Neonatology

Giuseppe Buonocore Rodolfo Bracci Michael Weindling Editors

Neonatology A Practical Approach to Neonatal Diseases Second Edition

Neonatology

Giuseppe Buonocore • Rodolfo Bracci Michael Weindling Editors

Neonatology A Practical Approach to Neonatal Diseases Second Edition

With 568 Figures and 386 Tables

Editors Giuseppe Buonocore Department of Pediatrics Obstetrics and Reproductive Medicine University of Siena Siena, Italy

Rodolfo Bracci Department of Pediatrics Obstetrics and Reproductive Medicine University of Siena Siena, Italy

Michael Weindling Liverpool Women’s Hospital Neonatal Unit Liverpool, UK

ISBN 978-3-319-29487-2 ISBN 978-3-319-29489-6 (eBook) ISBN 978-3-319-29488-9 (print and electronic bundle) https://doi.org/10.1007/978-3-319-29489-6 Library of Congress Control Number: 2018940273 1st edition: # Springer-Verlag Italia 2012 # Springer International Publishing AG, part of Springer Nature 2018 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, express or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Printed on acid-free paper This Springer imprint is published by the registered company Springer International Publishing AG part of Springer Nature. The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

Introduction

Neonatology is a science in rapid evolution. The speed of this evolution may cause some to doubt what a traditional textbook is able to achieve in bringing the most up-to-date developments to a reader’s attention. Although the interested reader will use other electronic means to access current information, this is not always possible. We firmly believe that, through their own experience, experts are able to bring their own perspective and interest to a subject and act as a guide to the interested and committed reader. We therefore believe that this textbook should act as a conduit of reliable information from the expert to the clinician. We have tried to make this textbook into a genuine guide to the best and most up-to-date answers for neonatologists who are striving to give the best and highest quality care to sick babies. All practicing clinicians work within their own culture and resources. Each has to make judgments about the best and most appropriate application of available resources to the care of their small sick patients. We hope that this textbook will support the dedicated clinician by providing the best evidence available in the various sub-specialisms of neonatology, particularly when the issue of best treatment continues to be debated. The reader who needs rapid and comprehensive information about a topic requires that the information provided should be synthetized intelligently, exhaustively, and clearly. Subjects should be updated as much as possible. We have endeavored to meet these requirements. We think that the aim of a modern textbook should be to describe the present state of the science, suggesting ways in which this might be improved, and to provide a sound understanding of pathophysiology and diagnostic and therapeutic procedures. Our overall aim is to support and optimize the care of the newborn. In this way, our approach is “practical” and aims to assist neonatologists in their daily work. In this second edition, the text has been largely revised by experts who contributed to the previous volume. They have added new information, some of it through short- and long-term follow-up, to support the evidence that underpins good clinical practice. Some chapters are completely new. We are grateful to all the authors for their time and contributions. We would also like to thank Andrew Spencer, Tina Shelton, Vasowati Shome, and the publication team of Springer for their great efforts in publishing this book. We sincerely hope that this volume has built on the success of its predecessor and continues to support clinicians in a readily accessible and useful way. v

Contents

Volume 1 Part I 1

Epidemiology and Fetal Neonatal Medicine . . . . . . . . . . . Development and General Characteristics of Preterm and Term Newborn . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Domenico Arduini, Gaia Pasquali, Stefano Parmigiani, Daniela Gianotti, and Giulio Bevilacqua

1

3

2

Risk Factors for Gestational Diseases . . . . . . . . . . . . . . . . . . Silvia Vannuccini, Michela Torricelli, Filiberto Maria Severi, and Felice Petraglia

27

3

Epigenetic Mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Felicia M. Low and Peter D. Gluckman

41

4

Congenital Malformations and Syndromes: Early Diagnosis and Prognosis in Neonatal Medicine . . . . . . . . . . . Giovanni Corsello and Mario Giuffrè

49

5

Prenatal and Postnatal Inflammatory Mechanisms Kirsten Glaser and Christian P. Speer

.......

73

6

The Fetus at Risk: Chorioamnionitis . . . . . . . . . . . . . . . . . . . Mikko Hallman and Tuula Kaukola

95

7

Diagnosis of Fetal Distress . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105 Silvia Vannuccini, Caterina Bocchi, Filiberto Maria Severi, and Felice Petraglia

8

In Vitro Fertilization and Multiple Pregnancies . . . . . . . . . . 129 Maria Angela Rustico, Mariano Lanna, and Enrico Ferrazzi

9

Intrauterine Growth Restriction: Obstetric and Neonatal Aspects. Intervention Strategies . . . . . . . . . . . . . . . . . . . . . . . 147 Enrico Bertino, Giovanna Oggè, Paola Di Nicola, Francesca Giuliani, Alessandra Coscia, and Tullia Todros vii

viii

Contents

10

Late Preterm Infants at Risk for Short-Term and Long-Term Morbidity and Mortality . . . . . . . . . . . . . . . . . . . 171 Avroy A. Fanaroff

11

Ethical Problems in Neonatal Medicine . . . . . . . . . . . . . . . . . 183 Otwin Linderkamp

12

Care of Extremely Low-Birth-Weight Infants and Timing of Discharge. Information and Psychosocial Intervention in Neonatology . . . . . . . . . . . . . . . . . . . . . . . . . . 203 Fabio A. Mosca, Monica Fumagalli, Maria Elena Bolis, and Massimo Agosti

13

The Process of Decision-Making in Neonatology . . . . . . . . . . 219 Endla K. Anday and Michael Spear

14

Follow-Up Outcomes of High-Risk Infants . . . . . . . . . . . . . . 229 Neil Marlow

15

Early Markers of Poor Outcome in Neonatal Medicine . . . . 237 Fabrizio Ferrari, Licia Lugli, Elisabetta Garetti, Isotta Guidotti, Marisa Pugliese, and Laura Lucaccioni

16

Quality of Neonatal Intensive Care and Outcome for High-Risk Newborn Infants . . . . . . . . . . . . . . . . . . . . . . . 251 Liz McKechnie and Kathryn Johnson

17

Cerebral Plasticity and Functional Reorganization in Children with Congenital Brain Lesions . . . . . . . . . . . . . . . . 265 Viviana Marchi, Andrea Guzzetta, and Giovanni Cioni

Part II

Perinatal and Neonatal Care . . . . . . . . . . . . . . . . . . . . . . . . .

277

18

Organization of Perinatal Care: Training of Doctors and Nurses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 279 Neil Marlow

19

Neonatal Transport Services . . . . . . . . . . . . . . . . . . . . . . . . . . 291 Rocco Agostino, Roberto Aufieri, and Maurizio Gente

20

Risk Management of Newborns . . . . . . . . . . . . . . . . . . . . . . . 305 Isabelle Ligi and Sophie Tardieu

21

Guidelines and Protocols for Newborns . . . . . . . . . . . . . . . . . 315 Rinaldo Zanini and Roberto Bellù

22

Physical Environment for Newborns: The Thermal Environment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 323 Daniele Trevisanuto and Gunnar Sedin

23

Neonatology and the Law . . . . . . . . . . . . . . . . . . . . . . . . . . . . 347 Vittorio Fineschi, Francesca Maglietta, and Emanuela Turillazzi

Contents

ix

24

Environment and Early Developmental Care for Newborns . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 357 Dominique Haumont

25

Neonatal Pain: Neurophysiology, Recognition, Prevention, and Management with Nonpharmacological Interventions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 365 Carlo Bellieni, Celeste Johnston, Marsha Campbell-Yeo, Britney Benoit, and Timothy Disher

26

Neonatal Anesthesia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 383 Nicola Disma, Leila Mameli, Rachele Bonfiglio, Clelia Zanaboni, and Pietro Tuo

27

Neonatal Care in the Delivery Room: Initial Management and Approach to Low Risk Newborns . . . . . . . . . . . . . . . . . . 395 Tara M. Randis and Jennifer M. Duchon

28

Early Detection of Neonatal Depression and Asphyxia . . . . . 409 Paolo Biban and Davide Silvagni

29

Resuscitation of the Newborn . . . . . . . . . . . . . . . . . . . . . . . . . 423 Ola D. Saugstad

30

Oxygen Toxicity in Newborns . . . . . . . . . . . . . . . . . . . . . . . . . 439 Rodolfo Bracci, Serafina Perrone, Maximo Vento, and Giuseppe Buonocore

31

Physical Examination of the Newborn . . . . . . . . . . . . . . . . . . 457 Alessandra Coscia, Paola Di Nicola, Enrico Bertino, and Claudio Fabris

32

Primary Investigations in the Term and Preterm Newborn . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 471 Diego Gazzolo, Francesco Risso, and Andrea Sannia

33

Oxygen Saturation Monitoring in Neonatal Period . . . . . . . . 481 Augusto Sola and Sergio Golombek

Part III Nutrition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

501

. . . . . 503

34

Physiology of the Gastrointestinal Tract in Newborns Arieh Riskin, Carlo Agostoni, and Raanan Shamir

35

Hormones and Gastrointestinal Function of Newborns . . . . 535 Flavia Prodam, Simonetta Bellone, Roberta Ricotti, Alice Monzani, Giulia Genoni, Enza Giglione, and Gianni Bona

36

Human Milk and Formulas for Neonatal Nutrition . . . . . . . 557 Riccardo Davanzo, Jenny Bua, and Laura Travan

37

Nutritional Recommendations for the Very-Low-Birth-Weight Newborn . . . . . . . . . . . . . . . . . . . . . 587 Ekhard E. Ziegler

x

Contents

38

Enteral Feeding of the Very-Low-Birth-Weight Infant . . . . . 595 Johannes B. (Hans) van Goudoever

39

Parenteral Nutrition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 605 Jacques Rigo and Thibault Senterre

40

Postdischarge Nutrition in Preterm Infants . . . . . . . . . . . . . . 619 Richard J. Cooke

41

Calcium and Phosphorus Homeostasis: Pathophysiology . . . 639 Jacques Rigo, Catherine Pieltain, Renaud Viellevoye, and Franco Bagnoli

42

Micronutrients and Vitamins . . . . . . . . . . . . . . . . . . . . . . . . . 669 Olivier Claris and Guy Putet

Part IV Pharmacology and Infants of Smoking, Addicted, and Diabetic Mother . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

675

43

Safety of Medications During Pregnancy and Breastfeeding: Infants of Drug-Addicted Mothers . . . . . . . . . . . . . . . . . . . . . 677 Karel Allegaert, Timvan Mieghem, and John N. van den Anker

44

Developmental Pharmacology and Therapeutics in Neonatal Medicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 693 Karel Allegaert, Janko Samardzic, Milica Bajcetic, and John N. van den Anker

45

Infants of Smoking Mothers . . . . . . . . . . . . . . . . . . . . . . . . . . 709 Roberto Paludetto, Letizia Capasso, and Francesco Raimondi

46

Infants of Diabetic Mothers . . . . . . . . . . . . . . . . . . . . . . . . . . 717 Erin A. Osterholm, Jane E. Barthell, and Michael K. Georgieff

Volume 2 Part V

Respiratory System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

731

47

Neonatal Lung Development and Pulmonary Malformations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 733 Corrado Moretti and Paola Papoff

48

Neonatal Pulmonary Physiology of Term and Preterm Newborns . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 759 Corrado Moretti and Paola Papoff

49

Control of Breathing in Newborns . . . . . . . . . . . . . . . . . . . . . 775 Ruben E. Alvaro and Henrique Rigatto

50

Meconium Aspiration Syndrome . . . . . . . . . . . . . . . . . . . . . . 791 Simone Pratesi and Carlo Dani

Contents

xi

51

Molecular Structure of Surfactant: Biochemical Aspects in Newborns . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 801 Tore Curstedt

52

Surfactant Metabolism in Neonatal Lung Diseases . . . . . . . . 809 Virgilio P. Carnielli and Paola E. Cogo

53

Respiratory Distress Syndrome: Predisposing Factors, Pathophysiology, and Diagnosis . . . . . . . . . . . . . . . . . . . . . . . 823 Mikko Hallman, Timo Saarela, and Luc J. I. Zimmermann

54

Treatment of Respiratory Failure in Newborn: Mechanical Ventilation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 843 Colin Morley and Gianluca Lista

55

Pulmonary Hemorrhage, Transient Tachypnea, and Neonatal Pneumonia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 865 Mary Elaine Patrinos and Richard J. Martin

56

Pulmonary Air Leakage in Newborns . . . . . . . . . . . . . . . . . . 873 Paola Papoff and Corrado Moretti

57

Bronchopulmonary Dysplasia/Chronic Lung Disease of the Newborn . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 887 Vineet Bhandari

58

Lung Ultrasound in Neonatal Diagnostic . . . . . . . . . . . . . . . . 913 Francesco Raimondi, Fiorella Migliaro, and Letizia Capasso

59

Rare Lung Diseases of Newborns . . . . . . . . . . . . . . . . . . . . . . 917 Paolo Tagliabue and Elena Ciarmoli

60

Persistent Pulmonary Hypertension of the Newborn Jason Gien, John P. Kinsella, and Steven H. Abman

61

Pulmonary Hypertension in Congenital Diaphragmatic Hernia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 963 Jason Gien, John P. Kinsella, and Steven H. Abman

62

Continuous Positive Airways Pressure and Other Noninvasive Respiratory Techniques in Newborns . . . . . . . . 971 Fabrizio Sandri, Gina Ancora, Gianluca Lista, and Luc J. I. Zimmermann

63

Lung Diseases: Surfactant Replacement Therapy in Newborns . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 995 Henry L. Halliday

64

Extracorporeal Membrane Oxygenation for Neonates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1007 Anne Greenough, Niovi Papalexopoulou, Munir Ahmed, and Adam P. R. Smith

. . . . . . 933

xii

Contents

65

Lung Diseases: Problems of Steroid Treatment of Fetus and Newborn . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1015 Henry L. Halliday

66

Apnea of Prematurity and Sudden Infant Death Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1021 Christian F. Poets

Part VI

Cardiovascular System

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1035

67

Cardiovascular Physiology, Pathology, and Clinical Investigation in Neonatal Medicine . . . . . . . . . . . . . . . . . . . . 1037 Luciane Piazza, Angelo Micheletti, Javier Fernandez Sarabia, Diana Negura, Carmelo Arcidiacono, Antonio Saracino, Mario Carminati, and Francesca R. Pluchinotta

68

Early Diagnosis of Congenital Heart Disease: When and How to Treat . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1065 Francesca R. Pluchinotta, Luciane Piazza, Angelo Micheletti, Javier Fernandez Sarabia, Diana Negura, Carmelo Arcidiacono, Antonio Saracino, and Mario Carminati

69

Patent Ductus Arteriosus Bart Van Overmeire

70

Cardiac Emergencies in the Newborn . . . . . . . . . . . . . . . . . . 1093 Liam Mahoney, Hector Rojas-Anaya, and Heike Rabe

71

Blood Pressure Disorders in the Neonate: Hypotension and Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1111 Jonathan M. Fanaroff and Avroy A. Fanaroff

72

Polycythemia and Hyperviscosity in Neonates . . . . . . . . . . . . 1125 Otwin Linderkamp

Part VII

. . . . . . . . . . . . . . . . . . . . . . . . . . . . 1079

Hyperbilirubinemia and Liver Diseases . . . . . . . . . . . . . 1141

73

Bilirubin Metabolism, Unconjugated Hyperbilirubinemia, and Physiologic Neonatal Jaundice . . . . . . . . . . . . . . . . . . . . 1143 Giovanna Bertini and Carlo Dani

74

Pathologic Unconjugated Hyperbilirubinemia–Isoimmunization, Abnormalities of Red Blood Cells, and Infections . . . . . . . . . . . . . . . . . . . . . . . 1151 Michael Kaplan, Ronald J. Wong, and David K. Stevenson

75

Kernicterus, Bilirubin-Induced Neurological Dysfunction, and New Treatments for Unconjugated Hyperbilirubinemia in Neonates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1169 Christian V. Hulzebos, Claudio Tiribelli, Frans J. C. Cuperus, and Petr H. Dijk

Contents

xiii

. . . . . . . . . . 1185

76

Treatment of Hyperbilirubinemia in Newborns Jon F. Watchko and M. Jeffrey Maisels

77

Pathology and Treatment of Liver Diseases in Newborns . . . 1207 Giuseppe Maggiore, Silvia Riva, and Marco Sciveres

78

Neonatal Cholestasis: Conjugated Hyperbilirubinemia . . . . 1223 Nandini Kataria and Glenn R. Gourley

79

Surgical Treatment of Biliary Tract Malformations in Newborns . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1243 Pierluigi Pedersini

Part VIII Orofacial and Gastrointestinal Malformations and Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1253 80

Orofacial Malformations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1255 Giorgio Iannetti, Maria Teresa Fadda, Marco Della Monaca, and Giulio Bosco

81

Esophageal Atresia of Newborns . . . . . . . . . . . . . . . . . . . . . . 1281 Mario Messina, Francesco Molinaro, Alfredo Garzi, and Rossella Angotti

82

Gastrointestinal Malformations of Newborns . . . . . . . . . . . . 1295 Marcello Dòmini

83

Rare Surgical Emergencies of Newborns . . . . . . . . . . . . . . . . 1331 Mario Messina, Francesco Molinaro, and Rossella Angotti

84

Meconium Plug Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . 1339 Mario Messina, Rossella Angotti, and Francesco Molinaro

85

Hirschsprung’s Disease in Newborns . . . . . . . . . . . . . . . . . . . 1345 Girolamo Mattioli, Maria Grazia Faticato, Alessio Pini Prato, and Vincenzo Jasonni

86

Gastroenteritis and Intractable Diarrhea in Newborns Andrea De Luca and Giacomo Zanelli

87

Rehydration After Diarrhea in Newborns . . . . . . . . . . . . . . . 1365 Carlo V. Bellieni

88

Necrotizing Enterocolitis of Newborns . . . . . . . . . . . . . . . . . . 1373 Sarah Bajorek and Josef Neu

89

Surgical Treatment in Newborns of Necrotizing Enterocolitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1395 Nigel J. Hall and Agostino Pierro

Part IX 90

. . . . 1355

Hematology, Immunology, and Malignancies . . . . . . . . 1403

Hematology and Immunology of Newborns: Overview Robert D. Christensen

. . . . 1405

xiv

Contents

91

Pathophysiology of Coagulation and Deficiencies of Coagulation Factors in Newborn . . . . . . . . . . . . . . . . . . . . . . 1431 Paola Saracco and Rodney P. A. Rivers

92

The Thrombotic Risk of the Newborn . . . . . . . . . . . . . . . . . . 1455 Molinari Angelo Claudio and Paola Saracco

93

Coagulation Disorders: Clinical Aspects of Platelet Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1471 Antonio Del Vecchio

94

Anemia in the Neonatal Period . . . . . . . . . . . . . . . . . . . . . . . . 1489 Robert D. Christensen and Robin K. Ohls

95

Fetal and Neonatal Hydrops . . . . . . . . . . . . . . . . . . . . . . . . . . 1515 Gennaro Vetrano and Mario De Curtis

96

Physiology and Abnormalities of Leukocytes in Newborns . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1523 Kurt R. Schibler

97

Neonatal Hereditary Neutropenia . . . . . . . . . . . . . . . . . . . . . 1549 Gaetano Chirico and Carmelita D’Ippolito

98

Recombinant G-CSF Treatment of Severe Chronic Neutropenia in Neonates and Infants . . . . . . . . . . . . . . . . . . . 1561 Robert D. Christensen

99

Fundamentals of Feto-Neonatal Immunology . . . . . . . . . . . . 1575 Akhil Maheshwari and Edmund F. La Gamma

100

Congenital Immunodeficiencies in Newborns . . . . . . . . . . . . 1607 Alessandro Plebani, Gaetano Chirico, and Vassilios Lougaris

101

Inflammatory Mediators in Neonatal Asphyxia and Infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1619 Kaoru Okazaki, Akira Nishida, and Hirokazu Kimura

102

Neonatal Malignancies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1641 Serena Catania, Stefano Chiaravalli, Franca Fossati-Bellani, and Maura Massimino

Volume 3 Part X

Fetal and Neonatal Infections

. . . . . . . . . . . . . . . . . . . . . . . 1661

103

Fetal Infections: Cytomegalovirus, Herpes Simplex, and Varicella . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1663 Giovanni Nigro

104

Fetal Infections: Rubella, HIV, HCV, HBV, and Human Parvovirus B19 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1681 Pier Angelo Tovo, Stefania Bezzio, and Clara Gabiano

Contents

xv

105

Fetal Infections: Congenital Syphilis and Tuberculosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1703 Pier Angelo Tovo, Carlo Scolfaro, Silvia Garazzino, and Federica Mignone

106

Toxoplasmosis in the Fetus and Newborn . . . . . . . . . . . . . . . 1711 Wilma Buffolano

107

Neonatal Bacterial and Fungal Infections . . . . . . . . . . . . . . . 1727 Mauro Stronati and Alessandro Borghesi

108

Neonatal Septic Shock . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1773 Rajesh K. Aneja, Ruby V. Aneja, Misty Good, and Joseph A. Carcillo

109

Neonatal Viral Infections: Enteroviruses and Respiratory Syncytial Virus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1785 Paolo Manzoni, Davide Montin, Elena Tavella, and Pier Angelo Tovo

110

Vaccinations and Neonatal Immunity . . . . . . . . . . . . . . . . . . . 1793 Alberto G. Ugazio and Alberto E. Tozzi

Part XI

Endocrine, Metabolic, and Renal Diseases . . . . . . . . . . . 1803

111

Inborn Errors of Metabolism and Newborns . . . . . . . . . . . . . 1805 Nicola Brunetti-Pierri, Giancarlo Parenti, and Generoso Andria

112

Endocrine Diseases and Disorders of Thyroid Function in Newborns . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1833 Paolo Ghirri, Antonio Balsamo, Massimiliano Ciantelli, Paolo Cavarzere, Alessandro Cicognani, Antonio Boldrini, and Alessandra Cassio

113

Disorders of Sexual Development in Newborns . . . . . . . . . . . 1893 Antonio Balsamo, Paolo Ghirri, Silvano Bertelloni, Rosa T. Scaramuzzo, Franco D’Alberton, Alessandro Cicognani, and Antonio Boldrini

114

Pathophysiology of Fetal and Neonatal Kidneys . . . . . . . . . . 1919 Farid Boubred and Umberto Simeoni

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Acute and Chronic Renal Failure in the Newborn Infant . . . 1935 Jean-Pierre Guignard and Uma Sankari Ali

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Diagnosis and Treatment of Renal and Urinary Tract Malformations in Newborns . . . . . . . . . . . . . . . . . . . . . . . . . . 1955 Vassilios Fanos, Marco Zaffanello, and Michele Mussap

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Contents

Part XII

Neurology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1997

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Brain Development and Perinatal Vulnerability to Cerebral Damage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1999 Luca A. Ramenghi, Monica Fumagalli, and Veena Supramaniam

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Inflammation and Perinatal Brain Injury . . . . . . . . . . . . . . . 2019 Henrik Hagberg, Carina Mallard, and Karin Sävman

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Normal and Abnormal Neurodevelopmental and Behavioral Outcomes of Very Low-Birth Weight (VLBW) Infants . . . . . 2031 Betty R. Vohr

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Neurological Examination of the Newborn Infant . . . . . . . . . 2055 Fabrizio Ferrari, Licia Lugli, Luca Ori, Elisa della Casa, Isotta Guidotti, Natascia Bertoncelli, and Laura Lucaccioni

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Neonatal Electroencephalography . . . . . . . . . . . . . . . . . . . . . 2081 Lena K. Hellström-Westas

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Neuroimaging Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2091 Luca A. Ramenghi and Petra S. Hüppi

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Malformations of Cortical Development in Newborns: Genetic Aspects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2113 Renzo Guerrini and Elena Parrini

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Congenital Malformations of the Brain: Spectrum and Causes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2125 Elie Saliba

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Biochemical Basis of Hypoxic-Ischemic Encephalopathy . . . 2143 Maria Delivoria-Papadopoulos, Panagiotis Kratimenos, and Endla K. Anday

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Clinical Aspects and Treatment of the Hypoxic-Ischemic Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2165 Floris Groenendaal and Frank van Bel

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Neuroprotective Strategies for Newborns . . . . . . . . . . . . . . . 2185 Bobbi Fleiss, Claire Thornton, and Pierre Gressens

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Cerebral Hemorrhage in Newborns . . . . . . . . . . . . . . . . . . . . 2201 Linda S. de Vries and Axel Heep

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Neonatal Stroke: Mechanisms . . . . . . . . . . . . . . . . . . . . . . . . 2225 Paul P. Govaert and Jeroen Dudink

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Neonatal Stroke: Clinical Presentation, Imaging, Treatment, and Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2251 Paul P. Govaert and Jeroen Dudink

Contents

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131

Neonatal Seizures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2287 Lena K. Hellström-Westas and Malcolm Levene

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The Timing of Neonatal Brain Damage . . . . . . . . . . . . . . . . . 2295 Serafina Perrone and Giuseppe Buonocore

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Epidemiology of Adverse Cerebral Outcome of Newborns . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2315 Neil Marlow

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Neuromuscular Disorders in Newborns . . . . . . . . . . . . . . . . . 2323 Salvatore Grosso and Silvia Ferranti

Part XIII

Ophthalmology, Orthopedics, and Skin Diseases

. . . 2337

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Ocular Malformations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2339 Elena Piozzi and Alessandra Del Longo

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Retinopathy of Prematurity . . . . . . . . . . . . . . . . . . . . . . . . . . 2349 José Carlos Rivera, Elsa Duchemin-Kermorvant, Allison Dorfman, Tianwei Ellen Zhou, Luis H. Ospina, and Sylvain Chemtob

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Neonatal Orthopedic Surgery . . . . . . . . . . . . . . . . . . . . . . . . . 2387 Peter D. Pizzutillo and Martin J. Herman

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Neonatal Skin Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2391 Michele Fimiani, Roberta Bilenchi, Filomena Mandato, Stefania Mei, Niccolò Nami, Rosa Maria Strangi, and Arianna Lamberti

Part XIV

Appendices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2427

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Laboratory Medicine: Reference Values and Evidence-Based Medicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2429 Mariangela Longini, Fabrizio Proietti, Francesco Bazzini, and Elisa Belvisi

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Laboratory Medicine: Reference Intervals for Laboratory Tests and Procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2433 Mariangela Longini, Fabrizio Proietti, Francesco Bazzini, and Elisa Belvisi

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2459

About the Editors

Giuseppe Buonocore is an Italian pediatrician, who is internationally recognized for his research on neonatal diseases, oxidative stress, and early identification of the newborn at high risk of brain damage. He is a full Professor of Pediatrics, Department of Molecular and Developmental Medicine, University of Siena, Italy, and Director of the Division of Pediatric-Neonatology, Azienda Ospedaliera-Universitaria of Siena, Italy. He is Chairman of Pediatrics at the School of Specialization in Pediatrics and Neonatology, University of Siena, Italy. He is the President and Coordinator of European scientific network EURope Against Infant Brain Injury (EURAIBI). He has been a Visiting Professor at the University of Pennsylvania, the University of Florida, the University Hospitals of New York, as well as at the University of Oulu, Finland, at Taipei Medical University, and at Chang Gung Memorial Hospital at Linkou, Taiwan. He is also the past President of ESPR and UENPS and currently President of the National College of University Full Professors of Pediatrics. He is involved in the coordination of numerous pan-European clinical trials as well as American and Australian. He has received many scientific awards: including the Seventh annual Dr. Donald V Eitzman lectures “Iron homeostasis metabolism and toxicity,” University of Florida (2000), and the “Goccia d’oro 2010” for the efforts and results in the scientific research in the field of xix

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Prenatal, Perinatal, and Neonatal Brain Damage. He also holds the patent of a scientific invention: the “Machine for automatic assessment of pain in neonates.” Dr. Buonocore has supervised more than 200 M.D./Ph.D. students (1994/ 2018) in Medicine and Surgery, Pediatrics, and Diagnostic Biochemistry. His current research interests are in the mechanisms of cell damage in the neonatal brain, with special reference to hypoxia, and the role of oxidant radicals in neonatal diseases and in babies with birth asphyxia. Additional research interest fields are ethics in perinatology and fetal and neonatal pain prevention. His research team is funded by several agencies including the Italian Ministry of University and Scientific Research as well as the European Community. Prof. Buonocore is author of more than 900 publications: 3 books and 27 book chapters, 300 peer-reviewed articles, and more than 617 presentations at international conferences and national meetings. He is currently Editor-inChief of Current Pediatric Reviews, Associate Editor of Journal of Pineal Research, and on the editorial board of several international scientific journals. He has organized more than 20 European conferences and has been the scientific coordinator or participant in several national and international clinical trials.

Rodolfo Bracci was born in Siena (Italy) in 1931. After graduating in Medicine and Surgery from the University of Siena Medical School in 1955, he became Assistant Professor of Pediatrics in the University of Siena. He was Post doctoral Trainee at the Albert Einstein College of Medicine, New York (1964–1965). At that time, working under the direction of Professor Ruth Gross, he made the first experiences on the antioxidant properties of the red cells of newborn. After his return to Italy, he became Assistant Professor of Pediatrics at the University of Florence and later at the University of Siena. He continued to be involved in the field of oxygen toxicity of the erythrocyte of newborn, and in 1967, he demonstrated that the red cells of newborn may have not only a low protection against reacting oxygen species but also an increased production of them. Professor of Neonatology of the University of Siena and Director of the Neonatal Intensive Care Unit of the Siena Hospital, he was leading a staff of researchers involved in the physiopathology of the neonate, particularly in the calcium homeostasis, in the opioids metabolism, and especially in the

About the Editors

About the Editors

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problems of oxygen toxicity in the red cells as well as in various organs. More than a hundred papers were published in important international journals by the doctors working under the guidance of Rodolfo Bracci. He was invited speaker in many international congresses and seminars in various cities in Europe and in America. He has been member of the European Society of Pediatric Hematology and Immunology, the European Society for Pediatric Research, the European Society for Perinatal Medicine, the Neonatal Intensive Care Collegium, the Italian Society of Pediatrics, and the Italian Society of Neonatology. Retired from University of Siena in 2001, he continued to publish papers, mainly together with Professor G. Buonocore. Michael Weindling is Emeritus Professor of Perinatal Medicine at the University of Liverpool and Honorary Consultant Neonatologist at Liverpool Women’s Hospital, where he was responsible for the care of newborn babies in a tertiary neonatal intensive care unit until he retired from clinical work in 2013. He is an Associate Editor of Acta Paediatrica. He continues with his research interest into the maintenance of appropriate brain oxygenation, cerebral hemodynamics, and the prevention of acquired damage of the developing brain. He studied medicine at Guy’s Hospital in London and qualified in 1973. His training in London included a period at the Great Ormond Street Hospital for Sick Children and then as research fellow at the University of Oxford, where he studied the cerebral hemodynamics of the developing brain. Michael Weindling was appointed a Senior Lecturer and consultant in Liverpool in 1985. During his early years as a consultant, he undertook a master’s degree in medical ethics at the University of Keele with a dissertation into the changing moral status of the developing human from conceptus to neonate. He was promoted to Professor in 1996 with a personal chair entitled Professor of Perinatal Medicine, a title chosen to reflect his interest into the rapidly changing requirements of the developing brain. He has a considerable interest in medical education and for several years was Head of the School of Paediatrics in Merseyside.

Contributors

Steven H. Abman University of Colorado Denver – Anschutz Medical Campus, Denver, CO, USA Massimo Agosti Neonatology and NICU – Maternal and Child Department, Ospedale ”F del Ponte”, Varese, Italy Rocco Agostino Ethics Committee, Pediatric Hospital Bambino Gesù, Rome, Italy Carlo Agostoni Pediatric Clinic, Department of Clinical Sciences and Community Health, University of Milan Fondazione, IRCCS Ca Granda, Ospedale Maggiore Policlinico, Milano, Italy Munir Ahmed Division of Asthma, Allergy and Lung Biology, MRC Centre for Allergic Mechanisms of Asthma, King’s College London, London, UK Uma Sankari Ali Nephrology Division and PICU, BJ Wadia Hospital for Children, Mumbai, India Karel Allegaert Neonatal Intensive Care Unit, University Hospitals Leuven, Leuven, Belgium Department of Development and Regeneration, KU Leuven, Leuven, Belgium Intensive Care and Department of Pediatric Surgery, Erasmus MC – Sophia Children’s Hospital, Rotterdam, The Netherlands Ruben E. Alvaro Department of Pediatrics, WR004 Women’s Hospital, University of Manitoba, Winnipeg, MB, Canada Gina Ancora Neonatology and Neonatal Intensive Care Unit, Ospedale Infermi, Rimini, Italy Endla K. Anday Department of Pediatrics, Drexel University College of Medicine, St. Christopher’s Hospital for Children, Neonatal-Perinatal Medicine, Philadelphia, PA, USA Generoso Andria Department of Translational Medicine, Section of Pediatrics, Federico II University of Naples, Naples, Italy xxiii

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Rajesh K. Aneja Departments of Critical Care Medicine and Pediatrics, University of Pittsburgh School of Medicine, Children’s Hospital of Pittsburgh, Pittsburgh, PA, USA Ruby V. Aneja Division of Neonatology, Temple University, West Penn Hospital, Pittsburgh, PA, USA Molinari Angelo Claudio Thrombosis and Hemostasis Unit, Giannina Gaslini Children’s Hospital, Genova, Italy Rossella Angotti Department of Pediatrics, Obstetrics and Reproductive Medicine, Section of Pediatric Surgery, University of Siena, Siena, Italy Carmelo Arcidiacono Department of Pediatric Cardiology, IRCCS Policlinico San Donato, San Siro, Milan, Italy Domenico Arduini Department of Obstetrics and Gynecology, University of Rome Tor Vergata, Rome, Italy Roberto Aufieri Division of Neonatology and Neonatal Intensive Care, Casilino General Hospital, Rome, Italy Franco Bagnoli Department of Pediatrics, Obstetrics and Reproductive Medicine, University of Siena, Siena, Italy Milica Bajcetic Institute of Pharmacology, Clinical Pharmacology and Toxicology, Medical Faculty, University of Belgrade, Belgrade, Serbia Clinical Pharmacology Unit, University Children’s Hospital, Belgrade, Serbia Sarah Bajorek Department of Pediatrics, Division of Neonatology, University of Florida, College of Medicine, Gainesville, FL, USA Antonio Balsamo Department of Medical and Surgical Sciences, Pediatric Unit, Center for Rare Endocrine Diseases (CARENDO BO), S.Orsola Malpighi University Hospital, Bologna, Italy Jane E. Barthell Children’s Hospitals and Clinics of Minnesota, Minneapolis, MN, USA Francesco Bazzini Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy Roberto Bellù NICU, Ospedale Manzoni, Lecco, Italy Franca Fossati-Bellani Pediatric Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy Carlo V. Bellieni Neonatal Intensive Care Unit, Siena University Hospital, Siena, Italy Simonetta Bellone Department of Health Sciences, Division of Pediatrics, University of Piemonte Orientale, Novara, Italy Elisa Belvisi Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy

Contributors

Contributors

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Britney Benoit School of Nursing, Centre for Pediatric Pain Research, Maternal-Newborn Program, Dalhousie University, IWK Health Centre, Halifax, Canada Silvano Bertelloni Adolescent Medicine Unit, Division of Pediatrics, S. Chiara Hospital, University of Pisa, Pisa, Italy Giovanna Bertini Neonatal Intensive Care Unit, Careggi University Hospital, Florence, Italy Enrico Bertino Neonatal Unit, University of Turin, Turin, Italy Natascia Bertoncelli Neonatal Intensive Care Unit, Department of Medical and Surgical Sciences of the Mother, Children and Adults, University Hospital of Modena, Modena, Italy Giulio Bevilacqua Department of Pediatrics and Neonatology, Eastern Liguria Hospital, La Spezia, Italy Stefania Bezzio Department of Pediatrics, University of Turin, Turin, Italy Vineet Bhandari Neonatology/Pediatrics, St. Christopher’s Hospital for Children/Drexel University College of Medicine, Philadelphia, PA, USA Drexel University, Philadelphia, PA, USA Paolo Biban Azienda Ospedaliera Universitaria Integrata Verona, Verona, Italy Roberta Bilenchi Department of Medical, Surgical and Neurological Sciences, Dermatology Section, University of Siena, Siena, Italy Caterina Bocchi Obstetrics and Gynecology, Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy Antonio Boldrini Department of Clinical and Experimental Medicine, Division of Neonatology and Neonatal Intensive Care Unit, Santa Chiara University Hospital, Pisa, Italy Maria Elena Bolis Neonatology and NICU – Maternal and Child Department, Ospedale ”F del Ponte”, Varese, Italy Gianni Bona Department of Health Sciences, Division of Pediatrics, University of Piemonte Orientale, Novara, Italy Rachele Bonfiglio Department of Anesthesia, Pediatric and Neonatal Intensive Care, Istituto Giannina Gaslini, Genoa, Italy Alessandro Borghesi Neonatal Intensive Care Unit, Fondazione IRCCS Policlinico ‘San Matteo’, Pavia, Italy Giulio Bosco Sapienza Università di Roma, Policlinico Umberto I di Roma, Rome, Italy Farid Boubred Division of Neonatology, La Conception Hospital, Marseille, France Rodolfo Bracci University of Siena, Siena, Italy

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Nicola Brunetti-Pierri Department of Translational Medicine, Section of Pediatrics, Federico II University of Naples, Naples, Italy Jenny Bua Division of Neonatology, Institute for Maternal and Child Health IRCCS ‘Burlo Garofolo’, Trieste, Italy Wilma Buffolano Heading Coordinating Centre for Perinatal InfectionCampania Region, Translational Medicine Department, Federico II Medical School, Naples, Italy Giuseppe Buonocore University of Siena, Siena, Italy Marsha Campbell-Yeo Departments of Pediatrics, Psychology and Neuroscience, Dalhousie University School of Nursing, Halifax, Canada Letizia Capasso Division of Neonatology, Department of Translational Medical Sciences, Università “Federico II” di Napoli, Naples, Italy Joseph A. Carcillo Departments of Critical Care Medicine and Pediatrics, University of Pittsburgh School of Medicine, Children’s Hospital of Pittsburgh, Pittsburgh, PA, USA Mario Carminati Department of Pediatric Cardiology, IRCCS Policlinico San Donato, San Siro, Milan, Italy Virgilio P. Carnielli Division of Neonatology, Salesi Hospital, Polytechnic University of Marche, Ancona, Italy Elisa della Casa Neonatal Intensive Care Unit, Department of Medical and Surgical Sciences of the Mother, Children and Adults, University Hospital of Modena, Modena, Italy Alessandra Cassio Department of Medical and Surgical Sciences, Pediatric Endocrinology Unit, S. Orsola-Malpighi University Hospital, Bologna, Italy Serena Catania Pediatric Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy Paolo Cavarzere Pediatric Unit, Department of Mother and Child, University Hospital of Verona, Verona, Italy Sylvain Chemtob Departments of Pediatrics, Ophthalmology and Pharmacology, Centre Hospitalier, Universitaire Sainte-Justine, Research Center, Montréal, QC, Canada Department of Ophthalmology, Maisonneuve-Rosemont Hospital Research Center, Montréal, QC, Canada Stefano Chiaravalli Pediatric Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy Gaetano Chirico Neonatology and Intensive Neonatal Therapy Unit, Spedali Civili of Brescia, Brescia, Italy

Contributors

Contributors

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Robert D. Christensen Divisions of Neonatology and Hematology, Department of Pediatrics, University of Utah School of Medicine, Intermountain Healthcare, Salt Lake City, UT, USA Massimiliano Ciantelli Department of Clinical and Experimental Medicine, Division of Neonatology and Neonatal Intensive Care Unit, S. Chiara University Hospital, Pisa, Italy Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy Elena Ciarmoli Neonatologia e Terapia Intensiva Neonatale, Fondazione MBBM, ASST-Ospedale San Gerardo-Monza, Monza, Italy Alessandro Cicognani Department of Medical and Surgical Sciences, Pediatric Unit, Center for Rare Endocrine Diseases (CARENDO BO), S.Orsola Malpighi University Hospital, Bologna, Italy Giovanni Cioni IRCCS Stella Maris, Department of Developmental Neuroscience, Pisa, Italy University of Pisa, Department of Clinical and Experimental Neuroscience, Pisa, Italy Olivier Claris Department of Neonatology, Hôpital Femme Mère Enfant, Bron, France Hospices Civils de Lyon and Université Claude Bernard, Lyon, France Paola E. Cogo Division of Pediatrics, Department of Medicine, S. Maria della Misericordia University Hospital, University of Udine, Udine, Italy Richard J. Cooke Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN, USA Giovanni Corsello Department of Sciences for Health Promotion and Mother and Child Care, University of Palermo, Palermo, Italy Alessandra Coscia Neonatal Unit, University of Turin, Turin, Italy Frans J. C. Cuperus Department of Gastroenterology and Hepatology, University Medical Center Groningen, Groningen, The Netherlands Tore Curstedt Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden Mario De Curtis Dipartimento Materno-Infantile, Università “La Sapienza”, Rome, Italy Carlo Dani Neonatal Intensive Care Unit, Careggi University Hospital, Florence, Italy Università degli Studi di Firenze, Florence, Italy Riccardo Davanzo Department of Mother and Child Health, Madonna delle Grazie Hospital, Matera, Italy

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Franco D’Alberton Department of Medical and Surgical Sciences, Pediatric Unit, Center for Rare Endocrine Diseases (CARENDO BO), S.Orsola Malpighi University Hospital, Bologna, Italy Andrea De Luca Department of Medical Biotechnologies, University of Siena, Siena, Italy UOC Malattie Infettive Universitarie, Azienda Ospedaliera Universitaria Senese, Siena, Italy Linda S. de Vries Department of Neonatology, Wilhelmina Children’s Hospital, University Medical Center, Utrecht, The Netherlands Antonio Del Vecchio Department of Women’s and Children’s Health, Neonatal Intensive Care Unit, Di Venere Hospital, ASL Bari, Bari, Italy Maria Delivoria-Papadopoulos Department of Pediatrics, Drexel University College of Medicine, St. Christopher’s Hospital for Children, NeonatalPerinatal Medicine, Philadelphia, PA, USA Marco Della Monaca Sapienza Università di Roma, Policlinico Umberto I di Roma, Rome, Italy Paola Di Nicola Neonatal Unit, University of Turin, Turin, Italy Petr H. Dijk Beatrix Children’s Hospital, University Medical Center Groningen, Groningen, The Netherlands Carmelita D’Ippolito Pediatric Oncohematology and Bone Marrow Transplant, Spedali Civili Hospital, Brescia, Italy Timothy Disher Centre for Pediatric Pain Research, Dalhousie University School of Nursing and IWK Health Centre, Halifax, Canada Nicola Disma Department of Anesthesia, Pediatric and Neonatal Intensive Care, Istituto Giannina Gaslini, Genoa, Italy Marcello Dòmini U.O. di Chirurgia pediatrica – Ospedale S.Orsola, Università degli Studi – Alma Mater Studiorum, di Bologna, Italy Allison Dorfman Department of Ophthalmology/Neurology, McGill University-Montreal Children’s Hospital Research Institute, Montreal, QC, Canada Elsa Duchemin-Kermorvant INSERM UMRS1138, Centre de Recherche des Cordeliers, Paris, France Jennifer M. Duchon Division of Neonatology, St. Joseph’s Regional Medical Center, Paterson, NJ, USA Jeroen Dudink Neonatology, Sophia Children’s Hospital, Erasmus MC Rotterdam, Rotterdam, Zuid-Holland, The Netherlands Claudio Fabris Neonatal Unit, University of Turin, Turin, Italy Maria Teresa Fadda Sapienza Università di Roma, Policlinico Umberto I di Roma, Rome, Italy

Contributors

Contributors

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Avroy A. Fanaroff Case Western Reserve University School of Medicine Rainbow Babies and Children’s Hospital, Cleveland, OH, USA Jonathan M. Fanaroff Case Western Reserve University School of Medicine Rainbow Babies and Children’s Hospital, Cleveland, OH, USA Vassilios Fanos Department of Surgery, Neonatal Intensive Care Unit, Neonatal Pathology and Neonatal Section, AOU and University of Cagliari, Cagliari, Italy Maria Grazia Faticato Department of Pediatric Surgery, University of Genoa, Genoa, Italy Giannina Gaslini Institute, Genoa, Italy Silvia Ferranti Department of Molecular Medicine and Development, University of Siena, Siena, Italy, Fabrizio Ferrari Neonatal Intensive Care Unit, Department of Medical and Surgical Sciences of the Mother, Children and Adults, University of Modena and Reggio Emilia, Modena, Italy Enrico Ferrazzi Prenatal Diagnosis and Fetal Surgery Unit, Dept. of Woman, Mother and Neonate, Buzzi Children’s Hospital Department of Clinical Sciences, University of Milan, Milan, Italy Michele Fimiani Dipartimento di Medicina Clinica e Scienze Immunologiche – Sezione di Dermatologia, Università degli Studi di Siena, Policlinico “Santa Maria alle Scotte”, Siena, Italy Department of Medical, Surgical and Neurological Sciences, Dermatology Section, University of Siena, Siena, Italy Vittorio Fineschi Department of Anatomical, Histological, Forensic Medicine and Orthopaedic Sciences, “Sapienza” University of Rome, Rome, Italy Bobbi Fleiss UMR1141, Insem-Paris Diderot University, Hôpital Robert Debré, Paris, France Centre for the Developing Brain, Department of Perinatal Imaging and Health, Division of Imaging Sciences and Biomedical Engineering, King’s College London, King’s Health Partners, St. Thomas’ Hospital, London, UK Monica Fumagalli NICU, Department of Clinical Sciences and Community Health, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico Milano, Università degli Studi di Milano, Milan, Italy Clara Gabiano Department of Pediatrics, University of Turin, Turin, Italy Silvia Garazzino Department of Pediatrics, University of Turin, Regina Margherita Childrens Hospital, AOU Città della Salute e della Scienza di Torino, Turin, Italy Elisabetta Garetti Neonatal Intensive Care Unit, Department of Medical and Surgical Sciences of the Mother, Children and Adults, University of Modena and Reggio Emilia, Modena, Italy

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Alfredo Garzi Department of Pediatrics, Obstetrics and Reproductive Medicine, Section of Pediatric Surgery, University of Siena, Siena, Italy Università degli Studi di Salerno, Fisciano, Italy Diego Gazzolo Neonatal Intensive Care Unit, Department of Maternal, Fetal and Neonatal Medicine, S. Arrigo Children’s Hospital, Alessandria, Italy Giulia Genoni Department of Health Sciences, Division of Pediatrics, University of Piemonte Orientale, Novara, Italy Maurizio Gente Department of Pediatrics and Infant Neuropsychiatry, Neonatal Emergency Transport Service, Sapienza University of Rome, Rome, Italy Michael K. Georgieff Division of Neonatology, Department of Pediatrics Center for Neurobehavioral Development, University of Minnesota, Minneapolis, MN, USA Paolo Ghirri Department of Clinical and Experimental Medicine, Division of Neonatology and Neonatal Intensive Care Unit, Santa Chiara University Hospital, Pisa, Italy Daniela Gianotti Department of Pediatrics and Neonatology, Eastern Liguria Hospital, La Spezia, Italy Jason Gien University of Colorado Denver, Denver, CO, USA Enza Giglione Department of Health Sciences, Division of Pediatrics, University of Piemonte Orientale, Novara, Italy Mario Giuffrè Department of Sciences for Health Promotion and Mother and Child Care, University of Palermo, Palermo, Italy Francesca Giuliani Neonatal Unit, University of Turin, Turin, Italy Kirsten Glaser University Children’s Hospital, University of Würzburg, Würzburg, Germany Peter D. Gluckman Liggins Institute, University of Auckland, Auckland, New Zealand Sergio Golombek New York Medical College, New York, USA Misty Good Division of Neonatology, University of Pittsburgh School of Medicine, Children’s Hospital of Pittsburgh, Pittsburgh, PA, USA Glenn R. Gourley Department of Pediatrics, University of Minnesota, Minneapolis, USA Paul P. Govaert Neonatology, Sophia Children’s Hospital, Erasmus MC Rotterdam, Rotterdam, Zuid-Holland, The Netherlands

