Child Health and Human Development Yearbook 2016 9781536109467, 9781536109580

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PEDIATRICS, CHILD AND ADOLESCENT HEALTH

CHILD HEALTH AND HUMAN DEVELOPMENT YEARBOOK 2016

No part of this digital document may be reproduced, stored in a retrieval system or transmitted in any form or by any means. The publisher has taken reasonable care in the preparation of this digital document, but makes no expressed or implied warranty of any kind and assumes no responsibility for any errors or omissions. No liability is assumed for incidental or consequential damages in connection with or arising out of information contained herein. This digital document is sold with the clear understanding that the publisher is not engaged in rendering legal, medical or any other professional services.

PEDIATRICS, CHILD AND ADOLESCENT HEALTH JOAV MERRICK - SERIES EDITOR NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT, MINISTRY OF SOCIAL AFFAIRS, JERUSALEM Child and Adolescent Health Yearbook 2012 Joav Merrick (Editor) 2012. ISBN: 978-1-61942-788-4 (Hardcover) 2012. ISBN: 978-1-61942-789-1 (e-book) Child Health and Human Development Yearbook 2011 Joav Merrick (Editor) 2012. ISBN: 978-1-61942-969-7 (Hardcover) 2012. ISBN: 978-1-61942-970-3 (e-book) Child and Adolescent Health Yearbook 2011 Joav Merrick (Editor) 2012. ISBN: 978-1-61942-782-2 (Hardcover) 2012. ISBN: 978-1-61942-783-9 (e-book) Tropical Pediatrics: A Public Health Concern of International Proportions Richard R Roach, Donald E Greydanus, Dilip R Patel, Douglas N Homnick and Joav Merrick (Editors) 2012. ISBN: 978-1-61942-831-7 (Hardcover) 2012. ISBN: 978-1-61942-840-9 (e-book) Child Health and Human Development Yearbook 2012 Joav Merrick (Editor) 2012. ISBN: 978-1-61942-978-9 (Hardcover) 2012. ISBN: 978-1-61942-979-6 (e-book) Developmental Issues in Chinese Adolescents Daniel TL Shek, Rachel CF Sun and Joav Merrick (Editors) 2012. ISBN: 978-1-62081-262-4 (Hardcover) 2012. ISBN: 978-1-62081-270-9 (e-book)

Positive Youth Development: Theory, Research and Application Daniel TL Shek, Rachel CF Sun and Joav Merrick (Editors) 2012. ISBN: 978-1-62081-305-8 (Hardcover) 2012. ISBN: 978-1-62081-347-8 (e-book) Understanding Autism Spectrum Disorder: Current Research Aspects Ditza A Zachor and Joav Merrick (Editors) 2012. ISBN: 978-1-62081-353-9 (Hardcover) 2012. ISBN: 978-1-62081-390-4 (e-book) Positive Youth Development: A New School Curriculum to Tackle Adolescent Developmental Issues Hing Keung Ma, Daniel TL Shek and Joav Merrick (Editors) 2012. ISBN: 978-1-62081-384-3 (Hardcover) 2012. ISBN: 978-1-62081-385-0 (e-book) Transition from Pediatric to Adult Medical Care David Wood, John G Reiss, Maria E Ferris, Linda R Edwards and Joav Merrick (Editors) 2012. ISBN: 978-1-62081-409-3 (Hardcover) 2012. ISBN: 978-1-62081-412-3 (e-book) Adolescence and Behavior Issues in a Chinese Context Daniel TL Shek, Rachel CF Sun, and Joav Merrick (Editors) 2013. ISBN: 978-1-62618-614-9 (Hardcover) 2013. ISBN: 978-1-62618-692-7 (e-book)

Advances in Preterm Infant Research Jing Sun, Nicholas Buys and Joav Merrick 2013. ISBN: 978-1-62618-696-5 (Hardcover) 2013. ISBN: 978-1-62618-775-7 (e-book) Child Health and Human Development: Social, Economic and Environmental Factors Leslie Rubin and Joav Merrick (Editors) 2013. ISBN: 978-1-62948-166-1 (Hardcover) 2013. ISBN: 978-1-62948-169-2 (e-book) Children, Violence and Bullying: International Perspectives Joav Merrick, Isack Kandel and Hatim A Omar (Editors) 2013. ISBN: 978-1-62948-342-9 (Hardcover) 2013. ISBN: 978-1-62948-345-0 (e-book) Chinese Adolescent Development: Economic Disadvantages, Parents and Intrapersonal Development Daniel TL Shek, Rachel CF Sun and Joav Merrick (Editors) 2013. ISBN: 978-1-62618-622-4 (Hardcover) 2013. ISBN: 978-1-62618-694-1 (e-book) Chronic Disease and Disability in Childhood Joav Merrick 2013. ISBN: 978-1-62808-865-6 (Hardcover) 2013. ISBN: 978-1-62808-868-7 (e-book) Environmental Health Disparities in Children: Asthma, Obesity and Food Leslie Rubin and Joav Merrick (Editors) 2013. ISBN: 978-1-62948-122-7 (Hardcover) 2013. ISBN: 978-1-62948-135-7 (e-book) Environmental Health: Home, School and Community Leslie Rubin and Joav Merrick (Editors) 2013. ISBN: 978-1-62948-155-5 (Hardcover) 2013. ISBN: 978-1-62948-158-6 (e-book)

Guidelines for the Healthy Integration of the Ill Child in the Educational System: Experience from Israel Yosefa Isenberg 2013. ISBN: 978-1-62808-350-7 (Hardcover) 2013. ISBN: 978-1-62808-353-8 (e-book) Internet Addiction: A Public Health Concern in Adolescence Artemis Tsitsika, Mari Janikian, Donald E Greydanus, Hatim A Omar and Joav Merrick (Editors) 2013. ISBN: 978-1-62618-925-6 (Hardcover) 2013. ISBN: 978-1-62618-959-1 (e-book) Playing with Fire: Children, Adolescents and Firesetting Hatim A. Omar, Carrie Howell Bowling and Joav Merrick (Editors) 2013. ISBN: 978-1-62948-471-6 (softcover) 2013. ISBN: 978-1-62948-474-7 (e-book) Promotion of Holistic Development of Young People in Hong Kong Daniel TL Shek, Tak Yan Lee and Joav Merrick (Editors) 2013. ISBN: 978-1-62808-019-3 (Hardcover) 2013. ISBN: 978-1-62808-040-7 (e-book) University and College Students: Health and Development Issues for the Leaders of Tomorrow Daniel TL Shek, Rachel CF and Joav Merrick (Editors) 2013. ISBN: 978-1-62618-586-9 (Hardcover) 2013. ISBN: 978-1-62618-612-5 (e-book) Break the Cycle of Environmental Health Disparities: Maternal and Child Health Aspects Leslie Rubin and Joav Merrick (Editors) 2013. ISBN: 978-1-62948-107-4 (Hardcover) 2013. ISBN: 978-1-62948-133-3 (e-book)

Human Developmental Research: Experience from Research in Hong Kong Daniel TL Shek, Cecilia Ma, Yu Lu and Joav Merrick (Editors) 2014. ISBN: 978-1-62808-166-4 (Hardcover) 2013. ISBN: 978-1-62808-167-1 (e-book) School, Adolescence and Health Issues Joav Merrick, Ariel Tenenbaum and Hatim A. Omar (Editors) 2014. ISBN: 978-1-62948-702-1 (Hardcover) 2014. ISBN: 978-1-62948-707-6 (e-book) Adolescence and Sexuality: International Perspectives Joav Merrick, Ariel Tenenbaum and Hatim A. Omar (Editors) 2014. ISBN: 978-1-62948-711-3 (Hardcover) 2014. ISBN: 978-1-62948-724-3 (e-book) Child and Adolescent Health Yearbook 2013 Joav Merrick (Editor) 2014. ISBN: 978-1-63117-658-6 (Hardcover) 2014. ISBN: 978-1-63117-668-5 (e-book) Adoption: The Search for a New Parenthood Gary Diamond and Eva Arbel (Israel) 2014. ISBN: 978-1-63117-710-1 (Hardcover) 2014. ISBN: 978-1-63117-713-2 (e-book) Adolescence: Places and Spaces Myra F. Taylor, Julie Ann Pooley and Joav Merrick (Editors) 2014. ISBN: 978-1-63117-847-4 (Hardcover) 2014. ISBN: 978-1-63117-850-4 (e-book) Pain Management Yearbook 2013 Joav Merrick (Editor) 2014. ISBN: 978-1-63117-944-0 (Hardcover) 2014. ISBN: 978-1-63117-959-4 (e-book)

Child Health and Human Development Yearbook 2013 Joav Merrick (Editor) 2014. ISBN: 978-1-63117-939-6 (Hardcover) 2013. ISBN: 978-1-63117-958-7 (e-book) Born into this World: Health Issues Donald E. Greydanus, Arthur N. Feinberg, and Joav Merrick (Editors) 2014. ISBN: 978-1-63321-667-9 (Hardcover) 2014. ISBN: 978-1-63321-669-3 (e-book) Caring for the Newborn: A Comprehensive Guide for the Clinician Donald E. Greydanus, Arthur N. Feinberg and Joav Merrick (Editors) 2014. ISBN: 978-1-63321-760-7 (Hardcover) 2014. ISBN: 978-1-63321-781-2 (e-book) Environment and Hope: Improving Health, Reducing AIDS and Promoting Food Security in the World Leslie Rubin and Joav Merrick (Editors) 2014. ISBN: 978-1-63321-772-0 (Hardcover) 2014. ISBN: 978-1-63321-782-9 (e-book) Pediatric and Adolescent Dermatology: Some Current Issues Donald E Greydanus, Arthur N Feinberg and Joav Merrick (Editors) 2014. ISBN: 978-1-63321-853-6 (Hardcover) 2014. ISBN: 978-1-63321-863-5 (e-book) A Pediatric Resident Pocket Guide: Making the Most of Morning Reports Arthur N. Feinberg 2015. ISBN: 978-1-63482-141-4 (Softcover) 2015. ISBN: 978-1-63482-186-5 (e-book) Tropical Pediatrics: A Public Health Concern of International Proportions Second Edition Richard R. Roach, Donald E. Greydanus, Dilip R. Patel and Joav Merrick (Editors) 2015. ISBN: 978-1-63463-381-9 (Hardcover) 2015. ISBN: 978-1-63463-404-5 (e-book)

Child and Adolescent Health Issues (A Tribute to the Pediatrician Donald E Greydanus) Joav Merrick (Editor) 2015. ISBN: 978-1-63463-574-5 (Hardcover) 2015. ISBN: 978-1-63463-576-9 (e-book) Child and Adolescent Health Yearbook 2014 Joav Merrick, MD (Editor) 2015. ISBN: 978-1-63482-162-9 (Hardcover) 2015. ISBN: 978-1-63482-206-0 (e-book) Child Health and Human Development Yearbook 2014 Joav Merrick (Editor) 2015. ISBN: 978-1-63482-163-6 (Hardcover) 2015. ISBN: 978-1-63482-207-7 (e-book) Behavioral Pediatrics, 4th Edition Donald E. Greydanus, Dilip R. Patel, Helen D. Pratt, Joseph L. Calles Jr., Ahsan Nazeer and Joav Merrick (Editors) 2015. ISBN: 978-1-63483-027-0 (Hardcover) 2015. ISBN: 978-1-63483-052-2 (e-book) Disability, Chronic Disease and Human Development Joav Merrick 2015. ISBN: 978-1-63483-029-4 (Hardcover) 2015. ISBN: 978-1-63483-057-7 (e-book) Caribbean Adolescents: Some Public Health Concerns Cecilia Hegamin-Younge and Joav Merrick (Editors) 2015. ISBN: 978-1-63483-341-7 (Hardcover) 2015. ISBN: 978-1-63483-343-1 (e-book) Adolescence and Health: Some International Perspectives Joav Merrick (Editor) 2015. ISBN: 978-1-63483-791-0 (Hardcover) 2015. ISBN: 978-1-63483-808-5 (e-book)

Youth Suicide Prevention: Everybody’s Business Hatim A. Omar (Editor) 2015. ISBN: 978-1-63483-786-6 (Softcover) 2015. ISBN: 978-1-63483-820-7 (e-book) Chronic Disease and Disability: The Pediatric Kidney Donald E Greydanus, Vimal Master Sankar Raj, Joav Merrick (Editors) 2016. ISBN: 978-1-63483-793-4 (Hardcover) 2015. ISBN: 978-1-63483-809-2 (e-book) Child and Adolescent Health Yearbook 2015 Joav Merrick (Editor) 2016. ISBN: 978-1-63484-512-0 (Hardcover) 2016. ISBN: 978-1-63484-543-4 (e-book) Child Health and Human Development Yearbook 2015 Joav Merrick (Editor) 2016. ISBN: 978-1-63484-513-7 (Hardcover) 2016. ISBN: 978-1-63484-544-1 (e-book) Pain Management Yearbook 2015 Joav Merrick (Editor) 2016. ISBN: 978-1-63484-515-1 (Hardcover) 2016. ISBN: 978-1-63484-545-8 (e-book) Children and Childhood: Some International Aspects Joav Merrick (Editor) 2016. ISBN: 978-1-63484-587-8 (Hardcover) 2016. ISBN: 978-1-63484-594-6 (e-book) Children and Adolescents: Future Challenges Daniel TL Shek, Tak Yan Lee, and Joav Merrick (Editors) 2016. ISBN: 978-1-63484-616-5 (Hardcover) 2016. ISBN: 978-1-63484-627-1 (e-book)

Adolescence: Positive Youth Development Programs in Chinese Communities Daniel TL Shek, Florence KY Wu, Janet TY Leung, and Joav Merrick (Editors) 2016. ISBN: 978-1-63484-044-6 (Hardcover) 2016. ISBN: 978-1-63484-677-6 (e-book) Sexuality: Some International Aspects Joav Merrick and Donald E Greydanus (Editors) 2016. ISBN: 978-1-63484-707-0 (Hardcover) 2016. ISBN: 978-1-63484-719-3 (e-book) Growing Up in the Middle East: The Daily Lives and Well-Being of Israeli and Palestinian Youth Yossi Harel-Fisch, Ziad Abdeen and Miriam Navot 2016. ISBN: 978-1-63484-746-9 (Hardcover) 2016. ISBN: 978-1-63484-765-0 (e-book) Chronic Disease and Disability: The Pediatric Heart Donald E. Greydanus, Devika Malhotra and Joav Merrick (Editors) 2016. ISBN: 978-1-63484-828-2 (Hardcover) 2016. ISBN: 978-1-63484-842-8 (e-book) Diabetes Mellitus: Childhood and Adolescence Manmohan K Kamboj, Donald E Greydanus and Joav Merrick (Editors) 2016. ISBN: 978-1-53610-095-2 (Hardcover) 2016. ISBN: 978-1-53610-104-1 (e-book) Chronic Disease and Disability: Abuse and Neglect in Childhood and Adolescence Donald E Greydanus, Vincent J. Palusci and Joav Merrick (Editors) 2016. ISBN: 978-1-53610-129-4 (Hardcover) 2016. ISBN: 978-1-53610-142-3 (e-book)

Clinical Aspects of Psychopharmacology in Childhood and Adolescence, Second Edition Donald E. Greydanus, Joseph L. Calles, Jr., Dilip R. Patel, Ahsan Nazeer, and Joav Merrick (Editors) 2016. ISBN: 978-1-53610-241-3 (Hardcover) 2016. ISBN: 978-1-53610-253-6 (e-book) Chronic Disease and Disability: The Pediatric Pancreas Donald E. Greydanus, Manmohan K Kamboj and Joav Merrick (Editors) 2016. ISBN: 978-1-53610-055-6 (Hardcover) 2016. ISBN: 978-1-53610-065-5 (e-book) Child and Adolescent Health Yearbook 2016 Joav Merrick (Editor) 2017. ISBN: 978-1-53610-948-1 (Hardcover) 2017. ISBN: 978-1-53610-957-3 (e-book) Child Health and Human Development Yearbook 2016 Joav Merrick (Editor) 2017. ISBN: 978-1-53610-946-7 (Hardcover) 2017. ISBN: 978-1-53610-958-0 (e-book)

PEDIATRICS, CHILD AND ADOLESCENT HEALTH

CHILD HEALTH AND HUMAN DEVELOPMENT YEARBOOK 2016

JOAV MERRICK EDITOR

Copyright © 2017 by Nova Science Publishers, Inc.

All rights reserved. No part of this book may be reproduced, stored in a retrieval system or transmitted in any form or by any means: electronic, electrostatic, magnetic, tape, mechanical photocopying, recording or otherwise without the written permission of the Publisher. We have partnered with Copyright Clearance Center to make it easy for you to obtain permissions to reuse content from this publication. Simply navigate to this publication’s page on Nova’s website and locate the “Get Permission” button below the title description. This button is linked directly to the title’s permission page on copyright.com. Alternatively, you can visit copyright.com and search by title, ISBN, or ISSN. For further questions about using the service on copyright.com, please contact: Copyright Clearance Center Phone: +1-(978) 750-8400 Fax: +1-(978) 750-4470 E-mail: [email protected]. NOTICE TO THE READER The Publisher has taken reasonable care in the preparation of this book, but makes no expressed or implied warranty of any kind and assumes no responsibility for any errors or omissions. No liability is assumed for incidental or consequential damages in connection with or arising out of information contained in this book. The Publisher shall not be liable for any special, consequential, or exemplary damages resulting, in whole or in part, from the readers’ use of, or reliance upon, this material. Any parts of this book based on government reports are so indicated and copyright is claimed for those parts to the extent applicable to compilations of such works. Independent verification should be sought for any data, advice or recommendations contained in this book. In addition, no responsibility is assumed by the publisher for any injury and/or damage to persons or property arising from any methods, products, instructions, ideas or otherwise contained in this publication. This publication is designed to provide accurate and authoritative information with regard to the subject matter covered herein. It is sold with the clear understanding that the Publisher is not engaged in rendering legal or any other professional services. If legal or any other expert assistance is required, the services of a competent person should be sought. FROM A DECLARATION OF PARTICIPANTS JOINTLY ADOPTED BY A COMMITTEE OF THE AMERICAN BAR ASSOCIATION AND A COMMITTEE OF PUBLISHERS. Additional color graphics may be available in the e-book version of this book.

