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GASTROENTEROLOGY AND NUTRITION
Neonatology Questions and Controversies Series Editor Other Volumes in the Neonatology Questions and Controversies Series HEMATOLOGY, IMMUNOLOGY AND INFECTIOUS DISEASE HEMODYNAMICS AND CARDIOLOGY INFECTIOUS DISEASE AND PHARMACOLOGY NEPHROLOGY AND FLUID/ELECTROLYTE PHYSIOLOGY NEUROLOGY THE NEWBORN LUNG
GASTROENTEROLOGY AND NUTRITION
Neonatology Questions and Controversies Third Edition
Josef Neu, MD Professor of Pediatrics University of Florida College of Medicine Gainesville, Florida
Brenda Poindexter, MD, MS Director, Clinical and Translational Research Perinatal Institute Cincinnati Children’s Cincinnati, Ohio
Consulting Editor
Richard A. Polin, MD William T. Speck Professor of Pediatrics College of Physicians and Surgeons Columbia University Director Division of Neonatology New York Presbyterian Morgan Stanley Children’s Hospital New York, New York
1600 John F. Kennedy Blvd. Ste 1800 Philadelphia, PA 19103-2899
GASTROENTEROLOGY AND NUTRITION: NEONATOLOGY QUESTIONS AND CONTROVERSIES, THIRD EDITION Copyright © 2019 by Elsevier, Inc. All rights reserved.
ISBN: 978-0-323-54502-0
No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein).
Notices Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. With respect to any drug or pharmaceutical products identified, readers are advised to check the most current information provided (i) on procedures featured or (ii) by the manufacturer of each product to be administered, to verify the recommended dose or formula, the method and duration of administration, and contraindications. It is the responsibility of practitioners, relying on their own experience and knowledge of their patients, to make diagnoses, to determine dosages and the best treatment for each individual patient, and to take all appropriate safety precautions. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. Previous editions copyrighted 2012 and 2008. Library of Congress Cataloging-in-Publication Data Names: Neu, Josef, editor. Title: Gastroenterology and nutrition : neonatology questions and controversies / [edited by] Josef Neu. Other titles: Neonatology questions and controversies. Description: Third edition. | Philadelphia, PA : Elsevier, [2019] | Series: Neonatology questions and controversies series | Includes bibliographical references and index. Identifiers: LCCN 2018006369 | ISBN 9780323545020 (alk. paper) Subjects: | MESH: Gastrointestinal Diseases | Infant, Newborn, Diseases | Infant Nutritional Physiological Phenomena | Infant, Newborn Classification: LCC RJ446 | NLM WS 310 | DDC 616.3/3--dc23 LC record available at https://lccn.loc.gov/2018006369 Senior Content Strategist: Sarah Barth Content Development Specialist: Lisa M. Barnes Book Production Manager: Jeff Patterson Project Manager: Abigail Bradberry Design Specialist: Paula Catalano Printed in China Last digit is the print number: 9 8 7 6 5 4 3 2 1
Contributors
Kjersti Aagaard-Tillery, MD, PhD, FACOG
Henry and Emma Meyer Chair in Obstetrics & Gynecology Professor & Vice Chair of Research Department of Obstetrics & Gynecology, Division of Maternal-Fetal Medicine Baylor College of Medicine and Texas Children’s Hospital Dallas, Texas Adult Consequences of Neonatal and Fetal Nutrition: Mechanisms Lauren Astrug, MD
Neonatal Necrotizing Enterocolitis: Neonatology Questions and Controversies Cheri Bantilan, MS
Adult Consequences of Neonatal and Fetal Nutrition: Mechanisms Erika Claud, MD
Professor of Pediatrics and Medicine Director, Neonatology Research University of Chicago Medical Center Chicago, Illinois Neonatal Necrotizing Enterocolitis: Neonatology Questions and Controversies Clotilde desRoberts, MD
Adult Consequences of Neonatal and Fetal Nutrition: Mechanisms Holly J. Engelstad, MD