Contributors

Contributors

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Anne Greenough Division of Asthma, Allergy and Lung Biology, MRC Centre for Allergic Mechanisms of Asthma, King’s College London, London, UK NIHR Biomedical Centre at Guy’s and St Thomas NHS Foundation Trust and King’s College London, London, UK NICU, King’s College Hospital, London, UK Pierre Gressens UMR1141, Insem-Paris Diderot University, Hôpital Robert Debré, Paris, France Centre for the Developing Brain, Department of Perinatal Imaging and Health, Division of Imaging Sciences and Biomedical Engineering, King’s College London, King’s Health Partners, St. Thomas’ Hospital, London, UK Floris Groenendaal Department of Neonatology, Wilhelmina Children’s Hospital, University Medical Center Utrecht, Utrecht, The Netherlands Salvatore Grosso Department of Molecular Medicine and Development, University of Siena, Siena, Italy, Renzo Guerrini Pediatric Neurology and Neurogenetics Unit and Laboratories, Neuroscience Department, A. Meyer Children’s Hospital – University of Florence, Florence, Italy Isotta Guidotti Neonatal Intensive Care Unit, Department of Medical and Surgical Sciences of the Mother, Children and Adults, University Hospital of Modena, Modena, Italy Jean-Pierre Guignard Lausanne University Medical School, Lausanne, Switzerland Andrea Guzzetta IRCCS Stella Maris, Department of Developmental Neuroscience, Pisa, Italy University of Pisa, Department of Clinical and Experimental Neuroscience, Pisa, Italy Henrik Hagberg Perinatal Center, Department of Obstetrics and Gynecology, Sahlgrenska Academy, University of Gothenburg, Goteborg, Sweden Centre for the Developing Brain, Division of Imaging Sciences and Biomedical Engineering, King’s College London, King’s Health Partners, St. Thomas’ Hospital, London, UK Nigel J. Hall University Surgery Unit, Faculty of Medicine, University of Southampton, Southampton, UK Henry L. Halliday Formerly Regional Neonatal Unit, Royal Maternity Hospital, Belfast, UK Formerly Department of Child Health, Queen’s University Belfast, Belfast, UK

xxxii

Mikko Hallman Department of Children and Adolescents, Oulu University Hospital, and PEDEGO Research Unit, Medical Research Center Oulu, University of Oulu, Oulu, Finland Dominique Haumont Department of Neonatology, Saint – Pierre University Hospital, Brussels, Belgium Axel Heep Department of Neonatology, Southmead Hospital, North Bristol NHS Trust, Bristol, UK Lena K. Hellström-Westas Department of Women’s and Children’s Health, Uppsala University and University Hospital, Uppsala, Sweden Martin J. Herman Department of Orthopaedic Surgery, Drexel University College of Medicine, St. Christopher’s Hospital for Children, Philadelphia, PA, USA Christian V. Hulzebos Beatrix Children’s Hospital, University Medical Center Groningen, Groningen, The Netherlands Petra S. Hüppi Division of Neonatology, Giannina Gaslini Children’s Hospital, Genoa, Italy Giorgio Iannetti Università degli Studi di Siena, Policlinico S. Maria alle Scotte, Siena, Italy Sapienza Università di Roma, Policlinico Umberto I di Roma, Rome, Italy Vincenzo Jasonni Department of Pediatric Surgery, University of Genoa, Genoa, Italy Giannina Gaslini Institute, Genoa, Italy Kathryn Johnson Centre for Newborn Care, Leeds Teaching Hospitals Trust, Leeds, UK Celeste Johnston School of Nursing, McGill University, Montreal, Canada Michael Kaplan Department of Neonatology, Shaare Zedek Medical Center, Jerusalem, Israel The Faculty of Medicine, Hebrew University, Jerusalem, Israel, Nandini Kataria Department of Pediatrics, University of Minnesota, Long Beach, California, USA Tuula Kaukola Department of Children and Adolescents, Oulu University Hospital, and PEDEGO Research Center, MRC Oulu, University of Oulu, Oulu, Finland Hirokazu Kimura Infectious Diseases Surveillance Center, National Institute of Infectious Diseases, Tokyo, Japan John P. Kinsella University of Denver, Denver, CO, USA Panagiotis Kratimenos Neonatologist, Children’s National Medical Center, Center for Research in Neuroscience, George Washington University School of Medicine and Health Sciences, Washington, DC, USA

Contributors

Contributors

xxxiii

Edmund F. La Gamma Division of Newborn Medicine, Maria Fareri Children’s Hospital, Westchester Medical Center – New York Medical College, Valhalla, NY, USA Arianna Lamberti Department of Medical, Surgical and Neurological Sciences, Dermatology Section, University of Siena, Siena, Italy Mariano Lanna Prenatal Diagnosis and Fetal Surgery Unit, Dept. of Woman, Mother and Neonate, Buzzi Children’s Hospital Department of Clinical Sciences, University of Milan, Milan, Italy Malcolm Levene Academic Unit of Paediatrics and Child Health, University of Leeds, Leeds, UK Department of Neonatal Medicine, Leeds Teaching Hospitals Trust, Leeds, UK Isabelle Ligi Division of Neonatology, La Conception Hospital, Marseille, France Otwin Linderkamp Division of Neonatology, Department of Pediatrics, University of Heidelberg, Heidelberg, Germany Gianluca Lista Neonatology and Neonatal Intensive Care Unit, Ospedale dei Bambini V. Buzzi, Milan, Italy Mariangela Longini Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy Alessandra Del Longo Department of Pediatric Ophthalmology, Niguarda Ca’ Granda Hospital, Milan, Italy Vassilios Lougaris Pediatrics Clinic, Department of Clinical and Experimental Sciences, University of Brescia and Spedali Civili of Brescia, Brescia, Italy Felicia M. Low Liggins Institute, University of Auckland, Auckland, New Zealand Laura Lucaccioni Neonatal Intensive Care Unit, Department of Medical and Surgical Sciences of the Mother, Children and Adults, University Hospital of Modena, Modena, Italy Licia Lugli Neonatal Intensive Care Unit, Department of Medical and Surgical Sciences of the Mother, Children and Adults, University Hospital of Modena, Modena, Italy Giuseppe Maggiore Department of Medical Sciences-Pediatrics, University of Ferrara, University Hospital Arcispedale Sant Anna di Cona, CONA (Ferrara), Italy Francesca Maglietta Department of Legal Medicine, University of Foggia, Foggia, Italy Akhil Maheshwari Division of Neonatology, University of South Florida, Tampa, FL, USA Liam Mahoney Academic Department of Paediatrics, Royal Alexandra Children’s Hospital, Brighton, UK

xxxiv

M. Jeffrey Maisels Department of Pediatrics, Oakland University William Beaumont School of Medicine, Beaumont Children’s Hospital, Royal Oak, MI, USA Carina Mallard Department of Physiology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden Leila Mameli Department of Anesthesia, Pediatric and Neonatal Intensive Care, Istituto Giannina Gaslini, Genoa, Italy Filomena Mandato Department of Medical, Surgical and Neurological Sciences, Dermatology Section, University of Siena, Siena, Italy Paolo Manzoni Division of Neonatology, Department of Obstetrics and Neonatology, AOU Città della Salute e della Scienza, Turin, Italy Viviana Marchi IRCCS Stella Maris, Department of Developmental Neuroscience, Pisa, Italy University of Pisa, Department of Clinical and Experimental Neuroscience, Pisa, Italy Neil Marlow Institute for Women’s Health, University College London, London, UK Richard J. Martin Rainbow Babies and Children’s Hospital, Division of Neonatology, Case Western Reserve University School of Medicine, Cleveland, OH, USA Maura Massimino Pediatric Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy Girolamo Mattioli Department of Pediatric Surgery, University of Genoa, Genoa, Italy Giannina Gaslini Institute, Genoa, Italy Liz McKechnie Centre for Newborn Care, Leeds Teaching Hospitals Trust, Leeds, UK Stefania Mei Department of Medical, Surgical and Neurological Sciences, Dermatology Section, University of Siena, Siena, Italy Mario Messina Department of Pediatrics, Obstetrics and Reproductive Medicine, Section of Pediatric Surgery, Policlinico “Le Scotte”, University of Siena, Siena, Italy Department of Medical, Surgical and Neurological Sciences, Section of Pediatric Surgery, University of Siena, Siena, Italy Angelo Micheletti Department of Pediatric Cardiology, IRCCS Policlinico San Donato, San Siro, Milan, Italy Fiorella Migliaro Division of Neonatology, Department of Translational Medical Sciences, Università “Federico II” di Napoli, Naples, Italy

Contributors

Contributors

xxxv

Federica Mignone Department of Pediatrics, University of Turin, Regina Margherita Childrens Hospital, AOU Città della Salute e della Scienza di Torino, Turin, Italy Francesco Molinaro Department of Pediatrics, Obstetrics and Reproductive Medicine, Section of Pediatric Surgery, Policlinico “Le Scotte”, University of Siena, Siena, Italy Department of Medical, Surgical and Neurological Sciences, Section of Pediatric Surgery, University of Siena, Siena, Italy Davide Montin Division of Neonatology, Department of Obstetrics and Neonatology, AOU Città della Salute e della Scienza, Turin, Italy Department of Pediatrics, University of Turin, Turin, Italy Alice Monzani Department of Health Sciences, Division of Pediatrics, University of Piemonte Orientale, Novara, Italy Corrado Moretti Università degli Studi di Roma “La Sapienza”, Rome, Italy Colin Morley Dept Obstetrics and Gynecology, University of Cambridge at Rosie Maternity Hospital, Cambridge, UK Fabio A. Mosca NICU, Department of Clinical Sciences and Community Health, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico Milano, Università degli Studi di Milano, Milan, Italy Michele Mussap Laboratory Medicine, Ospedale Policlinico San Martino, Genoa, Italy Niccolò Nami Department of Medical, Surgical and Neurological Sciences, Dermatology Section, University of Siena, Siena, Italy Diana Negura Department of Pediatric Cardiology, IRCCS Policlinico San Donato, San Siro, Milan, Italy Josef Neu Department of Pediatrics, Division of Neonatology, University of Florida, College of Medicine, Gainesville, FL, USA Giovanni Nigro Maternal-Infant Department, University of L’Aquila, L’Aquila, Italy Akira Nishida Department of Neonatology, Tokyo Metropolitan Children’s Medical Center, Tokyo, Japan Giovanna Oggè Maternal-Fetal Medicine Unit, University of Turin, Turin, Italy Robin K. Ohls Department of Pediatrics, Division of Neonatology, University of New Mexico, Albuquerque, NM, USA Kaoru Okazaki Department of Neonatology, Tokyo Metropolitan Children’s Medical Center, Tokyo, Japan

xxxvi

Luca Ori Neonatal Intensive Care Unit, Department of Medical and Surgical Sciences of the Mother, Children and Adults, University Hospital of Modena, Modena, Italy Luis H. Ospina Departments of Pediatrics, Ophthalmology and Pharmacology, Centre Hospitalier, Universitaire Sainte-Justine, Research Center, Montréal, QC, Canada Erin A. Osterholm Division of Neonatology, Department of Pediatrics Center for Neurobehavioral Development, University of Minnesota, Minneapolis, MN, USA Roberto Paludetto Translational Medical Sciences, Università “Federico II” di Napoli, Naples, Italy Niovi Papalexopoulou Division of Asthma, Allergy and Lung Biology, MRC Centre for Allergic Mechanisms of Asthma, King’s College London, London, UK Paola Papoff Pediatric Intensive Care Unit, Sapienza University of Rome, Rome, Italy Giancarlo Parenti Department of Translational Medicine, Section of Pediatrics, Federico II University of Naples, Naples, Italy Stefano Parmigiani Department of Pediatrics and Neonatology, Eastern Liguria Hospital, La Spezia, Italy Elena Parrini Pediatric Neurology and Neurogenetics Unit and Laboratories, Neuroscience Department, A. Meyer Children’s Hospital – University of Florence, Florence, Italy Gaia Pasquali Department of Obstetrics and Gynecology, University of Rome Tor Vergata, Rome, Italy Mary Elaine Patrinos Case Western Reserve University School of Medicine, Cleveland, OH, USA Pierluigi Pedersini National Center for Surgical Treatment of Pediatric Hepatobiliary Malformations, Pediatric Surgery, University of Brescia, Brescia, Italy Serafina Perrone Department of Molecular and Developmental Medicine, University Hospital of Siena, Siena, Italy Felice Petraglia Obstetrics and Gynecology, Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy Luciane Piazza Department of Pediatric Cardiology, IRCCS Policlinico San Donato, San Siro, Milan, Italy Catherine Pieltain Department of Neonatology, University of Liège, CHR de la Citadelle, Liège, Belgium Agostino Pierro Division of General and Thoracic Surgery, The Hospital for Sick Children, Toronto, Canada

Contributors

Contributors

xxxvii

Alessio Pini Prato Giannina Gaslini Institute, Genoa, Italy Elena Piozzi Department of Pediatric Ophthalmology, Niguarda Ca’ Granda Hospital, Milan, Italy Peter D. Pizzutillo Section of Orthopaedic Surgery, St. Christopher’s Hospital for Children, Philadelphia, PA, USA Tenet Healthcare, Dallas, TX, USA Alessandro Plebani Pediatrics Clinic, Department of Clinical and Experimental Sciences, University of Brescia and Spedali Civili of Brescia, Brescia, Italy Francesca R. Pluchinotta Department of Pediatric Cardiology, IRCCS Policlinico San Donato, San Siro, Milan, Italy Christian F. Poets Department of Neonatology, Tübingen University Hospital, Tübingen, Germany Simone Pratesi Neonatal Intensive Care Unit, Careggi University Hospital, Florence, Italy Flavia Prodam Department of Health Sciences, Division of Pediatrics, University of Piemonte Orientale, Novara, Italy Fabrizio Proietti Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy Marisa Pugliese Neonatal Intensive Care Unit, Department of Medical and Surgical Sciences of the Mother, Children and Adults, University of Modena and Reggio Emilia, Modena, Italy Guy Putet Department of Neonatology, Hopital de la Croix-Rousse, Hospices Civils de Lyon and Universite Claude Bernard, Lyon, France Heike Rabe Academic Department of Paediatrics, Royal Alexandra Children’s Hospital, Brighton, UK Francesco Raimondi Division of Neonatology, Department of Translational Medical Sciences, Università “Federico II” di Napoli, Naples, Italy Luca A. Ramenghi Division of Neonatology, Giannina Gaslini Children’s Hospital, Genoa, Italy Tara M. Randis Department of Pediatrics, New York University School of Medicine, New York, NY, USA Roberta Ricotti Department of Health Sciences, Division of Pediatrics, University of Piemonte Orientale, Novara, Italy Henrique Rigatto Department of Pediatrics, WR004 Women’s Hospital, University of Manitoba, Winnipeg, MB, Canada Jacques Rigo Department of Neonatology, University of Liège, CHR de la Citadelle, Liège, Belgium

xxxviii

Contributors

Arieh Riskin Department of Neonatology, Bnai Zion Medical Center, Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, Haifa, Israel Francesco Risso Neonatal Intensive Care Unit, Department of Emergency Medicine, G. Gaslini Children’s Hospital, Genoa, Italy Silvia Riva Pediatric Hepatology and Liver Transplant Unit, IRCCSISMETT - University of Pittsburgh Medical Center (UPMC), Palermo, Italy José Carlos Rivera Departments of Pediatrics, Ophthalmology and Pharmacology, Centre Hospitalier, Universitaire Sainte-Justine, Research Center, Montréal, QC, Canada Department of Ophthalmology, Maisonneuve-Rosemont Hospital Research Center, Montréal, QC, Canada Rodney P. A. Rivers Section of Paediatrics, Department of Medicine, Imperial College, London, UK Hector Rojas-Anaya Academic Department Alexandra Children’s Hospital, Brighton, UK

of

Paediatrics,

Royal

Maria Angela Rustico Prenatal Diagnosis and Fetal Surgery Unit, Dept. of Woman, Mother and Neonate, Buzzi Children’s Hospital Department of Clinical Sciences, University of Milan, Milan, Italy Karin Sävman Department of Pediatrics, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden Timo Saarela Department of Children and Adolescents, Oulu University Hospital, Oulu, Finland Elie Saliba Department of Neonatology and Pediatric Intensive Care, Université François Rabelais and CHRU de Tours, Tours, France Inserm U930, France, Université François Rabelais and CHRU de Tours, Tours, France Janko Samardzic Department of Paediatric Pharmacology, University Children’s Hospital Basel, Basel, Switzerland Institute of Pharmacology, Clinical Pharmacology and Toxicology, Medical Faculty, University of Belgrade, Belgrade, Serbia Fabrizio Sandri Neonatology and Neonatal Intensive Care Unit, Ospedale Maggiore, Bologna, Italy Andrea Sannia Neonatal Intensive Care Unit, Department of Emergency Medicine, G. Gaslini Children’s Hospital, Genoa, Italy Javier Fernandez Sarabia Department of Pediatric Cardiology, IRCCS Policlinico San Donato, San Siro, Milan, Italy Paola Saracco Pediatric Hematology, Department of Pediatrics, University Hospital Città della Salute e della Scienza, Torino, Italy

Contributors

xxxix

Antonio Saracino Department of Pediatric Cardiology, IRCCS Policlinico San Donato, San Siro, Milan, Italy Ola D. Saugstad Department of Pediatric Research, Rikshospitalet, Oslo University Hospital, University of Oslo, Oslo, Norway Rosa T. Scaramuzzo Neonatology and Neonatal Intensive Care Unit, Santa Chiara University Hospital, Pisa, Italy Kurt R. Schibler Perinatal Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA Marco Sciveres Pediatric Hepatology and Liver Transplant Unit, IRCCSISMETT - University of Pittsburgh Medical Center (UPMC), Palermo, Italy Carlo Scolfaro Department of Pediatrics, University of Turin, Regina Margherita Childrens Hospital, AOU Città della Salute e della Scienza di Torino, Turin, Italy Gunnar Sedin Department of Women’s and Children’s Health, University Children’s Hospital, Uppsala, Sweden Thibault Senterre Department of Neonatology, University of Liège, CHR de la Citadelle, Liège, Belgium Filiberto Maria Severi Obstetrics and Gynecology, Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy Raanan Shamir Institute of Gastroenterology Nutrition and Liver Diseases, Schneider Children’s Medical Center, Sackler Faculty of Medicine, Tel-Aviv University, Petach-Tikva, Israel Davide Silvagni Azienda Ospedaliera Universitaria Integrata Verona, Verona, Italy Umberto Simeoni Division of Pediatrics, CHUV and UNIL, Lausanne, Vaud, Switzerland Adam P. R. Smith Division of Asthma, Allergy and Lung Biology, MRC Centre for Allergic Mechanisms of Asthma, King’s College London, London, UK Augusto Sola Ibero American Society of Neonatology (SIBEN), Wellington, FL, USA Michael Spear Department of Pediatrics, Drexel University College of Medicine, St. Christopher’s Hospital for Children, Philadelphia, PA, USA Christian P. Speer University Children’s Hospital, University of Würzburg, Würzburg, Germany David K. Stevenson Department of Pediatrics, Stanford University School of Medicine, Medical School Office Building, Stanford, CA, USA Rosa Maria Strangi Department of Medical, Surgical and Neurological Sciences, Dermatology Section, University of Siena, Siena, Italy

xl

Mauro Stronati Neonatal Intensive Care Unit, Fondazione IRCCS Policlinico ‘San Matteo’, Pavia, Italy Veena Supramaniam Perinatal Imaging Group, Robert Steiner MR Unit, MRC Clinical Sciences Centre and Wigglesworth Perinatal Pathology Services, Hammersmith Hospital, Imperial College, London, UK Paolo Tagliabue Neonatologia e Terapia Intensiva Neonatale, Fondazione MBBM, ASST-Ospedale San Gerardo-Monza, Monza, Italy Sophie Tardieu Medical Evaluation Department, Public Health Department, La Conception Hospital, Marseille, France Elena Tavella Division of Neonatology, Department of Obstetrics and Neonatology, AOU Città della Salute e della Scienza, Turin, Italy Claire Thornton Centre for the Developing Brain, Department of Perinatal Imaging and Health, Division of Imaging Sciences and Biomedical Engineering, King’s College London, King’s Health Partners, St. Thomas’ Hospital, London, UK Claudio Tiribelli Liver Research Centre, University of Trieste, Trieste, Italy Tullia Todros Maternal-Fetal Medicine Unit, University of Turin, Turin, Italy Michela Torricelli Obstetrics and Gynecology, Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy Pier Angelo Tovo Department of Pediatrics, University of Turin, Regina Margherita Childrens Hospital, AOU Città della Salute e della Scienza di Torino, Turin, Italy Alberto E. Tozzi Multifactorial and Complex Diseases Research Area, Bambino Gesù Children’s Hospital, Rome, Italy Laura Travan Division of Neonatology, Institute for Maternal and Child Health IRCCS ‘Burlo Garofolo’, Trieste, Italy Daniele Trevisanuto Department of Women’s and Children’s Health, Azienda Ospedaliere di Padova, University of Padua, Padua, Italy Pietro Tuo Department of Anesthesia, Pediatric and Neonatal Intensive Care, Istituto Giannina Gaslini, Genoa, Italy Emanuela Turillazzi Department of Legal Medicine, University of Foggia, Foggia, Italy Alberto G. Ugazio Institute of Child and Adolescent Health, Bambino Gesù Children’s Hospital, Rome, Italy Frank van Bel Department of Neonatology, Wilhelmina Children’s Hospital, University Medical Center Utrecht, Utrecht, The Netherlands

Contributors

Contributors

xli

John N. van den Anker Division of Pediatric Clinical Pharmacology, Children’s National Health System, Washington, DC, USA Departments of Pediatrics, Integrative Systems Biology, Pharmacology and Physiology, George Washington University, School of Medicine and Health Sciences, Washington, DC, USA Intensive Care and Department of Pediatric Surgery, Erasmus MC – Sophia Children’s Hospital, Rotterdam, The Netherlands Johannes B. (Hans) van Goudoever Department of Pediatrics, Emma Children’s Hospital – AMC and VU University Medical Center, Amsterdam, The Netherlands Tim van Mieghem Department of Development and Regeneration, KU Leuven, Leuven, Belgium Obstetrics and Gynecology, University Hospitals Leuven, Leuven, Belgium Bart Van Overmeire Neonatology Service, Erasmus Hospital Université Libre de Bruxelles, Brussels, Belgium Silvia Vannuccini Obstetrics and Gynecology, Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy Maximo Vento Neonatal Research Unit, Health Research Institute Hospital La Fe, University and Polytechnic Hospital La Fe, Valencia, Spain Gennaro Vetrano U.O.C. Pediatria/Neonatologia/UTIN, Osp. “Sacro Cuore di Gesù”, Benevento, Italy Renaud Viellevoye Department of Neonatology, University of Liège, CHR de la Citadelle, Liège, Belgium Betty R. Vohr Department of Pediatrics, The Warren Alpert Medical School of Brown University, Providence, RI, USA Women and Infants Hospital, Providence, RI, USA Jon F. Watchko Division of Newborn Medicine, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA Ronald J. Wong Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA Marco Zaffanello Department of Surgical Sciences, Dentistry, Gynecology and Pediatrics, University of Verona, Verona, Italy Department of Life and Reproduction Sciences Pediatric Section, University of Verona, Verona, Italy Department of Surgery, University of Cagliari, Cagliari, Italy Clelia Zanaboni Department of Anesthesia, Pediatric and Neonatal Intensive Care, Istituto Giannina Gaslini, Genoa, Italy

xlii

Giacomo Zanelli Department of Medical Biotechnologies, University of Siena, Siena, Italy Rinaldo Zanini NICU, Ospedale Manzoni, Lecco, Italy Tianwei Ellen Zhou Departments of Pediatrics, Ophthalmology and Pharmacology, Centre Hospitalier, Universitaire Sainte-Justine, Research Center, Montréal, QC, Canada Ekhard E. Ziegler Department of Pediatrics, University of Iowa, Iowa City, IA, USA Luc J. I. Zimmermann Department of Pediatrics and Neonatology, School for Oncology and Developmental Biology (GROW), Maastricht University Medical Center, Maastricht, The Netherlands

Contributors

Part I Epidemiology and Fetal Neonatal Medicine

1

Development and General Characteristics of Preterm and Term Newborn Domenico Arduini, Gaia Pasquali, Stefano Parmigiani, Daniela Gianotti, and Giulio Bevilacqua

Contents 1.1

Salient Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

4

1.2 1.2.1 1.2.2 1.2.3 1.2.4 1.2.5

Part 1 The Development from Fetus to Newborn . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 Developmental Phases of the Fetus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 Fetal Constitutional Characteristics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 Diagnosis of Fetal Well-being . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 Fetal Injuries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 Fetal Response to Injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

1.3 Part 2 General Characteristics of Preterm and Term Newborn . . . . . . . . . . . . 19 1.3.1 History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23

Abstract

The embryonic phase is a critical stage of development. Fetal growth is mostly influenced by maternal, uteroplacental factors, as well as genetic and environmental factors. During pregnancy, noninvasive screening tests are used to evaluate a baby’s health. Severe acute or chronic intrauterine hypoxic stress in utero are responsible for compromised circulation, organ dysfunction,

D. Arduini (*) · G. Pasquali Department of Obstetrics and Gynecology, University of Rome Tor Vergata, Rome, Italy e-mail: [email protected]; [email protected]

and threaten survival or intact survival. The objective of modern obstetrics is the accurate detection of suboptimal fetal growth. Currently, sonography plays a critical role in providing a reliable estimate of fetal biometry, thus confirming the clinical suspicion of growth restriction and substantially influencing pregnancy management. Preterm birth, defined as birth at less than 37 weeks of gestation, is the main determinant of adverse infant outcome in terms of both survival and quality of life: the more preterm these infants are, the more serious are the complications. Because of advances in the care of these very vulnerable infants, survival at the earliest gestation is continuosly improving.

S. Parmigiani · D. Gianotti · G. Bevilacqua Department of Pediatrics and Neonatology, Eastern Liguria Hospital, La Spezia, Italy e-mail: [email protected]; [email protected]; [email protected] # Springer International Publishing AG, part of Springer Nature 2018 G. Buonocore et al. (eds.), Neonatology, https://doi.org/10.1007/978-3-319-29489-6_150

3

4

1.1

D. Arduini et al.

Salient Points

• Fetal hemoglobin has a higher affinity for oxygen than adult hemoglobin, which facilitates diffusion of oxygen from the maternal circulation to the fetus. • A continuous placental supply of glucose provides the substrate for energy metabolism to the fetus, and this converts after birth to intermittent feeding. • Individual characteristics based on the race, obstetric history, and the constitution of the parents, especially of the mother, should be taken into account to improve diagnostic accuracy and the construction of customized fetal growth charts and for the antenatal detection of the true small fetus, whose risk of adverse perinatal outcomes is substantially increased. • Hypoxemia produces various circulatory adaptations in the fetus that enhance fetal survival, including the development of tachycardia, hypertension, redistribution of blood flow toward the brain, myocardium and adrenals, and depression of fetal breathing and skeletal muscle activity. • The goal in the management of the preterm fetus is to deliver the most mature fetus possible, at least at 32–34 weeks, in the best possible condition by improving fetal and maternal monitoring. • The history of family, pregnancy, and delivery together with the first examination at birth has a pivotal role on assessing neonatal well-being. • A baby’s well-being is determined by periconceptional events. • Signs of immaturity should be recognized and a favorable environment should be created.

1.2

Part 1 The Development from Fetus to Newborn

1.2.1

Developmental Phases of the Fetus

The embryonic phase is a critical stage of development, when systems undergo important basic development.

The third week after conception marks the beginning of the embryonic period. It ends at the end of the tenth week, when the embryo comprises three layers from which all organs will develop. The second fetal phase begins after the tenth week and continues until the end of pregnancy. During this phase, organs (liver, kidneys) begin to function. From the 16th to 20th weeks, the fetus undergoes a rapid growth spurt. Fat develops under a thin skin. Cardiac output increases. Meconium accumulates in the bowel. The fetus hiccups and spends time awake and asleep. Fetal development slows down between the 21st and 24th weeks. By the 24th week, the fetus weighs approximately 1.3 pounds (600 g). Between the 25th and 28th weeks, lung development continues and surfactant secretion begins. By the 28th week, 90% of fetuses will survive ex utero with appropriate support. From the 29th to the 40th weeks, the amount of body fat rapidly increases. Thalamic brain connections, which mediate sensory input, form. Bones are fully developed. Most of the major systems and organs are complete. The immune system develops. By weeks 35–40, the fetus is sufficiently developed for life outside the uterus without any more support than that which would be required by any newborn baby delivered at term. At 37 weeks, the fetus will continue to add approximately one ounce (28 g) per day to its body weight and it will be 48–53 cm (19–21 inches) in length at birth.

1.2.2

Fetal Constitutional Characteristics

1.2.2.1 The Central Nervous System (CNS) The CNS is formed by four subdivisions of the neural tube that develop into distinct regions of the central nervous system. The neural tube is initially open both cranially and caudally. These openings close during the fourth week. Failure of closure of these neuropores can result in neural tube defects such as anencephaly or spina bifida.

1

Development and General Characteristics of Preterm and Term Newborn

The dorsal part of the neural tube comprises the alar plate, which is primarily associated with sensation. The ventral part of the neural tube comprises the basal plate, which is primarily associated with motor control. The spinal cord is a long, thin, tubular bundle of nervous tissue and supports cells that extend from the brain. The brain and spinal cord together make up the central nervous system. The spinal cord functions primarily for the transmission of neural signals between the brain and the rest of the body but also contains neural circuits that independently control numerous reflexes and central pattern generators.

1.2.2.2 The Fetal Circulation The essential difference between the circulatory system of a fetus and that of the baby after birth is that the lungs are not in use: the fetus obtains oxygen and nutrients from the mother through the placenta and the umbilical cord. Blood from the placenta is carried to the fetus by the umbilical vein. A large proportion enters the fetal ductus venosus and passes to the inferior vena cava, while the remainder enters the liver from vessels on its inferior border. The branch of the umbilical vein that supplies the right lobe of the liver joins the portal vein and blood then passes to the right atrium. In the fetus, there is an opening between the right and left atria (the foramen ovale), and most of the blood flows from the right into the left atrium, thus bypassing pulmonary circulation. The majority of blood flow is then into the left ventricle from where it is pumped through the aorta to supply the various organs. Blood then flows from the aorta through the internal iliac arteries to the umbilical arteries and reenters the placenta, where carbon dioxide and other waste products from the fetus are taken up and enter the maternal circulation. A small proportion (about 4%) of the blood from the right atrium does not enter the left atrium but enters the right ventricle and is pumped into the pulmonary artery. In the fetus, a connection between the pulmonary artery and the aorta, called the ductus arteriosus, directs most of the blood away from the lungs (which are not being used for respiration at this point, as the fetus is suspended in amniotic fluid).

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An important concept of the fetal circulation is that fetal hemoglobin has a higher affinity for oxygen than adult hemoglobin, which facilitates diffusion of oxygen from the maternal circulation to the fetus. The circulatory system of the mother is not directly connected to that of the fetus, so gas exchange takes place at the placenta. Oxygen diffuses from the placenta to the chorionic villus, an alveolus-like structure, from which it is then carried to the umbilical vein. Fetal hemoglobin enhances the fetal ability to draw oxygen from the placenta because the oxygen dissociation curve is shifted to the left, which has the effect of oxygen being taken up at a lower concentration than by adult hemoglobin. This enables fetal hemoglobin to take up oxygen from adult hemoglobin in the placenta, which has a lower partial pressure of oxygen than at the lungs after birth. A developing fetus is highly susceptible to anomalies of growth and metabolism, increasing the risk of birth defects.

1.2.2.3 Fetal Metabolism A continuous placental supply of glucose provides the substrate for energy metabolism to the fetus, and this converts after birth to intermittent feeding. While the fetus is dependent on maternal glucose as the main source of energy, it can also use lactate, free-fatty acids, and ketone bodies under some conditions (e.g., starvation or hypoxia). Fetal glucose utilization is augmented by insulin produced by the developing fetal pancreas in increasing amounts as gestation proceeds; this enhances glucose utilization in insulin-sensitive tissues (skeletal muscle, liver, heart, adipose tissue), which increase in mass and thus glucose requirement during late gestation. Glucose-stimulated insulin secretion increases with gestation. Glycogen stores are maximal at term, but even the term fetus only has sufficient glycogen available to meet energy needs for 8–10 h, and this store can be depleted even more quickly if demand is high. At 27 weeks’ gestation, only 1% of a fetus’s body weight is fat; this increases to 16% at 40 weeks. Inadequate glucose substrate can lead to hypoglycemia and fetal growth restriction. In cases of intrauterine growth restriction, fetal weight-specific tissue-glucose uptake rates

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and glucose transporters are maintained or increased, while synthesis of amino acids into protein and corresponding insulin-like growth factor (IGF) signal transduction proteins are decreased. These observations demonstrate the mixed phenotype of the intrauterine growth restriction (IUGR) fetus that has an enhanced capacity for glucose utilization, but a diminished capacity for protein synthesis and growth. Excess substrate can also lead to problems, as with infants of diabetic mothers (IDM). Thus, the normal fetus has a considerable capacity to adapt to changes in glucose supply (Way 2006).

1.2.2.4 Regulation of Fetal Growth Fetal growth depends on many different aspects, mostly influenced by maternal and uteroplacental factors. Role of the Mother in Fetal Growth Regulation Fetal growth and development are influenced by genetic as well as environmental factors. Maternal genes have an important specific influence on fetal growth; for example, maternal height is a major determinant of fetal size, representing uterine capacity and the potential for growth. In fact, the individual characteristic based on the race, obstetric history, and constitutional characteristics of the parents, especially of the mother, could be taken into account to improve diagnostic accuracy construction of customized fetal growth and for antenatal detection of the true small fetuses, whose risk of adverse perinatal outcomes is substantially increased (Ghi et al. 2016). Although the birth weights of siblings are similar and correlate, environmental influences are also important in determining growth. Maternal constraint refers to the limited capacity of the uterus to support fetal growth and is important in limiting fetal overgrowth and subsequent dystocia, to ensure the mother’s capacity for future successful pregnancies (Picciano 2003). Maternal Nutrient Intake

The mother is the supplier of oxygen and essential nutrients to the fetus via the placenta. Maternal diet, caloric intake, and metabolic function have

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an important role in supplying nutrients to the fetus. Increased caloric intake is necessary during the second and third trimesters to allow for fetal and placental growth (Christian et al. 2003). A Cochrane systematic review of six randomized controlled trials found that balanced protein-energy supplementation reduced the risk of small for gestational age (SGA) neonates by approximately 30% (Kramer and Kakuma 2003). Glucose is an important nutrient in the control of fetal growth. Studies of diabetic women have shown that low blood glucose levels during pregnancy as a result of excessively tight glycemic control lead to a greater incidence of SGA neonates, whereas high blood glucose levels increase the likelihood of macrosomia (Leguizamon and von Stecher 2003). Maternal Uterine Artery Blood Flow

Increased uterine blood flow is essential to meet the metabolic demands of the growing uterus as well those of the placenta and fetus (Kliman 2000). Uterine artery blood flow increases by more than threefold during pregnancy, partly influenced by an increased artery diameter and reduced resistance to flow. In addition to increased uterine blood flow during normal pregnancy, new blood vessels develop in the uterus, promoted by the placental hormones human chorionic gonadotropin (hCG) (Zygmunt et al. 2002) and IGF-II (Zygmunt et al. 2003). Using Doppler assessment of uterine arterial flow at 23 weeks’ gestation, Albaiges et al. (2000) found that increased uterine artery blood flow resistance was associated with an increased risk of an SGA baby. In the clinical practice, women with an abnormal uterine artery Doppler at 20–24 weeks (defined as a pulsatility index >95th centile) and women who have one major risk factor for SGA (maternal age > 40 years; chronic hypertension; diabetes with vascular disease; renal impairment; antiphospholipid syndrome; smoker >11cigarettes per day; cocaine; maternal or paternal SGA; previous SGA baby; previous still-birth; intensive exercise; previous pre-eclampsia; pregnancy interval 60 months; heavy bleeding similar to menses; PAPP-A < 0,4 MoM on first trimester screening) should be referred for serial ultrasound measurement of fetal size and

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assessment of well-being with umbilical artery Doppler commencing at 26–28 weeks of pregnancy (RCOG 2014). Maternal Smoking and Drug Use

Maternal cigarette smoking is associated with reduced birth weight. Early reports suggested a doubling of the rate of low birth weight in babies of smokers compared with those of nonsmokers and a dose-dependent effect with increasing number of cigarettes smoked. More recent studies demonstrated a 3.5-fold increased risk of SGA infants in women who smoked during pregnancy (Bamberg and Kalache 2004; Rich-Edwards et al. 2003), with a greater effect on low birth weight with increasing maternal age (Krampl et al. 2000). Growth restriction is usually symmetrical with reduced weight, head circumference, and abdominal circumference. The use of drugs, such as cocaine and marijuana, also has significant negative effects on fetal growth. Cocaine use contributes to an increased rate of low birth weight and a reduction in mean birth weight of at least 100 g. Maternal Hypoxia

Maternal hypoxia influences fetal growth. Its effect is independent of socioeconomic status, prematurity, maternal smoking, pregnancyinduced hypertension, and parity. The combination of hypoxia and pregnancy appears to be important in altering maternal physiology, including changes in immune pathways (Clapp 2003). Maternal hypoxia affects placental and uterine blood flow, which contribute to reduced nutrient transport to the fetus (Skomsvoll et al. 2002). Maternal Inflammatory Diseases

The presence of maternal inflammatory disease may contribute to reduced fetal growth. Several inflammatory diseases are associated with reduced fetal growth, including rheumatoid arthritis (McGaw 2002), inflammatory bowel disease, systemic lupus erythematosus, and periodontal disease (Bowden et al. 2001). Women with active inflammatory arthritis during pregnancy have smaller babies compared with healthy women or women whose disease is in remission (Xiao et al. 2003), suggesting that active inflammation during

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pregnancy may contribute to reduced fetal growth. Maternal health influences the maternal state during pregnancy with implications for fetal growth. In addition to inflammatory diseases, many other maternal factors, including preeclampsia (Allen 2001), anemia (Fowden and Forhead 2004), infections, and alcohol consumption, influence fetal growth via changes in placental function. Role of the Placenta in Fetal Growth Regulation The placenta receives and transmits endocrine signals between the mother and fetus and is the site of nutrient and waste exchange. During human pregnancy, the placenta is an important endocrine organ. It produces hormones, including estrogens and progesterone, hCG, human growth hormone (GH) variant, and human placental lactogen. Some of these play a role in the regulation of fetal growth. Fetal insulin promotes growth of the fetus, acting as a signal of nutrient availability (Ferrazzi et al. 2000). Insulin deficiency results in reduced fetal growth, as the fetal tissues decrease their uptake and utilization of nutrients. There is also a relationship between increased insulin production and increased fetal growth. It has been proposed that the fetus increases its own production of insulin in response to maternal hyperglycemia and that this increase in fetal insulin is responsible for the increased growth and macrosomia observed in diabetic pregnancies. Adequate placental growth is essential for adequate fetal growth. Several aspects of placental function are critical for human fetal growth and development, including adequate trophoblast invasion, an increase in uteroplacental blood flow during gestation, transport of nutrients such as glucose and amino acids from mother to fetus, and the production and transfer of growth-regulating hormones. Increased blood flow during pregnancy increases the flow of nutrients from mother to fetus, and uteroplacental blood flow has been shown to be reduced by up to 50% in women with preeclampsia (ACOG 2012). Doppler velocimetry is used to detect increased vascular resistance in the uterine arteries, which occurs

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as a result of abnormal trophoblast invasion of the spiral arteries. In addition, examination of the fetal circulation, particularly umbilical artery waveforms, may reflect placental insufficiency (ACOG 2012). Umbilical vein blood flow, measured by Doppler ultrasound, is decreased in IUGR fetuses, representing reduced perfusion of the fetal tissues.

1.2.3

Diagnosis of Fetal Well-being

During pregnancy, women are generally offered noninvasive screening tests, such as blood tests, ultrasound, and cardiotocography (CTG) to evaluate the baby’s health. Alternatively, more invasive tests, such as chorionic villous sampling (CVS) or amniocentesis, may be performed.

1.2.3.1 Ultrasound Obstetric ultrasound is usually used to: • Diagnose pregnancy • Assess possible risks to the mother (miscarriage or molar pregnancy) • Check for fetal malformation • Determine intrauterine growth restriction • Note the development of fetal body parts • Check the amniotic fluid and the umbilical cord

Fig. 1 Reconstructed 3-D imaging of fetal face (Image courtesy of G. Rizzo)

additional imaging of fetal structures. Today 3-D ultrasound is most commonly performed for the visualization of the baby’s face (Fig. 1). However, it has the potential to become part of routine care and many hospitals use the 3-D ultrasound to detect fetal anomalies, especially of the heart and of the CNS (Figs. 2 and 3).

7 weeks: Confirm pregnancy 11–13 weeks: Determine expected date of delivery and screening for aneuploidy 20–22 weeks: Perform a scan to assess anatomic integrity 32 weeks: Evaluate fetal growth, verify the position of the placenta, and perform the Doppler study to establish fetal well-being

1.2.3.2 Screening Tests for Aneuploidy Women should be offered prenatal assessment for aneuploidy by screening or diagnostic testing regardless of maternal age or other risk factors (Practice Bulletin No. 162 2016). Prenatal genetic diagnostic testing is intended to determine, with as much certainty as possible, whether a specific genetic disorder or condition is present in the fetus. In contrast, prenatal genetic screening is designed to assess whether a patient is at increased risk of having a fetus affected by a genetic disorder (Spencer et al. 1999). Two methods are currently available in the screening for aneuploidy:

Three-dimensional (3-D) and four-dimensional (4-D) ultrasound techniques are used to provide

1. At 11–13 weeks’ gestation, combination of maternal age, fetal nuchal translucency

Generally an ultrasound examination is ordered whenever an abnormality is suspected or following a schedule similar to that outlined below:

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Fig. 2 Reconstructed 3-D imaging of the eyes, palate, and mandible from the fetal profile

Fig. 3 Reconstructed 3-D imaging of the corpus callosum (Image courtesy of G. Rizzo) Fig. 4 Fetal profile at 12 weeks of gestation showing nuchal translucency (Image courtesy of G. Rizzo)

thickness measured by ultrasound (Fig. 4) and maternal serum concentration of free β-human chorionic gonadotropin and pregnancy-associated plasma protein-A could assess the risk for trisomy 21, trisomy 18, and trisomy 13 (Nicolaides 2004; Palomaki et al. 2011). The incidence of fetal trisomies is directly related to maternal age. The risk of having a child with Down syndrome increases in a gradual, linear trend until about age 30 and increases exponentially thereafter.

Nuchal translucency (NT) is the sonographic appearance of a collection of fluid under the skin behind the fetal neck in the first-trimester of pregnancy. NT normally increases with gestation. Increased NT thickness over the normal range for gestational age is related to chromosomal defects, especially trisomy 21, but is also associated with major abnormalities of the heart and great arteries and a wide range of genetic syndromes. The level of free b-hCG in maternal blood normally decreases with gestation. In trisomy 21

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pregnancies, free b-hCG is increased. The level of PAPP-A in maternal blood normally increases with gestation, and in trisomy 21 pregnancies the level is decreased. Some studies demonstrated that the detection rate of this test can increase to about 95% by also examining the nasal bone (absent or hypoplastic in a high proportion of fetuses with trisomy 21 and other chromosomal abnormalities), ductus venosus flow (a-wave absent or reversed in fetal aneuploidies or in fetal cardiac defects), and tricuspid flow (tricuspid regurgitation is a common finding in fetuses with trisomy 21, 18, and 13 and in those with major cardiac defects). 2. From the 10th week of gestation, analysis of cell-free DNA in maternal blood. Circulating cell-free DNA in the plasma of pregnant women is a mixture of genomic DNA fragments of maternal and fetal (placental) origin that could be extracted and analyzed (Sparks et al. 2012; Zimmermann et al. 2012; Canick et al. 2013; Botto et al. 1996). Screening for fetal aneuploidy in pregnant women using cellfree DNA has demonstrated high sensitivity and specificity to screen for common aneuploidies in high-risk populations. Recently, this method started to include microdeletion screening and whole genome screening.

1.2.3.3 Invasive Tests After an abnormal first-trimester ultrasound examination or screening test, it is necessary to confirm the diagnosis with an invasive procedure, chorionic villous sampling, or amniocentesis. The earlier CVS results allow for more management options, although amniocentesis also is an option for diagnosis (Spencer et al. 1999). Chorionic Villous Sampling Chorionic villus sampling for prenatal genetic diagnosis generally is performed between 10 and 13 weeks of gestation. In fact, before 10 weeks there is a risk of limb-reduction defects (Akolekar et al. 2015). The primary advantage of CVS over amniocentesis is that the procedure can be performed earlier in pregnancy and the viable cells obtained by CVS for analysis allow for shorter specimen

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processing time (5–7 days versus 7–14 days), so the results are available earlier in pregnancy. The most recent meta-analysis of studies calculated a procedure-related loss rate of 0.22% (Alfirevic et al. 2003). The incidence of culture failure, amniotic fluid leakage, or infection after CVS is less than 0.5% (Winsor et al. 1999). Amniocentesis Amniocentesis for the purpose of genetic diagnosis usually is performed between 15 weeks and 20 weeks of gestation, but it can be performed at any later gestational age. An amniotic fluid sample of 20–30 ml is obtained from a pocket free of fetal parts and umbilical cord. The most recent meta-analysis of studies calculated a procedure-related loss rate of 0.11% (Alfirevic et al. 2003). The incidence of culture failure is approximately 0.1% of samples (Winsor et al. 1999).

1.2.3.4 Cardiotocography Cardiotocography is a technique of surveillance of fetal well-being useful first of all during labor to identify the fetus compromise. When the risk of antepartum fetal demise is increased (e.g., pregestational and gestational diabetes mellitus; hypertension; gestational hypertension; preeclampsia; systemic lupus erythematosus; chronic renal disease; antiphospholipid syndrome; hyperthyroidism; hemoglobinopathies; heart disease; decreased fetal movement; oligohydramnios; fetal growth restriction; late-term or postterm pregnancy; isoimmunization; previous fetal demise; monochorionic multiple gestation), it may be necessary to monitor fetal activity during pregnancy with a nonstress test (NST) to identify some degree of uteroplacental compromise (Liston et al. 2007). The NST is based on the premise that the heart rate of a fetus that is not acidotic or neurologically depressed will temporarily accelerate with fetal movement. Heart rate reactivity is thought to be a good indicator of normal fetal autonomic function. Loss of reactivity may result from any cause of central nervous system depression, including fetal acidemia. Attention is required for the preterm fetuses; in

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fact, the NST of the normal preterm fetus is frequently nonreactive: from 24 weeks to 28 weeks of gestation, up to 50% of NSTs may not be reactive (Bishop 1981), and from 28 weeks to 32 weeks of gestation, 15% of NSTs are not reactive (Macones et al. 2008). For this reason, starting fetal monitoring after 32 weeks of gestation is appropriate for most at-risk patients. However, in pregnancies with very high-risk conditions, testing might begin at a gestational age when delivery would be considered for perinatal benefit (ACOG 2014).

1.2.4

Fetal Injuries

It is important during fetal development to maintain good fetal oxygen delivery to avoid irreversible fetal compromise. Fetal hypoxia from any cause leads to conversion from aerobic to anaerobic metabolism, which produces less energy and more acid. If the oxygen supply is not restored, the fetus dies. Hypoxia may be classified as follows: • Hypoxemic hypoxia: reduced placental perfusion with maternal blood and consequent decrease in fetal arterial blood oxygen content due to low pO2 • Anemic hypoxia: reduced arterial blood oxygen content due to low fetal hemoglobin concentration • Ischemic hypoxia: reduced blood flow to the fetal tissues Making this diagnose can be difficult, and some episodes of hypoxia before and during birth may pass unnoticed at the time but may affect the central nervous system and not become evident until much later in life.

1.2.4.1 Causes of Hypoxia Two major categories of neurological injury can be observed in the full-term infant: (1) hypoxicischemic encephalopathy (HIE) and (2) intracranial hemorrhage (ICH). Brain hypoxia and ischemia due to systemic hypoxemia, reduced cerebral blood flow (CBF), or both are the primary

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pathophysiological processes that lead to a hypoxic-ischemic encephalopathy. The first compensatory adjustment to a hypoxic-ischemic (asphyxic) event is an increase in CBF due to hypoxia and hypercapnia. This is associated with a redistribution of cardiac output so that the brain receives an increased proportion of the cardiac output. This is followed by a slight increase in systemic blood pressure (BP) due to increased release of epinephrine. In the fetus suffering from acute asphyxia (hypoxic ischemia), if early compensatory adjustments fail, cerebral blood flow (CBF) may become pressure passive, and brain perfusion becomes dependent on systemic BP. As BP falls, CBF falls below critical levels, and a diminished blood supply in the brain leads to insufficient oxygen to meet its needs and intracellular energy failure. Neuronal injury in hypoxic ischemia is an evolving process. During the early phases of brain injury, brain temperature drops, and there is local release of neurotransmitters, such as gaminobutyric acid transaminase (GABA). The magnitude of the final neuronal damage depends on both the severity of the initial insult and damage due to energy failure, injury during reperfusion, and apoptosis. The extent, nature, severity, and duration of the primary injury are all important in determining the magnitude of the residual neurological damage. Intracranial hemorrhage in the full-term infant can be intraventricular, subarachnoid, subdural, or intracerebellar. There is often ventilatory disturbance and hypoxia because of varying neurological depression. Intraventricular hemorrhage (IVH), which is unusual in term infants, may be associated with evidence of intrapartum asphyxia but may also be clinically silent and underdiagnosed, causing later deficits or hydrocephalus (Rohan and Golombek 2009). Approximately 20% of neonatal HIE is primarily related to antepartum events that lead to hypoxic ischemia. Maternal conditions such as hypotension, placental vasculopathy, and insulin-dependent diabetes mellitus may predispose the fetus to intrapartum hypoxic ischemia because there is little reserve to compensate for the stresses of labor (Volpe 2008). Intrapartum events such as

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prolapsed cord, abruptio placentae, and traumatic delivery have been linked to 35% of cases of HIE. Because of the limitations in determining the actual timing of the insult, it may be difficult to identify the antepartum contribution separately from the intrapartum. Other events besides intrapartum hypoxia may be responsible for HIE or CP, as less than 25% of these infants have symptoms of hypoxic ischemia at birth (Task Force on Neonatal Encephalopathy and Cerebral Palsy Staff American College of Obstetricians and Gynecologists with American Academy of Pediatrics Staff 2014). The true incidence of intracranial hemorrhage (ICH) in utero has not been determined. Significant subarachnoid hemorrhage can occur with intrapartum hypoxia or may result from trauma at delivery. It can be isolated or associated with subdural bleeding and cerebral contusion. The presentation is variable but generally includes CNS depression, irritability, and seizures. When subarachnoid hemorrhage is associated with other signs of physical injury and is caused by a difficult delivery, outcome is frequently poor.

