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Gastroenterology and Nutrition, a volume in Dr. Polin’s Neonatology: Questions and Controversies Series, offers expert authority on the toughest neonatal gastroenterologic and nutritional challenges you face in your practice. This medical reference book will help you provide better evidence-based care and improve patient outcomes with research on the latest advances.

  • Reconsider how you handle difficult practice issues with coverage that addresses these topics head on and offers opinions from the leading experts in the field, supported by evidence whenever possible.
  • Find information quickly and easily with a consistent chapter organization.
  • Get the most authoritative advice available from world-class neonatologists who have the inside track on new trends and developments in neonatal care.
  • Stay current in practice with coverage on what the controversies are and where the field is moving in terms of basic intestinal development and nutritional requirements for the neonate.


Derecho de autor
Cardiac dysrhythmia
Vitamin D
Autoimmune disease
Gastrointestinal physiology
Systemic disease
Abdominal distension
Blood in stool
Diabetes mellitus type 1
Developmental disability
Atopic dermatitis
Necrotizing enterocolitis
Gastrointestinal perforation
Protein S
Short bowel syndrome
Breast milk
Biological agent
Biliary atresia
Feeding tube
Insulin-like growth factor 1
Iron deficiency anemia
Toll-like receptor
Palmitic acid
Physician assistant
Positive airway pressure
Temperance (virtue)
Glycemic index
Bowel obstruction
Intensive-care medicine
Saturated fat
Medical ventilator
Parenteral nutrition
Gastroesophageal reflux disease
Posttranslational modification
Gene expression
Diabetes mellitus type 2
Intrauterine growth restriction
Medical ultrasonography
Cellular respiration
Human gastrointestinal tract
Mucous membrane
Coeliac disease
Crohn's disease
Large intestine
Vitamin A
Diabetes mellitus
Vitamin K
Transcription factor
Data storage device
Protein biosynthesis
Messenger RNA
Infectious disease
Fatty acid
Amino acid
Maladie infectieuse


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Gastroenterology and Nutrition
Neonatology Questions and Controversies
Second Edition
Josef Neu, MD
Professor of Pediatrics, University of Florida College of
Medicine, Gainesville, Florida
S a u n d e r sTable of Contents
Cover image
Title page
Series page
Series Foreword
Section A: Basic Science of the Intestinal Tract
Chapter 1: Overview of Digestion and Absorption
Chapter 2: Maturation of Motor Function in the Preterm Infant and
Gastroesophageal Reflux
Chapter 3: Development of Gastrointestinal Motility Reflexes
Chapter 4: Development of the Intestinal Mucosal Barrier
Chapter 5: The Developing Intestinal Microbiome and Its Relationship to
Health and Disease
Chapter 6: The Developing Intestine as an Immune Organ
Chapter 7: The Developing Gastrointestinal Tract in Relation to
Autoimmune Disease, Allergy, and Atopy
Chapter 8: What Are the Controversies for Basic Intestinal Development
and Where Will the Field Be Moving in the Future?
Section B: Nutritional Requirements and Strategies
Chapter 9: Nutritional Requirements of the Very-Low-Birthweight Infant
Chapter 10: Controversies in Neonatal Nutrition: Macronutrients and
Chapter 11: Regulation of Protein Synthesis and Proteolysis in the
Neonate by Feeding
Chapter 12: Lipids for Neonates
Chapter 13: Human Milk Feeding of the High-Risk Neonate
Chapter 14: Nutritional Requirements for the Neonate: What Are the
Controversies and Where Will the Field Be Moving in the Future?
Section C: Clinical Conditions
Chapter 15: Necrotizing Enterocolitis
Chapter 16: Special Nutrition of the Surgical Neonate
Chapter 17: Controversies in Short Bowel SyndromeChapter 18: Neonatal Cholestasis
Chapter 19: The Neonatal Gastrointestinal Tract as a Conduit to Systemic
Inflammation and Developmental Delays
Chapter 20: Adult Consequences of Neonatal and Fetal Nutrition:
Chapter 21: Technologies for the Evaluation of Enteral Feeding
Readiness in Premature Infants
Chapter 22: What Are the Controversies for These Clinical Conditions and
Where Will the Field Be Moving in the Future?
IndexSeries page
Neonatology Questions and Controversies
Series Editor
Richard A. Polin, MD
Professor of Pediatrics
College of Physicians and Surgeons
Columbia University
Vice Chairman for Clinical and Academic Affairs
Department of Pediatrics
Director, Division of Neonatology
Morgan Stanley Children’s Hospital of NewYork-Presbyterian
Columbia University Medical Center
New York, New York
Other Volumes in the Neonatology Questions and Controversies Series
1600 John F. Kennedy Blvd.
Ste 1800
Philadelphia, PA 19103-2899
Gastroenterology and Nutrition: Neonatology Questions and Controversies
second edition ISBN: 978-1-4377-2603-9
Copyright © 2012, 2008 by Saunders and imprint of Elsevier Inc.
All rights reserved. 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).
Knowledge and best practice in this 9eld 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 identi9ed, 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.
Library of Congress Cataloging-in-Publication Data
Gastroenterology and nutrition: neonatology questions and controversies /
[edited by] Josef Neu. — 2nd ed.
p. ; cm.
Includes bibliographical referencse and index.ISBN 978-1-4377-2603-9 (hardback)
I, Neu, Josef.
[DNLM: 1. Gastrointestinal Disease. 2. Infant, Newborn, Diseases. 3. Infant
Nutritional Physiological Phenomena. 4. Infant, Newborn. WS 310]
Content Strategist: Stefanie Jewell-Thomas
Content Development Specialist: Lisa Barnes
Publishing Services Manages: Peggy Fagen and Hemamalini Rajendrababu
Project Manager: Deepthi Unni
Designer: Ellen Zanolle
Printed in The United States of America
Last digit is the print number: 9 8 7 6 5 4 3 2 1 Contributors
Kjersti Aagaard-Tillery, MD, PhD
Assistant Professor
Baylor College of Medicine
Obstetrics and Gynecology
Houston, Texas
Adult Consequences of Neonatal and Fetal Nutrition: Mechanisms
Joel M. Andres, MD
Professor, Pediatrics
University of Florida College of Medicine
Gainesville, Florida
Neonatal Cholestasis
Tracy Gautsch Anthony, PhD
Associate, Professor
Department of Biochemistry and Molecular Biology
Indiana University School of Medicine
Evansville, Indiana
Regulation of Protein Synthesis and Proteolysis in the Neonate by Feeding
Carolyn Berseth, MD
Director, Medical Affairs North America
Mead Johnson Company
Evansville, Indiana.
