Fetal Cardiovascular Physiology

Venous Return to the Heart

Approximately 40% of total fetal cardiac output (i.e., approximately 200 mL/kg of fetal body weight per minute) is distributed to the placental circulation; a similar amount returns to the heart via the umbilical venous system. Because umbilical venous blood is the most highly oxygen-saturated blood in the fetal circulation, distribution of umbilical venous return is most important in determining oxygen delivery to fetal tissues. After entering the intraabdominal portion of the umbilical vein, a portion of umbilical venous blood flow supplies the liver; the remainder passes through the ductus venosus, which directly connects the umbilical vein–portal sinus confluence to the inferior vena cava (IVC) (see Fig. 13.1 ). In contrast to the umbilical and portal veins, the ductus venosus has no direct branches to the liver. Umbilical venous blood can enter the ductus venosus directly. However, portal venous return can reach the ductus venosus only through the portal sinus. Approximately 50% of umbilical blood flow passes through the ductus venosus; the remainder enters the hepatic-portal venous system and passes through the hepatic vasculature.

The fetal liver receives its blood supply from the umbilical vein as well as the portal vein and hepatic artery. In normal fetal lambs, umbilical venous blood flow contributes approximately 75% to 80% of the total blood supply of the liver. Portal venous blood flow accounts for about 15%, and hepatic arterial blood flow from the aorta represents only 4% to 5%. The blood from these sources is distributed differently to various parts of the liver. Hepatic arterial blood flow to the liver is equally distributed to the right and left lobes, but the left lobe is supplied almost exclusively (>95%) by umbilical venous blood. In contrast, the right lobe receives both umbilical venous blood (approximately 60%) and portal venous blood (approximately 30%). Because umbilical venous blood supplies a major portion of flow to the right liver lobe by traversing the portal sinus, little, if any, portal venous blood reaches the ductus venosus. Therefore the blood in the ductus venosus has pH, blood gas, and hemoglobin oxygen saturation values similar to those of umbilical venous blood. The portion of umbilical venous blood flow that passes via the ductus venosus directly into the IVC meets the systemic venous drainage from the lower body.

Blood flow through the thoracic IVC represents approximately 65% to 70% of venous return to the heart; flow from the ductus venosus accounts for about one-third of this amount. ^, The two streams (one from the abdominal IVC and one from the ductus venosus) do not mix, and they demonstrate definite streaming in the thoracic IVC; the well-oxygenated blood derived from the ductus venosus occupies the dorsal and leftward portion of the IVC. This separation of the more highly saturated umbilical venous stream and the desaturated IVC stream returning from the lower body produces preferential flow of umbilical venous return into the left atrium and then into the left ventricle and ascending aorta. Of particular importance is preferential streaming of umbilical venous blood to the brain and myocardium.

The preferential streaming of umbilical venous return to the left lobe of the liver and portal venous return to the right lobe also affects the distribution of oxygenated blood to the fetal body. The left hepatic lobe is perfused with umbilical venous blood, which has an oxygen saturation of 80% to 85%; the right lobe is perfused by a mixture of umbilical and portal venous blood, which has a much lower oxygen saturation (approximately 35%). The oxygen saturation of blood in the hepatic veins reflects this difference in perfusion saturation. ^, The oxygen saturation in left hepatic venous blood is about 10% lower than that in umbilical venous blood but about 10% higher than that in right hepatic venous blood, in which the saturation more closely approximates the saturation in the descending aorta.

In fetal lambs, the ductus venosus and left hepatic vein drain into the IVC, essentially at a common point; partial valves are seen over the entrance of the hepatic vein and ductus venosus into the IVC. Similarly, the entrance of the right hepatic vein into the IVC has a valvelike membrane overlying the ostium. This arrangement probably allows left hepatic venous blood to be distributed in a manner similar to that of ductus venosus blood, whereas right hepatic venous blood is distributed similarly to the abdominal IVC stream. This is particularly important because about half of umbilical venous return passes through the liver, accounting for approximately 20% of total venous return to the heart. In fetal lambs, left hepatic venous blood flow follows the same pattern as ductus venosus flow, with preferential streaming to the brain and heart. Similarly, right hepatic blood flow follows the distribution pattern of abdominal IVC blood flow.