1.2.5

Fetal Response to Injury

During normal development, cardiovascular and circulatory functions progress from fetal life, which is characterized by low PaO2 (20–24 mmHg; 2.66–3.19 kPa) through transition at birth, to normoxemia after birth (PaO2 70–80 mmHg; 9.31–10.64 kPa); the fetus and newborn are clearly able to thrive despite their “hypoxic” environment. Adaptive responses by the cardiovascular, metabolic, and endocrine systems allow fairly severe intrauterine hypoxic stress to be tolerated, with the fetus having relatively normal growth and development. However, severe acute or chronic intrauterine hypoxic stress in utero can cause compromised circulation, organ dysfunction, and threaten survival or intact survival. At the time of transition to extrauterine life, signs of a depressed circulatory system because of intrauterine hypoxia may become apparent because of the increased metabolic demands at birth and loss of placental gas exchange (Anderson et al. 2004).

The fetal heart also has a greater capacity for anaerobic metabolism than the adult heart (Philipps 2004). Renal impairment is commonly reported following a generalized hypoxic-ischemic insult at birth. The degree of insult varies in effect from oliguria with minor electrolyte abnormality and minimally elevated creatinine to complete renal failure requiring dialysis. An elevated blood concentration of liver enzymes, as a marker of hepatocellular injury due to perinatal hypoxia, is also common after acute hypoxia, but irreversible liver damage is rare. Fetal cardiovascular and endocrine responses may be altered, both in acute and in chronic hypoxia. Recurrence of mild hypoxia may occur in pregnancies where the blood flow to placenta, uterus, and fetus is repeatedly compromised by physiological and environmental influences. In chronic hypoxia, fetal growth restriction is not uncommon, and depression of growth factors during hypoxia has an important protective effect in conserving fetal substrate for energy as opposed to growth needs (Noori et al. 2004; Seri and Evens 2001). The full-term infant, while more likely to survive a severe hypoxic-ischemic insult at birth than a preterm infant (approximately 70% vs. 30%), is also more likely to have significant long-term morbidity (Cressens and Huppi 2006). In umbilical venous blood, mild hypoxemia may be manifest through an absence of hypercapnia or acidemia. In severe uteroplacental insufficiency, the fetus cannot compensate hemodynamically, and hypercapnia and acidemia increase exponentially (Bastek et al. 2008). Hypoxemic growthrestricted fetuses also demonstrate a range of hematological and metabolic abnormalities, including erythroblastosis, thrombocytopenia, hypoglycemia, deficiency in essential amino acids, hypertriglyceridemia, hypoinsulinemia, and hypothyroidism. Low birth weight increases the risk for perinatal mortality (death shortly after birth), asphyxia, hypothermia, polycythemia, hypocalcemia, immune dysfunction, neurologic abnormalities, and other long-term health problems (Petrini et al. 2009).

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1.2.5.1 Fetal Hemodynamic Aspects Acute hypoxemia produces various circulatory adaptations in the fetus that enhance fetal survival, including the development of tachycardia, hypertension, redistribution of blood flow toward the brain, myocardium and adrenals, and depression of fetal breathing and skeletal muscle activity. This results in an increased blood supply to the brain, myocardium, and adrenal glands and reduced perfusion of the kidneys, gastrointestinal tract, and the lower extremities. There is preferential delivery of nutrients and oxygen to vital organs, compensating for a diminished placental supply (Sheridan 2005). This compensation is manifest as cerebral vasodilatation and there is a decrease in the pulsatility index (PI) in cerebral vessels (Figs. 5 and 6). The PI index is an arterial blood-flow velocity waveform index designed to quantify the pulsatility or oscillations of the waveform. It is calculated by the formula PI = (Vmax
Vmin)/Vmax mean, where Vmax is the peak systolic velocity, Vmin is the minimum forward diastolic velocity in unidirectional flow or the

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maximum negative velocity in diastolic flow reversal, and Vmax mean is the maximum velocity averaged over one cardiac cycle. Cerebral vasodilatation produces a decrease in left ventricular afterload, while increased placental and systemic resistance result in an increased right ventricular afterload. In severe hypoxemia, there is also redistribution of umbilical venous blood towards the ductus venosus. Consequently, blood flow in the umbilical vein, which contributes to the fetal cardiac output, is increased. In contrast, a reduced afterload is associated with an increase in peak diastolic forward flow, indicating that fetal systemic vascular resistance has a major influence on venous return and filling patterns of the right heart. Increased placental resistance and peripheral vasoconstriction cause an increase in right ventricular afterload, and thus ventricular end-diastolic pressure increases. This may result in highly pulsatile venous blood flow waveforms and umbilical venous pulsations due to the transmission of atrial pressure waves through the ductus venosus.

Fig. 5 Flow velocity waveforms from the middle cerebral artery in a normal fetus (Image courtesy of G. Rizzo)

Fig. 6 Flow velocity waveforms from the middle cerebral artery in a growth-restricted fetus (Image courtesy of G. Rizzo)

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Investigations of the venous vascular system have become increasingly important in the assessment of fetal myocardial function, and different indices are used to evaluate the blood flow velocity during the different phases of the cardiac cycle in the ductus venosus. Reference values for ductus venosus flow velocities are represented by ventricular systole (S wave) and diastole (D wave), the lowest forward velocity during atrial contraction (A wave) (Fig. 7). Different indices are calculated, e.g., the S/A ratio. The most important parameter which represents the final stage of disease is the abnormal reversal of blood flow velocities in the ductus venosus, inducing an increase in the S/A ratio, mainly due to a reduced A component of the velocity waveforms (Fig. 8). Reference values should be used for ductus venosus flow velocities during ventricular systole (S wave) and diastole (D wave), the lowest forward velocity during atrial contraction (A wave) and different calculated indices as the S/A. In the inferior vena cava, there is an increase of reverse flow during atrial contraction with progressive fetal deterioration, suggesting a higher pressure gradient in the right atrium. (Figs. 9 and 10). A high venous pressure induces a reduced velocity at end-diastole in the umbilical vein, causing typical end-diastolic pulsations. The development of these pulsations is close to the onset of abnormal fetal heart rate patterns and is frequently associated with acidemia and fetal endocrine changes. At this stage, there may be an increased coronary blood flow velocity compared with that seen in normally grown third-trimester fetuses and, if the affected fetus is not delivered, intrauterine death may occur within a few days.

1.2.5.2 Fetal Growing Aspects Accurate detection of suboptimal fetal growth is among the objectives of modern obstetrics. To achieve this result, sonography plays a critical role in providing a reliable estimate of fetal biometry, thus confirming the clinical suspicion of growth restriction and substantially influencing pregnancy management. An approach based on customized charts has proved to be more accurate than traditional population-based charts for

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antenatal detection of the true small fetuses, whose risk of adverse perinatal outcomes is substantially increased (Ghi et al. 2016). The term small for gestational age (SGA) describes a condition in which the fetus is smaller than expected for the number of weeks of pregnancy (below the tenth percentile) and is unable to achieve its genetically determined potential size; when a SGA fetus shows also signs of placental insufficiency, it is defined an intrauterine growth restriction (IUGR) fetus. IUGR is not synonymous with SGA. Some, but not all, growthrestricted fetuses/infants are SGA, while 50–70% of SGA fetuses are constitutionally small, with fetal growth appropriate for maternal size and ethnicity. This functional definition is useful to identify a population of fetuses at risk of poor outcome. The clinician’s challenge is to distinguish between these two conditions and identify IUGR fetuses whose health is endangered in utero because of a hostile intrauterine environment and consequently to monitor and intervene appropriately. In fact, data support the notion that long-term consequences of IUGR last well into adulthood. These individuals are predisposed to the development of a metabolic syndrome later in life, manifesting as obesity, hypertension, hypercholesterolemia, cardiovascular disease, and type 2 diabetes. Several hypotheses suggest that intrauterine malnutrition results in insulin resistance, loss of pancreatic beta-cell mass, and an adult predisposition to type 2 diabetes. Although the causative pathophysiology is uncertain, the risk of a metabolic syndrome in adulthood is increased among individuals who were IUGR at birth (Engle et al. 2007). In addition to an increased risk for physical sequelae, mental health problems have been found more commonly in children with growth restriction.

1.2.5.3 Diagnosis Fetal arterial Doppler studies are useful in the differential diagnosis of SGA and IUGR fetuses. In normal pregnancies, umbilical artery (UA) resistance shows a continuous decline as the pregnancy progresses (Fig. 11), but this does not occur in fetuses with uteroplacental insufficiency.

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Fig. 7 Color Doppler examination of the ductus venosus with normal flow velocity waveforms (Image courtesy of G. Rizzo)

Fig. 8 Abnormal DV waveform with reversal of flow during atrial contraction and markedly increased pulsatility systole (S), diastole (D), atrial contraction (a)

Fig. 9 Doppler examination of the inferior vena cava with normal flow velocity waveforms

Fig. 10 Abnormal waveform with increase in reversed flow during atrial contraction in a growthrestricted fetus

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The most commonly used measure of gestational age-specific UA resistance is the systolicto-diastolic ratio of flow, the Pulsatility Index (PI), which increases with worsening disease. As the insufficiency progresses, end-diastolic velocity is lost and eventually reversed (Fig. 12). The status of UA blood flow supports the diagnosis of IUGR and provides early evidence of circulatory abnormalities in the fetus, helping clinicians to identify these high-risk fetuses. UA Doppler measurements may help the clinician decide whether a small fetus is truly growth restricted and to identify a small fetus at risk of chronic hypoxemia, but IUGR diagnosis is challenging and cannot only be based only on umbilical artery Doppler (CruzMartínez et al. 2011). In hypoxemic fetuses with impaired placental perfusion, the PI in the umbilical artery is

Fig. 11 Color Doppler of the umbilical artery with normal flow velocity waveforms (Image courtesy of G. Rizzo)

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increased and the fetal middle cerebral artery PI is decreased; consequently, the PI ratio of the middle cerebral artery to umbilical artery (MCA/UA), defined as cerebroplacental ratio, (CPR) is decreased. The CPR is emerging as an important predictor of adverse outcome not only for IUGR fetuses but also for SGA and appropriate for gestational age (AGA) fetuses close to term (DeVore 2015). Recent evidence suggests that a proportion of these SGA fetuses have milder forms of late-onset intrauterine growth restriction as suggested by an increased risk of adverse perinatal outcome (McCowan et al. 2000; Doctor et al. 2001; Figueras et al. 2008a), abnormal neonatal neurobehavioral performance (Figueras et al. 2009), and suboptimal neurodevelopment in childhood (McCowan et al. 2002; Figueras et al. 2008b). These findings add to the body of evidence suggesting that the diagnostic category of SGA includes a proportion of cases with true growth restriction and mild placental insufficiency, which is not reflected in the umbilical artery Doppler. Recent studies suggest that the risk of adverse outcome in these fetuses is best established by means of brain Doppler examination. Thus, brain sparing as measured by the middle cerebral artery Doppler is associated with poorer perinatal outcome, higher risk of cesarean delivery for nonreassuring fetal status (Severi et al. 2002), and increased risk of abnormal neurodevelopmental tests at birth (Oros et al. 2010) and at 2 years of age (Eixarch et al. 2008).

Fig. 12 Color Doppler of the umbilical artery with reversed flow (Image courtesy of G. Rizzo)

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Development and General Characteristics of Preterm and Term Newborn

1.2.5.4 Timing of Delivery and Management In the past, the period from 3 weeks before until 2 weeks after the estimated date of delivery was considered “term,” with the expectation that neonatal outcomes from deliveries in this interval were uniform and good. Increasingly, however, research has shown that neonatal outcomes, especially respiratory morbidity, vary depending on the timing of delivery within this 5-week gestational age range. To address this lack of uniformity, The American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine recommended that the label “term” be replaced with the designations below (ACOG 2013): • Early term (37 0/7 weeks of gestation through 38 6/7 weeks of gestation) • Full term (39 0/7 weeks of gestation through 40 6/7 weeks of gestation) • Late term (41 0/7 weeks of gestation through 41 6/7 weeks of gestation) • Postterm (42 0/7 weeks of gestation and beyond) Preterm birth, defined as birth at less than 37 þ 0 weeks of gestation, is the most important single determinant of adverse infant outcome in terms of both survival and quality of life (Saigal and Doyle 2008). An useful pragmatic definition for a “premature” infant is one who has not yet reached the level of fetal development that generally allows life outside the womb. In the normal human fetus, several organ systems mature between 34 and 37 weeks, and the fetus reaches adequate maturity by the end of this period. One of the main organs greatly affected by premature birth is the lung. In Europe and many developed countries, the preterm birth rate is generally 5–9%, and in the USA, it has risen to 12–13% in the last decades. There are three categories of preterm birth: (1) spontaneous preterm births are the 40–45% preterm births that follow preterm labor of spontaneous (i.e., idiopathic) onset; (2) 25–30% preterm births occur after premature rupture of the membranes; (3) the remaining 30–35% are preterm births that are induced for obstetric reasons.

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Babies born just a few weeks earlier than fullterm usually do not experience any problems related to their slight prematurity. However, the more premature these infants are, the more serious are the complications. Although there are recommendations that term IUGR fetuses should be monitored during delivery as high-risk pregnancies (Royal College of Obstetricians and Gynaecologists 2002), there is no consensus about the best strategy for delivery. The Lancet published data on brain development in survivors of the multicenter Growth Restriction Intervention Trial (GRIT) (Thornton et al. 2004). The aim of this study was to identify compromised fetuses between 24 and 36 weeks’ gestation and answer the question of whether it was safer to deliver them immediately or to delay until there was no clinical doubt that delivery was necessary. In the GRIT study, the 24 week gestation babies were very different from those at 36 weeks. In the absence of severe congenital abnormalities, the current infant mortality after 32 weeks’ gestation is low: the causes of this rare event include asphyxia, necrotising enterocolitis, and infection; respiratory distress syndrome is rare in this group. By contrast, before 32 weeks, and particularly in the extreme preterm fetus, there is a much higher mortality, and the levels of morbidity were also emphasized by the EPICure Study, in which 49% of surviving infants born at less than 26 weeks’ gestation had some disability at 30 months of age and 19% were severely disabled (Wood et al. 2000). The EPICure study reached some important conclusions. It demonstrated that 44% of infants born at 25 weeks’ gestation survived to discharge, whereas delivery at 22 weeks almost invariably resulted in neonatal death. Neonatologists, obstetricians, and parents must increasingly recognize that infants born less than 25 weeks’ gestation who survive are at risk of disability at school age. In the EPICure study, only 20% were totally free of disability at school age and so the prognosis must be guarded. Disability was classified as follows: 1. Severe: The child was likely to be highly dependent on care-givers, e.g., non-ambulant cerebral palsy, profound hearing loss, or blindness.

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2. Moderate: Children who were likely to be reasonably independent, e.g., ambulant cerebral palsy, some hearing loss, or some visual impairment. 3. Mild: Children with neurological signs with minimal functional consequences. In the EPICure study, over half of the survivors had moderate disability or no disability at school age. In addition, some of the 24% with moderate disability were improved with spectacles and hearing aids. There is uncertainty about whether iatrogenic delivery of the very preterm (before 33 weeks of gestation) growth-restricted fetus should be undertaken before the development of signs of severe hypoxemia, with a consequent risk of prematurity-related neonatal complications, or whether delivery should be delayed, incurring risks of prolonged exposure to hypoxia and malnutrition imposed by the hostile intrauterine environment (Walter et al. 2009). With every week that passes, there is a decreasing risk of complications including intraventricular hemorrhage, retinopathy of prematurity, and sepsis. However, delay may expose the growth-restricted fetus to ischemic injury of the brain, resulting in asphyxia, periventricular leukomalacia, and intraventricular hemorrhage, as well as a significant risk of intrauterine death. It is important to weigh the risks and benefits of early interventions. This is a dynamic process, in which advancements in both fetal and neonatal medicine are of crucial importance for the appropriate counseling of parents and the management of these pregnancies. The GRIT study showed a small increase in fetal death if the obstetrician delayed delivery, and a small increase in neonatal death if early delivery was chosen. Thus the monitoring of fetal health is particularly important if there is growth restriction. Such fetuses have few metabolic reserves, and sudden death during pregnancy may occur. Labor is an intermittently hypoxic event, and anaerobic metabolism may not be an option when there are inadequate stores of fat and glycogen.

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In recent years, placental and fetal arterial Doppler flow-velocity waveforms have guided the timing of delivery. Doppler has been particularly effective in assessing the growth-restricted pregnancy and has been a useful adjunct for the assessment of the very preterm fetus, when cardiotocographical monitoring is unhelpful. However, in the growth-restricted hypoxemic fetus, redistribution of well-oxygenated blood to vital organs, such as the brain, heart, and adrenals, represents a compensatory mechanism to prevent fetal damage, and when the reserve capacities of the circulatory redistribution reach their limits, fetal deterioration may occur rapidly. In clinical practice, serial Doppler investigations estimate the duration and degree of fetal blood flow redistribution. The onset of an abnormal venous Doppler recording indicates deterioration in the fetal condition and iatrogenic delivery should be considered. Delivery of IUGR fetuses remain a challenging problem for clinicians not only for preterm but also for fetuses near term. In practice, term pregnancies are often delivered, and the delivery of the late preterm (34 þ 0–36 þ 6 weeks) or early term (37 weeks) growth-restricted fetus is also recommended if there are additional risk factors for adverse outcome, such as maternal medical/ obstetrical disorders, arrest of growth over a 3–4 week interval, and/ or absence or reversal Doppler flow in the umbilical artery (Spong et al. 2011). A recent multicenter clinical trial, the Disproportionate Intrauterine Growth Intervention Trial At Term (DIGITAT), failed to demonstrate differences in perinatal outcome between expectant management compared with induction of labor in fetuses beyond 36 weeks’ gestation (Boers et al. 2010; Tajik et al. 2014). The study confirms that the relatively favorable neonatal outcomes in both study groups could reflect the fact that participants and clinicians were more alert to possible complications and monitoring was intensified. In conclusion, the goal in the management of the preterm fetus is to deliver the most mature fetus possible, at least at 32–34 weeks, in the best condition possible increasing fetal and maternal monitoring (Table 1).

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Development and General Characteristics of Preterm and Term Newborn

Table 1 Suggested management of the preterm fetus What to do

Considering

When

Where How

Perform parental counseling Share any type of decisions with the neonatologist, the anesthesiologist, and the couple, personalizing the specific situation Fill the informed consent as much detailed as it is possible Short-term consequences: RDS, NEC, IVH, PVL, pulmonary dysplasia, sepsis Long-term consequences: cerebral palsy, mental impairment, attention disorders Pregnancy age and prognosis age Etiology of the preterm labor (maternal causes, fetal causes) Maternal mortality related to the type of delivery Fetal presentation Obstetric anamnesis of the patient Combination of the multiple factors Better after 26 weeks Using corticosteroids between 48 h and 7 days before delivery Any hospital with NICU Trying to reduce the effects of the hypoxia Balance maternal and fetal morbidity Preterm delivery is not itself an indication of cesarean section unless associated with maternal or fetal consequences

1.3

Part 2 General Characteristics of Preterm and Term Newborn

1.3.1

History

A full family history is essential. This should include a full medical and social history. Note should be taken of alcohol ingestion and of any drugs (prescribed or recreational). It should enquire about the possibility of consanguinity – the question, “Are your families related?” to both parents is one way of approaching this often delicate subject. Enquiry should be made about the presence of possible transmissible and inheritable diseases in the families of both parents. Tall or short stature can generate a search for specific undiagnosed diseases in the parents (e.g., Marfan

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syndrome, gluten intolerance, achondroplasia). Anemia in the parents can be a marker of a hematological defect (e.g., thalassemia), as well as the place of origin and ethnicity of the parents (e.g., G6PD deficiency).

1.3.1.1 History of the Pregnancy and Delivery A baby’s well-being is determined by periconceptional events. The mother’s medical history is important, including the possibility of maternal diabetes mellitus and other illnesses and her immune status (HBV, HCV, HIV, CMV, toxoplasmosis, rubella, HSV-HZV, and syphilis). The possibility of seroconversion during pregnancy should be considered. Enquiry should be made about the course of the pregnancy. Account should be taken of the time of booking for antenatal care (late booking may be a sign of a disorganized life style and associated problems). The results of antenatal checks should be noted: fetal growth and ultrasound results, amniotic fluid volume, maternal anemia, urine results and maternal diabetes mellitus, and pregnancyinduced hypertension or pre-eclampsia. The results of vaginal and anal bacterial swabs within the month before delivery should be noted (group B streptococci or Listeria monocytogenes) and whether the mother was given appropriate intrapartum antibiotic prophylaxis. A history of the pregnancy should include note of drugs taken during the pregnancy and their indications. Consider evidence of infectious illnesses or fever close to the time of delivery and take note of the timing of membrane rupturing and the quantity and color (blood or meconium staining) of the amniotic fluid. Details of the delivery should be noted, i.e., whether vaginal, operative (forceps of vacuum extraction), cesarean section (planned or emergency, before or during the labor), and evidence of fetal distress. The baby’s presentation should be noted because abnormal limb position may be due to a breech presentation. The possibility of birth trauma (e.g., cephalohematoma, fracture of the clavicle) should be considered.

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Adaptation to postnatal life should be considered, bearing in mind that during the first hours after birth the baby is in a transitional period, passing from intra- to extrauterine life. A baby’s condition during the minutes just after birth is described by the Apgar score, usually recorded at 1 and 5 min (see Table 2). Although the Apgar score may be criticized (it is subjective on the part of the observer, often recorded some time after delivery), in its favor, it is almost universally recorded. The score was described in 1953 by Dr. Virginia Apgar, a North American pediatric anesthetist. She intended it to indicate whether or not resuscitation was needed. Although imperfect, there is no doubt that a low score (0 or 1, signifying an absent or slowly beating heart) indicates a baby who is barely alive at the time of birth, and a score of 8 or more indicates an individual whose general condition is good. However, the Apgar score is an imperfect indicator of subsequent progress or outcome. A baby who has a high initial score may develop difficulties with gas exchange in the minutes that follow, even if these problems are transient. More recent researches have shown that the great majority of normal term infants reach transcutaneous pre-ductal values of oxygen saturation 90% after 10 min from birth and that premature infants normal LBs

PAP

NDa

a ND not determined for type II cells; large, foamy alveolar macrophages filled with surfactant material or large vacuoles containing neutral lipids, or both, were observed with electron microscopy Abbreviations: ABCA3 ATP-binding cassette transporter A3, CPI chronic pneumonitis of infancy, CSF2R granulocytemacrophage colony-stimulating factor receptor, DIP desquamative interstitial pneumonia, ER endoplasmic reticulum, ILD interstitial lung disease, LB lamellar body, MVB multivesicular body, NSIP nonspecific interstitial pneumonia, PAP pulmonary alveolar proteinosis, RDS respiratory distress syndrome, SP/SFTP surfactant protein, UIP usual interstitial pneumonia

identified. Infants with SFTPC mutations usually exhibit features of chronic pneumonitis of infancy (Nogee 2004; Glasser et al. 2013). Mutations in ABCA3 on chromosome 16 are the most common cause of hereditary respiratory failure in newborns. Mutations have been identified throughout the ABCA3 gene that cause abnormal processing, misrouting, or impaired lipid transport as well as

secondary effects on processing SP-B and SP-C. Lung histology is consistent with congenital PAP or infantile DIP. While ABCA3 is expressed in various tissues, abnormalities are found only in the lung. Pulmonary disease associated with ABCA3 deficiency is generally fatal although a number of infants have been treated by lung transplantation. Prenatal and postnatal diagnoses are best made by identifying mutant ABCA3 alleles. Diseases

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Fig. 1 Histopathology of neonatal lung. (a) Normal neonatal lung histology with thin alveolar septa and airspaces devoid of debris. (b) Histopathology of the lung from a child who had fatal SP-B deficiency demonstrates thickened alveolar septa and eosinophilic, lipoproteinaceous material intermixed with large foamy alveolar

macrophages (arrow) filling the alveolar spaces. (c) Histopathology of the lung from a child who had fatal ABCA3 deficiency is similar to that for fatal SP-B deficiency, as shown in panel b. Original magnification is 10 (Downloaded from Gower et al. (2008))

related to ABCA3 and SFTPB are similar in onset and clinical course and are generally associated with severe respiratory failure, although several ABCA3 mutations have been associated with chronic ILD in older infants, children, and adolescents. Histopathological findings vary depending upon the age of the patient and the mutation and often overlap with those found in deficiencies of SP-B and SP-C (Bullard et al. 2006; Shulenin et al. 2004; Doan et al. 2008).

pulmonary artery from the right (pulmonary artery sling), sometimes with a cross-over arterial segment, with the right upper lobe supplied by a branch from the left pulmonary artery. The unilateral absence of a pulmonary artery leads to the lung on that side receiving only systemic blood, either through anomalous systemic arteries or enlarged bronchial arteries. One or both pulmonary arteries may take origin from the aorta. Bilateral origin from the aorta is part of the spectrum of common arterial trunk. Unilateral origin of a pulmonary artery from the aorta may be an isolated abnormality. Finally, a congenitally small unilateral pulmonary artery is usually seen in association with an ipsilateral congenitally small lung (CSL). Normal pulmonary blood flow is needed for normal lung development. Regarding systemic arterial tree, two groups of abnormalities are relevant to the lung. The first group consists of those producing a vascular ring.

59.3.3 Vascular Malformations 59.3.3.1 Abnormalities of the Arterial Tree (Pulmonary and Systemic) When a lung malformation was found, it is important that also abnormal vasculature is identified or excluded. Regarding pulmonary arterial tree, the first abnormality that is often associated with lung abnormality is the congenital origin of the left

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Rare Lung Diseases of Newborns

The second group consists of collateral vessels which may arise from the aorta and supply all or part of one or both lungs. This last group may be seen in association with direct pulmonary arteriovenous connections (pulmonary arteriovenous malformations). Aneurysms of aortopulmonary collateral vessels were described (Chowdhury et al. 2015).

59.3.3.2 Abnormalities of the Venous Tree (Pulmonary and Systemic) Anomalous pulmonary veins result in blood from the lungs returning to the right side of the heart. The anomaly may be total or partial, unilateral or bilateral, and isolated or associated with other cardiopulmonary developmental defects. Anomalous pulmonary venous connections are often narrow, and this may cause relatively mild pulmonary hypertension. Unilateral anomalous venous drainage may be part of complex lung malformations; it may also be seen in association with what appears to be a simple lung cyst. No congenital disorders of the systemic (bronchial) venous tree have been described (Chowdhury et al. 2015). A particular clinical problem is Scimitar Syndrome. Scimitar syndrome is a rare constellation, estimated to occur in two out of 100,000 births, with a 2:1 female preponderance. It consists in part of right pulmonary venous return to the inferior vena cava. In two thirds of cases, the Scimitar vein (SV) provides drainage for the entire right lung, but in one third the SV drains only the lower portion of the right lung. The developmental errors accounting for the observed anatomy in Scimitar syndrome are not understood at present. It is possible that some insult, occurring during week 11 of gestation when normally pulmonary venous drainage to the left atrium, results in the observed persistence of systemic arterial supply to the right lung from the abdominal aorta. There are unequivocally two forms of Scimitar syndrome in terms of clinical presentation: an infantile syndrome associated with significant mortality and a child/adult presentation that is a milder form of the syndrome and in fact is frequently asymptomatic, with diagnosis being made

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incidentally because of radiographic abnormalities. As a rule, patients with the infantile syndrome are diagnosed in the first few months of life, the median age at presentation being 2 months. Failure to thrive, tachypnea, and heart failure are the dominant features at presentation in these severely ill patients although cyanosis may be observed if pulmonary hypertension and the anatomy at hand predispose to right-to-left shunting of blood. The elevated Qp/Qs in the infantile syndrome is often reported. Medical treatment is indicated in the infantile presentation to offset heart failure and allow growth before undertaking surgical repair. However, the presence of pulmonary hypertension or failure of response to medical therapy demands prompt surgical intervention. Mortality is quoted at 45% in infantile presentation (Gudjonsson and Brown 2006). Abnormalities of the connections between the pulmonary, arterial, and venous trees.

59.3.3.3 Fistulae An important group of abnormalities which potentially involves systemic and pulmonary arterial and venous trees are the various forms of pulmonary arteriovenous fistulae. They range from the diffuse and microscopic to the single or multiple large abnormalities (Chowdhury et al. 2015). 59.3.3.4 Congenital Alveolar Capillary Dysplasia (ACD) Congenital alveolar capillary dysplasia (ACD) is a disorder of pulmonary vascular development associated with persistent pulmonary hypertension in the newborn (PPHN) and unremitting hypoxemia that is unresponsive to pulmonary vasodilators and various modes of mechanical ventilation. The incidence or prevalence of ACD is not yet known; it seems likely that some cases originally classified as idiopathic persistent pulmonary hypertension of the newborn (PPHN) may actually have been ACD. A slight male predominance (60%) has appeared in reported cases. No geographic pattern is apparent; cases have been distributed worldwide (Bishop et al. 2011). Autosomal recessive inheritance is suspected. DNA sequencing and comparative genomic

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hybridization have led to the identification of FOXF1 as one of the genes responsible for ACD and allowed for limited noninvasive diagnostic testing in some infants (Stankiewicz et al. 2009). For several reasons, these case reports almost certainly underestimate the true prevalence of ACD. The evidence is mounting to suggest that a less severe phenotype compatible with prolonged survival might exist, although definitive diagnostic criteria for this group are yet to be established. The diagnosis of ACD is confirmed at autopsy in 90% of cases and in 10% by lung biopsy. Failure of development of alveolar capillaries leads to absence of a normal air–blood barrier. ACD is characterized by paucity of capillaries adjacent to the alveolar epithelium, anomalous distended veins, immature alveolar development, and muscularisation of the arterioles. The pathological features are diffuse in 85% and patchy in 15% of subjects (Melly et al. 2008). The symptoms and timing of presentation are related to the distribution of capillary dysplasia and the extent of alveolar underdevelopment. More than 95% are full-term with normal transition. Respiratory distress progressing to untreatable respiratory failure is the most common presentation. The onset of symptoms is within the first hours of age in half the cases, while presentation at 2–6 weeks is reported in the 14% of cases (Boggs et al. 1994). The chest radiograph may show diffuse haziness or subtle ground-glass opacities but is often interpreted as normal. Pneumothoraces have been reported frequently in patients with fulminant disease, but it is not entirely clear whether this feature is related to abnormalities in lung architecture or surfactant function, a consequence of aggressive ventilator treatment to reverse hypoxemia, or is some combination of the two. To date, there are no reports of computed tomography or magnetic resonance lung imaging in infants with documented ACD (Cassidy et al. 2002). There is an association with other congenital malformations in 80% of cases, the commonest being gastrointestinal (30%), cardiac (30%), and renal anomalies (23%).

P. Tagliabue and E. Ciarmoli

The clinical approach to infants with ACD is no different than that for other neonates presenting with PPHN. However, the response to therapy is often minimal and/or not sustained, which may serve as an initial diagnostic clue. Most infants with ACD will develop progressive hypotension due to right ventricular failure and/or refractory hypoxemia. Because the hypoxemia and pulmonary hypertension cannot be effectively reversed, cardiotonic agents have only a minimal or transient effect in infants with ACD. Although transient responses to pulmonary vasodilator therapy can be observed in infants with ACD, no infant has been reported to have a sustained response to any available pulmonary vasodilator. ECMO is used at some point in the clinical course in most case series of ACD but deterioration and death followed within hours. Because none of the supportive therapies described above has changed the expected mortality due to ACD, lung transplantation is currently the only option that might prolong survival. If here is a high index of suspicion, diagnostic lung biopsy could be considered. ACD is generally fatal (Kinugasa et al. 2002; Fliman et al. 2006).

59.3.3.5 Abnormalities of the Lymphatic Tree Lymphatic tree disorders usually require histological confirmation. Lymphatic hypoplasia of varied distribution underlies yellow nail syndrome, in which lymphedema is accompanied by discoloration of the nails and pleural effusions. Klippel-Trenaunay syndrome, usually characterized by varicosities of systemic veins, cutaneous hemangiomas, and soft-tissue hypertrophy, is another congenital disorder. Pleuropulmonary abnormalities are described, including pulmonary lymphatic hyperplasia, pleural effusions, pulmonary thromboembolism, and pulmonary vein varicosities (Chowdhury et al. 2015). 59.3.3.6 Congenital Pulmonary Lymphangiectasia (CPL) A congenital malformation with presentation from fetal to early adulthood. CPL results from failure of the pulmonary interstitial connective tissue to regress, leading to dilatation of lymphatic capillaries. Radiological findings include diffuse

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Rare Lung Diseases of Newborns

thickening of the peribronchovascular interstitium and the interlobular septa with pleural effusions. Supportive therapy includes albumin infusions, diuretics, thoracocentesis, and paracentesis. Nutrition plays an important role in reducing lymphatic production. Enteral nutrition with medium-chain triglycerides and total parenteral nutrition have been successfully employed. CPL often is associated with congenital and genetic diseases, including Noonan, Ullrich-Turner, Ehlers-Danlos, and Down syndromes. In rare localized disease, surgical resection is curative. When present in the newborn, the clinical course might be fatal. For the majority of patients with neonatal presentations, gradual improvement and survival are possible, particularly if there are no significant co-existing abnormalities (Bouchard et al. 2000; Pinar 2004).

59.3.3.7 Congenital Chylothorax Congenital chylothorax may be an isolated abnormality or else associated with a congenital abnormality of the main lymphatic duct or pulmonary lymphatics. Associations with Noonan, Ullrich Turner, and Down syndrome, fetal thyrotoxicosis, H-type tracheo-esophageal fistula, and mediastinal neuroblastoma have been described; familial cases have been reported (Chowdhury et al. 2015). See also ▶ Chap. 47, “Neonatal Lung Development and Pulmonary Malformations.”.

59.4

Developmental Abnormalities

Pulmonary underdevelopment has been classified into three categories: pulmonary agenesis, pulmonary aplasia, and pulmonary hypoplasia. Pulmonary agenesis is a complete absence of the lung parenchyma, bronchus, and pulmonary vasculature. It has been hypothesized that abnormal blood flow in the dorsal aortic arch during the 4th week of gestation (embryonic phase) is the cause. Unilateral pulmonary agenesis is difficult to diagnose with prenatal US; however, it can be suspected on the basis of mediastinal shift. More than 50% of affected fetuses have other abnormalities involving other systems.

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Pulmonary aplasia is similar to agenesis, except for the presence of a short blind-ending rudimentary bronchus. Imaging findings are similar: postnatal radiography demonstrates diffuse opacification of the involved hemithorax with ipsilateral mediastinal shift (Biyyam 2010).

59.4.1 Pulmonary Hypoplasia In this condition alveoli are reduced in number or size. Severe hypoplasia may be incompatible with extrauterine life. Lung growth before birth is dependent on blood supply, availability of space, respiratory movements, and fluid filling the airways in utero. Malformations of the rib cage, pleural effusions, thoracic masses, or intestinal loops in congenital diaphragmatic hernia (CDH) compete with the developing lung for space. Adequate amniotic fluid is essential for normal lung development and any condition that produces oligohydramnios leads to diminished lung growth. Significant and prolonged oligohydramnios can result from chronic loss of liquor after preterm premature rupture of membranes, or from inadequate production or excretion of urine because of renal and urinary tract malformations. In these conditions, airway and arterial branching is inhibited, limiting the surface for gas exchange. In the oligohydramnios sequence, the common phenotype is a flattened nose, contractures, and growth impairment of extremities, known as Potter’s syndrome. The condition of prolonged preterm premature rupture of membranes is not universally lethal but depends on the degree of pulmonary hypoplasia. The following conditions increase the risk of mortality: (1) premature rupture of membranes at less than 25 weeks’ gestation, (2) severe oligohydramnios (amniotic fluid index 10 torr, or an O2 saturation gradient >5%. However, postductal desaturation can be found in ductus-dependent cardiac diseases, including hypoplastic left heart syndrome, coarctation of the aorta, or interrupted aortic arch. The response to supplemental oxygen can help to distinguish PPHN from primary lung or cardiac disease. Although supplemental oxygen traditionally increases PaO2 more readily in lung disease than cyanotic heart disease or PPHN, this may not be obvious with more advanced parenchymal lung disease. Marked improvement in SaO2 (increase to 100%) with supplemental oxygen suggests the presence of V/Q mismatch due to lung disease or highly reactive PPHN. Most patients with PPHN have at least a transient improvement in oxygenation in response to interventions such as high levels of inspired oxygen and/or mechanical ventilation. Acute respiratory alkalosis induced by hyperventilation to achieve PaCO2 7.50 may increase PaO2 >50 torr in PPHN, but rarely in cyanotic heart disease. The echocardiogram plays an important diagnostic role and is an essential tool for managing newborns with PPHN. The initial echocardiographic evaluation rules out structural heart disease causing hypoxemia or ductal shunting (e.g., coarctation of the aorta and total anomalous pulmonary venous return). Further, as stated above, not all term newborns with hypoxemia have PPHN physiology. Although high pulmonary artery pressure is commonly found in association with neonatal lung disease, the diagnosis of PPHN is uncertain without evidence of bidirectional or predominantly right-to-left shunting across the PFO or PDA. Echocardiographic signs suggestive of pulmonary hypertension (e.g., increased right ventricular systolic time intervals and septal flattening) are less helpful. In addition to demonstrating the presence of PPHN physiology, the echocardiogram is critical

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for the evaluation of left ventricular function and diagnosis of anatomic heart disease, including such “PPHN mimics” as coarctation of the aorta, total anomalous pulmonary venous return, hypoplastic left heart syndrome, and others. Studies should carefully assess the predominant direction of shunting at the PFO as well as the PDA. Although right-to-left shunting at the PDA and PFO is typical for PPHN, predominant rightto-left shunting at the PDA but left-to-right shunt at the PFO may help to identify the important role of left ventricular dysfunction to the underlying pathophysiology. In the presence of severe left ventricular dysfunction with pulmonary hypertension, pulmonary vasodilation alone may be ineffective in improving oxygenation. In this setting, efforts to reduce PVR should be accompanied by targeted therapies to increase cardiac performance and decrease left ventricular afterload. In the setting of impaired LV performance, cardiotonic therapies that increase systemic vascular resistance may further worsen LV function and increase pulmonary artery pressure. Thus, careful echocardiographic assessment provides invaluable information about the underlying pathophysiology and will help guide the course of treatment.

60.3.1 Insights into PPHN from the Laboratory Diverse animal models have been used in order to better understand the pathogenesis and pathophysiology of PPHN. Such models have included exposure to acute or chronic hypoxia after birth, chronic hypoxia in utero, placement of meconium into the airways of neonatal animals, sepsis, and others. Each model demonstrates interesting physiologic changes that may be especially relevant to particular clinical settings, but most studies examine only brief changes in the pulmonary circulation, and mechanisms underlying altered lung vascular structure and function of PPHN remain poorly understood. Neonates with severe PPHN who die during the first days after birth already have pathologic signs of chronic pulmonary vascular disease, suggesting that intrauterine

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Persistent Pulmonary Hypertension of the Newborn

events may play an important role in this syndrome (Geggel and Reid 1984). Adverse intrauterine stimuli during late gestation, such as abnormal hemodynamics, changes in substrate or hormone delivery to the lung, hypoxia, inflammation, or others, may potentially alter lung vascular function and structure, contributing to abnormalities of postnatal adaptation. Several investigators have examined the effects of chronic intrauterine stresses, such as hypoxia or hypertension, in animal models in order to attempt to mimic the clinical problem of PPHN. Whether chronic hypoxia alone can cause PPHN is controversial. A past report that maternal hypoxia in rats increases pulmonary vascular smooth muscle thickening in newborns, but this observation has not been reproduced in maternal rats or guinea pigs with more extensive studies (Murphy et al. 1986). Acute hypoxia alone is insufficient to account for PPHN, which is further reflected in recent clinical observations that PPHN is rare in patients with severe asphyxia who were enrolled in hypothermia studies. Pulmonary hypertension induced by early closure of the DA in fetal lambs alters lung vascular reactivity and structure, causing the failure of postnatal adaptation at delivery and providing an experimental model of PPHN (Levin et al. 1978; Morin and Eagan 1989; Abman and Accurso 1989). Over days, pulmonary artery pressure and PVR progressively increase, but flow remains low and PaO2 is unchanged (Abman and Accurso 1989). Marked right ventricular hypertrophy and structural remodeling of small pulmonary arteries develops after 8 days of hypertension. After delivery, these lambs have persistent elevation of PVR despite mechanical ventilation with high oxygen concentrations. Studies with this model show that chronic hypertension without high flow can alter fetal lung vascular structure and function. This model is characterized by endothelial cell dysfunction and abnormal smooth muscle cell vasoreactivity and growth, including findings of impaired NO production and activity and downregulation of lung endothelial NO synthase mRNA and protein expression (Storme et al. 1999; Villamor et al. 1997; Shaul et al. 1997; McQueston et al. 1995; Farrow et al. 2008a). Fetal pulmonary

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hypertension is also associated with decreased cGMP concentrations, associated with decreased soluble guanylate cyclase and upregulated cGMPspecific phosphodiesterase (PDE5) activities, suggesting further impairments in downstream signaling (Hanson et al. 1996; Steinhorn et al. 1995; Tzao et al. 2001). Thus, multiple alterations in the NO-cGMP cascade appear to play an essential role in the pathogenesis and pathophysiology of experimental PPHN, contributing to altered structure and function of the developing lung circulation and leading to failure of postnatal cardio-respiratory adaptation. Recent evidence indicates that excessive production of reactive oxygen species (ROS), such as superoxide in the pulmonary vasculature, may further contribute to the disruption in NO-cGMP signaling in this model and may contribute to poor responsiveness to inhaled NO therapy (Farrow et al. 2008a; Brennan et al. 2003; Chester et al. 2009). Upregulation of ET-1 may also contribute to the pathophysiology of PPHN. Circulating levels of ET-1, a potent vasoconstrictor and co-mitogen for vascular smooth muscle cell hyperplasia, are increased in human newborns with severe PPHN (Rosenberg et al. 1993). In the experimental model of PPHN due to compression of the DA in fetal sheep, lung ET-1 mRNA and protein content is markedly increased, and the balance of ET receptors is altered, favoring vasoconstriction (Ivy et al. 1996, 1998;). Chronic inhibition of the ET A receptor attenuates the severity of pulmonary hypertension, decreases pulmonary artery wall thickening, and improves the fall in PVR at birth in this model (Ivy et al. 1997). Thus, experimental studies have shown the important role of the NO-cGMP cascade and the ET-1 system in the regulation of vascular tone and reactivity of the fetal and transitional pulmonary circulation. Oxidant stress plays an important role in the pathogenesis of PPHN. Increased ROS such as superoxide (O2 ) and hydrogen peroxide (H2O2) have been demonstrated in pulmonary arteries in the ovine ductal ligation model of persistent pulmonary hypertension (Brennan et al. 2003; Fike et al. 2008). Mitochondrial dysfunction, increased expression and activity of NADPH oxidase, and uncoupled eNOS activity can each

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generate ROS (Brennan et al. 2003; Konduri et al. 2003, 2007; Wedgwood et al. 2005). Increased ROS production promotes vasoconstriction directly and through multiple mechanisms that may include increased endothelin levels (Wedgwood and Black 2003) and oxidization of free fatty acids to create vasoconstrictor metabolites, such as isoprostanes (Lakshminrusimha et al. 2006a). O2 rapidly combines and inactivates NO and forms peroxynitrite, a potent oxidant with the potential to produce vasoconstriction and cytotoxicity. Increased ROS in the pulmonary vasculature of the ductal ligation model promotes dysfunction of NO-cGMP signaling at multiple steps in the pathway, including blunted eNOS expression, uncoupled eNOS activity (thus further promoting ROS production), and increased activity and expression of cGMP-specific phosphodiesterases, and impaired sGC activity (Farrow et al. 2008a, b; Chester et al. 2009). Superoxide dismutases (SOD) catalyze the conversion of superoxide anions to H2O2 and O2. Due to the efficiency of the reaction between NO and superoxide, the local concentration of SOD is a key determinant of the biological half-life of endogenous NO (Faraci and Didion 2004). Evidence for a critical pathologic role for ROS in PPHN includes the recent observation that administration of a single intratracheal dose of rhSOD in neonatal lambs with PPHN produced a sustained increase in oxygenation over a 24-h period, reduced production of isoprostanes and peroxynitrite, and restored normal eNOS expression and function. In addition to vasoactive mediators, alterations of growth factors, such as VEGF and plateletderived growth factor (PDGF), likely play key roles in PPHN. VEGF is markedly decreased in experimental PPHN, and treatment with recombinant human VEGF restores endothelial function and lowers PVR in this model (Villamor et al. 1997; Grover et al. 2003, 2005). In addition, inhibition of PDGF-B attenuates smooth muscle hyperplasia in experimental pulmonary hypertension in fetal lambs, suggesting a potential role in the pathogenesis of PPHN (Balasubramaniam et al. 2003). Additional new data suggest that maternal exposure to selective serotonin reuptake inhibitors (SSRI) during late gestation is associated with a

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sixfold increase in the prevalence of PPHN (Chambers et al. 2006), although it is not clear how many infants developed severe disease. Newborn rats exposed in utero to fluoxetine develop pulmonary vascular remodeling, abnormal oxygenation, and higher mortality when compared with vehicletreated controls (Fornaro et al. 2007). However, these findings showed only mild changes in right ventricular hypertrophy and pulmonary vascular remodeling in the neonatal rat pups, with minimal changes in vasoreactivity after maternal SSRI exposure. Whether these effects were related to direct impact on the fetal lung circulation or secondary to altered maternal or umbilical-placental physiology remains unknown. As SSRIs have been reported to reduce pulmonary vascular remodeling in adult models of pulmonary hypertension, these findings also serve to highlight the unique vulnerability of fetal pulmonary vascular development.

60.3.2 Treatment of PPHN Several pathophysiologic disturbances contribute to hypoxemia in the newborn infant, including cardiac dysfunction, airway and pulmonary parenchymal abnormalities, and pulmonary vascular disorders. In some newborns with hypoxemic respiratory failure, a single mechanism predominates (e.g., extrapulmonary right-to-left shunting without significant parenchymal lung disease seen in patients with idiopathic PPHN). These patients have systemic arterial hypoxemia despite high alveolar and pulmonary venous oxygen tensions. More commonly, the clinical manifestations of severe PPHN and hypoxemic respiratory failure are rarely attributable to a single pathophysiologic disturbance. PPHN is often associated with severe parenchymal lung disease in conditions such as meconium aspiration syndrome, bacterial pneumonia, and surfactant deficiencies or dysfunction leading to both extrapulmonary and intrapulmonary shunting. Moreover, decreased cardiac performance and reduced left ventricular output can decrease systemic blood pressure, exacerbating the right-to-left shunting of blood at the ductus arteriosus. Although severe PPHN is commonly associated with near-term and term neonates, echocardiographic studies in premature infants with

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hyaline membrane disease (HMD) show that pulmonary hypertension may complicate the course of severe HMD. The treatment of PPHN commonly focuses only on pharmacologic therapy to reduce pulmonary vascular resistance. For the relatively small subset of neonatal patients with idiopathic PPHN who have pulmonary hypertension without concomitant lung disease, selective pulmonary vasodilation alone can cause marked improvements in oxygenation. However, PPHN often occurs with more common causes of neonatal respiratory distress, including disorders characterized by moderate to severe lung disease. Moreover, sepsis neonatorum and perinatal asphyxia can severely compromise systemic vascular tone and cardiac performance, leading to systemic hypotension in addition to severe pulmonary hypertension. The pulmonary vasculature in many newborns with severe PPHN has marked structural changes, which include endothelial swelling, smooth muscle hypertrophy, and increased adventitial thickening. Moreover, functional abnormalities lead to altered responses to vasodilator and vasoconstrictor stimuli. Therefore, the therapeutic approach to PPHN requires meticulous attention to all aspects of the cardiopulmonary perturbations (pulmonary hypertension, systemic vasodilation, decreased cardiac performance, and parenchymal lung disease) that characterize this syndrome. PPHN is a dynamic syndrome characterized by progressive changes in pulmonary vasoreactivity, cardiac performance, and parenchymal lung disease. In addition, the tendency for time-dependent changes in the relative contribution of each mechanism to hypoxemia requires continued vigilance as the disease progresses. Therefore, understanding the relative contribution of these different causes of hypoxemia becomes critically important as the inventory of therapeutic options expands. Therefore, management should be based on serial hemodynamic, echocardiographic, and radiographic assessments. Because of the diverse nature of diseases associated with PPHN, no single therapeutic approach is effective in all patients. In general, the goals of PPHN management are to optimize lung inflation and treat any underlying pulmonary parenchymal disease, to

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sustain cardiac performance and systemic hemodynamic stability, and to reduce pulmonary vascular resistance. In this section, management strategies for the patient with severe hypoxemic respiratory failure and PPHN are described, but it is important to recognize that many therapies advocated for the management of PPHN have not undergone rigorous evaluation with controlled clinical trials. In general, therapy includes optimization of systemic hemodynamics with volume and cardiotonic therapy (dopamine, epinephrine, and milrinone), in order to enhance cardiac output and systemic O2 transport. Beyond these agents, another therapeutic option for stabilizing hemodynamics is arginine vasopressin. In the systemic circulation, vasopressin acts via V1a receptors of the smooth muscle, leading to vasoconstriction of both arteries and veins (Share 1988). Work in animal models has shown that despite the vasoconstrictive effect systemically, vasopressin causes dilation of the pulmonary circulation, likely mediated via nitric oxide release from the endothelium (Evora et al. 1993; Russ and Walker 1992). Outside of the neonatal period, vasopressin is used in the setting of cardiac arrest, sepsis, vasodilatory shock, and cardiac surgery with improved systemic blood pressure, a decrease in catecholamine requirements, and increased urine output (Scheurer et al. 2005; Luccini et al. 2013; Agrawal et al. 2012). In studies of patients with pulmonary hypertension, vasopressin improves systemic hemodynamics without adverse effects on the pulmonary vasculature, making it an ideal agent for treatment of infants who have pulmonary hypertension and systemic hypotension (Radicioni et al. 2012; Filippi et al. 2011). Most recently in ten infants with severe PPHN, Mohammed et al. reported improvements in oxygenation index, peak effect, a reduction in iNO dose associated with a concomitant improvement in blood pressure and urine output after initiation of vasopressin supporting the applicability of this agent in this setting (Adel Mohamed et al. 2014). A profound natriuresis is often accompanied by the increase in urine output and close monitoring of urine and serum sodium advised with vasopressin administration (Luccini et al. 2013).