Development of the Gastrointestinal Motility Reflexes
Ricardo A. Caicedo, MD
Associate Professor
Pediatrics, Gastroenterology and NutritionLevine Children’s Hospital
Carolinas Medical Center
Charolotte, North Carolina
Development of the Intestinal Mucosal Barrier
Ashish N. Debroy, MD
Department of Pediatrics
Divisions of Gastroenterology and Neonatology
University of Texas Medical School at Houston
Houston, Texas
Controversies in Short Bowel Syndrome
Clotilde desRobert-Marandet, MD
Neonatal Intensive Care Unit
University Hospital of Nantes
Nantes, France
Adult Consequences of Neonatal and Fetal Nutrition: Mechanisms
Frank R. Greer, BS, MD
Professor, Pediatrics
University of Wisconsin School of Medicine and Public
Madison, Wisconsin
Controversies in Neonatal Nutrition: Macronutrients and Micronutrients
Allah B. Haafiz, MD
Assistant Professor of Pediatrics
University of Florida College of Medicine
Division of Gastroenterology and Hepatology
Gainesville, Florida
Neonatal Cholestasis
William W. Hay, Jr., MD
ProfessorDepartment of Pediatrics (Neonatology)
University of Colorado School of Medicine
Aurora, Colorado
Nutritional Requirements of the Very-Low-Birthweight Infant
Anna Maria Hibbs, MD, MSCE
Assistant Professor, Pediatrics
Case Western Reserve University
Cleveland, Ohio
Nutrition and Metabolism
Child and Family Research Institute
Scientific and Professional Staff
Division of Neonatology
B.C. Children’s and Women’s Hospitals
Vancouver, Canada
Maturation of Motor Function in the Preterm Infant and Gastroesophageal
Essam Imseis, MD
Department of Pediatrics
Divisions of Gastroenterology and Neonatology
University of Texas Medical School at Houston
Houston, Texas
Controversies in Short Bowel Syndrome
Sheila M. Innis, PhD
Professor, Pediatrics
University of British Columbia
Nutrition and Metabolism
Child and Family Research Institute
Scientific and Professional Staff
Division of Neonatology
British Columbia Children’s and Women’s Hospitals
Vancouver, CanadaLipids for Neonates
Sudarshan Rao Jadcherla, MD, FRCPI, DCH, AGAF
Professor, Department of Pediatrics
The Ohio State University College of Medicine
Sections of Neonatology and Pediatric Gastroenterology &
Columbus, Ohio
Development of Gastrointestinal Motility Reflexes
Tom Jaksic, MD
W. Hardy Hendren Professor
Harvard Medical School
Vice Chairman
Department of Pediatric General Surgery
Children’s Hospital Boston
Boston, Massachusettes
Special Nutrition of the Surgical Neonate
Lisa A. Joss-Moore, PhD
Assistant Professor, Pediatrics
University of Utah
Salt Lake City, Utah
Adult Consequences of Neonatal and Fetal Nutrition: Mechanisms
Jamie Kuang Horn Kang, MD
Research Fellow
Department of Surgery
Harvard Medical School
Research Fellow
Department of Surgery
Children’s Hospital Boston
Boston, Massachusettes
Special Nutrition of the Surgical NeonateEe-Kyung Kim, MD
Department of Pediatrics
Seoul National University Children’s Hospital
Seoul, Korea
Technologies for the Evaluation of Enteral Feeding Readiness in
Premature Infants
Robert H. Lane, MD, MS
Professor, Neonatology
University of Utah
University Health Care
Primary Children’s Medical Center
Intermountain Healthcare
Salt Lake City, Utah
Adult Consequences of Neonatal and Fetal Nutrition: Mechanisms
Patricia Lin, MD
Assistant Profesor of Pediatrics
Emory University School of Medicine
Atlanta, Georgia
The Developing Intestine as an Immune Organ
Volker Mai, PhD
Assistant Professor
Microbiology and Cell Science
University of Florida
Gainesville, Florida
The Developing Intestinal Microbiome and Its Relationship to Health and
Camilia R. Martin, MD, MS
Assistant Professor of PediatricsDepartment of Pediatrics
Division of Newborn Medicine
Harvard Medical School
Associate Director
Neonatal Intensive Care Unit
Department of Neonatology
Director For Cross Disciplinary Research Partnerships
Division of Translational Research
Beth Israel Deaconess Medical Center
Boston, Massachusettes
Development of the Intestinal Mucosal Barrier
Nicole Mitchell, MD
Adult Consequences of Neonatal and Fetal Nutrition: Mechanisms
Susan Hazels Mitmesser, PhD
Manager, Global Medical Communications
Medical Affairs
Mead Johnson Nutritiion
Evansville, Indiana
Regulation of Protein Synthesis and Proteolysis in the Neonate by Feeding
Ardythe L. Morrow, PhD
Environmental Health Nutrition
University of Cincinnati College of Medicine
Cincinnati, Ohio
Center for Interdisciplinary Research in Human Milk and
Perinatal Institute
Cincinnati Children’s Hospital
Cincinnati, Ohio
Human Milk Feeding of the High-Risk Neonate
Fernando Navarro, MDDepartment of Pediatrics
Divisions of Gastroenterology and Neonatology
University of Texas Medical School at Houston
Houston, Texas
Controversies in Short Bowel Syndrome
Ursula Nawab, MD
Department of Pediatrics
Divisions of Gastroenterology and Neonatology
University of Texas Medical School at Houston
Houston, Texas
Controversies in Short Bowel Syndrome
Andrew S. Neish, MD
Epithelial Pathobiology Unit
Department of Pathology and Laboratory Medicine
Emory University School of Medicine
Atlanta, Georgia
The Developing Intestine as an Immune Organ
Josef Neu, MD
Professor of Pediatrics
University of Florida College of Medicine
Gainesville, Florida
Overview of Digestion and Absorption
The Developing Intestinal Microbiome and Its Relationship to Health and
What Are the Controversies for Basic Intestinal Development and Where
Will the Field Be Moving in the Future?
Nutritional Requirements for the Neonate: What Are the Controversies
and Where Will the Field Be Moving in the Future?
Necrotizing Enterocolitis
The Neonatal Gastrointestinal Tract as a Conduit to Systemic
Inflammation and Developmental Delays
Technologies for the Evaluation of Enteral Feeding Readiness inPremature Infants
What Are the Controversies for These Clinical Conditions and Where Will
the Field Be Moving in the Future?
Sungho Oh, MD
Division of Neonatology
Department of Pediatrics
University of Florida
Technologies for the Evaluation of Enteral Feeding Readiness in
Premature Infants
Ravi M. Patel, MD
Assistant Professor of Pediatrics
Department of Pediatrics
Division of Neonatal-Perinatal Medicine
Emory University School of Medicine
Attending Neonatologist
Children’s Healthcare of Atlanta
Atlanta, Georgia
The Developing Intestine as an Immune Organ
J. Marc Rhoads, MD
Professor, Pediatrics
University of Texas
Houston, Texas
Controversies in Short Bowel Syndrome
Renu Sharma, MD
Neonatal Biochemical Nutrition and GI Development
Department of Pediatrics
Division of Neonatology
University of Florida
Gainesville, Florida
Necrotizing EnterocolitisPatti J. Thureen, MD
Department of Pediatrics (Neonatology)
University of Colorado School of Medicine
Aurora, Colorado
Nutritional Requirements of the Very-Low-Birthweight Infant
Outi Vaarala, MD, PhD
Professor of Pediatric Immunology
Immune Response Unit
National Institute for Health and Welfare
Biomedicum1 Helsinki
Helsinki, Finland
The Developing Gastrointestinal Tract in Relation to Autoimmune Disease,
Allergy, and Atopy
Christina J. Valentine, MD, MS, RD
Assistant Professor
Department of Pediatrics
The University of Cincinnati
Cincinnati, Ohio
Neonatologist, Principal Investigator
Division of Neonatology
Perinatal and Pulmonary Biology
Cincinnati Children’s Hospital Medical Center
Cincinnati, Ohio
Human Milk Feeding of the High-Risk Neonate
W. Allan Walker, MD
Conrad Taff Professor of Nutrition and Pediatrics
Department of Pediatrics
Division of Nutrition
Harvard Medical School
Director, Mucosal Immunology Laboratory
Massachusettes General HospitalBoston, Massachusettes
Development of the Intestinal Mucosal Barrier
James L. Wynn, MD
Assistant Professor of Pediatrics
Duke University
Durham, North Carolina
The Neonatal Gastrointestinal Tract as a Conduit to Systemic
Inflammation and Developmental Delays
Christopher Young, MD
Neonatal Biochemical Nutrition and GI Development
Department of Pediatrics
Division of Neonatology
University of Florida
Gainesville, Florida
Necrotizing Enterocolitis0
Series Foreword
Richard A. Polin, MD
“Medicine is a science of uncertainty and an art of probability.”
—William Osler
Controversy is part of every day practice in the NICU. Good practitioners
strive to incorporate the best evidence into clinical care. However, for much of
what we do, the evidence is either inconclusive or does not exist. In those
circumstances, we have come to rely on the teachings of experienced practitioners
who have taught us the importance of clinical expertise. This series, “Neonatology
Questions and Controversies,” provides clinical guidance by summarizing the best
evidence and tempering those recommendations with the art of experience.
To quote David Sackett, one of the founders of evidence-based medicine:
Good doctors use both individual clinical expertise and the best available external
evidence and neither alone is enough. Without clinical expertise, practice risks
become tyrannized by evidence, for even excellent external evidence may be
inapplicable to or inappropriate for an individual patient. Without current best
evidence, practice risks become rapidly out of date to the detriment of patients.
This series focuses on the challenges faced by care providers who work in the
NICU. When should we incorporate a new technology or therapy into every day
practice, and will it have positive impact on morbidity or mortality? For example,
is the new generation of ventilators better than older technologies such as CPAP,
or do they merely o er more choices with uncertain value? Similarly, the use of
probiotics to prevent necrotizing enterocolitis is supported by sound scienti c
principles (and some clinical studies). However, at what point should we
incorporate them into every day practice given that the available preparations are
not well characterized or proven safe? A more di cult and common question is
when to use a new technology with uncertain value in a critically ill infant. As
many clinicians have suggested, sometimes the best approach is to do nothing and
“stand there.”
The “Questions and Controversies” series was developed to highlight the
clinical problems of most concern to practitioners. The editors of each volume
(Drs. Bancalari, Oh, Guignard, Baumgart, Kleinman, Seri, Ohls, Maheshwari, Neu,
and Perlman) have done an extraordinary job in selecting topics of clinical
importance to every day practice. When appropriate, less controversial topics have
been eliminated and replaced by others thought to be of greater clinical
importance. In total, there are 56 new chapters in the series. During the
preparation of the “Hemodynamics and Cardiology” volume, Dr. Charles
Kleinman died. Despite an illness that would have caused many to retire, Charlie
worked until near the time of his death. He came to work each day, teaching
students and young practitioners and o ering his wisdom and expertise to families1
of infants with congenital heart disease. We are dedicating the second edition of
the series to his memory. As with the rst 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 (publishing director at Elsevier), who provided incredible assistance in
bringing this project to fruition.

