Table Of ContentPrinciples of
Perinatal-Neonatal Metabolism
Richard M. Cowett
Editor
Principles of
Perinatal-N eonatal
Metabolism
With 241 Illustrations
Springer-Verlag
New York Berlin Heidelberg London Paris
Tokyo Hong Kong Barcelona Budapest
Richard M. Cowett, MD
Professor of Pediatrics
Department of Pediatrics
Brown University Program in Medicine
Department of Pediatrics
Women and Infants Hospital of Rhode Island
Providence, RI 02905, USA
Library of Congress Cataloging-in-Publication Data
Principles of perinatal-neonatal metabolism 1 Richard M. Cowett,
editor.
p. cm.
Includes bibliographical references and index.
1. Infants (Newborn) - Metabolism. 2. Fetus - Metabolism.
3. Maternal-fetal exchange. I. Cowett, Richard M.
[DNLM: 1. Fetus-metabolism. 2. Infant, Newborn-metabolism.
3. Maternal-Fetal Exchange-physiology. 4. Pregnancy-metabolism.
WQ 210.5 P957]
R1252.P75 1991
618.3'2-dc20
DNLM/DLC
for Library of Congress 90-10558
Printed on acid-free paper.
© 1991 Springer-Verlag New York Inc.
Softcover reprint of the hardcover I st edition 1991
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errors or omissions that may be made. The publisher makes no warranty, express or implied, with respect
to the material contained herein.
Typeset by Publishers Service of Montana, Bozeman, MT.
987 6 5 4 3 2 1
ISBN-13: 978-1-4684-0402-9 e-ISBN-13: 978-1-4684-0400-5
DOl: 10.1007/978-1-4684-0400-5
In Memory of the Past:
To my Father,
Allen Abraham Cowett;
and
in Anticipation of the Future:
To my Children,
Beth Ellen,
Allison Ann,
and Allen Manz Cowett.
Preface
Over the last quarter century or so, specialization within obstetrics and gynecology, and
pediatrics has resulted in the development of the disciplines of maternal-fetal medicine
and neonatology, respectively. A primary focus of maternal-fetal medicine has been to
understand the mechanism(s) of premature delivery and develop treatment modalities for
improving the length of gestation. A primary focus of neonatology has been to under
stand the causes of respiratory distress in the neonate. Success has resulted, not only in
the lengthening of gestation, but an improved understanding of the causes and treatment
of neonatal respiratory disease. With increasing success has come the necessity to under
stand the metabolic principles of the parturient, the fetal/placenta unit, and the neonate.
These principles are clearly very important from multiple aspects. Increased understand
ing of metabolism of the pregnant woman would explain the aberrations occurring in
normal and abnormal pregnancy and improve nutritional support for the parturient. A
prime example of altered metabolism is the parturient with diabetes. Understanding
metabolism ofthe fetal/placenta unit is necessary to increase the probability that the fetus
will be born appropriate for size irrespective of the gestational age. The various compo
nents of neonatal metabolism are important, not only for understanding the changes in
physiology and biochemistry occurring in the developing neonate, but the principles by
which nutritional support should be provided.
Enough time has lapsed so that cogent analyses are possible for each component of the
metabolic principles of the perinatal-neonatal period. A general survey of the literature
documents that separate discussions of metabolism exist. There are chapters on maternal
metabolism as part of maternal-fetal medicine texts. There are textbooks on altered
metabolism such as diabetes mellitus in pregnancy. Texts of principles {)f fetal physiology
have been published, as have various analysis of neonatal metabolism and nutrition as sin
gle texts or chapters of general neonatology texts. To my knowledge there is no compre
hensive metabolic reference text which has evaluated the perinatal-neonatal period as a
continuum. It is obvious that the perinatal-neonatal period is a continuum in which each
stage is inexorably intertwined with the other. It is this continuum that we have attempted
to capture from a physiological and biochemical perspective metabolically.
In Section I the general principles of metabolism are analyzed. The first half evaluates
methodology used to study metabolism. Kinetic techniques have been responsible for
major advances that provide information above and beyond that of static measurements.
