Fetal and Neonatal Disorders

FETAL AND NEONATAL DISORDERS

Pathophysiology of Gestation

Volume III

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 Circulation

Publisher Summary

I Introduction

II Fetal Circulation at Term

III Disorders of Fetal Circulatory Functions

IV Isolated Ventricular Septal Defect*

V Aortic Runoff

VI Atrial Septal Defect

VII Transposition of the Great Arteries

VIII Ductal Dependence

IX Valvular Disease

X Pulmonary Venous Hypertension

XI Myocardial Diseases

XII Arrhythmias

XIII Metabolic Effects of Congestive Heart Failure and Hypoxemia

XIV Cardiorespiratory Symptoms without Congenital Cardiovascular Disease

XV Concluding Remarks

ACKNOWLEDGMENTS

Chapter 2: Disorders of Respiration

Publisher Summary

I Introduction

II Disorders of the Regulation of Respiration

III Etiology and Pathophysiology of Some Respiratory Disorders in the First Days of Life

IV Conclusion

Chapter 3: Disorders of the Endocrine System

Publisher Summary

I Introduction

II Thyroid

III Parathyroid

IV Insulin and Carbohydrate Metabolism

V Adrenal Cortex

VI Gonads

VII Anterior Pituitary

Chapter 4: Disorders of Water, Electrolyte, and Acid–Base Balance

Publisher Summary

I Introduction

II Dynamics of Water and Electrolytes

III Henderson-Hasselbalch Equation: Acid–Base Terminology

III Exchange of Water and Electrolytes between Body Compartments

V The Concept of Whole-Body Balance

VI Volume, Distribution, and Composition of Body Fluids and Electrolytes in the Adult, Fetus, and Neonate*

VII Disorders of Water and Electrolytes in the Fetus and Newborn

VIII General Principles of Acid–Base Balance

IX Disorders of Acid–Base Balance in the Fetus and Neonate

X Concluding Remarks

Chapter 5: Disorders of the Nervous System

Publisher Summary

I Introduction

II Disorders of Genetic Origin (see also Chapters 4 and 5 in Volume II)

III Disorders of Environmental Origin (see also Chapters 3 and 4 of Volume II)

IV Disorders of Iatrogenic Origin (see also Volume II)

V Neoplasms

ACKNOWLEDGMENTS

Chapter 6: Disorders of the Immunological Mechanisms

Publisher Summary

I Introduction

II Antibody-Mediated Immunity

III Cell-Mediated Immunity (see also Chapter 7 of this volume)

IV Cell Cooperation

V Ontogeny of Immunity

VI Immunological Deficiency Diseases (see also Chapter 7 of this volume)

Chapter 7: Disorders of Hematopoiesis

Publisher Summary

I Introduction

II The Erythrocyte

III The Leukocyte

IV Bone Marrow Examination

V Coagulation

Chapter 8: Disorders of Bilirubin Metabolism

Publisher Summary

I Introduction

II The Fetus (see also Volume II)

III The Newborn

IV Conjugated Hyperbilirubinemia of the Newborn

V Neonatal Hepatitis and Biliary Atresia

VI Hepatic Infections

VII Intrahepatic Biliary Atresia

VIII Choledochal Cyst and Other Biliary Obstructions

IX Dubin-Johnson and Rotor Syndromes

X Metabolic Defects Causing Conjugated Hyperbilirubinemia

XI Conclusion

ACKNOWLEDGMENTS

Author Index

Subject Index

Contributors

ARTHUR J. AMMANN, NICHOLAS S. ASSALI, MARY ELLEN AVERY, C.T. BARRETT, J.C. DEHAVEN, LAWRENCE M. GARTNER, MELVIN HOLLANDER, SAMUEL KAPLAN, SOLOMON A. KAPLAN, ROBERT C. NEERHOUT, PHILLIP STURGEON, PAOLA S. TIMIRAS and ANTONIA VERNADAKIS

Copyright

COPYRIGHT © 1972, BY ACADEMIC PRESS, 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 PHOTOCOPY, RECORDING, OR ANY INFORMATION STORAGE AND RETRIEVAL SYSTEM, WITHOUT PERMISSION IN WRITING FROM THE PUBLISHER.

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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 page on which the authors’ contributions begin.

ARTHUR J. AMMANN,     Department of Pediatrics, University of California, San Francisco Medical Center, San Francisco, California (305)

NICHOLAS S. ASSALI,     Department of Obstetrics and Gynecology, School of Medicine, The Center for the Health Sciences, University of California, Los Angeles, California (1, 153)

MARY ELLEN AVERY,     Department of Pediatrics, Faculty of Medicine, McGill University, Montreal, Canada (73)

C.T. BARRETT,     Department of Pediatrics, School of Medicine, The Center for the Health Sciences, University of California, Los Angeles, California (153)

J.C. DEHAVEN,     The Rand Corporation, Santa Monica, California (153)

SAMUEL KAPLAN,     University of Cincinnati, College of Medicine, and Children’s Hospital, Cincinnati, Ohio (1)

SOLOMON A. KAPLAN,     Department of Pediatrics, School of Medicine, The Center for the Health Sciences, University of California, Los Angeles, California (105)

LAWRENCE M. GARTNER,     Department of Pediatrics, Albert Einstein College of Medicine, of Yeshiva University, The Bronx, New York (455)

MELVIN HOLLANDER,     Department of Pediatrics, Fordham Hospital, Misericordia-Fordham, The Bronx, New York (455)

ROBERT C. NEERHOUT,     Department of Pediatrics, School of Medicine, The Center for the Health Sciences, University of California, Los Angeles, California (335)

PHILLIP STURGEON,     Department of Pediatrics, School of Medicine, The Center for the Health Sciences, University of California, Los Angeles, California (335)

PAOLA S. TIMIRAS,     Departments of Physiology and Anatomy, University of California, Berkeley, California (233)

ANTONIA VERNADAKIS,     Departments of Psychiatry and Pharmacology, University of Colorado Medical Center, Denver, Colorado (233)

Preface

This third volume of the treatise on Pathophysiology of Gestation deals with the mechanisms underlying the disorders that affect the fetus and the neonate, particularly those occurring in the early neonatal period. In the critical period following birth, the physiological functions of infants undergo marked transitional changes which serve to adapt every system of the body to the external environment. When these transitional changes are judged by either fetal or adult standards, they may often appear somewhat pathological. Yet, when analyzed properly in the light of the knowledge that has been gathered during the last decade regarding fetal life in utero and the effects of birth, these transitional changes appear mere physiological adjustment processes to extrauterine life. Therefore, it is during this period that the task of differentiating between what may be considered a normal physiological process and what may represent a pathological disorder of the neonate often becomes difficult. The principal object of this volume is to ferret these difficulties.