Over the past several years, with improved survival of critically ill and very
small preterm infants, neonatologists are focusing on nutrition of these infants as a
means to prevent morbidities associated with intensive care, such as chronic lung
disease and the complications of neurologic injuries. The intestine is being looked
upon as more than a digestive absorptive organ, with the recognition that it has a
very large surface area which serves as a barrier to potentially dangerous microbes
and food antigens. When this breaks down, there is a huge potential for
translocation of bacteria to the bloodstream, sepsis, in ammation, and
accompanying short- and long-term complications.
The microbes that reside within the lumen of the intestine are increasingly
being recognized as mediators of growth with the provision of nutrients that are
products of their metabolism, as well as major mediators of in ammatory processes
in the intestine. They play a major role in modulation of innate immunity as well as
development of adaptive immunity. Alterations of the normal microbiota in the
developing intestine of these infants (“dysbiosis”) are associated with diseases such
as necrotizing enterocolitis (NEC).
New technologies are rapidly evolving that may help us assess in ammatory
processes in the intestinal tract. Technologies that may assist the neonatologist to
determine feeding readiness as well as propensity to develop diseases such as NEC
and late onset sepsis are rapidly evolving. Methodologies to evaluate these as well
as epigenetic mechanisms that lead to diseases such as metabolic syndrome are
being developed and discussed.
In this revised edition, we continue to incorporate clinical neonatal
gastroenterology and nutrition with up-to-date research. We hope that it will not
only provide guidance for clinical care with clari cation of some of the
controversies related to nutrition, feeding, and neonatal intestinal disease but also
stimulate new avenues of research that will be pertinent to optimizing the care of
these infants and providing them the opportunity to reach their full genetic
Josef Neu, MDSection A
Basic Science of the Intestinal TractChapter 1
Overview of Digestion and Absorption
Josef Neu, MD
• Protein Digestion and Absorption
• Carbohydrate Digestion and Absorption
• Lipid Digestion and Absorption
Along with its role as the largest and most active immune organ of the body, the
intestine is involved in important endocrine and exocrine roles and also encompasses
neural tissue equivalent to that of the entire spinal cord. The intestinal luminal
microbiota interactions with the intestinal mucosa and submucosa are becoming
increasingly recognized as critical in health and disease. In addition to these
seemingly newfound functions of the gastrointestinal tract that will be discussed in
subsequent chapters, the intestine’s role in digestion and absorption of nutrients
remains of utmost importance in health. Its development during neonatal and early
childhood periods needs to be understood to optimize nutrition during these highly
critical windows of development. Here, basic physiology of some of the major aspects
of macronutrient (protein, carbohydrate, and lipid) digestion and absorption during
early life will be provided and related to developmental maturation and clinical
strategies based on these principles.
Growth: There is a close interplay between overall size of the intestine and surface
area. In the term infant, the length of the small intestine is about 200 cm, and the
villous and microvillous architecture provides a huge surface area that is much
larger than that of the skin. Half of the growth in length of the intestine occurs in
1the last trimester of gestation.
Digestion: Large molecular aggregates need to be processed by mechanical and
chemical means starting in the mouth, stomach, and upper small intestine. The
enzymatic and other chemical processes in luminal digestion involve interactions
between gastric acid, lipases (lingual, gastric, pancreatic, and milk derived),
salivary- and pancreatic-derived carbohydrases, pepsin, pancreatic-derived
proteases, lipases, and bile.
Absorption: The intestinal epithelium is composed of a population of diverse cells
whose functions di+ er along the aboral (or horizontal) as well as the crypt to villus
(vertical) gradients. As ingested nutrients travel through the intestine, they are
sequentially exposed to regions that have epithelia with very di+ erent absorptive
characteristics; permeability, transporter, and enzymatic functions di+ er markedly
along the proximal-distal portions of the intestine.
Processes for digestion and absorption of protein, carbohydrates, and lipids are
described separately in this chapter. A brief general review of major physiologicprocesses for each of the macronutrients is . rst provided, then development of these
processes during fetal and early postnatal life is described. Correlations of some of
these principles to patient care will also be presented.
Protein Digestion and Absorption
The composition of proteins ingested by neonates largely re0ects that in either
mother’s milk or commercial formulas. Digestion of proteins begins in the acidic
environment of the stomach and continues in the small intestine under the in0uence
of pancreatic proteases and peptidases.
Dietary proteins in human infants are, with very few exceptions, not absorbed
intact. Rather, they must . rst be digested into amino acids or dipeptides and
tripeptides. Proteolytic enzymes are secreted into the lumen of the upper digestive
tube from two primary sources: (1) the stomach secretes pepsinogen, which is
converted to the active protease pepsin by the action of acid; and (2) the pancreas
secretes a group of potent proteases, chief among them trypsin, chymotrypsin, and
carboxypeptidases, which require activation by enterokinase. Through the action of
these gastric and pancreatic proteases, dietary proteins are hydrolyzed within the
lumen of the small intestine predominantly into medium and small peptides
These small peptides, primarily dipeptides and tripeptides, are absorbed into the
+ 2,3small intestinal epithelial cell by cotransport with H ions. Once inside the
enterocyte, the vast bulk of absorbed dipeptides and tripeptides are hydrolyzed into
single amino acids by cytoplasmic peptidases and exported from the cell into blood.
Only a very small number of these small peptides enter blood intact.
The mechanism by which amino acids are absorbed by the epithelial cell is
similar to that of monosaccharides. The luminal plasma membrane of the absorptive
cell bears several sodium-dependent amino acid transporters—one each for acidic,
4basic, neutral, and amino acids. These transporters bind amino acids only after
binding sodium, after which a conformational change allows entry of sodium and the
amino acid into the cytoplasm, followed by its reorientation back to the original
form. Thus, absorption of amino acids is dependent on the electrochemical gradient
of sodium across the epithelium. Further, absorption of amino acids, like that of
monosaccharides, contributes to generating the osmotic gradient that drives water
absorption. The basolateral membrane of the enterocyte contains additional
transporters that export amino acids from the cell into blood. These are not
dependent on sodium gradients.
Developmental Aspects of Protein Digestion and Absorption
Gastric Acidity
5The . rst traces of gastric acidity appear in 4-month-old fetuses. The human fetus
has the potential to produce gastric acid and gastrin from the middle of the second
trimester. Parietal cell activity is present in the body, antrum, and pyloric regions in
5-7the fetus from 13 to 28 weeks. When comparing full-term and premature infants,
hydrochloric acid secretion was found to be much lower in premature infants than in8full-term infants.
Gastric acid secretion is limited in very-low-birthweight (VLBW) infants.
However, both basal and pentagastrin-stimulated acid secretion doubles from the first
9to fourth week of postnatal life in preterm infants. The actual pH of the stomach
contents in infants is substantially in0uenced by food intake. The entry of milk into
the infant’s stomach causes a sharp increase in the pH of the gastric contents and a
10slower return to lower pH values than in older children and adults.
Gastric Proteolytic Activity
The output of pepsin is low in the newborn infant and increases until the third
postnatal month. The range of values found in the second and third postnatal months
11is less than the range of adult values. In contrast, pepsin activity in biopsy
specimens from the stomachs of infants and children did not change between the
12ages of 6 months and 15 years. Formula feeding evokes an increase of pepsin
activity in the stomach content of 3- to 4-week-old orogastrically fed premature
Pancreatic Proteolytic Activity
The protease cascade in the small intestine is catalyzed by food-stimulated secretion
of enterokinase from the upper small intestinal epithelium. Enterokinase catalyzes the
conversion of pancreatic pro-proteases to active enzymes (Table 1-1). Even though
enterokinase is detectable at 24 weeks’ gestation, its concentration is relatively low
14and reaches only 25% of adult activity at term. This theoretically can be limiting
to protein digestion and may be responsible for an increased capability of larger
antigens or microorganisms to pass into the intestine without breakdown by luminal
Proteolytic enzymes contained in gastric juice
Requires acid environment of stomach to hydrolyze protein
Synthesized in the gastric chief cells as inactive pre-proenzymes (pepsinogen)
Intestine and Pancreas
Enterokinase—an intestinal brush border enzyme that activates pancreatic
proteases and is stimulated by trypsinogen contained in pancreatic juice
Pancreatic Endopeptidases
Trypsin: cleaves peptide bonds on the carboxyl side of basic amino acids (lysine and
Chymotrypsin: cleaves peptide bonds on the carboxyl side of aromatic amino acids(tryosine, phenylalanine and tryptophan)
Elastase: cleaves peptide bonds on the carboxyl side of aliphatic amino acids
(alanine, leucine, glycine, valine, isoleucine)
Pancreatic Exopeptidases
Carboxypeptidases A and B: zinc-containing metalloenzymes that remove single
amino acids from the carboxyl-terminal ends of proteins and peptides
Carboxypeptidase A: polypeptides with free carboxyl groups are cleaved to lower
peptides and aromatic amino acids
Carboxypeptidase B: polypeptides with free carboxyl groups are cleaved to lower
peptides and dibasic amino acids
15Pancreatic enzymes begin to form at about the third fetal month, and
pancreatic secretion starts at the beginning of the . fth month of gestation. Levels of
trypsin concentration encountered during the . rst 2 years of life are reached by the
age of 3 months. From birth onward, the concentration of chymotrypsin (after
pancreozymin-secretin stimulation) increases about threefold and reaches adult levels
in 3-year-old children. Serial measurement of fecal chymotrypsin concentrations in
preterm infants (23 to 32 weeks’ gestation) during the . rst 4 weeks of life
demonstrated values generally similar to those found in term infants. Premature
infants fed soy-based formula for 1 month exhibited higher trypsin activity after
cholecystokinin-pancreozymin stimulation than did those fed a milk-based
For a very few days after birth, most mammalian neonates have the ability to absorb
intact proteins. This ability, which is rapidly lost, is of importance because it allows
the newborn animal to acquire passive immunity by absorbing immunoglobulins in
colostral milk. The small intestine rapidly loses its capacity to absorb intact proteins
—a process called closure; and consequently, animals that do not receive colostrum
within the first few days after birth will likely die from opportunistic infections.