The IVC blood then enters the right atrium, and because of the position of the foramen ovale, further preferential streaming occurs. The foramen ovale is situated low in the interatrial septum, close to the IVC. The cephalad margin of the foramen, formed by the lower margin of the septum secundum, lies on the right side of the atrial septum; it is called the crista dividens and is positioned so that it overrides the orifice of the IVC. The crista dividens splits the IVC bloodstream into an anterior and rightward stream that enters the right atrium and a posterior and leftward stream that passes through the foramen ovale into the left atrium. This latter stream has the more highly oxygen-saturated blood returning from the umbilical circulation through the ductus venosus and left hepatic lobe. Despite this anatomic arrangement and the preferential streaming in the IVC, some mixing of blood does occur; a portion of the more highly saturated umbilical venous blood passes directly into the right atrium, and some desaturated abdominal IVC blood passes into the left atrium. However, the net result is still a significantly higher oxygen saturation in the left atrium than in the right atrium ( Fig. 13.2 ).

Blood returning to the heart via the superior vena cava also streams preferentially once it reaches the right atrium. The crista interveniens, situated in the posterolateral aspect of the right atrial wall, effectively directs superior vena caval blood toward the tricuspid valve. The coronary sinus, which drains blood from the left ventricular myocardium, enters the right atrium between the crista dividens and the tricuspid valve; the highly desaturated coronary venous return (saturation approximately 20%) is therefore also preferentially directed toward the tricuspid valve. This preferential streaming of superior vena caval and coronary sinus venous return to the right ventricle is also advantageous in the fetal circulation because this very desaturated blood is preferentially directed toward the placenta for reoxygenation. Pulmonary venous return to the heart enters the left atrium, where it mixes with the portion of IVC blood that has crossed the foramen ovale to enter the left atrium.

Approximately 65% of total cardiac output reaches the lower body and placenta and returns via the thoracic IVC to the heart. Of this IVC return, approximately 40% crosses the foramen ovale to the left atrium; the remaining 60% enters the right ventricle across the tricuspid valve. Therefore the amount of IVC return crossing the foramen ovale represents approximately 27% of total fetal cardiac output. This blood then combines with pulmonary venous return (approximately 8% of total fetal cardiac output) and represents the output of the left ventricle, or approximately 35% of total fetal cardiac output. The venous return from the superior vena cava, the coronary sinus, and the remainder of the IVC return (approximately 40% of total fetal cardiac output) enters the right ventricle and represents the portion of total fetal cardiac output ejected by the right ventricle (approximately 65% of total fetal cardiac output).

Cardiac Output and Its Distribution

In the fetus, because of the blood flow across the ductus arteriosus into the descending aorta, lower body organs are perfused by both the right and left ventricles (across the aortic isthmus). For this reason, and because of intracardiac shunting, it is customary to consider fetal cardiac output as being the total output of the heart, or the combined ventricular output. In fetal lambs, this is about 450 mL/kg/min. In contrast to the adult, and because of the various sites of intracardiac and extracardiac shunting, the left and right ventricles in the fetus do not eject in series and therefore do not need to have the same stroke volume. In fact, as shown in Fig. 13.3 , the right ventricle ejects approximately two-thirds of total fetal cardiac output (approximately 300 mL/kg/min), whereas the left ventricle ejects only a little more than one-third (approximately 150 mL/kg/min).

Echocardiographic studies in human pregnancy have suggested that in humans the right ventricle also dominates the left. Of the 65% of cardiac output ejected by the right ventricle, only a small amount (8%) flows through the pulmonary arteries to the lungs. The remainder (57%) crosses the ductus arteriosus and enters the descending aorta. Because right ventricular output contains all superior vena caval and coronary sinus return, it allows this unoxygenated venous blood to be preferentially returned to the placenta. Left ventricular output (approximately 35% of cardiac output) enters the ascending aorta; in the fetal lamb, approximately 21% reaches the brain, head, upper limbs, and upper thorax. About 10% of cardiac output traverses the aortic isthmus and joins the blood flowing across the ductus arteriosus to perfuse the descending aorta.