Fellow Department of Pediatrics Washington University in St Louis St. Louis, Missouri Nutrition for the Surgical Neonate
Steven D. Freedman, MD, PhD
Professor of Medicine Department of Medicine Beth Israel Deaconess Medical Center Boston, Massachusetts Lipid and Fatty Acid Delivery in the Preterm Infant: Challenges and Lessons Learned from Other Critically Ill Populations Kathleen M. Gura, BS, PharmD
Clinical Pharmacy Specialist GI/Nutrition Pharmacy Department Clinical Pharmacist Center for Nutrition; Clinical Pharmacist Center for Advanced Intestinal Rehabilitation Boston Children’s Hospital; Associate Professor Pharmacy Practice MCPHS University Boston, Massachusetts New Lipid Strategies to Prevent/Treat Neonatal Cholestasis Anna Maria Hibbs, MD, MSCE
Assistant Professor Department of Pediatrics Case Western Reserve University; Attending Neonatologist Rainbow Babies and Children’s Hospital Cleveland, Ohio Maturation of Motor Function in the Preterm Infant and Gastroesophageal Reflux
Julia B. Ewaschuk
Donor Milk Trials
v
vi
Contributors
Sudarshan R. Jadcherla, MD, FRCPI, DCH, AGAF
Professor Department of Pediatrics Sections of Neonatology and Pediatric Gastroenterology & Nutrition The Ohio State University College of Medicine; Attending Neonatologist Section of Neonatology; Director The Neonatal and Infant Feeding Disorders Program Nationwide Children’s Hospital; Principal Investigator Center for Perinatal Research The Research Institute at Nationwide Children’s Hospital Columbus, Ohio Development of Gastrointestinal Motility Reflexes Lisa A. Joss-Moore, PhD
Associate Professor Pediatrics University of Utah, Salt Lake City, Utah Adult Consequences of Neonatal and Fetal Nutrition: Mechanisms Robert H. Lane, MD, MS
Professor and Chair Department of Pediatrics Associate Director of Epigenomics Genomic Science Personalized Medicine Center Medical College of Wisconsin Pediatrician in Chief The Barri L. and David J. Drury Chair in Pediatrics Children’s Hospital of Wisconsin Milwaukee, Wisconsin Adult Consequences of Neonatal and Fetal Nutrition: Mechanisms Mary W. Lenfestey, MD
Postdoctoral Fellow Pediatric Gastroenterology University of Florida Gainesville, Florida Neonatal Gastrointestinal Tract as a Conduit to Systemic Inflammation
Camilia R. Martin, MD, MS
Assistant Professor of Pediatrics Harvard Medical School Boston, Massachusetts Lipid and Fatty Acid Delivery in the Preterm Infant: Challenges and Lessons Learned from other Critically Ill Populations Nicole Mitchell, MD
Department of Food Science and Human Nutrition Michigan State University Lansing, Michigan Adult Consequences of Neonatal and Fetal Nutrition: Mechanisms Ardythe L. Morrow, PhD, MSc
Professor of Pediatrics, Nutrition & Environmental Health University of Cincinnati Colleges of Medicine & Allied Health Perinatal Institute Cincinnati Children’s Hospital Medical Center Cincinnati, Ohio Human Milk Oligosaccharides Josef Neu, MD
Professor Department of Pediatrics University of Florida Gainesville, Florida Neonatal Gastrointestinal Tract as a Conduit to Systemic Inflammation What Are the Controversies, and Where Will the Field be Moving in the Future? David S. Newburg, PhD
DSN Medical Consulting NK Laboratories Newtonville, Massachusetts Human Milk Oligosaccharide Deborah L. O’Connor, PhD, RD
Professor Department of Nutritional Sciences University of Toronto, Senior Associate Scientist Physiology and Experimental Medicine The Hospital for Sick Children; Senior Associate Staff Pediatrics Mount Sinai Hospital, Toronto, Ontario, Canada Donor Milk Trials
Contributors
Brenda Poindexter, MD, MS
Sreekanth Viswanathan, MD, MS
Director, Clinical and Translational Research Professor of Pediatrics Cincinnati Children’s Cincinnati, Ohio What Are the Controversies, and Where Will the Field be Moving in the Future?