The ability of the gastrointestinal tract to exclude antigenically intact food
proteins increases with gestational age, and gut closure occurs normally before birth
17in humans. Using lactulose-to-mannitol ratios, preterm infants’ (26 to 36 weeks’
gestation) intestinal permeability was not related to gestational age or birthweight
but was higher during the . rst 2 days of life than 3 to 6 days later. It is higher in
preterm infants than in healthy term infants only if measured within 2 days of birth.
18This suggests rapid postnatal adaptation of the small intestine in preterm infants.
Proteolytic and Peptidase Activity
Beginning in the eighth week of gestation, villi are formed from the duodenum up to
the ileum, and after week 9, di+ erentiation of the crypts of Lieberkühn is observed.
The activity of proteases is high (especially DPP IV) in the di+ erentiating microvillous
zone of primitive enterocytes. The gradient of apex-base activity of the villus ismaximal on the apex of the villi. In one study, brush border and intracellular
proteolytic enzyme activities were measured in fetuses (8 to 22 weeks’ gestation),
children (7 months to 14 years of age), and adults. The peptidase activities in all
three of the groups were comparable, suggesting that the small intestine of the term
19and preterm newborn should be able to efficiently digest peptides.
Clinical Correlations
Acid secretion limitations in premature infants should be kept in mind when
considering the use of histamine-2 (H ) blockers, which are widely prescribed in2
many neonatal intensive care units. Studies suggest that critically ill premature
infants treated with H blockers have a higher incidence of nosocomial sepsis and2
20,21necrotizing enterocolitis. Although speculative, it is possible that with the
already limited hydrogen ion production in the stomach of the premature infant,
additional blockage further diminishes the acid barrier to microorganisms and allows
for a higher load of bacteria in the more distal regions of the intestine.
In terms of protein absorption, the mechanisms for brush border hydrolysis are
present early; dipeptides and tripeptides are absorbed faster than amino acids, and
22protein digestion and absorption rarely appear to be an issue in premature infants.
Despite the potential limitations of digesting and enzymatic capability in
premature infants, data showing signi. cant bene. ts using hydrolyzed protein
20,23fractions appear to o+ er only minimal advantage over whole protein formulas.
Studies have yet to demonstrate a bene. t of hydrolyzed protein formulas over human
Hydrolyzed formulas are also extensively prescribed to prevent allergic and
atopic disease. However, a recent Cochrane meta-analysis showed no evidence to
support feeding with a hydrolysed formula for the prevention of allergy over
exclusive breastfeeding. Furthermore, in high-risk infants who are unable to be
completely breastfed, there is limited evidence that prolonged feeding with a
hydrolyzed formula compared with a cow’s milk formula reduces infant and
24childhood allergy and infant cow’s milk allergy.
Carbohydrate Digestion and Absorption
Starches and complex carbohydrates must . rst be hydrolyzed to oligosaccharides by
digestive processes in the mouth, stomach, and intestinal lumen. This is accomplished
primarily through salivary and pancreatic amylases. Oligosaccharides must then be
hydrolyzed at the epithelial brush border to monosaccharides before absorption, and
the key catalysts in these processes are the brush border hydrolases, which include
maltase, lactase, and sucrase. Dietary lactose, sucrose, and maltose come in contact
with the surface of absorptive epithelial cells covering the villi where they engage
with brush border hydrolases: maltase, sucrase, and lactase.
Developmental Aspects of Carbohydrate Digestion and Absorption
Carbohydrate Digestion
There is no di+ erence in amylase activity in preterm and term human milk. The
isoamylase of preterm milk is of the salivary type, just as in term milk. There is nogreat variation in amylase activity during a feeding or from one feeding to
25,26another. This can survive the relatively mild acidity and the lower activity of
pepsin in the stomach of the newborn infant. Amylase in saliva is present in lower
27concentrations in children than in adults.
Pancreatic amylase activity has been demonstrated in amniotic 0uid and
28,29pancreatic tissue from 14- to 16-week-old fetuses. Although salivary amylase
activity rapidly increases shortly after term birth, pancreatic amylase remains low
30until 3 months and does not reach adult levels until nearly 2 years of age.
Carbohydrate Absorption
Activity of sucrase and lactase is lower in young fetuses than in specimens from the
14small intestinal mucosa of adults. Sucrase activity is present in the fetal colon and
31disappears before birth. The presence of lactase in the fetal colon (13 to 20 weeks
14 32of age) has also been described previously. Villa and coworkers con. rmed that
intestinal lactase is low between 14 and 20 weeks of gestation and exhibits a
relatively high level of activity at 37 weeks; amounts of lactase messenger RNA
(mRNA) correlated with the enzymatic activity. It is interesting that lactase mRNA
was not detectable in the colon of normal adult subjects, whereas it was detectable at
33low levels in fetal colon. Sucrase-isomaltase in the human fetal intestine is present
in a di+ erent form from that in adults, and it di+ ers in degree of glycosylation
34(di+ erent electrophoretic mobility) and in the size of the polypeptide. The
di+ erence in polypeptide length in fetuses and adults can be related to low activity of
pancreatic proteases in the fetal intestinal lumen.
Studies suggest that colonic fermentation activity is adequate for colonic salvage of
lactose even during the second week of life. Using a stable isotope method for serial
35assessment of lactose carbon assimilation, Kien and associates demonstrated
eJ cient absorption of lactose in premature infants (30 to 32 weeks’ gestation and 11
to 36 days of age). Despite that . nding, a study in which 130 preterm infants fed
standard preterm formula with and without lactase showed that lactase-treated
infants grew faster over the . rst 10 days of life but similarly thereafter, suggesting
36that limitations in lactose absorption are short-lived in the preterm infant.
Absorption of Monosaccharides
Glucose absorption in infants is less eJ cient than in adults (Table 1-2). Kinetics of
glucose absorption are related to gestational age and appear to be a+ ected by diet
37and exposure to glucocorticoids. Other studies demonstrated that carrier-mediated
monosaccharide absorption increases the . rst 2 postnatal weeks in infants born at 28
38to 30 weeks’ gestation.
+Glucose uptake is Na dependent.Fructose is absorbed through facilitated diffusion.
Galactose and glucose are actively transported.
+1 SGLT1 is the transport protein responsible for Na -dependent glucose
2 Glut-2 transports glucose out of the cell into the portal circulation.
Clinical Correlations
Because pancreatic secretion is poorly developed in the . rst several months after
birth, this mode of starch hydrolysis could serve as a limiting factor that leaves
substantial undigested starch in the intestine. Many infant formulas, including those
formulated for preterm infants, contain partially hydrolyzed starches. The more
extensively the starch is hydrolyzed, the less reliance is placed on an immature
digestive capability, but the greater the osmolality. Whether there is any advantage
of these hydrolyzed starch formulas over those containing disaccharides or lactose
has not been established.
A study in premature infants was designed to ascertain whether the timing of
feeding initiation a+ ected the development of intestinal lactase activity and whether
39there are clinical rami. cations of lower lactase activity. Early feeding increased
intestinal lactase activity in preterm infants. Lactase activity is a marker of intestinal
maturity and may in0uence clinical outcomes. Whether the e+ ects of milk on lactase
activity were due to the greater concentration of lactose in human milk compared
39with that in formula has not yet been determined.