As shown in Fig. 13.2 , the level of hemoglobin oxygen saturation in the ventricles and great arteries is determined by the streaming patterns into, through, and out of the fetal heart. The highly saturated umbilical venous return streams preferentially across the foramen ovale into the left atrium, where it mixes with the relatively small amount of desaturated blood returning from the pulmonary veins. The net result is that blood ejected by the left ventricle to the ascending aorta is relatively well oxygenated (saturation approximately 60%). The extremely desaturated coronary sinus venous return and the desaturated blood returning from the brain and upper body flow almost exclusively across the tricuspid valve into the right ventricle. This blood mixes with the IVC stream, which is primarily composed of desaturated blood returning from the lower body but also contains some umbilical venous return. The net result is that the oxygen saturation of blood in the right ventricle is lower than that in the left. This blood perfuses the fetal lungs or traverses the ductus arteriosus to the descending aorta, from which some perfuses lower body organs and some reaches the placenta for reoxygenation.

Blood gas and pH values in the fetus also reflect the preferential streaming patterns. The data shown in Table 13.1 represent values usually found in healthy catheterized fetal animals. Both daily variability and variability between animals are seen. During a normal uterine contraction, arterial blood has a lower partial pressure of oxygen than under truly resting conditions. In addition, during the last 7 to 10 days of gestation, the partial pressure of oxygen declines slightly, and the partial pressure of carbon dioxide increases commensurately.

Typical values for the distribution of blood flow to individual organs are shown in e-Fig. 13.4 . Because arterial blood supply to lower body organs is derived from both left and right ventricles, it is customary to express organ flow as a percentage of their combined output (i.e., combined ventricular output). ^, These values remain fairly constant throughout the last third of gestation, the period in which such measurements have been made. However, there is a slight increase in the percentage of combined ventricular output distributed to the heart, brain, and gastrointestinal tract during the 10 days before parturition. The flow distributed to the lungs increases from approximately 4% to 8% of combined ventricular output between 125 and 130 days of gestation (0.85 of term). Organ blood flows are shown in Table 13.2 . Similar to combined ventricular output, umbilical-placental blood flow usually is not considered in relationship to placental weight, which is quite variable, but rather is expressed in relationship to fetal weight. Placental blood flow is approximately 200 mL/kg/min.

Intracardiac and Vascular Pressures

Vascular pressure in the fetus reflects the preferential streaming patterns described previously. Although the ductus venosus is a fairly large and widely dilated structure, there is a high flow returning from the placenta through the umbilical veins and therefore this structure offers some resistance to flow. Umbilical venous pressure is generally 3 to 5 mm Hg higher than pressure in the IVC ( Fig. 13.5 ). Right atrial pressure is also higher than left atrial pressure because of the greater volume of flow through the right atrium. Although the ductus arteriosus is widely patent, it, too, offers a small resistance to flow. Therefore systolic pressures in the main pulmonary trunk and right ventricle are slightly higher (1 to 2 mm Hg) than pressures in the aorta and left ventricle.

The representative pressure data shown in Fig. 13.5 would be expected in a fetus close to term. Arterial pressures increase slowly and progressively over the last third of gestation, reaching these values shortly before parturition. Measurement of intravascular pressures in the fetus reflects the additional amniotic pressure not found after birth. Because intraamniotic pressure is used as the zero reference point, the values presented exclude this additional pressure and are therefore true vascular pressures.

Myocardial Function

Cardiac output is determined by the interrelationships of preload, afterload, myocardial contractility, and heart rate. Preload (ventricular filling pressure) reflects the initial muscle length, which by the Frank-Starling principle influences the development of myocardial force. Afterload (the impedance to ejection from the ventricles) is reflected basically by arterial pressure. Contractility reflects the intrinsic inotropic capability of the myocardium.

Studies of fetal myocardium show immaturity of structure, function, and sympathetic innervation relative to the adult myocardium. At all muscle lengths along the curve of length versus tension, the active tension generated by fetal myocardium is lower than that generated by adult myocardium. In addition, resting, or passive, tension is higher in fetuses than in adults, suggesting lower compliance of fetal myocardium.