Library of Congress Cataloging-in-Publication Data ISBN: 9 ISSN: 2152-3770

Published by Nova Science Publishers, Inc. † New York

CONTENTS Introduction Chapter 1

1 Prevention of prenatal maternal stress Joav Merrick

3

Section one: Neonatology

7

Chapter 2

Development: The human nervous system Ndu David Ugobi and Dilip Patel

9

Chapter 3

Neonatal neurology Noa Ofek-Shlomai and Itai Berger

25

Chapter 4

Cardiology and the newborn Monica Martin Goble, Jay Yeh, Johannes von Alvensleben and Chaitanya Panchangam

47

Chapter 5

Neonatal pulmonology Zivanit Ergaz-Shaltiel

91

Chapter 6

Neonatal nephrology Vimal MS Raj

117

Chapter 7

Neonatal hematology Renuka Gera, Roshni Kulkarni, Bradd Hemker and Ajovi Scott

129

Chapter 8

Neonatology and gastrointestinal issues Orhan Atay

151

Chapter 9

Neonatal endocrinology Manmohan K Kamboj and Rohan Henry

165

Section two: Birth rates, slum, leadership and Hong Kong

189

Chapter 10

191

The Greek economic crisis leads to declining birth rates Athanasios Farfaras, John Pateras, Elena Panariti, George Pierrakos, Markus Sarris, Sotiris Soulis and Panagiotis Skolarikos

viii Chapter 11

Chapter 12

Chapter 13

Chapter 14

Chapter 15

Chapter 16

Chapter 17

Contents Health and nutritional status of women and children: An empirical study in the slums of Delhi, India Shradhanvita Singh, Bikram K Pattanaik, Nehal A Farooquee, and Arup Mitra Qualitative evaluation of a credit-bearing leadership subject in Hong Kong Daniel TL Shek, Hung-Kit Fok, Charles TL Leung and Pecky PK Li Focus group evaluation of a subject on leadership and intrapersonal development in Hong Kong Daniel TL Shek, Florence KY Wu, Charles TL Leung, Hung-Kit Fok and Pecky PK Li

199

209

223

A study of time trend in global infant mortality rates: Regression with autocorrelated data Ming Yang and Dejian Lai

237

Dimensionality of the Chinese Parent-Child Subsystem Quality Scale: Confirmatory factor analyses Daniel TL Shek and Moon YM Law

251

Qualitative evaluation of a leadership and intrapersonal development subject for university students in Hong Kong Cecilia MS Ma, Daniel TL Shek, Pecky PK Li, Betty PW Mok and Edvina YK Leung Subjective outcome evaluation of a service leadership subject for university students in Hong Kong Daniel TL Shek, Jianqiang Liang and Xiaoqin Zhu

Chapter 18

Child health status and inequalities in the Indian Sundarbans Nilanjan Patra, and Arnab Mandal

Chapter 19

“I may not know you but I know you’ll make great parents”: An analysis of egg donor profiles Lindsay B. Gezinski, Sharvari Karandikar, Melinda White and Marissa Kaloga

263

273 283

309

Section three: Technology, rehab and special needs

323

Chapter 20

Speech development and therapy using the Kinect Simon Frost and Rachel J McCrindle

325

Chapter 21

The application of enhanced virtual environments for co-located childhood movement disorder rehabilitation Nicholas H Mumford, Jonathan Duckworth and Peter H Wilson

Chapter 22

User evaluation of a virtual rehabilitation system during reaching exercises: A pilot study Mohammad Al-Amri, Daniel Abásolo, Salim Ghoussayni and David Ewins

341

351

Contents Chapter 23

Chapter 24

Chapter 25

Chapter 26

Chapter 27

Cravings in a virtual reality room paired with chocolate predict eating disorder risk Robert S Astur, Andrew W Carew, Alexandra Palmisano, Bonnie E Deaton, Franchesca Kuhney, Rachel Niezrecki and Melissa Santos Virtual reality system for the enhancement of mobility in patients with chronic back pain Benjamin Bolte, Marc de Lussanet and Markus Lappe Virtual reality exposure for trauma and stress-related disorders for city violence crime victims Georgina Cárdenas López, Anabel de la Rosa Gómez, Raúl Durón Figueroa and Ximena Durán Baca Response latencies to postural disturbances when using a virtual reality balance trainer or wobble board in persons with low back pain Imre Cikajlo and Slavica Bajuk Comparing a finger dexterity assessment in virtual, video-mediated, and unmediated reality Jonathan Collins, Simon Hoermann and Holger Regenbrecht

Chapter 28

Effect of the Oculus Rift head mounted display on postural stability Paula Epure, Cristina Gheorghe, Thomas Nissen, Laurentiu O Toader, Alexandru N Macovei, Steven SM Nielsen, Daniel J Rosengren Christensen, Anthony L Brooks and Eva Petersson Brooks

Chapter 29

Kinecting the moves: The kinematic potential of rehabilitationspecific gaming to inform treatment for hemiparesis Stephanie MN Glegg, Chai-Ting Hung, Bulmaro A Valdés Benavides, Brandon DG Kim and HF Machiel Van der Loos

ix

363

371

385

397

409 421

431

Chapter 30

Web accessibility by Morse code modulated haptics for deaf-blind Lena Norberg, Thomas Westin, Peter Mozelius and Mats Wiklund

Chapter 31

Informed design for virtual environments: The impact of object shape on reaching performance Vaughan Powell and Wendy Powell

455

Usability and redesign of a university entrance test based on audio for learners who are blind Jaime Sánchez and Matías Espinoza

465

Chapter 32

Chapter 33

Towards a mobile exercise application to prevent falls: A participatory design process Marlene Sandlund, Helena Lindgren, Petra Pohl, Anita Melander-Wikman Birgitta Bergvall-Kåreborn and Lillemor Lundin-Olsson

443

477

x Chapter 34

Chapter 35

Contents Adapting a humanoid robot for use with children with profound and multiple disabilities Penny J Standen, David J Brown, Joseph Hedgecock, Jess Roscoe, Maria J Galvez Trigo and Elmunir Elgajiji Exploring arm movement pattern to discover strategy changes in a virtual catching task Takehiko Yamaguchi, Naoki Ishiura, Paul Richard, Déborah Alexandra Foloppe, Fabienne Veaux, Mickaël Dinomais and Sylvie Nguyen

489

501

Section four: Break the cycle

513

Chapter 36

Break the cycle annual project: Survey of past students. 2005-2011 I Leslie Rubin, Danielle Oves, Janice Nodvin, Robert J Geller, Maeve Howett, Kurt Martinuzzi, Benjamin A Gitterman, Laura Wells and Joav Merrick

515

Chapter 37

Impact of the home environment on the relationship between prenatal exposure to environmental tobacco smoke and child behavior Madeleine B Hopson, Amy Margolis, Virginia Rauh and Julie Herbstman

Chapter 38

Health disparities and factors that trigger asthma in AfricanAmerican children in low-income communities in Fort Valley, Georgia Jasmine Williams and Saul Mofya

Chapter 39

Impact of housing on pubertal timing Farah Dadabhoy and Maida Galvez

Chapter 40

Racial concentration as a determinant of access to health care in Georgia Shruthi Satyamurthy and Daniel Montanera

Chapter 41

Chapter 42

Chapter 43

A cross-sectional study to assess the relationship between environmental risk factors and malnutrition in children under the age of five living in the Chipata Compound of the Lusaka District, Zambia Chalwe Chanda and Nosiku S Munyinda Effects of heavy metal exposure on endocrine-related hormones in the neonates of Thai mothers working in agriculture Grant A Walter, Parinya Panuwet, Tippawan Prapamontol, Warangkana Naksen, P Barry Ryan, Anne Riederer and Dana B Barr Race, socioeconomic status, and proximity to nuclear power plants in the Eastern United States Christina Sauer, Julie Strominger and Pamela Maxson

531

545 557

571

583

595

605

Contents Chapter 44

Chapter 45

Chapter 46

Chapter 47

In-home interventions to mitigate asthma: Assessing the benefits to children, their caretakers, and the community Justin Babino Implementing community supports to lessen health disparities at kindergarten entry for very preterm survivors Amelia Dmowska, Bree Andrews, Michael Schreiber and Michael E Msall The family check-up in a pediatric clinic: An integrated care delivery model to improve behaviors in the home environment S Courtney Smith, Karen E Schetzina, Jodi Polaha, Katie Baker and David Wood Closing health disparities through a multi-level approach Naeemah Ruffin, Sharon Levine and Cappy Collins

xi

615

633

645

655

Section five: Acknowledgments

673

Chapter 48

About the editor

675

Chapter 49

About the National Institute of Child Health and Human Development in Israel

677

About the book series “Pediatrics, child and adolescent health”

681

Chapter 50

Section six: Index

685

Index

687

INTRODUCTION

In: Child Health and Human Development Yearbook 2016 ISBN: 978-1-53610-946-7 Editor: Joav Merrick © 2017 Nova Science Publishers, Inc.

Chapter 1

PREVENTION OF PRENATAL MATERNAL STRESS Joav Merrick*, MD, MMedSc, DMSc 1

National Institute of Child Health and Human Development, Jerusalem, Israel; 2 Office of the Medical Director, Health Services, Division for Intellectual and Developmental Disabilities, Ministry of Social Affairs and Social Services, Jerusalem, Israel; 3 Division of Pediatrics, Hadassah Hebrew University Medical Center, Mt Scopus Campus, Jerusalem, Israel; 4 Kentucky Children’s Hospital, University of Kentucky College of Medicine, Lexington, Kentucky, United States of America; 5 Center for Healthy, Development, School of Public Health, Georgia State University, Atlanta, United States of America

INTRODUCTION Prenatal maternal stress (PNMS) or prenatal stress is exposure of the expectant mother to distress, like environmental or stressful life events, which can result in hormone or immune system changes in the mother and result in harm to the fetus and later psychosocial development of the child (1). The theory is that glucocorticoids during stress pass the placenta to the fetus and results in long-term reprogramming and dysregulation of the fetal hypothalamic pituitary adrenal (HPA) axis (1). One study of the Iowa floods in 2008 on pregnant women and their offspring two years later showed that PNMS lead to long-term changes in the functioning of the HPA axis (1). Another study with a sample of 54 early adolescents (13 years old) from the 1998 Quebec ice storm showed that stress exposure in their mothers in their third trimester was later associated with increased eating disorder manifestations (2). A recent review (3) looked at maternal prenatal cortisol concentrations and child outcomes (physical/health, cognitive/motor, psychological/behavioral, and cortisol). They *

Correspondence: Professor Joav Merrick, MD, MMedSci, DMSc, Medical Director, Health Services, Division for Intellectual and Developmental Disabilities, Ministry of Social Affairs and Social Services, POBox 1260, IL91012 Jerusalem, Israel. E-mail: [email protected].

4

Joav Merrick

found in the few studies available that maternal cortisol was related to altered child outcomes, but most of the studies did not find significant associations, which might suggest that maternal cortisol may not to be the sole or even main underlying mechanism in the relation between maternal prenatal stress/anxiety and child outcomes (3).

POPULATION BASED STUDIES Prenatal stress associated with preterm birth, low birth weight, peripartum anxiety and depressive symptoms has been shown in epidemiologic studies (4). One study during 19901995 from 11 states in the United States found that 64% of women surveyed reported experiencing at least one stressful life event (SLE), although the prevalence declined slightly over the study period (4). A more recent study (4) used data for the years 2000-2010 and found that most women in the sample reported experiencing more than one SLE in the year before their infant's birth, although the prevalence of experiencing SLE decreased during 2000-2010 (4). In 2010 with data from 27 states, 70.2% of women reported more than one SLEs. The mean number of SLE was 1.81, ranging from 1.41 in New York City to 2.26 in Oklahoma. The most frequently reported life event was financial and younger, less educated, unmarried and Medicaid-covered women had the highest prevalence of SLE (4).

STRESS PREVENTION There are individual and collective stress factors in our lives. Some we are able to prevent and some without our range. A recent review (5) looked at ways to intervene and reduce stress for pregnant women. They found the following intervention studies: group prenatal care, care coordination, health insurance expansion, expanded prenatal education/support in the clinic, home visitation, telephone contact or stress-reduction strategies with group prenatal care the most evidence for prevention (5). These and other studies can be used by public health professionals to increase prevention programs and screening procedures for stressors during pregnancy so that our children can grow up and develop optimally.

REFERENCES [1]

[2]

[3]

Yong Ping E, Laplante DP, Elqbeili G, Hillerer KM, Brunet A, O'Hara MW, et al. Prenatal maternal stress predicts stress reactivity at 2½ years of age: The Iowa flood study. Psychoneuroendocrinology 2015;56:62-78. St-Hilaire A, Steiger H, Liu A, Laplante DP, Thaler L, Magill T, et al. A prospective study of effects of prenatal maternal stress on later eating-disorder manifestations in affected offspring: Preliminary indications based on the project ice storm cohort. Int J Eat Disord 2015 Mar 23. doi: 10.1002/eat.22391. [Epub ahead of print] Zijlmans MA, Riksen-Walraven JM, de Weerth C. Associations between maternal prenatal cortisol concentrations and child outcomes: A systematic review. Neurosci Biobehav Rev. 2015 Mar 17. pii: S0149-7634(15)00063-9. doi: 10.1016/j.neubiorev.2015.02.015. [Epub ahead of print].

Prevention of prenatal maternal stress [4] [5]

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Burns ER, Farr SL, Howards PP. Stressful life events experienced by women in the year before their infants' births: United States, 2000-2010. MMWR 2015;64(9):247-51. Straub H, Qadir S, Miller G, Borders A. Stress and stress reduction. Clin Obstet Gynecol 2014;57(3):579-606.

SECTION ONE: NEONATOLOGY

In: Child Health and Human Development Yearbook 2016 ISBN: 978-1-53610-946-7 Editor: Joav Merrick © 2017 Nova Science Publishers, Inc.

Chapter 2

DEVELOPMENT: THE HUMAN NERVOUS SYSTEM Ndu David Ugobi, MSc, MD and Dilip Patel*, MD, MBA Department of Pediatric and Adolescent Medicine, Western Michigan University Homer Stryker MD, School of Medicine, Kalamazoo, Michigan, United States of America

ABSTRACT An understanding of the basics of neurological development is important for optimal care of newborns, since it helps re-assure the provider when a child is developing within normal limits or alerts to abnormal patterns of development and the need for early intervention. This discussion reviews the most current understanding of the complex processes of development of the human nervous system, with emphasis on making the material readable and easier to comprehend without losing vital content. The pediatrician, the general practitioner or the mid-level provider who cares for newborns and infants will benefit from this summary, but the material will also be a good resource for the neurodevelopmental pediatrician and other experts who need a succinct refresher and update on this topic.

Keywords: development, nervous system, pediatrics, newborn

INTRODUCTION Traditionally, human nervous development has been studied or grouped into three broad chronological categories, namely embryogenic period, fetal period, and post-natal period. Recognized stages in pre-natal brain development include induction, proliferation, migration, differentiation, and synaptogensis while post-natal development can be further divided into the early childhood, childhood and adolescent/young adult stages. *

Corresponding author: Professor Dilip Patel, MD, MBA, Director, Pediatric Clinics, Department of Pediatric and Adolescent Medicine, Western Michigan University Homer Stryker MD School of Medicine, 1000 Oakland Drive, D48G, Kalamazoo, MI 49008-1284, United States. E-mail: [email protected].

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The development of the human nervous system is arguably the most fascinating of known life processes. Brain development is guided by both intrinsic and extrinsic factors. The intrinsic genetic codes predominantly determine form and symmetry and stimulate the neural circuitry for function while extrinsic factors starting early in-utero and continuing throughout life, modulate final brain form, adaptability and function for good or bad. The lengthy process of human brain development begins as early as the third week of gestation when neural progenitors differentiate. It continues through late adolescence and to some extent, throughout our lifespan, with continuous synaptic extensions and pruning. Broadly, primary neurulation (formation of neural tube, excluding those regions caudal to the lumbar region) occurs at week 3 to 4 post-conception, prosencephalic development occurs at 2 to 3 months post-conception, neuronal proliferation and migration between 3 and 5 months, canalization at 3 to 7 weeks; myelination take years to complete while neuronal/ synaptic pruning peaks in adolescence but goes on for life. Simply outlined:    

   





 

The bilaminar (epiblast and hypoblast) embryo becomes trilaminar through gastrulation The ectoderm from the epiblast gives rise to two types of progenitor cells including neuroectodermal cells and epidermal ectodermal cells. A complex cascade of molecular signaling is involved in the differentiation of the embryonic stem cells into neural and other progenitors. The notochord and somites form under the ectoderm and are involved with signaling and patterning of neurulation but do not form any intrinsic part of the nervous system. Next the neural plate forms from a primitive neural area (first seen at about embryonic day 18) in the ectoderm at 3 to 4 weeks post-conception The neural plate then folds into a neural grove and neural crest Next, the neural grove curls into a neural tube, with the neural crest still beside it The neural tube then differentiates into distinct regions (primary vesicles); the forebrain (Prosencephalon), midbrain (Mesencephalon), hindbrain (Rhobencephalon), and the spinal cord. Recent fetal gene expression studies strongly suggest that the regional differentiation of the CNS occurs in response to a genetically determined gradient of signaling by pathways such as the sonic hedgehog. In other words, the amount of signaling and its receptors vary according to the regions of neural tube resulting in differential expression of secondary pathways and key neural characteristics. The three primary vesicles of the brain later give rise to five secondary vesicles as follows:  Prosencephalon: (i) telencephalon - “endbrain, forms cerebral hemispheres, and (ii) diencephalon - “between brain”, forms optic outgrowth  Mesencephalon: mesacephalon  Rhombencephalon: (i) metencephalon - behind brain and (ii) myelencephalon – “medulla brain” The neural crest migration and derivatives occur Ectodermal placodes form components of the special senses, including lens placode, otic placode (otocyst), and nasal placode

Development: The human nervous system   

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The forebrain becomes di-hemispheric, expands to cover the midbrain, and by weeks 28 to 40 expands greatly in surface area via the formation of sulci and gyri. The spinal cord forms with alar and basal plats respectively developing into the dorsal (sensory) and anterior (motor) horns. The canal, ventricles, CSF and blood supply systems form and reorganize

Molecular events, such as gene expression and environmental inputs are essential for normal brain development, which happens within a tightly controlled but continually adapting genetically programmed context. However, neither genes nor environment is believed to bode determinative or definitive outcomes but disruption of either can significantly alter the final neural product. Instead, brain development follows a complicated succession of active, adaptive and neuroplastic processes, which act to promote the appearance and differentiation of new neural structures and functions. Some sources propose that inflammatory and endocrine stress mediators are major factors that influence fetal brain development, by altering key signaling critical pathways, such as the mammalian target of rapamycin, Sonic hedgehog, Wnt (wingless), and reelin signaling. Spanish histologist Santiago Ramon y Cajal (1852-1934) is credited with much of the basics we know about neurons. Cajal described neurons as the basic elements of the nervous system and laid out the life history of cells: birth, differentiation and growth, migration, maturation and death. He also initiated our understanding of their overproduction, pruning in development and interconnection into circuits. There are 8 stages of development, which are sequential for each neuron (see Table 1). However, when considering the entire brain, these stages are all happening concurrently throughout fetal development period. Production of neurons in humans starts at 42 days postconception (Embryonic Day 42) and is almost done by week 20 (mid-gestation). Freshly made neurons do not have axons or dendrites. As they are produced, the migrating neurons are guided by radial neuroglia, maturing as they migrate. On reaching their destinations in different regions of the brain, they make associations, via axons and dendrites, with other neurons resulting in elementary neural networks. Growth cones with their filopodia on the tips of these axons crawl forward as they ramify the axons training behind them in response to chemical cues by chemoattractants and chemorepellants. The major fiber pathways, including the thalamocortical pathway, are complete by the end of the prenatal period. Upon completion, the human brain is realistically estimated to contain; Table 1. Eight stages of development 1. Mitosis/Proliferation 2. Migration 3. Differentiation 4. Aggregation 5. Synaptogenesis 6. Neuron Death/Apoptosis 7. Synapse Rearrangement 8. Myelination

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Ndu David Ugobi and Dilip Patel      

100 billions of nerve cells generated at an estimated rate of up to 250,000 per minute 5 to 10 times as many glial cells (neuronal support cells) Made up of 1,000 different types Organized into 100 different regions With each nerve cell capable of making 10,000 connections with other nerve cells Estimated 3 trillion connections

EMBRYOGENIC PERIOD (CONCEPTION THROUGH 8 WEEKS GESTATION) Primary neurulation The early stages of the central nervous system (CNS) have been traced to the period of the zygote. Approximately day 18 to 21 post-conception, the notochord and chordal mesoderm induce the formation of the CNS by signaling a group of cells in the ectoderm at the dorsal portion of the embryo to form a thick and flat structure called the neural plate. Continuing induction by the chordal mesoderm causes the lateral margins of the neural plate to curl dorsally towards each other until a tubular structure called the neural tube emerges. The first part of the tube to fuse is around the medulla. This happens on about day 22. Fusion then progresses in both rostral (cephalic) and caudal directions, with closure of cephalic end (anterior neuropore) occurring on approximately day 24. The caudal end (posterior neuropore) of the neural tube closes at the upper sacral level on about day 26 as part of a different process called canalization and regressive differentiation, which also features formation of the caudal segments of the spinal cord from the caudal 1/3 of the neural tube. The dura mater and axial skeletal elements result from continuing interaction between the neural tube and neighboring mesoderm. Neural crest cells also appear at the time of the tube closure and later give rise to:            

Sensory ganglia of cranial nerves Dorsal root ganglia Parasympathetic and sympathetic ganglia Schwann cells Cells of arachnoid and pia mater Cardiac neural crest Craniofacial bones and connective tissue Tooth primordial Enteric plexi Thymus, parathyroid, thyroid glands Melanocytes Cells of the adrenal glands

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Details of molecular events involved in the processes above are still being investigated. For the sake of simplicity they include microfilaments (involved in tube formation), cell adhesion molecules (involved in cell-cell and cell-extracellular matrix recognition), signaling by regional patterning genes (especially sonic hedgehog – SHH), homeobox genes, transcription factors, surface receptors and second messengers. Until closure, the lumen of the neural tube, called the neural canal, communicates with the amniotic fluid. As the walls of the neural tube forms the brain and the spinal cord, the neural canal evolves into the ventricular system of the brain and the central canal of the spinal cord.

Secondary neurulation/formation of the caudal tube Secondary neurulation takes place following closure of the posterior (caudal) neuropore and involves the lower sacral and coccygeal regions. It occurs between week 4 and week 7, starting with canalization and progressing to retrogressive differentiation. On about day 28 to 32, the caudal cell mass (a yet undifferentiated mass of cells at the caudal end of the neural tube) becomes vacuolated, coalesces and then enlarges. Soon they come in contact with the central canal. Retrogression of much of the caudal mass starts at about 7 weeks and continues until a little after birth, giving rise to the ventriculus terminalis in the conus medullaris and the filum terminale.

Clinical implications of neurulation Perturbations of the processes involved in primary and secondary neurulation result in neural tube closure defects such as anencephaly and spinal dysraphisms, often with associated axial skeletal aberrations. Pre-natal diagnosis of these defects has become routine, especially with the combination of screening maternal serum alpha fetoprotein (AFP) levels (best done at 16 to 18 weeks) and ultrasonography. Ultrasound could be confirmatory but fetal MRI is assuming greater prominence for confirmation and characterization. Alpha fetoprotein is used as marker because it is the major fetal protein in humans and it can be detected from about day 30 post-conception, peaking in the amniotic fluid by about week 9 to 13. AFP levels will be elevated both in the amniotic fluid and in maternal serum with open neural tube defects as with any open lesion (such as gastroschisis).