No analysis of metabolism in the 1990s would be complete without a consideration ofthe
evolving techniques of a cellular and molecular basis which are ever increasingly provid
ing an explanation of metabolic parameters. It is also apparent that animal modeling is
required to evaluate mechanisms which cannot be analyzed by human investigation.
Within Section I metabolic control of glucose, protein and lipid is evaluated in the nor
mal non-pregnant adult as a "gold standard:' Subsequently, biochemical and physiologi
cal aspects of insulin, the contrainsulin hormones, and somatomedins are considered ,in
the non-pregnant adult.
Section II evaluates maternal metabolism during pregnancy. Metabolism of glucose,
protein, lipids, and prostaglandins are analyzed in detail from the perspective of changes
Vlll PREFACE
occurring during pregnancy. Studies that evaluate energy metabolism in pregnancy are
considered. The final chapter is a subject which is emerging as a major topic in the
metabolism of pregnancy-the effects of exercise.
Section III considers metabolism in the fetal/placenta unit. Glucose, protein, and lipid
are discussed comprehensively. Since metabolism is influenced to a great degree by
respiration and circulation within the fetal/placenta unit, these topics are considered as
well. Finally, water metabolism, of critical importance to the fetus, is explored in detail.
Section IV analyzes the various components of neonatal metabolism. A great deal of
research in metabolism of a perinatal-neonatal nature has evaluated the neonate and
the various components are considered comprehensively. Glucose metabolism and the
inborn errors of carbohydrate metabolism are analyzed as are neonatal protein
metabolism and inborn errors of amino acids and organic acids. Extensive research has
been performed on lipid and carnitine, on neonatal minerals, trace metals, vitamins,
both fat soluble and water soluble, and these topics are explored. Neonatal energy
metabolism is discussed in detail as is an offshoot of that subject, neonatal thermal regu
lation. Extensive research has been performed on water metabolism in the neonate and
this is analyzed as are studies of body composition which have been published. Two
specific aberrations of the norm are considered from a neonatal perspective; the first,
the small for gestational age neonate and the second, the infant of the diabetic mother.
Increasing success has occurred over the last quarter century relative to neonates under
going surgery and their metabolic needs are evaluated. Finally, nutritional support ofthe
neonate, specifically alternate fuels and routes of administration, are evaluated.
The text is cross-referenced between sections. With some topics there has been
enough research to allow for separate discussions (e.g., glucose, protein, lipid and
water) in separate sections. With others (e.g., minerals, trace elements, and vitamins)
the authors have evaluated the topics in a single chapter. Clinical correlations are
provided throughout the text.
We believe that this reference text will provide a comprehensive evaluation for
those individuals interested in metabolism in this continuum known as the perinatal
neonatal period.
It is appropriate to acknowledge a few individuals who have been most influential in
my career. Dr. Irwin B. Hanenson, Professor Emeritus of Medicine at the University of
Cincinnati College of Medicine, whom I first met when I was a teenager, introduced me
to research and allowed me to work as a technician in his laboratory at the May Institute
for Medical Research of the Jewish Hospital in Cincinnati, Ohio. He remains a very
close friend to this day. Professor Margaret Shea Gilbert, Professor of Biology Emeritus
at Lawrence College (University) in Appleton, Wisconsin, who recently passed away,
provided support and enthusiasm for my budding interest in research during an under
graduate honor's thesis. Dr. Robert Schwartz, Professor of Pediatrics and Medical
Sciences at Brown University, I first met when he was Chairman of the Department of
Pediatrics at Cleveland Metropolitan General Hospital, and Professor of Pediatrics at
Case Western Reserve University where I was an intern and junior assistant resident in
Pediatrics. He probably more than anyone should be given the credit for my interest in
carbohydrate metabolism in the perinatal-neonatal period. This interest was enhanced
when we both separately came to the Department of Pediatrics at Brown University in
the early 1970s. He remains a mentor, colleague and close friend. Dr. Leo Stern, who
passed away in 1989 unexpectedly, recruited me to Brown University as a fellow in
neonatology, and, during his lifetime as Chairman of the Department of Pediatrics at
Brown University, remained a special influence on me personally and professionally. I
first met Dr. William Oh when Dr. Stern recruited him to be Chief of the Division of
Neonatology and Professor of Pediatrics and Medical Sciences at Brown University. Dr.