In the various chapters included in this volume, be it that dealing with the circulation or water and electrolytes or hematopoiesis, the reader will first find summarized in a lucid manner the various physiological processes which assist the fetal organism to adjust to the intrauterine environment. This is followed by an analysis of the pathophysiological alterations underlying the disorders that may occur during fetal life. The normal physiological changes in each system that occur immediately after clamping of the umbilical cord and initiation of breathing are then described with an eye on pinpointing as to how they differ from both the fetal and adult standards. Finally, the pathophysiological mechanisms that may take part in generating the various disorders of the neonate are explained and the general principles of their management are outlined.

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 II Fetal-Placental Disorders

Disorders of Placental Tranfser

Lawrence D. Longo

Disorders of Placental Endocrine Functions

H. H. Simmer

Disorders of Amniotic Fluid

A. W. Liley

Genetic Disorders Affecting Growth and Development

Robert S. Sparkes and Barbara F. Crandall

Environmental Effects on Development—Teratology

James G. Wilson

Author Index—Subject Index

1

Disorders of Circulation

Samuel Kaplan and Nicholas S. Assali

Publisher Summary

This chapter discusses disorders of circulation. The development of new investigative techniques has permitted early detection of fetal cardiac arrhythmias and has shed light on the various factors that control the pulmonary and systemic circulation in the fetal and neonatal periods. Perinatal heart diseases encompass a wide variety of altered hemodynamic states, some of which may begin long before birth and may exert their influences in utero. In others, these abnormal states may only manifest during the transitional and dynamically changing situation in the immediate neonatal period when the circulation adapts to extrauterine life. At this time, dramatic changes occur because gas exchange is transferred from the placenta to the infant’s lung. The chapter briefly discusses the various factors that control the systemic and pulmonary circulation before and after birth. It also identifies the various hemodynamic abnormalities that underlie the various cardiovascular disorders that affect the fetus and the neonate. In the chapter, information concerning the fetal circulation near term has been derived primarily from lambs, which can be probably applied to humans.

I. Introduction

II. Fetal Circulation at Term

A. Dynamics of Fetal and Neonatal Circulation

B. Control of the Systemic and Pulmonary Vascular Resistances in the Fetal and Early Neonatal Period

III. Disorders of Fetal Circulatory Functions

A. Abnormalities in Fetal Heart Rate

B. Effects of Vasoactive Drugs on the Fetus

IV. Isolated Ventricular Septal Defect

V. Aortic Runoff

A. Patent Ductus Arteriosus

B. Arteriovenous Fistulae

VI. Atrial Septal Defect

VII. Transposition of the Great Arteries

VIII. Ductal Dependence

A. Hypoplastic Left Heart Syndrome

B. The Coarctation Syndrome

C. Obstruction to Right Ventricular Outflow

IX. Valvular Disease

A. Pulmonic Stenosis

B. Pulmonary Valve Incompetence

C. Aortic Stenosis

D. Tricuspid Valve Disease

E. Ebstein’s Malformation

F. Isolated Free Wall Hypoplasia of the Right Ventricle (Uhl’s Anomaly)

G. Congenital Tricuspid Insufficiency

H. Mitral Incompetence

X. Pulmonary Venous Hypertension

XI. Myocardial Diseases

A. Myocarditis

B. Endocardial Fibroelastosis

C. Cardiomyopathy

D. Glycogen Storage Disease

E. Hyperthyroidism

F. Hypothyroidism

XII. Arrhythmias

A. Supraventricular Tachycardia

B. Congenital Complete Heart Block

XIII. Metabolic Effects of Congestive Heart Failure and Hypoxemia

A. Acid–Base and Blood Gases

B. Hypoglycemia

C. Hypoxemia

XIV. Cardiorespiratory Symptoms without Congenital Cardiovascular Disease

A. Persistent Pulmonary Vascular Obstruction

B. Neonatal Polycythemia

C. Hypoglycemia

D. The Circulation in Birth Asphyxia and in Intracranial Disease

E. Hemolytic Disease and the Circulation

XV. Concluding Remarks

References

I Introduction

A striking increase has occurred during the last decade in our knowledge of the fetal circulation and the changes that occur at birth. The development of new investigative techniques has permitted early detection of fetal cardiac arrhythmias and has shed light on the various factors that control the pulmonary and systemic circulation in the fetal and neonatal periods. Among the various circulatory aspects that have been clarified are such important functions as the cardiac output and its relative distribution, the control of the systemic and pulmonary vasomotor tones particularly with respect to the role played by the respiratory gases and the placenta, the dynamics of ductus arteriosus circulation and the mechanisms of its closure, etc.

The availability of this wealth of information regarding the behavior of the fetal and neonatal cardiovascular system in the normal condition has provided a good background for understanding the pathophysiology of many of the perinatal circulatory disorders.

Perinatal heart diseases encompass a wide variety of altered hemodynamic states, some of which may begin long before birth and may exert their influences in utero. In others, these abnormal states may only become manifest during the transitional and dynamically changing situation in the immediate neonatal period when the circulation adapts to extrauterine life. At this time, dramatic changes occur because gas exchange is transferred from the placenta to the infant’s lung.

This review begins with a brief survey of the various factors that control the systemic and pulmonary circulation before and after birth. The survey will then be used to pinpoint the various hemodynamic abnormalities that underlie the various cardiovascular disorders that affect the fetus and the neonate.

II Fetal Circulation at Term

Information concerning the fetal circulation near term has been derived primarily from lambs and probably can be applied to man. Angiographic studies by Barclay et al. (22) and later by Lind and Wegelius (107) demonstrated the pattern of venous return to the fetal heart, the intracardiac blood flow, and the course of the blood ejected from the heart. Quantitative studies of flows, pressures and resistances have been made by many investigators (9, 11, 15–17, 49, 155, 156).