EARLY FETAL PERIOD (8 WEEKS TO 20 WEEKS OF GESTATION) Initially, the neural tube is a single layer of cells called germinal epithelium. These neural stem cells are pluripotent and give rise to both the glia and the neurons as interactions with

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notochord and prechordal mesoderm continue under the influence of strong molecular signaling cascades/pathways, which must maintain dorsal-ventral polarity in the neural tube.

Induction The “inductive cascades” can be summarized as follows:  



Segmental - along the length of the neural tube: Hox/Lim gene expression Dorsal identity: nodal pathway involving bone morphorgenic proteins (BMP) from epidermis: roof plate cells in neural tube  TGF-B cascade: cell differentiation (dorsal, sensory neurons)  Dorsalin Ventral identity: Shh pathway involving Sonic hedgehog (Shh) from notochord and retinoic acid from somites: floor plate cells of neural tube  Shh gradient, Patch receptor: cell differentiation (ventral, motor neurons)  BMP-7/chordin interactions.

Unequal rates of growth and migration of cells result in constrictions, flexures, thickenings, invaginations, and evaginations. Three dilations and two constrictions appear at the rostral end of neural tube prior to anterior neuropore closure. These three primary brain vesicles are evident at the 5 mm embryo stage. The three primary brain vesicles/dilatations divide into five secondary vesicles by week five. Marked proliferation of nervous tissue results in curvature of the embryo on its long axis. Continued dorsal curvature results in flexures and in the embryo being raised and isolated from its membranes. The usual sequence of flexures formation is:   

Cervical flexure at junction of the hind brain (rhombencephalon) and spinal cord during weeks 3 to 4 (Mesen)cephalic flexure at the level of the mid brain (mesencephalon): weeks 3 to 4 The Pontine flexure appears in between the above two flexures, following unequal growth of the hind brain. It appears at the junction of the myelencephalon and metencephalon during week 5. The pontine flexure is oriented in a direction opposite that of the cephalic and cervical flexures.

The appearance of the pontine flexure opens the lateral walls of neural tube out like a book, generating the fourth ventricle and causing the sulcus limitans (shallow groove separating the alar and basal plates on either side of the tube) to lie in its floor while the alar plate changes position in this region, from a dorsal to a more lateral orientation. A process called segmentation, which is crucial for the development of several structures and nuclei of the CNS, starts at the 5-vesicle stage of brain development.

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Segmentation Segmentation of the three anterior portions of the brain (telencephalon, diencephalon and mesencephalon) is driven by outward growth from the ventricles. The cortex is the first to grow, but not the first to differentiate. Then follows growth of the limbic areas in a mainly radial direction from the mesencephalon, which at this time, has folded into an inverted U figure. Structures of the telencephalon and diencephalon grow further faster and completely encase the mesencephalon (mid brain) and the anterior portions of the metencephalon (caudal hind brain). The cortex thus ends up the only outer brain structure in the anterior of the head. Segmentation in the hindbrain structures and spinal cord does not occur from the ventricles but from various specialized structures neighboring the neural tube. Cells derived from the neural crest aggregate into eight distinct segments called rhombomeres, which surround the hindbrain (metencephalon and myelencephalon). These segments are believed to determine the organization of the innervation of cranial nerves and nuclei in the hindbrain as well as surrounding non-neural tissues. Segmentation of the spinal cord is determined by non-neural tissues surrounding that section of the neural tube. At about 19 days of gestation, mesodermic tissue forms into a segment grid on each side of the developing and curling tube. These segments, known as somites, proceed to develop into the ribs and vertebrae. They also determine the development and aggregation of neurons into the motor ganglions of the spinal cord. In addition to paired telencephalic evaginations seen about day 29, which later form the cerebral hemispheres, the prosencephalon also gives rise to three other evaginations that develop into the specific structures in the brain: 

 

Optic vesicles, which form the optic nerve and retina. The optic vesicles are first to appear, before the anterior neuropore closes, but becomes more prominent on day 29 at a position just caudal to where the telencephalic evaginations will appear. A midline evagination in floor of forebrain which forms the posterior pituitary gland. Another midline evagination in caudal part of roof of forebrain forms the pineal gland.

The telencephalic evaginations are recognizable as developing cerebral hemispheres by the end of the embryogenic period (week 8). Their outer surface remains smooth until about week 12 when gyri formation is evident, starting from their sagittal portions closest to the falx cerebri. The CNS meninges result from a primordial meninx formed by mesenchymal condensation around the neural tube. The primordial meninx is initially 2-layered: the dura and leptomeninges. Later, a fluid-filled layer forms within the leptomeninges, resulting in the arachnoid and pia maters. The fluid-filled layer is the sub-arachnoid space. Meninges are mostly from mesoderm but parts of the leptomeninges surrounding the forebrain and midbrain are of neural crest origins. All brain structures and nuclei are differentiated between the third and seventh months. See Table 2 for adult derivatives of fetal brain structures.

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Ndu David Ugobi and Dilip Patel Table 2. Adult derivatives of early fetal structures of the human CNS

Neural Tube Brain

Primary Vesicles Prosencephalon

Secondary Vesicles Telencephalon

Diencephalon

Mesencephalon

Mesencephalon

Rhombencephalon

Metencephalon Myelencephalon

Major Adult Structures Rhinencephalon, Amygdala, Hippocampus, Cerebrum (cerebral cortex), Basal Ganglia, lateral ventricles Epithalamus, Thalamus, Subthalamus, Hypothalamus, Pituitary gland, Pineal gland, third ventricle Tectum, Cerebral peduncle, Pretectum, cerebral aqueduct Pons, Cerebellum, fourth ventricle Medulla Oblongata, fourth ventricle

CELL MIGRATION AND DIFFERENTIATION As the gross CNS structures are forming, histologic changes are also taking place in the respective regions of the developing CNS. Upon closure of the anterior neuropore of the neural tube, neuroepithelial cells begin to differentiate into the periventricular germinal layer. This layer will generate both the neuroblasts and glioblasts. Neurons and glia have the same early embryonic origins before undergoing a lengthy multifaceted developmental process of growth, differentiation, interaction and maturation. Neurons appear first as neuroblasts and migrate towards the cortical plate. spongioblasts (glioblasts), which will become the supportive glia, appear a little later except for a special type of developmental glial cell called radial glia, which extend processes from the periventricular layer to the pia matter, thus providing the channels for neuroblasts to migrate out from the proliferating ventricular layer. The radial glial cells are also involved in the ensuing columnar organization and lamination of the CNS. They have been shown by immunohistochemical staining of glial fibrillary acid protein (GFAP) as early as 12 weeks of gestation. The several different types of neuroglia, like radial glia, astroglia (fibrous and protoplasmic), oligodendroglia, microglia (phagocytic glia) and Schwann cells appear at different times in CNS development and have varying functions in the development and maintenance of the central and peripheral neural networks. The multiplying neuroblasts form a layer, peripheral to the neuroepithelial cells, called the mantle layer. Neuronal processes from these neuroblasts extend peripherally from the mantle layer. This collection of fibers forms the marginal layer. Mantle neuroblasts do not migrate but become the corpus striatum of basal ganglia in the brain and the gray matter of the spinal cord.

Spinal cord architecture As the mantle layer neuroblasts proliferate, they organize into dorsal (called alar plates) and ventral (called basal plates) columns on either side. The basal plates differentiate into somatic

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motor neurons of the ventral horn, whose axons exit the spinal cord as the ventral roots of spinal nerves, which innervate voluntary muscles. The alar plate neuroblasts differentiate into association neurons/interneurons, which interconnect the motor neurons of the basal plate and the neural-crest-derived sensory neurons of the dorsal root ganglia. Neuroblast collections between the dorsal and ventral horns in the regions T1 to L2/3 and S2 to S4 form the intermediate/lateral horns and differentiate into the sympathetic and parasympathetic preganglionic neurons. The marginal layer subsequently myelinates and in the spinal cord, becomes the white matter.

Cerebral architecture The periventricular germinal layer remains a dense continuous layer until it begins to slim out at about gestation week 30, after which it becomes a layer of cell islets, which are evident from about 36 weeks of gestation to about 12 months beyond birth. Recent gene expression studies strongly suggest that the capacity for producing neurons from progenitor cells is preserved in the hippocampal region of the human brain, even in adults. This is an area of intense research. In the brain, the 5-layered cerebral cortex is formed when the marginal layer of the 3-layered neural tube is invaded by neuroblasts, which assemble on the outer surface to develop into layered cortical grey matter in an Inside-out laminar pattern. In other words, the deepest cells of cortex are the earliest to form while the neurons arising later migrate to more superficial areas. This also explains why the cerebral grey matter is peripheral to the white matter. The basic ventral-basal and dorsal-alar columnar transformation of the neural tube is maintained in the brainstem but is modified significantly in the rest of the brain. In the forebrain, alar plates become more lateral instead of dorsal, the roof of the neural tube thins out and widens, and in the prosencephalon, the basal plates virtually involutes while alar plates grow. Thus the telencephalon is formed almost entirely from alar plate. Some differentiating neuroblasts, migrate and organize into groups within the brain. These groups are called nuclei and are either motor or sensory depending on whether they originate from basal or alar plates. These include specialized cranial nerve nuclei and other nuclei, which act as relays. The organization and depth of the cerebral hemispheres change over time and structures like the corpus striatum (basal nuclei), temporal lobes and hippocampus become identifiable. The internal capsule (IC) is formed by many of the nerve fibers running from cerebral neurons through the corpus striatum (caudate nucleus and lentiform nucleus), to the thalamus and lower CNS. Each IC lies lateral to the thalamus and medial to the lentiform nucleus. The corpus callosum consists of commissural nerve fibers joining the cerebral hemispheres. The structure that becomes the corpus callosum can be traced back to the dorsal lamina terminalis a small commissure constituting the most rostral midline structure of neural tube. It undergoes a caudal expansion during cerebral hemispheric growth. Also, the hippocampi apparently regress somewhat and the cerebral fissures form. Other commissural structures (linking the hemispheres) include the optic chiasm, the fornix, and the anterior and posterior commissures.

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The olfactory bulbs are formed by anterior projections from the telencephalon. The floors of the cerebral (telencephalic) vesicles are fused with the diencephalon by a thin roof plate, which will give rise to the choroid plexi of lateral ventricles. As in the telencephalon, the basal plates of the diencephalon do not contribute much. As a result, most of diencephalic structures derive from the alar plates. The third ventricle increases in size with growth of the diencenphalon. The alar plate is displaced laterally in this process. Neuroblasts from the most dorsal regions of alar plate form the thalamus while those from the ventral regions form the hypothalamus. Hypothalamic nuclei are mainly involved in the regulation of homeostasis and the management of pituitary gland function. The thalamus is essentially a complex relay of information (including auditory, olfactory and visual) from the lower parts of the CNS and other specialized brain centers to the cerebral cortex. The optic vesicles (developed much earlier, becoming CN II), the infundibulum (forms pituitary stalk and posterior pituituary), and the pineal gland (from a conjoined pair of buds), are all outcrops of the third ventricle. A choroid plexus also forms on the roof of the third ventricle. The typical basal and alar arrangement of the neural core in is largely unmodified in the mesencephalon. A pair of superior and a pair of inferior colliculi, which serve as sensory (visual and auditory, respectively) relays to the cortex, form within the alar plates and are collectively called the tectum. The basal plate of the mesencephalon becomes the tegmentum, in which somatic afferents of the CN III motor nuclei form, along with a smaller nucleus that innervates the sphincter of the pupil. CN IV motor nuclei are formed by neuroblasts which migrated from the metencephalon. The origin of the substantia nigra and red nuclei are uncertain but it is known that they relay visual and auditory information between the tectum and the cerebral cortex. Packs of fiber tracks develop from the marginal layer of the mesencephalon. These are the peduncles, which interconnect the cerebral cortex with the cerebellum and the spinal cord. Unlike in other segments of the brain, the central canal in the mesencephalon does not undergo morphogenic change, except that it narrows significantly due to growth of surrounding structures. This is the aqueduct of Sylvius, relatively prone to congenital stenosis causing obstructive hydrocephalus. Neuroblasts in the myelencephalon develop the somatic afferents of cranial nerves (CN) V to VII in a lateral to medial pattern; special visceral afferents also arise to the taste buds; and the heart and GI tract sensory nuclei. The major relay pair called olivary nuclei are also formed by neuroblasts, which migrate anteromedially. General visceral efferents arise from the basal plate to innervate the involuntary muscles of lungs, heart and GI tract. The special visceral efferents of CN IX to CN XI and somatic efferent of CN XII also form from the myelencephalic basal plates. Maintaining the general basal-to-motor and alar-to-sensory or alar-to-relay organization, the alar and basal plates in the metencenphalon develop the special visceral efferents of the CN V to VII and somatic efferent of CN VII. Three basic motor nuclei, which supply the caudal organs like the submandibular and sublingual glands also arise from basal plates in this region. Three main sensory nuclei are formed from the metencephalic alar plates, including trigeminal and vestibule-acoustic afferents as well special and general visceral afferents. The metencephalon also gives rise to the pons and the cerebellum.

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The formation of the cerebellum derives in large part from the rhombic lips of the pontine flexure. The cerebellum grows significantly towards the end of the embryonic period and by the end of the first trimester, the cerebellar hemispheres are well defined; their surfaces are still smooth and the vermis can be seen developing in the medial raphe. Foliation of the cerebellum starts around week 14 and by week 28, the surface area of the cerebellum has increased 2000-fold, covering the pons and the fourth ventricle in the process. Histologic changes in the cerebellum begin with an internal granular layer formed from germinal cells of the pontine flexure rhombic lip. During weeks 20 to week 30, purkinje cell precursors form a lean lamina separated from the internal granular layer by a clear zone called lamina dessecans, which disappears at about week 30 to 32. Neuroblast proliferation and peripheral migration results in a five-layer cerebellum starting with the formation of the outer granular layer by neuroblasts from the mantle layer of the 3-layer precursor. The outer granular contains cells that multiply the most, differentiate into diverse neuron types and form the cerebeller cortex. Other cell layers also form including the outermost molecular layer, the intermediate Purkinje layer and the innermost granular layer. During proliferation, some neuroblasts form the dentate nuclei and other deep cerebellar structures. Overall morphogenesis of the cerebellum is not finished until about 2 years after birth.

VENTRICULAR AND CSF SYSTEM As highlighted in Table 1, the diamond-shaped lumen of the neural develops into the ventricular system as the respective structural regions of the CNS are formed. The lumen of spinal cord is the central canal, the cavity of the rhombencephalon is the fourth ventricle, and the cavity of the diencephalon is the third ventricle, while the cavities of the cerebral hemispheres are the lateral ventricles. The lumen between the third and fourth ventricles is the narrow aqueduct of sylvius, the lateral ventricles communicate with the third ventricle via the foramina of monro while the fourth ventricle opens into the subarachnoid space through the midline foramen of magendie and the bilateral foramina of luschka. In a normally developed human CNS, the central canal and the ventricles are continuous, allowing the cerebrospinal fluid (CSF) to flow freely within the brain and between the brain and the spinal cord. CSF is produced by the choroid plexi found all through the ventricular system, except that none exists in the frontal or occipital horns of the lateral ventricles or within the cerebral aqueduct (aqueduct of Sylvius). The choroid plexi are essentially a blood-CSF barrier and filtration system made up of a network of blood capillaries and modified ventricular ependymal cells, the ependymal cells having originated from neuroepithelial cells. CSF is absorbed by arachnoid granulations found mainly in the superior sagittal sinus. The rate of CSF absorption matches or slightly exceeds the rate of production to maintain normal CSF pressures. Arachnoid granulations are small outcrops of the meningeal layers into the lumen of the venous sinus. CSF returns from the subarachnoid space into the venous system due to the mechanism of differential fluid pressure, whereby pressure within the subarachnoid space is higher than that within the venous system.

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Functions of the CSF include: shock absorption/protection, transportation of nutrients, hormones and waste, maintenance of intracranial pressure (ICP) and homeostasis. CSF volume auto-adjusts to maintain a normal ICP, until this natural capacity is exceeded.

CNS BLOOD SUPPLY DEVELOPMENT The blood supply and venous drainage of the CNS goes through several changes before maturation. Discussion of the detailed development is beyond the scope of this chapter. In the adult brain, the arterial blood supply is derived from two arterial systems: the carotid system and the vertebra-basilar system. The circle of Willis is a series of an anastomotic channels found at the base of the brain, which allows inter-flow between the two systems. Also in adults, the arterial blood supply to the spinal cord comes from two branches of the vertebral artery, which run the length of the spinal cord and form an irregular plexus around it. These are the single anterior spinal artery and two posterior spinal arteries. For the sake of simplicity, the venous drainage generally mirrors the arterial supply.

CNS GROWTH IN THE THIRD TRIMESTER Advanced image-processing studies have applied complex algorithms and three-dimensional magnetic resonance imaging (3-D MRI) to estimate total brain volumes, along with cerebral gray matter, myelinated /unmyelinated white matter and cerebrospinal fluid in a normally developing brain between gestation weeks 29 and 41. Some studies have involved premature and mature newborns in the same age-range. The studies show that the volume of total brain tissue grew linearly over this period at an average rate of 22 ml/week, with the total grey matter also increasing linearly at a rate of 15 ml/week. Relative to the total intracranial volume, the grey matter grew at approximately 1.4% extra. This rapid growth in total grey matter is equates to a fourfold increase in cortical grey matter over the third trimester. However, both intraventricular and extracerebral CSF volumes did not change significantly during the same period.

POST-NATAL DEVELOPMENT Brain development in the child is a complex process, which includes both linear and nonlinear development in structure and function (Table 3). Normal development and function of the CNS requires proper synaptic formations between neurons and adequate timely myelination of their nerve fibers. Extensive neural network extension and synaptogenesis takes place during the fetal period but a significant amount occurs in the post-natal period. Most myelination occurs after birth, especially during the first two years. Significant positive correlation have been found between cognitive function measures, such as intelligence quotient (IQ), and the volume of regional gray matter in several regions of the brain, including the prefrontal cortex, orbitofrontal cortex, and cingulate gyrus.

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Table 3. Phases of child psycho-motor development relative to brain development Phase Prenatal Infancy Childhood Adolescence and Early adulthood

Age Conception to birth Birth to 2 years old 2 to 12 years 13 to 25 years

Major Development Organogenesis, morphogenesis and Rapid size increase Motor and language development Abstract reasoning Identity, judgment (related directly to maturation of the “Prefrontal Cortex”)

LIFESTYLE AND BRAIN DEVELOPMENT - BREAKFAST HABITS Since the brain continues to develop throughout childhood and adolescence, proper nutrition, including appropriate breakfast habits diet during these periods affect brain development and cognitive function. Recent studies have revealed that eating breakfast has an instant positive effect upon the cognitive function in children studied. It was also shown that skipping breakfast adversely affects the subjects’ short-term memory, problem solving, and attention. Studies of school breakfast programs have also demonstrated the long-term effects of breakfast on cognitive performance, which was overall better in well-nourished children, adjusting for known confounders. Furthermore, a correlation has been found between breakfast staple type, gray matter volume in children and several cognitive functions. Taki and Kawashima recently used advanced imaging to study a large group of healthy children aged 5–18 years and reported that gray matter volume was not only related to daily breakfast habits but also depended on the glycemic index (GI) of the breakfast staple. They posited that foods with low GI when consumed in sufficient amounts were better at providing a more stable supply of glucose to the brain versus high GI foods, which are easily digested low-fiber carbohydrates that provided a rapid peak glycemic rush followed by overall lower circulating blood glucose two hours later. A major fraction of the glucose consumed by the brain is used to maintain the neuronal membrane resting potential. Moreover, cerebral rates of glucose consumption are approximately two times higher in children than in adults, especially in pre-adolescence when the mean number of synapses per neuron increases. As such, stable and efficient supply of glucose, determined by breakfast type, is considered vital for brain maturation in children.

LIFESTYLE AND BRAIN DEVELOPMENT - SLEEP HABITS Although the role of sleep in brain development remains debatable, recent studies strongly suggest that sleep is associated with hippocampal function and structure. One major school of thought is that memory consolidation happens mainly during sleep, when the hippocampus transfers information from the memory to the neocortex for long-term storage.

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Studies in rat have shown suppression of neurogenesis and decreased proliferation of cells in their hippocampus as result of sleep deprivation. A reduction in hippocampal volume has also been found in human patients who suffer primary insomnia. At least one study reports significant correlations between sleep and hippocampal gray matter volume based on MR images of healthy children aged 5–18 years. The study found the volume of the bilateral hippocampal bodies to correlate positively with the length of sleep by each child during weekdays, after adjusting for brain size, gender and other factors. While the mechanism underlying this significant positive correlation is yet to be explained, it is best to apply this finding to clinical practice and ensure adequate sleep in the pediatric patient, noting that this is the period of increased neurogenesis and synaptic reorganization in the human hippocampus.

