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Neonatology at a Glance

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This title is also available as an e-book. For more details please see www.wiley.com/buy/9781118767436 or scan this QR code:

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Neonatology at a Glance Editors Tom Lissauer mb bc hir frcpch Honorary Consultant Neonatologist imperial College Healthcare Trust London uK a vroy a. FaN aroFF md frcpe frcpch eliza Henry Barnes Professor of Neonatology rainbow Babies Children’s Hospital emeritus Professor of Pediatrics Case Western reserve university school of medicine Cleveland ohio usa La WreNCe miaLL mbbs bs c mmedsc frcpch Consultant Neonatologist Leeds Children’s Hospital Leeds uK Honorary senior Lecturer university of Leeds Leeds uK JoN a THaN FaN aroFF md jd Co-medical Director Neonatal intensive Care unit Director rainbow Center for Pediatric ethics rainbow Babies Children’s Hospital Cleveland ohio usa Associate Editors NiCHoLas Hoque mbbs bs c phd mrcpch Consultant Neonatologist Locum Chelsea and Westminster NHs Trust London uK moira a. Cro WLey md Co-director Neonatal eCmo Program rainbow Babies Children’s Hospital assistant Professor of Pediatrics Case Western reserve university school of medicine Cleveland ohio usa Third Edition

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This edition first published 2016 © John Wiley sons Ltd second edition © 2011 by Blackwell Publishing Ltd First edition © 2006 by Blackwell Publishing Ltd Registered Office John Wiley sons Ltd The atrium southern Gate Chichester West sussex Po19 8sq uK Editorial Offices 350 main street malden ma 02148-5020 usa 9600 Garsington road oxford oX4 2Dq uK The atrium southern Gate Chichester West sussex Po19 8sq uK For details of our global editorial offices for customer services and for information about how to apply for permission to reuse the copyright material in this book please see our website at www.wiley.com/wiley-blackwell. The right of Tom Lissauer a vroy a. Fanaroff Lawrence miall and Jonathan Fanaroff to be identified as the authors of the editorial material in this work has been asserted in accordance with the uK Copyright Designs and Patents act 1988. all rights reserved. No part of this publication may be reproduced stored in a retrieval system or transmitted in any form or by any means electronic mechanical photocopying recording or otherwise except as permitted by the uK Copyright Designs and Patents act 1988 without the prior permission of the publisher. Wiley also publishes its books in a variety of electronic formats. some content that appears in print may not be available in electronic books. Designations used by companies to distinguish their products are often claimed as trademarks. all brand names and product names used in this book are trade names service marks trademarks or registered trademarks of their respective owners. The publisher is not associated with any product or vendor mentioned in this book. Limit of Liability/Disclaimer of Warranty: While the publisher and authors have used their best efforts in preparing this book they make no representations or warranties with respect to the accuracy or completeness of the contents of this book and specifically disclaim any implied warranties of merchantability or fitness for a particular purpose. it is sold on the understanding that the publisher is not engaged in rendering professional services and neither the publisher nor the author shall be liable for damages arising herefrom. if professional advice or other expert assistance is required the services of a competent professional should be sought. Library of Congress Cataloging-in-Publication Data Neonatology at a glance / edited by Tom Lissauer a vroy a. Fanaroff Lawrence miall Jonathan Fanaroff associate editors Nicholas Hoque moira a. Crowley. – Third edition. p. cm. – at a glance series includes index. isBN 978-1-118-76743-6 pbk. i. Lissauer Tom editor. ii. Fanaroff a vroy a. editor. iii. miall Lawrence editor. iv. Fanaroff Jonathan m. editor. v. series: at a glance series oxford england. DNLm: 1. infant Newborn. 2. infant Care. 3. infant Newborn Diseases–therapy. 4. Neonatology–methods. Ws 420 rJ251 618.92′01–dc23 2015008082 a catalogue record for this book is available from the British Library. set in 9.5/11.5pt Times by sPi Global Pondicherry india 1 2016

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Contents v Preface vii Contributors viii How to use this textbook xi About the companion website xiv Part 1 Introduction 1 Milestones in neonatology 2 2 Epidemiology 4 Part 2 Perinatal medicine 3 Perinatal medicine 6 4 Prepregnancy care prenatal screening and fetal medicine 8 5 Maternal medical conditions 10 6 Intrauterine growth restriction 12 7 Multiple births 14 8 Preterm delivery 16 9 Birth defects and genetic disorders 18 10 Maternal drugs affecting the fetus and newborn infant 20 11 Congenital infection 22 Part 3 Delivery 12 Adaptation to extrauterine life 26 13 Neonatal resuscitation and post-resuscitation care 28 14 Hypoxic–ischemic encephalopathy 34 15 Birth injuries 38 Part 4 The normal newborn infant 16 Routine care of the newborn infant 40 17 Routine examination of the newborn infant 42 18 Neurologic examination 44 19 Care and support for parents 46 20 Feeding 48 21 Minor abnormalities in the first few days 50 22 Common problems of term infants 52 Part 5 The sick newborn infant 23 Admission to the neonatal unit 54 24 Developmental care 56 25 Stabilizing the sick newborn infant 58 26 Respiratory support 60 Part 6 The preterm infant 27 Preterm infants and their complications 66 28 Lung development and surfactant 68 29 Respiratory distress syndrome 70 30 Temperature control 72 31 Growth and nutrition 74 32 Intraventricular hemorrhage and periventricular leukomalacia 76 33 Patent ductus arteriosus PDA 78 34 Infection jaundice anemia osteopenia of prematurity 80 35 Apnea bradycardia and desaturations retinopathy of prematurity 82 36 Necrotizing enterocolitis 84 37 Bronchopulmonary dysplasia 86 38 Outcome of preterm infants 88 Part 7 Neonatal problems 39 Respiratory distress in term infants 90 40 Upper airway disorders 94 41 Jaundice 96 42 Neonatal infection 100 43 Specific bacterial infections 102 44 Viral infections 104 45 Hypoglycemia and hyperglycemia 106 46 Inborn errors of metabolism 108 47 Gastrointestinal disorders 110 48 Gastrointestinal obstruction 114 49 Cardiac disorders 116 50 Renal and urinary tract anomalies diagnosed prenatally 120 51 Renal and urinary tract disorders 122 52 Genital disorders 126 53 Disorders of sex development 128 54 Anemia and polycythemia 130 55 Neutrophil and thrombotic disorders 132 56 Coagulation disorders 134 57 Dermatological disorders 136 58 Seizures and perinatal strokes 138 59 Neural tube defects and hydrocephalus 140 60 The hypotonic infant 142 61 Bone and joint disorders 144 62 Hearing and vision 146 Contents

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vi Contents Part 8 Aspects of neonatal intensive care 63 Pain 148 64 Pharmacology 150 65 Quality improvement 152 66 Critical incidents 154 67 Evidence‐based medicine 158 68 Ethics 160 69 Research and consent 162 70 Palliative and end‐of‐life care 164 71 Discharge from hospital 166 72 Follow‐up of high‐risk infants 168 Part 9 Global 73 Global neonatology 170 Part 10 Transport 74 Transport of the sick newborn infant 174 Part 11 Practical procedures 75 Intubation and chest tubes 176 76 Common practical procedures 178 77 Umbilical catheters and intraosseous cannulation 180 78 Central venous catheters and exchange transfusions 182 79 Cranial ultrasound 184 80 Amplitude‐integrated electroencephalography aEEG 188 81 Perinatal neuroimaging 190 82 Echocardiography for the neonatologist 192 83 Gestational age assessment BP severity of illness scores jaundice treatment chart 194 Index 196

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Preface vii This book provides a concise illustrated overview of neonatal medicine. We have divided all of neonatology into only 83 topics with each covered in one or occasionally two or three double pages. This has been a challenging exercise it would have been easier to write a longer book but this format has forced us to identify the most important points and omit unnecessary details. The book has been designed to facilitate learning and to make it more enjoyable. Modern education emphasizes visual impact and this is reflected in this book. The layout photographs and illustrations have been chosen to assist learning and make the book attractive stimulating and interesting. In addition there are specific aids to learning with boxes to highlight key points and questions and answers. The book covers the wide range of common or important neonatal clinical conditions and their management. It also puts neonatology into context with sections on its history epidemi- ology perinatal medicine and a global overview together with the care of the normal newborn and how to recognize the sick infant. The challenging topics of ethical issues research quality assurance evidence‐based medicine palliative and end‐of‐life care autopsy and neonatal outcome are also considered. Practical procedures are described including neonatal resuscitation and neonatal transport descriptions of cranial ultrasound amplified EEG neuroimaging and echocardiography have been included to inform the practicing clinician about them even if they do not perform these procedures themselves. The book is written for pediatric interns and residents medical students neonatal nurse practitioners neonatal nurses therapists and midwives who care for newborn babies either on a neonatal unit or with their mothers in the normal newborn nursery postnatal wards. For neonatologists pediatricians and nurse tutors it will be a useful aid to teaching. Whilst the book describes the salient features of intensive care such as stabilizing the sick infant and respiratory support it is not a manual of neonatal intensive care of which there are many. The book has been a collaborative project between editors and contributors from both North America and the UK. Where prac- tices differ between the two sides of the Atlantic this has been acknowledged and described. This collaboration has been highly educational and hugely enjoyable for the editors and contributors as well as improving the book by forcing us to concentrate on the principles of practice instead of the details. This new edition has allowed us to update and revise the book. New topics have been added such as amplified EEG and perinatal neuroimaging. Another new and innovative development is video clips to enhance the teaching capacity of the book which have been pro- duced by Dr Lawrence Miall. To help ensure that the book has been thoroughly revised and updated the editorial team has been enlarged and now includes Drs Lawrence Miall and Jonathan Fanaroff as Editors and Drs Nicholas Hoque and Moira Crowley as Associate Editors. We would like to thank our many colleagues who have given their time to revise or review chapters and offer advice on improvements. Others have willingly contributed photographs and other images that enhance the book immensely. We are grateful to the many doc- tors nurses and therapists whose positive comments about the book encouraged us to produce this third edition. We would also like to thank our families for allowing us to spend so much time over many years on this project. Tom Lissauer Avroy A. Fanaroff Lawrence Miall Jonathan Fanaroff Preface

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viii Contributors The Editors are indebted to the following for writing or reviewing chapters for this edition many of whom also contributed to previous editions of the book: Mark Anderson Consultant Paediatrician Newcastle upon Tyne Hospitals NHS Trust Newcastle upon Tyne UK Pharmacology Tomoki Arichi Centre for the Developing Brain King’s College London St Thomas’ Hospital London UK Department of Bioengineering Imperial College London UK Perinatal neuroimaging Denis Azzopardi Professor of Neonatal Medicine Centre for the Developing Brain King’s College London UK Amplitude‐integrated electroencephalography aEEG Hannah Blencowe Research Fellow London School of Hygiene and Tropical Medicine London UK Global neonatology A David Edwards Chair in Paediatrics and Neonatal Medicine Centre for the Developing Brain King’s College London UK St Thomas’ Hospital London UK Department of Bioengineering Imperial College London UK Perinatal neuroimaging Afif EL‐Khuffash Consultant Neonatologist The Rotunda Hospital Dublin Ireland Children’s University Hospital Temple Street Dublin Ireland Patent ductus arteriosus and Echocardiography Sharon English Consultant Neonatologist Leeds Children’s Hospital Leeds UK Palliative and end‐of‐life care Cath Harrison Consultant Neonatologist Embrace Paediatric and Neonatal Transport Service Sheffield Children’s Hospital and Leeds Children’s Hospital Leeds UK Transport of the sick newborn infant Kathryn Johnson Consultant Neonatologist Leeds Children’s Hospital Leeds UK Maternal drugs affecting the fetus and newborn infant Larissa Kerecuk Consultant Paediatric Nephrologist Birmingham Children’s Hospital Birmingham UK Renal and urinary tract anomalies diagnosed prenatally Renal and urinary tract disorders Genital disorders Mark Kilby Professor of Fetal Medicine School of Clinical Experimental Medicine The College of Medical Dental Sciences University of Birmingham Birmingham UK Department of Fetal Medicine Birmingham Women’s Foundation Trust Birmingham UK Perinatal Medicine – Part 2 Joy Lawn Professor and Director of MARCH Centre London School of Hygiene and Tropical Medicine London UK Global neonatology David Lissauer Lecturer Department of Fetal Medicine Birmingham Women’s Foundation Trust Birmingham UK Perinatal medicine – Part 2 Hermione Lyall Consultant in Paediatric Infectious Diseases Imperial College Healthcare Trust London UK Congenital infection Neonatal infection Specific bacterial infections Viral infections Neil Marlow Professor of Neonatal Medicine UCL Institute for Women’s Health London UK Epidemiology Outcome of preterm infants Follow‐up of high‐risk infants Richard J. Martin Director Division of Neonatology Drusinsky–Fanaroff Chair in Neonatology Rainbow Babies Children’s Hospital Cleveland Ohio USA Apnea bradycardia and desaturations Patrick McNamara Associate Professor of Paediatrics and Physiology University of Toronto Toronto Canada Staff Neonatologist Associate Scientist Hospital for Sick Children Toronto Canada Patent ductus arteriosus and Echocardiography Liz McKechnie Consultant Neonatologist Leeds Children’s Hospital Leeds UK Pain Naaz Merchant Consultant Neonatologist West Hertfordshire NHS Trust Watford Hospital Watford UK Honorary Senior Clinical Lecturer Centre for the Developing Brain King’s College London Amplitude‐integrated electroencephalography aEEG Sam Oddie Consultant Neonatologist Bradford Royal Infirmary Bradford UK Stabilizing the sick newborn infant Contributors

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Contributors ix Irene Roberts Professor of Paediatric Haematology W eatherall Institute of Molecular Medicine University of Oxford Oxford UK Anemia and polycythemia Neutrophil and thrombotic disorders Coagulation disorders Robert Tulloh Professor of Paediatric Cardiology Bristol Congenital Heart Centre Bristol Royal Hospital for Children Bristol UK Cardiac disorders Chakrapani Vasudevan Consultant Neonatologist Bradford Royal Infirmary Bradford UK Seizures and stroke Neurological examination Inga Warren Consultant Therapist in Neonatal Developmental Care Imperial College Healthcare Trust London UK Developmental care Admission to the neonatal unit Pain Discharge from hospital We would like to thank Dr Sheila Berlin Assistant Professor of Radiology Rainbow Babies Children’s Hospital Cleveland Ohio USA for providing a range of radiographs Professor Brian Fleck Consultant Paediatric Ophthalmologist Royal Hospital for Sick Children Edinburgh UK for commenting on the sections on Retinopathy of prematurity and Vision and Dr Jeanette Kraft Consultant Radiologist Leeds Children’s Hospital Leeds UK for commenting on the section on Cranial ultrasound Dr David Clark Professor and Chairman The Children’s Hospital Albany New York USA and Dr Alan Spitzer Senior Vice President and Director The Center for Research and Education Pediatric Medical Group Sunrise Florida USA for contributing photographs and Dr Carlos Sivit Professor of Radiology and Director of Pediatric Radiology Rainbow Babies Children’s Hospital Cleveland Ohio USA for providing many of the cranial ultrasound photographs. We also would like to thank contributors or reviewers to the first two editions we have often drawn extensively upon their contributions: Ricardo J. Rodriguez Associate Editor first edition Michael Weindling Associate Editor first edition Karel Allegaert Pharmacology Nancy Bass Cerebral hemorrhage and periventricular leukomalacia Seizures and strokes Neural tube defects and hydrocephalus The hypotonic infant Monica Bhola Intubation and chest drains Common practical procedures Umbilical catheters and intraosseous cannulation Central venous catheters and exchange transfusions Paula Bolton‐Maggs Anemia and polycythemia Coagulation disorders Bernie Borgstein Hearing Subarna Chakravorty Anemia and polycythemia Neutrophil and thrombotic disorders Coagulation disorders Hugo Devlieger Pharmacology George Haycock Kidney and urinary tract disorders: antenatal diagnosis Kidney and urinary tract disorders Susan Izatt Neonatal resuscitation Helen Kingston Birth defects and genetic disorders Carolyn Lund Skin Cheryl Jones Congenital infection Neonatal infection Specific bacterial infections Viral infections Sam Lissauer Intubation and chest drains Common practical procedures Umbilical catheters Neil McIntosh Ethics Research and consent Maggie Meeks Common problems of term infants Common practical procedures Central venous catheters Simon Newell Growth and nutrition Mary Nock Jaundice

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x Contributors Michael Reed Pain Sam Richmond Adaptation to extrauterine life Neonatal resuscitation Stabilizing the sick newborn infant Clare Roberts Vision Jonathan Stevens Transport of the sick newborn infant Central venous catheters and exchange transfusions Umbilical catheters and intraosseous cannulation Chest tubes and exchange transfusions Eileen Stork Bone and joint disorders Nim Subhedar Respiratory support Lung development and surfactant Respiratory distress syndrome Dharmapuri Vidyasagar Milestones in neonatology Deanne Wilson‐Costello Outcome of very low birthweight infants F ollow‐up of high‐risk infants Qin Yao Neonatal resuscitation

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How to use this textbook xi How to use this textbook Features contained within this textbook Each topic is presented in a double‐page spread with clear easy‐to‐follow diagrams supported by succinct explanatory text. Your textbook is full of photographs illustrations and tables. Key point boxes highlight points to remember. Question boxes offer additional clinical insight.

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The anytime anywhere textbook Wiley E‐Text Your book is also available to purchase as a Wiley E‐Text: Powered by VitalSource version – a digital interactive version of this book which you own as soon as you download it. Your Wiley E‐Text allows you to: Search: Save time by finding terms and topics instantly in your book your notes even your whole library once you’ve downloaded more textbooks Note and Highlight: Colour code highlight and make digital notes right in the text so you can find them quickly and easily Organize: Keep books notes and class materials organized in folders inside the application Share: Exchange notes and highlights with friends classmates and study groups Upgrade: Your textbook can be transferred when you need to change or upgrade computers The Wiley E‐Text version will also allow you to copy and paste any photograph or illustration into assignments presentations and your own notes. To access your Wiley E‐Text: • Visit www.vitalsource.com/software/bookshelf/downloads to download the Bookshelf application to your computer laptop tablet or mobile device. • Open the Bookshelf application on your computer and register for an account. • Follow the registration process. xii How to use this textbook

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How to use this textbook xiii CourseSmart CourseSmart gives you instant access via computer or mobile device to this Wiley‐Blackwell e‐book and its extra electronic functionality at 40 off the recommended retail print price. See all the benefits at: www.coursesmart.com/students Instructors … receive your own digital desk copies CourseSmart also offers instructors an immediate efficient and environmentally friendly way to review this book for your course. For more information visit www.coursesmart.com/instructors. With CourseSmart you can create lecture notes quickly with copy and paste and share pages and notes with your students. Access your CourseSmart digital book from your computer or mobile device instantly for evaluation class preparation and as a teaching tool in the classroom. Simply sign in at http://instructors.coursesmart.com/bookshelf to download your Bookshelf and get started. To request your desk copy hit ‘Request Online Copy’ on your search results or book product page. We hope you enjoy using your new book. Good luck with your studies The VitalSource Bookshelf can now be used to view your Wiley E‐Text on iOS Android and Kindle Fire • For iOS: Visit the app store to download the VitalSource Bookshelf: http://bit.ly/17ib3XS • For Android and Kindle Fire: Visit the Google Play Market to download the VitalSource Bookshelf: http://bit.ly/ BSAAGP You can now sign in with the email address and password you used when you created your VitalSource Bookshelf Account. Full E‐Text support for mobile devices is available at: http://support.vitalsource.com

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xiv About the companion website About the companion website This book is accompanied by a companion website: www.ataglanceseries.com/neonatology The website includes: • videos demonstrating practical procedures • artwork from the book

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Neonatology at a Glance Third Edition. Edited by Tom Lissauer Avroy A. Fanaroff Lawrence Miall and Jonathan Fanaroff. © 2016 John Wiley Sons Ltd. Published 2016 by John Wiley Sons Ltd. 2 Introduction The care of newborn infants has evolved over the last century from simple and empirical care to modern evidence‐based high‐tech medicine. Neonatal mortality has correspondingly declined dramatically from 40/1000 live births in 1900 to 4/1000 in the US and UK. Improved obstetric care and maternal health and nutrition have also contributed. It was only in the 1950s that medical care of healthy and sick newborn infants was transferred from obstetricians to pediatricians. The specialty of neonatology developed only in the 1960s and the first certifying examination for physicians in the US was held in 1975. Thermal regulation • 1890s: Tarnier in France showed that a warm controlled environment reduced mortality of infants 2 kg from 66 to 38 Fig. 1.1. • 1893: Budin Tarnier’s student established the first unit for premature babies in Paris emphasizing thermal regulation and breast‐feeding. •  Early 1900s: premature babies in incubators were exhibited in fairs around Europe and the US Fig. 1.2. • 1950s: Silverman in the US conducted elegant randomized controlled trials to confirm the beneficial effects of thermal control including humidity on mortality. • 2000s: Heat loss at delivery of extremely preterm babies minimized by plastic wrapping. Nutrition •  1880s: Tarnier and Budin recommend early feeding and intragas - tric ‘gavage’ feeding via a rubber tube inserted through the mouth. •  1907: Rotch in US introduces infant formula. Breast‐feeding declines as some believed formula was superior. •  1940s: Gavage feeding via a nasogastric tube used in neonatal units. •  1940s: Feeding of preterm infants delayed up to 4 days to avoid aspiration. Adverse effects hypoglycemia increased bilirubin and impaired development recognized only in the 1960s and early feeding reintroduced. •  1960s: PN parenteral nutrition introduced by central venous catheter then via peripherally inserted PICC lines. • 1960s: Infant formula associated with neonatal tetany from hypocalcemia and hemolysis from vitamin E deficiency. •  1980s: Development of special formulas for very low birth‐ weight infants. •  1980s: Resurgence of use of breast milk. Human milk fortifiers developed for preterm infants. • 2000s: Addition of long‐chain polyunsaturated fatty acids LCPUFA to formula. Rhesus hemolytic disease Kernicterus from bilirubin deposition in the brain in rhesus disease was first described in 1938. Exchange transfusions became a common procedure in neonatal units and saved an estimated 8000 lives/year in the US alone. •  1925: Hart describes first exchange transfusion – blood given via saphenous vein removed from anterior fontanel. •  1940: Landsteiner discovers rhesus factor. •  1945: Coombs develops Coombs test direct antiglobulin test DAT to detect rhesus agglutinins. Milestones in neonatology 1 K L L L L L a L P W K Fig. 1.1 The Tarnier incubator. The water was heated by the oil flame. Heated air circulating around the incubator kept baby warm. Fig. 1.2 Incubators with premature babies at the Pan‐American Exposition Buffalo New York in 1901. Source: Silverman WA. Incubator‐baby side shows. Pediatrics 1979 64: 127. Courtesy of the American Academy of Pediatrics.

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Milestones in neonatology 3 •  1947: Diamond describes exchange transfusion via umbilical vein with rubber catheter. •  1963: Liley introduces intrauterine transfusion. • 1964: Freda and Clarke develop prophylaxis with anti‐D immunoglobulin. •  1968: RhoD immune globulin prophylaxis introduced. Rhesus disease now almost completely prevented in high income countries. Antibiotics Before antibiotics mortality from neonatal sepsis was almost 100 but it declined markedly when penicillin was introduced in 1944. The organisms causing sepsis have changed Fig. 1.3. Development of neonatal intensive care •  1922: First neonatal unit in US in Chicago by Hess in UK by Crosse in Birmingham in 1945. •  1960s and 1970s: Development of regional neonatal intensive care units with dedicated staff introduction of CPAP and mechanical ventilation. •  1970s: Ultrasound to identify intraventricular hemorrhage. •  1970s: Ability to safely perform surgery in tiny infants. •  1980s: Development of multicenter clinical trials national and international. •  1980s: ECMO extracorporeal membrane oxygenation. •  1990s: NO nitric oxide therapy for persistent pulmonary hyper - tension of the newborn. • 2000s: Mild hypothermia shown to reduce morbidity of hypoxic–ischemic encephalopathy. •  2010s: Non‐invasive prenatal testing NIPT – free fetal DNA analysis from maternal blood for Trisomy 21 etc. Challenges for the future • Reduce prematurity hypoxic–ischemic brain injury neonatal infection congenital abnormalities. • Prevent complications of prematurity: brain injury necrotizing enterocolitis bronchopulmonary dysplasia retinopathy of prematurity. •  Practice evidence‐based medicine. •  Improve quality assurance – reduce medication errors etc. •  Develop better non‐invasive monitoring. •  Enhance nursery environment and parental satisfaction. •  Confront ethical dilemmas at the limit of viability. •  Improve/extend care at home of technology‐dependent infants. •  Develop personalized medicine incorporating modern genetics. •  Global reduction of neonatal mortality 2.8 million in 2013. Before antibiotics Gram-positive organisms Post antibiotics Gram-negative organisms e.g. E coli 1950–60 Staphylococcus aureus 1970 onwards Group B streptococcus 1980s onwards Coagulase-negative staphylococcus and fungal infections in very low birthweight VLBW infants. Ampicillin resistant Gram negative organisms emerge Fig. 1.3 Change with time of main organisms causing neonatal infection. Respiratory distress syndrome RDS History of respiratory distress syndrome surfactant deficiency •  1955: Pattle describes properties of surfactant. •  1956: Clements isolates surfactant. •  1959: A very and Mead demonstrate lack of surfactant in preterm lungs. •  1972: Liggins and Howie show that prenatal corticosteroids to the mother induce fetal lung maturity. •  1980: Fujiwara – frst surfactant replacement therapy. •  1985: Multicenter clinical trials of natural and artifcial surfactant replacement therapy. •  1989: Surfactant therapy approved. Oxygen therapy monitoring and respiratory support Whereas about 25 000 infants died every year in the US from RDS in the early 1950s by 2003 there were fewer than 500 such deaths. This has resulted from: • understanding the pathogenesis of RDS which enabled development of surfactant replacement therapy •  antenatal corticosteroids to induce surfactant and lung maturation •  developments in respiratory support: – oxygen therapy – continuous positive airway pressure CP AP introduced by Gregory – mechanical ventilators first shown to improve survival by Swyer in Toronto and Reynolds in London 1965 •  ability to closely monitor vital signs and blood gases: – cardiorespiratory monitors for neonates – measurement of blood gases on small blood samples – umbilical/peripheral artery catheters – non‐invasive oxygen saturation monitors. •  2010s: increasing use of non‐invasive respiratory support to avoid or reduce mechanical ventilation. Key point Since the 1950s RDS has been a major focus of research in neona - tology. Understanding its pathophysiology and the biochemistry of surfactant has been the key to developing surfactant therapy and respiratory support which have dramatically improved survival.

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Neonatology at a Glance Third Edition. Edited by Tom Lissauer Avroy A. Fanaroff Lawrence Miall and Jonathan Fanaroff. © 2016 John Wiley Sons Ltd. Published 2016 by John Wiley Sons Ltd. 4 Introduction Epidemiology is the study of the patterns causes and effects of disease in a defined population. In perinatal medicine the focus is on the prevalence and causes of illness and death and long‐term disability in mothers the fetus and newborn infants. These indicators are valuable as measures of the health of a region or country and allow comparisons between them and moni- toring of changes over time. Births There are 4 million births per year in the US population 315 million and 813 000 in the UK population 64 million. The mean age of a mother giving birth has risen to 26 years in the US and to 29 years in the UK average age at first child 28 years. There has been a steady rise in the birth rate for women in their thirties and forties. Increased use of assisted reproduction has led to a rise in multiple birth particularly twins with increased risk of mortality. Maternal mortality The huge reduction in deaths directly and indirectly related to pregnancy is one of the most dramatic improvements in health outcomes in high income countries. In the US maternal mortality declined from 582/100 000 live births in 1936 to a nadir of 11.5/ 100 000 in 1990. This is due to reduced mortality from puerperal sepsis following the development of antibiotics improved obstetric care availability of blood and blood products and better maternal health including fewer pregnancies per woman. However maternal mortality in the US has subsequently risen to 18/100 000 in the last 5 years pos- sibly due to an increase in chronic health conditions including congen- ital heart disease. It was 12/100000 live births in the UK in 2010. Epidemiology 2 Definitions Newborn infant •  Preterm: 37 completed weeks of gestation. •  Term: 37–41 completed weeks of gestation. •  Post‐term: ≥42 completed weeks of gestation. •  Low birthweight LBW: 2500 g. •  Very low birthweight VLBW: 1500 g. •  Extremely low birthweight ELBW: 1000 g. Mortality •  Maternal mortality ratio: the number of maternal deaths during pregnancy and within 42 days postpartum per 100 000 live births. •  Stillbirth: Variable defnitions. In US fetal death no signs of life ≥20 weeks’ gestation. In the UK fetus born with no signs of life after 24 weeks. For international comparison WHO recommend defning stillbirth rate as fetal deaths 1000 g or 28 completed weeks per 1000 total births. •  Perinatal mortality rate PMR: stillbirths plus early neo- natal deaths up to 6 completed days of life per 1000 live and stillbirths adjusted as above for international comparisons. •  Neonatal mortality rate NMR: deaths in the frst 4 weeks 27 completed days of life per 1000 live births. •  Post‐neonatal mortality rate: deaths from 28 days until 1 year per 1000 live births. •  Infant mortality rate: deaths in the frst year of life per 1000 live births. 8 4 6 10 12 14 2 0 1980 1985 1990 1995 2000 Neonatal mortality Infant mortality Infant mortality rate per 1000 live births 2005 2011 Fig. 2.2 Decline in infant and neonatal mortality in the US since 1980 CDC 2013. 33 67 Stillbirths 5.2 per 1000 total births Unexplained antepartum fetal death 76 7 7 3 7 Intrapartum ‘asphyxia’ or ‘trauma’ Congenital malformation Infection Other Early neonatal deaths 2.6 per 1000 live births Immaturity 46 22 12 Congenital malformation Intrapartum causes Infection 7 Other 13 Fig. 2.1 Causes of perinatal mortality in UK Confidential Enquiry into Maternal and Child Health 2009. 8 4 6 10 12 14 2 0 1980 1985 1990 1995 Preterm Low birthweight Very low birthweight Live births 2005 2000 2010 Fig. 2.3 Percentage of live births born preterm low bithweight 2.5 kg and very low birthweight 1.5 kg since 1980 in the US CDC 2013.

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Epidemiology 5 Perinatal mortality The causes of perinatal mortality are shown in Fig. 2.1. The risk to the infant of perinatal death is about 100 times that for the mother. In the US the perinatal mortality fell from 13/1000 live and still- births in 1980 to 6/1000 in 2011. The decline has occurred not only because of advances in neonatal care but also from improved maternal health nutrition and obstetric care. Neonatal mortality Neonatal mortality rate in the US and England and Wales have declined markedly over the last 30 years Fig. 2.2. This has been achieved in spite of the rise in the proportion of preterm deliveries the main determinant of neonatal mortality Fig. 2.3 and Table 2.1. Epidemiologic data collection Neonatal epidemiologic data are gathered through several sys- tems including national vital registration birth and death certification and rapid reporting audit systems e.g. confidential enquiries. There are also special collaborative neonatal data- bases such as the Vermont–Oxford Neonatal Network NICHD National Institute of Child Health and Human Development Neonatal Research Network the Canadian Neonatal Network and the National Neonatal Audit Program in England and Wales which are used for benchmarking across a large number of neo- natal units. Particularly informative are the population‐based datasets Fig. 2.4 that combine obstetric and neonatal data with outcome information. Infant mortality The marked reduction in infant mortality since 1980 is shown in Fig 2.2. With the decline in deaths from infectious diseases since the 1900s and more recently from sudden infant death syndrome over two‐thirds of infant deaths are in the neonatal period and even after the first month of life many deaths are related to neo- natal problems. Sixty‐six percent of all infant deaths occur in the 8.3 of infants born with low birthweight 52 of infant deaths are among the 1.5 very low birthweight infants. Complications of preterm birth and congenital abnormalities are the largest contributors to both neonatal and infant deaths. Both preterm birth prevalence and mortality risk in the US are influenced by ethnicity the infant mortality rate of infants of black mothers is over twice that of infants of white or Hispanic mothers. The difference in the UK is similar. Table 2.1 Birthweight distribution and neonatal mortality. Birthweight g Births Neonatal mortality rate per 1000 live births 2500 91.7 0.8 2000–2499 5.2 5.6 1500–1999 1.6 17 1500 1.5 209 Outcome of extremely preterm infants − the EPICure studies Two countrywide epidemiological studies of infants at the limit of viability have been undertaken − the first in babies 26 weeks of gestation in the UK in 1995 and the second in babies born 27 weeks in England during 2006. 0 20 40 60 80 100 Admitted to NNU `Failed´ resuscitation Resuscitation withheld Percent 22 n 142 23 n 303 24 n 385 Gestation weeks 25 n 463 26 n 490 a 23 weeks 23 weeks 24 weeks 25 weeks 0 10 20 30 40 50 60 70 80 90 100 EPICure 1 1996 EPICure 2 2006 ns n 2/4 ns n 26/45 p .002 p .0006 Gestational age at birth Percent survival b Fig. 2.4 a Results of labor ward management for extremely preterm births England 2006. Source: EPICure 2 www.epicure.ac.uk. b Gestation − specific mortality rates for babies admitted for neonatal intensive care in England in 1995 and 2006. Sources: Costeloe K. et al. Pediatrics 2000 106: 659−671 www.epicure.ac.uk.

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Neonatology at a Glance Third Edition. Edited by Tom Lissauer Avroy A. Fanaroff Lawrence Miall and Jonathan Fanaroff. © 2016 John Wiley Sons Ltd. Published 2016 by John Wiley Sons Ltd. 6 Perinatal medicine Perinatal medicine aims to provide a ‘seamless’ care pathway for the fetus and infant with complex problems from before and during pregnancy through labor and delivery into the neonatal period. This requires expertise that is highly specialized rapidly advancing and multidisciplinary. In many countries this involves close collabora- tion between specialists in maternal–fetal medicine high‐risk obstetrics neonatology and pediatrics. Such care is usually provided centrally as a tertiary service although some services are available locally or as ‘shared care’ Fig. 3.1. Perinatal medicine 3 Mother Perinatal center Commonest problems High–risk obstetrics Fetal medicine Signicant complex problem identied in fetus or mother Serious problem with baby Antenatal care Low-risk delivery and healthy baby Prepregnancy assessment Screening for risk factors blood tests ultrasound and antenatal visits Maternal–fetal medicine Fetus Pregnancy induced hypertension Chronic hypertension Maternal diabetes chronic illness cardiac renal etc. Recurrent miscarriages Preterm rupture of membranes/ chorioamnionitis Preterm labor Other specialist services Genetics Perinatal pathology Advantage of perinatal centers Ready access to specialists in one place Allows rapid development of experience with rare problems Improved outcomes data inconclusive Facilitates staff training and research Cost effective use of scarce specialist expertise Potential disadvantages Parents may have to travel away from home De-skilling of staff at other centers Creates hierarchy of care Need dedicated transport service More difcult to ensure good communication with local healthcare services because of geographical separation Infant Preferably transferred in-utero otherwise postnatally Very preterm 32 weeks’ gestation Mechanical ventilation for 24 h Hypoxic–ischemic encephalopathy Inhaled nitric oxide iNO therapy Neonatal surgery Specialist pediatric services – cardiac renal metabolic neurosurgery etc. Extracorporeal membrane oxygenation ECMO Neonatal intensive care or specialist pediatric services Structural anomaly on ultrasound scan Increased risk of fetal abnormality from blood screening test or scan e.g. Trisomy 21 Down syndrome Intrauterine growth restriction IUGR Feto-fetal transfusion syndrome Multiple gestation Fig. 3.1 Organization of tertiary perinatal care. Neonatal involvement in perinatal care An increasing number of conditions requiring specialist neonatal or pediatric care are recognized antenatally. This allows counseling both obstetric and pediatric multidisciplinary discussion and transfer if necessary to a perinatal center. Parents require discussion of complex information about their baby’s condition and management options often on multiple occasions and with several healthcare professionals these may include neonatologists specialist pediatricians and pediatric surgeons. Interpretation of antenatal ultrasound scans may be difficult and defining prognosis may be problematic. This is facilitated by multidisciplinary team MDT meetings of relevant specialists which may include fetal medicine obstetrics genetics neonatology and pediatric surgery. Other pediatric specialists such as those involved in urology neurosurgery otolaryngology  ENT orthopedics and pediatric medical specialties may also be involved.

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Perinatal medicine 7 However specialist assessment and counseling need to be prompt to allow parents to make informed choices including termination of pregnancy in order to keep within national legal boundaries. Information about less severe problems identified antenatally also needs to be communicated to the neonatology and specialist pediatric teams so that appropriate assessment and follow‐up are arranged postnatally. Neonatal Networks The different levels of care required by newborn infants are shown in Fig 3.4. As it is not possible or efficient to provide all levels of care in every hospital neonatal or perinatal including maternity networks working across hospital boundaries have been developed. Their aim is to improve care for mother and baby by facilitating collaborative working unified protocols and minimizing geo- graphic variations in care. Fig. 3.2 Significant fetal abnormalities detected on prenatal ultrasound screening such as the omphalocele arrow shown will need to be assessed in a perinatal center to allow review by a fetal medicine specialist neonatologist and pediatric surgeon counseling with parents and planning for delivery and management. Examples of perinatal care Signifcant fetal abnormality diagnosed on prenatal ultrasound. An example is an omphalocele Fig. 3.2. Another is a diaphrag- matic hernia requiring antenatal planning for infant to be transferred for ECMO Fig. 3.3 and neonatal surgery. Fetus diagnosed with supraventricular tachycardia SVT The mother is treated with oral flecainide transplacental therapy to control the fetal heart rate and rhythm and prevent heart failure. Performed in conjunction with pediatric/ perinatal cardiologists. The neonate is delivered in a cardiac center to optimize medical management and radio‐ablation of an accessory conduction pathway. Fig. 3.3 An infant on extracorporeal membrane oxygenation ECMO which is provided at only a relatively small number of specialist centers. US UK Local Neonatal Units LNNU •Special care high dependency and very short term intensive care 48 hrs •Usually 27 weeks •May take in some babies from other network SCU’s. Level III – NICU • Comprehensive care for all infants • Full range of respiratory support including inhaled nitric oxide •Advanced imaging including CT MRI and echocardiography • Prompt access to pediatric medical subspecialists and surgical specialists Level II – special care nursery • Infants 32 weeks and 1500g and short term illness otherwise stabilize and transfer • Mechanical ventilation 24 or CPAP Level 1: well newborn nursery • Neonatal resuscitation • Stabilize and care for stable infants 35–37 weeks • Stabilize and transfer if ill or 35 weeks Neonatal Intensive Care Units NICU • All gestational ages •Provide all levels of care including nitric oxide and therapeutic hypothermia Advanced imaging available • •Co-located with specialist obstetrics and fetal medicine •Often located with cardiac surgical or pediatric subspecialties. Level IV – Regional NICU • Surgery for complex conditions • Full range of pediatric medical subspecialists • Facilitate transport Special Care Units SCBU •Care for local population •Some provide some HDU care Transitional care •Usually 33–37 weeks •May be on post-natal wards or separate unit. •Mothers care for own babies with support Normal care • Takes place in maternity units • No specialist pediatric input required Network wide Neonatal Transport Team Fig. 3.4 Levels of neonatal care.

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Neonatology at a Glance Third Edition. Edited by Tom Lissauer Avroy A. Fanaroff Lawrence Miall and Jonathan Fanaroff. © 2016 John Wiley Sons Ltd. Published 2016 by John Wiley Sons Ltd. 8 Perinatal medicine Prepregnancy care prenatal screening and fetal medicine 4 Examples of structural malformations identified on ultrasound Figs 4.1–4.3 see videos: Fetal echocardiogram 1 Fetal echocardiogram 2 Fetal myelomeningocele Prepregnancy care To optimize the chances of a healthy baby mothers are advised: •  Attend clinic for prenatal care. • Avoid or cease maternal smoking alcohol drug misuse medication unless essential prior to conception. •  Toxoplasmosis exposure – avoid eating undercooked meat and wear gloves when handling cat litter. •  Listeria infection – avoid unpasteurized dairy products and soft ripened cheeses e.g. brie. •  Folic acid supplements preconceptually to 12 weeks – to reduce risk of neural tube defects and cardiac malformations in countries without folic acid fortifcation of foods as in the UK and Europe. Higher dose if previous baby with neural tube defect. •  Avoid eating shark swordfish marlin and limit tuna as high levels of mercury. Limit oily fsh as contain pollutants. • Optimize management of pre‐existing maternal medical conditions such as diabetes and hypertension. Pregnancies at increased risk of fetal abnormality need to be identified: •  previous child with congenital anomaly •  family history of an inherited disorder consanguineous •  parents known carriers of an autosomal recessive disorder •  parents from ethnic group with specifc risk e.g. Ashkenazi Jews Tay–Sachs disease a neurodegenerative disorder •  parent with known balanced chromosomal rearrangement. Prenatal screening Maternal blood The routine screening tests vary geographically but include: •  maternal blood group antibodies against rhesus D and other red cell incompatibilities •  hepatitis B surface and e‐antigen status •  syphilis serology rubella HIV infection •  screening for chromosomal anomalies see below •  hemoglobin electrophoresis. Ultrasound Ultrasound screening is recommended for all mothers before 20 weeks. Usually involves two ultrasound scans: •  a late first‐trimester scan 11 weeks to 13 weeks 6 days •  a mid‐trimester scan 18 to 22 weeks. Ultrasound screening allows: •  Gestational age calculation optimal at late first trimester scan. •  Multiple pregnancy to be identified – number of fetuses and the chorionicity number of placentae and amniotic sacs. •  Structural malformations – up to 80 of major congenital malformations can be identified. •  Screening for trisomy 21 Down syndrome. First trimester – nuchal translucency measurement combined with serum maternal hormones. Second trimester – four fetoplacental and maternal hormones in serum adjusted for maternal age. Confirmed on amnio - centesis or chorionic villous sampling. Detects about 90 with trisomy 21 but 3–5 false positive rate and 1 risk of fetal loss. •  Non-invasive prenatal testing NIPT – fetal DNA from maternal blood for trisomies Rhesus gender. •  Fetal growth monitoring – by serial measurement of fetal head size biparietal diameter and head circumference abdominal circumference and femur length. •  Amniotic fluid volume assessment to identify: i oligohydramnios – may result in pulmonary hypoplasia and limb and facial deformities ii polyhydramnios – associated with maternal diabetes fetal bowel obstruction CNS anomalies and multiple births. •  Doppler ultrasound measurement of flow/velocity waveforms – maternal and fetal circulation if indicated. Screening – Group B streptococcal chlamydia cystic fbrosis In US but not UK. If at high risk of cystic fibrosis a panel of common gene mutations is used. Fig. 4.1 Increased nuchal translucency associated with trisomy 21 Down syndrome. Fig. 4.2 Sacral myelocele. Courtesy of Dr Venkhat Rahman. Fig. 4.3 Talipes equinovarus.

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Prepregnancy care prenatal screening and fetal medicine 9 Fetal medicine Fetal medicine Fig. 4.4 may allow: •  identification of congenital abnormalities structural and chro - mosomal with varying specificity and sensitivity of detection. •  therapy either indirectly or directly to be given for a limited but  increasing number of conditions e.g. fetal arrhythmias intrauterine blood transfusion for severe rhesus disease •  optimal multidisciplinary discussion to impart information on prognosis and allow parents to make informed decisions including option of termination of pregnancy for severe disorders • optimal obstetric management of the fetus e.g. timing of delivery •  neonatal management to be planned in advance e.g. counseling and transfer to specialty center. Amniocentesis Chromosome/micro-array and DNA analysis Fetal infection – PCR polymerase chain reaction for CMV toxoplasmosis rubella parvovirus Imaging High-definition ultrasound Fetal MRI For identification and delineation of fetal abnormalities Chorionic villous sampling Chromosome/micro-array and DNA analysis Enzyme analysis for inborn error of metabolism Fetal blood sampling Fetal hemoglobin for anemia Fetal infection serology Fetal blood transfusion Pre-implantation genetic diagnosis PGD In-vitro fertilization IVF allows genetic analysis of cells from a developing embryo before transfer to the uterus Fetoscopy Fetoscopic laser ablation for feto-fetal transfusion syndrome Ultrasound transducer Non-invasive prenatal testing NIPT Free fetal DNA obtained from maternal blood for identification of fetal gender for x-linked disorders fetal genotyping rhesus and exclusion of common aneuploidy especially trisomy 21. Likely to become increasingly refined and available in clinical service. Debate if should be offered alone or with nuchal translucency ultrasound screening. Fig. 4.4 Techniques in fetal medicine and their indications. Fetal surgery Creates media headlines as cutting‐edge technology. However the results are generally poor as the malformations justifying fetal surgery are severe and the risk of premature labor is high. Now practiced only in a few centers and mainly restricted to randomized trials. Cases must be carefully selected. Open fetal surgery Randomized trial MOMS for myelomeningocele showed fetal surgery after hysterotomy uterus opened at 19–25 weeks’ gestation reduced the need for shunting and improved motor outcomes at 30 months. But uterine scarring and increased risk of preterm births. Fetoscopic/minimally invasive fetal surgery Fetal endoscopic tracheal occlusion FETO for congenital dia - phragmatic hernia. As fetal tracheal obstruction promotes lung growth this is replicated by inflating a balloon in the trachea inserted at fetoscopy. Randomized controlled trial TOTAL shows slightly improved lung function in infancy though increased rate of preterm delivery and survival not improved see Chapter  38. Catheter shunts i For fetal pleural effusions usually a chylothorax lym - phatic fluid – inserted under ultrasound guidance Fig. 4.5. Reduces risks of fetal death from hydrops and pulmonary hypoplasia. Neonatal course often satisfactory. ii Congenital bladder neck obstruction – vesicoamniotic shunting. Controversial. A randomized controlled trial PLUTO showed shunt improved perinatal survival but did not reduce morbidity from renal disease or death at 2 years. Chylothorax Pigtail catheter Fig. 4.5 Fetus with pigtail catheter to drain a pleural effusion.

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Neonatology at a Glance Third Edition. Edited by Tom Lissauer Avroy A. Fanaroff Lawrence Miall and Jonathan Fanaroff. © 2016 John Wiley Sons Ltd. Published 2016 by John Wiley Sons Ltd. 10 Perinatal medicine Diabetes mellitus Maternal insulin‐dependent diabetes type 1 is associated with increased perinatal morbidity and mortality mainly from congen- ital malformations and intrauterine death. These can both be reduced by tight blood glucose control from preconception onwards. Multidisciplinary management and close prenatal sur- veillance are required. Fetal problems •  Congenital malformations. The overall risk is 6 four times normal with particularly increased risk of cardiac malformations and caudal regression syndrome sacral agenesis. •  Macrosomia Fig. 5.1. Maternal hyperglycemia results in fetal hyperinsulinemia which promotes growth. Depending upon pre- pregnancy and gestational control of blood glucose up to 25 of infants of diabetic mothers are macrosomic with a birthweight 4 kg compared with 8 of infants of non‐diabetic mothers. •  Macrosomia predisposes to cephalopelvic disproportion and increased risk of delivery‐related complications both to the mother cesarean section and forceps delivery and the fetus including birth injuries. •  Intrauterine growth restriction IUGR. Threefold increase usu- ally associated with maternal microvascular disease. •  Polyhydramnios. •  Preterm labor. Occurs in 10 either natural or induced. •  Sudden intrauterine death in third trimester. Less common with good diabetic control and induction at about 38 weeks. Neonatal problems •  Check for malformations and birth injuries. •  Hypoglycemia is common in first 48 h due to residual hyperinsu- linism. Monitor blood glucose before feeds until 45 mg/dL 2.6 mmol/L. Hypoglycemia is often prevented by early frequent feeding but may require gavage nasogastric feeds or intravenous glucose. Mothers can express breast milk before delivery in prepa- ration. Hypocalcemia and hypomagnesemia are often present. •  Polycythemia – plethoric appearance. Occasionally requires partial exchange transfusion. •  Hyperbilirubinemia. •  Respiratory distress syndrome – increased risk from delayed maturation of surfactant. •  Hypertrophic cardiomyopathy – uncommon. Rarely causes outflow tract obstruction treated with beta‐blockers. •  Renal vein thrombosis – rare. Type 2 and gestational diabetes The prevalence of type 2 diabetes is increasing. May be associ- ated with neonatal macrosomia hypoglycemia and polycythemia. Also increases future risk of diabetes in later life. Maternal red blood cell alloimmunization Maternal antibody is formed to fetal red blood cell antigens e.g. rhesus D anti‐Kell and anti‐c. Rhesus disease was a major cause of fetal and neonatal morbidity and mortality but prophylaxis with anti‐D has significantly reduced risks of alloimmunization most are now anti Kell and anti-c. Rhesus hemolytic disease Etiology Fig. 5.2 Presentation •  Antibodies usually anti‐D c or Kell found on routine antenatal antibody screen at first visit and 28 and 34 weeks. •  Previous pregnancy affected with hemolytic disease fetal hydrops or stillbirth. •  Fetal hydrops on ultrasound. •  Detection of fetal anemia by Doppler ultrasound screening mid- dle cerebral artery blood flow increased for gestational age. •  Maternal polyhydramnios. •  Neonatal – jaundice anemia hydrops hepatosplenomegaly. Prenatal management •  Increasing antibody levels on maternal blood screening – refer to specialist center if necessary. • Fetal rhesus genotyping can be determined non‐invasively through free fetal DNA detection in maternal plasma. •  Monitor with serial ultrasound for fetal anemia usually by serial middle cerebral artery Doppler blood flow and signs of hydrops. •  Measure fetal hematocrit from cordocentesis if fetal anemia. • Intrauterine blood transfusion – blood injected directly into umbilical vein under ultrasound guidance. •  Elective preterm delivery if necessary. Maternal medical conditions 5 Fig. 5.1 Macrosomic infant with birthweight 4.8 kg at 38 weeks’ gestation. There is excess adipose tissue and organomegaly liver and heart.

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Maternal medical conditions 11 Postnatal management •  Check cord blood for blood type hemoglobin bilirubin and direct antibody test DAT. •  Monitor bilirubin closely as level may increase rapidly and cause high‐frequency deafness or kernicterus. •  Start intensive phototherapy adequate fluid balance and give IVIG immunoglobulin and perform an exchange transfusion if severe anemia or rapidly rising bilirubin concentration. •  Often need ‘top up’ blood transfusion for anemia within first 3 months of age until antibodies are depleted. Prevention Anti‐D gammaglobulin has almost eliminated rhesus disease. It is given to rhesus‐negative mothers during pregnancy after potentially sensitizing events and after delivery. About 15 percent of white women are rhesus‐negative smaller percentage of black and Asian women less than 2 of them become sensitized from inadequate or failed prophylaxis. Perinatal alloimmune thrombocytopenia Analogous to rhesus disease – maternal antibodies directed against paternally inherited fetal platelets Human Platelet Antigen HP A-1a and 5b. It affects 1 in 5000 births. May occur in first pregnancy. Intracranial hemorrhage may occur secondary to fetal thrombocyto- penia. If identified from a previously affected infant with intracranial hemorrhage prevention options are mainly maternal infusions of intravenous immunoglobulin IVIG and maternal glucocorticoid therapy and delivery by cesarean section. Severe thrombocytopenia after birth is treated with platelets that are negative for the platelet antigen. IVIG may reduce need for repeated platelet transfusions. Etiology Table 5.1 Effect of hemolysis. Fetus Infant Anemia Hepatosplenomegaly Hydrops edema ascites Death Anemia Hyperbilirubinemia Hepatosplenomegaly Kernicterus death Fetoplacental circulation Maternal circulation Fetal red cells with ‘D’ antigen Maternal red cells without ‘D’ antigen Maternal anti-D antibodies cross placenta and cause hemolysis of fetal red cells D D D D D D D d d a b Maternal antibodies produced against fetal red cells Sensitization Fetal red cell destruction at next pregnancy Fig. 5.2 a A small number of Rhesus positive fetal red cells enter the Rhesus negative maternal circulation and antibodies are formed. This usually occurs at delivery but also at miscarriages placental abruption from blood transfusions and occasionally during normal pregnancies. b On re‐exposure to fetal red cells at subsequent pregnancy maternal antibodies cross the placenta and bind to fetal cells causing hemolysis see Table 5.1. Key point Over 50 of maternal red cell alloim- munization is now due to rarer red cell antigens Kell and c. Other maternal medical conditions Table 5.2 Table 5.2 Other maternal medical conditions that may affect the infant. Maternal condition Significance for the infant Maternal hyperthyroidism If mother is controlled on treatment fetus and infant are usually unaffected. Rarely causes: •  Transient hyperthyroidism – fetal tachycardia and neonatal hyperthyroidism 1–3 – tachycardia heart failure vomiting diarrhea and poor weight gain despite good intake jitteriness goiter and exophthalmos protuberant eyes. Treated for 2–3 months •  Transient hypothyroidism – from maternal drug therapy Maternal hypothyroidism Mothers treated with thyroxine neonatal problems are rare. Worldwide commonest cause is iodine deficiency. Important cause of congenital hypothyroidism leading to short stature and severe learning difficulties. Rarely seen in North America or Western Europe as iodine deficiency rare and identified on newborn biochemical screening Autoimmune thrombocytopenic purpura AITP Maternal autoantibodies against platelet surface antigens cross the placenta and cause fetal thrombocytopenia. Most fetuses unaffected. Main risk is maternal or fetal bleeding at delivery. Infants with severe thrombocytopenia or petechiae at birth should be given intravenous immunoglobulin. Platelet transfusions are reserved for severe thrombocytopenia or active bleeding because of the anti‐platelet antibodies. The platelet count declines over the first few days before increasing

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Neonatology at a Glance Third Edition. Edited by Tom Lissauer Avroy A. Fanaroff Lawrence Miall and Jonathan Fanaroff. © 2016 John Wiley Sons Ltd. Published 2016 by John Wiley Sons Ltd. 12 Perinatal medicine Definition IUGR is the failure of a fetus to achieve his or her genetic growth potential. Most will also be small for gestational age SGA although the two terms are not synonymous. SGA means that the infant is below a particular weight centile for gestation the 10th centile is most often chosen but the 3rd or other centiles are also used Fig.  6.1. The higher the centile chosen the higher the proportion of infants included who are normal but small the lower the centile used the higher the proportion with a pathologic cause. The fetus may have growth failure but may not be SGA as their weight is still above the 10th centile. For this reason a prenatal combination of ultrasound fea- tures are utilized to identify IUGR in the fetus: a estimated fetal weight or fetal abdominal circumference less than 10th centile for gestation i.e. SGA b a ‘reduced’ fetal growth velocity change in abdominal cir - cumference 1 standard deviation over 14 days c the presence of oligohydramnios d abnormal cerebroplacental ratio of middle cerebral artery to umbilical artery pulsitility index or absent or reversed end dia- stolic velocity on Doppler insonation. The presence of two or more of these conditions places the fetus at ‘high risk’ from IUGR. Etiology Maternal •  Undernutrition e.g. famine in developing countries eating disorders. •  Maternal hypoxia e.g. cyanotic heart disease chronic respiratory disease high altitude. •  Drugs e.g. cigarettes Fig. 6.2 alcohol illicit drug use. Placental • Reduced maternal uterine vascular supply – pre‐eclampsia chronic maternal disease e.g. hypertension diabetes mellitus renal disease. •  Placental vascular thrombosis and/or infarction e.g. maternal lupus anticoagulant antiphospholipid syndrome sickle cell disease. •  Unequal sharing of uteroplacental vascularity – multiple gestation. Fetal •  Chromosomal disorders e.g. trisomy 18 and other syndromes. Intrauterine growth restriction 6 Importance The prenatal identification of intrauterine growth restriction IUGR is important because it allows: •  timely delivery of the fetus with chronic hypoxia who is at risk of intrauterine death •  early identifcation of serious fetal abnormalities and fetal infection. The neonate is at risk of: •  preterm delivery •  birth asphyxia • hypoglycemia because of poor reserves of glycogen and other energy sources e.g. fat •  polycythemia from intrauterine hypoxia •  hypothermia •  increased mortality especially if also preterm. During childhood most show catch‐up growth but some remain short and thin. There is a slight increase in risk of learning difficulties with IUGR depending upon underlying etiology and gestation at birth. 3.0 2.0 2.5 4.0 3.5 4.5 1.0 0.5 Birthweight kg 24 1.5 10th 50th 90th 28 Gestation wks Preterm Term Post-term 26 30 32 34 36 38 40 42 Centiles Small for gestational age SGA Appropriate for gestational age AGA Large for gestational age LGA Fig. 6.1 Chart showing increase in birthweight with gestational age. Most small for gestational age fetuses or infants are constitutionally small. 0 –50 –100 –200 –150 –250 1–9 Cigarettes/day Reduction in birthweight g 10–19 20 –150 g –200g –250g Fig. 6.2 Reduction of birthweight with maternal smoking.

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Intrauterine growth restriction 13 •  Structural malformations. •  Congenital infection – CMV toxoplasmosis rubella. Pathophysiology Traditionally IUGR has been classified as symmetric or asym - metric though in clinical practice there is considerable overlap and this distinction is no longer important prenatally. •  Symmetric – growth failure affecting weight head and length. Caused by fetal factors e.g. chromosomal disorders syndromes or congenital infection. May be accompanied by polyhydramnios if there is reduced fetal swallowing of amniotic fluid e.g. trisomy 21 Down syndrome or gastrointestinal obstruction. The infant is likely to continue to be small throughout childhood. •  Asymmetric – growth failure with head reflecting brain growth relatively preserved. Classically caused by uteroplacental insuffi - ciency with reduced oxygen transfer to the fetus. Fetal adaptation to hypoxia is to preserve blood supply to the vital organs i.e. the brain myocardium and adrenal glands at the expense of the kidney gastrointestinal tract and liver limbs and subcutaneous tis- sues. This is reflected in maintained head growth but reduced abdominal circumference from reduced glycogen stores in the liver and oligohydramnios from reduced urine production. If it prog - resses it results in fetal acidemia and fetal death. Management Management is intensive fetal surveillance to maximize gestation without compromising the fetus Fig. 6.3. •  Establish if there is a fetal cause by detailed ultrasound scanning for fetal anomalies and karyotype if indicated. •  Monitor fetal growth and well‐being from measurements of growth parameters biophysical profile amniotic fluid volume fetal movement fetal tone fetal breathing movements fetal heart activity and Doppler blood flow velocity umbilical ductus venosus and middle cerebral artery. Timing of delivery will depend on gestational age if growth ceases or there is an abnormal biophysical profile or significant abnormality of the Doppler flow velocity waveform Figs 6.4 and 6.5. Postnatal •  After birth monitor for hypoglycemia and polycythemia and examine for dysmorphic features or congenital infection. Reduced growth velocity on biometry Decompensation of middle cerebral artery Doppler velocity with loss of preferential cerebral blood ow redistribution. Abnormal ductus venosus Doppler waveform denoting diastolic cardiac dysfunction Reducedfetalmovements Reduced fetal breathing movements and fetal tone on ultrasound Abnormalfetalheartrate tracingdecelerativeand thenterminal Poor renal perfusion fetal urine production and reduced liquor volume Abnormal umbilical artery Doppler waveform due to increased placental impedance absent and then reversed end-diastolic ow Intrauterine death or hypoxic damage to fetus Uteroplacental function denoting diastolic cardiac dysfu Reducedfetalm Abnorm tracing thente or renal rfusion al urine oduction d reduced uor volume Abnormal umbilical artery Doppler waveform due to increased placental impedance absent and then Fig. 6.3 Consequences of progressive uteroplacental failure with increasing base excess and worsening fetal blood pH acidemia which may result in intrauterine death. Progression may not follow sequentially. Fig. 6.4 Umbilical artery Doppler waveforms and diagrammatic representation. Normal a and b absent end‐diastolic velocity c and d reversed end diastolic velocity e and f. Doppler signals from the umbilical artery give information about fetoplacental blood velocities. Increased blood flow velocities in the fetal middle cerebral artery and absent or reversed flow in diastole in the fetal aorta indicate fetal hypoxia. a c e b d f a b Fig. 6.5 Doppler flow velocity waveform of the ductus venosus showing a normal and b reversed flow during atrial contraction. In the second‐ trimester growth‐restricted fetus this represents cardiac decompensation. It is a better predictor of stillbirth than umbilical artery Doppler alone.

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Neonatology at a Glance Third Edition. Edited by Tom Lissauer Avroy A. Fanaroff Lawrence Miall and Jonathan Fanaroff. © 2016 John Wiley Sons Ltd. Published 2016 by John Wiley Sons Ltd. 14 Perinatal medicine The incidence of spontaneous multiple gestation is: •  1 in 89 for twins •  1 in 89 2 1 in 8000 for triplets •  1 in 89 3 1 in 700 000 for quadruplets. However the number of multiple gestations has increased because of fertility enhancing therapies and the older age of childbearing. As a result 1 in 64 births in the UK is a multiple birth in the US it is 1 in 58 births. The rate of twin pregnancies has increased markedly since 1980 and was 15.3 per 1000 live births in the UK in 2012 Fig. 7.1 and 16.8 per 1000 live births in the US in 2013. The number of triplets and higher order births rose markedly in the 1990s but has declined since then following changes in assisted reproductive therapy practices. Twins may: •  have their own chorionic sac and placenta dichorionic 67 •  share a chorionic sac and placenta monochorionic 33. Ultrasound can show whether twins share a placenta chorionic- ity but not if they are identical zygosity which can often only be determined through DNA testing Fig. 7.2. Pregnancy complications The main pregnancy complications of twins are: •  Preterm delivery. The increased prematurity rate Table 7.1 is responsible for the increase in perinatal mortality which for twins is six times that of singletons. Monochorionic twins are at particularly increased risk of iatrogenic preterm delivery. In very high order pregnancies selective fetal reduction reduces the rate of preterm delivery and perinatal mortality. •  Intrauterine growth restriction IUGR. Severe IUGR with inter‐twin estimated fetal weight difference of 20 affects 20 of dichorionic twins and 40 of monochorionic twins. If one twin has IUGR the potential benefits of early delivery for that twin has to be weighed against the prematurity‐related complications of the normally grown twin. •  Congenital abnormalities. In dichorionic twins the risk is twice normal as there are two infants. However in monochorionic twins the risk is four times normal. Anomalies may be discordant or concordant. There is a particularly increased risk of congenital heart disease. • Twin–twin transfusion syndrome TTTS. This occurs in approximately 10 of monochorionic twin pregnancies due to placental arteriovenous anastomoses. The ‘donor’ has low perfu- sion pressures growth restriction oliguria and oligohydramnios. The recipient twin experiences hypervolemia which may result in high‐output cardiac failure polyuria and polyhydramnios. Before 26 weeks’ gestation this may result in preterm labor or intrauterine death in up to 90 if untreated. Potential in  utero treatment includes fetoscopic laser therapy to divide the placental blood ves- sels or periodic drainage of the amniotic fluid amniodrainage. The latter is utilized in relatively mild disease presenting after 26 weeks’ gestation. Such cases require prenatal evaluation in a peri- natal center by a fetal medicine subspecialist. Even when success- fully treated the infants may have anemia–polycythemia sequence TAPS where the hemoglobin difference at birth is 5 g/dL and 5–10 of survivors have neurologic morbidity. Multiple births 7 1982 4 6 8 10 Twins Triplets and higher order births 12 14 16 1986 1990 1994 1998 2004 2008 2012 0 0.1 Triplet plus deliveries/ 1000 live births Twin deliveries/1000 live births 0.2 0.3 0.4 0.5 0.6 Fig. 7.1 Change in the number of multiple births in the UK since 1980. There has been a marked increase in number of twin deliveries. The number of triplets and higher order deliveries increased markedly during the 1990s but have subsequently decreased. Changes in the US have followed a similar pattern but at a higher rate for triplet and higher order births. Dichorionic Monochorionic c One placenta one chorion two amnions d One placenta one chorion one amnion a Placentas are widely apart b Placentas are next to each other Two placentas two amnions two chorions. May be dizygous 80 or monozygous 20 Single placenta and either two amniotic sacs 98 or single amniotic sac 2. Always monozygous Placenta Chorion Amnion Fig. 7.2 Relationship between chorionicity and zygosity in twins. Placentation of monozygotic twins depends on the stage at which the split occurs. Early splits are dichorionic later splits are monochorionic.

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Multiple births 15 •  Death of a fetus. Intrauterine death of one twin may result in preterm labor. In monochorionic twins with associated placental anastomoses there may be blood loss from the live to the dead twin leading to hypovolemia severe anemia neurologic impair- ment 15–20 or death of the surviving twin 20. Mono- amniotic twins Fig 7.2d risk cord entanglement leading to hypoxia of one or both twins. •  Conjoined twins. If twinning of monozygotic twins occurs very late 14th day they may be conjoined with fused skin or organs. Monozygotic twins may also demonstrate “mirroring” where they have opposite asymmetry of certain features. Neonatal complications For multiple preterm births the immediate problem may be to identify sufficient intensive care capacity. Apart from prematurity other immediate medical problems may be twin–twin transfusion syndrome anemia may require blood or exchange transfusion polycythemia may require exchange trans- fusion IUGR and congenital malformations. Mortality of twins is over five times greater than for single births for triplets it is increased 10‐fold and for quadruplets more than 20‐fold. Families of multiple births may need additional assistance and support: •  Feeding – it is more difficult but often possible to breast‐feed twins fully but is usually not possible for higher order births. •  Practical – with their care and housework requires about 200 h/ week for triplets in infancy may require help to be able to leave the house Fig. 7.3. •  Emotional – can be exhausting to provide care. •  Privacy – loss of privacy as a couple and increased rate of separation and divorce. •  Financial – considerable additional costs cannot hand down clothes or equipment may need to move to larger living space. •  Increased incidence of parental depression especially if there was fetal or neonatal loss when every birthday or other achieve- ment of the survivor is a reminder that the co‐twin died. • Behavioral – problems in other siblings are increased threefold. •  Development – reduced opportunities for mother–infant interaction as mothers are busy and often tired. Increased risk of delayed language development and poor attention span. Although multiple births may provide companionship affection and stimulation between each other they may also engender domination dependency and jealousy. The rate of disability is increased e.g. the cerebral palsy rate for twins is 7 per 1000 live births and for triplets 27 per 1000 live births compared to 1.6 per 1000 live births in singletons. This is mainly related to prematurity. There are local and national support groups for parents of multiple births. Fig. 7.3 Quintuplets. Multiple births look endearing but families may need assistance with their care. Table 7.1 Peak gestation and mean birthweight for singleton and multiple births. Peak gestation weeks Birthweight mean kg Singleton 40 3.5 Twins 37 2.5 Triplets 34 1.8 Quadruplets 32 1.4

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Neonatology at a Glance Third Edition. Edited by Tom Lissauer Avroy A. Fanaroff Lawrence Miall and Jonathan Fanaroff. © 2016 John Wiley Sons Ltd. Published 2016 by John Wiley Sons Ltd. 16 Perinatal medicine Up to 12 of deliveries in developed countries are preterm. In the US 11.5 of births were preterm in 2012. In the UK 7.2 of births were preterm but only 5.9 in Sweden and Japan Fig. 8.1. The increase in the proportion of infants born preterm in the US since 1980 is shown in Fig 2.3. Causes Neonates may be born preterm following: •  spontaneous labor with intact membranes − 40 to 45 •  preterm premature rupture of the membranes PPROM – 25 to 30 •  labor induction or cesarean delivery for maternal or fetal indica- tions − 30 to 35. The main causes are shown Fig. 8.2. Epidemiological risk factors There are many risk factors which are poorly understood but gen- erally predispose the mother to infection or inflammation. These include: •  Previous preterm delivery – twofold increased risk increasing for each additional preterm delivery. •  Short inter‐pregnancy interval of 6 months − more than doubles the risk. •  Maternal age − increased risk if 20 or 35 years old. •  Maternal nutrition – low BMI body mass index increases risk of spontaneous preterm birth. Obese mothers are more likely to have preterm births for medical indications particularly pre‐eclampsia and diabetes mellitus. •  Ethnicity − whereas the preterm rate in the US is 10−11 in White or non‐Hispanic mothers it is 16 −18 in Black mothers. Women from south Asia have high rates of low‐birthweight infants rather than preterm delivery. • Multiple births − result in 15−20 of preterm births. Early delivery is recommended for monochorionic twins by 36 weeks in the UK 37 weeks in US. •  High levels of maternal psychological or social stress − increased risk − generally less than twofold. •  Smoking − increased risk–less than twofold. •  Substance misuse. •  Socio‐economic deprivation − inter‐relationship poorly defined. •  Maternal health − infections either localized i.e. ascending infec- tion or generalized e.g. malaria. Prevention Strategies to prevent preterm labor include: •  Progesterone − given prophylactically from 24 weeks reduces preterm birth and perinatal mortality in those at high risk of pre- term labor e.g. previous preterm birth or short cervix identified on ultrasound but not multiple births. •  Cervical ‘cerclage’ − purse‐string suture to maintain closure of the maternal cervix. Benefit uncertain but often offered if multiple preterm births mid‐trimester fetal losses or cervix is shortening. Non‐surgical ‘cervical pessary’ is being investigated. •  Genital infections e.g. bacterial vaginosis where overgrowth of anaerobic vaginal organisms displaces normal lactobacillus species. Remains controversial may be treated. •  Cessation of maternal smoking. •  Reduction in multiple births by limiting embryo transfer in IVF treatment. •  Reduction in elective preterm deliveries − see below. However the potential impact of these interventions to reduce the proportion of infants born preterm is relatively small. Management Antenatal corticosteroids Maternal corticosteroids administered before preterm birth reduce rates of respiratory distress syndrome by 44 intraven- tricular hemorrhage by 46 and neonatal death by 31. Also associated with a reduction in necrotizing enterocolitis respiratory support intensive care admissions and systemic infections in the first 48 hours of life see Fig. 67.2. A single course is administered to mothers at risk of preterm birth up to 35 weeks of gestation. In the UK it is also offered to women having an elective cesarean section prior to 39 weeks’ gestation to reduce the risk of respiratory morbidity. Preterm delivery 8 USA UK Canada France Sweden Japan Finland Germany 12.0 7.8 7.8 6.7 5.9 5.9 5.5 9.2 05 10 15 Preterm birth rate per 100 live births Fig. 8.1 Preterm birth rate in different countries in 2010 showing the high rate in the US and moderately high rate in the UK. Adapted from Chang HH et al. Preventing preterm births: analysis of trends and potential reductions with interventions in 39 countries with very high human development index. Lancet 2013381:223–34.

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Preterm delivery 17 Preterm premature rupture of the membranes PPROM Affects 2−3 of pregnancies but is associated with 25−30 of pre- term deliveries. Increases neonatal morbidity and mortality due to prematurity infection and pulmonary hypoplasia. Associated with ascending maternal infection from the lower genital tract about one‐ third have positive amniotic fluid cultures. Antibiotics reduce cho- rioamnionitis and neonatal infection. The decision to deliver or manage expectantly requires balancing of risk of intrauterine infec- tion compared with neonatal risks from prematurity. If 34 weeks corticosteroids are usually given. Beyond 34 weeks’ delivery is usu- ally indicated. Tocolysis Used to suppress uterine contractions. No clear evidence that any improve outcomes but widely used to try to suppress contractions to enable completion of course of antenatal corticosteroids or allow maternal transfer to a perinatal center. Magnesium sulfate Offered to mothers shortly before preterm delivery at 24−32 weeks’ gestation to reduce the risk of cerebral palsy. Several trials have shown a 30−40 reduction in cerebral palsy rates number needed to treat 63 to prevent one case of cerebral palsy. Delivery The aim is to prolong pregnancy for as long as possible while ensuring the safety of the mother and fetus. 1. Extreme preterm delivery 28 weeks Deciding about the timing of a preterm delivery is most difficult at the limit of viability 22−26 weeks and should involve the obstetrician neonatologist and parents. Decision‐making is helped by a detailed assessment of fetal well‐being including assessment of amniotic fluid volume fetal heart rate moni- toring Doppler studies fetal growth gestation and predicted birthweight with estimates of their accuracy. This should also be informed by knowledge of outcomes at these early gestational ages. National and international data are available but will need to be modified according to the circumstances. Delivery of high‐risk infants should occur at a perinatal center to avoid subsequent transfer and separation of the infant and mother. 2. Delivery at 34–38 weeks Although much of the attention of neonatologists and a significant proportion of this book is focused on the extremely preterm infant attention has recently turned to outcomes of infants delivered at 34–38 weeks. These infants have an increase in respiratory morbidity and increased length of stay in hospital compared with full term infants born at 39–41 weeks. Although the neurodisability rate is highest in extremely pre- term infants rates are higher in these infants than those born at full term Figs 8.3 and 38.2. There has been a marked reduction in the number of infants delivered before 39 weeks’ gestation in the US following new guidelines. Fig. 8.2 Causes of prematurity. IUGR intrauterine growth restriction PPROM preterm prolonged rupture of the membranes. Idiopathic Preterm delivery Intrauterine stretch Multiple gestation Polyhydramnios Uterine abnormality Endocrine maturation Premature onset of labor Intrauterine bleeding Abruption Antepartum hemorrhage Intrauterine infection Chorioamnionitis Bacterial vaginosis Preterm prolonged rupture of membranes PPROM Maternal medical conditions Pre-eclampsia hypertension Chronic medical conditions Urinary tract infection Cervical weakness Fetus IUGR Congenital malformations 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 Estimated gestational age weeks 0.05 0.1 0.2 0.4 0.6 0.8 Proportion with SEN log scale Fig. 8.3 Prevalence of special educational needs SEN by gestational age at birth showing increased proportion even at 34–39 weeks compared with full‐term births. Data based on 407 503 school‐aged children in Scotland in 2005. Source: MacKay D.F. et al. PLoS Medicine 2010 76: e1000289.

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Neonatology at a Glance Third Edition. Edited by Tom Lissauer Avroy A. Fanaroff Lawrence Miall and Jonathan Fanaroff. © 2016 John Wiley Sons Ltd. Published 2016 by John Wiley Sons Ltd. 18 Perinatal medicine Question. Which investigations to consider The underlying etiologies of congenital anomalies and mecha- nisms by which they arise are shown in Table 9.1 and Figure 9.1. When confronted with a neonate with a congenital anomaly there are a number of questions to ask Table 9.2 features to look for Table 9.3 and investigations to consider Table 9.4. This evaluation process to establish a diagnosis is also appropriate when congenital anomalies are identified prenatally on antenatal ultrasound. Birth defects and genetic disorders 9 Table 9.1 Causes of congenital anomalies. Teratogenic Environmental agents during pregnancy – infections drugs particularly anticonvulsants alcohol and radiation Sporadic or multifactorial Many single birth defects occur as isolated cases with low recurrence risk. These may be polygenic or due to faults in developmental pathways Single‐gene disorders May be family history or previous pregnancy losses. Many multiple malformation syndromes follow autosomal recessive inheritance but consider X‐linked recessive disorders in males and new dominant mutations in isolated cases Chromosomal Usually cause multiple congenital malformations and learning difficulties Defect in morphogenesis Disruption Due to ischemia hemorrhage or adhesion of denuded tissue Example: amniotic band disruption Deformation Example: positional talipes joint contractures due to congenital myotonic dystrophy Single birth defects association or malformation syndromes Examples: cleft lip and palate spina bida Malformation Dysplasia Often due to major mutant genes Example: multicystic renal dysplasia Destruction of a tissue that initially developed normally Extrinsic intrauterine constraint or deformity secondary to existing neuromuscular or skeletal abnormality Incomplete or abnormal progression of one or more developmental processes in early gestation Abnormal cellular organization or function in a specic tissue or organ Fig. 9.1 Mechanisms of birth defects. Question. What to look for on clinical exam Table 9.3 What to look for. Growth parameters Intrauterine growth restriction overgrowth microcephaly Movement and posture Hypotonia contractures seizures Minor anomalies Features with little cosmetic or functional significance. The presence of 2 or more should prompt a search for major anomalies Major birth defects May represent an association defects occurring together more often than by chance alone e.g. V ACTERL vertebral anal atresia cardiac tracheo‐ esophageal fistula renal and limb May represent a sequence one initial malformation resulting in the development of others e.g. renal agenesis resulting in Potter sequence May represent a syndrome defects occurring together which have a common specific etiology Dysmorphic features Unusual or distinctive external appearance of the face hands feet etc. Table 9.4 Investigations to consider. Clinical photographs Provide a valuable record especially if the phenotype changes with time Chromosome analysis Order chromosome analysis karyotype in all babies with multiple malformations or dysmorphic features. Consider requesting comparative micro-array test to analyze chromosomes in more detail. Biochemical analysis Examples are calcium for suspected Williams syndrome or DiGeorge syndrome and creatine kinase for suspected congenital muscular dystrophy Skeletal survey Suspected skeletal dysplasia such as achondroplasia Echocardiography Suspected congenital heart disease Renal ultrasound If renal anomalies suspected e.g. in some chromosomal disorders Brain CT/MRI/ultrasound scan Suspected CNS malformation Specific gene tests Specific disorders e.g. cystic fibrosis spinal muscular atrophy type 1 Question. What history is needed Table 9.2 What to ask about in history. Parental age and health Previous reproductive history Family history of congenital anomalies Consanguinity Maternal medications drugs alcohol and other potential teratogens Complications during pregnancy Ultrasound screening and further investigations

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Birth defects and genetic disorders 19 Chromosomal disorders In addition to trisomy 21 18 and 13 there are many hundreds of chromosomal deletions and rearrangements. Micro-array tech- nology is increasingly able to detect them in fetal or neonatal DNA. Trisomy 21 Down syndrome Incidence is 1 in 650 live births. Most 94 are due to non‐ disjunction of chromosome 21 during meiosis in the formation of eggs or sperm Fig. 9.2. The risk increases with maternal age Table 9.5 although most are born to mothers 35 years old. Approximately 5 are due to translocation in which chromosome 21 is relocated onto another chromosome usually onto chromosome 14. The risk of trisomy 21 is about 10 when the balanced translocation is carried by the mother. Most are identified prenatally. Non-invasive prenatal testing NIPT – free fetal DNA recovered from maternal serum in the late first tri- mester has 99.5 sensitivity for trisomy 21. Clinical features The facial appearance and other clinical signs Fig. 9.3 are usually recognizable at birth but diagnosis needs to be confirmed by chromosome analysis. Associated malformations include congen- ital heart disease duodenal atresia and Hirschsprung disease. Subsequently there is increased risk of: •  learning difficulties •  small stature •  secretory otitis media and visual impairment •  leukemia •  hypothyroidism •  Alzheimer disease. Trisomy 18 Edwards syndrome Incidence is 0.1/1000 live births. Most infants have intrauterine growth restriction. Dysmorphic features include prominent occiput narrow fore- head small mouth and jaw short sternum clenched hands with overlap- ping digits Fig.  9.4a prominent heels and rocker‐bottom feet Fig.  9.4b. Major malformations include heart defects neural tube defects ompha- locele esophageal atresia and radial defects. Most die shortly after birth. Trisomy 13 Patau syndrome Incidence is around 0.7/1000 live births. Dysmorphic features include scalp defects Fig. 9.5a and polydactyly. Major malforma- tions include holoprosencephaly brain is a single hemisphere microcephaly ocular malformations cleft lip and palate Fig. 9.5b heart defects and renal abnormality. Most babies die within 1 month. Parents 21 Non-viable Trisomy 21 21 Gametes Offspring Fig. 9.2 Trisomy 21 due to non‐disjunction. a b c Fig. 9.3 Trisomy 21 Down syndrome. a Facial features – upward slant of eyes epicanthic folds low set simple ears flat occiput third fontanel short neck. b Hands – single palmar crease and short little finger. c Feet – wide gap between first and second toes. Other features – hypotonia. a b Fig. 9.4 Characteristic abnormalities of trisomy 18 Edwards syndrome. a Typical clenched hand with overlying digits. b Rocker‐bottom feet. Table 9.5 Risk of trisomy 21 in liveborn infants by maternal age. Maternal age at delivery years Risk All ages 1 in 650 30 1 in 900 35 1 in 400 37 1 in 250 40 1 in 100 44 1 in 40 a b Fig. 9.5 Characteristic abnormalities of trisomy 13 Patau syndrome. a Scalp defect. b Cleft lip and palate.