Development of Gastrointestinal Motility Reflexes
Sharon L. Unger, MD, FRCP(C)
Neonatologist Pediatrics Sinai Health System; Associate Professor Medicine University of Toronto, Medical Director Rogers Hixon Ontario Human Milk Bank; Clinician Scientist Lunenfeld-Tanenbaum Research Institute Toronto, Ontario, Canada Donor Milk Trials
vii
Brad W. Warner, MD
Jessie L. Ternberg, MD PhD Distinguished Professor of Pediatric Surgery Surgeon-in-Chief Washington University School of Medicine St. Louis Children’s Hospital Nutrition for the Surgical Neonate Jacqueline J. Wessel, Med, RDN, CNSC, CSP, CLE, LD
Neonatal Nutritionist Nutrition Therapy, Intestinal Rehabilitation Cincinnati Children’s Hospital Cincinnati, Ohio Controversies in Short Bowel Syndrome
Series Foreword Richard A. Polin, MD
“To study the phenomena of disease without books is to sail an uncharted sea, while to study books without patients is not to go to sea at all”
—William Osler
Physicians in training generally rely on the spoken word and clinical experiences to bolster their medical knowledge. There is probably no better way to learn how to care for an infant than to receive teaching at the bedside. Of course, that assumes that the “clinician” doing the teaching is knowledgeable about the disease, wants to teach, and can teach effectively. For a student or intern, this style of learning is efficient because the clinical service demands preclude much time for other reading. Over the course of one’s career, it becomes clear that this form of education has limitations because of the fairly-limited number of disease conditions one encounters even in a lifetime of clinical rotations and the diminishing opportunities for teaching moments. The next educational phase generally includes reading textbooks and qualitative review articles. Unfortunately, both of those sources are often outdated by the time they are published and represent one author’s opinions about management. Systematic analyses (meta-analyses) can be more informative, but, more often than not, the conclusion of the systematic analysis is that “more studies are needed” to answer the clinical question. Furthermore, it has been estimated that if a subsequent large randomized clinical trial had not been performed, the meta-analysis would have reached an erroneous conclusion more than one third of the time. For practicing clinicians, clearly the best way to keep abreast of recent advances in a field is to read the medical literature on a regular basis. However, that approach is problematic given the multitude of journals, unless one reads only the two or three major pediatric journals published in the United States. That approach, however, will miss many of the outstanding articles that appear in more general medical journals (e.g., Journal of the American Medical Association, New England Journal of Medicine, Lancet, and the British Medical Journal), subspecialty journals, and the many pediatric journals published in other countries. Although there is no substitute to reading journal articles on a regular basis, the Questions and Controversies series of books provides an excellent alternative. This third edition of the series was developed to highlight the clinical problems of most concern to practitioners. The series has been increased from six to seven volumes and includes new sections on genetics and pharmacology. In total, there are 70 new chapters not included previously. The editors of each volume (Drs. Bancalari, Davis, Keszler, Oh, Seri, Ohls, Christensen. Maheshwari, Neu, Benitz, Smith, Poindexter, Cilio, and Perlman) have done an extraordinary job in selecting topics of clinical importance to everyday practice. Unlike traditional review articles, the chapters not only highlight the most significant controversies but also, when possible, incorporate basic science and physiological concepts with a rigorous analysis of the current literature. As with the first edition, I am indebted to the exceptional group of editors who chose the content and edited each of the volumes. I also wish to thank Lisa Barnes (Content Development Specialist at Elsevier) and Judy Fletcher (Global Content Development Director at Elsevier), who provided incredible assistance in bringing this project to fruition.
ix
Preface
Gastroenterology and Nutrition: Neonatology Questions and Controversies, 3e As in the previous editions, we address clinically relevant questions and controversies in neonatal nutrition and gastroenterology with up-to-date research in these areas. New information is emerging about the basic developmental physiology of upper intestinal motility as it relates to reflux and feeding tolerance. Immaturities in motility by altering composition of feedings and pharmacologic means is addressed. The composition of human milk in terms of oligosaccharides and clinical trials that address the efficacy of donor milk in comparison to formula and own mother’s milk has been a matter of controversy and is updated in this volume. The developing intestinal tract is known to be much more than a digestive-absorptive organ, and the role of inflammation in systemic diseases in other organs, as well as necrotizing enterocolitis, is addressed. In this volume, there is also an in-depth analysis of administering lipids to preterm infants, the complications that occur when these are not optimized, and strategies for optimization of providing lipids to infants who are at high risk for complications secondary to suboptimal lipid therapies. The editors and authors hope to provide continued guidance that will clarify some of the major controversies related to neonatal nutrition and intestinal diseases and help those caring for these vulnerable infants to provide optimal care.
xi
CHAPTER 1 Maturation of Motor Function in the Preterm Infant and Gastroesophageal Reflux Anna Maria Hibbs, MD, MSCE
Outline Upper Gastrointestinal Motility and Physiology Diagnosis of Gastroesophageal Reflux and Gastroesophageal Reflux Disease
Physiologic Gastroesophageal Reflux Gastroesophageal Reflux Disease-Symptoms
Gastroesophageal Reflux Disease-Diagnostic Tests Gastroesophageal Reflux Disease-Treatment Nonphar Measures
Phar
rapy edications
Gastroesophageal reflux (GER) is defined as the retrograde passage of gastric contents into the esophagus. In term and preterm infants, GER is usually a benign physiologic process, but it meets the definition of gastroesophageal reflux disease (GERD) if it causes clinical symptoms m complications. 1-3 A multitude of gastrointestinal (GI), respiratory, and other symptoms, including apnea, worsening of lung disease, irritability, feeding intole ance, failure to thrive, and stridor, have been attributed to GERO. However, determining whether reflux is the cause of symptoms in an individual patient can be challenging. The approach to an infant with suspected GERO is further complicated bY. the paucity of available medications demonstrated to be safe or effective in this population.