CONCLUSION The last half-century has witnessed remarkable insights into this area, a growth in knowledge, which derives from the human genome project, recent advances in neuroimaging, computational neurobiology and simulation, and also progress in the time-honored disciplines of histology, cell studies and molecular biology. Dynamic and interactive models of nervous system development are replacing previously-held rigid models. The nervous system continues to develop after birth, significantly depending on the environmental stimulation it receives. A strong persuasion for the potential role of the environment in human brain development is the fact that the human brain volume at birth is only about 35% of an adult brain. Compared to apes, the human baby is about 12 months less developed cognitively at birth but this soon changes as the brain grows and an adult brain ends up with about three to five times the brain capacity of apes, mainly due to an overall increased number of neurons and a larger cerebral cortex (encephalization). Twin-twin and adoption studies support the role of the environment but they also confirm the predominance of genetic factors. Update on the fundamental role of genetic signaling is provided and the impact of environmental influences is emphasized, including intra-partum factors and events as well as post-partum nutrition, home environment, education, toxicology, and early intervention. The steady rise in average performance on intelligence tests over the past few decades, called the Flynn effect, is arguably an environmental effect. The clinician who understands the basics of these complex but critical interactions is better positioned to guide families to the best neurologic outcome possible in each child, in health as well as in disease. As a specific example, understanding brain development in healthy children not only improves our understanding of the progress of brain maturation but also facilitates early evaluation and diagnosis of developmental disorders, including autistic spectrum disorders.

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REFERENCES [1] [2] [3] [4] [5] [6] [7]

Volpe JJ. Neurology of the newborn, 5th ed. Philadelphia, PA: Saunders-Elsevier, 2008. Hill MA. UNSW embryology, 14th ed, 2014. URL:http://php.med.unsw.edu.au/embryology. Stiles J, Jernigan TL. The basics of brain development. Neuropsychol Rev 2010; 20(4): 327-48. Taki Y, Kawashima R. Brain development in childhood. Open Neuroimaging J 2012; 6: 103-10. Moore KL, Persaud TVN, Torchia MG, eds. The developing human, 9th ed. Philadelphia, PA: Elsevier-Saunders 2008. Moscoso G. Early embryonic development of the CNS. In: Levene MI, Chervenak FA, eds. Fetal and neonatal neurology and neurosurgery, 4th ed. London: Churchill Livingstone, 2009: 13-21. GC Schoenwolf, SB Bleyl, PR Brauer, PH Francis-West, eds. Larsen’s human embryology, 4th ed. New York: Churchill Livingstone Elsevier, 2008.

In: Child Health and Human Development Yearbook 2016 ISBN: 978-1-53610-946-7 Editor: Joav Merrick © 2017 Nova Science Publishers, Inc.

Chapter 3

NEONATAL NEUROLOGY Noa Ofek-Shlomai1, MD and Itai Berger2,*, MD 1

Department of Neonatology, Hadassah Hebrew University Medical Center, Jerusalem, Israel 2 The Neuro-Cognitive Center, Pediatric Neurology Unit, Hadassah Hebrew University Medical Center, Jerusalem, Israel

ABSTRACT Neurology of the newborn is an expanding field. The available evidence-based data still have “gaps,” and practical approaches are changing rapidly. There are significant advances in neonatal neurology, reflecting an enormous progress that was made over the past decades in identifying and treating newborn brain diseases. There are still unanswered questions, and newly emerging data is rather the rule than the exception. The explosion of knowledge and interest in basic science and clinical management issues has impacted all the many practitioners involved in newborn care. There are still enormous opportunities for new knowledge through well designed longitudinal descriptive studies and multicenter clinical trials. These complicated situations require cooperation between neonatologists and neurologists. In this discussion we cover relevant sections in newborn neurology that are supposed to serve as a useful tool for professionals with special interests in neurology of the newborn.

Keywords: pediatrics, neonatalogy, neurology, brain development

INTRODUCTION Neonatal neurology requires an interdisciplinary approach that integrates maternal, placental, fetal, and neonatal perspectives into diagnostic and treatment algorithms concerning fetal/neonatal brain disorders (1-3). Most preterm newborns need neonatal neurology care. *

Corresponding author: Itai Berger, MD, The Neuro-Cognitive Center, Hadassah-Hebrew University Medical Center, Mount Scopus Campus, PO Box 24035, IL-91240 Jerusalem, Israel. E-mail: [email protected].

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But they are not the only group. Term babies born with congenital disorders, those who were born to sick mothers or after complicated pregnancies are also in such a need. Four million babies are born per year in the United States and 11% of those are born premature. One percent of term infants have significant illnesses at birth that also require care in the neonatal intensive care unit (NICU) (1). Ante-partum, peri-partum, and postnatal strategies for diagnosis and therapeutic intervention must adjust to the multiple time points and etiologies that define neonatal neurology disorders. Therefore, neonatal intensive care has grown extensively over the past 40 years (1). Currently, neonatology is a cost-efficient mode of intensive care (4). A greater number of infants at smaller gestational ages and weight are now surviving to discharge but this is only one step in a long journey for these small and often medically fragile infants (2). Newborn patients’ brain disorders are unique. The synthesis of historical, clinical, and laboratory data implicate ante-partum, intra-partum, or postnatal time periods when brain damage occurred or was exacerbated. Although the focus during the past decades has been on the saving of lives, it is also important to look beyond survival to issues of reducing morbidity and long-term neurological disabilities, as well as improving long-term developmental outcomes. There are promising interventions that can benefit survival as well as human development, and there is a huge public health needs to integrate these. Linking the agenda for maternal and newborn health with the emerging issues of long-term development, may well be the most appropriate strategy to ensure that we stay the course in solving one of the most important moral dilemmas of our times (3). In this review we discuss the main issues most relevant in newborn neurology care.

NEUROLOGIC EXAMINATION OF THE NEWBORN A comprehensive neurologic assessment should be performed in any newborn suspected to have a neurologic abnormality either based upon history or a physical finding detected during the routine neonatal assessment. Neurologists and neonatologists must frame the neurologic profile of the neonate in the context of the developmental niche (gestational maturity) during which an acquired or developmental disorder evolves. Therefore, every examination should start with estimation and mention of gestational age of the newborn. Several authors have reported assessment of neurological functions in newborn infants (4, 5). Some of these assessments have been adapted and validated for both infants born prematurely or at term. There have been number of publications that describe the newborn neurologic examination in different gestational ages aimed for different aspects (6). As in other age groups, the most relevant aspects of the newborn examination are: mental status, cranial nerves, motor and sensory examination, and the assessment of primitive reflexes (5). These assessments can be easily and reliably used in both term preterm infants. Previously published data can help as a reference when examining newborn infant to see where the individual child stands compared with age-matched newborn infants and to identify signs that may be outside the reported range.

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These assessment methods should be used routinely in the neonatal unit, at least in infants at risk of neurological abnormalities, since these examinations have been used and showed that they can reliably identify infants at risk of developing neurological abnormalities (6, 7). Identifying early neurological abnormalities will allow early intervention, protection, and referral of these infants for rehabilitation and appropriate support for the families (5). A detailed systematic examination method is described in “Neurology of the newborn” textbook by Volpe (4).

NEUROLOGY OF THE SICK NEWBORN Across the human lifespan, an individual faces the greatest risk of mortality during birth and the first 28 days of life, the neonatal period. Each year, nearly 4 million newborns die during this period – equivalent to around 10,000 per day. Three quarters of these deaths take place within one week of birth, and 1–2 million die during the first day following birth. Millions more suffer severe illness each year, and an unknown number are affected with lifelong disabilities (8). Among survivors, small groups of people account for a large proportion of health care costs. Many of these were sick newborn babies. There has been a growing focus on understanding these “high utilizers” because it is thought that improving aspects of care could improve their outcomes, reduce unnecessary health care utilization, and hopefully begin to bend the cost curve trends in health care (9). Complications during the neonatal period can be fatal or result in long-term injuries or disability. The early post-natal period (the first seven days of life) is the critical period for initiating treatment, help and appropriate care. Providing effective care for newborns during the early post-natal period has the potential to generate the greatest gains in survival and health of any period in the continuum of care (8). In the next pages we discuss the most common and/or important medical aspects concerning the sick newborn.

BIRTH INJURIES Birth injuries (BI) are defined as injuries sustained by the newborn during the course of labor (10). There is a wide spectrum of BI, ranging from self-limiting minor problems such as scalp injuries, to severe injuries that may lead to significant morbidity and mortality. The most common types of BI are scalp injuries and clavicle fractures (11). Linder et al. have reported an overall incidence of 24.3 per 1000 live newborns, in a retrospective study of 118,000 singleton newborns over 23 years (10). They reported several risk factors for BI including lower maternal age, lower parity, higher gestational age, higher birth weight, head circumference and length and a higher rate of instrumental deliveries and occipito -posterior position of the fetal head (10). A large cross-sectional study of 890,582 in-hospital birth discharges in the Unites States, estimated an incidence 29 per 1000 births.

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Scalp injuries Caput succedaneum is edema of the fetal head caused by pressure against the uterine cervix or the bony pelvis. This leads to an obstruction of venous return to the scalp and consequent extravasation of fluid into the interstitial tissue (12). On examination there is pitting edema that shifts with gravity and resolves within 48-72 hours after birth.

Cephalohematomas A cephalohematoma is a collection of seroanguinous fluid under the periosteum of the skull bones (13). The hemorrhage is confined by the sutures. The swelling is usually not present at birth, and develops within the first 24-48 hours afterwards. Cephalo-hematomas complicate 0.2–2.5% of all deliveries (14). Higher birth weight, parity and instrumental deliveries (both vacuum extraction and forceps deliveries) have been correlated with cephalohematomas. The main complication of cephalohematomas is hyperbilirubinemia (10) but in rare cases cephalohematomas may become infected, which could lead to osteomyelitis, sepsis and meningitis.

Subgaleal hematoma (SGH) SGH are caused by rupture of the emissary veins, connecting the dural and scalp veins. Blood accumulates between the epicranial aponeurosis and the periosteum. This space extends from the orbital ridge to the nuchal ridge and laterally to the temporal fascia, and can hold up to 260ml of blood in a term newborn. SGH is therefore a potentially life threatening condition which can lead to hypovolemia, hypotension and DIC, and is associated with up to up to 25% mortality in infants requiring intensive care (15). The incidence of moderate to severe SGH is estimated at 1.5/10000 births (15). It is most often associated with instrumental deliveries, but may occur also in spontaneous vaginal deliveries. Optimizing outcome of a newborn with SGH requires early diagnosis; close monitoring of head circumference, blood pressure, hematocrit and coagulation studies and supportive care with fluids and blood products as required. Figure 1 below demonstrates the anatomical layers of the scalp and skull. Please refer to this when reviewing the head injuries discussed above.

Brachial plexus injuries Erb’s palsy, also known as brachial plexus paralysis, results from damage to the cervical roots C5-C8, and T1 resulting in weakness or paralysis of the deltoid, infraspinatus muscles and the flexor muscles of the forearm. The affected arm is held straight and internally rotated with finger function usually left intact. When T1 is involved the infant may also exhibit Horner’s syndrome (16). Incidence of Erb’s palsy is increasing and is estimated at 0.5-4.4/1000 live births (16). Risk factors for Erb’s palsy include macrosomia, shoulder dystocia, gestational

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diabetes mellitus, maternal obesity, and instrumental vaginal delivery (16, 17). Most injuries are transient, with 80-92% recovery (17), however global lesions (C5-T1) have only 40% recovery, and may cause severe disability (16).

Facial nerve palsy Neonatal asymmetric crying facies, is a clinical phenotype resembling unilateral partial peripheral facial nerve paralysis, with an incidence of approximately 1 per 160 live births (18). Causes include perinatal trauma, intrauterine posture, intrapartum compression, and congenital aplasia of the nucleus (most commonly bilateral). Usually the cause is either facial nerve compression or faulty facial muscle and/or nerve development (18). Spontaneous resolution is expected with the former, but not necessarily with the latter etiology. Approximately 10% of the developmental cases have associated major malformations (18). Mandibular asymmetry and maxillary-mandibular non-parallelism of the gums are frequently overlooked visual clues to nerve compression. Ultrasound imaging of facial muscles and electro-diagnostic testing may be useful for differential diagnosis and management (18).

THE FLOPPY NEWBORN In the majority of newborns, hypotonia is often noticed at or soon after birth. The assessment of muscle tone is subjective (19). Neonatal hypotonia can be defined as a decrease of resistance to passive range of motion in joints versus weakness, which is a reduction in the maximum muscle power that can be generated in a newborn. Identifying the underlying cause of neonatal hypotonia remains difficult, despite advances in diagnostic laboratory and imaging techniques.

Figure 1. Anatomic layers of the scalp and skull.

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Clinical evaluation strategies and standardized developmental tests can assist in differentiating hypotonia resulting from primary involvement of the upper motor neuron (central hypotonia) versus that involving the lower motor neuron and motor unit (peripheral hypotonia). The underlying pathology of infantile hypotonia can be divided into four broad categories: the central nervous system (CNS), the peripheral nerves (motor and sensory), the neuromuscular junction, and the muscle (20). Usually the examination helps in the precise localization of lesion in the pathway for motor control (19). In the newborn, the differential must include acute illnesses and systemic diseases such as sepsis and congestive heart failure. To construct a meaningful differential diagnosis and eventually arrive at an appropriate diagnosis, the clinician must ascertain whether the patient is hypotonic or hypotonic and weak together. These may seem to be straightforward determinations but, in fact, are among the more difficult clinical determinations clinicians are called on to make, requiring careful history and examination plus serial examinations to be confident of the result. Based on research evidence, central hypotonia accounts for 60% to 88% of cases of hypotonia, whereas peripheral origins or unknown causes accounting for the balance (21). Disorders causing hypotonia often are associated with a depressed level of consciousness, predominantly axial weakness, normal strength accompanying the hypotonia, and hyperactive or normal reflexes (21). In addition, several congenital disorders that are characterized by hypotonia have both central and peripheral origins. Examples include congenital muscular dystrophy (in which infants have abnormalities of brain formation and central white matter abnormalities on magnetic resonance images), and congenital disorders of glycosylation, which can include cerebellar abnormalities as well as peripheral neuropathy. It is also worth noting that some infants may demonstrate ‘transient’ hypotonia, e.g., those born preterm, those with prenatal drug exposure, or those with acute infectious diseases. Approximately 50% of patients who have hypotonia are diagnosed by history and physical examination alone. To aid in the early diagnosis of hypotonia in the newborn, especially for disorders in which definitive laboratory or imaging tests are not available, clinicians should include a detailed history of the infant, as well as the family’s history, and clinical and developmental assessments. The continued value of clinical assessment of infants with hypotonia, despite the many technological diagnostic advances, cannot be overstated. An appropriate medical evaluation of hypotonia in infants also includes a karyotype, DNA-based diagnostic tests, cranial imaging, serologic tests, electroneuromyography, and muscle biopsy. Several studies state what should be done and what kind of tools and tests are included in the appropriate algorithm (19, 21). Treatment of the infant who has hypotonia must be tailored to the specific responsible condition. In general, therapy is supportive. Rehabilitation is an important therapeutic consideration, with the aid of physical and occupational therapists (21).

Neonatal hypertonia Hypertonia refers to abnormally increased resistance to externally imposed movements around a joint (22). Newborns with brain disorders commonly exhibit abnormalities of muscle tone and posture (23). Hypertonia can be an integral component of many chronic

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motor disorders. These disorders can result from dysgenesis or injury to developing motor pathways in the cortex, basal ganglia, thalamus, cerebellum, brainstem, central white matter, or spinal cord (4). Unlike discussions of hypotonia, a comprehensive approach to neonatal hypertonia is rare. Recognition of specific presentations of hypertonia at the bedside can guide the clinician down a more accurate diagnostic path (23). At least three descriptive terms are associated with different forms of childhood hypertonia: “spasticity,” “dystonia,” and “rigidity” (22). When the injury occurs in children before 2 years of age, the term cerebral palsy is often used. These general phenotypes can be helpful for the clinician when serial examinations are performed on neonates at successively older ages after birth. Some neonates can initially expresses hypotonia during the acute phase of encephalopathy and then later evolves into a hypertonic expression (23). Pathophysiologic mechanisms resulting in hypertonia may also contribute to suboptimal voluntary motor performance or involuntary muscle contractions, and therefore strength, dexterity, coordination, or involuntary movements must be separately assessed. Assessment of deep tendon and tactile reflexes must be carefully recorded. This evaluation is limited for the newborn, but descriptions of motor tone and posture should be compared over serial examinations since the documentation of neonatal hypertonia can assist in a more complete differential diagnosis based on etiology, localization, and timing of injury (23). Several authors have provided a set of definitions and differential diagnosis for the purpose of identifying different components of childhood hypertonia (4, 22, 23). It is clear that physical and neurological examination, combined with laboratory and electrophysiological assessments can provide a more accurate clinic-pathologic correlation with respect to the timing, character, and etiology of injury.

NEURAL TUBE DEFECTS Neural tube defects (NTDs) result from failure of the neural tube to close during the third or fourth week of gestation (24). During embryogenesis the central nervous system develops as a flat sheet of cells, which subsequently rolls up and fuses to form the neural tube. Disruption of this process causes NTDs. NTDs are of the most common birth defects (along with congenital heart anomalies and genitourinary defects, with a worldwide incidence of 1/1000 live births, ranging from 0.2 to 10/1000 in specific geographical locations. Clinical severity of NTDs varies greatly, depending on lesion type and location. Open lesions affecting the brain (anencephaly, craniorachischisis) are invariably lethal before or at birth. Encephalocele can also be lethal depending on the extent of brain damage during herniation. Open spina bifida is generally compatible with postnatal survival, although the resulting neurological impairment below the level of the lesion can lead to absence of sensation, inability to walk, and incontinence. Associated disorders include hydrocephalus, which often needs CSF shunting, Arnold Chiari type II malformation, vertebral deformities, and genitourinary and gastro- intestinal disorders. Closed spinal lesions are generally less severe and can be asymptomatic, as with spina bifida occulta. However, lumbosacral spinal cord tethering can be present in spinal dysraphism, and can lead to lower-limb motor and sensory deficits and a neurogenic bladder (24).

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Both genetic and environmental factors have been implicated in the pathogenesis of NTDs. Although there is an increased recurrence risk for siblings (2-5% risk vs. 0.1% in the general population, most cases are sporadic. Decades of research, including randomized and community based trials demonstrated that exogenous periconceptional maternal folic acid supplementation was found to reduce risk of NTD in the offspring (25). However, as maternal folate levels in most affected cases is within the normal range, NTDs are not the result of a simple vitamin deficiency disorder (26). Studies exploring candidate genes, within and outside of the folic acid pathways, as well as studies of epigenetics are looking at the environmental – genetic combination in NTD pathophysiology.

Anencephaly An invariably lethal condition characterized by absence of the cranial vault and severe defects of the cerebral hemispheres. The cerebellum is usually absent and the brain stem may be hypoplastic. Anencephaly comprises 40% of NTD’s, and is 3 times more common in females. It has been associated with gestational diabetes (24).

Cranioraschisis Anencephaly continuous with complete open spina bifida, an invariably lethal condition, which comprises 3% of NTD and was found to be highly prevalent in north China (24).

Encephalocele Encephalocele is a result of herniation of the meninges, with or without brain tissue through a skull defect. This defect is usually sporadic and comprises 7% of all NTD’s, with a female dominance. Clinical presentation of encephalocele includes a meningeal sac with or without brain tissue protruding from the skull, most commonly located in occipital, parietal or frontoethmoidal regions. Surgical repair is the main treatment, along with treatment of epilepsy and learning disorders, which are common sequelae (24).

Myelomeningocele This most common type of NTD, (50% of NTDs), is mostly sporadic and with no gender predominance (24). There are two main types. A meningocele is a cystic dilatation of the meninges associated with spina bifida and a defect in the overlying skin. The spinal cord and neural roots are normal in structure and there are typically no neurologic deficits. A mylomeningocele is an abnormality in the structure and position of the spinal cord (27). Myelomeningoceles are most commonly thoracolumbar, lumbar or lumbosacral and frequently associated with hydrocephalus (24). The extent of neural tissue involvement determines the severity of the deficit. Typically children with lesions, at L1-L2 or higher will

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be completely paraplegic (27). Surgery should be performed early, within the first 72 hours after birth, or in utero in some centers. The treatment includes surgical closure of the defect and insertion of a ventriculoperitoneal (VP) shunt. Supportive lifelong non-surgical treatment for associated anomalies and deficits is required (24, 28).

Spinal dysraphism Non-fusion of one or more of the posterior arches of the spine most commonly found in the lumbosacral region. This lesion, also called spina bifida occulta, is covered by skin, and an overlying hair tuft, lipoma, hemangioma or other cutaneous lesions may coexist. The defect can be detected radiographically (24). There are no neurological consequences for spina bifida occulta per se, but underlying cord tethering may exist and requires surgery as growth will create traction of the cord.

