Fetal Circulation and Its Relevance to Pediatric and Congenital Cardiac Care

John E. Mayer, Jr, MD

Fetal Circulation

An understanding of the fetal circulation and its differences from the ex utero circulation is essential for both the initial management of most forms of critical neonatal congenital heart disease and for understanding the clinical presentation and evolution of multiple other forms of congenital heart disease. The diagram below (Figure 1) demonstrates the fetal blood flow pathways.[1]

Figure 1
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The pathways for blood flow in the fetal circulation reflect the essential role that the placenta plays as the in utero gas-exchange organ. This placental localization of the gas-exchange function requires that the systemic venous blood returning to the right heart, with its reduced oxygen content, be directed to the descending aorta and then to the placenta, and that the blood flow from the umbilical veins with higher oxygen content be directed toward the left atrium, so that it can supply the developing heart and brain. The anatomic structures which allow these fetal blood flow patterns are the (patent) ductus arteriosus, the (patent) ductus venosus, and the valve-like anatomic structures in the right atrium, including the Eustachian valve and the flap-valve structure of the atrial septum. Thus, in utero, there are three sites for “fetal shunts”:

  1. the patent ductus venosus,
  2. the patent foramen ovale, and
  3. the patent ductus arteriosus.

First, the ductus venosus shunts a portion of umbilical venous blood flow directly to the inferior vena cava, allowing oxygenated blood from the placenta to bypass the liver.

Next, the Eustachian valve and foramen ovale direct the umbilical venous blood to the left atrium and left ventricle, and then to the developing heart and brain.

The fetal systemic venous blood with reduced oxygen content returns to the right heart and then is delivered to the descending aorta and then the placenta via the ductus arteriosus. Normally, all three of these “fetal shunts close soon after birth.

Based on flow studies in fetal sheep, 88% of the right ventricular output of lower oxygen content blood is carried through the (patent) ductus arteriosus (57% of the total output of both ventricles) to the descending aorta and then to the placenta.[1] As the more well-oxygenated placental venous blood returns to the right atrium, the combination of the Eustachian valve and the foramen ovale, (which results from the flap valve-like anatomy of the limbus of the septum secundum and septum primum) preferentially directs the more oxygenated placental venous blood to the left atrium and then to the ascending aorta (Figure 2).[1]

Figure 2
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The terms shown represent the percentage of the total blood flow reaching and passing through various parts of the circulation. Thus 66% of the total venous return passes through the right ventricle and 34% passes through the left ventricle. Of the blood ejected by the right ventricle, only about 15% (10% of 66%) passes through the fetal lungs, with the remainder passing right to left across the ductus arteriosus. Of the 34% of the total blood flow that is ejected by the left ventricle, approximately 2/3(21%/34%) supplies the head, and a little less than 1/3 (10%/34%) reaches the descending aorta.

It is important to recall that as the placenta serves as the fetal respiratory organ, the in utero arterial PO2 is in the range of 30-35 torr. This oxygen tension represents a hemoglobin saturation of 85-90% due to the left-shifted fetal oxyhemoglobin dissociation curve.[1] This relatively hypoxic environment is compatible with normal fetal organ function and overall fetal development both as a result of the left-shifted oxygen-hemoglobin dissociation curve for fetal hemoglobin (Figure 3) as well as fetal mitochondrial and other adaptations to this lower oxygen tension environment.[2] One important implication of this observation is that the newborn’s organ systems in the early post-natal period are fully capable of functioning with arterial PO2’s in the range of 30-35 torr, and thus therapeutic maneuvers that preserve the fetal circulatory patterns can be used to temporarily palliate many otherwise lethal forms of congenital heart disease. It is also important to note that whatever anatomic abnormalities were present in the newborn heart and fetal blood flow pathways, they were compatible with in utero survival and thus can be consistent with extra-uterine survival if the fetal blood flow pathways can be maintained.

Figure 3
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Fetal vs. adult oxyhemoglobin dissociation curve. The fetal hemoglobin has a high affinity for oxygen, which allows for increased oxygen uptake, even in the relatively low oxygenated environments, such as the placenta. For each PO2, the fetal hemoglobin is more saturated (carries more oxygen) than the adult hemoglobin.

Both the ductus arteriosus and the foramen ovale atrial communications normally close in the first few days after birth, while the orifice of the ductus venosus narrows and closes at birth due to loss of blood flow from the placenta and the resulting fall in intra-ductal blood pressures. Permanent closure of the ductus venosus begins days after birth and is completed by 1 to 3 months. The result of these anatomic changes is that the pulmonary and systemic blood flow patterns become separated into in series circulations with the lungs replacing the placenta as the organ of gas exchange. Importantly, interventions to maintain the fetal circulation have been developed, and these allow otherwise critical congenital heart defects to be palliated by maintaining the fetal blood flow pathways.