Oh, now Chairman of the Department of Pediatrics at Brown University, has been a
unique guide for me not only from a personal but from a professional standpoint. He
remains a mentor, colleague and close friend. The above individuals and especially
PREFACE ix
my father, Allen, whom I remember with love and affection, should probably be given
credit for my success, but none of the blame for my short comings. I remain deeply
indebted to all of them.
Many individuals at Springer-Verlag Publishers have been important from the begin
ning ofthis book to its completion. I am deeply indebted to all of them and to my former
secretary Mrs. Lori D. Krahenbill at Women and Infants' Hospital.
Finally, it goes without saying, that each of the senior authors that have contributed
to this text are "academic household names" in the areas about which they have written.
I very much appreciate the thoroughness that each of them has evidenced in completing
their assignment. I hope the reader is as pleased with the text as I am.
Providence, Rhode Island Richard M. Cowett, MD
March, 1991
Contents
Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Vll
Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. XVll
SECTION I: GENERAL PRINCIPLES OF METABOLISM
1 Methodology for the Study of Metabolism:
Kinetic Techniques. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Dennis M. Bier
Mass Spectrometry • Nuclear Magnetic Resonance • Positron Emission
Tomography • Stable Isotope Tracers • Mathematical Modeling • Conclusions
2 Methodology for the Study of Metabolism:
Cellular and Molecular Techniques. . . . . . . . . . . . . . . . . . . . . . . . . 15
Lewis P. Rubin
Analysis of Polynucleotides and Proteins • Analysis of Effector Pathways and
Metabolic Control 'Analysis of Gene Regulation' Conclusions and
Future Directions
3 Methodology for the Study of Metabolism:
Animal Models .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
John B. Susa
Overview of the Animal Model • Ideal Animal Model • Metabolic Fuels • Maternal
Metabolic Adjustments to Pregnancy • Metabolic Role of the Placenta • Fetal
Metabolism • Neonatal Metabolism
4 Control of Metabolism in the Normal Adult 61
Robert R. Wolfe and Farook Jahoor
Glucose Metabolism • Lipids in Energy Metabolism • Regulation of Protein Synthesis
5 Insulin: Biochemical and Physiological Aspects. . . . . . . . . . . . . 84
Philip A. Gruppuso
Structure and Biosynthesis of Insulin • Insulin Gene • Regulation of Insulin
Secretion • Mechanism of Insulin Action • Regulation of Intermediary Metabolism
by Insulin • Insulin as a Growth Factor' Conclusion: Physiological Integration
of Insulin's Biochemical Actions
xii CONTENTS
6 Contrainsulin Hormones:
Biochemical and Physiological Aspects. . . . . . . . . . . . . . . . . . . . . 103
John E. Gerich and Philip E. Cryer
Glucagon • Epinephrine • Growth Hormone • Cortisol • Summary and Conclusions
7 Somatomedins: Biochemical and Physiological Aspects 128
A. Joseph D'Ercole
Overview • IGFs and Nutrition • Mechanisms of Nutritional Regulation
of IGF-I • IGFs in Diabetes· IGFs and Development· Conclusions
SECTION Il: MATERNAL METABOLISM DURING PREGNANCY
8 Glucose Metabolism in Pregnancy ......................... 149
Lois Jovanovic-Peterson and Charles M. Peterson
First Trimester • Pathological Response to Pregnancy-Related Gluconeogenic
Hormones • Pathological Fetal Development • Second Trimester • Third
Trimester • Postpartum Period • Summary
9 Protein Metabolism in Pregnancy 163
Satish C. Kalhan and Barbara G. Assel
Plasma Amino Acids in Pregnancy· Urea Synthesis During Pregnancy· Protein Thmover
in Pregnancy • Protein Thmover and Its Measurement • Whole-Body Amino Acid and
Nitrogen Kinetics in Pregnancy
10 Lipid Metabolism in Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . .. 177
Robert H. Knopp, M. Scott Magee, Bartolome Bonet,
and Diego Gomez-Coronado
Basic Principles of Lipid and Lipoprotein Physiology • Effects of Estrogens and
Progestins on Lipoprotein Metabolism • Sex Differences in Lipoprotein
Metabolism • Fat Storage, Free Fatty Acid Metabolism, and Appetite Regulation in
Pregnancy • Lipoprotein Changes in Normal Pregnancy • Disorders of Lipoprotein
Metabolism in Pregnancy: Potential Significance for Fetal Growth and Development •
Lipoprotein Lipid Changes During Lactation • Management of Lipid Disorders in
Pregnancy • Summary
11 Prostaglandins in Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 204
Paul L. Ogburn Jr.
