hypotension, Hypoperfusion, and Their Treatment and Mortality or Neurodevelopmental Impairment Volume Administration Dopamine and Dobutamine Hemodynamic Effects of Dopamine Hemodynamic Effects of Dobutamine Dopamine Versus Dobutamine Epithelial and Neuroendocrine Effects Epinephrine, Norepinephrine, and Other Cardiovascular Agents and Hormones Epinephrine Norepinephrine Milrinone Vasopressin Steroid Administration Steroid Administration as Primary or Rescue Treatment Rationale for Hydrocortisone Treatment Clinical Applications of Hydrocortisone Short-term Side Effects Long-term Side Effects Extracorporeal Membrane Oxygenation (ECMO) for Circulatory Support General Supportive Measures References Suggested Readings References 47. Persistent Pulmonary Hypertension 47 Persistent Pulmonary Hypertension Introduction Normal Fetal Pulmonary Vascular Development and Transition at Birth Pathophysiology Risk Factors Abnormal Pulmonary Vasoregulation in PPHN Disorders Associated With Pulmonary Hypertension at Birth Congenital Diaphragmatic Hernia Alveolar Capillary Dysplasia Pulmonary Hypertension in Premature Infants Clinical Evaluation and Diagnosis General Management Oxygen Inhaled Nitric Oxide Other Therapeutic Agents Phosphodiesterase Inhibitors Prostanoids Milrinone Endothelin Receptor Antagonists Magnesium Sulfate Outcomes Summary References Suggested Readings References 48. Patent Ductus Arteriosus in the Preterm Infant 48 Patent Ductus Arteriosus in the Preterm Infant Introduction Diagnosis Incidence (Table 48.1) Regulation of Ductus Patency—Vasoconstriction and Vasorelaxation In Utero Regulation Chronic Inhibition of Prostaglandin Signaling In Utero Postnatal Regulation (Box 48.1) Developmental Regulation (Box 48.2) Anatomic Closure-Histologic Changes Relationship Between Vasoconstriction and Anatomic Closure (Fig. 48.1) Genetic Regulation Hemodynamic and Pulmonary Alterations Treatment Treatment Options for Closing a Patent Ductus Arteriosus Indomethacin and Intracranial Hemorrhage Patent Ductus Arteriosus and Neonatal Morbidity: To Close or Not to Close the Patent Ductus Arteriosus References Selected Readings References 49. Perinatal Arrhythmias 49 Perinatal Arrhythmias Conduction System of the Human Heart Sinus Node Atrioventricular Node His–Purkinje System Neonatal Arrhythmias Abnormalities in Cardiac Conduction First-Degree Atrioventricular Block Second-Degree Atrioventricular Block Third-Degree Atrioventricular Block Ventricular Preexcitation Abnormalities in Cardiac Rhythm Ectopic Beats Premature Atrial Complexes Premature Ventricular Complexes Tachyarrhythmias Orthodromic Reciprocating Tachycardia Permanent Form of Junctional Reciprocating Tachycardia Atrial Ectopic Tachycardia Junctional Ectopic Tachycardia Neonatal Atrial Flutter Ventricular Tachycardia Management Considerations for Neonatal Tachyarrhythmias Bradyarrhythmias Blocked Premature Atrial Complex Long QT Syndrome Congenital Complete Atrioventricular Block Fetal Arrhythmias Benign Arrhythmias Management of Benign Arrhythmias Fetal Tachycardias Orthodromic Reentrant Tachycardia Atrial Flutter Sustained Ventricular Tachycardia Rare Tachycardias Sinus Tachycardia Arrhythmia Medications Fetal Bradycardia Benign Fetal Bradycardia Ion Channelopathies Atrioventricular Block References Suggested Readings References 50. Congenital Heart Disease 50 Congenital Heart Disease General Considerations Fetal-to-Postnatal Transition Nomenclature Clinical Evaluation of the Newborn Laboratory Assessment of the Neonate Genetics and Congenital Heart Disease The Genetic Work-Up of Congenital Heart Disease Heart Transplantation Ventricular Assist Devices Murmurs in the Newborn—Congenital Cardiac Lesions Patent Ductus Arteriosus and Aortopulmonary Window Ventricular Septal Defect Atrial Septal Defects Atrioventricular Septal Defects Peripheral Pulmonic Stenosis Pulmonic Stenosis Aortic Stenosis Cyanosis in the Newborn Transposition of the Great Arteries Tetralogy of Fallot Tetralogy of Fallot Absent Pulmonary Valve Pulmonary Atresia With Intact Ventricular Septum Tricuspid Atresia Ebstein Anomaly of the Tricuspid Valve/Tricuspid Valve Dysplasia Truncus Arteriosus Total Anomalous Pulmonary Venous Return Double Outlet Right Ventricle Lesions That Present Primarily With Heart Failure Hypoplastic Left Heart Syndrome Obstructed Total Anomalous Pulmonary Venous Return Cor Triatriatum Mitral Stenosis Critical Aortic Stenosis Coarctation of the Aorta Interrupted Aortic Arch Anomalous Origin of the Left Coronary Artery From the Pulmonary Artery Systemic Arterial Malformations Cardiomyopathy Acknowledgments References Suggested Readings References 51. Long-Term Neurologic Outcomes in Children With Congenital Heart Disease 51 Long-Term Neurologic Outcomes in Children With Congenital Heart Disease Structural and Developmental Abnormalities of the Brain in Congenital Heart Disease Fetal Circulation in Congenital Heart Disease: Effects on Cerebral Blood Flow Preoperative Evidence of Delayed Brain Development by Magnetic Resonance Imaging Fetal Brain Magnetic Resonance Imaging Identifies Developmental Abnormalities in Congenital Heart Disease Trajectory of Brain Development in Congenital Heart Disease Acquired Brain Injury With Congenital Heart Disease: Characteristics and Risk Factors Risk Factors for Preoperative Brain Injury Risk Factors for Intraoperative Brain Injury Risk Factors for Postoperative Brain Injury Brain Immaturity as a Risk Factor for Brain Injury Neurodevelopmental Outcomes Immediate Neurologic Outcomes After Surgical Repair Short-Term and Long-Term Neurologic Outcomes After Surgical Repair Genetic Susceptibility to Neurodevelopmental Abnormalities Neurodevelopmental Signature of Congenital Heart Disease Conclusion References Suggested Readings References 52. Central Nervous System Development 52 Central Nervous System Development Neuronal Production and Migration Programmed Neuronal Death Organization of the Central Nervous System Subplate Neurons Axonal and Dendritic Growth Synaptogenesis Glial Proliferation, Differentiation, and Myelination Astrocytes Oligodendrocytes and Myelination Microglia The Environment and Epigenetics References Suggested Readings References 53. Congenital Malformations of the Central Nervous System 53 Congenital Malformations of the Central Nervous System Prosencephalic Cleavage and Related Events Normal Prosencephalic Development Disorders of Structures Derived From the Prosencephalon Aprosencephaly and Atelencephaly Holoprosencephaly Diagnosis Clinical Features Epidemiology and Etiology Genotype-Phenotype Variability Environmental Factors Agenesis of the Corpus Callosum Epidemiology and Etiology Prognosis Septo-Optic Dysplasia Diagnosis and Prognosis Epidemiology and Etiology Absent Cavum Septi Pellucidi Cortical Defects in Size and Organization Cortical Defects in Proliferation and Neuronal Survival Microcephaly Macrocephaly and Megalencephaly Cortical Defects in Migration Heterotopia Lissencephaly Clinical Features Cobblestone Malformation Syndromes Polymicrogyria Clinical Features Tubulinopathy-Related Dysgyria Destructive Lesions Malformations of Structures in the Posterior Fossa Normal Midbrain and Hindbrain Development