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Neonatology at a Glance Third Edition. Edited by Tom Lissauer Avroy A. Fanaroff Lawrence Miall and Jonathan Fanaroff. © 2016 John Wiley Sons Ltd. Published 2016 by John Wiley Sons Ltd. 20 Perinatal medicine Fetuses are often exposed to one or more of the following potential toxins: •  over‐the‐counter medications •  prescription drugs •  diagnostic agents e.g. X‐rays •  recreational drugs e.g. cigarettes alcohol or illicit drugs •  herbal and vitamin supplements •  environmental exposure e.g. pollutants. The potential consequences for the fetus are listed in Table 10.1. Neonatal withdrawal abstinence syndrome •  Serious problem because of widespread use of narcotics and other drugs of dependency during childbearing years. •  Situation often complicated by multiple drug use. •  Mothers on heroin are often encouraged to embark upon opiate replacement therapy ORT such as methadone or buprenorphine. •  Increased risk of blood‐borne viruses hepatitis B and C and HIV if intravenous drug user. •  Onset of clinical features in infant: – heroin 2 days old but can be delayed past one week – methadone 1–3 days but can be delayed up to 2 weeks. Clinical assessment This must be done systematically and repeatedly 6‐hourly Table  10.2. It is facilitated by using a scoring system e.g. Finnegan’s score to determine whether therapy is required. Meconium or infant hair can be analyzed to determine drug exposure during pregnancy but has clinical limitations. Treatment Infants who persistently demonstrate features of withdrawal are treated with an oral opiate usually morphine sulfate with gradual dose reduction titrated against clinical signs and symptoms. Breast feeding should usually be encouraged for mothers on a stable methadone regimen as concentration in breast milk is low. Maternal drugs affecting the fetus and newborn infant 10 Table 10.1 Potential consequences for the fetus or infant of perinatal drug exposure. Intrauterine growth restriction Intrauterine death or miscarriage Recognizable patterns of congenital anomalies Maladaptation to extrauterine life Neonatal withdrawal syndrome Toxic effects from drugs excreted into breast milk Delayed effects on neurodevelopment and behavior Maternal smoking In the fetus maternal cigarette smoking is associated with: •  increased risk of miscarriage abruption and stillbirth •  reduction in birthweight by an average of 170 g at term with severity of intrauterine growth restriction IUGR related to number cigarettes smoked per day. In the infant it is associated with: •  increased risk of sudden infant death syndrome SIDS •  increased wheezing in childhood. Alcohol Encompasses a spectrum of effects fetal alcohol spectrum disorder FASD from mild growth deficiency and neurodevel - opmental problems to the classical appearance of fetal alcohol syndrome Fig. 10.1. Advice to pregnant women from the American Academy of Pediatrics and the Department of Health in the UK is to avoid alcohol completely. Although the effect of occasional mild alcohol ingestion or occasional binge drinking is not known there is no safe lower limit for exposure. Features of fetal alcohol syndrome: • Characteristic facies • Symmetric growth failure – severe persistent • Cardiac defects 40–50 • Behavior problems – irritable in infancy hyperactive in childhood • Developmental delay – average I.Q. 63 – saddle-shaped nose – maxillary hypoplasia – absent philtrum ridges between the nose and upper lip – thin upper lip Fig. 10.1 Features of fetal alcohol syndrome. Photograph courtesy of Dr David Clark. Table 10.2 Clinical features of opiate withdrawal. Irritability V omiting Scratching Diarrhea Wakefulness Yawning Shrill cry Hiccoughs Tremors Salivation Hypertonicity Stuffy nose Seizures Sneezing Unexplained pyrexia 38 °C Sweating Tachypnea rate 60/min Dehydration

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Maternal drugs affecting the fetus and newborn infant 21 Multidisciplinary monitoring of the health and social situation of the mother and infant is required before and after delivery. Cocaine Cocaine causes problems from direct transfer of the drug rather than withdrawal: •  placental infarction which may lead to IUGR or placental abrup- tion and antepartum hemorrhage leading to fetal death •  neurobehavioral features ‐ irritability tremor high pitched cry on day 1–3 of life. Medicines Relatively few medicines produce recognizable patterns of malformation in the fetus Table 10.3. Adverse effects may not be recognized if they are subtle or have delayed presentation e.g. diethylstilbestrol DES was given for threatened miscarriage in mothers for 30 years before an association with clear‐cell adenocarcinoma of the vagina and cervix in female adolescent or adult offspring was identified. Pregnant women should avoid taking prescribed and over‐the‐ counter medications whenever possible. For prescribed drugs the benefits must outweigh the risks and appropriate maternal and fetal surveillance should be undertaken. Table 10.3 Some recognizable patterns of malformation or neonatal problems following maternal drug ingestion. Time in pregnancy Drug Malformations/problems Drug Malformations/problems Organogenesis 8 weeks’ gestation Thalidomide Anticonvulsants: •  carbamazepine •  valproic acid sodium valproate •  hydantoins phenytoin Short limbs Fig. 10.2 Absent auricles deafness Fetal carbamazepine/valproate/ hydantoin syndrome – midfacial hypoplasia CNS limb and cardiac malformations Developmental delay Autistic spectrum disorder with valproic acid Folic acid inhibitors methotrexate as cytotoxic therapy Coumarin warfarin Fetal syndrome – microcephaly neural tube defects short limbs Fetal coumarin warfarin syndrome – nasal hypoplasia microcephaly hydrocephalus optic atrophy congenital heart defects stippled epiphyses purpuric rash Pregnancy 8 weeks’ gestation Antithyroid drugs iodides propylthiouracil Androgens Aspirin/non‐steroidal anti‐inflammatory drugs Goiter Congenital hypothyroidism Masculinization of female Closure of ductus arteriosus in fetus Tetracyclines β‐Blockers and hypoglycemic agents Hypoplasia of tooth enamel yellow–brown staining of teeth Neonatal hypoglycemia Poor fetal growth Labor and delivery Opiate analgesia Respiratory depression at birth Key point Consider drug withdrawal abstinence if an infant has sugges- tive clinical features and no cause has been identifed. Fig. 10.2 Severe limb shortening phocomelia ‘like a seal’ from maternal thalidomide therapy which was widely marketed except in US for morning sickness from 1957. Teratogenic effects only recognized several years later.

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Neonatology at a Glance Third Edition. Edited by Tom Lissauer Avroy A. Fanaroff Lawrence Miall and Jonathan Fanaroff. © 2016 John Wiley Sons Ltd. Published 2016 by John Wiley Sons Ltd. 22 Perinatal medicine The term ‘congenital infection’ applies to infections acquired in utero Fig. 11.1 whereas ‘neonatal infection’ is acquired shortly before or at delivery or postnatally see Chapter 40. Most congenital infections are viral but other significant causes include toxoplasmosis and in terms of world‐wide prevalence syphilis. Maternal infection is usually primary i.e. it is a first infection when there is lack of maternal immunity. Risk of infection from recurrent maternal infection e.g. with CMV or HSV is usually markedly lower than from a primary infection. Maternal infection may be asymptomatic or associated with mild symptoms. Diagnoses may be made antenatally or postnatally Table 11.1. The placenta may play an important role in diagnosing congenital infection. Congenital infection 11 Congenital infection Timing of transmission In-utero Shortly before or at delivery or postnatally Neonatal infection Route of infection Time of presentation At birth or months/years later First few weeks of life – early-onset 72 h or late-onset 72 h infection Months or years later Examples CMV Rubella Parvovirus VZV Toxoplasmosis Syphilis Malaria rare TB rare Group B streptococcus Gram-negative organisms Listeria monocytogenes Coagulase negative staphylococcus Chlamydia Gonococcus HSV VZV Enterovirus Candida Fungal HIV Hepatitis B Hepatitis C HPV HTLV-1 Transplacental Viral Others Transplacental/birth canal/nosocomial/breast milk Bacteria Viral Fig. 11.1 Congenital and neonatal infections. CMV – cytomegalovirus VZV – varicellazoster virus HSV – herpes simplex virus HPV – human papilloma virus HTLV‐1 – human T‐cell leukemia virus 1. Diagnosis Table 11.1 Table 11.1 Diagnosis of congenital infection. Antenatal Postnatal Maternal Infant History e.g. rash ‘flu‐like’ illness contact Culture/PCR – blood urine CSF stool nasopharyngeal aspirate saliva skin lesions Screening serology – seroconversion IgG IgM IgA or low avidity IgG to identify if infection was recent CT or MRI head – for calcification microcephaly Ophthalmologic assessment – for retinitis Culture/PCR of lesion e.g. cervical herpes blood urine Paired serology – for comparison with maternal titers IgG IgM etc. but production of IgM may be delayed in the neonate Fetal Placenta Ultrasound or fetal MRI scanning for anomalies Histology/microscopic dark‐field examination for spirochetes in syphilis culture/PCR Amniocentesis for fluid or fetal blood sample for serology/platelet count/PCR PCR polymerase chain reaction. Key points •  Although clinicians sometimes refer to TORCH toxoplasmosis other rubella cytomegalovirus herpes screening a range of different tests is required. •  Collect samples as soon as possible after birth to optimize chances of diagnosis.

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Congenital infection 23 Clinical features Congenital infections may precipitate pregnancy loss or preterm delivery. The clinical features of the symptomatic infant are shown in Fig. 11.2. Congenital cytomegalovirus CMV infection •  Commonest congenital infection in the US and UK 0.5–1/1000 live births. •  1–2 of mothers seroconvert during pregnancy. •  Overall mother‐to‐infant transmission rate is 40. •  May be reactivated during pregnancy • May be transmitted postnatally in breast milk or blood transfusions. Infected infants •  5–10 severely affected Fig. 11.2. Poor prognosis for abnor- malities detectable on prenatal ultrasound/in utero MRI. These include significant intrauterine growth restriction IUGR central nervous system abnormalities including ventriculomegaly renal abnormality and oligohydramnios. In infants on postnatal CT or MRI scan they include microcephaly and periventricular calcifica- tion Fig. 11.4 •  80–90 asymptomatic at birth but 10–15 of them are at risk of sensorineural hearing loss. •  Most common infectious cause of sensorineural hearing loss. Diagnosis •  Viral DNA by PCR amplification from amniotic fluid fetal blood or infant’s blood urine CSF or saliva collected at less than 3 weeks of age. Treatment For infants with CNS involvement antiviral therapy with oral val- ganciclovir for 6 months has been shown to improve hearing and neuroevelopmental outcome in a randomized controlled trial. Intrauterine growth restriction Intracerebral calcication Hydrocephalus Pneumonitis Hepatomegaly Jaundice Hepatitis Heart defects – cardiomegaly – patent ductus arteriosus Microcephalus Deafness Splenomegaly Bone abnormalities Rash see Fig. 11.3 Cataracts Microphthalmia Retinitis Anemia Neutropenia Thrombocytopenia Fig. 11.2 The symptomatic infant. Fig. 11.3 Blueberry muffin rash in rubella and sometimes CMV . Key point It is not possible to reliably differentiate between CMV toxo- plasmosis rubella or syphilis either by prenatal ultrasound or physical examination of the neonate.

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24 Perinatal medicine Other points •  No vaccine yet for seronegative mothers. •  Infected infants may excrete CMV in urine for many months. •  All infected infants should be followed regularly for late‐onset sensorineural hearing loss until school age. Congenital toxoplasmosis •  Usually after primary maternal infection in pregnancy. •  Seronegative mothers are most at risk from poorly cooked meat. Small risk from handling feces of recently infected cats or ingest- ing contaminated soil from unwashed vegetables. •  The transmission rate and treatment are shown in Table 11.2 though this is controversial. The earlier in pregnancy the mother is infected the more severely the fetus is affected. •  The clinical features of the symptomatic infant are shown in Fig. 11.2. Subclinical disease includes retinitis Fig. 11.5 epilepsy and learning difficulties. •  Treatment of infants with congenital infection – pyrimethamine and sulfadiazine plus folinic acid for prolonged duration. Rubella •  Prevented by maternal vaccination. Now very rare in immunized populations. •  The earlier in pregnancy the mother is infected the more severely the fetus is affected. •  Clinical features are shown in Fig. 11.2. •  There is no effective treatment. Congenital syphilis In the US a marked increase in incidence occurred in the 1980s especially among drug users but it has since declined. In the UK it is extremely rare. Antenatal screening on maternal blood is per- formed routinely. If active infection is diagnosed or suspected the mother should be treated. Treatment more than 4 weeks before delivery prevents congenital infection. •  Transmission rate during primary infection in pregnancy is 100. •  Without treatment there is 40 abortion/stillbirth/perinatal death. •  Prenatally is associated with severe IUGR in developing countries. •  Clinical features are shown in Fig. 11.2. Those specific to con- genital syphilis include a characteristic rash and desquamation on the soles of the feet Fig. 11.6 and hands Fig. 11.7 and bone lesions Fig. 11.8. Table 11.2 Transmission rate and treatment of toxoplasmosis. Trimester Transmission rate Clinical features Treatment First 15 35 die before birth 40 severely affected Preventative – maternal spiramycin if 18 weeks Second 40 90 subclinical disease at birth clinical manifestations may present years later If severely affected – with antibiotics pyrimethamine and sulfadiazine and folinic acid Question Should babies with congenital CMV infection be isolated when on the neonatal unit No. About 1 of infants in newborn nurseries excrete CMV but most are asymptomatic. Pregnant staff are potentially at risk though most are immune. Attention to hand‐washing is the key to preventing infection of caregivers and should be strictly adhered to when touching any baby. Fig. 11.5 Retinitis from toxoplasmosis. This may present many years later. Fig. 11.4 Postnatal CT scan of the brain showing intracranial calcifica- tion from congenital CMV infection. The calcification may be identified on antenatal ultrasound.

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Congenital infection 25 • Treatment antenatally and/or postnatally is with penicillin. Effectiveness of treatment is monitored serologically. •  If the mother has not received adequate treatment or if there is physical laboratory or radiographic evidence of disease treat. If there is any doubt treat directly. Varicella: chickenpox varicella zoster virus VZV infection Primary maternal infection in pregnancy is uncommon as more than 90 of mothers are immune. Early in pregnancy •  Intrauterine infection is rare 2 risk. •  Can lead to eye and CNS damage skin scarring Fig. 11.9 and limb hypoplasia. •  1 risk of herpes zoster shingles in infancy. Late in pregnancy Infants born to mothers who develop chickenpox between 5 days before or 5 days after delivery should be given varicella zoster immune globulin VZIG. This reduces but does not eliminate the risk of neonatal varicella zoster virus VZV. They should be closely monitored and should be started on aciclovir intravenous if any signs of infection develop. Parvovirus B19 •  50 of pregnant women are susceptible to infection. •  Transmission rate is 20–30. •  In most cases there is a normal outcome of pregnancy but rarely infection in pregnancy leads to severe fetal anemia aplastic anemia causing hydrops fetalis edema and ascites from heart failure. Anemia is associated with an abnormally elevated middle cerebral artery velocity on Doppler ultrasound. Can lead to intrauterine death but if identified and treated by intrauterine transfusion prognosis is usually good. Fig. 11.6 Characteristic rash and desquamation on the feet in congenital syphilis. Courtesy of Dr Hermione Lyall. Fig. 11.9 Skin scarring from maternal VZV infection early in pregnancy. This is rare. Fig. 11.7 Characteristic rash and desquamation on hands in congenital syphilis. Courtesy of Dr Hermione Lyall. Fig. 11.8 X‐rays in congenital syphilis showing bilateral metaphyseal lucency of the long bones and destruction of the medial proximal metaphysis of the left tibia.

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Neonatology at a Glance Third Edition. Edited by Tom Lissauer Avroy A. Fanaroff Lawrence Miall and Jonathan Fanaroff. © 2016 John Wiley Sons Ltd. Published 2016 by John Wiley Sons Ltd. 26 Delivery The transition from intrauterine to extrauterine life involves a complex sequence of physiologic changes that begin before birth. Remarkably although infants experience some degree of intermit- tent hypoxemia during labor most undergo this transition smoothly and uneventfully. If not cardiorespiratory depression requires prompt and appropriate resuscitation. Physiologic changes in fetal–neonatal transition •  Before birth the lungs are filled with fluid. Oxygen is supplied by the placenta. On reaching the right atrium some of the oxygen- ated blood from the placenta flows directly to the left atrium via the patent foramen ovale bypassing the lungs. This ensures that the most oxygenated blood goes to the heart and brain. In addition the blood vessels that supply and drain the lungs are constricted providing high pulmonary vascular resistance so most blood from the right side of the heart bypasses the lungs and flows through the ductus arteriosus into the lower aorta Fig. 12.1a. •  Shortly before and during labor lung liquid production is reduced. •  During descent through the birth canal the infant’s chest is squeezed and some lung liquid exudes from the trachea. •  Multiple stimuli thermal chemical tactile initiate breathing. Serum cortisol ADH antidiuretic hormone TSH thyroid‐ stimulating hormone and catecholamines dramatically increase. •  The first gasp is usually within a few seconds of birth. A negative intrathoracic pressure is generated to achieve this. Most lung liquid is absorbed into the bloodstream or lymphatics within the first few minutes of birth. • Aeration of the lungs is accompanied by increased arterial oxygen tension the pulmonary artery blood flow increases and the pulmonary vascular resistance falls. •  Contraction of the umbilical arteries restricts access to the low resistance placental circulation. This results in increased peripheral vascular resistance and an increase in systemic blood pressure. •  The fall in pulmonary vascular resistance and the rise in systemic vascular resistance result in near equalization of pressures across the duct and virtual cessation of ductal flow and also closure of the foramen ovale Fig. 12.1b. Abnormal transition from fetal to extrauterine life The transition may be altered by a variety of antepartum or intrapartum events resulting in cardiorespiratory depression asphyxia or both Table 12.1. Adaptation to extrauterine life 12 Blood ow across the ductus arteriosus Pulmonary artery Lungs – lled with lung liquid Blood ow across foramen ovale Aorta Closed ductus arteriosus Closed foramen ovale Lungs – aerated a b Newborn circulation Fetal circulation Fig. 12.1 Changes in the circulation at birth. a Fetal circulation. b Newborn circulation. Table 12.1 Conditions assciated with abnormal neonatal adaptation to extrauterine life. Fetal Maternal Placental Preterm/post‐dates General anesthetic Chorioamnionitis Multiple birth Maternal drug therapy e.g. narcotics magnesium sulfate Placenta previa Forceps or vacuum‐assisted delivery Pregnancy‐induced hypertension Placental abruption Breech or abnormal presentation Chronic hypertension Cord prolapse Shoulder dystocia Maternal infection Emergency cesarean section Maternal diabetes mellitus Intrauterine growth restriction IUGR Polyhydramnios Meconium‐stained amniotic fluid Oligohydramnios Abnormal fetal heart rate trace Congenital malformations Anemia infection

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Adaptation to extrauterine life 27 The Apgar score The Apgar score named after Virginia Apgar an anesthesiologist is used to describe an infant’s condition during the first few min- utes of life Table 12.2. It is assigned at 1 and 5 minutes of life. If the score is still below 7 or the infant is requiring resuscitation it is continued every 5 minutes until normal or 20 minutes of age. Although often assigned few babies truly attain a score of 10 because it is uncommon for the baby to be pink all over. The Apgar score is useful as a shorthand record of the newborn infant’s condition after birth. Asphyxia Sustained severe asphyxia Fig. 12.2 in utero or during labor or postnatally results in the infant making increased respiratory effort followed by a period of apnea primary apnea. During primary apnea the heart rate falls to about half its normal rate but the blood pressure is initially maintained. With continuing asphyxia the infant starts to gasp the heart rate slowly falls as does the blood pressure. After several minutes after a last gasp there is secondary apnea. Anaerobic metabolism produces lactic acidosis and cardiac function deteriorates. To recover positive pressure ventilation if necessary accompa- nied by cardiac compressions is required. Minutes 0 40 120 160 80 Heart rate Blood pressure pH pCO 2 pO 2 Primary apnea Secondary apnea GaspingGasping Return of normal breathing Lung ination and positive pressure ventilation Intrapartum asphyxia Birth Breaths Fig. 12.2 Schematic representation of physiologic responses to intrapar- tum asphyxia and neonatal resuscitation. Adapted from Resuscitation Council UK Newborn Life Support. Table 12.2 Apgar score. Apgar score 0 1 2 Heart rate Absent 100 beats/min 100 beats/min Respiration Absent Slow irregular Good crying Muscle tone Limp Some flexion of extremities Active motion Reflex irritability response to stimulation No response Grimace Cough sneeze cry Color Blue or pale Body pink blue extremities Pink Key point The Apgar score is not used to determine the need for resuscitation. Evaluation for resuscitation is made second by second and is based on breathing heart rate and tone. Questions Does resuscitation alter how the Apgar score is assigned No. The Apgar score is assigned according to the infant’ s condition irrespective of whether or not resuscitation is being performed. Can one determine Apgar scores in preterm infants Yes. However the extremely preterm infant’s maximum score is reduced by poor muscle tone and weaker response to stimulation than term infants. Question What is the long‐term significance of a low Apgar score 3 or less An infant with a low Apgar score at 1 minute but responding rapidly to resuscitation has an excellent prognosis. An infant with a low Apgar score beyond 10 minutes of age in spite of adequate resuscitation is at markedly increased risk of neurologic damage resulting in cerebral palsy the longer the score remains low the greater the risk.

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Neonatology at a Glance Third Edition. Edited by Tom Lissauer Avroy A. Fanaroff Lawrence Miall and Jonathan Fanaroff. © 2016 John Wiley Sons Ltd. Published 2016 by John Wiley Sons Ltd. 28 Delivery Relatively few infants require resuscitation at birth. The aim of resus- citation is to optimize the airway breathing and circulation as quickly as possible. Most infants respond to lung inflation. Very few require chest compressions or medications. As the need for resuscitation has become uncommon there is increasing emphasis on simulation and teamwork training to ensure proficient resuscitation when it is required. Preparation The presence of antenatal or intrapartum risk factors often allows anticipation that resuscitation may be required. This enables those skilled in neonatal resuscitation to be present. However the need for resuscitation cannot always be predicted. There should always be at least one health professional skilled in basic resuscitation readily available at every delivery. Staff skilled in advanced resus- citation should attend high risk deliveries and be readily available at all times see video: Basic newborn resuscitation. Before delivery •  Introduce yourself to parents and explain why you are present. •  Review maternal history and obstetric records. •  Turn on the radiant warmer. •  Wash hands and put on gloves. •  Check equipment is present and functional: – several warm towels and plastic wrap or bag for preterm infants – clock – stethoscope – suction equipment – gas supply and pressure‐limited T‐piece circuit e.g. Neopuff ® or self‐inflating bag and mask – oropharyngeal Guedel airway – laryngoscope tracheal tubes and introducers – exhaled CO 2 detector – pulse oximeter – venous access equipment and drugs. Specific questions to consider •  Will you need help If so call for it early. •  Is neonatal transport going to be needed Cord clamping Delay in cord clamping of at least 1 minute from complete delivery of the infant is recommended for uncompromised infants. For the compromised infant resuscitation is the priority and a plan of action should be agreed with the obstetric team. Resuscitation tables that can be placed directly adjacent to the mother to allow resuscitation with intact cord have been developed studies are cur- rently determining their impact on outcomes. Temperature control Thermoregulation is critical as hypothermia contributes to hypo- glycemia acidosis and even mortality especially in extremely preterm inf ants see video: Resuscitation of preterm. Action •  Resuscitation area should be warm and draft free. •  Perform resuscitation under radiant warmer. •  Dry infant remove wet towel then wrap in dry towel. •  For preterm infants 30 weeks place wet infant directly in plastic wrap bag with only face exposed. Cover head with hat. An exothermic mattress may also be used. Initial assessment at birth Start the clock or note the time. Is the baby: •  term gestation •  crying or breathing vigorously •  good muscle tone If this is the case the baby should dried placed skin‐to‐skin with the mother if desired and covered with dry linen to maintain temperature. If not assess breathing rate depth and symmetry heart rate stetho- scope on apex color and tone and initiate resuscitation as required. Drying often produces enough stimulation to induce breathing. A – Airway If gasping or not breathing – open airway: •  Position – optimize head position avoiding head overextension or flexion using a towel beneath the shoulders if desired. •  Suction – only if obvious obstruction e.g. blood meconium and unable to achieve chest rise. Suction should be under direct vision with a wide‐bore suction device bulb syringe or Yankauer. Neonatal resuscitation and post-resuscitation care 13 Key point Thermoregulation is critical. The vigorous term infant can be dried then placed against the mother’s chest and covered with a warm towel. If resuscitation is required – rapidly dry and place under radiant warmer. Preterm babies should be placed wet in plastic wrapping under a radiant heater with head covered. If neonatal admission temperature is 36.5 °C 97.8 °F time on mechanical ventilation length of stay and mortality are reduced. After prolonged resuscitation in term infants passive cooling should be started pending a decision about therapeutic hypothermia. Hyperthermia can worsen the outcome and should be avoided

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Neonatal resuscitation and post-resuscitation care 29 Tracheal suctioning of meconium‐stained fluid is only indicated for depressed hypotonic babies. Care is required as pharyngeal suctioning may cause laryngeal spasm and vagal bradycardia. Suctioning meconium from the oropharynx at the perineum routinely practiced for many years does not improve outcome. •  For congenital airway abnormalities – choanal atresia severe micrognathia small jaw or macroglossia large tongue – consider using an oral airway or laryngeal mask airway. B – Breathing Assessment •  Look for chest movement – check if inadequate or absent or if heart rate is 100 beats/min. •  Attach oxygen saturation monitor to right hand if resuscitation is anticipated if baby remains cyanotic or if positive‐pressure venti- lation or supplementary oxygen required. Oxygen saturation mon- itors provide continuous reading of heart rate and oxygen saturation but take time to apply and may not function if poor perfusion. In healthy term infants following vaginal birth it takes about 10 min- utes for preductal oxygen saturation to reach levels 90. Action If inadequate respiratory effort gasping or not breathing or heart rate is 100 beats/min the priority is to inflate the lungs with mask ventilation Fig. 13.1 using a T‐piece pressure device or self‐ inflating bag Fig. 13.2. Mask ventilation Most infants will respond to lung inflation. •  Term infants – start with air. Titrate additional oxygen according to oxygen saturation level. •  Preterm infants – as above but use air/oxygen blender and pulse oximetry. Use minimum oxygen required according to preductal saturation targets in first 10 minutes of life. Avoid oxygen satura- tion above target range 91–95 as hyperoxemia can be damaging to eyes lungs and brain. Achieving lung inflation The aim is good chest rise using the lowest pressure. Assess regularly observing for: •  Increasing heart rate to 100 beats/min. •  Improving color or saturations. •  Spontaneous breathing. If lung inflation is not achieved and the heart rate is not respond- ing further airway maneuvers may be required. Recheck the airway position and consider suction if obstruction seen increased peak pressure and inspiratory time airway adjuncts Guedel airway or laryngeal mask airway or endotracheal intubation. Endotracheal intubation see Chapter 74 Indications •  If effective mask ventilation is not sustaining adequate ventilation but only when all the basic measures described above have been checked. • Consider in all babies who require cardiac compressions to maintain the airway. •  If prolonged ventilation is needed. • Congenital diaphragmatic hernia and some congenital upper airway abnormalities. •  If direct tracheal suction is needed for thick meconium or other obstruction in depressed hypotonic infant. However: •  Should only be attempted by those with advanced airway skills. •  Limit each attempt to 30 seconds. •  Confirm tube in trachea with symmetrical air entry and end‐tidal CO 2 detector. •  Provide effective mask ventilation between attempts if necessary. If no response to intubation consider DOPE: •  Displaced tube: – Is it in oesophagus no chest movement air entry over stomach greater than chest no CO 2 detected – Is it in one usually right main bronchus- asymmetrical chest rise or air entry CO 2 may still be detected. Correct Covers mouth nose and chin but not eyes Incorrect Too large: covers eyes and extends over chin Incorrect Too small: does not cover nose and mouth completely Fig. 13.1 Correct size and position of face mask. It should cover the mouth nose and chin. Fig. 13.2 Mask ventilation via a T‐piece connected to air/oxygen blender from a pressure‐limited circuit. Key point The Golden Minute: Initial assessment dry the baby observe breathing check heart rate and start positive‐pressure ventilation if required – all should be done in first minute after birth.

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30 Delivery •  Obstructed tracheal tube especially meconium – aspirate or replace tube or tube too small for baby •  Patient: – Lung disorders i.e. lung immaturity surfactant deficiency pneu- mothorax diaphragmatic hernia lung hypoplasia pleural effusion – Shock from blood loss anemia – Neonatal encephalopathy – perinatal asphyxia head trauma CNS hemorrhage or abnormality •  Equipment failure-exhausted or disconnected gas supply. C – Circulation •  Assess heart rate regularly with stethoscope or feel pulse at base of the umbilical cord or observe heart rate on saturation monitor if connected. •  Start chest compressions Fig. 13.3 if heart rate 60 beats/min despite adequate ventilation. •  Call for help – if not already available. There should be a 3:1 ratio of compressions to breaths approxi- mately 90 compressions and 30 breaths/minute to maximize ven- tilation at an achievable rate. Compressions and ventilations should be coordinated to avoid simultaneous delivery. Drugs Table 13.1 Drugs are rarely indicated only use if no response in spite of: •  visible lung inflation •  cardiac compressions for at least 30 seconds. Epinephrine adrenaline administered intravenously via umbilical venous catheter is recommended. Whilst intravenous access is obtained administration in higher dose via endotracheal tube may be considered but its efficacy has not been established. Volume expansion with saline or blood may be indicated when blood loss is suspected e.g. pale infant history of hemorrhage. The role of sodium bicarbonate is controversial. It may be consid - ered in prolonged resuscitation to correct metabolic acidosis but may potentially be harmful as it may exacerbate intracellular acidosis if breathing is inadequate. Prevention of hypoglycemia should be considered following prolonged resuscitation. Drugs should be flushed with a bolus of saline. Withholding and discontinuing resuscitation Difficult decisions arise at the margins of viability and for infants with conditions that have unacceptably high morbidity or almost certain early mortality. Attitudes and practices vary widely bet- ween practitioners institutions and countries. Whenever possible decisions should be made with parental agreement. Discontinuation of resuscitation should be considered if the heart rate is undetectable at birth and remains so for 10 minutes despite full resusci- tation. If there is doubt rather than hasty decisions in the delivery room it is often best to transfer to the neonatal unit for detailed assessment. a Landmarks for chest compression b Thumb technique for larger neonates: side by side d Two nger technique c Thumb technique for small neonates: one above the other Xyphoid Nipple line Sternum Sternum Nipple line Compression area Xiphoid Fig. 13.3 a Apply pressure to lower third of sternum just below an imaginary line joining the nipples. Avoid the xiphoid. Depress to reduce anteroposterior diameter of the chest by one‐third with no bounce. The thumb technique b and c is more effective than the two‐finger technique and is recommended but the two‐finger technique d is easier if you are alone. Key points • Before starting chest compressions ensure the lungs are infated i.e. good chest movement. If not chest compressions are unlikely to be effective. •  Call for help – giving chest compressions is easier with two people. Table 13.1 Resuscitation drugs Medication Concentration Dosage/route Indications Epinephrine adrenaline 1 in 10 000 0.1 mg/mL IV: 0.1 to 0.3 ml/kg Endotracheal: 0.5–1 ml/kg No response in spite of visible lung inflation and cardiac compressions V olume expander Normal saline Whole blood 10 mL/kg IV over 5–10 min Suspected acute blood loss and/ or signs of hypovolemia Sodium bicarbonate 0.5 mEq/mL 0.5 mmol/mL 1–2 mEq/kg 1–2 mmol/kg 2–4 mL/kg of 4.2 solution Consider only after prolonged arrest in spite of effective ventilation Glucose 10 2–2.5 mL/kg 250 mg/kg IV For documented hypoglycemia Key point In neonates drugs are not indicated unless there is no response to effective ventilation visible lung inflation and optimally performed cardiac compressions.

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Neonatal resuscitation and post-resuscitation care 31 •  Breathing – if not breathing or heart rate is not established give five inflation breaths preferably using air pressure of 30 cmH 2 O for 2–3 s for term babies 20–25 cmH 2 O for preterm. If heart rate increases but baby not breathing provide regular ventilation breaths at 30–40 breaths/min. If heart rate does not increase check that chest is moving effec- tively. If not check that baby’s head is in neutral position consider the need for jaw thrust longer inflation time a second person’s help with the airway Fig. 13.6 obstruction in the oropharynx or trachea need for oropharyngeal Guedel airway. If the heart rate remains at 60 breaths/min despite effective chest movement start cardiac compression. •  Cardiac compression – ratio of 3 compressions to 1 inflation rate of 90 compressions and 30 inflation breaths per minute. •  Drugs – rarely needed 1 in 1000 births if there is effective lung inflation and chest compression. If epinephrine required intravenous route is recommended. Tracheal route only if intravenous delivery not possible. If blood loss suspected give blood or 0.9 sodium chloride. Consider sodium bicarbonate and dextrose. •  Meconium‐stained liquor – aspirating meconium from the nose and mouth before complete delivery is not recommended. If breathing is compromised and infant is hypotonic inspect oral pharynx rapidly and aspirate obstructions to airway. Tracheal intubation may be helpful if expertise is available see video: Resuscitation after meconium. a b c Fig. 13.5 Head position the key to airway management. a Head in the correct neutral position. b Head overextended – incorrect. c Head flexed – incorrect. Question What are the guidelines used in the UK and Europe The UK/European Resuscitation guidelines are shown in Fig. 13.4. Particular features are: •  Airway – neutral position Fig. 13.5. Suction airway only if obvious airway obstruction not corrected by appropriate airway positioning and only under direct vision. At All Stages Ask: Do You Need Help Remove any wet towels and cover Start the clock or note the time Dry the baby Assess tone breathing and heart rate If gasping or not breathing: Open the airway Give 5 ination breaths Consider SpO 2 monitoring Re-assess If no increase in heart rate look for chest movement Acceptable pre-ductal SpO 2 2 min60 3 min70 4 min80 5 min85 10 min90 If no increase in heart rate look for chest movement When the chest is moving: If heart rate is not detectable or slow 60 min–1 Start chest compressions 3 compressions to each breath Reassess heart rate every 30 seconds If heart rate is not detectable or slow 60 min consider venous access and drugs If chest not moving: Recheck head position Consider 2-person airway control and other airway manoeuvres Repeat ination breaths Consider SpO 2 monitoring Look for a response Birth 30 sec 60 sec Fig. 13.4 Algorithm for newborn life support. Source: Resuscitation Council UK 2010. Fig. 13.6 Two‐person airway control – consider if mask inflation ineffective. One person holds the head in the correct position applies jaw thrust and holds the mask in place the assistant operates the T‐piece to provide lung inflation. Key point The principles of neonatal resuscitation are agreed internationally and regularly updated see ILCOR International Liaison Committee on Resuscitation. As details differ between coun- tries the UK/European and US algorithms are shown.

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32 Delivery Term gestation Breathing or crying Good tone Newborn resuscitation algorithm Warm clear airway if necessary dry stimulate HR below 100 gasping or apnea PPV SpO 2 monitoring Birth 30 sec 60 sec HR below 100 Take ventilation corrective steps Labored breathing or persistent cyanosis Clear airway SpO 2 monitoring Consider CPAP Postresuscitation care HR below 60 Consider intubation Chest compressions Coordinate with PPV HR below 60 IV epinephrine Take ventilation corrective steps Intubate if no chest rise Consider: Hypovolemia Pneumothorax Stay with mother Routine care Provide warmth Clear airway if necessary Dry Ongoing evaluation Targeted preductal SpO 2 after birth 1 min 2 min 3 min 4 min 5 min 10 min 60–65 65–70 70–75 75–80 80–85 85–95 Yes Yes Yes Yes Yes Yes No No No No No No Fig. 13.7 Neonatal resuscitation algorithm. Source: Kattwinkel J. et al. Neonatal Resuscitation: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Pediatrics 2010 126 e1400–e1413. © American Heart Association 2010 http://pediatrics.aappublications.org/content/126/5/e1400.full.html. Question What are the neonatal resuscitation guidelines used in the US The algorithm used is shown in Fig. 13.7. Particular features are: •  Airway – place head in slightly extended ‘sniffing position’ to open airway. Clear airway if necessary with bulb syringe or suction catheter only if obvious obstruction to breathing or require positive pressure ventilation. •  Breathing – positive‐pressure ventilation is started if the infants remains apneic or gasping or if heart rate remains at 100 beats/min. Initial inflation pressure of 20 cmH 2 O may be effective but 30–40 cmH 2 O may be required in some term babies. Ventilation should be delivered at 40–60 breaths/min to achieve promptly a heart rate 100 beats/min. Endotracheal intubation may be indicated at any stage if there is inadequate response to mask ventilation. •  Chest compression – indicated for heart rate 60 beats/min despite adequate ventilation with supplementary oxygen for 30 s. •  Drugs –if heart rate remains at 60 beats/min despite adequate ventilation usually with endotracheal intubation with 100 oxygen and chest compressions. Epinephrine adrenaline should be administered intravenously endotracheal administration may be considered while access is obtained. Volume expansion should be considered when blood loss is known or suspected. Intravenous glucose should be considered as soon as practical after resuscitation in order to avoid hypoglycemia. • Meconium‐stained liquor – Endotracheal suctioning of meconium‐stained amniotic fluid for non‐vigorous babies. Monitor for subsequent respiratory distress and persistent pulmonary hypertension.

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Neonatal resuscitation and post-resuscitation care 33 Post‐resuscitation care in the delivery room Following resuscitation stabilizing the extremely preterm or sick newborn infant starts in the delivery room before transfer to the neonatal unit Fig. 13.8. Airway and Breathing Assess for respiratory distress • Respiratory effort – both rate and pattern • Chest retractions • Nasal are • Grunting • Cyanosis If respiratory distress provide respiratory support: • CPAP/mechanical ventilation see below • consider surfactant Circulation Examination: Heart rate pulses capillary re‚ll time skin color Immediate circulatory support if required Thermoregulation: Aim to maintain normal temperature 36.5–37.5°C by: • Use of plastic wrap in preterm 30 weeks – apply prior to cord clamping within sterile ‚eld at caesarian section ensure wrap stays in place- make only small holes for oxygen saturation probe and umbilical catheter. • Radiant heat and a hat. Exothermic mattresses may be useful. • Monitor temperature regularly/continuously. Avoiding even moderate hypothermia reduces mortality morbidity and length of stay in hospital. Parents Parents appreciate opportunity to touch their baby and understand what has been done. With support fathers may be able watch delivery room stabilization and/or accompany baby to the NICU. Multi-disciplinary team The team of health professionals each with a clearly de‚ned role is required. If necessary call for additional help. Transport Move to neonatal unit on resuscitation platform or in transport incubator. Using resuscitation table minimizes handling. Investigations: Check blood glucose – if hypoglycemic give glucose Table 13.2 establish intravenous infusion to prevent hypoglycemia if indicated. Blood gas if indicated Mechanical ventilation: • Required prior to transfer in infants with signi‚cant respiratory distress and oxygen therapy in spite of non-invasive respiratory support and surfactant therapy. Oxygen saturation monitoring Provides real-time measurements also of heart rate. Apply probe to right hand for pre-ductal measurement. Titrate additional oxygen according to oxygen saturation using range listed in algorithm. If preterm keep oxygen saturation 91–95. Prophylactic CPAP: • Extremely preterm infants are increasingly started on non-invasive respiratory support from birth instead of intubation and mechanical ventilation. CPAP soon after birth helps babies establish resting lung volume. Surfactant can be given later if sustained oxygen requirement develops. • Given via face mask binasal or single nasal prongs • Use of CPAP ± surfactant in delivery room requires skill and experience. Surfactant: • Randomized trials have shown that routine prophylactic intubation and surfactant therapy is no longer indicated even in very preterm infants. • Indicated in preterm infants who have signi‚cant respiratory distress ± oxygen requirement in spite of respiratory support. • Requires tracheal instillation followed by mechanical ventilation or non-invasive respiratory support. Fig. 13.8 Post‐resuscitation care in the delivery room.

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Neonatology at a Glance Third Edition. Edited by Tom Lissauer Avroy A. Fanaroff Lawrence Miall and Jonathan Fanaroff. © 2016 John Wiley Sons Ltd. Published 2016 by John Wiley Sons Ltd. 34 Delivery Neonatal encephalopathy is a clinical description of generalized disordered neurologic function in the newborn. The most common cause is birth asphyxia. Asphyxia from the Greek word meaning pulseless is now used to mean a state in which gas exchange – placental or pulmonary – is compromised or ceases altogether resulting in cardiorespiratory depression. Hypoxia hypercarbia and metabolic acidosis follow. Compromised cardiac output dimin­ ishes tissue perfusion causing hypoxic–ischemic injury to the brain and other organs. The origin may be antenatal during labor and delivery or postnatal Fig. 14.1. Other causes of neonatal encephalopathy include transfer of maternal anesthetic agents cerebral malformations metabolic dis­ orders hypoglycemia hypocalcemia hyponatremia inborn errors of metabolism infection septicemia and meningitis hyperbiliru­ binemia neonatal withdrawal abstinence syndrome and intra­ cranial hemorrhage or infarction. The term “birth asphyxia” is best avoided because it is imprecise and implies that the baby’s enceph­ alopathy is a consequence of an asphyxial insult relating to birth which may have medicolegal implications. In hypoxic–ischemic encephalopathy HIE as opposed to other causes of encephalopathy there is: •  a significant hypoxic or ischemic event immediately before or during labor or delivery or consistent fetal heart rate monitor pattern •  fetal umbilical artery acidemia fetal umbilical artery pH 7.0 or base deficit / 12 mmol/L cord arterial pH 7.20 •  Apgar score of 5 at 5 and 10 minutes •  multisystem organ failure •  neuroimaging evidence of acute brain injury consistent with hypoxia­ischemia. In developed countries 0.5–1/1000 liveborn term infants develop HIE and 0.3/1000 have significant neurologic disability. HIE is more common in developing countries. Pathogenic mechanisms These include: •  failure of gas exchange across the placenta – excessive or pro­ longed uterine contractions placental abruption ruptured uterus •  interruption of umbilical blood flow – cord compression cord prolapse delayed delivery e.g. shoulder dystocia •  inadequate maternal placental perfusion maternal hypotension or hypertension – often with intrauterine growth restriction IUGR •  compromised fetus – anemia IUGR • failure of cardiorespiratory adaptation at birth – failure to breathe. Compensatory mechanisms These include: •  ‘diving reflex’ – redistribution of blood flow to vital organs brain heart and adrenals •  sympathetic drive – increase in catecholamines cortisol antidi­ uretic hormone ADH vasopressin • utilization of lactate pyruvate and ketones as an alternative energy source to glucose. Primary and delayed injury Following a severe ischemic insult some brain cells die rapidly primary cell death due to necrosis and an excitotoxic cascade is triggered including release of excitatory amino acids and free rad­ icals. When circulation is re‐established there is a variable time delay before secondary energy failure and delayed cell death due to apoptosis. This offers a potential therapeutic window to ameliorate secondary damage Fig. 14.2. Hypoxic–ischemic encephalopathy 14 Intrapartum 20 Antepartum None identified Antepartum and intrapartum 69 4 7 Fig. 14.1 Antepartum and intrapartum factors preceding neonatal hypoxic–ischemic encephalopathy. Data from Martinez‐Biarge M. et al. Antepartum and intrapartum factors preceding neonatal hypoxic– ischemic encephalopathy. Pediatrics 2013 132 e952–e959. Brain energy Time Secondary energy failure Delayed cell death Excitotoxicity Therapeutic window Hypoxia ischemia Return of circulation Energy depletion Primary cell death Fig. 14.2 Schematic diagram showing potential for prevention of secondary neuronal death.

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Hypoxic–ischemic encephalopathy 35 Clinical manifestations The clinical manifestations investigations and management are summarized in Fig. 14.3. Several large multicenter trials have demonstrated the benefit of therapeutic hypothermia in reducing death and disability and increasing survival with normal outcome at 18–24 months. The number needed to treat to prevent one death or disabled infant is seven. Selection criteria for cooling are gestation ≥36 weeks need for prolonged resuscitation clinical evidence of moderate or severe encephalopathy and severe metabolic acidosis within the first hour of life. aEEG or EEG are not required to initiate cooling but may confirm the severity of the encephalopathy and determine if subclinical seizures are present see Chapter  80. Cooling should be initiated within 6 h of birth. Core temperature is reduced to 33–34 °C and maintained for 72 h before slowly rewarming. Cooling is usually performed in a tertiary NICU but passive cooling turning off radiant heaters and allowing the baby to lose heat naturally may be commenced in the delivery room. Adjunct therapies to hypothermia that may further improve outcome are being evaluated including xenon melatonin and erythropoietin see video: Hypoxic–ischemic encephalopathy. Respiratory depression Circulatory depression Multi-organ dysfunction Hypoxemia Hypercarbia Respiratory acidosis Low cardiac output Decreased tissue perfusion Ischemia Metabolic acidosis Capillary leak edema Encephalopathy Abnormal neurologic exam Seizures Respiratory failure Persistent pulmonary hypertension of the newborn PPHN Hypoxemia Respiratory acidosis Myocardial dysfunction Hypotension Arrhythmias Ischemia Metabolic acidosis Metabolic Hypo/hyperglycemia Hypocalcemia Hypomagnesemia Lactic acidosis Hyponatremia – syndrome of inappropriate ADH secretion SIADH Acute kidney injury Renal failure acute tubular or cortical necrosis Oliguria Polyuria Hematuria Gastrointestinal Feeding intolerance Bleeding Gut ischemia – NEC Hepatic failure Hematology Elevated nucleated red blood cells Thrombocytopenia Bleeding – DIC Thrombosis Clinical features Delivery EEG aEEG Cerebral ultrasound MRI CT Evoked potentials Avoid overheating Therapeutic hypothermia Anticonvulsants Arterial blood gases Chest X-ray Blood gases Myocardial enzymes Echocardiography ECG – raised ST segment Blood glucose Calcium magnesium Lactate Electrolytes Serum and urine osmolarity Maintain normal blood glucose calcium and magnesium Correct metabolic acidosis Blood urea nitrogen BUN Creatinine Liver function tests Guaiac blood positive stools/ gastric aspirate Complete blood count Coagulation screen Respiratory support Maintain normal PaO 2 and PaCO 2 Inhaled nitric oxide to treat PPHN Maintain normal blood pressure Inotropes Restrict Žuids until passed urine Monitor urine output catheter Withhold feeds initially Blood products Vitamin K Investigations Management Fig. 14.3 Clinical manifestations investigations and management of hypoxic–ischemic encephalopathy. Investigations and management are selected according to clinical features. NEC – necrotizing enterocolitis DIC – disseminated intravascular coagulation EEG – electroencephalogram aEEG – amplitude‐ integrated EEG cerebral function monitor CTG – cardiotochography. Key point Avoid overheating – each degree above normal increases mortality and risk of brain injury. Key point Mild hypothermia 33–34 °C within 6 h of birth for 72 h has been shown to reduce morbidity and mortality of moderate and severe HIE see Fig. 67.1.

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36 Delivery Clinical staging of hypoxic–ischemic encephalopathy Severity of brain injury can be systematically evaluated using a staging system which is performed sequentially and is of prog­ nostic value. The most common is Sarnat Table 14.1 although the simpler Thompson score is increasingly used. Outcome In general: •  A normal neurologic examination and feeding orally by 2 weeks of age suggest good prognosis. •  Mild HIE – usually good outcome. •  HIE without cooling: – moderate HIE – increased risk for motor and cognitive abnor­ malities including cerebral palsy 15–20 – severe HIE – 50–75 will either die or have severe disability in childhood spastic quadriplegia learning difficulties visual and hearing impairment and seizures. •  HIE with cooling: – risk of death or disability is reduced by about 60. The postnatal markers of poor prognosis are shown in Table 14.3. Table 14.1 Sarnat staging of hypoxic–ischemic encephalopathy. Grade 1 mild Grade 2 moderate Grade 3 severe Level of consciousness Irritable/hyperalert Lethargy Coma Muscle tone Normal or hypertonia Hypotonia Flaccid Tendon reflexes Increased Increased Depressed or absent Myoclonus Present Present Absent Seizures Absent Frequent Frequent Complex reflexes Suck Active Weak Absent Moro Exaggerated Incomplete Absent Grasp Normal to exaggerated Exaggerated Absent Oculocephalic doll’s eye Normal Overactive Reduced or absent Autonomic function Pupils Dilated reactive Constricted reactive Variable or fixed Respirations Regular Periodic Ataxic apneic Heart rate Normal or tachycardia Bradycardia Bradycardia EEG Normal Low‐voltage periodic or paroxysmal Periodic or isoelectric Prognosis Good Variable High mortality and neurologic disability Neuroimaging and functional studies Table 14.2 Table 14.2 Neuroimaging and functional studies and their indications and interpretation. Procedure/test Indication and interpretation EEG or aEEG amplitude­ integrated EEG Fig. 14.4 Best initiated as soon after birth as possible. Identifies encephalopathy continuous seizure detection monitoring background activity and prognostic information. Good prognosis if normalizes in first 24 h. Cranial ultrasound Easy to perform at bedside. Useful for defining normal anatomy and for evidence of prenatal injury congenital infection intracranial hematoma or metabolic disorder. In HIE may detect cerebral edema hyperechogenic basal ganglia and/or abnormal blood flow velocity in middle and anterior cerebral arteries. Useful for following sequence and timing of any changes. MRI scan Imaging of choice for prognosis. Allows early recognition of injury to basal ganglia internal capsule white matter brainstem and cortex focal cerebral infarction hemorrhage and malformations Figs 14.5 and 14.6. Optimal between 7 and 21 days to determine the extent of cerebral injury. Diffusion‐weighted imaging may detect abnormalities within the first week.

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Hypoxic–ischemic encephalopathy 37 Fig. 14.5 Acute changes typically seen in the first week after perinatal asphyxia on MRI axial T1W at the level of the basal ganglia. There is an abnormal high signal in the posterolateral lentiform nuclei and thalami loss of the normal high signal from myelin in the posterior limb of the internal capsule arrow abnormal signal in the head of the caudate nuclei and low signal throughout the white matter. Courtesy of Dr Frances Cowan. a Normal 100V V 50 25 5 0 100 50 25 5 0 100 50 Transport 25 25 25 5 0 0 b Severe hypoxic– ischemic encephalopathy c Seizures in severe hypoxic–ischemic encephalopathy PhenobarbitalPhenytoin Fig. 14.4 Amplitude‐integrated EEG aEEG trace from cerebral function monitor showing a normal term newborn – normal baseline 5 μV b severe hypoxic–ischemic encephalopathy – low baseline amplitude c seizures in severe hypoxic–ischemic encephalopathy unresponsive to phenobarbital but responsive to phenytoin although the trace remains abnormal. Courtesy of Professor Andrew Wilkinson. Fig. 14.6 Cerebral atrophy on MRI axial T1W developing several weeks after perinatal asphyxia. At the level of the basal ganglia there is severe atrophy of the basal ganglia arrow thalami and white matter with enlarged ventricles and extracerebral space. There is also plagiocephaly. Courtesy of Dr Frances Cowan. Table 14.3 Postnatal markers of poor prognosis. Abnormal EEG from birth or aEEG from 6 h with isoelectric pattern or burst suppression in non­ cooled infants and later in cooled infants Abnormal MRI conventional or diffusion‐weighted – particularly basal ganglia/posterior limb of the internal capsule PLIC or marked brain atrophy or delayed myelination on later scan Persistence of clinical seizures Persistently abnormal neurologic exam after 1 week reasonable sensitivity poor specificity Not feeding orally by 2 weeks of age Poor postnatal head growth

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Neonatology at a Glance Third Edition. Edited by Tom Lissauer Avroy A. Fanaroff Lawrence Miall and Jonathan Fanaroff. © 2016 John Wiley Sons Ltd. Published 2016 by John Wiley Sons Ltd. 38 Delivery The incidence of severe birth injuries has fallen dramatically over the last 50 years. Prolonged obstructed labor and difficult instru- mental deliveries are usually avoided by cesarean section. However birth injuries still occur especially following instrumental deliveries shoulder dystocia malpresentation or preterm delivery. They are usually classified according to their anatomic location. Common or important birth injuries These are listed in Table 15.1. Scalp swellings can be differentiated by their position and relationship to the skull bones Fig. 15.1. Birth injuries 15 Skull bone Aponeurosis Skin Periosteum Extradural hemorrhage Subaponeurotic hemorrhage Cephalhematoma Caput Fig. 15.1 Anatomic location of injuries to the head. Table 15.1 Common or important birth injuries. Lesion Anatomic location Comments Clinical description and management Injuries to the head Caput Edema of the soft tissue of presenting part Crosses suture lines Common and benign Edema bruising of scalp No treatment necessary resolves in a few days good prognosis Chignon Over site of vacuum extraction Less common since soft flexible cups introduced Edema sometimes bruising skin damage Resolves over several days Cephalhematoma Subperiosteal Usually parietal Does not cross suture lines May be bilateral Relatively common Associated with prolonged or instrumental labor Hematoma maximal on second day May be associated with skull fracture May calcify Exacerbates jaundice Resolves in days to months Subgaleal subaponeurotic hemorrhage Between galea aponeurosis and periosteum arrow Rare Risk factors: •  prematurity •  vacuum extraction May have underlying coagulopathy Boggy appearance and pitting edema of scalp Anterior displacement of the ears Prompt recognition is crucial as may rapidly progress to hypovolemic shock Transfusion of blood fresh frozen plasma coagulation factors Skull fractures Usually parietal bone occipital in breech deliveries Uncommon Usually forceps delivery but also normal delivery Soft tissue edema and cephalhematoma Fractures may be linear or depressed Prognosis good Minor injuries Forceps marks From pressure of blades especially rotational forceps Less common as rotational forceps now seldom used Bruising and/or skin abrasion Heals rapidly

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Birth injuries 39 Lesion Anatomic location Comments Clinical description and management Scalpel lacerations Head or face At caesarean section May need tapes suturing plastic surgical referral Injuries to the face Facial palsy Usually unilateral right side in figure. If bilateral suspect congenital cause Pressure on maternal ischial spine or forceps delivery Unilateral facial weakness on crying Eye on affected side remains open Resolves in 2–3 weeks If eye permanently open use methylcellulose eye drops Asymmetric crying facies Unilateral absence of orbicularis oris muscle left side in figure More common than facial palsy. Not a birth injury needs to be differentiated from facial palsy In contrast to facial palsy eye can close naso‐labial crease is maintained Injuries to the neck and shoulders Fractured clavicle Midclavicular area Shoulder dystocia breech Snap may be heard during delivery Edema bruising crepitation at the site decreased active movement of arm Clavicular lump from callus formation during healing phase. Confirm on x-ray Heals spontaneously Brachial palsy Erb Nerves involved: C5 C6 ±C7 C3 Erb palsy C4 C5 C6 C7 C8 T1 Shoulder dystocia abnormal presentation obstructed labor macrosomia Phrenic nerve palsy – rare diaphragm is elevated Decreased shoulder abduction and external rotation supination of wrist and finger extension waiter’s tip. Hand movement and grasp reflex are preserved 90 resolve by 4 months. Surgical referral if not recovered To avoid contractures perform passive range of motion ± splints Other injuries Extremities – fractures Fracture of the humerus/ femur Breech shoulder dystocia. Deformity reduced movement of limb pain on movement Orthopedic referral Splint to reduce pain. Rarely hypovolemia from blood loss Bones rapidly remodel May have underlying bone/ muscle disorder Spinal cord Cervical thoracic lumbar spine Rare Instrumental delivery may occur prenatally Lack of movement below level of lesion Absent respiratory effort in high lesions Supportive care steroids for spinal shock Intra‐abdominal organs Ruptured liver spleen Renal injury Adrenal hemorrhage Macrosomia breech dystocia Pre‐existing hydronephrosis Prematurity neuroblastoma Abdomen – distension mass discoloration tenderness. Shock pallor Hematuria Hypoglycemia abdominal mass coma shock Intravascular volume support Abdominal ultrasound. Surgery unless bleed is contained subcapsular hematoma Genitalia Scrotum labia majora Breech Bruising hematoma. Resolves. Photograph of subgaleal hemorrhage reproduced with permission from Cheong J.L.Y . et al. Arch Dis Child Fetal Neonatal Ed 2006 91: F202–F203.

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Neonatology at a Glance Third Edition. Edited by Tom Lissauer Avroy A. Fanaroff Lawrence Miall and Jonathan Fanaroff. © 2016 John Wiley Sons Ltd. Published 2016 by John Wiley Sons Ltd. 40 The normal newborn infant Most term infants start to breathe several seconds after birth and become pink and active. If breathing normally the baby can be dried and placed directly on the mother’s front. This will allow direct skin‐ to‐skin contact the baby being kept warm with a towel. Alternatively the baby can first be wrapped in warm towels. It is at this time that most babies are alert and are ready to begin to establish nursing at the breast. After birth the midwife or pediatrician will examine the baby briefly to check there are no abnormalities. A more detailed exam- ination the routine examination of the newborn will be performed later but within 24 hours of birth see Chapter 17. Name tags will be attached to the baby and a record made to confirm that the baby passes urine and meconium within 24 hours of birth. Routine care of the newborn infant 16 Routine care Vitamin K Vitamin K as prophylaxis against vitamin K deficient bleeding hemorrhagic disease of the newborn is recommended. It is most reliable if given as a single large dose by intramuscular injection but its disadvantage is that it is an injection. It can also be given orally but this requires several doses to overcome its variable absorption and protection is less reliable. Infants are at increased risk if they are breast‐fed as breast milk is low in vitamin K if they have liver disease and if their mother is on anticonvulsant therapy. Eye prophylaxis In the US most newborn infants are given erythromycin eye drops as prophylaxis against gonococcal and chlamydia eye infection. Silver nitrate eye drops have also been used but can cause chemical conjunctivitis and do not prevent chlamydial infection. In the UK eye prophylaxis is not practiced but gonococcal or chlamydia eye infection is rare. Circumcision This is widely performed in the US but only for religious reasons in the UK. see Chapter 52. Breast‐feeding Mothers may need assistance and support to establish breast‐feeding. Umbilical cord care Always wash hands before handling. Keep dry and exposed to air. Clean with water avoid alcohol as it delays cord separation. Fold diaper nappy below umbilicus. In developing countries application of chlorhexidine is recommended. Meeting the family Visiting by siblings grandparents and other close family should be facilitated in order to be introduced to the new member of the family. Emotions Some mothers are emotionally labile during the first few days after birth. Even minor problems can cause considerable upset. Explanation and reassurance are required. Mothers who develop postnatal depression or who are unable to care for their baby or have no suitable accommodation may be identified during this postnatal period. Liaison with mental health or social services voluntary services or health visitors and other community health professionals may be required. Infants with disabilities or complex medical needs may require a multidisciplinary planning meeting before discharge. This is considered further in Chapter 71. Screening The use of a screening test depends on: •  prevalence of the disease •  ease with which the test can be performed •  false‐positive and‐false negative screening rates •  whether it significantly improves the prognosis •  cost. The availability of screening tests varies with judgment as to whether these criteria are satisfied. Biochemical screening Newborn bloodspot This is performed on all infants. Blood spots usually from a heel prick are placed on a card that is sent to a reference laboratory. In most centers in the US tandem mass spectrometry is used to screen a wide range of disorders particular disorders vary by state but all States screen for are least 29 disorders including: •  phenylketonuria •  hypothyroidism •  sickle cell disease •  thalassemia •  MCADD medium‐chain acyl‐CoA dehydrogenase deficiency •  Maple syrup urine disease MSUD •  Isovaleric aciduria IV A •  Glutaric aciduria type I GA1 •  Homocysteinuria HCU. Cystic fibrosis screening is performed by measuring serum immuno- reactive trypsin IRT and DNA analysis for mutations in CFTR cystic fibrosis transmembrane regulator gene. The trypsin level is raised

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Routine care of the newborn infant 41 because of obstruction of the pancreatic ducts. It has a high false‐positive rate which can be reduced by combining it with DNA analysis. In the UK screening is confined to the disorders listed above but an expanded program of tandem mass spectrometry is being assessed in some areas. Audiology see Chapter 62 Neonatal hearing screening is universal for infants in the UK and in most States in the US. Transcutaneous bilirubin Used to identify infants at increased risk of developing hyperbiliru- binemia and requiring more frequent monitoring see Chapter 41. Other possible screening tests Pulse oximetry Increasingly introduced in the US and UK to detect critical con- genital heart disease in all infants see Chapter 49. Ultrasound for DDH developmental dysplasia of the hips Used selectively in the UK and US e.g. breech position family his- tory but in all babies in some countries in Europe see Chapter 17. Routine hematocrit for polycythemia Not recommended as not proven that treatment improves prognosis. Health promotion Parents should be provided with verbal and written advice about: •  feeding •  jaundice •  the importance of immunizations •  safe sleep practices to reduce the risk of SIDS sudden infant death syndrome Fig. 16.1 •  the need for a car seat to take the baby home and whenever traveling in a car •  when to seek medical attention. Discharge Before discharge check that: •  feeding is being established successfully •  the nursing staff do not have concerns about the mother’s handling of the baby •  the baby is well and not significantly jaundiced •  timely follow‐up arrangements are in place. Key points In order to reduce the risk of SIDS: •  Back to sleep Fig. 16.1a •  Avoid exposure to cigarette smoke Fig. 16.1b •  Avoid overheating: – No more than 1 more layer of clothing than an adult would wear. – Head and face uncovered. •  Safe sleep environment: – Sleep in own crib cot in parents’ bedroom but not in their bed. – Never sleep with baby on a sofa or armchair. – Infant should sleep on a frm surface with no pillows or toys. •  Breast feed •  Consider pacifer at nap and bedtimes. Question Which immunizations should be given routinely in the immediate newborn period US: •  Hepatitis B: initial dose recommended as part of universal immunization program and given before discharge. UK: •  BCG for TB: increasingly offered if living in high‐risk area or for certain ethnic communities. Requires intradermal injection. •  Hepatitis B: given if mother is positive for hepatitis B surface antigen. b Avoid smoking during pregnancy and in your baby’s presence a Back to sleep Always put babies to sleep on their back not prone or side 0 2 3 4 1 Odds ratio for SIDS No. of cigarettes smoked per day in pregnancy 1–9 10 Fig. 16.1 Advice for parents to reduce the risk of SIDS. a Back to sleep. b Odds ratio for SIDS and number of cigarettes smoked per day in pregnancy. A more detailed list of advice for parents is listed above in the Key points. Adapted from Reduce the Risk of SIDS Department of Health UK 2009 and American Academy of Pediatrics 20011. Data from MacDorman M.F. et al. Sudden infant death syndrome and smoking in the United States and Sweden Am J Epidemiol 1997 146: 249–257. Key point Every effort should be made to ensure successful breast feeding. Human milk provides not only optimal nutrients but also provides hormones and enhances the immune system and gut microbiome.

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Neonatology at a Glance Third Edition. Edited by Tom Lissauer Avroy A. Fanaroff Lawrence Miall and Jonathan Fanaroff. © 2016 John Wiley Sons Ltd. Published 2016 by John Wiley Sons Ltd. 42 The normal newborn infant All babies are examined shortly after birth to check that transition to extrauterine life has proceeded smoothly and there are no major abnormalities. A comprehensive medical examination within 24 hours of birth the ‘routine examination of the newborn infant’ should be performed. The purpose is to: •  detect any abnormalities – a significant congenital anomaly is present at birth in 10–20 per 1000 live births •  confirm and plan the further management of any abnormalities detected antenatally • consider potential problems related to maternal pregnancy history or familial disorders •  allow the parents to ask any questions and raise any concerns about their baby •  determine whether there is concern by caregivers about the care of the baby following discharge. •  provide health promotion especially prevention of sudden infant death syndrome SIDS see Chapter 16. Preparation Maternal charts records: •  Check maternal antenatal labor and delivery charts. Equipment: •  Tape measure. •  Stethoscope. •  Ophthalmoscope. Environment: •  Warm room free from drafts. •  Privacy suitably lit. •  Examine on firm mattress in crib cot. •  Both parents present if possible. •  Always wash hands and clean stethoscope before each examination. The infant •  The baby must be completely undressed during the course of the examination so that all the body is observed. •  Need a content settled infant for successful examination. •  Examination is performed opportunistically i.e. eyes when open heart when quiet hips left until last. However the examination must be complete. Routine examination of newborn infants Table 17.1 Figs 17.2 and 17.3 see video: Newborn examination Routine examination of the newborn infant 17 Developmental dysplasia of the hip DDH congenital dislocation of the hip CDH Clinical examination: •  Performed on all infants – part of routine neonatal examination. •  Infant must be relaxed – if crying or kicking there is tightening of the muscles around the hip. •  There may be asymmetry of skin folds around an affected hip and shortening of the affected leg. •  Fully abduct both hips full abduction may not be possible if the hip is dislocated. Pelvis is stabilized with one hand with the other the examiner’s middle fnger is placed round the greater trochanter and the thumb around the distal medial femur. •  Check if dislocatable posteriorly Barlow maneuver Fig.  17.1a. •  Check if hip is dislocated and can be relocated into acetabulum Ortolani maneuver Fig. 17.1b Minimal force is required. Risk increased: •  in female infants 9:1 •  if positive family history 20 of affected infants •  if breech presentation 30 of affected infants •  in infants with a neuromuscular disorder. If abnormal or questionable clinical examination arrange con- sultation with experienced orthopedic surgeon. If normal exami- nation but breech presentation or in some centers positive family history arrange hip ultrasound at 4–6 weeks of age. Ultrasound screening of all infants can identify some missed on clinical exam- ination and some with shallow acetabular shelf not detectable on clinical examination but has appreciable false‐positive rate 7. Not recommended for all infants in US or UK. For management see Chapter 61. a Test for dislocatable hip. The hip is held exed and adducted. The femoral head is pushed downwards. If dislocatable the femoral head will be pushed posteriorly out of the acetabulum with a palpable clunk b Test for dislocated hip. Abduct hip with upward leverage of femur. A dislocated hip will return with a palpable clunk into the acetabulum b Ortolani maneuver a Barlow maneuver Fig. 17.1 Barlow and Ortolani maneuvers.

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Routine examination of the newborn infant 43 Table 17.1 Significant congenital abnormalities which may be identified on routine examination. Dysmorphic infant see Chapter 9 Cataracts see Chapter 62 Cleft lip and palate see Chapter 40 Congenital heart disease see Chapter 49 Urogenital – hypospadias undescended testes see Chapter 52 DDH developmental dysplasia of the hip Imperforate anus see Chapter 48 Spinal anomalies see Chapter 59 Fig. 17.2 Checking for red reflex. If absent i.e. the pupil is white cataracts glaucoma retinoblastoma refer directly to an ophthalmolo- gist. Also check eye looks normal e.g. for a coloboma a key‐shaped defect in the iris. see Chapter 62 General appearance posture movements – are they normal Facies – any dysmorphic features e.g. trisomy 21 Down syndrome Plethora or pale If suspected check hematocrit Ears – low-set malformed or preauricular tags/pits Breathing and chest wall movement – observe for respiratory distress: Increased respiratory rate Flaring of nostrils Grunting Chest retractions sternal and intercostal Hips – check for developmental dysplasia of the hips see Fig. 17.1 Eyes – check with ophthalmoscope for red re‚ex Cyanosis of tongue – if in doubt check oxygen saturation with pulse oximeter Hands – check for extra digits palmar creases Heart – auscultate. Normal heart rate 110–160 beats/min but may drop to 80 beats/min during sleep Heart murmur – see Chapter 49 Back and spine: check from top to bottom. Sacral dimples below the line of the natal cleft – common and benign. If proximal to natal cleft ultrasound to identify if there is a track to the spinal cord though rare. Check the back for a tuft of hair swelling nevus or other lesion over the spine which may indicate vertebral or spinal cord abnormality e.g. spina biŒda occulta or tethered cord. If present arrange ultra- sound but MRI scan may be required Genitalia – check testes in scrotum and normal penis without hypospadias in boys and normal anatomy in girls Measurements at 40 weeks: Birth weight Head circumference Length 3.2 kg 34 cm 49.5 cm 2.8–4.0 kg 32.5–35.5 cm 47–52 cm Maximal occipito-frontal diameter Routinely measured in US not in UK. Hips and knees must be straight 50th centile 10th–90th centile Comments Palate – inspect and palpate to identify cleft palate Jaundice – if present in Œrst 24 hours needs investigation Fontanel and skull structures feel normal check for caput or hematoma Skin – check for any birthmarks or rashes Abdomen: Normal liver edge palpable 1–2 cm below costal margin spleen tip and left kidney may be palpable Any masses – investigate with ultrasound Femoral pulses: Reduced in coarctation of the aorta. If suspected check by measuring blood pressure in all four limbs. Difference 20 mmHg is signiŒcant Bounding in patent ductus arteriosus Muscle tone: Observe for normal movements of limbs Feel when handling the baby support the head when picking up baby On holding prone term babies will lift their head to horizontal position Feet – check for talipes equinovarus Anus – observe patency Fig. 17.3 Routine examination of newborn infants. In the UK the Newborn Infant Physical Examination NIPE checklist is recorded in the child health record and communicated to the family practitioner.

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Neonatology at a Glance Third Edition. Edited by Tom Lissauer Avroy A. Fanaroff Lawrence Miall and Jonathan Fanaroff. © 2016 John Wiley Sons Ltd. Published 2016 by John Wiley Sons Ltd. 44 The normal newborn infant The newborn infant’s neurologic development progresses mark- edly with gestational age. This needs to be taken into account when performing a neurologic examination and accounts for many of the components of the neurologic examination used in the clinical assessment of gestational age Ballard or Dubowitz score see Chapter 83. A detailed neurologic examination is performed if there are any concerns about neurologic abnormality. A normal neurologic exam is helpful prognostically e.g. following hypoxic–ischemic enceph- alopathy a normal neurologic examination and normal feeding by 2 weeks of age are associated with a good prognosis. Very low birthweight infants with a normal neurologic examination and intracranial ultrasound at 40 weeks are highly unlikely to develop significant motor disability and the predictive value of combined assessment is better than ultrasound alone. The neurologic development described here is adapted from that described by Amiel‐Tison who has also devised a standardized exam- ination with 10 components see video: Neurological examination. States of alertness An infant’s state of alertness can be classified Prechtl scale: •  state 1: eyes closed regular respiration no movements •  state 2: eyes closed irregular respiration no gross movements •  state 3: eyes open no gross movements •  state 4: eyes open gross movements no crying •  state 5: eyes open or closed crying. For satisfactory neurologic assessment infants need to be in state 3 when they are quiet but alert i.e. able to fix and follow. However the clinician may have to bring the baby to this state. Inability to do this may occur because the infant is abnormally lethargic or hyperexcitable or deeply asleep or hungry. An abnormal cry may also indicate abnormal neurology. Visual fixing and following A normal term infant should fix and follow a face or target of con- centric black and white circles or a red ball moving from side to side. This starts at about 32 weeks’ gestation. The infant should make eye‐to‐eye contact when held about 30 cm from the observer. Hearing Infants respond to noise with a facial grimace turning of the head or startle. Consolability This is the response of the crying infant to a voice or soothing movements such as rocking from side to side. It indicates commu- nication between the infant and caregiver. Head circumference This is a surrogate measure of brain volume and subsequently of brain growth. Face cranial nerves There should be normal facial movements blinking of the eyes and ability to suck strongly. Posture and spontaneous motor activity Posture Posture at term is flexed Fig. 18.1. Movements are smooth symmetric and varied. The infant can move the fingers and can abduct the thumbs. Passive tone in limbs and trunk Develops from hypotonia at 24 weeks of gestation to strong flexor tone at 40 weeks initially in the lower then upper limbs Fig. 18.2. Active tone in limbs and trunk See Fig. 18.3. Neurologic examination 18 32 weeks 40 weeks Arms extended Some exion of the legs Full exion of all four limbs Fig. 18.1 Posture. 120°–110° 90° or less 40°–30°0° Very weak resistance Does not reach midline 32 weeks Term 32 weeksTerm 32 weeks Popliteal angle Foot dorsiexion Scarf sign With thigh beside abdomen extend knee as far as possible With knee exed ankle is dorsiexed Measure angle between dorsum of foot and anterior of leg Hand pulled across chest towards opposite shoulder Position of elbow noted Term Largely passes midline Very tight Fig. 18.2 Passive tone in limbs and trunk.

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Neurologic examination 45 Primary reflexes Primary or primitive reflexes reflect brainstem activity Fig. 18.4. They are a manifestation of central nervous system programming with later suppression by higher cortical function. If they cannot be elicited suggests central nervous system depression. More impor- tant their persistence suggests damage to upper cortical control Table 18.1. Deep tendon reflexes May be depressed with lower motor neuron lesions occasion- ally increased with upper motor neuron lesions. May reveal asymmetry. Ankle clonus is common and usually of no patho- logic significance. Plantar responses Elicited by stroking the lateral part of the foot from heel to toe. Unhelpful at this age as normal response may be flexor toe down or extensor toe up. Righting reaction Neck exor tone raise to sit Ventral suspension Holding infant upright under axillae Holding infants shoulders pull from lying to sitting Brief support of lower limbs only No movement of head forwards Some extension of head and back Upright and takes weight for few secs Minimal head lag. Similarly for neck extensor tone back to lying Head extended above body back extended and limbs fully exed 32 weeks40 weeks32 weeks40 weeks32 weeks40 weeks Fig. 18.3 Active tone in limbs and trunk. Table 18.1 Primary reflexes. Reflex Disappearance corrected age Placing 3 months Palmar grasp 3 months Plantar grasp 3 months Moro 4 months Asymmetric tonic neck reflex ATNR 6 months Key point The hypertonic term infant – increased tone and tendon reflexes and head extension when held prone. Often hypotonic in neonatal period and hypertonia develops during infancy. The hypotonic term infant – see Chapter 60. Placing reex When dorsum of foot is stimulated by edge of bed places foot on the surface Palmar grasp Flexion of ngers when object placed in the palm of the hand Plantar grasp Toes curl on stroking the ball of the foot Asymmetric tonic neck reex ATNR Fencing posture on turning head to one side Moro reex On sudden head extension but support the infant’s head in your hand symmetrical abduction and extension followed by exion and adduction of the arms Fig. 18.4 Primary reflexes.

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Neonatology at a Glance Third Edition. Edited by Tom Lissauer Avroy A. Fanaroff Lawrence Miall and Jonathan Fanaroff. © 2016 John Wiley Sons Ltd. Published 2016 by John Wiley Sons Ltd. 46 The normal newborn infant The family must of course be included in the care of all newborn infants whether well or critically ill. The birth of a healthy newborn infant is usually a joyous occasion fulfilling the dreams and hopes of the parents. If the baby is extremely premature sick has malfor- mations or dies these dreams will be shattered and the family will experience considerable distress. The family will need sensitive discussion and support. How this is done will influence their ability to cope and recover in the short and long term. Family centered care encourages parents to be partners in their infants’ care and in decisions about treatment. The way parents see themselves as par- ents respond to their baby and react to stressful situations is very individual and will be influenced by personal views and standards family background and culture. Psychological support from an appropriately trained professional may be helpful for parents to deal with their distress and anxiety. This may also be needed to help with psychological problems that occur after the infant leaves hospital. Care and support for parents 19 Attachment What is maternal attachment It is the intense relationship which develops between a mother and her child providing protection and nurturing for the child Fig. 19.1. In many animals e.g. ducks or penguins there is a critical sensitive period for mother–infant bonding immediately after birth when the mother and her offspring must be in direct contact. If this does not happen the mother fails to recognize that the new- born is hers. Attachment in humans does not necessarily happen instantly but develops over time. Although touching and nursing the baby shortly after birth is helpful in promoting attachment and should be encouraged humans can still become attached to their infants where this does not occur for example if the infant is admitted directly to the neonatal unit. Fathers and other family members also develop attachment with the newborn baby. Attachment is the foundation of healthy emotional development. In childhood secure attachment gives the child the confidence to explore and learn. Factors promoting attachment 1. Planning the pregnancy 2. Conrming the pregnancy 3. Accepting the pregnancy 1. Prenatal classes and preparation for breast-feeding 2. Presence of companion during labor and delivery female doula or father if desired by both parents 3. Minimize separation of mother from her infant 4. Seeing touching and taking care of the baby. Attachment grows as parents recognize that their infant is visually watching them responding to their voice and is comforted by them Risk factors for failure in establishing attachment Disharmony with partner or at home Unwanted pregnancy Adverse socio-economic circumstances e.g. single parent poverty Conception after death of close relative – parent grandparent or close friend or of previous child Lack of support during labor Serious problem with the infant – extremely premature has congenital malformation critically ill requiring neonatal intensive care Discrepancy between the conceptualized perfect baby and the actual baby may result in ‘anticipatory grief’ making it difcult to ‘attach’ to the baby while grieving Failure to visit baby in neonatal unit Maternal depression 4. Experiencing fetal movements quickening 5. Recognizing the fetus as an individual 6. Giving birth 7. Seeing the baby. Eye to eye contact with the newborn infant who is usually alert after birth appears to be a powerful stimulus to bonding 8. Touching smelling and nursing the baby 9. Providing care of the baby Fetal movements Infancy Increasing attachment Normal maternal attachment The process of attachment varies and strengthens with each step. Not all these steps apply to every mother and will be in™uenced by cultural background education parity etc. Birth Pregnancy Fig. 19.1 Steps in normal attachment.