NEONATAL ENCEPHALOPATHY - HYPOXIC ISCHEMIC ENCEPHALOPATHY The term ischemia refers to the lack of appropriate blood supply to the tissues. Hypoxia is a decrease in oxygen supply (29). Insufficient gas exchange may result in hypoxemia and hypercapnea. The combination of hypoxia and ischemia results in a cascade of biochemical changes including activation of inflammatory mediators, accumulation of oxygen free radicals, extracellular glutamate accumulation. That opens N-methyl-D-aspartate (NMDA) gates and allows an influx of calcium into the cell, therefore causing irreversible neuronal damage. This leads to neuronal cell death and brain damage, and with ongoing exposure and also to multisystem failure (29). Gestational age plays an important role in the changing susceptibility of the cerebral structures to hypoxia and ischemia. While a hypoxic ischemic insult in a preterm infant (up to 36 weeks gestation) will result in mainly white matter damage causing periventricular leukomalacia (PVL), the same insult in a term infant will result in deep grey matter damage; particularly posterior putamen and venterolateral nucleus of the thalamus. The prevalence of hypoxic ischemic encephalopathy (HIE) in term infants is estimated at 1-6/1000 live births. As the definitions are not clear, this estimate includes perinatal asphyxia, HIE and neonatal encephalopathy (30). Neonatal hypoxic ischemic encephalopathy is a clinical syndrome of abnormal neurological behavior in the neonate, which is frequently associated with multi-system dysfunction and follows severe injury before or during delivery. Diagnosis of perinatal asphyxia is based on low Apgar scores (31) (80%) and the hydrophobic surfactant proteins (SP), SP-B and SP-C, but not the hydrophilic SP-A and SP-D, which are removed during the extraction process. Natural preparations resulted in an improved outcome of preterm infants with RDS, fewer pneumothoraces and a reduction in mortality. To date, natural surfactants are the most widely used in neonatal units. Surfactant preparations demonstrate a variety of antiinflammatory and immunomodulatory properties. Chorioamnionitis may initiate an inflammatory cascade resulting in increased vulnerability of the premature lung for postnatal perturbations like oxygen toxicity, mechanical ventilation, patent ductus arteriosus and infections. The inflammatory process may lead to a secondary inactivation of surfactant and the development of BPD. Both natural and synthetic surfactant preparations decreased the release of pro-inflammatory cytokines. Surfactant preparations have been shown to affect the immune response of granulocytes, monocytes, alveolar macrophages, lymphocytes, natural killer cells and lymphokine-activated killer cells and to improve the remodeling processes following lung injury (42). To avoid lung injury infants stabilized on CPAP or non-invasive ventilation can be supplemented with

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surfactant via small diameter tube e.g., arterial catheter or suction or gastric catheter that is introduced through the vocal cords by direct visualization with a laryngoscope (43).

Ventilation strategies Advances in neonatal care have led to increasing survival of very immature neonates, but the improvements in survival have increased the incidence of chronic lung disease in survivors. Mechanical ventilation is lifesaving in critically ill neonates; however it may contribute to lung injury. New ventilation strategies may improve clinical outcomes. Ventilatory strategies to prevent the chronic lung disease bronchopulmonary dysplasia (BPD) are based on reducing the magnitude and duration of mechanical ventilatory support to the minimum possible necessary for achieving adequate gas exchange. This is achieved by redefining the blood gases goals or refining the methods of mechanical ventilation or using alternative techniques. By targeting a higher PCO2, lower oxygen goals and shorter inspiration time, less ventilatory support is needed. A fast ventilation rate with a low tidal volume is preferred to a slower ventilator rate with a larger tidal volume to reduce volutrauma. Numerous strategies that improve ventilatory outcome are: Synchronized intermittent mechanical ventilation: Mechanical breaths are synchronized with the onset of spontaneous inspiration. The positive pressure breath is in synchrony with the end of spontaneous inspiration or when inflation is completed. Respiratory signals used for synchronization include abdominal wall motion, esophageal pressure, thoracic impedance, airway pressure and gas flow. Patient triggered ventilation is a mode of ventilation where every adequate spontaneous inspiratory effort is assisted with a mechanical breath. It provides back-up ventilation in the absence of spontaneous breathing effort or when the inspiratory effort is insufficient to trigger a mechanical breath. Pressure support ventilation is a mode where flow cycling is used to assist every adequate spontaneous inspiratory effort and terminate the mechanical breath as the spontaneous inspiration ends or inflation is completed. Volume targeted ventilation is a modality aimed at reducing high inflation pressure by adjusting the peak pressure or duration of the mechanical breath to maintain tidal volume (44). High-frequency ventilation (HFV) is a form of mechanical ventilation that uses small tidal volumes and extremely rapid ventilator rates. HF oscillation (HFO) and HF jet ventilation (HFJV) or HF flow interruption (HFFI) are the techniques employed (45). Continuous tracheal gas insufflation: nasal continuous positive airway pressure (nCPAP) and heated, humidified high-flow nasal cannula (HHHFNC) are used in the NICU as a mode of non-invasive respiratory support (46) Non-invasive Intermittent pulmonary Ventilation (NIPPV): Synchronization techniques enable delivery of nasal synchronized ventilation. In comparison to nasal continuous positive airway pressure NIPPV reduces chest wall distortion in preterm infants, reduces breathing effort and improves ventilation.

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Prevention of RDS In order to reduce the risk of respiratory distress syndrome (RDS) in newborns, antenatal glucocorticoids have been administered to mothers at risk of premature delivery. The effect of glucocorticoids on the fetal lung is induction of surfactant synthesis and modulating lung development by thinning of the alveolar wall and increasing potential lung gas volume. Glucocorticoids also increase the effectiveness of postnatal surfactant therapy. However, prenatal exposure to glucocorticoids has been linked to cardiovascular, metabolic, and neuroendocrine disorders later in adulthood and multiple courses of antenatal glucocorticoids were associated with increased risk of low birth weight, a smaller head circumference, neonatal sepsis and prolonged adrenal suppression (7). The current recommendations are that women at risk of preterm delivery prior to 34 weeks gestational age should be treated with antenatal steroids. Betamethasone and dexamethasone are both considered effective in preventing neonatal RDS (47).

Air leak syndrome Air leak syndrome results from the collection of air that leaked from the tracheobronchial tree to various body spaces including pulmonary interstitial emphysema (PIE), pneumothorax, pneumome-diastinum, pneumopericardium, pneumoperitoneum, subcutaneous emphysema, and systemic air embolism. The most common cause of air leak is assisted mechanical ventilation with increased incidence in premature infants, neonates with hypoplastic lung, meconium aspiration and pneumonia.

Pulmonary interstitial emphysema (PIE) PIE occurs when air leak into the pulmonary interstitium or the lymphatic and venous circulation. PIE may also be due to rupture at the junction of the bronchiole and alveolar duct. Predisposing factors include prematurity, RDS, meconium aspiration and pneumonia. The diagnosis of PIE is made by chest radiography that shows oval or spherical cystic aircontaining spaces either in localized or diffuse distribution. PIE is usually managed conservatively, with gentle ventilation. Unilateral PIE may be treated by selective intubation of the uninvolved lung.

Pneumothorax Pneumothorax, the presence of gas in the pleural cavity between the visceral and parietal pleura is the most common air leak syndrome. Small pneumothorax may be asymptomatic but some may enlarge with subsequent deterioration of arterial blood gases and increased oxygen or ventilator requirement. Tension pneumothorax occurs when the air collection interferes with ventilation and circulation resulting in hypotension, bradycardia, barrel-shaped chest, and acute abdominal distension. Diagnosis is made by chest radiography but in the case of

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emergency the use of a chest transillumination may help to establish a preliminary diagnosis. In asymptomatic infants with small pneumothorax conservative treatment can be offered. In full-term neonates with small uncomplicated pneumothorax supplementation with 100% oxygen may improve the resolution of pneumothorax by nitrogen washout. Large pneumothorax and pneumothorax accompanied by clinical deterioration should be drained by chest tube insertion.

Pneumomediastinum Pneumomediastinum is air leak into the mediastinal space. The diagnosis is made on a chest radiograph that shows hyperlucent areas around the heart border and between the sternum and the heart border. Management is conservative.

Pneumopericardium Pneumopericardium is the collection of air in the pericardial space. It may cause abrupt onset of hemodynamic deterioration due to cardiac tamponade and be life threatening. It occurs mostly in mechanically ventilated preterm infants suffering from RDS with other air leak phenomena such as PIE and pneumothorax. The diagnosis is by chest radiograph that shows a gas shadow surrounding the heart. Management is mostly conservative and pericardial drainage is only applied in selected symptomatic infants.

Pneumoperitoneum Pneumoperitoneum occurs when extrapulmonary air gets into the peritoneal cavity. It may results from ruptured viscus which necessitate immediate surgical intervention. Treatment of pneumoperitoneum of intrathoracic origin is usually conservative.

Subcutaneous emphysema Subcutaneous emphysema is air leak into the subcutaneous tissue. Diagnosis is done by palpation of crepitations in the face, neck, axillary, or supraclavicular regions. Management is mainly conservative.

Systemic air embolism Systemic air embolism is when the air rupturing from the alveoli enters directly into the pulmonary capillaries and to the heart resulting in circulatory collapse. There is no specific treatment and when a large amount of air gets into the circulation the condition is fatal (48).

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Pulmonary hemorrhage Pulmonary hemorrhage in the newborn may vary from a focal, self-limited disorder to massive, lethal hemorrhage. Pulmonary hemorrhage usually occurs between the second and fourth days of life in infants being treated with mechanical ventilation. Risk factors include prematurity, intrauterine growth restriction, respiratory problems, patent ductus arteriosus, bleeding problems, ventilator usage, surfactant treatment and overwhelming sepsis and endotoxin production. The incidence of pulmonary hemorrhage varies between units ranging between 2.2-27.6% (49). However, it was found in about half of premature infants who died in the neonatal period and suffered from RDS (50). Hemorrhage results from damage to the vascular bed of the lung. Increased pulmonary blood flow can be caused by surfactant therapy that improves lung function and patent ductus arteriosus with left-to-right shunt, but both result in high pressure injuries to the vascular bed. Pulmonary hemorrhage is associated with increased incidence of intraventricular hemorrhage, probably due to alterations in the cerebral blood flow, coagulation disturbances and hypoxia. Diagnosis is made clinically by suctioning of blood tinged fluid from the upper airway. There is no effective emergent management for it except for supportive measures: positive-pressure ventilation, restoring blood volume, correcting hypotension, hypoxemia, acidosis and coagulation disorders.

Pulmonary hypertension Persistent pulmonary hypertension of the newborn (PPHN) is a condition of persistently elevated pulmonary vascular resistance, with right-to-left shunting of blood across the foramen ovale, ductus arteriosus, or both, causing significant hypoxemia. PPHN may be primary or associated with pulmonary morbidity. In the fetus, the placenta serves as the organ for gas exchange. Concurrently, the pulmonary vessels are constricted and the pulmonary and systemic arterial pressures nearly equal, hence 90% to 95% of the cardiac output by-pass the fetal lungs. At birth, the pulmonary artery pressure decreases to half the systemic artery pressure, and pulmonary blood flow increases almost tenfold, due to increased arterial pH and oxygen tension. The physical pulling open of capillaries accompanies lung inflation. The decline in pulmonary vascular resistance is greatest in the first 24 hours after birth and continues to fall over the first two postnatal weeks. Infants suffering with maladaptation fail to decrease the pulmonary vascular resistance despite normal pulmonary arterial number and muscularization. Chronic in-utero hypoxia may cause an increase in medial muscle thickness and PPHN. Decreased number of pulmonary arteries, as seen in pulmonary hypoplasia, congenital diaphragmatic hernia and the oligohydramnios sequence is accompanied by a thickened alveolar septum and alveolar capillary dysplasia. Either intra-uterine perturbations like maternal diabetes, illicit drug use and the use of nonsteroidal anti-inflammatory drugs or perinatal morbidities like perinatal asphyxia and meconium stained amniotic fluid predispose the infant to PPHN. Additionally infants born with RDS, TTN, pulmonary hypoplasia, diaphragmatic hernia and sepsis or pneumonia have increased rates of PPHN. Radiographic findings may reflect the underlying illness. Diagnosis is done by echocardiography showing

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right-to-left shunting across the foramen ovale and or ductus arteriosus, deviation of the atrial septum from right-to-left, right atrial enlargement, and tricuspid regurgitation. Treatment is by correction of the underlying condition, maintaining systemic blood pressure and selectively lowering pulmonary vascular resistance. Systemic blood pressure is maintained by adequate fluids supplementation and inotropic treatment such as dopamine. Pulmonary vascular resistance is lowered by of oxygen supplementation, inhaled nitric oxide (iNO) and prostacycline. iNO increases cyclic guanosine monophosphate (cGMP) production and activates a cascade causing calcium efflux with resultant vascular smooth muscle relaxation. For infants with resistant pulmonary hypertension extra-corporal membrane oxygenation (ECMO) provides cardiorespiratory support until the vasculature recovers. This is especially done in infants suffering from congenital diaphragmatic hernia who often fail to response to iNO. Survival in PPHN varies with the underlying disorder. Increased rate of neurodevelopmental handicaps is probably the result of underlying condition such as birth asphyxia and systemic hypotension (51).

Meconium aspiration Inhalation of meconium causes respiratory distress due to its biophysical properties, including high tenacity and the potent inhibition of surfactant function. It has a toxic effect to the pulmonary epithelium causing a haemorrhagic alveolitis (7). Meconium stained amniotic fluid occurs in about 13% of live birth and of these infants, 4% to 5% develop meconium aspiration syndrome. Meconium contains substances that are chemotactic to neutrophils and activate complement. Once inhaled, migration of meconium down the tracheobronchial tree initially causes obstruction of airways of progressively smaller diameter with “ball-valve” obstruction, with high resistance to airflow in expiration, resulting in gas trapping. The consequence of airway obstruction with meconium atelectasis may cause further deterioration due to hemorrhagic alveolitis and surfactant deficiency. Meconium aspiration occurs in utero or during labor. The volume of fetal lung fluid is regulated by the resistance to lung liquid efflux. The transpulmonary pressure is usually 1-2mm Hg above the amniotic sac pressure due to the elastic recoil of the chest wall. Lung fluid efflux is prevented by high resistance of the upper airways which prevents the lung fluid loss and maintains fetal lung expansion. During fetal breathing movements the larynx dilates, resistance to the fluid efflux decreases allowing fluid efflux (52). Passing meconium in utero may be a sign of fetal stress that led to relaxation of the anal sphincter. The hypoxia and acidosis associated with fetal stress can lead to gasping in utero, resulting in transpulmonary pressure below the amniotic sac and aspiration of the meconium stained amniotic fluid. Pathological findings from cases of severe meconium aspiration show alterations in the pulmonary vasculature, including remodeling and thickening of the muscular walls, suggesting chronic in utero stress. Infants born with severe meconium aspiration syndrome may suffer from resistant pulmonary hypertension. Due to airway obstruction and subsequent development of a one way valve phenomenon there is an increased incidence of air leak syndrome.

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Diagnosis is made by the evidence of meconium in tracheal aspirate and chest radiography which demonstrates areas of patchy atelectasis due to airway obstruction, and areas of over-inflation due to air trapping. During delivery, in the presence of meconiumstained fluid, suctioning of the mouth and trachea should be done if the infant is not vigorous to prevent upper airway obstruction by meconium; otherwise no intervention should be undertaken. Treatment of meconium aspiration syndrome includes mechanical ventilation, antibiotics, iNO, prostacyclines and ECMO in the case of failure of the other treatment modalities (39).

Pneumonia Pneumonia may develop in the antenatal, perinatal, or postnatal period, and the cause varies according to when the infection develops. Pneumonia may be associated with bacteremia, meningitis, abscesses and other infection in other body sites. Intrauterine infection by Rubella, herpes simplex virus, cytomegalovirus, adenovirus, Toxoplasma gondii, varicella zoster and Human immunodeficiency virus (HIV) is associated with congenital pmeumonia. Perinatally acquired infection is mostly bacterial including group B Streptococcus (GBS), Escherichia coli, Klebsiella, Listeria monocytogenes and Chlamydia trachomatis; post natal infection is mostly associated with underlying morbidity and is associated with various pathogens including bacterial, viral and fungal (39). Mycoplasma hominis and Ureaplasma species are associated with premature labor, and chorioamnionitis, causing the exposed neonate to develop pneumonia, bacteremia, meningitis, abscesses, and chronic lung disease (53). Underlying pathology like immotile cilia (54), cystic fibrosis (55) may be rarely associated with pneumonia in the neonatal period. Neonatal pneumonias are often difficult to diagnose since clinical manifestations and laboratory findings are often nonspecific. Additionally radiological evidence of pneumonia may result from non-infectious causes such as RDS, TTN and meconium aspiration. Detection of microorganism by cultures from blood, cerebrospinal fluid and urine has a limited efficacy. Culture and Gram stain of an endotracheal aspirate obtained by aseptic technique as soon as possible after intubation may be diagnostic if taken in the first few hours of life. Serologic and genetic analysis tests are also used to detect specific organisms. Treatment includes antibiotics and supportive care according to the infant’s condition (56).

Respiratory syncytial virus (RSV) bronchiolitis Premature infants are at risk for RSV bronchiolitis. RSV is an ssRNA virus and a member of the Paramyxoviridae genera. Treatments for infants hospitalized with RSV are primarily supportive and aimed at maintaining adequate oxygenation and ventilatory support. Palivizumab, a humanized monoclonal antibody with neutralizing activity against the F protein of RSV given on a monthly basis throughout the RSV season has significant benefit in protecting against RSV hospitalization in premature infants with underlying prematurity, chronic lung disease of infancy and congenital heart disease (57).

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Apnea of prematurity Apnea is the cessation of breathing for more than 20 seconds and may be accompanied by bradycardia and desaturation. It may be central, obstructive or mixed. Central apnea is the cessation of inspiratory efforts; obstructive apnea is the absence of airflow associated with respiratory movements against a closed larynx or pharynx. In preterm infants, mixed apnea is the most frequent. Periodic breathing is an oscillatory pattern of breathing that is characterized by ventilatory cycles of 10-15 seconds with pauses of 5-10 seconds and can be associated with desaturations. Premature infants have central and peripheral mechanisms which control breathing, which are immature so that breathing is both un-sustained and punctuated by frequent respiratory pauses. This respiratory pattern is suitable for fetal life but can be harmful to the premature infant for which breathing is a prerequisite for life. Apnea of prematurity occurs in infants born before 34 weeks gestational age and usually resolves by term. Apneic episodes can be hazardous if associated with intermittent hypoxemia. Chronic intermittent hypoxia increases free radical production and is associated with adverse neurodevelopmental outcome, retinopathy of prematurity and feeding difficulties. Respiratory rhythm is generated in the brain stem by endogenously bursting interneurons that project to premotor inspiratory neurons carrying inspiratory drive throughout the ventral respiratory column, and then to the diaphragm, external intercostal muscles and upper airway muscles. Active expiration is controlled by the retrotrapezoid nucleus/parafacial respiratory group (RTN/pFRG) (58). Premature infants with the lower baseline saturations have a higher number of hypoxic episodes. They often have inadequate end expiratory lung volumes due to excessive chest wall compliance leading to distal airway closure. To compensate for the immature control of breathing preterm infants have a higher respiratory rate then full term infants. Continuous measurements of oxygen saturation are needed for detection of hypoxemia events and for maintaining a safe oxygen saturation target range. Apnea of prematurity is a diagnosis of exclusion. Other reasons for apnea include: sepsis due to up-regulation of inflammatory cytokines that inhibit respiration; central nervous system pathology such as intraventricular hemorrhage and ischemic stroke; metabolic imbalance such as hypoglycemia and electrolyte imbalance. Treatment is indicated to prevent hypoxia. Supplemented oxygen, CPAP, invasive and non-invasive ventilation is used according to clinical indications. Medical treatment is by methylxanthynes mainly by caffeine. Its primary mechanism of action is thought to be blockade of inhibitory adenosine A1 receptors with resultant excitation of respiratory neural output. Caffeine treatment has a beneficial effect in decreasing the rate of BPD and improving neurodevelopmental outcome (59). Doxapram a central stimulant that activates medullary respiratory neurons may be used in the case of caffeine failure (60).

