Knowledge of fetal and perinatal circulation is an integral part of understanding the pathophysiology, clinical manifestations, and natural history of CHD, especially anomalies seen in the newborn period. Only a brief discussion of clinically important aspects of fetal and perinatal circulation is presented.
Fetal Circulation
Fetal circulation differs from adult circulation in several ways. Almost all differences are attributable to the fundamental difference in the site of gas exchange. In adults, gas exchange occurs in the lungs. In fetuses, the placenta provides the exchange of gases and nutrients.
Course of Fetal Circulation
There are four shunts in fetal circulation: placenta, ductus venosus, foramen ovale, and ductus arteriosus (Fig. 8-1). The following summarizes some important aspects of fetal circulation:
1. The placenta receives the largest amount of combined (i.e., right and left) ventricular output (55%) and has the lowest vascular resistance in the fetus.
2. The superior vena cava (SVC) drains the upper part of the body, including the brain (15% of combined ventricular output), and the inferior vena cava (IVC) drains the lower part of the body and the placenta (70% of combined ventricular output). Because the blood is oxygenated in the placenta, the oxygen saturation in the IVC (70%) is higher than that in the SVC (40%). The highest Po2 is found in the umbilical vein (32 mm Hg) (see Fig. 8-1).
3. Most of the SVC blood goes to the right ventricle (RV). About one third of the IVC blood with higher oxygen saturation is directed by the crista dividens to the left atrium (LA) through the foramen ovale, and the remaining two thirds enters the RV and pulmonary artery (PA). The result is that the brain and coronary circulation receive blood with higher oxygen saturation (Po2 of 28 mm Hg) than the lower half of the body (Po2 of 24 mm Hg) (see Fig. 8-1).
4. Less oxygenated blood in the PA flows through the widely open ductus arteriosus to the descending aorta and then to the placenta for oxygenation.
Dimensions of Cardiac Chambers
The proportions of the combined ventricular output traversing the heart chambers and the major blood vessels are reflected in the relative dimensions of these chambers and vessels (see Fig. 8-1).
Because the lungs receive only 15% of combined ventricular output, the branches of the PA are small. This is important in the genesis of the pulmonary flow murmur of newborns (see Chapter 2).
FIGURE 8-1 Diagram of the fetal circulation showing the four sites of shunts: placenta, ductus venosus, foramen ovale, and ductus arteriosus. Intravascular shading is in proportion to oxygen saturation, with the lightest shading representing the highest PO2. The numerical value inside the chamber or vessel is the PO2 for that site in mm Hg. The percentages outside the vascular structures represent the relative flows in major tributaries and outlets for the two ventricles. The combined output of the two ventricles represents 100%. a, artery; IVC, inferior vena cava; LA, left atrium; LV, left ventricle; PV, pulmonary vein; RA, right atrium; RV, right ventricle; SVC, superior vena cava; v, vein. (From Guntheroth WG, Kawabori I, Stevenson JG: Physiology of the circulation: Fetus, neonate and child. In Kelley VC [ed]: Practice of Pediatrics, vol 8. Philadelphia, Harper & Row, 1983.)
The RV is larger and more dominant than the left ventricle (LV). The RV handles 55% of the combined ventricular output, and the LV handles 45% of the combined ventricular output. In addition, the pressure in the RV is identical to that in the LV (unlike in adults). This fact is reflected in electrocardiograms (ECGs) of newborns, which show more RV force than adult ECGs.
Fetal Cardiac Output
Unlike the adult heart, which increases its stroke volume when the heart rate decreases, the fetal heart is unable to increase stroke volume when the heart rate falls because it has a low compliance. Therefore, the fetal cardiac output depends on the heart rate; when the heart rate drops, as in fetal distress, a serious fall in cardiac output results.
Changes in Circulation after Birth
The primary change in circulation after birth is a shift of blood flow for gas exchange from the placenta to the lungs. The placental circulation disappears, and the pulmonary circulation is established.