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Care and support for parents 47 Communicating with parents Parents and family want open communication about their baby. Professionals need to not only provide accurate and realistic information about the baby’s problems but also listen to and address the family’s anxieties and feelings. The needs of each of the family members should be elicited as they may differ. Fathers who may be at work much of the time particularly value opportu- nities for communication. Some specific circumstances regarding communicating with parents related to perinatal care are considered below. Antenatal identification of fetal abnormality or potential abnormality • Many problems including major malformations and preterm delivery are now identified before birth. The recognition of many minor malformations or the possibility of an abnormal finding in the fetus has become a common cause of additional anxiety for parents. •  The neonatal team should be involved and present a realistic picture. First discuss the positive aspects and present facts in a positive light – describe a glass as half full rather than half empty. Facts should be disclosed but acknowledge uncertainty and do not overemphasize unsubstantiated fears. • Problems should be anticipated and their consequences and management discussed with the family. If appropriate a tour of the neonatal intensive care unit NICU before delivery should be conducted. Admission of the infant to the neonatal unit Parents of infants in the NICU are at increased risk of acute stress and post-traumatic stress disorder. See Chapter 22 for further details. Infants with serious congenital malformations The crisis of the birth of a child with a serious malformation can result in emotional turmoil the parents mourning the loss of the normal child they expected whilst also needing to attach to their newborn. Doctors and other health professionals will need to explain the nature and implications of the disorder to the parents and family and may need to provide considerable emotional support to help families in this difficult situation Table 19.1. Table 19.1 How parents wish to be told about a serious problem or life‐threatening illness. Adapted from Wooley H. et al. Imparting the diagnosis of life‐threatening illness in children. BMJ 1989 298: 1623–1626. Setting In private and comfort Uninterrupted Unhurried Both parents present if possible If desired also a trusted person who can help review the conversation afterwards. Senior doctor Nurse present Translator if necessary Some families find it helpful to have a tape recording of the interview or to take notes Establish contact Find out what the family knows or suspects Respect family’s vulnerability Use the child’s name and parents’ names – do not call them mum and dad Do not avoid looking at them Be direct open sympathetic Provide information Flexibility is essential Pace rather than protect from bad news. Some families want a lot of information at once others prefer shorter interviews more often Name the illness or condition Describe symptoms relevant to child’s condition Discuss etiology – parents will usually want to know Anticipate and answer questions. Don’t avoid difficult issues because parents have not thought to ask Explain long‐term prognosis If child is likely to die listen to concerns about time place and nature of death Outline the support/treatment available Address feelings Be prepared to tolerate reactions of shock especially anger or weeping Acknowledge uncertainty How is it likely to affect the family What and how to tell other children relatives and friends Concluding the interview Elicit what parents have understood Clarify and repeat particularly highlighting immediate situation and next steps Acknowledge that it may be difficult for parents to absorb all the information and they should not be afraid to ask questions over and over again Mention sources of support Give parents a contact telephone number or e‐mail Give web‐site or address of self‐help group Check if there is anything else they would like to know Follow‐up Offer early follow‐up and arrange date Suggest to families that they write down questions before next appointment Ensure adequate communication of content of interview to other members of staff family practitioner and health visitor and other professionals e.g. a referring pediatrician

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Neonatology at a Glance Third Edition. Edited by Tom Lissauer Avroy A. Fanaroff Lawrence Miall and Jonathan Fanaroff. © 2016 John Wiley Sons Ltd. Published 2016 by John Wiley Sons Ltd. 48 The normal newborn infant Human milk is recommended as the exclusive food for all term infants for the first 6 months of life. Human milk is also recommended for preterm infants but may need fortification. Donor breast milk is increasingly available for preterm infants to supplement maternal milk. All mothers should be encouraged and supported to breast‐ feed. Counseling should commence early in pregnancy and mothers should be assisted by nursing or lactation specialists. The choice to breast‐ or bottle‐feed is personal and formula feeding should not be criticized. Nutritional characteristics of human milk compared with unmodified cow’s milk Protein •  Low protein content whey: casein 60:40 – more easily digestible. •  High free amino acids and urea glutamine the predominant amino acid stimulates enterotropic hormones enhancing feeding tolerance. Fat •  Unsaturated. •  Contains long‐chain polyunsaturated fatty acids LCPUFAs – needed for nervous system development now incorporated into formula as is arachidonic acid ARA. Carbohydrate •  High lactose. Minerals •  Low renal solute load. •  Reduced phosphate:calcium ratio. Vitamins Supplementation required to breast milk to meet daily requirements. Formula Formula is humanized i.e. manipulated to resemble human milk. However there are still differences in amino acid and fatty acid composition and it does not contain the anti‐infective properties of human milk. In developing countries infection from reconstituting milk powder with contaminated water is a major health problem. Unmodified cow’s goat’s and sheep’s milks are unsuitable for infants. Soy formula is sometimes used to prevent allergic disor ­ ders such as eczema and asthma although evidence for this is lack­ ing. About 10–30 of infants with cow’s milk protein intolerance become sensitive to soy. Soy formula is not recommended for pre­ mature infants. Feeding 20 Steps to successful breast‐feeding •  Place the infant on the breast either immediately or soon after birth. •  Provide quiet supportive environment with comfortable posi­ tioning Fig. 20.1. •  Demand feeding is preferable to a fxed schedule. This stimu­ lates milk production and reduces feeling of fullness and discom­ fort. May be put to the breast 8–12 or more times per 24 hours. •  Put to both breasts at each feeding. Switch sides when baby pauses and lets go of breast. Allow unrestricted duration of feeds. Begin each feeding with the breast last nursed from. •  Emptying the breast adequately avoids engorgement. •  Initial milk is colostrum – low in volume high in protein and immunoglobulin content. Takes 24–72 hours for breast milk to come in. •  Warn mothers that babies initially lose weight up to 7–10 of birthweight and only put on weight after day 4 of life. They should be back to birthweight by 10–14 days. •  Do not give supplementary water or formula unless medically indicated. • Allow mothers and infants to stay together rooming‐in 24 hours per day. •  Inform mothers of breast‐feeding support groups. Fig. 20.1 Positioning for breast‐feeding. Adapted from UNICEF UK Baby Friendly Initiative.

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Feeding 49 Breast‐feeding Advantages of breast‐feeding for the infant Immediate: •  Promotes mother–infant bonding. •  Ideal nutritional composition see below. •  Contains immune factors e.g. secretory IgA. •  Reduces gastroenteritis and respiratory infections. •  Less feeding intolerance. • Reduces incidence of necrotizing enterocolitis in preterm infants. •  Promotes ketone production as an alternative energy substrate to glucose in frst few days of life. Long term: •  Reduced risk of SIDS sudden infant death syndrome. • May decrease incidence and severity of eczema and asthma. •  Less obesity insulin‐dependent diabetes mellitus type 1 and infammatory bowel diseases Crohn disease and ulcerative colitis. Advantages of breast‐feeding for the mother •  Enhances mother–infant bonding. •  More rapid postpartum weight loss. •  Decreased risk of osteoporosis. •  Decreased risk of breast and ovarian cancer. •  Increases time between pregnancies which is important in developing countries. Potential complications of breast‐feeding for the infant •  Cannot tell how much milk the baby has taken. This is deter­ mined by monitoring baby’s weight and urine output. •  Dehydration may occur if: – inadequate milk supply/poor feeding technique – hot weather. •  Jaundice associated with breast milk: – common – exacerbated by dehydration – even if requiring phototherapy breast‐feeding should be continued – is prolonged 2 weeks of age in up to 15 – will require investigations to be performed. •  Multiple births: – twins can often be exclusively breast‐fed Fig. 20.2 but rarely higher‐order births. •  Vitamin K: – low level in breast milk may predispose to hemorrhagic disease of the newborn – prophylaxis is required. Potential complications of breast‐feeding for the mother •  Maternal feeling of inadequacy/upset if unsuccessful. • Breast engorgement cracked nipples – may be helped by manual expression or breast pump. •  Mastitis–requires maternal treatment and may disrupt feeding. Contraindications to breast‐feeding •  Maternal HIV – breast‐feeding contraindicated in devel ­ oped countries. In resource‐poor environment breast‐feeding is advised unless formula feeds can be given safely. Under these circumstances for Prevention of Mother‐to‐Child Trans­ mission PMCT the World Health Organization now recom­ mends lifelong combination antiretroviral therapy for all pregnant women exclusive breast‐feeding with antiretroviral therapy for the newborn for the frst 6 months or minimum of the frst 6 weeks. Mixed formula and breast‐feeding should be avoided see Chapter 73 Global neonatology. •  Maternal TB infection active. •  Inborn errors of metabolism – galactosemia phenylketonuria. Drugs in breast milk •  Most drugs are excreted in breast milk in such small quantities they do not affect the infant. •  Where possible all drugs including self‐medication should be avoided during breast‐feeding. Most mothers who need medi ­ cations can continue breast‐feeding but a few drugs preclude breast‐feeding. Some examples are listed in Table 64.1. Check a formulary. Fig. 20.2 Successful breast‐feeding of twins. Key point ‘Breast is best’ for feeding newborn infants.

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Neonatology at a Glance Third Edition. Edited by Tom Lissauer Avroy A. Fanaroff Lawrence Miall and Jonathan Fanaroff. © 2016 John Wiley Sons Ltd. Published 2016 by John Wiley Sons Ltd. 50 The normal newborn infant Minor abnormalities in the first few days 21 Traumatic cyanosis – skin discoloration and petechiae over the head and neck or presenting part from cord around the baby’s neck or from a face or brow presentation. The tongue is pink Swollen eyelids but no discharge from the eye Subconjunctival hemorrhages – from delivery Vernix: greasy yellow-white coating present at birth a mixture of desquamating cells and sebum which protects fetus from maceration in utero Cracking and peeling of skin particularly over hands and feet. Most pronounced in post-term infants. This scaling and desquamation is physiologic Small white cysts along the mid- line of the palate Epstein pearls. Cysts of the gums epulis or oor of the mouth ranula Breast enlargement may occur in newborn infants of either sex Fig. 21.2. A small amount of milk may be discharged Umbilical hernia – more common in Black infants usually resolves within 2–3 years Vaginal discharge – small white discharge or withdrawal bleed in girls. A prolapse of a ring of vaginal mucosa may be present Positional talipes Fig 21.3. Feet adopt in utero position. If marked parents can be shown passive exercises by physical therapist Lanugo: ne downy hair starts to shed at 32–36 weeks’ gestation Peripheral cyanosis of the hands and feet acrocyanosis. Present in most newborn infants on the rst day Distortion of the shape of the head from delivery molding Caput succedaneum cephalhematoma Chignon after vacuum extraction Fig. 21.1 Minor abnormalities noted in the first few days of life. Fig. 21.2 Breast enlargement. b a Fig. 21.3 Positional talipes. a Position of the feet. b The foot can be fully dorsiflexed to touch the front of the lower leg. In true talipes equinovarus this is not possible.

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Minor abnormalities in the first few days 51 Skin lesions Nevus fammeus stork bites Pink macules on upper eyelids mid‐forehead also called salmon patch and nape of the neck Fig.  21.4. Common. Dilated superficial capillaries. Those on the eyelids and forehead fade over the first year. Those on the neck persist but are covered with hair. Milia White pinhead‐sized pimples on the nose and cheeks and fore‐ head. Resolve during first month of life. Are from retention of keratin and sebaceous material in the pilosebaceous follicles. Miliaria Pin‐sized vesicles particularly over the neck and chest. Usually develop at 2–3 weeks. Caused by sweat that is retained due to obstructed eccrine glands. Avoid excessive clothing and heating. Erythema toxicum Small firm white or yellow pustules on erythematous base Fig. 21.5. It is the most common transient lesion usually appears at 1–3 days but up to 2 weeks of age primarily on trunk extrem- ities and perineum. Moves to different sites within hours. Contains eosinophils. May be present at birth. Mongolian spots Blue–black macular discoloration at base of the spine and on the buttocks Fig. 21.6. Usually but not invariably in Black or Asian infants. Sometimes also on the legs and other parts of the body. Fade slowly over the first few years. Of no significance unless misdiagnosed as bruises. Transient pustular melanosis transient neonatal pustulosis Resembles miliaria but present at birth and may continue to appear for several weeks. Superficial vesiculo‐pustular lesions rupture within 48 hours to leave small pigmented macules with white surround. More common in Black infants in whom the lesions are often hyperpigmented. Harlequin color change Sharply demarcated blanching down one half of the body – one side of the body red while the other is pale. Lasts a few minutes. Thought to be due to vasomotor instability. It is benign. Sucking blisters Vesicles on hand fingers or lips from vigorous sucking in utero. Fig. 21.4 Stork bite nevus flammeus salmon patch. a b Fig. 21.5 a Erythema toxicum showing patchy pustules on erythema- tous base. Courtesy of Dr Nim Subhedar. b Close‐up of skin lesion. Fig. 21.6 Mongolian spot. Other minor abnormalities Figs 21.7–21.9 Fig. 21.7 Natal teeth. Front lower incisors present at birth. Remove if loose to avoid the risk of aspiration. Fig. 21.8 Extra digits. Usually connected by a skin tag but may contain bone. Common anomaly – often hereditary. Cosmetic outcome is better if removed surgically rather than tying off with silk thread which may leave residual neuroma. Fig. 21.9 Ear tags. Consult plastic surgeon. Check that the ear and hearing is normal. If there is an ear anomaly some centers ultrasound the kidneys as slight increased risk of renal abnormalities.

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Neonatology at a Glance Third Edition. Edited by Tom Lissauer Avroy A. Fanaroff Lawrence Miall and Jonathan Fanaroff. © 2016 John Wiley Sons Ltd. Published 2016 by John Wiley Sons Ltd. 52 The normal newborn infant Anticipation Many neonatal problems can be anticipated or prevented by aware- ness of conditions that are detected antenatally Tables 22.1 and 22.2 or which develop during labor or delivery Table 22.3. This necessitates close liaison between the health professionals caring for the mother and fetus and pediatricians. Some common exam- ples of problems and management plans which may occur in the neonatal period are listed below. They are described in more detail in the relevant chapters. Common problems of term infants 22 Maternal or antenatal conditions Table 22.1 Table 22.1 Neonatal problems associated with maternal conditions. Maternal medical condition Neonatal problem Diabetes mellitus Neonatal hypoglycemia Polycythemia Jaundice Congenital malformations Maternal hyperthyroidism Neonatal hyperthyroidism or hypothyroidism from maternal drug treatment Autoimmune thrombocytopenia Neonatal thrombocytopenia SLE systemic lupus erythematosus Heart block rash Red blood cell isoimmunization Rhesus and other red cell antibodies. ABO incompatibility mother group O infant A or B Jaundice anemia Hepatitis B positive Immunization ± prophylaxis HIV infection Preventative therapy advice about breast‐feeding Syphilis serology positive Treatment if necessary Chlamydia screening in US Chlamydia trachomatis identified Check for conjunctivitis Maternal drugs Drug abuse Neonatal drug withdrawal Alcohol Fetal alcohol syndrome Prolonged rupture of membranes Neonatal infection Chorioamnionitis Neonatal infection Maternal fever 38 °C Neonatal infection Maternal group B streptococcal bacteriuria or colonization Neonatal infection Fetal conditions Table 22.2 Table 22.2 Neonatal problems associated with fetal conditions. Fetal condition Neonatal problem Abnormal ultrasound Renal commonest e.g. hydronephrosis May need prophylactic antibiotics ultrasound and VCUG vesicocystourethrogram Cardiac May need repeat echocardiography – liaise with pediatric cardiologist Other abnormalities Management as planned antenatally Intrauterine growth restriction IUGR or large for gestational age Hypoglycemia Polycythemia Multiple births Anemia/polycythemia Twin–twin transfusion syndrome Congenital malformations Intrauterine growth restriction IUGR Labor and delivery Table 22.3 Table 22.3 Neonatal problems associated with abnormal labor and delivery. Labor and delivery Neonatal problem Antepartum hemorrhage Hypoxic–ischemic encephalopathy anemia Markedly abnormal fetal heart trace Hypoxic–ischemic encephalopathy Cesarean section TTNB transient tachypnea of the newborn Vacuum extraction Chignon jaundice Subgaleal subaponeurotic hemorrhage – anemia shock Forceps Localized bruising Facial palsy Breech position DDH developmental dysplasia of the hip Birth injuries Hypoxic–ischemic encephalopathy Shoulder dystocia Hypoxic–ischemic encephalopathy Erb palsy Fractured clavicle or humerus Meconium Meconium aspiration Need for prolonged resuscitation at delivery Hypoxic–ischemic encephalopathy

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Common problems of term infants 53 Overview of common medical problems Most newborn infants are healthy but may develop some of the clinical problems described below. Differentiating the clinically significant from the transient and benign can be difficult. An approach to these problems is given in Fig. 22.1. For details see specific chapters. Respiratory distress Most common cause – TTNB transient tachypnea of the newborn but need to exclude infection and other causes Check Airway Breathing Circulation Oxygen saturation Give oxygen respiratory and circulatory support as required Admit to neonatal unit Check – complete blood count blood culture C-reactive protein and chest X-ray Start antibiotics Conjunctivitis Sticky eyes – common Clean with sterile water If conjunctivitis purulent or eyelids red and swollen exclude bacterial cause including gonococcus and chlamydia Hypoglycemia Monitor if preterm small or large for gestational age maternal diabetes or ill infant. Clinical features include: • Jitteriness/irritability/high-pitched cry • Depressed consciousness/lethargy/hypotonia • Apnea • Seizures. Apneic attacks The pauses in normal periodic breathing are sometimes misinterpreted as apnea by parents True apnea with desaturation is uncommon in term infants and is a serious symptom infection must be excluded Jitteriness/seizures/lethargy Jittery movements are common. They stop on holding the limb in contrast to seizures. If pronounced check blood glucose and consider other causes e.g. drug withdrawal Seizures can be subtle but are rhythmic jerky movements of the limbs Seizures require prompt treatment and investigation – admit to the neonatal unit Lethargy may be a sign of sepsis hypoglycemia or inborn error of metabolism Collapse rare but important Maintain Airway Breathing Circulation Causes: Sepsis – bacterial or viral Duct-dependent heart disease – closure of ductus arteriosus Inborn error of metabolism Umbilical cord Red are in skin around umbilicus – usually staphylococcal or streptococcal. Give intravenous antibiotics Delay in passing meconium 48 hours Check for intestinal obstruction Delay in voiding urine 24 hours Voiding may be unobserved – often void immediately after birth Consider urinary outow obstruction palpable bladder ultrasound or renal impairment serum creatinine ultrasound Weight loss Babies initially lose weight 1–2 of birth weight per day up to 7–10 of birth weight. They may take up to 10–14 days to regain their birth weight Vomiting Babies often vomit milk. If persistent or bile stained may be from intestinal obstruction. If it contains blood malrotation must be excluded but is usually sallowed maternal blood from maternal cracked nipple or delivery Abdominal distension may be from lower intestinal obstruction Poor feeding Usually related to problems in establishing breast-feeding However can be presentation of: Infection Hypoglycemia Electrolyte disturbance Inborn error of metabolism Cyanotic/dusky spells Normal infants sometimes become dusky or cyanosed around the mouth often during feeds in the rst few days. Conditions which need to be excluded are: Cyanotic congenital heart disease Polycythemia Infection Mucus Many babies produce a considerable amount of mucus on the rst day. This needs to be differentiated from the infant with esophageal atresia who is unable to swallow saliva which pools in the mouth Skin lesions Erythema toxicum or milia – common and harmless Septic lesions – contain pus Bullous impetigo – serious staphylococcal or streptococcal infection. Sacs of serous uid their roof is easily broken leaving denuded skin Fig. 43.4 Sepsis A combination of some of these clinical features: Apnea and bradycardia Slow feeding or vomiting or abdominal distension Fever hypothermia or temperature instability Respiratory distress Irritability lethargy or seizures Jaundice Petechiae or bruising Reduced limb movement bone or joint infection Collapse or shock Hypoglycemia In meningitis late signs: Tense or bulging fontanel Head retraction opisthotonus Management: Admit to neonatal unit Check – complete blood count blood and other cultures C-reactive protein/procalcitonin and chest X-ray Consider lumbar puncture Start antibiotics Provide supportive care Pallor/plethora Check breathing and circulation Check hematocrit for anemia or polycythemia Jaundice Signicant level on transcutaneous monitor Jaundice at 24 hours of age Check bilirubin on blood sample if: Fig. 22.1 Common medical problems of term infants in the first few days of life.

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Neonatology at a Glance Third Edition. Edited by Tom Lissauer Avroy A. Fanaroff Lawrence Miall and Jonathan Fanaroff. © 2016 John Wiley Sons Ltd. Published 2016 by John Wiley Sons Ltd. 54 The sick newborn infant Newborn infants should not be separated from their mothers unless it is essential for their well‐being. Additional nursing and medical care can be provided on postpartum postnatal wards or by providing continuing transitional care facilities beside their mother. However 6–10 of newborn infants are admitted to a neo- natal unit and 1–2 require intensive care. Families often find neonatal units daunting and frightening. The environment is unfamiliar and their small and fragile baby is sur- rounded by high‐tech equipment. There are large numbers of highly skilled nurses doctors and other health professionals caring for their baby and parents and families often feel superfluous as they are unable to help and care for their baby. Much can be done for parents and families to avoid these difficulties or help them cope with them. If premature delivery or other reason for admission is antici- pated arrangements should be made for the parents to visit the neonatal unit and meet the neonatal team before the birth. Welcoming parents and families •  Parents and families should always be made welcome by staff however busy they are. •  Parents should be shown around to make sure they know what facilities are available for them e.g. where they can rest prepare food and drink make phone calls use the internet. •  Ask them how they would like to be addressed and call them by name. •  Always make sure you use the correct gender and name when talking about the baby. Open access •  Open visiting policy for parents Fig. 23.1 and ability to exchange information 24 hours per day. Mothers should be transported to be near their baby. •  Visits by grandparents Fig. 23.2 and close family members who are part of the parents’ support network as well as supervised sibling visits Fig. 23.3 should be encouraged. Explanation and facilitating communication •  Explain the infant’s medical condition and equipment. Provide written information. •  Check with parents how they think their baby is doing and deter- mine their level of understanding about their infant’s condition and care. Correct misconceptions. Listen to the parents. Use interpreters if necessary. •  Arrange privacy for more detailed discussions. Parents appreciate respect for personal values and being involved in decision‐making as appropriate. •  Assist the family to experience their new baby as a little person by visualizing the infant beyond the tubes and devices. •  Utilize other professionals e.g. counselors social workers. They may also provide helpful liaison between the neonatal intensive care unit NICU team and family as they may be perceived by the family as being less threatening than health‐care professionals. •  The primary nurse who is responsible for that baby can facili- tate identification of areas of concern and organize discharge. •  Arrange care conferences with the family including all subspe- cialists involved in the care of infants with complex problems. These meetings are invaluable in keeping the family up‐to‐date and planning for discharge and subsequent care. •  Make sure that fathers do not miss out on communications. • Listen and aknowledge parents when they express concerns about changes in their baby’s behavior. Admission to the neonatal unit 23 Fig. 23.1 Encourage parents to visit at any time. Fig. 23.2 Grandparents on the neonatal unit visiting the latest additions to their family. Fig. 23.3 Supervised sibling visits should be encouraged.

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Admission to the neonatal unit 55 Assisting attachment •  Give the mother the opportunity to touch and hold her baby in delivery room if at all possible. •  Explain the value of breast milk and encourage the mother to express breast milk if the baby cannot be nursed at the breast. This enables her to make a unique contribution to her baby’s care. Success depends on support and encouragement by staff. •  Encourage parents to touch their baby Fig. 23.4 even if on a ventilator the parents can soothe their baby. Like all new parents the parents of premature infants need time to watch their baby to learn their ways of responding. • Encourage parents to actively participate in their infant’s care Fig. 23.5. From the beginning parents can provide comfort and begin to take part in caregiving e.g. with mouth care and tube feeds. When the baby is stable enough parents may hold their baby during feeding Fig.  23.6 and provide kangaroo care Fig.  23.7a and b. Individualized nursing plans address the baby’s behavioral and environmental needs and may reduce morbidity and length of stay see Chapter 24. •  Encourage parents to keep a diary or journal and to collect mementos. Refer to the baby by name. Ensure the family has or is provided with good quality photos of their baby. Enable parents to personalize the incubator or crib cot with family pictures religious texts etc. Fig.  23.8. Providing a family‐friendly environment •  Make appearance of the unit as family‐friendly as possible. •  Provide space and facilities for parents and families to have some privacy with their baby. •  Try to create a quiet calm environment with soft lighting •  Provide facilities for families to relax near but separate from the bedside with play area for siblings. •  Provide rooms for parents to stay overnight. This is particularly important if their infant is critically ill or prior to discharge. Fig. 23.4 Mother touching her baby after the baby was stabilized in the neonatal unit. Fig. 23.5 Mother gavage tube feeding her ill baby. Parents also need to feel comfortable to watch their baby for as long as they like. Fig. 23.8 Parents may like to add personal touches to their baby’s bed with toys and in this case flags to represent the baby’s home country. a b Fig. 23.7 a and b Kangaroo care with direct skin‐to‐skin contact with parent. In many developing countries continuous kangaroo mother care is used for stable preterm babies instead of incubator care mortality is lower than with incubator care and it promotes breast‐feeding and attachment. Fig. 23.6 Mother gavage tube feeding her baby. One of many activities that give mother and baby an opportunity to get to know each other.

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Neonatology at a Glance Third Edition. Edited by Tom Lissauer Avroy A. Fanaroff Lawrence Miall and Jonathan Fanaroff. © 2016 John Wiley Sons Ltd. Published 2016 by John Wiley Sons Ltd. 56 The sick newborn infant Developmental care complements high‐tech medical and nursing care with strategies that reduce stress and promote the development of infants in NICU. Some of these strategies are of general benefit to all infants e.g. adapting the nursery environment and require under­ standing and commitment rather than skill. Others are individualized to suit the condition stage of development and characteristics of the infant these depend on professionals and parents understanding infant behavioral cues. Observing newborn behavior Babies tell us how they are coping by their behavioral cues. These include physiological signs e.g. color changes breathing pattern heart rate and blood oxygen motor signs e.g. muscle tone smooth­ ness of movements pattern of movement and posture signs of state organization e.g. level of arousal quality of sleep and alertness and capacity to pay attention. There are many different behavioral patterns that are helpful in understanding when a baby is comfort­ able and ready to interact approach cues or uncomfortable and needing rest or support avoidance cues Table 24.1. These observations take into account the context in which pat­ terns of behavior occur helping us to adjust the infant’s experience and challenges to fit current developmental needs. The nursery environment Preterm infants are not ready to deal with bright light loud mechanical noises hard surfaces drafts being moved through space and frequent sleep disruption. These experiences can be modified e.g. ambient lighting can often be safely reduced and shade can be provided with incubator covers and crib cot canopies Fig. 24.4 noise can be reduced with acoustic engineering by lowering the volume of alarms and encouraging staff to work and talk quietly nesting and soft bedding can be used to support the baby in a comfortable position Fig. 24.5. Adapting care All caregiving activities and procedures can be adapted to make them go smoothly and provide opportunities for communication Fig. 24.6. Infants in intensive care are frequently disturbed for Developmental care 24 Table 24.1 Behavioral observation. Approach behavior Avoidance behavior Autonomic Regular gentle breathing Breathing irregular fast labored Healthy pink coloring Pale dusky flushed or mottled Comfortable digestion Straining gagging vomiting Motor Smooth varied movement Jerky disorganized movement Softly flexed posture Extended Fig. 24.1b or flat posture Modulated muscle tone Flaccid or stiff tone State Restful sleep Restless sleep Attention Sustained focused alertness Fig. 24.1a Glazed strained hyperalert look Self‐regulation Self‐calming Inconsolable Socially responsive Shut down a b Fig. 24.1 a This baby’s controlled posture and focused expression show successful self‐regulation and readiness for interaction i.e. approach behavior. b Extended limbs and turning away suggest avoidance behavior. Parent participation Developmental care can help parents to tune into their baby’s behavior laying the foundations for a secure attachment relation­ ship the basis of healthy emotional and social development. Parents are the baby’s most consistent and dedicated carers and even in intensive care they can be involved e.g. by placing a finger in the palm of the baby’s hand or comforting their baby by cra­ dling with still hands Wherever possible plan the baby’s day with parents to make opportunities to participate Fig. 24.2. Share with parents observations about how their baby reacts to sounds touch and movement to build up a picture of each infant’s individual characteristics and preferences Fig. 24.3. Close physical contact including skin to skin ‘kangaroo care’ helps parents to enjoy loving contact with their baby and grow in confidence. Fig. 24.2 Promotion of parental attachment by involvement with their baby’s care. Fig. 24.3 Promotion of parental attachment through touch.

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Developmental care 57 nursing observations examinations diaper nappy changes blood and other tests giving medications etc. Procedures can often be performed together to minimize disturbing a sleeping baby even if this means being flexible about timing routine observations and care or when to perform tests and therapy. Very sensitive babies may find this too challenging and will need periods of rest between procedures. A soft spoken greeting with gentle touch helps the baby to adjust at the start. Timing and pacing of procedures can be adjusted according to the behavioral cues that show when the baby needs time out to rest and recover. Ask parents or a colleague to soothe a sensitive or agitated baby. Wrap the baby when moving through space e.g. for weighing or bathing Fig. 24.7. Try posi­ tioning the baby on the side for procedures and diaper nappy change. Give the baby opportunities to steady him or herself by grasping your finger sucking a pacifier or pressing feet against the nest wall. Fig. 24.4 Incubator covered to shade the baby. A flap always folded back so that the baby can be observed. Fig. 24.6 Many activities can be done with the baby lying on one side to give more control of movement – lying quietly and calmly with legs folded in one hand holding onto his head and the other grasping the pacifier which he is sucking. Fig. 24.5 Soft bedding with supportive nesting can contain disorganized movement and provide the baby with comforting boundaries. Fig. 24.7 Help sensitive infants to find bathing pleasurable by loosely wrapping in a towel. Questions What is the Newborn Behavioral Assessment Scale NBAS A neurobehavioral assessment suitable for infants from term to 2 months. It reveals infant maturity and individuality with a series of maneuvers designed to test habituation orientation to visual and auditory stimuli state regulation motor maturity and reflex responses. The baby’s reactions to increasingly demanding activities are noted. The examiner must be skillful in eliciting the baby’s best response as well as in scoring the assessment. It enables parents and professionals to enhance the parent–infant relationship and promote the baby’s capacity for self‐regulation. The Assessment of Preterm Infant Behaviour APIB is an adap­ tation of the NBAS to give a detailed description of preterm infant development. The Newborn Behavioral Observation NBO is a recent shorter version. What is NIDCAP ® This is the Newborn Individualized Developmental Care and Assessment Program. Promotes preterm and newborn devel opment using strategies based on systematic behavioral observation and understanding of fetal preterm and newborn neurodevelopment. These strategies are individualized to fit each infant’s current needs and to support family participation.

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Neonatology at a Glance Third Edition. Edited by Tom Lissauer Avroy A. Fanaroff Lawrence Miall and Jonathan Fanaroff. © 2016 John Wiley Sons Ltd. Published 2016 by John Wiley Sons Ltd. 58 The sick newborn infant Seriously ill newborn or extremely preterm infants need to be stabilized following resuscitation in the delivery room Fig. 25.1. Stabilizing the sick newborn infant 25 Central nervous system Examination: Response to handling Posture Movements Tone Reexes Monitoring Oxygen saturation Heart rate Respiratory rate Apnea 20 seconds Temperature – peripheral and central if ill Blood pressure Blood glucose Blood gases Weight Transcutaneous O 2 and CO 2 —used in some centers Antibiotics Usually given before results of cultures and other investigations are available although most infants are not septic Pain/sedation Analgesia and sedation given according to assessment of need e.g. painful procedures arti‡cial ventilation Blood pressure Circulation Examination: Heart rate pulses capillary re‡ll time skin color and temperature Treat shock—see facing page Venous and arterial lines Peripheral intravenous line: R equired for intravenous uids glucose antibiotics other drugs Umbilical venous catheter: S ometimes used for immediate intravenous access or for CVP central venous pressure monitoring or obtaining blood samples or administration of uid or medications. Some centers use multilumen catheters to avoid the need for peripheral IV lines Arterial line: Inserted if frequent blood gas analysis blood tests and continuous blood pressure monitoring is required. Usually umbilical artery catheter UAC sometimes peripheral cannula if for short period or no umbilical artery catheter possible Central venous line for parenteral nutrition: Inserted peripherally when infant is stable and parenteral nutrition Investigations Hemoglobin/hematocrit Neutrophil count Platelets Blood urea nitrogen urea creatinine Electrolytes Culture—blood CSF urine if indicated Blood glucose CRP/acute phase reactant Surface cultures if indicated Coagulation screen if indicated X-rays Chest X-ray +/– abdominal X-ray assist in identifying cause of respiratory distress position of tracheal tube and central lines Ensure gavage nasogastric tube is placed prior to CXR to rule out esophageal atresia. Airway Breathing Assess for respiratory distress: Tachypnea 60 breaths/min Chest retractions Expiratory grunting nasal aring Cyanosis Respiratory support as required: Clear the airway/oxygen/CPAP/high-ow nasal therapy/ mechanical ventilation Vitamin K Routine prophylaxis against vitamin K de“ciency bleeding hemorrhagic disease of the newborn if not already given Parents Time needs to be found to explain to parents and immediate relatives what is happening. If the mother cannot see the baby e.g. following cesarean section or severe hypertension photographs or videos are reassuring Advise mother of bene“ts of early breast milk expression and ensure given practical advice and support Surfactant Given to preterm infants with respiratory distress syndrome needing respiratory support or as prophylaxis in extremely preterm infants according to unit policy Temperature control To keep the infant warm stabilization is performed under a radiant warmer or in an incubator Exothermic mattress may be helpful Aim for 36.5–37.5°C Team of health professionals each with clearly de“ned roles is required Multidisciplinary team Fig. 25.1 Stabilization in the neonatal unit. Heart rate What information can be obtained by monitoring heart rate Table 25.1 Interpreting the heart rate is best done in conjunction with respiratory rate and oxygen saturation. Episodes of apparent desaturation are mostly transient. They may be caused by movement artifact but if more severe and prolonged will be accompanied by bradycardia and require prompt attention. Circulation How is the need for circulatory support determined Difficult but features of circulatory impairment are: •  Heart rate – usually tachycardia bradycardia is a late sign. Table 25.1 Some causes of isolated changes in heart rate. Increased heart rate 160 beats/min Movement/crying Respiratory distress Hypovolemia Fever infection Pain Fluid overload e.g. heart failure patent ductus arteriosus Supraventricular tachycardia or other tachyarrhythmias Anemia Thyrotoxicosis Inotropes Iatrogenic hyperthermia Artifact Decreased heart rate 100 beats/min Apnea hypoxia Seizures Shock uncompensated Heart block arrhythmia Raised intracranial pressure Hypothermia therapeutic or environmental Artifact

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Stabilizing the sick newborn infant 59 •  Central – peripheral ‘toe−core’ temperature difference 2 °C. Can also be caused by a cold environment. •  Capillary refill time − prolonged if 3 seconds. •  Metabolic acidosis increased lactate levels. •  Oliguria. •  Echocardiography – used to help identify low cardiac output secondary to cardiac underfilling suggesting hypovolemia and/or poor contractility from myocardial dysfunction see Chapter 82 Echocardiography for the neonatologist. •  Chest X‐ray – cardiovascular function may be compromised by overinflation of lungs or high mean airway pressure on mechanical ventilation especially high frequency obstructing venous return to both the right and left atrium. •  Blood pressure ideally invasive. After 1 hour of age hypotension often defined by mean blood pressure mmHg persistently below the baby’s gestational age completed weeks. However a large PDA patent ductus arteriosus can lead to a low mean blood pressure due to low diastolic pressure. Management of shock is directed at the underlying cause wherever possible Fig. 25.2. Fluid resuscitation with or without inotropic support may be needed Fig. 25.3 and Table 25.2. Treatment thresholds and management of hypotension or circulatory impairment without shock are uncertain. CAUSES OF SHOCK Cardiac injury secondary to hypoxia–ischemia Hypoxia–ischemia Sepsis Arrhythmia Inborn error of metabolism Congenital heart disease Tension pneumothorax Pneumopericardium/ pericardial effusion Congenital diaphragmatic hernia Impaired cardiac output from mechanical obstruction Acidosis-mediated impairment of cardiac contractility Peripheral vasodilatation and capillary leak Impaired cardiac contractility Duct-dependent lesions e.g. hypoplastic left heart Obstructive left-sided lesions e.g. critical aortic stenosis Total anomalous pulmonary venous drainage Cardiomyopathy Lung overination due to excessive mean airway pressure on mechanical ventilation Abdominal distension e.g. NEC Hypovolemia Blood loss fetomaternal bleed placental abruption ruptured vasa-previa subgaleal aponeurotic hemorrhage Necrotizing enterocolitis NEC intestinal obstruction Fig. 25.2 Causes of shock. Hypovolemia Volume support: Normal saline 10 mL/kg aliquots or blood if anemic or blood loss Myocardial dysfunction Inotropes: Dopamine – increase dose if no response Dobutamine – reserved for pure myocardial dysfunction No response No response Consider corticosteroids Consider other inotropes Epinephrine adrenaline and/or norepinephrine Milrinone Fig. 25.3 Circulatory support. This differs between centers. Table 25.2 Inotropes. Inotrope Pharmacology Main effect Dopamine D1 D2 β 1 β 2 agonist Increases contractility and SVR. Increases BP but may not increase cardiac output Dobutamine β 1 agonist Increases heart rate and contractility without affecting SVR. May improve cardiac output Norepinephrine noradrenaline α 1 α 2 β 1 agonist Mainly increases SVR by vasoconstriction Epinephrine α 1 α 2 β 123 agonist Mainly increases SVR by vasoconstriction Milrinone Phosphodiesterase‐ III inhibitor‐ increases cAMP Increased contractility and vasodilatation reduces afterload. Little research Hydrocortisone Unknown mechanism Proven inotrope and vasopressor sparing effect SVR − Systemic vascular resistance.

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Neonatology at a Glance Third Edition. Edited by Tom Lissauer Avroy A. Fanaroff Lawrence Miall and Jonathan Fanaroff. © 2016 John Wiley Sons Ltd. Published 2016 by John Wiley Sons Ltd. 60 The sick newborn infant Forms of respiratory support Respiratory support includes: •  supplemental oxygen •  CPAP – continuous positive airway pressure •  high‐flow nasal therapy HFNT/high‐flow nasal cannulae HFNC •  non‐invasive mechanical ventilation NIMV/NIPPV •  positive‐pressure ventilation PPV •  HFOV – high‐frequency oscillatory ventilation •  iNO – inhaled nitric oxide •  ECMO – extracorporeal membrane oxygenation. The approach to respiratory support is continually evolving and new strategies and modes of support are being introduced. Whilst aiming to maintain adequate gas exchange there is an emphasis on minimizing the risk of ventilator‐induced lung injury . Hyperinflation from high pressures volutrauma and repeated opening and closing of alveoli atelectotrauma may cause lung damage. Non‐ invasive respiratory support which includes CPAP high‐flow nasal therapy and non‐invasive mechanical ventilation with or without surfactant therapy in preterm infants are used increasingly either as the primary mode of support or following extubation to avoid reintubation Fig 26.1. Positive‐pressure ventilation is required for infants with significant respiratory distress that cannot be managed with non‐invasive respiratory support some of the newer approaches are described in this chapter. Supplemental oxygen therapy Oxygen is given to prevent hypoxia Fig. 26.2 which may cause ischemic damage to the brain and other organs apnea and pulmonary hypertension. Hyperoxia should also be avoided as elevated levels of oxygen in the blood may cause tissue damage due to the release of oxygen free radicals and retinopathy of prematurity in preterm infants. The optimal values for arterial oxygen tension and saturation have not been established but in practice: •  In preterm infants arterial oxygen tension PaO 2 is maintained at 45–80 mmHg 6.0–10.5 kPa and oxygen saturation at 91–95. Lower saturations are associated with less retinopathy of prematurity but increased mortality. Saturation above 95 in infants receiving supplemental oxygen may represent dangerously high oxygen tensions Fig. 26.3. •  Term infants – maintain oxygen saturation at 95−99 and PaO 2 between 60–80 mmHg 8–10.5 kPa. Respiratory support 26 1991 1994 70 80 Conventional ventilation Surfactant Nasal CPAP High ow nasal cannula Postnatal steroids HFOV Nasal ventilation 30 60 40 10 50 20 0 Respiratory interventions 2004 2008 1999 Fig. 26.1 Changes in use of respiratory interventions in VLBW very low birthweight infants with time. Vermont−Oxford Network data from Soll R.F. et al. Obstetric and neonatal care practices for infants 501−1500 g from 2000 to 2009. Pediatrics 2013 132: 222−228 and Dr Jeff Horbar. Fig. 26.2 Oxygen delivered via nasal cannula. PO 2 mmHg 40 60 80 100 Neonatal blood 20 0 20 040 Oxygen saturation 60 100 80 PO 2 kPa 2.5 0 5.0 7.510 12.5 A saturation 95 may represent any value of PO 2 80 mmHg 10.5 kPa Fig. 26.3 Saturation measurements above 95 in preterm infants receiving supplemental oxygen may represent dangerously high oxygen tensions.

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Respiratory support 61 Continuous positive airway pressure CPAP Distending pressure is usually applied via nasal prongs Fig. 26.4 in the nasal airway or by a close‐fitting nasal mask. CPAP aims to prevent alveolar collapse at end expiration stabilize the chest wall and reduce the work of breathing. It also allows supplemental oxygen to be delivered continuously. It is used for infants with moderate respiratory distress and for recurrent apnea. There is increasing use of early CPAP as respiratory support immediately after birth even for very preterm infants with mechanical ventilation used only as rescue. CPAP may also facilitate weaning from mechanical ventila- tion. Larger infants may not tolerate CPAP well. CPAP may be delivered as: •  bubble CPAP – the pressure is determined using a water manometer •  flow‐driver CPAP – the flow driver provides a constant stream of air/oxygen special nasal prongs maintain a constant pressure throughout the infant’s respiratory cycle by changing the direction of gas flow during expiration fluidic flip. A pressure of 6−8 cmH 2 O is used and there needs to be minimal air leak around the nasal prongs or mask. Complications of CPAP are: •  pneumothorax •  feeding difficulties due to gaseous distension of the stomach •  nasal trauma causing nasal septum breakdown or erosion and nasal deformity minimized by correct size and fixation of prongs or mask. If respiratory failure develops mechanical ventilation is required. CPAP can be stopped abruptly or weaned by gradually reducing the PEEP or increasing the period of time off CPAP. The limited evidence suggests that gradually weaning pressure is superior and reduces length of stay. If weaned too quickly there may respiratory deterioration or poor growth. Some infants with bronchopulmonary dysplasia require nasal CPAP for many weeks. High‐flow nasal therapy Increasingly used as an alternative for CPAP or to wean off venti- lators or CPAP. Warmed humidified oxygen/air is delivered at a high flow rate 2 L/min via nasal cannulae. It probably gener- ates some distending pressure to the lungs but works mainly by flushing CO 2 from the nasopharynx. Babies especially when more mature tolerate it better than CPAP. In contrast to CPAP there is leakage of gases around loose- fitting cannulae. Its efficacy as a mode of support compared with CPAP is being evaluated for weaning infants off mechanical ventilation it appears to have sim- ilar efficacy to CPAP with less nasal trauma. Non‐Invasive Mechanical Ventilation NIMV The terms NIMV non‐invasive mechanical ventilation or nasal intermittent mandatory ventilation and NIPPV nasal intermittent positive pressure ventilation are used interchangeably for positive‐ pressure respiratory support without the use of a tracheal tube. It is gaining popularity as a primary means of respiratory support and also after extubation to prevent reintubation. Whereas CPAP provides only continuous positive airway pressure NIMV also delivers intermittent peak inspiratory pressure either mandatory or triggered via rigid nasal prongs. This is postu- lated to provide better oxygenation and CO 2 removal than CPAP. There is currently no convincing evidence that it is better than CPAP in preventing reintubation or bronchopulmonary dysplasia in preterm infants. Positive‐pressure ventilation PPV Indications •  Increasing oxygen requirement or work of breathing or increasing PaCO 2 while on nasal CPAP/HFNT. •  Respiratory failure – inadequate oxygenation hypoxia and/or CO 2 elimination hypercarbia. •  Apnea – prolonged/recurrent. •  Upper airway obstruction or vocal cord paralysis. •  Congenital diaphragmatic hernia. •  Perioperative respiratory support for anesthesia. •  Circulatory failure. Intermittent positive‐pressure ventilation IPPV Respiratory support is administered using a mechanical ventilator through a tracheal tube. With conventional ventilation intermittent positive‐pressure ventilator breaths are given on a background of continuous distending pressure positive end‐expiratory pressure PEEP Fig. 26.5. Alveolar ventilation CO 2 clearance is deter- mined by the difference between peak inspiratory pressure PIP and PEEP and the respiratory rate. Oxygenation is determined by the mean airway pressure area under the curve and adminis- tered oxygen concentration FiO2. Conventional ventilation is pressure limited and time cycled. Peak inspiratory pressure is set by the operator and tidal volume varies from breath to breath depending upon lung compliance and airway resis- tance. This may increase the risk of volutrauma and atelectotrauma. Volume‐limited or targeted ventilation is increasingly used. In volume-limited ventilation instead of setting the desired peak inspi- ratory pressure a maximum tidal volume is set limited by the Fig. 26.4 Nasal CPAP continuous positive airway pressure with flow driver that maintains a constant pressure by changing the direction of gas flow during expiration fluidic flip.

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62 The sick newborn infant operator so that the peak inspiratory pressure generated will only rise to meet the desired volume. In volume-targeted ventilation a desired tidal volume is set targeted and the peak inspiratory pressure will automatically adjust to achieve the desired tidal volume. Tidal volumes are usually 4−6 mL/kg the normal tidal volume of neonates but higher volumes may be required by infants with bronchopulmonary dysplasia and lower volumes with lung hypoplasia. This mode of ventilation is particularly useful when lung compliance is changing rapidly e.g. rapid improvement of compli- ance after surfactant administration when the ventilator will be able to deliver the desired tidal volume using lower pressures reducing the risk of an air leak. It is less useful if there is a large leak around the tracheal tube 40. Advances in ventilator technology allow the measurement and delivery of small tidal volumes which was not previously possible. Studies suggest that there may be a decreased risk of pneumothorax and bronchopulmonary dysplasia compared with pressure‐limited ventilation. Key points In the presence of marked chest retractions provide respiratory support including mechanical ventilation if necessary even if the blood gases are normal. Evidence of respiratory failure on blood gases is a late feature. Question How are the settings of conventional ventilators adjusted Monitoring Continuous oxygen saturation vital signs regular blood gases transcutaneous PaO 2 and PaCO 2 if available – to identify acute changes in infant’s condition. Target arterial blood gases •  PaO 2 : 45–80 mmHg 6–10.5 kPa •  PaCO 2 : 40−65 mmHg 5−8.5 kPa •  pH: 7.20–7.4. Abnormal blood gases Check: •  Infant – for satisfactory chest wall movement bilateral air entry exclude pneumothorax transilluminate chest if necessary check airway patency and ventilator functioning correctly. •  Breathing and circulation – adjust ventilator settings if necessary. Consider rechecking blood gases 30−60 minutes after changing settings or if there has been a change in the infant’s condition. Oxygen To increase oxygenation options are: •  increase inspired oxygen concentration •  increase mean airway pressure – increase PIP PEEP or inspi- ratory time or flow Fig. 26.5. Consider surfactant therapy or HFOV high‐frequency oscillation. Carbon dioxide •  Keep PaCO 2 in normal range during first 72 h in preterms – to keep cerebral blood flow stable during time of maximum risk of intraventricular hemorrhage. Thereafter allow somewhat higher levels of PaCO 2 permissive hypercapnia to minimize ventilator‐ induced lung injury but keep pH above 7.20. •  Avoid low PaCO 2 40 mmHg 5 kPa as this lowers cerebral blood flow and is associated with ischemic brain injury periven- tricular leukomalacia. To reduce PaCO 2 : •  increase ventilator rate but allow sufficient expiratory time for carbon dioxide removal •  increase breath size – increase PIP or reduce PEEP. Consider if tracheal tube is blocked suction or replace if necessary or if excessive dead space in circuit. Metabolic acidosis In extremely preterm infants this may be due to: •  circulatory hypoperfusion •  hypoxemia •  urinary loss of bicarbonate alkaline urine •  anemia •  parenteral nutrition •  acute kidney injury renal failure Ventilation strategy When adjusting ventilator aim to minimize ventilator‐induced lung injury inflammation air leaks by: • using lowest PIP to reduce volutrauma and adequate PEEP to reduce atelectotrauma. Aim to synchronize ventilator with the infant’s breathing – can use patient‐triggered ventilation PTV or synchronous intermittent mandatory ventilation SIMV sedation analgesia and occasionally muscle relaxants. Oxygenation MAP Airway pressure Time PEEP PIP MAP T i 0 Fig. 26.5 Intermittent positive‐pressure ventilation IPPV. Diagram of change in airway pressure with time. PIP – peak inspiratory pressure PEEP – positive end‐expiratory pressure Ti – inspiratory time MAP – mean airway pressure.

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Respiratory support 63 Question How do ventilator graphics assist ventilator management Increasingly ventilators display breath‐by‐breath measure- ments of pressure flow and volume that can help to monitor lung physiology and individualize mechanical support. Pressure−volume loop Fig. 26.6 Recognizing problems: •  As airway resistance increases the loop widens e.g. blocked ETT. •  As compliance decreases the loop gradient flattens e.g. RDS. •  In overdistension the curve flattens or ‘beaks’ at the end of expiration. •  If the expiratory part of the loop does not return to baseline it suggests there is a leak. Pressure‐time waveform − pressure modes Fig. 26.7 •  Pressure increases rapidly from the level of PEEP until it reaches the level of PIP then remains constant for the inspiratory time. •  Expiration is a passive process and pressure decreases gradu- ally until it reaches the level of PEEP before the next breath. • The waveform is not affected by changes in resistance or compliance. •  The area under the curve represents the mean airway pressure MAP. •  There is a negative deflection just before the inspiratory part of the waveform with patient‐triggered breaths. •  The higher the flow rate the squarer is the waveform increases MAP. Pressure−time waveform − volume modes Fig. 26.8 The waveform is affected by changes in resistance and com- pliance because pressure is variable. At the beginning of inspiration the ventilator generates pressure P res to overcome airway resistance and no volume is delivered. Then pressure increases until the PIP is reached and the gradient depends on compliance. When the set tidal volume is delivered the pressure quickly falls to a plateau pressure before passive expiration. Recognizing problems: •  Increased resistance leads to higher P res . •  Decreased compliance leads to increased PIP. Fig. 26.7 Pressure−time waveform with pressure mode. Pressure Time Inspiration Expiration PEEP PIP 0 Volume Airway pressure Inspiration Expiration PEEP PIP Above this pressure upper inection point there is little change in volume - overdistension Below this pressure lower inection point there is little change in volume - atelectasis Optimal ventilation occurs at pressures between the inection points Hysteresis describes the higher pressure at any given volume during inspiration compared to expiration Tidal volume 0 Fig. 26.6 Pressure−volume loop. Fig. 26.8 Pressure−time waveform with volume modes. Pressure Time Inspiration Expiration PEEP PIP P res 0

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64 The sick newborn infant Patient‐triggered ventilation PTV and synchronous intermittent mandatory ventilation SIMV Two forms of synchronized mechanical ventilation are available to promote synchrony between the ventilator and an infant’s own respiratory efforts – patient‐triggered ventilation PTV and synchro nous intermittent mandatory ventilation SIMV. Both methods use the infant’s own spontaneous respiration to trigger the ventilator to deliver a breath usually from the change in airway pressure or flow measured in the ventilator circuit or from a recording of the infant’s respiration. In patient‐triggered ventilation also called assist control AC or spontaneous inter- mittent positive‐pressure ventilation SIPPV each breath is sup- ported by the ventilator in SIMV only a preset number of breaths in a given time is supported by the ventilator and other breaths are unsupported. In both there is a backup ventilation rate if the infant does not breathe. High‐frequency oscillatory ventilation HFOV High‐frequency ventilators operate at frequencies approximately 10 times greater than conventional ventilators and can achieve good gas exchange despite using tidal volumes smaller than dead space Fig. 26.11. The rationale for using high‐frequency ventilation is to recruit collapsed alveoli ‘open’ the lung and minimize venti- lator‐induced lung damage. The mechanism of gas exchange is unclear but may include facilitated diffusion and turbulence. Rescue treatment with high‐frequency ventilation in term and pre- term infants with severe respiratory failure is associated with short‐ term improvement in gas exchange especially when used in combination with inhaled nitric oxide. Some units choose to venti- late all their extremely preterm infants by HFOV to minimize baro- trauma. Studies have failed to show a decrease in duration of Question What are the causes of deterioration of a ventilated infant Sudden deterioration acronym DOPE: •  Displaced tracheal tube. •  Obstructed tracheal tube e.g. secretions blood. •  Pneumothorax or pneumomediastinum air leaks. •  Equipment failure e.g. ventilator circuit disconnected. Slow deterioration: •  Increased lung secretions. •  Infection. •  Patent ductus arteriosus. •  Anemia. •  Developing bronchopulmonary dysplasia. HFOV Airway pressure Time MAP Amplitude Frequency Fig. 26.11 High ‐ frequency oscillatory ventilation HFOV. Diagram showing changes in airway pressure with time. MAP – mean airway pressure. Flow−time waveform •  The area underneath the flow curve represents the transferred volume. • In pressure modes the waveform is a slope because flow decreases when PIP is reached Fig. 26.9. •  In volume modes the waveform is square because flow remains constant during inspiration Fig. 26.10. •  If the waveform does not return to baseline before the next breath there may be a leak or air trapping. Fig. 26.9 Flow‐time waveform in pressure mode. Flow Time Inspiration Expiration 0 0 Expiration Inspiration Flow Time Inspiration Expiration 0 0 Expiration Inspiration Fig. 26.10 Flow‐time waveform in volume mode.

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Respiratory support 65 ventilation incidence of bronchopulmonary dysplasia mortality or need for extracorporeal membrane oxygenation ECMO com- pared with conventional ventilation. Inhaled nitric oxide iNO Inhaled nitric oxide causes selective pulmonary vasodilation. It is used in infants with hypoxemic respiratory failure with or without persistent pulmonary hypertension of the newborn PPHN to improve oxygenation Fig. 26.12. It reduces the need for ECMO in term and near‐term infants with severe respiratory failure. There is increasing evidence that sildenafil is as effective with reduced expense and complexity but is not currently approved in the US for this purpose. The efficacy of inhaled nitric oxide in preterm infants remains to be established. Respiratory failure The severity of hypoxemic respiratory failure can be assessed by calculating the oxygenation index OI: OI meanairway pressure cmHO FiO PaO mmHg 22 2 100 In term infants OI ≥40 is associated with a 40 risk of mortality. In preterm infants OI ≥20 is associated with a 50 risk of mortality. Therapeutic options for respiratory failure if on conventional mechanical ventilation with high pressures and in high concentration of oxygen are: •  extra rescue doses of surfactant •  high‐frequency ventilation •  nitric oxide or sildenafil therapy although sildenafil is not cur- rently approved in the US for this purpose •  ECMO for infants of ≥34 weeks’ gestation. Extracorporeal membrane oxygenation ECMO Infants are placed on heart–lung bypass for up to 2−3 weeks to allow the lungs to recover Figs  26.13 and 3.3. Blood is removed from the circulation oxygenated and then returned to the circulation. It is performed in relatively few specialized cen- ters. Because of the need for anticoagulation and large surgical catheters there is a risk of intraventricular hemorrhage in pre- term infants and it is therefore reserved for infants of ≥34 weeks’ gestation and birthweight 2 kg. Conditions that cause recov- erable respiratory failure which may respond to ECMO are listed in Table 26.1. Indication is an oxygenation index of ≥40 in spite of  optimal mechanical ventilation and circulatory support. Other requirements are 10−14 days’ mechanical ven- tilation no lethal congenital abnormalities and no significant intracranial hemorrhage. The need for ECMO has declined markedly since the introduction of inhaled nitric oxide surfac- tant and HFOV. The most common indication is now congenital diaphragmatic hernia. Table 26.1 Conditions that may require ECMO. •  congenital diaphragmatic hernia •  meconium aspiration syndrome •  persistent pulmonary hypertension of the newborn PPHN •  sepsis •  respiratory distress syndrome RDS •  severe airway obstruction/malformation •  heart disease – congenital or cardiomyopathy O 2 blender CO 2 O 2 Membrane oxygenator Fluids Heparin Venous cannula Heat exchanger Arterial cannula Pump Fig. 26.13 ECMO extracorporeal membrane oxygenation circuit. The infant’s venous blood is pumped through a membrane oxygenator an artificial lung which extracts carbon dioxide and adds oxygen. The blood is returned to the baby into the right carotid artery veno‐arterial ECMO as shown in the diagram. In veno‐venous ECMO blood is removed and returned into the right atrium through a double‐lumen catheter. The lungs continue to be ventilated but at a low resting level. Expiratory limb Inspiratory limb Scavenger Flowmeter NO/N 2 Ventilator NO/NO 2 Monitor Humidier Fig. 26.12 Components in delivery of inhaled nitric oxide. There is a scavenger for removing nitric oxide released into the atmosphere. The blood concentration of methemoglobin a potentially toxic by‐product is checked periodically. Inspired nitrogen dioxide NO 2 levels a by‐product of mixing nitric oxide and oxygen are monitored continuously.

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Neonatology at a Glance Third Edition. Edited by Tom Lissauer Avroy A. Fanaroff Lawrence Miall and Jonathan Fanaroff. © 2016 John Wiley Sons Ltd. Published 2016 by John Wiley Sons Ltd. 66 The preterm infant The preterm infant differs markedly from the term infant in size appearance and development. Some of these differences are shown schematically in Figs 27.1–27.4. Preterm infants and their complications 27 Gestation 23–25 weeks 29–31 weeks37–42 weeks term Birthweight 50th centile At 24 weeks – Female: 620 g Male: 700 g At 30 weeks – Female: 1.4 kg Male: 1.5 kg At 40 weeks – Female: 3.4 kg Male: 3.55 kg Skin Very thin gelatinous Dark red all over body Medium thickness Pink Thick skin with cracking on hands and feet. Pale pink: pink all over ears lips palms and soles Ears Breast Pinna soft no recoil No breast tissue palpable Cartilage to edge of pinna in places recoils readily One or both breast nodules 0.5–1.0 cm Firm pinna cartilage to edge of pinna recoils immediately Genitalia Male: scrotum smooth testes impalpable Female: prominent clitoris. Labia majora widely separated labia minora protruding Male: scrotum – few rugae testes – in inguinal canal Female: labia minora and clitoris partially covered Male: scrotum – rugae testes in scrotum Female: labia minora and clitoris covered Vision Eyelids may be fused or partially open Absent or infrequent eye movements Pupils react to light Looks at faces. Follows faces curvy lines and light/dark contrast in all directions Breathing Needs respiratory support. Apnea common No coordinated sucking Sometimes needs respiratory support. Apnea common Need for respiratory support uncommon. Apnea rare Taste Reacts to bitter taste Differentiates between sweet sour bitter. Prefers sweet Interaction Seldom available for interaction Easily overloaded by sensory stimulation Makes eye contact and alert wakefulness Cry Very faint Loud Sleep/wake cycle Intermediate sleep state Clearly dened sleeping and waking states Feeding Usually need PN parenteral nutrition Gavage nasogastric feeds Sometimes need PN parenteral nutrition At term cries when hungry. Takes full feeds on demand Coordinates breathing sucking and swallowing Sucking and swallowing Coordinated at 32–34 weeks’ gestation Hearing Startles to loud noise Turns head and eyes to sound Prefers speech and mothers voice Posture Flexed smooth limb movements Some exion of legs Extended jerky uncoordinated One or both nodules 1.0 cm Fig. 27.1 Maturational changes in appearance posture and development with age. a b Fig. 27.2 Preterm infant at 23 weeks’ gestation showing thin gelatinous skin and fused eyelids Legs flexed as nested. Tracheal and gavage nasogastric tubes. a b Fig. 27.3 Preterm infant at 30 weeks’ gestation showing medium‐thickness skin and ear with cartilage to edge of pinna. a b Fig. 27.4 Term infant showing flexed posture and thick skin and well‐formed ear.

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Preterm infants and their complications 67 Morbidity Being born preterm has many disadvantages including stress for the parents and family prolonged hospitalization and being extremely expensive. After 30 weeks of gestation most preterm infants in developed countries survive without neurologic or other impairment. However at lower gestational age there is a consider- able complication rate Fig. 27.5. The rate is highly dependent on gestational age. Mortality Mortality is mainly determined by gestational age Fig. 27.6 and birthweight Fig. 27.7. They interact with each other as well as with other risk factors: •  gender males have higher mortality •  ethnicity •  multiple birth increases mortality. There has been a marked improvement in survival in infants born at the limit of viability i.e. 23–25 weeks of gestational age. However mortality morbidity and adverse neurodevelopmental outcome are highest in these infants. This is considered further in Chapters 8 and 72. Short-term complications of prematurity Other complications: Poor weight gain Jaundice Hypothermia Hypoglycemia Electrolyte disturbance Anemia of prematurity Coagulopathy Metabolic bone disease Inguinal hernias Extravasation injuries Intraventricular hemorrhage – 19 Severe Grade III/IV – 8 Cystic periventricular leukomalacia PVL – 2.6 Retinopathy of prematurity ROP severe – 6 Laser treatment – 5 Respiratory distress syndrome/lung immaturity – 70 Ventilation any – 66 Conventional ventilation – 59 High frequency ventilation – 26 Nasal CPAP before tracheal ventilation – 49 Nasal CPAP – 73 High flow nasal cannula – 51 Inhaled nitric oxide – 5 Surfactant therapy – 60 Air leaks – pneumothorax – 3 Bronchopulmonary dysplasia O 2 therapy at 36 weeks – 23 PDA patent ductus arteriosus – 29 treated with indomethacin – 21 treated with ibuprofen – 13 ligation – 5 Infection – 21 Early – 2 Late – 13 Necrotizing enterocolitis NEC – 4 NEC surgery – 3 Other surgery – 7 Fig. 27.5 Short‐term complications of very low birthweight 1.5 kg infants. Percentages are based on Vermont–Oxford Network data for 2013. 60 30 50 20 0 Birthweight g 501– 600 Survival 601– 700 701– 800 801– 900 901– 1000 1001– 1100 1101– 1200 1201– 1300 1301– 1400 1401– 1500 40 100 70 90 80 10 Fig. 27.7 Survival by birthweight of very low birthweight VLBW infants. Overall survival 88. Vermont–Oxford Network 2012. 100 80 2012 40 60 20 0 Gestational age weeks 23 23 24 25 26 27 28 29 30 Survival Fig. 27.6 Survival by gestational age of very low birthweight VLBW infants. Data from over 900 neonatal units from throughout the world. Vermont–Oxford Network 2012.

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Neonatology at a Glance Third Edition. Edited by Tom Lissauer Avroy A. Fanaroff Lawrence Miall and Jonathan Fanaroff. © 2016 John Wiley Sons Ltd. Published 2016 by John Wiley Sons Ltd. 68 The preterm infant Structural development The fetal lung passes through five main stages of lung development during gestation Fig. 28.1. Lung development and surfactant 28 Esophagus Trachea Splanchnic mesoderm Embryonic phase 3–5 weeks a Canalicular phase 17–24 weeks Saccular phase 24 weeks to term Alveolar phase Term c d e Distal airways develop. Epithelial cells subdivide into type I pneumocytes for gas exchange and type II pneumocytes for surfactant production Terminal sacs alveolar ducts and nally alveoli form. Incr easing surfactant production from 23 weeks One f th the number of alveoli of adult. Alveolar multiplication and maturation continues into early childhood Pseudoglandular phase 6–16 weeks The respiratory bud arises from the ventral surface of the foregut Bronchial tree from trachea to terminal bronchioles are formed. Pulmonary arterial and venous systems develop b Left superior lobe Left inferior lobe Right superior lobe Right middle lobe Right inferior lobe Respiratory bronchiole Terminal bronchiole Terminal bronchiole Terminal sac Squamous epithelium Alveoli Fig. 28.1 Phases of lung development. Physiology and composition of surfactant Figs 28.2–28.4 a b Fig. 28.2 a It is hard to blow up a balloon that is collapsed small radius. Surfactant‐ deficient lungs are like this. b It is easier to blow up once the balloon is partially filled with air larger radius. Lungs with surfactant are like this. P P r r T T The pressure P required to open an alveolus depends on: i its radius r ii the surface tension T within it Laplace equation P 2T r Fig. 28.3 In the absence of surfactant the pressure at the surface of the alveolus is greater in the smaller than in the larger alveolus so the small alveoli collapse and the large ones expand. Surfactant lowers the surface tension T and prevents alveolar collapse. Saturated phosphatidylcholine Other phospholipids Phosphatidylglycerol Surfactant proteins SP-A SP-B SP-C SP-D Unsaturated phosphatidylcholine Neutral lipids 8 8 6 50 8 20 Fig. 28.4 Composition of surfactant.

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Lung development and surfactant 69 Surfactant Surfactant: •  Is a naturally occurring substance containing lipids 90 and proteins 10. •  Is synthesized in type II pneumocytes in the lung and released onto the alveolar surface. •  Lowers surface tension at the air–water interface in the alveolus through the action of its lipid components mainly dipalmitoylphos- phatidylcholine DPPC. •  Production starts late in the second trimester and early third trimester. •  Deficiency causes respiratory distress syndrome RDS. Clinical implications of surfactant deficiency In surfactant deficiency the lung has low compliance i.e. is stiff so the change in lung volume for a given change in airway pressure is much less than in the normal healthy newborn lung Fig. 28.5. The pressure required to initiate lung inflation ‘opening pressure’ is also higher. Without surfactant the lung alveoli collapse during expiration and the next breath starts from a low lung volume. These changes result in increased work of breathing and hypoxemia Fig. 28.6. Antenatal corticosteroids Corticosteroids promote surfactant synthesis and lung maturation. Recommended for preterm labor at 24–34 weeks and to be consid- ered at earlier gestations see Chapter 67. Surfactant therapy Surfactant therapy is administered directly into the lungs. There are two types of surfactant: •  natural surfactants – made from animal lung extracts: porcine – poractant alfa Curosurf ® calf – beractant Survanta ® . •  synthetic surfactants – available but not widely used. Aerosolized surfactant development is at an advanced stage. Preterm infants are given surfactant to either prevent or treat RDS. The strategies used are: •  prophylactic surfactant – elective intubation and surfactant given in the first few minutes after birth irrespective of the presence or absence of respiratory distress. •  rescue surfactant therapy – once the baby develops significant RDS. Once surfactant has been administered it becomes incorporated into an endogenous pool that is recycled within the pneumocytes. Occasionally a second dose is needed 6−12 hours later but after that endogenous surfactant production takes over. Although early systematic reviews showed prophylactic therapy to be more effective than rescue treatment many centers have switched to rescue therapy commencing with CPAP in the delivery room and administering surfactant only if CPAP alone is ineffective aiming to avoid positive‐pressure ventilation. This approach is adopted even in very low birthweight infants only 60 of them now receive surfactant therapy. Surfactant can be administered in these circumstances by the INSURE intubation surfactant extubation technique or instilled through a catheter into the trachea called ‘minimal invasive surfactant treatment’ MIST. Otherwise in infants on mechanical ventilation it is administered down the tra- cheal tube either as prophylaxis or rescue treatment. Surfactant therapy may also be beneficial in term infants with severe meconium aspiration pulmonary hemorrhage or pneumonia who develop secondary surfactant deficiency see video: INSURE technique. 3 2 1 0 10 020 Airway pressure cmH 2 O Volume mL/g 30 40 Surfactant decient lungs Normal newborn lungs Expiration Inspiration Opening pressure Fig. 28.5 Difference in lung volume for a given airway pressure between normal and surfactant‐deficient lungs. If surfactant is present there is a lower opening pressure a larger change in volume for a given change in pressure and the lungs do not collapse on expiration. Surfactant deciency and structural lung immaturity Atelectasis lung collapse Hypoventilation Hypoxemia Hypercarbia Acidosis Respiratory distress syndrome Pulmonary vasoconstriction + Right-to-left shunting of blood within lung ductus arterious foramen ovale + Proteinaceous exudate in alveoli hyaline membrane Ventilation/perfusion mismatch Fig. 28.6 Effect of surfactant deficiency and lung immaturity in preterm infants. Key point •  Surfactant therapy has been a major advance in neonatal care.

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Neonatology at a Glance Third Edition. Edited by Tom Lissauer Avroy A. Fanaroff Lawrence Miall and Jonathan Fanaroff. © 2016 John Wiley Sons Ltd. Published 2016 by John Wiley Sons Ltd. 70 The preterm infant Respiratory distress syndrome RDS is: •  also called hyaline membrane disease HMD or surfactant defi- cient lung disease SDLD •  the commonest respiratory disorder affecting preterm infants see Table 29.1 •  a major cause of morbidity and mortality in preterm infants although this has decreased markedly in recent years. Risk factors The predominant risk factor is: •  prematurity Fig. 29.1 as surfactant is only produced towards the end of the second trimester and early third trimester. Other risk factors are: •  maternal diabetes mellitus •  sepsis •  hypoxemia and acidemia •  hypothermia. Pathology Characteristic histopathologic features include: •  collapsed terminal air saccules •  overdistended terminal airways •  influx of inflammatory cells into the airway lumen •  interstitial edema and protein leak onto the surface of the airways and air saccules • hyaline membrane formation in distal and terminal airways Fig. 29.2 •  necrotic damage to airway epithelial cells. Pathogenesis Caused by a deficiency in surfactant production or function. This results in alveolar collapse which in turn leads to poor lung com- pliance stiff lungs and impaired gas exchange. Immature lung architecture may also contribute. Clinical features Onset within 4 hours of birth of respiratory distress: •  tachypnea 60 breaths/min •  chest retractions sternal and intercostal retractions Fig. 29.3 •  nasal flaring •  expiratory grunting •  cyanosis if severe. Diagnosis is based on history physical signs characteristic chest X‐ray Fig. 29.4 and clinical course. Causes of respiratory distress in preterm infants are listed in T able  29.1. Natural course The natural course is for the illness to become worse over the first 24–72 hours and then improve over the next few days. There is initially tissue edema from transudation of fluid into alveoli and subcutaneous tissues which resolves with improvement of lung dis- ease leading to diuresis. These features are ameliorated by antenatal corticosteroids and postnatal surfactant therapy see video. Management This includes: •  reduced morbidity and mortality with antenatal corticosteroids •  surfactant therapy – prophylaxis/rescue see Chapter 28 •  oxygen therapy •  prevention of alveolar collapse – by applying CPAP continuous positive airway pressure high flow nasal therapy or PEEP positive end‐expiratory pressure on a mechanical ventilator •  lung expansion – by applying a peak inspiratory pressure with a mechanical ventilator if necessary •  provision of intensive care see Chapter 25. Respiratory distress syndrome 29 24–26 24 27–29 Gestational age weeks 100 60 20 80 40 0 Percent 30–32 Respiratory distress syndrome Pneumothorax Surfactant therapy Fig. 29.1 Decline in incidence of RDS with gestation in very low birthweight infants. The use of surfactant and incidence of pneumothorax is also shown. Vermont–Oxford Network data for 2012. a b Fig. 29.2 Histology showing a characteristic features of RDS. The hyaline membrane is shown arrows. b Normal preterm lung for comparison.

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Respiratory distress syndrome 71 Complications The main complications are: •  infection/lung collapse •  air leaks •  patent ductus arteriosus •  pulmonary hemorrhage •  intraventricular hemorrhage •  bronchopulmonary dysplasia. Air leaks Pulmonary interstitial emphysema PIE There is tracking of air from the overdistended terminal airways into the interstitium. Increases risk of pneumothorax and broncho- pulmonary dysplasia. Pneumothorax Occurs in 5–10 of infants ventilated for RDS. Presents with: •  increased oxygen requirement •  reduced breath sounds and chest movement on affected side •  hypoxemia hypercarbia and acidosis on blood gases •  shock. Confirmed by transillumination or chest X‐ray see Chapter 26. A tension pneumothorax is treated by urgent aspiration and insertion of a chest tube. Pneumothorax may occur spontaneously but is less likely if the ventilator is well synchronized with the baby’s breathing and high pressures are avoided. Pulmonary hemorrhage This is hemorrhagic pulmonary edema. In preterm infants it is usually associated with left heart failure from a patent ductus arte- riosus left‐to‐right shunting and respiratory distress syndrome requiring mechanical ventilation. Causes blood staining of tracheal aspirate with or without shock. Occurs in about 3 of infants with respiratory distress syndrome requiring mechanical ventilation. Most of these infants will have received surfactant but this is no longer considered to be a risk factor. Coagulation may be deranged. Treatment: •  increase ventilation especially PEEP. •  surfactant •  if necessary administer blood/volume and clotting factors but avoid fluid overload •  close patent ductus arteriosus. Massive pulmonary hemorrhage has a high mortality. Table 29.1 Causes of respiratory distress in preterm infants. Common Respiratory distress syndrome surfactant deficiency Pneumonia/sepsis Transient tachypnea of the newborn Uncommon Pulmonary hypoplasia Pneumothorax Congenital heart disease Rare Diaphragmatic hernia Non‐respiratory – anemia hypothermia metabolic acidosis Other causes These are listed in Chapter 39 Fig. 29.3 Chest retraction in a preterm infant with respiratory distress. Fig. 29.4 Chest X‐ray after 4 hours of age in RDS showing: •  diffuse uniform granular ground glass appearance of the lungs from atelectasis •  air bronchogram – outline of air‐filled large airways against opaque lungs •  reduced lung volume •  indistinct heart border as the lung fields are opaque ‘white‐out’. A tracheal tube is in place.

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Neonatology at a Glance Third Edition. Edited by Tom Lissauer Avroy A. Fanaroff Lawrence Miall and Jonathan Fanaroff. © 2016 John Wiley Sons Ltd. Published 2016 by John Wiley Sons Ltd. 72 The preterm infant Hypothermia Temperature regulation is fundamental to neonatal care. Hypothermia can cause: •  increased oxygen and energy consumption resulting in hypoxia metabolic acidosis and hypoglycemia •  apnea •  neonatal cold injury – redness of the skin from dissociation of hemoglobin •  coagulopathy •  poor weight gain •  increased mortality. Newborn babies are particularly liable to hypothermia as: •  they have a large surface area relative to their mass so there is an imbalance between heat generation related to mass and heat loss surface area •  their skin is thin and permeable to heat •  they have little subcutaneous fat for insulation •  they have a limited capacity to generate heat as they mainly rely on non‐shivering thermogenesis using a special form of adipose tissue brown fat which is distributed in the neck between the scapulae and surrounding the kidneys and adrenals •  their ability to produce heat from sympathetic responses is poor – shivering occurs only at an ambient temperature of 16 °C in term infants and does not occur in preterm infants until 2 weeks of age •  preterm infants are unable to curl up to reduce skin exposure. There is only one scenario where hypothermia is beneficial – for brain protection in term babies with perinatal asphyxia see therapeutic hypothermia Chapter 14. Evaporative heat loss in preterm infants Transepidermal water loss: •  is markedly increased in very premature infants Fig. 30.2a •  is increased by radiant warmers phototherapy if not using LED lights and if the skin is denuded •  declines with increasing postnatal age as the skin thickens •  is reduced by humidity Fig. 30.2b. Temperature control 30 How newborn infants lose heat Convection Fig. 30.1a Determined by: •  temperature difference between skin and air •  area of skin exposed to the air •  movement of surrounding air. Is an important cause of heat loss minimized by: •  clothing the infant •  raising temperature of ambient air •  avoiding drafts. Radiation Fig. 30.1b Depends on temperature difference between skin and surrounding surfaces i.e. walls of incubator or if under radiant warmer win- dows and walls of room is independent of the air temperature. Reduced in incubators by having a double wall. Evaporation Fig. 30.1c Important: •  at birth when skin is wet • in preterm infants as their skin is very thin and water‐ permeable •  from the respiratory tree with artifcial ventilation/nasal CPAP unless air/oxygen is heated and humidifed. Minimized at birth by drying the infant and wrapping in a warm towel preterm infants 30 weeks placed directly in plastic wrapping with only the face exposed and head covered with a hat. Conduction Fig. 30.1d Loss is small as babies are on mattresses which may be heated. Convection Radiation Evaporation Conduction Heat is lost to currents of air Heat loss via electromagnetic waves from skin to surrounding surfaces Heat loss when water evaporates from skin or breath Direct heat loss to solid surfaces with which they are in contact a b c d Fig. 30.1 a–d How newborn infants lose heat.

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Temperature control 73 Keeping neonates warm Infants should be nursed in their thermoneutral environment with a core body temperature of 36.5–37.5 °C Fig. 30.3. If the infant needs to be naked for observation/procedures: •  place under radiant warmer for resuscitation/stabilization or care of some term infants incubator if preterm. •  ensure the NICU is warm and draft‐free •  use warm humidified ventilator gases •  cover the head with a hat important as the surface area of babies’ heads are large. If premature but stable: •  clothe •  place in incubator or heated mattress in crib/cot •  wrap keep in a warm draft‐free room •  can be kept warm with kangaroo mother care even if gavage nasogastric feeding See Chapter 73 Global Health. Incubators Advantages •  Provide constant warm environment even when doors are open. •  Can minimize transepidermal water loss – with high relative humidity . •  Can reduce radiant heat loss if the baby is covered and the incu- bator has double walls. • Allows continuous observation of infant’s breathing and condition. Disadvantages •  Reduced access for procedures but improved in modern incubators •  May inhibit parental interaction. •  Noise from incubator’s motor and doors. Radiant warmers Advantages •  Ease of access for resuscitation/stabilization and some practical procedures and care of term infants. •  Rapid increase in temperature. Disadvantages •  High transepidermal water loss from radiant heat – makes fluid balance problematic in preterm infants so best avoided. •  Difficult to provide extra humidity •  High convective heat losses. Combined incubators with inbuilt radiant warmers Now widely used for infants requiring intensive care. Radiant heat is used only when access is required e.g. for procedures. 30 20 40 Ambient relative humidity 70 b 50 60 40 20 10 30 0 Transepidermal water loss g/m 2 /hour 50 60 80 100 90 70 26 weeks 28 weeks 33 weeks Term 26 24 28 Gestation weeks a 60 40 20 80 0 Transepidermal water loss g/m 2 /hour 30 32 36 42 40 38 34 Fig. 30.2 a Transepidermal water loss increases with decreasing gestation. b Transepidermal water loss is reduced by humidity. From Hammerlund et al. Transepidermal water loss in newborn infants. Acta Paediatr Scand 1983 72: 721–728. Decreased body temperature 37°C Body temperature maintained Neutral thermal environment Increased energy expenditure Increased body temperature Body temperature Death from hypothermia Death from hyperthermia Fig. 30.3 The neutral thermal environment is the temperature range where heat production is at the minimum needed to maintain normal body temperature. It depends on birthweight gestational and postnatal age and whether the infant is clothed or naked. Key point At birth preterm infants 30 weeks should be placed in a plastic wrap bag with a hat and under a radiant heater until they are in a warm humidifed incubator. Key point A normal core temperature does not mean a neutral thermal envi- ronment – it may be achieved by increased energy expenditure. Question When are heated mattresses useful They may allow stable preterm infants to be nursed in a crib cot instead of an incubator. Also useful to warm infants who have become cold or in the operating room during imaging studies or transport.