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Failure to respond to medical management, as evidenced by the failure to sustain improvement in oxygenation with good hemodynamic function, often leads to treatment with extracorporeal membrane oxygenation (ECMO). Although ECMO can be a life-saving therapy, it is costly and labor intensive and can have severe side effects, such as intracranial hemorrhage. Since arterio-venous ECMO usually involves ligation of the carotid artery, the potential for acute and long-term CNS injuries continues to be a major concern. Longterm follow-up of 250 neonatal ECMO survivors revealed significant abnormalities in motor performance at 12 years of age (van der Cammen-van Zijp et al. 2014) with the presence of chronic lung disease correlating with adverse motor outcomes. In this study, abnormal motor development was more subtle at 5 and 8 years of age, stressing the need for continued follow-up of neurodevelopmental outcomes in ECMO survivors (van der Cammen-van Zijp et al. 2014).

60.3.3 Nitric Oxide Therapy in PPHN 60.3.3.1 Rationale for Inhaled NO Therapy Early laboratory studies demonstrated that inhaled nitric oxide (NO) therapy caused marked and sustained reduction in pulmonary vascular resistance (PVR) in newborn animal models (Kinsella et al. 1992a; Roberts et al. 1993), and initial pilot studies showed marked improvement in oxygenation in term newborns with PPHN (Roberts et al. 1992; Kinsella et al. 1992b). Subsequent trials confirmed the safety and efficacy of inhaled NO in this population, and it is now an integral component of PPHN therapy (Kinsella et al. 1997; Roberts et al. 1997; Wessel et al. 1997; Davidson et al. 1998a; Neonatal Inhaled Nitric Oxide Study Group 1997; Clark et al. 2000). As described above, the physiologic rationale for inhaled NO therapy in the treatment of PPHN is based upon its ability to achieve potent and sustained pulmonary vasodilation without decreasing systemic vascular tone (Kinsella and Abman 1995). As a syndrome, PPHN is associated with diverse neonatal cardiac and pulmonary

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disorders that are characterized by high PVR causing extrapulmonary right-to-left shunting of blood across the arterial duct and/or oval foramen. The ability of inhaled NO therapy to selectively lower PVR and decrease extrapulmonary venoarterial admixture accounts for the acute improvement in oxygenation observed in newborns with PPHN (Kinsella et al. 1993). However, oxygenation can also improve during inhaled NO therapy in critically ill patients who do not have extrapulmonary right-to-left shunting (Abman et al. 1994; Gerlach et al. 1993). Hypoxemia in these cases is primarily due to intrapulmonary shunting caused by continued perfusion of lung units that lack ventilation (e.g., atelectasis), with variable contributions form ventilation/perfusion (V/Q) inequality. Distinct from its ability to decrease extrapulmonary right-to-left shunting by reducing PVR, low dose inhaled NO therapy can also improve oxygenation by redirecting blood from poorly aerated or diseased lung regions to better aerated distal air spaces (“microselective effect”) (Rossaint et al. 1993). Finally, the diagnostic value of inhaled NO therapy is also important, in that failure to respond to inhaled NO raises important questions about the specific mechanism of hypoxemia. Poor responses to inhaled NO should lead to further diagnostic evaluation for “unsuspected” functional/structural cardiovascular or pulmonary disease.

60.3.3.2 Inhaled NO for Treatment of PPHN Due to its selective pulmonary vasodilator effects, inhaled NO therapy is an important adjunct to available treatments for term newborns with hypoxemic respiratory failure. Inhaled nitric oxide (iNO) therapy at low doses (5–20 ppm) improves oxygenation and decreases the need for ECMO therapy in patients with diverse causes of PPHN (Clark et al. 2000; Davidson et al. 1998; Kinsella et al. 1992b, 1997; Neonatal Inhaled Nitric Oxide Study Group 1997; Roberts et al. 1997b). Multicenter clinical trials support the use of iNO in near-term (>34 weeks gestation) and term newborns, although the use of iNO in infants less than 34 weeks gestation remains largely

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investigational. Studies support the use of iNO in infants who have hypoxemic respiratory failure with evidence of PPHN, who require mechanical ventilation and high inspired oxygen concentrations. The most common criterion employed has been the oxygenation index (OI; mean airway pressure times FiO2 times 100 divided by PaO2). However, hypoxemic respiratory failure in the term newborn represents a heterogeneous group of disorders, and disease-specific responses have clearly been described. For example, patients with extapulmonary right-to-left shunting (PPHN) show acute improvement in oxygenation when PVR becomes subsystemic during NO therapy, and patients with predominantly intrapulmonary shunting (e.g., RDS) have less dramatic responses. Clinical trials of inhaled NO in the term newborn have incorporated ECMO treatment as an endpoint. Therefore, most patients have been enrolled in the first few days of life. Although one of the pivotal studies used to support the new drug application for inhaled NO therapy included as an entry criterion a postnatal age up to 14 days, the average age at enrollment in that study was 1.7 days (Neonatal Inhaled Nitric Oxide Study Group 1997). Currently, clinical trials support the use of inhaled NO before treatment with ECMO, or usually within the first week of life. However, clinical experience suggests that inhaled NO may be of benefit as an adjuvant treatment after ECMO therapy in patients with sustained pulmonary hypertension (e.g., congenital diaphragmatic hernia). Thus, postnatal age alone should not define the duration of therapy in cases where prolonged treatment could be beneficial. Studies support the use of inhaled NO in infants who have hypoxemic respiratory failure with evidence of PPHN, who require mechanical ventilation and high inspired oxygen concentrations. The most common criterion employed has been the oxygenation index. Although clinical trials commonly allowed for enrollment with OI levels >25, the mean OI at study entry for these studies approximated 40. Whether treatment at lower OI levels reduces ECMO use is uncertain (Konduri et al. 2004). Thus, it is unclear whether infants with less severe hypoxemia would benefit

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from inhaled NO therapy. However, Davidson et al. reported a controlled clinical trial in which the average OI at study entry was 24  9 (Davidson et al. 1998). It is important to note that inhaled NO treatment did not reduce ECMO utilization in this study. Although entry criteria for this trial included echocardiographic evidence of pulmonary hypertension, only 9% of the patients had clinical evidence of right-to-left ductal shunting. Because of the mechanism of action of inhaled NO as a selective pulmonary vasodilator, it is likely that acute improvement in oxgyenation caused by decreased pulmonary vascular resistance and reduced extrapulmonary right-to-left shunting would be most predictive of clinical improvement. Therefore, current multicenter studies suggest that treatment with inhaled NO may include an OI >25 with echocardiographic evidence of extrapulmonary right-to-left shunting. The first studies of inhaled NO treatment in term newborns reported initial doses that ranged from 80 ppm (Roberts et al. 1992) to 6–20 ppm (Kinsella et al. 1992b). The rationale for doses used in these clinical trials was based on concentrations which had previously been found to be effective in animal experiments by the same investigators (Geggel and Reid 1984; Levin et al. 1978). Roberts et al. reported that brief (30 min) inhalation of NO at 80 ppm improved oxygenation in patients with PPHN, but this response was sustained in only one patient after NO was discontinued (Roberts et al. 1992b). In the second report, rapid improvement in oxygenation in neonates with severe PPHN was also demonstrated, but this was achieved at lower doses (20 ppm) for 4 h (Kinsella et al. 1992b). This study also reported that decreasing the inhaled NO dose to 6 ppm for the duration of treatment provided sustained improvement in oxygenation. The relative effectiveness of low-dose inhaled NO in improving oxygenation in patients with severe PPHN was corroborated in a study by Finer et al. (1994). Acute improvement in oxygenation during treatment was not different with doses of inhaled NO ranging from 5 to 80 ppm. These laboratory and clinical studies established the boundaries of inhaled NO dosing

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protocols for subsequent randomized, clinical trials in newborns (Morin and Eagan 1989; Abman and Accurso 1989; Storme et al. 1999; Villamor et al. 1997; Shaul et al. 1997; McQueston et al. 1995). Increasing the dose to 40 ppm does not generally improve oxygenation in patients who do not respond to the lower dose of 20 ppm. The initial dose in the NINOS trial was 20 ppm, but the dose was increased to 80 ppm if the improvement in PaO2 was less than 20 torr (Neonatal Inhaled Nitric Oxide Study Group 1997). In this study, only 3 of 53 infants (6%) who had little response to 20 ppm had an increase in PaO2 >20 torr when treated with 80 ppm inhaled NO. Whether a progressive increase in PaO2 would have occurred with continued exposure to 20 ppm could not be determined with this study design. Roberts et al. initiated treatment with 80 ppm NO and subsequently weaned the inhaled NO concentration if oxygenation improved; thus, the effects of lower initial inhaled NO doses could not be evaluated and the effects on ECMO utilization were not evaluated (Roberts et al. 1992b). These studies did not systematically evaluate individual doses in an interpretable fashion. Davidson et al. reported the results of a randomized, controlled, dose-response trial in term newborns with hypoxemic respiratory failure (Davidson et al. 1998). In this study, patients were randomized to treatment with either 0 (placebo), 5, 20, or 80 ppm NO. Each inhaled NO dose improved oxygenation compared to placebo, but there was no difference in responses between groups. However, at 80 ppm, methemoglobinemia (blood levels >7%) occurred in 13 of 37 patients (35%) and high inspired NO2 concentrations (>3 ppm) were reported in 7 of 37 patients (19%). Thus, 80 ppm inhaled NO was not more effective in improving oxygenation than 5 or 20 ppm, but was associated with adverse effects. Unfortunately, this trial was limited by early termination due to slow enrollment and the exclusion of lung recruitment approaches to optimize inhaled NO efficacy. The available evidence, therefore, supports the use of doses of inhaled NO beginning at 20 ppm in term newborns with PPHN. Although brief exposures to higher doses (40–80 ppm) appear to be

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safe, sustained treatment with 80 ppm NO increases the risk of methemoglobinemia. The lowest effective starting dose for inhaled NO in term newborns with PPHN has not been determined. Cornfield et al. reported that initiating treatment at 2 ppm does not acutely improve oxygenation and may diminish the subsequent response to 20 ppm (Cornfield et al. 1999). However, this effect was refuted by Finer et al. who found that initial exposure to low NO doses (1–2 ppm) did not compromise subsequent responses to higher doses (10–20 ppm), and dose increases were required in 80% of the low dose group (Finer et al. 2001). Sustained improvement in oxygenation (after >4 h of treatment with 20 ppm) has been demonstrated for doses 15% after inhaled NO withdrawal. Early clinical studies reported rapid and sometimes dramatic decreases in oxygenation and increases in PVR after abrupt withdrawal of inhaled NO during prolonged therapy. These responses are often mild and transient, and many patients with decreased oxygenation after inhaled NO withdrawal will respond to brief elevations of FiO2 and careful observation. In patients with a persistent need for treatment with higher inspired oxygen concentrations or with increased pulmonary hypertension after inhaled NO withdrawal, restarting inhaled NO treatment will generally cause rapid clinical improvement. In general, this so-called “rebound” response appears to

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decrease over time after more prolonged therapy. However, inhaled NO withdrawal can be associated with life-threatening elevations of pulmonary vascular resistance, profound desaturation, and systemic hypotension due to decreased cardiac output. Mechanisms that contribute to these “rebound” effects are incompletely understood, but may be related to downregulation of endogenous NO production during exogenous NO therapy. Alternatively, the rise in pulmonary vascular resistance and drop in oxygenation after inhaled NO withdrawal may simply represent the presence of more severe underlying pulmonary vascular disease with loss of treatment effect of inhaled NO. The sudden increase in pulmonary artery pressure after rapid withdrawal of vasodilator therapy is not unique to inhaled NO and has been observed in other clinical settings, such as prostacyclin withdrawal in adults with primary pulmonary hypertension and in postoperative cardiac patients.

60.3.3.3 Inhaled NO in the Premature Newborn Early reports of iNO therapy in a premature newborn with pulmonary hypertension demonstrated marked improvement in oxygenation caused by effective treatment of severe pulmonary hypertension and resolution of extra-pulmonary right-to-left shunting (Peliowski et al. 1995), as well as other preterm infants with severe respiratory failure (Meurs et al. 1997). Subsequently, several randomized, controlled trials (RCTs) have confirmed the acute improvement in oxygenation caused by iNO treatment. However, in contrast to the direct pulmonary vasodilator effects of iNO, the focus of the most recently published studies has been on the potential beneficial effects of prolonged iNO administration on lung parenchymal and vascular development (Abman 2001). In a small, unmasked, randomized trial of iNO (20 ppm) and dexamethasone treatment, Subhedar et al. reported no differences in survival, chronic lung disease, or ICH between iNO-treated infants and controls (Subhedar et al. 1997). In a randomized, masked, multicenter clinical trial of low dose iNO therapy (5 ppm) in severely ill premature newborns with RDS who had marked hypoxemia

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despite surfactant therapy (a/A O2 ratio 15. Sildenafil was delivered by continuous IV infusion to evaluate the effect on OI. While the majority of infants were already receiving therapy with iNO, sildenafil use was associated with a significant decrease on OI especially in the groups receiving higher dose infusion. In a smaller subset of infants, sildenafil administration obviated the need for initiation of iNO (Shekerdemian et al. 2002). In this study, hypotension was the most common adverse effect noted. The availability of IV sildenafil for clinical use provides an alternate option for infants with pulmonary hypertension; unresponsive to inhaled NO, however, should be administered with caution in infants with hemodynamic instability. Prostacyclin is a potent vasodilator that causes pulmonary vasodilation through stimulation of adenylate cyclase to increase intracellular cAMP levels. Although iv prostacyclin may worsen gas exchange in PPHN patients with lung disease and systemic vasodilation, inhaled PGI2 may enhance oxygenation in infants that are poorly responsive to iNO (Shekerdemian et al. 2004). Another potential approach taking advantage of cAMP signaling is inhibition of phosphodiesterase type 3 (PDE3) that metabolizes cAMP. Milrinone, a

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PDE3 inhibitor, has been shown to decrease pulmonary artery pressure and resistance and to act additively with iNO in animal studies. A recent report indicates that the addition of intravenous milrinone to neonates with severe PPHN and poor iNO responsiveness was associated with improvements in oxygenation without compromising hemodynamic status (Steinhorn et al. 2007). Milrinone is of additional benefit by lowering systemic afterload in the setting of PPHN newborns with poor LV function. Until recently, experience with bosentan, a dual endothelin-1 receptor antagonist, was limited to a few case reports in the management of PPHN. More recently a double-blind, placebocontrolled, prospective study of bosentan for the treatment of persistent pulmonary hypertension of the newborn was performed with study endpoints of oxygenation index 2/3) was 56.1% compared with 1.4% in infants with mild PH (RVSP/SBP 2/3) was 56.1% compared with 1.4% in infants with mild PH (RVSP/ SBP 60%) (Verder et al. 1999). This last work, aside from demonstrating the efficacy of the INSURE approach, permitted the establishment of a limit to the oxygen requirement in patients with RDS undergoing N-CPAP (FiO2 about 40%) above which the administration of surfactant is indicated. A study conducted in Italy on 155 newborns of gestational age  28 and 40% showed no difference in requirements for surfactant and mechanical ventilation comparing two groups to which N-CPAP had been applied: in the first group, N-CPAP was applied within 300 of birth, regardless of the clinical picture; in the second group, N-CPAP was applied only in the presence of respiratory distress with oxygen requirements >40% (Sandri et al. 2004). A systematic review of the INSURE approach reported a reduced need for MV in the first week of life, when used early in respiratory distress syndrome (Stevens et al. 2007). Either prophylactic surfactant or delivery room N-CPAP to maintain functional residual volume was identified as potentially beneficial practice which, if adopted in extremely preterm infants, could reduce lung injury (Burch et al. 2003). Recently, the CURPAP study compared the administration of prophylactic surfactant followed by N-CPAP (prophylactic INSURE) with early N-CPAP followed by early selective surfactant given through a brief course of endotracheal intubation (early rescue INSURE) to preterm newborns of GA 25–28 weeks not intubated at birth (Sandri et al. 2010). In both groups, MV was started after surfactant in the absence of good respiratory drive. Infants who were extubated to N-CPAP after surfactant were eligible for MV if the following N-CPAP failure criteria occurred: FiO2 > 0.40 on N-CPAP to maintain oxygen saturation of 85–92% for at least 30 min unless rapid clinical deterioration occurred, intractable apnea, respiratory acidosis defined as pCO2 > 65 mmHg (8.5 kPa), and pH 4 h 2. OI > 20 with lack of improvement despite prolonged (>24 h) maximal medical therapy or persistent episodes of decompensation 3. Severe hypoxic respiratory failure with acute decompensation (PaO2< 40 mmHg) unresponsive to intervention 4. Progressive respiratory failure and/or pulmonary hypertension with evidence of right ventricular dysfunction or continued high inotropic requirement Contraindications include: • Lethal chromosomal (includes trisomy 13 and 18 but not 21) or congenital disorder • Irreversible brain damage • Uncontrolled bleeding • Grade  III intraventricular hemorrhage Relative contraindications include: 1. Irreversible organ damage, unless candidate for transplantation. 2. Weight less than 2 kg and/or gestation less than 34 weeks as such infants are at increased risk of intracranial hemorrhage. 3. Mechanical ventilation greater than 10–14 days. 4. In infants with congenital diaphragmatic hernia, the absence of an initial period with a

preductal saturation >85% and a PaCO2 12 kPa for 3 h. Infants were then randomized to either remain on conventional therapy at their neonatal unit or be transferred for ECMO at one of five UK centers. Overall, there was a significant reduction in mortality for the ECMO group (relative risk (RR) 0.55, 95% CI 0.39–0.77; p = 0.0005). There was a benefit for ECMO in all diagnoses, although the effect in CDH infants was marginal; 17 CDH infants supported conventionally died before discharge and 14 of 18 supported with ECMO died before 1 year of age (ELSO 2015). A systematic review of results of 244 infants entered into randomized trials demonstrated that ECMO was associated with a reduction in mortality (RR 0.44, 95% CI 0.31–0.61) and the number needed to treat was three (Mugford et al. 2008). Up to July 2015, over 35,500 cases of neonatal ECMO have been reported to the ELSO registry;

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the majority (28,271) received ECMO for respiratory causes. The cumulative survival to hospital discharge or transfer is currently 74%. In 2015 survival of neonatal respiratory cases was 63% compared to 81% in 1990, while the average “run” time has increased to 203 h from 144 h in 1990 (Vasavada et al. 2011). Those data (Vasavada et al. 2011) reflect the change in the nature of the population now undergoing ECMO (see later). Survival remains best in neonates with MAS (94%) and worst in those with CDH (51%). VA ECMO was used in approximately 72% of cases with a cumulative survival of 71% and VV ECMO in 28% of cases with 82% survival (Rais and Van Meurs 2014). Late mortality (>90 days post ECMO) has been reported to occur in 5.5% of patients, those with CDH being at the most risk (Ijsselstijn and van Heijst 2014). Approximately 17% of cases reported to the ELSO Registry had a primary cardiac problem, with an overall survival of 41%. ECMO is also used during cardiopulmonary resuscitation (n = 1,188) with 41% survival (Organization ELS 2015). Overall survival to hospital discharge of 641 infants who received extracorporeal cardiopulmonary resuscitation was 39% (McMullan et al. 2014). Lower birth weight and pre-extracorporeal cardiopulmonary resuscitation oxygenation, as well as complications including CNS hemorrhage, increased the odds of death (McMullan et al. 2014). Analysis of data from the ELSO registry has demonstrated that neonates requiring prolonged ECMO support (>20 days) have only a 24% survival to hospital discharge; many had CDH (Prodhan et al. 2014). Complications were common with prolonged ECMO, but only receipt of inotropes was shown to be independently associated with mortality (Prodhan et al. 2014).

64.3.5 Morbidity Chronic respiratory, neurological, and growth problems have been reported following ECMO. Review of 7,910 neonates supported by ECMO between 2005 and 2010 demonstrated that 1,412 (20%) had neurological complications (brain

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death, cerebral infarction, intracranial hemorrhage, or seizures) during ECMO support. Mortality was higher in patients with neurological complications (62% vs. 36%, p < 0.001) (Polito et al. 2013). The only long-term data on outcome following randomization to ECMO or conventional management, however, comes from the UK ECMO trial. Follow-up at 1 year revealed that ECMO was associated with a reduction in mortality without an increase in severe disability (defined as having a Griffiths quotient less than 50 or being unable to participate in quantitative developmental assessment due to severity of disability). At 4 years of age, more of the ECMO surviving infants had no disability (50% vs. 37%) (Bennett et al. 2001). Ninety of the infants (56 ECMO; 34 conventional) were seen at 7 years, and there were no significant differences in overall cognitive ability between the two groups; 76% of infants had an overall performance within the normal range (McNally et al. 2006). Overall, the study showed a continuing benefit of ECMO for the primary outcome of death or severe disability (relative risk 0.64, 95% CI 0.47–0.86; p = 0.004). Longitudinal assessment of motor performance at 5, 8, and/or 12 years after neonatal ECMO of a Dutch cohort of 254 survivors demonstrated that motor problems persist throughout childhood and become more obvious with time (Van der Cammen-van Zijp et al. 2014). Beardsmore et al. showed that ECMOsupported infants from the UK RCT had better lung function at 1 year of age than those who remained on conventional ventilation (Beardsmore et al. 2000). At 7 years of age, more children from the “conventional” group had evidence of respiratory morbidity, 32% had intermittent wheeze during the 12 months prior to questioning, and 41% regularly used inhalers, compared to 11% and 25%, respectively, of the ECMO group (McNally et al. 2006). Spoel et al. undertook a prospective longitudinal study evaluating outcomes of 121 infants supported by ECMO at 5, 8, and/or 12 years. They demonstrated long-term pulmonary sequelae in the CDH patients with a tendency for lung function to deteriorate with time (Spoel et al. 2012).

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64.3.6 Cost-Effectiveness of ECMO The costs of ECMO at 1 year are dominated by the expense of initial hospital care, reflecting partly the cost of ECMO provision itself, but also that the reduced mortality results in an increased average duration of stay in conventional neonatal intensive care. Cost-effectiveness improves over time, with the 7-year follow-up analysis from the UK ECMO trial estimating that the incremental cost per life year gained was £13,385 (2002–2003 prices) (Petrou et al. 2006). While treatment of infants was cost-effective in most diagnostic groups, the cost ratio for infants with CDH was far poorer.

A. Greenough et al.

that it may delay ECMO treatment, which in non-randomized studies has been associated with prolongation of both ECMO and conventional treatment, as well as increased mortality (Prodhan et al. 2014; Coppola et al. 2008). Acknowledgments We thank Dr Nicholas Barrett (Consultant in Critical Care at Guy’s and St Thomas’s Hospital NHS Foundation Trust) for providing data on the current mortality and Mrs Deirdre Gibbons for secretarial assistance. The research was supported by the National Institute for Health Research (NIHR) Clinical Research Facility at Guy’s and St Thomas’ NHS Foundation Trust and NIHR Biomedical Research Centre based at Guy’s and St Thomas’ NHS Foundation Trust and King’s College London. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health.

64.3.7 Changes in ECMO Requirements with Time Advances in other respiratory support techniques for term and near-term infants, including highfrequency oscillation and nitric oxide, have reduced the number of cases referred for ECMO and altered the profile of such patients. Data from the ELSO registry highlight that neonatal respiratory cases fell from a peak of 1,516 in 1992 to 627 in 2015 and that the proportion of cases with MAS fell from 35% to 25%, while CDH cases rose from 18% to 28% (Qureshi et al. 2013). Conversely the number of neonatal cardiac cases has been increasing with improved survival. Infants with CDH are now the commonest patient population requiring ECMO (Rais and Van Meurs 2014). A retrospective review of 18,130 all neonates undergoing noncardiac ECMO between 1990 and 2010 demonstrated that neonates of ethnic minorities have continued to disproportionally require ECMO support compared to their birth rates (Qureshi et al. 2013). A comparison of infants with severe respiratory failure treated at a single center during two time periods showed a decrease in ECMO utilization from 42.8% to 27.7% (Hintz et al. 2000). There were concomitant increases in the use of HFOV (36.7–87.2%), surfactant (26.5–89.3%), and iNO (0–44.7%). One potential concern with the institution of newer methods of respiratory support is

References Arzuaga BH, Groner A (2013) Utilization of extracorporeal membrane oxygenation in congenital hypertrophic cardiomyopathy caused by maternal diabetes. J Neonatal Perinatal Med 6:345–348 Bartlett RH, Gazzaniga AB, Jefferies MR et al (1976) Extracorporeal membrane oxygenation (ECMO) cardiopulmonary support in infancy. Trans Am Soc Artif Int Organs 22:80–93 Bartlett RH, Roloff DW, Cornell RG et al (1985) Extracorporeal circulation in neonatal respiratory failure: a prospective randomized study. Pediatrics 76:479–487 Beardsmore C, Dundas I, Poole K et al (2000) Respiratory function in survivors of the United Kingdom Extracorporeal Membrane Oxygenation Trial. Am J Respir Crit Care Med 161:1129–1135 Bennett CC, Johnson A, Field DJ et al (2001) UK collaborative randomised trial of neonatal extracorporeal membrane oxygenation: follow-up to age 4 years. Lancet 357:1094–1096 Coppola CP, Tyree M, Larry K et al (2008) A 22-year experience in global transport extracorporeal membrane oxygenation. J Pediatr Surg 43:46–52 Dyamenahalli U, Tuzcu V, Fontenot E et al (2012) Extracorporeal membrane oxygenation support for intractable primary arrhythmias and complete congenital heart block in newborns and infants: short- term and medium-term outcomes. Pediatr Crit Care Med 13:47–52 ELSO (2015) Guidelines for neonatal respiratory failure 2013. [Cited 18 Dec 2015]. Available from: https:// www.elso.org/Portals/0/IGD/Archive/FileManager/ 8588d1a580cusersshyerdocumentselsoguidelinesforneo natalrespiratoryfailure13.pdf

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Frenckner B, Radell P (2008) Respiratory failure and extracorporeal membrane oxygenation. Semin Pediatr Surg 17:34–41 Gibbon JH Jr (1954) Application of a mechanical heart and lung apparatus to cardiac surgery. Minn Med 37: 171–185 Gross SJ, Bifano EM, D’Euqenio DB et al (1994) 86 prospective randomized controlled trial of conventional treatment or transport for ecmo in infants with severe persistent pulmonary hypertension (PPHN): two year follow up. Pediatr Res 36:17A-A Hintz SR, Suttner DM, Sheehan AM et al (2000) Decreased use of neonatal extracorporeal membrane oxygenation (ECMO): how new treatment modalities have affected ECMO utilization. Pediatrics 106: 1339–1343 Ijsselstijn H, van Heijst AF (2014) Long-term outcome of children treated with neonatal extracorporeal membrane oxygenation: increasing problems with increasing age. Semin Perinatol 38:114–121 McMullan DM, Thiagarajan RR, Smith KM et al (2014) Extracorporeal cardiopulmonary resuscitation outcomes in term and premature neonates. Pediatr Crit Care Med 15:e9–e16 McNally H, Bennett CC, Elbourne D et al (2006) United Kingdom collaborative randomized trial of neonatal extracorporeal membrane oxygenation: follow-up to age 7 years. Pediatrics 117:e845–e854 Morris AH, Wallace CJ, Menlove RL et al (1994) Randomized clinical trial of pressure-controlled inverse ratio ventilation and extracorporeal CO2 removal for adult respiratory distress syndrome. Am J Respir Crit Care Med 149:295–305 Mugford M, Elbourne D, Field D (2008) Extracorporeal membrane oxygenation for severe respiratory failure in newborn infants. Cochrane Database Syst Rev 3, CD001340 Noah MA, Peek GJ, Finney SJ et al (2011) Referral to an extracorporeal membrane oxygenation center and mortality among patients with severe 2009 influenza A (H1N1). JAMA 306:1659–1668 O’Rourke PP, Crone RK, Vacanti JP et al (1989) Extracorporeal membrane oxygenation and conventional medical therapy in neonates with persistent pulmonary hypertension of the newborn: a prospective randomized study. Pediatrics 84:957–963 Organization ELS (2015) ECLS registry report – international summary 2015 July. Available from: https:// www.elso.org/Registry/Statistics/InternationalSummary. aspx Peek GJ, Mugford M, Tiruvoipati R et al (2009) Efficacy and economic assessment of conventional ventilatory

1013 support versus extracorporeal membrane oxygenation for severe adult respiratory failure (CESAR): a multicentre randomised controlled trial. Lancet 374: 1351–1363 Petrou S, Bischof M, Bennett C et al (2006) Costeffectiveness of neonatal extracorporeal membrane oxygenation based on 7-year results from the United Kingdom Collaborative ECMO Trial. Pediatrics 117:1640–1649 Polito A, Barrett CS, Wypij D et al (2013) Neurologic complications in neonates supported with extracorporeal membrane oxygenation. An analysis of ELSO registry data. Intensive Care Med 39:1594–1601 Prodhan P, Stroud M, El-Hassan N et al (2014) Prolonged extracorporeal membrane oxygenator support among neonates with acute respiratory failure: a review of the extracorporeal life support organization registry. ASAIO J 60:63–69 Qureshi FG, Jackson HI, Brown J et al (2013) The changing population of the United States and use of extracorporeal membrane oxygenation. J Surg Res 184: 572–576 Rais BK, Van Meurs KP (2014) Venoarterial versus venovenous ECMO for neonatal respiratory failure. Semin Perinatol 38:71–77 Rais-Bahrami K, Van Meurs KP (2014) Venoarterial versus venovenous ECMO for neonatal respiratory failure. Semin Perinatol 38:71–77 Rehder KJ, Turner DA, Cheifetz IM (2013) Extracorporeal membrane oxygenation for neonatal and pediatric respiratory failure: an evidence-based review of the past decade (2002–2012). Pediatr Crit Care Med 14: 851–861 Spoel M, Laas R, Gischler SJ et al (2012) Diagnosisrelated deterioration of lung function after extracorporeal membrane oxygenation. Eur Respir J 40: 1531–1537 UK Collaborative ECMO Trial Group (1996) UK collaborative randomised trial of neonatal extracorporeal membrane oxygenation. Lancet 348:75–82 Van der Cammen-van Zijp M, Janssen A, Raets M et al (2014) Motor performance after neonatal extracorporeal membrane oxygenation: a longitudinal evaluation. Pediatrics 134:e427–e435 Vasavada R, Feng Q, Undar A (2011) Current status of pediatric/neonatal extracorporeal life support: clinical outcomes, circuit evolution, and translational research. Perfusion 26:294–301 Zapol WM, Snider MT, Hill JD et al (1979) Extracorporeal membrane oxygenation in severe acute respiratory failure. A randomized prospective study. JAMA 242: 2193–2196

Lung Diseases: Problems of Steroid Treatment of Fetus and Newborn

65

Henry L. Halliday

Contents 65.1

Salient Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1015

65.2

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1016

65.3

Results from Randomized Trials of Prenatal Corticosteroids . . . . . . . . . . . . . 1017

65.4

Results from Randomized Trials of Postnatal Steroids . . . . . . . . . . . . . . . . . . . . 1018

65.5

Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1019

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1020

Abstract

Corticosteroids given in the perinatal period have a multitude of biologic effects on the developing lung. Clearly, some of these will be beneficial to the immature fetus or neonate, while others will be detrimental. For the fetus at risk of preterm birth, a single course of betamethasone or dexamethasone leads to lung maturity and reduces the risk of RDS and other important complications of prematurity. Consensus seems to support repeat courses of prenatal steroids when there is a high risk of preterm birth before 29 weeks’ gestation even if there are some controversies. The beneficial pulmonary effects of early postnatal dexamethasone, in the

H. L. Halliday (*) Formerly Regional Neonatal Unit, Royal Maternity Hospital, Belfast, UK Formerly Department of Child Health, Queen’s University Belfast, Belfast, UK e-mail: [email protected]

first week of life, do not seem to outweigh the adverse effects on neurodevelopment. However, late postnatal steroid therapy, after the first week of life, seems to be associated with similar beneficial pulmonary effects without significant increase in neurodevelopmental sequelae. Late steroid therapy with dexamethasone is probably still indicated for preterm infants with CLD who cannot be weaned from ventilation. Thus, administration of corticosteroids in the perinatal period must be based upon clinical judgment of the balance of benefits and risks. Further evaluation should be done considering long-term follow-up in order to confirm their safety before they can be recommended for routine use.

65.1

Salient Points

• Corticosteroids given in the perinatal period have a multitude of biological effects on the developing lung and other organs.

# Springer International Publishing AG, part of Springer Nature 2018 G. Buonocore et al. (eds.), Neonatology, https://doi.org/10.1007/978-3-319-29489-6_212

1015

1016

H. L. Halliday

• Prenatal steroids accelerate fetal lung maturity reducing neonatal mortality, respiratory distress syndrome, intraventricular hemorrhage, and necrotizing enterocolitis without affecting maternal health. • Betamethasone and dexamethasone have been used to enhance fetal lung maturity. • Repeat doses improve neonatal outcomes except for a reduction in some measures of weight at birth. • Early (first week) postnatal steroids lead to earlier extubation and decreased bronchopulmonary dysplasia (BPD), patent ductus arteriosus, and retinopathy of prematurity (ROP) but increased gastrointestinal (GI) bleeding and perforation, hyperglycemia, hypertension, hypertrophic cardiomyopathy (HOCM), growth failure, and cerebral palsy (CP), although an outcome combining death and CP is not increased. • Hydrocortisone (low dose) and dexamethasone were used in these trials, and benefits and adverse effects were limited to treatment with the latter. • The recent PREMILOC trial of early low dose hydrocortisone suggests an increase in survival without BPD although there was increased sepsis in infants of 24–25 weeks’ gestation. • Inhaled budesonide (first 12 h) reduced BPD in one large trial, but there was a trend toward increased neonatal mortality. • Late (after first week) postnatal steroids lead to earlier extubation and reduced neonatal mortality, BPD, death, or BPD, while there is increased GI bleeding, hyperglycemia, hypertension, HOCM, and severe ROP, but no significant increase in CP. • It is prudent to reserve late postnatal steroids for infants who cannot be weaned from ventilation. • Early low dose hydrocortisone improves survival without BPD (OR 1.48; 95%CI 1.02–2.16; p = 0.04) with higher sepsis rate in infants of 24–25 weeks’ gestation.

65.2

Introduction

Corticosteroids given in the perinatal period have many biologic effects on the developing lung (Grier and Halliday 2004). These include reduced

alveolarization, increased production of surfactant lipids and proteins, increased absorption of lung fluid, and increased antioxidant activity. Clearly, some of these will be beneficial to the immature fetus or neonate, while others will be detrimental. Thus administration of corticosteroids in the perinatal period must be based upon clinical judgment of the balance of benefits and risks. The first randomized trials of corticosteroids in the perinatal period were published in 1972 in the same issue of a pediatric journal (Liggins and Howie 1972; Baden et al. 1972). They were aimed at either preventing or treating respiratory distress syndrome (RDS), a condition of predominantly preterm infants, which then had a high mortality rate. RDS is due to primary deficiency of pulmonary surfactant (Avery and Mead 1959), and Mont Liggins, an obstetrician in New Zealand, had shown that an infusion of cortisol into fetal lambs seemed to prevent RDS (Liggins 1968). He and a colleague from pediatrics, Ross Howie, performed a large randomized trial of prenatal betamethasone that showed this not only decreased the risk of RDS in neonates but also reduced mortality (Liggins and Howie 1972). Since 1972, many randomized trials have confirmed the benefits of prenatal corticosteroids (Roberts and Dalziel 2006), and long-term follow-up of the original cohort at age 31 years has been published (Dalziel et al. 2005). Detrimental effects of prenatal corticosteroids and the controversy over any additional benefit of repeat courses will be discussed in this chapter. The trial of Baden et al. recruited only 44 infants with RDS to test the effects of hydrocortisone on blood gases, need for assisted ventilation and survival (Baden et al. 1972). Unfortunately, there were no beneficial effects of hydrocortisone, and the authors also concluded that there were no immediate detrimental effects of the therapy. However, two subsequent followup publications raised concerns about an excess of severe intraventricular hemorrhage (IVH) and neurosensory and electroencephalographic abnormalities (Fitzhardinge et al. 1974; Taeusch et al. 1973) in hydrocortisone-treated infants. Despite these early concerns, dexamethasone was used to treat infants with bronchopulmonary

65

Lung Diseases: Problems of Steroid Treatment of Fetus and Newborn

dysplasia (BPD) and ventilator dependence less than a decade later (Mammel et al. 1983; Avery et al. 1985). The rationale for dexamethasone therapy was to reduce inflammation in the lung, an important precursor to the development of BPD. However, the doses of dexamethasone used in these trials were very large (about 0.5 mg/kg/day as a starting dose) giving pharmacologic rather than physiologic effects. It was not surprising that the acute beneficial effects on lung function (Mammel et al. 1983; Avery et al. 1985) would later be shown to have had adverse longterm effects on the developing central nervous system when dexamethasone was given in the first week of life (Yeh et al. 1998).

65.3

Results from Randomized Trials of Prenatal Corticosteroids

The most recent Cochrane Review of a single course of prenatal steroids for accelerating fetal lung maturation includes 21 studies and 4,269 infants (Roberts and Dalziel 2006). The authors conclude that prenatal steroid treatment does not increase risk of death to the mother, chorioamnionitis, or puerperal sepsis. However, treatment was associated with an overall reduction in neonatal death (RR 0.69, 95%CI 0.58–0.81), RDS (RR 0.66, 95%CI 0.59–0.73), IVH (RR 0.54, 95%CI 0.43–0.69), necrotizing enterocolitis (NEC) (RR 0.46, 95%CI 0.29–0.74), respiratory support and intensive care admissions (RR 0.80; 95%CI 0.65–0.99), and systemic infections in the first 48 h of life (RR 0.56, 95%CI 0.38–0.85). Prenatal steroid use is also effective in women with premature rupture of membranes and pregnancy-related hypertension syndromes (Roberts and Dalziel 2006). The authors concluded that a single course of prenatal steroids should be considered routinely for preterm delivery with few exceptions. Further information is needed concerning optimal dose to delivery interval, optimal steroid to use, effects in multiple pregnancies, and confirm long-term effects into adulthood (Roberts and Dalziel 2006; Wapner and Jobe 2011). A recent review assessed different steroid regimens for accelerating lung

1017

maturity and concluded that no clear advantages were found, although dexamethasone may have some benefits compared to betamethasone with less IVH and a shorter length of NICU stay (Brownfoot et al. 2013). An Australasian trial is currently underway to address this question (Crowther et al. 2013). In 2015 a systematic review concluded that a single course of prenatal steroids in women at high risk for preterm birth appears to improve most neurodevelopmental outcomes in offspring born before 34 weeks of gestation (Sotiriadis et al. 2015). Recently, however, there has been concern about the ineffectiveness of prenatal steroids in low-income and middle-income countries (Azad and Costello 2014; Dalziel et al. 2014). This concern is based on the findings of the WHO Multicountry Survey on Maternal and Newborn Health involving more than 300,000 births in 359 hospitals in 29 countries (Vogel et al. 2014). The results have been criticized because of poor treatment coverage and underreporting of preterm birth, but it is agreed that prenatal steroids are not a panacea for preterm mortality in low-income and middle-income countries, and drugs should be included in a package of simple efficacious measures (Dalziel et al. 2014). The most recent systematic review of repeat doses of prenatal steroids for women at risk of preterm birth for preventing RDS included ten trials and involved 4,733 women and 5,700 babies (Crowther et al. 2015). Treatment with repeat dose(s) of steroids was associated with a reduction in RDS (RR 0.83, 95%CI 0.75–0.91) and serious infant outcome (RR 0.84, 95%CI 0.75–0.94). Mean birth weight was reduced by 75.9 g (95%CI 34.0–117.6 g) with repeat doses, but after adjustment of birth weight for gestational age, these differences disappeared. The authors concluded that repeat dose(s) of prenatal steroids reduces the occurrence of RDS and serious health problems in the first few weeks of life. The shortterm benefits for babies support the use of repeat dose(s) of prenatal steroids for women at risk of preterm birth. However, these benefits are associated with a reduction in some measures of weight at birth, and more research is needed on the longerterm benefits and risks (Crowther et al. 2015).

1018

65.4

H. L. Halliday

Results from Randomized Trials 0.04) in preterm infants (7 days) may not outweigh actual or potential adverse effects. Although there continues to be concern about an increase in adverse neurological outcomes in infants treated with early postnatal steroids, this review of late steroids suggests that this may reduce neonatal mortality without significantly increasing the risk of adverse long-term neurodevelopmental outcomes. However, the methodological quality of the studies determining long-term outcomes is limited in some cases, and no study was sufficiently

1019

powered to detect increased rates of important long-term outcomes. Given the evidence of both benefits and harms of treatment and the limitations of the evidence at present, it appears prudent to reserve the use of late postnatal steroids to infants who cannot be weaned from mechanical ventilation and to minimize the dose and duration of any course of treatment (Doyle et al. 2014b).

65.5

Conclusions

There are some problems with steroid treatment of the fetus and newborn, but on the whole if used according to accepted guidelines, the benefits outweigh the risks. For the fetus at risk of preterm birth, a single course of betamethasone or dexamethasone leads to lung maturity and reduces the risk of RDS, neonatal mortality, and other important complications of prematurity (Roberts and Dalziel 2006). The current recommendation is to give two doses of 12 mg betamethasone, 24 h apart, to women who may deliver within 7 days and are less than 35 weeks pregnant (Sweet et al. 2013). There remains some controversy about repeat courses of prenatal steroids, as they are associated with reduced fetal growth, but consensus seems to support their use when there is a high risk of preterm birth before 29 weeks’ gestation (Wapner and Jobe 2011). The beneficial pulmonary effects of early postnatal dexamethasone, in the first week of life, do not outweigh the adverse effects on neurodevelopment (Doyle et al. 2014a). However, late postnatal steroid therapy, after the first week of life, seems to be associated with similar beneficial pulmonary effects without significant increase in neurodevelopmental sequelae (Doyle et al. 2014b). Infants at higher risk of BPD have increased rates of survival free of cerebral palsy after postnatal steroid treatment (Doyle et al. 2014c). Late steroid therapy, with low-dose, short duration dexamethasone, is probably still indicated for preterm infants with CLD who remain ventilator dependent and have severe respiratory disease (Halliday 2011). Inhaled steroids may be a promising method of reducing BPD with reduced adverse effects, but further evaluation in randomized clinical trials with long-term follow-up is needed to confirm their

1020

safety before they can be recommended for routine use (Bassler et al. 2015; Halliday 2011).

References Avery ME, Mead J (1959) Surface properties in relation to atelectasis and hyaline membrane disease. Am J Dis Child 97:517–523 Avery GB, Fletcher AB, Kaplan M et al (1985) Controlled trial of dexamethasone in respirator-dependent infants with bronchopulmonary dysplasia. Pediatrics 75:106–111 Azad C, Costello A (2014) Extreme caution is needed before scale-up of antenatal corticosteroids to reduce preterm deaths in low-income settings. Lancet Glob Health 2:e191–e192 Baden M, Bauer CR, Colle E et al (1972) A controlled trial of hydrocortisone therapy in infants with respiratory distress syndrome. Pediatrics 50:526–534 Bassler D, Plavka R, Shinwell ES et al (2015) Early inhaled budesonide for the prevention of bronchopulmonary dysplasia. N Engl J Med 373:1497–1506 Baud O, Maury L, Lebail F et al (2016) Effect of early low-dose hydrocortisone on survival without bronchopulmonary dysplasia in extremely preterm infants (PREMILOC): a double-blind, placebo-controlled, multicentre, randomised trial. Lancet 387: 1827–1836 Brownfoot FC, Gagliardi DI, Bain E et al (2013) Different corticosteroids and regimens for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database Syst Rev 8, CD006764 Crowther CA, Harding JE, Middleton PF et al (2013) Australasian randomized trial to evaluate the role of maternal intramuscular dexamethasone versus betamethasone prior to preterm birth to increase survival free of childhood neurosensory disability. BMC Pregnancy Childbirth 13:104 Crowther CA, McKinlay CJ, Middleton et al (2015) Repeat doses of prenatal corticosteroids for women at risk of preterm birth for improving health outcomes. Cochrane Database Syst Rev 7, CD003935 Dalziel SR, Lim VK, Lambert A et al (2005) Antenatal exposure to betamethasone: psychological functioning and health related quality of life 31 years after inclusion in randomised controlled trial. BMJ 331:665–668 Dalziel SR, Crowther CA, Harding JE (2014) Antenatal steroids 40 years on: we can do better. Lancet 384:1829–1831 Doyle LW, Ehrenkranz RA, Halliday HL (2010) Postnatal hydrocortisone for preventing or treating bronchopulmonary dysplasia in preterm infants: a systematic review. Neonatology 98:111–117 Doyle LW, Ehrenkranz RA, Halliday HL (2014a) Early (7 days) postnatal corticosteroids for chronic lung disease in preterm infants. Cochrane Database Syst Rev 5, CD001145 Doyle LW, Halliday HL, Ehrenkranz RA et al (2014c) An update on the impact of postnatal systemic corticosteroids on mortality and cerebral palsy in preterm infants: effect modification by risk of bronchopulmonary dysplasia. J Pediatr 165:1258–1260 Fitzhardinge PM, Eisen A, Lejtenyi C (1974) Sequelae of early steroid administration to the newborn infant. Pediatrics 53:877–883 Grier DG, Halliday HL (2004) Effects of glucocorticoids on fetal and neonatal lung development. Treat Respir Med 3:295–306 Halliday HL (2011) Postnatal steroids: the way forward. Arch Dis Child Fetal Neonatal Ed 96:F158–F159 Liggins GC (1968) Premature parturition after infusion of corticotrophin or cortisol into foetal lambs. J Endocrinol 42:323–329 Liggins GC, Howie RN (1972) A controlled trial of antepartum glucocorticoid treatment for prevention of the respiratory distress syndrome in preterm infants. Pediatrics 50:515–525 Mammel MC, Green TP, Johnson DE et al (1983) Controlled trial of dexamethasone therapy in infants with bronchopulmonary dysplasia. Lancet 1:1356–1358 Peltoniemi OM, Lano A, Yliherva A, Kari MA, Hallman M, Neonatal Hydrocortisone Working Group (2016) Randomised trial of early neonatal hydrocortisone demonstrates potential undesired effects on neurodevelopment at preschool age. Acta Paediatr 105:159–164 Roberts D, Dalziel S (2006) Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database Syst Rev 3, CD004454 Sotiriadis A, Tsiami A, Papatheodoros S et al (2015) Neurodevelopmental outcome after a single course of antenatal steroids in children born preterm: a systematic review and meta-analysis. Obstet Gynecol 125: 1385–1396 Sweet DG, Carnielli V, Greisen G et al (2013) European consensus guidelines on the management of neonatal respiratory distress syndrome in preterm infants – 2013 update. Neonatology 103:353–368 Taeusch HW Jr, Wang NS, Baden M et al (1973) A controlled trial of hydrocortisone therapy in infants with respiratory distress syndrome: II. Pathol Pediatr 52:850–854 Vogel JP, Souza JP, Gulmezoglu AM et al (2014) Use of antenatal corticosteroids and tocolytic drugs in preterm births in 29 countries: an analysis of the WHO Multicountry Survey on Maternal and Newborn Health. Lancet 384:1869–1877 Wapner R, Jobe AH (2011) Controversy: antenatal steroids. Clin Perinatol 38:529–545 Yeh TF, Lin YJ, Huang CC et al (1998) Early dexamethasone therapy in preterm infants: a follow-up study. Pediatrics 101, e7

Apnea of Prematurity and Sudden Infant Death Syndrome

66

Christian F. Poets

Contents 66.1

Salient Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1022

66.2 66.2.1 66.2.2

Apnea of Prematurity (AOP) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1022 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1022 Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1023

66.3 66.3.1 66.3.2 66.3.3 66.3.4 66.3.5

Sudden Infant Death Syndrome (SIDS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Genetic Studies in SIDS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1027 1028 1029 1030 1030 1030

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1032

Abstract

Apnea of prematurity is a self-resolving, yet very common condition in preterm infants. Recent observational data suggest that the intermittent hypoxemia often occurring with it may be associated with an increased risk of adverse outcome, including cerebral palsy, retinopathy of prematurity, and death. Treatment should follow an incremental approach, starting with head elevated positioning, followed by caffeine administration and nasal respiratory support. Sudden infant death syndrome has decreased markedly in incidence following

C. F. Poets (*) Department of Neonatology, Tübingen University Hospital, Tübingen, Germany e-mail: [email protected]

primary prevention campaigns in many countries, yet continues to be a leading cause of death beyond the neonatal period. Although still incompletely understood, it seems that death is the result of an external trigger (e.g., prone sleep position) occurring in a vulnerable infant (e.g., born to a mother who smoked during pregnancy) during a critical developmental period (e.g., 2–4 months of age). Memory monitor recordings obtained during SIDS suggest that bradycardia, probably resulting from severe hypoxemia, is the primary abnormality in the sequence of events ultimately resulting in these deaths. Prevention should focus on a safe sleep environment, i.e., supine sleep position, a smoke-free environment, avoidance of overheating, use of a sleeping bag, and room but not bed sharing.