The pertinent information regarding the anatomical characteristics of the fetal circulation is illustrated in Fig. 1; the pathways followed by the blood in the fetal and early neonatal periods are schematically represented in the diagrams of Figs. 2 and 3. The morphology of the fetal circulation may be summarized as follows: Umbilical venous blood which returns from the placenta, flows at an average of about 175 ml/kg min−1 and at a pressure of about 12 mm Hg (9). This blood is relatively well oxygenated with a saturation of almost 85% and a PO2 of about 30 mm Hg. About one-half of the umbilical venous blood bypasses the hepatic circulation and flows through the ductus venosus to the inferior vena cava (Fig. 1). Although this oxygenated blood becomes mixed with other blood returning from the caudal part of the body through the inferior vena cava, it is still relatively more oxygenated than the other blood columns entering the right heart. The blood from the inferior vena cava passes to the left atrium after traversing the foramen ovale; it then flows into the left ventricle and is ejected into the ascending aorta. Thus the coronary, cerebral and upper extremity arteries are perfused with blood having a higher PO2 than that perfusing other parts of the body except the liver. On the other hand, the superior caval blood which is considerably less oxygenated than the inferior vena cava blood traverses the tricuspid valve and flows primarily to the right ventricle and pulmonary artery (Figs. 2 and 3). Only a negligible portion of the superior caval blood crosses the foramen ovale to the left atrium. About 65% of the blood ejected by the right ventricle into the main pulmonary artery bypasses the lungs and is shunted across the ductus arteriosus into the descending aorta; the remaining portion goes to the lung (9, 17, 49). Hence, the blood in the descending aorta has a PO2 of about 19–22 mm Hg. The combined blood flow of the ductus arteriosus and the left ventricular output constitute the total amount of blood distributed by the fetal heart to organs and tissues, and has been termed the fetal effective cardiac output (9); it amounts to about 220 ml/kg min-1 (Table I). Approximately 65% of this total output returns to the placenta via the umbilical arteries; the remaining 35% is distributed to the various organs and regions of the fetal body (9, 49).

Table I

Data on Blood Flows in the Fetal and Neonatal Conditions, and in the Adult at Resta

aFigures are the average of various series and are expressed in milliliters per kilogram, per minute.

bAscending aortic flow does not include coronary flow.

cTSR = total systemic resistance.

dTRP = total pulmonary resistance.

FIG. 1 Anatomy of the circulatory system in the fetal lamb.

FIGS. 2 and 3 Diagrams of the circulation in the normal fetus and in the transitional period soon after birth.

FIG. 2 (left). In the fetus a large fraction of the umbilical venous blood enters the ductus venosus (DV) and bypasses the liver. This relatively well oxygenated blood flows across the foramen ovale to the left heart, which preferentially perfuses the head and upper trunk. Superior vena caval blood (SVC) is ejected by the right heart into the pulmonary artery (PA) and ductus arteriosus. This flows to the placenta as well as to the abdominal viscera and lower trunk. Interrupted lines indicate a low pulmonary blood flow and that flow from ascending aorta across the aortic isthmus is also diminished.

FIG. 3 (right). In the transitional neonatal period, placental flow is obliterated and pulmonary blood flow is greatly increased. Potential bidirectional shunting may occur across the ductus arteriosus or right to left shunting across the foramen ovale. DV = ductus venosus; IVC = inferior vena cava; SVC = superior vena cava; RA = right atrium; LA = left atrium; RV = right ventricle; LV = left ventricle; PA = pulmonary artery; DA = ductus arteriosus.

A Dynamics of Fetal and Neonatal Circulation

A number of studies have shown that the salient hemodynamic differences between the fetal and the adult circulation are as follows (9, 15–17, 27, 37, 38, 49, 155):

1. In the fetus, the pulmonary vascular resistance is considerably higher than the systemic vascular resistance. Net pulmonary blood flow, estimated from the algebraic difference between main pulmonary artery and ductus flows, is very reduced. Immediately after lung expansion and umbilical cord clamping, pulmonary vascular resistance falls precipitously, while systemic vascular resistance rises. Net pulmonary flow increases five- to sixfold because all of the right ventricular output supplemented by whatever blood is still flowing through the patent ductus now goes to the lung. Table I compares fetal, neonatal, and adult values for the various blood flows and for the pulmonary and systemic vascular resistances.

2. Because of the higher pulmonary vascular resistance, mean pressures in the pulmonary artery and right ventricle are higher than those in the aorta and left ventricle (Table I; Fig. 4). This pressure gradient during intrauterine life drives the blood flow in the ductus arteriosus from right to left. Also, probably because of the elevated pulmonary vascular pressure and resistance, the right ventricle of the fetus is more prominent in terms of work and thickness than the left ventricle.

FIG. 4 Pattern of pressure changes in the four heart chambers and in the pulmonary and systemic circulation before and after lung expansion and cord clamping. After lung ventilation, right ventricular and pulmonary artery pressures fall precipitously. Left ventricular and aortic pressures initially fall because of the change in the direction of ductus blood flow; these pressures increase thereafter particularly after cord clamping. The increase in systemic pressure after elimination of the placenta occurred despite high blood oxygenation. Both atrial pressures increase, but the increment in the left is greater than that in the right (From N. S. Assali, ed., Biology of Gestation, Vol. II. Academic Press, New York, 1968.)

Immediately after lung expansion and cord clamping, pulmonary artery and right ventricular pressures fall progressively while aortic and left ventricular pressures rise promptly (Table I; Fig. 4). Because of the reversal in the pressure gradient, ductus arteriosus blood flow changes direction and becomes left to right. Also, because of the reduction in pulmonary vascular resistance, the right ventricle begins to lose its dominance and its walls become progressively thinner. In contrast, the left ventricle begins to gain functional dominance and slowly becomes thicker and thicker.

3. The effective cardiac output of the fetus (estimated from the algebraic sum of left ventricular output and ductus flow) is three times as high as that of the adult per kilogram of body weight (Table I). This high output is brought about by the presence of the ductus arteriosus which diverts about 65% of the right ventricular output toward the systemic circulation.

After lung expansion and cord clamping effective cardiac output falls for two reasons (9, 15–17). The first reason is related to the change in ductus flow direction which becomes from left to right. This change diverts some blood from the aorta toward the pulmonary vascular bed. When the ductus eventually closes, the two ventricles begin working in series and the output of one becomes equal to that of the other.

The second factor responsible for the decrease in the effective cardiac output is the rise in the systemic vascular resistance subsequent to the elimination of the low resistance system of the placental circulation.

It is clear from the description of these hemodynamic characteristics that the ductus arteriosus circulation influences a great deal the magnitude of the blood flow destined to the systemic circulation including the placenta and that going to the lungs in both the fetal and in the early neonatal periods. The factors that control the blood flow through the ductus arteriosus are somewhat complex (9, 17, 120). They include: (1) the pressure gradient between the pulmonary and systemic circuits; (2) the magnitude of the right ventricular output; (3) the degree of asynchrony which exists between the two ventricles; (4) the inertial effects of blood ejection by the right ventricle; (5) the PO2 of the blood passing through the ductus; and (6) the status of the pulmonary vascular resistance. Changes in any one or a combination of these factors may alter ductus flow, and may thereby increase or decrease the effective cardiac output or the pulmonary blood flow. (For more details on the dynamics of ductus circulation, see references 9 and 120).

Among the various factors listed as playing a role in ductus circulation, the role of blood PO2 is probably the most important in determining closure of this shunt after birth. In vitro as well as in vivo studies in both fetal and neonatal experimental preparations have shown that, when the PO2 of the blood passing through the ductus reaches a level of about 50 mm Hg, the ductus walls contract and blood flow decreases strikingly (Fig. 5) (9, 14, 18, 19).