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Neonatology at a Glance Third Edition. Edited by Tom Lissauer Avroy A. Fanaroff Lawrence Miall and Jonathan Fanaroff. © 2016 John Wiley Sons Ltd. Published 2016 by John Wiley Sons Ltd. 74 The preterm infant Growth Between 24 and 36 weeks’ gestation a fetus growing along the 50th centile gains 15 g/kg/day. Infants who are fed enterally require 110–135 kcal/kg/day 85–95 kcal/kg/day if parenterally fed to maintain this rate of growth. As these high energy requirements often cannot be met the weight of extremely preterm infants is often initially static or may decline and the infant may take up to 21 days to regain birthweight. Thereafter their growth improves but is often suboptimal. The reason for this growth failure includes: •  the infant is unable to tolerate high volumes of nutrients •  fluids may be restricted e.g. patent ductus arteriosus •  feeds restricted because of intercurrent illness e.g. infection •  lower volume of milk given than protocol for fear that infant will not tolerate it or that it predisposes to necrotizing entero- colitis NEC. Nutrition Which milk Breast milk Is the milk of choice. Advantages over formula feeds also see Chapter 20 are: •  better tolerated •  associated with a lower incidence of necrotizing enterocolitis and provides some protection against infection •  contains hormones and growth factors •  has better absorption of fats and improved bioavailability of trace minerals •  promotes mother–infant bonding •  it is associated with improved cognitive development later in childhood. Disadvantages are: •  depends on the mother being able to express sufficient milk over a prolonged period this can usually be achieved with support. •  growth of the preterm infant may be suboptimal. Breast milk may need to be enhanced with human milk fortifier to increase its energy protein and mineral content. Human milk fortifiers contain cow’s milk protein. Fortification is usually stopped once the infant is entirely breast‐fed or weighs more than 2 kg. Donor human milk An increasing number of neonatal units give donor breast milk to extremely preterm infants or infants at increased risk of NEC necrotizing enterocolitis when maternal breast milk is not available especially during the first few days of life. Donors are screened by questionnaire and serological testing for infection the milk is pasteurized and screened for bacteria. Donor milk has been shown to have a lower incidence of feeding intolerance and necrotizing enterocolitis than preterm formula. Low birthweight infant formulas These have been developed to supply the increased energy 24 kcal/ oz 80 kcal/100 mL protein sodium calcium and phosphate required by low birthweight infants Table 31.1. They are increas- ingly further modified to be more like breast milk with the addition of long‐chain polyunsaturated fatty acids which are used as structural fats in nervous tissue and oligosaccharides which act as prebiotics to encourage a more breast‐fed‐like gut bacterial flora. Supplements •  Iron is given to preterm infants once they are on full enteral feeds and not receiving blood transfusions unless fully formula fed. Supplementation is for six months to one year. •  Multivitamins A B 12 C D and E are given routinely. Folic acid is given in some centers. •  Vitamin K is given to all infants including the preterm as prophylaxis against vitamin K deficient bleeding hemorrhagic disease of the newborn. Growth and nutrition 31 Table 31.1 Composition of various milks. Mature term breast milk Preterm breast milk Fortified preterm breast milk Low birthweight formula Term formula Energy kcal/100 mL 70 67 74 80 66 Carbohydrate g/100 mL 7 7.6 8 10–11 7.6 Fat g/100 mL 4.2 4 4 5 4.4 Protein g/100 mL 1.3 1.8–2.4 2.9 2.2–2.5 2.5 Na mmol/L 7 13 18 13–20 8 K mmol/L 15 15 17 18 17 Ca mmol/L 9 6 22 30 12–20 Phosphate mmol/L 5 5 18 21 12–18 Source: ESPGHAN 2010. MCT – medium chain triglyceride. Question What is the daily recommended nutritional requirement of a fully enterally fed very low birthweight infant It is per kg/day: Fluids 135–200 mL Energy 110–135 kcal Protein 3.5–4 g Carbohydrate 11–13 g Fat 4.8–6.6 g 40 MCT Sodium 2–3 mmol Potassium 2–3 mmol Calcium 120–140 mg Phosphate 60–90 mg

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Growth and nutrition 75 Feeding Whereas the healthy newborn term infant can be put to the breast shortly after birth extremely preterm infants cannot feed for themselves as they: •  are unable to suck and swallow until about 32–34 weeks of gestation Figs 31.1–31.3 •  are initially unable to tolerate milk in sufficient quantity to meet their nutritional requirements. A number of strategies are adopted to overcome these problems. Minimal enteral non‐nutritive feeding A small volume e.g. 10–20 mL/kg/day preferably with expressed breast milk is given during the first few days to stimulate gut hormone production even when the infant is too unwell or unstable to tolerate the expected volume of feeds. This helps intestinal maturation motility and gallbladder function decreasing the time taken to establish full enteral feeding it also lowers serum bilirubin concentrations. Feeding should be advanced cautiously in infants who are growth‐restricted and have reversed end‐diastolic blood flow velocity on antenatal Doppler ultra- sound because of their increased risk of necrotizing enterocolitis. Gavage tube feeding Used when infants are too immature 34 weeks’ gestational age or ill to feed for themselves but are able to tolerate enteral feeds. The volume of milk is gradually increased. Gastric residuals should not slow down advancement of feeding volumes unless bilious with abdominal distension blood in the stool or other features suggesting necrotizing enterocolitis. Reduced gut motility in very low birth- weight infants may necessitate suppositories for constipation. The tube may be orogastric or nasogastric. As nasogastric tubes lie in the narrowest part of the upper airway just behind the nose a size 5 French gauge tube increases airway resistance by 30–50 in pre- term infants. This increases the work of breathing and may increase the frequency of apnea. Some units avoid nasogastric tubes in extreme preterm infants but orogastric tubes are more difficult to fix securely. There is conflicting evidence regarding continuous versus bolus feeding in relation to weight gain and the incidence of apnea and bradycardia. The infant’s oxygen tension falls with feeds in both preterm and term infants. It has been argued that continuous feeding is more physiologic for preterm infants because it is a closer approx- imation to the way a fetus is fed in utero. However bolus feeds are preferred as the response of gut hormones is more physiologic. Parenteral nutrition PN A mixture of carbohydrate protein fat vitamins and trace elements allows nutrition to be provided whilst oral feeding is established. It is usually given via a central venous line but may be given peripher- ally. It is associated with a number of complications: •  line‐related infection •  conjugated hyperbilirubinemia •  electrolyte disorders •  hyperglycemia •  chemical burns from extravasation •  pleural or pericardial effusion – if tip of the central line lies in the heart and becomes displaced. Volume of fluids A guide to average total fluid intake is shown in Table 31.2. It is adjusted according to plasma electrolytes creatinine acid–base status and the infant’s weight all of which are measured regularly over the first few days. It is markedly affected by: •  gestational age •  thermal environment radiant warmer or incubator •  evaporative water loss reduced by humidity etc.. Once the preterm infant is stable and on full enteral feeds electrolytes creatinine and phosphate calcium and alkaline phos- phatase can be checked weekly. Fig. 31.1 Preterm infant learning to suck at the breast whilst still on continuous positive airway pressure CPAP. Fig. 31.2 Preterm infant learning to breast‐feed whilst still receiving gavage tube feeds. Fig. 31.3 Preterm twins successfully learning to feed at the breast. Table 31.2 Typical fluid intake according to postnatal age. Postnatal age Fluid intake mL/kg/24 h 2.5 kg 2.5 kg Birth 60–100 60–80 Day 1 90–120 60–100 Day 2 120–150 90–120 Day 3 150 120–150 Days 4 and over 150–180 150

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Neonatology at a Glance Third Edition. Edited by Tom Lissauer Avroy A. Fanaroff Lawrence Miall and Jonathan Fanaroff. © 2016 John Wiley Sons Ltd. Published 2016 by John Wiley Sons Ltd. 76 The preterm infant These are the most common causes of acquired brain injury in premature infants. Their incidence is inversely related to gesta­ tional age. •  Hemorrhage – occurs in about 20 of VLBW very low birth­ weight infants. Involves the germinal matrix an immature capil­ lary network which overlies the head of the caudate nucleus. The  hemorrhage may be confined to the germinal matrix GMH − IVH may extend into the ventricle IVH or involve the parenchyma. Parenchymal hemorrhages result from venous infarction. Hemorrhage usually occurs within 72 hours of birth. It is uncommon beyond 32 weeks’ gestation by which time the germinal matrix has involuted. •  Cystic periventricular leukomalacia PVL – loss of periven­ tricular white matter in watershed areas around the lateral ventricles from hypoxia–ischemia. Probably most occur before birth but some postnatally. Periventricular flare or echodensity PVE may resolve or evolve into small cysts in fronto‐parietal region or extensive periventricular or deep white matter cysts which are visible on ultra­ sound after 2–3 weeks in 3 of VLBW infants. Diagnosis This is by bedside cranial ultrasound Table 32.2. In VLBW infants it is performed shortly after birth to identify antenatal lesions during the first week of life and after serious illness to identify hemorrhages and repeated periodically to identify and monitor hydrocephalus and appearance of cystic periventricular leukomalacia PVL. It is excellent for detecting hemorrhage and ventricular dilatation see Chapter 79 Cranial ultrasound. It is relatively insensitive in detecting white matter damage MRI when older is more sensitive see Chapter 81 Perinatal neuroimaging. Intraventricular hemorrhage and periventricular leukomalacia 32 Pathogenesis Figs 32.1 and 32.2 and incidence Table 32.1 Table 32.1 Incidence of severe intraventricular hemorrhage IVH and cystic periventricular leukomalacia PVL by gestational age Vermont– Oxford Network data for 2012. Gestational age weeks Severe IVH Grades III/IV Cystic PVL 24 35 6.5 24 − 26 17 5 27 − 29 5 3 30 − 32 1.4 1 Postnatal risk factors • Preterm • Respiratory distress syndrome • Cardiovascular instability • Pneumothorax • Rapid volume expansion Postnatal risk factors • Hypocarbia and alkalosis • Cardiovascular instability/ collapse Hemorrhage – germinal layer – intraventricular – parenchymal Prenatal risk factors • Preterm IUGR • Hypoxia–ischemia • Chorioamnionitis • Twin–twin transfusion Hypoperfusion of periventricular white matter and infammatory cytokine r esponse: – oligodendroglial injury – myelin loss Cystic periventricular leukomalacia PVL White matter injury • Immature germinal matrix capillary network • Systemic blood pressure fuctuations with impaired cerebral autoregulation • Coagulopathy Fig. 32.1 Pathogenesis of cerebral hemorrhage and cystic periventricular leukomalacia PVL. a b Fig. 32.2 Autopsy specimen showing a large parenchymal and intraventricular hemorrhage and b ventricular dilatation and cystic periventricular leukomalacia PVL. Question What is meant by cerebral autoregulation It is the maintenance of normal cerebral blood flow over a wide range in blood pressure. This blood pressure range is narrow in pre­ term infants falls in blood pressure lead to cerebral hypoperfusion leading to ischemic damage and hemorrhagic infarction. Key point There has been a marked reduction in the incidence of severe periventricular leukom­ alacia and post‐hemorrhagic hydrocephalus requiring shunts.

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Intraventricular hemorrhage and periventricular leukomalacia 77 Clinical features Most infants are asymptomatic more likely with large bleeds. Clinical features of intraventricular hemorrhage include: •  increased ventilatory support •  abnormal neurologic signs including seizures •  apnea and bradycardia •  shock. Laboratory findings Mostly not specific. For intraventricular hemorrhage may include: •  acute anemia •  hyperglycemia hyperkalemia electrolyte imbalance •  unexplained metabolic acidosis •  coagulation abnormalities. Management Optimize: • airway and breathing – provide oxygenation/ventilation as needed avoid hypo‐ or hypercarbia synchronize infant’s breathing and ventilator •  circulation – maintain adequate intravascular volume and blood pressure •  comfort – avoid unnecessary or uncomfortable manipulation. Treat seizures. Correct significant coagulation abnormalities. Monitor for complications Fig. 32.3 – sequential head circumfer­ ence measurements and serial head ultrasound for ventricular dila­ tation see Chapter 79. Prognosis •  Small germinal matrix or intraventricular hemorrhage – slightly increased risk of neurodevelopmental problems. •  Large parenchymal hemorrhage/large porencephalic cyst − may cause hemiplegic cerebral palsy and visual defect. •  Hydrocephalus needing shunt – appreciable mortality high risk of neurodisability. •  Transient echodensities – normal. •  Widespread cysts – most have cerebral palsy usually spastic diplegia or quadriplegia with or without learning difficulties and visual impairment. Prevention •  Avoid delivery before 30 weeks of gestation unless essential. •  Give antenatal corticosteroids. •  Avoid perinatal hypoxia–ischemia when possible. •  Efficient resuscitation and stabilization at birth. •  Minimal handling •  Optimize intensive care – minimize hypotension and hypo­ carbia  PCO 2 30 mmHg 4kPa which causes cerebral vasoconstriction. Prophylactic indomethacin reduces the incidence of severe hemorrhage but does not improve neurodevelopmental outcome. Table 32.2 A classification of lesions identified on intracranial ultrasound. Hemorrhage Grade I – isolated germinal matrix hemorrhage GMH Grade II – intraventricular hemorrhage GMH − IVH 50 of ventricular area on parasagittal view Grade III – intraventricular hemorrhage GMH–IVH with dilatation 50 of ventricular area on parasagittal view usually distends lateral ventricle Grade IV – hemorrhagic parenchymal infarct parenchymal lesion Periventricular white matter echodensity PVE – echogenicity is comparable with that of choroid plexus Cystic periventricular leukomalacia PVL Porencephalic cyst – single large cyst Posthemorrhagic ventricular dilatation/hydrocephalus PHVD Hemorrhage Periventricular hemorrhage Germinal matrix hemorrhage Intraventricular hemorrhage Parenchymal hemorrhagic infarct Porencephalic cyst Localized small cysts Bilateral parenchymal echodensities Multiple large cysts Resolve Ventricular dilatation transient or progresses to hydrocephalus May communicate with ventricle Porencephalic cyst Disappear Coalesce Cerebral atrophy with ventricular dilatation Fig. 32.3 Natural history and complications of cerebral hemorrhage and periventricular leukomalacia.

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Neonatology at a Glance Third Edition. Edited by Tom Lissauer Avroy A. Fanaroff Lawrence Miall and Jonathan Fanaroff. © 2016 John Wiley Sons Ltd. Published 2016 by John Wiley Sons Ltd. 78 The preterm infant The ductus arteriosus connects the pulmonary artery with the descending aorta Fig. 33.1. In utero patency of the arterial duct is maintained by a low PaO 2 and high concentrations of vasodilating prostaglandins PGE 2 and PGI 2 . In the fetus the ductus arteriosus allows 90 of the right cardiac output to bypass the lungs and helps deliver oxygenated blood form the placenta to the brain and other vital organs see Chapter 12. Patent ductus arteriosus PDA 33 Murmur features: Systolic or pansystolic murmur Loudest at left sternal edge Gallop rhythm Loud second heart sound If the shunt is large no murmur may be present Volume of left to right blood flow across the shunt is related to: The size of the PDA trans-ductal diameter Systemic vascular resistance usually higher Pulmonary vascular resistance usually lower Excessive pulmonary blood flow: Physiological effects Reduced lung compliance Pulmonary edema Reduced gas exchange Eventually reduced PVR pulmonary vascular resistance Clinical effects Tachypnea Increased oxygen requirements Increased CO 2 retention Ventilator dependence Apnea and bradycardia Morbidity Increased risk of bronchopulmonary dysplasia Reduced systemic blood flow: Physiological effects Fall in aortic end diastolic flow velocity Reduction of renal perfusion Reduction of mesenteric perfusion Lactic acidosis Clinical effects Low diastolic blood pressure Wide pulse pressure Bounding pulses Hepatomegaly right heart failure Feeding intolerance Low urine output Morbidity Increased risk of necrosing enterocolitis Increased risk of IVH Patent ductus arteriosus Aorta to body Pulmonary artery Fig. 33.1 Anatomy of the ductus arteriosus after birth with left to right flow across it and clinical/physiologic consequences. Ductal closure After birth ductal constriction is promoted by: •  the rise in oxygen tension with the first breaths •  the fall in pulmonary vascular resistance and rise in systemic vascular resistance •  a fall in PGE 2 and PGI 2 . Ductal closure takes place in two stages: •  functional closure – 24–48 hours after birth •  anatomic closure – may take 2–3 weeks. In preterm infants there may be delay in anatomical closure. As pulmonary resistance falls blood flows “left to right” across the patent ductus from the higher systemic to the lower pulmonary vascular resistance. In severe respiratory distress syndrome pulmonary artery pressure is increased and the shunt may be bidi- rectional. Eventually the duct will close spontaneously but inter- vention is sometimes required to achieve this. In contrast to preterm infants in term infants a patent ductus arteriosus is due to a permanent defect in the muscle wall of the duct and is unlikely to close spontaneously. Ongoing patency of the ductus arteriosus may be beneficial in pulmonary hypertension or some forms of ‘duct dependent’ con- genital heart disease as it augments systemic or pulmonary circulation See Chapter 49 Cardiac disorders. Risk factors •  prematurity – incidence increases with decreasing gestational age most common in those less than 32 weeks’ gestational age. •  respiratory distress syndrome •  fluid overload •  sepsis •  pulmonary hypertension. Clinical features A PDA becomes significant when the volume of left–right blood flow leads to hemodynamic compromise Fig. 33.1. The clinical features are attributable to excessive pulmonary blood flow and reduced systemic perfusion from shunting of blood across the duct. The degree of shunting depends on the size of the duct and the difference between systemic and pulmonary vascular resistance. Investigations Chest X‐ray Fig. 33.2 May show cardiomegaly and increased pulmonary vascularity or pulmonary edema.

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Patent ductus arteriosus PDA 79 Echocardiography with pulsed color Doppler •  Confirms the diagnosis. •  Provides visualization of the size and direction of the shunt and its hemodynamic consequences Fig. 33.3a and b. Significant if: •  Left atrial enlargement left atrial:aortic root ratio 1.5:1. •  Left ventricular enlargement cardiomegaly. •  High cardiac output 350 mL/kg/min. •  Absent or retrograde diastolic flow in postductal aorta. •  Absent or retrograde diastolic flow in celiac renal and middle cerebral arteries. Management Medical management The aim is to eliminate the left to right shunt thereby reducing pulmonary blood flow and restoring systemic blood flow. However the duct often closes spontaneously and indications for medical or surgical closure remain uncertain. •  Fluid management – Fluid restriction is widely practiced to limit pulmonary edema and is appropriate during treatment with indomethacin or ibuprofen if oliguria/anuria and/or fluid retention ensue. However prolonged fluid restriction may further worsen systemic hypoperfusion. •  Shunt limitation strategies – Through permissive hypercapnemia elevated positive end‐expiratory pressure and avoidance of excessive oxygen. •  Diuretics – Used only if in heart failure. Furosemide leads to increased renal production of prostaglandins which may actually promote ductal patency. May also further compromise systemic blood flow. May be needed while awaiting surgery. •  Prostaglandin synthase inhibitors also called cyclooxy- genase inhibitors COXi – See Table 33.1. Indomethacin was used for many years. Prophylactic indomethacin will reduce the incidence of PDA and severe IVH but does not alter long‐term neurodevelopmental outcome and risks intestinal perforation. Ibuprofen has similar efficacy but less reduction in cerebral renal and mesenteric blood flow. Usually given over 3 days. The duct closes in 60 after a single course a second course may be required. Most effective in the first week of life. Paracetamol has recently been used if COXi are unsuccessful or contraindicated. Although it appears promising its widespread use is not currently recommended owing to lack of safety data. Surgical closure Only if medical treatment fails. Thoracotomy usually to clip or ligate duct minimally invasive gaining popularity. Complications of surgery are: •  Postligation cardiac syndrome – hypotension and difficulty with oxygenation secondary to impaired left ventricular function. May benefit from prophylactic milrinone in immediate postoperative period. •  Recurrent laryngeal nerve damage – vocal cord paralysis. •  Chylothorax from damage to thoracic duct. •  Pneumothorax. •  Ligation of pulmonary artery by mistake. •  Adverse neurological outcome mortality 1. Fig. 33.2 Chest X‐ray showing increased pulmonary vasculature markings and cardiomegaly. But often unhelpful diagnostically. Courtesy of Dr Sheila Berlin. a RV LA PA DAo PDA bBidirectional flow: PVR SVR Left to right flow: PVR SVR Fig. 33.3 a Pulsed color Doppler showing shunting across the ductus arteriosus arrow. b Different patterns of PDA flow. PVR pulmonary vascular resistance SVR systemic vascular resistance. Table 33.1 Indomethacin and ibuprofen. Side effects Contraindications Decreased platelet aggregation may worsen bleeding Abnormal renal function with oliguria Gastrointestinal bleeding Gastrointestinal bleeding Focal intestinal perforation Thrombocytopenia Fluid retention leading to hyponatremia Seldom effective if 4 weeks old

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Neonatology at a Glance Third Edition. Edited by Tom Lissauer Avroy A. Fanaroff Lawrence Miall and Jonathan Fanaroff. © 2016 John Wiley Sons Ltd. Published 2016 by John Wiley Sons Ltd. 80 The preterm infant Infection Infection is a major cause of morbidity and mortality in preterm infants. They are especially vulnerable because: •  they have reduced cellular and humoral immunity because IgG antibodies are transferred from mother to fetus mainly during the third trimester •  their skin is thin and readily denuded by skin electrodes cathe- ters and tape providing a portal of entry and a site of colonization for organisms •  central venous catheters and tracheal tubes are a potential focus for infection especially if left in place for prolonged periods •  cross‐infection is readily spread from infant to infant in neo- natal nurseries on the hands of staff and from contaminated equipment. Early‐onset infection 72 hours Acquired before birth from chorioamnionitis or maternal bacteremia or from the birth canal. The most common organisms are group B streptococci and Gram‐negative bacteria. Late‐onset sepsis 72 hours Mainly due to nosocomial hospital‐acquired infection rather than community‐acquired infection. The most common cause is coagulase‐negative staphylococcus CONS. Other organisms are shown in Fig. 34.1. There is marked variation in nosocomial infection rates among units. This results in wide variation in infection‐related morbidity duration of hospitalization cost and mortality. Recent quality improvement initiatives with care bundles to reduce central line‐ associated bloodstream infection CLABSI have markedly reduced late‐onset sepsis. Fungal infections In very low birthweight infants: •  incidence 1–10 •  mortality up to 35. Candida albicans is the most common organism Fig. 34.2. The source of infection is colonization of the gastrointestinal tract. In some neonatal units antifungal agents are given prophylactically to extremely low birthweight infants. However this practice is not uni- formly accepted. Broad‐spectrum antibiotics parenteral nutrition and central venous catheters are risk factors for fungal infection. Treatment is with amphotericin B fluconazole or flucytosine depending on infection site and fungus species. Presentation and management These are described in Chapter 42. Jaundice Most preterm infants develop jaundice from unconjugated hyper‐ bilirubinemia in the first week of life. The level of bilirubin that is potentially damaging is lower than in more mature infants. The bili- rubin peaks at around day 5 of life and should be closely monitored. Conjugated hyperbilirubinemia is mainly associated with par- enteral nutrition PN necrotizing enterocolitis and congenital infection. Management is described in Chapter 41. Infection jaundice anemia osteopenia of prematurity 34 Staphylococcus coagulase negative Staphylococcus aureus Group B streptococcus 2 Other Gram-positive 77 Klebsiella Enterobacter spp. Pseudomonas spp. 2 Serratia spp. 1 Other Candida albicans Other Fungi 7 Gram-negative 16 53 11 11 4 3 6 4 3 Fig. 34.1 Organisms causing late‐onset sepsis in very low birthweight infants. NICHD Neonatal Research Network. Boghossian N.S. et al. Late‐onset sepsis in very low birth weight infants from singleton and multiple‐gestation births. J Pediatr 2013 162: 1120–1124. Fig. 34.2 Fungal ball arrow in the kidney from Candida sepsis on renal ultrasound.

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Infection jaundice anemia osteopenia of prematurity 81 Anemia Common in VLBW very low birthweight infants mainly because of: •  blood loss from repeated blood sampling and the preterm infant’s small blood volume of only about 90 mL/kg •  physiologic anemia of prematurity. This occurs at 1–3 months of age due to: – reduced red cell production – shortened red cell survival – markedly increased requirements from growth. Treatment Blood transfusions Aim is to restore or maintain adequate tissue oxygen delivery but as there are no reliable symptoms or signs to determine this the indications in neonates are controversial and vary between centers Table 34.1. Blood transfusions are kept to a minimum because of potential hazards. Splitting adult donor bags to allow several trans- fusions from the same donor is recommended to reduce potential risk of blood‐borne pathogens by reducing number of donors. Oral iron therapy Given to prevent anemia of prematurity unless the infant has received a recent blood transfusion or iron‐fortified formula. Oral folic acid Given in some centers. Osteopenia of prematurity Metabolic bone disease may occur at several weeks of age causing: •  reduced bone mineralization with widening and cupping of the wrists knees and ribs on X‐ray as with rickets Fig. 34.3a and b •  failure in linear growth •  pathologic fractures particularly of ribs and long bones. Investigations show: •  calcium – normal or raised •  phosphate – low •  alkaline phosphatase a marker of bone turnover – markedly raised. Osteopenia of prematurity is due to phosphorus deficiency from urinary loss and increased requirements. It can be prevented by providing additional phosphate in paren- teral nutrition by fortifying expressed breast milk or by giving oral phosphate to maintain age‐appropriate plasma phosphate levels. It can be problematic to provide sufficient phosphate for infants requiring parenteral nutrition for a prolonged period. Treatment is with sodium or potassium acid phosphate and vitamin D supplements. Table 34.1 An example of indications for blood transfusions in preterm infants College of American Pathologists 1998. Acute blood loss with shock Hb 12 g/dL – if in oxygen with mechanical ventilation congenital heart disease with cyanosis or heart failure Hb 10 g/dL – if moderate oxygen requirement via nasal cannula Hb 8 g/dL – if apnea and bradycardia sustained tachycardia failure to gain weight mild oxygen requirement Hb 7 g/dL and reticulocyte count 100 000/mL – even if asymptomatic Question Is erythropoietin therapy helpful in newborn infants Recombinant human erythropoietin EPO could potentially reduce the need for red cell transfusions. However it does not significantly reduce the transfusion requirements in the first 2 weeks of life when sick neonates are most dependent on transfusion. It is therefore used selectively. It may be useful for treatment of chronic anemia when transfusion is declined e.g. for religious or cultural reasons. It is not useful for treatment of acute anemia because of the lag of 1 week after starting treatment before the hemoglobin increases significantly. Fig. 34.3 Osteopenia of prematurity. a Reduced bone mineralization with some widening fraying and cupping of the metaphyses. b Marked widening fraying and cupping of the metaphyses of the wrist bones. Courtesy of Dr Sheila Berlin. a b

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Neonatology at a Glance Third Edition. Edited by Tom Lissauer Avroy A. Fanaroff Lawrence Miall and Jonathan Fanaroff. © 2016 John Wiley Sons Ltd. Published 2016 by John Wiley Sons Ltd. 82 The preterm infant Apnea bradycardia and desaturations Common in VLBW very low birthweight infants. Definition Fig. 35.1 Interrelationship between apnea bradycardia and desaturation is complex so monitor not only respiration but also heart rate and oxygen saturation. Hypoxemia with bradycardia is harmful if prolonged. Classification •  Central – cessation of chest wall motion due to loss of respiratory neural output no signal is sent to breathe. •  Obstructive – persistence of obstructed inspiratory efforts throughout the apnea with no airflow. May be associated with neck flexion. Presents with bradycardia with or without desaturation. May not be detected on standard clinical impedance respiratory monitor as they detect chest wall movement as a breath although there is no airflow. •  Mixed – most common for prolonged apnea a combination of both of above with obstructed inspiratory efforts intermittently throughout the apnea. Episodes of desaturation •  May accompany short 5–10 seconds respiratory pauses espe- cially if baseline SaO 2 is low. •  During assisted ventilation they are secondary to hypoventilation. •  Variable relationship with bradycardia. Causes Usually due to prematurity – must consider or exclude: •  infection most common •  necrotizing enterocolitis •  heart failure – patent ductus arteriosus etc. •  hypoglycemia electrolyte abnormality •  inborn error of metabolism •  anemia •  seizures. Treatment Most apneic spells are brief and self‐limiting. If not: •  Check airway. •  Gentle tactile stimulation. •  Nasal CPAP continuous positive airway pressure – very effective eliminates obstructive apnea. Non-invasive ventilation may also be used. •  Methylxanthines – caffeine or theophylline. Caffeine more widely used as fewer side‐effects and drug level monitoring not needed. Caffeine lowers the incidence of bronchopulmonary dysplasia BPD and improves neurodevelopmental outcome. •  Mechanical ventilation. Prognosis Apnea and bradycardia continue in some preterm infants beyond 36 weeks of gestational age particularly in association with bron- chopulmonary dysplasia chronic lung disease but rarely beyond 43–44 weeks. Continue to hospitalize if symptomatic apnea and bradycardia until absent for several days. Not a risk factor for later SIDS sudden infant death syndrome. Retinopathy of prematurity ROP Eye disease of prematurity. Highest incidence in extremely low birthweight infants. Hyperoxia restricts retinal vascular growth by inhibiting vascular endothelial growth factor VEGF. Subsequent hypoxia acts as a stimulus for inappropriate and excessive growth of retinal vessels mediated by increased VEGF. Keeping preterm infants in inappropriately high oxygen concentrations results in a high inci- dence of ROP causing blindness see Chapter 67. However in VLBW infants even with oxygenation closely monitored attempt- ing to keep PaO 2 at 50–80 mmHg i.e. 6.5–10.5 kPa oxygen satura- tion 91–95 about 30–40 develop ROP which is severe in 6 treatment is needed in 3 and 1 have severe visual impairment. Visual outcome also depends on associated neurologic injury myopia and squint. Apnea bradycardia and desaturations retinopathy of prematurity 35 Apnea Bradycardia Desaturation Fig. 35.1 Apnea is absence of breathing for more than 10–15 seconds and may result in bradycardia and/or desaturation. Question What is the relationship of apnea to feeding Hypoventilation apnea and even cyanosis commonly accom- pany onset of oral especially bottle feeds. These episodes of hypoventilation typically resolve rapidly without the need for further intervention. Gastroesophageal reflux and apnea are both common in preterm infants but rarely temporally related. Pharmacologic treatment of reflux often fails to abolish apnea.

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Apnea bradycardia and desaturations retinopathy of prematurity 83 ROP causes 3–10 of childhood visual impairment in developed countries. Visual impairment from ROP is also emerging as a problem in low and middle income countries in preterm infants 1500g birth- weight from use of excessively high concentrations of oxygen. Screening Preterm infants are screened selectively Table 35.1. Findings are classified according to the stage of advancement and the zone affected Table 35.2 and Fig. 35.2. Treatment Stage 1 or 2 disease resolves spontaneously. Severe retinopathy requires treatment with laser therapy to ablate the peripheral avas- cular retina Fig. 35.6. Intravitreal injections of VEGF blocking antibody fragments are under investigation as an alternative form of treatment. Table 35.1 Screening guidelines for retinopathy of prematurity. US 2013 UK 2008 Who Birth: ≤1500 g or ≤30 weeks Birth: 1501 g or 32 weeks Bigger/older infants who are particularly unstable When ≤27 weeks gestational age at 31 weeks 27 weeks gestational age at 30–31 weeks ≥28 weeks at 4 weeks postnatal age 27 weeks at 4–5 weeks postnatal age Follow up Screen until retinopathy shows signs of regression or until fully vascularized Post‐discharge follow‐up of visual development Fig. 35.5 Stage 5 retinopathy of prematurity showing retinal detachment. Fig. 35.6 Following laser therapy for retinopathy of prematurity. Fig. 35.4 Stage 3 retinopathy of prematurity in a Black infant. Courtesy of Prof. Alistair Fielder. Table 35.2 International classification of retinopathy of prematurity revised 2005. Stage 1 – flat demarcation line between normally vascularized and non‐vascularized retina Fig. 35.3 Stage 2 – demarcation line extends off the retina as a ridge Stage 3 – new vessels behind the ridge with or without vitreous hemorrhage extraretinal fibrovascular proliferation Fig. 35.4 Stage 4 – partial retinal detachment Stage 5 – total retinal detachment Fig. 35.5 Plus disease – abnormal dilatation and tortuosity of posterior pole vessels Pre‐plus disease – mild abnormal dilatation and tortuosity of posterior pole vessels Aggressive posterior ROP – rapidly progressing severe form 12 6 9 x 3 Zone 1 Zone 2 Zone 3 Fig. 35.2 Zones of retina. Numbers at the periphery indicate clock hour. Fig. 35.3 Stage 1 retinopathy of prematurity. Courtesy of Prof. Alistair Fielder.

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Neonatology at a Glance Third Edition. Edited by Tom Lissauer Avroy A. Fanaroff Lawrence Miall and Jonathan Fanaroff. © 2016 John Wiley Sons Ltd. Published 2016 by John Wiley Sons Ltd. 84 The preterm infant Necrotizing enterocolitis NEC is the most serious abdominal disorder of preterm infants. It occurs in 2–10 of VLBW very low birthweight infants and has a mortality of 15–25. The incidence increases with decreasing gestational age it is rare in term infants. It is characterized by abdominal distension bilious aspirates bloody stools and intramural air pneumatosis intestinalis on abdominal X‐ray. There is inflammation of the bowel wall which may progress to necrosis and perforation. It may involve a localized section of bowel most often the terminal ileum or be generalized. It is usually sporadic but occasionally occurs in epidemics. In preterm babies the onset is usually at 1–2 weeks but may be up to several weeks of age. In term babies it occurs earlier usually after an ischemic insult. Risk factors Pathogenesis is unknown but several risk factors have been identified Fig. 36.1. Exclusive feeding with human milk reduces the risk of NEC. There is a change in the microbiome pattern in the gut preceding NEC and late onset sepsis revealing less diversity and changes in the community of gut microorganisms which become dominated by Proteobacteria and Firmicutes. Clinical features Onset is at 1–2 weeks but may be up to several weeks of age with: •  bilious aspirates/vomiting •  feeding intolerance •  blood or mucus in stools • abdomen – distension distended veins discoloration of the abdominal wall and tenderness Fig. 36.2 which may progress to perforation Table 36.1. •  features of sepsis – temperature instability apnea and brady- cardia jaundice lethargy hypoperfusion and shock. Laboratory findings These include: •  raised acute‐phase reactant C‐reactive protein CRP or procalcitonin •  thrombocytopenia •  neutropenia neutrophilia •  anemia •  blood culture positive •  coagulopathy •  metabolic acidosis •  hypoxia hypercapnia •  hyponatremia hyperkalemia •  increased BUN blood urea nitrogen/urea •  hyperbilirubinemia. Necrotizing enterocolitis 36 Ischemia and infection of intestinal mucosa Necrotizing enterocolitis Prematurity The main risk factor Feeding • Formula feeds breast milk • Rapid increase in enteral feeds • Hypertonic formula • Altered gut microbiome Infection Bacteria in intestinal wall and blood stream Hypoxia–ischemia to the bowel Prenatal: • IUGR especially if antenatal absent/reversed end-diastolic ow of umbilical and fetal arteries • Perinatal asphyxia Postnatal: • PDA reduced blood ow indomethacin • Postnatal asphyxia Fig. 36.1 Risk factors in the pathogenesis of necrotizing enterocolitis. Fig. 36.2 Abdominal distension and shiny discolored abdominal skin in severe necrotizing enterocolitis. Table 36.1 Clinical signs of peritonitis/perforation. Abdominal tenderness Guarding Tense discolored abdominal wall Abdominal wall edema Absent bowel sounds Abdominal mass

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Necrotizing enterocolitis 85 Radiologic abnormalities •  Dilated loops of bowel. •  Thickened intestinal wall. •  Inspissated stool mottled appearance. •  Intramural air pneumatosis intestinalis pathognomonic sign Fig. 36.3. •  Air in portal venous system Fig. 36.4. •  Bowel perforation: – gasless abdomen/ascites – pneumoperitoneum – air below diaphragm/around the falciform ligament Fig. 36.5. Management Table 36.2 Sequelae •  Complications of prolonged parenteral nutrition – infection electrolyte derangement conjugated hyperbilirubinemia etc. Short bowel syndrome following bowel resection: •  Diarrhea from loss of bowel mucosa and rapid gastrointestinal transit •  Growth failure •  Vitamin B 12 deficiency if terminal ileum resected •  Dependence on parenteral nutrition •  Stricture formation – causes intestinal obstruction and/or intestinal hemorrhage. Prevention •  Use breast milk if possible. •  Avoid hyperosmolar feeds. •  Avoid rapid increase in feed volume in very immature infants especially if intrauterine growth restriction with absent/reversed end‐diastolic Doppler waveform antenatally. •  Probiotics with or without prebiotics and lactoferrin help maintain normal gut flora and may reduce risk of NEC. Fig. 36.3 Abdominal X‐ray showing dilated loops of bowel and intramural air arrow. Courtesy of Dr Sheila Berlin. Fig. 36.4 Air in portal venous system arrow. This is often a transient sign. Courtesy of Dr Annemarie Jeanes. Fig. 36.5 Bowel perforation showing air under the diaphragm on lateral x-ray arrow. Courtesy of Dr Sheila Berlin. Table 36.2 Management of necrotizing enterocolitis. Management Rationale/goals Secure airway and support breathing Abdominal distension may compromise breathing May require artificial ventilation Circulation •   establish vascular access Infusion of fluids •   give intravascular volume replacement saline blood fresh frozen plasma Treat hypoperfusion/hypovolemic shock •   correct metabolic acidosis Improve organ and tissue perfusion Place large‐bore naso/orogastric tube Intestinal decompression bowel rest NPO nil by mouth – start parenteral nutrition Support nutritional demands for growth Broad‐spectrum antibiotics Gram‐positive ‐negative and anaerobic coverage Consider antifungal agents Treat coagulopathy fresh frozen plasma platelets cryoprecipitate Avoid bleeding complications Monitor regularly – clinical radiographic and laboratory investigations Necrotizing enterocolitis can worsen very quickly to bowel perforation Surgery – options are: •   peritoneal drainage at bedside Indications – bowel perforation or failure to resolve on medical treatment •   laparotomy – resection of non‐viable bowel and anastomosis or ileostomy or colostomy However peritoneal drainage alone is associated with worse neurodevelopmental outcome than laparotomy Key point NEC is often suspected before all the classic clinical features are present. Treatment may need to be started whilst awaiting investigation results and before the clinical course becomes evi- dent. Surgical consultation should be initiated early.

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Neonatology at a Glance Third Edition. Edited by Tom Lissauer Avroy A. Fanaroff Lawrence Miall and Jonathan Fanaroff. © 2016 John Wiley Sons Ltd. Published 2016 by John Wiley Sons Ltd. 86 The preterm infant Bronchopulmonary dysplasia BPD develops in 20−30 of very low birthweight infants and is a major cause of morbidity and mortality. The incidence is highest in the extremely preterm Fig. 37.1 it is uncommon in infants born after 32 weeks’ gestational age. Definition A consensus conference recommended the following definitions: •  oxygen requirement at 28 days of age used in many trials •  oxygen requirement and characteristic chest X‐ray at 28 days •  oxygen requirement confirmed by physiologic challenge at 36 weeks’ postmenstraual age. This is ascertained by checking if oxygen saturation is maintained in spite of a stepwise reduction in supplemental oxygen until breathing room air. This is the most widely used definition as it identifies infants most likely to have long‐term complications. The conference also recommended that the term ‘bronchopulmo- nary dysplasia’ be used rather than ‘chronic lung disease’. Predisposing factors Bronchopulmonary dysplasia is a multifactorial disorder Fig. 37.2. It most often develops in extremely preterm infants with sur- factant deficiency or immature lungs who require mechanical ventilation. Higher pressures causing barotrauma excessive tidal volumes causing volutrauma high oxygen concentration and longer time on mechanical ventilation all contribute to an increased risk of developing bronchopulmonary dysplasia. However with current respiratory management of minimal venti- latory support bronchopulmonary dysplasia is increasingly seen in extremely preterm infants with minimal lung disease during the first few days of life and whose lungs are subjected to minimal barotrauma and volutrauma. Developmental arrest or delay in pulmonary maturation is thought to be primarily responsible ‘new’ BPD where the histology shows minimal airway lesions pulmonary edema with little fibrosis but decreased alveolar divi- sions and vascular development. There may be a genetic predis- position. This contrasts with the postnatal insults causing structural lung injury which were the main causes of bronchopul- monary dysplasia in the past ‘old’ BPD where there was emphysema and atelectasis interstitial fibrosis smooth muscle hyperplasia of the airways and pulmonary vessels and right ven- tricular hypertrophy. Clinical features In addition to the need for oxygen with or without respiratory support: •  skin pallor •  tachypnea •  hyperexpanded chest •  chest retractions Bronchopulmonary dysplasia 37 80 60 30 50 20 0 Gestational age weeks BPD 40 70 10 24 24–26 27–29 30–32 Fig. 37.1 Incidence of bronchopulmonary dysplasia BPD at 36 weeks by gestational age at birth in VLBW very low birthweight infants. Vermont − Oxford Network data for 2012. Preterm Inammation Mechanical ventilation Oxygen toxicity antioxidant deciency Infection +/– chorioamnionitis Poor nutrition PDA patent ductus arteriosus Excessive uid intake Bronchopulmonary dysplasia BPD Airways damage Airways obstruction Atelectasis collapse and emphysema overdistension Vascular injury Pulmonary edema Pulmonary hypertension Interstitial lung damage Arrest or delay in pulmonary maturation Fibrosis Number of alveoli reduced Fig. 37.2 Pathogenesis of bronchopulmonary dysplasia.

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Bronchopulmonary dysplasia 87 •  auscultation – crackles and wheezes •  fluid retention heart failure •  recurrent pneumonia •  growth failure. Investigations •  chest X‐ray Fig. 37.3 •  overnight oxygen saturation monitoring. Management Management of BPD includes: •  Oxygen and respiratory support low‐flow nasal cannula high‐ flow nasal therapy CPAP or mechanical ventilation but with oxy- genation SaO 2 targeted to 91–95 Fig. 37.4. •  Attention to nutritional problems of: – increased caloric requirements 130–150 kcal/kg because of increased work of breathing – delay in establishing feeding – gastroesophageal reflux may result in aspiration – prevention of osteopenia of prematurity with phosphate supplements. •  Drug therapy may be considered: – inhaled bronchodilators short-term benefit only – diuretics transient improvement only – corticosteroid therapy see below. – sildenafil if severe pulmonary hypertension. Long‐term consequences of severe BPD • Prolonged oxygen therapy and non-invasive or invasive respiratory support may be required for many months. May need to be provided at home. •  Feeding problems requiring prolonged nasogastric/gastrostomy feeding. •  Inguinal hernias from raised intra‐abdominal pressure and muscular weakness associated with suboptimal growth. •  Risk of RSV respiratory syncytial virus infection causing bron- chiolitis risk of hospitalization reduced by passive immunization with monoclonal antibody palivizumab. •  Rehospitalization because of respiratory infection. •  Increased risk of asthma and sleep‐disordered breathing including obstructive sleep apnea. •  Increased risk of neurodevelopmental problems. • Rarely death from acute chest infection or cor pulmonale pulmonary hypertension. Strategies for prevention These include: •  antenatal corticosteroids •  surfactant therapy •  minimizing exposure to mechanical ventilation •  non‐invasive respiratory support CP AP or high flow nasal therapy •  avoidance of fluid overload •  closure of patent ductus arteriosus •  vitamin A given in some centers •  mesenchymal stem cells via endotracheal tube – encouraging results in initial therapeutic trials. Fig. 37.3 Chest X‐ray in bronchopulmonary dysplasia showing generalized patchy opacification of lung fields lung collapse cystic changes and overdistension of the lungs. Courtesy of Dr Sheila Berlin. Fig. 37.4 Infant with bronchopulmonary dysplasia receiving low‐flow nasal oxygen. Question What is the controversy about postnatal corticosteroid therapy In infants still requiring oxygen at several weeks of age corticosteroid therapy was widely used as it dramatically reduces their oxygen requirement and allows weaning from mechanical ventilation. But high‐dose corticosteroid therapy is associated with serious side‐effects especially if prolonged: •  short term – high blood pressure hyperglycemia increased risk of sepsis • longer term – Cushingoid facies hypertrophic cardio- myopathy osteopenia failure of growth in length and head circumference and increase in cerebral palsy. As a result of the increased incidence of cerebral palsy and other side‐effects it is now used sparingly in ventilator‐dependent infants using only a low dose and as short a course as possible see Fig. 26.1 showing reduction in use of postnatal corticoste- roid therapy.

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Neonatology at a Glance Third Edition. Edited by Tom Lissauer Avroy A. Fanaroff Lawrence Miall and Jonathan Fanaroff. © 2016 John Wiley Sons Ltd. Published 2016 by John Wiley Sons Ltd. 88 The preterm infant Survival in high‐income countries of extremely preterm 28 weeks infants has increased dramatically and many babies of 23–24 weeks of gestation now survive Figs.  27.6 and 27.7. However this increased survival has been achieved at the expense of high rates of neurodisability although recent outcome data suggest that the neu- rodisability rates in early life are falling Fig. 38.1. The development of VLBW infants is monitored in a neonatal follow‐up program see Chapter 72 or in the community. Data from these programs can then be compared with other programs but such comparisons may be misleading if based on an individual unit as the sample size will be small with wide variations from year to year and there may be differences in the demography of the mothers and referral patterns. The most meaningful outcome data are regional or national provided that the data collection is standardized and complete. A follow‐up rate greater than 90 is desirable for all cohorts but difficult to achieve. Growth At discharge from hospital over 90 of VLBW infants are below the 10th centile for weight length and head circumference. Many show catch‐up growth in the first 2–3 years first of head circumference then weight and then length. Growth is better if the infant is in good health. Catch‐up growth may occur across childhood and adoles- cence but may be less in infants with intrauterine growth restriction. Medical complications These include: •  bronchopulmonary dysplasia BPD – may require additional oxygen therapy for many months •  pneumonia/wheezing/asthma – more common with BPD •  bronchiolitis from RSV respiratory syncytial virus infection hospitalization reduced by giving RSV monoclonal antibody palivizumab •  gastroesophageal reflux – especially with BPD •  complex nutritional and gastrointestinal disorders – following necrotizing enterocolitis or gastrointestinal surgery •  inguinal hernias – require surgical repair. Rehospitalization rate is increased mainly for respiratory dis- orders and surgical repair of inguinal hernias. Disability and impairment Neurodisability at 18 months to 2 years is usually classified Table 38.1 as: •  severe – unable to walk very low IQ blind or profoundly deaf •  moderate – walk with support IQ 55–70 hear with aids •  mild – less severe impairments IQ 70–85. Many studies combine the severe and moderate categories. The risk of developing cerebral palsy rises steeply as gestational age falls Fig. 38.2 but severe cerebral palsy with functional impairment has become relatively uncommon comprising only 8 of babies at 23 weeks and 5−6 of babies at 24−25 weeks of gestation. 1–2 of extremely preterm infants have hearing impair- ment requiring amplification. 1 are blind in both eyes but a much greater proportion have refraction errors requiring glasses and squints probably related to resolved retinopathy of prematurity. Cognitive impairment By far the most common impairments following very preterm birth are learning difficulties which become apparent when performance is compared with that of their peers at nursery and become increas- ingly evident during school years Fig. 38.3 The prevalence of cognitive impairment and of other associated difficulties increases with decreasing gestational age at birth Fig. 38.4. In addition children may have difficulties with: •  fine motor skills e.g. threading beads •  concentration with short attention span Outcome of preterm infants 38 60 254 24 161 241 41 68 12 36 100 80 60 40 20 0 Percent of total n 496 n 749 n 233 1982–1989 1990–1999 2000–2002 158 306 117 No impairment Lost to follow-up Died Impairment 3 Fig. 38.1 Neurodevelopmental outcome for babies of 1000 g birthweight over 20 years in a tertiary perinatal center. The proportion with impairment has decreased. Source: Wilson‐Costello D. et al. Pediatrics 2007 119: 37–45. 37+ 80 60 40 20 0 Prevalence per 1000 livebirths 29 29–32 33–36 Gestational age weeks Fig. 38.2 Gestation‐specific prevalence of cerebral palsy in 4 Child Register 1984–2003. Data from Surman G. et al. 4Child Annual Report 2009. Oxford: National Perinatal Epidemiology Unit 2009.

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Outcome of preterm infants 89 •  abstract reasoning e.g. mathematics •  processing several tasks simultaneously. Deficits in working memory and processing of information seem to underpin many of the difficulties found at middle school age. Behavioral outcomes Children born very preterm have more behavioral difficulties than their term peers. Some have autism spectrum disorder. Although uncommon a typical phenotype has been characterized with ADHD‐I where inattention rather than hyperactivity predomi- nates as well as anxiety and reduced social skills. The prevalence of behavioral difficulties is related to gestational age as with learning outcomes indeed there is much comorbidity Fig. 38.4. School performance Many very preterm children are either not ready to start school at the standard chronological age or are kept back a year. At school age problems with low IQ poor executive function and behavior are evident in the need for special educational support. Around two‐ thirds of UK children born at 26 weeks of gestation have special needs at 11 years including learning behavior and physical support needs and 13 require separate educational provision Fig. 8.2. Strategies to support the specific educational difficulties of very preterm infants are being developed. There are also concerns about adult mental health outcomes following childhood behavioral disorders this will be clarified by longitudinal studies which are now evaluating survivors into their fourth decade. Table 38.1 Definitions of disability for use at 18–24 months of corrected age in follow‐up of very preterm infants. Source: Classification of Health Status at 2 Years as a Perinatal Outcome. London: BAPM 2008. Severe neurodevelopmental disability Moderate neurodevelopmental disability Domain Any one of below: Any one of below: Motor Cerebral palsy with GMFCS level 3 4 or 5 Cerebral palsy with GMFCS level 2 Cognitive function Score 3 standard deviations below norm DQ 55 Score 2 standard deviations below norm DQ 55–70 Hearing No useful hearing even with aids profound 90 dBHL Hearing loss corrected with aids usually moderate 40–70 dBHL or Some hearing but loss not corrected by aids usually severe 70–90 dBHL Speech and language No meaningful words/signs or unable to comprehend cued sign Some but fewer than 5 words or signs and able to comprehend cued sign Vision Blind or can only perceive light Moderately reduced vision or blind in one eye Other disabilities Respiratory Requires continued respiratory support or oxygen Limited exercise tolerance Gastrointestinal Requires PN NG or PEG feeding On special diet or has stoma Renal Requires dialysis or awaiting transplant Renal impairment requiring treatment or special diet GMFCS Gross Motor Function Classification System: level 2 – walks with limitations level 3 – walks using hand‐held mobility device level 4 – self‐mobility with limitations may use powered wheelchair level 5 – manual wheelchair. DQ developmental quotient PN parenteral nutrition NG nasogastric PEG percutaneous endoscopic gastrostomy. 2.5 years6 years 11 years 0 20 40 60 80 100 No impairment Mild disabilty/ Impaired Moderate disabilty Severe disability Age of assessment Percent children assessed Fig. 38.3 Evolution of disability from birth to 11 years in births 22–25 weeks of gestation in the UK. About 55 have moderate or severe impairment at 11 years after allowing for loss of children with severe disability from follow‐up. Source: Johnson S. et al. Pediatrics 2009 124: e249–e257. School performance 50 30 20 10 0 Percent Limited academic skills Impaired cognitive function Behavioral problems Special educational placement 750 g 750–1499 g Term 40 Fig. 38.4 Increased incidence of impaired cognitive function academic skills behavioral problems and special education placement in infants with birthweight below 750 g and 750–1499 g compared with term infants. Adapted from Hack M. et al. School‐age outcomes in children with birthweights under 750 g. N Engl J Med 1994 331: 753–759.

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Neonatology at a Glance Third Edition. Edited by Tom Lissauer Avroy A. Fanaroff Lawrence Miall and Jonathan Fanaroff. © 2016 John Wiley Sons Ltd. Published 2016 by John Wiley Sons Ltd. 90 Neonatal problems Respiratory distress in term infants 39 Overview The clinical features of respiratory distress are shown in Fig. 39.1. Monitoring •  Oxygen saturation maintain 95 in term infants. •  Respiratory rate heart rate BP temperature. •  Arterial blood gases if needing oxygen 30. Investigations •  Chest X‐ray – confrms respiratory disease look for pneumo- thorax diaphragmatic hernia lung malformations. •  Complete blood count blood cultures C‐reactive protein consider lumbar puncture. Management •  Airway and breathing – oxygen/nasal high‐fow therapy/CPAP/ mechanical ventilation as required. •  Circulatory support if necessary. •  Intravenous fuids or frequent nasogastric feeds. •  Intravenous antibiotics – broad‐spectrum coverage. Respiratory distress: Tachypnea RR 60/min + Nasal aring + Grunting prolonged expiration against closed glottis + Chest retraction – suprasternal – intercostal – subcostal + Cyanosis if severe Fig. 39.1 Clinical features of respiratory distress see video: Signs of respiratory distress. Causes Fig. 39.2 Surfactant deciency Diaphragmatic hernia Tracheo-esophageal stula Pulmonary hypoplasia Pleural effusion chylothorax Milk aspiration Airway obstruction e.g. choanal atresia Lung anomalies – congenital pulmonary airway malformation CPAM lobar emphysema pulmonary sequestration Neuromuscular disorders Severe anemia Metabolic acidosis inborn error of metabolism Causes of respiratory distress in term infants Pneumonia/sepsis Meconium aspiration Pneumothorax Congenital heart disease/heart failure Persistent pulmonary hypertension of the newborn PPHN Hypoxic–ischemic encephalopathy Less common Transient tachypnea of the newborn Common Rare Fig. 39.2 Causes of respiratory distress in term infants. Common causes Transient tachypnea of the newborn TTNB This is by far the most common cause of respiratory distress in term infants. Caused by delay in the absorption of lung liquid Figs. 39.3 and 39.4 especially following elective cesarean sec - tion. Absence of pressure on the thorax squeezing lung liquid from the chest is thought to be a factor. However clearance of fetal lung fluid is largely dependent on reabsorption of alveolar fluid via sodium channels in the lung epithelium which is influenced by the level of circulating catecholamines. The lower concentration of circulating catecholamines particularly following elective delivery results in reduced absorption of lung liquid. Usually settles within first day or two of life but may have low oxygen requirement and tachypnea for several days.

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Respiratory distress in term infants 91 Less common causes Pneumonia •  Risk factors – prolonged rupture of the membranes PROM maternal fever chorioamnionitis. •  All infants with respiratory distress should be started on broad‐ spectrum antibiotics until the results of the blood culture C‐ reactive protein CRP complete blood count CBC lumbar puncture if performed are known. •  Group B streptococcus is the most common cause. Meconium aspiration The proportion of infants who pass meconium at birth increases with gestational age affecting 20–25 at 42 weeks. Asphyxiated infants may start gasping and aspirate meconium before delivery. At birth infants may inhale thick meconium see Chapter 13 which results in mechanical obstruction chemical pneumonitis and inactivation of surfactant Fig. 39.5. There is a high incidence of air leak pneumothorax. Surfactant therapy may be beneficial. Mechanical ventilation is often required. Accompanying persistent pulmonary hypertension PPHN may require nitric oxide and sometimes ECMO extracorporeal membrane oxygenation i.e. cardiopulmonary bypass. Sildenafil may be considered. Pneumothorax see Chapter 29 May occur spontaneously or more commonly as a complication of mechanical ventilation or CPAP. Diagnosed clinically with unilat- eral decreased breath sounds or by transillumination of the chest Fig. 39.6 or on chest X‐ray. Fig. 39.3 Lung liquid in the mouth of a newborn term infant with transient tachypnea of the newborn receiving nasal CPAP. a b Fig. 39.4 Chest X‐ray in transient tachypnea of the newborn showing fluid in the horizontal fissure and some streaky infiltrates with hyperinflation and perihilar haziness a. Some hours later the perihilar haziness has cleared but there is still fluid in the horizontal fissure and hyperinflation b. Fig. 39.5 Chest X‐ray in meconium aspiration. There is hyperinflation of the lungs flattened diaphragm and widespread patchy areas of collapse evident in coarse irregular densities with areas of overinflation. There is a tracheal tube and umbilical artery catheter. Courtesy of Dr Sheila Berlin.

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92 Neonatal problems Heart failure see Chapter 49 Check for evidence of heart failure – including active precordium enlarged heart gallop rhythm heart murmurs and enlarged liver. and that femoral pulses are palpable reduced in coarctation of the aorta hypoplastic left heart syndrome. Persistent pulmonary hypertension of the newborn PPHN Pulmonary hypertension leads to right‐to‐left shunting of blood Fig. 39.7: •  across the patent foramen ovale •  across the patent ductus arteriosus •  intrapulmonary. Causes Usually secondary to: •  birth asphyxia •  meconium aspiration •  sepsis •  diaphragmatic hernia. Occasionally it is the primary disorder. Presentation •  Cyanosis or difficulty in oxygenation. •  Reduction between pre and post ductal saturations. Specific investigations •  Chest X‐ray – shows underlying cause or may be normal or show pulmonary oligemia diminished vascularity. •  Echocardiography is needed to exclude congenital heart dis- ease. It can also allow estimation of the magnitude of pulmonary hypertension see Chapter 82. Management •  Oxygen. •  Optimize mechanical ventilation. •  Circulatory support as required. •  Consider surfactant therapy. •  Pulmonary vasodilator – inhaled nitric oxide NO. Oral or i.v. sildenafil may be considered. •  Consider high‐frequency oscillatory ventilation HFOV. • Extracorporeal membrane oxygenation ECMO as rescue therapy for severe respiratory failure. Rare causes Surfactant deficiency Rare in term infants. May occur in infants of maternal diabetes or with surfactant protein B deficiency a rare genetic disorder. Diaphragmatic hernia Main problems • Pulmonary hypoplasia as herniated bowel reduces lung development in the fetus. •  Lung compression by the bowel which increases in size as air enters it. •  Pulmonary hypertension PPHN – pulmonary arterioles reduced in number and size and smooth muscle is hypertrophied. •  Other anomalies – present in 15–25. Incidence 1 in 4000 births. Most common site Left‐sided hernia of bowel through the posterolateral foramen of the diaphragm Bochdalek. Fig. 39.6 Transillumination of the chest showing the presence of pneumothorax. Across foramen ovale Across patent ductus arteriosus Intrapulmonary Fig. 39.7 Pulmonary hypertension leads to right‐to‐left shunting.

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Respiratory distress in term infants 93 Presentation •  Prenatal – on ultrasound screening polyhydramnios. Most identified antenatally. For antenatal management with fetal endo - scopic tracheal occlusion see Chapter 4. •  Resuscitation – failure to respond deteriorates with bag and mask ventilation. •  Respiratory distress – but onset may be delayed if underlying lung well developed. Physical signs •  Respiratory distress. •  Asymmetry of chest. •  Reduced air entry on affected side. •  Apex beat displaced. •  Scaphoid abdomen – from reduced content of bowel. Diagnosis X‐ray‐chest and abdomen Fig. 39.8. Management •  Intubate and ventilate from birth. Gentle ventilation allowing permissive hypercapnia i.e. PaCO 2 60 mmHg 8kPa but main- taining pH 7.25. Avoid mask ventilation. •  Pass large nasogastric tube and apply suction. •  Stabilize and support circulation. •  Early PN parenteral nutrition. •  Surgical repair – delay until stable and PPHN is resolving. •  Nitric oxide for PPHN sildenafil may be considered. •  Extracorporeal membrane oxygenation ECMO – pre‐ and post‐ surgery in selected cases. Mortality 20–30. Milk aspiration Risk of aspiration if infant has cleft palate neurologic disorder affecting sucking and swallowing or has respiratory distress. Infants with bronchopulmonary dysplasia often have gastroesoph - ageal reflux which predisposes to aspiration. Fig. 39.8 Chest X‐ray showing diaphragmatic hernia. There is bowel in the left chest and the heart and trachea are displaced to the right. There is a gavage nasogastric tube umbilical artery and venous catheters and a radio-opaque umbilical tie.

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Neonatology at a Glance Third Edition. Edited by Tom Lissauer Avroy A. Fanaroff Lawrence Miall and Jonathan Fanaroff. © 2016 John Wiley Sons Ltd. Published 2016 by John Wiley Sons Ltd. 94 Neonatal problems Cleft lip and palate Incidence – 1 in 1000 live births. Inheritance – polygenic but increased risk if family history. Varies in severity from a mild unilateral cleft lip to severe bilateral cleft palate Figs. 40.1 and 40.2. It is increasingly diagnosed on antenatal ultrasound scanning. This allows counseling of the parents and family before birth. Showing parents photographs is often helpful to minimize the shock at birth as the defect is unsightly photos after surgery provide reassurance that the defect can be corrected Fig. 40.3. A specialist multidisciplinary team from a tertiary center is required to provide: •  a key worker usually a specialist nurse for advice and to act as advocate for the child and family. Will visit the parents shortly after birth and also gives advice about feeding. •  craniofacial surgeon orthodontist speech and language therapist and audiologist. •  surgical repair of the lip usually at 3 months of age for best long‐ term results but some centers perform it immediately after birth. The palate is usually repaired at 6–12 months of age. Further sur- gery may be required when the child is older. Long‐term complications include middle ear infection and otitis media with effusion difficulties with speech and orthodontic problems. There are active self‐help groups for parents who provide information and practical help. In the US there is Wide Smiles in the UK it is CLAPA the Cleft Lip and Palate Association. Upper airway disorders 40 a c b d Fig. 40.1 Types of cleft lip and palate. a Unilateral cleft lip. b Unilateral cleft lip and palate. c Bilateral cleft lip and palate. d Cleft palate. Fig. 40.2 Bilateral cleft lip and palate. The deformity looks very unsightly. Antenatal ultrasound diagnosis allows preparation before birth. a b Fig. 40.3 Showing parents photographs a before and b after cleft lip surgery is reassuring. Courtesy of Mr Alistair Smyth. Questions Can babies with a cleft lip and palate breast‐feed Yes it is often possible with expert assistance and encouragement. What help with feeding can be provided for parents if their infant has a cleft lip and palate Special nipples teats are available and a dental plate may need to be made to occlude the cleft palate.

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Upper airway disorders 95 Choanal atresia The condition A rare bony obstruction between the nasal cavity and the naso- pharynx Fig. 40.4. Main problem Bilateral lesions cause respiratory distress and cyanosis immedi- ately after birth due to airways obstruction as newborn infants are obligatory nose breathers. The airway obstruction is relieved on crying or opening the mouth. Treatment •  Initial – insert oral airway or tracheal tube. •  Definitive – surgical correction. Pierre Robin sequence This comprises Fig. 40.5: •  micrognathia small jaw •  posteriorly displaced tongue •  posterior palatal defect •  increased incidence of other anomalies especially of the heart. Most serious complication is respiratory obstruction may lead to hypoxia and cor pulmonale pulmonary hypertension. Management •  Avoid obstruction by the tongue: – nurse prone – may need CPAP continuous positive airway pressure via nasopharyngeal tube. •  Micrognathia and airway obstruction improve over the first 2 years. •  Surgery to the posterior palate is usually performed at about 1 year. •  Feeding can be problematic and initially gavage nasogastric feeding may be required. Fig. 40.4 Choanal atresia on MRI scan. There is a bony bar across the posterior nasal space arrow. Fig. 40.5 Pierre Robin sequence showing micrognathia. Courtesy of Dr David Clark.

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Neonatology at a Glance Third Edition. Edited by Tom Lissauer Avroy A. Fanaroff Lawrence Miall and Jonathan Fanaroff. © 2016 John Wiley Sons Ltd. Published 2016 by John Wiley Sons Ltd. 96 Neonatal problems Visible jaundice occurs in more than 80 of term and preterm infants during the first week. Bilirubin metabolism is shown in Fig. 41.1. Elevated bilirubin levels are due to: •  High hemoglobin Hb concentration at birth so considerable heme degradation. •  A newborn’s red blood cell lifespan in shorter than an adult’s. •  Liver enzyme conjugation is reduced. •  Enterohepatic circulation is enhanced. This ‘physiologic’ jaun- dice peaks at 2–5 days and then usually clears by 14 days but may persist for several weeks in breast‐fed infants. Significance of severe hyperbilrubinemia Kernicterus describes bilirubin encephalopathy. In acute bilirubin encephalopathy there may be hyptonia lethargy poor feeding irri - tability high‐pitched cry fever apnea hypertonia with arching of the neck and trunk-opisthotonus Fig. 41.2 seizures coma and death. In chronic bilirubin encephalopathy there is permanent neurologic injury resulting from the deposition of unconjugated bilirubin in the basal ganglia and brainstem nuclei Fig. 41.3. Long‐term consequences include dental dysplasia with yellow staining of the teeth high‐ frequency sensorineural hearing loss auditory neuropathy paralysis of upward gaze of the eyes choreoathetoid cerebral palsy and learning difficulties. Kernicterus is rare in developed countries. Jaundice 41 Increased number or destruction of red blood cells: Polycythemia Bruising/cephalhematoma Hemolysis – rhesus and other red cell antibodies G6PD deciency spherocytosis Maternal diabetes Increased enterohepatic circulation: Preterm Breast milk Bowel obstruction Conjugated bilirubin Excretion in bile Decreased conjugation: Preterm Crigler–Najjar syndrome Gilbert syndrome Low albumin Hypoxia Metabolic acidosis Infection Free unconjugated bilirubin Can cross blood–brain barrier and cause kernicterus Enterohepatic circulation Stercobilinogen stool Aggravating factors Unconjugated bilirubin bound to albumin Conjugation glucuronyl transferase Breakdown of hemoglobin and other heme proteins Urobilinogen Fig. 41.1 Metabolism of bilirubin. Bilirubin is the product of the metabolism of hemoglobin and other heme proteins. The initial breakdown product is unconjugated bilirubin indirect bilirubin which is carried in the blood bound to albumin. When the albumin binding is saturated free unconjugated lipid‐soluble bilirubin can cross the blood–brain barrier. Unconjugated bilirubin bound to albumin is conjugated in the liver direct bilirubin which is excreted via the biliary tract into the gut. Some bilirubin is reabsorbed from the gut enterohepatic circulation. Risk factors for jaundice are shown in green. Fig. 41.2 Opisthotonus from kernicterus. This is now rarely seen in developed countries. Question What level of bilirubin is safe There is no single level of bilirubin that causes kernicterus but in term infants it is extremely uncommon with bilirubin levels below 26 mg/dL 450 μmol/L. It may occur at lower levels if infants are preterm or sepsis hypoxia seizures acidosis or hypoalbuminemia are present.

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Jaundice 97 Causes of early‐onset jaundice 24 hours Table 41.1 Hemolysis Jaundice within 24 hours of birth is most likely to be hemolytic. Bilirubin levels may rise rapidly. Rhesus disease see Chapter 5 This is the most severe form of hemolytic disease with onset in utero. At birth infants may have anemia hydrops edema jaun - dice and hepatosplenomegaly. It is now uncommon because of anti‐D prophylaxis 0–2/100 000 live births in developed countries but more common in resource‐limited countries. ABO incompatibility •  Mother’s blood type O infant’s blood type A or B. Maternal anti‐A or anti‐B IgG crosses the placenta causing hemolysis. • Direct antibody test DAT or Coombs test is positive but positive test is poor predictor of significant jaundice. •  Generally less severe than rhesus but can still cause significant hemolysis and jaundice. Onset is after birth. •  Hemolysis may progress during the first few weeks of life and requires monitoring for anemia. Minor antigen Incompatibility Kell Duffy Kidd etc. •  Infant’s direct antibody test DAT or Coombs test is positive. •  Usually moderate hemolysis and jaundice. G6PD glucose‐6‐phosphate dehydrogenase deficiency This X‐linked disorder is the most common enzyme defect in the world affecting 200–400 million people. It affects males but females can have a mild form especially if they also have Gilbert syndrome liver enzyme defect. It can cause severe jaundice and  kernicterus in people originating from central Africa the Mediterranean or Middle or Far East. It is diagnosed by measuring G6PD activity in red blood cells. However during hemolytic crises this may be misleadingly elevated owing to the increased reticulo- cytes which have a higher enzyme concentration. A repeat assay is required to avoid missing the diagnosis. Affected infants should avoid certain medications i.e. some antimalarials and antibiotics contact with mothballs naphthalene and eating fava broad beans when older. Hereditary spherocytosis Red blood cells are spherical with limited deformability causing splenic sequestration and hemolysis. Autosomal dominant inheri- tance – family history positive in 75. Uncommon. Congenital infection Increases hemolysis and may impair conjugation causing elevated conjugated bilirubin. Other stigmata of congenital infection will be present. Causes of jaundice 24 hours to 2 weeks Breast‐feeding jaundice Common. Exacerbated if there is difficulty in establishing breast‐ feeding. Cause uncertain may be related to low volume of breast milk and increased enterohepatic circulation of bilirubin. Breast‐ feeding should be continued but support may be needed. Continues beyond 2 weeks of age in up to 15 of breast fed infants. Infection Always consider infection including urinary tract infection. Jaundice occurs because of hemolysis impaired conjugation reduced fluid intake and increased enterohepatic circulation. Other causes These include: •  hemolysis – may develop after first 24 hours of life •  bruising cephalhematoma •  polycythemia • liver enzyme defects e.g. Crigler–Najjar syndrome Gilbert syndrome •  gastrointestinal obstruction e.g. pyloric stenosis •  metabolic disorders e.g. galactosemia. Fig. 41.3 Cross‐section of the brain at autopsy showing yellow staining predominantly in basal ganglia from deposition of unconjugated bilirubin. Table 41.1 Causes of jaundice by age of onset. 24 hours old 24 hours to 2 weeks old Prolonged jaundice Hemolytic: Breast‐feeding jaundice Unconjugated: •  Rhesus disease Hemolytic •  Breast milk jaundice •  Hypothyroidism •  Gastrointestinal obstruction •  Sepsis •  Liver enzyme defects Conjugated: •  Neonatal hepatitis syndrome •  ABO incompatibility Infection Bruising/ cephalhematoma Gastrointestinal obstruction Polycythemia Metabolic disorders Liver enzyme defects •  Minor antigen incompatibility •  G6PD defciency •  Hereditary spherocytosis Congenital infection •  Biliary atresia

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98 Neonatal problems Clinical examination and assessment Jaundice is clinically detectable from skin color on blanching the skin with digital pressure or yellow color of the sclerae when bili- rubin exceeds 5 mg/dL 85 μmol/L. It starts on the head spreads to the abdomen and then to the limbs. It is harder to detect in preterm and dark‐skinned infants. The severity of jaundice cannot be reliably assessed by clinical examination. However an infant who is not jaundiced clinically is unlikely to have significant hyperbilirubinemia. If jaundiced also check for: •  pallor •  evidence of infection •  bruising cephalhematoma •  hepatosplenomegaly hemolysis •  weight loss dehydration •  family history of neonatal jaundice. Investigations Term infants who become jaundiced should have a transcutaneous bilirubin TcB measured. However a serum measurement should be obtained if: •  the infant is 24 hours old • transcutaneous bilirubinometer measurement 13 mg/dL 230 μmol/L 14.5 mg/dL 250 μmol/L in the UK •  transcutaneous bilirubinometer TcB not available •  infant ≤34 weeks’ gestational age •  on phototherapy treatment. Further tests other than total bilirubin that may be required but in most infants no pathologic cause is found •  direct conjugated bilirubin •  complete blood count reticulocyte count and smear for red cell morphology •  blood packed cell volume or hematocrit •  blood group mother and baby •  direct antibody test DAT or Coombs test •  G6PD testing •  microbiological cultures of blood urine and/or cerebrospinal fluid for infection. Management The need for treatment is determined by plotting the total bilirubin level on a gestation‐specific graph of bilirubin against age. This will determine whether: •  no treatment is needed •  bilirubin should be repeated in 6–12 hours •  to start phototherapy •  to perform exchange transfusion. Treatment will change according to the absolute level of bili- rubin reached and the rate of rise on serial measurements start if bilirubin rising at 0.5 mg/dL/h 8.5 μmol/L/h. The evidence for treatment thresholds is very limited but national guidelines assist uniformity of practice see American Academy of Pediatrics in US – Table 41.2 NICE guidelines in the UK. Different cut‐off criteria are used for preterm infants for whom the treatment threshold is lower NICE guidelines include graphs for different gestational ages – see Appendix. If an exchange transfusion is being considered a low serum albumin may be an additional risk factor for kernicterus. Other treatment to be considered: •  Ensure baby is well hydrated. •  Sepsis – requires investigation and treatment. Phototherapy Conventional phototherapy units use a blue–green light wave- length 425–475 nm above the baby which converts unconjugated bilirubin to harmless isomers. If the bilirubin is rising rapidly or does not fall after 6 hours of treatment then add in multiple units ideally with one source underneath the infant. Phototherapy is most effective when there is an effective light source LED lights high irradiance usually ≥30 μW/cm 2 /nm the light is as close to the infant as possible if LED lights are used can be as close as 10 cm from the infant with maximum skin exposure. Disadvantages of phototherapy: •  Separates baby and parents. •  Eyes need to be covered. • Bronze‐baby syndrome if phototherapy given with elevated conjugated bilirubin. •  Unstable temperature while in open crib cot with majority of skin exposed. •  Increased insensible water loss less with modern LED light sources. •  Slightly loose more frequent stools. Exchange transfusion Baby’s blood is removed in aliquots usually twice blood volume ‘double volume exchange’ 2 × 90 mL/kg and replaced with trans- fused blood see Chapter 78. Removes bilirubin and hemolytic antibodies and corrects anemia. Complications include thrombosis embolus volume overload or depletion metabolic abnormalities infection coagulation abnormalities and death 1. Intravenous immunoglobulin IVIG Can be used in rhesus disease or ABO incompatibility when total bilirubin levels are rising despite continuous multiple phototherapy to try to prevent the need for exchange transfusion. Discharge and follow‐up In view of the re‐emergence of kernicterus in otherwise healthy infants particularly at 35–37 weeks’ gestation the American Academy of Pediatrics 2004 recommends predischarge measurement of bilirubin and/or assessment of clinical risk

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Jaundice 99 factors for the development of jaundice for all infants. The risk of developing significant hyperbilirubinemia in healthy term and near‐term newborns can be determined by plotting the bilirubin level on an hour‐specific chart Fig. 41.4. It also recommends a follow‐up assessment for jaundice depending on their length of stay in the nursery: •  discharge at 24 hours follow‐up by 72 hours of life •  discharge at 24–48 hours follow‐up by 96 hours of life •  discharge at 48–72 hours follow‐up by 120 hours of life. Earlier assessment may be needed if risk factors are present. In the UK the recommendation is further assessment by 48 hours of age if risk factors are present gestational age 38 weeks a previous sibling had neonatal jaundice requiring phototherapy breast‐fed visible jaundice in the first 24 hours of life otherwise by 72 hours of age. Parents should also be given written and verbal information about jaundice. Prolonged jaundice 14 days Jaundice present at more than 2 weeks of age for term or 3 weeks for preterm infants can be considered prolonged jaundice and requires further assessment. First it needs to be determined if the jaundice is unconjugated or conjugated. Unconjugated jaundice Causes are: •  breast milk jaundice – due to increased enteric reabsoption can last for several months • hypothyroidism – usually identified on newborn blood spot screening •  gastrointestinal obstruction e.g. pyloric stenosis •  sepsis •  liver enzyme disorders. Conjugated jaundice direct bilirubin 1.5 mg/dL 25 μmol/L The infant will pass pale clay‐colored stools no stercobilino- gen and dark urine from bilirubin. Caused by: •  biliary atresia – uncommon but important to identify as delay in surgery adversely affects outcome •  neonatal hepatitis syndrome. Detailed investigation of infants with conjugated jaundice is required. Table 41.2 Indications for phototherapy and exchange transfusion in infants ≥35 weeks’ gestation. Adapted from American Academy of Pediatrics Subcommittee on Hyperbilirubinemia. Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics 2004 114: 297–316. Age hours Phototherapy Exchange transfusion Higher risk Medium risk Lower risk Higher risk Medium risk Lower risk 24 8 mg/dL 137 µmol/L 10 mg/dL 171 µmol/L 12 mg/dL 205 µmol/L 15 mg/dL 257 µmol/L 17 mg/dL 291 µmol/L 19 mg/dL 325 µmol/L 48 11 mg/dL 188 µmol/L 13 mg/dL 222 µmol/L 15 mg/dL 257 µmol/L 17 mg/dL 291 µmol/L 19 mg/dL 325 µmol/L 22 mg/dL 376 µmol/L 72 13 mg/dL 222 µmol/L 15 mg/dL 257 µmol/L 18 mg/dL 308 µmol/L 18 mg/dL 308 µmol/L 21 mg/dL 359 µmol/L 24 mg/dL 410 µmol/L 96 14 mg/dL 239 µmol/L 17 mg/dL 291 µmol/L 20 mg/dL 342 µmol/L 19 mg/dL 325 µmol/L 22 mg/dL 376 µmol/L 25 mg/dL 428 µmol/L Lower risk: ≥38 weeks and well. Medium risk: ≥38 weeks and risk factor listed below or 35–37 weeks and well. Higher risk: 35–37 weeks and risk factor listed below. Risk factors: isoimmune hemolytic disease G6PD deficiency asphyxia significant lethargy temperature instability sepsis acidosis or albumin 3.0 g/dL 30 g/L if measured. 12 0 Percentile 95th 75th 40th 24 20 15 5 10 0 340 255 85 170 0 Serum bilirubin mg/dL Serum bilirubin micromol/L 36 48 84 120 108 96 72 60 Postnatal age hours Low-risk zone High intermediate risk zone Low intermediate risk zone High-risk zone Fig. 41.4 Nomogram for determination of risk of development of severe hyperbilirubinemia for infants ≥35 weeks’ gestation and ≥2.5 kg birthweight. From Bhutani V .K. et al. Predictive ability of a predischarge hour‐specific serum bilirubin for subsequent significant bilirubinemia in healthy term and near‐term newborns. Pediatrics 1999 103: 6–14.

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Neonatology at a Glance Third Edition. Edited by Tom Lissauer Avroy A. Fanaroff Lawrence Miall and Jonathan Fanaroff. © 2016 John Wiley Sons Ltd. Published 2016 by John Wiley Sons Ltd. 100 Neonatal problems Bacterial sepsis Newborn infants are particularly susceptible to bacterial sepsis clinical features of systemic infection with positive bacterial blood culture. Early‐onset sepsis EOS: 72 hours of birth Results from vertical exposure to high bacterial load during birth and few protective antibodies. Late‐onset sepsis LOS: 72 hours after birth Within the hospital mostly from organisms acquired by nosoco- mial transmission from person to person. May also be caused by community‐acquired organisms. Risk factors Early‐onset infection •  Preterm. •  Prolonged rupture of membranes 18 hours. •  Maternal fever in labor 38 °C. •  Chorioamnionitis. •  Maternal colonization with Group B streptococcus GBS. •  Previous infant with invasive GBS disease. Late‐onset nosocomial infection •  Preterm. •  Indwelling venous or arterial catheters or tracheal tube. •  Prolonged antibiotics parenteral nutrition gastric acid suppression therapy. •  Damage to skin from tape skin probes etc. Clinical presentation •  Usually non‐specific deterioration. •  Apnea and bradycardia. •  Respiratory distress/increased ventilatory requirements. •  Slow feeding/vomiting/abdominal distension. •  Fever/hypothermia/temperature instability. •  Tachycardia/collapse/shock. Neonatal infection 42 This is a common and serious problem in the neonatal period affecting 1–5/1000 live births Fig. 42.1. The highest incidence is in very low birthweight VLBW infants see Chapter 34. Congenital infections are considered in Chapter 11. Key point Infection needs to be considered in all sick newborn infants. If suspected a blood culture and other investigations should be performed and antibiotics and supportive therapy started immediately as it may progress and disseminate very rapidly. Neonatal infection Shortly before delivery at birth or postnatally Other organisms some of which have a specic presentation: Gonococcus chlamydia herpes simplex varicella zoster Timing of transmission Early-onset sepsis 72 hours Late-onset sepsis 72 hours Months or years later Time of presentation Transplacental Chorioamnionitis Birth canal Nosocomial Community acquired Birth canal Birth canal Nosocomial Breast milk Route of infection Term Preterm Group B streptococcus Gram-negative organisms Coagulase-negative staphylococcus CONS Gram-negative organisms Group B streptococcus Staphylococcus aureus Enterococcus Fungal HIV Hepatitis B Hepatitis C HPV human papilloma virus Examples Group B streptococcus Gram-negative organisms Listeria monocytogenes Staphylococcus aureus Fig. 42.1 Overview of neonatal infection.