Malformations With Major Cerebellar Involvement Dandy–Walker Malformation Epidemiology and Etiology Clinical Features and Management Rhombencephalosynapsis Malformations With Both Cerebellar and Brainstem Involvement Joubert Syndrome and Related Disorders Pontocerebellar Hypoplasias Malformations With Brainstem Involvement Chiari Malformations Neural Tube Defects and Spinal Cord Dysraphisms Epidemiology and Etiology Gene–Environment Association of Neural Tube Defects Fetal Diagnosis of Neural Tube Defects Open Neural Tube Defects Anencephaly Myelomeningocele Myeloschisis Skin-Covered Neural Tube Defects Encephalocele Meningocele Occult Spinal Dysraphisms Clinical Features and Diagnosis Acknowledgment References Suggested Readings References 54. Brain Injury in the Preterm Infant 54 Brain Injury in the Preterm Infant General Principles of Preterm Brain Injury Intraventricular and Periventricular Hemorrhage Pathogenesis Site, Incidence, and Timing of Hemorrhage Clinical Presentation Grading of Intraventricular Hemorrhage Outcome and Prognosis Prevention Management White Matter Injury Spectrum of White Matter Injury Physiologic Factors Related to the Pathogenesis of White Matter Injury Role of Hypoxia-Ischemia Pressure-Passive Circulation Factors That Influence the Distribution of White Matter Injury Clinical Factors Related to the Severity of White Matter Injury Pathogenesis of Chronic White Matter Injury Emerging Roles for Myelin in Brain Development, Learning, and Memory Pathogenesis of Chronic Myelination Failure and Potential Therapeutic Strategies Preterm Cerebral Gray Matter Injury Summary References Suggested Readings References 55. Neonatal Encephalopathy 55 Neonatal Encephalopathy Neonatal Encephalopathy Hypoxic-Ischemic Encephalopathy Epidemiology Pathophysiology Clinical Presentation Evaluation Neuromonitoring Electroencephalography Near-Infrared Spectroscopy Neuroimaging Ultrasound Magnetic Resonance Imaging and Magnetic Resonance Spectroscopy Computed Tomography Management Hypothermia Therapy Outcomes Electroencephalogram Findings and Seizures Predictive Value of Magnetic Resonance Imaging and Spectroscopy Adjunctive Neuroprotective Treatments Plus Therapeutic Hypothermia Erythropoietin Xenon Argon Melatonin Stem Cells Cannabinoids Allopurinol Azithromycin Other Causes of Neonatal Encephalopathy Metabolic Causes of Neonatal Encephalopathy Neonatal Hypoglycemia Inborn Errors of Metabolism Metabolic Encephalopathies due to Toxic Metabolite Accumulation Urea Cycle Disorders Methylmalonic Acidemia Molybdenum Cofactor Deficiency Nonketotic Hyperglycinemia Energy Deficiency Disorders Mitochondrial Disorders Genetic Causes of Neonatal Encephalopathy Holoprosencephaly Neuronal Proliferation Defects Neuronal Migration Defects—Lissencephaly Postmigrational Development Defects—Polymicrogyria 1p36 Deletion Syndrome Hypophosphatasia Central Nervous System Infections and Neonatal Encephalopathy Bacterial Meningitis Human Parechovirus Cytomegalovirus Zika Virus Toxoplasmosis References Suggested Readings References 56. Neonatal Neurovascular Disorders 56 Neonatal Neurovascular Disorders Perinatal Stroke Epidemiology Pathophysiology Clinical Presentation Evaluation Management Outcomes Sinus Venous Thrombosis Epidemiology Pathophysiology Clinical Presentation Evaluation Management Outcomes Subdural and Subarachnoid Hemorrhages Epidemiology Pathophysiology Clinical Presentation Evaluation Management Outcomes Vascular Malformations Vein of Galen Malformation Epidemiology Pathophysiology Cardiovascular Findings Neurologic Findings Clinical Presentation Evaluation Management Outcomes Acknowledgment References Suggested Readings References 57. Neonatal Neuromuscular Disorders 57 Neonatal Neuromuscular Disorders Neonatal Neuromuscular Disorders Primary Muscle Disorders Congenital Muscular Dystrophies LAMA2-Related Congenital Muscular Dystrophy (Merosin-Deficient Congenital Muscular Dystrophies MDC1A) Dystroglycanopathies Collagen VI-Related Disorders LMNA-Related Congenital Muscular Dystrophy SEPN1-Related Myopathies Congenital Myopathies Core Myopathies Nemaline Myopathy Centronuclear Myopathy Congenital Fiber-Type Size Disproportion Myopathy Myosin Storage Myopathy Congenital Myotonic Dystrophy Metabolic Myopathies Motor Neuron Disorders 5q Spinal Muscular Atrophy Non-5q Spinal Muscular Atrophies Spinal Muscular Atrophy With Respiratory Distress Pontocerebellar Hypoplasia Plus Spinal Muscular Atrophy Neonatal Neuromuscular Junction Disorders Transient Neonatal Myasthenia Gravis Congenital Myasthenic Syndromes Peripheral Neuropathies Approach to the Hypotonic Newborn Creatine Phosphokinase Electromyography Muscle Biopsy Genetic Testing References Suggested Readings References 58. Neonatal Seizures 58 Neonatal Seizures Neonatal Seizures Classification of Neonatal Seizures Motor Seizure Automatisms Clonic Seizures Myoclonic Seizures Epileptic Spasms Tonic Seizures Nonmotor Seizure Autonomic Seizure Behavioral Arrest Sequential Seizure Nonepileptic Neonatal Movements Tremulousness or Jitteriness Myoclonus Without Electrographic Correlate Dyskinesias Hyperekplexia Evaluation of Neonatal Seizure Neurophysiologic Diagnosis of Seizure Amplitude-Integrated Electroencephalography Continuous Electroencephalography Quantitative Electroencephalography Electroclinical Uncoupling Interictal Abnormalities Etiologies of Neonatal Seizures Hypoxic–Ischemic Encephalopathy Cerebrovascular Lesions Infection Metabolic Derangements Hypoglycemia Hypocalcemia Hyponatremia and Hypernatremia Drug Withdrawal and Intoxication Congenital Brain Malformations Inborn Errors of Metabolism Benign Familial Neonatal Seizures Neonatal Epilepsy Syndromes Management of Neonatal Seizures Antiseizure Medication Pyridoxine Discontinuation of Antiepileptic Drugs Post-neonatal Epilepsy Outcomes of Neonatal Seizures References Suggested Readings References 59. Enteral Nutrition 59 Enteral Nutrition Macronutrient Requirements Protein Energy Carbohydrates Fat Micronutrients, Vitamins, Minerals, and Trace Element Requirements Calcium and Phosphorus Magnesium Trace Elements Zinc Copper Selenium Iron Sodium and Potassium Vitamins Vitamin A Vitamin D Vitamin E Vitamin K Options for Enteral Nutrition Human Milk Benefits of Human Milk Neurodevelopmental Outcome Effects Human Milk Nutrient Content Protein Colostrum Carbohydrate Human Milk Oligosaccharides Roles of Human Milk Oligosaccharides Fat Essential Fatty Acids Carnitine Human Milk Enzymes Vitamins and Minerals Preterm Milk Special Issues/Contraindications to Mother’s Own Milk Breastfeeding and Substances of Abuse Opioids Methadone Marijuana Alcohol Human Immunodeficiency Virus/Undetectable Viral Load in Human Immunodeficiency Virus COVID-19 COVID Vaccination Donor Human Milk Differences Between Maternal and Donor Human Milk Donor Milk as a Bridge to Breastfeeding for Term and Late-Preterm Infants Informal Milk Sharing Human Milk Fortification Standard Fortification Adjustable Fortification Targeted (or Individualized) Fortification Initiation, Mode, and Advancement of Enteral Feedings Tube Feeding Infant Nutrition and Growth Assessing Growth and Body Composition in Infants Growth and Developmental