# Springer International Publishing AG, part of Springer Nature 2018 G. Buonocore et al. (eds.), Neonatology, https://doi.org/10.1007/978-3-319-29489-6_213

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1022

C. F. Poets

List of Abbreviations

AAP ALTE AOP BPD CDC CI CO2 IH LQTS MCAD N-CPAP N-IPPV NNT OR PaO2 PAR RCT ROP RR SIDS SpO2 TPN VLBW

66.1

American Academy of Pediatrics Apparent life-threatening event Apnea of prematurity Bronchopulmonary dysplasia Centers for Disease Control Confidence interval Carbon dioxide Intermittent hypoxemia Long-QT-syndrome Medium-chain acyl-CoA dehydrogenase Nasal continuous positive airway pressure Nasal intermittent positive pressure ventilation Number needed to treat Odds ratio Partial pressure of oxygen in arterial blood Population-attributable risk Randomized controlled trial Retinopathy of prematurity Relative risk Sudden infant death syndrome Arterial oxygen saturation measured by pulse oximetry Total parenteral nutrition Very low birth weight

Salient Points

• Apnea of prematurity is a self-resolving and very common condition in preterm infants. • The intermittent hypoxemia accompanying it may be associated with an increased risk of adverse outcome (cerebral palsy, retinopathy of prematurity, and death). • Treatment consists of head elevated positioning, followed by caffeine administration and nasal up to nasal respiratory support. • The incidence of sudden infant death syndrome (SIDS) has markedly decreased even if it remains a leading cause of death in the postneonatal period. • It seems that death is the result of an external trigger (position) occurring in a vulnerable

infant during a critical developmental period. • Prevention should focus on a safe sleep environment (supine positioning), a smoke-free environment, and avoidance of overheating.

66.2

Apnea of Prematurity (AOP)

66.2.1 Introduction Apnea of prematurity (AOP) is a developmental and thus self-resolving disorder, which nonetheless may cause serious long-term sequelae through accompanying hypoxemia. Almost every infant born at less than 29 weeks gestation exhibits AOP, but little was known when it became potentially harmful. Recently, a secondary analysis of pulse oximeter saturation (SpO2) and pulse rate data recorded for a mean duration of 68 days in 1035 participants in the Canadian Oxygen Trial (COT), who were born at 23–27 weeks GA and survived to 36 weeks postmenstrual age (PMA), showed the following (Poets et al. 2015): – Mean percentages of recorded time with hypoxemia (pulse oximeter saturation (SpO2) 28 days of age with focal neurological deficits (hemisyndrome with early handedness, ophtalmoplegia) or epilepsy and a corresponding chronic infarct in arterial distribution in whom it is presumed that injury occurred between the 28th week of fetal life through the 28th postnatal day but was not detected during that period. Sinovenous thrombosis is suspected when a parenchymal lesion (three-fourth hemorrhagic, one-fourth purely ischemic) is near a partial or completely occluded sinus or large vein. Pure sinus thrombosis without parenchymal injury is rare but can be included. Primary hemorrhage is diagnosed when a parenchymal bleeding is not compatible with an arterial template and when regional veins and sinuses are patent. The most common venous infarct is parenchymal white matter injury of the preterm infant. The involvement of a vein is possible in many instances of lobar cerebral hematoma, often difficult to prove however. Focal brain lesions due to vessel occlusion are inherent to the definition of stroke. Lesions due to infection and watershed injury can mimic stroke to such extent that their inclusion is warranted in any neonatal stroke register (Fig. 1).

130.3 Clinical Presentation Seizures are the usual (at least 70% of the time) presentation of NAIS (Sreenan et al. 2000). Onset is fifty-fifty divided between day 1 and later in the

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first week, rarely beyond day 3 (Jan and Camfield 1998). Focal seizures are a more common first sign of NAIS than general seizures. Because the interval insult to seizures may be short (less than an hour) but also add up to several hours, the timing in hours of an arterial insult in relation to labor stages is impossible. Acute embolic stroke may cause seizures within the hour of the event (Pellicer et al. 1992) or onset of seizures may be delayed for several hours (Fischer et al. 1988). Seizures tend to occur earlier in HIE associated with intrapartum asphyxia than in relation to stroke (Rafay et al. 2009). Many newborns with stroke present with apneic spells or cyanotic attacks, often of epileptic nature (Hoogstraate et al. 2008; Chabrier et al. 2010). Seizures can be repetitive and lead to status epilepticus, typically projected on one hemisphere against a normal or only mildly altered EEG background. Most children seem to be alert between seizures and even accept oral feeding. Some present with temperature instability (Roodhooft et al. 1987), others with bouts of hyper- or hypotension due to hypothalamic injury. In some infants hemiplegia can be predicted from neonatal appreciation of asymmetrical general movements (Guzzetta et al. 2003), but most often future hemiplegia is inconspicuous in the neonatal period. Abnormal tone or altered level of consciousness has on occasion been the presenting sign, as have feeding problems. Neurologic alarm signs, except occasional clinical seizures, are usually lacking in perforator stroke and in the preterm, where stroke is often a surprise finding at brain US scanning. In the context of NAIS, an alarming event may be acute pallor and loss of pulsation of (part of) a limb due to arterial embolism (or spasm ?), as reported by several authors ((Asindi et al. 1988; Raine et al. 1989; Gudinchet et al. 1991; Silver et al. 1992; Guajardo et al. 1994), one personal observation). Most of these limb-brain strokes present with limb pallor within minutes of delivery, strongly suggesting that embolic stroke preceded delivery for hours. In some cases, antiphospholipid antibodies in newborn serum were associated, and aortic thrombosis has been documented in this context (Raine et al. 1989; Gudinchet et al. 1991), personal observation], as

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Fig. 1 Algorithm for focal lesions in the neonatal brain

has subclavian steal from the vertebrobasilar circulation documented with MRI (Broxterman et al. 2000; Beattie et al. 2006) (Fig. 2). Clinical signs due to CSVT suggest that parenchymal destruction around veins followed an increase of venous tension above the arterial pressure level (hemorrhagic lesions) or an arterial ischemic response to venous occlusion. Neonates with NCSVT present either with seizures in the majority or with focal neurological signs like hemimotor paresis or cranial nerve palsies (Berfelo et al. 2010; Fitzgerald et al. 2006; Nwosu et al. 2008). Most often this

is within the first days of life, not necessarily so in infants with congenital heart disease and dehydration or in preterms. A context of mechanical cranial trauma is possible. Fever, altered level of consciousness, or jitteriness is possible but not typical. The underlying cause may dominate the picture as with asphyxia, congenital heart disease or dehydration. Thrombosis without infarction is asymptomatic and thus an incidental finding (for instance, in a search for the cause of a low platelet count or during ECMO). Platelet consumption is seen with extensive NCSVT, with or without venous

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Fig. 2 Limb-brain arterial ischemia on day 1 of life

infarction, ant it can be observed with NAIS if the arterial process causes organ or limb necrosis (Berfelo et al. 2010). Propagation of thrombosis is possible in the first week, perhaps explaining evolving clinical signs. A recent report referred to ALTE following acute thalamic unilateral stroke in infancy (Gupta et al. 2009). This finding adds to the description of apnea following temporal lobe lesions, such that a work-up of supratentorial injury is warranted in unexplained apnea. Extensive stroke lesions (mainly hemorrhagic) in cerebellum can lead to hypertension in the posterior fossa with Cushing response (bradycardia, hypertension) and several types of respiratory problems (sighing, apnea). Cranial nerve palsy is a rare presentation of posterior fossa stroke. Some of the more specific

clinical signs of hindbrain infarction are mentioned in the section on “stroke templates” (Fig. 3).

130.4 Imaging 130.4.1 Staging with Any Type of Imaging 130.4.1.1 Swelling From 30 min to a few hours cytotoxic edema increases water content. Changes in water diffusion occur within minutes on DWI; nadir ADC is on average around 33 h after the insult and it takes 4–10 days before ADC normalizes and overshoots the normal (Pellicer et al. 1992; Hill et al. 1983; Raybaud et al. 1985; Bode

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Fig. 3 Term vaginal breech delivery leading to occipital osteodiastasis, contusion of the inferomesial cerebellar hemispheres, and left cranial nerve XII compression`

et al. 1986; Hernanz-Schulman et al. 1988; Taylor et al. 1993; Koelfen et al. 1995; Mader et al. 2002; Cowan et al. 2005) (Fig. 4). In the vessel, flow void is lost in the affected artery for hours: this dampening disappears within 24 h (d’Orey et al. 1999). Most neonatal strokes present with reopened vessel at clinical detection.

130.4.1.2 Necrosis From 6 h to about 6 days, edema and coagulation necrosis are associated with breakdown of the blood-brain barrier. Maturation of the infarct follows reperfusion of a pressure-passive vascular bed, through recanalized or anastomotic arteries. The peak of events is 2–4 days following acute infarction. Invading macrophages and glial cells visualize the infarct at postmortem and on images between 24 and 72 h after onset. If very large,

swelling produces mass effect for about a week. As measured on DWI, large strokes reach a maximal size around 70 h after onset. In adults the penumbra shows restricted diffusion: consequently the final T2 lesion is smaller than the volume of diffusion restriction. Changes on T2 and PD images likely represent definitive damage. Disappearance of the cortical ribbon in the affected pial area is typical.

130.4.1.3 Organization From 3 days to 6 weeks, this involves gliosis, breakdown of myelin, microcyst formation, and neovascularization. Disappearance of edema accounts for the loss of mass effect. Total necrosis may lead to central liquefaction with ensuing cyst formation. Microscopically it is represented by petechial (capillary) hemorrhage in cortex and

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Fig. 4 Mixed image panel to illustrate stages of arterial ischemic stroke

basal ganglia: starting at about 3–6 days, this event peaks at 9–14 days when up to 90% of the infarcts are affected, and it regresses in half of the instances near the end of the first month.

130.4.1.4 Tissue Loss From the second month onward infarction within a major cerebral artery will be recognized as an area of cortico-subcortical tissue loss, based against the skull bone. Because all tissue has disappeared, including cortex, this cystic remnant opens into the subarachnoid space. Infarction close to the occlusion site or central in the arterial territory may not present with the typical triangular tissue distribution. Wallerian degeneration of the ipsilateral pyramidal tract and transsynaptic degeneration of ipsilateral thalamus and contralateral cerebellar hemisphere will proceed for several months after the initial injury. Thalamus on the side of extensive frontoparietal (sub)cortical tissue loss will shrink by 20–40% in 3–6 months.

130.4.2 Ultrasound in NAIS NAIS can nearly always be visualized with US, except for small cortical infarcts far away from the transducer. It may, however, take several days before hyperechoic change is apparent beyond doubt (de Vries et al. 1997; Pellicer et al. 1992; Hill et al. 1983; Bode et al. 1986; HernanzSchulman et al. 1988; Cowan et al. 2005; d’Orey et al. 1999; Pape and Wigglesworth 1979; Donaldson 1987; Govaert et al. 2000; Sreenan et al. 2000). Even in cases of temporal or occipital infarction targeted insonation from asterion or posterior fontanelle can detect the lesion. Perforator stroke in thalamus and striatum is particularly sensitive to detection with ultrasound. Pial strokes gradually become sharply demarcated within arterial template confines. On recuperation, discrepant high flow velocities may be recorded up to 160 cm/s; this is regional luxury perfusion and may persist for

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Fig. 5 Top of the basilar artery stroke with luxury perfusion in the infarct area, also confirmed by high velocities in the basilar artery (Govaert et al. 2009)

over a week (Steventon and John 1997; Taylor et al. 1993; Taylor 1994). Systolic but even more diastolic velocity increases, with a reduction of the resistance index compared with the healthy contralateral vessel. In this subacute stage, power Doppler imaging may suggest an increase in size and number of visible vessels in the periphery of large infarcts. Deep venous blood flow velocity about doubles on the affected side (measured in the internal cerebral vein) during the stage of hyperperfusion (Fig. 5). Ultrasound staging is as follows: – Day 1: decreased pulsatility of affected vessel and mild, inconspicuous hyperechogenicity. – Over the next few days, increase of echogenicity in core and penumbra, due to the increasing presence of cell nuclei from neutrophils and

macrophages; associated hemorrhage increases inhomogeneity; the hyperechoic stage persists for 3–4 weeks; cavitation follows an intermediate checkerboard pattern. – Swelling for about a week, with effaced sulci and mass effect in case of complete MCA infarction. – A CSF cavity is fully developed after 6–10 weeks; compensatory neuropil growth around the infarct may create the impression that the defect shrinks over the ensuing months; some have interpreted this as compensatory growth of the area adjacent to the infarct (Fig. 6).

130.4.3 MRI in NAIS See Raybaud et al. (1985), Mader et al. (2002), Bouza et al. (1994a), Krishnamoorthy

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Fig. 6 The possibilities and limitations of detecting NAIS with ultrasound (Cowan et al. 2005)

et al. (2000), Mercuri (2001), Seghier et al. (2004), Dudink et al. (2009), de Vries et al. (2011), and Gunny and Lin (2012) Technical background of advanced MRI modalities is a complex matter, and imaging accuracy depends on many aspects, including acquisition and processing methodology. MRI provides the highest anatomic resolution and the best sensitivity to detect acute ischemia. Specific sequences to obtain include diffusion-weighted imaging (DWI, from insult to about 7 days later), T1- and T2- weighted imaging (T1W and T2W), and susceptibility weighted imaging. A magnetic resonance angiography (MRA) of the head and neck should be considered because it can easily be added to the initial MR evaluation. Contrast MRA/V is not needed. MRA may detect arterial variation, carotid dissection or asymmetry between the MCAs. Advanced MRI techniques such as diffusion tensor (DTI), functional MRI, volumetric MRI, and proton magnetic resonance spectroscopy are used in research to better

determine the full spectrum of brain injury. From DTI diffusion anisotropy measures such as fractional anisotropy (FA) can be computed. DWI is used to depict cytotoxic edema and in neonates is sensitive enough to provide image alterations within hours of the initial injury, similar to adults. Visualization of the lesion using DWI is best observed within the first 2–4 days from the moment of the initial injury. As measured on DWI large strokes reach a maximal size around 70 h after onset. In adults the penumbra shows restricted diffusion: consequently the final T2 lesion is smaller than the volume of diffusion restriction. Changes on T2 (and PD, proton density) images likely represent definitive damage. On conventional MRI sequences term infants with neonatal stroke in the first postnatal weeks have on T2W images a high signal intensity in affected cortical gray matter and white matter during the first week of life, whereas T1W imaging reveals a low signal intensity in the involved cortical gray matter (missing cortex). From

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Fig. 7 Sequential aspects of T1 and T2 appearances in NAIS (Dudink et al. 2009)

1 week to 1 month after birth, cortical gray matter signal intensity is high on T1W and low on T2W imaging (cortical highlighting). Serial MRI studies confirm that in neonates with AIS, the onset of injury is around the time of delivery. Tissue breakdown is maximal around 6 weeks. Three-site involvement of the hemisphere (cortex and/ or white matter), the basal ganglia, and the posterior limb of the internal capsule is strongly associated with later contralateral hemiplegia irrespective of the size of the infarct (Fig. 7). In the acute stage intensity changes are seen on DWI along the pyramidal tract; this phenomenon has prognostic value especially at mesencephalic and pontine level and is referred to as pre-Wallerian degeneration (Fig. 8). The extent of such acute corticospinal changes may predict severity of the hemisyndrome and also of recruitment of ipsilateral tracts for maintaining function in the affected limbs (Mazumdar et al. 2003; de Vries et al. 2005; Kirton et al. 2007; Lama et al. 2011; van der Aa et al. 2013). Advanced

postacquisition quantification of diffusion tensor imaging data allows mapping of white matter connections, so-called tractography. Tractography is able to refine subjective prediction of motor dysfunction (Roze et al. 2012). The presence of a penumbra has been demonstrated with ASL sequences, showing hyperperfusion compared to healthy tissue in the acute stage (5–6 days after birth); in some the whole infarct area can be hyperperfused (Wintermark and Warfield 2012; De Vis et al. 2013) (Fig. 9). This type of early visualization may in the future guide immediate postlesional treatment with neuroprotective agents. Connected nuclei – like pulvinar – may also secondarily suffer from cell injury with restriction of water diffusion in the acute phase, referred to as network injury (Govaert et al. 2008; Dudink et al. 2012; Okabe et al. 2014) (Fig. 10). Response to injury in a developing brain may be faster than that in a mature one. Acute callosal changes reflect

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Fig. 8 Differences in hypersignal on DWI at the level of the cerebral peduncles relate to differences in cortical involvement

network injury to connected tracts, similar to the corticospinal tract (Righini et al. 2010). Crossed cerebellar atrophy (diaschizis) related to supratentorial stroke has recently been demonstrated in children (Mah et al. 2013). Susceptibility-weighted imaging (SWI) is useful, improving the differentiation between small ischemic and hemorrhagic lesions. Recent evidence suggests that SWI may depict changes in the veins involved in an arterial infarct, and a mismatch with DWI may be helpful to define windows of opportunity for intervention (Meoded et al. 2014; Kidwell et al. 2003; Lequin et al. 2009). Hypoxemia and stasis in veins draining an infarct make the vessels stand out on SWI, of course dependent on the timing of imaging after the insult. Hemorrhagic conversion of any focal lesions is also well seen with SWI. Functional MRI and transcranial magnetic stimulation will certainly help to study how the brain adapts to focal neonatal lesions; these methods will be needed to document the effect

of targeted rehabilitation (Staudt et al. 2005; Fair et al. 2006; Walther et al. 2009).

130.4.4 Stroke Templates (Focus on Sonographic Aspects) General references (Vander 1959; Stephens and Stilwell 1969; Govaert 2009; Lee 1995; Bogousslavsky and Caplan 1995) Multiple strokes on either side of the brain occur often; a case of hydranencephaly would be classified as bilateral ACA plus MCA stroke; multicystic encephalopathy could be classified as bilateral ACA, MCA plus cortical PCA stroke; infarction within the ICA can be scored as ipsilateral ACA + MCA stroke; complete MCA stroke is different from combined ipsilateral anterior and posterior truncal MCA stroke (the latter with intact striatum). It is advised to visualize the carotid arteries and the circle of Willis in some conditions mentioned; withering of large cerebral

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Fig. 9 Near-term infant with second day apnea due to partial left MCA stroke: low ADC values (on day 3 of life) in the ischemic area but high perfusion on the ASL image in the area around the infarct core. This was presumed embolism from partial internal carotid artery thrombosis

arteries involved in the cavitation may be secondary to stroke.

130.5 Pial Arteries See Fig. 11

M2-4: entire convex cortical and immediate subcortical area except for a margin of 1–2 cm perfused by either anterior or posterior cerebral artery pial branches; insular gyri and lateral orbital gyri (de Vries et al. 1997; Bode et al. 1986; Hernanz-Schulman et al. 1988; Koelfen et al. 1995; Govaert et al. 2000; Steventon and John 1997; Govaert 2009; Ramenghi et al. 2010)

130.5.1 MCA Stroke M1 (origin to limen insulae): medial parts of striatum including anterior commissure and ventral striatum, genu capsulae internae in its lower part, anterior pallidum internum; lateral parts of striatum (aa putamino-capsulo-caudate) including lateral and dorsal caudate head and corpus, crus anterius lateral part, entire putamen except for a ventral posterior portion, pallidum externum; thalamus is perfused from anterior choroidal, posterior communicating and posterior cerebral artery

MCA complete infarction. Hyperechoic change in caudate or pallidum can be the first indicator of complete MCA stroke. Hyperechoic change spreads in neostriatum as well as lateral pallidum and in white matter, from the ventricular border to the (sub)cortex, in and around the insula. A true linear medial margin appears from near the cranial midline to the midtemporal base; the only condition with comparable linear hyperechoic margination is bacterial encephalitis. Complete purely cortical infarction of the MCA, without involvement of striatum, is rare, as is infarction within the

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Fig. 10 Examples of network injury to pulvinar

striatal nuclei plus partial pial infarction, in the MCA anterior or posterior cortical field. Variation in vascular anatomy and anastomoses influencing the size of the penumbra may explain such unusual infarcts; multifocal arterial occlusion is the alternative, for example, distal migration of a thrombus wedged temporarily in the M1 part. MCA anterior truncal infarction. The anterior trunk splits into several arteries: prefrontal, precentral, central, and anterior parietal. These vessels irrigate the cortex on the cerebral convexity up to the level of the postcentral gyrus. Complete infarction of the anterior trunk would often involve motor cortex, whereas partial infarction limited to the premotor and/or supplementary motor area could lead to contralateral disturbances in motor coordination without hemiplegia. The hyperechoic focus is a triangle with its point at the insular limen and its base spread across the parasagittal sector from frontal bone to central

groove. The anterior part of the insular gyri is involved as well. Lobar frontal hematoma at term may sometimes represent hemorrhagic conversion of anterior truncal MCA stroke. MCA posterior truncal infarction. The posterior trunk perfuses temporal and occipital lobe convexity and a variable portion of posterior parietal lobe. Its terminal, the angular artery, runs a course prolonging the horizontal lower border of the insula behind the postcentral gyrus. Extension of this truncus as far anterior as the motor cortex is uncommon. Infarction within this territory affects the posterior temporal and occipital lobe on the convexity. Recognition can be difficult if the insula is not inspected. The hyperechoic focus points towards the posterior insula on parasagittal section and has a triangular extension with fuzzy base against the occiput. On coronal view a blurred hyperechoic area is seen behind and underneath the circular groove of the insula.

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Fig. 11 Pial arterial templates

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Neonatal Stroke: Clinical Presentation, Imaging, Treatment, and Prognosis

130.5.2 ICA Stroke Some MCA strokes are part of a larger event, including ACA (ipsi- or contralateral) or PCA stroke (Campbell et al. 1988; Bergevin et al. 1991; Alfonso et al. 2001; Lequin et al. 2004; Hamida et al. 2014). This suggests occlusion of the ICA, for instance, due to embolism or to local thrombosis following trauma. In those cases it is important to exclude dissection of the carotid artery as the mechanism. Arterial dissection results from disruption of the intima, resulting in intramural hematoma; hematoma narrows the lumen, and impedes flow, which predisposes to thrombus formation and distal embolization. Dissection is demonstrable with noninvasive techniques, like MRI, MRA, and US. It may not be possible to recognize dissection of the wall in vivo facing complete thrombotic occlusion, although crescentic hyperintensity on T1 in the carotid wall is strongly suggestive of intramural changes. Segments of the ICA are defined as follows: C1, cervical (bifurcation of common carotid artery to carotid canal); C2, petrous; C3, cavernous; and C4, supraclinoid. Only a few cases of neonatal carotid artery dissection have been reported. The most common site of dissection is at C1 or C4. Neck rotation may be the cause of the dissection below the skull base, due to an intimal tear by compression of the vessel against the transverse processes of the upper cervical vertebra. Both carotid and vertebral artery dissection in one patient is possible (Hamida et al. 2014). The enlarged artery may compress lower cranial nerves. Carotid ligation during ECMO is another risk factor for ICA stroke.

130.5.3 ACA Stroke A1 (pars precommunicalis): chiasma, fasciculus and tractus opticus, hypothalamus anterior, septum pellucidum, columna fornicis, commissura anterior medialis, anterior and inferior striatum and crus anterius; a communicans anterior: chiasma opticum,

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rostrum corporis callosi, lamina terminalis, area pre-optica hypothalami, commissura anterior A2-4: cortical areas between falx and the area perfused by the arteria cerebri media, including gyrus cinguli; corpus callosum and septum pellucidum in front of the splenium (Billard et al. 1982; Huang et al. 1987; Sashikumar et al. 2014) Infarction within pial branches of the ACA may present with seizures limited to one limb. If occluded close to the anterior communicating artery, the hyperechoic focus should involve gyrus cinguli, mesial frontal cortex against the falx, a 1–2 cm broad cortical area on the cerebral convexity near the superior sagittal sinus (extending caudally up to the parieto-occipital sulcus), and part of corpus callosum. In case of occlusion of A1, due to the very common existence of an anterior communicating artery with perfusion of the distal portions from the other side, simultaneous necrosis in caudate head and cortical areas is rare. Partial infarction can be seen along the midline in the premotor cortical area due to occlusion of a branch of the internal frontal artery. Association with ipsilateral MCA stroke suggests either ICA involvement or compression of the ACA by swelling from the MCA area.

130.5.4 PCA Stroke Posterior hypothalamus, medial subthalamus, all but the polar thalamic area, posterior part of lateral geniculate, medial geniculate, splenium of the corpus callosum, middle part of posterior limb and of cerebral peduncle, quadrigeminal plate, choroid plexus of third and lateral ventricle, mesial cortical area of cuneus (visual cortex) and posterior precuneus, posterior temporal cortex, optic radiation caudal to the lateral ventricle. (Anderson et al. 1995; de Vries et al. 1996; Correa et al. 2004)

Cortical PCA stroke is recognized by insonation from the posterior fontanelle. One hardly spots the area of ischemia from the anterior fontanelle: upon scrutiny subcortical white matter may be hyperechoic at the far caudal end of the sector.

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Brain swelling or the presence of a spaceoccupying process in the supratentorial compartment can shift the temporal lobe towards the tentorial edge (uncal herniation), endangering perfusion of the visual cortex through compression of the ambient segment of the PCA and of the ipsilateral basal vein. The triad following such lesion, in its typical form, consists of: temporal lobe epilepsy, homonymous hemi- or quadrantanopia and enlargement of the occipital horn. Oculomotor palsy may be part of this spectrum.

130.5.5 Interarterial Watershed Injury Watershed injury, or cell loss in border zones between the major cerebral and cerebellar arteries, is best known in the context of global peripartum forebrain ischemia or against a background of hypotension, due to endotoxin mediated shock or blood loss for instance (Swarte et al. 2009; Harteman et al. 2013). This type of injury can be asymmetrical and can be mixed rostral or caudal. It can mimic distal partial AIS. Hyperechoic change is present in periventricular and subcortical white matter and is not maximal in the cingular area and in the corpus callosum. This type of injury is not always confidently visualized with US. It can be hemorrhagic or not and lead to cavitation or not.

130.5.6 Anterior Choroidal Artery Stroke 1 proximal branches to optic tract, crus posterius and pallidum mediale; 2 medial branches to pedunculus cerebri, nu. ruber, su. nigra, subthalamus, anterolateral thalamus; 3 lateral branches to uncus, parahippocampal gyrus, dentate gyrus, amygdaloid nuclei, caudate tail; 4 distal branches to optic radiation and lateral geniculate; 5 plexus segment for plexus of temporal horn] (Takahashi et al. 1994, details in (Abels et al. 2006)

Abbie’s syndrome due to AChA infarction (hemiparesis, hemihypoesthesia, homonymous

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hemianopia) is reported in the newborn. A hyperechoic lesion is seen between pallidum and thalamus, covering the middle and lower part of the posterior limb of the internal capsule (PLIC). Because lower limb corticospinal fibers course more posteriorly through PLIC, leg monoplegia can be the sequel. Extensive infarction involves pial areas near the optic tract.

130.5.7 Perforator Stroke Templates for perforator stroke (the artery occluded is not a cortical branch but a perforator artery stemming from the proximal parts of the circle of Willis arteries) are available (Abels et al. 2006; De Vries et al. 1992; Garg and DeMyer 1995; Donzelli et al. 1998; van WezelMeijler et al. 1999; Miller et al. 2000; Roitberg et al. 2002; Feekes et al. 2005; Marinkovic et al. 2005; Bain et al. 2009) (Fig. 12). Perforator has to be differentiated from hemorrhage due to limited thrombosis in one of the veins drained by the internal cerebral or basal vein.

130.5.7.1 MCA Perforator Stroke Many striate perforators arise from the MCA. The term giant lacunar infarction is used to describe the wedge of infarcted striatal tissue within lateral lenticulostriate M1 branches. This hyperechoic triangular focus is sufficiently typical in US: it has curved regular margins, the inner one through pallidum and the outer one just beneath the insular cortex. The base of the triangle is the posterior and superior part of the head of caudate. The infarct does not reach far into white matter, sustaining the angiographic finding that perforators from the MCA do not end in long ventriculofugal terminals. 130.5.7.2 ACA Perforator Stroke The basilar side branches of the anterior cerebral artery (ACA) are the aa. striatae mediales, three or four very thin branches perforating directly the substantia perforata. One of them stands out by a wider caliber: the a. recurrens of Heubner. The

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Fig. 12 Perforator arterial templates

level of its origin varies in relation to the anterior communicating artery. This recurrent artery runs in a lateral and dorsal direction, gives off a fine branch for the tuber olfactorium, and finally

penetrates into the lateral part of the anterior substantia perforata. Heubner’s artery stroke is recognized as a focal lesion in the lateral, anterior caudate head in front of the foramen of Monro.

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Heubner’s artery, large in the late fetal and perinatal period because of its contribution to matrix perfusion, seems to be a common route for emboli. In children with this type of stroke, contralateral upper limb dystonia has been reported. An important perforator from the anterior communicating artery, the subcallosal artery, perfuses columna fornicis and anterior commissure, leading to basal forebrain amnesia when this territory is infarcted in the adult (no neonatal reports).

130.5.7.3 PCA Perforator Stroke Around the brain stem the PCA gives off a series of side branches subdivided into two groups, branches from the crural part (of interest here) and those from the distal cortical part. The branches from the crural part are deep penetrating vessels (perforating or choroidal). First, there are the arteriolae retromammilares which are divided in an anteromedial and a posteromedial group. The anteromedial (thalamostriate) group supplies the median-posterior part of the mammillary bodies; to them belong the aa. perforantes thalami which vascularize the median anterior part of thalamus, the superior part of nucleus ruber, the median part of subthalamic nucleus, the posterior part of hypothalamus, and the superior part of the brachia conjunctiva. In adults the presence of an unpaired median thalamic perforator artery (Percheron’s artery) has led, if obstructed, to bilateral paramedian thalamic infarction. The posteromedial group supplies the middle part of the crus cerebri after having perforated the intercrural substantia perforata. The a. quadrigemina arises close to the origin of the PCA, just medial to the point where the posterior communicating artery joins the latter. It forms a pericrural arc. The aa. choroideae posteriores are usually double and originate separately or via a common stem. They also curve around the crus cerebri. The first, the a. chorioidea posterior medialis, takes a posteroanterior course towards the pineal body, to which it gives off some small branches; it diminishes in size in the choroid plexus of the third ventricle. The second, the a. chorioidea posterior lateralis gives two end branches. One follows the median part of the

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upper side of the thalamus, the supero-median part of which it irrigates. The other reaches the choroid plexus of the lateral ventricle opposite the lateral part of the pulvinar. It also vascularizes the posterior part of the caudate nucleus. During their ascending course the posterior choroidal arteries give off small branches entering the median part of the pulvinar. The aa. thalamogeniculatae usually arise just beyond the point where the posterior communicating artery joins the posterior cerebral artery. Thalamogeniculate arteries are five or six thin branches penetrating into posterior thalamus, to supply corpus geniculatum mediale and laterale, the lower half of the lateral thalamus, the lateral part of the pulvinar, and also the median part of the crus occipitale of the internal capsule.

130.5.7.4 PCoA Perforator Stroke The posterior communicating artery (PCoA) runs beneath the optic tract and above the oculomotor nerve and joins the PCA at a small distance from the division of the basilar artery. Five to six small arteries arise from the PoCA, participating in the vascularization of the floor of the third ventricle (hypothalamic nuclei), and of the supero-anterior part of the medial thalamic nuclei. A lateral branch, the premamillary artery, irrigates the caudal hypothalamus, the medial subthalamus (the substantia nigra, Forel’s field, and the zona incerta), and a rostral portion of the thalamus (the ventral part of the anterior group of nuclei, the ventral anterior nucleus, the rostral part of the midline and reticular thalamic nuclei, as well as the rostral part of the mediodorsal nucleus). Finally, peduncular branches nourish the ventromedial part of the rostral crus cerebri. A focal, lentiform lesion in thalamus, anteriorly and slightly laterally, is not uncommon in sick newborn infants of any gestational age. One type with a focus in thalamus superior and anterior, next to the genu capsulae internae and with a free bridge of unaffected tissue between infarct and midline, may be due to premamillary artery stroke. An up- and outward oblique direction accords with perforator trajectories from MCA or circle of Willis. The other with a lower and

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more mesial location, abutting on the midline, may be one of the variants of PCA perforator stroke. Outcome of unilateral thalamic focal infarction can appear normal in infancy and early childhood. The PLIC (posterior limb of the internal capsule) containing the corticospinal tract can be involved in stroke within: (1) lateral striatal perforator from MCA, (2) premamillary a., (3) anterior choroidal artery, (4) thalamogeniculate a., and (5) medial posterior choroidal a.

vertebral artery. Although the labyrinthine artery may occasionally branch from the basilar, it most frequently originates from the anterior inferior cerebellar artery. Many vessels that arise ventrally course around the brainstem to serve dorsal structures (circumferential branches); others perforate near the midline (paramedian branches). Pontine anterior strokes have been linked to neonatal GBS meningitis with arteritis around the circle of Willis.

130.5.7.5 Centrum Semiovale Stroke An echodense nodule is occasionally encountered within the centrum semiovale immediately next to the lateral ventricle. Context and imaging are often indicative of an embolic ischemic lesion. Infarction in a terminal lateral striatal MCA branch is a likely possibility. The alternative explanation would be stroke of one ventriculopetal cortical arterial branch of the ACA, MCA, or PCA; depending on the site of occlusion this mechanism might also lead to focal subcortical infarction, e.g., in the pericentral area. If hemorrhagic, one must also consider isolated paraventricular venous thrombosis to explain these lesions, an associated germinal matrix hemorrhage would sustain that hypothesis.

130.5.9 Spinal Cord Arterial Ischemic Stroke

130.5.8 Hindbrain Arterial Ischemic Stroke There are a limited number of neonatal descriptions of cerebellar or brainstem stroke (Govaert et al. 2009; Norman 1974; Pollack et al. 1983) (Fig. 13). As for the forebrain, hindbrain arteries are well formed early in fetal life (details beyond this discussion), so recognizable patterns of infarction in superior, anterior inferior, and posterior inferior cerebellar arteries are present in the perinatal period. Because of a similar endstage for hemorrhage and infarction of the cerebellar hemisphere, i.e., a permanent cleft disrupting foliation around it, the existing literature on purely ischemic cerebellar stroke is limited. The posterior spinal artery usually originates from the posterior inferior cerebellar artery, but it may arise from the

The spinal cord is irrigated by: (i) a single median anterior spinal artery derived from both vertebral arteries, extending down to the cauda equina; neck hyperextension may lead to occlusion/spasm in this vessel at low cervical level and cause the central cord syndrome; (ii) a posterior spinal artery on each side from the inf. post. cerebellar arteries, extending medial to the posterior root; (iii) segmental arteries from vertebral, subclavian, intercostal, and hypogastric arteries or from the aorta; the post (Young et al. 1983; de Vries et al. 1995; Ruggieri et al. 1999; Carrascosa-Romero et al. 2002; Simanovsky et al. 2004). radicular and spinal arteries are provided along the cord in 12 unpaired vessels and form a rich posterior spinal collateral network; there are 7–10 unpaired anterior radicular and spinal feeders, with a much less efficient collateral circulation; there is usually a large (70% on the left) anterior segmental artery from the aorta at T9 to L2 level (high or low position) called the Adamkiewicz artery; this vessel is vulnerable to hypoperfusion of the aorta (coarctation, aortic surgery) or to aortic catheterinduced emboli or vasospastic agents (UAC in high position, above T9–L2). Most of the lateral and the entire anterior column, including spinal gray matter, are perfused from central branches of the anterior spinal artery. These branches alternate sides; hypoperfusion within the anterior spinal artery may cause necrosis on both sides (central cord syndrome) or on one side (partial Brown-Séquard syndrome), facilitated by the

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Fig. 13 Hindbrain and cord vessel templates

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Neonatal Stroke: Clinical Presentation, Imaging, Treatment, and Prognosis

absence of important anastomoses between anterior and posterior spinal circulation. The clinical features of spinal cord infarction in children include: initial radicular pain; flaccid para- or quadriplegia later evolving into spasticity (lesions of corticospinal and rubrospinal tract); loss of pain and temperature sensitivity below the upper level of the infarct with preserved touch and vibration sensitivity; bowel and bladder paralysis. Patients with posterior spinal artery syndrome have back pain and leg paresthesias together with loss of touch, vibration sensitivity, and position sense below the lesion; due to partial damage to the lateral corticospinal tract a milder degree of flaccid paralysis may be associated. Interarterial watershed injury will cause centrospinal infarction syndrome (pencil shaped on sagittal MRI, en crayon); this may be seen above and below a genuine anterior spinal infarct. To differentiate cord stroke from cervical spinal cord, birth trauma is important.

130.5.10 Venous Thrombosis Templates (Fig. 14) 130.5.10.1 Superior Sagittal Sinus Almost all infarctions due to venous thrombosis are hemorrhagic (Review Raets et al. 2015). Typical SSS thrombosis can lead to parasagittal hemorrhagic infarction particularly in the arm area of the motor homunculus, explaining hemimotor sequelae in some children. Thrombosis within the SSS usually starts in the vicinity of the parietal lobe, probably due to the peculiar forward course – against sinus flow direction – of the posterior frontal, parietal, and occipital bridging veins as they drain the convexity. Underneath the anterior fontanelle and further distally under the tip of the occipital squame, the sinus is exposed to mechanical forces during (difficult) delivery. It is long known that about half of SSS thromboses are associated with TS thrombosis and that about a third of sinus thromboses are associated with deep involvement (Berfelo et al. 2010; Bailey 1959; Bailey and Hass 1958; Byers and Hass 1933; Ehlers 1936).

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Sinus thrombosis can propagate into the deep venous system, and probably the reverse exists as well. There have been anecdotal reports of neonatal cavernous sinus thrombosis with eyelid chemosis, facial swelling, and external ophtalmoplegia (Fumagalli et al. 2004). Exceptionally an infarct is purely ischemic but clearly related to sinus thrombosis, which is possibly due to reactive arteriospasm. For unknown reasons hemorrhagic infarction associated with SSS thrombosis is within the parasagittal cerebral (sub)cortex and not within parenchyma bordering the interhemispheric fissure or deeper down along the convexity. The existence of transmedullary, transnuclear (through basal ganglia), and meningeal collaterals is of importance in avoiding infarction, depending on probably many factors such as the speed of occlusion, rheology of blood, and presence of prothrombotic risk factors. A typical red infarct leaves hemosiderin and gliosis in the residual scar, sometimes with figured calcification along the vein. Over a period of weeks to months a sinus usually gradually recanalizes (Moharir et al. 2011; Moharir 2006).

130.5.10.2 Internal Cerebral Vein or Straight Sinus Thrombosis of the GCV and/or the ICV puts fragile veins under pressure in the vicinity of germinal matrix or choroid plexus. This may lead to deep venous infarction (Govaert et al. 1992). The phenomenon is nearly always associated with IVH. An infarct related to ICV thrombosis may stretch as far as corpus callosum and periventricular white matter, sparing subcortical areas. When a single branch of the ICV is thrombosed, the most striking phenomenon may be unilateral hemorrhagic infarction in thalamus or caudate nucleus: thalamoventricular hemorrhage. Collaterals mitigate injury when occlusion of the deep venous system is not abrupt. At the moment of diagnosis the affected vein may not be without flow due to recanalization. Besides propagation from thrombosis in the superior sagittal sinus along the straight sinus to the deep venous system, risk factors of primary deep venous thrombosis are similar to sinus thrombosis.

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Fig. 14 Sinovenous templates

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130.5.10.3 Basal Vein of Rosenthal Basal vein thrombosis can induce hemorrhage with feathered margins in the center of the temporal lobe and extending upward into inferolateral hemistriatum (Govaert et al. 2001). The hematoma does not reach the temporal lobe convexity. The typical ends-tage BVR runs around the brainstem and drains posteriorly into the Galenic system, in three segments: striate, peduncular, and mesencephalic. The BVR is derived around the 11th fetal week from the formation of longitudinal anastomoses between embryonic precursors. Its formation is sensitive to anatomic variation (Chung and Weon 2005). Prospective tributaries may drain almost independently of each other into various sinuses. In about 10% the BVR does not even connect to the GCV. The sonographic study of the BVR is possible with high-quality Doppler technique, but its horizontal course and variability present sources of difficulty. 130.5.10.4 Transverse Sinus Hemorrhage into the temporal lobe (basal and temporal parts) or around the tentorium and in cerebellum may be associated with TS thrombosis (Baram et al. 1988; Eichler et al. 2007a). In adults several patterns of TS bridging veins have been described. Tentorial lakes of type I mainly drain to straight sinus, torcular and mesial/middle TS, of type II to lateral TS and transverse-petrosal junction (Guppy et al. 1997; Muthukumar and Palaniappan 1998). A large draining vein of the cerebral convexity into the TS, the vein of Labbé, is connecting the SMCVs to the vein of Trolard and indirectly to the SSS, but this vein can also be absent, such that its absence alone does not seem robust enough to name its thrombosis as the cause of underlying temporal lobe hematoma. Young infants are more vulnerable to subdural hematoma because of relatively large venous lakes in the dura around the posterior fossa (Browder et al. 1975). Smooth muscle layers at bridging vein orifices suggest that they are sphincters (Dagain et al. 2009). Variation in end-stage anatomy and maturation of these sphincters

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will codetermine what type of temporal lobe hematoma follows thrombosis of affected veins. Ultrasound can confirm or refute flow gaps observed with MR venography (Miller et al. 2012). That ultrasound, including color Doppler, can depict sinovenous thrombosis at an early stage, presents therapeutic options prior to parenchymal injury. The transverse to sigmoid transmission may be a developmental, neonatal venous Achilles heel because of: (i) relative jugular obstruction in the fetal period; (ii) asymmetrical development of the transverse sinus; (iii) dwindling of the tentorial sinus (summarized in Raets et al. (2015)).

130.5.10.5 Sinovenous Thrombosis and Its Relation to Hemorrhage SSS. As stated above, thrombosis of a brain sinus may lead to hemorrhage in the newborn period (Raets et al. 2015; Nwosu et al. 2008). The parasagittal location of injury in SSS thrombosis induces lesions similar to hemorrhagic watershed injury. Thrombosis of cortical veins is often, but not obligatory observed in situations where thrombosis of a sinus led to brain injury. In the newborn about three-fourth sinus thrombosis are associated with brain injury, itself hemorrhagic in about 80%) (Nwosu et al. 2008; Eichler et al. 2007b). TS. In adults cerebellar bleeding has been associated with TS thrombosis (Ushiwata et al. 1989). Temporal lobar hematoma is linked to TS thrombosis (Nwosu et al. 2008; Baram et al. 1988; Huang and Robertson 2004; Miller et al. 2012), not unexpected given drainage of temporal veins via bridging veins and the vein of Labbé into TS. Helpful diagnostic sign may be subarachnoid hemorrhage (SAH) near the thrombosis (Kato et al. 2010). With perfusion CT congestion may present as low perfusion hyperemia, associated with subsequent vessel rupture into the subarachnoid space. This phase, vasogenic edema and SAH, may present with increased ADC values on MRI. Be it from trauma or thrombosis, the

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tentorial sinus, vein of Labbé, and the temporal diploic vein are candidates for temporal lobe/fossa bleeding. Peritentorial subdural bleeding has been linked to neonatal transverse sinus thrombosis (Eichler et al. 2007b). An infected cephalhematoma may also lead to TS thrombosis (Chan et al. 2002). Recanalization of the affected sinus is the rule (Nwosu et al. 2008). Deep veins. Deep thrombosis in the galenic venous system causes thalamoventricular hemorrhage (Govaert et al. 1992; Wu et al. 2003), in the basal vein territory hemorrhage in striatum and mesial temporal lobe (Govaert et al. 2001). Reversible dilatation of the vein of Galen and sinuses following difficult delivery may be one way of documenting the link between trauma and IVH (Komiyama et al. 2001; Hunt et al. 2002). Dilatation may mimic vein of Galen malformation on superficial inspection. Purely ischemic damage due to this mechanism has not yet been described. Tables 1 and 2 summarize some morphological lesion patterns.

130.5.11 EEG Findings in the Acute Stage The area of infarction is the focus of epileptic discharge (Jan and Camfield 1998; Mercuri et al. 1999), but exceptions of epileptic focalization contralateral to the infarct confirm the rule. Clinical status epilepticus is always correlated with abnormal EEG (van Rooij et al. 2007). EEG monitoring may be an aid in detecting stroke in ventilated and sedated infants, e.g., with pulmonary hypertension (Clancy et al. 1985; Klesh et al. 1987; Scher and Beggarly 1989; Koelfen et al. 1995; Evans and Levene 1998; Clancy 2006; Plouin and Kaminska 2013). Stroke types with subclinical seizures, escaping detection with routine serial US, like NAIS due to PCA occlusion, can be suspected through EEG monitoring. Ischemic stroke is associated with early (though often beyond 12 h after birth) and focal seizures (Rafay et al. 2009). Interictal EEG is asymmetrical, with focal or unilateral patterns. The best EEG predictor of hemiplegia is not neonatal epileptic activity but

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a disturbed background (Mercuri et al. 1999; Mercuri 2001), a finding not shared by all authors (Sreenan et al. 2000). Children with later cerebral palsy may keep numerous unilateral postictal positive rolandic slow sharp waves (Selton et al. 2003). Anticonvulsants have a different effect on the neonatal brain than on adults (Jennekens et al. 2012). Midazolam induces immediate suppression of the aEEG background pattern for 30–60 min, with a decrease of total and absolute frequency band powers; relative delta power decreases, theta power increases while alpha and beta powers remain constant. Lidocaine induces no aEEG background pattern suppression; total and absolute EEG band powers remain unchanged; relative delta power decreases, theta and alpha power increases, and beta power remains constant. Effects of lidocaine are pronounced in the stroke-affected hemisphere. In a term infant with left MCA infarction, before the onset of seizures, monitoring of the EEG from birth permitted observation at 3 h after delivery of occasional focal sharp waves over the stroke region (Walsh et al. 2011). After electroclinical seizures, focal sharp waves became more frequent, complex, and of higher amplitude, particularly in “quiet sleep”. In “active sleep,” sharp waves often disappeared. Diffuse optical tomography has potential as a valuable clinical tool for the early detection of functional deficits and for providing prognostic information in newborns with brain injury (White et al. 2012).

130.5.12 Genetic Aspects Although the classification of cerebrovascular disorder in the categories AIS, CVT, and primary hemorrhagic stroke is essential for perinatal management, this subclassification is of less use for neurogeneticists. Several genetic factors underlying infantile cerebrovacular disorders have been identified. However, mutations in the same gene may underly a broad spectrum of cerebrovascular disorders, presenting as either ischemic or hemorrhagic stroke. In addition, in

Arterial other

Arterial perforator

Arteries Arterial cortical

Brainstem Spinal cord

AChA Circle of Willis

PCA

MCA

ACA

Basilar a. Cerebellara.

Superolateral parts Basilar a, PCA, circle of Willis branches Anterior spinal a., posterior spinal aa., Adamkiewicz a.