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Neonatal infection 101 •  Purpura or bruising from disseminated intravascular coagulation DIC. •  Irritability/lethargy/seizures. •  Jaundice. •  Rash. •  Reduced limb movement in bone or joint. •  In meningitis late signs: – tense or bulging fontanel – head retraction opisthotonus. •  On monitoring: – hypo/hyperglycemia – neutropenia neutrophilia left shift i.e. increase in immature neutrophils thrombocytopenia – acute phase reactants – raised C‐reactive protein CRP or procalcitonin. – thrombocytopenia coagulopathy Investigations Sepsis work‐up: •  complete blood count CBC differential platelets •  C‐reactive protein/procalcitonin •  blood culture •  urine – microscopy and culture for LOS •  cerebrospinal fluid CSF if indicated •  chest X‐ray if indicated •  sites of infection – consider needle aspirate or biopsy for Gram stain and direct microscopy •  tracheal aspirate if ventilated. Consider: •  placental tissue culture and histopathology •  rapid antigen screen •  blood gases •  coagulation screen. Interpretation of laboratory investigations Blood cultures: •  Gold standard but may be negative if insufficient volume of blood or maternal treatment with intrapartum antibiotics. •  If central line sepsis suspected also take blood sample from it. Blood count – infection is suggested by: •  neutropenia or neutrophilia •  increased ratio of immature bands: total neutrophils •  thrombocytopenia. C‐reactive protein/procalcitonin •  Raised in infection 12 hours after onset also following meco- nium aspiration asphyxia post‐surgery. •  Takes time to rise – may be normal initially. CSF – in meningitis: •  More than 30/mm 3 white blood cells 30 × 10 9 /L but more than 20/mm 3 white blood cells 20 × 10 9 /L and more than 5/mm 3 5 × 10 9 /L neutrophils is suspicious of meningitis. •  Protein – term infants 200 mg/dL 2 g/L. •  Glucose – less than 30 of blood glucose. •  May be able to observe group B streptococci on Gram stain even without any white cells present. Treatment • Supportive care – Airway Breathing Circulation. Check blood glucose. •  Treat with antibiotics immediately on suspicion of sepsis immediately after taking cultures but whilst awaiting results. •  Antibiotic choice depends on local incidence and practice. Early‐onset sepsis Cover Gram‐positive and Gram‐negative organisms. For example: •  penicillin/ampicillin + aminoglycoside e.g. gentamicin/ tobramycin. Late‐onset sepsis Need to also cover coagulase‐negative staphylococcus and enterococcus. For example: •  nafcillin/flucloxacillin + gentamicin •  or cephalosporin e.g. ceftazidime/gentamicin + vancomycin. If central venous catheter in place remove it if unresponsive to antibiotics persistent positive culture Gram‐negative organ- isms cultured or seriously ill. Question When should a lumbar puncture LP be performed If blood culture is positive. If there are clinical features of meningitis. Consider whenever performing sepsis work‐up but delay if infant clinically unstable. Questions How long should antibiotics be continued If blood cultures are negative and CRP/procalcitonin remains normal and no clinical signs of sepsis – stop antibiotics at 36–48 hours. If blood cultures negative but CRP/procalcitonin significantly raised – treat as infected. If blood cultures are positive – treat until clinical improvement and CRP has returned to normal 7–10 days longer if Gram‐ negative or Staphylococcus aureus infection. Meningitis – 14–21 days. Septic arthritis/osteomyelitis – 6 weeks. What supportive strategies are being evaluated Early studies suggest that specific IgG‐ and IgM‐enriched immunoglobulin may be of benefit.

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Neonatology at a Glance Third Edition. Edited by Tom Lissauer Avroy A. Fanaroff Lawrence Miall and Jonathan Fanaroff. © 2016 John Wiley Sons Ltd. Published 2016 by John Wiley Sons Ltd. 102 Neonatal problems Group B streptococcal GBS infection This is the leading cause of bacterial sepsis in term infants. •  Early‐onset infection usually presents with respiratory distress and septicemia more than 90 present in first 24 hours. •  Late‐onset infection – higher proportion with meningitis also causes focal infection in bones or joints. It is a serious disease with 4 mortality. Before active pre- vention the incidence in the US was approximately 1.5/1000 live births for early-onset disease 0.35/1000 for late-onset disease causing a total of 7600 cases of invasive disease per year with 300 deaths. Now the early‐onset infection rate has declined to 0.35/1000 live births. Up to 30 of pregnant women have rectal or vaginal carriage of group B streptococcus. The 2010 CDC Centers for Disease Control and Prevention guideline recommends active prevention by culturing all mothers at 35–37 weeks and offering intrapartum prophylactic antibiotics to those who are positive for group B streptococcus Fig. 43.1. However the efficacy of this practice has not been demonstrated in a systematic review of well‐designed clinical trials. Most infected infants are now preterm or born to unscreened mothers. Listeria monocytogenes •  Rare. From maternal ingestion of unpasteurized milk soft cheeses and undercooked poultry. •  Mother develops flu‐like symptoms. Fetal infection acquired transplacentally or from birth canal. • Causes abortion preterm delivery. Green staining of liquor before term has been claimed to be characteristic. •  Early‐onset infection – usually with pneumonia septicemia and widespread rash. Mortality 30. •  Late‐onset infection – mostly with meningitis. Specific bacterial infections 43 Maternal GBS screening at 35–37 weeks Newborn infant Maternal chorioamnionitis GBS prophylaxis indicated for mother Mother received intravenous antibiotics for ≥ 4 hours before delivery Yes Yes Yes Yes Yes No No Intrapartum antibiotic prophylaxis if: Positive cultur e Previous infant with invasive GBS disease GBS bacteruria in current pregnancy Unknown GBS status and: Delivery at 37 weeks’ gestation Amniotic membrane rupture 18 hours Intrapartum temperature 38°C Not required for cesarian section before onset of labor with intact membranes Full diagnostic evaluation Antibiotic therapy Limited evaluation Antibiotic therapy Signs of neonatal sepsis Routine clinical care Observation for ≥ 48 hours ≥ 37 weeks and duration of membrane rupture 18 hours No No No Observation for ≥ 48 hours Either 37 weeks or duration of membrane rupture ≥ 18 hours Limited evaluatio n Observation for ≥ 48 hours Yes Fig. 43.1 Group B streptococcal GBS prophylaxis guidelines in the US. Full diagnostic evaluation: blood culture complete blood count CBC including white blood cell differential and platelet count chest radiograph if respiratory distress and lumbar puncture if stable and sepsis suspected. Limited evaluation: blood culture at birth and CBC with differential and platelets at birth and/or at 6–12 hours of life. Based on revised CDC guidelines 2010. Question What is the GBS policy in the UK In the UK the incidence of early‐onset GBS is about 0.5/1000 live births and routine culturing of mothers is not recommended UK National Screening Committee 2012. Their recommen- dation is that intrapartum antibiotics: •  should be offered if previous baby with GBS infection •  should be considered if preterm labor prolonged rupture of membranes PROM 18 hours or fever in labor 38 °C.

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Specific bacterial infections 103 Gram‐negative infection •  Less common than group B streptococcal infection. •  Presents as early‐ or late‐onset infection. •  Significant morbidity and mortality. Conjunctivitis Sticky but white eyes Common 3rd–5th day of life. Clean with sterile water. If eye becomes red may be staphylococcal or streptococcal infection so treat with a topical antibiotic ointment e.g. neomycin. If persistent sticky eye but conjunctiva is white and uninflamed then usually due to obstruction of the nasolacrimal duct. Purulent conjunctivitis with swelling of eyelids Fig. 43.3 If onset within 48 hours of birth likely to be gonococcal oph- thalmia neonatorum. The discharge should be Gram‐stained and cultured and systemic treatment started immediately. Where penicillin resistance is common as in the US and UK a third‐ generation cephalosporin is given. The eye is cleaned frequently. In the US all infants are given eye prophylaxis with erythromycin eye ointment. In the UK no prophylaxis is given but the condition is rare. Chlamydia trachomatis can cause a similar condition usually at the end of the first week may coexist with gonococcal infection. The diagnosis is made with a monoclonal antibody test or culture of the discharge. Treatment is with oral erythromycin. No topical treatment required. These conditions must be treated promptly to avoid damage to the eye. The mother and her partner also need treatment. Herpes simplex must also be considered with this presentation. Skin Bullous impetigo Superficial blisters readily burst leaving denuded skin Fig. 43.4 with crust formation. Staphylococcus aureus or streptococcal. Give systemic antibi- otics to prevent spread. Remove crusts with warm water. Identify and treat source. Usually from nasal colonization. The condition needs to be differentiated from transient pustular melanosis which is benign see Chapter 21. Staphylococcal scalded skin syndrome SSSS •  Rare but serious infection. Toxin mediated. •  Fever. •  Bullae with shedding of skin leaving raw areas. •  Requires systemic antibiotics. •  Congenital candida may resemble SSSS. Fig. 43.3 Purulent conjunctivitis with swelling of eyelids at 6 days from Chlamydia trachomatis. Fig. 43.4 Bullous impetigo. There are superficial blisters some have been denuded. Some specific sites of bacterial infection Fig. 43.2 Conjunctivitis Sticky eyes Purulent conjunctivitis with swelling of eyelids Pneumonia Presents with respiratory distress Diagnosed on CXR and evidence of infection Neonatal meningitis Most common organism – Group B streptococcus then Gram-negative organisms Rare – Listeria monocytogenes High mortality and morbidity hearing loss hydrocephalus and developmental delay Umbilical infection Slight redness around umbilicus is common. Red are around umbilicus needs antibiotic therapy Abscess Localized swelling – red warm often uctuant May be at site of intravenous infusion/ extravasation Urinary tract infection Non-specic presentation. Can only be diagnosed if satisfactory urine sample has been obtained Paronychia Systemic antibiotics are given Osteomyelitis and septic arthritis Skin – generalized Bullous impetigo Staphylococcal scalded skin syndrome SSSS See Chapter 61 Fig. 43.2 Some specific sites of bacterial infection.

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Neonatology at a Glance Third Edition. Edited by Tom Lissauer Avroy A. Fanaroff Lawrence Miall and Jonathan Fanaroff. © 2016 John Wiley Sons Ltd. Published 2016 by John Wiley Sons Ltd. 104 Neonatal problems Herpes simplex virus HSV Infection in the newborn is rare the incidence in the US is only 5–33/100 000 live births in the UK about 2/100 000 live births. Most 85 are HSV type II in US but in UK a relatively higher proportion are HSV type I associated with increased genital HSV type I infection. Seroconversion rate in pregnancy is 4. At any time in pregnancy 1 of HSV‐2 seropositive women are excreting virus in genital tract. Most infections 85 are acquired by passage through an infected birth canal 10 are acquired postnatally from infected caregiver and 5 are true intrauterine infections. Risk of vertical transmission •  High 50–60 with primary maternal infection which is usually asymptomatic but is rarely symptomatic with fever systemic illness and painful genital lesions. Risk of transmission is increased if membranes have ruptured for more than 6 hours or following birth canal interventions e.g. scalp electrode. However in 70 of infected neonates maternal infection is undiagnosed. • Low 2 with recurrent maternal infection which is often asymptomatic or genital lesions are localized. Potential interventions to reduce transmission of symptomatic primary infection are: •  delivery by cesarean section •  maternal aciclovir acyclovir therapy for primary infection. • Reduced use of invasive obstetric procedures mechanically assisted deliveries fetal scalp electrodes during delivery. Neonatal infection There are three modes of presentation: •  Disseminated infection – presents at 10–12 days with pneu- monia hepatic failure DIC disseminated intravascular coagula- tion. Two‐thirds develop encephalitis. •  Encephalitis – presents in second week. Lethargy is a prominent clinical feature as well as focal or generalized seizures and coma •  Localized lesions – skin eye or mouth – presents with vesicles at 10–11 days. One‐third progress to encephalitis. Rarely there may be congenital infection – presents at birth with triad of eye skin and neurologic signs. Diagnosis Difficult as maternal infection often undiagnosed and vesicles are pre- sent in only 60–80 of disseminated disease or encephalitis. Rapid diagnosis with PCR polymerase chain reaction of infant’s blood CSF cerebrospinal fluid nasopharyngeal aspirates or local lesions. Management Infected infant: •  Intensive care support if required. •  High‐dose intravenous aciclovir acyclovir therapy for 3 weeks. Suppressive oral treatment is subsequently given for 6–12 months to prevent relapse. •  In spite of treatment morbidity mortality and risk of relapse remain high. Maternal HSV lesions at delivery: – History of genital herpes before pregnancy: •  Low transmission risk. Surface viral cultures and blood DNA PCR at 24 hours delay to avoid contamination from maternal secre- tions. Observe. Only treat if positive results or clinical features. – No history of genital herpes before pregnancy: • May be high transmission risk. Investigations as above but include CSF PCR. Start intravenous aciclovir acyclovir. Hepatitis B HBV • Highest incidence in the Far East and sub‐Saharan Africa Fig. 44.1. Increased risk with intravenous drug use. •  Screening of all mothers for HBsAg hepatitis B surface antigen is universal in the US and UK. •  HBV is transmitted from mother to infant during labor or at birth from ingestion of maternal blood and from breast milk. Also horizontal spread within families during childhood can occur. •  Infants are at high risk if their mother is hepatitis B e‐antigen positive HBeAg positive or has high HBV viral load the risk is markedly reduced if e‐antibodies are present. •  Infants who become infected are usually asymptomatic during childhood but 30–50 develop chronic HBV liver disease which in 10 progresses to cirrhosis. There is also a long‐term risk of hepatocellular carcinoma. Prevention All infants born to HBsAg‐positive mothers should be given HBV vaccination as soon as possible after birth with boosters during infancy. In the US this is part of the standard immunization program in the UK it is restricted to these high‐risk infants. Viral infections 44 HBsAg prevalence : 0.1–1 1–5 5–20 Fig. 44.1 Global overview of prevalence of maternal HbsAg hepatitis B surface antigen.

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Viral infections 105 In the US HBIG hepatitis B immunoglobulin for short‐term protection from passive antibody is given within 12 hours of birth to infants of HBsAg‐positive mothers or for infants 2 kg when maternal HepB status is unknown in the UK it is confined to infants of mothers who are HBeAg‐positive. Immunization protects more than 90 of infants. There is no contraindication to breast‐feeding when the infant is immunized. Hepatitis C Vertical transmission is uncommon and almost exclusively in women with high Hep C viral load in late pregnancy 5 unless there is co‐infection with HIV when it is 10–20. Although viral DNA is present in breast milk transmission via breast milk has not been proven so breast‐feeding is not contraindicated. Carriers are at risk of chronic liver disease and hepatocellular carcinoma in later life. HIV The global prevalence of HIV infection in children is shown in Fig. 44.2 and the annual incidence in children is shown in Fig. 44.3. Main route of vertical transmission is at birth but also transpla- cental and via breast‐feeding. V ertical transmission rate where mothers breast‐feed and without any intervention is 25–40. Factors which increase transmission •  Advanced maternal disease. •  High maternal plasma viral load. •  Primary infection during pregnancy or breast‐feeding. •  Concomitant sexually transmitted infections. •  Rupture of the membranes longer than 4 hours. •  Chorioamnionitis. •  Vaginal delivery with a detectable viral load. •  Blood exposure/instrumental delivery. Interventions that reduce transmission •  Combination antiretroviral therapy is given to the mother to fully suppress plasma viral load antenatally and during delivery. •  Treat other maternal sexually transmitted infections to reduce birth canal transmission. •  Elective cesarean section with avoidance of labor and contact with the birth canal if the mother still has detectable viral load. Mothers with fully suppressed plasma viral load may have a vag- inal delivery. •  Post-exposure prophylaxis PEP antiretroviral therapy to the infant for 4 weeks. Where the mother has a fully suppressed viral load monotherapy may be used but if the mother has detectable viral load the infant should receive triple antiretroviral therapy for 4 weeks. •  In a resource‐rich setting mothers are advised to formula feed the infant to reduce all risk of postnatal infection. •  These interventions can reduce transmission rate below 0.5. •  Refer to national guidelines for details of treatment of infants. •  In a resource-poor setting mothers may breast‐feed exclusively if they are on combination antiretroviral therapy with fully sup- pressed plasma viral load. If not the baby should continue on daily post-exposure antiretroviral therapy during the entire period of breast‐feeding. See Chapter 73 for further details. Diagnosis A first test for evidence of in utero infection is undertaken at birth. Confirmation that the infant is uninfected then relies on at least two further negative tests for the viral genome DNA/RNA PCR after cessation of PEP or in the breast‐feeding infant after cessation of breast‐feeding. The HIV antibody test cannot be used until 18 months as maternal antibody is still present. Management Infants at high risk of infection i.e. those born to mothers with significant viral load should receive cotrimoxazole as prophylaxis against Pneumocystis jiroveci carinii pneumonia PCP from 4 weeks of age until negative HIV results are available. North Africa and Middle East 20000 Sub-Saharan Africa 2.9 million Latin America 40000 Caribbean 16000 North America 4500 Western and Central Europe 1600 Eastern Europe and Central Asia 19000 East Asia 8200 South and South-East Asia 200000 Oceania 3100 Total: 3.3 million children living with HIV infection in 2012 Fig. 44.2 Number of children 15 years old living with HIV infection in 2012. UNAIDS WHO 2013. North Africa and Middle East 3000 Sub-Saharan Africa 230.000 Latin America 2100 Caribbean 500 North America 200 Western and Central Europe 200 Eastern Europe and Central Asia 1.000 East Asia 1500 South and South-East Asia 21000 Oceania 500 Total: 260 000 newly infected children in 2012 Fig. 44.3 Estimated number of newly HIV‐infected children 15 years old during 2012. Most are in sub‐Saharan Africa. UNAIDS WHO 2013.

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Neonatology at a Glance Third Edition. Edited by Tom Lissauer Avroy A. Fanaroff Lawrence Miall and Jonathan Fanaroff. © 2016 John Wiley Sons Ltd. Published 2016 by John Wiley Sons Ltd. 106 Neonatal problems Hypoglycemia Prolonged symptomatic hypoglycemia can cause neurologic damage. However during the first few days of life many breastfed infants have low blood glucose levels but are asymptomatic they are able to utilize ketones and other energy substrates. Therefore the defini- tion of hypoglycemia in the neonatal period has been the source of considerable controversy. A serum glucose level of less than 45 mg/dL 2.6 mmol/L during the first days of life is currently accepted as a useful cut‐off to establish the diagnosis of hypoglycemia and to initiate active evaluation and treatment Fig. 45.1. Normal newborn infants require 4–5 mg/kg/min 0.22–0.28 mmol/kg/min of glucose in order to maintain glucose homeostasis. Risk factors Maternal •  Maternal diabetes mellitus Fig. 45.2 and obesity. •  Large or rapid infusions of glucose immediately before delivery. •  Maternal β‐adrenergic agonist or antagonist therapy. Neonatal •  IUGR intrauterine growth restriction Fig. 45.3. •  Small for gestational age birthweight 10th centile •  Large for gestational age birthweight 90th centile. •  Preterm. •  Ill infant – sepsis etc. •  Iatrogenic – reduced feeds with inadequate intravenous glucose. •  Polycythemia. •  Hypoxic–ischemic encephalopathy HIE. •  Hypothermia. •  Rhesus disease. Causes Risk factors for transient hypoglycemia are listed above. Persistent hypoglycemia is uncommon its causes are shown in Fig. 45.4. Clinical features Most are asymptomatic. Clinical features include: •  jitteriness/irritability/high‐pitched cry •  depressed consciousness/lethargy/hypotonia •  apnea •  seizures. Some abnormal physical signs may assist in identifying the cause Table 45.1. Hypoglycemia and hyperglycemia 45 Asymptomatic late preterm or term baby with risk factors - SGA/maternal diabetes/LGA Birth–4 hours of age Early oral/enteral feed 1h of birth Check blood glucose 30 mins after feed If 25 mg/dL 1.4 mmol/l feed and recheck after 1 hr Sick neonate Preterm 34 weeks Neonatal intermediate/intensive care Check blood glucose Give IV glucose if not taking oral/enteral feeds Regular blood glucose monitoring Symptomatic and blood glucose 45 mg/dL 2.6 mmol/l IV glucose 10 Bolus 2 ml/kg 200 mg/kg and/or 5–8 mg/kg/min 80–100 ml/kg/24h If 25 mg/dL 1.4 mmol/l If 35 mg/dL 1.9 mmol/l If 35–45 mg/dL 1.9–2.6 mmol/l refeed or IV glucose Increase dextrose volume and/or concentration up to 12–14 mg/kg/min glucose if 15 give via central venous catheter 4–24 hours of age Feed every 2–3 hours Blood glucose before each feed If blood glucose is 35 mg/dL 1.9 mmol/l feed and recheck Consider glucagon corticosteroids diazoxide after investigations No response No response Key point: Aim: 45 mg/dL 2.6 mmol/l on 2 occasions Persistent hypoglycemia If due to hyperinsulinism – may require drug therapy with diazoxide and somatostatin or surgery with partial pancreatectomy If due to specic endocrine deciencies – replacement therapy is indicated Key point Conversion of glucose infusion rate: mg/kg/min Glucose concentration × volume infused in mL/kg/24h ___________________________________ 144 If 25–40 mg/dL 1.4–2.2 mmol/l refeed or IV glucose Severe hypoglycemia may occur if the intravenous dextrose is stopped suddenly or extravasates Key point Fig. 45.1 An example of a guideline for the prevention and treatment of hypoglycemia. Adapted from Committee on Fetus and Newborn. Postnatal blood glucose homeostasis in late‐preterm and term infants. Pediatrics 2011 127: 575–579.

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Hypoglycemia and hyperglycemia 107 Monitoring Infants with risk factors should be fed regularly and frequently at least every 3h and their blood glucose monitored until it is above 45 mg/dL 2.6 mmol/L on two occasions Fig. 45.1. Blood glucose should not be monitored in appropriately grown term infants establishing breast‐feeding. All infants requiring intermediate or intensive care should have their blood glucose monitored. Blood glucose determination should be performed at the bedside with a glucometer and hypoglycemia confirmed by the laboratory as bedside monitors are not designed to measure low glucose levels accurately. Investigation These are performed for persistent or symptomatic hypoglycemia. Blood tests •  Plasma glucose concentration – true laboratory measurement. •  Serum insulin concentration. If no features of hyperinsulinism e.g. excessive glucose require- ments to prevent hypoglycaemia check: •  pituitary hormones •  for inborn error of metabolism and acylcarnitine see Chapter 46. Other investigations that may be indicated •  Ultrasound of brain and/or MRI – for structural anomaly. •  Ultrasound adrenals – for adrenal hemorrhage. •  Ophthalmologic examination – for septo‐optic dysplasia. Management Prevention and treatment of hypoglycemia are shown in Fig. 45.1. Hyperglycemia No agreed definition but 125–180 mg/dL 7–10 mmol/L on two occasions. Frequent in extremely preterm infants. Often associated with: •  higher than required rate of IV glucose infusion 9 mg/kg/min from dextrose infusion or parenteral nutrition •  sepsis often associated with fungal infections •  corticosteroid therapy high doses or cortisol response to stress •  insufficient insulin secretion – neonatal diabetes rare. Management – check infusion rates then treat cause or admin- ister insulin therapy but avoid hypoglycemia. Fig. 45.2 Macrosomic infant of mother with diabetes mellitus. Maternal hyperglycemia causes β‐cell hyperplasia of pancreas and hyperinsulinism in the fetus that lasts for up to 48 hours after birth. Fig. 45.3 Term twins the one on the left with IUGR intrauterine growth restriction. IUGR newborn infants are prone to hypoglycemia. Persistent hypoglycemia Inborn errors of metabolism Infant of diabetic mother Beckwith–Wiedemann syndrome see Table 45.1 Persistent hypoglycemic hyperinsulinism of infancy PHHI/nesidioblastosis Iatrogenic – sudden cessation of parenteral nutrition or high concentration glucose infusion Hyperinsulinism: Panhypopituitarism Growth hormone deciency Cortisol deciency – adrenal hemorrhage/ACTH unresponsiveness Endocrine deciency: Fig. 45.4 Causes of persistent hypoglycemia. Table 45.1 Clinical features associated with specific causes of persistent hypoglycemia. Clinical feature Cause Hepatomegaly with or without splenomegaly Glycogen storage disease infection Hepatomegaly large tongue omphalocele horizontal ear lobe crease Beckwith–Wiedemann syndrome Micropenis hypoplastic optic disk Panhypopituitarism Need to rule out midline brain defects e.g. septo‐optic dysplasia Lethargy coma vomiting unusual body odor Hyperammonemia lactic acidosis urea cycle disorders or other inborn error of metabolism

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Neonatology at a Glance Third Edition. Edited by Tom Lissauer Avroy A. Fanaroff Lawrence Miall and Jonathan Fanaroff. © 2016 John Wiley Sons Ltd. Published 2016 by John Wiley Sons Ltd. 108 Neonatal problems Inborn errors of metabolism are individually rare Table 46.1 but almost 100 may present in the neonatal period Table 46.2. Delay in diagnosis can result in irreversible neurologic sequelae or death. In the US tandem mass spectrometry on blood screen­ ing spots is used to identify a wide range of disorders in the UK metabolic screening is currently limited to phenylketon­ uria PKU medium‐chain acyl‐CoA dehydrogenase defi­ ciency MCAD maple syrup urine disease MSUD isovaleric aciduria IV A glutaric aciduria type I GA1 and homocystein­ uria HCU. Age of presentation Inborn errors can present at any age to adulthood including in utero as hydrops fetalis. Presentation is often non­specific with a wide differential diagnosis see below. A characteristic presentation is with acute deterioration or sudden death in the first 3−7 days of life when a previously well term infant who is feeding accumulates toxic metabolites of intermediary metabolism that were previously removed by the placenta. However feeding is not an obligatory trigger except for galactosemia. When to suspect an inborn error of metabolism Clinical features •  Neurologic: – poor feeding vomiting – apnea tachypnea secondary to central respiratory stimulation by hyperammonemia or acidosis – irritability progressive lethargy hypotonia seizures encepha­ lopathy coma. •  Acid–base abnormality: – persistent unexplained metabolic acidosis or lactic acidosis – respiratory alkalosis secondary to hyperammonemia – respiratory distress from metabolic acidosis. •  Hypoglycemia – severe and persistent. •  Acute liver disease: – conjugated hyperbilirubinemia coagulopathy hepatomegaly or hepatosplenomegaly. •  Cardiac disease: – cardiac failure or arrest from arrhythmias or cardiomyopathy. •  Dysmorphic features. •  Failure to gain weight. •  Abnormal body or urine odor. Suggestive clues •  Positive family history. •  Parental consanguinity. •  Sibling or family members with unexplained severe illness recur­ rent miscarriages or neonatal death. •  Maternal fatty liver of pregnancy in fetal fatty acid oxidation defects. •  Sudden onset of symptoms in previously well term infant. •  Progressive deterioration or death despite supportive treatment. Differential diagnosis •  Sepsis – ill with non‐specific features. •  Congenital heart disease – heart failure low oxygen saturation. • CNS disease – seizures encephalopathy infection herpes simplex virus intracranial hemorrhage non‐accidental injury. •  Gastrointestinal – vomiting from obstruction liver disease. •  Endocrine – hyperinsulinism hypopituitarism adrenal insufficiency. • Hypoxic–ischemic encephalopathy HIE – seizures and encephalopathy. Management •  Early intervention Table 46.5 is imperative to prevent neuro­ logic sequelae or death. Families will need genetic counseling which may include screening siblings. Inborn errors of metabolism 46 Table 46.1 Examples of inborn errors of metabolism that may present in the neonatal period with incidence. Amino acid disorders Urea cycle – ornithine transcarbamylase Maple syrup urine disease MSUD Carbohydrate disorders Galactosemia Glycogen storage disease Organic acidemias Propionic acidemia PA Methylmalonic acidemia MMA Fatty acid oxidation defects LCAD long‐chain acyl‐CoA dehydrogenase deficiency MCAD medium‐chain acyl‐CoA dehydrogenase deficiency Energy defects Lactic acidosis LA Table 46.2 Incidence of some inborn errors of metabolism. Disorder Incidence Phenylketonuria 1 in 10 000–20 000 Homocystinuria 1 in 200 000–335 000 Galactosemia 1 in 30 000–60 000 Maple syrup urine disease 1 in 185 000 If screened with tandem mass spectrometry: Amino acid disorders 1 in 4800 Fatty acid oxidation defects 1 in 14 000 Organic acid disorders 1 in 20 000

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Inborn errors of metabolism 109 Investigations Tables 46.3 and 46.4 Fig. 46.1 Table 46.3 First‐line investigations when inborn error of metabolism is suspected. Investigation Abnormality Possible disorder Blood gas Metabolic acidosis Organic acidemia disorders of carbohydrate metabolism mitochondrial disorder Respiratory alkalosis due to hyperammonemia Urea cycle disorder Glucose Hypoglycemia with ketosis Organic acidemias glycogen storage Hypoglycemia without ketosis Fatty acid oxidation hyperinsulinism Ammonia Hyperammonemia Fig. 46.1 See Fig 46.1 Lactate High Respiratory chain defects pyruvate dehydrogenase deficiency pyruvate carboxylase deficiency hypoxia Blood urea nitrogen urea Low Urea cycle Electrolytes Raised anion gap Lactic acidosis organic acidemia Liver transaminases High Tyrosinemia galactosemia Complete blood count Neutropenia Thrombocytopenia Organic acidemias Coagulation Prolonged Liver disease galactosemia tyrosinemia Urine Abnormal odor Organic acidemia PKU MSUD Urine reducing substances Negative for glucose Galactosemia Urine ketones Positive Organic acidemias including MSUD Low/negative Fatty acid oxidation disorders MSUD – maple syrup urine disease PKU – phenylketonuria. Table 46.4 Second‐line investigations guided by clinical picture and discussion with specialist. Urine organic acids Urine amino acids Plasma uric acid Plasma amino acids Plasma carnitine and acylcarnitine Biotinidase Galactosemia screening tests CSF glucose and lactate paired with venous samples done pre‐lumbar puncture and amino acids neurotransmitters Blood for mutation analysis or enzyme assay Biopsies: e.g. enzyme assay on skin fibroblasts or blood cells DNA mutation analysis metabolite assays mitochondrial studies and histochemistry on muscle or liver biopsy. Symptoms 24 h old Preterm Term Transient hyperammonemia of newborn Inborn error of metabolism Glutaric aciduria type II Fatty acid oxidation Pyruvate carboxylase deciency Neonatal hyperammonemia Inborn error of metabolism Acidosis±ketosis YesNo Organic acidemia Urea cycle disorder Symptoms 24 h old Fig. 46.1 Simplified diagnostic approach to investigation of significant hyperammonemia. Table 46.6 Examples of vitamins used to treat IEM. Carnitine Pyridoxine and pyridoxal phosphate for seizure control Vitamin B 12 Biotin for biotinidase deficiency Hydroxycobalamin for vitamin B 12 ‐responsive methylmalonic acid Riboflavin for glutaric aciduria type II Thiamin for pyruvate dehydrogenase deficiency Also coenzyme Q for respiratory chain support sodium benzoate biopterin Table 46.5 Approach to management. Basic support Cardiorespiratory support treat sepsis anticonvulsants as required Nutrition Stop protein‐containing feeds Stop galactose‐containing feed if galactosemia possible. Avoid catabolism – give intravenous dextrose minimum 10 to ensure normoglycemia Consider insulin to control blood glucose and to promote anabolism rather than reduce glucose intake Consider use of vitamin therapies Table 46.6 Fluids Consider bicarbonate to correct acidosis Toxin removal Ammonia scavenging medications sodium benzoate sodium phenylbutyrate or carglumic acid Substrate support with arginine and/or carnitine Consider hemodialysis or hemodiafiltration Key point If an inborn error of metabolism is suspected consult a specialized center for advice on management. Key point Measure ammonia in any patient with unexplained lethargy or altered conscious level.

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Neonatology at a Glance Third Edition. Edited by Tom Lissauer Avroy A. Fanaroff Lawrence Miall and Jonathan Fanaroff. © 2016 John Wiley Sons Ltd. Published 2016 by John Wiley Sons Ltd. 110 Neonatal problems Vomiting This is the forceful return of gastric contents through the mouth or nose. In contrast to regurgitation or possetting the effortless return of small quantities of milk which is very common during the first few months of life. The significance of the vomiting will depend on: •  infant’s age •  frequency amount and characteristics of vomiting e.g. if projectile •  presence of bile or blood Fig. 47.1 •  abdominal distension Fig. 47.2 •  stool characteristics – delayed passage of meconium or absent transitional stools •  presence of dehydration weight loss •  evidence of a systemic illness – poor feeding fever lethargy. Causes Physiologic: •  Gastroesophageal reflux •  Ingestion of maternal blood •  Overfeeding •  Incorrectly positioned nasogastric tube Infection: •  Systemic – septicemia urinary tract infection meningitis •  Local – gastroenteritis Mechanical/surgical: •  Intestinal obstruction – see Chapter 48 •  Paralytic ileus – sepsis electrolyte disturbance •  Necrotizing enterocolitis – see Chapter 36 CNS: •  Raised intracranial pressure – cerebral edema intracranial or subdural bleed hydrocephalus •  Kernicterus Drugs: •  Side‐effects – caffeine theophylline antibiotics •  Withdrawal abstinence – heroin methadone Cow’s milk protein intolerance Inborn errors of metabolism rare Endocrine: •  Congenital adrenal hyperplasia rare Diagnostic clues Bile‐stained vomiting yellow–green Causes: •  Intestinal obstruction – distal to ampulla of Vater. •  Necrotizing enterocolitis. •  Incorrectly positioned nasogastric tube. • Feeding intolerance in extreme preterm infants establishing feeds common and presence of bile not significant unless there is abdominal distension or features of necrotizing enterocolitis. Vomiting with abdominal distension Causes: •  Intestinal obstruction Fig. 47.3. •  Paralytic ileus – sepsis electrolyte disturbance. •  Necrotizing enterocolitis. Blood‐stained vomiting Flecks of fresh blood or dark‐brown coffee grounds not uncommon in otherwise well infants and usually resolve spontaneously. Gastrointestinal disorders 47 Fig. 47.1 This infant presented with blood-stained vomiting at 12 hours of age. Water‐soluble contrast upper gastrointestinal study demonstrates coiled corkscrew appearance of second and third parts of duodenum due to midgut volvulus from malrotation. Courtesy of Dr Annemarie Jeanes. Fig. 47.2 Abdominal X‐ray showing distended loops of bowel in an infant with persistent vomiting. Key point Bile‐stained vomiting in term infants should always be regarded as intestinal obstruction until proven otherwise.

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Gastrointestinal disorders 111 Causes: •  Swallowed maternal blood – from delivery or cracked nipple. Can be differentiated from fetal blood with the Apt test see Table 47.1. •  Trauma – laryngoscopy at resuscitation passing a nasogastric tube. •  Malrotation – uncommon but important to diagnose early Fig.  47.2. •  Stress ulcer – hypoxic–ischemic encephalopathy. • Abnormal coagulation–thrombocytopenia vitamin K deficient bleeding liver disease DIC disseminated intravascular coagula- tion etc. •  Drug‐induced – corticosteroids indomethacin ibuprofen. Investigations Most infants will require no or limited investigations. Those to be considered are listed in Table 47.1. Management Depends upon severity and cause. Intravenous fluids may be required to correct electrolyte disturbances acid–base imbalance and dehydration. Gastroesophageal reflux Incidence is increased in: •  preterm infants particularly with bronchopulmonary dysplasia or on caffeine • following necrotizing enterocolitis and tracheoesophageal fistula repair •  infants with neurodevelopmental delay e.g. following hypoxic– ischemic encephalopathy or hypotonia. Associated features •  Failure to thrive. •  Irritability arching of the back from esophagitis. •  Anemia iron deficiency. •  Aspiration pneumonia. •  Apnea. •  Acute life‐threatening events ALTE. Investigations •  Usually clinical diagnosis. • Esophageal pH study impedance study may show non-acid reflux sometimes upper gastrointestinal contrast or endoscopy. Management Most do not need treatment. If required use stepwise approach. •  Reduce interval between feeds thicken feeds alginate/antacid Gaviscon upright positioning. •  Prokinetic e.g. domperidone but concerns about arrhythmias. •  H 2 receptor antagonist e.g. ranitidine proton pump inhibitors e.g. omeprazole – reduce gastric acidity. •  Surgery – fundoplication with or without gastrostomy. •  Evidence of efficacy of medication in neonates is limited. Fig. 47.3 Abdominal distension from Hirschsprung disease. Table 47.1 V omiting – investigations to consider and their purpose. Imaging Blood tests Urine and stool tests Plain abdominal X‐ray: Electrolytes and acid‐base – for imbalance Urine – microscopy and culture •  intestinal obstruction – distended loops of bowel bowel perforation Sepsis work‐up – to exclude infection Creatinine/blood urea nitrogen urea – for dehydration and renal function Stool – for blood Other: •  Apt test of vomit/stool – to differentiate between maternal and fetal blood. Fetal hemoglobin is alkali‐ resistant remains pink on addition of sodium hydroxide •  NEC necrotizing enterocolitis Ultrasound scans: •  cranial for hemorrhage ventricular dilatation •  abdominal for pyloric stenosis intra-abdominal fluid collections and cysts. Contrast X‐rays: •  malrotation strictures •  site of intestinal obstruction Glucose – for hypoglycemia Calcium magnesium phosphorus liver function tests Coagulation screen – if blood in vomit or sepsis Consider: •  17‐hydroxyprogesterone – for congenital adrenal hyperplasia •  blood ammonia – for urea cycle abnormalities •  drug screen – for drug overdose or withdrawal

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112 Neonatal problems Esophageal atresia •  More than 85 associated with tracheoesophageal fistula Fig.  47.4. •  1 in 3500 live births. •  Often associated with other abnormalities e.g. VACTERL syn- drome vertebral anomalies anal atresia cardiac tracheoesophageal renal limb. Presentation •  Prenatal – polyhydramnios absent stomach bubble associated abnormalities. •  Birth onwards – frothing of oral secretions Fig. 47.5 with choking and cyanosis. Investigations •  Unable to pass wide‐bore orogastric tube confirmed on chest X‐ray shows tube curled in esophageal pouch. Air in the stomach indicates a distal fistula is present. Management •  Pass large orogastric tube and aspirate pouch to avoid aspiration pneumonia. •  Intravenous fluids for resuscitation and maintenance. Early PN parenteral nutrition. •  Surgical correction is required. Abdominal masses Often detected in utero on ultrasound screening. The causes are shown in Fig. 47.6. Abdominal wall defects Omphalocele Exomphalos Defect in umbilicus with herniation of abdominal contents. The bowel is covered by peritoneum and amnion Fig. 47.7. V ary in size from small defects where some bowel herniates into the umbilical cord to large defects where there is herniation of both bowel and liver. Occurs in 1 in 5000 fetuses. Most are diagnosed on prenatal ultra- sound screening see Fig. 3.2 40 are associated with trisomy 13 or 18 Beckwith–Wiedemann see Chapter 45 or other syndromes. 86 – atresia with stula between distal esophagus and trachea 8 – atresia without stula 4 – H-type stula without atresia Fig. 47.4 Different types of esophageal atresia and tracheoesophageal fistula. Fig. 47.5 Frothing of oral secretions after birth from esophageal atresia. Renal 55 Hydronephrosis Multicystic dysplastic kidney MCDK Polycystic kidney disease Wilms tumor Renal vein thrombosis Adrenal 5 Adrenal hemorrhage Neuroblastoma Retroperitoneal non-renal 5 Teratoma Hepatobiliary 5 Hepatomegaly – infection metabolic/storage disease heart failure Hemolytic disorders e.g. spherocytosis Duplication Obstruction Mesenteric/omental cysts Genitalia 15 Splenomegaly Gastrointestinal 15 Fig. 47.6 Abdominal masses and their causes. Fig. 47.7 Omphalocele.

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Gastrointestinal disorders 113 Management see video: Gastroschisis •  Pass a large‐caliber nasogastric tube at delivery to limit passage of air into the bowel and nothing by mouth. •  Place infant’s lower body into a sterile plastic wrap bag to limit heat and fluid loss and protect the bowel from damage and infection. •  Give intravenous fluids. •  Check for other anomalies including echocardiography. •  Surgical repair is usually performed on the first day of life. If the defect is large the viscera may be placed in a silastic silo and gradually placed in the abdomen over several days. Gastroschisis Defect in anterior abdominal wall usually to right of umbilicus with herniation of the bowel Fig. 47.8. In contrast to omphalocele there is no protective covering of the bowel and the incidence of associated anomalies is low other than intestinal atresia. The condition is usu- ally diagnosed on prenatal ultrasound screening Fig. 47.9. Management •  The infant’s lower body is placed into a sterile plastic wrap bag or cling film. •  Pass a large‐caliber nasogastric tube at delivery to limit passage of air into the bowel. •  Give intravenous fluids colloid may be required to replace fluid losses from the exposed bowel. Closely monitor electrolytes. Give broad‐spectrum antibiotics. •  Surgical repair can be performed directly or the abdominal con- tents can be gradually reduced after placing into a silo Fig. 47.10. •  Prolonged parenteral nutrition is usually required to establish feeds. Prognosis is good. Imperforate anus • Incidence 1 in 5000 births. Associated anomalies of genitourinary and gastrointestinal tract common and seen in VACTERL association. •  In boys most often with fistula to urethra in girls to vestibule adjacent to vagina-so may still pass meconium. Some lesions are complex. •  Surgery is with anoplasty or colostomy followed by repair. Fig. 47.8 Gastroschisis. Fig. 47.10 Gastroschisis in silastic silo. There is also a central venous catheter for PN. Fig. 47.9 Gastroschisis on prenatal ultrasound scan. Courtesy of Dr David Lissauer.

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Neonatology at a Glance Third Edition. Edited by Tom Lissauer Avroy A. Fanaroff Lawrence Miall and Jonathan Fanaroff. © 2016 John Wiley Sons Ltd. Published 2016 by John Wiley Sons Ltd. 114 Neonatal problems Most of the conditions causing gastrointestinal obstructions are serious but their prognosis has improved with advances in medical anesthetic and surgical care. They are relatively uncommon but are important to recognize because: •  failure or delay in diagnosis may result in electrolyte imbalance dehydration and shock •  malrotation with midgut volvulus is a surgical emergency in order to avoid bowel necrosis. Causes – see Fig. 48.1 Diagnostic clues Prenatal: •  Polyhydramnios – from obstruction to the passage of amniotic fluid through the gastrointestinal tract. • Abnormal ultrasound – dilated bowel hyperechoic bowel ascites calcified lesions. May be difficult to diagnose. •  Fetus with trisomy 21 Down syndrome – 30 have associated duodenal atresia. •  Family history of cystic fibrosis – associated with meconium ileus. Delivery room: •  Bubbly oral secretions – esophageal atresia. •  Peri‐umbilical abdominal wall discoloration – in utero bowel perforation. Clinical presentation •  V omiting – usually bile yellow-green stained. Bile is present if the obstruction is distal to ampulla of Vater. Presents within 24–48 hours of birth with high gastrointestinal lesions may be delayed for several days for lower lesions. Hematemesis blood‐stained vomit may occur with malrotation. •  Feeding intolerance. •  Abdomen – distension with visible loops of bowel or peristalsis erythema/edema of abdominal wall abdominal mass peritonitis and shock. •  Failure to pass meconium within 48 hours of birth. •  Blood in stool fresh or altered. Diagnosis Abdominal X‐ray: •  Bowel obstruction – distended loops of bowel with air‐fluid levels with absence of gas distally see Fig. 47.2. •  Bowel perforation – free air under diaphragm intrahepatic or around falciform ligament. Management • Abdominal decompression with nasal or orogastric tube. In esophageal atresia aspirate pouch to avoid aspiration pneumonia. • Intravenous fluids for resuscitation and maintenance. Early parenteral nutrition PN. •  Antibiotics preoperatively. •  Evaluate and correct bleeding diathesis. •  Surgical intervention for most lesions. •  Evaluate for other anomalies. Karyotype and microarray analysis may be necessary. Some specific conditions Esophageal atresia Chapter 47 Pyloric stenosis Hypertrophy of circular smooth muscle of pylorus of stomach. •  Presentation – projectile vomiting in a hungry infant at 4–8 weeks of age. Occurs at same age in preterm infants. •  Examination – visible peristalsis. A firm olive‐like mass is palpable in right upper abdomen during feeds. •  Investigation – abdominal ultrasound – hypertrophy of pylorus. •  Management – correct electrolyte imbalance hypochloremic hypokalemic alkalosis. Surgery-muscle incision pyloromyotomy. Duodenal atresia •  Lesion – obstruction may be due to atresia webs stenosis or fibrous cord. •  Incidence – 1 in 7500 births. Check for trisomy 21 and other anomalies. •  Antenatal – polyhydramnios distended fluid‐filled stomach on ultrasound. •  Presentation – vomiting – bilious or non‐bilious upper abdom- inal distension and feeding intolerance. •  Diagnosis – double bubble on X‐ray Fig. 48.2. May be accen- tuated by injecting 20 mL of air through gastric tube. Gastrointestinal obstruction 48 Esophageal atresia Pyloric stenosis Annular pancreas Incarcerated inguinal hernias see Chapter 52 Malrotation Imperforate anus Strictures – post necrotizing entercolitis Large bowel atresia Meconium plug syndrome Small bowel atresia Hirschsprung disease Duodenal atresia Meconium ileus Fig. 48.1 Causes of intestinal obstruction.

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Gastrointestinal obstruction 115 Malrotation Failure of the developing bowel to undergo the normal counter‐ clockwise rotation during the 4th to 10th weeks of embryogenesis. Peritoneal bands which normally attach the bowel to the central body axis posteriorly and are also known as Ladd bands compress the duodenum partially obstructing it. Because the mesentery is not fixed malrotation predisposes to midgut volvulus twisting of a loop of bowel around its mesenteric attachment. In addition to intestinal obstruction compression of the superior mesenteric artery leads to ischemia of the small bowel. Presentation Sudden bilious vomiting is malrotation until proven otherwise. Usually in first few weeks of life but can occur at any age. With acute volvulus also abdominal distension and tenderness followed by shock. Hematemesis may occur. Investigation Doppler ultrasound of mesenteric vessels may be helpful at the bedside. Upper gastrointestinal exam contrast swallow is diag- nostic. The normal position of the duodenal‐jejunal junction Treitz angle is to the left of the spine. Any other position indicates mal- rotation. Volvulus classically appears as a spiral corkscrew of the duodenum see Fig. 47.1. Management Volvulus is a surgical emergency. Ischemia can lead to small bowel infarction requiring bowel resection. Extensive resection of the small bowel carries a poor prognosis. To relieve the obstruction the peritoneal bands around the duo- denum are divided. Appendectomy is also performed to avoid future confusion if the child has abdominal pain. Meconium ileus • Small bowel obstruction from inspissated putty‐like sticky meconium. •  Affects 10–15 of patients with cystic fibrosis whereas 95 of infants with meconium ileus have cystic fibrosis. Presentation Bilious vomiting failure to pass meconium abdominal distension abdominal mass. Edema of abdominal wall suggests peritonitis. Complications include volvulus and perforation. Investigation and management •  Abdominal X‐ray – dilated loops of bowel air fluid levels and ground glass soap‐bubble appearance of meconium. •  Intra‐abdominal calcification indicates intrauterine perforation and peritonitis. •  Gastrograffin water‐soluble contrast enema may wash out the meconium otherwise surgery is required. •  Test for cystic fibrosis. Meconium plug syndrome Presentation – low bowel obstruction as in Hirschsprung disease. Hirschsprung disease •  Congenital absence of ganglionic cells in the myenteric plexus secondary to defective migration of ganglion cell precursors from neural crest to hind gut. Abnormal bowel extends from rectum for variable distance of large bowel. Proximal bowel is normal. •  Incidence – 1 in 5000 births male: female ratio 5:1. •  May be associated with trisomy 21 Down syndrome. •  Accounts for 20–25 of cases of neonatal intestinal obstruction. Presentation •  Delayed passage of stools – more than 50 do not stool for 48 hours. •  About 50 of affected children present with abdominal disten- sion see Fig. 47.3 and vomiting in neonatal period others when older with constipation. •  May present with enterocolitis – explosive liquid stools fever and shock. Investigation Abdominal X‐ray shows distal bowel obstruction – multiple dis- tended loops of bowel with lack of air in the rectum. Diagnosis •  Rectal suction biopsy for histology. •  Barium enema – excludes other causes of intestinal obstruction and may show transition zone between normal and aganglionic bowel Fig. 48.3. Treatment Rectal washouts followed by surgical repair. Fig. 48.2 Abdominal X‐ray showing double bubble in duodenal atresia. Courtesy of Dr Sheila Berlin. Fig. 48.3 Barium enema showing transition zone between normal and aganglionic bowel in Hirschsprung disease. Courtesy of Dr Sheila Berlin.

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Neonatology at a Glance Third Edition. Edited by Tom Lissauer Avroy A. Fanaroff Lawrence Miall and Jonathan Fanaroff. © 2016 John Wiley Sons Ltd. Published 2016 by John Wiley Sons Ltd. 116 Neonatal problems Congenital heart disease: Is the most common group of structural malformations accounting for 30 of all congenital abnormalities •  affects 6–9 per 1000 live births. In children with congenital heart disease: •  10–15 have complex heart disease with multiple lesions •  10–15 have abnormalities of other systems. A classification is shown in Table 49.1. Risk factors •  Chromosomal disorders and syndromes e.g. trisomy 21 A VSD or VSD chromosome 22q11 microdeletion aortic arch abnormality Turner coarctation of aorta Noonan pulmonary stenosis Williams supravalvular aortic stenosis and others. • Maternal – diabetes mellitus TGA teratogenic drugs e.g. anticonvulsants lithium fetal alcohol syndrome. •  Congenital infection e.g. rubella. •  Siblings of affected child – only slight increase in risk. Presentation •  Antenatal detection on ultrasound screening. •  Detection of a heart murmur on newborn examination. •  Heart failure – respiratory distress or shock. •  Cyanosis. •  Postnatal detection with oxygen saturation screening. Antenatal diagnosis About 70 of major lesions are diagnosed antenatally especially those detectable on the four‐chamber view used for antenatal ultra- sound screening Fig. 49.1 e.g. hypoplastic left heart. Lesions such as transposition of the great arteries and coarctation of the aorta are more difficult to identify. If an abnormality is suspected referral to a perinatal cardiac specialist is indicated. Antenatal detection allows parents to be counseled and delivery to be planned in a cardiac center if indicated. Heart Murmur Heart murmurs are heard in 1–2 of infants during routine exami- nation of the newborn. May be due to: •  A transient flow murmur related to circulatory changes following birth. The murmur is soft systolic at the left sternal edge or pulmonary area in a well infant whose examination including four‐limb blood pressure measurements and oxygen saturation is otherwise normal. •  Branch pulmonary artery stenosis. The murmur is best heard in the pulmonary area and radiates to the axilla and back with otherwise normal examination. Resolves in a few weeks. •  Congenital heart disease. Murmurs due to turbulence through narrowed valves e.g. aortic or pulmonary stenosis or shunts e.g. VSD. Although uncommon the most worrying of these are duct‐dependent lesions which may result in circulatory failure or cyanosis when the ductus arteriosus closes soon after birth. The definitive diagnosis is by echocardiography. A chest X‐ray and ECG are of limited value. Pulse oximetry will establish if the arterial oxygen saturation is normal 95. If there are features of an inno- cent flow murmur the infant should be reassessed within days to Cardiac disorders 49 Fig. 49.1 Fetal ultrasound showing atrioventricular septal defect A VSD. Table 49.1 Classification of congenital heart disease with examples and frequency of more common lesions . Acyanotic Cyanotic Shunts ‘holes’ left‐to‐right shunting Right‐to‐left shunting reduced pulmonary blood flow: •  VSD ventricular septal defect 32 •  Tetralogy of Fallot 6 •  PDA patent ductus arteriosus 12 •  Pulmonary atresia •  ASD atrial septal defect 6 •  Tricuspid atresia •  A VSD atrioventricular septal defect Transposition of the great arteries TGA 5 Obstruction ‘narrowing’ Common mixing: •  Pulmonary stenosis 8 •  Coarctation of the aorta 6 •  Truncus arteriosus •  Double outlet right ventricle •  Aortic stenosis 5 •  Hypoplastic left heart Total anomalous pulmonary venous connection TAPVC Pump failure •  Supraventricular tachycardia SVT •  Cardiomyopathy Key point Acyanotic lesions usually pre- sent with shock or with heart failure and breathlessness. Key point Cyanotic lesions usually present with cyanosis at birth or when the duct closes. Key point About one‐quarter of infants with congenital heart disease pre- sent in the neonatal period and usually have severe lesions.

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Cardiac disorders 117 check that the murmur has disappeared. The parents need to be informed that they should seek medical assistance should the infant develop symptoms suggestive of heart failure Fig.  49.2. If the murmur persists or has pathologic features or the infant has other abnormal clinical signs referral to a pediatric cardiologist is indicated. Heart failure The main cardiac causes are considered below. Non‐cardiac causes include severe anemia or polycythemia or rarely arteriovenous malformation e.g. vein of Galen in the brain. Left‐to‐right shunting high‐output failure Usually presents with clinical features of heart failure Fig. 49.2 several weeks after birth when the pulmonary vascular resistance falls and pulmonary blood flow increases. Patent ductus arteriosus in preterm infants See Chapter 33. Atrioventricular septal defect AV canal defect •  Common 40 in trisomy 21 Down syndrome. •  Surgery at 2–4 months. Isolated atrial septal defects rarely cause heart failure. Large ventricular septal defect • Typically presents at about 1–3 months when pulmonary vascular resistance is low and left‐to‐right shunt is maximal. •  Small muscular ventricular septal defects close spontaneously but large perimembranous defects may require surgery if medical therapy fails. Left ventricular outflow obstruction Presents with low‐output heart failure/shock when duct closes Fig. 49.2. Key is to maintain ductal patency with prostaglandin infusion until surgery can be performed. Severe coarctation of the aorta/interruption of the aortic arch Key clinical sign is weak or absent femoral pulses. Blood pressure in the arms is markedly higher than in the legs 20 mmHg. Post ductal saturation is low. Blood lactate may be elevated. Prostaglandin infusion then cardiac catheter aortoplasty or sur- gical repair is required. Less severe lesions may present as hypertension in adults. Hypoplastic left heart Fig. 49.3 Presents with signs of low cardiac output when ductus arteriosus closes. Pulses are weak at presentation and there is severe metabolic acidosis. Fatal without treatment – options include a series of pallia- tive operations Norwood procedure or heart transplantation. Pump failure Supraventricular tachycardia •  Heart rate 220–300 beats/min Fig. 49.4. • Heart is usually structurally normal but accessory pathway Wolff–Parkinson–White syndrome is present in 40. •  Place ice pack on face give rapid bolus of intravenous adenosine. If these measures unsuccessful perform DC cardioversion. Cyanosis Central cyanosis •  is clinically detectable if there is over 5 g/dL of reduced hemo- globin so apparent cyanosis may be seen in polycythemia. •  is best detected in tongue/mucous membranes •  in the absence of respiratory distress is usually due to cyanotic congenital heart disease Table 49.1. Hepatomegaly Failure to gain weight/ failure to thrive Cool peripheries Tachypnea RR 60/min Weak pulses shock collapse Tachycardia Active precordium Enlarged heart Gallop rhythm Heart murmur Clinical symptoms Breathlessness Slow to feed Sweating on forehead Recurrent chest infections Fig. 49.2 Clinical features of heart failure. Hypoplastic left heart Fig. 49.3 Hypoplastic left heart syndrome. Fig. 49.4 ECG showing supraventricular tachycardia. Key point The absence of a murmur does not exclude congenital heart disease.

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118 Neonatal problems If there is respiratory distress the cause may be: •  congenital heart disease •  pulmonary disease •  PPHN persistent pulmonary hypertension of the newborn. Peripheral cyanosis acrocyanosis Hands and feet are blue. Common in infants in the first couple of days of life and in children of any age when cold. The tongue and mucous membranes are pink. Oxygen saturation is normal. It is of no clinical significance in the absence of hypovolemia or shock. ‘Traumatic’ cyanosis Apparent cyanosis of the head from venous congestion often accompanied by petechiae. Causes include umbilical cord around neck or face presentation. Tongue is pink. Oxygen saturation is normal. Resolves spontaneously. Selected causes of cyanotic congenital heart disease Table 49.1 Transposition of the great arteries In transposition of the great arteries there are two parallel circulations – the aorta arises from the right ventricle and the pulmonary artery from the left ventricle Fig. 49.5. For survival mixing of blood between the two circulations must occur e.g. via the foramen ovale or ductus arteriosus. The less mixing between the circulations the more severe the cyanosis and the earlier the presentation. Presentation Profound cyanosis occurs in the first day or two of life when the duct closes but may be delayed if there is appreciable mixing of blood from an associated anomaly e.g. ventricular or atrial septal defect. Management This is to promote mixing of the two circulations: •  maintain ductal patency with a prostaglandin infusion •  perform a balloon atrial septostomy to enlarge the foramen ovale Fig. 49.6. A definitive ‘switch’ operation is usually performed within the first 2 weeks in which the pulmonary artery and aorta are switched over. The coronary arteries also have to be transferred to the new aorta which is technically challenging. Outcome is good. Total anomalous pulmonary venous connection TAPVC Instead of connecting to the left atrium the pulmonary veins con- nect into the right atrium sometimes via a shunt below the diaphragm. If the connection is narrow obstructed presentation is with cyanosis respiratory distress and poor cardiac output. May be  difficult to distinguish from respiratory distress syndrome. Treatment is surgical sometimes as an emergency. Oxygen saturation screening for critical congenital heart disease An increasing number of centers perform oxygen saturation screening in the first 24 hours of life to identify duct‐dependent congenital heart disease. Either a postductal oxygen saturation of 95 or a pre‐ right arm and postductal either foot oxygen saturation drop of 3 is used as cut‐off to prompt medical review and echocardiography. False‐positive results may occur but many with low oxygen saturation have respiratory problems or sepsis. Early diagnosis of duct‐dependent lesions is important as it can prevent collapse when the duct closes 24–48 hours after birth. Investigations The immediate problem in symptomatic neonates is usually to distinguish between a respiratory disorder congenital heart disease CHD and persistent pulmonary hypertension of the newborn PPHN. Complete transposition of the great arteries Fig. 49.5 Transposition of the great arteries. Balloon septostomy Catheter Inflated balloon pulled back through atrial septum Fig. 49.6 Balloon atrial septostomy to enlarge the foramen ovale. Key point Oxygen saturation screening enables infants with duct‐dependent lesions to be detected while still asymptomatic.

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Cardiac disorders 119 Chest X‐ray Helpful to exclude pulmonary disease but rarely diagnostic of congenital heart disease as heart size and shape and pulmonary vasculature are difficult to determine in the neonatal period. An enlarged heart border may be due to normal thymus. However a chest radiograph may show: •  Cardiomegaly 60 diameter of thorax e.g. outflow obstruc- tion from coarctation of the aorta or volume overload patent ductus arteriosus. •  Abnormal shape e.g. boot shape with tetralogy of Fallot ‘egg on side’ with TGA but often only recognized retrospectively •  Prominent pulmonary vascular markings plethoric from excess blood flow to the lungs e.g. left‐to‐right shunt from patent ductus arteriosus. •  Reduced vascular markings oligemic from reduced pulmonary blood flow to the lungs e.g. tetralogy of Fallot. ECG •  Seldom diagnostic interpretation requires considerable skill. •  Can be useful if there is a superior axis e.g. AVSD tricuspid atresia. •  Helpful for arrhythmias and as baseline. Hyperoxia test May be helpful to distinguish respiratory from cardiac causes especially if echocardiography not readily available. The infant is placed in 100 oxygen for 10 minutes Fig. 49.7. Interpretation of right radial preductal artery oxygen tension is: •  If PaO 2 110 mmHg 15 kPa – unlikely to be cyanotic heart dis- ease – usually lung disease or PPHN persistent pulmonary hyper- tension of the newborn. •  If PaO 2 110 mmHg 15 kPa – likely to be cyanotic heart disease but can be severe lung disease or PPHN. Echocardiography with Doppler see Chapter 79 Allow definitive anatomic diagnosis and identification of shunts in most instances. Need experienced operator. Doppler will iden- tify the direction of any shunting and patency of the ductus arteriosus. Cardiac catheterization Sometimes required for hemodynamic measurements and to confirm collateral blood vessels and increasingly used for interventional procedures e.g. pulmonary valvuloplasty or placing an occlusion device within the ductus in term infants. Management of congenital heart disease •  Maintain Airway Breathing Circulation. Provide ventilatory support if necessary. •  Correct metabolic acidosis hypoglycemia and hypocalcemia. •  If duct‐dependent defect suspected or confirmed: – give prostaglandin intravenously to keep the ductus arteriosus patent expect apnea after high‐dose prostaglandin – do not give additional oxygen unless SaO 2 falls below 75 oxygen will make the duct more likely to close. •  If in heart failure: – high‐output failure after first week of life – fluid restriction acute only diuretics ACE inhibitors e.g. captopril – low‐output failure/shock – inotropes volume support arrhyth- mias require specific treatment. •  Refer to pediatric cardiac center for expert advice diagnostic imaging and management. Headbox oxygen Oxygen supply Oxygen analyzer Right radial artery cannulated Measure arterial oxygen tension In 100 oxygen for 10 min Fig. 49.7 Hyperoxia nitrogen washout test to identify cyanotic congenital heart disease. Question Why may giving prostaglandin be life‐saving By keeping the ductus arteriosus patent when the circulation is duct‐dependent. For example: •  with obstruction to outflow of the left ventricle when the systemic circulation is maintained by blood flowing right to left across the patent ductus e.g. severe coarctation of the aorta Fig. 49.8 •  with reduced pulmonary blood flow when the pulmonary circulation is maintained by blood flowing from left to right through the duct e.g. pulmonary atresia Fig. 49.9. Duct-dependent coarctation Fig. 49.8 Severe coarctation of the aorta an example of duct‐ dependent systemic circulation. Pulmonary atresia with intact septum Fig. 49.9 Pulmonary atresia an example of duct‐dependent pulmonary circulation.

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Neonatology at a Glance Third Edition. Edited by Tom Lissauer Avroy A. Fanaroff Lawrence Miall and Jonathan Fanaroff. © 2016 John Wiley Sons Ltd. Published 2016 by John Wiley Sons Ltd. 120 Neonatal problems Most significant structural abnormalities of the kidneys and urinary tract are now identified prenatally on ultrasound screening. They account for 20–30 of all prenatally detected abnormalities. Early recognition and treatment may prevent or ameliorate complications such as urinary tract infection failure to thrive and renal failure. When indicated it may allow prenatal referral to a tertiary center. The disadvantage is that many minor or transient genitourinary anomalies are identified resulting in unnecessary concern for the parents and additional investigations for the child. Embryology The kidneys and genitourinary tract are embryologically interdepen- dent. If one system is abnormal look for abnormalities of the other. Structural abnormalities of the kidneys Outflow obstruction In the fetus with outflow obstruction Fig. 50.1 there may be: •  hydronephrosis – unilateral or bilateral with renal parenchyma that may be normal or malformed or dysplastic •  dilatation of the ureters and/or bladder •  reduced or absent amniotic fluid volume. Unilateral hydronephrosis •  Hydronephrosis is dilatation of the proximal collecting system Fig. 50.2. • It is the commonest abnormality diagnosed antenatally and accounts for 50 of all prenatally detected urologic anomalies. It occurs in 1 in 500–700 infants. Most common cause is physiologic hydronephrosis but others are obstruction at the pelviureteric or vesicoureteric junction or urinary reflux. •  Management is shown in Fig. 50.3. •  Most but not all resolve spontaneously. Prognosis is dependent on degree of kidney damage resulting from obstruction. •  If the anteroposterior diameter does not exceed 15 mm either antenatally or postnatally intervention is rarely needed. Bilateral hydronephrosis Less common than unilateral hydronephrosis but more likely to be serious. Renal and urinary tract anomalies diagnosed prenatally 50 Hydronephrosis Hydroureters Thickened bladder wall Bladder neck obstruction Posterior urethral valves Pelviureteric junction obstruction Vesicoureteric junction obstruction Vesicoureteric reux Unilateral hydronephrosis PUJ pelviureteric obstruction or VUJ vesicoureteric obstruction Bilateral hydronephrosis Bladder neck obstruction or Posterior urethral valves Dilated renal pelvis Dilated ureter Fig. 50.1 Features of unilateral and bilateral outflow obstruction. Fig. 50.2 Ultrasound showing unilateral hydronephrosis. As a measure of its severity the anteroposterior renal pelvis diameter is measured. Courtesy of Dr Annemarie Jeanes. VCUG voiding cystourethrogram micturating cystourethrogram Bladder drainage Repeat ultrasound scan at 4–6 months when glomerular ltration rate further increased Bilateral hydronephrosis and/or dilated lower urinary tract in a male Prophylactic antibiotics Start immediately after birth to prevent urinary tract infection Prophylactic antibiotics Benet of prophylaxis is unproven for mild unilateral hydronephrosis although usually given if the dilatation is severe i.e. 15mm Ultrasound Scan is delayed as low glomerular ltration rate during the rst few days of life may mask outow obstruction Further investigations Ultrasound To exclude posterior urethral valves Other anomalies 24 hours after birth 4–6 weeks Abnormal Abnormal Normal Normal Fig. 50.3 Example of a guideline of the initial management of renal and urinary tract abnormalities detected on antenatal ultrasound.

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Renal and urinary tract anomalies diagnosed prenatally 121 Posterior urethral valves • Mucosal folds or a membrane obstruct urine flow causing bilateral hydronephrosis hydroureter and thickened bladder. One‐third develop end‐stage renal failure. •  Incidence is 1 in 5000–8000 live male births. •  Most are diagnosed on prenatal ultrasound when antenatal interven- tion may be considered. Options include percutaneous vesicoamniotic shunt placement bladder aspiration and drainage of a severely dis- tended kidney. However outcome after intervention has been disap- pointing. As amniotic fluid is mainly derived from fetal urine there may be severe oligohydramnios resulting in Potter syndrome/sequence Fig. 50.4 the dominant features are from compression of the fetus and pulmonary hypoplasia resulting in stillbirth or early neonatal death. •  Presentation in the infant not diagnosed antenatally includes a pal- pable distended bladder poor urinary flow renal and respiratory failure. • Management postnatally is shown in Fig.  50.3. It is with prophylactic antibiotics renal and urinary tract ultrasound within 24 hours of birth and VCUG voiding cystourethrogram mictu- rating cystourethrogram see Fig. 51.2. •  Treatment – drainage of the urinary tract initially by urinary catheter later by ablation of the valves. Careful fluid and electrolyte management. Polycystic kidney disease Autosomal dominant polycystic kidney disease ADPKD Fig. 50.5a •  Common: 1 in 500–1000 live births. •  Wide spectrum of severity usually asymptomatic in childhood causes renal failure in late adulthood. •  Extrarenal features: cysts in liver and pancreas cerebral aneu- rysms and mitral valve prolapse. Autosomal recessive polycystic kidney disease ARPKD Fig. 50.5b •  Rare: 1 in 10 000–40 000 live births. •  Cysts form in the collecting duct. •  Neonates may present with pulmonary hypoplasia secondary to oligohydramnios Potter syndrome/sequence Fig. 50.4. May also present with abdominal masses hypertension and renal failure. •  Associated with congenital hepatic fibrosis. •  May cause renal failure requiring renal transplant. Multicystic dysplactic kidney MCDK •  Uncommon: 1 in 4000 live births. •  Renal parenchyma replaced by cysts of various sizes Fig. 50.6a and b. •  Kidney is functionless accompanied by atresia of the ureter. •  If bilateral it leads to Potter syndrome/sequence. • Kidney may be large and palpable but more often is small. Contralateral kidney is usually normal should have undergone compensatory hypertrophy but at increased risk of vesicoureteric reflux. • Half will have involuted by 2 years. Nephrectomy is only indicated if cysts increase in size or hypertension develops both of which are rare. Renal agenesis •  Unilateral agenesis present in 1 in 1000 live births is only significant if the contralateral kidney is abnormal. •  Bilateral agenesis Potter syndrome is fatal from pulmonary hypoplasia due to severe oligohydramnios Fig. 50.4. Key point Bilateral hydronephrosis with bladder distension in a boy should be assumed to be posterior urethral valves until proven otherwise. Limb deformities arthrogryposis Pulmonary hypoplasia causing respiratory failure Bilateral renal agenesis Oligohydramnios from lack of fetal urine excretion causing fetal compression Potter facies Low set abnormal ears Flattened nose Prominent epicanthic folds and downward slant to eyes Fig. 50.4 Potter syndrome Potter sequence. a b Fig. 50.5 a Autosomal dominant polycystic kidney disease ADPKD. There are separate cysts of varying size between normal renal parenchyma. b Autosomal recessive polycystic kidney disease ARPKD. There is diffuse bilateral enlargement of the kidneys. a b Fig. 50.6 a Multicystic dysplastic kidney MCKD. The kidney is replaced by cysts of variable size with atresia of the ureter. b Renal ultrasound shows discrete cysts of variable size in multicystic dysplastic kidney MCKD.

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Neonatology at a Glance Third Edition. Edited by Tom Lissauer Avroy A. Fanaroff Lawrence Miall and Jonathan Fanaroff. © 2016 John Wiley Sons Ltd. Published 2016 by John Wiley Sons Ltd. 122 Neonatal problems Electrolyte problems Sodium Normal range 135–145 mmol/L. Hyponatremia – Na 130 mmol/L Results from excess water relative to sodium or insufficient sodium relative to water. Key is to assess fluid status overall. If detailed assessment required measure paired urinary and serum sodium osmolality and creatinine to establish fractional excretion of sodium. Fractional excretion of sodium FENa UNa/PNa × PCr/UCr × 100 where UNa is urinary sodium PNa plasma sodium PCr is plasma crea­ tinine UCr urinary creatinine. Term infants hyponatremia usually from giving excessive volume of IV dextrose containing no or insufficient sodium. Especially in first 48 hours of life and when there is intravascular Renal and urinary tract disorders 51 Renal function in the newborn Almost all infants void by 24 hours of life. If it is suspected that urine has not been passed within the first day it is usually that voiding has not been recorded especially immediately after birth. Consider obstruction or intrinsic renal problem but they are usually detected on antenatal ultrasound screening. Some key points regarding renal function are listed in Fig. 51.1. The fetal kidney plays no role in excretion or homeostasis – which is performed by the placenta In the fetus the function of the kidney is to produce amniotic uid. The fetal circulation is in chemical equilibrium with that of the mother. Fetal or cord blood measurements of renal function e.g. blood urea nitrogen urea or creatinine reect renal function of the mother not the fetus Glomerular ltration rate GFR is low in newborns even if adjusted for body size Glomerular ltration rate GFR in A preterm infant at 28 weeks – 10mL/min/1.73m 2 body surface area BSA A healthy term infant – 30 mL/min/1.73m 2 Adult – 120mL/min/1.73 m 2 range 80–120 reached by the second year of life. Some argue that it is more appropriate to quote GFR in infancy by weight the mean value being 1 mL/min/kg range 0.5–1.5 mL/min/kg The newborn kidney is optimized for retention of dietary solutes for growth not for excretion The healthy newborn infant grows very rapidly i.e. is strongly anabolic. Breast milk is just sufcient to provide the nutrients needed for this growth. There is little excess dietary solute requiring excretion so infants can thrive despite biochemical evidence of renal insufciency that would be inadequate for an adult. There are two practical consequences of this: The newborn kidney is optimized for retention not excretion of essential substances such as sodium and other minerals If growth ceases e.g. infection the low renal reserve of the infant is exposed and biochemical derangements are common Both these are even more true of the preterm than of the term infant Term infants produce urine almost free of sodium and can thrive on human milk that contains 10 mmol/L of sodium. This is not true of the preterm infant 32 weeks’ gestational age fed mature human milk or an articial formula of similar composition . Under these circumstances they are prone to become sodium-depleted and hyponatremic typically at about 10 days postnatal age late hyponatremia of prematurity. This can be prevented by increasing the dietary sodium intake to 4–6 mmol/kg/day for the vulnerable period of 4–14 postnatal days. Mature human milk would only provide 1.25mmol/kg/day. Neonates with renal tract malformations such as dysplasia or obstructive uropathy are also prone to becoming hyponatraemic and acidotic and require sodium and bicarbonate supplements respectively. The term kidney conserves sodium the preterm kidney loses sodium Term infants are less able to concentrate urine than adults. This is even more pronounced in preterm infants Reduced urine osmolality in the newborn is physiologic Fig. 51.1 Some key points about renal function in newborn infants.

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Renal and urinary tract disorders 123 volume depletion with water reabsorption. Also excess IV fluids to mother during labor oliguric renal failure renal impairment with little urine output and fluid overload. Preterm – marked Na loss in urine poor at conserving sodium as tubular reabsorptive capacity not fully developed. This results in hyponatremia of prematurity see Fig. 51.1. Other causes include: •  insufficient Na supplementation low FENa •  gastrointestinal losses – diarrhea vomiting low FENa •  renal losses – diuretics high FENa renal dysplasia congenital adrenal hyperplasia renal tubulopathies • SIADH syndrome of inappropriate antidiuretic hormone high FENa low POsm and high UOsm – probably rare in newborn infants. Hypernatremia – Na 150 mmol/L Result of excessive water loss over sodium or excess sodium intake over water. If detailed assessment required assess fluid status and measure FENa. Hypernatraemic dehydration may be from: •  insufficient input of fluids e.g. insufficient breast milk • excessive water losses e.g. evaporative through skin in extremely preterm phototherapy radiant heater or gastrointes­ tinal losses •  excess sodium intake e.g. sodium containing flushes of lines sodium bicarbonate sodium phosphate etc high UOsm and high FENa Rare causes – diabetes insipidus central e.g. septo‐optic dysplasia or nephrogenic no ADH or ADH effect low UOsm low FENa deliberate salt poisoning. Potassium normal range 3.5–5.5 mmol/L Hyperkalemia – K 6.0 mmol/L Serious condition as can result in arrhythmias and death. But most common reason is hemolyzed blood sample. Other causes – renal impairment transient is relatively common in extremely preterm infants excess K supplementation congen­ ital adrenal hyperplasia. Neonates tolerate hyperkalemia better than older children so only treat if K 6.5 mmol/L. ECG monitoring is required. Treatment involves giving calcium gluconate to stabilize myo­ cardium salbutamol IV or nebulized correcting acidosis stopping all K changing to low K feed infusion of glucose and insulin calcium resonium orally or rectally but can cause gastrointestinal obstruction. Hypokalaemia – K 3.0 mmol/L Causes include insufficient supplementations diuretics diarrhea vomiting renal tubular losses e.g. Bartter syndrome drugs e.g. amphotericin. Calcium and phosphate Hypocalcemia Relatively common problem and can lead to seizures. Causes: birth trauma/asphyxia infants of diabetic mothers exchange transfusion with blood reconstituted in citrate maternal hyperparathyroidism Di George syndrome associated with hypo­ magnesemia maternal vitamin D deficiency. Hypophosphatemia Usually results from insufficient supplementation in feeds or parenteral nutrition. Question What is the significance of hypernatremia in breast fed babies Most breast fed babies have a normal serum sodium. However if there is insufficient intake of breast milk the infant may develop hypernatremic dehydration. On examination the infants may not appear to have severe dehydration as the ante­ rior fontanel may not be sunken and skin turgor may be normal as the extracellular fluid volume is relatively well maintained. However the baby may be lethargic and quiet and feed poorly because of cerebral intracellular dehydration. Movement of water from brain cells may cause a decrease in brain volume and rupture of intracerebral veins and bridging blood vessels resulting in hemorrhage and seizures. The definitive sign is significant weight loss often in excess of 12 birth weight. Once recognized it is important that the serum sodium is corrected slowly over 24­48 hours. Serum sodium may be extremely high 160 mmol/L. Too rapid correction can result in seizures from too rapid expansion of cells in the brain. Lactation advice and support should be given to try to re­establish successful breastfeeding. Hypernatremia has also been seen after accidental over­concentration of formula milk feeds or due to deliberate salt poisoning although both are very rare. Question What are the ECG changes in hyperkalemia ECG changes progress with increasing potassium con centration: •  Initial changes – prolonged PR interval peaked T waves •  Progression – absent P waves ST depression peaked T waves •  Further progression – QRS widening ST depression peaked T waves danger of ventricular fibrillation and other arrhyth­ mias and asystole Key point Unexpected hyperkalemia – repeat measurement as often due to hemolyzed blood sample.

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124 Neonatal problems Urinary tract infection UTI •  Commoner in boys than in girls – the reverse of older children. •  Should be suspected in any infant who is non‐specifically unwell. Presentation •  Fever or sometimes low temperature or temperature instability •  Poor feeding •  V omiting •  Prolonged jaundice •  Diarrhea •  Failure to thrive Investigations Urine – collecting urine samples: •  clean catch specimen •  urethral catheterization •  suprapubic aspiration see Chapter 76. Blood culture and sepsis work‐up with or without lumbar puncture should be performed as urinary tract infection is often accompanied by septicemia in neonates. Diagnosis Is made by culture of a single strain of any organism on a catheter sample or suprapubic aspirate. However may get false‐positive supra­ pubic aspirate result from skin commensal or bowel perforation. White cells may or may not be present on microscopy or urinalysis. E. coli is the commonest organism 75 remainder caused by Klebsiella Proteus Enterobacter. Management Intravenous antibiotics – start immediately whilst awaiting the result of the urine culture. Subsequent choice of antibiotics will depend on the sensitivities of the cultured organism. Should be continued at full dosage until the infant has been well for 2–3 days and a negative follow‐up urine culture obtained. Following treatment of culture positive UTI oral prophylactic antibiotics e.g. trimethoprim or cefalexin should be given until the results of imaging of the kidneys and urinary tract are known. Imaging – if culture is positive ultrasound of the kidneys and urinary tract is performed to detect renal tract abnormalities. A VCUG voiding cystourethrogram micturating cystourethrogram is performed to identify bladder outflow obstruction e.g. from posterior urethral valves or vesicoureteral reflux Fig.  51.2. A  radionuclide scan DMSA dimercaptosuccinic acid is per­ formed 3 months later to identify renal scarring Fig. 51.3. Acute kidney injury AKI acute renal failure In acute kidney injury acute renal failure there is sudden impair­ ment in renal function leading to inability of the kidney to excrete nitrogenous waste and electrolytes. It is defined as a rise in the plasma creatinine concentration to twice the upper limit of normal i.e. 1.5 mg/dL 130 mmol/L accompanied by a reduction in urine flow rate to 1 mL/kg/hour. However renal failure can occur without oliguria. It results from a significant fall in glomerular filtration rate with failure of tubular reabsorption of salt and water. Causes Different in neonates from children and adults as usually prerenal Table 51.1. Mild renal impairment is not uncommon in the first few days of life particularly in preterm infants and is usually transient. Clinical features •  Creatinine concentration raised – at birth it reflects maternal creatinine falls over the next 4­ 6 weeks a rising creatinine after day 1 suggests acute kidney injury •  Urinary features – oliguria hematuria proteinuria • Clinical features – edema dehydration vomiting lethargy seizures h ypertension Fig. 51.3 Bilateral renal scarring more severe on right on DMSA radionuclide scan on investigation following a urinary tract infection. Fig. 51.2 VCUG voiding cystourethrogram micturating cystourethro­ gram showing trabeculation of the bladder wall hypertrophy of the bladder and dilated posterior urethra from posterior urethral valves.

