415.1 The Fetal Circulation

Daniel Bernstein

The human fetal circulation and its adjustments after birth are similar to those of other large mammals, although rates of maturation differ. In the fetal circulation, the right and left ventricles exist in a parallel circuit, as opposed to the series circuit of a newborn or adult (see Fig. 415-1A on the Nelson Textbook of Pediatrics website at www.expertconsult.com). In the fetus, the placenta provides for gas and metabolite exchange. Since the lungs do not provide gas exchange, the pulmonary vessels are vasoconstricted, diverting blood away from the pulmonary circulation. Three cardiovascular structures unique to the fetus are important for maintaining this parallel circulation: the ductus venosus, foramen ovale, and ductus arteriosus.

Figure 415-1 A, The human circulation before birth (partly after Dawes). Red indicates more highly oxygenated blood, and arrows indicate the direction of flow. More highly oxygenated blood from the placenta passes through the foramen ovale from the right to the left atrium, thus bypassing the lungs. B, Percentages of combined ventricular output that return to the fetal heart, that are ejected by each ventricle, and that flow through the main vascular channels. Figures are those obtained from studies of late-gestation fetal lambs. Ao, aorta; DA, ductus arteriosus; IVC, inferior vena cava; LA, left atrium; LV, left ventricle; PA, pulmonary artery; PV, pulmonary veins; RA, right atrium; RV, right ventricle; SVC, superior vena cava.

(From Rudolph AM: Congenital diseases of the heart, Chicago, 1974, Year Book.)

The placenta is not as efficient an oxygen exchange organ as the lungs, so that umbilical venous PO₂ (the highest level of oxygen provided to the fetus) is only about 30-35 mm Hg. Approximately 50% of the umbilical venous blood enters the hepatic circulation, whereas the rest bypasses the liver and joins the inferior vena cava via the ductus venosus, where it partially mixes with poorly oxygenated inferior vena cava blood derived from the lower part of the fetal body. This combined lower body plus umbilical venous blood flow (PO₂ of ≈26-28 mm Hg) enters the right atrium and is preferentially directed by a flap of tissue at the right atrial–inferior vena caval junction, the eustachian valve, across the foramen ovale to the left atrium (see Fig. 415-1B). This is the major source of left ventricular blood flow, since pulmonary venous return is minimal. Left ventricular blood is then ejected into the ascending aorta where it supplies predominantly the fetal upper body and brain.

Fetal superior vena cava blood, which is considerably less oxygenated (PO₂ of 12-14 mm Hg), enters the right atrium and preferentially flows across the tricuspid valve, rather than the foramen ovale, into the right ventricle. From the right ventricle, the blood is ejected into the pulmonary artery. Because the pulmonary arterial circulation is vasoconstricted, only about 5% of right ventricular outflow enters the lungs. The major portion of this blood bypasses the lungs and flows right-to-left through the ductus arteriosus into the descending aorta to perfuse the lower part of the fetal body, including providing flow to the placenta via the 2 umbilical arteries. Thus, the upper part of the fetal body (including the coronary and cerebral arteries and those to the upper extremities) is perfused exclusively from the left ventricle with blood that has a slightly higher PO₂ than the blood perfusing the lower part of the fetal body, which is derived mostly from the right ventricle. Only a small volume of blood from the ascending aorta (10% of fetal cardiac output) flows all the way around the aortic arch (aortic isthmus) to the descending aorta.

The total fetal cardiac output—the combined output of both the left and right ventricles—is ≈450 mL/kg/min. Approximately 65% of descending aortic blood flow returns to the placenta; the remaining 35% perfuses the fetal organs and tissues. In the sheep fetus, where most of these circulatory pathways were studied, right ventricular output is approximately 2 times that of the left ventricle. In the human fetus, which has a larger percentage of blood flow going to the brain, right ventricular output is probably closer to 1.3 times left ventricular flow. Thus, during fetal life the right ventricle is not only pumping against systemic blood pressure but is also performing a greater volume of work than the left ventricle.

It has been postulated that blood flow is an important determinant of growth of fetal cardiac chambers, valves, and blood vessels. Thus, in the presence of a narrowing (stenosis) of an upstream structure such as the mitral valve, flow downstream into the left ventricle is limited and left ventricular growth may be compromised, leading to hypoplastic left heart syndrome (Chapter 425.10). Similarly, stenosis of a downstream structure such as the aortic valve can similarly disrupt flow into the left ventricle and lead to hypoplastic left heart syndrome. Fetal cardiac interventional treatments, currently experimental, are aimed at opening stenotic aortic valves in mid-gestation fetuses, and allowing more normal left ventricular growth.

415.2 The Transitional Circulation

Daniel Bernstein

At birth, mechanical expansion of the lungs and an increase in arterial PO₂ result in a rapid decrease in pulmonary vascular resistance. Concomitantly, removal of the low-resistance placental circulation leads to an increase in systemic vascular resistance. The output from the right ventricle now flows entirely into the pulmonary circulation, and because pulmonary vascular resistance becomes lower than systemic vascular resistance, the shunt through the ductus arteriosus reverses and becomes left to right. In the course of several days, the high arterial PO₂ constricts and eventually closes the ductus arteriosus, which eventually becomes the ligamentum arteriosum. The increased volume of pulmonary blood flow returning to the left atrium from the lungs increases left atrial volume and pressure sufficiently to close the flap of the foramen ovale functionally, although the foramen may remain probe patent for several years.