The . nding of low lactase activities in the intestine of fetuses has led to the
14notion that premature babies cannot tolerate lactose. The presence of a high
lactose concentration in human milk should not be a contraindication for its use in
the VLBW infant. Microbial salvage pathways that convert nonabsorbed lactose to
short-chain fatty acids that can be absorbed and utilized for energy production are
35functional in these infants (Fig. 1-1). Furthermore, feedings for VLBW infants
rarely are initiated at levels intended to meet the infants’ entire nutritional
requirements and usually are advanced slowly. The rationale for using a lactose-free
formula instead of human milk or even a commercial lactose-containing formula is
weak and theoretically may be harmful. Slow initiation of enteral feedings is unlikely
to exceed the lactose hydrolytic and salvage capability of the small and large
intestines.Figure 1-1 Lactase de. ciency, fermentation by microbes in the distal intestine and
production of short-chain fatty acids (SCFA).
Lipid Digestion and Absorption
The bulk of dietary lipid is triglyceride, composed of a glycerol backbone with each
carbon linked to a fatty acid through an ester moiety. Foodstu+ s typically also
contain phospholipids, cholesterol, and many minor lipids, including fat-soluble
vitamins. In order for the triglyceride to be absorbed, two processes must occur (Fig.
• Large aggregates of dietary triglyceride, which are virtually insoluble in an aqueous
environment, must be broken down physically and held in suspension—a process
called micellar emulsification.
• Triglyceride molecules must be enzymatically digested through triglyceride
hydrolysis to yield monoglyceride and fatty acids, both of which can eJ ciently
diffuse or be transported into the enterocyte .
Figure 1-2 A, Bile acid emulsification of lipids. B, Lipase hydrolysis of triglyceride.
The key mediators in these two transformations are bile acids and lipases. Bile
acids are also necessary to solubilize other lipids, including cholesterol.
Emulsification, Hydrolysis, and Micelle Formation
Bile acids promote lipid emulsi. cation. Bile acids have both hydrophilic and
hydrophobic domains (i.e., they are amphipathic). On exposure to a large aggregateof triglyceride, the hydrophobic portions of bile acids intercalate into the lipid, with
the hydrophilic domains remaining at the surface. Such coating with bile acids aids
in breakdown of large aggregates or droplets into smaller and smaller droplets. For a
given volume of lipid, the smaller the droplet size, the greater the surface area, which
provides greater surface area for interaction with lipase.
Hydrolysis of triglyceride into monoglyceride and free fatty acids is
accomplished predominantly by pancreatic lipase. The activity of this enzyme is to
clip the fatty acids at positions 1 and 3 of the triglyceride, leaving two free fatty acids
and a 2-monoglyceride. As monoglycerides and fatty acids are liberated through the
action of lipase, they retain their association with bile acids and complex with other
lipids to form micelles, which are small aggregates (4 to 8 nm in diameter) of mixed
lipids and bile acids suspended within the ingesta. Micelles, providing much greater
lipid surface area than the original fat globule, allow for ampli. ed interaction with
the brush border of small intestinal enterocytes, where the monoglyceride and fatty
acids are taken up into the epithelial cells.
The major products of lipid digestion—fatty acids and 2-monoglycerides—enter
the enterocyte by simple di+ usion across the plasma membrane. A considerable
fraction of the fatty acids also enter the enterocyte through a speci. c fatty acid
transporter protein in the membrane.
After entry into the cell, medium-chain triglycerides, which require only minimal
emulsi. cation by bile acids, undergo a relatively simple process of assimilation in
which they do not undergo re-esteri. cation and chylomicron formation, as the
longchain lipids do. Medium-chain triglycerides are taken directly into the portal venous
system; chylomicrons formed from long-chain fats enter the lymphatics. In conditions
that involve obstruction of the lymphatics, feeding formulas containing primarily
medium-chain triglycerides rather than long-chain triglycerides are recommended.
Developmental Aspects of Lipid Digestion and Absorption
Bile Acids
Bile acids are critical to eJ cient fat digestion and absorption. These processes are
limited in VLBW infants because the duodenal concentration of bile acids is low
40owing to lower synthesis and ileal reabsorption. Lower micellar solubilization leads
to ineJ cient cell-mucosal interaction and subsequently lower absorption of the
molecules of the mucosal–cell surface interface. Long-chain fatty acids but not
medium-chain fatty acids depend on bile acids for solubilization and, thus, are the
most susceptible to inefficient absorption.
Bile Salt–Stimulated Lipase
41Human milk contains esterolytic activity that is not detectable in bovine milk. It
has been shown that the digestion of long-chain triglycerides proceeded only in the
presence of bile salts by an enzyme, later classi. ed as bile salt–stimulated lipase
42-44(BSSL), which is present in human colostrum and in preterm and term milk. It
has been estimated that in milk produced during the . rst 2 weeks of lactation, 40%
of triglycerides are hydrolyzed within 2 hours, and during later lactation, only 20% of
44,45triglycerides are hydrolyzed. This apparent decrease is caused by an increase in
milk fat content during lactation, rather than a real change in absolute BSSL activity.
The signi. cance of the presence of BSSL for the digestion of milk lipids is
supported further by studies of low-birthweight preterm infants (3 to 6 weeks old) fedraw or heat-treated (pasteurized or boiled) human milk. Fat from the former was
46absorbed more (74%) than the latter two (54% and 46%, respectively).
Pancreatic Lipases
In adults, pancreatic juice contains two enzymes involved in triglyceride hydrolysis.
The so-called pancreatic lipase is more active against insoluble, emulsi. ed substrates
than against soluble ones. The second lipase, also called pancreatic carboxylase
esterase, is more active against micellar or soluble substrates than against insoluble,
emulsi. ed substrates. In contrast to the . rst lipase, it is strongly stimulated by bile
salts. Colipase removes the inhibiting e+ ect of bile salts on lipase. Studies usually do
not di+ erentiate between these lipases. Generally, lipases show the lowest values after
47birth. The increase toward adult values occurs within the . rst 6 months of life,
which is earlier than in the case of amylase. Premature and VLBW infants have lower
48values than do full-term neonates. During the . rst week of life, lipase activity
47increases about fourfold in premature infants.
In healthy preterm infants between days 3 and 40 postnatally, this activity
increased linearly (both in infants at gestational age 29 to 32 weeks and 33 to 36
40weeks). At 1 month of age, values reached 35% of values found in 2- to 6-week-old
Clinical Correlations
Although it has been mentioned that there appear to be di+ erences for long-chain
versus medium-chain triglycerides in the need to for bile acids, studies have shown
medium-chain triglycerides to be just as readily absorbed as long-chain
49triglycerides. The mechanisms of this are speculated to reside in greater gastric
lipolytic activity of the longer-chain lipids. This is supported by a Cochrane review
that showed no di+ erences in growth, necrotizing enterocolitis, or other morbidities
50in babies fed primarily medium- versus long-chain triglycerides.
Most essential fatty acids provided to neonates are derived from the -6 family
(linoleic acid). This is because much of the lipid derived from formulas or
intravenous lipid solutions is from vegetable oil, which is rich in the -6 but not the
-3 fraction. The likelihood of health bene. ts to babies provided greater quantities of
the -3 lipids than they are currently receiving requires additional study and is
discussed in Chapter 12.
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28 Davis MM, Hodes ME, Munsick RA, et al. Pancreatic amylase expression in human
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36 Erasmus HD, Ludwig-Auser HM, Paterson PG, et al. Enhanced weight gain in
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37 Shulman RJ. In vivo measurements of glucose absorption in preterm infants. Biol
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38 Rouwet EV, Heineman E, Buurman WA, et al. Intestinal permeability and
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41 Tarassuk NP, Nickerson TA, Yaguchi M. Lipase action in human milk. Nature.
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Database Syst Rev. 2003. CD00277

Chapter 2
Maturation of Motor Function in the Preterm Infant and
Gastroesophageal Reflux
Anna Maria Hibbs, MD, MSCE
• 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
• Summary
Gastroesophageal re ux (GER) is de ned 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 de nition of
1,2gastroesophageal re ux disease (GERD) if it causes clinical symptoms or complications. A multitude of
gastrointestinal, respiratory, and other symptoms have been attributed to GERD, including apnea, worsening of
lung disease, irritability, feeding intolerance, failure to thrive, and stridor. However, determining whether reflux
is the cause of symptoms in an infant can be challenging. The approach to an infant with suspected GERD is
further complicated by the paucity of available medications demonstrated to be safe or e) ective in this
Upper Gastrointestinal Motility and Physiology
An understanding of GER in infants must begin with the physiology of the upper gastrointestinal tract.
3,4Esophageal motor function is well-developed in infants as early as 26 weeks gestational age. Swallowing
triggers coordinated esophageal peristalsis and lower esophageal sphincter (LES) relaxation, as it does in more
3 5mature patients. However, the velocity of propagation is signi cantly faster in term than preterm infants.
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
3in preterm infants than adults.