Nodule lateral to and above lateral ventricle, isolated white matter damage, without GMH Lesion in any part of thalamus except for anterolateral parts perfused by AChA or from circle of Willis Caudal end of PLIC with surrounding parts of thalamus and pallidum/putamen, parts of temporal lobe near optic radiation

Centrumsemiovale

Hypothalamus Thalamus

Up to lateral ventricle, including posterior caudate head; pointing to MCA origin near limen insulae; medial striate arteries around caudothalamic groove and to pallidum, lateral striate arteries to putamen; vary variable size

Caudate head rostral and lateral, lateral ALIC

Inferomedial surface

PCA pial stroke plus superior cerebellar a. Stroke Superior cerebellar surface Inferolateral surface and dentate region

Includes putamen, PLIC adjacent to thalamus, part of caudate, entire MCA cortical area MCA cortical area from insula on rostrally MCA cortical area from insula on caudally Focal cortical lesion within anterior or posterior trunk, or within a central artery between these trunks Mesial occipital cortex and occipital pole

Lesion description Mesial orbitofrontal and supracallosal cortex

Lenticulostriate

Complete pial Partial pial Top of basilar Superior Anterior inferior Posterior inferior Heubner’s a.

PCA

MCA

Vessel Complete pial Partial pial Complete, begin M1 Anterior trunk Posterior trunk Pial other

Vessel ACA

Table 1 Arterial lesions

Absence of pons, midbrain disconnection: focal brainstem infarction presenting as segmental cavitation and distortion of the brainstem or cord; to be differentiated from genetic causes of brainstem malformation

Ventral porencephaly: orbitofrontal arteries from the ACA, MCA, or circle of Willis; cavity from lateral or third ventricle near the midline towards the orbita Porencephaly due to arterial perforator stroke: cavity in striatum or thalamus, not communicating with ventricle, sparing most of the white matter except for a small area above the line between caudate and lateral fissure; the cavity may be a triangle with point towards the circle of Willis except for PCA perforator stroke Simple paraventricular white matter cyst in the middle of healthy centrum semiovale

Resulting cavity –Transmantle porencephaly: triangular cortical and subcortical defect extending from ventricle to pia limitans, often not communicating with ventricle; with time defects may appear to be covered by surrounding healthy tissue in partial pial stroke; bordered by polymicrogyria if insult at or before 25 weeks –Schizencephaly: some instances are due to bleeding or vascular insufficiency, leading to transmantle necrosis (a cleft bordered by grey matter) with communication from ventricle to pia; always prenatal onset (before 20 weeks) –Hydranencephaly, cerebral hemiatrophy (hemihydranencephaly): complete destruction with expansive cavitation of ICA territories, atrophic separated thalami and atrophic basal ganglia, intact posterior fossa; may be associated with hypoplasia of the carotid canal; hemiatrophy follows destruction of an area perfused by ICA on one side; basket brain with uni- or bilateral tissue remnants in ACA Multicystic encephalopathy: is an intermediate stage before hydranencephaly, arterial occlusion often not documented

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Table 2 Venous lesions Veins Venous

Vessel Sinus

Subclass SSS Other

Deep vein

Internal cerebral vein

Basal vein Other

Pial vein, sinus patent

Vessel SSS anterior SSS complete Transverse sinus L/R Straight sinus, great cerebral vein of Galen Cavernous sinus Complete: anterior and posterior terminal vein PVI Posterior terminal (thalamostriate) vein PVI Anterior terminal (caudate) vein PVI Septocallosal vein PVI Striatal vein PVI Para-atrial vein PVI Other PVI Basolateral striatal vein PVI Temporal vein PVI Cerebral Cerebellar

the perinatal period, developmental defects often intermingle with vascular disorders. Examples of known pathophysiological processes for genetic cerebrovascular disorders are: (i) structural changes of blood-brain barrier integrity: mutations in genes coding for basement membrane components (i.e., COL4A1 and COL4A2), tight junction proteins (i.e., JAM3 and OCLN), and components of the cytoskeleton involved in the anchoring of tight junction proteins in the cell membrane (i.e., ACTA2); (ii) dysregulation of innate immune response/cerebrovascular inflammation: dysregulation of the type I interferon (IFN) signaling has been demonstrated to underly a broad range of cerebrovascular disorders (such as Aicardi-Goutières syndrome and mutations in the recently identified USP18 gene); another example of dysregulated inflammation in cerebrovascular disease is incontinentia pigmenti, due to aberrant NF-kB activation. Methods to study genetic causes of stroke in the newborn include a targeted gene panel, whole exome sequencing and RNA-profiling (Barr et al. 2010; Vandeweyer

Resulting cavity

–Thalamostriatal porencephaly: periventricular cavity extending into caudate and thalamus; can communicate with ventricle, spares putamen and white matter; hemosiderin in cavity walls –Periventricular porencephaly: periventricular cavity, communicating with ventricle, sparing subcortex; may contain hemosiderin in cavity walls; may be expansive; some infarcts only cause mild ventricular dilatation

et al. 2014). Of course genetic patterns exist in certain presentations of arteriovenous malformation, brain cavernous hemangioma, arterial aneurysm, moya-moya sequence, and hemostatic and prothrombotic disorders: they are not discussed here. Genetic mechanisms are elucidated further in the chapter on stroke mechanisms, elsewhere in this book.

130.5.13 Medical Treatment There are guidelines for the treatment of pediatric arterial ischemic childhood stroke: outside proactive transfusion policy in sickle cell disease the suggested treatment schedules are mainly based on cohort studies and extrapolation from adult stroke insights (reviews Bernard et al. 2008; Monagle et al. 2008; Roach et al. 2008: summarized in table). There are, therefore, no evidencebased treatment options. In the acute phase of NAIS, supportive measures such as hydration and anticonvulsants are

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part of standard care. Thrombolysis is not recommended as neither effectiveness nor safety has been demonstrated in neonates. Recommendations propose heparinization (for a period of months in some cases) in instances with ongoing thrombosis in the heart or a large systemic vein or with carotid artery dissection (Nowak-Gottl et al. 2003; Chalmers 2005). For the remainder, anticoagulation or antiplatelet therapy is not recommended as the risk of recurrent stroke is low (Fullerton et al. 2007). A study of 215 neonates with AIS followed for a median of 3.5 years, documented symptomatic recurrence in seven (AIS in four, CVST in two, and deep venous thrombosis in one patient). Factors associated with an increased recurrence rate include thrombophilia and the presence of comorbidities such as complex congenital heart disease or dehydration. Only when AIS reoccurs, therapy is suggested. A heparinization protocol following cardiac catheterization may be useful (Weissman et al. 1985). It seems obvious that efforts be undertaken to maintain and salvage tissue, particularly within the ischemic penumbra. The synthesis of suggestions for pharmacological intervention from animal stroke experiments is beyond the scope of this chapter (Ashwal and Pearce 2001; Ashwal et al. 2007; Ginsberg 2008). Easily applicable candidates could be albumin or hypothermia (Fehlings et al. 2000). Insight has to be gained in many areas of NAIS to arrive at treatment options. Theoretically this may facilitate intervention at five levels: (i) prevention of risk factors (like vaginal breech delivery or difficult instrumental traction, like catheter-related embolism), (ii) reopening of an occluded vessel with fibrinolytics and/or maintaining collateral patency, (iii) protection of cells in the penumbra from secondary excitotoxic or apoptotic death (by maintaining perfusion and metabolic homeostasis), (iv) prevention of recurrence (in children with important risk factors), and finally (v) specific rehabilitation strategies. Some of these will have to be tested in trials including identical strokes, e.g., complete MCA stroke, to avoid the confounding influence of stroke type on outcome (Boyd et al. 2001; Eliasson et al. 2003; Kenet et al. 2007). Experimental data suggest that subventricular zone neural progenitor cells proliferate and

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migrate to the site of injury after neonatal stroke and multiple doses of EPO, with a shift in cell fate toward neurogenesis and oligodendrogliosis at both early and late time points (Gonzalez et al. 2013). rhEPO in neonates with perinatal arterial ischemic stroke had no adverse effects on red blood cells, white blood cells, platelets counts, or coagulation. rhEPO, 3,000 IU/kg in total, given during a 3-day period, thus appears to be safe. The beneficial effects remain to be demonstrated in a randomized, double-blind, placebo-controlled trial (Benders et al. 2014). Melatonin and stem cell injections are also in the stage of promising animal research for mitigation of injury in focal ischemic insults. The role of anticoagulants in NCSVT is controversial as recurrency is also rare. Recurrent thrombotic episodes occurred in 6% of children during a mean follow-up period of 36 months (Kenet et al. 2007). Strikingly, children younger than 2 years of age did not develop recurrent thrombosis at all. However, extension of the initial thrombus 1 week after diagnosis has been reported in a cohort study of 68 neonates: in 10 out of 40 neonates without anticoagulation (25%), in comparison to one of 28 neonates on anticoagulants (3%). Extension of the thrombus was asymptomatic in all but one neonate, who presented with a novel venous infarction (Moharir et al. 2011). Although randomized controlled trials were not performed, safety of anticoagulation in NSVT has been monitored (deVeber et al. 2001; Fitzgerald et al. 2006). In the Canadian Stroke Registry no patients died or showed signs of neurologic deterioration due to bleeding during heparin treatment (deVeber et al. 2001). Consequently, the ACCP guidelines recommend treatment of neonates with SVT without significant intracranial hemorrhage, with UFH or LMWH initially, followed by LMWH or vitamin K antagonists for 6–12 weeks. For neonates with SVT and significant hemorrhage, radiological monitoring is recommended and anticoagulation warranted if extension of the thrombus occurs, 5–7 days after the onset of the initial hemorrhage (Monagle et al. 2008). There may be a place for use of heparin to prevent (recurrent) infarction in bacterial meningitis (Boelman et al. 2014). “Regional attitudes of treatment” should be replaced by

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Table 3 Guidelines for treatment of neonatal stroke Acute AIS

Acute systemic thrombolysis Acute intraarterial thrombolysis Acute heparinization

Secondary prevention of AIS

Dissection Cardioembolic stroke APL antibodies or inherited thrombophilia

Sinovenous thrombosis

RCP (UK) No evidence to support use of thrombolytic agents such as tissue plasminogen activator (tPA) Not recommended

ACCP (USA) Use of thrombolytic agents in children with AIS has been rare, and the risk/benefit ratio is unknown Not recommended

Not recommended, except in case of dissection or cardioembolic stroke Anticoagulation for 6 months Anticoagulation in consultation with cardiologist No recommendations

UFHeparin or LMWHeparin for 5–7 days and until cardioembolic stroke and vascular dissection have been excluded Anticoagulation with heparin for 3–6 months Anticoagulation with heparin for 3–6 months

Consider anticoagulation (LMWH or UFH) in selected neonates with Severe thrombophilic disorders Multiple cerebral or systemic emboli Propagating SVT despite supportive therapy Thrombolytic agents are not recommended

Heparin (first unfractionated, later fractionated) is recommended if no significant intracranial hemorrhage is associated, for 6 (if early recanalization is observed) up to 12 weeks (if recanalization is incomplete at 6 weeks)

No recommendations

AIS arterial ischemic stroke, SVT sinovenous thrombosis, RCP Royal College of Physicians, ACCP American College of Chest Physicians, LMWH low molecular weight heparin, UFH unfractionated heparin

evidence in the near future (Jordan et al. 2010; Greenway and Massicotte 2004) (Table 3).

130.5.14 Prognosis Corticospinal axons reach the spinal cord before 24 weeks postmenstrual age and innervate spinal gray matter prior to birth. Monosynaptic corticomotoneuronal connections are probably present in human term newborns (Eyre et al. 2000). Since development of fine motor control occurs at 6–12 months after birth, there seems to be a window for cortical influence on spinal motor centers in the fetal third trimester and in the early months of life. In the perinatal period the corticospinal tract still has bilateral representations from one cortical area to both sides of the cord; the same was observed for somatosensory lateralization, emerging in this period. There is research going on about the options of a perinatal brain to adapt to

injury in an attempt to preserve function. Digital and manual dexterity may also be altered in the nonparetic hand because of bilateral effects of the lesion at spinal motor centers. Many (around 50%) strokes lead to hemiplegia or contralateral motor dysfunction (Koelfen et al. 1995; Bouza et al. 1994a; Neville and Goodman 2001; Golomb et al. 2007), but most hemiplegic children walk alone at 2 years of age. CP is predicted by large stroke size, but specific regional injury (to Broca’s or Wernicke’s areas and to PLIC) is also important. Spasticity develops when at cortical level both the primary and premotor/supplementary motor cortices are affected, not with pure M1 lesions. Only large strokes would involve damage to basal nuclei, PLIC, and cortex and thus predict hemiplegia. Besides plasticity, the extent of infarction does influence outcome. Upper limb corticospinal fibers are injured more by lesions lateral and anterior to sites where lower limb fibers are injured (Staudt et al. 2000). Asymmetry of

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tone in the neonatal period is not helpful to predict hemiplegia: tone can be postictally altered and the focus of seizures is not the lesion core. Hemimotor symptoms are subtle before 6 months of age: a tight popliteal angle and asymmetrical kicking in vertical suspension are early signs (Bouza et al. 1994b). By 6 months of age hand preference is obvious. This timing agrees with transition from bimanual skills to single hand preference in normal infants. In some deterioration may seem present due to loss of preexisting skills, without explanation from seizure onset. Thalamic shrinkage from transneuronal atrophy is associated with a reduction in SSEP amplitude, suggesting a clinical effect on sensory perception. Following venous white matter infarction in preterm infants, MRI around term of myelination in the PLIC may aid to predict hemiplegia. DWI provides quantitative data of acute corticospinal tract injury at an early time point after the insult. The presence of increased SI on DW-MRI at the level of the PLIC and the cerebral peduncles in newborn infants with NAIS is followed by Wallerian degeneration and subsequent development of hemiplegia (Mazumdar et al. 2003; de Vries et al. 2005; Kirton et al. 2007; Lama et al. 2011; van der Aa et al. 2013). Visual dysfunction originating in cortex injured by NAIS is more common in children with complete than truncal MCA stroke; visual dysfunction is often but not always associated with the involvement of optic radiations or occipital primary visual cortex (Mercuri et al. 1996, 2003). The recuperation of visual function following stroke can be followed with fMRI in combination with diffusion weighted imaging (Seghier et al. 2004). The relation between neonatal stroke and mental, motor, and language development was investigated in detail. Motor is as a rule worse than mental performance. The psychomotor development index is below 90 in many children with severe or moderate hemiplegia (Kolk et al. 2001). Epilepsy in congenital hemiplegia affects cognition in children with normal IQ; cognitive dysfunction is more severe in contralateral to lesion handedness (absence of interhemispheric

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transfer). Persistent dysphasia develops with leftsided lesion, expressive more than receptive; not all left hemiplegics have a language deficit (Vargha-Khadem et al. 1985). Language delay already presents in the earliest communicative efforts (babbling) (Wulfeck et al. 1991). Cortical language areas may differ transiently from normal in perinatal posterior truncal MCA stroke (Fair et al. 2006). Epilepsy following stroke may be of late onset (after 2 years or more) and weigh on cognitive function (Kolk et al. 2001). The contrasting low incidence of epilepsy in cohorts gathered from the neonatal period on could be due to short followup. In the long run epilepsy affects 25–50% of the affected (Gaggero et al. 2001): severe epilepsy correlates with cortical lesions and onset before 2 years; mental retardation develops in 14/34 hemiplegic children with epilepsy; the first epileptic insult is after 3 years in about half of the affected children. Pharmacoresistance (epilepsy failing response to treatment with at least three first choice antiepileptics) is expected in cases with mixed and frequent seizures in infancy and early childhood. Hippocampal sclerosis is uncommon in children with early onset strokes but develops in many children whose strokes are of later origin (Squier et al. 2003). Cognitive dysfunction is worse in children with partial epilepsy and hemiplegia than in children with partial epilepsy only. The association of stroke with neonatal presentation and later infantile spasms carries a bad prognosis (Golomb et al. 2006). Children with cerebral palsy after perinatal stroke who had neonatal presentation are more likely to have severe cognitive impairment or severe epilepsy than children with presentation in infancy. An early developmental insult can cause later sleep induced epilepsy. Patients with prominent sleep-potentiated epileptiform activity have a higher frequency of early developmental lesions and thalamic lesions than a comparable population of patients without sleep epilepsy (Sanchez Fernandez et al. 2012). Vascular lesions are the type of early developmental lesions most related. Neonates with thalamic hemorrhage associated with straight sinus thrombosis, without evidence of more widespread cerebral damage, are at high

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risk of developing electrical status epilepticus in slow wave sleep (35%), sleep-induced epileptic activity (14%), or focal epilepsy (14%) (Kersbergen et al. 2013). Electrographic abnormalities may already be present prior to recognition of cognitive deficits. Plasticity by reorganization of cortical maps and tracts can be studied at several levels. Small lesions permit ipsilateral use of cortex as primary motor area, premotor reorganization happens in unaffected cortex; severe lesions do not permit ipsilateral cortical use, primary motor reorganization occurs in unaffected contralateral cortex (Staudt et al. 2005). Axonal sprouting can be shown from unlesioned CST to ipsilateral proximal and distal arm muscles of the hemiplegic side (Maegaki et al. 1995). Competition in unaffected cortex leads to impaired dexterity of the unaffected hand; dysfunction of the paretic hand is a.o. due to differences in fingertip force and time shifts between muscle activations (Thonnard et al. 2003). In young children with hemispherectomy because of unilateral clastic lesions leading to refractory epilepsy, paradoxical lateralization of the EEG to the “good” hemisphere was sustained by recording prominent ictal rhythms with either 3–7 Hz spike and wave complexes or beta frequency sharp waves (paroxysmal fast) over the unaffected (contralesional) hemisphere (Garzon et al. 2009). This EEG pattern was compatible with seizure free outcome after surgery, provided other clinical findings and tests were concordant with origin from the abnormal hemisphere. Ongoing research on plasticity, combined with early rehabilitation sustained by evidence from controlled trials, will be very interesting in the near future (Golomb 2009).

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Neonatal Seizures

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Lena K. Hellström-Westas and Malcolm Levene

Contents 131.1

Salient Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2287

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Incidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2288

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Diagnosing Seizures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2289

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Treatment of Neonatal Seizures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2290

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Prophylactic Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2291

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Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2292

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Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2292

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2292

Abstract

Neonatal seizures affect 1–3 infants per 1000 newborns in the general population. The incidence of neonatal seizures is higher in preterm infants than in term infants. The most common etiologies of neonatal seizures are perinatal hypoxic-ischemic and hemorrhagic insults, resulting in hypoxic-ischemic encephalopathy, stroke, and intracranial hemorrhages. Since most

L. K. Hellström-Westas (*) Department of Women’s and Children’s Health, Uppsala University and University Hospital, Uppsala, Sweden e-mail: [email protected] M. Levene Academic Unit of Paediatrics and Child Health, University of Leeds, Leeds, UK Department of Neonatal Medicine, Leeds Teaching Hospitals Trust, Leeds, UK

neonatal seizures occur as a result of perinatal insults, a majority of neonatal seizures emerge during the first 3 days of life. Infants with suspected seizures should be evaluated immediately. EEG and aEEG/EEG should be recorded early since several studies have shown that clinical recognition of neonatal seizures is not reliable. The prognosis is usually dependent on the underlying condition; the overall mortality is 10–30%, and 30–40% of survivors develop neurodevelopmental sequels with less than 20% developing postnatal epilepsy.

131.1 Salient Points • Neonatal seizures are mainly due to previous hypoxic-ischemic, hemorrhagic, or metabolic insults, while seizures due to epileptic

# Springer International Publishing AG, part of Springer Nature 2018 G. Buonocore et al. (eds.), Neonatology, https://doi.org/10.1007/978-3-319-29489-6_277

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•

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syndromes and congenital conditions are rare in newborns. The most common causes of neonatal seizures are hypoxic-ischemic brain injury, intracranial hemorrhages, and stroke. Clinical recognition of neonatal seizures is unreliable since a majority of neonatal seizures are subclinical, or have only subtle clinical expression, and also since clinically observed seizure-suspected motor activity may not have an epileptic origin. EEG or aEEG/EEG is necessary for correct identification of neonatal seizures and is associated with earlier detection of seizures, more precise treatment of seizures, and less use of antiepileptic medications. Clinically important questions that need to be addressed include: Do all neonatal seizures require antiepileptic treatment? Is antiepileptic treatment associated with less brain injury and better outcome? Which medications should be used? For how long should antiepileptic treatment be administered?

131.2 Incidence Neonatal seizures affect 1–3 infants per 1000 newborns in the general population (Ronen et al. 1999; Sheth et al. 1999). The incidence in different populations varies according to differences in diagnostic criteria (clinical seizures or EEG required for diagnosis) and the studied time period, but may also be associated with differences in maternal characteristics (parity, smoking, obesity), living conditions, and standard of perinatal care. The incidence of neonatal seizures is higher in preterm infants than in term infants (Ronen et al. 1999; Sheth et al. 1999; Scher et al. 1993). Seizures are more prevalent in high-risk populations such as infants requiring neonatal intensive care (NICU); older studies indicate that 3–5% of infants may be affected but the exact numbers are difficult to establish (Scher et al. 1993; Hellström-Westas et al. 1995). Recent studies indicate that the seizure incidence may be quite high in extremely preterm infants and associated with intraventricular

L. K. Hellström-Westas and M. Levene

hemorrhages and mortality (Vesoulis et al. 2014). A majority of these seizures are brief and subclinical and only possible to detect with EEG or aEEG/ EEG. The most common etiologies of neonatal seizures are perinatal hypoxic-ischemic and hemorrhagic insults, resulting in hypoxic-ischemic encephalopathy, stroke, and intracranial hemorrhages (Scher et al. 1993; Weeke et al. 2015; Glass et al. 2016). Other relatively common causes of seizures include infections and metabolic disturbances such as hypoglycemia and metabolic diseases. Seizures are prevalent in metabolic diseases, and intense seizures (mainly subclinical) can be seen in infants with disorders of energy metabolism, hyperammonemia, peroxisomal disorders, and organic/amino acidopathies (Olischar et al. 2012). Pyridoxine (vitamin B6) dependent seizures are rare but should always be considered in infants with therapy-resistant seizures. Hereditary familial seizures are caused by various mutations, including genes coding for voltage-gated sodium and potassium channels. They usually have a variable clinical course and outcome. So-called fifth day fits were previously described as being relatively prevalent but they are now rarely seen. Othahara syndrome, or early infantile epileptic encephalopathy (EIEE), and early myoclonic epileptic encephalopathy (EMEE) are severe conditions caused by a variety of disorders including cerebral malformations and various mutations. They are characterized by burst-suppression pattern in the EEG (constant in EIEE and during sleep in EMEE) and severe outcomes (Hart et al. 2015) (Table 1). Since most neonatal seizures occur as a result of perinatal insults, a majority of neonatal seizures emerge during the first 3 days of life. This is a strong argument for using routine aEEG/EEG or EEG monitoring of high-risk infants during the first 3 days of life in order to enhance epileptic seizure detection and cerebral compromise in these infants. Only in moderately preterm infants, the peak of incidence is somewhat later, because seizures in these

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Table 1 Etiologies of neonatal seizures (Ronen et al. 1999; Weeke et al. 2015; Glass et al. 2016; Tekgul et al. 2006; Yildiz et al. 2012) Etiology Hypoxic-ischemic encephalopathy Intracranial hemorrhage Perinatal stroke Infections, including sepsis Metabolic, including hypoglycemia Cerebral dysgenesis Epileptic syndromes, other

Prevalence (%) 29–46 12–18 13–18 7–20 9–19 3–5 1–2

infants are more often caused by infections (Sheth et al. 1999).

131.3 Diagnosing Seizures Observation of clinically suspected seizures in newborn infants is the most common way of diagnosing neonatal seizures. Suspected clinical seizures in a newborn infant in the NICU, maternity unit, or at home, if the baby was already discharged from the hospital, should be given prompt attention. These infants should immediately be examined clinically: blood glucose should be checked, a decision should be taken whether antiepileptic treatment should be administered, and the baby should be referred to a NICU for further observation and evaluation (Table 2). The first strategy should be to identify the potential etiology and to rule out disorders that could be treatable with a timely intervention, e.g., hypoglycemia, infection, and intracranial hemorrhages requiring surgery. Clinical description of suspected neonatal seizures can give important clues to the etiology. Clinical seizures are clinically observed events suspected of being electroclinical seizures. Electroclinical seizures are clinical seizures with simultaneous epileptic activity in the EEG, while electrographical seizures denote presence of epileptic seizure activity in the EEG but no clinical symptoms (often called subclinical seizures). Clinical seizures were traditionally classified by Volpe as subtle, clonic (focal or multifocal), tonic (focal or generalized), or myoclonic (focal,

Table 2 Suggested initial management of infants with suspected seizures Prompt clinical evaluation should include perinatal medical history and physical examination. Blood glucose should be checked immediately since hypoglycemia is a treatable condition. A decision should be taken regarding administration of antiepileptic treatment. Further observation and evaluation in a NICU should include a standard EEG or video EEG, continuous monitoring with aEEG/EEG, and cranial ultrasound. Biochemical evaluation should include hemoglobin, blood gas, glucose, lactate, electrolytes (Na, K, Mg, Ca), bilirubin, CRP, white blood cell count, and platelets. Decision should be taken on further investigations, e.g., lumbar puncture, MRI, other biochemical tests.

multifocal, or generalized) (Volpe 1989). More recently, Nagarajan et al. classified clinical features of electroclinical seizures (seizure semiology) with brief and for neonatologist’s clinically very useful definitions as: (1) clonic (repetitive clonic jerking of the limbs, head, or trunk), (2) tonic (stiffening of limbs or trunk), (3) myoclonic (single jerk or slow serial jerking of the limbs, head, or trunk), (4) ocular (features around eyes, e. g., blinking, wide opening, eye deviation, nystagmus), (5) orolingual (mouthing/chewing type movements, tongue thrusting/ movements, crying/grimacing type of movements, noises/ vocalizations, dry retching), (6) autonomic (color change, change in breathing pattern, oxygen desaturation, apneas, blood pressure changes, changes in heart rate), (7) hypomotor (obvious decrease or cessation of behavioral activity, staring), and (8) other (Nagarajan et al. 2012). Several studies have shown that clinical recognition of neonatal seizures is not reliable and that many clinically suspected seizures do not have corresponding EEG seizure activity. Furthermore, a majority of neonatal seizures are actually subclinical. Mizrahi and Kellaway demonstrated that some clinical seizure types are more closely associated with EEG seizures: focal clonic, generalized myoclonic, and focal tonic seizures, including tonic eye deviation. Other clinical seizures types were more inconsistently associated with electrographic seizure activity, including

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generalized tonic and myoclonic seizures, motor automatisms including oral-buccal and ocular movements, progression movements including pedaling, stepping and rotatory arm movements (Mizrahi and Kellaway 1987). Term and preterm infant seem to exhibit similar types of clinical seizures, although subclinical seizures are more prevalent in preterm infants (Scher et al. 1993). In a video-EEG study of term asphyxiated infants less than 10% of all seizures were correctly identified by clinical observation in the NICU due to the fact that a majority of seizures were subclinical and many clinically suspected events could not be confirmed as seizures in the EEG (Murray et al. 2008). Although some clinical manifestations of seizures are very typical for specific etiologies, e.g., unilateral clonic seizures in babies with stroke, many electroclinical seizures contain different clinical seizure types. Orolingual and autonomic symptoms are common at the onset of seizures, while ocular events more often appear during seizures (Nagarajan et al. 2012). It has been suggested that clinical differentiation between epileptic and nonepileptic movements could be enhanced by applying mild restraint to the active limb or part of the body since nonepileptic movements are expected to stop. However, it may still be difficult to differentiate epileptic from nonepileptic movements clinically, and recording of EEG or aEEG/EEG is best way to increase the certainty of the epileptic nature of such movements. In spite of the nonconsistent association between clinically suspected seizures and epileptic activity in the EEG, abnormal movements suspected to be clinical seizures are still conditions associated with increased risk for adverse outcome both in term and preterm infants (Davis et al. 2010; Glass et al. 2009). Seizure-suspected movements may be caused by immaturity, jitteriness, tremors, or other abnormal movements in compromised infants (Facini et al. 2016). Some of these infants (usually with severe cerebral compromise) may also display subcortical epileptic seizures that are not possible to recognize in the EEG or aEEG/EEG.

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131.4 Treatment of Neonatal Seizures Treatment of neonatal seizures is very much based on traditions and old studies assessing efficacy on clinical seizures. However, newer data demonstrates how administration of antiepileptic medications can abolish clinical seizures while electrographical (subclinical) seizures persist or even increase (Boylan et al. 2002). There is a lack of evidence as regards best treatment of neonatal studies, since only a few randomized studies compared antiepileptic medications while assessing electrographical seizures with EEG and none included structured follow-up and long-term outcome. Two small randomized studies evaluated whether the use of aEEG/EEG monitoring was associated with decreased seizure burden. In both studies, there was a decrease in seizure burden when using aEEG/EEG, but the differences were only border-line significant (Lawrence et al. 2009; van Rooij et al. 2010). One interesting observation in one of the studies was that there was a correlation between seizure burden and the severity of brain injury (scored by MRI); higher seizure burden was associated with more severe brain injury. This correlation was, however, not present in the group allocated to aEEG/EEG with the option of treating also electrographical seizures. The results indicate that treatment of subclinical seizures can limit brain injury in newborns. Other studies have demonstrated that use of EEG monitoring or aEEG/EEG is associated with more precise management, i.e., earlier identification of seizures which is associated with similar number or fewer administered antiepileptic drugs (Shellhaas and Barks 2012; Wietstock et al. 2015). Consequently, EEG monitoring or aEEG/EEG should be standard of care for infants with neonatal seizures. The benefits and limitations of aEEG/EEG as compared to standard EEG are discussed in ▶ Chap. 121, “Neonatal Electroencephalography”. Phenobarbital (or phenobarbitone) is the first drug of choice in many centers and countries, and bensodiazepines (diazepam, midazolam, clonazepam) are also commonly used. Lidocaine (or lignocaine) is frequently used in northern Europe, while phenytoin or fosphenytoin is

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more commonly used in southern Europe, in the UK, and the USA as presented in a number of surveys on treatment strategies. Phenobarbital and fenytoin seem to be equally efficient as first-line medications and abolish seizures in around 45% of term infants receiving these drugs, when adding the two drugs efficacy is seen in around 60% of infants (Painter et al. 1999). There are only observational studies regarding the efficacy of bensodiazepines (e.g., diazepam, lidocaine, clonazepam). Care should be taken when administering bensodiazepines to preterm infants, since these drugs may cause arterial hypotension. The GABA receptor is excitatory in early life and seizure-like events have been observed after midazolam although even more worrying is recent data indicating abnormal hippocampal growth and neurodevelopmental outcome in preterm infants related to midazolam (Duerden et al. 2016). Lidocaine was previously considered an efficient second-line medication after phenobarbital (lidocaine should not be combined with phenytoin or fosphenytoin), but a large evaluation demonstrated that it was actually only efficient as a third-line drug after administration of phenobarbital and bensodiazepines (Weeke et al. 2016). Levetiracetam is a drug that has gained increased use in many countries, but so far there are no randomized trials published on this drug. Topiramate is another promising drug that has been used off-label, but so far no controlled neonatal studies have been conducted (Glass et al. 2011). When neonatal seizures become difficult to treat, it is usually advisable to consult with neurologists, both for evaluation of the potential etiology of the seizures and for more effective management. The possibility of pyridoxine-dependent seizures should always be considered. Administration of pyridoxine should be done when the infant is monitored with EEG or aEEG/ EEG and when the infant is in the NICU, since hypotone reactions with EEG depression and apnea have occurred in pyridoxine-dependent infants after administration of pyridoxine (Hellström-Westas et al. 2002). Table 3

2291 Table 3 Commonly used antiepileptic medications Drug Phenobarbital Midazolam Lorazepam Clonazepam Phenytoin/ fosphenytoin Lidocainea

Pyridoxine

Loading dose 20–40 mg/kg in 20 min i.v. 0.05 mg/kg in 10 min i.v. 0.05–0.1 mg/ kg i.v. 0.01 mg/kg i. v. 20 mg/kg in 30 min i.v. 2 mg/kg in 10 min i.v.

Maintenance 5 mg/kg/day (target level: 40–60 μg/mL) 0.15 mg/kg/h (max. dose: 0.5 mg/kg/h)

0.1–0.5 mg/kg per 24 h 5 mg/kg/day (target level: 10–20 μg/mL) Body weight 2.5–4.5 kg: 7 mg/kg/h for 4 h (3.5 h during hypothermia) 3.5 mg/kg/h for 12 h 1.75 mg/kg/h for 12 h

100 mg i.v.

a

Lidocaine should not be combined with phenytoin/ fosphenytoin. Please note that lidocaine metabolism is affected by hypothermia treatment and that the initial dosage reduction should be faster than in non-cooled babies. For dosage recommendations of infants below 2.5 kg, please see van Rooij et al. (2013)

summarizes suggested doses of some commonly used antiepileptic medications (van Rooij et al. 2013; Painter et al. 1999).

131.5 Prophylactic Treatment Prophylactic long-term antiepileptic treatment is frequently administered to infants with neonatal seizures. A recent meta-analysis included data from more than 4538 children in 44 studies and demonstrated that the average risk of epilepsy after neonatal seizures was 17.9% (Pisani et al. 2015). Of the children developing epilepsy, 68.5% had seizure recurrence during the first year of life and 80.7% had neurological impairments (Pisani et al. 2015). There is little data to guide which infants could benefit from prophylactic treatment. In a NICU cohort of infants, in which aEEG/EEG and EEG was used for diagnosis and treatment of neonatal seizures, antiepileptic treatment was discontinued after a

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median of 4.5 days. Recurrence rate during the first year of life was 8.3% and two of the three children developing epilepsy were already receiving prophylactic phenobarbital due to recurring neonatal seizures and persisting abnormalities in the EEG (Hellström-Westas et al. 1995).

131.6 Prognosis The overall mortality in infants with neonatal seizures is around 10–30%, but the prognosis is usually dependent on the underlying condition (Ronen et al. 1999; Sheth et al. 1999; Scher et al. 1993; Weeke et al. 2015; Glass et al. 2016; Tekgul et al. 2006; Yildiz et al. 2012; van Rooij et al. 2013). Neurodevelopmental sequels develop in 30–40% of survivors, while less than 20% develop postnatal epilepsy.

131.7 Conclusion There are many unsolved question as regards optimal management of neonatal seizures. Clinically important questions that need to be addressed in the future include: Do all neonatal seizures require antiepileptic treatment? Is antiepileptic treatment associated with less brain injury and better outcome? Which medications should be used? For how long should antiepileptic treatment be administered?

References Boylan GB, Rennie JM, Pressler RM, Wilson G, Morton M, Binnie CD (2002) Phenobarbitone, neonatal seizures, and video-EEG. Arch Dis Child Fetal Neonatal Ed 86:F165–F170 Davis AS, Hintz SR, Van Meurs KP et al (2010) Seizures in extremely low birth weight infants are associated with adverse outcome. J Pediatr 157:720–725 Duerden EG, Guo T, Dodbiba L et al (2016) Midazolam dose correlates with abnormal hippocampal growth and neurodevelopmental outcome in preterm infants. Ann Neurol 79:548–559 Facini C, Spagnoli C, Pisani F (2016) Epileptic and nonepileptic paroxysmal motor phenomena in newborns. J Matern Fetal Neonatal Med 29:3652–3659

L. K. Hellström-Westas and M. Levene Glass HC, Glidden D, Jeremy RJ, Barkovich AJ, Ferriero DM, Miller SP (2009) Clinical neonatal seizures are independently associated with outcome in infants at risk for hypoxic-ischemic brain injury. J Pediatr 155:318–323 Glass HC, Poulin C, Shevell MI (2011) Topiramate for the treatment of neonatal seizures. Pediatr Neurol 44:4439–4442 Glass HC, Shellhaas RA, Wusthoff CJ et al (2016) Contemporary profile of seizures in neonates: a prospective cohort study. J Pediatr 174:98–103 Hart AR, Pilling EL, Alix JJ (2015) Neonatal seizures – part 2: aetiology of acute symptomatic seizures, treatments and the neonatal epilepsy syndromes. Arch Dis Child Educ Pract Ed 100:226–232 Hellström-Westas L, Blennow G, Lindroth M, Rosén I, Svenningsen NW (1995) Low risk of seizure recurrence after early withdrawal of antiepileptic treatment in the neonatal period. Arch Dis Child Fetal Neonatal Ed 72:F97–F101 Hellström-Westas L, Blennow G, Rosén I (2002) Amplitude-integrated encephalography in pyridoxine-dependent seizures and pyridoxine-responsive seizures. Acta Paediatr 91:977–980 Lawrence R, Mathur A, Nguyen The Tich S, Zempel J, Inder T (2009) A pilot study of continuous limitedchannel aEEG in term infants with encephalopathy. J Pediatr 154:835–841 Mizrahi EM, Kellaway P (1987) Characterization and classification of neonatal seizures. Neurology 37:1837–1844 Murray DM, Boylan GB, Ali I, Ryan CA, Murphy BP, Connolly S (2008) Defining the gap between electrographic seizure burden, clinical expression and staff recognition of neonatal seizures. Arch Dis Child Fetal Neonatal Ed 93:F187–F191 Nagarajan L, Palumbo L, Ghosh S (2012) Classification of clinical semiology in epileptic seizures in neonates. Eur J Paediatr Neurol 16:118–125 Olischar M, Shany E, Aygün C et al (2012) Amplitudeintegrated electroencephalography in newborns with inborn errors of metabolism. Neonatology 102:203–211 Painter MJ, Scher MS, Stein AD et al (1999) Phenobarbital compared with phenytoin for the treatment of neonatal seizures. N Engl J Med 341:485–489 Pisani F, Facini C, Pavlidis E, Spagnoli C, Boylan G (2015) Epilepsy after neonatal seizures: literature review. Eur J Paediatr Neurol 19:6–14 Ronen GM, Penney S, Andrews W (1999) The epidemiology of clinical neonatal seizures in Newfoundland: a population-based study. J Pediatr 134:71–75 Scher MS, Aso K, Beggarly ME, Hamid MY, Steppe DA, Painter MJ (1993) Electrographic seizures in preterm and full-term neonates: clinical correlates, associated brain lesions, and risk for neurologic sequelae. Pediatrics 91:128–134 Shellhaas RA, Barks AK (2012) Impact of amplitude-integrated electroencephalograms on clinical care for neonates with seizures. Pediatr Neurol 46:32–35

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Sheth RD, Hobbs GR, Mullett M (1999) Neonatal seizures: incidence, onset, and etiology by gestational age. J Perinatol 19:40–43 Tekgul H, Gauvreau K, Soul J et al (2006) The current etiologic profile and neurodevelopmental outcome of seizures in term newborn infants. Pediatrics 117:1270–1280 van Rooij LG, Toet MC, van Huffelen AC et al (2010) Effect of treatment of subclinical neonatal seizures detected with aEEG: randomized, controlled trial. Pediatrics 125:e358–e366 van Rooij LG, Hellström-Westas L, de Vries LS (2013) Treatment of neonatal seizures. Semin Fetal Neonatal Med 18:209–215 Vesoulis ZA, Inder TE, Woodward LJ, Buse B, Vavasseur C, Mathur AM (2014) Early electrographic seizures, brain injury, and neurodevelopmental risk in the very preterm infant. Pediatr Res 75:564–569

2293 Volpe JJ (1989) Neonatal seizures: current concepts and revised classification. Pediatrics 84:422–428 Weeke LC, Groenendaal F, Toet MC et al (2015) The aetiology of neonatal seizures and the diagnostic contribution of neonatal cerebral magnetic resonance imaging. Dev Med Child Neurol 57:248–256 Weeke LC, Toet MC, van Rooij LG et al (2016) Lidocaine response rate in aEEG-confirmed neonatal seizures: retrospective study of 413 full-term and preterm infants. Epilepsia 57:233–242 Wietstock SO, Bonifacio SL, McCulloch CE, Kuzniewicz MW, Glass HC (2015) Neonatal neurocritical care service is associated with decreased administration of seizure medication. J Child Neurol 30:1135–1141 Yildiz EP, Tatli B, Ekici B et al (2012) Evaluation of etiologic and prognostic factors in neonatal convulsions. Pediatr Neurol 47:186–192

The Timing of Neonatal Brain Damage

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Contents 132.1

Salient Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2296

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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2296

132.3

Fetal Programming Hypothesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2297

132.4

Placental Pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2297

132.5

Cardiotocography and Fetal Doppler Studies . . . . . . . . . . . . . . . . . . . . . . . . . 2299

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Neuroimaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2299

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Electroencephalography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2301

132.8

Hematology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2302

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Clinical Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2302

132.10 Biomarkers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2303 132.10.1 Oxidative Stress Biomarkers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2304 132.10.2 Inflammatory Biomarkers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2305 132.11

Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2308

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2309

Abstract

Brain injury in newborns is a complex process involving multiple pathways, which may complicate the determination of timing of the injury and the early identification of infants at risk for

S. Perrone (*) Department of Molecular and Developmental Medicine, University Hospital of Siena, Siena, Italy e-mail: [email protected] G. Buonocore University of Siena, Siena, Italy e-mail: [email protected]

neonatal encephalopathy. Much of the injury occurs before birth and may be the result of more than a single injury. An abnormal insult applied to a critical point in intrauterine life determines permanent changes in phenotype disrupting the normal fetal development and leading to fetal programming of diseases. Additionally, brain development, including maturation and structure, may render the baby more or less susceptible to perinatal injury. At present there is no universal agreement on objective laboratory biomarkers as a gold standard to

# Springer International Publishing AG, part of Springer Nature 2018 G. Buonocore et al. (eds.), Neonatology, https://doi.org/10.1007/978-3-319-29489-6_278

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support the diagnosis of perinatal asphyxia. Placental findings can serve as markers for processes occurring in the mother or fetus. An expert assessment of the placental pathology can provide temporally and mechanistically specific data not available from any other source. Magnetic resonance imaging (MRI) of the infants with neonatal encephalopathy is very contributive to elucidate the mechanism and timing of asphyxia in conjunction with the clinical examination. Evidence of multi-organ failure in infants with severe encephalopathy is helpful and used as an additional diagnostic criterion in the recognition of the hypoxic–ischemic insult; however, it is not specific or essential. Several tissue biomarkers suggestive of brain injury in newborns with neonatal encephalopathy have been identified; however, they are not still validated as useful in clinical practice. In the event of newborn with clinical signs of perinatal hypoxia at birth, it is necessary to have access to a readable cardiotocography, a welldocumented partogram, a complete analysis of umbilical cord gases, a placental pathology, and an extensive clinical work-up of the newborn infant including cerebral MRI. Placental histologic examination should be required in order to confirm sudden catastrophic events occurring before or during labor or to detect occult thrombotic processes affecting the fetal circulation, patterns of decreased placental reserve, and adaptive responses to chronic hypoxia.

132.1 Salient Points • Timing of neonatal brain damage is fundamental for exact diagnosis and prevention, in addition to being a key element in the legal arena. • A thorough placental examination in all potential cases of adverse neurological outcomes is recommended, since placental pathology might play a pivotal role in perinatal asphyxia. • Fetal Doppler studies and cardiotocography, especially if combined with pulse oximetry, fetal blood pH analysis, and fetal ECG help the clinician in the recognition of situations of

S. Perrone and G. Buonocore

•

•

•

•

•

inadequate intrapartum fetal oxygenation, which may lead to relevant complications. Neuroimaging remains the gold standard for identification, characterization, and prevention of brain injury in infants with neonatal encephalopathy: combined use of serial cranial ultrasound and magnetic resonance imaging improves detection of common patterns of brain injury. Advanced MR techniques provide perspectives on neonatal brain metabolism, microstructure, and connectivity. Neurodiagnostic tests, such as standard EEG and amplitude-integrated EEG, identify the presence of brain injury and may determine the severity of outcome. Raised nucleated red blood cell counts in newborns may indicate perinatal hypoxia and can predict brain injury and neurological outcomes in asphyxiated infants. Clinical assessment of newborns with perinatal encephalopathy could be difficult due to the variable clinical presentation: health-care providers need to carefully investigate causes of neonatal brain injury. Although most evidence to date emanate from small single-centered studies in research settings, the use of a panel of biomarkers seems to be very promising in the setting of neonatal brain injury evaluation.

132.2 Introduction Early abnormalities of brain development and underlying genetic factors can affect brain susceptibility to the injury (Ambalavanan et al. 2006; Fily et al. 2006; Yager and Miller 2009). Some infants may inherit a predisposition to have significant injury in the event of a normally sublethal insult (Nelson 2005). These newly identified risk factors for brain damage in different periods make the timing of lesions important for exact diagnosis and prevention. Incidence of neonatal encephalopathy is estimated as 3.0 per 1000 live births (95%CI 2.7–3.3) and for hypoxic–ischemic encephalopathy is 1.5 (95%CI 1.3–1.7) (Kurinczuk et al. 2010). Hypoxic–ischemic encephalopathy

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ranges from about 1.0 to 8.0 per 1000 live births. Epidemiological data shows that 30% of cases of neonatal encephalopathy in developed populations and 60% in developing populations have some evidence of intrapartum hypoxic ischemia. Perinatal hypoxic–ischemic brain injury was demonstrated to be a major contributor to developmental disabilities in children, accounting for 25% of all cases (Shevell 2001). Of the antepartum events that contribute significantly to the development of neonatal encephalopathy, fetal growth restriction ranks high. Increasingly, a strong role for fetal inflammation as one of the most frequent causes of acquired brain damage in perinatal period is being recognized.

132.3 Fetal Programming Hypothesis Fetal development may be influenced by inherited genetic profile as well as external stimuli. Early intrauterine life is particularly vulnerable to perturbations. Perturbation of fetal environment implies both short-term complications, including altered fetal growth and increased perinatal morbidity, and long-lasting consequences on offspring’s subsequent health. The concept of fetal programming focuses on the processes of developmental plasticity, which in normal situations provide the settings for homeostatic mechanisms to ensure proper growth and development (Perrone et al. 2016a, b). Fetal programming of later diseases occurs when the normal pattern of fetal development is disrupted by an abnormal stimulus or an “insult” during intrauterine life, which leads to adaptations by the fetus to allow its survival, but could finally result in permanent structural and physiological changes with consequences to short- and long-term outcome. Permanent changes in fetal phenotype can generate a mismatch with extrauterine environment. In sight of this theory, impaired neonatal transition and cardiovascular or metabolic diseases in adult life can be traced back to their intrauterine origins (Fig. 1).

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132.4 Placental Pathology The placenta has been described as a diary of intrauterine life, and placental pathology assists in characterizing the antenatal environment. Dramatic, but at least common, are sentinel lesions, each of which can cause hypoxia sufficient to result in brain injury (Redline 2006). There are three mechanisms for sudden catastrophic injury: (1) the placenta becomes prematurely separated from the underlying maternal uterine vascular supply: abruptio placenta or uterine rupture; (2) fetal placental blood vessels rupture; or (3) prolonged umbilical venous blood flow interruption. Placental findings that support a diagnosis of massive feto-maternal hemorrhage include a profound increase in the number of circulating nucleated red blood cells in the villous circulation, the finding of a large intervillous hematoma, villous edema, fetal arterial constriction, and villous capillaryvenous dilatation. Large vessel hemorrhages generally affect vessels that are not protected by Wharton’s jelly or the chorionic plate. Pathologic lesions associated with complete umbilical vessel occlusion include tight true umbilical cord knots, occlusive umbilical vein thrombi, tightly twisted (hypercoiled) umbilical cords, prolapse, or tight entanglements around body parts. When this occurs, there may be an abrupt change in umbilical cord color, shape, or diameter that suggests chronicity. Other pathologic umbilical cord lesions, such as an excessively long cord length, lesser degrees of hypercoiling, abnormal cord insertion sites, and paucity of Wharton’s jelly, are significantly more common in infants with cerebral palsy (Redline 2006; Machin et al. 2000; Nasiell et al. 2016; McDonald et al. 2004). The mechanisms by which feto-placental large vessel lesions act on the vascular wall include toxic damage (meconium-associated vascular necrosis), maternal antifetal vasculitis (obliterative fetal vasculopathy), infiltration by activated fetal neutrophils (chorioamnionitis with intense fetal inflammatory response), and thrombosis (fetal thrombotic vasculopathy) (Nasiell et al. 2016; McDonald et al. 2004; Chau et al. 2013). Fetal thrombotic vasculopathy and chronic villitis with obliterative fetal vasculopathy begin weeks

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S. Perrone and G. Buonocore

Prenatal Period

Genetic susceptibility

Maternal nutrition

Utero-placenta blood flow

Maternal hormones

Cortisol

Hypoxia

Oxidative stress

Perinatal Period

Lipid and protein oxidation

Fetal or developmental programming

Gene expression changes

IUGR

Preterm birth

Macrosomia

Neonatal Period SGA newborn Impaired neonatal transition

Fig. 1 The peculiar susceptibility of fetal period of development to environmental cues. Oxidative stress may be the link between adverse insults (associated with preterm birth

or adverse fetal growth) and developmental programming. Oxidative stress acts indirectly by lipid and protein oxidation or modifying gene expression

before delivery and continue to evolve and progress until parturition (Perrone et al. 2016c). Vascular occlusion is the result of an inflammatory vasodestructive process that develops when maternal leukocytes inappropriately cross the trophoblastic barrier to enter fetal tissue. Chorioamnionitis with a severe fetal inflammatory response (intense chorionic vasculitis) and meconiumassociated necrosis of vascular smooth muscle cells develop as a consequence of subacute processes beginning days before delivery (Chau et al. 2013; Perrone et al. 2016c; Redline et al. 2003; Altshuler et al. 1992). An increased time of exposure to meconiumstained amniotic fluid leads to a gradual progression of pigment through the amnion into the chorionic plate and eventually into contact with large fetal vessels. Placentas can be abnormally small and have a decreased total gas-exchanging surface area. Alternatively, they may have decreased efficiency owing to diffuse chronic injury. Other placental findings are markers for processes affecting

either mother or fetus. In some cases, they may represent attempts to ameliorate an adverse environment; in others, they may be maladaptive consequences of it. Perhaps the most controversial of these findings is a significant increase in the number of circulating nucleated red blood cells to more than 2500/cm3 in the fetal placental capillary circulation (Hermansen 2001; Naeye and Lin 2001). An increase of this magnitude represents a fetal bone marrow response to hypoxia that takes 6–12 h or more to mount (Blackwell et al. 2004). A second adaptive response is a generalized increase in the number of fetal capillaries per terminal villous cross section or chorangiosis (Ogino and Redline 2000; Stanek 1999). Placental pathology assists in characterizing the antenatal environment. Histological examination of the placenta is a sensitive and accurate diagnostic system for identifying lesions that can either directly cause or decrease the threshold for brain injury. Less than 10% of placentas from term infants that later develop cerebral palsy lack any evidence of

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placental abnormalities potentially related to adverse outcome, supporting the importance of a thorough placental examination in all potential cases of adverse neurologic outcomes.