FIG. 5 Example of an experiment in which the PO2 of the blood passing through the ductus and pulmonary bed was raised by placing the pregnant ewe in a hyperbaric oxygen chamber. It can be seen that when the pulmonary blood PO2 begins to rise above 37 mm Hg, ductus blood flow begins to decrease and pulmonary blood flow begins to increase. This opposite action of oxygen on the ductus and pulmonary vessels is reversible in that when the chamber was decompressed, the flows returned to fetal levels.

The mechanisms by which oxygen activates ductus constriction are still controversial. It has been suggested that oxygen releases bradykinin and this substance triggers ductus closure (77). Recent experiments (12), however, have shown that the primary action of bradykinin in the fetus is pulmonary vasodilatation; the decrease in ductus blood flow that follows bradykinin injection was shown to be secondary to the pulmonary vasodilatation and not to a primary direct action on the ductus.

Fay (63) has recently presented data which suggest that the muscle cells in the media of the ductus wall are oxygen receptors. He further showed that inhibitors of oxidative phosphorylation selectively inhibit the contractile response to oxygen. On the basis of his physiological and electron microscopical studies, he formulated the hypothesis that oxygen triggers ductus contraction through an increase in the rate of oxidative phosphorylation; this latter results from increased availability of oxygen to the terminal cytochrome component, presumably cytochrome a3.

Although this hypothesis is very intriguing, it requires further validation. Furthermore, as already stated, in vivo experiments show that a high oxygen tension constricts the ductus but dilates the pulmonary vessels. Hence, if the above-stated hypothesis is true, an opposite mechanism must be found to explain the vasodilatating action of oxygen on vessels which are contiguous to the ductus. (For more discussion on the effects of O2 on the pulmonary circulation, see Section II,B.)

Genetic factors may also play a role in maintaining a patent ductus after birth. Recently, Patterson and his co-workers were able to maintain and reproduce a patent ductus arteriosus in a beagle colony by genetic manipulation (138). The mechanisms by which the genetic factors act are not clear.

B Control of the Systemic and Pulmonary Vascular Resistances in the Fetal and Early Neonatal Period

From the analyses of the dynamic characteristics of the fetal and neonatal circulation as described above, the following two questions promptly emerge.

1. What are the factors responsible for maintaining the systemic resistance low in the fetus and those contributing to its rise after birth?

2. Similarly, what are the factors which maintain the pulmonary vascular resistance so high in the fetal state, and what are the factors that contribute to its precipitous fall in the neonatal period?

A rise in the systemic arterial pressure of the fetus after cord compression or cord clamping was first observed by Barcroft and subsequently by many other investigators. Barcroft (23) attributed the rise to the asphyxia which would result from clamping the cord before lung expansion and before lung ventilation becomes efficient enough to oxygenate the fetal blood.

Data gathered during the last 10 years have demonstrated that the rise in systemic vascular pressure and resistance is due not to asphyxia but to other factors (9, 11, 15, 17, 18); these data may be summarized as follows:

1. If a lamb is delivered and the lungs are ventilated with air or oxygen prior to cord clamping, the blood PO2 rises significantly. Yet, when the cord is clamped, the arterial pressure rises despite the absence of hypoxia or asphyxia (Fig. 4).

2. During studies on the effects of hyperbaric oxygen, Assali et al. (14) were able to increase the fetal blood oxygen tension up to 300–400 mm Hg. Despite this fetal hyperoxia, the arterial pressure increases promptly after cord clamping.

3. Studies on the effects of varying degrees of hypoxia on the fetus and early neonate have shown that the blood pressure rarely rises in a manner similar to that which occurs after cord clamping (32) (see Fig. 13).

FIG. 13 Effects during hypoxia expressed as percent change over control of fetal systemic circulation (±S.E.). Hypoxia was produced by ventilating the ewe’s lung with 6% O2. Arterial pressure (AP) decreases slightly, but ascending aortic flow (QAA), ductus flow (QDA) and effective cardiac output (ECO) all fall significantly and the systemic resistance of the fetus rises. [From Brinkman et al. (32). Courtesy of the Amer. J. Obstet. Gynecol.]

These data, together with computer simulation of the various fetal and neonatal cardiovascular functions have led to the conclusion that the rise in the systemic resistance and pressure after cord clamping is related to elimination of the low resistance system of the placental circulation (9). Such an increase in resistance is related to purely physical effects and does not seem to involve the autonomic nervous system (9).

The factors that control the pulmonary vascular tone in the fetal and neonatal states are more complex than those which control the systemic vascular resistance. They are also more important from the pathophysiological and clinical viewpoints because of their possible relation to the problem of respiratory distress syndrome.

Data gathered during the last eight years have shed light on the relative contribution to the control of the pulmonary vasomotor tone of the following factors: (1) mechanical effects of expanding the pulmonary alveoli; (2) the biochemical action of oxygen; (3) the role of blood PCO2, pH and tonicity; (4) the role of the autonomic nervous system; (5) the effects of bradykinin; and (6) the baroreceptor activities.

1 MECHANICAL EFFECTS OF ALVEOLAR EXPANSION

The physical status of the fluid-filled pulmonary alveoli plays an important role in maintaining a high pulmonary vascular resistance in the fetal state (13); this factor is a major determinant of its fall in the initial phase of pulmonary expansion and ventilation. The mechanical effects of alveolar expansion on pulmonary vascular resistance and blood flow in the fetal lamb are illustrated in Fig. 6. It is clear that when the alveoli are cleared of fluid and ventilated either with helium or nitrogen or any other neutral gas, the pulmonary vascular resistance falls and the pulmonary blood flow increases promptly.

FIG. 6 Experiment in which the mechanical effects of alveolar expansion and the effects of blood PO2 on pulmonary circulation of the fetal lamb are shown. In the fetal state (control period), pulmonary artery pressure is higher than aortic pressure; net pulmonary flow is low and pulmonary vascular resistance is relatively high. Blood respiratory gases and pH are stable at fetal levels. The umbilical cord is intact. Ventilation of the fetal lung with helium decreases pulmonary vascular pressure and resistance and increases pulmonary blood flow promptly without changing blood PO2 or pH. When hypoxia is superimposed by ventilating the maternal lung with 6% O2 or helium, pulmonary vascular resistance increases and blood flow decreases despite the fact that the alveoli had already been expanded. Cord clamping and lung ventilation with 100% O2 increase blood PO2 and at the same time decrease pulmonary vascular resistance and augment pulmonary blood flow markedly. [From Assali et al. (13). Courtesy of Amer. J. Obstet. Gynecol.]