Removal of the placenta from the circulation also results in closure of the ductus venosus. The left ventricle is now coupled to the high-resistance systemic circulation, and its wall thickness and mass begin to increase. In contrast, the right ventricle is now coupled to the low-resistance pulmonary circulation, and its wall thickness and mass decrease. The left ventricle, which in the fetus pumped blood only to the upper part of the body and brain, must now deliver the entire systemic cardiac output (≈350 mL/kg/min), an almost 200% increase in output. This marked increase in left ventricular performance is achieved through a combination of hormonal and metabolic signals, including an increase in the level of circulating catecholamines and in the density of myocardial β-adrenergic receptors through which catecholamines have their effect.

When congenital structural cardiac defects are superimposed on these dramatic physiologic changes, they often impede this smooth transition and markedly increase the burden on the newborn myocardium. In addition, because the ductus arteriosus and foramen ovale do not close completely at birth, they may remain patent in certain congenital cardiac lesions. Patency of these fetal pathways may either provide a lifesaving pathway for blood to bypass a congenital defect (a patent ductus in pulmonary atresia or coarctation of the aorta or a foramen ovale in transposition of the great vessels) or present an additional stress to the circulation (patent ductus arteriosus in a premature infant, pathway for right-to-left shunting in infants with pulmonary hypertension). Therapeutic agents may either maintain these fetal pathways (prostaglandin E₁) or hasten their closure (indomethacin).

415.3 The Neonatal Circulation

Daniel Bernstein

At birth, the fetal circulation must immediately adapt to extrauterine life as gas exchange is transferred from the placenta to the lungs (Chapter 95.1). Some of these changes are virtually instantaneous with the 1st breath, whereas others develop over a period of hours or weeks. With the onset of ventilation, pulmonary vascular resistance is markedly decreased as a consequence of both active (PO₂-related) and passive (mechanical related) pulmonary vasodilation. In a normal neonate, closure of the ductus arteriosus and the fall in pulmonary vascular resistance decreases pulmonary arterial and right ventricular pressures. The largest decline in pulmonary resistance from the high fetal levels to the low “adult” levels in the human infant at sea level usually occurs within the 1st 2-3 days but may be prolonged for 7 days or more. Over the next several weeks of life, pulmonary vascular resistance decreases even further, secondary to a remodeling of the pulmonary vasculature, including thinning of the vascular smooth muscle and recruitment of new vessels. This decrease in pulmonary vascular resistance significantly influences the timing of the clinical appearance of many congenital heart lesions that are dependent on the relative levels of systemic and pulmonary vascular resistances. The left-to-right shunt through an large ventricular septal defect may be minimal in the 1st wk after birth when pulmonary vascular resistance is still high. As pulmonary resistance decreases in the next week or two, the volume of the left-to-right shunt through the ventricular septal defect increases and eventually leads to symptoms of heart failure within the 1st month or two of life.

Significant differences between the neonatal circulation and that of older infants include: (1) right-to-left or left-to-right shunting may persist across the patent foramen ovale; (2) in the presence of cardiopulmonary disease, continued patency of the ductus arteriosus may allow left-to-right, right-to-left, or bidirectional shunting; (3) the neonatal pulmonary vasculature constricts more vigorously in response to hypoxemia, hypercapnia, and acidosis; (4) the wall thickness and muscle mass of the neonatal left and right ventricles are almost equal; and (5) newborn infants at rest have relatively high oxygen consumption, which is associated with relatively high cardiac output. The newborn cardiac output (about 350 mL/kg/min) falls in the 1st 2 mo of life to about 150 mL/kg/min and then more gradually to the normal adult cardiac output of about 75 mL/kg/min. Although fetal hemoglobin is beneficial to delivery of oxygen in the low PO₂ fetal circulation, the high percentage of fetal hemoglobin present in the newborn may actually interfere with delivery of oxygen to tissues in the high systemic PO₂ neonatal circulation (Chapter 95.1).

The foramen ovale is usually functionally closed by the 3rd mo of life, although it is possible to pass a probe through the overlapping flaps in a large percentage of children and in 15-25% of adults. Functional closure of the ductus arteriosus is usually complete by 10-15 hr in a normal neonate, although the ductus may remain patent much longer in the presence of congenital heart disease, especially when associated with cyanosis. In premature newborn infants, an evanescent systolic murmur with late accentuation or a continuous murmur may be audible, and in the context of respiratory distress syndrome, the presence of a patent ductus arteriosus should be suspected (Chapter 95.4).

The normal ductus arteriosus differs morphologically from the adjoining aorta and pulmonary artery in that the ductus has a significant amount of circularly arranged smooth muscle in its medial layer. During fetal life, patency of the ductus arteriosus appears to be maintained by the combined relaxant effects of low oxygen tension and endogenously produced prostaglandins, specifically prostaglandin E₂. In a full-term neonate, oxygen is the most important factor controlling ductal closure. When the PO₂ of the blood passing through the ductus reaches about 50 mm Hg, the ductal wall begins to constrict. The effects of oxygen on ductal smooth muscle may be direct or mediated by its effects on prostaglandin synthesis. Gestational age also appears to play an important role; the ductus of a premature infant is less responsive to oxygen, even though its musculature is developed.

415.4 Persistent Pulmonary Hypertension of the Neonate (Persistence of Fetal Circulatory Pathways)

See Chapter 95.7.