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Renal and urinary tract disorders 125 • Other biochemical features – hyperkalemia acidosis hyper­ phosphatemia and hypocalcemia Investigations Ultrasound of kidneys and urinary tract – identifies if there are abnormal kidneys outflow obstruction abnormal blood flow in renal arteries and veins. Management Prevention •  Monitor the creatinine blood urea nitrogen urea and electro­ lytes of newborn infants who have been exposed to risk factors for acute kidney injury such as birth asphyxia or sepsis •  Early treatment of hypovolemia •  Relief of obstruction •  Avoid nephrotoxic agents if possible Electrolyte and fluid management •  Restrict sodium potassium and phosphate. Use calcium carbonate as phosphate binder. Correct metabolic acidosis. •  High‐dose furosemide 2–5 mg/kg to convert oliguric into non‐ oliguric renal failure. •  Nutritional support. •  Renal replacement therapy – rarely needed only if fluid and metabolic abnormalities cannot be corrected. Peritoneal dialysis is preferable but may not be possible e.g. abdominal wall defects or necrotizing enterocolitis. Hemodialysis is difficult due to vascular access and risks associated with anticoagulation. Continuous veno‐venous hemofiltration is more gentle and better tolerated especially in the sick neonate unable to tolerate inter­ mittent hemodialysis. Prognosis Infants who develop acute kidney injury in the neonatal period have increased mortality highest in extremely preterm. Infants who have chronic kidney disease and need to start renal replacement therapy in the neonatal period have a 2‐year survival rate of 81 with infection being the most common cause of death. The 5‐year survival rate is 76. However there is significant comorbidity in the survivors with growth problems anemia and hypertension. Table 51.1 Causes of acute kidney injury acute renal failure in neonates. Prerenal Renal Postrenal Hypovolemia Dehydration sepsis necrotizing enterocolitis Blood loss: antepartum neonatal Heart failure Hypoxia including birth asphyxia Acute tubular necrosis secondary to an uncorrected prerenal cause Congenital renal abnormality e.g. polycystic kidney disease renal agenesis renal hypodysplasia Vascular insult – renal vein thrombosis renal artery thrombosis associated with use of umbilical arterial lines Nephrotoxins e.g. aminoglycosides Congenital obstructive uropathy – posterior urethral valves etc. Neurogenic bladder Infection – pyelonephritis

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Neonatology at a Glance Third Edition. Edited by Tom Lissauer Avroy A. Fanaroff Lawrence Miall and Jonathan Fanaroff. © 2016 John Wiley Sons Ltd. Published 2016 by John Wiley Sons Ltd. 126 Neonatal problems Features of the normal male genitalia are listed in Table 52.1. Most abnormalities arise from abnormal embryology Fig. 52.1. Inguinal hernia This results from the processus vaginalis remaining patent. Much more common in males than females and usually on the right side. Common in preterm infants particularly those with broncho‐ pulmonary dysplasia as they have weak muscles and increased intra‐abdominal pressure. Presents as a swelling in the groin or scrotum on crying Fig. 52.2. It should be repaired promptly to avoid the risk of strangulation in both term and preterm infants unless the anes- thetic risk necessitates delaying the operation. If the hernia becomes irreducible the lump is firm and tender the infant vomits or becomes unwell then an attempt should be made to reduce it after sustained gentle compression together with opioid analgesia. If possible surgery is delayed for 24–48 hours to allow the edema to resolve. If reduction is unsuccessful emergency surgery is required to avoid bowel strangulation and damage to the testis. Hydrocele This is fluid around the testis from a processus vaginalis that is wide enough to allow peritoneal fluid to flow down it but too narrow to form an inguinal hernia. Tense transilluminates Fig. 52.3. Often bilateral. Most resolve spontaneously. Genital disorders 52 Table 52.1 Features of normal male genitalia at term. Length and diameter – normal size Meatus – at tip Testes – palpable in scrotum Scrotum – rugae Peritoneum Abdominal descent Inguinoscrotal descent third trimester Gubernaculum Scrotum Phallus Processus vaginalis a c b d Inguinal hernia Normal Hydrocele Testis retroperitoneal on posterior abdominal wall Vas deferens Pubic tubercle Bowel Internal inguinal ring Obliterated patent processus vaginalis Thinly patent track Tunica vaginalis Anterior superior iliac spine Fig. 52.1 a Embryology of testicular descent. The testis migrates from the posterior abdominal wall to the scrotum. It is preceded by a tongue of peritoneum the processus vaginalis. This is obliterated in the normal infant b. It remains widely patent in an inguinal hernia c. With a hydrocele it is patent but narrow d. Fig. 52.2 Inguinal hernia in a newborn infant arrow. Courtesy of Dr Mike Coren. Fig. 52.3 Hydrocele on transillumination. Courtesy of Dr Mike Coren.

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Genital disorders 127 Undescended testis Failure of the testis to descend into the scrotum. Present in 5 of term male infants. Incidence is higher in preterm infants as testic- ular descent through the inguinal canal only occurs in the third tri- mester of pregnancy. Testicular descent may continue after birth by 3 months of age only 1.5 are affected but few descend thereafter. Examination With warm hands the contents of the inguinal canal are gently mas- saged towards the scrotum. If undescended no testis is palpable in the scrotum and the overlying scrotum is often poorly formed. The undescended testis may be palpable in the groin but may some- times be in the abdomen or outside the normal line of descent. A descended testis sometimes subsequently retracts upwards into the inguinal region retractile testis. Investigations For bilateral undescended testes pelvic ultrasound and karyotype may be needed to establish the infant’s gender i.e. male and not a virilized female. The presence of testicular tissue can be confirmed by detecting testosterone production after hormonal stimulation. Sometimes laparoscopy is required to locate the testis. Management Surgery to place the testis in the scrotum orchidopexy is performed soon after 6 months of age definitely by 2 years because: •  fertility is optimized – the testis needs to be in the scrotum to be below body temperature •  malignancy – increased risk which for a unilateral undescended testis is reduced to nearly the same as a normal testis •  it is cosmetic and avoids psychologic upset. Torsion of the testis There is interruption of the blood supply to the testis and epidid- ymis. The testis and surrounding area may be inflamed and the scrotum is dark red or black. Must be differentiated from a strangu- lated hernia and scrotal hematoma. Doppler ultrasound of testic- ular blood supply is helpful to determine testicular viability. Torsion must be relieved promptly for testis to remain viable. Occasionally present at birth when testis is seldom viable. Hypospadias Common affecting 1 in 300 boys. In the fetus the urethra is cre- ated by flat tissue folding over from the perineum towards the tip. If this is not completed the meatal opening may not reach the normal site at the tip of the penis Fig. 52.4. In hypospadias there is: •  a ventral urethral meatus – usually on the glans of the penis but can be on the shaft or perineum Fig. 52.5 •  a hooded foreskin – from failure to fuse •  chordee – tethering resulting in ventral curvature of the penis most obvious on erection. This is associated with the more severe forms. Surgical correction is performed by 18 months of age so that the urethral meatus is at the tip of the penis erection is straight and the penis looks normal. In most cases of hypospadias affecting only the glans surgery is not required except sometimes for cosmetic reasons. Circumcision At birth the foreskin adheres to the surface of the glans penis. These adhesions subsequently separate allowing the foreskin to become retractile. The foreskin cannot be retracted in 50 of boys at 1 year of age and in 10 at 4 years but in only 1 by 16 years. The advantages and disadvantages of circumcision are contro- versial and emotive. Advantages are: •  hygiene – easier to keep clean •  prevents possibility of pathologic phimosis scarring or recurrent balanitis infection requiring circumcision when older •  slightly reduced incidence of urinary tract infection •  reduced risk of heterosexual HIV transmission as adults. However it is not a trivial operation as healing can take up to 10 days. Complications of neonatal circumcision include: •  pain during and after the operation – adequate analgesia should be provided •  bleeding infection damage to glans penis but this is uncommon. In the US circumcision is widely performed. In the UK the main indication is religious among Jews and Muslims. In coun- tries in Sub‐Saharan Africa with high HIV prevalence the WHO recommends consideration as a component of HIV prevention. Glanular Coronal Distal penile Mid shaft Proximal Perineal Fig. 52.4 Classification of hypospadias. Fig. 52.5 Hypospadias. The arrow shows the urethral meatus. Key point Infants with hypospadias must not be circumcised as the fore‐ skin may be needed at surgery.

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Neonatology at a Glance Third Edition. Edited by Tom Lissauer Avroy A. Fanaroff Lawrence Miall and Jonathan Fanaroff. © 2016 John Wiley Sons Ltd. Published 2016 by John Wiley Sons Ltd. 128 Neonatal problems In newborn infants disorders of sex development DSD present with ambiguous genitalia. There may be: •  virilized female – clitoromegaly labial fusion •  undervirilized male – micropenis bilateral undescended testes poorly developed or bifid scrotum •  true hermaphrodite now called ovotesticular DSD – complex external phenotype with both testicular and ovarian tissue present. They are rare but require prompt evaluation and skilled management to avoid emotional turmoil for parents. Family support and counseling are of utmost importance. Sex development The fetal gonad is initially bipotential Fig. 53.1. The testis‐determining gene on the Y chromosome SRY causes differentiation of gonads into testes. Production of testosterone and its metabolite dihydrotestosterone results in the development of male genitalia. Undervirilization in the male may result from: •  inadequate androgen action from: – abnormal testes – inability to convert testosterone to dihydrotestosterone 5α‐reductase deficiency – abnormalities of the androgen receptor androgen insensitivity syndrome •  gonadotropin insufficiency from: – congenital pituitary dysfunction – several syndromes e.g. Prader–Willi syndrome. In the absence of the SRY gene the gonads become ovaries and the genitalia female. Virilized female is from excessive androgens the most common cause of this is congenital adrenal hyperplasia. Ovotesticular DSD is from chromosomal rearrangement and is rare. Birth When a baby is born the parents immediately want to know if they have a girl or boy. If the genitalia are ambiguous Fig. 53.2 it is imperative not to guess but to inform the parents that further evaluation is needed. Birth registration must be delayed until this has been completed. Investigations Detailed assessment may include: •  karyotype •  sex and adrenal hormones: – blood glucose and electrolytes – 17α‐hydroxyprogesterone – testosterone dihydrotestosterone and androstenedione – hormone GnRH or HCG stimulation tests •  ultrasound of internal genitalia and gonads. Laparoscopic examination and biopsy of internal structures are sometimes required. Disorders of sex development 53 Male Female Male external genitalia Male internal genitalia vas cord seminal vesicles Dihydrotestosterone Testosterone Anti-Müllerian hormone Testes 5- reductase Inhibits uterus and fallopian tubes Female internal and external genitalia Undifferentiated gonads in fetus Gonadotropin secretion from pituitary Y chromosome SRY gene No SRY gene Genes suppress testicular development Fig. 53.1 Sex development in the fetus. Fig. 53.2 Ambiguous genitalia at birth. Do not assign a gender before expert opinion. Courtesy of Dr David Clark.

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Disorders of sex development 129 Management Ensure good communication between all health‐care professionals so that they do not ascribe a gender to the infant inadvertently. Most are reared as females as it is easier to create female external genitalia than a functioning penis but it is increasingly recognized that this may not necessarily be in the long‐term best interest of the child. There is increasing evidence of problems with gender identity as teenagers and adults of males reared as females and evidence of good sexual functioning and satisfaction in males who had a poorly formed penis in the neonatal period. Early referral expert multidisciplinary assessment and long‐term management are required. Congenital adrenal hyperplasia •  Autosomal recessive condition. •  About 1 in 5000 live births. •  Most common cause is a deficiency of an enzyme 21‐hydroxylase required for cortisol biosynthesis Fig. 53.3. There is a deficiency in the production of cortisol aldosterone salt loss and an excess of adrenal steroids virilization. Presentation May be with: •  virilization of female external genitalia Fig. 53.4 • enlarged penis and pigmented scrotum in male but rarely recognized •  salt‐losing adrenal crisis with hyponatremia and hyperkalemia at 1–3 weeks of age there is vomiting weight loss circulatory collapse which may be fatal may be accompanied by hypoglycemia •  tall stature precocious puberty in males. Diagnosis Raised blood level of 17α‐hydroxyprogesterone. Management Short term: • Salt‐losing crisis – requires intravenous saline glucose hydrocortisone. •  Corrective surgery of external genitalia in females is occasionally needed during infancy. Long term: •  Glucocorticoids throughout life. • Mineralocorticoids if salt loss infants may need extra oral sodium chloride. •  Monitoring of growth and pubertal development. •  Additional hormone replacement stress doses if ill or prior to surgical procedures. •  Further corrective surgery in adolescence to external genitalia in females. •  Psychologic support. Prenatal testing and screening Prenatal testing and treatment of affected fetuses are available. Screening 17α‐hydroxyprogesterone concentration is now performed in most routine biochemical screening programs of newborn infants in the US but not in the UK. Fig. 53.4 Virilized female from congenital adrenal hyperplasia. There is clitoral hypertrophy and fusion of the labia. Courtesy of Dr David Clark. Congenital adrenal hyperplasia Mineralocorticoids Glucocorticoids Sex hormones 17-hydroxyprogesterone Testosterone Progesterone Aldosterone Cortisol Block in 21-hydroxylase ACTH Feedback loop Fig. 53.3 Abnormal adrenal steroid biosynthesis in the commonest form of congenital adrenal hyperplasia 21‐hydroxylase deficiency.

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Neonatology at a Glance Third Edition. Edited by Tom Lissauer Avroy A. Fanaroff Lawrence Miall and Jonathan Fanaroff. © 2016 John Wiley Sons Ltd. Published 2016 by John Wiley Sons Ltd. 130 Neonatal problems Anemia Physiology In the fetus the oxygen tension is low. t he oxygen affinity of fetal red cells containing hemoglobin F HbF is increased compared to adult red cells Fig. 54.1 and this favors uptake of more oxygen. t he hemoglobin concentration Hb is also much higher than in adults. After birth the concentration of Hb is greatly affected by the time of cord clamping and the position of the infant relative to the placenta. Delaying cord clamping by more than 1 minute after birth may allow blood to flow from placenta to baby significantly increasing Hb levels and iron stores and stability of blood pressure. Clinical features t able 54.1 and management Blood transfusion Kept to a minimum because of potential hazards unless there has been clinically significant blood loss e.g placental abrup- tion placenta previa. t ransfusion thresholds vary between neo- natal units and are based on severity of illness of the infant and respiratory support required. Anemia of prematurity is consid- ered in Chapter 34. Oral folic acid Given as prophylaxis if chronic hemolysis e.g. hereditary sphe- rocytosis. Some neonatal units prescribe it for VLBW infants for the first few months as their folate stores are low the folate content of breast milk is low and there is increased demand from rapid growth. Anemia and polycythemia 54 PO 2 mmHg 40 60 80 100 Neonatal blood Adult blood 20 0 20 040 HbO 2 saturation 60 100 80 PO 2 kPa 4 08 12 Fig. 54.1 Oxygen dissociation curve showing the higher oxygen affinity of neonatal than adult hemoglobin. Causes and investigation of anemia Fig. 54.2 Anemia and jaundice Anemia without jaundice Hemolysis Causes Investigations Immune – rhesus or ABO incompatibility or other red cell antibodies Enzyme – G6PD deciency pyruvate kinase deciency Red cell membrane defects – spherocytosis Acquired – infection DIC Fetal – fetomaternal twin–twin transfusion Obstetric – placenta previa abruption cord accidents Neonatal – subgaleal or cranial hemorrhage gastrointestinal hemorrhage Iatrogenic – blood sampling accidental loss from an arterial line Congenital – Diamond-Blackfan Sepsis – e.g. parvovirus Complete blood count – hemolysis suggested on smear blood lm Bilirubin increased unconjugated Direct antiglobulin test DAT Coombs test: Positive – rhesus or ABO incompatibility or other r ed cell antibodies N egative – enzyme defects red cell membrane defects Reticulocyte count – increased Blood loss Reduced red blood cell production Complete blood count – smear suggests blood loss Reticulocyte count – increased Maternal Kleihauer Fig. 53.3 – may be positive identies acid resistant fetal red blood cells in maternal blood smear Cranial ultrasound – may show site of hemorrhage Complete blood count Reticulocyte count – reduced PCR for parvovirus Fig. 54.2 Causes and investigation of anemia. a b Fig. 54.3 Fetomaternal hemorrhage. a Anemia number of red cells are reduced nucleated red cells erythroblasts and reticulocytes on a blood smear film from a term neonate with severe anemia at birth 4.5 g/dL due to fetomaternal hemorrhage. b Kleihauer test on maternal blood from of the same baby showing several intensely pink‐stained cells containing HbF which is resistant to acid lysis.

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Anemia and polycythemia 131 Oral iron therapy In preterm infants given after the age of 4–6 weeks to prevent anemia of prematurity. Not given if the infant has recently had a blood transfusion or is on iron‐supplemented formula feeding. Polycythemia Usually defined as a venous hematocrit Hct above 0.65. t he hematocrit depends on the site of sampling: capillary hemato- crit peripheral venous central venous arterial. Potential danger of high hematocrit is hyperviscosity which causes sludging of red blood cells and formation of microthrombi leading to vascular occlusion Fig. 54.4. Causes Increased erythropoietin production: •  Intrauterine hypoxia – IUGR intrauterine growth restriction. •  Maternal diabetes. •  High altitude. Trisomy 21 Down syndrome Increased blood volume: •  Excessive placental transfusion from delayed cord clamping. •  t win–twin transfusion. Clinical features and complications t able 54.2 Treatment t reatment is to reduce the hematocrit by replacing a proportion of the infant’s blood with 0.9 saline plasma is no longer used to minimize blood product usage by partial exchange transfusion see Chapter 78. As treatment has not been shown to be of long-term benefit criteria are controversial: •  venous hematocrit 0.65 and infant symptomatic or hemato- crit 0.70 even if asymptomatic – generally agreed that a partial dilutional exchange transfusion should be performed. •  If venous hematocrit 0.65–0.70 and asymptomatic – observe and treat only if becomes symptomatic. Table 54.1 Clinical features of anemia. History Examination History – blood loss Family history – anemia jaundice splenomegaly from hemolytic disease Obstetric history – antepartum hemorrhage Maternal blood type – rhesus or other red cell antibodies potential for ABO incompatibility Ethnic origin – hemoglobinopathies and G6PD deficiency Pallor Jaundice from hemolysis Apnea and bradycardia t achycardia Heart murmur – systolic flow murmur Respiratory distress heart failure Hepatomegaly and/or splenomegaly hydrops Inadequate weight gain from poor feeding 5 3 2 1 0 00.8 0.6 0.4 Hematocrit Adult Gestation: 38–41wk 30–36wk 24–29wk 0.2 Blood viscosity mPa s 4 Fig. 54.4 Hematocrit is the main determinant of blood viscosity. Blood viscosity rises exponentially when hematocrit is 0.65. Fig. 54.5 Plethoric term infant. Nasogastric tube is because of poor feeding. Table 54.2 Clinical features and complications of polycythemia. Plethora Fig. 54.5 Hypoglycemia/hypocalcemia Irritability lethargy seizures Poor feeding Hyperbilirubinemia Priapism Respiratory distress Heart failure Intestinal – necrotizing enterocolitis Renal – renal vein thrombosis hematuria oliguria t hrombocytopenia Neurologic impairment. Question Should all babies be screened for polycythemia Screening all infants is not recommended because of lack of evidence of benefit of treatment American Academy of Pediatrics.

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Neonatology at a Glance Third Edition. Edited by Tom Lissauer Avroy A. Fanaroff Lawrence Miall and Jonathan Fanaroff. © 2016 John Wiley Sons Ltd. Published 2016 by John Wiley Sons Ltd. 132 Neonatal problems Neutrophil and thrombotic disorders 55 Neutrophil disorders There is a physiologic rise in neutrophils between 12 and 24 hours of life and thereafter the number falls Fig. 55.1. Neutrophilia The most common causes are: •  acute bacterial infection •  maternal chorioamnionitis usually without active infection in the baby. Much less common causes are fungal infection and postnatal corticosteroid therapy. When neutrophilia is accompanied by a left shift i.e. increase in immature neutrophils such as band forms Fig. 55.2 it is used as a marker for bacterial infection. The combination of an abnormal absolute neutrophil count and immature:total neutrophil ratio increases the likelihood of infec- tion to about 65. Neutrophilia from bacterial infections often develops 12–24 hours after the onset of infection. Serial measure- ments are more informative than isolated values. However inter- pretation of the blood smear requires technical expertise. In the UK band counts have largely been replaced by measuring acute phase reactants C‐reactive protein or procalcitonin. In many units in the US both band counts and acute phase reactants are measured. Neutropenia This is a neutrophil count of less than 1500 cells/mm 3 1.5 × 10 9 /L. Neutropenia is usually caused by sepsis necrotizing enterocolitis cytomegalovirus CMV and other congenital infections intrauterine growth restriction IUGR maternal preeclampsia and the chromosome trisomies 13 18 and 21. Alloimmune neutropenia and inherited causes are uncommon. Most types of neonatal neutropenia are self‐limiting and treatment is primarily of the underlying cause. Intravenous immunoglobulin is non‐ specific and has not been shown to be beneficial. The recombinant hematopoietic growth factor G‐CSF granulocyte colony stimu- lating factor will increase the neutrophil count but has not been shown to improve outcome except in the rare disorder severe con- genital neutropenia. White cell transfusions are rarely effective. 6000 9000 12 000 3000 00 12 024 Time hours Total neutrophils per mm 3 36 60 48 15 000 6 9 12 3 Total neutrophils × 10 9 /L 15 Fig. 55.1 Total neutrophil count showing the rise with age and the normal range. From Manroe B.L. et al. J Pediatr 1979 95: 89–98. Fig. 55.2 Blood smear showing four neutrophil ‘band’ cells in a neonate with bacterial sepsis. The ‘band’ cells also show toxic granulation in the cytoplasm another useful sign of acute bacterial infection.

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Neutrophil and thrombotic disorders 133 Thrombotic disorders thrombophilia These are a group of disorders characterized by an increased tendency for abnormal clot formation. Thrombosis occurs in approximately 5 per 100 000 births 50 of episodes are arterial and 50 are venous. Predisposing factors These are: •  indwelling catheters 80–90 of episodes •  acute bacterial and viral infection •  asphyxia ischemia shock •  cardiac abnormality •  polycythemia •  prematurity •  twin–twin transfusion •  genetic. Maternal and familial conditions associated with thrombophilia These include: •  multiple fetal losses •  anticardiolipin antibodies •  SLE systemic lupus erythematosus •  maternal diabetes •  placental abruption •  myocardial infarction •  deep venous thrombosis •  pulmonary embolism. Inherited causes of thrombosis Gene mutations have been identified for some of the most common thrombotic disorders: •  protein C deficiency Fig. 55.3 •  protein S deficiency •  antithrombin deficiency •  factor V Leiden mutation APC resistance •  prothrombin gene mutation. Diagnosis Most thrombi are asymptomatic. Clinical signs of thrombosis depend on location of the clot which may embolize: •  Arterial – limb may become mottled in color cool and dis colored with reduced pulses. In time may become gangrenous with zone of demarcation see Fig. 66.5. Thrombus in aorta may lead to heart failure or stroke. •  Venous – portal vein renal vein thrombosis causing abdominal mass hematuria oliguria and hypertension. Thrombus in right atrium may lead to stroke. Imaging Depends on site: • Ultrasound echocardiography MRI for diagnosis and follow‐up. •  Angiography is the gold standard but may become difficult or impossible to perform or not justified e.g. for stroke. MR angiog- raphy is now available. Management Options include: •  If catheter‐related may be due to arterial spasm or too large a catheter or hypovolemia. If does not respond promptly to partial withdrawal of the catheter or correction of hypovolemia the catheter should be removed. •  Observe and follow up for increase in clot size and functional compromise. •  Anticoagulation with unfractionated or low molecular weight heparin e.g. enoxaparin. •  Clot lysis with fibrinolytic agents tissue plasminogen activator but contraindicated if there has been a recent intraventricular hemorrhage. •  Surgical thrombectomy – rarely required or possible. • Factor concentrate if thrombosis and inherited deficiency e.g. protein C antithrombin. Question Which neonates should be screened for inherited thrombophilia Any neonate with clinically significant thrombosis e.g. severe purpura renal vein thrombosis extensive thrombosis or a family history of severe neonatal purpura. Fig. 55.3 Infant with microthrombi in the skin from protein C deficiency.

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Neonatology at a Glance Third Edition. Edited by Tom Lissauer Avroy A. Fanaroff Lawrence Miall and Jonathan Fanaroff. © 2016 John Wiley Sons Ltd. Published 2016 by John Wiley Sons Ltd. 134 Neonatal problems In the newborn abnormal bleeding may be due to: •  a platelet abnormality number or function •  abnormal coagulation system •  vascular endothelial damage/abnormality. Thrombocytopenia This is the most common platelet disorder. It is defined as a platelet count of less than 150 000/mm 3 150 × 10 9 /L. It is usually identi- fied on the complete blood count CBC but if severe may cause petechiae Fig. 56.1 or bleeding. A convenient classification is according to the time of onset Table 56.1. The most common causes are maternal pre‐eclampsia and diabetes mellitus intrauterine growth restriction and neonatal infection. Treatment is directed to the underlying cause. For infants who are sick or septic where production may be compromised platelet transfusion is considered if: •  platelets 30 000/mm 3 30 × 10 9 /L in term infants •  platelets 50 000/mm 3 50 × 10 9 /L in preterm infants •  if actively bleeding or before surgery platelets 100 000/mm 3 100 × 10 9 /L. Abnormal coagulation Coagulation factors are a group of proteins that when activated will promote the formation of a fibrin‐rich clot or hemostatic plug Fig. 56.2. These proteins are formed early in gestation in the fetus and do not cross the placenta. The most common acquired cause of coagulopathy is a combination of coagulation activation and poor liver reserve in a sick or septic infant. Deficiency of certain coagulation factors will lead to bleeding disorders Table 56.2. Indications for performing clotting studies These are: •  family history of bleeding disorder •  clinical signs of abnormal bleeding: – oozing from venepuncture/surgical sites – bleeding umbilical cord stump – extensive bruising or large cephalhematoma or subgaleal subaponeurotic bleed – gastrointestinal bleeding •  septic infant •  necrotizing enterocolitis Coagulation disorders 56 Fig. 56.1 Petechiae from thrombocytopenia in an infant. Table 56.1 Classification of fetal and neonatal thrombocytopenia most common causes in bold type. Time of presentation Condition Fetus Neonatal alloimmune thrombocytopenia NAITP Maternal autoimmune thrombocytopenia ITP SLE Congenital infection CMV rubella herpes syphilis Severe rhesus disease Chromosome abnormalities trisomy 21 18 13 Inherited very rare Neonatal 72 h Placental insufficiency PIH IUGR diabetes Neonatal infection Birth asphyxia Neonatal alloimmune thrombocytopenia NAITP Maternal autoimmune thrombocytopenia ITP SLE Thrombosis renal vein aortic Congenital infection CMV rubella herpes syphilis Inherited very rare Neonatal 72 h Late‐onset bacterial infection necrotizing enterocolitis Disseminated intravascular coagulation DIC Giant hemangioma Kasabach–Merritt syndrome ITP idiopathic thrombocytopenic purpura SLE systemic lupus erythematosus CMV cytomegalovirus PIH pregnancy‐induced hypertension IUGR intrauterine growth restriction. Adapted from Murray N. Semin Neonatol 1999 4: 27–40. Intrinsic pathway Contact system Extrinsic pathway Cellular injury Blood vessel wall FXII FXIFXIa FXII FVII FVIIa FX Activated platelet surface FIXFXIa FVIIIa FIXa + FVIIIa FX FXaF Xa Va Complex Prothrombin FXa F Xa Va complex Thrombin Fibrinogen Fibrin FXIIIa Fibrin cross link CLOT FV FVa Soluble FXIa Tissue Factor FV FVa Fig. 56.2 The coagulation pathway.

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Coagulation disorders 135 •  rapidly falling platelet counts in a sick infant •  severe hypoxic–ischemic encephalopathy. Investigations Coagulation screen consists of: •  PT prothrombin time •  APTT activated partial thromboplastin time •  TT thrombin time. May include: •  fibrinogen •  D‐dimers – a measure of fibrin breakdown may be useful for diagnosis of disseminated intravascular coagulation DIC. Interpretation of abnormal clotting studies Table 56.3 The normal values for preterm and term infants are derived locally as different hospitals use different assays. The coagulation values in preterm and term neonates differ significantly from older children and adults: •  Prothrombin time tends to be a few seconds longer at birth but will reach the normal adult range within a week. • Activated partial thromboplastin time may not reach adult normal range for several months because of low levels of the ‘liver’ factors e.g. IX XI XII. •  Thrombin time may be slightly prolonged in early life due to the presence of a fetal form of fibrinogen. This is of no clinical significance. Management of abnormal clotting If there is active bleeding a correct diagnosis must be established. Vitamin K should be given while results are awaited and fresh‐ frozen plasma FFP if there is severe bleeding. Intramuscular injections must not be given to any neonate with a known or sus- pected major coagulation disorder e.g. hemophilia and care must also be taken after venepuncture and/or heelprick testing in such babies – pressure for 5 minutes is recommended. If there is disseminated intravascular coagulation DIC treat the underlying cause. In the interim platelets FFP and cryoprecipitate only if the fibrinogen level is low may be indicated. Their need is determined by the coagulation tests which should be repeated reg- ularly as this is an evolving disorder. FFP contains all coagulation factors and is suitable for emer- gencies but does not contain sufficient of any single factor for severe single factor deficiencies. Replacement by a suitable concentrate is optimal once a firm diagnosis has been established. Severe congenital coagulation factor deficiencies – consult pediatric hematologist. Table 56.2 Bleeding disorders. Deficiency Disorder Comments Vitamin K Vitamin K deficient bleeding VKDB Hemorrhagic disease of newborn Deficiency of vitamin K‐dependent coagulation factors factors II VII IX and X Associated with breast‐feeding or severe liver disease in the infant or maternal use of anticonvulsants Factor VIII Classic hemophilia A X‐linked inheritance – positive family history in 80. Mild and moderate forms usually asymptomatic during the newborn period but 20 of cases present in the newborn usually after circumcision or other surgery. Severe form may result in life‐threatening hemorrhage Factor IX Christmas disease – hemophilia B X‐linked inheritance. Similar presentation to hemophilia A V on Willebrand factor V on Willebrand disease Most common inherited bleeding disorder Autosomal dominant inheritance Only rare subtypes present in the newborn period Table 56.3 Interpretation of abnormal clotting studies. Test Vitamin K deficiency DIC Liver impairment Hemophilias Platelets Normal Reduced Normal Normal PT Prolonged Prolonged Prolonged Normal PTT Prolonged Prolonged Prolonged Prolonged TT Normal Prolonged Prolonged Normal Fibrinogen Normal Reduced Reduced Normal The prothrombin time PT may be reported by some laboratories in the form of an INR international normalized ratio. Although this may be useful for adults the INR is not a reliable measure of coagulation for neonates. PTT partial thromboplastin time TT thrombin time. Question What is special about taking blood samples for coagulation studies Blood sample must be free‐flowing. Squeezed and slow- flowing samples cause tissue activation and can give abnormal results including a normal result in a baby with severe hemophilia. If the sample is taken from a heparinized line it may not be possible to interpret the thrombin time. Instead fibrinogen levels and reptilase time must be used as they are unaffected by heparin. If an inherited coagulation disorder is suspected it is advisable to test the parents as well as the baby since neonatal coagulation tests are often difficult to interpret.

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Neonatology at a Glance Third Edition. Edited by Tom Lissauer Avroy A. Fanaroff Lawrence Miall and Jonathan Fanaroff. © 2016 John Wiley Sons Ltd. Published 2016 by John Wiley Sons Ltd. 136 Neonatal problems Functions of the skin include: •  mechanical protection •  barrier against microorganisms and toxins •  thermoregulation and fluid balance •  sensory input and tactile communication with the environment. There are marked differences in the structure and function of the skin of preterm infants term infants and adults Table 57.1. Goals of neonatal skin care •  Avoid traumatic injury during routine care. •  Prevent skin dryness leading to cracking and fissures. •  Minimize exposure to topical agents that are potentially toxic when absorbed Table 57.2. Diaper nappy dermatitis Much less of a problem since disposable diapers nappies used. •  Keep skin dry with super-absorbent diapers and frequent changes. •  Treat underlying cause-of excessive stooling such as infectious diarrhea malabsorption opiate withdrawal. •  Apply zinc oxide and pectin paste barriers liberally to excoriated skin to prevent reinjury from fecal enzymes and allow skin to heal. •  Add 1 hydrocortisone if unresponsive. •  Identify candida dermatitis with distinctive pattern of redness on perineum groin and thighs and red pustular satellite lesions apply antifungal ointment or cream. Consider oral antifungal treatment if mouth lesions present. Infection •  Bacterial – bullous impetigo staphylococcal scalded skin syndrome SSSS see Chapter 43. •  Viral – herpes simplex virus infection see Chapter 44 CMV and rubella see Chapter 11. •  Fungal – see Chapter 34. Dermatological disorders 57 Table 57.1 Developmental differences between the skin of infants and adults. Developmental differences Significance Stratum corneum Term infants and adults: 10–20 layers Preterm infants susceptible to: 30 weeks of gestation: 2–4 layers •  evaporative and transepidermal water loss 24 weeks of gestation: virtually no stratum corneum. Also diminished cohesion between epidermis and dermis as fewer fibrils •  transcutaneously transmitted infection and toxicity from topical agents •  epidermal stripping with adhesives Dermis Term – only 60 the depth of adults Preterm – even thinner dermis less collagen and fewer fibrils Preterm – excess fluid edema accumulates in the dermis which is prone to injury Sweating Term – limited ability during first few days Preterm – unable to sweat before 31 weeks’ gestational age in response to heat although sweat glands are present Emotional sweating of hands and feet – present at term poorly developed in preterm infants Thermal sweating in adults is important to avoid overheating but newborn infants cannot do this Emotional sweating to measure response to pain – can be used in term infants but not in preterm Table 57.2 Toxicity reported from topical antiseptic use in preterm infants. Antiseptic Toxicity Hexachlorophene Spongiform encephalopathy Povidone‐iodine Hypothyroidism goiter Chlorhexidine in alcohol Scalds avoid alcohol containing solution in extreme preterm Question What is the significance of a pustular rash in a newborn infant There is a wide differential diagnosis. By far the most common cause is erythema toxicum which typically presents within the first week with new lesions rapidly appearing at dif- ferent sites. Transient pustular melanosis may be present at birth and has a scaly halo around the pustule. Both are benign. Herpes simplex infection and disseminated staphylococcal aureus infection - uncommon but should be considered espe- cially if the infant is at all unwell.

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Dermatological disorders 137 Vascular skin lesions Port wine stain nevus flammeus Present at birth in 0.3 of newborns. Most often on the face. Permanent malformation of the capillaries in the dermis. Laser therapy may improve the appearance of disfiguring lesions. Rare associations: •  trigeminal nerve distribution Sturge–Weber syndrome associ- ated with intracranial vascular anomaly in 10 Fig. 57.1a b • severe limb and bone hypertrophy – Klippel–Trenaunay syndrome. Strawberry nevus hemangioma Not usually present at birth. Appears in first month of life Fig. 57.2. Preterm infants at increased risk. Increases in size until 8–18 months of age then gradually regresses. No treatment is indi- cated unless lesions are large with potential for disfigurement ulcerating threaten vital function e.g. vision hearing breathing or feeding. Oral propranolol sometimes combined with laser therapy has replaced corticosteroids as the treatment of choice for compli- cated lesions. Recently topical beta-blocker therapy applied directly to the lesion has been shown to be beneficial. Congenital melanocytic nevus CMN pigmented nevus Small lesions 1.5 cm – observe may remove when older for cosmetic reasons. Small but possible increased risk in malignant melanoma this contrasts with the much higher risk in giant lesions 20 cm Fig. 57.3 which are usually treated aggressively by surgical removal. Genetic syndromes There are a large number of rare conditions Table 57.3. a b Fig. 57.1 a Port wine stain with trigeminal distribution Sturge‐Weber syndrome. b MRI scan following gadolinium administration showing choroidal enhancement from choroidal angiomas arrows. Neuroimaging is only performed in infancy if specific ocular or neurological abnormalities are present. MRI scan courtesy of Dr Sheila Berlin. Fig. 57.2 Strawberry nevus. Courtesy of Dr David Clark. Fig. 57.4 Epidermolysis bullosa. Rare group of disorders. Bullae or blisters are caused by trauma or friction to the skin. There are scarring and non‐scarring subgroups. Courtesy of Prof. Julian Verbov. Table 57.3 Some skin lesions associated with genetic syndromes. Skin lesion Diagnostic group Unformed skin Aplasia cutis absent patch of skin ± bony defect may be associated with trisomy 13 Thin skin Dermal hypoplasia collagen disorders Blisters/erosions Bullous disorders e.g. epidermolysis bullosa Fig. 57.4 Thick/scaly skin Ichthyoses e.g. collodion infant or more severe harlequin ichthyosis White skin/hair Pigment deficient disorders e.g. oculocutaneous albinism piebaldism tuberous sclerosis Palpable brown patches Syndromes with melanocytic nevi Flat brown patches Syndromes with café‐au‐lait macules e.g. neurofibromatosis Deficient hair nails sweat Ectodermal dysplasias. Syndromes with abnormal hair Fig. 57.3 Giant congenital melanocytic nevus GCMN. Rare but serious condition because of 5–15 risk of malignant melanoma in first decade of life. The lesion may be hairy and satellite lesions are often present.

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Neonatology at a Glance Third Edition. Edited by Tom Lissauer Avroy A. Fanaroff Lawrence Miall and Jonathan Fanaroff. © 2016 John Wiley Sons Ltd. Published 2016 by John Wiley Sons Ltd. 138 Neonatal problems Seizures and perinatal strokes 58 Seizures Table 58.1 Table 58.1 Recognition causes investigation and management of seizures. Recognition see video: Seizures Seizures may present with clonic or tonic involuntary movements of one or more limbs. Often difficult to recognize with certainty as manifestations are often subtle: •  apnea or transient cyanosis or episodes of oxygen desaturation •  lip smacking •  transient eye rolling altered consciousness floppiness. Causes Cerebral Hypoxic–ischemic: •  encephalopathy birth trauma •  focal ischemia arterial/venous Subarachnoid or subdural hemorrhage Parenchymal hemorrhage in preterm infants Cerebral malformations of the brain including vascular anomalies Metabolic Hypoglycemia Hypocalcemia Hypomagnesemia Hyponatremia Hypernatremia Hyperammonemia Inborn errors of metabolism Sepsis Septicemia Meningitis Encephalitis Drugs Drug withdrawal: •  maternal abuse •  following neonatal narcotic therapy Side‐effect of drugs Others Kernicterus Pyridoxine dependent Benign genetic seizure disorders Investigations Always performed Blood glucose immediate at bedside Blood urea nitrogen urea and electrolytes Calcium and magnesium Complete blood count Blood cultures Lumbar puncture – protein glucose gram stain and culture Blood gases Cranial ultrasound to identify hemorrhage or parietal infarcts or cerebral malformation or abnormalities may miss subarachnoid hemorrhage EEG Multichannel EEG Fig. 58.1 or aEEG amplitude integrated EEG preferably with video observation See Fig. 14.4 for seizures on aEEG and Chapter 80 on aEEG. To be considered CT to identify hemorrhage traumatic injury MRI to identify ischemia malformations Metabolic screen – plasma for ammonia amino acids lactate urine for amino acids and organic acids Screen for congenital infection Urine for drug toxicology Specific biochemical tests in suspected neurometabolic conditions Management Airway Breathing Circulation. Check for hypoglycemia. Anticonvulsants: •  Administer if seizure is prolonged more than about 5 minutes or clusters. Controversy about how aggressively to treat electrical seizures seizures on EEG or aEEG but no clinical manifestations •  No drug shown to be superior to others. Those used include phenobarbital most common first‐line drug phenytoin levetiracetam midazolam clonazepam lidocaine lignocaine with ECG monitoring. •  Acute seizures often respond poorly. •  Use as few anticonvulsants as possible. •  Treat the underlying cause if possible e.g. sepsis. •  If unresponsive to treatment consider therapeutic trial of pyridoxine. Prognosis Depends on cause. Epilepsy in 15–20 and abnormal neurodevelopment in 25. Poor prognosis – if poor response to initial anticonvulsant treatment abnormal EEG background and presence of electro‐clinical dissociation on EEG. If caused by acute brain insult most seizures resolve and anticonvulsant therapy can usually be slowly withdrawn. If maintenance anticonvulsant therapy required – is usually with phenobarbital clonazepam or sodium valproate. Fig. 58.1 EEG being performed.

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Seizures and perinatal strokes 139 Perinatal strokes Defined as cerebral injury from vascular cause that originates between 20 weeks of gestation and 28 days of life. Occurs in as many as 0.2–1 per 1000 live births. Types •  Perinatal arterial ischemic stroke PAIS – the most common site is left middle cerebral artery. • Hemorrhage – may be parenchymal subarachnoid or intraventricular. •  Cerebral sinovenous thrombosis CSVT – can cause venous infarction often with hemorrhage. Based on neuroimaging strokes may be classified as fetal if diagnosed before birth neonatal if diagnosed in the first 4 weeks of life or presumed perinatal ischemic stroke PPIS if diagnosed after 28 days of life. Etiology Complex and multifactorial. Often no maternal fetal or neonatal risk factors can be identified. Perinatal arterial ischemic stroke PAIS may be due to thrombo- embolism. The emboli may originate from thrombosis of placental vessels from venous thrombi that cross the patent foramen ovale from right‐to‐left shunts in congenital heart disease and from thrombi from umbilical vessel catheters. Sepsis or meningitis trauma and prothrombotic dis orders e.g. protein C or protein S deficiency may also contribute. Further details of prothrombotic disorders are con- sidered in Chapter 56 Coagulation disorders. The contribution of maternal risk factors and intrapartum events is unclear. Hemorrhagic stroke may result from intraparenchymal hemor- rhage from vascular anomalies or hemorrhage into ischemic infarction periventricular hemorrhagic infarction is associated with intraventricular hemorrhage in extremely preterm infants. In cerebral sinovenous thrombosis CSVT perinatal compli- cations such as hypoxia or prolonged rupture of membranes or maternal infection may be present. Head trauma during birth and prothrombotic disorders are other risk factors. Clinical presentation Most often with seizures within the first 3 days of life usually focal but can be non‐specific. Some present with encephalopathy. Many are asymptomatic in the neonatal period. Specifc investigations • Cranial ultrasound is abnormal in most infants but is not always diagnostic. •  MRI scan for accurate diagnosis and prognosis Fig. 58.2. •  In focal cerebral infarction investigations to rule out underlying thrombophilic disorders are indicated. Management Treatment of seizures with anticonvulsants and supportive therapy. The role of anticoagulation for neonates with cerebral venous thrombosis is controversial. Prognosis Nearly 50 of infants with perinatal stroke develop motor disability often a hemiplegia on the contralateral side presenting in infancy or childhood and cognitive dysfunction. Occipital lesions may be associated with visual impairment. Large lesions may lead to epilepsy. Fig. 58.2 MRI scan showing left cerebral infarct see arrow. Courtesy of Dr Frances Cowan.

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Neonatology at a Glance Third Edition. Edited by Tom Lissauer Avroy A. Fanaroff Lawrence Miall and Jonathan Fanaroff. © 2016 John Wiley Sons Ltd. Published 2016 by John Wiley Sons Ltd. 140 Neonatal problems Neural tube defects In the embryo the flat neural plate folds to become the brain and spinal cord. Neural tube defects NTDs arise from a deficiency in this process: •  anencephaly – from failure of cranial development of most of the cranium and brain •  spina bifida – from failure of caudal development of the vertebral bodies •  midline defects – from failure of fusion e.g. of the skull as an encephalocele. Most are now diagnosed antenatally by ultrasound or α‐fetoprotein measurement in maternal serum. Prevalence NTDs result from a combination of environmental and genetic factors. The risk of having a second affected child is 3–5 and of a third 5–10. The risk is increased 10–20‐fold in mothers taking valproate. In the US 7 per 10 000 pregnancies are affected with a birth prevalence of 4 per 10 000 live births and in the UK 12 per 10 000 pregnancies with a birth prevalence of 2 per 10 000 live births. Maternal folic acid supplementation pre‐ and periconceptually and during early pregnancy has been shown to reduce prevalence. In the US but not in the UK or most countries in Western Europe cereal grain products are fortified with folic acid. The prevalence of affected infants has decreased markedly over the last 30 years with better maternal nutrition folic acid supple- ments food fortification in the US prenatal screening with maternal ultrasound and raised maternal serum a‐fetoprotein together with the option of termination of pregnancy. Trial of open fetal surgery for myelomeningocele is described in Chapter 4. Anencephaly The condition is lethal most are stillborn. There has been consid- erable debate about the ethics of the use of their organs for donor transplantation. However the situation rarely arises because few anencephalic infants are now born as most are diagnosed antena- tally and parents opt for termination of pregnancy. Encephalocele Herniation of sac containing CSF and may contain brain through a midline skull defect. Most are occipital Fig.  59.1. Developmental impairment is likely if brain tissue is in the sac or there are other cerebral malformations. Spina bifida There is a spectrum of increasing severity: •  spina bifida occulta Fig. 59.2a •  meningocele Fig. 59.2b •  myelomeningocele Figs 59.2c and d. Neural tube defects and hydrocephalus 59 Fig. 59.1 Occipital encephalocele. Hairy patch on skin Neural plaque Skin CSF Spina bida occulta Meningocele Myelomeningocele Skin and dura Pia and arachnoid Nerve root Spinal cord a b c d Fig. 59.2 a Spina bifida occulta. Defect in the vertebral arch with intact spinal cord. May be an incidental finding on X‐rays – asymptomatic. More extensive lesions indicated by overlying patch of hair or nevus or other skin abnormality. b Meningocele. Bony defect with herniation of meninges but not the spinal cord. The lesion is covered with skin. c Myelomeningocele. Defect in the lumbar or thoracic spine with herniation of the meningeal sac and spinal cord tissue with leakage of CSF. d Photograph of myelomeningocele myelo cord meninges covering cele sac showing exposed neural tissue and patulous neuropathic anus.

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Neural tube defects and hydrocephalus 141 Spina bifida occulta Spina bifida occulta is often suggested by a skin lesion over the lower spine and is confirmed with further diagnostic imagining such as spinal ultrasound and/or MRI. Usually there is no neuro- logic deficit at birth but tethering of the spinal cord may occur dur- ing childhood. Neurosurgical opinion should be obtained. May be an incidental finding on X-rays. Meningocele Prognosis following surgery is usually good. Myelomeningocele Wide range of complications Fig. 59.3. Most lesions are detected antenatally and a management plan made before the baby is born. Management requires an extensive multidisciplinary team pedi- atrics orthopedics neurosurgery urology child development working with the family. The back lesion is usually closed immediately after birth to minimize the risk of infection and surveillance performed for hydrocephalus. Hydrocephalus This is from an excessive volume of cerebrospinal fluid CSF. It is usually from blockage of CSF flow or a defect in CSF reabsorption. Causes Congenital •  Aqueduct stenosis. •  Chiari malformation. •  Atresia of outflow foramina of fourth ventricle Dandy–Walker syndrome. •  Congenital infection. Acquired •  Post‐intraventricular hemorrhage in preterm infants. •  Post‐intracranial infection. •  Post‐subdural/subarachnoid hemorrhage. Clinical features •  Ventricular dilatation on imaging precedes symptoms or signs Fig. 59.4. •  Increasing head circumference. •  Separation of sutures. •  V omiting. •  Apnea abnormal muscle tone seizures depressed consciousness. •  Dilatation of head veins. •  Sun-downing sign setting-sun sign eyes deviate downwards. •  Full then bulging fontanel. Monitoring and treatment In neonates hydrocephalus is monitored by serial cranial ultra- sound measurements of ventricular size and head circumference See Chapter 79 Cranial ultrasound. If severe and progressive or the infant becomes symptomatic a  ventriculoperitoneal shunt is inserted surgically. It carries a significant complication rate. Hydrocephalus in preterm infants Usually secondary to intraventricular hemorrhage causing fibrosis and impaired CSF reabsorption. V entricular dilatation may need treatment if progressing rapidly or causing symptoms. V entriculoperitoneal shunt insertion in small infants may be delayed because of the risk of skin breakdown or shunt blockage if the CSF protein is high. Instead CSF may be removed by lumbar or ventricular puncture or from a neurosur- gically inserted reservoir. No difference in long‐term outcome between repeated lumbar/ventricular taps compared with removal of CSF only when symptomatic. Intraventricular fibrinolytics and acetazolamide which reduce CSF production have not been shown to be of benefit. Hydrocephalus from associated Chiari malformation herniation of the cerebellar vermis through the foramen magnum A ventriculoperitoneal shunt is often required. Often associated with long-term neurodevelopmental impairment. Kyphoscoliosis developmental dysplasia of the hip talipes equinovarus. Neuropathic bladder – palpable bladder dribbling urine. Predisposes to urinary tract infections vesico-ureteric reux hypertension chronic renal failure. Neuropathic bowel – patulous anus. Paralysis of the legs. Sensory decit over the legs resulting in skin damage from incidental trauma. Fig. 59.3 Complications associated with severe myelomeningocele. These depend on the extent and level of the lesion. Fig. 59.4 CT scan axial view showing ventricular dilatation in a term infant with aqueductal stenoisis. Courtesy of Dr Sheila Berlin.

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Neonatology at a Glance Third Edition. Edited by Tom Lissauer Avroy A. Fanaroff Lawrence Miall and Jonathan Fanaroff. © 2016 John Wiley Sons Ltd. Published 2016 by John Wiley Sons Ltd. 142 Neonatal problems The ‘hypotonic infant’ describes marked hypotonia or floppiness i.e. less resistance to passive movement than normal and is usually accompanied by muscle weakness Fig. 60.1a b and c. The cause of the hypotonia is either: •  central – central nervous system or •  peripheral – lower motor neuron neuromuscular junction or muscle disorders. Transient hypotonia may result from systemic infection electro- lyte disorders hypermagnesemia seizures or drugs administered to the infant or mother. Preterm infants have reduced tone and strength compared to term infants. These circumstances are not considered in this chapter. Clues from the history •  Family history – consanguinity unexplained deaths multiple miscarriages. •  May be increasing severity with succeeding generations e.g. muscular dystrophy. •  Clinical features in mother – ptosis in myasthenia gravis absence of facial expression and weak grip in myotonic dystrophy and family history of cataracts. •  Pregnancy – polyhydramnios and reduced fetal movements. Causes and clinical features Table 60.1 The hypotonic infant 60 a b c Fig. 60.1 a When held upright the hypotonic infant slides through one’s hands. b When held prone the infant flops like a rag doll. c On traction of the arms there is marked head lag. Table 60.1 Causes and clinical features of central and peripheral hypotonia. Central hypotonia Peripheral hypotonia Causes Cerebral malformation Encephalopathy: •  Hypoxic–ischemic encephalopathy •  Meningitis/encephalitis •  Hypoglycemia. Chromosomal/ syndromes: •  Trisomy 21 Down syndrome •  Prader–Willi syndrome Metabolic: •  Hypothyroidism •  Inborn errors of metabolism e.g. hyperammonemia amino acidopathy Spinal cord injury Anterior horn cell: •  Spinal muscular atrophy Werdnig–Hoffmann syndrome Neuromuscular junction: •  Neonatal myasthenia gravis Muscles: •  Congenital myopathies •  Myotonic dystrophy Clinical features Antigravity movements present Normal or brisk tendon reflexes Features of brain dysfunction may be present Weak or absent antigravity movements from severe muscle weakness Reduced or normal tendon reflexes Other features – see Fig. 60.2

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The hypotonic infant 143 Investigations May include: •  karyotype/DNA analysis •  gene tests for specific disorders •  imaging of brain/spinal cord – MRI or ultrasound •  blood glucose calcium magnesium and lactate •  acid–base status urine and plasma amino acids urine organic acids plasma ammonia lactate acylcarnitines CSF lactate •  CPK creatine phosphokinase – raised in muscular dystrophy •  thyroid function tests •  congenital infection screening tests •  EMG electromyogram •  nerve conduction studies •  muscle biopsy. Some specific conditions Central Hypoxic–ischemic encephalopathy Hypotonia may be replaced by spasticity when older. Prader–Willi syndrome •  70 have partial chromosomal 15q deletion imprinting where the deletion occurs on the active paternal chromosome 15 and the maternal copy is inactive. Also uniparental disomy two maternal copies of the 15q region. •  Characteristic facies with narrow forehead almond-shaped eyes and triangular mouth Fig. 60.3. •  Hypotonia. •  Hypogonadism/cryptorchidism. •  Obesity after the neonatal period. •  Behavior problems developmental delay. Peripheral rare Spinal muscular atrophy type 1 Werdnig–Hoffmann syndrome •  Autosomal recessive – anterior horn cell degeneration. •  Pregnancy – decreased or loss of fetal movements. •  At birth – arthrogryposis contractures may be present. •  Characteristic feature – fasciculation of tongue. •  Severe progressive disorder with death from respiratory failure during first year of life. •  DNA test available. Neonatal myasthenia gravis •  Affects 10–20 of infants of mothers with myasthenia gravis. • Transient condition from maternal anti‐acetylcholine IgG antibodies. • Presentation – generalized weakness facial diplegia rarely ptosis weak suck and cry tendon reflexes normal. •  Use neostigmine not tensilon to confirm diagnosis. Myotonic dystrophy •  Autosomal dominant – inherited from the mother trinucleotide repeat expansion mutations. Earlier and more severe presentation in successive generations anticipation. •  Pregnancy – polyhydramnios and decreased fetal movement. • Neonate – weakness edema and petechiae at birth with or without arthrogryposis. •  Facial diplegia ptosis tent‐shaped mouth talipes equinovarus. • Brain abnormalities present in some forms of muscular dystrophies. •  Feeding difficulties due to poor gut motility. •  CPK may be elevated EMG and biopsy are diagnostic. Congenital myopathies •  Most are recessively inherited. •  Clinical features – weak hypotonic areflexic. •  Abnormal swallowing normal extra‐ocular movements. •  Muscle weakness usually slowly progressive. Hypogonadism Ptosis of the eyelids Ophthalmoplegia Associated orthopedic problems Arthrogryposis Dislocated hips Respiratory distress Difculty swallowing Weak limb recoil which does not improve with time Lies in frog-like position as anti- gravity movement poor Decreased or normal tendon reexes Tongue fasciculation Fig. 60.2 Clinical features that may be present with a peripheral neuromuscular disorder. Fig. 60.3 Prader–Willi syndrome. Characteristic facies and hypogonad- ism. The nasogastric tube is required because of poor feeding. Courtesy of Dr Mike Coren.

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Neonatology at a Glance Third Edition. Edited by Tom Lissauer Avroy A. Fanaroff Lawrence Miall and Jonathan Fanaroff. © 2016 John Wiley Sons Ltd. Published 2016 by John Wiley Sons Ltd. 144 Neonatal problems Congenital abnormalities of the hip and feet Developmental dysplasia of the hip DDH Hip is dislocatable dislocated and/or has shallow acetabulum. Incidence •  6 per 1000 live births have abnormal clinical examination on screening. •  0.5–2 per 1000 live births are treated. Risk factors clinical examination and initial management These are described in Chapter 17. Treatment •  Pavlik harness for 1–3 months Fig. 61.1: – maintains flexion and abduction and limits adduction – redirects femoral head towards acetabulum. •  Orthoses or open reduction and derotation femoral osteotomy may be required. Outcome •  80–95 identified on screening do not need surgery. •  5 of treated cases develop avascular necrosis ischemic damage of the femoral head. •  Impact of neonatal screening on need for surgery is uncertain. Talipes equinovarus Anatomy Foot held in rigid equinovarus position Fig. 61.2a and b. Needs to be distinguished from positional talipes see Chapter 21. Incidence 1 in 1000 live births. Bilateral in 50. Risk factors •  Multifactorial inheritance. •  3–4 risk if affected parent. •  2 risk for subsequent siblings. •  May be secondary 20: – oligohydramnios – neuromuscular disorder e.g. spina bifida – malformation syndrome. •  May be associated with developmental dysplasia of the hip but this has recently been questioned. Management •  Refer to orthopedic surgeon as soon after birth as possible. Ponseti regimen now followed worldwide as highly successful and avoids surgical correction: • Initially foot is manipulated into the maximum position of correction and held in a plaster cast Fig. 61.3. Changed regularly to correct deformity of the midfoot and forefoot. Bone and joint disorders 61 Fig. 61.1 Pavlik harness for treatment of developmental dysplasia of the hip. Talipes equinovarus Tight achilles tendon Thin calf muscles Heel rotated inwards varus Entire foot inverted and supinated Forefoot adducted and plantiexed- equinus Short foot a b Fig. 61.2 a and b Talipes equinovarus. The foot is inverted and supinated and the forefoot is adducted. The affected foot is shorter and the calf muscles thinner than normal. The position of the foot is fixed and cannot be corrected by passive manipulation. Fig. 61.3 Treatment of talipes equinovarus with serial plaster casts courtesy of Mr Brian Scott.

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Bone and joint disorders 145 •  If foot still in equinus position Achilles tenotomy performed. •  If correction is complete “boots and bar” to hold feet abducted externally rotated and dorsiflexed worn all the time for about 3 months then at night until 4 years old. •  Monitor for recurrence. Tibialis anterior tendon transfer may be required for supination of the forefoot. •  Foot should be supple and corrected may be smaller and calf thinner than unaffected side. Infection Septic arthritis •  Rare in newborn. •  Usually via extension from underlying bone infection rather than primary infection of the joint but can be from hematogenous spread. Signs •  Decreased joint movement. •  Joint is swollen warm red Fig. 61.4. Effusion may be present. Diagnosis Joint aspiration for cell count 50 000 white blood cells/mm 3 50 white blood cells × 10 9 /L Gram stain culture. Imaging •  Ultrasound – fluid in joint space. •  Radionuclide bone scan if indicated – hot spot. •  MRI scan of bone if necessary. Plain X‐ray is of limited value – may show widened joint space. Treatment •  Single or repeated joint aspiration. •  Surgical drainage of hip joint if no improvement. •  Antibiotics – prolonged course for 3–6 weeks. Long‐term complications •  Erosion of articular surface. Joint ankylosis. Osteomyelitis •  Rare in newborn. •  Most are hematogenous in origin in metaphysis. •  Usually presents within first 2 weeks of life. Pathogens Commonest are Staphylococcus aureus and streptococci. Signs •  No movement pseudoparalysis of limb. •  Red warm swollen painful limb. Diagnosis •  Blood culture positive. •  Bone aspiration for cultures if indicated. Imaging •  Ultrasound – periosteal elevation and soft tissue swelling. •  Radionuclide bone scan if indicated – hot spot needle aspiration does not produce positive bone scan. •  Plain X‐ray – limited use at this stage as only shows periosteal elevation and soft tissue swelling. •  MRI scan of bone if necessary. Treatment Antibiotics – prolonged course for approximately 6 weeks. Continued for 2–3 weeks after symptoms resolve and CRP normalizes. Skeletal dysplasias There are several hundred with shortening of the limbs and spine resulting in short stature. Achondroplasia •  Short bowed limbs normal trunk large head. •  Midface hypoplasia frontal bossing. •  Trident hand short and broad protuberant abdomen. Osteogenesis imperfecta •  Inherited disorder of type 1 collagen formation. •  Rare – 1 in 20 000 live births. Clinical features •  Increased bone fragility susceptibility to fracture from mild to lethal depending on sub‐type Fig. 61.3 scoliosis and kyphosis. •  Blue sclerae defective tooth formation in some patients. •  Hearing loss. Fig. 61.4 Septic arthritis showing swollen left knee arrow. Fig. 61.5 X‐ray of osteogenesis imperfecta showing multiple fractures.

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Neonatology at a Glance Third Edition. Edited by Tom Lissauer Avroy A. Fanaroff Lawrence Miall and Jonathan Fanaroff. © 2016 John Wiley Sons Ltd. Published 2016 by John Wiley Sons Ltd. 146 Perinatal medicine Hearing Congenital hearing loss affects 1–2/1000 live births. If the infant receives neonatal intensive care risk is increased 10‐fold. Hearing loss is: •  conductive – involves conduction of sound in the middle or outer ear often occurs in childhood from secretory otitis media •  sensorineural – involves the hair cells of the cochlea in the inner ear or the cochlear branch of cranial nerve VIII as in congenital or neonatal hearing loss. The speech and language of children with severe hearing impair- ment are delayed or do not develop. The earlier in life hearing can be restored or specialist assistance provided the better the out- come. Screening infants with risk factors Table 62.1 identifies only 40–60 of significant bilateral hearing loss. Universal screen- ing in the first few days of life and certainly by the age of 3 months is therefore conducted in both the US and UK Table 62.2. Neonatal hearing screening Performed using otoacoustic emissions OAE Fig. 62.1. Repeated if necessary followed by automated auditory brainstem response AABR Fig. 62.2 if fails OAE. Some centers use AABR as initial test or for high risk infants. Hearing and vision 62 Table 62.1 Risk factors for hearing loss. Family history Syndromes with hearing loss Malformations of the ears including pits and tags Perinatal Very low birthweight Congenital infection – e.g. CMV cytomegalovirus rubella Severe hyperbilirubinemia Ototoxic medications e.g. furosemide aminoglycosides Mechanical ventilation or extracorporeal membrane oxygenation Hypoxic–ischemic encephalopathy Bacterial meningitis Table 62.2 Rationale for universal hearing screening. Is hearing impairment common Yes – more common than hypothyroidism phenylketonuria or hemoglobinopathy Is the condition serious Yes. Results in marked speech and language delay Is treatment available Yes. Sound amplification including hearing aids cochlea implantation finger‐spelling lip‐reading use of gestures and sign language to maximize early development of language skills Are reliable screening tests available Yes. Acceptable sensitivity and specificity Are other methods of detection available Other methods e.g. parental concern are unreliable Does it improve outcome Yes. The earlier amplification and specialist intervention for infant and family the better the outcome Offers possibility of preventing progression in certain cases e.g. treatment if caused by congenital CMV Can it be done at reasonable cost Y es but requires skilled facilities for diagnostic confirmation and habilitation Automated auditory brainstem response audiometry AABR Auditory stimulus – short duration stimuli at different intensities via earphones Screens hearing pathway from ear to brainstem this test is required to identify auditory neuropathy Good for testing speech wavelengths Detects moderate hearing loss Few false negatives false positive rate 3 Advantages Affected by movement so infants need to be asleep or very quiet so time consuming Complex computerized equipment but is mobile Requires electrodes applied to infants head which parents may dislike Disadvantages Signal via ear and auditory nerve to brain Auditory nerve to brain EEG waveforms – computerized analysis determines if normal or abnormal Fig. 62.2 Automated auditory brainstem response AABR. Otoacoustic emissions OAE Stimuli generated from ear phones. The emissions are normal sound vibrations from the cochlea Simple and quick to perform but affected by ambient noise Advantages Misses auditory neuropathy False positive rate of up to 30 in rst 24 hours after birth as vernix or amniotic uid are still in ear canal Referral rate of 6–8 with risk of loss to follow-up Can reduce referral rate to 1 by doing AABR if fail OAE testing but adds complexity to screening program Disadvantages Fig. 62.1 Otoacoustic emissions OAE.

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Hearing and vision 147 Vision The normal term infant will fix and follow horizontally a moving face a brightly colored object e.g. a red ball or a picture of a target of black and white concentric circles by about 6 weeks. They prefer to look at high‐contrast patterned objects rather than plain ones. Visual acuity is initially reduced – only about 6/36. It improves over the first few months to 6/18 at 4 months and 6/9 at 8 months but adult visual acuity is not reached until about 3 years. At birth many have mild hypermetropia far‐sightedness which per- sists through early childhood clarity of vision is achieved by accommodation. This contrasts with preterm infants who often become myopic nearsighted. The eyes of newborn infants are often not aligned and an inter- mittent squint strabismus is common during the first weeks of life. A constant squint or one persisting beyond 12 weeks post term should be referred to an ophthalmologist. Lesions needing urgent ophthalmologic referral During early childhood failure of focused visual images to reach the retina e.g. from a cataract or glaucoma results in permanent loss of vision amblyopia. Optimal vision is achieved if surgery and optical correction are performed soon after birth by 6 weeks of age. Affected infants must therefore be referred urgently to an ophthalmologist for surgery. Cataracts Fig. 62.3 Cataracts may be detected by parents or on checking the red reflex with an ophthalmoscope during the routine examination of the newborn but may otherwise present with blindness at several months of age. Many are genetic but congenital infection and other causes must be excluded. They are infrequent. Congenital glaucoma Fig. 62.4 Intraocular pressure is raised. There is watering of the eyes photo- phobia and irritability. The eye becomes enlarged and the cornea hazy. Most are bilateral. Other congenital abnormalities There are numerous rare congenital abnormalities of the eye including: •  anophthalmos/microphthalmos absent or extremely small eye •  coloboma Fig. 62.5 may affect iris ciliary body choroid and optic nerve. Vision may be normal in mild cases but poor if optic nerve involved •  aniridia absence of iris •  albinism lack of melanin pigment in iris and retina – may be ocular or generalized often resulting in macular hypoplasia nystagmus and poor vision •  white pupil leukocoria or white reflex on ophthalmoscopy – causes include retinoblastoma cataract retinopathy of prematurity. Affected infants should be referred to an ophthalmologist. The causes of severe visual impairment and blindness in children are listed in Table 62.3. Most visually disabled children also have other disabilities. Other eye conditions •  Retinopathy of prematurity – see Chapter 35. •  Conjunctivitis – see Chapter 43. •  Chorioretinitis in congenital infection – see Chapter 11. Table 62.3 Sites and causes of severe visual impairment and blindness in children 16 years. Whole globe and anterior segment 7 Glaucoma cornea lens cataract 10 Congenital infection 2 Retina 29 Retinopathy of prematurity 3 Oculocutaneous albinism 4 Optic nerve cerebral/visual pathways 76 In some children there was more than one cause. From Rahi J.S. et al. Severe visual impairment and blindness in children in the UK. Lancet 2003 362: 1359–1365. Cataract Fig. 62.3 Cataract in right eye of a newborn infant. Courtesy of Prof. Alistair Fielder. Glaucoma Fig. 62.4 Congenital glaucoma of right eye. Courtesy of Prof. Alistair Fielder. Coloboma Fig. 62.5 Iris coloboma. Keyhole‐shaped pupil due to defect of the iris inferiorly.

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Neonatology at a Glance Third Edition. Edited by Tom Lissauer Avroy A. Fanaroff Lawrence Miall and Jonathan Fanaroff. © 2016 John Wiley Sons Ltd. Published 2016 by John Wiley Sons Ltd. 148 Aspects of neonatal intensive care Pain is a subjective cortical experience. Newborn infants cannot describe a painful experience but there is good evidence from physiologic and behavioral responses that they respond to pain and it causes distress Table 63.1. Pain is one of the main parental concerns for infants in intensive care or undergoing procedures. Parents often also worry about long‐term consequences. There is evidence that children who undergo repeated painful experiences as neonates show increased sensitivity to pain in childhood e.g. to an immunization and are more fearful of pain than their peers. Development of pain pathways in the fetus and preterm infant Pain pathways are well described in the fetus: • 20 weeks – sensory receptors and cortical neurons have developed •  24 weeks – cortical synapses are present •  30 weeks – myelination of pain pathways and development of spinal cord synapses with sensory fibers. This implies that even preterm infants have anatomic neuro- physiologic and hormonal components to perceive pain. Central descending inhibitory control is less well developed – so response to painful stimuli is actually greater than in older children and adults. Factors that modify pain responses Infants requiring intensive care are subjected to an average of 2–10 painful procedures per day. They are also repeatedly disturbed e.g. for examination nursing care. The pain they experience will be affected by: •  procedure being performed Fig. 63.1 the skill of the operator and their concern about minimizing discomfort •  gestational age and postnatal age •  behavioral state •  number of previous painful experiences •  time since last painful experience •  severity of their illness. Assessment of pain Pain can be assessed clinically according to: •  Physiologic responses: – heart rate respiratory rate oxygen requirement blood pressure palmar sweating. •  Behavioral responses: – facial expression body movements crying. •  Metabolic responses: – stress hormones e.g. cortisol – blood glucose lactate. These may be used as proxy measures of pain. Obtaining reliable results is problematic and their interpretation is difficult. Pain assessment scales A variety of neonatal pain assessment scales have been developed Table 63.2 mainly for clinical research or postoperative pain assessment CRIES NFCS PIPP scores. The simpler scales can also be used for regular systematic pain assessment for infants undergoing intensive care or as guidance for staff on pain assessment NPASS. Pain 63 Table 63.1 Some early milestones in neonatal pain. 1987 Proven that surgical thoracotomy for PDA ligation caused greater physiologic and hormonal disturbance if performed without analgesia 2000 American Academy of Pediatrics Policy Statement on Prevention and Management of Pain and Stress in the Neonate. Updated 2006 2001 International Consensus Statement for the Prevention and Management of Pain in the Newborn Severe Moderate Mild Abdominal surgery Circumcision Lumbar puncture Eye exam for retinopathy of prematurity Chest tube insertion Tracheal intubation without induction Arterial puncture Peripheral insertion of central catheter Heelstick blood sample Venipuncture Tracheal suction Urinary catheterization Umbilical artery catheter insertion Nasal swab Physical examination Other uncomfortable/painful conditions Presence of tracheal tube for mechanical ventilation Presence of nasal prongs for CPAP Necrotizing enterocolitis acute Meningitis Pain Fig. 63.1 Postulated hierarchy of pain from procedures. Adapted from Porter F. et al. Procedural pain in newborn infants: the influence of intensity and development. Pediatrics 1999 104: 1–10.

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Pain 149 Minimizing pain There are both non‐pharmacologic and pharmacologic approaches. Always consider: •  Is the procedure really necessary •  Timing the procedure for when the infant is awake if possible. •  Grouping procedures together but limit the number of proce- dures occurring within a short time of each other as with physical training we all need recovery time. •  Using equipment or methods designed to minimize discomfort e.g. appropriately sized heel lancets non‐invasive monitoring venous or arterial catheters to avoid repeated skin punctures avoid- ing intramuscular injections. Non‐pharmacologic These include: •  Environmental modification: – quiet low lighting talking to baby slow stroking rocking skin‐to‐skin contact. •  Non‐nutritive sucking on a pacifier dummy or sucking on breast. •  Sucrose and breast milk both reduce pain responses. •  Positioning on side swaddling comfort holding with still hands Fig. 63.2. Pharmacologic approaches Infants on mechanical ventilation Use of analgesic/anesthetic agents differs between units. The most widely used are: •  morphine – side‐effects include hypotension respiratory depres- sion and withdrawal syndrome if there is a too rapid dose reduction after prolonged use •  fentanyl – side‐effects include respiratory depression tolerance occasionally tongue and chest wall rigidity. Procedures Optimal analgesia aims to prevent rather than treat pain. In the past fear of side‐effects limited the use of opioids and anesthetic agents but it should now be possible to provide adequate pain relief especially postoperatively. Options include: •  Opioids –continuous opioid infusion is preferable as intermittent boluses are associated with poor outcome. •  General anesthesia – all major or surgical procedures. •  Regional anesthesia – e.g. peripheral nerve blocks spinal or epidural local infiltration e.g. for chest tube insertion. • Non‐opioids – e.g. acetaminophen paracetamol sometimes used for minor procedures or postoperatively. Table 63.2 Some validated pain assessment scales in newborn and preterm infants. Neonatal Pain Agitation and Sedation Scale NPASS Premature Infant Pain Profile PIPP Neonatal Facial Coding Scale NFCS CRIES score Behavioral cues: •  Sleep in preceding hour •  Facial expression of pain •  Motor activity tone •  Consolability cry Physiologic cues: •  Heart rate •  Systolic blood pressure •  Respiratory frequency and pattern •  Oxygen saturation Gestational age Behavioral state Brow bulge Eye squeeze Nasolabial furrow Heart rate Oxygen saturation Brow bulge Eye squeeze Nasolabial furrow Open lips Stretch mouth Lip purse Taut tongue Chin quiver Tongue protrusion Crying Requires increased oxygen Increased vital signs Expression Sleeplessness Fig. 63.2 Containing the infant helps reduce pain. This involves secure supported non‐restrictive positioning not tight swaddling to prevent moving. Here during the insertion of a nasogastric tube the mother is containing her baby and the infant is grasping the nurse’s finger. Question How can the pain of heelsticks be minimized Pain is mainly from squeezing the foot so keep this to the minimum. Autostylets are less painful than lancets. Venepuncture is less painful than heelsticks and adequate samples are obtained twice as often but not suitable for repeated sampling. Topical analgesia – not effective for heelsticks and not licensed in the US in newborns. Analgesia – sucrose breast milk or nurse at the breast.

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Neonatology at a Glance Third Edition. Edited by Tom Lissauer Avroy A. Fanaroff Lawrence Miall and Jonathan Fanaroff. © 2016 John Wiley Sons Ltd. Published 2016 by John Wiley Sons Ltd. 150 Aspects of neonatal intensive care Pharmacology includes the study of: •  the effects of drugs on the body pharmacodynamics •  the effect of the body on drugs pharmacokinetics – absorption distribution metabolism elimination •  the use of drugs. The pharmacology and in particular the pharmacokinetics of drugs in neonates differs significantly from that in children and adults. Primarily this is the result of their different physiology Fig. 64.1. Drug prescription and administration The wide variation in absorption metabolism excretion and body composition is mainly related to the neonate’s gestational age and postnatal age together with their variation in size from less than 500 g in the extreme preterm to 5000 g in the large term infant. As a result drug regimens are complex and vary according to age and are usually calculated as a dose per kilogram. Drug monitoring Monitoring plasma levels of drugs is useful if there is a known concentration range within which the drug works and has no tox- icity. This applies to only a few drugs but some of them are in routine use in neonatology e.g. gentamicin vancomycin. Monitoring may involve the measurement of peak and trough plasma concentrations or trough levels only. Measurements are made once the drug has reached the steady state Fig. 64.2. Drugs in breast milk Neonates may be exposed to maternal drugs through their con- sumption of breast milk. Breast milk has a lower pH than blood pH 7.0 versus pH 7.4 and a high fat content and will therefore concentrate basic and fat‐soluble drugs. Highly protein‐bound drugs do not tend to transfer into milk as easily. The concentration Pharmacology 64 Parenteral absorption Poor blood supply and little muscle mass lead to irregular absorption following subcutaneous or intramuscular administration and the potential for toxic drug levels if perfusion suddenly improves High surface area to weight ratio and immature epidermis enhances unwanted percutaneous absorption e.g. topical polymixin has caused hearing loss Renal excretion Glomerular ltration rate is low at birth and tubular secretory function is immature leading to longer half-lives of some drugs e.g. gentamicin. In addition to age affected by co-medication e.g. indomethacin ibuprofen Hepatic metabolism Half of all drugs are metabolized in the liver by the cytochrome P450 CYP enzyme superfamily Metabolic activity of individual members of this family may take several months to mature leading to longer half-lives of some drugs e.g. diazepam Gastrointestinal absorption Low gastric acid secretion in preterm infants may lead to increased absorption of acid-inactivated drugs administered orally e.g. penicillins Reduced bile acid and lipase secretion may lead to reduced absorption of lipid-soluble drugs administered orally e.g. benzodiazepines Body composition Water accounts for 70–80 of body weight cf. 50–60 in adults leading to lower concentrations of water-soluble drugs when administered per kilogram bodyweight Little body fat leads to decreased accumulation of lipid-soluble drugs e.g. diazepam fentanyl leading to prolonged and higher plasma concentrations Bilirubin competes with protein- bound drugs for plasma protein binding sites leading to their displacement and potential problems with toxicity e.g. kernicterus from sulfonamides or ceftriaxone Blood–brain barrier Immature barrier results in faster uptake of some drugs e.g. morphine into the central nervous system leading to increased sensitivity Fig. 64.1 Key physiologic factors affecting neonatal pharmacology.

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Pharmacology 151 of a drug in breast milk will vary with its concentration in maternal plasma drugs with a short half‐life that may be given after feeding are to be preferred. The majority of drugs are transferred into breast milk in concentrations too low to affect neonatal health certain drugs must be avoided and general advice should be to avoid the use of any medications wherever possible Table 64.1. Drug licensing and neonatalogy Up to 80 of drugs administered in neonatal intensive care are not licensed by a national licensing body FDA Food and Drug Administration in the US EMA European Medicines Agency in Europe for use in this population unlicensed or are used outside their license e.g. other dosing regimens other formulation off‐ label. Doctors can prescribe and nurses can administer unlicensed and off‐label medicines but it imposes additional responsibility on prescribers to ensure that the use of a particular drug is sup- ported by the best available evidence. Considerable effort and finance are now being devoted to the development research and licensing of medicines for children. Steady-state trough level: monitor to avoid toxicity from accumulation Steady-state peak level: monitor to ensure ef cacy Steady-state: reached when drug amount entering over a period equals amount leaving Drug given by IV bolus at regular intervals Peak concentration : mainly depends on total body content. Therefore higher dosage per kg body weight required in preterm than term infants Trough level: aminoglycoside toxicity related to average concentration i.e. area under curve. As preterm have reduced renal clearance compared with term infants time interval between doses is longer Time Drug concentration in plasma Fig. 64.2 Drug monitoring – steady‐state peak and trough levels. Table 64.1 Examples of drugs used in breast‐feeding mothers that may affect nursing infant. A formulary should always be consulted. Maternal drug Effect on infant Examples of drugs to avoid Radioactive iodine May cause thyroid suppression Cytotoxic agents Risk of cytotoxic effect Diazepam May cause sedation and may accumulate Tetracycline Possibility of permanent staining of teeth Lithium Risk of neurologic effects cardiac malformations Question What lessons in neonatal pharmacology have been learnt from the past 1886: Aniline dyes used to stamp names on diapers absorbed percutaneously and cause methemoglobinemia. 1956: Sulfonamides displace bilirubin from plasma protein binding sites and cause kernicterus. 1959: Chloramphenicol causes the ‘gray baby’ syndrome of circulatory collapse due to immature glucuronidation. 1982: Benzyl alcohol added to intravenous flush solutions as a bacteriostatic agent accumulates in newborns causing death intraventricular hemorrhage and the ‘gasping baby’ syndrome. 1985: Polysorbate 80 a carrier in a parenteral vitamin E prep- aration associated with liver failure. 1989: Topical iodine‐containing antiseptics noted to be absorbed and may cause hypothyroidism – now used sparingly and excess removed.