Outcomes in Preterm Infants Post-Discharge Nutrition for the Premature Infant References Suggested Readings References 60. Parenteral Nutrition for the High-Risk Neonate 60 Parenteral Nutrition for the High-Risk Neonate Components of Parenteral Nutrition Protein Energy Glucose Lipids Electrolytes, Minerals, Trace Elements, and Vitamins Complications of Parenteral Nutrition Use of Parenteral Nutrition in the Neonatal Intensive Care Unit: A Practical Approach References Suggested Readings References 61. Structural Anomalies of the Gastrointestinal Tract 61 Structural Anomalies of the Gastrointestinal Tract Disorders of the Oral Cavity Mouth Tongue Salivary Glands Disorders of the Neck Branchial Anomalies Thyroid Other Neck Masses Disorders of the Esophagus Esophageal Atresia Epidemiology Etiology and Associated Anomalies Classification Diagnosis Management Outcomes Laryngotracheoesophageal Cleft Congenital Esophageal Stenosis Esophageal Duplication Cyst Esophageal Perforation Disorders of the Stomach Pyloric Atresia Gastric Duplication Pyloric Stenosis Gastric Perforation Disorders of the Intestine Malrotation and Volvulus Intestinal Atresia Duodenal Atresia Jejunoileal and Colonic Atresia Meconium Ileus Enteric Duplication Cysts Intussusception Disorders of the Colon and Anus Neonatal Appendicitis Hirschsprung Disease Meconium Plug Anorectal Malformations Acknowledgment References Suggested Readings References 62. Abdominal Wall Defects 62 Abdominal Wall Defects Abdominal Wall Problems Abdominal Wall Defects Gastroschisis Epidemiology Pathophysiology Clinical Presentation Management Outcomes Omphalocele Epidemiology Pathophysiology Clinical Presentation Management Outcomes Other Abdominal Wall Defects Body Stalk Anomaly Bladder Exstrophy Cloacal Exstrophy Prune Belly Syndrome Umbilical Abnormalities Umbilical Granulomas Delayed Separation of the Umbilical Cord Umbilical and Periumbilical Infections Persistent Remnants of Urachus and Omphalomesenteric Duct Abdominal Wall Hernias Inguinal Hernia and Hydrocele Umbilical Hernia Epigastric Hernia Diastasis Recti Umbilical Cord Abnormalities Acknowledgment References Suggested Readings References 63. Neonatal Gastroesophageal Reflux 63 Neonatal Gastroesophageal Reflux Gastroesophageal Reflux Epidemiology Pathophysiology Evaluation Clinical Presentation Behavioral and Feeding Issues Apnea, Bradycardia, and Desaturation Respiratory Disease Management Nonpharmacologic Approaches Pharmacologic Management References Suggested Readings References 64. Necrotizing Enterocolitis and Short Bowel Syndrome 64 Necrotizing Enterocolitis and Short Bowel Syndrome Necrotizing Enterocolitis Epidemiology Defining Necrotizing Enterocolitis: A Conundrum NEC Stages Pathology/Pathophysiology Animal Models “Classic” Necrotizing Enterocolitis Pathophysiology Intestinal Microbiota, Mucosal Immune System, and Vascular Immaturities Intestinal Mucosal Immune System Microbial Colonization and Dysbiosis Antibiotics Human Milk Clinical Presentation Evaluation Ultrasound and Radiographs Laboratory Findings Differential Diagnosis Cardiogenic Intestinal Ischemia Spontaneous Intestinal Perforation Food Protein Intolerance Enterocolitis Syndrome Medical Management Surgical Management Laparotomy Versus Primary Peritoneal Drainage as Initial Therapy for NEC Outcomes Mortality Necrotizing Enterocolitis-Associated Strictures Neurodevelopmental Disability Prevention The Future of Necrotizing Enterocolitis Short Bowel Syndrome Epidemiology Management Enteral Autonomy Parenteral Nutrition Enteral Nutrition Medical Management Surgical Management Outcomes References Suggested Readings References 65. Disorders of the Liver 65 Disorders of the Liver Neonatal Liver Disease Cholestatic Liver Disease Biliary Atresia Choledochal Cysts Alagille Syndrome (Arteriohepatic Dysplasia) α-1 Antitrypsin Deficiency Cystic Fibrosis Liver Disease Disorders of Bile Acid Synthesis Progressive Familial Intrahepatic Cholestasis Congenital Hepatic Fibrosis Infections Parenteral Nutrition–Associated Liver Disease Metabolic Liver Disease Disorders of Carbohydrate Metabolism Galactosemia Hereditary Fructose Intolerance Glycogen Storage Diseases Disorders of Amino Acid Metabolism Tyrosinemia Type 1 Maple Syrup Urine Disease Disorders of Organic Acid Metabolism Fatty Acid Oxidation Defects Urea Cycle Defects Mitochondrial Hepatopathies Lysosomal Storage Disorders Gestational Alloimmune Liver Disease Vascular Malformations Arteriovenous Malformations Congenital Portosystemic Shunts Hereditary Hemorrhagic Telangiectasia Infantile Hepatic Hemangiomas Liver Masses Hepatoblastoma Congenital Hepatic Cysts References Suggested Readings References 66. Developmental Hematology 66 Developmental Hematology Introduction to Embryonic Hematopoiesis Stem Cell Biology Developmental Aspects of Erythropoiesis Primitive and Definitive Erythropoiesis Switch of the Primary Site of Erythropoiesis Yolk Sac Aortogonadomesonephron Liver Bone Marrow Factors Influencing the Sites of Erythropoiesis Extramedullary Hematopoiesis Ontogeny of Erythrocytes Developmental Changes in the Regulation of Erythropoiesis Ontogeny, Organization, and Structure of Hemoglobins Changes in Hemoglobin Synthesis With Development Red Blood Cell Transfusion Bilirubin Metabolism Developmental Aspects of Megakaryocytopoiesis Sites of Megakaryocyte Production Megakaryocyte Precursors Control of Megakaryocytopoiesis Thrombopoietin Developmental Changes in Platelet Count Platelet Transfusions Developmental Aspects of Granulocytopoiesis Hematopoietic Cytokines Acknowledgment References Suggested Readings References 67. Neonatal Bleeding and Thrombotic Disorders 67 Neonatal Bleeding and Thrombotic Disorders The Neonatal Hemostatic System Developmental Hemostasis Bleeding Disorders in the Neonate Laboratory Investigation Hemophilia von Willebrand Disease Other Rare Inherited Coagulation Disorders Acquired Coagulation Disorders Vitamin K Deficiency Disseminated Intravascular Coagulation Liver Disease Neonatal Thrombosis Epidemiology Risk Factors for Neonatal Thromboembolism Prothrombotic Disorders: Pathophysiology and Their Role in Neonatal Thromboembolism Locations of Neonatal Thromboses, Imaging Modalities to Diagnose Them, and Management Guidelines for Specific Thromboses Arterial Thromboses Neonatal Arterial Ischemic Stroke Iatrogenic/Spontaneous Arterial Thromboses Venous Thrombosis Catheter-Related Venous Thrombosis (Umbilical Venous Catheters and Peripherally Inserted Central Venous Catheters) Intracardiac Thromboses and Thromboses in Infants With Complex Congenital Heart Disease Renal Vein Thrombosis Portal Vein Thrombosis Cerebral Sinovenous Thrombosis Evaluation of Neonatal Thromboses Management of Arterial and Venous Thromboses Unfractionated Heparin Low-Molecular-Weight Heparin Recombinant Tissue Type Plasminogen Activator Surgery References References Suggested Readings 68. Neonatal Platelet Disorders 68 Neonatal Platelet Disorders Fetal and Neonatal Platelet Production Platelet Counts During Development and Reference Ranges Platelet Function and Primary Hemostasis Neonatal Thrombocytopenia Early-Onset Thrombocytopenia (Fig. 68.2, Table 68.1) Late-Onset Thrombocytopenia (Fig. 