2 EFFECTS OF OXYGEN

Although the mechanical effects of alveolar expansion play a leading role in the initial period of pulmonary ventilation, the biochemical action of oxygen on the pulmonary arteriolar tone begins shortly thereafter. Figure 6 illustrates dramatically this action. It can be seen that, after the alveoli had been expanded and the pulmonary resistance had fallen, the imposition of hypoxia raises the pulmonary vascular resistance and decreases the pulmonary blood flow to levels seen in the fetal state. Increasing the blood PO2 through lung ventilation with 100% O2 promptly decreases the pulmonary resistance and increases the flow (10, 13) (Fig. 5).

But the role that oxygen plays in the control of pulmonary vasomotor tone was more dramatically demonstrated by the experiments carried out in the hyperbaric oxygen chamber (14). In these experiments, fetal blood PO2 was increased up to 300–400 mm Hg without expanding the lungs. Figures 5 and 7 present examples of these experiments. It is clear that despite the unexpanded alveoli, a striking increase in pulmonary blood flow and a decrease in ductus flow occurs when the fetal blood PO2 is raised. When the pressure in the chamber is lowered to sea level and the fetal blood PO2 is decreased back to normal fetal levels, pulmonary blood flow returns to control values (Figs. 5 and 7). In Fig. 8, data on the relationship between blood PO2 and pulmonary vascular resistance are pooled from various series of experiments. It is clear that a good correlation exists between these two parameters.

FIG. 7 Effects of hyperbaric oxygenation on the pulmonary circulation of the fetal lamb. When the fetal blood PO2 was increased to 300–400 mm Hg through raising the hyperbaric chamber to 3 atm, ductus blood flow became negligible and pulmonary artery blood flow increased strikingly despite the fact that the fetal lung was still unexpanded. When the chamber pressure was lowered to 1 atm., the ductus flow rebounded with a marked increase and the pulmonary flow decreased. [From Assali et al. (18). Courtesy of Circ. Res. and Academic Press.]

FIG. 8 Changes in pulmonary vascular resistance as a function of blood PO2; data collected from various series of experiments in which fetal blood PO2 was raised or lowered by various methods. [Courtesy Amer. J. Obstet. Gynecol. (13).]

These experiments demonstrate (1) that the fetal pulmonary circulation can be transformed into a neonatal type of circulation by merely elevating blood PO2; (2) that the pulmonary vessels are as sensitive to oxygen as the ductus arteriosus, but in the opposite direction; oxygen constricts the ductus but dilates the pulmonary vessels. Teleologically speaking, it seems that the low blood oxygen tension that prevails during fetal life may be designed to keep the ductus patent and the pulmonary vessels constricted so that more blood can bypass the lung and go to the systemic circulation. After birth and with the first breath, the oxygen tension rises, and this aids in opening the pulmonary vessels and closing the ductus (9, 10).

3 ROLE OF THE AUTONOMIC NERVOUS SYSTEM

The contribution of the autonomic nervous system to the fall in pulmonary vascular resistance that follows lung expansion was investigated in fetal lambs subjected to blockade of the autonomic ganglia (184). These experiments showed that, despite the blockade of the autonomic nervous system, expansion of the lung and elevation of blood PO2 produces the same fall in pulmonary vascular resistance and pressure and the same increase in pulmonary blood flow as that seen in animals with intact autonomic nervous system. Hence, the autonomic nervous system does not seem to play an important role in the initial pulmonary hemodynamic changes that occur at birth (184).

4 ROLE OF BLOOD pH, PCO2, AND BLOOD TONICITY

The influence of changes in blood pH and PCO2 on the pulmonary vasomotor tone is controversial. There are data in the literature which suggest that acidosis produces a certain degree of pulmonary vasoconstriction (157). In most of these experiments, however, blood PO2 was also changing. Alkalosis produced by infusion of NaHCO3 or THAM is thought to produce pulmonary vasodilatation.

Recent studies carried out on fetal and neonatal lambs on the effects of metabolic acidosis (HCl infusion) and metabolic alkalosis (NaHCO3 0.6 M) have shown the following (86): Infusion of 0.6 M NaHCO3 solution into either the fetus or neonate produces a marked pulmonary vasodilatation (Fig. 9). Pulmonary blood flow increases and pulmonary vascular resistance decreases; blood pH increases during the infusion. The same vasodilatation occurs in the systemic circulation, wherein the cardiac output increases and the systemic vascular resistance decreases. After cessation of the infusion, the pulmonary and systemic hemodynamic changes return to control values despite the fact that the blood continues to be alkalotic (Fig. 9). In other words, if the resistance values are plotted against blood pH, the correlation is very poor (13) (Fig. 10).

FIG. 9 Effects of bicarbonate infusion in the fetus (0.6 M), pulmonary vascular resistance (PVR), and pulmonary blood respiratory gases and pH. Base infusion decreased pulmonary vascular resistance and increased pulmonary blood flow markedly during the state of alkalosis. Such a circulatory response, however, subsided during the recovery period despite the persistance of alkalosis. These findings indicate that the pulmonary response may not be related to the blood pH changes. [From Johnson et al. (S6). Courtesy of Amer. J. Physiol]

FIG. 10 Changes in pulmonary vascular resistance as a function of blood pH; the data was pooled from various experiments. No correlation exists between these two parameters. [From Assali et al. (13). Courtesy of the Amer. J. Obstet. Gynecol.]

Acid infusion produces minimal effects on fetal and neonatal pulmonary and systemic vascular resistances despite a marked drop in blood pH as long as the blood PO2 remains within normal ranges (86).

Infusion of neutral solutions such as saline and glucose solutions having the same osmolality (about 900 mOsm/liter) as that of bicarbonate produces the same decrease in pulmonary and systemic vascular resistance as that elicited by the base infusion despite the absence of any blood pH changes (86) (Fig. 11).

FIG. 11 Effects of infusion of glucose solution (900 mOsm/1) on fetal pulmonary circulation. Pulmonary blood flow increases in a manner similar to that which occurs during base infusion From Johnson et al. (86). Courtesy of the Amer. J. Physiol.]

These studies led to the conclusion that the pulmonary and systemic vasodilatation produced by base infusion is not related to the blood pH changes, but rather to the hypertonicity of the blood caused by the infusate (for detailed discussion, see ref. 86). Base infusion increases plasma osmolality and blood volume significantly (86), and these changes probably play a role in the vasodilatation produced by hypertonic solutions. It is also possible that plasma hypertonicity increases the lumen of the arterioles through abstracting fluids from their walls or through liberation of vasoactive substances such as kinins.

5 BRADYKININ

Some reports have suggested that bradykinin may play an important role in the circulatory changes that occur at birth, particularly with respect to ductus closure and pulmonary vasodilatation (77).