Upper Gastrointestinal Motility and Physiology An understanding of GER in infants begins with the physiology of the upper GI tract. Esophageal motor function is well developed in infants as early as 26 weeks' gestational age. 4 ,5 Swallowing triggers coordinated esophageal peristalsis and lower esophageal sphincter (LES) relaxation, as it does in more mature patients. 4 However, the velocity of propagation is significantly faster in term infants than in preterm infants. 6 Manometry has also documented that spontaneous esophageal activity unrelated to swallowing tends to take the form of incomplete or asynchronous waves; this type of nonperistaltic motor activity occurs more frequently in preterm infants than in adults. 4 The LES, which blocks GER, is made up of intrinsic esophageal smooth muscle and diaphragmatic skeletal muscle. 7 Although premature infants were once thought to have impaired LES tone, several manometry studies have documented good LES tone, even in extremely low-birth weight infants. 4 ,8 ,9 In term and preterm infants, as in older patients, transient LES relaxations (TLESRs) unrelated to swallowing are the major mechanism that allows GER by abruptly dropping lower esophageal pressure below gastric pressure. 4,9, 10 These TLESRs may occur several times per hour in preterm infants, although the majority of TLESR events are not associated with GER. 10 Preterm infants with GERD and those without GERO experience a similar
2
A
Gastroenterology and Nutrition
frequency of TLESRs, but infants with GERD have a higher percentage of acid GER events during TLESRs.10 It has been hypothesized that straining or other reasons for increased intra-abdominal pressure may increase the likelihood of a GER event during a TLESR. Although LES relaxations also occur during normal swallowing, these are less often associated with GER events than with isolated TLESR events.10 In addition to the anatomic and physiologic factors described that increase the likelihood of the retrograde passage of gastric contents into the esophagus, infants ingest a much higher volume per kilogram of body weight, approximately 180 mL/ kg/day, compared with older children and adults.11 In the neonatal intensive care unit (NICU) population, preterm and term patients with nasogastric or orogastric feeding tubes may experience more reflux episodes as a result of mechanical impairment of the competence of the LES.12,13 Gastric emptying is also an important factor in the passage of fluids through the upper GI tract. One small study showed that between 25 and 30 weeks, gastric emptying time seems to be inversely and linearly correlated with gestational age at birth. This study also found that simultaneously decreasing the osmolality and increasing the volume of feeds accelerated gastric emptying, although changes in osmolality or volume alone did not have a significant effect.14 Emptying also occurs faster with feeding of human milk than of formula. Several small studies suggest that prebiotics, probiotics, and hydrolyzed formulas may speed gastric emptying time in formula-fed infants.15-17 Fortification of human milk may slow gastric emptying time.18 The clinical significance of these findings with regard to GER remains uncertain, however. Although it seems logical that slower gastric emptying would be associated with increased GER, a study on the relationship between gastric emptying and GER in preterm infants found no such association.19
Diagnosis of Gastroesophageal Reflux and Gastroesophageal Reflux Disease Although infants have a propensity to experience frequent GER, the majority of GER is physiologic and nonpathologic. GERD is defined as GER that causes complications.1,2 Unfortunately, in infants, particularly preterm infants, complications of GER are difficult to characterize. Clinicians disagree about which symptoms are caused by GER or GERD.20 There is mixed evidence in the literature to support or refute most of the proposed complications of GER, including apnea,21-31 worsening of lung disease,32-35 and failure to thrive, in infants.36 An ongoing problem, particularly in the preterm population, is that many of the putative symptoms of GERD also frequently occur for other reasons. For instance, preterm infants without GERD also frequently experience apnea, lung disease, or feeding intolerance.
