Fetal-Placental Disorders

FETAL-PLACENTAL DISORDERS

Pathophysiology of Gestation

NICHOLAS S. ASSALI

DEPARTMENT OF OBSTETRICS AND GYNECOLOGY, SCHOOL OF MEDICINE, THE CENTER FOR THE HEALTH SCIENCES, UNIVERSITY OF CALIFORNIA, LOS ANGELES, CALIFORNIA

Table of Contents

Cover image

Title page

Contributors

Copyright

Dedication

List of Contributors

Preface

Contents of Other Volumes

Chapter 1: Disorders of Placental Transfer

Publisher Summary

I Introduction

II Physiological Transfer Mechanisms

III Normal Transfer of Specific Substances

IV Relation between Normal Placental Structure and Function

V Alterations in Placental Transfer Mechanisms

VI The Placenta and the Small-for-Gestational-Age Infant

VII Diagnostic Tests of Altered Placental Transfer

VIII Sequelae of Altered Placental Function

IX Possible Therapy for Altered Placental Transfer

X Summary

Acknowledgments

Chapter 2: Disorders of Placental Endocrine Functions

Publisher Summary

I Introduction

II Methodology

III Altered Placental Estrogen Production

IV Altered Placental Progesterone Production

V Altered Placental Production of Polypeptide Hormones

VI Endocrinology of Placental Lesions

Acknowledgments

Chapter 3: Disorders of Amniotic Fluid

Publisher Summary

I Introduction

II Volume

III Composition

IV The Dynamics of Amniotic Fluid Constituents

V The Routes of Exchange of Amniotic Fluid Constituents

VI The Regulation and Aberrations of Amniotic Fluid Volume

VII Variation and Aberrations of Amniotic Fluid Constituents—Relation to Fetal Maturity

VIII Conclusion

Chapter 4: Genetic Disorders Affecting Growth and Development

Publisher Summary

I Introduction

II Genetics of Gametes

III Anomalies of Fertilization

IV Chromosomes in Man

V Molecular and Biochemical Considerations

VI Mendelian Factors—Chromosomal Inheritance

VII Polygenic Inheritance

VIII Extrachromosomal Inheritance

IX Genetics of Sex Development

X Genetic Factors in Environmental Teratology (5, 92)

XI Prenatal Diagnosis

XII Experimental Approaches in Mammals

XIII Modification of Genetic Aspects of Development (Principles of Treatment)

XIV Genetic Counseling

XV Future Prospects

Acknowledgments

Chapter 5: Environmental Effects on Development—Teratology

Publisher Summary

I Introduction

II Scope of Teratology Today

III The Degree of Teratological Risk for Man

IV Causes of Developmental Defects in Man

V Concluding Comment

Author Index

Subject Index

Contributors

BARBARA F. CRANDALL, LAWRENCE D. LONGO, A.W. LILEY, H.H. SIMMER, ROBERT S. SPARKES and JAMES G. WILSON

Copyright

Copyright © 1972, by Academic Press, Inc.

all rights reserved

no part of this book may be reproduced in any form, by photostat, microfilm, retrieval system, or any other means, without written permission from the publishers.

ACADEMIC PRESS, INC.

111 Fifth Avenue, New York, New York 10003

United Kingdom Edition published by

ACADEMIC PRESS, INC. (LONDON) LTD.

24/28 Oval Road, London NW1 7DD

Library of Congress Catalog Card Number: 77-182605

printed in the united states of america

Dedication

This treatise is dedicated to the many research trainees, fellows, associates, and collaborators, whose devotion to science and concern for the care of the patient provided the stimulus for this work.

List of Contributors

Numbers in parentheses indicate the pages on which the authors’ contributions begin.

BARBARA F. CRANDALL,     Departments of Medicine, Pediatrics, and Psychiatry, University of California School of Medicine, Los Angeles, California (207)

LAWRENCE D. LONGO,     Departments of Physiology and Obstetrics and Gynecology, Loma Linda University, Loma Linda, California (1)

A.W. LILEY,     Postgraduate School of Obstetrics and Gynecology, University of Auckland, Auckland, New Zealand (157)

H.H. SIMMER,     Department of Obstetrics and Gynecology, University of California School of Medicine, Los Angeles, California (77)

ROBERT S. SPARKES,     Departments of Medicine, Pediatrics, and Psychiatry, University of California School of Medicine, Los Angeles, California (207)