Recent studies carried out in the fetal lamb by Assali and his co-workers (12) have shown that bradykinin produces a profound systemic and pulmonary vasodilatation. Ductus blood flow decreases invariably after bradykinin, and the decrement is exactly equal to the increment in pulmonary blood flow. These experiments have further shown that the decrease in ductus blood flow produced by bradykinin is secondary to the pulmonary vasodilatation (12).

6 BARORECEPTORS

The problem as to whether or not the baroreceptor reflexes are active in the fetus and the neonate has been debated for a long time. Recently, the effects of baroreceptor stimulation on systemic and pulmonary pressures, flows, and resistances were investigated in near-term fetal lambs; a mathematical model for computer simulation of baroreceptor functions was simultaneously used (31). The results of these studies have shown that the baroreceptors are definitely active in the near-term fetal lamb; but the fetal response to a given baroreceptor stimulus seems to be somewhat damped and is not as intense as that of the adult animal. Two main factors probably contribute to the damped response. The first is the existence of the vascular shunts and of the low resistance system of the placental circulation. The second factor is probably related to incomplete maturation of the adrenergic system.

III Disorders of Fetal Circulatory Functions

A Abnormalities in Fetal Heart Rate

1 NORMAL HEART RATE AND ITS CONTROL

Monitoring of the fetal heart rate has become the most widely used procedure for the diagnosis of fetal distress (36, 52, 52a, 82). This enthusiasm was generated by an outburst of a new technology in electronic amplifying and recording devices. Unfortunately, despite this enthusiasm, very little has been done to elucidate the mechanisms which control the fetal heart rate, particularly with respect to its hemodynamic relevance.

The heart rate during fetal life varies among the various animal species and according to the age of the fetus (9). In any given species, however, the establishment of criteria for normal and abnormal fetal heart rates often presents difficult problems.

It is well accepted that the normal human fetal heart rate varies between 120 and 160 beats per minute. In the sheep, it ranges between 180 and 220.

Morphologically, the neural control of the heart is thought to be present early in the developing fetus (9). Physiologically, however, the role of the sympathetic and parasympathetic innervation is not very clearly defined. In the fetal lamb, section of both cervical vagal nerves does not alter the heart rate significantly. Stimulation or traction of the distal end, however, produces bradycardia and often arrhythmia from which the heart may escape (30). Administration of atropine to a fetus with bradycardia usually accelerates the heart rate; the atropine action, however, may not be as evident in a fetus with a normal heart rate.

Stimulation of the cervical or thoracic sympathetic chain does not seem to elicit any consistent changes in the fetal heart rate. Injection of epinephrine, however, produces a consistent tachycardia (9, 49).

Stimulation of the whole conducting system at the atrial level usually results in severe arrhythmia (30).

All these considerations serve to emphasize the fact that we know very little about what controls the heart rate. From all the available evidence, it appears that the cardioaccelerator system (sympathetic) is working at a high gear in keeping the fast fetal heart rate and that the cardiodecelerator (parasympathetic) may be the brakes which slow down the heart rate in response to a variety of stimuli (see Section III,B).

From the hemodynamic viewpoint, the relevance of the heart rate stems from the fact that it is one of the two factors which determine the cardiac output; the other is the stroke volume. (For more information on this subject, the reader is referred to Chapter 4, Vol. I.)

In the adult animal or man, changes in heart rate are usually accompanied by reciprocal changes in the stroke volume so that the cardiac output is not altered significantly. Only during extreme bradycardia or tachycardia is the stroke volume unable to compensate and the cardiac output may fall.

The relationship between heart rate and stroke volume in the fetal lamb has recently been investigated by Brinkman and Assali (30). Their studies also included assessment of the influence of heart rate changes on vascular pressures, flows, and resistance. Their results show that, as in the adult, a decrease in the fetal heart rate by about 50% is accompanied by a reciprocal increase in stroke volume, as long as the heart rhythm remains normal. Only when the bradycardia is accompanied by arrhythmia does the stroke volume, arterial pressure, and blood flow fall (Fig. 12).

FIG. 12 Relationship between heart rate and stroke volume in the near-term fetal lamb. When the bradycardia is eurythmic (solid dots and solid line), the stroke volume compensates well for the decrease in heart rate even when the decrease reaches 50% of the control values. Cardiac output may not be altered significantly. When the heart rate decreases and becomes arrhythmic, the stroke volume does not compensate and the fetal circulation becomes compromised. (Courtesy of Amer. J. Physiol., to be published.)

2 PATHOPHYSIOLOGY OF THE DISORDERS IN FETAL HEART RATE

Irregularities in fetal heart rate are widely accepted as an indication of intrauterine distress. The advent of continuous monitoring techniques has permitted early detection of heart rate changes during normal and abnormal labor.

The most consistent heart rate change in fetal distress, regardless of the etiology, is bradycardia. A great deal has been written during the last few years about the significance of transitory slowing of the heart rate and the temporal relationship to uterine contractions. These episodes of transitory bradycardia are termed early and late decelerations or, in clinical jargon, type I and type II dips (36, 52, 52a, 82). Undoubtedly, these transitory changes may suggest a certain degree of stress on one or more of the factors that control fetal heart rate. But as stated above, experimental evidence indicates that the stroke volume compensates for this transitory bradycardia so that the dynamics of the fetal circulation may not be appreciably affected. Hence, while the transitory bradycardia should be taken as an alert signal that a closer observation for that particular patient is required, it should not be construed as an indication for immediate intervention to deliver the patient.

Sustained bradycardia lasting more than 3–5 minutes, particularly if it is present during uterine relaxation, should definitely be taken as a signal of fetal circulatory distress. If the bradycardia is associated with arrhythmia, then alarm is justified and immediate delivery is indicated. This is because, under these circumstances, the blood flow to organs and tissues is compromised and cellular hypoxia may ensue.

The pathogenesis of fetal bradycardia comprises many factors; but the mechanisms by which these factors act to produce fetal cardiac deceleration are poorly understood.

It is well established now that during strong uterine contractions, a transitory fetal bradycardia may appear (for more information on this subject, see Chapter 3, Vol. I). The bradycardia caused by uterine contraction may be due to (1) compression of the fetal head by the contracting uterus; (2) compression of the umbilical cord, particularly the umbilical veins by the contracting uterus; (3) decreased uterine blood flow and oxygen transfer subsequent to increased intramural resistance; (4) increased pressure in the intervillous space with altered hemodynamics on both the maternal and fetal sides; and (5) a combination of several of these factors. Usually, any one factor or a combination of factors which may produce fetal hypoxia or may interfere with the return of blood to the right side of the heart would lead to bradycardia.