The LES, which blocks GER, is made up of intrinsic esophageal smooth muscle and diaphragmatic skeletal
6muscle. Although premature infants were once thought to have impaired LES tone, several manometry studies
3,7,8have documented good LES tone, even in extremely low-birthweight infants. In term and preterm infants,
as in older patients, transient LES relaxations (TLESRs) unrelated to swallowing are the major mechanism
3,8,9allowing GER by abruptly dropping lower esophageal pressure below gastric pressure. These TLESRs may
9occur several times per hour in preterm infants, although most TLESR events are not associated with GER.
Preterm infants with and without GERD experience a similar frequency of TLESRs, but infants with GERD have
9a higher percentage of acid GER events during TLESRs. 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
9than isolated TLESR events.
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
10weight, about 180 mL/kg per day, than older children and adults. In the neonatal intensive care unit (NICU)
population, preterm and term patients with nasogastric or orogastric feeding tubes may experience more re ux
11,12episodes owing to mechanical impairment of the competence of the LES.
Gastric emptying is also an important factor in the passage of uids through the upper gastrointestinal
tract. One small study showed that between 25 and 30 weeks gestational age, 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
13osmolality or volume alone did not have a signi cant e) ect. Emptying also occurs faster with human milk
feedings than with formula. Several small studies suggest that prebiotics, probiotics, and hydrolyzed formulas

14-16may speed gastric emptying time in formula-fed infants. Forti cation of human milk may slow gastric
17emptying time. The clinical signi cance of these ndings with regard to GER remains uncertain, however.
Although it seems logical that slower gastric emptying would be associated with increased GER, a study of the
18relationship between gastric emptying and GER in preterm infants found no association.
Diagnosis of Gastroesophageal Reflux and Gastroesophageal Reflux Disease
Although infants have a propensity to experience frequent GER, most GER is physiologic and nonpathologic.
1,2GERD is de ned as GER that causes complications. Unfortunately, in infants, particularly preterm infants,
complications of GER are diB cult to characterize. Clinicians disagree about which symptoms are caused by
19GER or GERD. There is mixed evidence in the literature to support or refute most of the proposed
20-30 31-34 35complications of GER in infants, including apnea, worsening of lung disease, and failure to thrive.
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
3624 hours was 31.28, with a standard deviation of 20.68. The re ux index, the percentage of time the
esophageal pH was less than 4, ranged from less than 1 to 23, with the median and 95th percentile being 4 and
10, respectively. For this reason, a re ux index of 10 is often considered the threshold value for an abnormal
study, but it must be remembered that none of the infants in this study were thought to su) er from
symptomatic GERD, and clinical correlation with symptoms is required to make the diagnosis of GERD. Among
the neonates in this study, the 95th percentile for the reflux index was as high as 13.
In a smaller study of 21 asymptomatic preterm neonates with a median postmenstrual age of 32 weeks,
continuous combined esophageal pH and impedance monitoring detected re uxed uid in the esophagus by
impedance for a median of 0.73% (range, 0.3% to 1.22%) of the recording time, and acid exposure detected by
pH monitoring for a median of 5.59% (range, 0.04% to 20.69%) of the recording time. When using combined
pH and MII monitoring, detection of acid exposure may exceed volume exposure because the esophageal pH
may remain depressed for a time after most of the bolus has been cleared, as well as for a variety of other
37technical reasons. Norms for acid and nonacid re ux are less well de ned in preterm than term infants owing
to the practical and ethical barriers involved in placing esophageal pH probes in a large number of
asymptomatic preterm infants. However, the data from this small study make it clear that GER events occur
frequently in asymptomatic infants, and a wide range of re ux measurements may be seen in healthy preterm
infants without GERD.
In a study of otherwise healthy infants seen in general pediatric practice, half of all parents reported at
38least daily regurgitation at 0 to 3 months of age. The peak prevalence occurred at 4 months, with 67%
reporting regurgitation, but thereafter declined rapidly. Thus, benign regurgitation was the norm in the first few
months of life. Parents reported regurgitation to be a problem when it was associated with increased crying or
fussiness, perceived pain, or back arching. The prevalence of regurgitation perceived as a problem peaked at
23% at 6 months but was down to 14% by 7 months. Most of these children did not receive treatment for GERD
from their pediatrician, suggesting that a diagnosis of GERD was only made in a minority of these patients.
Infants who did and did not experience frequent regurgitation between 6 and 12 months of age were
39subsequently followed a year later. At this time, none of the parents described regurgitation as a current
problem, and only one child experienced spitting at least daily. That child had not experienced frequent
regurgitation at 6 to 12 months of age. Infants who had frequent spitting at 6 to 12 months of age did not
experience more infections of the ear, sinuses, or upper respiratory tract, nor did they experience more
wheezing. In general, this cohort demonstrates that in most infants regurgitation is a benign process that is
outgrown. However, it was noted that in the 1-year follow-up assessment, parents of infants who had frequent
regurgitation at 6 to 12 months were more likely to report prolonged meal times (8% versus 0%) and frustration
about feeding their child (14% versus 4%), even though regurgitation symptoms were no longer present. It is
not clear whether this represents a true di) erence in feeding behavior or parental perception in a group likely
to be sensitized to feeding issues.
Gastroesophageal Reflux Disease Symptoms
Although the de nition of GERD hinges on the presence of troublesome symptoms or complications, identifying
1,2whether symptoms are in fact caused by re ux can be challenging in infants. Symptoms frequently
attributed to GERD in infants include regurgitation, Sandifer posturing, worsening of lung disease, food refusal
or intolerance, apnea, bradycardia, crying or fussiness, and stridor. Regurgitation may be a symptom of GERD

2in infants but in itself is not a suB ciently sensitive and speci c nding to make a diagnosis. In addition,
otherwise healthy infants without sequelae from their regurgitation, so-called happy spitters, do not require
1treatment. Clustering regurgitation with other symptoms may increase the accuracy of diagnosis, as
2,40demonstrated by the I-GERQ-R infant re ux questionnaire. However, the validity of such questionnaires
has not been established in the NICU population, which includes preterm infants and sick term neonates who
have multiple competing causes for the symptoms frequently attributed to GERD.
Although GERD and bronchopulmonary dysplasia seem to be associated, the presence or direction of
2,31-34causality have not been determined. Patients with increased work of breathing may generate more
negative intrathoracic pressures, thereby promoting the passage of gastric contents into the esophagus.
Conversely, aspirated re uxate could injure the lungs. Finally, there may be no causal link in most patients,
with immaturity and severity of illness predisposing to both conditions. In addition, part of the apparent
association between BPD and GERD may be due to an increased index of suspicion for GERD in patients with
33BPD, leading to increased rates of diagnosis.
A similar issue exists for apnea in premature infants. Although in animal models esophageal stimulation
41may trigger airway protective re exes, there is insuB cient evidence in human infants to con rm that re ux
2,30 42,43causes apnea. In addition, apnea may itself trigger reflux. Finally, it may be that immature infants are
44simply prone to both apnea and re ux, with no causal association. In a cohort of infants referred for
overnight esophageal and respiratory monitoring for suspicion of GERD as a cause of apnea, desaturation, or
45bradycardia, fewer than 3% of all cardiorespiratory events were preceded by a re ux event. The infant with
the highest percentage had 4 of 21 cardiorespiratory events preceded by GER. Conversely, 9.1% of reflux events
were preceded by a cardiorespiratory event. This study shows that it is more common for a cardiorespiratory
event to precede re ux than for re ux to precede a cardiorespiratory event. Cardiorespiratory events preceded
by re ux were not more severe than those not preceded by re ux. Furthermore, even in this population referred
for suspicion of GER-triggering cardiorespiratory events, only a small minority of cardiorespiratory events were
in fact preceded by re ux. This suggests that even if all of these temporally related events were also causally
related, and even if a treatment were completely eB cacious at eliminating GERD, most cardiorespiratory events
would not be eliminated by GERD treatment. However, data from small or moderately sized research cohorts
cannot rule out the possibility that re ux can trigger most cardiorespiratory events in a small subset of patients.
Because bedside recording of apnea events is known to be inaccurate, correlation of apnea with feeding or
reflux events in a specific patient requires formal simultaneous respiratory and esophageal monitoring studies.
It is unclear what component of the re uxate triggers complications. Infants experience less acid GER than
older children or adults, owing in large part to frequent bu) ering of gastric contents by milk. Although most
46,47GER events in infants are nonacid, at least some preterm infants are able to experience signi cant acid
22,36GER, often de ned as an esophageal pH of less than 4 for more than 10% of the recording. Acid GER
44,46predominates in infants preprandially, and nonacid GER postprandially. However, it is not clear whether
2acidity is the mechanism by which re ux causes complications in infants. The other characteristics of the
re uxate that have been postulated to be associated with symptoms include the height of the bolus in the
esophagus, the volume of the bolus, or the pressure exerted on the esophagus.