JAMES G. WILSON,     Children’s Hospital Research Foundation and Departments of Pediatrics and Anatomy, University of Cincinnati, Cincinnati, Ohio (269)

Preface

The last decade has witnessed a rapid expansion of our knowledge in such important areas of reproduction as maternal–fetal interrelationship, biochemistry and physiology of the fetoplacental unit, fetal development and its relation to genetic and environmental factors, and the use of amniotic fluid constituents as diagnostic tools for fetal well-being. This wealth of information resulted from the combined efforts of investigators from all over the world in nearly all branches of biological sciences. Although basic data on these subjects are currently available and are continuously being accumulated on normal gestation, very little has been reported on the mechanisms of their behavior in abnormal pregnancies. The object of this second volume of the treatise on the pathophysiology of gestational disorders is to make use of the normal basic data to explain the underlying mechanisms of some of the disorders of maternal–fetal–placental–amniotic fluid interrelationships.

Chapter 1 deals with the disorders of placental transfer. The different physical and biochemical processes involved in placental exchanges between mother and fetus are clearly illustrated. The mechanisms by which substances such as respiratory gases, carbohydrates, amino acids, vitamins, water, and electrolytes are exchanged are given in detail, and the pathophysiological alterations that may disrupt these mechanisms and lead to fetal disorders are discussed. The relationship between placental dysfunctions and the small-for-gestational-age infant is meticulously dissected and its clinical implications outlined. The various physiological and pharmacological tests used to assess placental functions are given with discussion of their pitfalls and degree of reliability.

Chapter 2 deals with the disorders of placental endocrine functions. The various methods used for studying placental hormone production are discussed, and the errors in analysis and interpretation of the results are outlined. The endocrine interrelationships between mother, fetus, and placenta in the normal state are used to explain the pathogenesis of placental endocrine dysfunctions; a central part is the role of altered extraplacental supply of precursors for estrogen synthesis. The pathophysiology of altered placental production of progesterone and polypeptide hormones is also discussed, together with its clinical implications. Finally, the endocrine patterns of the diseased trophoblast such as hydatidiform mole and choriocarcinoma are given.

In Chapter 3 the pathophysiology of amniotic fluid disorders is discussed. The normal composition, volume, and dynamic state of the amniotic fluid are described, and the abberations that may occur are given in detail. The use of the amniotic fluid constituents as diagnostic tests for fetal disorders is discussed, together with the clinical implications of each test. The pathogenesis of amniotic fluid volume abnormalities such as polyhydramnios and oligohydramnios is explained.

Chapters 4 and 5 deal with the pathophysiology of the disorders of fetal growth and development. In Chapter 4 the genetic factors affecting growth and development from the gamete stage through fertilization and organ formation are described. The various chromosome abnormalities and their clinical implications are given, together with the various tests that can be used to detect early congenital defects. The molecular and biochemical basis for the inborn errors of metabolism in the fetus is clearly illustrated. The various ways in which the science of genetics can be used to counsel prospective parents are given.

In Chapter 5 the teratologic impact of the environmental factors on fetal growth and development is discussed. The mechanisms by which various environmental factors can produce teratologic abnormality and the clinical manifestations of these disorders are clearly illustrated. The various maternal factors, drugs, radiations, and environmental chemicals that may produce fetal defects are outlined and some possible preventive measures are discussed.

NICHOLAS S. ASSALI

Contents of Other Volumes

Volume I Maternal Disorders

Disorders of Ovulation

Guy E. Abraham, John R. Marshall, and Thomas A. Daane

Disorders of Gamete Transport and Implantation

Robert W. Noyes

Disorders of Uterine Functions during Pregnancy, Labor, and Puerperium

Helmuth Vorherr

Disorders of Maternal Circulatory and Respiratory Adjustments

N. S. Assali and C. R. Brinkman III

Disorders of the Kidney, Fluids, and Electrolytes

Leon C. Chesley

Disorders of the Liver in Pregnancy

Burton Combes and Reuben H. Adams

Disorders of Lactation and the Mammary Gland

M. Reynolds

Author Index—Subject Index

Volume III Fetal and Neonatal Disorders (Tentative)