Broadly speaking, however, it is reasonable to state that fetal hypoxia is the underlying cause of most sustained fetal bradycardia. Whether the hypoxia is related to interference in transplacental transfer of oxygen or to impairment of delivery of oxygen to the fetal tissues, such as occurs during compression of the umbilical cord, is immaterial; the result is nearly always fetal cardiac deceleration.

The umbilical vein in the cord is very vulnerable to varying degrees of compression by the presenting part, by the fetal body or by the contracting uterus because of its thin walls. Compression of the umbilical vein will decrease the venous return to the heart and the cardiac output. This will lead to bradycardia, hypotension, and hypoxia.

In the adult animal or man, hypoxia usually produces tachycardia, increased cardiac output, and a slight change in the systemic arterial pressure (55). In the fetus, however, hypoxia of any significant degree produces bradycardia, and a decrease in the cardiac output, arterial pressure, and umbilical blood flow (32) (Fig. 13). Hence, whenever the oxygen transfer from mother to fetus across the placenta is compromised, or whenever the oxygen delivery to the fetal tissues is impaired, bradycardia may appear.

Fetal tachycardia is seen occasionally and, in human pregnancy, is usually defined as a heart rate above 160 or 170.

It has been difficult to assess the clinical significance and the pathophysiological basis of fetal tachycardia. Experimentally, in the adult animal, heart rate acceleration is usually elicited by sympathetic stimulation or by cutting the vagus nerve or by the administration of the neurotransmitter—epinephrine. But as stated before, neither sympathetic stimulation nor vagal section in the fetal lamb has produced any consistent effect on heart rate. Administration of epinephrine to the fetus, however, produces a consistent tachycardia depending on the dose. It is expected, therefore, that pathological conditions which may increase the output of epinephrine in the fetus may be accompanied by tachycardia. The nature of these conditions and the degree of adrenal stimulation, however, have not been well defined. The main reason is that the fetal heart responds with bradycardia to a number of stimuli which, in the adult, would elicit tachycardia.

B Effects of Vasoactive Drugs on the Fetus

Vasodepressor and vasopressor drugs are very frequently used in pregnant women as a part of the management of pathological conditions such as hypertension, supine hypotension, circulatory shock, etc. (see Chapter 4, Vol. I). Since almost all of these pharmacological compounds have a relatively small molecular weight, they nearly always cross the placenta to the fetus. The question then is, how do the vasoactive drugs affect the fetal cardiovascular system?

The cardiovascular response of the fetus to several vasoactive drugs has been studied in the sheep during the past few years (9, 12, 101, 184). The effects on the fetal circulation were monitored when the drug was administered to the mother in doses large enough to produce significant maternal hemodynamic changes; the fetal circulatory parameters were also monitored when the drug was injected intravenously in the fetus.

In general, the results have shown that the fetus tolerates 5–10 times (or more depending on the drug) the dose given to the mother when the dosage is converted as per unit of weight. An example of this tolerance is illustrated in Fig. 14 in which the pregnant ewe’s response to 15 mg (0.2 mg/kg) of hydralazine (Apresoline) is depicted (101). With this dose, a marked fall in arterial pressure and uterine blood flow occurred. The effects on the fetal circulation of this drug when injected into the mother were negligible except for a fall in fetal blood PO2 due to the marked decrease in uterine blood flow. When the same dose was injected into the fetus, no effect on the fetal cardiovascular system was observed. It required 10–20 times the dosage per kilogram of body weight given to the mother to elicit a hypotensive effect in the fetus (101).

FIG. 14 Effects of intravenous injections of hydralazine (Apresoline) into the ewe on maternal and fetal circulation and oxygenation. Administration of 15 mg decreases maternal arterial pressure and uterine blood flow markedly. On the fetal side, the circulatory effects were minimal although the fetal blood pO2 fell. When the same dose is injected into the fetus, no effects on the circulation are observed. Ten to twenty times this dose are necessary to produce a mild hypotension in the fetus. [From Ladner et al. Courtesy of Amer. J. Obstet. Gynecol.]

Similar tolerance of the fetus to the injection of E. coli endotoxin and to hemorrhage has recently been observed by Brinkman and Assali (29a). These authors believe that the fetal cardiovascular response to vasoactive stimuli is buffered by the low resistance system of the placental circulation, as well as by the existence of the various vascular shunts. Incomplete maturation of the neural control of blood vessels may also play a role. These anatomic characteristics of the fetal circulation dampen the increase or decrease in the systemic vascular resistance necessary to increase or decrease the arterial pressure in response to a variety of stimuli. For instance, the injection of 0.2 mg/kg of endotoxin into the mother produces a marked fall in the arterial pressure and cardiac output. In the fetus, the injection of 1 mg/kg produces a minor fall in the systemic arterial pressure. The same occurs with hemorrhage. The withdrawal of 20% of the maternal blood volume elicits hypovolemic shock in the mother. In the fetus, it is necessary to reduce the blood volume by about 30% to produce the same degree of circulatory shock.

These same circulatory buffering mechanisms operate to provide a transitory protection for the fetal cardiovascular system when stresses of various forms are imposed on the mother. For instance, when spinal, hemorrhagic, or endotoxic shock are imposed on the maternal organism, the oxygen delivery to the fetus is curtailed. Fetal blood oxygen tension falls. The fall in fetal blood PO2 produces a dilatation of the ductus arteriosus and a vasoconstriction in the pulmonary vascular bed. These changes serve to shift blood from the lungs toward the systemic circulation of the fetus. This shift may prevent a major fall in the fetal effective cardiac output, maintaining, thereby, the fetal arterial pressure at near-normal levels.

IV Isolated Ventricular Septal Defect

*

It is speculated that the fetal circulation is not at jeopardy even in the presence of a large communication between the ventricles. Since pulmonary vascular resistance is greatly elevated, it is probable that in utero, blood is shunted from right to left ventricles across the defect. This may decrease the PO2 of the blood in the ascending aorta. Rudolph (152) suggested that this decrease does not affect intrauterine growth and development or the response of the fetal circulation. This was based on the analogy that the ascending aortic PO2 in arterial transposition does not appear to retard fetal development. After birth the dominant shunt across the ventricular septal defect is from left to right. The magnitude of the shunt is determined by the size of the defect and the ratio of systemic to pulmonary vascular resistance. Left to right shunting occurs as pulmonary vascular resistance falls. The increased pulmonary blood flow returns to the left heart and the resultant left ventricular diastolic overload produces a larger stroke volume which stimulates left ventricular hypertrophy.