Physiologic Gastroesophageal Reflux Nonpathologic GER occurs frequently in both preterm and term infants. Among 509 healthy asymptomatic infants aged 3 to 365 days monitored with an esophageal pH probe, the mean number of acid reflux episodes in 24 hours was 31.28, with a standard deviation of 20.68.37 The reflux index, the percent of time the esophageal pH was
GASTROENTEROLOGY AND NUTRITION
Neonatology Questions and Controversies Series Editor Other Volumes in the Neonatology Questions and Controversies Series HEMATOLOGY, IMMUNOLOGY AND INFECTIOUS DISEASE HEMODYNAMICS AND CARDIOLOGY INFECTIOUS DISEASE AND PHARMACOLOGY NEPHROLOGY AND FLUID/ELECTROLYTE PHYSIOLOGY NEUROLOGY THE NEWBORN LUNG
GASTROENTEROLOGY AND NUTRITION
Neonatology Questions and Controversies Third Edition
Josef Neu, MD Professor of Pediatrics University of Florida College of Medicine Gainesville, Florida
Brenda Poindexter, MD, MS Director, Clinical and Translational Research Perinatal Institute Cincinnati Children’s Cincinnati, Ohio
Consulting Editor
Richard A. Polin, MD William T. Speck Professor of Pediatrics College of Physicians and Surgeons Columbia University Director Division of Neonatology New York Presbyterian Morgan Stanley Children’s Hospital New York, New York
1600 John F. Kennedy Blvd. Ste 1800 Philadelphia, PA 19103-2899
GASTROENTEROLOGY AND NUTRITION: NEONATOLOGY QUESTIONS AND CONTROVERSIES, THIRD EDITION Copyright © 2019 by Elsevier, Inc. All rights reserved.
ISBN: 978-0-323-54502-0
No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein).
Notices Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. With respect to any drug or pharmaceutical products identified, readers are advised to check the most current information provided (i) on procedures featured or (ii) by the manufacturer of each product to be administered, to verify the recommended dose or formula, the method and duration of administration, and contraindications. It is the responsibility of practitioners, relying on their own experience and knowledge of their patients, to make diagnoses, to determine dosages and the best treatment for each individual patient, and to take all appropriate safety precautions. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. Previous editions copyrighted 2012 and 2008. Library of Congress Cataloging-in-Publication Data Names: Neu, Josef, editor. Title: Gastroenterology and nutrition : neonatology questions and controversies / [edited by] Josef Neu. Other titles: Neonatology questions and controversies. Description: Third edition. | Philadelphia, PA : Elsevier, [2019] | Series: Neonatology questions and controversies series | Includes bibliographical references and index. Identifiers: LCCN 2018006369 | ISBN 9780323545020 (alk. paper) Subjects: | MESH: Gastrointestinal Diseases | Infant, Newborn, Diseases | Infant Nutritional Physiological Phenomena | Infant, Newborn Classification: LCC RJ446 | NLM WS 310 | DDC 616.3/3--dc23 LC record available at https://lccn.loc.gov/2018006369 Senior Content Strategist: Sarah Barth Content Development Specialist: Lisa M. Barnes Book Production Manager: Jeff Patterson Project Manager: Abigail Bradberry Design Specialist: Paula Catalano Printed in China Last digit is the print number: 9 8 7 6 5 4 3 2 1
Contributors
Kjersti Aagaard-Tillery, MD, PhD, FACOG
Henry and Emma Meyer Chair in Obstetrics & Gynecology Professor & Vice Chair of Research Department of Obstetrics & Gynecology, Division of Maternal-Fetal Medicine Baylor College of Medicine and Texas Children’s Hospital Dallas, Texas Adult Consequences of Neonatal and Fetal Nutrition: Mechanisms Lauren Astrug, MD
Neonatal Necrotizing Enterocolitis: Neonatology Questions and Controversies Cheri Bantilan, MS
Adult Consequences of Neonatal and Fetal Nutrition: Mechanisms Erika Claud, MD
Professor of Pediatrics and Medicine Director, Neonatology Research University of Chicago Medical Center Chicago, Illinois Neonatal Necrotizing Enterocolitis: Neonatology Questions and Controversies Clotilde desRoberts, MD