Bronchopulmonary dysplasia (BPD) Bronchopulmonary dysplasia (BPD) was first described in 1967 in premature infants with respiratory distress syndrome (RDS) who developed chronic lung disease after being treated with intermittent positive pressure ventilation and oxygen supplementation. Following the infants it was found that clinically significant respiratory symptoms early in life may have

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lifelong consequences. Today, newborns consistently survive at gestational ages of 23 to 26 weeks and new mechanisms of lung injury have emerged, and the clinical and pathological characteristics of pulmonary involvement have changed profoundly. Hence, bronchopulmonary is defined as an old and new disease evaluated at different time frames (61). Current definition of bronchopulmonary dysplasia is according to gestational age. Old BPD: Infants born above 32 weeks gestation that were oxygen dependent for at least 28 postnatal days; and new BPD: infants born below 32 weeks gestation that were oxygen dependent at 36 weeks corrected age. Infants with old BPD are re-evaluated at the 56 day of life and given similar score as infants with new BPD at 36 weeks: Mild — FIO2-0.21, Moderate — FIO2-0.22-0.29, Severe — FIO2 ≥ 0.30 or continuous positive airway pressure or mechanical ventilation required (62). Old BPD: The infants with old BPD were mostly infants who suffered from severe respiratory failure, received aggressive ventilation, and had a prolonged exposure to high inspired oxygen concentrations. Chest radiography demonstrated severe morphologic changes including emphysema, atelectasis and fibrosis. Histopathology from such infants demonstrated marked epithelial squamous metaplasia and smooth muscle hypertrophy in the airways and in the pulmonary vasculature. The survivors suffered from severe respiratory failure with airway obstruction, pulmonary hypertension, and cor pulmonale (61). New BPD: The new BPD is mostly a developmental disorder. The introduction of antenatal corticosteroids, new methods of gentle and non-invasive ventilation and surfactant replacement therapy allowed the survival of infants born during the canalicular and saccular stages of lung development before alveolarization begins. Even with gentle ventilation oxygen toxicity, volutrauma and barotrauma are hazardous to the immature lung. Additional factors including inflammatory processes due to ante or post-natal infections, persistent ductus arteriosus (PDA), difficulty to provide enough nutrients and genetic susceptibility may aggravate the lung damage. The main histopathological finding is a decrease in alveolar septation and impaired vascular development associated with lung edema, mild inflammatory response, and decrease in surface area for gas exchange. The pulmonary vasculature remodeling includes medial hypertrophy and distal muscularization of small peripheral arteries that can lead to pulmonary hypertension. The disrupted microvascular development decrease VEGF expression by the endothelium of the capillaries and lead to further decrease in alveolization (63). Treatment of BPD is mainly a preventive strategy. Delivery room care should avoid aggressive ventilation during resuscitation. Early surfactant treatment, methylxanthines to promote extubation and the use CPAP or non-invasive ventilation modalities are the main modalities to prevent lung injury. The golden hour concept is to allow optimal postresuscitation care in order to stabilize ventilation, thermoregulation, blood glucose level, fluids homeostasis and sepsis management (64). The aim of active nutritional management is to support a rate of growth that approximates the intrauterine rate of growth and meets the estimated fluid, protein, and energy needed. Since excessive fluid intake in first days of life increase the risk of BPD fluid restriction is indicated to prevent lung edema. Parenteral nutrition is used until full enteral nutrition is achieved. Enriched formulas and supplementation of breast milk with human milk fortifier,

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multi-vitamins and iron supplementations are given to promote growth and prevent nutritional deficiencies and osteopenia of prematurity (65). Diuretics are commonly used in BPD to increase reabsorption of fluid from the lung. Capillary leak from inflammation, infection, ventilator-induced lung injury, or left to right shunting through a patent ductus arteriosus (PDA) may increase pulmonary edema and lead to decreased lung compliance. The two most common diuretics used in BPD are loop diuretics and thiazides. Systemic and inhaled steroids are used to reduce the inflammatory response, decrease airway edema, stabilize capillary leakage and decrease lung fibrosis. Previous reports of poor neurological outcome associated with ante and post natal steroids led to the reservation of the treatment with steroids to the more complicated cases (66). Infants with BPD have pulmonary sequelae during childhood and adolescence. Respiratory syncytial virus (RSV) is one of the most clinically important viruses infecting infants with BPD resulting in severe pulmonary deterioration. A humanized monoclonal antibody directed against the fusion (F) protein given routinely on a monthly basis to premature infants prevents most of these cases (67). Children with BPD exhibit lower average IQ then infants born in corresponding gestational age. Additionally they face academic difficulties, delayed speech and language development, visual-motor integration impairments, and behavior problems (68).

CONCLUSION Normal lung branching in coordination with pulmonary vascular development provides a surface area for adequate gas exchange. Maturation of the lung and associated vasculature allows the transition to air breathing at birth. Congenital malformations may result from primary developmental defect of the lung or secondary to anomalies in other organs. Premature infants suffering from respiratory distress due to immaturity of the lung may suffer from chronic lung disease associated with mechanical ventilation, inflammatory response and genetic predisposition. Integrated approaches to therapy that reflect the basic pathology and treatment options have the promise for better prognosis.

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Zivanit Ergaz-Shaltiel Connell F, Brice G, Jeffery S, Keeley V, Mortimer P, Mansour S. A new classification system for primary lymphatic dysplasias based on phenotype. Clin Genet 2010;77(5):438-52. Ergaz Z, Bar-Oz B, Yatsiv I, Arad I. Congenital chylothorax: clinical course and prognostic significance. Pediatr Pulmonol 2009;44(8):806-11. Connell FC, Gordon K, Brice G, Keeley V, Jeffery S, Mortimer PS, et al. The classification and diagnostic algorithm for primary lymphatic dysplasia: an update from 2010 to include molecular findings. Clin Genet 2013;84(4):303-14. McDonnell MJ, Reynolds C, Tormey V, Gilmartin JJ, Rutherford RM. Pulmonary alveolar proteinosis: report of two cases in the West of Ireland with review of current literature. Ir J Med Sci 2014;18(3):123-7. Citti A, Peca D, Petrini S, Cutrera R, Biban P, Haass C, et al. Ultrastructural characterization of genetic diffuse lung diseases in infants and children: a cohort study and review. Ultrastruct Pathol 2013;37(5):356-65. Jain L, Eaton DC. Physiology of fetal lung fluid clearance and the effect of labor. Semin Perinatol 2006;30(1):34-43. Liggins GC. The role of cortisol in preparing the fetus for birth. Reprod Fertil Dev 1994;6(2):141-50. Hillman NH, Kallapur SG, Jobe AH. Physiology of transition from intrauterine to extrauterine life. Clin Perinatol 2012;39(4):769-83. Warren JB, Anderson JM. Newborn respiratory disorders. Pediatr Rev 2010;31(12):487-95. Turell DC. Advances with surfactant. Emerg Med Clin North Am 2008; 26(4): 921-8, viii. Rojas-Reyes MX, Morley CJ, Soll R. Prophylactic versus selective use of surfactant in preventing morbidity and mortality in preterm infants. Cochrane Database Sys Rev 2012;3:CD000510. Bersani I, Kunzmann S, Speer CP. Immunomodulatory properties of surfactant preparations. Expert Rev Anti Infect Ther 2013;11(1):99-110. Herting E. Less invasive surfactant administration (LISA) - ways to deliver surfactant in spontaneously breathing infants. Early Hum Dev 2013;89(11):875-80. Hummler H, Schulze A. New and alternative modes of mechanical ventilation in neonates. Semin Fetal Neonatal Med 2009;14(1):42-8. Lampland AL, Mammel MC, The role of high-frequency ventilation in neonates: evidence-based recommendations. Clin Perinatol 2007;34(1): 129-44, viii. Yoder BA, Stoddard RA, Li M, King J, Dirnberger DR, Abbasi S. Heated, humidified high-flow nasal cannula versus nasal CPAP for respiratory support in neonates. Pediatrics 2013;131(5):e1482-90. Wapner R, Jobe AH. Controversy: antenatal steroids. Clin Perinatol 2011;38(3):529-45. Jeng MJ, Lee YS, Tsao PC, Soong WH. Neonatal air leak syndrome and the role of high-frequency ventilation in its prevention. J Chin Med Assoc 2012;75(11):551-9. Chen YY, Wang HP, Lin SM, Chang JT, Hsieh KS, Huang FK, et al. Pulmonary hemorrhage in very low-birthweight infants: risk factors and management. Pediatr Int 2012;54(6):743-7. van Houten J, Long W, Mullett M, Finer H, Derleth D, McMurray B, et al. Pulmonary hemorrhage in premature infants after treatment with synthetic surfactant: an autopsy evaluation. The American Exosurf Neonatal Study Group I, and the Canadian Exosurf Neonatal Study Group. J Pediatr 1992;120(2 Pt 2):S40-4. Rothstein R, Paris Y, Quizon A. Pulmonary hypertension. Pediat Rev 2009; 30(2):39-46. Davis RP, Mychaliska GB. Neonatal pulmonary physiology. Semin Pediatr Surg 2013;22(4):179-84. Waites KB, Schelonka RL, Xiao L, Grigsby PL, Novy MJ. Congenital and opportunistic infections: Ureaplasma species and Mycoplasma hominis. Semin Fetal Neonatal Med 2009;14(4):190-9. Losa M,Ghelfi D, Hof E, Felix H, Fanconi S. Kartagener syndrome: an uncommon cause of neonatal respiratory distress? Eur J Pediatr 1995; 154(3):236-8. Al-Khadra ES, Chau KW,Barone CP, Colin AA. Invasive pneumonia and septic shock in infants as a presentation of cystic fibrosis with vitamin-deficiency. Pediatr Pulmonol 2012;47(7):722-6. Nissen MD, Congenital and neonatal pneumonia. Paediatr Respir Rev 2007;8(3):195-203. Krilov LR. Respiratory syncytial virus disease: update on treatment and prevention. Expert Rev Anti Infect Ther 2011;9(1):27-32.

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Feldman JL, Del Negro CA, Gray PA, Understanding the rhythm of breathing: so near, yet so far. Ann Rev Physiol 2013;75:423-52. [59] Di Fiore JM, Martin RJ, Gauda EB, Apnea of prematurity--perfect storm. Respir Physiol Neurobiol 2013;189(2):213-22. [60] Yost CS. A new look at the respiratory stimulant doxapram. CNS Drug Rev 2006;12(3-4):236-49. [61] Baraldi E, Filippone M. Chronic lung disease after premature birth. New Engl J Med 2007;357(19):1946-55. [62] Bancalari E, Claure C. Definitions and diagnostic criteria for bronchopulmonary dysplasia. Semin Perinatol 2006;30(4):164-70. [63] Jobe AH. The new bronchopulmonary dysplasia. Curr Opin Pediatr 2011; 23(2):167-72. [64] Bhandari A, Panitch HB. Pulmonary outcomes in bronchopulmonary dysplasia. Semin Perinatol 2006;30(4):219-26. [65] Biniwale MA, Ehrenkranz RA. The role of nutrition in the prevention and management of bronchopulmonary dysplasia. Semin Perinatology 2006;30(4):200-8. [66] Baveja R, Christou H. Pharmacological strategies in the prevention and management of bronchopulmonary dysplasia. Semin Perinatol 2006; 30(4):209-18. [67] Chu HY,Englund JA. Respiratory syncytial virus disease: prevention and treatment. Curr Top Microbiol Immunol 2013;372:235-58. [68] Anderson PJ, Doyle LW. Neurodevelopmental outcome of bronchopulmonary dysplasia. Semin Perinatol 2006;30(4):227-32.

In: Child Health and Human Development Yearbook 2016 ISBN: 978-1-53610-946-7 Editor: Joav Merrick © 2017 Nova Science Publishers, Inc.

Chapter 6

NEONATAL NEPHROLOGY Vimal MS Raj, MD Department of Pediatric Nephrology, Children’s Hospital of Illinois, Peoria, Illinois, United States of America

ABSTRACT This discussion is a review of neonatal nephrology geared toward the practitioner in the newborn nursery. First, basic embryology and physiology of the newborn kidney are explained. Then there is a discussion of the more common problems encountered in the neonatal period including hydronephrosis, abdominal mass, and failure to thrive of renal origin. Infection and electrolyte imbalance are also quite common in the newborn period and this summary considers their etiology and management. Finally, information is given regarding several congenital anatomic problems with which the practitioner should be familiar.

Keywords: pediatrics, neonatology, newborn, nephrology

INTRODUCTION Kidneys are vital organs with a complex morphogenesis. Functional development of kidneys continues until 2 years of life after birth. Developmental abnormalities of the kidneys account for almost 50% of cases of end stage renal disease (ESRD) in the United States. The following is a brief review on development, physiologic changes and some common neonatal renal pathology.



Correspondence: Vimal MS Raj, MD, Department of Pediatric Nephrology, Children’s Hospital of Illinois, 530 NE Glen Oak Ave, Peoria, IL 61637, United States. E-mail: [email protected].

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RENAL DEVELOPMENT Mammalian kidneys follow a complex evolutionary process. In humans there are three stages in renal development. Pronephros and mesonephros are rudimentary kidneys that start rostrally and progress to metanephros caudally. The rudimentary kidneys disappear towards the end of the first trimester. Induction of the metanephros starts at 5 weeks of gestation and this involves ureteric bud invagination of the metanephric mesenchyme. Several important genes including PAX2, WT-1 and signaling pathway including Glial derived neurotrophic factors (GDNF) are involved in the initial cross talk between the ureteric bud and metanephric mesenchyme. Kidneys formed initially are in the pelvic region and ascend up to their abdominal location by about 10 weeks of gestation. Around the same time urine generation is initiated as well. Nephrogenesis continues until 34 to 36 weeks of gestation. Babies born prematurely might continue to form new nephrons but different factors including IUGR, NICU mortality and morbidity might affect the ultimate total. The number of functioning nephrons (nephron endowment) varies significantly and follows a bell shaped curve in the normal population. The range for nephron endowment varies between 300,000 to 1 million in each kidney. There are many studies linking a reduced nephron endowment early in life with hypertension (1) and vulnerability to secondary renal insults in adulthood (2).

PHYSIOLOGY OF THE NEONATAL KIDNEY Fetal urine formation increases from 2 ml/hour at 20 weeks of gestation progressively up to 26 ml/hr by the end of 34 weeks contributing to the amniotic fluid (3). Babies with decreased amniotic fluid secondary to renal agenesis, exposure to angiotensin blockers or with bilateral renal obstruction will have the Potter (oligohydramnios) sequence. If the oligohydramnios is severe babies can be stillborn with characteristic facial features including flattened nose, prominent bilateral epicanthal folds and low set ears with wide pinnae. Most of these babies suffer from severe lung hypoplasia which contributes to mortality. There are skeletal malformations including prominent bilateral club feet and bowing of legs. After birth multiple changes occur in renal physiology. Rapid increase in glomerular filtration rate (GFR) occurs with increase in mean arterial pressure and decreased renal vascular resistance. But when compared to adults GFR within the first week of life is only 40 ml/min/1.73m2 and reaches adult equivalent (120 ml/min/1.73m2) at 2 years of age. Serum creatinine which is a measure of GFR is elevated in the first days of life as it mainly reflects maternal creatinine levels and reaches newborn value of 0.4 ± 0.02 mg/dl at 2 weeks of life. The Schwartz formula is used in calculation of GFR from serum creatinine in children 14.16%.

Multilevel logistic regression analysis Table 3 shows the estimated log-odds coefficients from the unadjusted and adjusted multilevel logistic regression models with no interactions. Across all models, tertiles of proportion NHB, proportion Hispanic, and proportion in poverty were significantly associated with close proximity to a nuclear power plant. Unadjusted models (models 1 through 3) indicated that block groups characterized by a medium or high proportion NHB or Hispanic were more likely to be in close proximity to a nuclear power plant compared to those characterized by a low proportion. In contrast, compared to block groups characterized by a low proportion in poverty, those characterized by a medium or high proportion in poverty were less likely to be in close proximity to a nuclear power plant. In the adjusted model with no interactions (model 4), the estimated log-odds coefficients did not substantively change, except for proportion NHB, which decreased in magnitude. Based on nested likelihood ratio tests, we found evidence of all two-way and three-way interactions (likelihood ratio test

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comparing model 6 to model 5: 𝜒 2 = 47.20, 𝑝 < 0.001). As including the three-way interaction (model 6) resulted in an improved model fit, subsequent interpretation of stratumspecific associations will focus on model 6.

Figure 1. Eastern United States block groups located within a 30-mile buffer of a nuclear power plant. Generated using ArcMap 10.1.1.

Non-Hispanic black and proximity to a nuclear power plant Table 4 presents the stratum-specific odds ratios. Within the low Hispanic stratum, the odds of proximity to a nuclear power plant among block groups with a high versus low proportion NHB appeared to increase with increasing poverty. In fact, in the low Hispanic and low poverty stratum, high proportion NHB appeared protective (OR, 0.81; 95% CI, 0.68-0.97). In contrast, among block groups within the high Hispanic stratum, estimated ratios for high versus low proportion NHB appeared protective independent of poverty. Further, the estimated ratios for high and medium proportion NHB (compared to low proportion) were similar. In the medium Hispanic stratum, patterns in associations were less clear.

Hispanic and proximity to a nuclear power plant Across NHB stratum, the odds of proximity to a nuclear power plant among block groups characterized by high versus low proportion Hispanic appeared to increase with increasing poverty. Interestingly, within the high NHB and low poverty stratum, the estimated odds of being proximate to a nuclear power plant among block groups characterized by a medium

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versus low proportion Hispanic (OR, 1.48; 95% CI, 1.22-1.81) were larger than the odds associated with a high versus low proportion Hispanic (OR, 1.18; 95% CI, 0.97-1.44).

SES and proximity to a nuclear power plant Within the low NHB stratum, medium or high proportion in poverty appeared protective, except when proportion Hispanic was high. In fact, in the low NHB and low Hispanic stratum, a high proportion in poverty appeared very protective (OR, 0.39; 95% CI, 0.34-0.46), while in the low NHB and high Hispanic stratum, this protection waivered (OR, 0.98; 95% CI, 0.83-1.17). Associations within the medium NHB stratum were similar, except when proportion Hispanic was high. When proportion Hispanic was high, a medium proportion in poverty appeared protective (OR, 0.88; 95% CI, 0.80-0.98). Within the high NHB stratum, estimated ratios for high versus low proportion in poverty appeared protective only when proportion Hispanic was medium. Further, within the high NHB and high Hispanic stratum, the estimated odds of being proximate to a nuclear power plant among block groups characterized by a high versus low proportion in poverty were 1.27 (95% CI, 1.13-1.42).

DISCUSSION In the Eastern United States, certain impoverished and minority communities are at an increased risk of living in close proximity to a nuclear power plant. Communities with characteristics outside of those defined by Reference Man (white, male and young adult) are more likely to reside in close proximity to a nuclear power plant. Since all radiation emission standards are based upon Reference Man, the majority of the populations around nuclear power plants are not being protected. Thus, in order to protect those who are (a) most vulnerable to the effects of ionizing radiation and (b) most likely to reside in close proximity to a nuclear power plant, we recommend that Reference Man be redefined as Reference Most Vulnerable. Reference Most Vulnerable will ensure that the standard upon which radiation emissions levels are calculated will protect the health of all individuals regardless of their racial or socioeconomic background throughout the United States. Our study was not without limitations. First, we used 2013 poverty data with 2010 racial composition data, as the American Community Survey replaced the census long form and the census no longer collects poverty or income information. Second, we looked at racial and SES disparities in the population surrounding operating nuclear power plants. As nuclear power plants that have been closed or decommissioned also emit low levels of ionizing radiation, it may be of interest in the future to include closed and decommissioned nuclear power plants in the study. Additionally, we did not take into account natural and built environmental effects or population count. Although we found block groups characterized by a high proportion NHB to be protective when proportion Hispanic and proportion in poverty were concentrated, this may speak to confounding caused by urban/rural status, as large cities not in close proximity to a nuclear power plant contain areas of concentrated poverty and minority status. Further studies should examine this relationship by urban rural status. Due to

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certain block groups being located in large cities that contain concentrated areas of high disadvantage and high proportion minority, our next step is to perform an analysis stratified by rural and urban areas. Finally, future studies should consider whether the 30-mile buffer zone encompasses all individuals exposed to low levels of ionizing radiation and if the individual level would be more precise. Table 3. Log odds coefficient estimates (betas) and 95% confidence intervals (CIs) in models of proximity to a nuclear power plant (N = 103,517)

% NHB

Tertile

Model 1 Beta (95% CI)

Low Medium

0 [Reference] 0.15*** (0.11, 0.19) 0.15*** (0.10, 0.19)

High % Hispanic

Low Medium

Low Medium

0 [Reference] -0.25*** (-0.30, -0.21) -0.16*** (-0.20, -0.12)

High

Intercept

Model 3 Beta (95% CI)

0 [Reference] 0.29*** (0.25, 0.33) 0.44*** (0.40, 0.49)

High % in poverty

Model 2 Beta (95% CI)

-1.80 (-2.38, -1.23) 1.75

-1.93 (-2.49, -1.36) 1.69

-1.57 (-2.15, -1.00) 1.76

Model 4 Beta (95% CI) 0 [Reference] 0.04* (-0.004, 0.08) 0.08*** (0.03, 0.13) 0 [Reference] 0.27*** (0.23, 0.32) 0.46*** (0.41, 0.51) 0 [Reference] -0.28*** (-0.33, -0.24) -0.25*** (-0.29, -0.20) -1.79 (-2.35, -1.23) 1.65

Between state variation Log likelihood -46579.2 -46418.3 -46528.7 -46306.1 Degrees of 4 4 4 8 freedom (df) Abbreviations: CI, confidence interval. * P < 0.1, ** P < 0.05, *** P < 0.01. Likelihood ratio tests comparing models 1, 2, 3, and 5 to model 4, respectively [𝜒 2 , 𝑝 − 𝑣𝑎𝑙𝑢𝑒]: 546.23 (p < 0.001), 224.55 (p < 0.001), 445.2 (p < 0.001), 352.52 (p < 0.001). Likelihood ratio test comparing model 6 to model 5 [𝜒 2 , 𝑝 − 𝑣𝑎𝑙𝑢𝑒]: 47.20 (p < 0.001). Low, medium, and high represent the following tertile categories: proportion NHB - < 2.68%, 2.68% - 18.43% and > 18.43%, proportion Hispanic - 10.87%, and proportion in poverty - < 3.66%, 3.66% - 14.15%, and > 14.16%.