Overt congestive cardiac failure is uncommon in the neonate with a large ventricular septal defect (79) and in our experience it is extremely rare for these babies to die a cardiac death in the first 4 weeks of life (94) (Fig. 15). This may be due to the fact that there is a slower fall of pulmonary vascular resistance in these babies. A number of factors appear to contribute to this slow fall. Although the pulmonary vessels are normal in the fetus with a ventricular septal defect, normal involution of these vessels does not occur so that medial smooth muscle persists (186). Primarily this is the response to continuing pulmonary hypertension since a decrease in the amount of pulmonary vascular smooth muscle parallels the fall in pulmonary arterial resistance (124, 141, 153). During the 2-year period 1969–1970 we have evaluated 21 babies with large isolated ventricular septal defects who were admitted to a special newborn care unit for investigation of cyanosis noted intermittently during the first week of life, but more frequently during the second, third, and fourth week. In these babies, persistent elevation of pulmonary vascular resistance resulted in a bidirectional shunt across the ventricular septal defect. Since the neonatal pulmonary vasculature retains its ability to constrict vigorously in response to hypoxemia, the right to left shunt contributed significantly to the maintenance of a high pulmonary vascular resistance. This cycle could be broken by the administration of oxygen. Of interest is the fact that pulmonary vascular resistance did fall somewhat in 16 of these 21 babies so that at the ages of 1 to 6 months surgical treatment was required to alleviate signs and symptoms of a torrential left to right shunt and associated pulmonary hypertension.

FIG. 15 Age at time of death in 52 autopsies of patients in whom the only cardiac anomaly was an isolated ventricular septal defect (VSD), Total in each age group indicates all patients where a VSD was found at autopsy. Significant refers to the patients in whom the VSD was the primary cause of death. 6983 refers to the number of protocols of consecutive autopsies examined in the adult age group. These protocols were studied for the presence or absence of a VSD. Of interest is the rarity of death due to isolated ventricular septal defect under the age of one month. [Reproduced with permission, Kaplan et al. (78).]

In some neonates the fall of pulmonary vascular resistance is sometimes more rapid than usual. This applies particularly to premature infants who may develop heart failure early. Rudolph (152) has attributed this finding to the fact that the medial muscle layer of the pulmonary vessels of the immature is less fully developed so that the premature at birth has less muscle in the pulmonary arteries. This may allow a more rapid fall in pulmonary vascular resistance after birth, the development of a large left to right shunt, and early onset of heart failure.

Grover and his colleagues (74) suggested that the response of the human pulmonary vasculature to hypoxemia is variable. Some patients hyperreact with a marked increase in pulmonary vascular resistance, whereas others show a less intense or even mild reaction. The hypoxemic stimulus of altitude in the dynamics of ventricular septal defect was studied by Vogel et al. (185). They noted a greater pulmonary blood flow with a higher incidence of congestive cardiac failure at sea level. Infants at the moderate elevation of Denver, Colorado had a higher pulmonary vascular resistance which limited the left to right shunt and pulmonary blood flow. Sime, Penáloza, and their colleagues (139, 168) have shown that pulmonary arterial pressure and resistance is increased at altitude. This is expected in patients with large ventricular defects at altitude since persistence of thick muscular media of pulmonary vessels is associated with a delay in fall of pulmonary vascular resistance.

Hypoxemia due to complicating lung disease such as pneumonitis, segmental collapse, and compensatory emphysema has the same effect on pulmonary vascular resistance with the development of temporary right to left shunt (151). Similar effects result from alveolar hypoventilation due to central nervous system disease (129).

It has already been indicated that death from heart failure due to a ventricular septal defect is rare in the first 4 weeks of life. However, in many neonates who die a small incidental ventricular septal defect is found at autopsy (94). This applies particularly to prematures who have a high mortality rate from noncardiac causes and who have a higher than normal incidence of ventricular septal defect (78). Mature babies under 4 weeks of age who have succumbed to severe extracardiac malformations may also have small to moderate sized ventricular septal defects at autopsy. Since these defects were asymptomatic and were not associated with signs of heart failure, pulmonary hypertension, or cardiomegaly, it is assumed that they were insignificant hemodynamically (94).

SMALL VENTRICULAR SEPTAL DEFECTS

The hallmark of the bedside diagnosis of a small ventricular septal defect is the presence of a long, loud, generally harsh systolic murmur. This murmur is generated by the turbulence created as blood flows from the left to right ventricle. This flow is dependent on the ratio of systemic to pulmonary vascular resistance. Therefore, the murmur may not be audible in the first few days of life if pulmonary vascular resistance remains elevated. This explains the common clinical experience of hearing the murmur for the first time during the 6-week checkup when it was inaudible at the time of discharge from the nursery. Hoffman (78) estimated that 50–80% of small defects close spontaneously so that failure to recognize minute ventricular septal defects does not place the baby in jeopardy.

V Aortic Runoff

The hemodynamic changes associated with large aortic pulmonary communications depend largely on the relationship between systemic and pulmonary vascular resistances. These changes apply particularly to isolated large patent ductus arteriosus, truncus arteriosus, and aortic-pulmonary window. Although arteriovenous fistulae and aortic-cardiac communications such as ruptured sinus of valsalva aneurysms, aortic valve incompetence, and aortic-left ventricular tunnel (28) produce aortic runoff, the primary hemodynamic abnormality is related to the pressure gradient across the communication. Since patent ductus arteriosus is by far the commonest of the abnormalities certain features related to this anomaly will be described in detail.

A Patent Ductus Arteriosus (see also Biology of Gestation Volume II)

In most normal full-term infants, the ductus arteriosus is functionally closed by the age of 10–15 hours (1, 47) although anatomic closure may be delayed for 1–8 weeks (2, 4, 5, 47). If the ductus remains open temporarily in the normal neonate, small volumes of blood are shunted from aorta to pulmonary artery since pulmonary vascular resistance is falling while systemic resistance is rising. Functional ductal closure is primarily due to muscular contraction and it may reopen, especially if arterial PO2 falls. Moss et al. (121) demonstrated that hypoxemia could reopen the ductus up to 3 days after birth.

1 PREMATURITY

Delayed closure of the ductus arteriosus occurs in 13% of prematures (151). Many of these babies are asymptomatic, have a small left to right shunt and do not require specific treatment. These prematures have jerky pulses and, although many have the typical continuous murmur, in others the murmur is audible only in systole with either mid-or late-systolic accentuation. In others a moderate to large left to right shunt is present and results in cardiac enlargement and failure. Many of these babies respond to medical measures (digitalis and diuretics) with subsequent spontaneous ductal closure, frequently at the age of 4–6 weeks. However, delayed closure of the ductus arteriosus in some prematures is associated with a torrential left to right shunt and severe congestive heart failure (20, 47). Although many of these babies respond to medical therapy with subsequent spontaneous closure, surgery may be necessary to obliterate the ductus because of uncontrollable heart failure.

Mature babies seldom develop heart failure from a patent ductus arteriosus within the first month of life,