Gastroesophageal Reflux Disease Diagnostic Tests
Numerous tests exist to measure acid and nonacid GER in infants (Table 2-1). Esophageal pH probes measure
acid re ux, and esophageal multichannel intraluminal impedance measures the presence of uid in the
esophagus regardless of pH. Impedance and pH sensors can be combined in one esophageal probe to give the
most information about the frequency and timing of both acid and nonacid GER. Many systems have the
capacity to be run in conjunction with respiratory monitoring, or for a family member or health care provider
to mark the timing of a clinical symptom, in order to attempt to temporally correlate symptoms and GER
events. An upper gastrointestinal radiographic series is useful for assessing anatomic abnormalities that may
contribute to or mimic GER but is a poor measure of the frequency or severity of GER because it only captures a
brief window in time. A nuclear medicine scintigraphy study can identify postprandial re ux and aspiration
and quantify gastric emptying time. There is no current gold standard diagnostic modality for GERD in infants.
In part, this is because it is still not clear what component of re ux, such as its frequency, volume, acidity, or
height, is most likely to cause complications in infants, and each test measures di) erent parameters. A recent
international consensus statement on GERD concluded that no single diagnostic test can prove or exclude
2extraesophageal presentations of GERD in pediatrics. Furthermore, many NICU patients are too small for
endoscopy to directly assess esophagitis, so esophageal symptoms can only be inferred from vague symptoms,
such as food refusal or fussiness. Finally, because the diagnosis of GERD relies on the presence of clinical
complications, no physiologic test that only characterizes the frequency or characteristics of GER events in a
patient can by itself confirm the diagnosis of GERD.

Gastroesophageal Reflux Disease Treatment
Nonpharmacologic therapies for GERD include positioning, thickening feeds, and decreasing the volume while
increasing the frequency of feeds. When milk protein allergy is thought to be mimicking or triggering GERD,
changing to a more elemental formula may also be appropriate. In the run-in period for a randomized control
trial of a pharmacotherapeutic intervention for GERD, the majority of infants seemed to improve over a 2-week
period with such a multipronged conservative management strategy, although this e) ect simply could also be
48attributed to time and maturation. Thickening feeds has been shown to decrease episodes of clinical
49vomiting, although it does not seem to decrease physiologic measures of GER. Although typical positioning
precautions for an infant with a diagnosis of GERD include elevating the head of the bed, there is not an
49advantage to supine upright versus supine at positioning. Prone positioning seems to be associated with
fewer GER events than supine but is generally contraindicated owing to the increased risk for sudden infant
49,50death. Lateral positioning with the right side down results in more frequent re ux events than left lateral
51positioning, but it is not clear whether this results in more symptoms.
52-54Medications for the treatment of GERD are among the most common drugs prescribed in the NICU. In
the United States, pharmacotherapy primarily consists of drugs to decrease gastric acidity, such as the
histamine-2 (H ) receptor antagonists and proton pump inhibitors (PPIs), and prokinetics, such as2
metoclopramide and erythromycin (Table 2-2).

Because both GER and the symptoms commonly linked to GERD, such as feeding intolerance and apnea,
change rapidly with time and maturation, valid studies of GERD in infants must account for this e) ect in their
study design. A study that simply measures symptoms before and after a therapy is likely to nd improvement
related to maturational e) ects, whether or not the therapy was truly eB cacious. In addition, although many
studies have demonstrated physiologic changes in response to pharmacotherapy, the gold standard for the
treatment of GERD must be improvement in the symptoms that de ne the disease. Several recent
wellconducted studies accounting for maturational changes have raised further questions about the eB cacy and
55-57safety of common GERD drugs.
Because of the diB culties in proving that a putative complication of GER is indeed caused by re ux, along
with the questionable eB cacy of available GERD medications, it must be remembered when treating an
individual patient that a treatment failure may stem from either the application of drugs to symptoms not
caused by GERD or a failure of pharmacotherapy to improve true GERD. Apparent treatment successes may
result from either a true treatment e) ect or natural maturational changes in the GERD or symptoms
misclassi ed as resulting from GERD (Table 2-3). Pharmacotherapy should be stopped if symptoms fail to
improve with therapy. If an improvement is seen, a trial o) therapy in several weeks should be considered
because maturational changes may have been the cause of the initial apparent response or may obviate the
need for therapy in the near future.
Symptoms Correctly Attributed to Symptoms Erroneously Attributed to GERD
Improvement The therapeutic intervention was The therapeutic intervention was not successful
after successful. The therapy is efficacious because the symptoms were not triggered by GERD,
initiation of in treating GERD symptoms. but improvement in the symptoms due to maturation
therapy or caused the apparent response to therapy. The therapy
The therapeutic intervention was not may or may not be efficacious in treating true GERD.
successful owing to lack of efficacy
of the therapy, but improvement in
the symptoms due to maturation
caused the apparent response to

No The therapeutic intervention was not The therapeutic intervention was not successful
improvement successful owing to lack of efficacy because the symptoms were not triggered by GERD.
after of the therapy. The therapy may or may not be efficacious in treating
initiation of true GERD.
* The severity of gastroesophageal re ux disease (GERD) and the symptoms frequently attributed to GERD, such
as apnea, feeding diB culties, or lung disease, rapidly change with time and maturation in infants. Interpretation
of a response or lack of response to therapy hinges on understanding that both GERD symptoms and causally
unrelated symptoms may change with time, complicating the interpretation of an apparent response to therapy.
In addition, many of the symptoms that have been proposed to be triggered by GERD have many other competing
causes in preterm infants, and it is difficult to definitively determine whether they are caused by GERD.
Acid-Blocking Medications
H receptor antagonists and PPIs decrease the acidity of gastric uid and esophageal re uxate. They act on the2
H2 receptors in acid-producing gastric parietal cells, decreasing acid production below normal fasting basal
secretion rates as well as suppressing meal-associated acid production. Acid in the esophagus or airway is
thought to trigger many of the proposed complications of re ux in NICU patients, such as food refusal, failure
to thrive, and pharyngeal or vocal cord edema. Examples of H2 receptor antagonists include ranitidine,
cimetidine, and famotidine.
Few randomized clinical trials of H receptor antagonists have assessed their impact on GERD symptoms in2
either neonates or premature infants. In a small but statistically signi cant crossover trial of combined
ranitidine and metoclopramide in preterm infants with bradycardia attributed to GERD, infants experienced
56signi cantly more bradycardic events when receiving re ux medications than when receiving placebo. This
unexpected nding is biologically plausible; histamine receptors are present in the heart, and ranitidine has
58-64been implicated in causing bradyarrhythmias. Because most cardiorespiratory events are not associated
45with GER, the lack of e) ect found in this study could have been driven either by the misattribution of
frequent bradycardia to GERD or by a lack of drug eB cacy. Bradycardia is likely to have poor speci city for
the identi cation of GERD given the multiple other triggers for bradycardia in premature infants, including
apnea of prematurity and vagal stimulation, and most cardiorespiratory events are not preceded by re ux even
45among infants suspected of having GERD. Notably, this crossover study of ranitidine and metoclopramide,
which appropriately accounted for maturational changes, also demonstrated a clinically and statistically
signi cant decrease in bradycardic events over a 2-week period in both the treatment and placebo groups. This
nding underscores the importance of accounting for temporal changes in processes in uenced by maturation,
such as GER, apnea, and bradycardia.
In a randomized trial of H receptor antagonists, very-low-birthweight infants were randomized to2
65cimetidine or placebo. The investigators hypothesized that cimetidine could decrease liver enzyme–mediated
oxidative injury in the lung. Although this was not a study of GERD treatment, it is one of the few studies in
which very-low-birthweight infants were randomized to an H receptor antagonist early in life. Strikingly, it2
was stopped by the data safety monitoring committee for increased death and intraventricular hemorrhage in
the treatment group. The mechanism of these apparent adverse e) ects is unknown. The increase in adverse
events could have occurred by chance or could be a true adverse event related to cimetidine, which may or
may not be generalizable to other H2 receptor antagonists.
In a small double-blind study, infants aged 1 to 11 months were randomized to a higher or lower dose of
57famotidine, with a subsequent placebo-controlled withdrawal. Infants receiving famotidine had less frequent
emesis than those receiving placebo. Infants on the higher famotidine dose also had a decreased crying time
and smaller volume of emesis. However, famotidine was associated with increased agitation and a
headrubbing behavior attributed to headache, raising some concerns about possible side e) ects in the general infant
PPIs irreversibly block the gastric hydrogen/potassium adenosine triphosphatase responsible for secreting
hydrogen ions into the gastric lumen. Currently, no PPIs are labeled for use in patients younger than 1 year.
Nevertheless, between 1999 and 2004, PPI prescriptions for infants increased exponentially, with the highest
66rates of use in infants younger than 4 months. Common PPIs include omeprazole, lansoprazole,
dexlansoprazole, esomeprazole, pantoprazole, and rabeprazole.