68.3, see Table 68.1) Immune Thrombocytopenia Neonatal Alloimmune Thrombocytopenia Epidemiology Pathophysiology Clinical Presentation Evaluation Management Management of the Neonate With Suspected NAIT (Unknown Pregnancy) Management of the Neonate With Known NAIT Management of Pregnant Women With Previous History of NAIT Autoimmune Thrombocytopenia Epidemiology Pathophysiology Evaluation Management Congenital Thrombocytopenias Management Platelet Transfusions Alternative Tests to Guide Platelet Transfusions Non-Transfusional Therapies Outcomes Platelet Function Disorders Pathophysiology Clinical Presentation Evaluation Management References Suggested Readings References 69. Neonatal Erythrocyte Disorders 69 Neonatal Erythrocyte Disorders​ Normal Erythrocyte Physiology in the Fetus and Newborn Fetal Erythropoiesis Red Blood Cell Physiology at Birth Fetal and Neonatal Hemoglobin Function Anemia in the Fetus and Newborn Evaluation of Anemia Red Blood Cell Count, Hemoglobin, Hematocrit, and Red Blood Cell Indices Reticulocyte Count Peripheral Blood Smear Direct Antiglobulin Test Management of Anemia Causes of Fetal and Neonatal Anemia Hemorrhagic Anemia Fetal Hemorrhage Twin-Twin Transfusion Placental Blood Loss Umbilical Cord Bleeding Hemorrhage After Delivery Hemolytic Anemia Immune Hemolysis Rh Hemolytic Disease: Erythroblastosis Fetalis ABO Incompatibility Minor Blood Group Incompatibility Immune Hemolytic Anemia Due to Maternal Disease Nonimmune Acquired Hemolytic Disease Infection Schistocytic Anemias Hereditary Red Blood Cell Disorders Membrane Defects Hereditary Spherocytosis Hereditary Elliptocytosis Red Blood Cell Enzyme Abnormalities Glucose-6-Phosphate Dehydrogenase Deficiency Pyruvate Kinase Deficiency Hemoglobin Disorders Thalassemia Syndromes Alpha Thalassemia Beta Thalassemia Hemoglobin E/Beta Thalassemia Other Variants Within the Hemoglobin Beta Gene Cluster Sickle Cell Disease Hypoplastic Anemia Diamond-Blackfan Anemia Deficiency of Adenosine Deaminase 2 Pearson Marrow-Pancreas Syndrome Congenital Dyserythropoietic Anemia Osteopetrosis Congenital Infections Physiologic Anemia of Infancy and Anemia Prematurity Physiologic Anemia of Infancy Anemia of Prematurity Treatment of Anemia of Prematurity With Recombinant Human Erythropoietin Red Blood Cell Transfusion Therapy in Premature Infants Polycythemia Methemoglobinemia Acknowledgment References References Suggested Readings 70. Neonatal Transfusion 70 Neonatal Transfusion​ Overview Red Blood Cell Transfusion Components of Red Blood Cell Transfusion Preparation of Red Blood Cell Transfusion Indications for Red Blood Cell Transfusion Risks of Red Blood Cell Transfusion Immunologic Complications Transfusion-Related Acute Lung Injury Transfusion-Related Acute Gut Injury Nonimmunologic Complications Infection Transfusion-Associated Circulatory Overload Hypothermia Metabolite Derangements Transfusion-Related Death Platelet Transfusion Component of Platelet Transfusion Indications for Platelet Transfusion Risks of Platelet Transfusion Plasma and Cryoprecipitate Transfusion Components of Plasma and Cryoprecipitate Transfusion Indications for Plasma and Cryoprecipitate Transfusion Risks of Plasma and Cryoprecipitate Transfusion Special Circumstances Massive Transfusion Exchange Transfusion Intravenous Immune Globulin Neonatal Alloimmune Thrombocytopenia Decreasing the Need for Red Blood Cell Transfusion References Suggested Readings References 71. Neonatal Leukocyte Physiology and Disorders 71 Neonatal Leukocyte Physiology and Disorders​ Neutrophil Physiology and Function Ontogeny Circulating and Marginated Blood Neutrophil Pools Neutrophil Heterogeneity Neonatal Neutropenia Sepsis-Induced Neutropenia Immune-Mediated Neonatal Neutropenia Maternal Hypertension–Associated Neutropenia Idiopathic Neutropenia of Prematurity Treatment of Neonatal Neutropenia Monocyte Physiology and Dysfunction Ontogeny Circulating Monocytes Monocyte Subsets Monocyte Function Developmental Defects in the Phagocytic Immune System in Neonates Lymphocyte Contributing to Acquired Immunity T-Lymphocyte Physiology and Function Ontogeny T-Cell Receptor Repertoire T-Cell Subtypes T-Helper Cells Regulatory T Cells Cytotoxic T Lymphocytes Gamma-Delta (γδ) T Cells Natural Killer T Cells Circulating T Cells Neonatal T-Lymphocyte Function B-Lymphocyte Physiology and Function Ontogeny B-Cell Subtypes Circulating B Cells Neonatal B-Lymphocyte Function Immunoglobulin Production Immunoglobulin Repertoire Serum Immunoglobulin Levels Dendritic Cell Physiology and Function Ontogeny Dendritic Cell Subtypes Morphology Function Innate Lymphoid Cell Physiology and Function Natural Killer Cell Physiology and Function Ontogeny Natural Killer Cell Subtypes Function Noncytotoxic Innate Lymphoid Cell Physiology and Function Ontogeny Innate Lymphoid Cell Subtypes Function Summary Acknowledgments References Suggested Readings References 72. Neonatal Hyperbilirubinemia and Kernicterus 72 Neonatal Hyperbilirubinemia and Kernicterus Hyperbilirubinemia Increased Hepatic Bilirubin Load: Hemolytic Disease Red Cell Membrane Defects Red Cell Enzyme Deficiencies Glucose-6-Phosphate Dehydrogenase Deficiency Hemoglobinopathies Acquired Causes of Hemolysis Immune-Mediated Hemolytic Disease Non-ABO Alloantibodies ABO Hemolytic Disease Decreased Hepatic Bilirubin Clearance Hepatic Bilirubin Uptake Hepatic Bilirubin Conjugation Gilbert Syndrome Enhanced Enterohepatic Circulation of Bilirubin Other Clinically Relevant Icterogenic Conditions Late-Preterm Gestation Breast-Milk Feeding East Asian Ethnicity Jaundice Observed in the First 24 Hours of Life Hemorrhage or Significant Bruising Previous Sibling Treated With Phototherapy African Ethnicity Combining Clinical Risk Factor Assessment With Predischarge Bilirubin Measurement Clinical Evaluation of Jaundice Kernicterus Spectrum Disorders Molecular Pathogenesis Preterm Neonates and Low-Bilirubin Kernicterus Clinical Efforts at Kernicterus Prevention Treatment Considerations Phototherapy Intravenous Immunoglobulin Exchange Transfusion Acknowledgments References Suggested Readings References 73. Congenital Malignant Disorders 73 Congenital Malignant Disorders Epidemiology, Etiology, and Diagnosis of Neonatal Malignancy Epidemiology: Incidence and Mortality Etiology Genetic Predisposition Syndromes and Congenital Defects Transplacental Tumor Passage Twin-to-Twin Transmission Environmental Factors Diagnosis and Evaluation Specific Neoplasms Neuroblastoma Overview Etiology Presentation Unusual Presentations Catecholamine Secretion Diagnosis Pathologic Classification Genetic Prognostic Factors: Tumor Biology Staging Treatment Prenatal Diagnosis Congenital Leukemia Epidemiology Clinical Manifestations Laboratory Manifestations Differential Diagnosis Cellular Morphology and Immunophenotype Genetics Treatment and Prognosis Transient Myeloproliferative Disorders and Leukemia in Patients With Down Syndrome Transient Myeloproliferative Disorder Germ Cell Tumors Pathology Evaluation Sacrococcygeal Teratomas Differential Diagnosis Treatment Renal Neoplasms Congenital Mesoblastic Nephroma Wilms Tumor Clinical Manifestations Hereditary Associations and Congenital Anomalies Prognostic