Disorders of Circulation

Samuel Kaplan and N. S. Assali

Disorders of Respiration

M. E. Avery

Disorders of the Endocrine System

Solomon A. Kaplan

Disorders of Water and Electrolytes

N. S. Assali, James De Haven, and Cynthia Barrett

Disorders of the Nervous System

Antonia Vernadakis and Paola S. Timiras

Disorders of Immune Mechanisms

Arthur Ammann

Disorders of Hematopoeisis

Robert Neerhout and Philip Sturgeon

Disorders of the Liver and Bilirubin Metabolism

L. Gartner

Author Index—Subject Index

1

Disorders of Placental Transfer

Lawrence D. Longo

Publisher Summary

This chapter discusses the factors adversely affecting placental transfer and their possible implications on fetal metabolism and development. A distinguishing feature of mammalian development is the provision of nutrients from the maternal organism. Adequate exchange across the placenta between the maternal and fetal circulations is essential for normal fetal metabolism and growth. The placenta is unique in its function from several points of view. Its lifetime is short relative to the fetus, and its size and function change continually during the course of gestation. For the fetus, the placenta serves as lung, gastrointestinal tract, kidneys, liver, and even endocrine organ. Its morphology changes during gestation in ways that could only be termed pathological in any other organ. Innumerable substances are transferred from the maternal to fetal circulations. The exchange rates and transfer mechanisms vary for different substances. Either physiological limitations or pathological changes may affect the rate of exchange or the metabolism of various substances by placental cells. Alterations in placental transfer may be either acute or chronic and associated with pathological changes of the maternal or fetal placental circulations or in the chorion or amnion of the placenta per se. The term placental insufficiency is used often in a clinical sense to imply abnormal placental function or some specific alteration in fetal heart rate pattern. Maternal factors include decreases in blood constituents and decreases in uteroplacental blood flow. Placental factors include abnormalities of trophoblast or vascular tissues, which may be primary or secondary to maternal or fetal abnormalities. Fetal factors include alterations in the rate of umbilical blood flow.

I. Introduction

II. Physiological Transfer Mechanisms

A. Simple Diffusion

B. Facilitated Diffusion

C. Active Transport

D. Pinocytosis

E. Bulk Flow or Ultrafiltration

F. Breaks in Placental Villi

III. Normal Transfer of Specific Substances

A. Gases

B. Carbohydrates

C. Amino Acids, Polypeptides, and Proteins

D. Lipids and Steroids

E. Nucleic Acids

F. Vitamins

G. Electrolytes

H. Water Transfer

IV. Relation between Normal Placental Structure and Function

A. Gross Morphology

B. Microscopic Morphology

C. Cellular Changes

D. Relation of Placental Weight to Fetal Weight

E. Physiological Changes during the Course of Gestation

V. Alterations in Placental Transfer Mechanisms

A. Maternal Blood Nutrients

B. Maternal Oxygen Supply

C. Circulatory Disturbances

D. Parenchymal Alterations Affecting Placental Transfer

E. Abnormal Gross Placental Development

VI. The Placenta and the Small-for-Gestational-Age Infant

A. Definitions and Incidence

B. Association with Various Conditions

C. Role of Placenta in Abnormal Fetal Growth and Development

VII. Diagnostic Tests of Altered Placental Transfer

A. Atropine Transfer

B. Isoxsuprine Infusion

C. Fetal Response to Maternal Exercise

D. Fetal Response to Induced Fetal Contractions

E. Selenomethionine Uptake

F. Placental Transfer of Dye

VIII. Sequelae of Altered Placental Function

IX. Possible Therapy for Altered Placental Transfer

X. Summary

References

I Introduction

A distinguishing feature of mammalian development is the provision of nutrients from the maternal organism. Adequate exchange across the placenta between the maternal and fetal circulations is essential for normal fetal metabolism and growth. The placenta is unique in its function from several points of view. Its lifetime is short relative to the fetus and its size and function change continually during the course of gestation. For the fetus the placenta serves as lung, gastrointestinal tract, kidneys, liver, and even endocrine organ. Its morphology changes during gestation in ways which could only be termed pathological in any other organ. Finally, contrary to the belief of early investigators that the placenta is simply a passive, semipermeable sieve, there is probably no organ of the body in which as many mechanisms of transfer operate simultaneously. For example, respiratory gases diffuse between the maternal and fetal circulations; carbohydrates exchange by facilitated diffusion; amino acids and some vitamins are actively transported; macromolecules such as immunoglobulins are probably transported by pinocytosis and water is probably exchanged by bulk flow in response to small hydrostatic or osmotic pressure gradients (see Sections II,E and III,H).