Although PPIs have been shown to decrease gastric acidity in infants in physiologic studies, there is a
paucity of masked randomized studies in infants that assess PPI impact on GERD symptoms and account for
underlying maturational changes over time. In a study by Orenstein and colleagues, outpatient infants who had
55failed a run-in period of nonpharmacologic management were randomized to lansoprazole or placebo. There
was no di) erence in symptoms between the groups, with slightly more than half of the infants in each group
experiencing improvement over the study period. However, a signi cant increase in serious adverse events in
the lansoprazole group was seen; among these adverse events, a nonsigni cant increase in lower respiratory
tract infections was noted.

In addition to drug-speci c side e) ects, such as leukopenia and thrombocytopenia with ranitidine, class
effects resulting from the change in gastric pH may be seen with H2 receptor antagonists and PPIs. For instance,
increasing evidence suggests that gastric acidity may play an important role in host immune defense. In an
67observational study, use of H2 receptor antagonists was associated with increased necrotizing enterocolitis. In
68another cohort study, ranitidine use was associated with late-onset sepsis in NICU patients. However, in these
observational studies, confounding by indication or severity of illness cannot completely be excluded as the
cause of this apparent association. Consistent with the ndings in the observational studies, in one small
69interventional study, gastric acidi cation was shown to decrease necrotizing enterocolitis. Higher rates of
gastric colonization with bacteria or yeast have also been associated with ranitidine, but without a detectable
70increase in clinical infection. In older patients, a possible association between acid suppression and lower
respiratory tract infections, including ventilator-associated pneumonia, remains controversial in the
71-79literature. Acid suppression has also been associated with Clostridium di cile infection in some adults.
PPIs seem to carry a higher risk than H receptor antagonists, presumably owing to more e) ective acid2
80,81suppression. The relationship between PPI use and C. di cile colonization or infection has not been
reported in infants.
Increasing gastric pH can theoretically also have nutritional consequences. Acid reduction may decrease
calcium absorption as a result of decreased ionization of calcium in the stomach. The U.S. Food and Drug
Administration (FDA) recently released a class labeling change for PPIs based on concerns that adults on high
82,83doses or prolonged courses of PPIs seem to experience more fractures. The impact of acid suppression by
PPIs or H receptor antagonists on bone health in either healthy neonates or preterm infants with osteopenia of2
prematurity is unknown. Vitamin B absorption is also dependent on gastric acidity, but the impact of gastric12
acid suppression on B12 status in infants has also not been described.
Drugs to promote gastrointestinal motility are thought to act by improving esophageal motility and LES tone.
Prokinetics are also often used to shorten gastric emptying time, although a relationship between GER and
18delayed gastric emptying in infants has not been proved.
Metoclopramide and erythromycin are the primary prokinetics currently approved in the United States.
Cisapride was removed from the market because of the risk for serious cardiac arrhythmias and QT
84prolongation. Domperidone is not approved in the United States because of concerns about QT prolongation
85in neonates.
Metoclopramide is a dopamine receptor antagonist. The Cochrane systematic review of GERD therapies in
86children found both therapeutic bene t and increased adverse e) ects with metoclopramide treatment.
However, most of the improvements seen were in physiologic measures of GER and not in the symptoms of
GERD. A subsequent systematic review of metoclopramide therapy for GERD in infants found insuB cient
87evidence for either eB cacy or safety in this population. Published after these reviews, the previously
described placebo-controlled crossover study of ranitidine and metoclopramide demonstrated a lack of eB cacy
and an increase in bradycardia in the treatment group, although this nding could be attributed to ranitidine
56and not metoclopramide.
Metoclopramide can cause neurologic sequelae because it crosses the blood-brain barrier and acts on
central dopamine receptors. Possible neurologic complications of metoclopramide in infants include irritability,
87drowsiness, oculogyric crisis, dystonic reaction, and apnea. In 2009, the FDA issued a warning about the risk
88for tardive dyskinesia with prolonged or high-dose metoclopramide use. Tardive dyskinesia has no known
treatment and consists of involuntary body movements, which may persist after the drug is stopped. It is
unknown whether term or preterm infants are at greater or lesser risk for tardive dyskinesia than older patients.
Erythromycin is an analog of motilin, a hormone normally produced by duodenal and jejunal
89-91enterochromaB n cells that promotes gastrointestinal migrating motor complexes. The prokinetics dose of
erythromycin is typically lower than the antimicrobial dose, but a standard promotility dose has not been
established in neonates or preterm infants. Infants older than 32 weeks gestational age may be better able than
92,93less mature infants to respond to stimulation of the motilin receptor.
Most studies of erythromycin in preterm infants have focused on improving feeding intolerance and not
92,93speci cally on GERD treatment. In a masked randomized trial of erythromycin to promote feeding
94tolerance in 24 preterm infants, GER was measured as a secondary endpoint. Erythromycin did not decrease
the time to reach full enteral feeds, and there were no changes in GER measured by pH probe. GERD symptoms
were not reported in this study. A systematic review of erythromycin to promote feeding tolerance in premature
infants concluded that erythromycin could promote the establishment of enteral feeding and was not associated
95with any adverse events. However, the authors cautioned that since long-term adverse events had not been
fully studied, erythromycin should be reserved for infants with severe dysmotility.
When used as an antibiotic, erythromycin may promote pyloric stenosis in infants. It is unknown whether a
similar e) ect could occur with the lower doses and longer duration of therapy associated with use as a

95prokinetic, although pyloric stenosis was not reported in most of the current trials in preterm infants. Chronic
administration of erythromycin has the potential to impact gastrointestinal colonization, but the impact in the
NICU population is unknown.
Erythromycin may increase serum levels of theophylline, digoxin, sildenafil, and some benzodiazepines and
has been implicated in arrhythmias and QT prolongation when coadministered with cisapride. In addition, it
96also has a direct proarrhythmic e) ect due to prolongation of the QT interval. In older patients, the risk for
sudden death may be increased when erythromycin is used with other inhibitors of the same hepatic enzyme
96(CYP3A), such as cimetidine and methadone.
GER is common in term and preterm infants. The primary mechanism allowing re ux is TLESRs. Although the
diagnosis of GERD requires the presence of complications resulting from re ux, ascertaining whether symptoms
in a given patient are caused by GERD can be challenging. There is no gold standard diagnostic modality to
diagnose GERD in the NICU population. Although esophageal impedance and pH measurements are the most
commonly reported, linking measured GER with symptoms is still required to diagnose GERD. In the NICU
population, few symptoms have been de nitively shown to be caused by GERD, and most of the putative
symptoms of GERD, such as feeding intolerance or apnea, have many possible etiologies. Furthermore, no
pharmacologic interventions have been proved safe and e) ective in this population. Therefore,
nonpharmacologic expectant management should be the mainstay of treatment for most infants.
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Chapter 3
Development of Gastrointestinal Motility Reflexes
Sudarshan Rao Jadcherla, MD, FRCPI, DCH, AGAF,
Carolyn Berseth, MD
• Embryologic Aspects of Motility Development
• Pharyngoesophageal Motility Reflexes in Human Neonates
• Gastrointestinal Motility Reflexes in Human Neonates
• Developmental Colonic Motility in Human Neonates
• Summary
• Implications and Controversies of Gut Motility
Gastrointestinal motility is very complex and is in uenced by embryologic
development and aberrations, vulnerable neurologic systems, maturational changes
in central and enteric nervous systems, and rapidly changing anatomy and
physiology during infancy. In the vulnerable high-risk infants in intensive care
units, the in uence of hypoxia, in ammation, sepsis, and other comorbidities
complicates the feeding process and gastrointestinal transit. Despite the
complexities, the simple physiologic functions of the neonatal foregut, midgut, and
hindgut, respectively, are to facilitate the feeding process safely to steer the
feedings away from the airway, gastrointestinal transit of luminal contents to
modulate absorption and propulsion, and evacuation of excreta to maintain
intestinal milieu homeostasis. These functions continue to advance through infant
development, from fetus to adult. In this chapter, we review and summarize the
developmental aspects of pharyngoesophageal motility, gastrointestinal motility,
and colonic motility.
Embryologic Aspects of Motility Development
The airway and lung buds, pharynx, esophagus, stomach, and diaphragm are all
derived from the primitive foregut and or its mesenchyme and share similar control
1-4systems. By 4 weeks of embryologic life, tracheobronchial diverticulum appears
at the ventral wall of the foregut, with left vagus being anterior and right vagus
posterior in position. At this stage of development, the stomach is a fusiform tube
with its dorsal side growth rate greater than its ventral side, creating greater and
lesser curvatures. At 7 weeks of embryonic life, the stomach rotates 90 degrees
clockwise, and the greater curvature is displaced to left. The left vagus innervates
the stomach anteriorly, and the right vagus innervates the posterior aspect of
stomach. At 10 weeks’ gestation, the esophagus and stomach are in proper position,
with circular and longitudinal muscle layers and ganglion cells in place. By 11