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Neonatology at a Glance Third Edition. Edited by Tom Lissauer Avroy A. Fanaroff Lawrence Miall and Jonathan Fanaroff. © 2016 John Wiley Sons Ltd. Published 2016 by John Wiley Sons Ltd. 152 Aspects of neonatal intensive care Quality assurance Clinical governance and quality improvement are frameworks for assuring the quality of clinical services and improving them Fig.  65.1. They are key issues for all who provide care for newborn infants. Clinical audit Aims to assess patient care and outcomes through systematic comparison against explicit standards. Change is then implemented and re-audit follows. The audit cycle is shown in Fig. 65.2 and questions about audit are addressed in Table 65.1. More recently neonatal services have been using quality improvement QI meth- odology to implement improvements in care. This uses PDSA plan-do-study-act cycles with run-charts to show progress over time. It has the advantage of continuous measurement of outcomes rather than ‘snapshots’ of data at specific time points as measured by audit. PDSA is described in Fig. 65.3. Changes should be evidence based and action plans should be SMART specific mea- surable achievable realistic and timely. Simulation Simulation has become an important component of quality assurance in neonatal care. Clinical scenarios are used to train multidisci- plinary teams in a safe and educational environment sometimes using sophisticated models. Widely used in life support courses e.g. neonatal resuscitation and emergencies and increasingly for simulated emergencies in the neonatal unit delivery room and lying‐in postnatal wards. It can also be used to develop human factor skills in leadership teamworking and communication. It also allows training in some practical or uncommon procedures before performing them on patients. Simulation can be used to re-create critical incidents identified through risk reporting systems and can also identify latent risks accidents waiting to happen that can be fed back into the risk management system of the unit. Quality improvement 65 National standards In US: JCAHO Joint Commission: Accreditation Health Care Certication National Patient Safety Goals In UK: National Service Specications British Association of Perinatal Medicine National Institute for Health and Care Excellence NICE Clinical audit Incident reporting Guidelines Continuing professional development Appraisal and revalidation – personal department Dashboards – to show performance and identify outliers Quality assurance National monitoring In US: JCAHO Leapfrog Group In UK: Care Quality Commission CQC NHS Commissioning Board Special Health Authority. MBRRACE-UK Mothers and babies- reducing risk through Audits and Condential Inquiries across the UK Fig. 65.1 Framework for quality assurance. Table 65.1 The clinical audit process. Who should be involved All health professionals multi-disciplinary How are topics selected Observing current practice Clinical incidents complaints and claims etc. Design Set or identify standards Identify data sample Only collect relevant data Analysis and recommendations Were standards met Feedback results Identify improvements Develop an action plan Re‐audit to check improvement The audit cycle Implement change Select a topic Analysis Re-audit Literature review Set standard Design audit Data collection Fig. 65.2 The audit cycle.

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Quality improvement 153 Critical incident reporting Table 65.2 It is important that the whole neonatal team develops a culture of quality and safety. Reporting critical incidents not only those that have caused harm but also those that could have caused harm are a key component of quality assurance. The most common and serious critical incidents in neonatal practice and ways to minimize their occurrence are considered in Chapter 66. P L 2. Identify most likely causes through data 1. Problem identication and desired outcome 3. Identify potential solutions data needed for evaluation A N A C T S T U D Y D O 6. Recommand further study and/or action 4. Implement solution collect data needed for evaluation 5. Analyze data and develop conclusions Fig. 65.3 The PDSA cycle to rapidly initiate change in practice and evaluate it. Table 65.2 Questions and answers about critical incidents. What are they Unexpected events that cause or could cause harm to the patient. Include near‐misses Who should report them Everyone What should be reported The facts Why report To identify causes To develop a strategy to prevent recurrence To act as warning for complaints/litigation To provide information for external monitoring Who is to blame A no‐blame culture should be developed – disciplinary action will not follow except where acts or omissions are malicious criminal or constitute professional misconduct What level of investigation is required Depends on extent of harm to the patient and assessment of likelihood of recurrence by taking the whole circumstance of the event into account not just the incident itself If risk of harm or recurrence is high perform root cause analysis What is root cause analysis A structured method used to analyze serious adverse events with the goal of identifying contributing factors What if major harm has occurred or major damage to the organization Because of potential litigation the hospital risk management group and senior managers should be informed. A more detailed formal causal analysis FMEA failure mode and effect analysis should be undertaken Question Are there any quality improvement initiatives specifically for neonatal care Many local and national initiatives but the most comprehen- sive dedicated to neonatal care is the Vermont‐Oxford Neonatal Quality Improvement Collaboratives Program. It aims to improve the quality and safety of medical care for newborn infants and their families by: •  providing an information resource which also uses material from other disciplines in health‐care and other high‐reliability organizations e.g. aviation industry •  providing expert faculty •  promoting four key habits to improve outcome Fig. 65.4 •  organizing collaborative safety improvement projects e.g. reducing nosocomial infection by visits between units or via the internet •  voluntary anonymous collection of errors on internet. Vermont–Oxford Network: 4 key habits Better practices Clinical Organizational Operational Habit for change Habit for systems thinking Habit for evidence-based practice Habit for collaborative learning Fig. 65.4 Four key habits for better outcomes promoted by the Vermont–Oxford Network. Reproduced with permission of J. Horbar Vermont–Oxford Network. Question How can parents help improve quality in the NICU •  Offering family-centred care is crucial to support families at a time of high stress and to enable successful bonding with their baby. •  Parent representatives should be involved in the management of neonatal networks and in the development of new services. •  Family integrated care is an innovative program in some units. Pioneered in Canada parents provide most of the care for their baby even in the NICU. Nurses and doctors teach and support parents who may provide some highly technical care. This approach has been shown to improve outcomes such as improved weight gain reduced sepsis and increased rate of breastfeeding at discharge.

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Neonatology at a Glance Third Edition. Edited by Tom Lissauer Avroy A. Fanaroff Lawrence Miall and Jonathan Fanaroff. © 2016 John Wiley Sons Ltd. Published 2016 by John Wiley Sons Ltd. 154 Aspects of neonatal intensive care A survey in the US showed that medical errors were responsible for 98 000 deaths per year i.e. more people die in a year in the US from medical errors than from motor vehicle accidents or breast cancer. In a prospective study of pediatric admissions to hospital poten- tial adverse events were highest in the NICU neonatal intensive care unit: •  91 of admissions had a medication error •  46 of admissions had a potential adverse event •  74 of errors involved physician ordering. Neonatal critical incidents which may relate to fetal or obstetric care will need to be considered in conjunction with maternal–fetal medicine e.g. hypoxic–ischemic encephalopathy or seizures within 48 hours of birth. Other aspects of quality improvement involving neonatal care are considered in Chapter 65. The most common critical incidents are medication errors and extravasation injuries but a selection of frequent or important examples follows. Some approaches to their prevention are given but each critical incident will need to be considered by the multi‐ disciplinary risk management team. Prevention of critical incidents requires a culture of safety throughout the unit Fig. 66.1. Being honest and open with parents is vital. Extravasation of intravenous infusions Figs 66.2 and 66.3 Cause •  Fragile tissues. •  Small catheter difficult to fix securely. •  Movement by infant. •  Irritant infusion – e.g. calcium high concentration of dextrose parenteral nutrition. Prevention •  Expert fixation of catheters. •  Leave potential extravasation area visible. •  Avoid occluding limb with tape. •  Regular checks pressure‐sensitive alarms. •  Give irritant infusions via central lines if possible. Critical incidents 66 Culture of safety i.e. how we do things in our unit Shared vision required Safety is considered important Clear guidelines in place on safe practices for all staff Expected pattern of behavior Good teamwork Leadership in safety Environment geared to safe practices Fig. 66.1 Requirements of a culture of safety in the neonatal unit. Adapted from J. Horbar Vermont–Oxford Network. Medication errors Why •  Prescription errors occur as there is a wide range of dosage – varies 10‐fold if baby weighs 0.5 kg or 5 kg unlike adults where there is usually a standard dose. •  Dilutions often needed – common source of error. •  Use of potentially dangerous drugs – insulin inotropes aminoglycosides digoxin narcotics heparin. Prevention •  Staff training utilising a pediatric pharmacist. •  Clear formulary. •  Minimize range of drugs used. •  Computer‐assisted guidance on dosage and dilutions. •  Avoid abbreviations e.g. micrograms not µg. •  Use limited number of standard dilutions drawn up in pharmacy where possible. •  Clear differentiation between vials e.g. by color. •  Checking by two trained professionals but do not rely on this. •  Remove undiluted dangerous drugs e.g. high concentration KCl. •  Use pre-programmed infusion pumps. •  Pay special attention to potentially dangerous drugs. Fig. 66.2 Extravasation injury. Fig. 66.3 Scarring from extravasation injury.

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Critical incidents 155 What to do if extensive extravasation •  Aspirate cannula. •  Flush affected area with saline via several skin punctures. Some cen- ters inject hyaluronidase into extravasation site. Elevate affected limb. •  Consult plastic surgeons if concern about long‐term scarring. Excessive fluid volume infused Cause •  Incorrect settings on pump. •  Malfunction of pump. Prevention •  Electronic ‘guard-rails’ built into pumps max and minimum rate based on infusion. •  Check and monitor infusion. Giving wrong breast milk to wrong patient Cause •  Similar patient names. •  Poor labeling. •  Multiple milk containers kept in same fridge. •  Inadequate checking procedures. Prevention •  Clear labeling. •  Double‐checking. •  Warning mechanism name alert tags for staff if babies have similar names. •  Electronic milk storage and dispensing systems. What to do if occurs •  Inform parents. •  Test donor mother for blood‐borne viruses. Complications of umbilical arterial catheters UAC Incorrect vessel •  Inserted into umbilical vein instead of artery. Prevention •  Check for presence of arterial pulsation to confirm in artery and arterial waveform on monitor. •  Check position on abdominal X‐ray Fig. 66.4. This is important – if in umbilical vein by mistake excessively high oxygen could be given which could damage eyes retinop- athy of prematurity ROP if preterm. Thrombosis/emboli/vasoconstriction Consequences •  Occlusion of the artery causes mottling of skin loss of pulses cool limb and cyanosis in one or both legs. May result in gangrene/ amputation of limb. •  Emboli may affect distant organs. Prevention •  Regular observation. If skin becomes discolored reposition or remove catheter. •  Position catheter either high at T6–10 or low at L3–4 to avoid catheter tip near renal vessels to reduce risk of renal artery throm- bosis hematuria renal failure hypertension. •  Flush catheter gently heparin infusion. •  Ensure infant’s intravascular volume is adequate. Blood loss from arterial catheters Cause •  Disconnection of catheter. Prevention •  Clear labeling that catheter is arterial. •  Connections screwed together. •  Pressure‐sensitive alarm. UAC in correct position UVC in portal vein Incorrect position – must be withdrawn Fig. 66.4 X‐ray showing umbilical arterial and venous catheters. Catheter in umbilical artery red line – initial course caudally towards groin then cranially up middle of spine. Catheter in umbilical vein blue line – cranial course to right of spine. This catheter is in the portal vein a potentially dangerous position and must be withdrawn. In addition overlapping catheters as shown here can easily lead to misinterpretation.

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156 Aspects of neonatal intensive care Ischemic damage from peripheral artery catheters Cause •  Small size of vessel. •  Inadequate collateral supply. Prevention •  Choose suitable artery: •  use radial artery only if ulnar artery shown to be patent Fig. 66.5 see Chapter 76 for Allen test. • avoid superficial temporal artery as can cause ischemia of parietal lobe. •  avoid brachial artery as end artery and occlusion may result in loss of distal limb and median nerve may be damaged. •  Only use for sampling not injecting. •  Remove if any significant blanching other than transient. Portal vein thrombosis from umbilical venous catheters Cause •  Catheter in portal vein causing portal vein thrombosis. Prevention •  Check on X‐ray that catheter is in the inferior vena cava and not the portal vein Fig. 66.4. Extravasation of parenteral nutrition PN from central venous lines Cause •  Catheters may migrate and PN may be infused into: – the tissues causing swelling and inflammation – the lungs causing pleural effusion – the pericardium causing pericardial effusion and tamponade – the liver causing hepatitis. Prevention •  Check catheter tip is in the inferior or superior vena cava not the right atrium or portal vein. Burns and scalds Cause •  Overheating of humidifier in CPAP/ventilator circuit. •  Disconnection of temperature probe or malfunctioning of radiant warmer Fig. 66.6. •  Failure to move transcutaneous O 2 /CO 2 probes regularly. Prevention •  Temperature alarms. Scarring of skin Cause •  Poorly keratinized skin prone to long‐term scarring especially if black ethnicity keloid formation. Prevention •  Minimize skin damage: – care with adhesive tape regularly reposition probes and avoid undue pressure from attachments for tracheal tubes nasal CP AP etc. – if transcutaneous O 2 /CO 2 electrodes used rotate to different skin sites regularly – procedures e.g. chest tube for pneumothorax avoid breast-bud area Fig. 66.7. Nasal damage from tracheal tube Cause •  Dilatation of nostril or damage to the nasal septum by tube. Fig. 66.5 Ischemic damage from radial artery catheter. Fig. 66.6 Scalding of skin from excessive heat from radiant warmer after dislodging of skin temperature probe. It resolved within a few hours.

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Critical incidents 157 Prevention •  Avoid excessively large tracheal tubes. •  Avoid leaving in situ for long periods. •  Fix tube securely to prevent leverage. Nasal damage from nasal CPAP Cause •  Pressure on nostrils or nasal septum. Prevention •  Correct positioning size and fixing of nasal prongs avoiding excessive pressure on the nostrils or nose regular repositioning and monitoring. •  Consider high flow nasal oxygen therapy as causes less nasal trauma. Tracheal stenosis Cause •  Damage to subglottic area from tracheal tube Fig. 66.8. Prevention •  Avoid excessively large tubes. •  Minimize time left in place. •  Secure to prevent tube movement and irritation. Infection Cause •  Nosocomial infection – inadequate hand-hygiene. •  Catheter related – at insertion or subsequently e.g. breaking of long line and dressing. •  Procedures – infection where skin denuded from monitor probes or tape. Prevention •  Meticulous hand hygiene. •  Sterile insertion. •  Minimize interference of lines. •  Remove lines as soon as possible. •  Care bundles of procedures to minimize infection shown to reduce central line-associated bloodstream infections CLABSIs. Aspiration pneumonia from misplaced gavage nasogastric feeding tubes Cause •  Tube inserted into trachea instead of stomach. Prevention •  Check correct position with pH indicator paper to confirm gastric aspirate is acidic pH 5.5. •  If in doubt X-ray to confirm below the diaphragm and in the stomach to the left of mid-line. Fig. 66.7 Scarring from chest tubes. Fig. 66.8 Tracheal stenosis following prolonged mechanical ventilation. The narrowed trachea is shown with an arrow.

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Neonatology at a Glance Third Edition. Edited by Tom Lissauer Avroy A. Fanaroff Lawrence Miall and Jonathan Fanaroff. © 2016 John Wiley Sons Ltd. Published 2016 by John Wiley Sons Ltd. 158 Aspects of neonatal intensive care What is evidence‐based medicine EBM It is the conscientious explicit and judicious use of current best evidence in making decisions about the care of individual patients. Steps in the practice of evidence‐based medicine See Fig. 67.1. Evidence‐based medicine 67 Search the literature using key textwords. Use search lters to limit it to high quality evidence. For high quality systematic reviews of selected topics use the Cochrane Collaboration in Neonatology. Otherwise use an on-line data base e.g. MEDLINE 2. Search for the best evidence 1. Frame your question Formulate your question—e.g. should a term infant with moderate or severe hypoxic–ischemic encephalopathy be treated with therapeutic hypothermia Clinical problems can usually be converted into answerable questions that have four elements What is the patient population Term infants What are the proposed interventions Therapeutic hypothermia What are the alternative interventions Supportive treatment What are the clinical outcomes Appraise the validity and relevance of the evidence. For interventional studies it is assessed using a hierachy of validity and grade of recommendation 3. Appraise the quality of the evidence Grade of recommendation Strong evidence from at least one systematic review of multiple well designed randomized controlled trials Highly recommended A Recommended B Might be appropriate C Have to adopt consensus view D I II III IV Vb Va Level Grade Strength of evidence adapted from Muir Gray Evidence from well designed trials without randomization single group pre-post cohort time series or matched case-control Evidence from well designed non-experimental studies from more than one center Opinions of well respected experts Clinical evidence descriptive studies or reports of expert committees Strong evidence from at least one properly designed randomized controlled trial of appropriate size Make a decision about the validity and relevance of the evidence available. Studies report outcomes that may or may not be truly relevant clinically. Is the treatment safe cost effective and feasible to perform in your organization Are your patients similar to those studied Evidence-based medicine informs clinical decision making but does not replace it as clinical problems are complex and de‚nitive evidence rare 5. Make a decision 4. Analyze the evidence The data from articles must be synthesized and an estimate of the effect of the treatment developed. Helpful statistical methods include estimate of relative risk in randomized controlled trials or cohort studies and the number needed to treat NNT to obtain one improved outcome measure. The con‚dence interval is less than 1 i.e. favors treatment with therapeutic hypothermia. Meta-analysis of outcome at 18 months of age mainly of three large multicenter international trials of cooling from before 6 hours of age for 72 hours showed a reduction in death or major neurodevelopmental disability with risk ratio 0.75 and number needed to treat for an additional bene‚cial outcome of 7 95 CI 5–10. There was improved survival with normal neurological function risk ratio 1.53 number needed to treat 8. Data are from multiple well designed randomized trials i.e. level I evidence level of recommendation grade A Severe disability Cerebral palsy Developmental delay Death or severe disability Cerebral palsy Relative risk 95 CI Death or major neurodevelopmental disability Severe neurodevelopmental disability 0.74 0.54–0.92 0.10.2 0.51 Relative risk 95 CI 25 10 CI Con‚dence interval Developmental delay 2SD below mean 0.77 0.63–0.94 0.66 0.54–0.82 0.75 0.68–0.83 Fig. 67.1 Steps in the practice of EBM evidence‐based medicine. CI confidence interval. Data from Jacobs S.E. et al. Cooling for newborns with hypoxic ischaemic encephalopathy. Cochrane Database Syst Rev 2013 1: CD003311.

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Evidence-based medicine 159 Examples of evidence‐based medicine in neonatology The following are some examples from neonatal medicine of therapy proven to be beneficial or harmful. However for most decisions in clinical practice guidance from evidence‐based medicine is not available is inconclusive or may be conflicting. Clinicians have to base their decisions on the best available information clinical experience and the evaluation of potential benefits and risks for the individual patient. Beneficial therapies Examples of therapies shown to be beneficial are: •  Maternal prophylactic corticosteroids for preterm birth Fig. 67.2. •  Maternal anti‐D Rho immunoglobulin – to rhesus negative mothers to prevent rhesus disease of the newborn. •  Surfactant therapy in preterm infants. •  Moderate hypothermia for moderate or severe HIE hypoxic– ischemic encephalopathy Fig. 67.1. Harmful therapies Examples of therapies shown to be harmful are: • Uncontrolled oxygen therapy causing blindness in preterm infants. This demonstrates the dangers of the introduction of a new therapy oxygen followed by restriction in its use without evi- dence from randomized controlled trials Fig. 67.4. •  Antibiotic side‐effects: – chloramphenicol unmonitored – gray baby syndrome circulatory collapse – sulfonamides – displacement of bilirubin resulting in kernicterus – tetracycline – yellow staining of teeth and bones. •  Early prophylactic corticosteroids in preterm infants to reduce severity of respiratory distress syndrome and BPD bronchopul- monary dysplasia – gastrointestinal perforation growth failure hypertension and probable neurodevelopmental deficit. Intraventricular hemorrhage Relative risk 95 condence interval Neonatal death Respiratory distress syndrome 0.1 0.2 0.5 1 Relative risk 95 CI 25 10 0.69 0.58–0.81 0.54 0.43–0.69 0.66 0.58–0.81 Fig. 67.2 Meta-analysis of prophylactic corticosteroids for preterm birth showing reduction in respiratory distress syndrome intraventricular hemorrhage and neonatal death. Data from Roberts D. Dalziel S.R. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database Syst Rev 2006 3. CD004454. Question What is the evidence determining the optimal range for oxygen saturation in preterm infants In three international randomized controlled trials BOOST and BOOST II and SUPPORT trials oxygen saturation range 85–89 lower target group was compared with 91–95 higher target group. Recruitment to the BOOST II trial was stopped early when an interim analysis of all the results showed an increased rate of death before discharge in the lower target group 23.1 vs 15.9. The lower target group had a reduced rate of retinopathy of prema- turity 10.6 vs 13.5 and an increased rate of necrotizing enterocolitis 10.4 vs 8 Fig. 67.3. There were no significant differences in other outcomes. Changes in oxygen therapy with time 1940s - oxygen noted to be benecial Giving oxygen to preterm infants was noted to correct cyanosis and improve their survival rate. It became wide- spread practice to leave small babies in high concentrations of oxygen for several weeks Early 1960s - increase in blindness Huge increase in blindness in preterm infants was noted. Its cause was unclear. When oxygen was implicated there was a great reluctance to curb its use because of its benecial effects. By 1953 about 10 000 children were blind from retinopathy of prematurity ROP 7000 in the US 1953 - trial of oxygen therapy Randomized controlled trial of VLBW very low birthweight infants given 50 oxygen for 4 weeks versus oxygen given only for cyanosis – showed severe retinopathy in 23 v 7 1954 - Curtailment of oxygen therapy Maximum concentration of 40 allowed. This in turn is thought to have resulted in an excess of early neonatal deaths from hypoxemia Blood-gas analysis This development allowed the ambient oxygen concentration to be adjusted according to the infants requirements. Incidence of ROP fell although is still problematic in extremely low birth-weight infants 2010s Trials of high versus low oygen saturation in preterm infants 1980s Oxygen saturation monitoring Fig. 67.4 Changes in oxygen therapy with time. Death before discharge Retinopathy of prematurity Necrotizing enterocolitis 0.25 0.5 1.0 2.0 4.0 Relative risk Less common with lower target Less common with higher target Relative risk 95 CI 1.16 0.98–1.37 0.79 0.63–1.0 1.31 1.02–1.68 Fig. 67.3 Outcomes in preterm infants with oxygen saturation in lower and higher target ranges. Data from The BOOST II United Kingdom Australia and New Zealand collaborative groups. Oxygen saturation and outcomes in preterm infants. N Engl J Med 2013 368: 2094–2104.

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Neonatology at a Glance Third Edition. Edited by Tom Lissauer Avroy A. Fanaroff Lawrence Miall and Jonathan Fanaroff. © 2016 John Wiley Sons Ltd. Published 2016 by John Wiley Sons Ltd. 160 Aspects of neonatal intensive care Sick newborn infants have the same rights to life and access to care as any other person. Their care is dependent on a successful partnership between parents and the clinical team Fig. 68.1. The withholding or withdrawal of life‐saving medical treatment There are a number of situations in neonatal practice where with‐ holding or withdrawal of life‐saving medical treatment is consid- ered morally permissible. Their management is influenced by the parents’ religious beliefs and cultural background the laws of the country and national guidelines e.g. American Academy of Pediatrics Royal College of Paediatrics and Child Health Tables 68.2 and 68.3 These decisions are stressful not only for Ethics 68 The best interest of the child Both clinicians and parents have this aim in common Agreement Usually there is agreement and all parties work harmoniously in partnership together. Good communication This minimizes conict. Trust and condence usually grow with time spent listening and talking. Communication must be open and honest Conict Arises when there is disagreement over what constitutes the best interests of the child and who should decide. May occur not only between clinicians and parents but between the parents between some of the doctors or nurses in the team or between doctors and other care professionals. It causes distress to all parties. It can usually be resolved by further discussion involving all parties. It may be helpful to obtain a second independent opinion. This is of most benet if the expert is truly independent and may be chosen by the family. In some hospitals ethics committees can be consulted. Rarely if conict cannot be resolved legal advice will be required and the case may go to court Rights and duties of clinicians Clinicians have a duty of care to protect their patients life and health. Negligence is the failure to full this duty in accordance with accepted practice by a responsible body of doctors skilled in that branch of medicine. Treatment decisions must be based on the ethical principles of doing good benecence and avoiding harm non-malecence Table 66.1 Rights and duties of parents Medical treatment can only proceed in the presence of valid consent. Newborns cannot consent so parents have the responsibility to make appropriate choices for their child Fig. 68.1 Ethical framework of clinical practice. Question What is the role of clinical ethics committees Increasingly being developed as a resource for doctors and other health‐care professionals and parents facing difficult ethical problems. US hospitals are required to have mecha- nisms in place to address ethical issues in patient care. Ethics committees are often diverse including physicians nurses lay members pastoral care and others. In the US and some centers in the UK the committee can be rapidly constituted to discuss an individual problem proactively. Ethics committee decisions are generally advisory. In those circumstances where there is continued conflict after ethics committee involvement referral to court may be required. In addition to assisting with individual cases institutional ethics committees are becoming more involved in organizational ethical issues such as conflict of interest and the impact of performance incentives on patient care. Table 68.1 Definitions of the principles of medical ethics. Beneficence Do good Non‐maleficence Do no harm Justice Legal justice respect for rights fair distribution of resources Respect for autonomy Respect for the individuals’ right to make informed and thought‐out decisions for themselves Trust Parents need to develop trust in their physician who has a responsibility to ensure that this trust is not misplaced

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Ethics 161 the parents but also for the health‐care team amongst whom con- sensus and an agreed management plan should be reached. Consent must be obtained from the parents but the extent to which they may wish to be involved in the decision‐making depends on the individual family. Repeated discussion without coercion may be necessary. If life‐saving support is going to be withheld or withdrawn all aspects of palliative care including symptom management and psy- chosocial support should be in place see Chapter 70. Many parents will accept the appropriateness of withdrawal of mechanical venti- lation and appreciate the opportunity to spend time with their baby away from the technology of intensive care but with staff to support them. The baby’s comfort should be the priority and pain or distress alleviated. Parents need to know that the infant may continue to breathe for some time after disconnection from the ventilator. If there is dissent or uncertainty about the best course of action it is likely to be best to continue to provide full intensive care. Table 68.2 Situations in neonatal care where withholding or withdrawing life-sustaining treatments may be considered ethically justified if considered not to be in the child’s best interest in the UK Larcher V . et al. Arch Dis Child 2015 100Supp 2s1–s23. i When life is limited in quantity If treatment is unable or unlikely to prolong life significantly: • Brain stem death • Imminent death irrespective of treatment • Inevitable death where prolongation of life confers no overall benefit. ii When life is limited in quality Where treatment may prolong life but will not alleviate: • Burdens of treatments which produce sufficient pain and suffering to outweigh potential or actual benefits • Burdens of the child’s underlying condition which produces such pain and distress as to overcome benefits in sustaining life • Lack of ability to benefit where the severity of the child’s condition makes it difficult or impossible for them to derive benefit from continued life. Table 68.3 Situations where treatment of disabled infants can be withheld in the US – the Baby Doe case. Legislation regarding the treatment of infants with birth defects was introduced following the case of Baby Doe who was born in 1982 with Trisomy 21 Down syndrome and esophageal atresia. Partly on the advice of their obstetrician the parents refused to consent to life‐saving surgery to repair the esophageal defect. They felt that a ‘minimally acceptable quality of life was never present for a child suffering from such a condition’. Without the surgery the infant was unable to eat. Legal dispute The hospital disagreed with the parent’s refusal to consent and filed in court an emergency petition seeking authorization to perform the surgery. The trial court felt that the parents had a right to choose a medically recommended course of treatment. The obstetrician had recommended against surgery. The court did not give permission for surgery. The hospital appealed the decision but the baby died when 6 days old. Political consequences The case drew widespread media attention and ignited a national debate over the treatment of infants with birth defects. President Reagan disagreed with the decision – ‘The judge let Baby Doe starve and die.’ The Surgeon General C. Everett Koop a pediatric surgeon became involved in getting Congress to pass the Baby Doe Amendments. The Child Abuse Prevention and Treatment Act CAPTA 1973 reauthorized 2003 This prevents the withholding of ‘medically indicated treatment’ from disabled newborns with life‐threatening conditions. Five circumstances under which treatment can be withheld are: 1. Chronically and irreversibly comatose 2. Treatment would merely prolong dying 3. Treatment would not be effective in ameliorating or correcting all of the infant’s life‐threatening conditions 4. Treatment would be futile in terms of survival 5. Treatment would be virtually futile and the treatment itself under such circumstances would be inhumane Questions What is the difference between withholding and withdrawing intensive care There is no ethical or legal distinction between them though emotionally it may be easier not to start treatment than to withdraw it. If there is uncertainty provide intensive care and subsequently withdraw it after full assessment. Is euthanasia allowed Giving a medicine with the primary intent to hasten death is unlawful in both North America and Europe though in the Netherlands and Belgium it is accepted on a carefully regulated basis. Giving a medicine to relieve pain which as a side effect may hasten death the principle of double effect is ethically appropriate if its primary purpose is to alleviate distress or suffering.

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Neonatology at a Glance Third Edition. Edited by Tom Lissauer Avroy A. Fanaroff Lawrence Miall and Jonathan Fanaroff. © 2016 John Wiley Sons Ltd. Published 2016 by John Wiley Sons Ltd. 162 Aspects of neonatal intensive care Research Health professionals wish to provide the best possible care for newborn infants. This should be evidenced‐based but this is only possible when evidence is available from properly conducted research. It is therefore unethical for properly conducted research on newborn infants not to be performed. Failure to do research leads to stagnant and second‐rate medical care. Research may be interventional e.g. evaluation of a new therapy or non‐interventional e.g. descriptive or observational Table 69.1. There are a number of obstacles to overcome in order to perform research in newborn infants. These are practical and ethical. Practical difficulties in conducting research in infants These include: •  The number of newborn infants who are preterm or have a specific problem or condition is small and usually requires trials to be multi­ centered which adds enormously to the complexity and cost of each study. However a number of networks have been established to facilitate this such as the V ermont–Oxford and NICHD National Institute of Child Health and Human Development Neonatal Research Network and the Canadian Australian and New Zealand Italian and other national neonatal networks and many multi­ centered trials have been performed throughout the world see Cochrane neonatal reviews. •  Funding is difficult to obtain as the number of newborn infants with a specific problem is small making pharmaceutical companies less likely to develop new products or conduct trials. •  In order to proceed with a trial the information required about a potential new drug or therapy is becoming ever more stringent. This also applies to pilot studies making it increasingly difficult to obtain the data required to conduct a larger study. Ethical difficulties in conducting research in infants All research must be peer‐reviewed and sanctioned by an independent ethics advisory committee – Institutional Review Board in North America appropriate research ethics committee REC in the UK. Parents must be able to make informed choices when asked to give consent for their infant to take part in research. This can be problematic when decisions need to made rapidly e.g. when a baby suddenly becomes ill especially immediately after delivery when parents are emotionally stressed. Key factors of informed consent are outlined in Table 69.2. Criteria for informed consent for research include: •  Competence of the person giving consent. •  Information – sufficient for informed choice including a writ­ ten information sheet for parents and the use of an interpreter if there are concerns about the parents’ understanding of English. •  Understanding – parents must have understood the research sufficiently to be able to evaluate choices. In the US and UK con­ sent can be provided by one parent with parental responsibility in some countries in Europe both parents must agree. •  Written consent should be obtained with one copy for the par­ ents and another filed in the case record. •  Voluntary – parents must be aware that they can decline or with­ draw from the research without jeopardizing their baby’s care. All large multicenter trials have a Data Safety and Monitoring Committee which ensures the safety and well‐being of the par­ ticipating subjects. They have the power to terminate enrollment if they have the evidence that the intervention is harmful or if continuing the study cannot demonstrate benefit. Consent in clinical practice Health professionals are under pressure to allow parents greater involvement in decision‐making and enable them to give consent to treatment. Parental consent should be obtained for complex procedures or treatment and for all surgical procedures. Documentation about the communication with the parents explaining the basis benefits and risks of the procedure or treatment is more important than obtaining a signature on a consent form. Consent for a surgical procedure must be obtained by someone familiar with and capable of performing the Research and consent 69 Table 69.1 Differences between interventional and non‐interventional research. Interventional therapeutic research Research which directly affects the treatment an individual receives. They may receive a new treatment or in a randomized trial a new or conventional treatment or placebo. At the start of the project the answer to the question about which treatment is better will not be known equipoise. Use of a placebo instead of treatment is unethical if there is an accepted treatment. The new and potentially better therapy should be compared with accepted treatment. Non‐interventional non‐therapeutic research Research that will not benefit directly the person involved. This is observational research – e.g. the normal levels of vitamin A in a particular group of infants. The infants themselves will in no way benefit – so the invasiveness of obtaining the information must be minimal a small extra volume of blood when venepuncture is required for other reasons or a single venepuncture well performed with analgesia. Table 69.2 Key factors in informed consent for research. Diagnosis – include description of medical steps leading to the diagnosis Research – nature and purpose of proposed research Risks – common risks less common but severe risks such as death brain damage loss of organ function Alternatives – other options including their risks and benefits. It is always an option not to participate in a study and to receive standard therapy

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Research and consent 163 Question – What issues have arisen relating to randomization Issues may arise when infants are in the group which turns out to have a poorer outcome. An example is the SUPPORT trial where preterm infants were randomized to be cared for with oxygen saturation targeted to low 85–89 and high 91–95 ranges. The hypothesis was that the lower range would result in lower rates of retinopathy of prematurity. It was found that infants randomized to the low range did have less retinopathy of prematurity but also had higher mortality see Fig 67.3. Allegations both in the press and via social media and legally have been made that parents were not given sufficient information when consent was obtained and were not fully aware of the implications of being randomized into the low range and in particular the risk of death. While these alle­ gations have been vigorously disputed it is likely that they will result in more stringent consent requirements in neonatal clinical trials. procedure. For infants receiving intensive or special care in a neo­ natal unit it would be impractical to obtain detailed consent from parents for the multitude of low‐risk procedures performed on their baby. However parents should be given an overview about what the care of their infant involves and what range of procedures will be performed both verbally and in an information booklet. In clinical practice consent is most problematic about the initial resuscitation and immediate management of extremely premature infants at the limit of viability and when withdrawal of treatment is being considered. The former is considered in Chapter 13 on neonatal resuscitation the latter in Chapter 68 on ethics. Question – What were the research issues relating to cooling for hypoxic–ischemic encephalopathy HIE Can research be conducted on infants who become acutely ill at birth Yes the hypothermia studies are a good example. What was the research question Does cooling term infants with hypoxic–ischemic encephalopathy HIE reduce death and severe neurodevelopmental disability What was the basis Studies in adult and newborn animals showed that a reduction of body temperature of 3–4 °C after a cerebral insult is associated with improved histological and behavioral outcome. Pilot studies of cooling infants with encephalopathy showed no complications but the numbers treated were too small to evaluate benefit. What was the study design Several multicenter prospective randomized studies of term infants after perinatal asphyxia compared ‘intensive care plus cooling for 72 hours’ with those allocated to ‘intensive care without cooling’. Treatment needed to be started within 6 hours of birth. What were the results Babies randomized to cooling have lower mortality and less neurodevelopmental handicap see Fig 67.1. What were the challenges Many including: •  Infants had to be identified assessed transferred to a tertiary center and treatment started all within 6 hours of birth. •  Consent had to be obtained rapidly shortly after parents discovered that their newborn infant was dangerously ill. Many of the mothers were recovering from emergency Cesarean section. A strategy of obtaining consent from all parents prior to delivery was not practicable as HIE needing treatment is very uncommon. •  Parents needed to understand the concept of randomization i.e. their baby may but may not receive the new treatment. •  Clear study inclusion criteria had to be developed and researchers trained. •  Study infants had to be closely monitored for side‐effects. •  Follow‐up studies had to be arranged and conducted. •  Difficult to organize and expensive. Only following meta‐analysis of several studies in different countries was significant improvement shown see Fig 67.1. What questions still need to be answered Many including: •  Must therapy be started within 6 hours •  What is optimal temperature and duration of cooling •  Can it be effective in preterm infants •  Can adjunctive therapy be developed as 48 of cooled infants with moderate or severe encephalopathy die or have major neuro­ developmental disability at 18 months Erythropoietin melatonin and cord blood stem cells are being investigated. •  As the number of large multicenter clinical trials including long‐term follow‐up that can be conducted is limited and take many years are there reliable more immediate markers of neurological damage e.g. with neuroimaging that can reliably predict long term outcome

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Neonatology at a Glance Third Edition. Edited by Tom Lissauer Avroy A. Fanaroff Lawrence Miall and Jonathan Fanaroff. © 2016 John Wiley Sons Ltd. Published 2016 by John Wiley Sons Ltd. 164 Aspects of neonatal intensive care The aim of palliative care is to provide comfort to the baby who is dying or has a life‐limiting condition and holistic support for the family. Extreme prematurity congenital malformations neonatal encephalopathy and infection account for most neonatal deaths. The decision to offer palliative care may be made antenatally soon after delivery or later during neonatal care. It should involve the multidisciplinary team caring for the baby together with the family. National guidelines on end-of-life care are available see Chapter 68. Discussions should be led by the senior clinician in a private and quiet environment. Parents should be offered the chance to involve extended family or friends. These decisions are difficult and parents must be given time to consider the issues. Involving religious or cultural representatives or a second opinion from an independent clinician may be helpful. Care Plans When it becomes clear that the baby is unlikely to survive and treatment aimed at prolonging life is no longer appropriate a care plan focusing on palliative care should be developed to ensure that the baby dies free of pain or discomfort and with dignity. Pediatric palliative care services may assist. Regular assessment of comfort pain and physiological status should be undertaken. Physical care including positioning mouth care and skin‐to‐skin contact should be offered. Analgesia should not be reduced for fear that it might hasten death it may need to be increased for pain or distress. Other forms of treatment such as antibiotics oxygen anticonvulsants and antireflux medication may be required for symptom control. Electronic monitoring is not usually recommended. The aim of feeding in palliative care is to provide comfort and reduce hunger not to achieve growth. A baby who can feed orally should do so. Breast‐feeding may be comforting even when non‐ nutritive. Gavage nasogastric feeding may be appropriate for a baby who cannot feed orally but shows signs of hunger. Parenteral nutrition is rarely indicated. Place of care When death is expected the baby should be cared for in a private area with the family. This may be in the hospital their home or a hospice depending on preference available support and how long the baby is expected to live. If mechanical ventilation is withdrawn extremely preterm infants usually die shortly afterwards but mature infants may live for a considerable period. Parents need to be forewarned and the place of care may change if the baby survives longer than expected. If parents are taking their baby home for end‐of‐life care appropriate support must be in place including medications not only for current but also potential symptoms information about who to contact for routine and emergency problems and what to do after the infant has died. Support for the parents siblings and family The needs of each member of the baby’s family should be consid- ered including parents siblings grandparents and extended family. It is now uncommon for people to have experience of death or to have seen a dead person and many have fears about what will hap- pen around the time of death. This needs to be discussed. The family should be given the opportunity to create and collect mementoes before the baby dies and siblings can help with this. For example a ‘journey’ or ‘memory’ box can be provided Fig. 70.1. Mementoes might include antenatal scan pictures photographs foot and hand prints a lock of hair and name tags. Religious cere- monies including blessings and baptisms should be supported. Care after death Parents should be encouraged to hold the baby before death and afterwards if they want to. They may wish to bathe and dress their baby. Give unhurried sympathetic care of the body after death and provide unrestricted access for family. Cultural and religious rituals should be respected. Many parents value photographs of them and their baby at this time especially if this is the first occasion they have held their baby without tubes lines and monitors. ‘Cold cots’ can extend the amount of time available for the family to be with their baby after death Fig. 70.2. Some families may wish to take the baby home and this should be facilitated. Information about registering the death and funeral arrangements should be provided. Inform the family practitioner or pediatrician health visitor obste- trician and other professionals involved that the baby has died. Some units have remembrance books and hold memorial services. Palliative and end‐of‐life care 70 Fig. 70.1 Memory boxes can be used to collect mementoes of the baby’s life.

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Palliative and end-of-life care 165 Grief is a normal response to an infant’s death. Parents and staff need to know that it is normal to show emotion and be given the opportunity to express their feelings. Grief may include shock denial anger sadness or relief. There may be physical symptoms of anxiety depression tearfulness loss of appetite fatigue insomnia and inability to concentrate. Grief may last years but is highly individual in many it is most intense in the first few months. Parents may need advice about supporting siblings and other family members. Each parent may have a different pattern of grief and this may place stress on their rela- tionship. Provide information about professional resources and self‐ help groups for bereavement support and counseling. Families often find it helpful to have ongoing communication with the health‐care team. A meeting arranged a few weeks after the child has died provides an opportunity to discuss the circum- stances and to answer any questions and address any unresolved issues. It may be helpful if the obstetrician is also present. Health‐ care providers must be good listeners in order to learn how the family is feeling. If there are concerns about abnormal grieving professional assessment and support are recommended. Caring for staff The death of a baby may be distressing for staff especially after protracted periods of intensive care during which staff and parents become closely involved. The infant’s death may be perceived as a failure. Open discussion between all members of staff is crucial so that all are fully informed and are able to express their feelings and concerns. Dialogue is especially important when withdrawal of life support is being considered. Many units provide personal psychological support for staff. Organ donation Donation of a baby’s tissue or organs may provide hope to families in an otherwise hopeless situation. Until recently neonatal whole organ transplant was not widely available in the UK as guidelines on the diagnosis of death by neurological criteria in neonataes had not been published. However donation of tissues or organs from neonates after circulatory death has sometimes been possible. This includes but is not limited to heart valves. The US does have published criteria for the determination of brain death in term infants and also protocols for donation. This has allowed trans- plantation of a number of organs including heart lung kidney liver and small bowel. Autopsy Why is it performed An autopsy should be offered even if the cause of death is thought to be known. Advanced imaging and genetic tests mean that clini- cians and families sometimes feel that autopsies are unnecessary and the autopsy rate has fallen markedly in the US and UK in the past 20 years. However autopsy findings differ from the clinical diagnosis in 10 − 32. Autopsy can be a legal requirement e.g. after a sudden unexpected death or recent surgery or if unnatural causes are implicated. Usually it is performed to: •  help parents understand why their baby died •  aid genetic counseling and planning future pregnancies •  help clinicians audit their management •  confirm the diagnosis or identify diagnoses that were missed. •  contribute to medical education and research. It should be per- formed by a pediatric pathologist. What is involved in an autopsy Imaging: •  Photographs particularly helpful for dysmorphology. •  X‐rays and MRI if indicated for skeletal and other pathology not evident on clinical examination. External and internal examination: •  Involves a full‐length incision which should be invisible when clothed. •  All organs are removed inspected and weighed. Samples are taken for microbiological and histological analysis. Organ retention: •  Some organs may need to be retained temporarily for fixing mainly the brain and heart. •  For teaching or research. This requires explicit consent. Consent Detailed consent must be obtained unless the autopsy is legally required. All procedures must be described and agreement reached about retention and disposal of tissues in a lawful and respectful way or whether tissues should be returned for burial. Even if autopsy is legally required parents should be informed about the procedure. Are there alternatives to autopsy Post‐mortem MRI focused autopsy or specific tissue biopsy may be performed but may miss diagnoses such as infection and meta- bolic disorders conventional autopsy remains the gold standard. Fig. 70.2 Cold mattresses can be used with traditional cribs cots to prolong the time that family can spend with the baby after death.

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Neonatology at a Glance Third Edition. Edited by Tom Lissauer Avroy A. Fanaroff Lawrence Miall and Jonathan Fanaroff. © 2016 John Wiley Sons Ltd. Published 2016 by John Wiley Sons Ltd. 166 Aspects of neonatal intensive care Taking home a preterm baby who required intensive care and many weeks in a neonatal unit is often daunting for parents Fig. 71.1. Their fears are shared by parents of term infants who became seriously ill or have complex problems. Discharge from hospital 71 Intensive care High tech Frightening Expert staff +++ Monitoring +++ Nursery Bed Appearance and size Stability Feeding Parents Extremely small and fragile if preterm Isolette incubator then heated crib or crib cot PN parenteral nutrition Gavage nasogastric feeding Provide comfort without disturbing baby Home Preterm infants usually still smaller and more fragile at discharge than if born term Full breast/formula feeding Provide all care Need to establish new routines Medications need to be given Preterm infants often more demanding of attention than infants born at term Special care and rooming-in Isolette incubator Limits parental contact and bonding Condition unstable: Immediate – desaturations May develop complications e.g. infection NEC Signicant mortality Less technology Less monitoring Expert staff available if needed Crib cot Allows parental contact without restriction Stable but fear of: Sudden complications e.g. respiratory infection Long-term neurodisability and other problems Full parental responsibility No monitoring usually Fig. 71.1 Transition from intensive care to home. Questions When can babies go home Most go home when their condition is stable and they have established feeding. Parents must be able to care for the baby and provide health‐care needs. Some babies requiring long‐term oxygen therapy e.g. for BPD bronchopulmonary dysplasia or gavage tube feeding can be managed at home Fig. 71.2. Establishing such care at home will depend on the nature of the infant’s medical condition its likely time course and if otherwise stable the parents home circum- stances and community support available. Should babies with bronchoulmonary dysplasia have a  24‐hour saturation recording done before going home This is performed in some units a few days after oxygen therapy is stopped to confirm the absence of significant desatura- tions. Its value has not been established. All infants who were preterm should be checked to ensure that they are able to maintain their airway and saturations when placed in a car seat. a b Fig. 71.2 a Infant receiving oxygen therapy and gavage nasogastric feeding at home. b Same infant receiving oxygen therapy via an oxygen cylinder in a stroller at home. Long‐term oxygen provided via an oxygen concentrator adjusted according to oxygen saturation from a monitor.

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Discharge from hospital 167 Discharge planning Good discharge planning aims to minimize parental anxiety and ensure seamless transfer of care between professionals in the hospital and community. This can be achieved by: •  having a named nurse with this responsibility •  starting discharge planning as soon as the baby is stable • considering discharge arrangements Fig.  71.3 during regular updates with parents and if necessary arranging pre- discharge meetings with the parents and other professionals involved e.g. the family’s pediatrician or family practitioner community nurses health visitors therapists child devel- opment team. Facilities where parents can room in with their baby for several days or longer ‘step‐down units’ before going home are helpful especially when establishing full breast‐feeding. Some units have specialist nurses who provide care in the fam- ily’s home and liaise with community‐based services. Some of these nurses may also work on the unit and know the baby and family before discharge. Medications What to give how often how to give them and for how long Follow-up arrangements Who when and where Immunizations Which have been given when are the next ones due Is RSV respiratory syncytial virus prophylaxis palivizumab a monoclonal antibody indicated If so who will give it and when Health promotion i SIDS sudden infant death syndrome prevention particularly: Sleep on back not prone Avoid overheating Avoid smoking near baby ii Resuscitation training: Demonstration may be complemented by video Past and potential medical problems Check that parents have good understanding Parents should have a copy of the discharge summary in case professional help is needed Ongoing or new medical problems Who to contact and how to manage them Awareness of most likely problems requiring hospitalization e.g. respiratory infections inguinal hernias Feeding Is breast milk fortier or a preterm formula feed required If so how can they be obtained and for how long Parent support group Would it be helpful e.g. multiple births etc If sodo parents have contact address or is there a helpful internet site Vision and hearing Have they been checked Are further checks required Fig. 71.3 Parents and their baby leaving the neonatal unit. The items that need to be considered prior to discharge are listed.

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Neonatology at a Glance Third Edition. Edited by Tom Lissauer Avroy A. Fanaroff Lawrence Miall and Jonathan Fanaroff. © 2016 John Wiley Sons Ltd. Published 2016 by John Wiley Sons Ltd. 168 Aspects of neonatal intensive care Goals The goals of high‐risk follow‐up are: •  early identification of disability or developmental or behavior problems •  management of ongoing medical issues •  facilitation of early intervention with referral if necessary •  family support •  monitoring of neonatal outcomes. Criteria High‐risk infants include: •  very preterm usually 1500 g or 32 weeks of gestation •  neurologic abnormality including: – neonatal seizures – hypoxic−ischemic encephalopathy – neonatal meningitis •  mechanical ventilation/nitric oxide therapy/ECMO •  severe IUGR intrauterine growth restriction •  congenital malformations significant •  maternal drug misuse •  significant parental psychosocial problems. Organization and timing Timing of visits will vary with different programs and with the extent of pediatric neurodevelopmental expertise available to the family locally. It will also depend on whether neurodevelopmental outcome is being monitored at standard times. A typical program for clinic visits and reason for their timing is shown in Fig. 72.1. Who should conduct neonatal follow‐up Many neonatologists provide neonatal follow‐up with or without support from other physicians. This has the advantage of continuity of care for the parents. It also gives direct feedback on the sequelae of neonatal care but demands out‐of‐service referral if specialist help is required. Good follow‐up programs are multidisciplinary and include: •  developmental specialists − particularly for older children when developmental assessment and management become more special- ized and complex in some programs all follow‐up is performed by developmental specialists •  community nursing team − if involved with the family •  dietitian •  therapists •  psychologist •  social services. The family practitioner/pediatrician provides general pediatric care and other pediatric specialists may be required for specific problems such as pulmonary or ophthalmology. Components •  Growth monitoring. •  Neurologic and developmental assessment including behavior. •  Vision and hearing. •  Social/family integration. •  Monitor chronic health conditions. •  School performance. Outcome measures Evaluation is tailored to the child’s age. Most follow‐up programs conduct formal data collection at 18−24 months of age corrected for prematurity including a disability assessment neurologic Follow‐up of high‐risk infants 72 Expected date of delivery Check for ongoing medical problems weight gain and growth 4–6 months Most severe motor disorders cerebral palsy become evident Many mild neurologic abnormalities are present but often resolve Speech and language delay identied Mild neurologic decits become appare nt Behavior and attention problems become evident 8–12 months 18–24 months Speech and language delay Behavior and attention problems at home and nursery Abnormal ne motor skills and cognitive functio n Pre-school The number of visits are adjusted according to need Some programs continue follow-up into adolescence if indicated Fig. 72.1 An example of a high‐risk follow‐up program. Table 72.1 Widely used developmental assessments. Bayley Scales of Infant Development 3rd edition Griffiths Mental Development Scales − Revised Age range: 0–42 months Age range: 0–24 months Baby scales 24–96 months Extended Subscales: •  Fine motor •  Gross motor •  Receptive language •  Expressive language •  Cognitive scale Subscales: •  Locomotor •  Personal social •  Hearing and language •  Eye − hand coordination •  Performance •  Practical reasoning from 2 years

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Follow-up of high-risk infants 169 evaluation and a developmental assessment using a standardized assessment see Chapter 38. Widely used developmental assessments at this age are the Bayley Scales or the Griffiths Scales Table 72.1. They are stan- dardized to a population mean of 100 with a standard deviation of 15 points. Children with scores 55 −3 standard deviations have severe developmental impairment likely to persist children with scores 55−70 have moderate impairment and are highly likely to have low scores at later ages while children with scores 70−85 have milder impairment and may catch up. A formal classification of disability at 2 years is shown in Table 38.1. Such definitions are useful for comparing outcomes between centers and for evaluating the results of trials. Follow up of older children Fig. 72.2 is outside the remit of most neonatal follow‐up programs because it requires formal IQ and behavioral screening. School evaluation by the class teacher is valuable for identifying need for support. a b c d e f g h i Fig. 72.2 Tiny preterm babies do grow up Sally and William from birth at 26 weeks to adulthood. a Sally at a few hours in intensive care. b William shortly after extubation. c Together at last at 4 weeks d At a year. e Just walking. f At 5 years. g At 18 years William completing the London marathon. h At 19 years Sally and William on vacation in New Zealand. i The next generation has arrived rather larger at birth than her father With thanks to Sally and William for permitting the use of these photographs.

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Neonatology at a Glance Third Edition. Edited by Tom Lissauer Avroy A. Fanaroff Lawrence Miall and Jonathan Fanaroff. © 2016 John Wiley Sons Ltd. Published 2016 by John Wiley Sons Ltd. 170 Global Enormous efforts have been made in many low‐ and middle‐income countries to achieve Millennium Development Goal 4 MDG 4 a two‐ thirds reduction in child mortality from 1990 to 2015. The mortality rate for children under 5 years old has declined markedly since 1990 particularly from improved coverage of immunization early treatment and prevention of malaria and HIV Fig. 73.1. However: •  Neonatal mortality has declined much more slowly with 44 of all deaths at age 5 years now in first 28 days of life Fig. 73.1. •  Progress is slowest in reducing early neonatal deaths first week of life when 75 of neonatal deaths occur 40 in the first 24 hours. The Every Newborn Action Plan launched in 2014 a global campaign to reduce neonatal mortality beyond the Millennium Development Goal time period proposes that all countries should reach a target of 10 newborn deaths per 1000 live births by 2035 compared with current neonatal mortality of 4 per 1000 live births in the US and UK. Through scale‐up of known effective interven- tions this should be feasible. Geography of newborn deaths Only 1 of neonatal deaths occur in high‐income countries. About three‐quarters of all newborn deaths occur in sub‐Saharan Africa and South Asia. The same regions have the highest risk and numbers of maternal deaths and stillbirths. Ten countries account for two‐thirds of the world’s neonatal deaths Fig. 73.2. India alone has 0.8 million neonatal deaths per year. Some resource-poor countries including Malawi Bangladesh and Rwanda have shown that achieving substantial reductions in neo- natal mortality rates is possible. However even when neonatal mortality has been reduced wealth‐related inequity remains a significant problem with lack of access to skilled birth attendants and adequately equipped facilities being particularly marked in rural compared with urban areas and in slums in urban areas. Causes of newborn deaths The main causes of neonatal death globally are: •  preterm birth •  intrapartum‐related conditions previously more loosely called ‘birth asphyxia’ •  neonatal infections including sepsis pneumonia tetanus and diarrhea Fig. 73.3. Many infants have growth restriction mortality is markedly increased in infants who are both preterm and growth restricted. Global neonatology 73 0 50 100 150 200 250 1960 1970 19801990 48 20 20002004200820122015 Mortality rate per 1000 live births Neonatal mortality Global mean under-5 mortality rate Target for MDG 4 32 Fig. 73.1 Global progress towards Millennium Development Goal 4 for child survival. Source: Lawn J.E. Newborn survival in low resource settings – are we delivering BJOG 2009 116 Suppl. 1: 49–59 updated 2014 for data to 2012. Key point Globally every year there are: •  135 million births •  6.6 million deaths at age 5 years •  3 million neonatal deaths frst 28 days. 0–5 5–15 15–30 30–50 Neonatal mortality per 1000 live births No data 3 2 1 6 5 4 9 10 8 7 Nine countries with NMR ≥40 Central African Republic 40.9 Mali 41.5 Pakistan 42.2 Democratic Republic of the Congo 43.5 Lesotho 45.3 Angola 45.4 Guinea-Bissau 45.7 Somalia 45.7 Sierra Leone 49.5 Ten countries with highest neonatal death numbers 1 India 779000 2 Nigeria 267000 3 Pakistan 202400 4 China 157400 5 Democratic Republic of the Congo 118100 6 Ethiopia 87800 7 Bangladesh 75900 8 Indonesia 72400 9 Angola 41200 10 Kenya 40000 Fig. 73.2 Variation between countries in neonatal mortality rate in 2012. Adapted from Lawn J.E. et al. Every newborn: survival and beyond. Lancet 2014 384: 189–205.

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Global neonatology 171 Deaths from neonatal tetanus have declined rapidly due to improved coverage of maternal tetanus toxoid immunization and improved hygiene at birth especially cord care practices. However slower progress has been made in reducing deaths and disability from other infections complications of childbirth or preterm birth. Timing of newborn deaths The birth of a baby should be a time of celebration yet all too often it is a time of tragedy. The risk of dying during labor or the first day of life is high. Globally every year one million newborns 36 of all neonatal deaths and 125 000 mothers nearly half of maternal deaths die and there are 1.2 million stillbirths during this short time‐period. Birth and the early neonatal period are also a time of high risk for neurologic injury resulting in long‐term impairment. Maternal health and obstetric care Maternal health and obstetric care have a substantial impact on reducing neonatal morbidity and mortality. The following are pri - orities to achieve this: •  Before conception: – Reduce barriers to family planning – delaying first pregnancy to at least 18 years of age and 3‐year birth intervals are proven health strategies for mother and baby. – Optimize maternal nutrition – including calories protein iodine folic acid iron. – Optimize prevention and treatment of infections – malaria tetanus and sexually transmitted diseases such as syphilis and HIV see Chapter 43 Viral infections. – Optimize management of chronic conditions e.g. hypertension diabetes. •  During pregnancy: – Improve coverage of key interventions such as mosquito nets and prophylaxis for malaria. – Improve quality and uptake of antenatal care. – Improve detection and management of complications of preg - nancy including maternal infections and hypertensive disorders. •  During labor and delivery: – Ensure skilled attendants at all births including essential equipment and logistical support. – Appropriate use of antenatal steroids for preterm labor. – Timely management of complications for mother or baby. Worldwide 70 of all births are with a skilled birth attendant but in some countries such as Ethiopia Niger Chad and Sudan this is not achieved in three‐quarters of births. Improved access to skilled attendants and referral pathways to health facilities equipped to deal with obstetric emergencies is urgently required. Both participatory women’s groups offering peer counseling and community mobilization Fig. 73.4 and home‐visit packages by Sepsis 15 5 Preterm 36 23 Congenital 10 Other 8 Intrapartum Pneumonia Diarrhea 1 Tetanus 2 Fig. 73.3 Cause of neonatal death distribution in 194 countries in 2012. Source: Lawn J.E. et al. Every newborn: survival and beyond. Lancet 2014 384: 189–205. Fig. 73.4 Women’s group meeting in Nepal. Participatory women’s groups have been shown to reduce neonatal deaths in rural high‐mortality settings. Courtesy of Save the Children. Photographer Joanna Morrison. Question In HIV infected mothers what PMTCT prevention of mother‐to‐child transmission interventions should be undertaken in resource‐limited settings Without intervention the risk of perinatal transmission is 20–45. It occurs in utero peripartum and postnatally via breast‐feeding. In 2013 the WHO recommended universal lifelong combination antiretroviral therapy for all pregnant women or at least until breast‐feeding has ceased aiming to suppress maternal HIV viral load and minimize transmission to the infant. Countries need to either promote breast‐feeding and provide antiretroviral therapy or provide safe nutrition with formula depending on the degree of increased risk of mortality from gastroenteritis and pneumonia associated with formula. In resource-poor countries exclusive breast‐feeding in combination with antiretroviral therapy for the newborn for a minimum of 6 weeks is recommended for first the 6 months. Thereafter complementary foods continuing to breast‐feeding until 12 months of age. Formula‐fed infants should also receive antiretroviral therapy for 6 weeks to prevent transmission from exposure during delivery.

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172 Global community health workers during pregnancy and after birth have been shown to provide an opportunity to empower women to have better outcomes for themselves and for their newborns. Newborn care in low‐resource settings – what works It is estimated that over 1 million lives could be saved each year even with simple care that can be provided outside hospitals and does not require intensive care or high‐tech machines. Care around the time of birth Newborn survival would be improved if: •  Skilled birth attendants were not only present at birth but able to provide care not only for the mother but also for the newborn including basic resuscitation with a bag and mask and recognition of infants needing additional care. •  Essential newborn care was provided Table 73.1: – Infection control – hand‐washing of the birth attendant clean delivery surface clean cutting and tying of cord and ongoing cord care with application of chlorhexidine to prevent neonatal infections including tetanus. – Adequate thermal care – including drying the baby at birth keeping warm with skin‐to‐skin contact having a warm environ- ment covering the baby including the head and delaying bathing. – Early and exclusive breast‐feeding – starting within 1 hour of birth and avoiding any formula milk. Exclusive breast‐feeding plays a crucial role in prevention of infection and should be strongly encouraged in all countries Fig. 73.5. Breast milk is especially important for low‐birthweight infants. – Early detection of problems and appropriate care‐seeking. Education of mothers and communities on ‘danger signs’ but care‐seeking may be impeded by cost distance or in some cul- tures by strong pressure on mothers and newborn babies not to go outside their home for the first 4–6 weeks. In addition the hospital or health facility must be able to provide quality care for sick babies. When this is not available home‐based treatment may be an alternative. Several studies in South Asia have shown that treatment of infections with antibiotics by injection can be provided at home by community health workers with reduction of 30 or more in neonatal deaths. Hospital‐based care Hospitals should be able to provide safe quality care for sick or small newborns a key priority for improving newborn survival and health. This includes: • Health‐care professionals specifically trained in providing newborn care. •  Neonatal resuscitation available. •  Up‐to‐date evidence based guidelines for common conditions. •  Measures for infection control practiced e.g. hand hygiene and sterile procedures equipment cleaned. •  Thermal regulation – warm delivery room skin‐to‐skin policy clothing and hats for babies. Other warming devices such as radiant heaters incubators or warming mattresses are used appropriately and maintained. •  Feeding support for mothers of preterm babies and supplemental feeding – help for mothers to express milk cup feeding gavage nasogastric tube feeding if needed. •  Intravenous IV fluids closely monitored. •  Antibiotic treatment for babies at increased risk or signs of infection. •  Management of jaundice. a b Fig. 73.5 Examples of the promotion of breast‐feeding: a Nepal b Oman. Courtesy of Dr Saleh Al‐Khusaiby. Key point •  Breastmilk offers major health benefits to infants compared to formula milk. • The promotion and marketing of infant formula milk is restricted by the International Code of Marketing of Breast Milk Substitutes WHO UNICEF. Fig. 73.6 Kangaroo mother care for a preterm newborn. Photo courtesy of Save the Children South Africa.

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Global neonatology 173 •  Kangaroo mother care – provided continuously by mothers for stable preterm babies Fig. 73.6. This is a cost‐effective interven- tion which improves thermal care breast‐feeding and bonding and reduces infection and neonatal mortality in low‐ and middle‐ income countries. Allows limited staff resources to be focused on the sickest babies. Often limited by lack of space. •  Respiratory support – oxygen aminophylline or caffeine for apnea bubble CPAP continuous positive airway pressure or other forms of non-invasive respiratory support. Artificial ventilation may be appropriate in some settings with well‐functioning neonatal units able to provide basic respiratory support but requires a high level of resources. • Supportive care e.g. control of seizures in hypoxic–ischemic encephalopathy. •  Monitoring including oxygen monitoring with pulse oximetry – blindness from retinopathy of prematurity has been reported in many middle‐income countries affecting relatively mature infants from use of excessively high concentrations of oxygen without appropriate monitoring. Further reading and resources •  The Lancet Every Newborn series 2014. • Health Newborn Network Topic Resources: http://www. healthynewbornnetwork.org/topics Question What role can doctors and neonatologists in developed countries play in improving global newborn health They can help by: •  Advocacy – promoting newborn care in resource‐poor countries. •  Assisting with training courses for health professionals in resource-poor countries e.g. Helping Babies Breathe neonatal resuscitation ETAT+ Emergency Triage Assessment and Treatment plus Admission. •  Participating in one of the many collaborative programs or partnerships. These need to be appropriate for local conditions but still retain scientific rigor and be evidence based. Programs must also be aligned to local and national strategy. Question Why is neonatal mortality in resource‐poor countries not declining rapidly Many reasons including: •  Improving maternal care – maternal nutrition health and educa- tion and care antenatally during labor and delivery all of which markedly affect the newborn – is complex and takes time. •  Essential newborn care following birth – often not provided indeed in some countries newborn care practices following hone births are harmful e.g. delay in initiating breast‐feeding early bathing which results in hypothermia cutting the cord with dirty implements Table 73.1. •  Early recognition of illness in newborn infants – often difficult and illness progresses rapidly – urgent transfer from home or health center for effective hospital care requires a responsive integrated health system. •  Inadequate hospital care for sick or preterm infants – health professionals insufficient in number and not trained in neona- tology equipment not available or not maintained poor facilities that are often hot and cramped. • Insufficient focus on and investment in newborn‐specific nursing skills. •  Neonatal care is wrongly considered too ‘high‐tech’ and diffi- cult to provide. •  Many doctors including some pediatricians lack interest and experience in newborn care. •  Lack of data on newborn health outcomes contributes to lower visibility and investment and political will for improvement. Table 73.1 Summary of survey of newborn care in rural Nepal before 2002 when the neonatal mortality was 50/1000 live births. By addressing these and other issues neonatal mortality declined to 24/1000 in 2012. 90 Gave birth at home 6 Skilled attendant at delivery 11 Alone at delivery 33 Cord cut with household sickle 64 Wrapped baby only at 30 minutes of age 92 Bathed in first hour high risk of hypothermia 99 Breast‐fed Adapted from Osrin D. et al. Cross sectional community based study of care of newborn infants in Nepal. BMJ 2002 325: 1063.

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Neonatology at a Glance Third Edition. Edited by Tom Lissauer Avroy A. Fanaroff Lawrence Miall and Jonathan Fanaroff. © 2016 John Wiley Sons Ltd. Published 2016 by John Wiley Sons Ltd. 174 Transport The need for neonatal transport is increasing with centralization of specialist services. Infants must be moved to the right place by the right team by the right mode of transport. Infrastructure •  Specialized trained teams. •  Dedicated equipment Fig. 74.1. •  A ‘transport hotline’ – providing efficient referral process advice and bed locator if available. •  Contracts and protocols for transport – ambulance helicopter fixed‐wing airplane. •  Insurance liabilities to cover adverse events. •  Outreach training for less specialized units. Why transfer •  Uplift in care level e.g. extreme prematurity unstable term infants. •  For subspecialty care – cardiology surgery etc. •  Transport back to referral hospital after specialist care. Equipment •  Transport incubator or lightweight Baby Pod. •  Airways – mask oro- and nasopharyngeal tracheal tubes. •  Respiratory support – ventilator CPAP air oxygen nitric oxide. •  Full ICU monitoring. •  IV access – cannulae syringes infusion pumps. •  Hand‐held blood testing – glucose electrolytes hemoglobin blood gases. •  Power source – available in ambulance aircraft or hospital. Battery for transfers between power supply. Equipment is heavy – needs handling skills and special equip- ment to assist. Documentation •  Use standardized clinical assessment and treatment records. •  Necessary for debriefing audit legal records. The ACCEPT principle is a comprehensive system to ensure that all aspects of the transfer process are managed optimally: A – Assessment •  Determine the appropriate destination for the identified specialist care needs. C – Taking Control of the situation and Communication with all teams involved These include transport team receiving unit and subspecialists. Ideally done through central coordinating center using call con- ferencing facilities. Initial communication: •  Record all clinical details necessary to plan the retrieval. •  Give appropriate advice for stabilization and ongoing care: – ensure that vital signs laboratory tests and blood gases are up‐to‐date and appropriate – request respiratory support vascular access infection treatment specialist care for cardiac or surgery to be initiated if necessary. •  Ask referring hospital to prepare: – full documentation of pregnancy birth and postnatal course radiographs laboratory results vitamin K status – names of baby and parents and contact details – maternal blood for cross‐match. •  Record exact location of patient city hospital ward. •  Estimate arrival time and inform referring hospital. •  Provide ongoing contact number for clinical advice from specialist if needed. E – Evaluation of the infant to be moved. On arrival of transport team: •  Ensure detailed handover of patient’s condition. •  Review current treatment and management. Before transport the infant should have: •  normal temperature except during therapeutic hypothermia •  secure airway and breathing •  IV access – two lines preferably if critically ill •  gavage naso‐/orogastric tube •  optimized blood pressure circulation urine output – consider arterial access •  optimized blood results – glucose electrolytes complete blood count CBC blood gases etc. •  immediate treatment given e.g. antibiotics transfusion prosta - glandin Prostin anticonvulsants as appropriate. •  further specialized treatment started if required e.g. active or passive cooling. Transport of the sick newborn infant 74 Fig. 74.1 Dedicated specialized equipment.

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Transport of the sick newborn infant 175 P – Preparation by transport team Prepare emergency medications including fluid boluses and emergency equipment e.g. airways endotracheal tubes. IV lines that may be needed en route. P – Packaging • The infant’s clinical status needs to be rechecked after transfer to the transport incubator ensuring that all transport equipment is functioning i.e. ventilator monitors infusion pumps. •  Check that all lines endotracheal tubes catheters etc. are secure. •  Make baby as comfortable as possible. •  Secure infant in the transport incubator with harnesses. The incu - bator monitors and infusion pumps must be well secured to the transport trolley. T – Transfer •  Transport trolley must be secured in ambulance Fig. 74.2. •  Continuous monitoring record vital signs regularly as in ICU. •  Avoid all unnecessary interventions. On arrival at receiving hospital: •  Hand over to receiving staff. •  Ensure stable transfer to ICU monitoring and therapy. •  Complete documentation. Fig. 74.2 Securing trolley in ambulance. Aeromedical considerations Figs 74.3 and 74.4 •  May be faster if ground transport takes more than 2 hours. •  Helicopter maximum distance is about 300 miles then use fxed‐wing airplane. Local conditions will determine the choice. Problems: •  Expensive. •  Multiple transfers between vehicles. •  Cramped space/diffcult access to baby. •  Noise and vibration. •  Decreased barometric pressure – fxed‐wing airplanes are pressurized at about 8000 ft 2500 m so for example 50 FiO 2 at ground level will require 67 at 8000 ft 2500 m. There will be expansion of closed air‐flled cavities: – Ensure gavage naso‐/orogastric tube on free drainage and aspirated regularly. – Air leaks may worsen. – Blood pressure cuffs may cause occlusion of blood vessels. Key points •  Remember   parents   –   the y   need   information   support   trans- port accommodation fnance child care and counseling. •  Ideally   should   be   of fered   the   opportunity   to   tra v el   with   their baby. •  They   will   remember   this   experience   for   the   rest   of   their  lives. Fig. 74.4 Long distance repatriation of twins by fixed wing airplane. Fig. 74.3 Helicopter transfer in Northern Canada. Pitfalls for all modes of transport •  Extreme weather. •  Vehicle failure. •  Equipment failure. •  Battery or medical gas failure. •  Accidents. •  Travel sickness. •  Be prepared

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Neonatology at a Glance Third Edition. Edited by Tom Lissauer Avroy A. Fanaroff Lawrence Miall and Jonathan Fanaroff. © 2016 John Wiley Sons Ltd. Published 2016 by John Wiley Sons Ltd. 176 Practical procedures Endotracheal intubation Indications •  Neonatal  resuscitation  see  Chapter  13  to  aspirate  meconium  or in advanced resuscitation. •  Mechanical ventilation for respiratory failure:   – prolonged/recurrent apnea not responding to non-invasive  respiratory support   – increasing  respiratory  distress  or  inadequate  oxygenation  hypoxemia and/or carbon dioxide elimination hypercarbia on  CPAP or high-flow nasal cannulae. •  To replace a blocked or dislodged tracheal tube. •  For administration of surfactant see video: INSURE technique. •  Upper airway obstruction – to provide a secure airway. •  Congenital diaphragmatic hernia – to avoid bowel distension. •  Prior to surgical procedures/general anesthesia. Procedure •  Ensure you have assistance and prepare equipment in advance. •  Premedicate e.g. with propofol or a combination of fentanyl  suxamethonium and atropine unless an emergency. •  Ensure  good  oxygen  saturation  but  avoid  hyperoxia.  Monitor  oxygen saturation and heart rate continuously. •  Place  head  in  the  midline  in  a  slightly  extended  position.  Pressure on the cricoid by an assistant can be helpful to visualize  vocal cords. •  Insert laryngoscope with left hand to just beyond base of tongue  and epiglottis. •  Lift  entire  blade  Fig.  75.1.  Suction  to  clear  secretions  if  needed. •  Insert tracheal tube with right hand into right side of infant’s  mouth and pass through the vocal cords Fig. 75.2 to the level  of  the  black  line  near  the  tube  tip. A  stylet  may  help  stiffen  the tube but must not protrude beyond the end as it may cause  trauma. •  Note depth of insertion from the lips see Table 75.1. •  Verify correct tube placement by:   – observing symmetrical chest rise and an improvement in heart  rate and oxygen saturation   – observing color change in a CO 2  detector this shows the tube  has passed into the trachea but it may still be malpositioned   – auscultation: hearing air entry over upper lungs and none over  the stomach. If air entry is greater on right side than left tube is  in right main bronchus withdraw until breath sounds equal. •  Secure tube and confirm position with chest X-ray. •  Limit attempts to 20–30 seconds and avoid bradycardia. •  Mask-ventilate and oxygenate infant between attempts. Nasal intubation gives better stability of the tracheal tube but can  be more difficult to insert and can cause nasal trauma. A lubricated  ET tube is passed through the nostril to back of throat once the  cords and tube are visualized with the laryngoscope the tube is  lifted into the airway using McGill forceps if necessary and then  advanced. Intubation and chest tubes 75 Table 75.1 Guide to endotracheal tube size. Weight kg Gestation weeks ET tube size mm Depth of insertion oral tube cm from upper lip 1 28 2.5 6–7 1–2 28–34 3.0 7–8 2–3 35–38 3.5 8–9 3 38 3.5–4 9–10 Fig. 75.1 Technique of laryngoscopy for endotracheal intubation. Place  tip of blade at base of epiglottis or lift epiglottis. Lift the entire blade to  visualize the vocal cords. Do not tilt blade upwards as it may damage  gum or palate. Cricoid pressure may help. Epiglottis Vocal cords Fig. 75.2 View of vocal cords at intubation.

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Intubation and chest tubes 177 Chest tubes chest drain Indications •  Pneumothorax. •  Pleural effusion. Technique The Seldinger technique insertion over a guidewire has largely  replaced open dissection see video: Chest drain insertion. •  Site: preferably lateral – third to fifth intercostal space anterior axil- lary line or otherwise anteriorly second intercostal space mid-clavicular  line. Just above rib to avoid neurovascular bundle. •  Avoid nipple and breast bud. •  Sterile technique. •  Local anesthesia – 1 lidocaine. •  Seldinger  technique  –  insert  needle  into  chest  aiming  apicaly  and anteriorly for pneumothoraces and posteriorly and basally for  fluid and aspirate small volume of air or fluid. •  Insert guidewire into needle Fig. 78.3 then remove needle over  wire. •  Thread chest tube 8 or 10 FG over the guide wire Fig. 75.4.  Some  chest  tubes  change  color  on  entry  into  the  pleural  space.  Remove guidewire. •  Connect tube to three-way tap and underwater seal observe air  bubbles and swinging with respiration. •  Fix to chest wall with sterile strips and adhesive dressing. Avoid  suturing round the tube as it may leave scars see Fig. 66.7. •  X-ray to check tube position and lung re-expansion Fig. 75.5. Complications •  Hemothorax. •  Infection. •  Surgical emphysema. •  Scarring of skin or breast tissue. Needle thoracotomy chest needling Indication •  Immediate treatment of tension pneumothorax. Technique •  Quickly confirm by auscultation and transillumination. •  Site – second or third intercostal space mid-clavicular line. •  Approach – upper edge of rib to avoid neurovascular bundle. •  Insert  butterfly  needle.  Create  underwater  seal  or  aspirate  air  from chest with syringe via a three-way tap. •  Usually followed by chest tube insertion. Pleural tap Indications •  Pleural fluid e.g. chylothorax pleural effusion. Technique •  Sterile technique. •  Use ultrasound to identify fluid. •  Local anesthesia – 1 lidocaine. •  Insert a 22G cannula just above the rib. •  Attach to three-way tap and aspirate fluid. If pleural fluid reaccumulates insert a chest drain. Complications •  Pneumothorax or hemothorax. Fig. 75.3 Insertion of guidewire into needle red using the Seldinger  technique. Fig. 75.4 Chest tube has been threaded over guidewire which has been  withdrawn and attached to underwater seal. Fig. 75.5 X-ray showing a right chest tube pigtail to drain a pneumo- thorax. There is also a left pneumothorax with mediastinal shift.

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Neonatology at a Glance Third Edition. Edited by Tom Lissauer Avroy A. Fanaroff Lawrence Miall and Jonathan Fanaroff. © 2016 John Wiley Sons Ltd. Published 2016 by John Wiley Sons Ltd. 178 Practical procedures Neonatal care involves a large number of practical procedures. Each has specific advantages and risks. Team training and preparation are the key to success and avoiding complications. Minimize pain with sucrose gentle wrapping and positioning. Optimize timing from the baby’s perspective in relation to feeds and other procedures. Ensure appropriate consent is obtained. For all these procedures meticulous attention to asepsis is important – both to avoid the risk of intro- ducing infection and to prevent contamination of sterile samples leading to overuse of antimicrobials. Skin preparation with cleansing agents should be used to clean the skin. Dispose of all sharps safely directly into a sharps bin. Some common procedures are shown in Table 76.1. Common practical procedures 76 Table 76.1 Some common procedures. Procedure Preparation and equipment Comments Technique Advantages Potential complications Capillary blood sampling heelstick Clean procedure Gloves sterile alcohol swab automatic mini-lancet tubes gauze Autostylets less painful than stylets inserted by hand. Avoid undue squeezing of heel as painful and gives misleading results. Catch drops in bottle. Stop bleeding with gauze Simple technique for blood glucose hematocrit complete blood count electrolytes and blood gases If results are abnormal confirm with venepuncture Bruising Infection Rarely osteomyelitis Venous blood sampling Clean procedure Gloves sterile alcohol swab needle tubes for blood sample gauze Use venepuncture needle. Avoid potential central line sites Good flow of blood – avoids hemolysis of sample Bruising Infection Difficult access in some infants Loss of veins for cannulation Peripheral venous cannulation Clean procedure Gloves sterile alcohol swab cannulae flushed T-piece stopper syringe tape clear dressing splint if necessary Avoid potential central line access sites Fiber-optic light may facilitate visualization of veins Dress with sterile clear adhesive dressing with entry site visible Usually achieved relatively quickly Best method for blood culture Bruising/ Hemorrhage Inflammation Infection Extravasation injury Fig. 76.1 Shaded areas show sites for capillary sampling. Fig. 76.2 Venous blood sampling from back of the hand. Fig. 76.3 Peripheral venous cannulation. When blood flows back advance cannula over and withdraw stylet.