132.5 Cardiotocography and Fetal Doppler Studies Cardiotocography (CTG) is an indirect sign of fetal well-being with various technical pitfalls and a high incidence of false positives. Currently the technique is improved in the determination of the risk and timing of brain injury. In particular, the evaluation of trends and the speed of CTG changes in deceleration patterns make it possible to distinguish harmful ischemic events from other forms of hypoxia which do not necessarily injure the fetal brain (Ugwumadu 2013). A newly defined CTG pattern, the “conversion” pattern, appears to be a specific marker of ischemic injury and could help to redefine the role of CTG monitoring. The majority of infants with HIE have normal CTG traces on admission but develop pathological CTG patterns within hours of delivery. More severe encephalopathy was associated with normal admission CTG and acute sentinel events shortly before deliver. CTG combined with pulse oximetry, fetal blood pH, and ECG provides further advantages (Murray et al. 2009). Fetal electrocardiography (ECG) wave form analysis indicates the ability of the fetal heart to respond to the stress of labor. An increased T/QRS ratio identifies a fetal heart muscle that responds to hypoxia by increased utilization of heart glycogen (Brand-Niebelschutz and Saling 1994). ST segment depression may indicate a situation in which the heart does not respond fully and a negative ST may signify cardiac dysfunction and hypotension. It has been suggested that an increase in T/QRS ratio maintained for more than 10 min is associated with aggravation of fetal condition when intrapartum hypoxia may progress to asphyxia. Automatic analysis of CTG and ECG has been reported to enable a reduction in the incidence of newborns with severe neurological symptoms (Rosèn et al. 2004). Doppler ultrasound of the

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blood flow in the umbilical artery (UA), descending fetal aorta (DAo), and middle cerebral artery (MCA) gives insight into fetal cardiovascular responses to intrauterine growth restriction, fetal anemia, and fetal hypoxia (Graves 2007). Blood flow is classified as abnormal when pulsatility index (PI) values of MCA falling below the 5th percentile or PI value of UA, DAo, UA/MCA ratio, and Dao/MCA ratio above the 95th (Arduini and Rizzo 1990). Absent or reversed end diastolic flow of the UA, absent or retrograde net blood flow of the aortic isthmus, and absent or retrograde end-diastolic flow of the ductus venosus are also classified as abnormal. The presence of a notch, as signal of increased perinatal vascular impedance and of brain sparing, is also highly significantly related to maternal blood serum concentration of tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) level (Dubiel et al. 2005). Severe abnormalities in fetal blood flow might result in neuroanatomical or functional changes that correlate to later cognitive capacity (Maunu et al. 2007).

132.6 Neuroimaging Cranial ultrasound (US) has been used for many years to determine the type and evolution of brain damage. The ultrasound criteria of cerebral cavitation have been selected in order to give assurance that the damage may have occurred before delivery. US and postmortem studies of the evolution of brain abnormalities suggest that cystic lesions develop over 14 days (Weindling et al. 1985; Levene 1988). Serial US images have been used to study the timing of hypoxic–ischemic injury, though the reliability of US is limited by poor visualization of the subarachnoid space, cerebral cortex, and posterior fossa. It is also difficult to distinguish between hemorrhagic and non-hemorrhagic ischemic damage. Traditionally, CUS is used to detect germinal matrix hemorrhage and intraventricular hemorrhage (GMH-IVH) and periventricular leukomalacia (PVL). Its value in detecting other lesions as well is increasing owing to technical developments such as high-resolution ultrasound

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(2,000 IU/mL Eosinophilia Increased incidence of lymphoma (both Hodgkin and non-Hodgkin) Scoliosis, osteopenia, minimal trauma fractures, hyperextensibility Craniosynostosis Arterial aneurisms Facial asymmetry, deep-set eyes, prominent forehead Retained primary dentition High arched palate Alteration of oral mucosa and tongue

mastocytosis, a more diffuse erythrodermic rash is found, and some patients may show generalized thickening of the skin, often described as “doughy” or additional nodular lesions (Fig. 9). Sometimes, rubbing, bullous lesions may develop. All forms of cutaneous mastocytosis improve with time, sometimes healing completely

Fig. 8 Solitary mastocytoma of the trunk

at puberty. The major mediators secreted by mast cells are histamine, heparin, and prostaglandins, the effects of which account for many of the clinical features of mastocytosis. The predominant symptom in all is pruritus. Additional mediatorrelated symptoms include flushing, hypotension, fatigue, diarrhea, vomiting, and abdominal pain.

138.7.1.3 Incontinentia Pigmenti (IP) IP is a rare, X-linked dominant genodermatosis, usually lethal in males. It affects the skin and its appendages, bones, eyes, and central nervous system (Minić et al. 2014; Nelson 2006). Cutaneous lesions usually appear at birth or in the first days of life and have three distinct morphological stages

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Fig. 9 Diffuse cutaneous mastocytosis

(vesiculopustular, verrucous, and pigmented) with stage one occurring in the neonatal period (Hull et al. 2015). Initially there are clear-to-yellow vesicles, measuring 2–4 mm, clustered in a linear configuration, mostly on the trunk and distal limbs. They may sometimes be pustular or crusted. At this stage, peripheral blood eosinophilia is often associated. Vesicular and pustular lesions are replaced within several weeks by gray to brown, linear and swirled verrucous papules and plaques, the second stage of the disease, and after years by brown to gray macular hyperpigmentation in streaks and whorls. The diagnosis of IP is based on clinical findings (Babu et al. 2015). It should be considered when inflammatory linear groups of vesicles are seen in a newborn female infant. Biopsy of a blister reveals a subcorneal vesicle filled with eosinophils. Lyonization accounts for the linear pattern of this disease, typical of mosaic disorders (Happle 2006). Ocular, skin appendage, dental, and skeletal abnormalities may also occur (Chang et al. 2008). No specific treatment is required for the skin lesions, as spontaneous healing usually occurs.

138.7.1.4 Neonatal Pemphigus Vulgaris (NPV) The term “pemphigus” refers to a group of diseases characterized by cutaneous or mucosal blisters and erosions and antiepidermal autoantibodies against

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desmoglein 1 and desmoglein 3 (Gushi et al. 2008). NPV is caused by passive transfer of maternal IgG antibodies across the placenta in pregnancy from mothers with PV or pemphigus foliaceus (Lorente Lavirgen et al. 2012; Meurer 2009). Lesions are usually present at birth, ranging from flaccid bullae and/or vesicles to large erosions on the whole body. The mucous membranes are rarely involved. Histopathology findings include intraepithelial blisters and acantholytic cells. Direct immunofluorescence is always positive and indirect immunofluoresence, almost always positive. Neonatal prognosis is excellent: non-corticosteroid ointments usually produce prompt epithelialization of the erosive lesions, and skin eruptions generally disappear within 3 weeks.

138.7.1.5 Herpes Gestationis (HG) HG is an uncommon, autoimmune, bullous disease that appears during the second or third trimester of pregnancy (Bedocs et al. 2009). It almost invariably recurs in subsequent pregnancies. Anti-180-kDa bullous pemphigoid autoantibody is the cause. The disorder may be evident at birth or within several hours in neonates from mothers affected by HG. The skin eruption consists of red macules or papules, often progressing to vesicles or bullae. The typical rash usually starts around the umbilicus and spreads over the trunk and extremities. Rapid improvement occurs over few days with spontaneous recovery by 1 month of age (Panko et al. 2009).

138.8 Disease with Systemic Involvement Presenting with Pustulas, Blistering, and Erosions 138.8.1 Acrodermatitis Enteropathica (AE) This rare autosomal recessive disease is caused by the impaired absorption of zinc in the gastrointestinal tract. Signs and symptoms of AE may be neurological-behavioral, gastrointestinal (diarrhea),

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138.8.3 Langerhans Cell Histiocytosis (LCH)

Fig. 10 Acrodermatitis enteropathica with perianal and genital lesions

ophthalmologic, infectious, or dermatological. Cutaneous manifestations of zinc deficiency are obligatory and diagnostic. Skin lesions are erythematous with peripheral crusting. Margins are well-defined, progressing to vesiculobullous, erosive, or pustular lesions. Typical distribution is periorificial and acral (Fig. 10) (Lakdawala and Grant-Kels 2015). AE patients need zinc supplementation for life. The main differential diagnoses are diaper dermatitis, chronic mucocutaneous candidiasis, atopic dermatitis, impetigo, epidermolysis bullosa, psoriasis, and seborrheic dermatitis.

138.8.2 Hyper-immunoglobulin E Syndrome (HIES) Hyper-immunoglobulin E syndrome, also called Job’s syndrome, is a very rare primary immunodeficiency, characterized by chronic eczematous dermatitis, recurrent skin and respiratory tract infections, markedly elevated serum IgE (>2,000 IU/ml), and a variety of connective tissue and skeletal abnormalities (Table 14) (Freeman et al. 2009). In almost all cases, an eczematoid rash, first affecting the face, scalp, and upper trunk and later progressing over the whole body, with papules or pustules, usually due to S. aureus infection, manifests in the first month of life (Freeman and Holland 2009). Blistering is a classic finding in this disease. To control the rash antibiotic prophylaxis is indicated.

LCH is a rare group of disorders of the monophagocytic system, with a peak of incidence at 1–4 years of age, characterized by proliferation of a distinct cell type that is CD1a, S100, CD207 positive and contains Birbeck granules, in various organs. Cutaneous involvement is encountered in 50% of the cases. It includes four main clinical forms: Letterer-Siwe disease, Hand-Schuller-Christian disease, eosinophilic granuloma, and congenital selfhealing Langerhans cell histiocytosis (CSHLCH) (Kilborn et al. 2003). CSHLCH is most frequently found in newborns. It presents at birth or in the neonatal period with papulonodules or less commonly with vesiculopustules and blisters. It usually affects otherwise healthy infants. Systemic involvement must be excluded anyway (Simko et al. 2014).

138.8.4 Porphyrias Porphyrias are a group of metabolic disorders of heme biosynthesis that may present with acute neurovisceral symptoms, skin lesions, or both (Karim et al. 2015). Of the cutaneous porphyrias, erythropoietic protoporphyria (EPP), congenital erythropoietic porphyria (CEP), hepatoerythropoietic porphyria (HEP), and the hereditary form of porphyria cutanea tarda can present in infancy.

138.8.4.1 Erythropoietic Protoporphyria (EPP) EPP is characterized by acute photosensitivity, with rare subepidermal bullae in exposed areas. It may occur in neonates during phototherapy. Liver disease is an uncommon, potentially fatal complication of EPP. 138.8.4.2 Congenital Erythropoietic Porphyria (CEP) CEP presents soon after birth with typical reddish urine, severe photosensitivity, hypertrichosis of the face and extremities, mechanical fragility leading to formation of bullae, erythrodontia, and hemolytic anemia. The blisters cause scarring, dyschromia, and deformations (Katugampola et al. 2012).

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Table 14 Neonatal erythroderma: more common causes and management Disease Infections SSSS

Toxic shock syndrome Congenital cutaneous Candidiasis Ichthyoses Nonbullous ichthyosiform erythroderma Bullous ichthyosiform erythroderma Netherton’s syndrome ConradiHunermann syndrome Drugs Ceftriaxone Vancomycin Others Seborrheic dermatitis Atopic dermatitis Psoriasis

Pityriasis rubra pilaris

Diffuse mastocytosis

Clinical features

Etiology

Treatment

Preceding purulent infection, skin tenderness, superficial blisters, positive Nikolsky sign Concomitant maternal infection, skin tenderness hypotension/shock Maternal vaginal candida infection, oral cavity spared, may have paronychia and nail dystrophy

Bacterial infection

Antibiotic, contact tracing

Bacterial infection

Antibiotic, intravenous Ig

Mycological infection

Antimycotics

Collodion baby; when shed leaves disseminated ichthyosiform scaling

Transglutaminase 1 gene defect and other genetic defects Keratine gene 1,2,10 defects

Emollients, bland keratolytic creams

Genetic defects

Emollients, adequate hydration

Genetic defects

Emollients

Infection for which it was prescribed “The red man syndrome,” sudden hypotension, and erythema

Allergic reaction Allergic reaction

Reversible on discontinuation Reversible on discontinuation

Cradle cap, accentuation in skin folds of neck, axilla, and nappy area

Multifactorial

Encrusted eczema on the scalp and face, generalized eczematous skin, family history for atopy Erythematosquamous patches, can be pustular, may have positive family history Similar to psoriasis, follicular accentuation, skin thickening of palms and soles, may have positive family history Darier’s sign often with blistering

Allergy

Moisturizing agents, miconazolehydrocortisone ointment, protective cream nappy area Weak topical steroid, systemic antibiotics if the skin is infected

Superficial blistering and erosions, ichthyosiform erythroderma, family history, linear epidermal nevus parents or sibling Diarrhea, failure to thrive atopy, sparse hair, trichorrhexis invaginata (bamboo hair) Linear and swirled patterns

Emollients, bland keratolytic creams

Multifactorial

Bland emollient creams, wet dressing is helpful

Cornification disorder

Along same lines as psoriasis

Abnormal proliferation of mastocytes

H1 and H2 antagonists, oral sodium cromoglycate, avoidance of substances with potential for mast cell degranulation

Modified from Hoeger and Harper (1998)

138.8.4.3 Hepatoerythropoietic Porphyria (HEP) HEP appears at birth or in the first years of life. It is characterized by early severe photosensitivity

resulting in bullae, erosions, crusts in sun areas, and severe hypertrichosis. Patients must be protected from light by clothing, sunscreen, and beta-carotene.

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Whenever photosensitivity is observed in a neonate, porphyrin levels in red cells, plasma, urine, and feces should be measured (Gross et al. 2000).

138.8.5 Skin Manifestation in Down Syndrome Skin manifestations are rare but characteristic. There have been few reports in the literature describing crusted, erythematous, vesiculopustular eruptions associated with trisomy 21 concentrated in the face and spreading to the trunk and extremities.

138.9 Red Scaly Skin in the Newborn The term neonatal or infantile erythroderma denotes diffuse erythema with variable scaliness affecting more than 90% of the body surface. A number of major conditions can present with erythroderma in the neonate or young baby (Table 15) (Ott et al. 2008; Dhar et al. 2012). Prognosis is poor, especially in babies with immune deficiency or chronic disease (mortality 26.2%). Severe skin diseases persist in 60% of survivors (Dhar et al. 2012).

138.9.1 Immunodeficiencies (ID) Because of the protective effect of maternal immunity, congenital ID syndromes are rarely symptomatic at birth. It is now clear that what was described in the past as Leiner’s disease is a phenotype of non-congenital early-onset erythroderma, diarrhea, and failure to thrive.

138.9.1.1 Omenn’s Syndrome Omenn’s syndrome is an autosomal recessive form of severe combined ID characterized by exfoliative erythroderma that occurs at birth or in the early neonatal period in association with diffuse alopecia, lymphadenopathy, hepatosplenomegaly, recurrent infections, and failure to thrive. 138.9.1.2 Graft Versus Host Reaction Graft versus host reaction from maternal engraftment can occur as a result of transplacental passage of maternal lymphocytes during intrauterine or postnatal transfusions. In immunocompetent newborns, clinical manifestations are minimal, often resulting in only a transient macular rash. In contrast, in newborns with congenital ID, GVH reaction occurs within the first 2 or 3 weeks of life with fever, eosinophilia, lymphocytosis, lymphadenopathy, and hepatosplenomegaly, but may be present at birth as a morbilliform rash which evolves into erythroderma (Mallory 1991). In the first weeks of life, ID should be suspected in cases in which the presenting features include pruritic erythroderma combined with skin induration; nondysplastic alopecia of hair, eyelashes, and eyebrows; widespread lymphadenopathy; and deep systemic infection. Skin infiltration is strongly indicative of Omenn’s syndrome or ID, although true atopic dermatitis with marked lichenification can have a similar appearance. An association with diarrhea and extreme failure to thrive should also suggest the diagnosis. Histological findings in these cases are helpful.

Table 15 Common versus rare forms of non-syndromic ichthyosis

Inheritance First appearance Affected gene(s) Histopathology Cutaneous clinical features

X-linked ichthyosis XR Infancy (not at birth) STS Retention hyperkeratosis Brown scales also on the trunk

Lamellar ichthyosis (or CIE) AR At birth

Bullous ichthyosis (or EHK) AD At birth

TGM1, Ichthyin, ALOXE3/12B, etc. Hyperproliferative hyperkeratosis

KRT 1,2,10 Hyperproliferative hyperkeratosis

Collodion baby; dry, scaly skin; ectropion; hypohidrosis, erythema

Intense blistering at birth, verrucous hyperkeratosis, and erythema

CIE congenital ichthyosiform erythroderma, EHK epidermolytic hyperkeratosis, STS steroid sulfatase gene, TGM1 transglutaminase 1 gene, ALOX lipoxygenase gene, KRT keratin gene

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138.9.2 Ichthyoses Congenital ichthyoses are a large and heterogeneous group of monogenic disorders of cornification, sometimes associated with systemic symptoms (Table 16). A common feature is rough, dry scaly skin. Some patients have complex ichthyoses, with systemic manifestations, mainly involving the CNS, immune system, and skeleton. The two most common forms of ichthyosis, autosomal dominant ichthyosis vulgaris (IVU) and X-linked recessive ichthyosis (XRI), start early in life, but are not present at birth. Lamellar ichthyosis, with its variants nonbullous ichthyosiform erythroderma and bullous ichthyosiform erythroderma, is invariably present at birth with variable degrees of erythroderma (Alper 1986). Table 16 Clinical manifestations of neonatal lupus erythematosus Organ Skin

Heart

Blood

Liver

Others

Clinical manifestations Annular-polycyclic erythematous plaques Persistent telangiectasias, atrophy, or pigmentation (less frequent) Confluent erythema around the eyes, giving an “owl eye” or “eye mask” appearance Congenital heart block with or without NLE. Cardiac blocks usually develop in utero between weeks 18 and 20 of pregnancy. Once established it is irreversible. Most surviving children require permanent pacemaker implantation Cardiomyopathy, present in some cases usually in association with heart block, is evident at or prior to birth, and is often life threatening Thrombocytopenia Pancytopenia Anemia Neutropenia Hypocomplementemia Hepatomegaly with mild elevation of aminotransferase levels Neonatal hemochromatosis Cholestasis with conjugated hyperbilirubinemia and minimal elevation of transaminase Macrocephaly Hydrocephalus Gastrointestinal bleeding

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138.9.2.1 Nonbullous Ichthyosiform Erythroderma Nonbullous ichthyosiform erythroderma, an autosomal recessive congenital ichthyosis, is characterized by fine white-grayish scales and erythroderma. Many patients suffer from deep skin fissures, and some develop flexion contractures. About 90% of patients with nonbullous ichthyosiform erythroderma present as “collodion babies” enveloped in a glistening membrane resembling sausage skin that may produce ectropion, lip eversion, nasal obstruction, temperature instability, and fluid loss. The membrane peels off in days or weeks, and this may be a presentation of various forms of ichthyosis besides congenital ichthyosiform erythroderma. The most severe phenotype of autosomal recessive congenital ichthyosis is “harlequin ichthyosis,” in which neonates are covered with platelike scales and massive hyperkeratosis, leading to severe disfigurement, particularly of the face. The skin soon splits forming bleeding fissures and then peels off leaving red scaly skin.

138.9.2.2 Bullous Ichthyosiform Erythroderma Bullous ichthyosiform erythroderma presents with generalized erythema and superficial blisters. Bullous lesions become less prominent as the infant grows and may eventually disappear completely. These children later develop typical ichthyosiform hyperkeratosis, with hyperkeratosis more pronounced in the flexural areas, in which the dark, warty scales often acquire a ridged pattern with frequent maceration that causes a strong unpleasant odor.

138.9.2.3 Netherton’s Syndrome Netherton’s syndrome is a complex ichthyosis with high mortality (30–40%) characterized by a triad of generalized exfoliative dermatitis, sparse hair with trichorrhexis invaginata (bamboo hair), and atopic features. It usually presents at birth as erythroderma. Patients are atopic and suffer from recurrent angio-edema and urticaria.

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Fig. 11 Seborrheic dermatitis of the scalp (a) and forehead (b) in a 40-day-old baby

138.9.3 Drugs Although many drugs can determine an erythematous maculopapular rash, erythroderma has only been described in neonates treated with ceftriaxone and vancomycin.

138.9.4 Seborrheic Dermatitis (SB) Infantile SB is a papulosquamous eruption that typically develops in the first 12 weeks of life. The characteristic feature is yellowish, inflammatory scaling of the scalp (cradle cap) which spreads over the face, including the forehead, eyebrows, ear, and nose (Fig. 11a, b). Lesions often involve skin folds of the neck, postauricular regions, midtrunk, umbilicus, axilla, and groin. The scales may be absent in the flexures, and secondary candidiasis is common. Other forms of presentation include a psoriasiform variant or rarely erythroderma. Pityrosporum ovale is usually found in this disorder. SD is often asymptomatic and self-limiting after the early months of life. Scales on the scalp may be treated with mild baby shampoo and a soft-bristled toothbrush.

138.9.5 Atopic Dermatitis Although about 18% of all children develop skin symptoms within the first 4 weeks of life, this

Fig. 12 Flexural lesion of the upper limb in a 30-day-old boy affected by atopic dermatitis

condition rarely presents in the neonatal period with an erythrodermic rash. These patients are likely to go on to difficult long-term disease. In young infants, the primary lesion of atopic eczema is frequently vesicular and exudation is common. Atopic dermatitis more often involves the face, especially the cheeks, and flexural creases of the limbs and usually spares the nappy area (Fig. 12). In atopic dermatitis, itching is usually not apparent until 2–3 months of age. Total IgE and eosinophil count, usually considered to be markers of atopy, are neither constant nor specific. Management involves emollients and careful use of weak topical steroids, sometimes with wet dressing.

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138.9.6 Psoriasis Psoriasis may rarely present at birth or shortly after as generalized erythroderma, sometimes evolving into pustular psoriasis. A dramatic form of psoriasis seen in babies is napkin (diaper) psoriasis with dissemination. Starting with a brightred napkin rash, this form of the disease later develops with small scaly patches beyond the margins. An explosive psoriasic eruption develops on the scalp and face and all over the trunk, self-limiting in a few weeks.

2413 Table 17 Epidermal nevi Verrucous epidermal nevus

Sebaceous nevus

Nevus comedonicus

138.9.7 Pityriasis Rubra Pilaris (PRP) Eccrine nevus

This disease is characterized by scaly erythematous plaques similar to psoriasis and follicular hyperkeratosis. They may coalesce to larger plaques and become generalized as erythroderma. Palmoplantar keratoderma is frequently associated. Congenital erythrodermic PRP is inherited as an autosomal dominant trait and, unlike the acquired forms of PRP, tends to last a lifetime.

Apocrine nevus

Becker’s nevus

138.10 Neonatal Lupus Erythematosus (NLE) NLE is a rare condition caused by transplacental passage of maternal antibodies against SS-A/Ro and SS-B/La (Inzinger et al. 2012). Only 1% of infants with positive maternal autoantibodies develop NLE, when the mothers have clinical or subclinical LES, LECS, or Sjogren syndrome. Most infants have heart and skin manifestations, but some may also have blood and liver involvement (Table 17). Skin lesions occur in the first month of life or may be present at birth. Cutaneous findings usually disappear at about the sixth month of life. Lesions resemble those of subacute cutaneous lupus erythematosus (SCLE): mild scaling erythematous plaques with well-defined margins, often annular, predominately affecting the scalp, neck, and face (Singalavanija et al. 2014). The plaques are typically periorbital, but may appear on the trunk or extremities. In male babies they are more often crusted. Solar

White sponge nevus

Consists of hyperplasia of the surface epidermis and typically appears as verrucous papules that coalesce to form well-demarcated, skin-colored to brown, papillomatous plaques Includes many of the surface findings of verrucous epidermal nevus, but also contains malformations of the dermis, most prominently hyperplasia and malpositioning of the sebaceous glands Manifests as groups of closely set, dilated follicular openings with dark keratin plugs resembling comedones Is a rare cutaneous condition histologically characterized by an increase in size or number of eccrine secretory coils Is an extremely rare cutaneous condition found more often on the upper chest and axilla histologically composed of hyperplastic mature apocrine glands First appears as an irregular pigmentation (melanosis or hyperpigmentation) on the trunk or upper arm and gradually enlarges irregularly, becoming thickened and often hairy Consists of bilateral white keratotic macules and plaques found especially on the buccal mucosae, but labial, lingual, vaginal, and rectal mucosa may be involved

exposure can precipitate the eruption. In some cases, erythema spreads over the entire body. Thrombocytopenia and hepatic disease may also be common. Healing tends to be associated with mild cutaneous atrophy, with or without telangiectasia. The histologic aspect of the cutaneous lesions is similar to that of SCL. NLE is the most common cause of congenital complete heart block and is associated with significant morbidity and mortality. Treatment of the mother with corticosteroids early in pregnancy may prevent heart block.

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138.11 Congenital Disorders of Melanin Pigmentation Depigmented nevi simplex type 1 (DNS type 1) is the most frequently found white spot on newborns and infants (Ruiz-Maldonado 2007). Up to 1 in 130 otherwise healthy newborns have at least one depigmented nevus present at birth, more commonly on the trunk, usually measuring 2–3 cm. The lesions are well circumscribed with irregular borders, nonprogressive, lighter than the surrounding skin but seldom white. Depigmented nevi simplex type 2 (DNS type 2) is larger than 10 cm, blocklike or linear lesions, with or without whorls. They may or may not follow Blaschko lines, are usually present at birth, and involve one or several body segments. There is no associated pathology. Metameric or segmental nevi have also been described. In such cases, the main differential diagnosis is metameric or segmental vitiligo, but this condition does not occur at birth. Rarely depigmented maculae are a part of multisystemic disorders (e.g., hypomelanosis of Ito (HI) or neurocutaneous melanosis).

138.11.1 Nevus Anemicus Nevus anemicus resembles an achromic nevus, 1–3 cm in diameter, round, slightly hypochromic, and with a ragged outline. If pressure is applied with a convex glass, the nevus disappears, and if stroked, no flare is elicited.

138.11.2 Neurofibromatosis Neurofibromatosis 1 (NF1) is a common neurocutaneous condition with autosomal dominant inheritance (Hersh 2008). Some cutaneous features of NF are present at birth, others are age related. Café au lait spots are usually the initial clinical manifestation of NF1 and may be present at birth or appear in infancy. They may be found anywhere on the skin but rarely on the face and scalp. They tend to increase in number and size throughout early childhood. Plexiform neurofibromas, found in at least 25% of patients with

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NF1, are also congenital. They feel like a bag of worms and cause gross disfigurement. They may also affect deep structures and cause pulmonary or vascular involvement. Early in life, the lesions may only be recognized as soft tissue enlargement or a patch of cutaneous hyperpigmentation with or without hypertrichosis. The other typical cutaneous findings of NF appear later.

138.11.3 Tuberous Sclerosis (TS) The TS complex is an autosomal dominant multisystem neurocutaneous disorder characterized by widespread hamartomas in several organs, including the brain, heart, skin, eyes, kidney, lung, and liver (Curatolo et al. 2008). Most features of tuberous sclerosis only become evident after 3 years of age. The earliest cutaneous lesion to appear in TS is the hypopigmented macule, also called “ash leaf” macule, frequently present at birth. These lesions often come in other shapes: they may be round but most are polygonal, usually 0.5–2.0 cm in diameter, resembling a thumbprint. Another manifestation of TS that may be seen at birth is a hypopigmented tuft of hair. However, these findings are not pathognomonic of TS. Any newborn with a hypopigmented macule or white tuft of hair should be followed for development of other manifestations of TS.

138.11.4 Hypomelanosis of Ito (HI) Initially described as incontinentia pigmenti achromians, IH is a congenital multisystemic neurocutaneous disorder often characterized by neurological, musculoskeletal, and eye abnormalities (Gómez-Lado et al. 2004). The disease is characterized by depigmented maculae disposed on the limbs, where they appear as lines and on the trunk where they appear as whorls or have a mottled appearance. These maculae appear at birth or during the first year of life. They may be asymmetric, unilateral, or bilateral and may occur anywhere, except on the palms, soles, and mucous membranes. No bullous or verrucous stages are seen. The skin returns to its normal color late in

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childhood or early adulthood. The most severe complications concern the central nervous system (CNS), causing mental retardation and epilepsy, which are both present in more than 50% of cases and are the two most severe and frequent disorders.

detection of skin cancer should be offered. Persons with OCA have normal lifespan, development, intelligence, and fertility.

138.11.5 Piebaldism

WS is an autosomal dominant disorder classified into four types. WS type 1 is clinically characterized by dystopia canthorum, sensorineural hearing loss, congenital patches of achromic skin, white forelock, broad nasal root, synophrys, and heterochromia of irides.

Piebaldism is a rare autosomal dominant disorder. It is due to a defect in migration and maturation of melanoblasts from the neural crest. It is characterized by congenital, extensive, and symmetrically white patches on the forehead, anterior thorax, and limbs and a tuft of white hair on the forehead. Small patches of normally pigmented skin are characteristically observed inside depigmented areas. In stable piebaldism, cutaneous depigmentation remains unchanged through life (Sa et al. 2007).

138.11.6 Albinism Genetic abnormalities of the melanin pigment system in which the synthesis of melanin is reduced or absent are called albinism. Oculocutaneous albinism (OCA) is a group of inherited disorders of melanin biosynthesis characterized by a generalized reduction in pigmentation of the hair, skin, and eyes (Summers 2009). The reduction in melanin synthesis can also be localized primarily to the eye, resulting in ocular albinism. The clinical spectrum of OCA ranges with OCA1A being the most severe type with a complete lack of melanin production throughout life. Foveal hypoplasia is invariably present and individuals with albinism often have other characteristic ocular symptoms. The degree of skin and hair hypopigmentation varies with the type of OCA, but is in general reduced. The incidence of skin cancer may be increased. All four types of OCA are inherited as autosomal recessive disorders. The diagnosis is based on findings of hypopigmentation of the skin and hair, in addition to ocular symptoms. Strabismus and nystagmus should be corrected and sunscreens are recommended. Regular skin checks for early

138.11.7 Waardenburg Syndrome (WS)

138.11.8 Chediak-Higashi Syndrome (CHS) This autosomal recessive condition is due to a gene defect localized in chromosome 1q. CHS is clinically characterized by lighter skin than parents and siblings in sun-protected skin areas, slategray hair, and periodic, life-threatening “accelerated phase” of systemic involvement, with fever and hepatic, splenic, and lymph node enlargement. Epstein-Barr induced malignant lymphoma is usually fatal.

138.11.9 Xeroderma Pigmentosum (XP) XP is a rare, recessive disorder based on a deficiency in nucleotide excision repair (NER) or postreplication repair (PRR) (Lichon and Khachemoune 2007). The earliest manifestation of the disease is recognized as acute sun sensitivity. This is noted as irritability followed by prolonged erythema, edema, and blistering. The severe actinic changes lead to early onset of skin cancers. Most patients do not reach adulthood, but die from metastatic cutaneous malignancies. Diagnosis can be confirmed by unscheduled DNA synthesis. XP must be distinguished from other so-called DNA repair deficiency syndromes, including Cockayne syndrome and trichothiodystrophy.

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138.11.10 Neurocutaneous Melanosis (NCM) NCM is a rare congenital phakomatosis characterized by a focal or diffuse proliferation of melanin-producing cells in both the skin and the leptomeninges (Burstein et al. 2005). This syndrome is believed to result from an error in the morphogenesis of embryonal neuroectoderm. Two-thirds of patients with NCM have giant congenital melanocytic nevi, and the remaining one-third have numerous lesions but no giant lesions. Patients may present with neurologic manifestations early in life secondary to intracranial hemorrhages, impairment of cerebrospinal fluid circulation, or malignant transformation of the melanocytes. The prognosis of patients with symptomatic NCM is poor. In their follow-up of patients with large or multiple congenital melanocytic nevi, physicians should be aware of this condition, to aid in prompt diagnosis and treatment.

138.12 Birthmarks

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underlying neurocutaneous melanosis. Malignant potential increases with the size of lesion and the numbers of satellite nevi near the large lesion (Krengel et al. 2006). Smaller nevi are not well studied, but malignant changes in lesions projected to grow to less than 1.5 cm in adulthood and appear to occur rarely and only after puberty. There are various treatment options for the management of giant CMN: surgical excision (total or staged), exploiting grafts, tissue expanders, dermabrasion, and curettage. Curettage is best performed before 2 weeks of age (Batta 2000).

138.12.1.2 Use of Dermoscopy in Management of Congenital Melanocytic Nevi Dermoscopy is a noninvasive technique that allows visualization of structures that are not visible by clinical examination. If expertly performed, it has been shown to increase diagnostic accuracy for pigmented skin lesions, especially for malignant melanoma. Dermoscopic features of congenital nevi are equally distributed between reticular, globular (Fig. 13), and homogeneous patterns (Fig. 14).

138.12.1 Pigmented Birthmarks 138.12.1.1 Congenital Melanocytic Nevi (CMN) CMN are thought to arise from disrupted migration of melanocyte precursors in the neural crest and occur in 0.2–2.1% of infants at birth. CMN have been arbitrarily divided into three size ranges: small, intermediate, and giant with diameters of less than 1.5 cm (Fig. 13), 1.5–20 cm (Figs. 14 and 15), and over 20 cm, respectively. Colors range from brown to black and the commonest site is the lower back and thigh area. At birth they are often flat and pink or pale brown and most are small. Giant CMN are immediately obvious at birth. They are extremely rare and darken as the infant grows, the surface often becoming rugose or warty with nodules developing within it. The hairy component, typical of 95% of lesions, tends to become more prominent at puberty. Giant CMN of the head, neck, or posterior midline area may be associated with

138.12.1.3 Dermal Melanocytosis (DM) DM includes Mongolian spots, nevi of Ota and Ito, and the blue nevi. Mongolian spots are flat, blue-gray, or brown lesions with poorly defined margins that arise when melanocytes are trapped

Fig. 13 A small (less than 1.5 cm) congenital nevus of the buttock, showing on dermoscopic evaluation a homogeneous distribution of globules (globular pattern)

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2417 Table 18 Types of epidermal nevus syndromes Well-defined syndromes, based on histopathology, extracutaneous manifestations, and genetic features

Fig. 14 An intermediate (1.5–20 cm) congenital nevus of the cheek, showing on dermoscopic evaluation a diffuse homogeneous pattern

Fig. 15 An intermediate congenital nevus of the penis

deep in the skin. These lesions may be single or multiple and generally occur on the back or buttocks, although other areas may be involved. They may easily be mistaken for bruises. They are more common in black, Native American, Asian, and Hispanic populations. Most lesions fade by 2 years of age and do not require treatment. Nevus of Ota, a persistent patchy blue-gray discoloration of the face, is usually unilateral and often accompanied by an ipsilateral patchy blue discoloration of sclera, conjunctiva, cornea, retina, or oral mucosa. It is most common in Orientals and is present at birth in more than 50% of cases of associated glaucoma. Very rarely melanoma may occur in adult life (Sinha et al. 2008). Nevi of Ito are distinguished from those of Ota for

Sebaceous nevus syndrome (SNS) Nevus comedonicus syndrome (NCS) Becker nevus syndrome (BNS) Phacomatosis pigmentokeratotica (PPK) Proteus syndrome Congenital hemidysplasia with ichthyosiform nevus and limb defects (CHILD)

their location in the supraclavicular, scapular, or deltoid regions. It may be associated with an Ota nevus with ipsilateral or bilateral distribution. Common blue nevi are acquired dome-shaped blue-black papules measuring less than 1 cm in diameter. They are often located on the backs of the hands or feet or nearly.

138.12.1.4 Epidermal Nevi (EN) EN are hamartomas characterized by epidermal and adnexal hyperplasia. They may be classified into distinct variants (Table 18). The lesions may be deeply or slightly pigmented, have unilateral or bilateral distribution, and involve any area of the skin, though they are usually located on the extremities along Blaschko lines. On the face and scalp, EN are yellowish due to prominent sebaceous glands and devoid of hair. They often have a linear distribution. In infancy they are flat, tending to become warty and papillomatous in puberty in response to androgens. Most EN remain stable. However, benign or malignant tumors can arise within them. Sebaceous nevi of Jadassohn (SNJ) are a well-known congenitally hamartoma of the skin and its adnexa. They can present as isolated lesions or as rare, more complex syndrome. Sebaceous nevus syndrome (SNS) is characterized by a sebaceous nevus and extracutaneous abnormalities, usually involving organs derived from the neuroectoderm. Today at least six different types of epidermal nevus syndromes (ENS) are known (Table 19) (Harrison-Balestra et al. 2007).

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Table 19 Nail disorders in newborns Nail disorder Anonychia

Micronychia

Onychoschizia

Infantile ingrowing toenails

Racket nails or brachyonychia

Polyonychia

Congenital malalignment of the great toenail

Description Absence of nails; rare; may be the result of a congenital ectodermal defect or anomalies like epidermolysis bullosa, severe exfoliative diseases, or infections Small nail plate, shorter or narrower than normal; unusual; it is associated with syndromes or toxin exposure Splitting of the distal nail plate into layers of the free edge. It is most noted on the big toes and thumbs, with thumb-sucking being an exacerbating factor The thin, sharp edge of the big toenail implants into the hypertrophic lateral nail folds of the hallux. Often bilaterally, this condition improves spontaneously with age Nails are broad and shortened and reflect an underlying disturbance in the formation of distal phalanx Rare; several nails on the same digit due to bifurcation of the distal phalanx. A history of maternal teratogen exposure should be searched Lateral deviation of the nail plate from the longitudinal axis of the distal phalanx. Spontaneous improvement occurs in approximately 50% of patients

138.12.2 Vascular Birthmarks Vascular birthmarks are divided in vascular tumors and vascular malformations on the basis of their cellular features, clinical characteristics, and natural history. Vascular tumors, also called hemangioma, are associated to vascular proliferation and can be infantile or congenital. Vascular malformations have an initial rapid proliferative phase followed by an involutional phase, and they

Fig. 16 A bright strawberry-red color hemangioma of the abdomen

are developmental anomalies classified according to the type of vessel involved: capillary, vein, lymphatic vessel, artery, or mixed malformations. They are present at birth, grow proportionally with the child, and do not spontaneously involute (Krengel et al. 2006).

138.13 Vascular Tumors 138.13.1 Hemangiomas (Strawberry Nevi) Hemangiomas are the most common benign vascular tumors of infancy, occurring in 1.1–2.6% of newborns (Fig. 16). Females are three times more likely to have hemangiomas than male infants, and prematurity increases the risk. At birth, the lesions may vary from bright strawberry-red-colored lesions to pale patches or telangiectasias surrounded by blanched halo maculae. Hemangiomas may proliferate for 18 months and then begin to involute. Approximately 50% of hemangiomas disappear by 5 years of age and 90% by 10 years of age. After spontaneous disappearing, there may be residual epidermal atrophy, telangiectasia, hypopigmentation, or scarring (Moure et al. 2007). Despite their benign nature, hemangiomas can be complicated by ulceration, pain, infections, hemorrhage, and scarring (Fig. 17). Hemangiomas that compress the eye, nose, mouth, auditory canal, or vital organs require

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Fig. 17 Ulceration of a genital hemangioma

immediate referral in the neonatal period. Uncomplicated hemangiomas should be observed with reassurance. Systemic steroids are the elective treatment for problematic proliferating hemangiomas. Laser treatment is an option if the lesion threatens to interfere with the airway or the ocular axis. Propranolol is also a treatment for lifethreatening hemangiomas (Smolinski and Yan 2005; Denoyelle et al. 2009). The high efficacy rate and low adverse event rates reported with propranolol explain why this treatment is now widely considered a first-line treatment for complicated hemangiomas (Yang et al. 2015).

138.13.2 Kasabach-Merritt Syndrome (KMS) KMS is a form of consumptive coagulopathy in patients with rapidly spreading hemangiomas, vascular tumors, and other malformations. It consists of thrombocytopenia which is secondary to platelet trapping within the lesions, microangiopathic hemolytic anemia, and localized consumptive coagulopathy. In some cases there is true disseminated intravascular coagulation (DIC) (Abass et al. 2008). KMS is not associated with classical hemangiomas, but rather kaposiform hemangioendotheliomas or tufted hemangiomas. They are usually deep red/blue and firm and have an equal male/ female distribution. If untreated, KMS can be life threatening. It requires aggressive therapy including corticosteroids, interferon alpha, vincristine,

Fig. 18 Capillary malformation (port-wine stains or nevus flammeus) of the face in a newborn

radiation therapy, and surgery. Antiplatelet drugs and transfusion of blood products can be required too.

138.14 Vascular Malformations 138.14.1 Capillary Malformation (PortWine Stains or Nevus Flammeus) Capillary malformation is a vascular birthmark, occurring in 0.3% of newborns, composed of mature dilated capillaries in the dermis that appear as variably sized pink to dark red maculae. The face is most frequently affected, often unilaterally (Fig. 18) (Ch’ng and Tan 2008). The lesions grow proportionally with the child and tend to darken with age. Port-wine stains in the ophthalmic distribution of the trigeminal nerve are associated with ipsilateral glaucoma.

138.14.2 The Sturge-Weber Syndrome The syndrome is classically defined by the triad of glaucoma, convulsions, and port-wine stain and involves angiomas of the brain and meninges. Port-wine stains in the ophthalmic branch of the trigeminal nerve distribution (V1) are a strong indication of underlying neurological and/or ocular disorders that require ongoing ophthalmologic

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surveillance and/or neurological or neurosurgical management (Hennedige et al. 2008).

138.14.3 Nevus Simplex Nevus simplex is a vascular birthmark that occurs in 33% of newborns. These flat, salmon-colored lesions are caused by telangiectasias in the dermis. They occur over the eyes, scalp, and neck, with a symmetric pattern and fade when compressed.

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a mass or lump, the latter as a large cyst or pocket of lymphatic fluid resulting from blocked lymphatic vessels. Both usually present as slowly enlarging, non-tender masses. Frequent sites are the head and neck followed by the trunk, axilla, and extremities. There is a predominance of right-sided lesions. Laryngeal and oral involvement is not uncommon. In such cases and when other vital structures are involved, surgical extirpation is usually the treatment of choice (Bloom et al. 2004).

138.15 Adnexal Congenital Disorders 138.14.4 Venous Malformations (VM) 138.15.1 Congenital Nail Disorders VM are always present at birth, but they may manifest clinically later in life depending on their location. Appearance varies from a vague blue patch to a soft blue mass. When venous pressure increases, for example, during crying, they usually swell, though some may remain asymptomatic throughout life. Episodic thromboses are common in VM, even in infants under 2 years of age.

138.14.5 Arteriovenous Malformation (AVM) AVM is a congenital defect in which arteries and veins are tangled and not connected by capillaries. In early developmental stages, large shunts exist between future arteries and veins, and a defect or arrest occurring at this stage may allow some of these connections to persist. AVM manifests as a skin-colored mass with warm overlying skin that pulsates on auscultation. It is often asymptomatic, but symptoms depend on site. Localization in the CNS is not rare and may be associated with major neurological symptoms.

The most common nail disorders in newborns and infants are listed in Table 20. A number of genodermatoses primarily involving the skin and mucosa are associated with more or less characteristic nail changes (Fistarol and Itin 2002). In epidermolysis bullosa nail changes are seen especially in junctional and dystrophic types. In X-linked dyskeratosis congenita, the nail plate is completely absent or hypoplastic. A pterygium formation may also be present. Pachyonychia congenita (PC) is a rare, autosomal dominant genodermatosis, characterized by symmetrical thickening and discoloration of the nails with a wedge-shaped, pinchedup, or claw-like appearance. Cutaneous cysts, hair abnormalities, and presence of teeth at birth can be observed (Das et al. 2009). Nail-patella syndrome is a genodermatosis with autosomal dominant transmission associated with bone and renal disorders. Table 20 Congenital alopecia Circumscribed alopecia Neonatal telogen effluvium Neonatal occipital alopecia Tinea capitis

138.14.6 Lymphatic Malformations (LM) LM are considered rare. There are two main types: lymphangioma and cystic hygroma. The former manifest as a group of lymphatic vessels forming

Alopecia areata Congenital triangular alopecia Congenital aplasia cutis Underlying meningocele or cystic lesion Congenital nevi

Diffuse alopecia Alopecia areata Marie Unna hypotrichosis Rothmund-Thomson syndrome Ectodermal dysplasia Epidermolysis bullosa

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Table 21 Systemic distribution of associated findings of aplasia cutis congenita Central nervous system

Cardiovascular system Gastrointestinal system Eyes

Miscellaneous

Hydrocephaly Meningocele Spastic paralysis and mental retardation Occult spinal dysraphism Arterovenous malformation Coarctation of aorta Congenital heart defects Cleft lip-palate Intestinal lymphangiectasia Omphalocele Myopia and cone-rod dysfunction Oculo-ectodermal syndrome Ventral body wall and/or neural tube Closure defects Cutis marmorata Piebaldism

The nail abnormalities recognized at birth include micronychia or anonychia, especially on the thumbs. The lunula can be triangular or V shaped.

138.16 Main Causes of Alopecia in Newborns Alopecia in newborn can be classified as circumscribed and diffuse as shown in Table 21. Some manifestations as neonatal occipital alopecia and telogen effluvium may be observed frequently and are considered as physiological skin changes, others are rare.

138.16.1 Alopecia Areata (AA) AA is a form of nonscarring hair loss, rarely reported in the neonatal period (Lenane et al. 2005).

138.16.2 Congenital Triangular Alopecia (CTA) CTA is a triangular, lancet, or oval-shaped area of hair loss usually behind the frontotemporal

Fig. 19 Congenital temporal zone

triangular

alopecia

of

the

hairline (Fig. 19). It may be congenital but usually appears in childhood. The hair loss may be uni- or bilateral, and complete or fine vellus hairs may remain. CTA may occur as a paradominant trait.

138.16.3 Marie Unna Hypotrichosis (MUH) MUH is a rare autosomal dominant pilar dysplasia which can be seen at birth as a progressive hair loss.

138.17 More Common Congenital Tumors 138.17.1 Dermoid Cyst (DC) DC is a benign, congenital, solitary or occasionally multiple, hamartomatous tumor. It is covered in a thick dermis-like wall that contains multiple sebaceous glands and almost all skin adnexa. Hair and abundant fatty masses cover poorly to fully differentiated structures derived from the ectoderm. These growths are usually located at the midline and commonly have a deep sinus that connects to the epidermis. Common sites include the forehead, lateral eye, and neck (Rosa et al. 2008). A superficial DC on the dorsal nose is referred to as a fistula and is characterized by a central tuft of hair or intracranial communication. DC can be located deep in the subcutaneous tissue, intracranially or intraorbitally. Infections, rupture, and abscess formation from manipulation of DC are possible

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serious complications. Surgical excision is the treatment of choice in any localization.

138.17.2 Congenital Leukemia (CL) CL associated with skin infiltration in 25–30% of patients and usually presents as firm blue, red, or purple nodules in a generalized distribution. CL cutis may precede other manifestations of leukemia by as much as 4 months.

Fig. 20 Congenital aplasia cutis

138.17.3 Meningocele Meningocele is a developmental defect related to abnormal attachment and closure of the neural tube during embryogenesis. It typically presents as a skin-colored nodule on the scalp over the midline or along the spine. The treatment of choice is surgical excision.

138.17.4 Granuloma Gluteale Infantum (GGI) GGI is a benign granulomatous eruption involving the gluteal region that may simulate a neoplastic process. It arises as a complication of primary irritant diaper dermatitis and typically resolves without treatment.