Factors Evaluation and Staging Treatment Persistent Nephrogenic Rests and Nephroblastomatosis Rhabdoid Tumor of the Kidney Retinoblastoma Genetics Clinical Manifestations Treatment Prognosis Central Nervous System Tumors Incidence and Epidemiology Clinical Manifestations Treatment Sarcomas Histiocytosis Hepatoblastoma Hepatic Hemangioendothelioma Treatment Considerations in Infants Chemotherapy Dosing Radiation Effects Pain Management Nutrition Intravenous Access Transfusions Immunizations Psychosocial Considerations Late Effects Conclusion References Suggested Readings References 75. Developmental Abnormalities of the Kidneys 75 Developmental Abnormalities of the Kidneys Abnormalities of Kidney Number Unilateral Kidney Agenesis Bilateral Kidney Agenesis Abnormalities of Kidney Position Ectopic Kidney Horseshoe Kidney Abnormalities of Kidney Organization Multicystic Dysplastic Kidney Isolated Kidney Dysplasia Renal Coloboma Syndrome Brachio-Oto-Renal Syndrome Hypothyroidism-Deafness-Renal Dysplasia Syndrome VACTERL Eagle-Barrett Syndrome Abnormalities With Kidney Overgrowth Abnormalities Predominated by Kidney Cysts Ciliopathies Autosomal Recessive Polycystic Kidney Disease Autosomal Dominant Polycystic Kidney Disease Tuberous Sclerosis Complex Bardet-Biedl Syndrome Jeune Syndrome Nephronophthisis Meckel-Gruber Syndrome Joubert Syndrome and Joubert-Related Disorders Orofaciodigital Syndrome Cranioectodermal Dysplasia Renal-Hepatic-Pancreatic Dysplasia Glomerulocystic Kidney Disease Renal Tubular Dysgenesis Kidney Teratogens Inborn Errors of Metabolism Multiple Acyl-CoA Dehydrogenase Deficiency Smith-Lemli-Opitz Syndrome Zellweger Syndrome Congenital Disorders of Glycosylation Acknowledgments References Suggested Readings References 76. Developmental Abnormalities of the Genitourinary System 76 Developmental Abnormalities of the Genitourinary System Early Kidney and Urinary Tract Embryologic Development Anomalies of the Kidney Renal Agenesis Renal Ectopia and Fusion Supernumerary Kidney Cystic Disease of the Kidney Autosomal Recessive Polycystic Kidney Autosomal Dominant Polycystic Kidney Tuberous Sclerosis Multicystic Dysplastic Kidney Renal Tumor Renal Vein Thrombosis Adrenal Hemorrhage Anomalies of the Ureters Duplication of the Ureters Ureteral Ectopia Ureterocele Ureteropelvic Junction Obstruction Ureterovesical Obstruction Vesicoureteral Reflux Anomalies of the Bladder Bladder Exstrophy Cloacal Exstrophy Patent Urachus Posterior Urethral Valves Genital Abnormalities in Males Cryptorchidism Testicular Tumors Testicular Torsion Hydrocele Hypospadias and Chordee Phimosis Other Penile Anomalies Webbed Penis Buried Penis Micropenis Aphallia Epispadias Urethral Duplication Disorders of Sexual Differentiation Urinary Tract Infections Myelodysplasia Prune-Belly Syndrome VACTERL Association Female Genital Anomalies Female Genital Tract Development Hydrocolpos and Hydrometrocolpos Vaginal Agenesis Cloacal Anomalies and Urogenital Sinus Müllerian Duplication Anomalies Introital Masses in Children References Suggested Readings References 77. Acute Kidney Injury 77 Acute Kidney Injury​ Acute Kidney Injury Epidemiology Neonates With Perinatal Asphyxia Neonates Undergoing Cardiac Pulmonary Bypass Surgery Neonates Requiring Extracorporeal Membrane Oxygenation Very Low Birth Weight and Extremely Low Birth Weight Neonates Pathophysiology Prerenal Azotemia Intrinsic Acute Kidney Injury Ischemic Acute Kidney Injury Nephrotoxic Acute Kidney Injury Postrenal Acute Kidney Injury Evaluation and Management Step 1: Understand the Cause of Acute Kidney Injury Step 2: Intervene to Preserve or Prevent Further Acute Kidney Injury Step 3: Manage Consequences of Kidney Failure Kidney Support Therapy With Dialysis Indications for Dialysis Initiation Access Peritoneal Dialysis Hemodialysis and Continuous Renal Replacement Therapy Acute Kidney Injury as a Cause of Long-Term Chronic Kidney Disease Renal Vascular Disease in the Newborn Renal Arterial Thrombus Renal Vein Thrombosis References References Suggested Readings 74. Renal Development 74 Renal Development Factors Influencing Organogenesis Development of the Renal Vascular Bed Renal Morphogenesis Glomerular Development Ureteral Growth and Development Renin–Angiotensin System Interaction for Programming Fetal Development Renal Ascent Fetal Programing of Renal Function and the Perinatal Environmental Factor’s Influence Development of Renal Function and Adult Renal Disease Conclusion References Suggested Readings References 78. Chronic Kidney Disease 78 Chronic Kidney Disease​ Chronic Kidney Disease Epidemiology Pathophysiology Congenital Causes of Neonatal CKD Congenital Anomalies of the Kidney and Urinary Tract Polycystic Kidney Disease and Ciliopathies Acquired Causes of Neonatal Chronic Kidney Disease Prematurity and Low Birth Weight Acute Kidney Injury Renal Cortical and Medullary Necrosis Clinical Sequelae of Neonatal Chronic Kidney Disease/End-Stage Kidney Disease Anemia Malnutrition and Growth Failure Nutritional Assessment Nutritional Management Fluid and Electrolyte Derangements Chronic Kidney Disease Mineral and Bone Disorder Management Kidney Replacement Therapy Peritoneal Dialysis Hemodialysis Transplantation Outcomes Neurocognitive Impairment Hospitalization Survival Ethics of Initiating or Withdrawing Kidney Replacement Therapy References References Suggested Readings 79. G­lo­merulonephropathies and Disorders of Tubular Function 79 G­lo­merulonephropathies and Disorders of Tubular Function Glomerulonephropathies Congenital Nephrotic Syndrome Primary Congenital Nephrotic Syndromes Finnish-Type Congenital Nephrotic Syndrome (MIM #256300) Congenital Nephrotic Syndrome Type 2 (MIM #600995) Wilms Tumor Suppressor Gene Mutation Syndromes (MIM #194072, 136680, 194080) Pierson Syndrome (MIM #609049) Other Primary Causes of Congenital Nephrotic Syndrome (MIM #251300, 161200) Management of Primary Congenital Nephrotic Syndromes Secondary Causes of Congenital Nephrotic Syndrome Other Glomerular Diseases Renal Tubular Disorders Renal Tubular Acidosis Distal Renal Tubular Acidosis (Type 1 RTA) Isolated Proximal Renal Tubular Acidosis (Type 2 RTA) Hyperkalemic Tubulopathies (Type 4 RTA) Hypoaldosteronism Pseudohypoaldosteronism Type 1 Pseudohypoaldosteronism Type 2 (MIM #145260, 614491, 614492, 614495, 614496) Fanconi Syndrome Nephropathic Cystinosis (MIM #219800) Hypokalemic Tubulopathies Bartter Syndrome (MIM #601678, 241200, 607364, 613090, 602522, 601198) Gitelman Syndrome (MIM #263800) Liddle Syndrome (MIM #177200, 618114, 618126) Other Tubulopathies Nephrogenic Diabetes Insipidus (MIM #304800, 125800) References Suggested Readings References 80. Urinary Tract Infections and Vesicoureteral Reflux 80 Urinary Tract Infections and Vesicoureteral Reflux Urinary Tract Infection Epidemiology Pathophysiology Clinical Presentation Bacteriology Risk Factors Evaluation Urine Sample Renal Imaging Renal Bladder Ultrasound Voiding Cystourethrography Contrast-Enhanced Voiding Urosonography 99Tc-Dimercaptosuccinic Acid Renal Scan Management Antibiotic Resistance Vesicoureteral Reflux Epidemiology Pathophysiology Management Continuous Antibiotic Prophylaxis Antibiotic Resistance on