Adult Consequences of Neonatal and Fetal Nutrition: Mechanisms Holly J. Engelstad, MD
Fellow Department of Pediatrics Washington University in St Louis St. Louis, Missouri Nutrition for the Surgical Neonate
Steven D. Freedman, MD, PhD
Professor of Medicine Department of Medicine Beth Israel Deaconess Medical Center Boston, Massachusetts Lipid and Fatty Acid Delivery in the Preterm Infant: Challenges and Lessons Learned from Other Critically Ill Populations Kathleen M. Gura, BS, PharmD
Clinical Pharmacy Specialist GI/Nutrition Pharmacy Department Clinical Pharmacist Center for Nutrition; Clinical Pharmacist Center for Advanced Intestinal Rehabilitation Boston Children’s Hospital; Associate Professor Pharmacy Practice MCPHS University Boston, Massachusetts New Lipid Strategies to Prevent/Treat Neonatal Cholestasis Anna Maria Hibbs, MD, MSCE
Assistant Professor Department of Pediatrics Case Western Reserve University; Attending Neonatologist Rainbow Babies and Children’s Hospital Cleveland, Ohio Maturation of Motor Function in the Preterm Infant and Gastroesophageal Reflux
Julia B. Ewaschuk
Donor Milk Trials
v
vi
Contributors
Sudarshan R. Jadcherla, MD, FRCPI, DCH, AGAF
Professor Department of Pediatrics Sections of Neonatology and Pediatric Gastroenterology & Nutrition The Ohio State University College of Medicine; Attending Neonatologist Section of Neonatology; Director The Neonatal and Infant Feeding Disorders Program Nationwide Children’s Hospital; Principal Investigator Center for Perinatal Research The Research Institute at Nationwide Children’s Hospital Columbus, Ohio Development of Gastrointestinal Motility Reflexes Lisa A. Joss-Moore, PhD
Associate Professor Pediatrics University of Utah, Salt Lake City, Utah Adult Consequences of Neonatal and Fetal Nutrition: Mechanisms Robert H. Lane, MD, MS
Professor and Chair Department of Pediatrics Associate Director of Epigenomics Genomic Science Personalized Medicine Center Medical College of Wisconsin Pediatrician in Chief The Barri L. and David J. Drury Chair in Pediatrics Children’s Hospital of Wisconsin Milwaukee, Wisconsin Adult Consequences of Neonatal and Fetal Nutrition: Mechanisms Mary W. Lenfestey, MD
Postdoctoral Fellow Pediatric Gastroenterology University of Florida Gainesville, Florida Neonatal Gastrointestinal Tract as a Conduit to Systemic Inflammation
Camilia R. Martin, MD, MS
Assistant Professor of Pediatrics Harvard Medical School Boston, Massachusetts Lipid and Fatty Acid Delivery in the Preterm Infant: Challenges and Lessons Learned from other Critically Ill Populations Nicole Mitchell, MD
Department of Food Science and Human Nutrition Michigan State University Lansing, Michigan Adult Consequences of Neonatal and Fetal Nutrition: Mechanisms Ardythe L. Morrow, PhD, MSc
Professor of Pediatrics, Nutrition & Environmental Health University of Cincinnati Colleges of Medicine & Allied Health Perinatal Institute Cincinnati Children’s Hospital Medical Center Cincinnati, Ohio Human Milk Oligosaccharides Josef Neu, MD
Professor Department of Pediatrics University of Florida Gainesville, Florida Neonatal Gastrointestinal Tract as a Conduit to Systemic Inflammation What Are the Controversies, and Where Will the Field be Moving in the Future? David S. Newburg, PhD
DSN Medical Consulting NK Laboratories Newtonville, Massachusetts Human Milk Oligosaccharide Deborah L. O’Connor, PhD, RD
Professor Department of Nutritional Sciences University of Toronto, Senior Associate Scientist Physiology and Experimental Medicine The Hospital for Sick Children; Senior Associate Staff Pediatrics Mount Sinai Hospital, Toronto, Ontario, Canada Donor Milk Trials
Contributors
Brenda Poindexter, MD, MS
Sreekanth Viswanathan, MD, MS
Director, Clinical and Translational Research Professor of Pediatrics Cincinnati Children’s Cincinnati, Ohio What Are the Controversies, and Where Will the Field be Moving in the Future?