The transfer between the human maternal intervillous space and the fetal placental capillaries is mainly through the chorion frondosum of the discoidal hemochorial placenta. While the role of the yolk sac is important in some rodents and other mammals, its role in the human during early gestation is not clear. The role of the chorion laeve and amnion in the transfer of nutrients whose exchange is limited by blood flow (such as oxygen) is probably not great, since it has been shown that these membranes receive only a small fraction of the total placental flow. On the other hand, these structures may have a role in the transfer of water.

Innumerable substances are transferred from the maternal to fetal circulations. The exchange rates and transfer mechanisms vary for the different substances. Either physiological limitations or pathological changes may affect the rate of exchange or the metabolism of various substances by placental cells. These alterations may be secondary to maternal factors, to fetal factors, or to changes in the placental cells per se, and may act to limit the availability of various substances for normal fetal growth and development.

The purpose of this review is to discuss normal placental transfer mechanisms; the factors adversely affecting placental transfer and their possible implications on fetal metabolism and development; and the diagnosis of abnormal placental function and possible means of treatment of this condition.

II Physiological Transfer Mechanisms

The transfer of substances across biological membranes occurs by several different mechanisms, including simple diffusion, facilitated diffusion, active transport, pinocytosis, and bulk flow. Their importance varies for different substances and several may act simultaneously.

A Simple Diffusion

Movement of a molecular species by random thermal motion from an area of high concentration to one of low concentration is passive diffusion (Fig. 1). While simple diffusion is usually in response to a chemical gradient, charged ionic species may move in response to electrochemical gradients. Simple diffusion is characterized by the net quantity of a substance transferred being directly proportional to both the concentration or electrochemical difference across the membrane and certain characteristics of the membrane such as area, diffusivity, and thickness [see Eq. (1)]. Simple diffusion is a passive process, involving no energy or work by the membrane and continues downhill (Fig. 1) only until uniform concentration or electrochemical equilibrium is obtained.

FIG. 1 Diagrammatic representation of simple diffusion. A thin membrane separates compartments 1 and 2, which may be considered to be maternal and fetal plasma, respectively, or extracellular and intracellular compartments, respectively. A substance, S, diffuses from a higher concentration in compartment 1, [S]1, across the membrane downhill to a lower concentration in compartment 2, [S]2. The rate of diffusion is proportional to the concentration difference across the membrane and to certain characteristics of the membrane [area, thickness, etc.; see Eq. (1)].

The rate of diffusion is determined by physicochemical factors in accordance with Fick’s first law (104):

(1)

= net rate of exchange or flux (amount per unit time), K = permeability of the membrane, A = area of exchange, x = membrane thickness, and ΔC = concentration difference across the membrane. Strictly speaking, it is the difference of chemical activity of the species, rather than the concentrations per se, that is important in driving a given substance across the membrane.

For gases, where the concentration is proportional to the partial pressure:

(2)

where α = the Bunsen solubility of the gas in the membrane and ΔP = partial pressure difference.

Several physicochemical factors affect the rate of diffusion across membranes and include the following:

Molecular size: In general, substances of smaller molecular size diffuse more rapidly than larger molecules. The Graham-Exner relation (102) states the diffusivity is inversely proportional to the square root of the molecular weight, a relation found to hold fairly well for many cell membranes for substances with molecular weights below 250. Indeed, small, uncharged lipid-soluble molecules are found to diffuse so rapidly that their concentrations equilibrate during a single capillary transit (207, 237). Substances with molecular weights greater than 700–1000 such as polypeptides and proteins cross the placental membrane more slowly if at all.

Electrical charge influences the rate of transfer across most membranes including those of the placenta. Placental membranes are permeable to Na+, K+, and Cl−, although these ions probably cross more slowly than water, urea, and other small uncharged molecules. Placental membranes are less permeable to bicarbonate ions (41, 206) and some other charged ions.

Lipid solubility is also important in determining the rate of transfer. Lipid-soluble substances are likely to diffuse through the entire cell membrane—in accord with its lipid nature—and to rapidly approach equilibrium between maternal and fetal circulations. Lipid-soluble substances such as antipyrine (227, 237) and thiopenthal are examples. Lipid-in-soluble substances, on the other hand, are likely to diffuse more slowly through membrane pores or aqueous channels between cells (195). Indeed, lipid-insoluble substances that are highly charged, such as succinylcholine, barely penetrate the placental membranes at all (248).