Continuous Antibiotic Prophylaxis Neonatal Continuous Antibiotic Prophylaxis References Suggested Readings References 81. Systemic Hypertension 81 Systemic Hypertension Factors that Influence Neonatal Blood Pressure Definition of Hypertension Epidemiology Pathophysiology Renovascular Causes Bronchopulmonary Dysplasia Congenital and Acquired Kidney Disease Genetic Causes Miscellaneous Causes Coarctation of the Aorta Endocrine Disorders Tumors Iatrogenic Causes Extracorporeal Membrane Oxygenation Postsurgical Evaluation Blood Pressure Measurement History and Physical Examination Laboratory Testing and Imaging Management Outcomes References Suggested Readings References 82. Developmental Endocrinology 82 Developmental Endocrinology Endocrine Systems Endocrine Organ Development and Perinatal Transition The Maternal-Placental-Fetal Unit Hypothalamic and Pituitary Development Diseases of Hypothalamic or Pituitary Maldevelopment Adrenal Gland Development Thyroid Gland Development Reproductive Axis Development Development of the Endocrine Pancreas Development of Parathyroid Glands and Fetal Mineral Homeostasis Hormonal Regulation of Fetal Growth Insulin Insulin-Like Growth Factor 1 Insulin-Like Growth Factor 2 Placental Factors Developmental Origin of Health and Disease References Suggested Readings References 83. Disorders of Calcium and Phosphorus Metabolism 83 Disorders of Calcium and Phosphorus Metabolism Homeostatic Control of Calcium and Magnesium Homeostatic Control of Phosphorus Parathyroid-Renal Hormonal Axis Parathyroid Hormones Vitamin D Calcitonin Perinatal Mineral Metabolism Pregnancy The Neonate Neonatal Hypocalcemia Clinical Presentation Early Neonatal Hypocalcemia Late Neonatal Hypocalcemia Hypocalcemia Caused by Hypoparathyroid Syndromes Neonatal Hypocalcemia Associated With Maternal Hyperparathyroidism Hypocalcemia Resulting From Vitamin D Disorders Phosphate-Induced Hypocalcemia Other Causes of Neonatal Hypocalcemia Management of Hypocalcemia Hypocalcemic Crisis Nonemergency Treatment Magnesium Administration Vitamin D Treatment Recombinant Parathyroid Hormone Analogue Neonatal Hypercalcemia Neonatal Hyperparathyroid Syndromes Associated With CaSR Mutations Neonatal Hyperparathyroidism Not Associated With CaSR Mutations Williams Syndrome and Idiopathic Infantile Hypercalcemia Neonatal Hypercalcemia Associated With Subcutaneous Fat Necrosis Hypercalcemia Due to Iatrogenic Causes Other Causes of Neonatal Hypercalcemia Treatment of Hypercalcemia Neonatal Disorders of Serum Magnesium Metabolic Bone Disease in Newborns and Infants Metabolic Bone Disease of Prematurity Clinical Presentation Pathophysiology Evaluation Vitamin D–Deficiency Rickets Renal Osteodystrophy Inherited Metabolic Bone Disease in Infancy References Suggested Readings References 84. Disorders of the Adrenal Gland 84 Disorders of the Adrenal Gland The Adrenal Gland Embryology Morphology Adrenal Functions Control of Glucocorticoid and Mineralocorticoid Production Molecular Basis of Adrenal Development Assessing Adrenal Function in the Newborn Primary Adrenal Disorders Steroidogenic Defects Caused by Adrenal Enzyme Deficiency Disorders That Lead to Virilization in Females 21-Hydroxylase Deficiency Epidemiology Pathophysiology Clinical Presentation Management 11β-Hydroxylase Deficiency Epidemiology Pathophysiology Clinical Presentation Management Disorders That Lead to Males With Undervirilization 17α-Hydroxylase/17,20-Lyase Deficiency Epidemiology Pathophysiology Clinical Presentation Management 3β-Hydroxysteroid Dehydrogenase Type 2 Deficiency Epidemiology Pathophysiology Clinical Presentation Management Lipoid Congenital Adrenal Hyperplasia Cytochrome P450 Oxidoreductase (POR) Deficiency Familial Glucocorticoid Deficiency Triple A Syndrome Neonatal Adrenoleukodystrophy Defective Cholesterol Metabolism: Smith–Lemli–Opitz Syndrome Adrenal Insufficiency Associated With Other Syndromic Disorders Lysosomal Storage Disorders Mitochondrial Disorders IMAGe Syndrome MIRAGE Syndrome Adrenal Hypoplasia Congenita Adrenal Hypoplasia as Part of Contiguous Gene Deletion Syndrome Abnormalities of Development: DAX-1 and Steroidogenic Factor-1 Deficiency Adrenal Hemorrhage Secondary and Tertiary Adrenal Insufficiency Iatrogenic Adrenal Insufficiency Developmental Adrenal Insufficiency Management Adrenal Crisis in the Neonate Initial Management Maintenance Therapy Stress Replacement References Suggested Readings References 85. Differences in Sex Development 85 Differences in Sex Development General Considerations in the Approach to the Newborn With Ambiguous Genitalia Embryology of Sex Determination and Differentiation Clinical Assessment of Differences of Sex Development History Physical Examination Clitoris Penis (Phallus) Labioscrotal Folds Gonads Hypospadias or Urogenital Sinus Dysmorphic Features Radiologic Investigations Pelvic Ultrasonography Genitourethrogram Magnetic Resonance Imaging Laboratory Investigations 46,XX Differences in Sex Development Androgenization of the Female Congenital Adrenal Hyperplasia P450 Oxidoreductase Deficiency Increased Levels of Maternal Androgens and Progestins Placental Aromatase Deficiency 46,XX Ovotesticular and 46,XX Testicular Disorders of Sex Development Disorders of Ovarian Development 46,XY Differences in Sex Development Disorders of Testosterone Biosynthesis and Action Androgen Receptor Defects (Androgen Insensitivity) Complete Androgen Insensitivity Partial Androgen Insensitivity 5α-Reductase Type 2 Deficiency Testosterone Biosynthetic Defects StAR Deficiency or Congenital Lipoid Adrenal Hyperplasia Side Chain Cleavage Cytochrome P450 17α-Hydroxylase/17,20-Lyase Deficiency POR Deficiency 3β-Hydroxysteroid Dehydrogenase Deficiency 2 17β-Hydroxysteroid Dehydrogenase Type 3 Deficiency (17-Ketosteroid Reductase Deficiency) Leydig Cell Hypoplasia Persistent Müllerian Duct Syndrome Gonadal Differentiation and Chromosomal Disorders 46,XY Complete Gonadal Dysgenesis 46,XY Partial Gonadal Dysgenesis Single Genes Important in Normal Testicular Development SRY NR5A1 SOX8 NROB1 MAMLD1 MAP3K1 GATA4 DMRT1 and DMRT2 Testicular Regression Syndrome 46,XY Ovotesticular Disorder Syndromes Associated With Ambiguous Genitalia Denys-Drash Syndrome Campomelic Dysplasia Smith-Lemli-Opitz Syndrome Robinow Syndrome Other Disorders of Genital Differentiation Hypospadias Cryptorchidism Sex Chromosome Disorders of Sex Development Klinefelter Syndrome Turner Syndrome Mixed Gonadal Dysgenesis 46,XX/46,XY Chimerism Surgical Management of Disorders of Sexual Differentiation Feminizing Genitoplasty Clitoral Reduction Vaginoplasty Flap Vaginoplasty Total Urethral Mobilization Pull-Through Vaginoplasty Vaginal Reconstruction Gonadectomy Removal of Müllerian Remnants References Suggested Readings References 86. Disorders of the Thyroid Gland 86 Disorders of the Thyroid Gland Regulation of Thyroid Function Thyroid Hormone Synthesis Serum Protein Binding and Transport Embryogenesis of Hypothalamic-Pituitary-Thyroid Axis Fetal–Placental–Maternal Thyroid Interaction Thyroid System Maturation Fetal Thyroid Hormone Metabolism Extrauterine Thyroid Adaptation Congenital Hypothyroidism Epidemiology Pathophysiology Clinical Presentation Evaluation