138.18 Other Skin Malformations 138.18.1 Congenital Aplasia Cutis (CAC) CAC is a rare anomaly presenting with localized or widespread absence of the skin at birth (Fig. 20). Lesions are commonly present as noninflammatory ulcerated or membranous defects with well-defined borders of variable size, near the midline of the scalp vertex. Absent hair is a constant feature. Most single defects are oval shaped and small (0.5–3 cm) and heal

Fig. 21 Amniotic band syndrome (ABS) caused by entrapment of lower limb in fibrous amniotic bands during intrauterine life

gradually during the first week after birth, leaving a residual atrophic or hypertrophic scars with alopecia (Aloulou et al. 2008). Extensive scalp defects may extend to and involve the dura mater. Differential diagnoses include scalp infection, small meningocele, heterotopic brain or glial tissue, traumatic lesions, “en coup de sabre” morphea, sebaceous nevus, herpes simplex type 2, incontinentia pigmenti, and epidermolysis bullosa. The condition may be associated with specific teratogens, intrauterine infections, epidermolysis bullosa, chromosomal abnormalities, ectodermal dysplasia, or other syndrome of malformation (Table 21) (Burkhead et al. 2009).

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138.18.2 Supernumerary Nipples (SN) SN are a common congenital malformation with male predominance, consisting of extra nipples and/or related tissue besides the two nipples normally appearing on the chest. They are usually located along the embryonic milk line. Sometimes pigmented, they may be mistaken for congenital melanocytic nevi.

138.18.3 Accessory Tragus (AT) AT is a common congenital defect linked to maldevelopment of the first and second branchial arches, which appears as a small skin-colored tag or nodule arising near the tragus. It is composed of normal epidermis with dermal adipose tissue, pilosebaceous units, eccrine glands, elastic fibers, and cartilage.

138.18.4 Branchial Cleft Cysts (BCC) BCC are congenital epithelial cysts, which arise on the lateral part of the neck, usually near the front edge of the sternocleidomastoid muscle, from a failure of obliteration of branchial cleft in embryonic development (Koch 2005). BCC are the most common of congenital neck masses, and they are bilateral in about 2–3% of the cases. Usually asymptomatic, but, if infected, they may form a deep neck abscess or a draining fistula. Depending on the size and the anatomical extension of the mass, dysphagia, dysphonia, dyspnea, and stridor may occur. Surgery is indicated for branchial anomalies because of the lack of spontaneous regression, a high rate of recurrent infection and rare malignant degeneration.

138.18.5 Amniotic Band Syndrome (ABS) ABS is a rare congenital disorder caused by entrapment of fetal parts (usually a limb or digits)

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in fibrous amniotic bands during intrauterine life (Goldfarb et al. 2009). Prognosis depends on the location and severity of the constricting bands. In mild cases, a band may result in amputations of the fingers or toes or syndactyly (Fig. 21). In more severe cases, an amniotic band can become extremely constrictive leading to decreased blood supply and possible amputation of the limb. The most severe and life-threatening complication of amniotic band syndrome is fetal death, if a band becomes wrapped around vital areas such as the head or umbilical cord.

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2425 Sa J, Khachemoune A, Guldbakke KK (2007) Piebaldism: a case report and a concise review of the literature. Cutis 80:411–414 Scheck O, Horny HP, Ruck P et al (1987) Solitary mastocytoma of the eyelid. A case report with special reference to the immunocytology of human tissue mast cells, and a review of the literature. Virchows Arch 412:31–36 Serna-Tamayo C, Janniger CK, Micali G, Schwartz RA (2014) Neonatal and infantile acne vulgaris: an update. Cutis 94(1):13–16 Simko SJ, Garmezy B, Abhyankar H et al (2014) Differentiating skin-limited and multisystem langerhans cell histiocytosis. J Pediatr 165(5):990–996 Singalavanija S, Limpongsanurak W, Aoongern S (2014) Neonatal lupus erythematosus: a 20-year retrospective study. J Med Assoc Thai 97(6):S74–S82 Sinha S, Cohen PJ, Schwartz RA (2008) Nevus of Ota in children. Cutis 82:25–29 Sket KV, Giachetti A, Sojo M, Garrido D, Lupo E, Brener P (2013) Congenital cutaneous candidiasis. Arch Argent Pediatr 111(6):556–558 Smith CK, Arvin AM (2009) Varicella in the fetus and newborn. Semin Fetal Neonatal Med 14:209–217 Smolinski KN, Yan AC (2005) Hemangiomas of infancy: clinical and biological characteristics. Clin Pediatr (Phila) 44:747–766 Summers CG (2009) Albinism: classification, clinical characteristics, and recent findings. Optom Vis Sci 86:659–662 Visscher MO, Adam R, Brink S, Odio M (2015) Newborn infant skin: physiology, development, and care. Clin Dermatol 33(3):271–280 Wiechers T, Rabenhorst A, Schick T et al (2015) Large maculopapular cutaneous lesions are associated with favorable outcome in childhood-onset mastocytosis. J Allergy Clin Immunol 136(6):1581–1590 Yang B, Li L, Zhang LX et al (2015) Clinical characteristics and treatment options of infantile. Medicine 94 (40):1–9

Part XIV Appendices

Laboratory Medicine: Reference Values and Evidence-Based Medicine

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Mariangela Longini, Fabrizio Proietti, Francesco Bazzini, and Elisa Belvisi

Contents 139.1

Salient Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2429

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2432

Abstract

Accurate and reliable laboratory tests are essential for appropriate clinical management. Individual variability means that there are wide ranges in laboratory test results that are nonpathological and it is necessary for reference intervals to be defined in statistical terms. Rational interpretation of laboratory tests is a critical part of the clinical decision-making process and must take account of not only the test value but also the clinical condition. Evidence-based medicine is the conscientious, explicit, and judicious use of current best evidence in making decisions about the care of individual patients; it means avoiding doing laboratory investigations without a specific clinical suspicion.

M. Longini (*) · F. Proietti · F. Bazzini · E. Belvisi Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy e-mail: [email protected]; [email protected]; [email protected]; [email protected]

139.1 Salient Points • Analytical procedures should provide results with appropriate reference ranges. • Interpretation of laboratory results should take into account not only the test value but also the patient’s clinical condition. • An appropriate test is a test that is able to give a clear answer to a clear clinical question. • The application of diagnostic tests without specific clinical suspicion is an important cause of increased cost and a source of anxiety for the patient (Ulysses syndrome). The accuracy and reliability of laboratory test results is essential for appropriate clinical management decisions. Use of appropriate analytical procedures providing results traceable to an appropriate reference measurement system may allow one to minimized errors. The use of adequate reference intervals may further minimize variations caused by the presence of physiological changes and by analytical or biological variation. Because there are wide ranges in the nonpathological values of laboratory tests, linked to the fact of enormous individual variability (age, gender, race, lifestyle, work, physical training,

# Springer International Publishing AG, part of Springer Nature 2018 G. Buonocore et al. (eds.), Neonatology, https://doi.org/10.1007/978-3-319-29489-6_286

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hormonal activity), some individuals, while presenting values within those reference, may have a disease not yet diagnosed or may belong to a population at high risk of developing a disease, or they may be sick, but for various reasons do not have values altered in that specific test. Moreover, in a pediatric population it is difficult to establish these conditions. The range of reference values for a specific test can be evaluated and defined in statistical terms. Considering, as typically occurs, a symmetric Gaussian distribution in the distribution values of the results of a test applied to a given population (reference) the reference values are with 95% interval, so the 5% of nonpathological values of laboratory tests are outside to reference values. Test values outside of the reference range are a sign for the laboratory that indicates the probability of the presence of the disease. The more narrow are the limits of these intervals, the higher will be the percentage of individuals that the ranking indicates are sick but for which there is no presence of the disease (false positive, low specificity of the test). On the other hand a wider range of reference values leads to an increase in the percentage of sick individuals with normal values tests (false negatives, low sensitivity of the test). On the other hand a wider range of the reference values implies the increase in the percentage of diseased individuals who have normal values (false negatives, low sensitivity of the test) (Geffré et al. 2009). Careful interpretation of laboratory results must consider not only the test value but also the clinical valutation. A rational clinical interpretation of the data is crucial. Hence the concept of “evidence-based medicine” (EBM). The term EBM was coined at McMaster Medical School in Canada in the 1980s to label the clinical learning strategy, which people at the school had been developing for over a decade (Rosenberg and Donald 1995). EBM is the conscientious, explicit, and judicious use of current best evidence in making decisions about the care of individual patients. The practice of EBM means integrating individual

M. Longini et al.

clinical expertise with the best available external clinical evidence from systematic research (Sackett et al. 1996). The principles of EBM were developed in the early 1990s (Guyatt 1991) and slowly began to be put into practice soon after. At the beginning of the next decade, the impact of the principles of EBM in laboratory medicine was recognized (Price 2000). EBM embraces the diagnostic modalities while evidence-based laboratory medicine (EBML) focuses on the use of diagnostic tests and the goal of improving patient outcomes. A definition of EBLM, developed from the definition of EBM given by Sackett et al. (Sackett et al. 1996), is “the conscientious, judicious and explicit use of best evidence in the use of laboratory medicine investigations for assisting in making decisions about the care of individual patients.” Laboratory medicine is an integral part of the practice of medicine and so any analysis of the impact of EBLM on the practice of laboratory medicine has to look at the quality of evidence that can be used to inform clinical decisionmaking and the success with which this evidence is adopted. Laboratory testing significantly contributes to the clinical decision-making, and the number of tests that a modern clinical laboratory can now perform is considerable. The impact of Laboratory Medicine in Neonatology has substantially evolved and increased over the past years. Today many new diagnostic techniques and laboratory tests have been introduced as a result of both research on the fundamental pathogenesis of diseases and the development of new methods in themselves. Laboratory tests provide from two thirds to three fourths of the information used for making medical decisions. The age-old “truth standard” for the quality of evidence describes three dimensions that are important – a test should tell the truth, the whole truth, and nothing but the truth. This three-dimensional model can be used to characterize the clinical and analytical reliability of laboratory tests and guide the translation of

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outcome criteria, or quality goals, into practical specifications for method performance (Westgard and Darcy 2004). An appropriate test is a test that is able to give a clear answer to a clear clinical question. This will enable the clinician to make a decision and initiate some form of action leading to a benefit for the patient. An appropriate test may also be one in which there is an operational or economic benefit, without any adverse health benefit detriment to the patient (Price 2003). The application of diagnostic tests without a specific clinical suspicion is the main cause of cost increase and a source of apprehension for the patient. This is the well-known “Ulysses syndrome” which is caused by unnecessary and inappropriate investigations or wrong interpretation of results. Patients with Ulysses syndrome find themselves caught in a web of further investigations, referrals, and sometimes treatment before finally being recognized as healthy, which they were in the first place. It was first described 40 years ago (Rang 1972) and the number of tests available is now much greater. With greater choice comes greater responsibility and the need for greater discernment. In this age of evidence-based medicine, nothing is more important than the quality of laboratory tests. Advising on the optimal use of laboratory tests is, and has always been, a fundamental part of the clinical biochemists remit. Many difficulties faced by pathology have their origin in a relentless increase in activity in the face of diminishing budgets rather than in the efficiency or inefficiency of service delivery. (Waine 2002) Besides this, there are the potential benefits of improved practice, reducing the number, particularly and in particular the unnecessary repetitions, of tests, greatly decreases costs not only of the general practitioner, but also of the laboratory nonreagent materials (forms, bottles, collection materials, etc.). Changing the list of tests which make up a given profile can quickly effect change, for example: the profiles of routine electrolyte and liver function tests, those for diagnosing and

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monitoring thyroid dysfunction, for diagnosing the acute coronary syndrome, and for urine analysis and microscopy. These changes, whether made on the initiative of an individual laboratory or as a result of changing national trends, produce large changes in test numbers (Van Walraven et al. 1998). This type of intervention is possible only when there is a widespread consensus on benefits. Several studies have demonstrated the power of the laboratory request form to effect change, usually in combination with other behavioral changes (Van Walraven et al. 1998; Solomon et al. 1998; Novich et al. 1985; Zaat et al. 1992). The move away from test profile requests towards more diagnosis-based requesting undoubtedly enables the laboratory to optimize analyses. Changes in health service structure and funding make it possible for more active interaction between laboratories and primary care trusts in addressing encouraging best practices in the use of pathology tests. This requires ongoing dialogue between the laboratory and clinicians and must be seen in a context of mutual help and not one of criticism or prescriptive testing practice. These initiatives will succeed only with the active support of both of laboratories and of users and will require the composition of best-practice advice across the range of pathology tests, supported by the professional bodies. Although excellent work has been done already, there is a need to bring the matter of appropriateness of testing up on top of the pathology agenda, not just with the production of guidelines but with the design of suitable systems to help improve appropriateness. On the subject of how to bring about change, Lundberg in 1998 wrote both pessimistically and optimistically: know the literature; set up an appropriate group; agree terms of reference; implement change; educate; accept positive (and negative) criticism; respond to valid complaints; enjoy a better service (Lundberg 1998a; Lundberg 1998b). The advent of “omics” science has had a massive impact in the clinic, for better understanding of the function of genes, proteins, metabolites, and

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their interactions with the environment. The omics sciences would be able to identify many physiological and pathophysiological mechanisms of many diseases. The future application of these techniques could have an enormous potential in the clinical practice as with regards to the diagnosis, prognosis, and follow-up (Rinaudo et al. 2016).

References Geffré A, Friedrichs K, Harr K et al (2009) Reference values: a review. Vet Clin Pathol 38(3):288–298 Guyatt GH (1991) Evidence-based medicine. ACP J Club 114:A16 Lundberg GD (1998a) The need for an outcomes research agenda for clinical laboratory testing. JAMA 280:565–566 Lundberg GD (1998b) Changing physician behaviour in ordering tests. JAMA 280:2036–2037 Novich M, Gillis L, Tauber AI (1985) The laboratory test justified: an effective means to reduce routine laboratory testing. Am J Clin Pathol 84:756–759 Price PC (2000) Evidence-based laboratory medicine: supporting decision-making. Clin Chem 46:1041–1050

M. Longini et al. Price CP (2003) Application of the principles of evidencebased medicine to laboratory medicine. Clin Chim Acta 333(2):147–154 Rang M (1972) The Ulysses syndrome. Can Med Assoc J 106:122–123 Rinaudo P, Boudah S, Junot C et al (2016) Biosigner: a new method for the discovery of significant molecular signatures from omics data. Front Mol Biosci 3:26 Rosenberg W, Donald A (1995) Evidence based medicine: an approach to clinical problem-solving. BMJ 310 (6987):1122–1126 Sackett DL, Rosenberg WMC, Muir Gray JA et al (1996) Evidence based medicine: what it is and what it isn’t. BMJ 312:71–72 Solomon DH, Hideki H, Daltroy L et al (1998) Techniques to improve physicians’ use of diagnostic tests. JAMA 280:2020–2027 Van Walraven C, Goel V, Chan B (1998) Effect of population-based interventions on laboratory utilization. JAMA 280:2028–2033 Waine C (2002) Pathology in primary care. Address to the opportunities in UK pathology meeting. Laing and Buisson (organizers), London Westgard JO, Darcy T (2004) The truth about quality: medical usefulness and analytical reliability of laboratory tests. Clin Chim Acta 346(1):3–11 Zaat JOM, van Eijk JTM, Bonte HA (1992) Laboratory test form design in•uences testordering by general practitioners in The Netherlands. Med Care 30:189–9839

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140

Mariangela Longini, Fabrizio Proietti, Francesco Bazzini, and Elisa Belvisi

M. Longini (*) · F. Proietti · F. Bazzini · E. Belvisi Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy e-mail: [email protected]; [email protected]; [email protected]; [email protected] # Springer International Publishing AG, part of Springer Nature 2018 G. Buonocore et al. (eds.), Neonatology, https://doi.org/10.1007/978-3-319-29489-6_288

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4.75

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3.75

3.75

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th

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Gestational age at birth (weeks) Fig. 1 International standards for size at birth (boys)

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Laboratory Medicine: Reference Intervals for Laboratory Tests and Procedures

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Gestational age at birth (weeks) Fig. 2 International standards for size at birth (girls) (Villar J, Cheikh Ismail L, Victora CG et al (2014) International standards for newborn weight, length, and head

circumference by gestational age and sex: the Newborn Cross-Sectional Study of the INTERGROWTH-21st Project. Lancet 384(9946):857–868. PMID: 25209487)

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Table 1 Hematologic values in normal fetuses at different gestational ages in cord blood Week of gestation 18–21 (N = 760) 22–25 (N = 1200) 26–29 (N = 460) >30 (N = 440)

Hematocrit Hemoglobin RBCs (g/dL) (106 mL) (%) 11.69
1.27 2.85
0.36 37.3
4.32 12.2
1.6

Mean corpuscular volume (fL) 131.1
11.0

3.09
0.34 38.59
3.94 125.1
7.8

Total WBCs (106 μL) 4.68
2.96

Corrected WBCs (106 μL) 2.57
0.42

Platelets (106 μL) 234
57

4.72
2.82

3.73
2117

247
59

12.91
1.38 3.46
0.41 40.88
4.4

118.5
8.0

5.16
2.53

4.08
0.84

242
69

13.64
2.21 3.82
0.64 43.55
7.2

114.4
9.3

7.71
4.99

6.4
2.99

232
87

Partially modified from Forestier P, Daffos F, Catherine N et al (1991) Developmental hematopoiesis in normal human fetal blood. Blood 77:2360 RBCs Red blood cells, WBCs white blood cells Hematologic data obtained with a Coulter S plus II instrument. Total WBC count included nucleated red blood cells. Corrected WBC count included only WBCs, after subtracting the nucleated red cell component, based on a 100-cell manual differential

Table 2 WBC manual differential counts in normal fetuses at different gestational ages in cord blood Week of gestation 18–21 (N = 186) 22–25 (N = 230) 26–29 (N = 144) >30 (N = 172)

Lymphocytes (%) 88
7

Neutrophils (%) 6
4

Eosinophils (%) 2
3

Basophils (%) 0.5
1

Monocytes (%) 3.5
2

Nucleated RBCs (% of WBCs) 45
86

87
6

6.5
3.5

3
3

0.5
1

3.5
2.5

21
23

85
6

8.5
4

4
3

0.5
1

3.5
2.5

21
67

68.5
15

23
15

5
3

0.5
1

3.5
2

17
40

From Forestier F, Daffos F, Catherine N et al (1991) Developmental hematopoiesis in normal human fetal blood. Blood 77:2360 RBCs Red blood cells, WBCs white blood cells

Table 3 Hematologic values for cord blood (vaginal delivery and cesarean section) Characteristic WBC (109 per l) RBC (1012 per l) Hb (g/dL) Hct (%) MCV (fl) MCH (pg) MCHC (g/dL) RDW (%) PLT (109 per l) MPV (fl) Plateletcrit (%) CD34+ cells (106 per l)

Vaginal delivery (N Mean 18.4 4.78 17.6 54.7 114 36.5 32.3 17.4 297 8.7 0.26 47.7

= 63) Range 12.0–34.1 3.89–6.30 14.0–23.0 41.9–73.1 105–127 31.4–41 30.8–35.9 14.9–23.6 169–607 7.7–11.4 0.15–0.48 15.9–253

Cesarean section (N Mean 13.6 4.62 17.1 52.6 112 36.6 32.4 17.4 254 8.8 0.23 39.9

= 104) Range 8.54–39.7 3.46–6.62 13.0–23.4 40.1–72.2 97.7–125 32–39.9 30.3–34.4 14.2–23.3 161–424 7.5–11.5 0.15–0.36 7.14–120

Partially modified from Eskola M, Juutistenaho S, Aranko K et al (2011) J Perinatol 258–262. Data obtained with Sysmex K-1000 analyzer (Sysmex, Kobe Japan) Hb Hemoglobin, Hct hematocrit, MCH mean corpuscular hemoglobin, MCHC mean corpuscular hemoglobin concentration, MCV mean corpuscular volume, MPV mean platelet volume, plateletcrit MPV  PLT, PLT platelet, RBC red blood cell, RDW red blood cell distribution width, WBC white blood cell

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Table 4 Red cell and reticulocyte indices and serum marker of iron status in cord blood Parameter Cellular indices Hb, g/dL HCT,% MCV, fL MCVr, fL MCH, pg MCHC, g/dL %Retic, % IRF-H, % CI-Im, pg CHr, pg %HYP0m, % %HYPOr, % Serum measurements TFR, mg/L Ferritin, μg/L TfR-F index Iron, μmol/L Transferrin, g/L TfSat, %

Mean

SD

Reference range

15.9 49 109 124 35 32.5 4.0 24.1 34.9 35.6 3.0 42.0

1.5 0.5 4 6 1 1.0 0.8 7.8 1.3 1.3 3.0 15.6

14.6–18.9 44–58 102–118 115–136 33–38 30.6–34.2 2.6–5.4 10.2–40.0 32.5–37.2 33.1–38.6 0.4–9.9 18.3–76.8

2.0 198 0.95 27.4 2.0 55

0.7 137 0.43 7.7 0.4 19

1.2–4.0 45–636 0.49–2.1 12.2–42.1 1.2–2.9 21–111

From Ervasti M, Kotisaari S, Sankilarnpi U et al (2007) The relationship between red blood cell and reticulocyte indices and serum markers of iron status in the cord blood of newborns. Clin Chem Lab Med 45:1000–1003 CHm Cellular hemoglobin in red blood cells, CHr cellular hemoglobin in reticulocytes, Hb hemoglobin, HCT hematocrit, %HYPOm percentage of hypochromic red blood cells, %HYPOr percentage of hypochromic reticulocytes, IRF-H high immature reticulocyte fraction, MCH mean cell hemoglobin, MCHC mean cell hemoglobin concentration, MCV mean cell volume of red blood cells, MCV mean cell volume of reticulocytes, %Retic proportion of reticulocytes, TfR transferrin receptor, TfR-F index transferrin receptor/log (ferritin), TfSar transferrin saturation Hematologic data obtained in 199 full-term newborn infants with a ADVIA 120 analyzer (Siemens Diagnostic Solutions)

Table 5 Reference ranges for NRBC at birth in cord blood Week of gestation 26–28 (N = 120) 29–31 (N = 128) 34–36 (N = 215) 38–40 (N = 232)

Birth weight (g) 780–1105 1100–1720 1940–2520 2905–3590

Upper reference value of NRBC 22583 11420 3748 2329

90% CI 14080–31709 8348–14002 3200–4182 1806–2580

Partially modified from Perrone S, Vezzosi P, Longini M et al (2005) Nucleated red blood cell count in term and preterm newborns: reference values at birth. Arch Dis Child Fetal Neonatal 90:174–175 NRBC was expressed as absolute count (NRBC/mm3), calculated by light microscope examination of May–Grunwald–Giemsa stained blood smears

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Table 6 Reference ranges for HCt, Retic. Parameters, S-TfR during the first 15 weeks of life

Age, week 0.5 1.5 2.5 3.5 4.5 5.5 7.0 9.0 11.0 13.0 15.0

Age, week 0.5 1.5 2.5 3.5 4.5 5.5 7.0 9.0 11.0 13.0 15.0

Hb, g/dL Reference Mean 15.0 13.8 12.8 12.0 11.3 10.8 10.2 9.7 9.5 9.6 10.0 CHr, pg Reference Mean 35.7 35.0 34.3 33.7 33.1 32.6 31.9 31.2 30.6 30.2 30.0

Lower 10.2 9.8 9.4 9.0 8.6 8.2 7.8 7.3 7.1 7.2 7.6

Upper 22.2 19.6 17.6 16.1 15.0 14.2 13.3 12.7 12.5 12.7 13.3

Lower 31.5 31.1 30.6 30.1 29.5 29.0 28.3 27.5 26.9 26.5 26.4

Upper 39.9 38.9 38.1 37.4 36.7 36.2 35.5 34.8 34.3 33.9 33.6

Hct, % Reference Mean 45 41 38 36 34 32 30 29 28 28 30 IRF Reference Mean 36.6 35.5 34.3 33.3 32.2 31.3 29.9 28.4 27.0 25.9 24.9

Lower 30 29 28 27 26 25 23 22 21 21 22

Upper 65 58 52 47 44 42 39 38 37 37 39

Lower 13.5 13.7 13.6 13.1 12.4 11.6 10.3 8.6 7.4 6.7 6.7

Upper 59.7 57.2 55.1 53.4 52.1 50.9 49.6 48.1 46.7 45.0 43.3

Reticulocyte, 109/L Reference Mean Lower Upper 59.5 20.2 66.8 24.7 74.1 29.2 81.2 33.7 87.9 37.8 96.7 43.1 105.2 48.4 109.0 51.3 107.6 51.4 101.2 48.1 S-TfR, mg/L Reference Mean Lower

175.6 181.1 187.9 195.8 204.3 216.7 228.8 231.9 225.2 212.9

1.4 1.3 1.3 1.2 1.2 1.1 1.1 1.1 1.2 1.3

2.4 2.3 2.1 2.0 1.9 1.8 1.8 1.9 2.0 2.2

0.9 0.8 0.8 0.7 0.7 0.7 0.7 0.7 0.7 0.8

Upper

Proni Mäkelä E, Takal TI, Suomine P et al (2008) Hematological parameters in preterm infants from birth to 16 weeks of age with reference to iron balance. Clin Chem Lab Med 46:551–557 CHr Reticulocyte hemoglobin content, Hb hemoglobin, Hct hematocrit, IRF immature reticulocyte fraction, S-Tfr soluble transferrin receptor Hematologic data obtained with ADVIA 120, Siemens Medical Solutions, Tarrytown, NY. S-TfR measured with an automated immunoturbidimetric methods (IDeA sTfR-IT, Orion Diagnostica), Espoo, Finland. Ferritin assayed with Elecsys ferritin electrochemiluminescence immunoassay on a Modular E analyzer (Roche Diagnostics)

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Table 7 Reference ranges for ferritin during the first 15 weeks of life

Age, week 1.5 2.5 3.5 4.5 5.5 7.0 9.0 11.0 13.0 15.0

Ferritina, μg/L Reference interval Mean Lower 221.4 77 199.9 65.6 180.4 52.8 162.8 41.4 147.0 32.3 126.0 22.6 102.6 14.9 83.5 10.6 68.0 8.2 55.3 6.9

Upper 636.8 609.2 616.5 640.2 668.4 702.3 708.7 659.1 563.0 444.8

Ferritin, No Transfusionsb, μg/L Reference interval Mean Lower 215.5 73.5 178.5 56.9 149.2 43.9 125.9 34.1 107.2 26.8 85.7 19.2 65.7 13.3 52.3 10.1 43.2 8.3 37.0 7.5

Upper 631.6 559.8 507.2 465.4 429.7 382.1 324.6 271.7 224.0 182.9

Proni Mäkelä E, Takal TI, Suomine P et al (2008) Hematological parameters in preterm infants from birth to 16 weeks of age with reference to iron balance. Clin Chem Lab Med 46:551–557 a The information under the column “Ferritin” shows the values calculated for the neonates who had not been transfused at least 2 weeks of measurements b The information under the column “Ferritin, no transfusions” shows the values calculated for those neonates who had not been transfused at all (indicating ferritin level development in the most stable preterm neonates) Ferritin assayed with Elecsys ferritin electrochemiluminescence immunoassay on a Modular E analyzer (Roche Diagnostics)

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Table 8 Reference ranges for CBC, retieulocytes, ferritin, and S-TfR during the first year of life in preterm and term infants Age, weeks Preterm 20 25 30 35 40 45 50 55 60 Term 20 25 30 35 40 45 50 55 Age, weeks Preterm 20

Hb, g/dL Mean

95% RI

Hct% Mean

95% RI

RBC count, × 1012/L Mean 95% RI

MCV, fL Mean

95% RI

11.2 11.6 12.0 12.4 12.7 12.9 13.0 13.1 13.0

9.2–13.7 9.8–13.8 10.3–14.1 10.6–14.4 10.8–14.8 10.9–15.2 11.0–15.3 11.1–15.3 11.2–15.1

32.7 34.0 35.1 36 36.8 37.4 37.8 38 37.9

27.1–39.5 28.7–40.1 30.0–41.1 30.9–42.1 31.5–43.1 31.9–43.8 32.3–44.2 32.6–44.2 32.9–43.7

4.03 4.27 4.47 4.64 4.76 4.85 4.89 4.90 4.87

81.6 80.1 79.0 78.1 77.5 77.3 77.3 77.6 78.2

73.2–90.0 72.3–88.0 71.2–86.7 70.1–86.0 69.3–85.7 68.9–85.6 69.0–85.6 69.6–85.7 70.7–85.8

3.15–4.92 3.48–5.07 3.70–5.25 3.83–5.44 3.92–5.60 3.98–5.71 4.03–5.75 4.07–5.73 4.11–5.62

12.0 10.2–14.1 11.9 10.2–13.8 11.8 10.1–13.7 11.8 10.1–13.7 11.8 10.2–13.7 11.9 10.3–13.7 12.0 10.4–13.8 12.1 10.5–14.0 MCH, pg Mean 95% RI

34.5 29.3–40.7 34.5 29.6–40.2 34.5 29.8–40.0 34.6 30.0–40.0 34.8 30.3–40.0 35.1 30.7–40.1 35.4 31.3–40.2 35.9 31.9–40.3 Retie, × 109/L Mean 95% RI

4.32 3.76–4.87 4.38 3.84–4.92 4.44 3.90–4.98 4.48 3.93–5.03 4.51 3.96–5.06 4.54 3.99–5.08 4.55 4.01–5.08 4.55 4.04–5.06 Ferritin, μg/L Mean 95% RI

28.1

77.4

37.8

25.2–31.0

39.0–153.5

80.3 79.0 78.1 77.6 77.4 77.6 78.2 79.1 S-TIR, mg/L Mean

7.37–193.9

74.2–86.4 73.1–84.9 72.3–83.9 71.8–83.4 71.6–83.2 71.7–83.5 72.2–84.1 73.1–85.1 95% RI 1.07–2.16

1.52 25

27.7

24.8–30.5

69.7

36.7–132.5

30.1

7.48–120.8

1.10–2.15 1.54

30

27.3

24.4–30.3

64.1

34.3–119.6

24.7

7.06–86.6

1.12–2.16 1.56

35

27.1

24.0–30.2

60.1

32.4–111.8

21.1

6.41–69.5

1.14–2.17 1.57

40

26.9

23.7–30.1

57.6

30.9–107.2

18.6

5.80–59.9

1.16–2.19 1.59

45

26.8

23.5–30.0

56.3

30.1–105.1

17.1

5.41–53.8

1.17–2.21 1.61

50

26.7

23.6–29.9

56.1

30.0–105.2

16.2

5.25–49.8

1.18–2.25 1.63

55

26.8

23.7–29.8

57.2

30.3–107.7

15.9

5.31–47.5

1.18–2.30 1.65

60

26.9

24.0–29.7

59.4

31.1–113.5

16.2

5.44–47.9

1.18–2.36 1.67

Term 20 25 30 35 40 45

27.9 27.3 26.8 26.5 26.3 26.3

25.6–30.2 24.9–29.6 24.3–29.2 23.9–29.0 23.7–28.9 23.6–29.0

45.5 45.2 45.4 46.0 47.1 48.7

25.3–82.2 25.1–81.5 26.1–78.9 27.6–76.6 28.8–76.8 28.7–82.5

71.7 51.1 38.5 30.6 25.8 22.9

21.5–239.7 16.1–162.2 11.5–128.7 8.76–107.0 7.46–89.1 7.01–75.0

1.49 1.52 1.54 1.57 1.60 1.63

1.06–2.08 1.08–2.12 1.09–2.19 1.09–2.27 1.08–2.37 1.07–2.48

(continued)

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Table 8 (continued) Age, weeks Preterm 50 55 Age, weeks Preterm 20 25 30 35 40 45 50 55 60 Term 20 25 30 35 40 45 50 55

MCH, pg Mean 95% RI 26.5 26.9

Retie, × 109/L Mean 95% RI

23.8–29.2 50.9 24.2–29.6 53.7 CHr, pg Mean 95% RI

Ferritin, μg/L Mean 95% RI

S-TIR, mg/L Mean 95% RI

26.9–96.3 21.6 6.78–68.6 1.66 1.05–2.62 23.9–121.0 21.5 5.90–78.0 1.69 1.04–2.76 WBC count, × 109/L Platelet count, × 109/L Mean 95% RI Mean 95% RI

29.8 29.6 29.4 29.3 29.2 29.2 29.3 29.4 29.5

26.6–33.1 26.4–32.8 26.2–32.7 26.0–32.6 25.9–32.6 25.8–32.6 25.8–32.7 25.8–32.9 25.9–33.2

9.48 9.60 9.71 9.83 9.94 10.1 10.2 10.3 10.4

5.63–16.0 5.73–16.1 5.82–16.2 5.92–16.3 6.01–16.5 6.09–16.6 6.17–16.8 6.24–17.0 6.31–17.2

478 465 452 439 427 415 403 391 380

294–777 290–744 286–714 280–687 274–663 268–642 260–623 252–607 244–593

29.8 29.2 28.8 28.7 28.9 29.2 29.9 30.8

27.4–32.1 25.7–32.6 24.7–32.9 24.5–32.9 25.1–32.6 26.4–32.1 27.6–32.2 27.0–34.5

9.36 9.19 9.02 8.85 8.68 8.52 8.36 8.21

5.84–15.0 5.73–14.7 5.57–14.6 5.37–14.6 5.14–14.7 4.88–14.9 4.61–15.2 4.33–15.5

426 415 404 394 383 373 363 354

282–646 269–640 258–634 247–628 237–621 227–614 218–607 209–599

From Takale TI, Mäkelä E, Suomine P et al (2010) Blood cell and iron status analytes of preterm and full-term infants from 20 weeks onward during the first year of life. Clin Chem Lab Med 48:1295–1301 CBC complete blood count, CHr reticulocyte hemoglobin content, Hb hemoglobin, Hct hematocrit, MCH mean corpuscular hemoglobin, MCV mean corpuscular volume, RBC red blood cell, Retic reticulocyte, RI reference interval, S-Tfr soluble transferrin receptor, WBC white blood cell Hematologic data obtained with ADVIA 120, Siemens Medical Solutions, Tarrytowrz, NY. S-TfR measured with an automated immunoturbidimetric methods (IDeA sTfR-IT, Orion Diagnostica), Espoo, Finland. Ferritin assayed with Elecsys ferritin electrochemiluminescence immunoassay on a Modular E analyzer (Roche Diagnostics)

Table 9 Circulating platelet counts at different ages Age categories Core blood 2 days 5 days 1 month 2–11 months 1–2 years 3–4 years 5–6 years 7–10 years 11–15 years

Platelet count (109/L) 288
53 303
48 338
59 343
72 365
49 314
78 304
66 303
65 295
58 251
40

Partially modified from Ishiguro A, Nakahata T, Matsubara K et al (1999) Age-related changes in thrombopoietin in children: reference interval for serum thrombopoietin levels. Br J Haematol 106(4):884–888

F Il (U/mL) 0.52 (0.25) 0.48 (0.26) 0.45 (0.22) 0.45 (0.26) 0.45 (0.25) 0.35 (0.21)

Fibrinogen (mg/dL) 240 (150) 283 (177) 246 (150) 300 (120) 243 (150) 240 (150)

1.1 (0.50) 1.36 (0.21)

0.93 (0.54)

1.0 (0.50) 168 (0.50)

1.5 (0.55)

F VIII (U/mL)

0.35 (0.19) 0.35 (0.10)

0.41 (0.20)

0.53 (0.25) 0.40 (0.20)

0.35 (0.15)

F IX (U/mL)

0.38 (0.10) 0.22 (0.09)

0.33 (0.23)

0.53 (0.20) 0.44 (0.16)

0.44 (0.16)

F XII (U/mL)

0.38 (0.14) 0.35 (0.10)

0.40 (0.25)

0.63 (0.25) 0.52 (0.20)

0.56 (0.32)

Antithrombin (U/mL)

0.28 (0.12) 0.28 (0.12)

0.24 (0.18)

0.35 (0.17) 0.31 (0.17)

0.32 (0.16)

Protein C (U/mL)

Hathaway W, Bonnar J (1987) Hemostatic disorders of the pregnant woman and newborn infant. Elsevier, New York; Manco-Johnson M, Marlar R et al (1988) Severe protein C deficiency in newborn infants. J Pediatr 113:359 Andrew M, Paes B, Milner R et al (1987) Development of the human coagulation system in the full-term infant. Blood 70:165; Andrew M, Paes B, Milner R et al (1988) Development of the human coagulation system in the healthy premature infant. Blood 72:1651 Corrigan JJ Jr (1992) Normal hemostasis in fetus and newborn: coagulation. In: Polin RA, Fox WW (eds) Fetal and neonatal physiology. Saunders, Philadelphia, pp 1368–1371 a Data are expressed as mean and lower limits of normal. Preterm = 30–36-weeks’ gestational age

Age Term Hathaway and Bonnar (1987) and Manco-Johnson et al. (1988) Andrew et al. (1987, 1988) Corrigan (1992)5 Preterm Hathaway and Bonnar (1987) and Manco-Johnson et al. (1988) Andrew et al. (1987, 1988)a Corrigan (1992)s

Table 10 Comparison of selected coagulation factor values in newbornsa

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Table 11 Reference ranges for coagulation parametersa, inhibitors and fibrinolysis in preterm newborns

1

INR PT (s) 2 APTT (s) 1 Fibrinogen (mg/dL) 1 IIc (%) 1 Vc (%) 1 VIIc (%) 1 VIIIc (%) 2 IXc (%) 1 Xc (%) 1 XIc (%) 1 XIIc (%) 1 AT Act (%) 2 PC Act (%) 1 FREE PS Act (%) 2 APCR 2 tPA (ng/ml) 2 PAI-1 (ng/ml) 1 VWF Ag (%) 1

Premature SGA newborns (N = 68) (mean
SD and 2.5th–97.5th percentile) 1.35
0.22 (1.02–2.09) 16.6
2.1 (13.2–23.1) 51
11 (35.4–97.6) 158
46 (65–243)

Premature AGA newborns (N = 71) (mean
SD and 2.5th–97.5th percentile) 1.32
0.20 (1.02–1.85) 16.4
1.98 (13.3–21.4) 51
12(34.2–102.9) 183
80 (64–478)

37.6
6.5 (23.4–53) 61
22 (23–128) 61.2
20.5 (17.9–116.5) 142
80 (26–389) 32
22 (11.8–107.5) 41.2
9.7 (18.2–65.5) 33.5
14.2 (11.3–76.9) 50
22 (16–110.7) 37.2
11.0 (19.5–67.8) 24
8 (11.0–50.3) 31.5
9.0 (17–57)

37.2
9 (20.5–58) 62
20.4 (22.6–120) 68.8
23.7 (27.8–124.2) 116
57 (28–276) 28
11 (11.6–60.5) 41.5
10 (27.0–68.7) 30.5
11.0(13.2–60.4) 47
24 (12.7–119.6) 39.0
13.7(16.7–80.3) 24
9 (10.4–52) 31.1
5.9 (20–47.6)

2.3
0.30 (1.32–3.13) 13.8
8.2 (4.5–44.1) 55.3
24.4 (14.9–102.6)

2.2
0.34 (1.43–3.16) 11.4
7.0 (3.2–34.6) 46
24 (16.5–122)

202
64 (105–355)

193
59 (95–339)

Partially modified from Mitsiako G, Giougi E, Chatziioannidis I et al (2010) Haemostatic profile of healthy premature small for gestational age neonates. Thromb Res 126:103–106. 1: T test; 2: Mann–Whitney U test; Act activity, Ag antigenic value, c coagulant activity a All parameters were determined utilizing a STA Compact Analyzer and reagents from Diagnostica Stago (Asnières sur Seine, France)

Table 12 Reference ranges for coagulation tests in healthy, term newborns Test PT (s) aPTT (s) Platelets (109/L) Fibrinogen (mg/dL) Factor II (%) Factor V (%) Factor VII (%) Factor VIII (%) Factor IX (%) Factor X (%) Hematocrit (%)

Newborns 13.1
0.9 35
4.5 214
55 251
51 73
7 93
13 88
12 113
38 86
18 72
10 59
3.0

Partially modified from Cerneca F, de Vonderweid U, Simeone R et al (1994) The importance of hematocrit in the interpretation of coagulation tests in the term newborn infant. Hematologica 79:25 a Data were obtained in 71 newborns and expressed as mean
standard deviation. Samples were collected with a constant anticoagulant-to-blood ratio, based on a previous determination of hematocrit level

28 Weeks 29–32 Weeks BT PL MPV BT PL 204
80 255.5
69.4 8.9
1.02 207
105 286.6
81.0 152
59 286.0
81.1 9.7
1.3 146
79 300.9
124.3 104
45 277.5
99.8 9.9
1.4 173
86 306.1
125.0

33–37 Weeks (N = 104) MPV BT PL 10.8
1.0 157
68 307.0
106.1 10.4
1.4 163
92 347.6
93.9 10.5
1.4 146
92 314.1
120.9

38 Weeks (N = 104) MPV BT PL 10.6
0.8 107
38 315.9
80.9 10.7
1.1 88
31 344.2
99.4 10.3
1.3 82
39 352.3
139.3

MPV 10.5
1.4 10.5
1.6 11.3
1.2

Partially modified from Del Vecchio A, Latini G, Henry E et al (2008) Template bleeding times of 240 neonates born at 24–41 weeks gestation. J Perinatol 28:427–431 BT bleeding time, DOL day of life, MPV mean platelet volume, PL platelets a Patients were tested on either day of life 1 (N 1/420 in each gestational age group), day of life 10 (N 1/420 per group), or day of life 30 (N 1/420 per group)

DOL 1 10 30

Table 13 Template bleeding time in neonate according to gestational age

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Table 14 Coagulation screening tests and factor levels in fetuses and term newborns Parameter PT (s) PT (INR) APTT (s) TCT (s) Factor I (g/L Von Clauss) I Ag (g/L) IIc (%) VIIc (%) IXc (%) Xc (%) Vc (%) VIIIc (%) XIc (%) XIIc (%) PK (%) HMWK (%)

Fetuses (weeks’ gestation) 19–23 (N = 20) 24–29 (N = 22) 32.5 (19–45) 32.3 (19–44) 6.4 (1.7–11.1) 6.2 (2.1–10.6) 168.6 (83–250) 154.0 (87–210) 34.2 (24–44) 26.2 (24–28)

30–38 (N = 22) 22.6 (16–30) 3.0 (1.5–5.0) 104.8 (76–128) 21.4 (17.0–23.3)

Newborns (N = 60) 16.7 (12.0–23.5) 1.7 (0.9–2.7) 44.3 (35–52) 20.4 (15.2–25.0)

0.85 (0.57–1.50) 1.08 (0.75–1.50) 16.9 (10–24) 27.4 (17–37) 10.1 (6–14) 20.5 (14–29) 32.1 (21–44) 34.5 (18–50) 13.2 (8–19) 14.9 (6–25) 12.8 (8–19) 15.4 (10–22)

1.35 (1.25–1.65) 1.94 (1.30–2.40) 27.9 (15–50) 45.9 (31–62) 12.3 (5–24) 28.0 (16–36) 48.9 (23–70) 50.1 (27–78) 14.8 (6–26) 25.8 (11–50) 18.1 (8–28) 23.6 (12–34)

1.68 (0.95–2.45) 2.65 (1.68–3.60) 43.5 (27–64) 52.5 (28–78) 31.8 (15–50) 39.6 (21–65) 89.9 (50–140) 94.3 (38–150) 37.2 (13–62) 69.8 (25–105) 35.4 (21–53) 38.9 (28–53)

1.12 (0.65–1.65) 1.93 (1.56–2.40) 19.9 (11–30) 33.8 (18–48) 9.9 (5–15) 24.9 (16–35) 36.8 (25–50) 35.5 (20–52) 12.1 (6–22) 22.7 (6–40) 15.4 (8–26) 19.3 (10–26)

Partially modified from Reverdiau Moalic P, Delahouse B, Body G et al (1996) Evaluation of blood coagulation activators and inhibitors in the healthy human fetus. Blood 88:900 Ag antigenic value, c coagulant activity Values are the mean, followed in parentheses by the lower and upper boundaries including 95% of the population

Table 15 Coagulation inhibitors in fetuses and term newborns Parameter AT (%) HCII (%) TFPI (ng/ML) PC Ag (%) PC Act (%) Total PS (%) Free PS (%) Ratio of free PS to total PS C4b-BP (%)

Fetuses (weeks’ gestation 19–23 (N = 20) 24–29 (N = 22) 20.0 (12–31)a 30.0 (20–39) 10.3 (6–16) 12.9 (5.5–20) 21.0 (16.0–29.2) 20.6 (13.4–33.2) 9.5 (6–14) 12.1 (8–16) 9.6 (7–13) 10.4 (8–13) 15.1 (11–21) 17.4 (14–25) 21.7 (13–32) 27.9 (19–40) 0.82 (0.75–0.92) 0.83 (0.76–0.95) 1.8 (0.6) 6.1 (1–12.5)

30–38 (N = 22) 37.1 (24–55) 21.2 (11–33) 20.7 (10.4–31.5) 15.9 (8–30) 14.1 (8–18) 21.0 (15–30) 27.1 (18–40) 0.79 (0.70–0.89) 9.3 (5–14)

Newborns (N = 60) 59.4 (42–80) 52.1 (19–99) 38.1 (22.7–55.8) 32.5 (21–47) 28.2 (14–42) 38.5 (22–55) 49.3 (33–67) 0.64 (0.59–0.98) 18.6 (3–40)

Partially modified from Reverdiau Moalic P, Delahouse B, Body G et al (1996) Evaluation of blood coagulation activators and inhibitors in the healthy human fetus. Blood 88:900 Values are the mean, followed in parentheses by the lower and upper boundaries including 95% of the population Ag antigenic value, AT antithrombin, c coagulant activity, HCII heparin cofactor II, TFPI tissue factor pathway inhibitor, PC protein C, PS protein S, C4b-BP C4b-binding protein

Androstenedione (p) (Garagorri et al. 2008)

4d 4d

nmol/L

0d 15 d 30 d

0–30 d

3d 1w 1m

U/L

5–635 19–141

0–30 d

μmol/L

Aluminium (p, s) (NHS Supraregional Assay Service Handbook 1998) Ammonia (p) (Diaz et al. 1995) Amylase (p) (Soldin et al. 1995)

26–28 31–35

μmol/L

ng/dL

M 1.47–13 1.0–8.7 0.6–5.9

0–6

21–95

7–18 45–175 5–90 0.07–0.80

0–30 d 50.0–100,000

ng/mL

M 121–351 138–486 0.79–2.23

F 0.8–12 0.7–7.9 0.5–5.3

F 107–357 107–474

Reference range M F 6–40 7–40 10–40 8–32 M F 24–39 19–40 21–45 19–44

0–30 d

1–7 d 8–30 d

Age 1–7 d 8–30 d

g/L

21–33 23–34 22–35 22–35 22–36

Reference range

1–7 d 8–30 d

27 29 31 33 35

Age

Term

IU/L

g/L

Unit IU/L

Aldosterone (s) (Soldin et al. 1999)

Alkaline phosphatase (ALP) (p, s) (Ghoshal and Soldin 2003) α1-antitrypsin (s) (Davis et al. 1996) α-fetoprotein (AFP) (s) (Dugaw KA et al. 2001)

Analyte Alanine aminotransferase (ALT) (p, s) (Soldin et al. 1997) Albumin (p, s) (Ghoshal and Soldin 2003)

Preterm Gestational age (weeks)

Table 16 Neonatal biochemical reference ranges – PLASMA/SERUM

Preterm and/or sick babies may have concentrations up to 200 μmol/l Method: Hitachi 717 using Boehringer Mannheim reagents (Boehringer Mannheim Diagnostic, Indianapolis, IN)

Method: Dade Behring Dimension RxL analyzer (Dade Behring Inc., Newark, De) Method: Beckman Array 360 (Beckman Instruments, Brea CA) Method: Chemiluminescent Immunoassay, Vitros Eci (orthoclinical Diagnostics Raritan, NJ)

Comment Method: Vitro 500 (ortho-clinical Diagnostics Raritan, NJ)

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C-reactive protein (CRP) (p, s) (Soldin et al. 2004) Creatine kinase (CK) (s) (Jedeikin et al. 1982)

IU/L

mg/L

73–562

Cord blood 5–8 h 24–33 h 72–100 h

24

mmoL/L

0–14 d

0–5 d 5–28 d 0d 3d 15 d 30 d

28–34

1d 3d 5d 0–30 d

0–7 d 8–30 d

μmoL/L 3.0–8.3

1 d0.81–1.41 2d 0.72–1.44 3d 1.04–1.52

2.14–2.65

1–30 d

mmoL/L

Chloride (p, s) (Ghoshal and Soldin 2003) Cholesterol (p, s) (Hicks et al. 1996) Copper (s) (Lockitch et al. 1988) Cortisol (p) (Heckmann et al. 1991; Garagorri et al. 2008)

25–36

21–28

Birth-1 d 1–2 d 3–5 d 0–30 d 1–30 d

1–7 d 8–30 d

mmoL/L

mmoL/L

mmoL/L

mg/L

μmol/L

U/L

Ionised (Wandrup et al. 1988; Nelson et al. 1989)

Conjugated Caeruloplasmin (p, s) (Soldin et al. 1997a) Calcium (p, s) Total (Thaime 1962; Ghoshal and Soldin 2003)

Aspartate transaminase (AST) (p, s) (Ghoshal and Soldin 2003) Bilirubin(s) (Soldin et al. 1999a) Total

70–380 214–1175 130–1200 87–725

M 1.4–3.9 1.4–7.2 4.0–11.0 54–839 54–814 54–728 55–645