1. The removal of the placenta results in the following:
a. An increase in systemic vascular resistance (SVR) results (because the placenta has the lowest vascular resistance in the fetus)
b. Cessation of blood flow in the umbilical vein results in closure of the ductus venosus
FIGURE 8-2 Changes in pulmonary artery pressure, pulmonary blood flow, and pulmonary vascular resistance during the 7 weeks preceding birth, at birth, and in the 7 weeks after birth. The prenatal data were derived from lambs and the postnatal data from other species. (From Rudolph AM: Congenital Diseases of the Heart. Chicago, Mosby, 1974.)
2. Lung expansion results in the following:
a. A reduction of the pulmonary vascular resistance (PVR), an increase in pulmonary blood flow, and a fall in PA pressure (Fig. 8-2)
b. Functional closure of the foramen ovale as a result of increased pressure in the LA in excess of the pressure in the right atrium (RA). The RA pressure falls as a result of closure of the ductus venosus
c. Closure of patent ductus arteriosus (PDA) as a result of increased arterial oxygen saturation
Changes in the PVR and closure of the PDA are so important in understanding many CHDs that further discussion is necessary.
Pulmonary Vascular Resistance
The PVR is as high as the SVR near or at term. The high PVR is maintained by an increased amount of smooth muscle in the walls of the pulmonary arterioles and alveolar hypoxia resulting from collapsed lungs. (The role of alveolar hypoxia in increasing pulmonary vascular resistance is further discussed in Chapter 29.)
With expansion of the lungs and the resulting increase in the alveolar oxygen tension, there is an initial, rapid fall in the PVR (Fig. 8-3). This rapid fall is secondary to the vasodilating effect of oxygen on the pulmonary vasculature. Between 6 and 8 weeks after birth, there is a slower fall in the PVR and the PA pressure. This fall is associated with thinning of the medial layer of the pulmonary arterioles. A further decline in the PVR occurs after the first 2 years. This may be related to the increase in the number of alveolar units and their associated vessels.
Many neonatal conditions causing inadequate oxygenation may interfere with the normal maturation (i.e., thinning) of the pulmonary arterioles, resulting in persistent pulmonary hypertension or delay in the fall of PVR (Box 8-1). A few examples of clinical importance follow:
1. Infants with a large ventricular septal defect (VSD) may not develop congestive heart failure (CHF) while living at a high altitude, but they may develop CHF if they move to sea level. This is because of the delayed fall in the PVR associated with high altitudes.
2. Premature infants with severe hyaline membrane disease usually do not develop CHF because of their high PVR, which restricts the left-to-right shunt. Acidosis, which is often present in these infants, may contribute to maintaining a high PVR. CHF may develop as their hyaline membrane disease improves because the resulting increase in arterial Po2 dilates pulmonary vasculature.
FIGURE 8-3 Postnatal changes in pulmonary vascular resistance. (From Moller JH, et al: Congenital Heart Disease. Kalamazoo, MI, Upjohn Company, 1974.)
BOX 8-1 Neonatal Conditions That May Interfere with the Normal Maturation of Pulmonary Arterioles
Hypoxia or altitude
Lung disease (e.g., hyaline membrane disease)
Acidemia
Increased pulmonary artery pressure secondary to large ventricular septal defect or patent ductus arteriosus
Increased pressure in the left atrium or pulmonary vein
3. In infants with large VSDs, a high PA pressure, resulting from a direct transmission of the LV pressure to the PA through the defect, delays the fall in the PVR. As a result, CHF does not develop until 6 to 8 weeks of age or older. In contrast, the PVR falls normally in infants with a small VSD because direct transmission of the LV pressure to the PA does not occur in this situation.
Closure of the Ductus Arteriosus
Functional closure of the ductus arteriosus occurs within 10 to 15 hours after birth by constriction of the medial smooth muscle in the ductus. Anatomic closure is completed by 2 to 3 weeks of age by permanent changes in the endothelium and subintimal layers of the ductus. Oxygen, prostaglandin E2 (PGE2) levels, and maturity of the newborn are important factors in closure of the ductus. Acetylcholine and bradykinin also constrict the ductus.