Screening for Neonatal Hypothyroidism Thyroid Function Tests Interpreting Thyroid Function Tests Specific Causes of Hypothyroidism Thyroid Dysgenesis Thyroid Dyshormonogenesis Central Hypothyroidism Down Syndrome Consumptive Hypothyroidism Transient Primary Hypothyroidism Euthyroid Sick Syndrome Transient Hypothyroxinemia of Prematurity Low Triiodothyronine Syndrome in Premature Infants Iodine Deficiency Disorders of Thyroid Hormone Carrier Protein Thyroxine-Binding Globulin Deficiency Treatment of Hypothyroidism Neonatal Hyperthyroidism Epidemiology and Pathophysiology Clinical Presentation Evaluation Management Specific Causes of Hyperthyroidism Familial Dysalbuminemic Hyperthyroxinemia Thyroxine-Binding Globulin Excess References Suggested Readings References 87. Neonatal Hypoglycemia and Hyperglycemia 87 Neonatal Hypoglycemia and Hyperglycemia Introduction Neonatal Hypoglycemia Fetal to Neonatal Transition and Energy Metabolism Transitional Neonatal Hypoglycemia Signs and Symptoms of Hypoglycemia Blood Glucose Monitoring Normoinsulinemic Hypoglycemia Hypoglycemia in Premature and Small for Gestational Age Infants Counterregulatory Hormone Deficiency Hypopituitarism Isolated Adrenocorticotropic Hormone Deficiency Primary Adrenal Insufficiency Congenital Adrenal Hyperplasia X-linked Adrenal Hypoplasia Congenita IMAGe Syndrome Adrenocorticotropic Hormone Resistance Adrenal Hemorrhage Inborn Errors of Metabolism Glycogen Storage Diseases Defects of Fatty Acid Catabolism and Ketogenesis Galactosemia Hereditary Fructose Intolerance Hyperinsulinemic Hypoglycemia Mechanism of Insulin Secretion Diagnosis of Hyperinsulinism Hypoglycemia in Infants of Diabetic Mothers Perinatal Stress and Transient Hyperinsulinism Genetic Causes of Hyperinsulinemic Hypoglycemia Pathogenic Variants in the KATP Channel Genes KCNJ11 and ABCC8 Activating Variant of the Glutamate Dehydrogenase 1 Gene: Hyperinsulinemia-Hyperammonemia Syndrome L-3-Hydroxyacyl-Coenzyme A Dehydrogenase Gene Pathogenic Variants Glucokinase Pathogenic Variants Hepatocyte Nuclear Factor-4-Alpha and Hepatocyte Nuclear Factor-1-Alpha Pathogenic Variants Beckwith-Wiedemann Syndrome Other Genetic Causes of Hyperinsulinism Postfundoplication Hypoglycemia Differentiation Between Focal Adenomatous and Diffuse Pancreatic Hyperplasia Management of Hyperinsulinemic Hypoglycemia Neonatal Hyperglycemia Transient Stress-Related Hyperglycemia Neonatal Diabetes Mellitus Transient Neonatal diabetes Mellitus due to Chromosome 6q24 Anomalies Transient Neonatal Diabetes Mellitus due to KATP Pathogenic Variants Additional Genetic Causes of Transient Neonatal Diabetes Mellitus Nonsyndromic Causes of Permanent Neonatal Diabetes Mellitus Syndromic Causes of Neonatal Diabetes Mellitus Management of Neonatal Hyperglycemia Acknowledgments References Suggested Readings References 88. Craniofacial Conditions 88 Craniofacial Conditions Micrognathia/Robin Sequence Diagnosis and Etiology Phenotype Intensive Care Unit Concerns Management Screening and Surveillance Stickler Syndrome Orofacial Clefts Diagnosis and Etiology Anatomy Phenotype Syndromes Associated With Cleft Lip and/or Palate Intensive Care Unit Concerns Management Screening and Surveillance 22q11.2 Deletion Syndrome Diagnosis and Etiology Phenotype Intensive Care Unit Concerns Management Screening and Surveillance Craniosynostosis Diagnosis and Etiology Single Suture Synostosis Multiple Suture Synostosis Intensive Care Unit Concerns Management Screening and Surveillance Disorders of the First and Second Branchial Arches Craniofacial Microsomia Diagnosis and Etiology Phenotype Branchial Arch Malformation Syndromes Moebius Syndrome Treacher Collins Syndrome Intensive Care Unit Concerns Management Screening and Surveillance for Craniofacial Microsomia CHARGE Syndrome Diagnosis and Etiology Phenotype Intensive Care Unit Concerns Management Screening and Surveillance Macroglossia/Beckwith-Wiedemann Syndrome Diagnosis and Etiology Phenotype Intensive Care Unit Concerns Management Screening and Surveillance Other Notable Craniofacial Conditions Frontonasal Dysplasia, Hypertelorism, Encephalocele Diagnosis and Etiology Phenotype Intensive Care Unit Concerns Management Congenital Nasal Pyriform Aperture Stenosis Diagnosis and Etiology Phenotype Intensive Care Unit Concerns Management and Screening Prenatal Screening for Fetal Face Anomalies Acknowledgment References Suggested Reading References 89. Common Neonatal Orthopedic Conditions 89 Common Neonatal Orthopedic Conditions Developmental Dysplasia of the Hip Foot Deformities Torticollis Torsional and Angular Deformities of the Lower Extremities Congenital Vertebral Malformations Obstetric Trauma Neonatal Osteomyelitis and Septic Arthritis References Suggested Readings References 90. Skeletal Dysplasias and Heritable Connective Tissue Disorders 90 Skeletal Dysplasias and Heritable Connective Tissue Disorders Clinical Spectra of Disorders With Common Molecular or Cellular Bases Approach to Diagnosis Clinical and Molecular Evaluation Disorders of Bone Fragility Osteogenesis Imperfecta Types II and III Presentation Radiographic Features Etiology Inheritance Differential Diagnosis Management Handling an Infant With Osteogenesis Imperfecta Perinatal Hypophosphatasia Presentation Radiographic Features Etiology Inheritance Differential Diagnosis Management FGFR3 Spectrum Achondroplasia Presentation Radiographic Features Etiology Inheritance Differential Diagnosis Management Thanatophoric Dysplasia Presentation Radiographic Features Etiology Inheritance Differential Diagnosis Management COL2A1 Spectrum Spondyloepiphyseal Dysplasia Congenita Presentation Radiographic Features Etiology Inheritance Differential Diagnosis Management Achondrogenesis Type II–Hypochondrogenesis Presentation Radiographic Features Etiology Inheritance Differential Diagnosis Management SLC26A2 Spectrum Diastrophic Dysplasia Presentation Radiographic Features Etiology Inheritance Differential Diagnosis Management Achondrogenesis Type IB Presentation Radiographic Features Etiology Inheritance Differential Diagnosis Management Other Skeletal Dysplasias Campomelic Dysplasia Presentation Radiographic Features Etiology Inheritance Differential Diagnosis Management Heritable Connective Tissue Disorders Early-Onset/Rapidly Progressive (Congenital Neonatal, Infantile) Marfan Syndrome Presentation Radiographic Features Etiology Inheritance Differential Diagnosis Management Congenital Arachnodactyly (Beals Syndrome Distal Arthrogryposis Type 9) Presentation Radiographic Features Etiology Inheritance Differential Diagnosis Management Ehlers–Danlos Syndromes Presentation Radiographic Features Etiology Inheritance Differential Diagnosis Management Cutis Laxa Presentation Radiographic Features Etiology Inheritance Differential Diagnosis Management Menkes Syndrome Presentation Radiographic Features Etiology Inheritance Differential Diagnosis Management Family Support and Education References Suggested Readings References 91. Newborn Skin Development-Structure and Function 91 Newborn Skin Development: Structure and Function Epidermis Dermoepidermal Junction Dermis and Subcutis Appendages Specialized Skin Cells Epidermal Stem