Among the most notable clinical interventions to preserve the fetal circulatory pattern is the administration of prostaglandin E1 which serves to maintain patency of the ductus arteriosus. Patency of the ductus arteriosus allows the right ventricular output to continue to reach the systemic circulation, which is particularly useful in the presence of congenital left heart abnormalities. Conversely, maintaining patency of the ductus arteriosus provides a source of pulmonary blood flow in the presence of right heart abnormalities, particularly defects that include pulmonary valvar atresia. Thus, PGE1 infusion to maintain ductal patency can be applied for a variety congenital heart defects ranging from hypoplastic left heart syndrome and coarctation of the aorta to pulmonary and/or tricuspid atresia. Once the ductus arteriosus has been closed for more than 24-48 hours, PGE1 administration becomes progressively less likely to re-establish ductal patency. In order to maintain an atrial level communication, the other site of intra uterine communication between the right and left sides of the circulation, balloon atrial septostomy was introduced to allow mixing of the oxygenated pulmonary and de-oxygenated systemic venous returns at the atrial level and/or to relieve left atrial hypertension. The establishment of an inter-atrial communication is an extremely important intervention in patients with transposition of the great arteries as this allows pulmonary venous blood to reach the systemic circulation. A second set of defects for which establishment of a communication at the atrial septal level is important include left heart abnormalities such as mitral valvar stenosis/atresia or left ventricular hypoplasia. In these situations, establishment of an atrial level communications is necessary in order to decompress the left atrium and allow pulmonary venous blood to reach the systemic arterial circulation via the right heart and patent ductus arteriosus.

In addition to the macroscopic differences between the fetal and ex utero circulations, major changes occur in the state of the pulmonary vasculature between the in utero and post-natal state. The in utero pulmonary vascular resistance (PVR) is significantly higher than systemic resistance (Rp:Rs >8-9) as can be inferred from the observation that only 8-10% of right ventricular output passes through the pulmonary vascular bed and the remaining 90% crosses the ductus arteriosus to reach the descending aorta.[1] The anatomic substrate for this increased PVR is a significantly thicker media layer in the fetal pulmonary arterioles compared to the mature pulmonary vascular bed.[3] In addition, the fetal pulmonary arteriolar endothelial layer is significantly thicker as well.[4] As soon as ventilation begins following birth, the endothelial cells lining the nonmuscular arterioles in the alveolar walls become significantly thinner, likely due to stretching of the vasculature with ventilation.[4] Similar thinning of the smooth muscle cells in the media also occurs, along with reduced overlapping between adjacent cells.[4],[5] Within the first month of life the medial layer of the distal muscular pulmonary arteries undergoes significant thinning, and the ratio of wall thickness to external diameter falls from 14-20% in utero to the adult level of 6%.[3] In addition, after birth there are ongoing significant increases in the number of intra-acinar pulmonary arteries and arterioles due to post-natal vasculogenesis with a significant increase in the cross-sectional area of the pulmonary vascular bed.[5] This growth in the pulmonary vascular bed coincides with the post-natal addition of alveolar gas exchanging units and continues through the first few years of life.[5]

The physiologic consequence of these anatomic changes in the pulmonary vascular bed is that there is normally an immediate fall in pulmonary vascular resistance in the first 24 hours following birth as the lungs expand,[6] and then a further progressive reduction in pulmonary vascular resistance over the next 4-6 weeks of life.[6] In patients with large inter-ventricular and/or great vessel communications, this normal pattern of progressively decreasing pulmonary vascular resistance in the first weeks of life is thought to explain the typical delayed onset of congestive heart failure until 4-6 weeks of age that is seen in patients with these defects.[7] A falling PVR allows a progressive increase in left-to-right shunting through both ventricular and great vessel communications, thus producing a volume overload of the pulmonary circulation.[7]

A second consequence of these anatomic changes is that the reactivity of the pulmonary vascular bed to stimuli can be much more pronounced in the young infant compared to the normal older patient.[8],[9] However, in many cases where there are large inter-ventricular and/or great vessel communications, the elevated pulmonary artery pressures and flows have been observed to stimulate persistence of the elevated in utero pulmonary vascular resistance and can also preserve or augment an exaggerated pulmonary vascular responsiveness, particularly in the post-operative period.[10] These exaggerated increases in pulmonary vascular resistance have been termed pulmonary hypertensive crises,[8],[9] and they are a significant potential source of morbidity and mortality in the post-operative congenital heart disease patient.[8],[9]

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Last updated: October 19, 2021