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Fetal circulation

Fetal circulation is the specialized pattern of blood flow in the developing human fetus that enables the exchange of oxygen, nutrients, and waste products with the mother's bloodstream via the placenta, rather than through functional lungs or a mature gastrointestinal system. This system features three key shunts—foramen ovale, ductus arteriosus, and ductus venosus—that bypass the nonfunctional lungs and partially bypass the liver, directing oxygenated blood preferentially to vital organs like the brain and heart.^[1] Unlike adult circulation, where the heart pumps deoxygenated blood to the lungs for oxygenation, fetal circulation maintains a right-to-left shunt, with the placenta acting as the primary site for gas and nutrient exchange through the umbilical cord, which contains two arteries for returning deoxygenated blood and one vein for delivering oxygenated blood.^[2] The fetal heart rate typically ranges from 110 to 160 beats per minute, supporting this efficient, low-resistance flow adapted to intrauterine life.^[1] In fetal circulation, oxygenated blood from the placenta, saturated at 70–80%, enters the fetus via the umbilical vein and flows to the liver, where the ductus venosus diverts approximately 20–30% of it directly to the inferior vena cava to avoid hepatic circulation.^[1] This blood then reaches the right atrium of the heart, where the crista dividens and Eustachian valve direct the stream through the foramen ovale—a flap-like opening between the right and left atria—into the left atrium, ventricle, and ascending aorta, ensuring that the most oxygen-rich blood supplies the brain, heart, and upper body.^[2] Meanwhile, deoxygenated blood returning from the superior vena cava mixes in the right atrium and is pumped by the right ventricle into the pulmonary artery; however, due to high pulmonary vascular resistance, most of this blood (about 90%) bypasses the collapsed lungs via the ductus arteriosus, joining the aorta to perfuse the lower body and returning to the placenta through the umbilical arteries for reoxygenation.^[1] This parallel circulation results in systemic blood saturation of around 60%, sufficient for fetal needs.^[3] At birth, dramatic physiological changes transition fetal circulation to the adult pattern: clamping of the umbilical cord eliminates placental flow, increasing systemic vascular resistance, while the first breath expands the lungs, reducing pulmonary resistance and boosting oxygen levels, which triggers closure of the shunts.^[3] The foramen ovale functionally closes due to left atrial pressure exceeding right atrial pressure, eventually forming the fossa ovalis; the ductus arteriosus constricts in response to rising oxygen tension and falling prostaglandin levels, becoming the ligamentum arteriosum within days to weeks; and the ductus venosus closes shortly after birth, transforming into the ligamentum venosum.^[2] These adaptations establish separate pulmonary and systemic circuits, with the lungs now responsible for oxygenation, though incomplete closure of shunts can lead to congenital defects like patent ductus arteriosus or atrial septal defects.^[1]

Overview

Definition and key features

Fetal circulation refers to the unique circulatory system of the developing fetus, present throughout gestation until birth, with the heart initiating circulation around 4 weeks and the full placental system established by the end of the first trimester, which operates in a parallel configuration between the right and left sides of the heart due to the non-functional lungs.^[1] Unlike the adult series circulation, this system relies on the placenta for gas exchange and nutrient supply, directing blood flow to bypass the pulmonary and hepatic circulations efficiently.^[4] Key features include high pulmonary vascular resistance, which promotes right-to-left shunting of blood away from the lungs, and the entry of oxygenated blood from the placenta through the umbilical vein.^[1] Deoxygenated blood, laden with waste products, returns to the placenta via the umbilical arteries for elimination and reoxygenation.^[5] This arrangement supports the fetus's dependence on maternal circulation for oxygenation. The system ensures efficient delivery of oxygen and nutrients to fetal tissues despite the immature lungs, while accommodating rapid growth through elevated hemoglobin concentrations, primarily fetal hemoglobin (HbF), which exhibits higher oxygen affinity than adult hemoglobin.^[1] Fully established by the end of the first trimester, fetal circulation maintains a total blood volume of approximately 80-100 mL/kg body weight to meet these demands.^[6]