Table 4. Stratum-specific odds ratios (ORs) and 95% confidence intervals (CIs) for close proximity to a nuclear power plant OR (95% CI) by tertiles of % Hispanic and % in poverty % Hispanic low % Hispanic medium % in poverty % in poverty % in poverty % in poverty % in poverty low medium high low medium % NHB Low Medium

1 [Reference] 1 [Reference] 1 [Reference] 1.10 1.58*** 1.30** (0.98, 1.26) (1.39, 1.81) (1.04, 1.61) High 0.81** 1.72*** 1.92*** (0.68, 0.97) (1.49, 1.98) (1.65, 2.25) OR (95% CI) by tertiles of % NHB and % in poverty % NHB low % in poverty % in poverty % in poverty low medium high % Hispanic Low 1 [Reference] 1 [Reference] 1 [Reference] Medium 1.09* 1.97*** 1.64*** (1.00, 1.19) (1.77, 2.20) (1.34, 2.00) High 1.41*** 2.96*** 3.53*** (1.25, 1.59) (2.58, 3.40) (2.91, 4.28)

% NHB low % Hispanic low % in Poverty Low 1 [Reference] Medium 0.45*** (0.41, 0.50) High 0.39*** (0.34, 0.46)

% in poverty high

% Hispanic high % in poverty % in poverty % in poverty low medium high

1 [Reference] 1.01 (0.91, 1.13) 1.14** (1.00, 1.29)

1 [Reference] 1.28** (1.06, 1.55) 1.37*** (1.16, 1.62)

1 [Reference] 0.84*** (0.74, 0.95) 0.68*** (0.58, 0.78)

1 [Reference] 0.78*** (0.69, 0.89) 0.74*** (0.65, 0.85)

% NHB medium % in poverty % in poverty low medium

% in poverty high

% NHB high % in poverty low

% in poverty % in poverty medium high

1 [Reference] 1.48*** (1.22, 1.81) 1.18* (0.97, 1.44)

1 [Reference] 1.30*** (1.12, 1.51) 1.28*** (1.10, 1.48)

1 [Reference] 1.17*** (1.05, 1.30) 1.60*** (1.46, 1.76)

% NHB high % Hispanic low

% Hispanic medium

% Hispanic high

1 [Reference] 0.96 (0.78, 1.18) 0.93 (0.78, 1.12)

1 [Reference] 0.84** (0.73, 0.97) 0.74*** (0.64, 0.84)

1 [Reference] 1.04 (0.91, 1.18) 1.27*** (1.13, 1.42)

1 [Reference] 1.02 (0.93, 1.11) 1.10 (0.97, 1.25)

% Hispanic medium

% Hispanic high

1 [Reference] 1 [Reference] 1 [Reference] 1.00 1.26*** 1.62*** (0.89, 1.13) (1.10, 1.44) (1.32, 2.00) 1.07 1.46*** 2.24*** (0.95, 1.21) (1.28, 1.67) (1.86, 2.69) OR (95% CI) by tertiles of % NHB and % Hispanic % NHB medium % Hispanic % Hispanic % Hispanic low medium high

1 [Reference] 0.82*** (0.74, 0.91) 0.59*** (0.51, 0.70)

1 [Reference] 0.95 (0.81, 1.10) 0.98 (0.83, 1.17)

1 [Reference] 0.65*** (0.56, 0.75) 0.46*** (0.38, 0.56)

1 [Reference] 0.82*** (0.74, 0.90) 0.75*** (0.65, 0.85)

1 [Reference] 0.88** (0.80, 0.98) 0.96 (0.87, 1.06)

1 [Reference] 0.82** (0.70, 0.96) 0.87* (0.75, 1.01)

Abbreviations: OR, odds ratio; CI, confidence interval. * P < 0.1, ** P < 0.05, *** P < 0.01 Low, medium, and high represent the following tertile categories: proportion NHB - < 2.68%, 2.68% - 18.43% and > 18.43%, proportion Hispanic - 10.87%, and proportion in poverty - < 3.66%, 3.66% - 14.15%, and > 14.16%.

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In conclusion, although our study was limited, it does elucidate a flaw in the current radiation protection standards. Our results suggest that certain disadvantaged and minority communities in the Eastern United States are at an increased risk of being located near a nuclear power plant, indicating that these communities are also at an increased risk of being exposed to low levels of radiation emitted from a nuclear power plant. As the current radiation protection standard is based on a white, adult male, Reference Man should be expanded to consider characteristics of the most vulnerable in these impoverished and minority communities.

ACKNOWLEDGMENTS The preparation for this paper and project were supported Rebecca Anthopolos and Nicki Sandberg of the Children’s Environmental Health Initiative at the University of Michigan’s School of Natural Resources and Environment.

REFERENCES [1] [2] [3] [4]

[5] [6] [7]

[8] [9] [10] [11]

[12] [13] [14] [15] [16]

Bullard R. Unequal protection: Environmental justice and communities of color. San Francisco, CA: Sierra Club Books, 1997. Mangano J. Excess infant mortality after nuclear plant startup in rural Mississippi. Int J Hlth Serv 2008;38(2). Gray S, Edwards S. Miranda M. Race, socioeconomic status, and air pollution exposure in North Carolina. Environ Res 2013;126:152-8. Cousins E, Karban C, Li F, Zapanta M. Nuclear power and environmental justice: A mixed-methods study of risk, vulnerability, and the victim experience. Comprehensive exercise. Carelton, MN: Carleton College, 2013. Sherman D. Critical mechanisms for critical masses: Exploring variation in opposition to low-Level radioactive waste site proposals. Mobilization 2011; 16(1):81-100. Alldred M, Shrader-Frechette K. Environmental injustice in siting nuclear plants. Environ Just 2009;2:1-11. Sermage-Faure C, Lauroier D, Goujon-Bellec S, Chartier M, Guyot-Goubin A, Rudant J, et al. Childhood leukemia around French nuclear power plants: The Geocap study, 2002-2007.” Int J Cancer 2012;131(5):E769-80. Kaatsch P, Spix C, Jung I, Blettner M. Childhood leukemia in the vicinity of nuclear power plants in Germany. Deutsches Arzteblatt Int 2008;105(42):725-32. Jablon S. Cancer in populations living near nuclear facilities. JAMA 1990;265:1403. National Academy of Sciences. Health risks from exposure to low levels of ionizing radiation: BEIR VII Phase 2. Washington, DC: National Academies Press, 2006. Makhijani A, Smith B. Thorne M. Science for the vulnerable setting radiation and multiple exposure environmental health standards to protect those most at risk. Takoma Park, MD: Institute Energy Environmental Research, 2006:1-107. National Academy of Sciences. Analysis of cancer risks in populations near nuclear facilities. URL: http://nas-sites.org/cancerriskstudy/. Nuclear Regulatory Commission. Operating nuclear power reactors by location or name, Updated 2015. URL: http://www.nrc.gov/info-finder/reactor/. Gonyeau J. The virtual nuclear tourist, 2011. URL: http://www.nucleartourist.com. United States Census Bureau. 2010 Census, 2011. URL: http://www.census.gov/2010census. United States Census Bureau. 2013 population estimates, 2013. URL: http://www.census.gov/.

In: Child Health and Human Development Yearbook 2016 ISBN: 978-1-53610-946-7 Editor: Joav Merrick © 2017 Nova Science Publishers, Inc.

Chapter 44

IN-HOME INTERVENTIONS TO MITIGATE ASTHMA: ASSESSING THE BENEFITS TO CHILDREN, THEIR CARETAKERS, AND THE COMMUNITY Justin Babino, BA Center for the Comparative Study on Metropolitan Growth, Collage of Law, Georgia State University, Atlanta, Georgia, United States of America

ABSTRACT Improving substandard housing conditions will reduce pediatric exposure to asthma triggers, which can achieve a broad range of valuable public health objectives. These objectives include: reducing costs to families with asthmatic children, diminishing significant burdens on the health care delivery system, reducing the number of asthmatic attacks, ER visits and hospitalizations, cutting school absences, and lowering the incidence of parents’ lost work days. In-home interventions supplement the health care strategies that directly address asthma’s symptoms and effects. Implemented in selected cities throughout the country beginning in 2008, the Green and Healthy Homes Initiative (GHHI) introduced a comprehensive program of in-home interventions to integrate lead hazard control and healthy homes with weatherization and energy efficiency improvements. The GHHI attempted to address the health and energy efficiency characteristics of a home through a holistic intervention model, and as a secondary effect reduced asthma triggers in homes. This paper evaluates GHHI’s Atlanta, Georgia inhome intervention services to assess the ways in which this intervention strategy improved health as well as economic and social outcomes for minority low and moderate income families through healthier, more energy efficient and safer homes. Based on interviews we completed concurrent with analysis of the participants’ pre and postintervention experiences, this evaluation of the GHHI program suggests high participant interest, but an indeterminate follow-up concerning the specific issue of the GHHI program’s success in eliminating in-home asthma triggers.



Correspondence: Justin Babino, BA, 5864 Cobblestone Creek Cir, Mableton, GA 30126, United States. E-mail: [email protected].

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Keywords: asthma, intervention, in-home intervention, healthy home, public health

INTRODUCTION Among Americans, asthma continues to be a significant public health and economic concern. It is one of the most common chronic diseases affecting American children, the third leading cause of preventable hospitalizations, and one of the chief causes of school absenteeism. In Georgia, there are about 259,000 children living with asthma, and the prevalence of asthma in black children (18.4%) is more than two times higher than in white children (7.8%) (2). Asthma incurs high costs, in terms of the direct cost of care, lost workdays and productivity, and lower quality of life for the individual and the family. However, asthma not only burdens the individual and the family, but is onerous to society as a whole. For example, in 2010 asthma related hospitalizations cost the State of Georgia approximately $200 million (2). There are myriad factors associated with asthma that may result in exacerbation of asthmatic episodes, leading to unnecessary visits to the emergency department and, in some cases, hospitalization. These include: lack of access to pediatric physicians and specialists, a lack of family education on the best practices for managing childhood asthma, and lower quality of the indoor home environment. Americans spend 90% of their time indoors, two-thirds of which is spent in the home. Thus, children have extensive exposure to indoor allergens. For children living in substandard or unhealthy housing conditions, this means that their health outcomes are at even greater risk of being affected adversely, because indoor triggers of asthma are typically encountered more often in poor quality housing stock. One study reports that 40% of asthma cases in low income, minority children result from allergens in the home (3). In-home interventions break the link between unhealthy housing and sick children by reducing or eliminating indoor allergens that trigger asthma. This strategy benefits children, their caretakers, and the community by improving child health and development, boosting school attendance rates and adult work productivity, reducing healthcare costs for society, and decreasing racial and economic health disparities. The paper examines the Green and Healthy Homes Initiative’s in-home intervention program, which aimed in-part at eliminating in-home triggers of asthma. The Atlanta GHHI program did not conduct a comprehensive post-intervention analysis to evaluate the efficacy of its in-home interventions targeted at asthmas triggers. Perhaps this is because the interventions were primarily targeted at reducing lead hazards and not at asthma triggers. According to the GHHI staff person who primarily oversaw the Atlanta program, there were 170 lead hazard reduction implementations and 163 health and safety interventions (4). Nonetheless, using pre and post-intervention interview data that we have collected, our review of GHHI’s work helps demonstrate that a relatively modest investment to improve inhome systems and conditions could yield significant benefits for families that are beneficiaries of the interventions and, as result, likely generates significant savings in healthcare costs.

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Objective This study was undertaken to assess the estimated cost savings to a health care system by employing in-home interventions with an environmental focus aimed at reducing exposure of children with asthma to multiple indoor asthma triggers (allergens and irritants). From the data derived from Atlanta post-intervention reviews, we are trying to ascertain outcomes for children with asthma and their families. In addition, we aim to use information concerning these outcomes to consider potential citywide and statewide effects. We hypothesize that homes in poor state of repair benefit from in-home interventions more than homes in a relatively good state of repair. Furthermore, we posit that in-home interventions will reduce the likelihood of acute exacerbations of asthma, reduce emergency department visits and hospitalizations, reduce school absenteeism, reduce lost work days and productivity, and improve the quality of life for children with asthma and their families as well as provide significant medical cost savings.

Design This is a pilot study based on GHHI participants’ anecdotal reports concerning their experience with in-home interventions aimed at helping eliminate in-home asthma triggers. We did not intend to extract medical reports, count school absences, or verify the participants’ statements. Rather, the purpose of the study was to investigate whether participants in the GHHI Atlanta program perceived any benefits in conjunction with their participation in the GHHI program. We sought to understand whether or not those who participated in the program recognized a change in their status, positively or negatively. Initially, a total of 40-50 participants were targeted for this study; however, due to challenges encountered in obtaining participant contact information, we were able to locate only 12 participants, and collect information from 8 of them, through visits to their homes and request for brief interviews. Data were obtained from a survey questionnaire prepared and administered by the researcher with assistance. Institutional review board approval was obtained from Georgia State University for this study. Participants were recruited from internal records of the Green and Healthy Homes Initiative’s implementation. Former GHHI participants provided consent for the collection of the information examined in this study.

METHODS In an effort to understand the health and economic benefits of the in-home interventions implemented by GHHI in Atlanta, we sought to build on the body of work that already existed in the measurement of asthma outcomes obtained from the pre and post-intervention surveys administered under GHHI. Therefore, we designed a questionnaire, to be administered in-person or telephonically, based on participants’ recall. This questionnaire was modeled after the GHHI post-intervention survey. From the questionnaire, we sought to understand what circumstances, if any, changed in the lives of the participants due to GHHI. The questionnaire also sought to ascertain how the participants perceived their health and

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well-being before and after GHHI. Further, we asked participants whether they believed the GHHI program made a difference in their lives. For example, we asked the participants to consider, both before and after the GHHI intervention, how many days per month the child missed school because of his or her asthma; how many days per month the child’s asthma caused the parent(s)/caretaker(s) to miss part of or a full day of work; and how many times per month was the child’s asthma responsible for taking the child to the physician’s office, urgent care, emergency department, and/or asthma related hospitalizations. Additionally, the questionnaire was designed to understand who bore the health system’s cost for asthma emergency department visits/hospitalizations before and after the GHHI program. Eligible participants were recruited from a partial set of records of the GHHI Atlanta implementation. We planned to contact the GHHI recipients via telephone or email to set up an initial interaction. However, the available records of the GHHI implementation listed only the physical street address of the recipients, and further information was not able to be obtained from GHHI. As a result, we chose instead to contact potential participants in person and visit twenty-six homes [26] where pediatric asthma was present in an effort to conduct the interviews in-person. Yet, we were able to locate only 12 participants where pediatric asthma was present, and collect information from 8 of them. Essential to this research project was determining the age, size, and quality of the homes occupied by the GHHI participants. Physical housing characteristics (i.e., number of bedrooms and bathrooms, availability of air conditioning or central air systems, year built, total and assessed value, square footage, etc.) for-forty six of the GHHI homes were obtained through the Fulton County Board of Assessors website. To compare the quality of housing stock occupied by GHHI participants with surrounding housing stock, census tract data describing housing characteristics was obtained by accessing the United States Census Bureau website. We used the data from the pre and post GHHI surveys and the physical characteristics obtained from the Fulton County Board of Assessors website to run an analysis using Microsoft Excel (see Tables 1, 2 and Figure 1). Census data from 2011 shows that the housing stock information in Atlanta (Atlanta, Sandy Springs, Marietta) is as follows: median year built is 1989; median square footage per unit is 2,200; percentage with central air is 94.2%; housing inventory includes 1,263,200 total units: 58.1% owner-occupied, 29.4% renter-occupied; owner-occupied housing units with 4+ bedrooms is 43%; owner-occupied housing units with 2+ bathrooms is 90% (5). What that census data seems to tell us about our GHHI housing stock is that it is much older than average, much smaller, and generally does not contain the preferred market amenities. For example, many homes have just one bathroom while census data suggests two is standard. There were a total of 49 addresses (all in Fulton County, Georgia) on the pre and postsurvey records. However, there were three addresses for which the researcher was unable to gather information (i.e., physical characteristics) from the Fulton County Tax Assessor’s site. According to the GHHI data, the homes that we were unable to get the physical characteristics for were homes that reported having no occupants with asthma. Additionally, for one of the homes that reported having occupants with asthma the record was duplicated in the pre and post GHHI data. In essence, that means that instead of twenty seven households with self-reported asthma, there were actually twenty six out of forty eight homes where asthma was present. Next, there were two sets of records that had the same street number and name, but different zip codes. For example, 123 ABC St. Atlanta 30310 and 123 ABC St. Atlanta 30315

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and 789 XYZ St. Atlanta 30314 and 789 XYZ St. Atlanta 30331. We decided to pull information for the home in the 30315 zip code, which was built in 1952, as opposed to the home located in 30310, which was built in 2007. This particular home reported not having any occupants with household asthma. By selecting the older home, this did not change the median age for homes without asthma; the median age remained 1945. However, by selecting the older home, it did impact the median square footage per unit for homes without asthma. The home built in 1952 was 1,000 square feet as opposed to the 2007 home that was 2,556 square feet. Selection of the newer home changes the median square footage of homes without asthma to 1,218 square feet; Table 1 reports this figure as 1,161 square feet, which was slightly smaller than the median square footage for homes with asthma. For the next set, we chose the home in zip code 30314, which was built in 1948. The other home in zip code 30331 was built in 1940. This particular home reported having occupants with asthma. Under the improvement information on the Fulton County Tax Assessor site, to figure out whether there was central air conditioning (A/C) present in the homes, we looked under the heating system and heat columns. We noted that the heating system column either had: “”Warm air,” “Electric,” or “None.” The heat column either had: “Central with A/C,” “Central,” or “Non central.” For every address that listed “Central with A/C” or “Central” under the heat column, we marked the home as having central A/C. On the other hand, for every address that concurrently listed “Non Central” under the heat column and “”None” under the heating system column, we marked the home as not having central A/C. Lastly, in order to get a comprehensive assessment of the situation, we contacted the following entities or organizations to access previous data on this area of study: Executive Director of the GHHI and a signatory/funder for the GHHI at the Annie E Casey Foundation; health scientist at the Centers for Disease Control (CDC); and a children’s environmental health coordinator and asthma program coordinator at the Environmental Protection Agency (EPA), Region 4.

RESULTS In an effort to identify whether any significant relationship existed between the in-home interventions and the condition of participants’ housing stock, we researched information about the age, size and amenities of participants’ homes. A significant finding over the study period was that the housing stock information for the GHHI homes program is as follows: median year built is 1950; median square footage per unit is 1,166; percentage with central air is 80.4%; median number of bedrooms was three; median number of bathrooms is 1. Additional data concerning housing characteristics is shown immediately below in Table 1.

Results of interviews We visited 12 out of 26 (46%) of the homes that reported having occupants with asthma. When cross referenced with the GHHI pre-assessment data, the twelve homes visited reported having a total of 18 asthmatic occupants, nine of which were children under the age of 18. However, based on participants’ answers to interview questions C-5 and C-6, GHHI Atlanta

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and Asthma Outcomes Questionnaire in the appendix section, the interviews show that three asthmatic children were unaccounted for (one child each for three different homes). We were not able to get any information or make contact with resident(s) for four of the addresses visited because two individuals declined to participate in the interview; one home had a pit bull tied to the front entrance; and another home was vacant. However, despite the relatively small sample size, based on five interviews we completed concurrent with analysis of the participants’ pre and post-intervention experiences, this evaluation of the GHHI program suggests high participant interest, but a likely absence of follow-up concerning the specific issue of the GHHI program’s success in eliminating in-home asthma triggers. For example, three of the five (60%) participants informed us that GHHI did not perform a post assessment survey. Table 1. Characteristics Median (Med) year built Med year built with asthma Med year built without asthma Med total value of all homes Med total value of homes with asthma Med total value of homes without asthma Med assessed value of all homes Med assessed value of homes with asthma Med assessed value of homes without asthma Med sq. footage per unit of all homes Med sq. footage per unit of homes with asthma Med sq. footage per unit of homes without asthma Med # of bedrooms for all homes Med # of bedrooms for homes with asthma Med # of bedrooms for homes without asthma Med # bathrooms for all homes Med # bathrooms for homes with asthma Med # bathrooms for homes without asthma % of all homes with a/c (37/46) % of all homes with a/c and asthma (24/27) % of all homes with a/c without asthma (13/19)

1950 1950 1945 $28,000 $33,000 $21,700 $11,200 $13,200 $8,680 1166 1166 1161 3 3 3 1 1 1 80 89 68

Four out of five participants (80%) reported that the GHHI program helped them. Only one participant reported that GHHI did not affect her either positively or negatively. See Question D-8, GHHI Atlanta and Asthma Outcomes Questionnaire in the appendix section. Some of the participants’ answers to this question include: “The program helped my family as well as others on my street…especially those that can’t afford it.” One participant stated, “The initiative helped us…my granddaughter has asthma and I notice the difference when she visits now. She doesn't have any issues.” Another participant stated, “I wasn't even aware how much better off we are until you asked me these questions.” This participant also stated that she got rid of her carpet and dog as part of her family’s asthma management plan prior to the GHHI implementation, because her children would miss one to two days of school per month

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and adult(s) would miss six partial and fifteen full days of work per month due to the children’s asthma. Additionally, she reported that before GHHI, pediatric asthma resulted in taking the children to the physician and/or urgent care two times per month, the emergency department two times per month, and one hospitalization per month. The participant further shared that before GHHI, she spent five to seven hundred dollars for asthma related health care costs. She went on to state that, “Before GHHI, my children were not doing well in school. But after GHHI, my children are doing ‘very good’ in school, I don’t have health care cost, there aren’t any more school absences, and no missed days of work.”