Development of Gastrointestinal Motility Reflexes
Sharon L. Unger, MD, FRCP(C)
Neonatologist Pediatrics Sinai Health System; Associate Professor Medicine University of Toronto, Medical Director Rogers Hixon Ontario Human Milk Bank; Clinician Scientist Lunenfeld-Tanenbaum Research Institute Toronto, Ontario, Canada Donor Milk Trials
vii
Brad W. Warner, MD
Jessie L. Ternberg, MD PhD Distinguished Professor of Pediatric Surgery Surgeon-in-Chief Washington University School of Medicine St. Louis Children’s Hospital Nutrition for the Surgical Neonate Jacqueline J. Wessel, Med, RDN, CNSC, CSP, CLE, LD
Neonatal Nutritionist Nutrition Therapy, Intestinal Rehabilitation Cincinnati Children’s Hospital Cincinnati, Ohio Controversies in Short Bowel Syndrome
Series Foreword Richard A. Polin, MD
“To study the phenomena of disease without books is to sail an uncharted sea, while to study books without patients is not to go to sea at all”
—William Osler
Physicians in training generally rely on the spoken word and clinical experiences to bolster their medical knowledge. There is probably no better way to learn how to care for an infant than to receive teaching at the bedside. Of course, that assumes that the “clinician” doing the teaching is knowledgeable about the disease, wants to teach, and can teach effectively. For a student or intern, this style of learning is efficient because the clinical service demands preclude much time for other reading. Over the course of one’s career, it becomes clear that this form of education has limitations because of the fairly-limited number of disease conditions one encounters even in a lifetime of clinical rotations and the diminishing opportunities for teaching moments. The next educational phase generally includes reading textbooks and qualitative review articles. Unfortunately, both of those sources are often outdated by the time they are published and represent one author’s opinions about management. Systematic analyses (meta-analyses) can be more informative, but, more often than not, the conclusion of the systematic analysis is that “more studies are needed” to answer the clinical question. Furthermore, it has been estimated that if a subsequent large randomized clinical trial had not been performed, the meta-analysis would have reached an erroneous conclusion more than one third of the time. For practicing clinicians, clearly the best way to keep abreast of recent advances in a field is to read the medical literature on a regular basis. However, that approach is problematic given the multitude of journals, unless one reads only the two or three major pediatric journals published in the United States. That approach, however, will miss many of the outstanding articles that appear in more general medical journals (e.g., Journal of the American Medical Association, New England Journal of Medicine, Lancet, and the British Medical Journal), subspecialty journals, and the many pediatric journals published in other countries. Although there is no substitute to reading journal articles on a regular basis, the Questions and Controversies series of books provides an excellent alternative. This third edition of the series was developed to highlight the clinical problems of most concern to practitioners. The series has been increased from six to seven volumes and includes new sections on genetics and pharmacology. In total, there are 70 new chapters not included previously. The editors of each volume (Drs. Bancalari, Davis, Keszler, Oh, Seri, Ohls, Christensen. Maheshwari, Neu, Benitz, Smith, Poindexter, Cilio, and Perlman) have done an extraordinary job in selecting topics of clinical importance to everyday practice. Unlike traditional review articles, the chapters not only highlight the most significant controversies but also, when possible, incorporate basic science and physiological concepts with a rigorous analysis of the current literature. As with the first edition, I am indebted to the exceptional group of editors who chose the content and edited each of the volumes. I also wish to thank Lisa Barnes (Content Development Specialist at Elsevier) and Judy Fletcher (Global Content Development Director at Elsevier), who provided incredible assistance in bringing this project to fruition.
ix
Preface
Gastroenterology and Nutrition: Neonatology Questions and Controversies, 3e As in the previous editions, we address clinically relevant questions and controversies in neonatal nutrition and gastroenterology with up-to-date research in these areas. New information is emerging about the basic developmental physiology of upper intestinal motility as it relates to reflux and feeding tolerance. Immaturities in motility by altering composition of feedings and pharmacologic means is addressed. The composition of human milk in terms of oligosaccharides and clinical trials that address the efficacy of donor milk in comparison to formula and own mother’s milk has been a matter of controversy and is updated in this volume. The developing intestinal tract is known to be much more than a digestive-absorptive organ, and the role of inflammation in systemic diseases in other organs, as well as necrotizing enterocolitis, is addressed. In this volume, there is also an in-depth analysis of administering lipids to preterm infants, the complications that occur when these are not optimized, and strategies for optimization of providing lipids to infants who are at high risk for complications secondary to suboptimal lipid therapies. The editors and authors hope to provide continued guidance that will clarify some of the major controversies related to neonatal nutrition and intestinal diseases and help those caring for these vulnerable infants to provide optimal care.
xi
CHAPTER 1 Maturation of Motor Function in the Preterm Infant and Gastroesophageal Reflux Anna Maria Hibbs, MD, MSCE
Outline Upper Gastrointestinal Motility and Physiology Diagnosis of Gastroesophageal Reflux and Gastroesophageal Reflux Disease
Physiologic Gastroesophageal Reflux Gastroesophageal Reflux Disease-Symptoms
Gastroesophageal Reflux Disease-Diagnostic Tests Gastroesophageal Reflux Disease-Treatment Nonphar Measures
Phar
rapy edications
Gastroesophageal reflux (GER) is defined as the retrograde passage of gastric contents into the esophagus. In term and preterm infants, GER is usually a benign physiologic process, but it meets the definition of gastroesophageal reflux disease (GERD) if it causes clinical symptoms m complications. 1-3 A multitude of gastrointestinal (GI), respiratory, and other symptoms, including apnea, worsening of lung disease, irritability, feeding intole ance, failure to thrive, and stridor, have been attributed to GERO. However, determining whether reflux is the cause of symptoms in an individual patient can be challenging. The approach to an infant with suspected GERO is further complicated bY. the paucity of available medications demonstrated to be safe or effective in this population.