B Facilitated Diffusion

This differs from simple diffusion in that: the rate of transfer is faster than would be predicted on a physiochemical basis; the kinetics deviate from Fick’s law, showing a decreased transfer rate at high concentration (saturation); and substances with similar molecular spatial configuration show competition, i.e., their rate of transport is decreased. Facilitated diffusion does not occur against an electrochemical gradient and does not require energy. Metabolic inhibitors have no effect on the process unless they compete with the substrate for the carrier.

The mechanism of facilitated diffusion is not definitely established. The simplest working hypothesis is that a given substance combines chemically with a carrier in the membrane (Fig. 2). This carrier–substrate complex then crosses the membrane at a rate faster than that of the substrate alone (Fig. 3). For example, the rate of placental transfer of naturally occurring d-xylose is more rapid than that of the l-isomer (82). Other monosaccharides vary widely in their rate of intracellular accumulation by slices of placental chorionic tissue (209).

FIG. 2 Diagrammatic representation of carrier-mediated facilitated diffusion. The carrier, C, has the same affinity for the substance on both sides of the membrane. The substrate–carrier complex, SC, diffuses across the membrane more rapidly than the substrate alone; hence the concentration of substances in compartment 2 equilibrates more rapidly with that in compartment 1 than in the case of simple diffusion. The concentration of substance in compartment 2 will reach the same, but cannot be greater than, the concentration in compartment 1.

FIG. 3 Facilitated diffusion is also downhill, but occurs at a more rapid rate than predicted on a physicochemical basis, as indicated by the heavy arrows.

C Active Transport

This is the transfer of molecules by processes requiring expenditure of metabolic energy. Active transport is usually uphill against an electrochemical gradient. The mechanism of active transport has not been established, but again the simplest working hypothesis involves a membrane carrier that combines chemically with the substrate (Fig. 4). The carrier or the substrate–carrier complex is believed to undergo endergonic chemical alteration and is linked to an adenosine triphosphate (ATP) energy source.

FIG. 4 Diagrammatic representation of a carrier system capable of active transport. An important difference between this model and the one illustrated in Fig. 2, is that the carrier undergoes a change at the inner surface of the membrane from a form X with a relatively high affinity for the substance, to form Y which has a relatively low substrate affinity. Energy is required in the reversible transformation of the carrier between X and Y forms. This is generally assumed to be supplied at the inner surface of the membrane.

Active transport is characterized by net transfer in the direction opposite to the concentration or electrochemical gradient (Fig. 5); presence of a chemical or electrochemical gradient at equilibrium in the absence of any other factors affecting transfer of the substances in question, such as Donnan equilibrium or protein binding; inhibition of the transport process by metabolic poisons; competition for the transport by molecules with similar structural or molecular configuration; and decreased transport rate at high concentration of substrate. The exact chemical nature of the membrane pump is not clear, but considerable evidence suggests that it is related to ATPase. Substances actively transported by the placenta include amino acids, probably the water-soluble vitamins, and ions such as calcium (see Sections, III,C,F, and G).

FIG. 5 Active transport occurs from a given concentration in compartment 1 uphill against an electrochemical gradient to a higher concentration in compartment 2.

D Pinocytosis

In this process cell membranes invaginate engulfing tiny droplets of solute and water then cross the cell discharging their contents on the other side. Macropinocytosis may be observed with light microscopy. Coated micropinocytotic vesicles, that histochemical studies suggest have a high protein content have been demonstrated in the placenta using electron microscopy (324).

Pinocytosis is seen commonly in a variety of cells, but the process is poorly understood. Histochemical studies demonstrate that the pinocytotic vesicles are surrounded by high concentrations of ATPase, suggesting an energy dependence. While the rate of the transport process may be relatively slow, it still may be an important mechanism when considered over a prolonged period of time for the transfer of immune globulins and other large proteins or drugs.

E Bulk Flow or Ultrafiltration

Hydrostatic or osmotic pressure gradients will cause a transfer of water molecules, a process referred to as bulk flow (Fig. 6). Water movement will carry dissolved particles (solvent drag) (Fig. 6). This results in a more rapid rate of transfer of water and solutes than predicted on the basis of simple diffusion. Water movement is rapid between amniotic fluid, fetus, and mother (172, 268, 269). The mechanism responsible for these rapid turnover rates is unknown, but they may be in response to small or intermittent maternal to fetal osmotic or hydrostatic pressure gradients.