Figure 1. GHHI homes sorted by decade.

We learned from the interviews that two of the GHHI participants had to leave their homes for three weeks during the implementation. One participant with one asthmatic child in the home before and after the implementation shared that GHHI installed insulation in November 2012. Another participant with two asthmatic children in the home before and after the implementation shared that in March 2014 GHHI sealed the home, performed lead remediation around the doors and windows, and treated mold in the basement. Both participants stated that the program accommodated their families in a hotel during the implementation. Other participants shared that GHHI’s weatherization and energy efficiency improvements included: installation of ceiling fans, air purifiers and dehumidifiers, installation of exterior lighting, sealing of cracks in the home, and remediation of lead inside and outside of the home (e.g., lead paint removal from the porch). From the information obtained from the interviews, we were able to reconcile some of the GHHI pre and post assessment data, which is reflected in Table 3. After our interviews and adjustments for incorrect, duplicate, and/or incomplete GHHI records, the data derived shows that 26 out of 48 of the homes (54%) prior to the in-home interventions had occupants with asthma. Twenty-three out of 26 of the homes (89%) had children under 18 years of age with asthma. Specifically, during the pre-intervention assessment a total of 59 household occupants reported asthma symptoms, 34 of them children (57.6%). This study does account for homes that reported having more than one child with asthma. The age range for the children extended from 1 to 18 years, the mean age being 7.8 years (median age 6 years).

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Other changes noted in the interview data table also shows that in a twelve month period before the interventions, pediatric asthma in 34 children was responsible for: 24 (previously 22) (10) urgent care/physician visits; ten (previously 9) emergency department visits; and 8 hospitalizations (11). Additionally, in a thirty day period, pediatric asthma for this sample of children caused: 97 or more uses of asthma medication (12); 19 nights of interrupted sleep; 212 (previously 210) days of missed school; and 41 (previously 20) days of missed work by adults. Sixteen out of 26 homes with asthma (62%) reported that Medicaid bore health system cost for asthma related visits and hospitalizations. No insurance information was reported for the remaining 10 out of 26 homes with asthma (32%). On the post-assessment data, in a twelve month period after the interventions, pediatric asthma in 34 children was responsible for: Two urgent care/physician visits; no emergency department visits; and no hospitalizations. Additionally, in a thirty day period, pediatric asthma for this sample of children caused: seven uses of asthma medication; three nights of interrupted sleep; no days of missed school; and no days of missed work by adults. Some information in the post-intervention assessment data section is presumed to have stayed the same. However, this does not take into consideration factors such as recipients who might have moved prior to GHHI performing the post-intervention assessment or incomplete data. Our interviews and reconciliation of the GHHI intervention results are set forth immediately below in Table 2.

DISCUSSION The GHHI developed as an opportunity to break the link between unhealthy housing and sick children. The initiative was designed to establish national housing standards and programs that implement a holistic housing approach that combines comprehensive environmental assessments and single stream interventions in the areas of: lead hazard reduction, Healthy Homes, weatherization, and energy efficiency. By blending healthy home dollars with energy efficiency dollars, GHHI is able to achieve a fourfold set of benefits: 1) More efficient use of public dollars; 2) the creation of sustainable green jobs; 3) healthier, more energy efficient homes and 4) better health outcomes for children in terms of reducing asthma, household injury and poisonings (6). Regarding the rationale for selection, the GHHI staff person who oversaw the Atlanta implementation shared that there was a broad outreach program for the GHHI. This outreach included: educational events, school events, city advertising through MARTA buses and trains, billboards, radio broadcasts, and canvassing of neighborhoods. The majority of the outreach occurred in City of Atlanta Neighborhood Planning Units (NPU’s) V, T, and R. Several of these neighborhoods were targeted because they had “ideal” homes, meaning due to the age of the homes it was suspected that they would have lead paint. According to the GHHI staff person, the selection for GHHI was mostly self-selection, meaning the applicants most often applied after viewing advertisement about the program (4). GHHI staff handed out literature on how to eliminate in-door asthma triggers (4). Additionally, the program’s asthma focus was the installation of air purifiers, MIRV 8 filters, mold remediation, carpet removal, and mattress and pillow covers. He explained that asthma interventions cost approximately $500 per home and require relatively low-level skills (4).

Table 2. Relation to asthma # of homes w/asthma occupants

# of homes w/ children under 18 w/asthma

# of children with asthma

Avg. Age

# of UC/ clinic visits

# of ER visits

# of asthma related hospitalizations

# of times rescue inhaler or nebulizer used

# of nights that child was up in the middle of the night

# of missed days of school/ daycare

# of total days of work missed by adult(s)

Who bore health system cost for asthma ER visits/ hospitalizations

Pre-Intervention Asthma Assessment

26

23

34

7.8

24

10

8

97+

19

212

41

Post-Intervention A Asthma Assessment

16 Medicaid 10 not reported

26

23

34

7.8

2

0

0

7

3

0

0

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Participants had to submit required documentation to prove that they owned the home. If they rented, then they had to submit documentation from the landlord that he/she owned the property. Furthermore, participants had to submit proof that children lived in the home. Additionally, participants had to submit income statements and, if they did not work, then proof of unemployment was required. Notably, asthma was not a requirement for eligibility to participate in the program. Also, we learned from an interview with a GHHI staff member that filling out the pre or postassessment survey was not required (4). Perhaps this explains why the sub-set of data we received from GHHI was incomplete. According to the GHHI staff person who oversaw implementation of the Atlanta in-home interventions, the relatively low yield of data resulted from the fact that he had difficulty contacting the recipients (e.g., recipients would not return GHHI’s calls, they had moved, etc.) (4). The data listed in Table 1 shows that the homes with asthma are marginally newer and larger. Our hypothesis that homes in poor state of repair benefit from in-home interventions more than homes in a relatively good state of repair could not be validated because of an unsubstantiated correlation between the age and size of the GHHI housing stock and the state of repair. We were unable to find out whether there is a presumptive rule of thumb that suggest houses of a certain size (i.e., 1200 sq. ft. or less) or age (i.e., 50 years or older) are “substandard” (due to size, presence of lead paint, asbestos, etc.). However, there is literature that suggest that unsafe and unhealthy housing (i.e., those marked with elevated levels of dust mites, mice allergens, mold spores, water damage, inadequate insulation and air leakage) results in housing-based illness like asthma (5, 6). Furthermore, the data in Table 1 shows that the homes with asthma had a higher total and assessed value than the homes without asthma. Also, the percentage of homes with asthma and A/C is higher than the percentage of homes without asthma and A/C. We noted that for air circulation, the homes visited relied on air conditioning (non-central or central), open windows, and electric fans. Although the homes without A/C have a lower incidence of pediatric asthma, perhaps this so because they rely on open windows for air circulation. Older homes that rely on A/C may circulate asthma triggers throughout the system, hence retaining and exacerbating in-door allergens and irritants. However, a possible limitation regarding the home circulation is that just because a home reports “Central” heat may not mean that there is also central air conditioning. This became obvious when we were doing field interviews and noted that one of the homes listed as having central A/C, based on Fulton County Tax Assessor information, in fact had a few window air conditioning units. Thus, the percentage of GHHI homes with central A/C may be overstated. Further, because we were not able to visit every address in the data set to confirm whether they had central A/C, the data analysis is limited with respect to knowing for sure this particular physical characteristic of the properties. While this analysis sought to evaluate the cost benefit of GHHI’s Atlanta, Georgia inhome intervention services, it is important to note that the information reported is limited. Although the data listed in Table 2 shows dramatic changes, we were not able to calculate the estimated cost of the interventions versus the major benefit to the health for minority low and moderate income families and to the cost savings of the health care delivery system. Unfortunately, we were not able to interview all 26 homes that reported having children with asthma and we have no way of knowing for sure how accurate and reliable the pre and post GHHI records are. For example, the post-assessment records reported that one home had one

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asthmatic child living in the home after the implementation, but the participant stated there were two. Another home was reported as having no children under 18 years of age with asthma and there was one. Moreover, two of the homes that participated in the GHHI preassessment were not accounted for in the GHHI post-assessment due to relocation and death. However, we inadvertently visited the homeowner that GHHI reported as deceased and learned that the homeowner was not deceased, but had lived there for nineteen years and recalled the GHHI implementation. We also visited the home GHHI reported as a relocation and this home was vacant. This study is limited by the retrospective nature of the data and by the method of data collection and limited GHHI Atlanta data. Specifically, limitations regarding the interviews included: a couple of participants indicated that another family member (i.e., primary caretaker would have more information regarding the number of missed days of school, cost of healthcare, etc.); recipients who promised to conduct telephone interviews did not return the researcher’s calls; and recipients did not have time to participate in the interview. Furthermore, the study is limited by lack of response to emails and phone calls made to GHHI professionals, which presented a significant barrier to securing federal summary data for the GHHI program. Lastly, this research is limited by constraints of time. Despite the limitations, this study has important implications for leveraging public and private resources to support comprehensive initiatives like GHHI, which can ultimately yield health care cost savings as well as break the link between unhealthy housing and sick children. There is literature that supports our hypothesis that in-home interventions will provide medical cost savings, reduced school absenteeism, reduced lost work days and productivity, and improved quality of life for children with asthma and their families (6-9). A 1997 Atlanta program, known as ZAP Asthma, was a 16 member public, private partnership created to reduce preventable morbidity and mortality from asthma for children living in Atlanta's Empowerment Zone (34 of Atlanta’s poorest neighborhoods). Utilizing an “action research/participatory research model,” known asthma triggers in the home environment of study participants were identified and ameliorated, utilizing the skills of trained community health workers, who assisted families in sustaining the in-home interventions. The study monitored the impact of reductions in exposure to cockroach antigens, dust mites, and environmental tobacco smoke on the severity of the disease, and, on cost of care, schools days missed, and parent work days missed. Despite funding obstacles, ZAP concluded in-home interventions provided medical cost savings, reduced school absenteeism, reduced lost work days and productivity, and improved quality of life for children with asthma and their families (7). Next, a mayoral newspaper reports that using the GHHI approach, cities can: improve school performance and attendance and reduce health care costs caused by reductions in asthma episodes (6). The same report also noted that the first 180 homes in the initial GHHI Pilot Project in Baltimore evidenced cost savings in some homes over 25% (6). In effect, the money invested in interventions in the home for one case study paid for itself by avoided health care cost from the asthmatic child not having to be repeatedly hospitalized for asthma episodes. Another example that helps children and their families manage asthma more effectively and saves the healthcare system money is the Community Asthma Initiative (CAI) based in Boston, Massachusetts. CAI uses community health workers to visit families of children with serious asthma, in an effort to help them understand what can trigger attacks and how to avoid

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them. The CAI even pays for equipment such as vacuum cleaners and pest management supplies to help reduce indoor environmental pollutants that exacerbate asthma symptoms (16). Researchers who performed a cost analysis for the CAI reported that these programs work. The CAI saved more than $80,000 in the first three years of the program and demonstrated a return on investment (ROI) of 1.33. The initiative also contributed to reductions in ED visits (57 percent) and hospital admissions (80 percent), and fewer reported school and work absences (8, 9). In-home interventions provide significant opportunities to break the link between unhealthy housing and sick children. However, comprehensive initiatives like GHHI must account for other factors that contribute to in home asthma triggers. For example, we observed that two of the participants smoked cigarettes, and another participant had a dog; two of these homes had children with asthma. Additionally, we observed that one home that was elevated on bricks was near train tracks (MARTA and freight rails), a tire depot, and next to several of abandoned homes. Because the link between the environment and asthma is complicated by other factors including tobacco smoke and environmental pollution, in-home interventions is only one component of a multifaceted approach to decreasing asthma prevalence.

CONCLUSION This paper has focused narrowly on a population of 26 homes in several of Atlanta’s low and moderate income, predominantly African American neighborhoods. The paper underscores the importance of an in-home intervention program (such as the GHHI program studied in detail here) as one, low-cost, way to create more healthy living environments for some of our most vulnerable children – asthmatic children from low-income minority families. This report also highlights the much broader policy implication for cities across the country, such as Atlanta, that have a significant population of older, smaller, substandard housing stock. The serious deficiencies of older housing stock and the acute vulnerability of asthmatic children are destined to continue to be a costly combination for tens of thousands of asthmatic minority children for decades to come. It is critical that federal, state, and local governments consider how to fund in-home intervention programs, because the economics of building construction and the housing industry do not favor developers replacing these older homes short of massive shifts at the neighborhood level in a city’s residential real estate market. The age and condition of this urban housing stock forces average home values so low that developers are, at a minimum, hard-pressed from an economic standpoint to develop new homes in such low-cost markets that would include amenities and features that would help fight asthma triggers. In short, the problem of older housing stock exacerbating pediatric asthma is likely an issue of long-term concern. It is, therefore, critical to continue efforts to identify and implement the most effective and cost-efficient in-home interventions to eliminate asthma triggers.

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APPENDIX GHHI Atlanta and Asthma Outcomes Questionnaire Section A. *Introduction* Omitted. Section B. *Consent to Conduct Questionnaire* Omitted. Section C. *Asthma History Pre-GHHI Intervention* C-1. How many people, including you, lived in your home?

C-2. How many were children?

C-3. Did any household occupants, of any age, have asthma? Yes

No

C-4. If yes, how many?

C-5. Do any children under the age of 18 have asthma? Yes

No

C-6. How many of those children under the age of 18 suffered from asthma?

C-7. Before the GHHI program entered your home to make its changes, did the children living at home miss school/daycare because of their asthma? Yes

No

C-8. If yes, approximately how many days per month was asthma responsible for their missing school?

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C-9. If yes, approximately how many days per month the child’s/children’s asthma cause adult(s) in the household to miss part of a day of work?

C-9B. How many times per month did it cause adult(s) in the household to miss a full day of work?

C-10. If yes, approximately how many times per month was asthma responsible for your taking the child/children to: the clinic and/or urgent care

the emergency room department

asthma related hospitalizations

C-11. How much money did you spend per month on asthma urgent care/ER visits/hospitalizations before the GHHI program??

C-12. Who bore health system cost for asthma ER visits/hospitalizations before the GHHI program? Medicaid

Medicare

Private Insurance

Hospital

Self

C-13. Before the GHHI program entered your home to make its changes, how were the child/children doing in school? not well

well

good

very good

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Did the same number of people live in your home after the GHHI program began? Yes

No

•

How many were children?

•

How many of those children suffered from asthma?

Section D: *Asthma History Post GHHI Intervention* D-1. After the GHHI program in-home modifications, did the children living at home miss school/daycare because of their asthma? Yes

No

D-2. If yes, approximately how many days per month was asthma responsible for their missing school?

D-3. If yes, approximately how many days per month the child’s/children’s asthma caused adult(s) in the household to miss part of a day of work?

D-3B. How many times per month did it cause adult(s) in the household to miss a full day of work?

D-4. If yes, approximately how many times per month was asthma responsible for your taking the child/children to: the clinic and/or urgent care

the emergency room department

asthma related hospitalizations

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D-5. How much money do you spend per month on asthma urgent care/ER visits/hospitalizations post GHHI program??

D-6. Who bears health system cost for asthma ER visits/hospitalizations after the GHHI program? Medicaid Medicare Private Insurance Hospital Self D-7. After the GHHI program entered your home to make its changes, how are the child/children doing in school? not well

well

good

very good

D-8. Do you believe that the GHHI program

helped you didn’t affect you positively or negatively had a negative impact on you and those with whom you live. Is there anything else you would be willing to share with me about your feelings concerning the GHHI program?

ACKNOWLEDGMENTS Funding for development of this study was provided, in part, by the Southeast Pediatric Environmental Health Specialty Unit at Emory University. The first author would like to acknowledge John T. Marshall, assistant professor of law at Georgia State University College of Law in Atlanta. His guidance, wisdom, and valuable comments contributed tremendously to the completion of this project. Additionally, the author wishes to express his gratitude to Lauline Babino for her unwavering support and encouragement, which also contributed to the completion of this project.

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REFERENCES [1] [2]

[3]

[4] [5] [6]

[7] [8]

[9]

Georgia Asthma Surveillance Report, 2013. URL: http://dph.georgia.gov/sites/dph.georgia.gov/files /related_files/site_page/2014%20Asthma%20Prevalence%20Report.pdf. Strategic Plan for Addressing Asthma in Georgia, 2013. URL: http://dph.georgia.gov/ sites/dph.georgia.gov/files/related_files/site_page/DPH%20Asthma%20Strategic%20Plan%20for%20 Asthma%202013_2018%20Final.pdf. Pettignano R, Bliss LR, Caley SB, McLaren S. Can access to a medical-legal partnership benefit patients with asthma who live in an urban community? J Health Care Poor Underserved. 2013;24(706): 706-17. Brooks W. Telephone interview GHHI program manager. Atlanta, GA: Georgia State, 2014 Sept 2. 2011 Housing Profile: Atlanta-Sandy Springs-Marietta, GA. www.census.gov/prod/2013pubs/ahs113.pdf. US Mayor Newspaper: Baltimore Green, Healthy Homes Initiative transforms low-Income communities. URL: http://usmayors.org/usmayornewspaper/document s/07_19_10/pg20_baltimore_ bp.asp. Evaluation of the ZAP Asthma Project. URL: http://zap asthma.org/index.html. Accessed September 5, 2014. Rivlin AM, George M. Can we reduce childhood asthma and lower costs, too? URL: http://www.brookings.edu/blogs/up-front/posts/2014/11/12-asthma-payment-reform-policyrivlin?utm_campaign=Brooking s+Brief&utm_source=hs_email&utm_medium=email&utm_content= 14881937&_hsenc=p2ANqtz—nBJKTM Nq6hUVGC51dYZ47-LY_UtIv0w4AcgAodgShPDRv kocmRJT5Z7o4fRtLhK1YMpm566kZeB_8jA0ncO2X4W6Q&_hsmi=14881937. Bhaumik U, Norris K, Charron G, Walker SP, Sommer SJ, Chan E, et al. A cost analysis for a community-based case management intervention program for pediatric asthma. J Asthma 2013;50(3):310–7.

In: Child Health and Human Development Yearbook 2016 ISBN: 978-1-53610-946-7 Editor: Joav Merrick © 2017 Nova Science Publishers, Inc.

Chapter 45

IMPLEMENTING COMMUNITY SUPPORTS TO LESSEN HEALTH DISPARITIES AT KINDERGARTEN ENTRY FOR VERY PRETERM SURVIVORS Amelia Dmowska, Bree Andrews, MD, Michael Schreiber, MD and Michael E Msall, MD University of Chicago Medicine Comer Children’s Hospital, Chicago, Illinois, United States of America Joseph P Kennedy Jr Research Center on Intellectual and Developmental Disabilities, University of Chicago, Chicago, Illinois, United States of America Section of Developmental and Behavioral Pediatrics and Illinois LEND, University of Illinois at Chicago, Chicago, Illinois, United States of America

ABSTRACT Our goal was to evaluate the impact of accessing quality community interventions in the preschool years and to develop an economic model of how access to these services decreases long term special-education costs. Methods: The cohort for this study included 121 very preterm infants who received surfactant replacement and ventilation and were enrolled in a randomized controlled study of nitric oxide for respiratory distress syndrome. These children were prospectively followed to monitor health, growth, and development during the first six years of life. Results: Using our models, for every 100 very low-birth weight infants without Early Intervention (EI) or Early Head Start (EHS), the lifetime cost of special education was $13.2 million. For every 100 very low-birth weight infants who do receive comprehensive Early Intervention or Early Head Start services, special education costs decrease by $7.4 million. In order to increase access to comprehensive early intervention early head start and early child education services (EIEHS-ECE) from 35% to 90%, we calculated that these services would require an investment of $40K per child between birth and kindergarten entry. Conclusion: Our preliminary data demonstrate that children of very low birth weight status benefit from 

Correspondence: Amelia Dmowska, 950 E 61st St, Woodlawn, Chicago, IL 60637, United States. E-mail: [email protected]; [email protected].

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Amelia Dmowska, Bree Andrews, Michael Schreiber et al. access to comprehensive early intervention, Early Head Start, and preschool early child education services. These services dramatically improve outcomes and reduce disparities and long-term educational costs. Additional studies will need to examine the impact of these interventions on long term physical and behavioral, health and employment outcomes.

Keywords: very preterm birth, early intervention, special education, prevention, vulnerable children, childhood disability

INTRODUCTION Over the past three decades, advances in obstetrics and neonatal care have dramatically increased the survival of children born preterm, or