Studies in chronically instrumented intact fetal lambs showed that after volume loading by the infusion of blood or saline, the right ventricle is unable to increase stroke work or output to the same extent as in the adult. This is particularly true in less mature fetuses, in whom right ventricular end-diastolic pressure is markedly elevated without any obvious change in right ventricular stroke work. Similar results are found for both the left and right ventricles but with some ability to increase output or work at lower pressures, between 2 and 5 mm Hg. Limitations in the increase in stroke work with increasing filling pressure have been shown to be afterload dependent and, for the left ventricle, are probably affected by right ventricular mechanical constraint. ^,

Fetal and adult sarcomeres have equivalent lengths, but there are major ultrastructural differences between fetal myocardium and adult myocardium. The diameter of the fetal cells is smaller and, perhaps more important, the proportion of noncontractile mass (i.e., of nuclei, mitochondria, and surface membranes) to the number of myofibrils is significantly greater than in the adult. In the fetal myocardium, only about 30% of the muscle mass consists of contractile elements; in the adult, the proportion is about 60%. These ultrastructural differences are probably responsible for the age-dependent differences in performance.

In newborn lambs, stroke volume is decreased at afterload levels that would be considered low for adult animals. Gilbert showed in fetal animals that an increase in arterial pressure of about 15 mm Hg, produced by methoxamine infusion, depresses the cardiac function curve so that cardiac output averages 25% to 30% less than normal. The extent of shortening is less in the fetus compared with the adult at any level of tension—a potential explanation for the effects of afterload on stroke volume.

In chronically instrumented fetal lambs, there is a close relationship between cardiac output and heart rate. Spontaneous and induced changes in heart rate are associated with corresponding changes in left or right ventricular output. Increasing heart rate from the resting level of about 180 beats/min to 250 to 300 beats/min increases cardiac output by 15% to 20%. Likewise, decreasing heart rate below the resting level significantly decreases ventricular output.

The fetal heart normally appears to operate near the top of its cardiac function curve. An increase in heart rate results in only a modest increase in output; however, bradycardia can reduce output significantly. At an atrial filling pressure greater than approximately 8 mm Hg, there is little or no increase in output because the length-to-tension relationship has reached a plateau. In addition, the fetal heart is sensitive to changes in afterload.

Sympathetic and Parasympathetic Innervation

Isolated fetal cardiac tissue has a lower threshold of response to the inotropic effects of norepinephrine than adult cardiac tissue and is more sensitive to norepinephrine throughout the dose-response curves. Because isoproterenol, a direct β-adrenergic agonist that is not taken up and stored in sympathetic nerves, has similar effects on fetal and adult myocardium, the supersensitivity of fetal myocardium to norepinephrine is probably the result of incomplete development of sympathetic innervation in fetal myocardium. Myocardial concentrations of norepinephrine in the fetus within several weeks of term are significantly lower than those in newborn animals, and activity of tyrosine hydroxylase, the intraneuronal enzyme responsible for the first transformation in catecholamine biosynthesis, is also reduced. In contrast, adrenal gland tyrosine hydroxylase activity at the same gestational age is not suppressed, possibly because the decrease in myocardial activity is related to delayed sympathetic innervation rather than to a generalized immaturity.

Monoamine oxidase, the enzyme responsible for oxidative deamination of norepinephrine, is also present in lower concentrations in the fetal heart than in the adult. Histochemical evaluation of the development of sympathetic innervation using the monoamine fluorescence technique has further substantiated the delayed development of sympathetic innervation of the fetal myocardium. At term, sympathetic innervation is incomplete. Patterns of staining indicate a progression of innervation, starting at the area of the sinoatrial node and progressing toward the left ventricular apex. ^,

Although sympathetic nervous innervation appears to begin developing in the fetal heart by about 0.55 of term, β-adrenergic receptors seem to be present much earlier and can be stimulated by appropriate agonists before 0.4 of term. Before about 0.55 of term (80 days of gestation in the lamb), fetal myocardium may be affected by circulating catecholamines, but local reflex activity through the sympathetic nervous system is not likely to play a major role in circulatory regulation.

Vagal stimulation at about 0.85 of term produces bradycardia. Administration of atropine at 0.55 of term produces a modest increase in fetal heart rate, indicating that vagal innervation is present by this stage of development. Histochemical staining for acetylcholinesterase in close-to-term fetuses has shown that the concentrations of this enzyme, which is responsible for metabolism of acetylcholine, are similar to concentrations found in adults.