Differences from adult circulation

Fetal circulation exhibits profound structural differences from the adult system, primarily through specialized shunts and vessels that facilitate nutrient uptake and waste removal via the placenta rather than through independent pulmonary and hepatic functions. The foramen ovale allows oxygenated blood to pass directly from the right atrium to the left atrium, bypassing the non-functional lungs, while the ductus arteriosus connects the pulmonary artery to the aorta, diverting blood away from the high-resistance pulmonary circuit. Additionally, the ductus venosus shunts a portion of umbilical venous blood past the liver into the inferior vena cava, and the umbilical vein and arteries provide the critical link to the placenta for gas and nutrient exchange.^[1] In contrast, adult circulation lacks these shunts, which close shortly after birth, resulting in a closed foramen ovale and ligamentum arteriosum derived from the ductus arteriosus, with no placental connections.^[4] Functionally, fetal circulation is adapted to a non-respiratory environment where the lungs remain collapsed and fluid-filled, imposing high vascular resistance that minimizes blood flow to them, estimated at approximately 16-21% of combined cardiac output.^[7] The placenta serves as the primary site for oxygenation and waste elimination, functioning as surrogate lungs and kidneys, while the fetal right ventricle generates higher pressures to propel most blood through the shunts to the systemic circulation and back to the placenta.^[1] In adults, the lungs are fully expanded and aerated, enabling low-resistance pulmonary flow where the right ventricle exclusively pumps deoxygenated blood to the lungs for gas exchange, and the left ventricle dominates systemic output without placental involvement.^[1] Oxygenation in the fetus differs markedly, with blood entering via the umbilical vein at approximately 70-80% saturation and a partial pressure of oxygen (PaO₂) of 30-35 mmHg, which then mixes to yield lower systemic levels tolerated due to fetal hemoglobin (HbF), which has a higher oxygen affinity than adult hemoglobin (HbA).^[4] Fetal arterial PaO₂ typically ranges from 20-25 mmHg, supporting tissue needs in a low-oxygen environment without the high PaO₂ (around 100 mmHg) seen in adult arterial blood post-pulmonary oxygenation. This reliance on placental diffusion and HbF contrasts with adult circulation, where lungs achieve near-100% saturation using HbA, and no such hemoglobin adaptation is required.^[1] Flow patterns in the fetus form a parallel circuit, with about 85-90% of cardiac output shunted away from the lungs, primarily through the ductus arteriosus (approximately 50-60% of cardiac output) and additional streaming via the foramen ovale (approximately 30-35%), prioritizing delivery to the placenta (around 40-55% of total output) and vital organs.^[8] Adult circulation, however, operates in series, with all deoxygenated blood routed sequentially through the low-resistance pulmonary circuit for full oxygenation before returning to the left heart for systemic distribution, ensuring no significant shunting.^[4]

Placental Exchange

Nutrient and gas delivery

The placenta facilitates nutrient and gas delivery to the fetus through its specialized villous chorion structure, where fetal blood circulates within capillaries surrounded by maternal blood in intervillous spaces, enabling efficient diffusion across the syncytiotrophoblast layer.^[9] This barrier, a multinucleated epithelial layer, separates maternal and fetal circulations while permitting selective transfer without direct mixing.^[10] Gas exchange occurs primarily via passive diffusion driven by partial pressure gradients. Oxygen diffuses from maternal blood, where it binds to adult hemoglobin with a P50 of approximately 26 mmHg, to fetal blood bound to fetal hemoglobin F, which has a higher oxygen affinity with a P50 of about 19 mmHg, facilitating uptake despite lower fetal partial pressures.^[11] Carbon dioxide diffuses in the opposite direction from fetal to maternal blood, aiding in waste removal while supporting overall gas equilibration.^[12] Nutrient transfer across the placenta involves both passive and active mechanisms tailored to essential substrates. Glucose, the primary energy source, crosses via facilitated diffusion mediated by glucose transporter proteins such as GLUT1 and GLUT3 on the syncytiotrophoblast membranes.^[13] Amino acids are transported actively against concentration gradients using sodium-dependent transporters, ensuring fetal levels often exceed maternal ones to support protein synthesis and growth. Lipids, including fatty acids, are transferred via specific fatty acid transport proteins, while iron is acquired through receptor-mediated endocytosis involving transferrin receptors on the maternal-facing syncytiotrophoblast surface, which bind maternal transferrin-bound iron for internalization and delivery to fetal circulation.^[14] The efficiency of these exchanges is enhanced by the placenta's large functional surface area of approximately 12-14 m² at term and high blood flow rates, with maternal uteroplacental flow reaching 500-700 mL/min near term, optimizing diffusion despite the fetus maintaining an arterial PO2 of about 30 mmHg.^[5]^[15] Placental hormones, particularly human placental lactogen (hPL), further support nutrient delivery by inducing maternal insulin resistance and lipolysis, thereby increasing circulating glucose and free fatty acids available for placental uptake and fetal supply.^[16]