FIG. 6 Diagrammatic representation of bulk flow or ultrafiltration. Increased hydrostatic pressure, indicated by the piston in compartment 1, results in more solvent crossing the membrane into compartment 2 than would be predicted by the laws of diffusion. Molecules such as sodium ion may be carried along with the solvent, so-called solvent drag. Osmotic pressure, caused by a higher concentration of solute in compartment 2 than in compartment 1, may have a similar effect.

F Breaks in Placental Villi

These may explain the passage of fetal erythrocytes into the maternal circulation. The significance of minute leaks under normal circumstances is unknown, but they are important as the initiating events in sensitization of the Rh negative matter to Rh positive fetal erythrocytes.

In summary, the transfer of various substances from maternal to fetal blood occurs by several mechanisms. A given substance may be transferred by more than one of these processes simultaneously. For instance, while amino acids are being actively transported by the membrane carrier, some of the amino acids may cross by simple diffusion and some by micropinocytosis. The relative importance of these various mechanisms has not been determined for any substance.

III Normal Transfer of Specific Substances

The processes by which various substances exchange between the maternal and fetal circulations have been noted above. It is now appropriate to consider the factors limiting placental transfer under physiological circumstances.

A Gases

The respiratory gases O2, CO2, and CO and the metabolically inert gases are presumed to cross the placenta by simple diffusion, no evidence having been found for active transport (23, 211, 237).

1 OXYGEN

The study of oxygen transfer has attracted considerable interest among investigators and recently the field was reviewed by Metcalfe, Bartels, and Moll (239). On one hand, the rate of fetal O2 utilization is rapid, about 13.5–15 ml/min for a 3-kg fetus, whereas, on the other hand, the supply of fetal oxygen in reserve is small, about 30 ml, and there are no mechanisms by which the fetus can increase its O2 stores. Thus an uninterrupted O2 supply is vital for fetal survival; irreversible brain lesions appear after 7–10 min of O2 deprivation in monkeys (365).

Placental O2 transfer is determined by several principal factors (208). These are the placental diffusing capacity, oxygen diffuses from a high partial pressure in maternal blood to a lower partial pressure in fetal blood in accordance with Fick’s law (Fig. 7 and Table I), the uterine and umbilical arterial O2 tensions, the characteristics of the maternal and fetal oxyhemoglobin saturation curves, the maternal and fetal placental hemoglobin flow rates, the pattern of maternal to fetal blood flows, and the amount of CO2 exchanging. Each of these determinants of O2 exchange are in turn functions of other factors.

TABLE I

Normal Values of Oxygen, Carbon Dioxide, and pH in Human Maternal and Fetal Blood

FIG. 7 Schematic representation of the uterine and umbilical placental circulations. Maternal blood is supplied to the exchange area via the uterine artery and drains via the uterine vein. Fetal blood is supplied via the umbilical artery and leaves via the umbilical vein. Oxygen and other nutrients are transferred across the placenta from maternal to fetal blood.

a Diffusing Capacity.

Placental diffusing capacity (DP) expresses the rate of O2 transfer for a given partial pressure difference between maternal and fetal blood. The particular value depends on the characteristics of the placental membranes, the exchange vessels, and the blood. For O2 the diffusing capacity may be determined by rearranging Eq. (2):

(3)

is the mean O2 tension difference between maternal and fetal placental blood. The rate of placental O2 exchange may be readily calculated to be about 4.5 ml/(min × kg of fetal weight), from the product of the umbilical blood flow and the arteriovenous O2 content difference. The mean maternal to fetal O2 tension difference is less readily calculated, however.

difference from measurements of the O2 tensions in uterine and umbilical arterial and venous blood (in maternal intervillous space blood is 40–50 mmHg (Fig. 8) while that in the fetal placental blood is 20–25 mmHg, with a mean difference of about 25 mmHg (Fig. 8). Using these values the placental diffusing capacity for O2 would be about 0.5 ml/(min × mmHg) for a 3-kg fetus ((4.5 × 3)/25). However, neither the mean nor the end capillary O2 tensions in the exchange vessels can be determined with any precision from the O2 tensions in the uterine and umbilical mixed venous blood (210), since O2 is consumed by placental tissues and there are probably both vascular shunts (242, 286) and nonuniform distribution of maternal to fetal placental blood flows (280) in the placenta.

FIG. 8 difference between uterine and umbilical veins. The arrow indicates the average maternal to fetal partial pressure difference of about 25 mmHg calculated by this method.

differences can be more accurately determined indirectly by measurements of carbon monoxide (CO) exchanges (difference and certain other values, one can calculate that O2 tensions in maternal and fetal blood would equilibrate at about 32 mmHg at the end of a single transit in the placental exchange vessels (Fig. 9) (162). This suggests that under normal conditions the placental transfer of O2 is not limited by the resistance to diffusion of the placental membrane, but rather by other factors, namely, the maternal and fetal blood flow rates (208).