Upper Gastrointestinal Motility and Physiology An understanding of GER in infants begins with the physiology of the upper GI tract. Esophageal motor function is well developed in infants as early as 26 weeks' gestational age. 4 ,5 Swallowing triggers coordinated esophageal peristalsis and lower esophageal sphincter (LES) relaxation, as it does in more mature patients. 4 However, the velocity of propagation is significantly faster in term infants than in preterm infants. 6 Manometry has also documented that spontaneous esophageal activity unrelated to swallowing tends to take the form of incomplete or asynchronous waves; this type of nonperistaltic motor activity occurs more frequently in preterm infants than in adults. 4 The LES, which blocks GER, is made up of intrinsic esophageal smooth muscle and diaphragmatic skeletal muscle. 7 Although premature infants were once thought to have impaired LES tone, several manometry studies have documented good LES tone, even in extremely low-birth weight infants. 4 ,8 ,9 In term and preterm infants, as in older patients, transient LES relaxations (TLESRs) unrelated to swallowing are the major mechanism that allows GER by abruptly dropping lower esophageal pressure below gastric pressure. 4,9, 10 These TLESRs may occur several times per hour in preterm infants, although the majority of TLESR events are not associated with GER. 10 Preterm infants with GERD and those without GERO experience a similar
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Gastroenterology and Nutrition
frequency of TLESRs, but infants with GERD have a higher percentage of acid GER events during TLESRs.10 It has been hypothesized that straining or other reasons for increased intra-abdominal pressure may increase the likelihood of a GER event during a TLESR. Although LES relaxations also occur during normal swallowing, these are less often associated with GER events than with isolated TLESR events.10 In addition to the anatomic and physiologic factors described that increase the likelihood of the retrograde passage of gastric contents into the esophagus, infants ingest a much higher volume per kilogram of body weight, approximately 180 mL/ kg/day, compared with older children and adults.11 In the neonatal intensive care unit (NICU) population, preterm and term patients with nasogastric or orogastric feeding tubes may experience more reflux episodes as a result of mechanical impairment of the competence of the LES.12,13 Gastric emptying is also an important factor in the passage of fluids through the upper GI tract. One small study showed that between 25 and 30 weeks, gastric emptying time seems to be inversely and linearly correlated with gestational age at birth. This study also found that simultaneously decreasing the osmolality and increasing the volume of feeds accelerated gastric emptying, although changes in osmolality or volume alone did not have a significant effect.14 Emptying also occurs faster with feeding of human milk than of formula. Several small studies suggest that prebiotics, probiotics, and hydrolyzed formulas may speed gastric emptying time in formula-fed infants.15-17 Fortification of human milk may slow gastric emptying time.18 The clinical significance of these findings with regard to GER remains uncertain, however. Although it seems logical that slower gastric emptying would be associated with increased GER, a study on the relationship between gastric emptying and GER in preterm infants found no such association.19
Diagnosis of Gastroesophageal Reflux and Gastroesophageal Reflux Disease Although infants have a propensity to experience frequent GER, the majority of GER is physiologic and nonpathologic. GERD is defined as GER that causes complications.1,2 Unfortunately, in infants, particularly preterm infants, complications of GER are difficult to characterize. Clinicians disagree about which symptoms are caused by GER or GERD.20 There is mixed evidence in the literature to support or refute most of the proposed complications of GER, including apnea,21-31 worsening of lung disease,32-35 and failure to thrive, in infants.36 An ongoing problem, particularly in the preterm population, is that many of the putative symptoms of GERD also frequently occur for other reasons. For instance, preterm infants without GERD also frequently experience apnea, lung disease, or feeding intolerance.
Physiologic Gastroesophageal Reflux Nonpathologic GER occurs frequently in both preterm and term infants. Among 509 healthy asymptomatic infants aged 3 to 365 days monitored with an esophageal pH probe, the mean number of acid reflux episodes in 24 hours was 31.28, with a standard deviation of 20.68.37 The reflux index, the percent of time the esophageal pH was