Cells Impact of Prematurity Care of Preterm Skin General Care of Newborn Skin Morphologic Approach to Skin Pathology Collodion Membrane Vesicopustular and Bullous Eruptions Blueberry Muffin Babies Erythroderma Birthmarks With Neurologic Implications References Suggested Readings References 92. Congenital and Hereditary Disorders of the Skin 92 Congenital and Hereditary Disorders of the Skin Ichthyoses Collodion Baby Autosomal Recessive Congenital Ichthyosis: Harlequin Ichthyosis, Lamellar Ichthyosis, and Nonbullous Congenital Ichthyosifo ... Epidermolytic Ichthyosis Diagnosis of Ichthyoses Prognosis and Treatment of Ichthyoses Epidermolysis Bullosa Classification of Epidermolysis Bullosa Epidermolysis Bullosa Simplex Junctional Epidermolysis Bullosa Dystrophic Epidermolysis Bullosa Diagnosis of Epidermolysis Bullosa Management of Epidermolysis Bullosa Ehlers–Danlos Syndrome Cutis Laxa Ectodermal Dysplasias Hypohidrotic Ectodermal Dysplasia Incontinentia Pigmenti Cutaneous Findings Extracutaneous Findings Diagnosis Prognosis and Treatment Focal Dermal Hypoplasia (Goltz Syndrome) Disorders With Generalized Hypopigmentation Diagnosis of Oculocutaneous Albinism Treatment of Oculocutaneous Albinism Disorders With Localized Hypopigmentation Piebaldism Porphyrias Congenital Erythropoietic Porphyria Erythropoietic Protoporphyria and X-Linked Erythropoietic Protoporphyria Hepatoerythropoietic Porphyria References Suggested Readings References 93. Infections of the Skin 93 Infections of the Skin Staphylococcus aureus Infections Impetigo Clinical Findings Etiology Diagnosis Treatment Staphylococcal Scalded Skin Syndrome Clinical Findings Etiology Diagnosis Treatment Streptococcus Species Infections Omphalitis Clinical Findings Diagnosis Treatment Candida Species Infections Localized Candida Infection (Primary Cutaneous) Oral Candidiasis (Thrush) Candida Diaper Dermatitis Diagnosis of Localized Cutaneous Candida Infection Treatment Congenital (Intrauterine) Candidiasis Clinical Findings Diagnosis Treatment Disseminated/Invasive Candidiasis Clinical Findings Diagnosis Prognosis and Treatment Primary Cutaneous Aspergillosis Diagnosis and Treatment Clinical Findings Diagnosis and Treatment Tinea Capitis and Tinea Corporis Herpes Simplex Virus Infection Clinical Findings Etiology Epidemiology Diagnosis Treatment Acknowledgments References Suggested Readings References 94. Common Newborn Dermatoses 94 Common Newborn Dermatoses Erythema Toxicum Neonatorum Clinical Findings Diagnosis Etiology Treatment and Prognosis Transient Neonatal Pustular Melanosis Clinical Findings Diagnosis Etiology Treatment and Prognosis Eosinophilic Pustular Folliculitis Clinical Findings Diagnosis Etiology Treatment and Prognosis Acropustulosis of Infancy Clinical Findings Diagnosis Etiology Treatment and Prognosis Milia Clinical Findings Diagnosis Etiology Treatment and Prognosis Miliaria Clinical Findings Diagnosis Etiology Treatment and Prognosis Epstein Pearls and Bohn Nodules Clinical Findings Diagnosis Etiology Treatment and Prognosis Sebaceous Hyperplasia Clinical Findings Diagnosis Etiology Treatment and Prognosis Neonatal Cephalic Pustulosis (Neonatal Acne) Clinical Findings Diagnosis Etiology Treatment and Prognosis Seborrheic Dermatitis Clinical Findings Diagnosis Etiology Treatment and Prognosis Atopic Dermatitis Clinical Findings Diagnosis Etiology Treatment and Prognosis Diaper Dermatitis Clinical Findings Diagnosis Etiology Treatment and Prognosis Harlequin Color Change Clinical Findings Diagnosis Etiology Treatment and Prognosis Subcutaneous Fat Necrosis Clinical Findings Diagnosis Etiology Treatment and Prognosis Cutis Marmorata Clinical Findings Diagnosis Etiology Treatment and Prognosis Dermal Melanocytosis Clinical Findings Diagnosis Etiology Treatment and Prognosis Aplasia Cutis Congenita Clinical Findings Diagnosis Etiology Treatment and Prognosis References Suggested Readings References 95. Vascular Anomalies and Other Cutaneous Congenital Defects 95 Vascular Anomalies and Other Cutaneous Congenital Defects Vascular Anomalies Vascular Tumors Infantile Hemangiomas Clinical Features Pathogenesis Diagnosis Complications Local Complications Disfigurement. Functional Complications Potential Life-Threatening Complications Treatment Topical Therapies. Systemic Therapies Surgical Therapies Segmental Hemangiomas Vascular Malformations Nevus Simplex Capillary Malformation (Port-Wine Stain) Venous Malformations Lymphatic Malformations Arteriovenous Malformations Lymphedema Disorders of Pigmentation Hypopigmented Lesions Nevus Depigmentosus (Nevus Achromicus) Pigmentary Mosaicism Ash Leaf Macules Hyperpigmented Lesions Café au Lait Macules Lentigines Congenital Dermal Melanocytosis (Mongolian Spots) Nevus of Ota/Ito Melanocytic Nevi Congenital Melanocytic Nevi Nevus Spilus Congenital Tumors of Epithelial Origin Epidermal Nevus Nevus Sebaceous Epidermal (Linear Sebaceous) Nevus Syndrome Congenital Tumors of Dermal and Subcutaneous Origin Juvenile Xanthogranuloma Mastocytosis Connective Tissue Nevus (Connective Tissue Hamartoma) Neurofibroma Developmental Anomalies of the Skin Midline Anomalies Preauricular Pits and Sinuses Accessory Tragus Congenital Cartilaginous Rests of the Neck (Cervical Tabs, Wattles) Supernumerary Digits (Rudimentary Polydactyly) Supernumerary Nipples (Polythelia, Accessory Nipples) Median Raphe Cysts (Congenital Sinus and Cysts of Genitoperineal Raphe, Mucous Cysts of the Penile Skin, Parameatal Cysts) References Suggested Readings References 96. Eye and Vision Disorders 96 Eye and Vision Disorders General Examination Techniques The Newborn Eye Examination: Approach and Equipment Common Diagnostic Problems Leukocoria and Abnormal Red Reflex Cataract Retinoblastoma Persistent Hyperplastic Primary Vitreous (Persistent Fetal Vasculature) Coloboma Corneal Clouding Red Eye/Eye Discharge Motility Abnormalities and Nystagmus Ptosis and Other Eyelid and Lacrimal Abnormalities Ocular Trauma in the Neonatal Period Retinal Hemorrhages and Abusive Head Injury Common Ophthalmic Manifestations of Systemic Diseases Role of the Neonatal Healthcare Provider Retinopathy of Prematurity Pathogenesis of Retinopathy of Prematurity Classification of Retinopathy of Prematurity Prevalence and Incidence of Retinopathy of Prematurity Detection of Serious Disease Prediction of Retinopathy of Prematurity Prevention of Retinopathy of Prematurity Establishment of a Retinopathy of Prematurity Program Telemedicine Screening for Retinopathy of Prematurity Treatment of Retinopathy of Prematurity References Suggested Readings References 97. Ear and Hearing Disorders 97 Ear and Hearing Disorders Normal Hearing Permanent Hearing Loss—The Challenge Hearing Disorders Methods for Newborn Hearing Screening Risk Factors for Permanent Hearing Loss in Infants and Children F amily Neonatal After Newborn Hearing Screening: Audiology Diagnostic Protocols Medical Work-Up for Hearing Loss Multidisciplinary Care Imaging Communication Options Assistive Technologies Comprehensive Early Intervention Neonatal Intensive Care Unit Infants, Risk Factors, and Hearing Loss The Brain, Language Outcomes, and Access to Language References Suggested Readings References