FIG. 9 difference of about 6 mmHg.

Placental diffusing capacity is not only a function of membrane diffusion, but also the diffusing capacity of the maternal and fetal placental capillary blood, since O2 must dissociate from maternal hemoglobin and combine with fetal hemoglobin. Membrane diffusion is a function of the area, thickness, diffusivity, and permeability of the placental membrane as noted in Eq. (2). Thus, placental diffusing capacity will be decreased in clinical conditions that thicken the placental membranes or decrease the surface area of exchange, such as placental infarctions, diabetes mellitus, toxemia of pregnancy, other hypertensive disorders, lues, and erythroblastosis.

b Maternal and Fetal O2 Partial Pressures.

The amount of O2 transferred across the placenta, and the resulting placental end capillary O2 tensions are critically dependent upon the oxygen tensions of uterine and umbilical arterial blood (falls below about 75 mmHg, the amount of O2 transferred will decrease sharply.

FIG. 10 mmHg, 38°C from Hellegers and Schruefer (152).

Figure 10 indicates that the fetal oxyhemoglobin saturation curve lies to the left of the maternal curve under standard conditions (152of about 30 mmHg, that the O2 is actually moving against a concentration gradient. In this instance from a concentration of about 11 ml/100 ml in maternal blood to a concentration of about 18 ml/100 ml in fetal blood.

FIG. 11 Relation of O2 content (ml/100 ml blood) to O2 partial pressure for maternal and fetal blood, assuming O2 capacities of 12 and 16 gm/ml, respectively.

c Maternal and Fetal Hemoglobin Flow Rates.

values also depend on both the rate of blood flow and the hemoglobin concentration of maternal and fetal placental vessels. (The hemoglobin concentration determines blood O2 capacity; capacity = hemoglobin × 1.34.) Changes in blood flow and hemoglobin concentration are similar in their effect and may be considered together. At normal O2 tensions most of the O2 is combined with hemoglobin and physically dissolved O2 accounts for less than 2% of the total amount exchanging.

Maternal hemoglobin flow rates may be decreased in toxemia of pregnancy, other hypertensive vascular disorders, shock, and anemia. Decreases of fetal hemoglobin concentration apparently occur only in the presence of hemolytic disorders in utero. Less O2 is transferred in each case, unless compensatory adjustments can be made.

2 CARBON DIOXIDE

The exchange of carbon dioxide from fetal to maternal blood also occurs by passive diffusion and is affected by the same factors influencing O2 exchange, although their relative importance differs. Normal values for the CO2 partial pressure, total CO2 content, bicarbonate, and pH are shown in Table I. About 0.8–0.9 ml CO2 are produced for each milliliter of O2 consumed (105, 289).

of umbilical vein blood is higher than that of the uterine vein, it has been suggested that the placental membrane resistance limits CO2 transfer. The movement of CO2 normally involves the reactions:

proceeding to the right in fetal placental blood and to the left in maternal placental blood. Under normal circumstances, the reaction CO2 + H2O + H2CO3 is catalyzed by the enzyme carbonic anhydrase in the red blood cells. Recent studies (difference of 4–5 mm thus probably results from a combination of CO2 production by placental tissue, vascular shunts, and uneven distribution of fetal to maternal placental blood flows.

B Carbohydrates

The transfer of glucose and other carbohydrates is of interest since glucose is the major metabolic fuel of the fetus. Quantitatively, the placenta transfers about 5.9 mg glucose/(min × kg fetal weight) or about 18 mg/min near term. Originally it was thought that glucose crossed the placenta by passive diffusion, but Widdas (353) demonstrated that facilitated diffusion would be required to account for the observed transfer rates. Additional evidence for a carrier-mediated facilitated diffusion has been provided by the evidence that d-xylose is transferred more rapidly than the l-isomer (82); that d-glucose is transferred much more rapidly than l-glucose (209) and that glucose (an aldohexose) is transported more rapidly than fructose [a ketohexose (59)] or other sugars with similar molecular weights (84, 85, 165, 184). Glucose concentration in human uterine venous blood exceeds that in umbilical venous blood. The mean maternal glucose concentration is about 90–100 mg/100 ml while the mean fetal concentration is about 70–75 mg/100 ml (265, 385). Placental metabolism of glucose probably accounts for part of the maternal-to-fetal glucose concentration difference (84).