Essential Fatty Acids • Physiological Actions and Effects of Prostaglandins •
Pregnancy and Lipid Metabolism· Preeclampsia· Low-Dose Aspirin Therapy· Fetal
Circulation • Glucose Metabolism • Pharmacological Considerations • Preterm
Labor • Conclusion
12 Energy Metabolism in Pregnancy 228
John V.G.A. Durnin
Factors Influencing the Increased Energy Requirements in Pregnancy • Summary
CONTENTS xiii
13 Exercise in Pregnancy: Effects on Metabolism. . . . . . . . . . . . .. 237
Marshall W. Carpenter and Stanley A. Sady
Cardiovascular Physiology During Pregnancy • Respiratory Physiology During
Pregnancy • Acute Cardiovascular Response to Exertion in the Nonpregnant State •
Acute Respiratory Response to Exertion in the Nonpregnant State • Effects of
Pregnancy on Acute Cardiovascular and Respiratory Exercise Response • Acute Effects
of Maternal Exercise on the Fetus • Acute Metabolic Response to Exercise in the
Nonpregnant State • Acute Metabolic Response to Exercise During Pregnancy • Acute
Neuroendocrine Response to Exertion in the Nonpregnant and Pregnant States • Other
Acute Endocrine Responses to Exertion in the Pregnant and Nonpregnant
States • Summary
SECTION III: FETAL-PLACENTAL METABOLISM
14 Glucose Metabolism in the Fetal-Placental Unit. . . . . . . . . . . .. 250
William W. Hay Jr.
Methods for Determining and Quantifying Placental-Fetal Glucose Exchange •
Placental Glucose Flux and Metabolism • Fetal Glucose Metabolism
15 Protein Metabolism in the Fetal-Placental Unit 276
Edward A. Liechty and James A. Lemons
Methodology • Fetal Nitrogen Accretion • Protein Metabolism in Specific Fetal
Tissues • Relation Between Protein Synthesis and Energy Consumption • Interorgan
Metabolism of Amino Acids and Effects of Maternal Fasting • Adaption and
Regulation of Fetal Nitrogen Metabolism • Effect of Fetal Growth on Maternal
Metabolism
16 Lipid Metabolism in the Fetal-Placental Unit 291
Robert E. Kimura
Fetal Lipid Metabolism • Developmental Changes in Fetal Body Composition •
Changes in Maternal Blood Lipid Concentrations • Placental Fatty Acid Transfer •
Factors Controlling Placental Fatty Acid Transfer • Fetal Lipogenesis • Fatty Acid
Oxidation • Conclusions
17 Respiration in the Fetal-Placental Unit 304
Lawrence D. Longo
Respiratory Gas Exchange in the Placenta' Respiratory Gas Exchange in the Neonatal
Lung • Comparison of Gas Exchange in the Placenta and Lung
18 Circulation in the Fetal-Placental Unit 316
Abraham M. Rudolph
Course of Blood Flow • Fetal Circulation • Fetal Blood Gases and Oxygen
Saturation • Fetal Vascular Pressures • Methods for Studying the Fetal
Circulation' Cardiac Output and Its Distribution • Circulatory Regulation in the
Fetus • Fetal Circulatory Response to Reduced Oxygen Delivery • Circulatory
Changes After Birth