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Common practical procedures 179 Procedure Preparation and equipment Comments Technique Advantages Potential complications Peripheral arterial cannulation Clean procedure Gloves sterile alcohol swab cannulae flushed T-piece stopper tape dressing Use limited by potential complications Identify artery by pulse and transillumination. Hand: radial artery check for collateral circulation Fig 76.4 Foot: posterior tibial dorsalis pedis Never use temporal brachial or ulnar artery Infuse heparinized saline Clearly mark as arterial Sample and flush slowly Access for repeated blood sampling Invasive BP measurement unless poor peripheral circulation Short functioning time hours to few days Variable success at insertion Blood loss if line disconnected If poor perfusion of fingers/toes –REMOVE Rarely ischemia or gangrene Urinary catheter Sterile procedure Gloves sterile towel cleaning fluid lubricated urinary catheters 4 or 5 FG To obtain sterile urine Treatment of urinary retention Monitor urinary output Simpler More reliable to obtain sterile specimen than suprapubic aspirate and no needlestick Urethral damage Hemorrhage Contaminated urine sample Infection Suprapubic aspirate bladder tap Sterile procedure Gloves sterile alcohol swab needle syringe sterile pot gauze To obtain sterile urine sample Higher success rate if ultrasound abdomen to check if bladder is full In an infant the bladder extends into the abdomen. Sterile sampling for reliable diagnosis of urinary tract infection No urine obtained Rare – hemorrhage or needlestick injury to bowel Lumbar puncture Sterile procedure Gown mask and sterile gloves. sterile towels cleaning fluid gauze LP needles containers for CSF samples Position infant lying on side or sitting with spine flexed Minimize discomfort topical analgesia Prepare sterile field Slowly advance needle with stylet in direction of umbilicus. May feel a “give” when pierce dura and enter subarachnoid space. Remove stylet and check for CSF. Collect 5–10 drops into each of 3 sterile containers and glucose bottle. Replace stylet remove needle apply sterile adhesive dressing. Identifies meningitis Withdrawal of CSF in treatment of post- hemorrhagic hydrocephalus Rarely identification of metabolic disorder No CSF obtained. Blood-stained CSF – trauma or hemorrhage intraventricular or subarachnoid Contraindicated: • bleeding disorder e.g. thrombocytopenia • cardiorespiratory instability • Local skin infection 1 cm Slight negative pressure on advancing Ultrasound probe Fig. 76.5 Suprapubic aspiration under ultrasound guidance. Adapted from Lissauer T. and Clayden G. Illustrated T extbook of P aediatrics Elsevier 2012. Fig. 76.4 Peripheral arterial cannulation. Check for collateral circulation Allen test – hand blanches when both arteries occluded color returns when occlusion of one artery is released. Usually L3/4 space is just below line joining iliac crests Avoid neck exion as may cause apnea Fig. 76.6 Lumbar puncture see video: Lumbar puncture. Back curved. Skilled assistance required. Infant may also be held upright. Table 76.1 continued

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Neonatology at a Glance Third Edition. Edited by Tom Lissauer Avroy A. Fanaroff Lawrence Miall and Jonathan Fanaroff. © 2016 John Wiley Sons Ltd. Published 2016 by John Wiley Sons Ltd. 180 Practical procedures Umbilical catheters Umbilical artery catheter UAC Indications •  Continuous measurement of arterial blood pressure. •  Frequent blood gases or other blood samples. •  Exchange transfusion – to remove blood. Contraindications •  Vascular compromise in the lower extremities or gluteal area. •  Necrotizing enterocolitis peritonitis. •  Omphalitis infection of the umbilical cord. •  Omphalocele. Insertion see video: Umbilical catheter insertion arterial and venous Easiest on first day possible within first 3–4 days. •  Wear gown mask and sterile gloves prepare sterile field. •  Prime catheter with saline. •  Clean  the  umbilicus  and  skin  with  chlorhexidine  2/70  isopropyl alcohol swabs ensure no pooling under baby. •  Place nylon tape around the base to control bleeding then cut  umbilical cord 1–2 cm from skin. •  Identify artery Fig. 77.1. Dilate the artery with fine forceps or  a dilator. •  Insert  gently  a  3  or  4.5  French  gauge  catheter  to  predetermined  length Table 77.1. There is gentle resistance from the muscular wall  of the artery. Check that blood can be withdrawn Fig. 77.2. •  Secure catheter Fig. 77.2. •  Check position with X-ray Figs 77.3 and 77.4 or ultrasound. •  Flush with heparinized saline. •  Label line as arterial or use red three-way tap. Complications •  False track by catheter. •  Poor  perfusion  of  lower  limbs.  If  ischemic  immediately  REMOVE catheter. •  Blood loss if line disconnects. •  Aortic thrombosis and emboli. •  Infection remove line as soon as no longer needed. •  Anemia from repeated excess blood volume sampling. Umbilical catheters and intraosseous cannulation 77 Umbilical arteries Umbilical vein Head Feet Fig. 77.1 Two arteries and one vein in umbilicus. The arteries are small  circular and have a muscular wall the vein is larger thin-walled and  irregular. Table 77.1 Formula to calculate length of umbilical lines. Type of line Length cm – add on the length of the umbilical stump Umbilical artery catheter UAC  high position 3 × weight kg + 9 cm Umbilical vein catheter UVC Half the UAC length + 1 cm Umbilical artery catheter UAC UAC and thread within tape Thread sutured in cord Fig. 77.2 Insertion and fixation of umbilical artery catheter. Transverse  cutting of cord as shown here or cut down onto artery. Dilate with fine  forceps or dilator. Magnification may be helpful. The umbilical cord is  tied to a strip of tape to avoid tape on the skin. In some units tape is  placed in an H-shape on the abdominal wall and incorporates the  catheter and thread suture from the cord. L3–4 T6–10 IVC Fig. 77.3 Position of catheters. For an arterial catheter red the high  position T6–10 is above the diaphragm avoiding the celiac axis T12  superior mesenteric artery T12–L1 and renal arteries. This is the ideal  position with less vascular complications. The low position L3–4 is  below the inferior mesenteric artery but above the aortic bifurcation. IVC  inferior vena cava. The position of the venous catheter is shown in blue.

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Umbilical catheters and intraosseous cannulation 181 Umbilical vein catheter UVC Indications •  Resuscitation – for urgent venous access. •  Inotropes. •  Parenteral nutrition. •  Exchange transfusion. Contraindications •  Omphalitis. •  Omphalocele exomphalos. •  Peritonitis. Insertion •  Insert umbilical arterial catheter first if also required. •  Prepare sterile field and clean stump as for UAC. •  Select single- or double-lumen catheter. •  UVC can sometimes be inserted several days after birth. •  Prime  catheter  with  saline  and  insert  to  required  length  see  Table 77.1. •  Check position with X-ray Fig. 77.4 or ultrasound. Tip should  lie in the inferior vena cava 1 cm below the diaphragm. •  Label clearly that it is a venous line. Complications •  Thrombosis or emboli. •  Extravasation of fluid e.g. PN into liver. •  Infection. •  Pleural or pericardial effusion if in right atrium. •  Remove as soon as no longer essential. Intraosseous cannulation Indication •  Emergency infusion of fluids and drugs when no venous access  possible. Preparation •  Clean the skin and prepare sterile field. •  Position infant with knee flexed and supported. Insertion •  Proximal tibia 1–3 cm below tibial tuberosity – medial flat surface  Fig. 77.5. •  Use neonatal intraosseous needle. •  Insert needle at 10–15° from vertical towards foot avoids growth  plate. •  Use twisting motion or use drill device. •  Place dressing around base to secure needle. •  Aspirate marrow to confirm position. •  Infuse drugs using syringe. Complications •  Fracture. •  Extravasation causing cellulitis. •  Osteomyelitis. Fig. 77.4 X-ray to confirm position of the umbilical artery red and  umbilical vein blue catheters which need to be withdrawn. The artery  first goes towards the groin before going towards the head just to the left  of the vertebral column. Also check position of tracheal tube satisfactory  and gavage nasogastric tube missing. Fig. 77.5 Intraosseous infusion into tibia.

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Neonatology at a Glance Third Edition. Edited by Tom Lissauer Avroy A. Fanaroff Lawrence Miall and Jonathan Fanaroff. © 2016 John Wiley Sons Ltd. Published 2016 by John Wiley Sons Ltd. 182 Practical procedures Central venous catheters CVC In neonatal practice central catheters are usually peripherally inserted but sometimes a surgically placed subclavian or internal jugular catheter is required for long-term management or if venous access is very difficult. Peripherally inserted central catheters PICC lines Indications •  Parenteral nutrition. •  Inotropes due to vasoconstriction. •  Hyperosmolar infusions e.g. glucose 12.5. •  Prolonged administration of antibiotics. Site •  Common veins – brachial saphenous sometimes scalp. Insertion Figs 78.1–78.3 •  Prepare infant – optimize position minimize discomfort see Chapter 63 temperature control monitoring. •  Measure length of insertion from cannulation site to inferior or superior vena cava as appropriate. •  Prepare equipment – gauze polyurethane catheter cannula or needle for insertion T-piece and connection dressing saline flush. •  Sterile procedure – wear gown and mask and two sets of gloves – remove outer gloves once the area is cleaned and sterile. Quality improvement care bundles to reduce central line- associated bloodstream infection CLABSI have markedly reduced late-onset sepsis rates. Achieved through practical training and improving procedures to optimize infection control root cause analysis of positive blood cultures feedback and use of results to further improve guidelines. Line tip position and management •  Ideal position of the tip is in the inferior or superior vena cava outside the right atrium. •  Position of the long line should be checked by X-ray or ultra- sound Fig. 78.4 to ensure it is not in the right atrium. If position in doubt inject sterile intravenous contrast and X-ray. •  If line inserted in upper arm perform X-ray with arm abducted. •  If line inserted in lower limb ensure it has passed superior to the lumbar venous plexus. •  Line management – usually last several weeks. They must be handled aseptically. Complications •  Infection. •  Thrombus and emboli. •  Extravasation – pleural effusion pericardial effusion tampon- ade tissue edema. •  Superior vena caval obstruction. •  Blockage. •  Leakage at connection sites. •  Line breaking off on removal. Surgically tunneled subclavian or jugular line Indications •  Long-term central access. •  Peripheral insertion not successful. Insertion • Usually by a pediatric surgeon or interventional radiologist under general anesthetic in operating theater. •  Tunneled under skin. •  Tip position in superior vena cava. Central venous catheters and exchange transfusions 78 Fig. 78.1 An example of placing a peripherally inserted central catheter PICC line. Needle is inserted into vein. The central line is threaded through the cannula. Non-toothed forceps may be used. Figs 78.1 and 78.2 Courtesy of Dr Sunit Godambe. Fig. 78.2 The cannula is removed and then split leaving the long line in place. Fig. 78.3 Securing the line using sterile strips followed by clear adhesive dressing incorporating loops of the central line. Ensure that insertion site is visible that the infant is comfortable and that the dressing is not constricting the line or arm.

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Central venous catheters and exchange transfusions 183 Complications •  Pneumothorax. •  Surgical scar. •  Superior vena caval obstruction. •  Blockage or extravasation. •  Infection. Exchange transfusion Indications •  Severe hyperbilirubinemia – exchange with fresh blood 2 × blood volume i.e. 2 × 90 mL/kg. •  Severe polycythemia hematocrit 0.75 or symptomatic – exchange with normal saline to reduce hematocrit to 0.55 usually 20 mL/kg. Exchange transfusion is performed infrequently for hyperbili- rubinemia since the introduction of routine anti-D antibody to rhesus-negative mothers better phototherapy and intravenous immunoglobulin for severe jaundice. Technique see video: Haemolytic disease of the newborn •  Use fresh CMV-negative irradiated whole blood or plasma reduced red cells not packed red cells ideally with hematocrit 0.5–0.6. •  Prepare sterile field. Ensure operator will not be disturbed during procedure. Blood withdrawn via umbilical or peripheral arterial line infused via umbilical or peripheral vein •  Infuse blood at a constant rate through the vein via a blood warmer. •  Withdraw blood from arterial line in aliquots 5 mL extremely preterm 20 mL term. Via umbilical venous catheter Fig. 78.5 •  Alternate between withdrawing and infusing aliquots 5–20 mL of blood. Use a closed system designed for exchange transfusion to reduce the risk of error. Monitoring •  Heart rate blood pressure temperature throughout. •  V olume infused and withdrawn separate observer. •  Glucose electrolytes calcium acid–base. •  Allow time for equilibration – perform over several hours for double volume exchange. •  No feeds during procedure. Complications •  Technical problems e.g. loss of access. •  Air embolization or thrombosis. •  V olume overload or depletion. •  Electrolyte imbalance – hyperkalemia hypocalcemia acidosis or alkalosis. •  Hypoglycemia. •  Infection. •  Hypothermia. •  Mortality – possibly up to 1. Fig. 78.4 X-ray demonstrating the importance of confirming catheter position. Central line may be radiopaque or need contrast flushed into it. The central venous catheter inserted into a vein in the left arm arrow is in the right atrium arrows and must be withdrawn. Blood warmer Three-way tap Three-way tap 10ml syringe Umbilical venous catheter Waste bag Donor blood Fig. 78.5 An example of exchange transfusion via umbilical vein with 10 ml aliquots. 1. Withdraw 10 mL of baby’s blood into syringe. 2. Inject baby’s blood into waste bag. 3. Draw 10 mL of donor blood into syringe. 4. Inject 10 mL of blood into baby. Repeat to replace calculated blood volume.

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Neonatology at a Glance Third Edition. Edited by Tom Lissauer Avroy A. Fanaroff Lawrence Miall and Jonathan Fanaroff. © 2016 John Wiley Sons Ltd. Published 2016 by John Wiley Sons Ltd. 184 Practical procedures The anterior fontanel provides a window through which the brain can be visualized using ultrasound see video: Cranial ultrasound. This allows the identification of a range of brain lesions in newborn infants. The examination is non‐invasive and can be safely performed at the bedside with minimal distur- bance to the infant. It allows injuries to be timed. Serial imaging allows monitoring of progression or resolution of lesions. It provides prognostic information and may assist in decision‐ making about continuation or withdrawal of intensive care. The appearance of the brain varies with gestation and age. At 23–25 weeks the cortex is relatively smooth with few cerebral fissures sulci and gyri and the ventricles are prominent. By term the surface of the cortex appears convoluted and sulci and gyral patterns are well developed with slit‐like ventricles. These changes can also be seen on MRI scans see Chapter 81. Indications •  Infants 1500 g birthweight or 32 weeks’ gestation. •  Infants requiring mechanical ventilation. •  Neurologic abnormality – abnormal tone seizures encephalopathy. •  Antenatally detected neurologic abnormality. •  Suspected genetic syndrome. •  Major congenital anomaly. Lesions that can be identified Preterm infants •  Hemorrhage in germinal matrix ventricles or parenchyma. •  Ventricular dilatation. •  Parenchymal infarcts and porencephalic cysts. •  Periventricular leukomalacia. All infants •  Structural brain malformation. •  Ventricular dilatation. •  Cerebral edema. •  Calcification from congenital infection. •  Basal ganglia lesions in hypoxic–ischemic encephalopathy. •  Stroke e.g. middle cerebral artery infarction. •  Hematoma see below. Cranial ultrasound 79 Standard views for scans Coronal views Fig. 79.1 Coronal views: 1 Anterior to frontal horns 2 Frontal horns of lateral ventricles 3 3rd ventricle 4 Body of lateral ventricles and cerebellum 5 Lateral ventricles posterior horns 6 Occipital lobes 5 6 4 3 2 a b c d 1 Fig. 79.1 Coronal views. a Frontal horns view 2. b Third ventricle view 3. c Lateral ventricles posterior horns view 5. d Periventricular white matter view 6.

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Cranial ultrasound 185 Sagittal views Fig. 79.2 Hemorrhage Germinal matrix hemorrhage GMH Grade I Fig. 79.3 Intraventricular hemorrhage GMH‐IVH Grade II – no ventricular dilatation Fig. 79.4 a b Fig. 79.3 Left germinal matrix subependymal hemorrhage Grade I. a Coronal view. b Sagittal view. b c 5 3 2 1 4 a Sagittal views: 1 Right Sylvian ssure for deep white matter 2 Right lateral ventricle 3 Midline 4 Left lateral ventricle 5 Left Sylvian ssure for deep white matter Fig. 79.2 Sagittal views. a Sylvian fissure for deep white matter view 1 and 5. b Lateral ventricle view 2 and 4. c Midline view 3. a b Fig. 79.4 Bilateral intraventricular hemorrhage GMH‐IVH Grade II. a Coronal view. b Sagittal view. continued

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186 Practical procedures a b Fig. 79.5 Bilateral intraventricular hemorrhage GMH‐IVH with ventricular dilatation Grade III. a Coronal view. b Sagittal view. a b Fig. 79.6 Right hemorrhagic parenchymal infarct Grade IV. a Coronal view. b Sagittal view. Fig. 79.7 Porencephalic cyst at site of a unilateral hemorrhagic parenchymal infarct. Fig. 79.8 Marked bilateral post‐hemorrhagic ventricular dilatation PHVD and hemorrhage in right ventricle on coronal scan arrow. Regular ultrasound and head circumference monitoring is indicated. If symptoms of raised intracranial pressure develop or head circumference rapidly crosses centiles a ventricular access device or ventriculo‐ peritoneal shunt will need to be inserted to remove CSF. Lateral ventricle Foramen of Monro Third ventricle RVI LVI Coronal view L Fig. 79.9 Ventricular index measured from the midline to the lateral border of the ventricle on a coronal scan in the plane of the third ventricle to aid monitoring of ventricular dilatation. Other indices can be used. LVI left ventricular index RVI right ventricular index. 10 28 30 32 Postmenstrual age weeks 34 38 36 40 97th centile 4 mm over 97th centile Ventricular width mm 12 14 20 18 16 Fig. 79.10 Centiles for ventricular index showing 97th centile. Used to monitor progression or resolution of ventricular dilatation. See Chapter 59 Neural tube defects and hydrocephalus. Source: Levene M.I. Arch Dis Child 1981 56: 900–904. Intraventricular hemorrhage GMH‐IVH with dilatation Grade III – ventricular dilatation Fig. 79.5 Hemorrhagic parenchymal infarct Grade IV Fig. 79.6 Porencephalic cyst Fig. 79.7 Post‐hemorrhagic ventricular dilatation PHVD Fig 79.8 Ventricular index Figs 79.9–79.10

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Cranial ultrasound 187 Color Doppler flow velocity measurements Cranial ultrasound can be combined with color Doppler flow velocity measurements to distinguish vascular from non vascular structures and  to ensure that the blood flow is normal. Abnormalities in flow after severe HIE may guide prognosis. Additional windows Other fontanels may be used to provide additional views if indicated: •  Posterior fontanel – occipital and temporal horns of lateral ven- tricles occipital and temporal parenchyma and posterior fossa. •  Temporal window positioned above ear – brain stem and cerebellum. •  Mastoid fontanel at junction of temporal occipital and posterior parietal bones – posterior fossa and mid‐brain Fig. 79.13. Limitations of ultrasound Poor sensitivity in identifying: •  cerebral white matter injury •  cerebral edema •  subdural subgaleal subaponeurotic hemorrhage Cannot reliably distinguish between hemorrhage and infarction. MRI imaging is more sensitive in identifying these lesions. Practical issues •  Sonographer should be specially trained. •  Probe must be cleaned before and after use with each infant. •  Ensure the probe marker is on the right hand side of the baby’s head and that the screen is correctly labeled. •  Images are recorded digitally for review and storage. •  Abnormality should be visible on both coronal and sagittal views. •  Written report by experienced neonatologist or radiologist or radiographer into patient record. Fig. 79.11 Bilateral echodensities on coronal view. a b Fig. 79.12 Widespread periventricular cysts on day 55 in a coronal and b sagittal views. Initial scans were normal and then showed some increased periventricular echogenicity evolving into cystic PVL. Cerebellum Temporal lobe Brain stem Fig. 79.13 Mastoid fontanel view showing cerebellum. Echodensities Fig. 79.11 Cystic periventricular leukomalacia PVL Fig. 79.12 View from additional window Fig. 79.13 Question When can brain injury in preterm infants be identified on ultrasound Shortly after birth – identifies antenatal and early injury – small cysts periventricular flare hemorrhage. During first week – hemorrhage early ventricular dilatation periventricular flare. At 3–4 weeks old – ventricular dilatation evolving PVL cysts progression of lesions. Discharge or term – prognosis is good if ventricles are normal there is no cerebral atrophy no cystic lesions and head circum- ference is increasing along normal centile.

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Neonatology at a Glance Third Edition. Edited by Tom Lissauer Avroy A. Fanaroff Lawrence Miall and Jonathan Fanaroff. © 2016 John Wiley Sons Ltd. Published 2016 by John Wiley Sons Ltd. 188 Practical procedures Amplitude-integrated electroencephalography aEEG is a bedside tool for continuous monitoring of changes in the amplitude of the electroencephalogram using a cerebral function monitor CFM. It compares well with standard EEG when used to assess the severity of neonatal encephalopathy but a standard EEG is still required to provide additional important information about changes in fre- quency and in the synchrony distribution and other characteristics of cerebral cortical activity. Use of aEEG in neonates Term infants • To assess the severity of hypoxic–ischemic encephalopathy HIE. •  For prediction of neurologic outcome following HIE. •  For seizure detection. •  To monitor response to anticonvulsant therapies. •  To select infants for clinical trials of neuroprotection. •  To monitor and assess etiology of neonatal encephalopathy. Preterm infants •  To detect complications such as intraventricular hemorrhage and posthemorrhagic ventricular dilatation. •  T o predict neurodevelopmental outcome following preterm delivery . Cerebral function monitor The CFM records one or two channels of EEG from scalp electrodes the signal is filtered and the signal amplitude is displayed. Frequencies 2 and 15 Hz are selectively filtered to reduce artifacts caused by movement ECG and other electronic equipment. The speed is usually set at 6 cm/hour making every major division equal to 10 minutes. Interpretation The standard CFM display appears as a band of activity moving slowly across the display screen. The lower edge of the band indi- cates the lowest peak-to-peak amplitude reached by the filtered EEG over a period of time whereas the upper edge is related to the highest levels. The width of the band indicates the variability of the EEG amplitude. In term infants the aEEG trace can be classified according to voltage or pattern of trace Fig. 80.1. Normal The upper margin of the trace is above 10 μV and the lower margin is greater than 5 μV. The width of the band fluctuates between 10 and 50 μV changing with the sleep–awake state of the infant sleep–awake cycling and is called a continuous pattern. Moderately abnormal The upper margin is 10 μV and the lower margin is 5 μV . Hence the band appears wider and is called a discontinuous pattern. This is seen in infants with moderately severe encephalopathy. It may also be seen immediately after administration of anticonvulsants and sedatives. The aEEG should therefore not be used for assess- ing severity of encephalopathy during the first 30–60 minutes after therapy with these medications. A discontinuous pattern may be normal in preterm infants. Severely abnormal The upper margin is 10 μV and lower margin is usually 5 μV. Hence the band appears narrow and is called a low-voltage pattern. Rarely the lower margin may be raised above 5 μV because of inter- ference from ECG. This low-voltage pattern may be accompanied by brief bursts of higher voltage spikes which appear as single spikes above the background activity. This is called ‘burst suppression’. A severely abnormal trace is usually seen with severe encephalopathy and is often accompanied by seizure activity. Isoelectric EEG Absent cerebral electrical activity is seen as a flat line or narrow band of activity with very low voltage. Amplitude‐integrated electroencephalography aEEG 80 Classification of aEEG based on voltage and pattern Voltage classification Normal Lower margin 5µV Upper margin 10µV Moderately abnormal Lower margin ≤5µV Upper margin 10µV Severely abnormal Lower margin 5µV Upper margin 10µV Normal trace Abnormal trace Pattern classification aEEG trace 6cm/hour CNV Continuous normal voltage DNV Discontinuous normal voltage BS Burst suppression LV Low voltage FT Flat trace isoelectric Normal trace Abnormal trace 100 25 50 10 5 0 100 25 50 10 5 0 100 25 50 10 5 0 100 25 50 10 5 0 100 25 50 10 5 0 CNV DNV BS LV FT 6cm Sleep-wake cycling Fig. 80.1 Classification of aEEG. This is based on voltage upper and lower margins of the trace shown on the left or on pattern of the trace shown on the right. They overlap.

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Amplitude-integrated electroencephalography aEEG 189 Seizure detection and response to anticonvulsants •  Seizures are characterized by a sudden rise and narrowing of the trace reflecting the increase in EEG voltage. The trace returns to the previous appearance or is depressed when the seizure activity stops Fig. 80.2. •  Very frequent or continuous seizure activity status epilepticus may result in a ‘sawtooth’ appearance or in an elevated narrow band of activity. •  Inspection of the underlying EEG helps to confirm seizures sus- pected from the CFM trace. •  Since the aEEG is usually displayed at 6 cm/hour brief seizures less than 1–2 minutes will not be seen. •  A standard EEG is needed to document the electrographic characteristics and distribution of seizures. •  aEEG is often used to monitor the response to treatment with anticonvulsants Fig. 80.3. Artifacts on an aEEG trace •  Poor contact with electrodes causes high amplitude artifact. •  An artifact from electrical activity of the heart may result in elevation of the band of activity even in the absence of cerebral activity. •  Muscle or movement artifact can result in an artificially broad band or sudden changes in the band of activity. •  The underlying raw EEG should always be inspected if artifact is suspected. aEEG as a prognostic tool in HIE •  The aEEG in conjunction with other neurophysiologic investi- gations and imaging is helpful in predicting neurodevelopmental outcome following neonatal HIE. Combining clinical assessment with the aEEG trace further improves prognostic accuracy. •  Hypothermia improves neurologic outcomes when started within the first 6 hours of age in infants with HIE with a moderately or severely abnormal aEEG trace. As normalization of the aEEG occurs later in cooled infants it should not be relied upon as the sole prog- nostic factor before 48h of age. •  In cooled infants normal background amplitude or recovery of background amplitude within 6 hours of birth is associated with a likely normal outcome. •  Many infants with recovery to normal EEG activity within 36–48 hours of birth go on to make a good clinical recovery. • A burst suppression pattern or depressed trace persisting beyond 48 hours or absence of sleep–awake cycling by 96 h indicates a high probability of abnormal neurodevelopmental outcome •  It is not clear whether the occurrence of seizures in HIE alters the prognosis in infants with a suppressed EEG. Use of aEEG in preterm infants •  There are well-characterized developmental changes in the EEG of preterm infants the EEG is discontinuous at 24–25 weeks’ ges- tation and gradually becomes less discontinuous with increasing maturity. •  Sleep–awake cycles begin to emerge from about 30 weeks but remain incomplete until about 37 weeks’ gestation. •  A semiquantitative scoring system of maturity based on sleep– awake cycling pattern continuity and bandwidth has been described and shown to correlate with subsequent neurologic outcome although its reliability is not proven. 08/06/06 13:00 SUN 14:00 08/06/06 15:00 CFM V EEG V –40 40 05 10 25 50 100 0 Fig. 80.2 aEEG showing seizures arrows with rise in baseline and lack of variability in voltage. The corresponding raw EEG with high amplitude spikes is shown in the lower panel. AB C 03:00 SAT 04:00 11/11/06 05:00 SAT CFM V EEG V –40 40 05 10 25 50 100 0 Fig. 80.3 Seizures and response to anticonvulsants. Point A: phenobarbitone was given followed by a second dose at point B resulting in termination of seizures. Seizure activity is seen again at point C.

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Neonatology at a Glance Third Edition. Edited by Tom Lissauer Avroy A. Fanaroff Lawrence Miall and Jonathan Fanaroff. © 2016 John Wiley Sons Ltd. Published 2016 by John Wiley Sons Ltd. 190 Practical procedures The human brain follows a highly programmed sequence of organi- zation and maturation which begins in the first few weeks of fetal life and continues to young adulthood. Neuroimaging provides detailed characterization of brain development and can provide accu- rate biomarkers with which to quantitatively study particular clinical states and therapies. Magnetic resonance imaging MRI is ideal as images with high spatial resolution can be acquired without ionizing radiation even in the fetus and extremely preterm infant. MRI brain scans are increasingly used in neonatology as MRI has high sensitivity for detecting adverse neurologic outcome particularly cerebral palsy. Early in human gestation the brain is relatively lissencephalic smooth surface with subsequent gyrification following a clearly defined sequence starting with the large interhemispheric fissure 10–15 weeks post-menstrual age PMA and sylvian fissure 14–19 weeks PMA. The secondary and tertiary sulci such as the central sulcus which separates the primary motor and somatosen- sory cortices are not visible until approximately 20 weeks PMA when neuronal migration from the ventricular zone is completed. As the brain matures through the third trimester Fig. 81.1 there is an exponential increase in surface area through the formation of gyri and sulci compared with a slower linear increase in whole brain volume deviation from this relationship in preterm infants predicts adverse cognitive outcome later in childhood. In addition to developmental changes in the structure of the brain marked maturational changes in the contrast of specific tissues can be visualized particularly in the periventricular white matter Fig. 81.2. They represent underlying changes in tissue composition and water content. Functional mapping of the brain Diffusion MRI can be used to delineate axon fiber bundles accu- rately and thus provide a detailed map of the structural ‘connec- tivity’ of the neonatal brain Fig. 81.3. Functional MRI fMRI can provide information about the brain’s activity through rapidly sampling changes in the localized MR signal that result from dif- ferences in the magnetic properties of hemoglobin when bound to oxygen Fig. 81.4. Through the combination of such techniques it may be possible to characterize accurately a detailed ‘connectome’ of the neonatal brain in which all of the structural and functional connections of the developing brain are mapped. Practical and safety considerations There are drawbacks to MRI scanning: •  it is expensive •  long time required to acquire good-quality images minimum 20 minutes with head kept still some infants can be ‘fed and wrapped’ but others need general anaesthesia Perinatal neuroimaging 81 29 weeks PMA 25 weeks PMA 34 weeks PMA 37 weeks PMATerm 40 weeks PMA 32 weeks PMA Fig. 81.1 Three-dimensional rendered T2-weighted images in preterm infants at different gestation showing the dramatic evolution of cortical folding up to term. PMA – post-menstrual age. T2–weighted MRI T1–weighted MRI 27 weeks PMA 34 weeks PMA 40 weeks PMA 52 weeks PMA 2 years old adult Fig. 81.2 Tissue-specific changes during brain maturation. Early in the third trimester myelin is not seen in the periventricular white matter and concentric ‘bands’ of tissue can be seen including migrating cells and an important structure called the subplate which acts as a ‘waiting area’ for branching axons white arrow. Myelination is not clearly seen until term 40 weeks PMA first in the posterior limb of the internal capsule PLIC yellow arrow proceeding in a caudal to cephalic direction with the frontal white matter the last to myelinate. Myelination continues through to young adulthood when it can be seen throughout the white matter.

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Perinatal neuroimaging 191 •  possible distress from transfer and being inside scanner •  metal-containing objects/implants are contraindicated in the MRI scanner due to the powerful magnetic field. There are only a handful of neonatal units worldwide with dedi- cated MRI facilities but standard MRI scanners can increasingly produce faster and motion-tolerant image acquisition sequences and MR-compatible equipment e.g. incubators is now available. Prognostic information Cranial ultrasound and MRI have similar high specificity for pre- dicting later cerebral palsy a normal cranial ultrasound allows confident prediction of normal motor outcome. Therefore although MRI scanning has a clear role in particular infants where accurate delineation of a pathologic lesion can provide diagnostic and prog- nostic information such as HIE and stroke in standard neonatal care it is complementary to cranial ultrasound. However MRI is providing important information about early brain development and the pathophysiology of neonatal brain injury and potentially the evaluation of the effectiveness of new therapies. Fig. 81.3 Diffusion MRI can be used to delineate axon fiber bundles accurately and thus provide a detailed map of the structural ‘connectivity’ of the neonatal brain. In this example the brain of an infant at term is shown in the coronal plane with the delineated connections shown by color for their directionality those running superior–inferior or vice versa in blue those left–right in red and those anterior–posterior or vice versa in green. Reproduced and adapted with permission from Pandit A.S. et al. Diffusion magnetic resonance imaging in preterm brain injury. Neuroradiology 2013 5S Suppl 2: 65–95. RL RL RL RL Stimulation of the right hand Stimulation of the right hand Fig. 81.4 MRI can accurately characterize patterns of functional and structural connectivity in the neonatal brain and allows visualization of neuroplasticity following brain injury as demonstrated in these two infants born prematurely and scanned at term equivalent PMA. Top row: following passive motor stimulation of the right hand in a normal infant fMRI has identified a cluster of functional brain activity red/yellow in the contralateral left hemisphere which is structurally connected to the thalamus via a nerve fiber bundle top right yellow that has been delineated with diffusion MRI. Bottom row: this infant has a large right-sided porencephalic cyst following grade IV intraventricular hemorrhage. Following stimulation of the right hand the induced functional activity has been displaced posteriorly by the cyst while the structural connections have similarly grown to circumvent the damaged area. Key point MRI neuroimaging provides: •  high resolution images for detecting brain injury •  prognostic information following HIE

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Neonatology at a Glance Third Edition. Edited by Tom Lissauer Avroy A. Fanaroff Lawrence Miall and Jonathan Fanaroff. © 2016 John Wiley Sons Ltd. Published 2016 by John Wiley Sons Ltd. 192 Practical procedures Targeted neonatal echocardiography functional echocardiography provides physiologic information in real time in order to support clinical decision-making. It enhances clinical judgment provides a better understanding of active physiologic processes and allows monitoring the response to treatment. It enables one to: •  assess the hemodynamic impact of a PDA Chapter 33 •  assess cardiac function in hypotensive neonates to determine the need and efficacy of inotropes and volume support •  identify the position of umbilical and central venous lines •  exclude major cardiac defects •  identify pulmonary hypertension PPHN its severity and impact on right ventricular performance and cardiac output •  exclude pericardial effusion. It may be performed by a pediatric cardiologist or trained neo- natologist working in close collaboration with a pediatric cardiac center. However echocardiography of complex congenital heart disease is the responsibility of the pediatric cardiologist. Views see videos The standard views Figs 82.1 and 82.2 are: •  four- and five-chamber views from the apex •  parasternal short-axis view •  parasternal long-axis view •  subcostal view. High-quality images must be obtained. Four‐chamber view •  Confirms Fig. 82.3a and b that: – there are four chambers and allows evaluation of their size – there are normal mitral and tricuspid valves and that tricuspid is offset i.e. nearer the apex – ventricular septum is intact. •  Quantifies the degree of tricuspid regurgitation – useful for estimating pulmonary artery pressure. •  Detection of thrombi or vegetations in the atria or valves. If the probe is angled more anterior to the four-chamber view the five-chamber view is obtained which allows direct visualiza- tion of the left ventricular outflow tract. This allows indirect measurement of left ventricular output. Short‐axis view This view Fig. 82.4a and b allows the identification of: •  patent ductus arteriosus and flow direction •  perimembranous ventricular septal defect VSD •  PPHN persistent pulmonary hypertension of the newborn Echocardiography for the neonatologist 82 Echocardiography Parasternal short-axis view Apical four-chamber view Subcostal four-chamber view Parasternal long-axis view Fig. 82.1 Positions of probe and views obtained. Ao Views: LV RV RA PA Short axis plane Long axis plane Four chamber plane Fig. 82.2 The planes of the long-axis short-axis and four-chamber apical or subcostal views. The five-chamber view is obtained by aiming the probe anterior to the subcostal view to visualize the left ventricular outflow tract. RA RV LA LV TV Tricuspid valve IVS Interventricular septum IAS Interatrial septum MV Mitral valve Moderator band RA LA RV LV Tricuspid valve Mitral valve a b Right atrium Right ventricle Left atrium Left ventricle Fig. 82.3 a Four-chamber view. The right ventricle can be identified from a band of tissue the moderator band. b Ultrasound showing four-chamber view.

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Echocardiography for the neonatologist 193 •  usual arrangement of pulmonary artery and aorta •  structural defects e.g. transposition of the great arteries pulmonary stenosis. Long‐axis view This view Fig. 82.5 is used to: •  identify correct position of pulmonary artery and aorta •  assess myocardial performance using shortening fraction. •  detect structural defects e.g. tetralogy of Fallot •  assess volume overload in a patent ductus arteriosus left atrial: aortic root ratio. Subcostal view This view Fig 82.6 is used to: •  assess shunting at atrial level •  check liver on right and aorta on left side i.e. situs solitus •  obtain high-quality images if other views are affected by lung hyperinflation or high-frequency oscillation HFOV •  check position of central lines in inferior vena cava or aorta. Assessment of left ventricular function in critically ill neonates Targeted neonatal echocardiography can determine if there is poor myocardial performance or volume depletion better than clinical examination alone by: •  Subjective assessment of myocardial performance from the variation in left ventricle size. •  Estimation of systolic function from the left ventricular short- ening fraction. •  Intravascular volume estimation from inferior vena caval filling – it is collapsed with hypovolemia however assessment of cardiac volume loading is particularly difficult in the first few days of life when the transitional circulation is present. • Calculating left ventricular output – to determine whether impaired systolic performance hypovolemia or increased left ven- tricular afterload is leading to compromised systemic blood flow. Assessment of PPHN Echocardiography allows the diagnosis of increased pulmonary artery pressure and its impact on right and left ventricular performance. Right ventricular systolic pressure may be estimated if tricuspid regurgitation is present. A flat interventricular septum or one that bows into the left ventricle indicates elevated pulmonary pressures. The magnitude of the pulmonary hyperten- sion may also be estimated from the direction of blood flow across the ductus arteriosus: •  pure right-to-left from pulmonary artery to aorta flow implies suprasystemic pulmonary artery pressure Chapter 33 •  bidirectional ductal flow right-to-left during systole and left- to-right during diastole implies that pulmonary artery pressure approximates systemic arterial pressures •  left-to-right transductal flow implies pulmonary artery pressure less than systemic arterial pressure. Calculation of right and left ventricular output allows rational use of therapies such as nitric oxide and milrinone. RA LA RV MPA Aortic valve Pulmonary valve PDA RPA LPA a b Fig. 82.4 a Short-axis view. b Ultrasound of short-axis view. RA Right atrium RV Right ventricle LA Left atrium PDA Patent ductus arteriosus MPA Main pulmonary artery RPA Right pulmonary artery LPA Left pulmonary artery. Fig. 82.5 Ultrasound showing long-axis view. RV Right ventricle LA Left atrium LV Left ventricle AoV Aortic valve MV Mitral valve IVS Interventricular septum Fig. 82.6 Ultrasound showing subcostal atrial view.

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Neonatology at a Glance Third Edition. Edited by Tom Lissauer Avroy A. Fanaroff Lawrence Miall and Jonathan Fanaroff. © 2016 John Wiley Sons Ltd. Published 2016 by John Wiley Sons Ltd. 194 Practical procedures Gestational age assessment: Ballard exam The most accurate gestational age estimate is usually by first tri- mester ultrasound. Gestational age can also be assessed clinically ±2 weeks from the changes in neuromuscular and physical maturity with gestation. The most widely used scoring systems are the revised Dubowitz and the somewhat shorter new Ballard score shown in Fig. 83.1 and Table 83.1. Calculating an estimated gestational age The exam is most accurate when performed between 30 and 42 hours of life. Add up the individual neuromuscular and physical maturity scores for the 12 categories then obtain the estimated gestational age from Table 83.2. The neuromuscular maturity score may be unreliable if the infant is sedated or ill. Gestational age assessment BP severity of illness scores jaundice treatment chart 83 Table 83.1 Physical maturity scores. Sign −1 0 1 2 3 4 5 Skin Sticky friable transparent Gelatinous red translucent Smooth pink visible veins Superficial peeling and/or rash few veins Cracking pale areas rare veins Parchment deep cracking no vessels Leathery cracked wrinkled Lanugo None Sparse Abundant Thinning Bald areas Mostly bald Plantar creases Heel-toe 40–50 mm −1 40 mm −2 Heel–toe 50 mm no creases Faint red marks Anterior transverse crease only Creases over anterior 2/3 Creases over entire sole Breast Imperceptible Barely perceptible Flat areola no bud Stippled areola bud 1–2 mm Raised areola bud 3–4 mm Full areola bud 5–10 mm Eye and ear Lids fused loosely −1 tightly −2 Lids open pinna flat stays folded Slightly curved pinna soft with slow recoil Well-curved pinna soft but ready recoil Formed and firm with instant recoil Thick cartilage ear stiff Genitalia male Scrotum flat smooth Scrotum empty faint rugae Testes in upper canal rare rugae Testes descending few rugae Testes down good rugae Testes pendulous deep rugae Genitalia female Clitoris prominent labia flat Prominent clitoris small labia minora Prominent clitoris enlarging minora Majora and minora equally prominent Majora large minora small Majora cover clitoris and minora Posture Square window Arm recoil Popliteal angle Scarf sign Heel to ear 12 –1 03 4 60 45 90 90 30 0 140–180 110–140 180 90–110 90 140 120 180 160 100 90 90 5 Fig. 83.1 Neuromuscular maturity. Table 83.2 Gestational age estimated from summed neuromuscular and physical maturity scores. Total score Gestational age weeks −10 20 −5 22 0 24 5 26 10 28 15 30 20 32 25 34 30 36 35 38 40 40 45 42 50 44

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Gestational age assessment BP severity of illness scores jaundice treatment chart 195 Blood pressure charts Fig. 83.2 There is no consensus either on the definition of hypotension or on when low blood pressure should be corrected. Blood pressure spontaneously increases in preterm infants during the first 24 hours. Infants hypotensive by gestational age criteria but with clinical evidence of good perfusion have as good an outcome as normotensive patients. When there is severe hypotension or it is associated with poor perfusion treatment includes fluid bolus inotropes and corticosteroids in a stepwise approach see Chapter 24 Stabilizing the sick newborn infant. Functional echo- cardiography can provide information on cardiac contractility and intravascular volume see Chapter 82 Echocardiography for the neonatologist. Severity of illness scores Scores have been devised in order to be able to compare and pre- dict morbidity and mortality while allowing for severity of illness. They incorporate measures of physiologic instability in the first 12 postnatal hours. Clinically these scoring systems are not help- ful to guide care decisions for individual patients but provide a method to compare outcomes between various centers and countries. The most widely used in neonatology are: •  SNAP-PE II score •  CRIB II score. The SNAP-PE II Score Neonatal Acute Physiology Perinatal Extension is based on the physiologic derangement in a number of organ systems urine output mean blood pressure worst PaO 2 / FiO 2 ratio lowest serum pH occurrence of seizures in the first 12 hours after admission to the NICU birthweight Apgar score at 5 minutes and whether there is IUGR. The CRIB II Clinical Risk Index for Babies score is for very low birthweight VLBW infants and is based on birthweight gestation maximal base excess in the first 12 hours of life and temperature on admission. The use of the SNAP-PE is limited by the complexity of the data required and the CRIB score by the overwhelming effects of birth- weight and gestational age on outcome. Jaundice treatment chart The recommended bilirubin levels for treatment with phototherapy and exchange transfusion in the UK for infants ≥ 38 weeks gestation are shown in Fig 83.3. Charts at earlier gestational ages are publishes in NICE guidelines. ≤ 28 weeks 29–32 weeks 33–36 weeks ≥37 weeks 80 75 70 65 60 55 50 45 40 01 23 45 67 30.0 Systolic BP mmHg a Postnatal days 60 55 50 45 40 35 30 01 23 45 67 30.0 Mean BP mmHg b Postnatal days Fig. 83.2 Increase in a systolic and b mean blood pressure measured oscillometrically in hemodynamically stable infants during the first month of life. Source: Pejovic B. et al. Blood pressure in non-critically ill preterm and full-term neonates. Pediatr Nephrol 2007 22: 249–257. 0 0 50 100 150 200 250 300 Total serum bilirubin micromol/litre Total serum bilirubin mg/dL 350 400 450 500 550 0 2.9 5.8 8.7 11.6 14.6 17.5 20.5 23.4 26.3 29.2 1234 56 7 Days Exchange transfusion Phototherapy Fig. 83.3 Treatment thresholds for hyperbilirubinemia in infants ≥ 38 weeks in the UK. NICE Clinical Guideline 2010.

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Neonatology at a Glance Third Edition. Edited by Tom Lissauer Avroy A. Fanaroff Lawrence Miall and Jonathan Fanaroff. © 2016 John Wiley Sons Ltd. Published 2016 by John Wiley Sons Ltd. 196 Index figures are in italics tables/boxes are in bold abdominal injuries 39 abdominal masses 112 abdominal wall defects omphalocele 7 112 gastroschisis 112 abnormalities congenital birth defects/genetic disorders 18 multiple births 14 routine examination of newborn infants 43 43 abnormalities fetal perinatal medicine 7 prenatal identification 47 abnormalities minor in first few days breast enlargement 50 description 50 ear tags 51 extra digits 51 natal teeth 51 talipes positional 50 see also skin lesions ABO incompatability 97 abstinence syndrome 20 achondroplasia 145 adaptation to extrauterine life abnormal transition from fetal to extrauterine life 26–7 26 Apgar score 27 27 asphyxia 27 27 circulation at birth 26 acute kidney injury 124 acute renal failure 124 admission to neonatal unit family–friendly environment 54 55 55 56 57 ‘kangaroo care’ 55 56 mother gavage tube 55 aEEG see amplitude‐integrated electroencephalopathy age assessment gestational 194 air leaks 71 alcohol maternal 20 ambiguous genitalia 128 amniocentesis 9 amplitude‐integrated electroencephalography aEEG artifacts 189 cerebral function monitor 188 classification 188 HIE 36 37 189 seizure detection 36 37 189 189 anemia causes/investigations 130 clinical features/management 130–1 131 preterm 80 81 blood transfusions 81 oral folic acid 81 oral iron therapy 81 anencephaly 140 anticonvulsants maternal 21 antithyroid drugs maternal 21 anus imperforate 113 aorta coarctation 117 119 119 Apgar score 27 27 apnea bradycardia and desaturations 82 arterial catheters 155 156 179 180 181 arthritis septic 145 145 aspiration of milk 93 aspiration pneumonia 157 aspirin congenital anomalies 21 asphyxia see also HIE 27 Assessment of Preterm Infant Behaviour APIB 57 asymmetric crying faces 39 atresia biliary 97 99 choanal 95 95 duodenal 114 115 115 esophageal 112 112 atrioventricular septal defect ASVD 116 117 attachment maternal 46 54 audiology see hearing audit 152 152 153 autoimmune thrombocytopenic purpura AITP 11 automated auditory brainstem response AABR 146 147 autopsy 165 Baby Doe 161 bacterial infections see neonatal infection Ballard score 194 Barlow maneuver 42 Bayley Scales of Infant Development 3rd edition 168 169 Beckwith–Widermann syndrome 107 112 behavioral observation 56 56 57 behavioral problems 88 88 89 89 beta‐blockers congenital anomalies 21 biliary atresia 97 99 bilirubin jaundice 96–9 exchange transfusions 183 preterm 80 transcutaneous 41 birth defects see congenital anomalies birth injuries 38–9 38 38 39 births rate 4 birthweight and neonatal mortality 5 bladder tap 178 blisters sucking 50 blood loss from arterial catheters 155 blood pressure charts 195 195 blood spot biochemical screening 40 blood sampling 178 blood transfusions 81 81 blueberry muffin rash 23 bone and joint disorders congenital abnormalities of hip and feet 144 144 infection osteomyelitis and septic arthritis 145 145 skeletal dysplasias 145 BOOST/BOOST II trials oxygen saturation 159 159 brachial palsy 39 breast enlargement 50 breast milk composition 48 49 74 75 critical incidents 155 donor 74 drugs in 49 150 151 jaundice 97 breast‐feeding advantages for infant/mother 49 171 172 172 contraindications 49 drugs in breast milk 49 150 151 global 171 172 hypernatremia 123 jaundice 97 palliative and end‐of‐life care 164 sudden infant death syndrome 49 twins 49 75 bronchopulmonary dysplasia BPD chest X‐ray 87 clinical features 86 87 definition 86 discharge from hospital 88 166 incidence 67 86 bullous impetigo 103 103 burns and scalds 156 156 calcium balance 123 candida albicans 80 80 cannulation intraosseous 181 181 peripheral artery 155 156 156 179 179 peripheral venous 178 178 capillary blood sampling 178 178 caput 38 50 car seats 166 carbamazepine congenital anomalies 21 cardiac disorders – congenital heart disease 116–19 aorta coarctation 117 acyanotic 116 Index

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Index 197 atrioventricular septal defect 116 balloon atrial septostomy 118 classification 116 cyanosis 118 femoral pulses 43 heart failure 117 heart murmur 116–17 hyperoxia test 119 hypoplastic left heart syndrome 117 117 left ventricular outflow obstruction 117 oxygen saturation screening 118 prostaglandins 119 total anomalous pulmonary venous connection 118 transposition of great arteries 118 118 capillary blood sampling heelstick 178 cataract 147 147 catheters critical incidents 154–7 fetal shunts 9 9 central venous 182–3 chest tubes 177 177 peripheral arterial 154–7 156 179 179 central venous catheters 182–3 182 183 umbilical artery 155 180–1 umbilical vein 156 181 183 central venous catheters 182–3 182 183 cephalhematoma 38 50 cerebral function monitor CFM 188 189 cerebral palsy 88 88 89 cerebral sinovenous thrombosis CSVT 139 cerebrospinal fluid 101 chest needling 71 177 chest tubes chest tubes chest drain 71 176–7 177 needle thoractomy chest needling 71 177 pleural tap 71 177 chickenpox 25 25 chignon 38 chlamydia screening 8 Chlamydia trachomatis 103 103 choanal atresia 94 95 95 chorionic villous sampling 9 chorionicity 14 14 15 Christmas disease 135 chromosomal disorders trisomy 13 Patau syndrome 19 trisomy 18 Edwards syndrome 19 19 trisomy 21 Down syndrome 19 19 circumcision 40 127 clavicular fracture 39 cleft lip and palate 19 94 94 clinical ethics committees 160 clotting studies 134–5 coagulase‐negative staphylococcus CONS 80 coagulation disorders 134–5 134 134 135 coagulation pathway 134 coarctation of aorta 117 119 119 cocaine maternal 21 coloboma 147 147 common practical procedures capillary blood sampling heelstick 178 lumbar puncture 179 179 peripheral arterial cannulation 179 179 peripheral venous cannulation 178 178 suprapubic aspiration bladder tap 179 179 urinary catheter 179 venous blood sampling 178 178 communication with parents 47 congenital adrenal hyperplasia 129 129 congenital infection 22–5 22 blueberry muffin rash 23 cytomegalovirus 22 23–4 23 jaundice 97 parvovirus B19 25 rubella 24 syphilis 24–5 25 toxoplasmosis 24 24 varicella: chickenpox varicella zoster virus 25 congenital melanocytic nevus CMN 137 congenital myopathies 143 conjunctivitis 51 103 consent for autopsy 185 for research 162–3 162 continuous positive airway pressure CPAP apnea 82 bronchopulmonary dysplasia 87 endotracheal intubation 176 growth and nutrition 75 nasal damage 157 neonatal intensive care 2–3 Pierre Robin sequence 95 post resuscitation 33 respiratory distress syndrome 70 respiratory support 60–1 67 cooling studies meta‐analysis 158 study design 163 cord clamping 33 corticosteroids antenatal 16 69 70 postnatal 59 69 87 prophylactic meta‐analysis 159 cranial ultrasound 184–7 additional windows 187 187 standard views 184 185 cystic periventricular leukomalacia 187 echodensities 187 hemorrhagic parenchymal infarct 186 HIE 36 post‐hemorrhagic ventricular dilitation 186 intraventricular haemorrhage 185 186 porencephalic cyst 186 prognosis 187 191 ventricular index 186 CPAP see continuous positive airway pressure CRIB score 195 CRIES score pain scale 149 critical incidents aspiration pneumonia from misplaced gavage nasogastric feeding tubes 157 blood loss from arterial catheters 155 burns and scalds 156 156 excessive fluid volume infused 155 extravasation of intravenous infusions 154–5 154 extravasation of parenteral nutrition PN from central venous lines 156 infection 157 ischemic damage from peripheral artery catheters 156 156 reporting 153 medication errors 154 nasal damage from nasal CPAP 157 nasal damage from tracheal tube 156–7 portal vein thrombosis from umbilical venous catheters 156 cyanosis central 51 117–18 cyanosis traumatic 50 118 cyanosis peripheral 50 118 cyclooxygenase inhibitors 79 79 cystic fibrosis screening 8 40–1 cystic periventricular leukomalacia CVL 76 187 cytomegalovirus CMV congenital 22 23–24 23 isolation 24 hearing loss 146 intrauterine growth restriction 12 neutropenia 132 cytotoxic drugs in breast milk 151 death see palliative and end‐of‐life care definitions newborn infants 4 mortality rates 4 dermatological disorders 136–7 congenital melanocytic nevus 137 diaper nappy dermatitis 136 epidermolysis bullosa 137 genetic syndromes 137 giant congenital melanocytic nevus 137 port wine stain 137 pustular rash 136 strawberry nevus 137 desaturations 82 82 developmental care 56 57 adapting care 56–7 newborn behaviour 56 nursery environment 56 parent participation 56 56 developmental dysplasia of hip DDH 41 42 42 144 144 diabetes mellitus fetal problems 10 neonatal problems 10 diaper dermatitis 136 diaphragmatic hernia 9 92 93

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198 Index digits extra 50 disability 88 89 168 169 discharge from hospital bronchopulmonary dysplasia 166 gavage nasogastric feeding 166 oxygen therapy 166 transition from intensive care to home 166 when can babies go home 166 health promotion 167 immunizations 167 medications 167 ongoing/new medical problems 167 parent support group 167 potential medical problems 167 disorders of sex differentiation ambiguous genitalia 128 congenital adrenal hyperplasia 129 sex differentiation 128 128 disseminated intravascular coagulation DIC 111 135 dobutamine 59 donor human milk 74 dopamine 59 Doppler flow velocity waveforms fetal 10 13 patent ductus arteriosus 78 79 Down syndrome trisomy 21 chromosomal disorders 19 19 clinical features 19 19 115 116 nuchal translucency 8 polycythemia 131 screening prenatal 8 drugs in breast milk 49 150 151 151 duct dependent circulation 26 78 119 duodenal atresia 114–15 115 ear tags 50 echocardiography 192 193 left‐ventricular function 193 patent ductus arteriosus views 192–3 192 193 echodensity white matter 77 187 ECMO 7 65 Edwards syndrome trisomy 18 12 19 19 EEG HIE 36 37 Seizures 138 aEEG 188 189 effusion pleural 9 electrolyte imbalance 122 123 encephalocele 140 140 encephalopathy see hypoxic–ischemic encephalopathy endotracheal intubation 29 30 31 176 176 176 end‐of‐life care 164 EPICure studies 5 epidemiology definitions 4 infant mortality 5 maternal mortality 4–5 neonatal mortality 5 perinatal mortality 5 epidermolysis bullosa 137 epinephrine adrenaline 30 31 59 erythropoietin EPO 81 131 erythema toxicum 50 esophageal atresia 14 112 ethics 160 160 161 161 clinical ethics committees 160 withholding/withdrawal of life‐saving medical treatment 160–1 161 Every Newborn Action Plan global campaign 170 evaporative heat loss 72 73 evidence‐based medicine 158–9 158 159 harmful therapies 159 oxygen saturation in preterm infants 159 159 maternal prophylactic corticosteroids 159 moderate hypothermia for severe HIE 159 oxygen therapy in preterm infants 159 surfactant therapy in preterm infants 159 oxygen therapy causing blindness in preterm infants 159 excessive fluid volume infusion 155 exchange transfusion indications 183 183 jaundice 98 polycythemia 131 Rhesus haemolytic disease 2 technique 183 183 exomphalos omphalocele description 112–13 112 fetal 7 7 extracorporeal membrane oxygenation ECMO meconium aspiration 91 neonatal intensive care 3 7 PPHN 92 respiratory support 60 64 65 65 extravasation of intravenous infusions 154–5 154 extravasation of parenteral nutrition 156 extremely preterm infants EPICure studies 5 eyes conjunctivitis 51 prophylaxis 40 red reflex 43 43 facial palsy 39 factor IX deficiency 135 factor VIII deficiency 135 feeding formula 48 human milk/cow’s milk comparison 48 preterm 74–5 see also breast‐feeding fetal alcohol spectrum disorder FASD 20 fetal growth 8 fetal medicine 9 fetal surgery 9 fetomaternal haemorrhage 130 fluconazole 80 flucytosine 80 fluid intake 75 fluids excessive volume infused 155 folic acid 8 130 follow‐up 168 169 formula milk 48 74 fractures skull 38 clavicle 39 fresh frozen plasma FFP 135 fungal infection 80 G6PD deficiency 97 gastroesophageal reflux 111 gastrointestinal disorders 110–13 abdominal wall defects 112–13 112 113 esophageal atresia 112 112 gastroschisis 113 113 imperforate anus 113 omphalocele 7 112–13 vomiting 51 110–11 110 111 111 gastrointestinal obstruction 114–15 114 115 duodenal atresia 114–15 115 esophageal atresia 114 Hirschsprung disease 115 115 malrotation 115 meconium ileus 115 meconium plug syndrome 115 pyloric stenosis 114 gavage feeding 55 75 75 166 genetic disorders chromosomal disorders 19 genital disorders ambiguous genitalia 128 circumcision 127 embryology of testicular descent 126 hydrocele 126 127 hypospadias 127 127 inguinal hernia 126 126 gestational age assessment 8 194 194 gestational diabetes 10 glaucoma congenital 147 147 glucose‐6‐phosphate dehydrogenase deficiency 97 global neonatology 170–3 Every Newborn Action Plan 170 HIV infected mothers 171 ‘kangaroo care’ 172 173 Millenium Development Goals 170 newborn death 170–1 171 glutaric aciduria type 1 GA1 108 GMFCS Gross Motor Function Classification Systems 89 Golden Minute resuscitation 29 grief 164 Griffiths Mental Development Scales revised 168 169 group B streptococcal GBS

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Index 199 infection 102 102 screening 3 8 102 growth 74 harlequin color change 50 head circumference 43 44 heat loss 72 73 hearing automated auditory brainstem response AABR 146 hearing loss conductive/sensorineural 146 otoacoustic emissions 146 risk factors 146 screening 40 44 147 heart failure 90 92 117 117 119 patent ductus arteriosus 79 80 heart murmur 116 heart rate changes 58 heelstick 178 178 Helping Babies Breathe 173 hemangioma 137 137 haemophilia 135 hemorrhagic parenchymal infarct 76 77 187 hepatitis B HBV neonatal withdrawal abstinence syndrome 20 virus infection 104 hepatitis B immunoglobulin HBIG 105 hepatitis C 20 105 hereditary spherocytosis 97 herpes simplex virus HSV 103 congenital infection 22 dermatological infection 136 see also viral infections high‐flow nasal therapy HFNT/high‐flow nasal cannulae HFNC 60 61 67 high‐frequency oscillatory ventilation HFOV 60 64 high‐risk infants follow‐up components 168 developmental assessments 168 organization and timing 168 outcome measures 168 Hirschsprung disease 111 115 115 HIV Human Immunodeficiency Virus blood‐borne viruses 20 breast‐feeding 49 global neonatology 170 maternal 49 52 171 prenatal screening 8 viral infection 105 homocysteinuria HCU 108 human T‐cell leukaemia virus 1 HTLV 1 22 hydantoins congenital anomalies 21 hydrocele 126 127 hydrocephalus causes 141 clinical features 141 preterm infants 77 141 ultrasound 184–6 hydronephrosis 120 121 hyperammonemia 109 hyperbilirubinemia see jaundice hyperglycemia 106 hyperkalemia 123 hypernatremia breast‐feeding 123 renal/urinary tract disorders 123 hyperoxia test 119 hyperthyroidism maternal 11 hypocalcemia 123 hypoglycemia clinical features 106 107 hypokalemia 123 hyponatremia 122 123 hypophosphatemia 81 123 hypoplastic left heart syndrome 117 117 hypospadias 127 127 hypothermia 2 28 72 158 163 hypothyroidism maternal 11 hypotonic infants causes/clinical features 142 143 hypoxic–ischemic encephalopathy HIE aEEG 189 antepartum/intrapartum factors 34 clinical manifestations 34 35 35 clinical staging 36 36 critical incidents 154 EEG 37 hearing loss 146 hypothermia meta‐analysis 159 hypothermis study design 163 hypotonic infant 143 MRI 36 37 191 outcome 36–7 37 research 163 Sarnat staging 36 stress ulcer 111 ibuprofen 79 immunoglobulin intravenous IVIG 11 98 injuries birth 38 39 immunization 41 imperforate anus 113 inborn errors of metabolism 108 108 109 109 hyperammonemia 109 incubators 2 57 73 indomethacin 79 infection bacterial specific 102 103 bones and joints 145 clinical features 100 101 congenital 22–4 fungal 80 preterm 67 80 prevention 157 viral 104 105 171 see also specific organisms inguinal hernia 126 inotropes 59 INSURE intubation surfactant extubation 69 intermittent positive‐pressure ventilation 61 62 63 intraosseous cannulation 181 181 intrauterine growth restriction IUGR 12 12 13 13 associations 10 14–15 20 21 23 34 52 106 168 131 132 intravenous infusions extravasation of 164 intraventricular hemorrhage clinical features 67 76–7 diagnosis 76–7 185 186 187 intubation endotracheal intubation 176 endotracheal tube size 176 iodine radioactive in breast milk 151 iron supplements 74 131 isovaleric aciduria IV A 108 IVIG immunoglobulin 11 98 jaundice 96–9 causes 97 97 exchange transfusions 98 99 183 195 intravenous immunoglobulin IVIG 98 phototherapy 98 99 195 preterm 80 prolonged 14 days 99 Rhesus disease 10–11 97 treatment chart UK 195 ‘kangaroo care’ 55 56 172 173 kernicterus 2 96 kidney injury acute causes 124 125 clinical features 124 management 125 kidneys outflow obstruction bilateral hydrenephosis 9 121–2 121 unilateral hydrenephosis 120 121 Kleihauer test 130 large for gestational age LGA 12 12 106 left ventricular function 193 Listeria monocytogenes 8 102 lithium in breast milk 151 lumbar puncture 179 179 lung development 68 68 macrosomia 10 10 magnetic resonance imaging MRI choanal atresia 95 hypoxic–ischemic encephalopathy 36 37 191 perinatal neuroimaging 190–1 190 191 magnesium sulphate 17 malrotation 115 maple syrup urine disease MSUD 40 108 109

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200 Index maternal attachment 46 maternal drugs affecting fetus/newborn infant 20–1 alcohol 20 medicines 21 neonatal withdrawal abstinence syndrome 20–1 smoking 8 12 16 20 maternal medical conditions autoimmune thrombocytopenic maternal purpura 11 diabetes mellitus 10 hyper/hypothyroidism 11 red blood cell alloimmunization 10–11 11 maternal mortality 4 170 171 maternal red blood cell alloimmunization 10–11 11 97 Rhesus hemolytic disease 10 97 meconium aspiration 91 ileus 115 meconium plug syndrome 115 medication errors 154 medium chain acyl CoA dehydrogenase deficiency MCAD 108 melanocytic nevus 137 melanosis transient pustular 50 meningitis 101 102 103 meningocele 8 140 milestones in neonatology antibiotics 3 incubators 2 neonatal intensive care 3 nutrition 2 organisms causing infections 2 respiratory distress syndrome 3 Rhesus hemolytic disease 2–3 Tarnier incubator 2 thermal regulation 2 milia 50 miliaria 50 milk aspiration 93 breast 85 see also nutrition Millenium Development Goals 170 milrinone 59 minimal enteral feeding 75 minor antigen incompatibility 10 11 97 Mongolian spots 50 mortality infant mortality 4 maternal mortality 4 neonatal 5 perinatal 5 preterm infants 67 67 MRI 37 190 191 multicystic dysplastic kidney MCKD 121 121 multiple births 14–15 14 15 chorionicity/zygosity 14 multivitamins 74 myasthenia gravis 143 myelocele 8 140 myelomeningocele 140 140 myotonic dystrophy 143 nasal damage 156 157 nasogastric gavage feeding 55 75 75 166 natal teeth 51 necrotizing enterocolitis NEC 84–5 clinical features 67 84 84 84 85 radiologic abnormalities 85 needle thoracotomy 177 neonatal care levels of 7 7 low income settings 172–3 Neonatal Facial Coding Scale NFCS 149 neonatal infection bacterial specific 102 103 bones and joints 145 clinical features 100 101 congenital 22–4 conjunctivitis 103 103 fungal 80 Gram‐negative 102 group B streptococcus 102 Listeria monocytogenes 102 preterm 67 80 prevention 157 skin 103 103 viral 104 105 171 see also specific organisms neonatal intensive care development 3 neonatal intensive care levels 7 7 neonatal intensive care unit NICU admission 47 critical incidents 154 family communication 54 parents 47 153 neonatal mortality rate NMR 4 170 neonatal mortality 4 4 170–1 170 171 and birthweight 5 causes 171 171 global burden 170 prevention 172 172 172 timing 171 neonatal resuscitation 28–33 airway 28–33 breathing 28–33 circulation 30–3 drugs 30 30 31–3 ethical decisions 30 intubation 28–33 176 176 warmth/stimulation 28 neonatal unit admission to 54–5 neonatal withdrawal syndrome 20–1 neonatal myasthenia gravis 143 Neonatal Pain Agitation and Sedation Scale NPASS 149 nerve palsy brachial and Erb 39 networks neonatal 7 neural tube defects NTDs anencephaly 140 aqueductal stenosis 141 encephalocele 140 140 fetal surgery 9 meningocele 140 myelocele fetal 8 myelomeningocele 140–1 1 prevalence 140 spina bifida 140–1 140 spina bifida occulta 43 140 neurologic examination 44–5 neutral thermal environment 73 neutropenia 133 neutrophilia 133 133 nevus flammeus stork bites 51 51 Newborn Behavioral Assessment Scale NBAS 57 Newborn Behavioral Observation NBO 57 Newborn Individualized Developmental Care and Assessment Program NIDCAP 57 Newborn Physical Examination NIPE checklist in UK 43 NIDCAP 57 nitric oxide inhaled iNO 60 64 64 67 non‐invasive mechanical ventilation NIMV 60 61 non‐invasive prenatal testing NPIT 3 8 9 norepinephrine 59 NSAIDs congenital anomalies 21 nuchal translucency 8 nutrition 48–9 74–5 neonatology milestones 2 milk composition 48–9 74–5 supplements 74 oligohydramnios 8 121 121 omphalocele exomphalos description 112–13 112 fetal 7 7 opiate withdrawal 20 opisthotonus from kernicterus jaundice 96 organ donation 165 Ortolani maneuver 42 osteogenesis imperfect 145 osteomyelitis 145 181 osteopenia of prematurity 81 81 otoacoustic emissions OAE 146 outcomes preterm infants 5 67 88 89 oxygen dissociation curve 130 oxygen saturation BOOST Trial 159 resuscitation 31 32 33 preterm infants 159 159 screening critical congenital heart disease 41 118 SUPPORT Trial 159 163

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Index 201 oxygen therapy BOOST and SUPPORT Trials 159 changes with time 159 outcomes in preterm infants 159 respiratory support 71 60–3 90 resuscitation 28–33 stabilizing sick newborns 58–9 oxygenation index OI 64–5 pain 148–9 assessment 148 149 heelsticks 149 milestones in neonatal pain 148 minimizing 149 palliative and end‐of‐life care autopsy 165 care after death 164 care plans 164 caring for staff 165 cold mattresses 165 memory boxes 164 organ donation 165 support for parents siblings and family 164 paracetamol 79 parenchymal infarct 186 parenteral nutrition PN 2 75 80 parents care and support for parents attachment maternal 46 communication 47 54 56 parvovirus B19 25 Patau syndrome trisomy 13 19 patent ductus arteriosus PDA chest X‐ray 78 79 clinical features 78 ductal closure 26 78 duct‐dependent circulation 117 118 119 echocardiography with pulsed color Doppler 79 79 fetal circulation 26 heart failure 118 indomethacin/ibuprofen 79 preterm infants 78 79 117 patient‐triggered ventilation PTV 64 Pavlik harness 144 perinatal arterial ischemic stroke PAIS 139 perinatal medicine 6–7 perinatal mortality rate PMR 4 perinatal neuroimaging brain maturation 190 MRI 190 191 neuroplasticity following brain injury 191 191 peripheral artery catheters ischemic damage 156 cannulation 179 179 peripherally inserted central catheters PICC lines 182–3 182 183 periventricular leucomalacia 67 76 187 persistent pulmonary hypertension of the newborn PPHN 64 65 91–3 118 193 pharmacology breast‐feeding mothers 151 drug licensing 151 drug monitoring 150 151 drug prescription and administration 150 drugs in breast milk 150 lessons from history 151 physiologic factors 150 phocomelia 21 phosphate balance 81 123 phenylketonuria PKU 108 109 phototherapy 96–9 195 Pierre Robin sequence 95 95 plantar responses 45 pleural tap 177 plethora 131 pneumatosis intestinalis 85 85 pneumonia 91 157 pneumothorax chest drains 177 respiratory distress 67 70 71 91 92 polycystic kidney disease autosomal dominant ADPKD 121 121 autosomal recessive ARPKD 121 121 polycythemia 131 Ponseti regimen 144 porencephalic cyst 77 186 187 188 port wine stain nevus flammeus 137 137 portal vein thrombosis 156 positive‐pressure ventilation PPV 61–2 posthemorrhagic ventricular dilatation 77 187 posterior urethral valves 9 121 124 potassium balance 123 Potter syndrome sequence 120 121 PPHN 64 65 91–3 118 193 Prader–Willi syndrome hypotonic infants 143 143 pre‐implantation genetic diagnosis 9 Premature Infant Pain Profile PIPP 148 149 prepregnancy care 8 prenatal screening 8 preterm delivery antenatal corticosteroids 17 causes 16 epidemiological risk factors 16 magnesium sulfate 17 multiple births 14 preterm premature rupture of membranes 17 prevention 17 tocolysis 17 preterm infants anemia 80 apnea 82 appearance and development 66 bronchopulmonary dysplasia 86 87 complications 67 growth and nutrition 74 75 infection 80 intraventricular haemorrhage and periventricular leukomalacia 67 76 77 185 186 187 jaundice 80 lung development 68 morbidity 67 mortality 4 5 67 necrotising enterocolitis 84 85 osteopenia of prematurity 80 outcome 4 5 88 89 patent ductus arteriosus 78 79 respiratory distress syndrome 70 71 retinopathy of prematurity 83 surfactant deficiency 69 temperature control 72–3 preterm premature rupture of membranes PPROM 17 prevention of Mother‐to‐Child Transmission PMCT 49 primary reflexes asymmetric tonic neck 45 45 Moro 45 45 palmer grasp 45 45 placing 45 45 plantar grasp 45 45 prolonged jaundice 97 99 prostaglandin synthase inhibitors 79 79 prostaglandin – congenital heart disease coarctation of aorta 119 119 pulmonary atresia 119 119 protein C deficiency 133 139 protein S deficiency 139 pulmonary atresia 119 119 pulmonary hemorrhage 71 pulmonary hypertension of newborn PPHN 64 65 92 118 193 pulmonary interstitial emphysema PIE 71 pustular melanosis transient 51 pyloric stenosis 114 quality assurance/improvement audit 152 152 critical incident reporting 153 153 PDSA cycle 153 radiant warmers 73 red blood cell isoimmunisation 10–11 97 red reflex 43 reflexes 45 45 45 renal agenesis 121 renal and urinary tract anomalies 120–1 multicystic dysplastic kidney MCDK 121 121 outflow obstruction 120–1 polycystic kidney disease 121 121 posterior urethral valves 121 Potter syndrome 121 renal agenesis 121 121 renal and urinary tract disorders acute kidney injury 124 renal function in newborn infants 122 urinary tract infections presentation 123–4

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202 Index renal and urinary tract disorders – electrolyte problems calcium and phosphate 123 hypokalemia 123 hyperkalemia 123 hyponatremia 122–3 hypernatremia 123 sodium 122–3 renal and urinary tract disorders – urinary tract infections UTI 123–4 renal scarring 124 VCUG imaging 124 research 162–3 ethical difficulties 162 practical difficulties 162 respiratory distress syndrome RDS 3 67 70–1 causes 70 chest X‐ray 71 clinical features 67 70–1 histology 70 history 3 respiratory distress in term infants 90–93 causes 90 91 91 clinical features 90 diaphragmatic hernia 92–3 93 heart failure 92 milk aspiration 93 persistent pulmonary hypertension of the newborn PPHN 92 92 pneumonia 91 pneumothorax 91 92 meconium aspiration 91 91 surfactant deficiency 92 transient tachypnea of newborn 90 91 respiratory failure 65 respiratory support 60–5 CPAP 61 extracorporeal membrane oxygenation 65 high‐flow nasal therapy/high‐flow nasal cannulae 60 61 high‐frequency oscillatory ventilation HFOV 60 64 64 65 inhaled nitric oxide 60 64 64 non‐invasive mechanical ventilation 61 oxygen therapy 60 60 positive‐pressure ventilation 60 61–2 PTV/SIMV 64 respiratory failure 64–5 supplemental oxygen therapy 60–1 ventilators 62–4 63 resuscitation 28–32 A – airway 28–9 31 B – breathing 29 29 31 C – circulation 30 30 cardiac compression 31 cord clamping 28 drugs 30 30 31 endotracheal intubation 29–30 facemask ventilation 29 meconium‐stained liquor 31 preparation 28 temperature control 28 UK/Europe guidelines 31 United States guidelines 32 withholding/discontinuation 32 retinopathy of prematurity ROP description 67 82–3 83 international classification 83 screening 83 treatment 83 zones of retina 83 Rhesus hemolytic disease 10–11 11 97 history 2–3 rocker‐bottom feet 19 routine care of newborn infants audiology 41 breast‐feeding 40 circumcision 40 discharge 41 emotions 40 eye prophylaxis 40 health promotion 41 immunizations 41 transcutaneous bilirubin 41 umbilical cord care 40 vitamin K 40 see also screening routine examination of newborn infants 42–3 development dysplasia of hip 42 42 red reflex 43 RSV respiratory syncytial virus 87 88 rubella 12 23 24 136 146 Sarnat staging 37 screening – neonatal audiology 41 146 biochemical 40 group B streptococcal screening 102 102 hematocrit for polycythemia 41 131 pulse oximetry 41 116 red reflex 43 retinopathy of prematurity 83 routine examination 42–3 transcutaneous bilirubin 41 98–9 DDH 41 42 screening – prenatal chlamydia 8 cystic fibrosis 8 group B streptococcal screening 8 maternal blood 8 ultrasound 8–9 scarring of skin 156 seizures 138 138 139 139 HIE 37 Seldinger technique 177 septic arthritis 145 sex differentiation 128 128 129 severity of illness scores 195 shock 59 simulation 152 skeletal dysplasias 145 145 skin development 136 diaper dermatitis 136 erythema toxicum 51 51 genetic syndromes 139 harlequin color change 51 infections 103 103 milia 51 miliaria 51 Mongolian spots 51 51 nevus flammeus 51 51 preterm 66 72–3 136 sucking blisters 51 transient pustular melanposis 51 vascular lesions 137 137 skull fractures 38 38 small for gestational age SGA 12 12 smoking maternal 8 12 16 SNAP‐PE II score 195 sodium balance 122–3 sodium bicarbonate in resuscitation 30 special educational needs SEN 17 88‐89 spherocytosis hereditary 97 spina bifida 41 140 141 spinal cord injuries 39 spinal muscular atrophy type 1 Werdnig–Hoffman syndrome 143 staphylococcal scalded skin syndrome SSSS 103 136 Staphylococcus aurueus 103 145 stork bites 50 strawberry nevus hemangioma 137 strokes perinatal 139 139 Sturge‐Weber syndrome 137 subaponeurotic hemorrhage 38 subgaleal hemorrhage 38 sucking blisters 51 sudden infant death syndrome SIDS breast‐feeding 49 health promotion 41 SUPPORT trial oxygen saturation 159 163 suprapubic aspirate 178 supraventricular tachycardia SVT 7 117 surfactant deficiency 69 92 physiology/composition 68 68 therapy 33 67 69 70 syphilis 8 24–5 25 talipes equinovarus 8 144 144 talipes positional 50 50 Tarnier incubator 2 temperature control 28 72–3 cooling therapeutic see HIE evaporative heat loss 72 neutral thermal environment 73 transepidermal water loss 73 teeth natal 50

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Index 203 teratogens 20–1 testis 126–7 tetracycline in breast milk 151 congenital anomalies 21 thalidomide 21 21 thermal regulation 2 28 72 73 thrombocytopenia 134 134 134 perinatal alloimmune 11 thrombophilia 133 133 thrombotic disorders thrombophilia 133 thrombosis/emboli/vasoconstriction 155 TORCH toxoplasmosis other rubella cytomegalovirus herpes screening 24 torsion of the testis 127 total anomalous venous connection TAPVC 118 toxoplasmosis 8 12 22 24 tracheal intubation 29–32 156–7 176 tracheal stenosis 157 tracheoesophageal fistula 112 transepidermal water loss 72 73 transient tachypnea of newborn TTNB 90–1 transfusion blood 80 transport of sick newborn infants 174–5 174 175 aeromedical considerations 175 175 management of infant 174–5 transposition of the great arteries 118 118 trisomy 13 see Patau syndrome trisomy 18 see Edwards syndrome trisomy 21 see Down syndrome twins breast‐feeding 49 75 conjoined 15 multiple births 14 15 twin–twin transfusion syndrome TTTS 14 ultrasound abdominal masses 114 abdominal obstruction 114 bone and joint infection 145 cardiac 116 116 118 192–3 cranial 76 77 184–7 developmental dysplasia of hips 41 echocardiography 116 116 118 192–3 fetal abnormalities 7 8 52 gastroschisis 113 113 kidneys 80 120 myelocele 9 nuchal translucency/trisomy 21 Down syndrome 9 omphalocele 7 osteomyelitis 145 posterior urethral valves 121 renal/urinary tract abnormalities 120 120 121 121 124 124 125 stroke 133 suprapubic aspiration 179 talipes equinovarus 9 testis 127 umbilical artery catheters UACs blood loss 155 complications 155 description 180–1 181 formula for line length 180 incorrect vessel 155 position 180 thrombosis/emboli/vasoconstriction 155 umbilical cord arteries/veins 180 artery Doppler velocity 12 care 40 clamping 28 Doppler waveforms 13 exchange transfusions 183 umbilical hernia 50 umbilical vein catheters 58 180 181 undescended testis 127 upper airway disorders choanal atresia 94–5 cleft lip and palate 94 94 Pierre Robin sequence 95 95 urinary catheter 178 urinary tract anomalilies 9 120–1 urinary tract infection 124–5 urine delay in voiding 53 uteroplacental failure 13 vaginal discharge 50 valproic acid congenital anomalies 21 varicella chickenpox varicella zoster virus VZV in pregnancy 25 25 vascular endothelial growth factor VEGF 82 VCUG voiding cystourethrogram micturating cytstourethrogram 121 124 124 vein umbilical catheter 181 181 venous blood sampling 178 178 venous cannulation peripheral 178 178 ventilation artificial see respiratory support ventricular dilatation 77 184 185 186 187 ventricular index 186 ventricular septal defect 116 117 vernix 50 video‐assisted thoracoscopic surgery VATS 79 viral infections hepatitis B 104 104 105 hepatitis C 105 herpes simplex virus 104 HIV 8 20 49 52 105 105 170–1 virilisation 128 129 129 vision cataracts 147 147 chorioretinitis see congenital infection congenital abnormalities 147 coloboma 147 conjunctivitis see bacterial infections glaucoma 147 14 red eye reflex 43 retinopathy of prematurity 67 82–3 83 visual impairment/blindness 147 vitamin K 40 74 135 volvulus 115 vomiting see gastrointestinal disorders V on Willebrand disease 135 Werdnig–Hoffman syndrome spinal muscular dystrophy 143 withholding or withdrawal of life‐saving treatment 160 161 withdrawal abstinence syndrome 20

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