The placenta contains large amounts of glycogen, most of which is synthesized from maternal glucose. The role of placental glycogen in fetal transport and metabolism is not clear. Villee (343) has shown that the placental glycogen content changes during pregnancy; with a maximum concentration at about 8 weeks that declines throughout the course of gestation to the lowest concentration at term. This decrease in placental glycogen is accompanied by a reciprocal increase in the glycogen of the fetal liver. There is a continuous exchange between maternal glucose, placental glycogen, and fetal glucose. As yet there is no satisfactory explanation of either the physiological role of placental glycogen or its necessity in the presence of adequate maternal glucose concentrations.

The uptake of glucose by placental tissue may be stimulated by insulin, but the evidence for this is equivocal. Villee (344) demonstrated a moderate increase in glucose uptake by human placental slices in the presence of insulin. Litonjua (202) confirmed this finding, and demonstrated an increased formation of lactic acid, glycogen, and proteins from labeled glucose by placental slices. On the other hand, such an effect was not demonstrated by other workers in sheep, goat (30), or human placenta (330). If insulin does in fact increase placental glucose uptake, it is not known whether this results from increased transfer across the trophoblast cell membrane, whether intracellular glucose metabolism is stimulated, or both.

In humans, the principal fetal carbohydrate is glucose and the placenta contains large amounts of glycogen. In ungulates (cattle, sheep, goats, etc.) and cetacea (whales) fructose is the main carbohydrate in fetal blood and the placenta contains only small amounts of glycogen. Fructose is present in small amounts in human fetal blood (<5 mg/100 ml), but its role in fetal metabolism is not known. Fetal fructose is produced by the placenta from maternal glucose (143). Fructose crosses the human placenta at about one-tenth the rate of glucose (165) and the fetal concentration shows only slight increases with increases in maternal glucose concentration.

Mesoinositol (53) and sorbitol are also present in higher concentrations in fetal than in maternal blood. While sorbitol can be produced by the placenta from glucose, the placenta apparently does not metabolize inositol (53). The role of these other carbohydrates in fetal metabolism is unknown.

C Amino Acids, Polypeptides, and Proteins

The fetus probably synthesizes most of its proteins from amino acids derived from the maternal circulation, with the possible exception of the γ-globulins. Rabinovitch (283) first observed that the free amino acid concentrations in fetal blood were higher than in maternal blood. These observations have been extended by others (61, 67, 81, 83, 127). The normal fetal-to-maternal ratio varies from about 1.2–4.0, with a mean of about 1.8 (377).

It is now well established that the amino acids are transferred by active transport. Page et al. (262) demonstrated that naturally occurring l-histidine crosses the placenta more rapidly than does the d-isomer, which only crosses at a rate consistent with diffusion. There is a competition between amino acids, such as histidine and glycine, for the transfer process (61). The transport mechanism becomes saturated at high concentrations (83) and the rate of transfer is decreased in the presence of energy uncoupling inhibitors such as dinitrophenol (81).

The concentration of amino acids is lower in the plasma of pregnant women than in nonpregnant women (43), and the concentrations decrease near term (127). The concentrations of amino acids in the blood of both monozygotic and dizygotic twins may be quite different. This probably reflects differences in the transfer mechanisms in the placentas that nourish them (66), such as occurs in the parabiotic syndrome.

Polypeptides cross the placenta slowly if at all. Since the fetal adrenal usually fails to develop normally in an anencephalic fetus, significant amounts of ACTH probably do not cross the placenta. Failure of thyroid-stimulating hormone to cross is similarly inferred from failure of thyroid development in decapitated rabbit (180) and rat (189) fetuses. Insulin also probably crosses only slowly and in insignificant amounts (179).

Several reviews of placental protein transfer are available (16, 47). In humans, the site of protein transfer is probably the chorion, although in rabbits and other species the major pathway is the yolk sac splanchnopleure (47). Albumin, 7 S γ2-globulin and its F and S fragments, 19 S macroglobulin, fibrinogen, transferrin, and acid glycoprotein have all been demonstrated to cross the placenta of humans (130). The fetal plasma concentration of γ-globulin (IgG) before 26 weeks gestation is only about 5–20% the concentration in the mother but from 26 weeks to term the concentrations are about the same. Recently, Morphis and