Oxygen and the Ductus. A postnatal increase in oxygen saturation of the systemic circulation (from Po2 of 25 mm Hg in utero to 50 mm Hg after lung expansion) is the strongest stimulus for constriction of the ductal smooth muscle, which leads to closure of the ductus. The responsiveness of the ductal smooth muscle to oxygen is related to the gestational age of the newborn; the ductal tissue of a premature infant responds less intensely to oxygen than that of a full-term infant. This decreased responsiveness of the immature ductus to oxygen is due to its decreased sensitivity to oxygen-induced contraction; it is not the result of a lack of smooth muscle development because the immature ductus constricts well in response to acetylcholine. It may also be due to persistently high levels of PGE2 in preterm infants (see later section).
Prostaglandin E and the Ductus. A few clinical situations are worth mentioning to show the importance of the PG series in maintaining the patency of the ductus arteriosus in fetuses.
1. A decrease in PGE2 levels after birth results in constriction of the ductus. This decrease results from removal of the placental source of PGE2 production at birth and from the marked increase in pulmonary blood flow, which allows effective removal of circulating PGE2 by the lungs.
2. Constricting effects of indomethacin or ibuprofen and the dilator effects of PGE2 and PGI2 are greater in the ductal tissues of an immature fetus than of a near-term fetus.
3. Prolonged patency of the ductus can be maintained by intravenous infusion of a synthetic PGE1, in newborn infants such as those with pulmonary atresia, whose survival depends on patency of the ductus.
4. Indomethacin or ibuprofen, a cyclooxygenase inhibitor (or “PG synthetase inhibitor”), can be used to close a significant PDA in premature infants (see Chapter 12).
5. Maternal ingestion of a large amount of aspirin, an inhibitor of PG synthetase, may harm fetuses, because the aspirin may constrict the ductus during fetal life and may result in persistent pulmonary hypertension in the newborn (PPHN). It has been suggested that some cases of PPHN (or persistent fetal circulation syndrome) may be caused by a premature constriction of the ductus arteriosus.
Reopening of a Constricted Ductus. Before true anatomic closure occurs, the functionally closed ductus may be dilated by a reduced arterial Po2 or an increased PGE2 concentration. The reopening of the constricted ductus may occur in asphyxia and various pulmonary diseases (as hypoxia and acidosis relax ductal tissues). Ductal closure is delayed at high altitude. There is a much higher incidence of PDA at high altitudes than at sea level. In some newborn infants (e.g., those with coarctation of the aorta) intravenous infusion of PGE1, can open a partially or completely constricted ductus.
Responses of Pulmonary Artery and Ductus Arteriosus to Various Stimuli. The PA responds to oxygen and acidosis in the opposite manner from the ductus arteriosus. Hypoxia and acidosis relax the ductus arteriosus but constrict the pulmonary arterioles. Oxygen constricts the ductus but relaxes the pulmonary arterioles. The PAs are also constricted by sympathetic stimulation and α-adrenergic stimulation (e.g., epinephrine, norepinephrine). Vagal stimulation, β-adrenergic stimulation (e.g., isoproterenol), and bradykinin dilate the PAs.
Premature Newborns
Two important problems that premature infants may face are related to the rate at which PVR falls and the responsiveness of the ductus arteriosus to oxygen.
The ductus arteriosus is more likely to remain open in preterm infants after birth because premature infants’ ductal smooth muscle does not have a fully developed constrictor response to oxygen. In addition, premature infants have persistently high circulating levels of PGE2 (caused by decreased degradation in the lungs), and the premature ductal tissue exhibits an increased dilatory response to PGE2.
In premature infants, the pulmonary vascular smooth muscle is not as well developed as in full-term infants. Therefore, the fall in PVR occurs more rapidly than in mature infants. This accounts for the early onset of a large left-to-right shunt and CHF.