Waste elimination

The placenta serves as the primary organ for eliminating metabolic wastes produced by the fetus, including carbon dioxide (CO₂), urea, and bilirubin, which are transferred from fetal blood to maternal circulation for processing and excretion. Fetal kidneys begin producing urine around 10-12 weeks of gestation, but their glomerular filtration rate remains low (approximately 1 mL/min at term) and they do not assume a major role in waste elimination until late gestation; instead, the placenta handles the bulk of waste removal to support fetal homeostasis. Deoxygenated blood carrying these wastes returns to the placenta via the umbilical arteries for exchange.^[1]^[17]^[18] Transfer of these wastes across the placental barrier occurs primarily through diffusion-based mechanisms, leveraging the thin syncytiotrophoblast layer and large surface area (up to 11 m² at term). CO₂ diffuses passively down its concentration gradient, facilitated by carbonic anhydrase enzymes in placental trophoblast cells that accelerate the conversion between CO₂ and bicarbonate, enabling efficient elimination and preventing fetal acidosis (maintaining fetal arterial pH around 7.35). Urea, a byproduct of fetal protein metabolism, crosses via passive diffusion, while unconjugated bilirubin—derived from fetal red blood cell breakdown—binds to albumin in fetal plasma and is transported via facilitated diffusion systems, allowing ready passage to the maternal side where it is conjugated and excreted by the maternal liver.^[19]^[20]^[21] Placental clearance efficiency is high for these solutes, with urea clearance approximating 50% of an equivalent glomerular filtration rate due to blood flow limitations rather than diffusion barriers, ensuring steady removal without accumulation. This process is crucial for averting acid-base imbalances, as effective CO₂ offloading buffers fetal pH. However, limitations exist: in Rh incompatibility, maternal antibodies can cross the placenta, causing fetal hemolysis and bilirubin buildup, which overwhelms transfer capacity and risks kernicterus—a form of bilirubin-induced brain damage. The placental barrier provides partial protection against maternal toxins by restricting passage of larger or ionized molecules, though smaller lipophilic substances like certain drugs can still traverse, potentially affecting the fetus.^[22]^[23]^[24] In terms of volume, the placenta manages substantial fluid and waste loads, including excess water via aquaporin channels (notably AQP1 and AQP9) that facilitate transplacental water movement to regulate amniotic fluid balance. Fetal urine output, containing dilute wastes, reaches approximately 500 mL/day by 31-34 weeks of gestation (increasing to 600-1200 mL/day near term), which the fetus swallows as part of amniotic fluid circulation, with the placenta absorbing net excess to prevent polyhydramnios.^[25]^[18]^[26]

Fetal Blood Flow Pathway

Venous return via umbilical vein

The umbilical vein is a single large vessel that transports oxygenated blood from the placenta to the fetus, constituting approximately 30% of the fetal combined ventricular output, or about 120 mL per minute per kilogram of fetal weight.^[27]^[28] This vein originates at the placenta, courses through the umbilical cord—where it is embedded and protected by Wharton's jelly, a mucoid connective tissue that safeguards against compression—and inserts into the fetal liver at the porta hepatis, entering the left portal vein to form the portal sinus.^[29] Upon reaching the liver, the blood in the umbilical vein, which has an oxygen partial pressure (PO₂) of approximately 32 mmHg and saturation of 70–80%, branches such that about half perfuses the hepatic sinusoids for liver oxygenation and nutrient exchange, while the remainder bypasses the liver entirely.^[30] The ductus venosus serves as a critical low-resistance shunt connecting the portal sinus directly to the inferior vena cava (IVC), allowing the majority of the highly oxygenated umbilical venous blood—roughly 50% of the incoming flow—to avoid sinusoidal resistance and proceed preferentially toward the heart. This shunt features a narrow inlet sphincter mechanism that regulates flow based on fetal needs, ensuring efficient delivery of nutrient-rich, oxygen-laden blood to vital organs while minimizing hepatic perfusion under normal conditions.^[31] In this manner, the ductus venosus maintains streamlined circulation, with the shunted blood maintaining its high oxygenation levels en route to the IVC. Within the IVC, the incoming oxygenated stream from the ductus venosus adheres preferentially to the medial and posterior walls, forming a distinct layer that limits turbulent mixing with the more desaturated venous return from the lower body and kidneys (PO₂ approximately 15 mmHg).^[32] This streaming effect preserves higher oxygen content in the blood directed toward the right atrium, optimizing delivery to the brain and heart before further intra-cardiac processing occurs.^[1] Overall, this venous pathway ensures that the fetus receives sustained blood flow of about 120 mL/min/kg, supporting oxygenation needs.^[27]

Mixing and shunting in the heart

In the fetal heart, blood entering the right atrium is preferentially streamed based on its origin and oxygenation level to optimize delivery to vital organs. Oxygenated blood from the inferior vena cava (IVC), primarily derived from the placenta, is directed toward the foramen ovale and into the left atrium by the crista dividens, a ridge on the interatrial septum that acts as a divider, while desaturated blood from the superior vena cava (SVC), returning from the upper body, is preferentially routed to the right ventricle.^[33]^[34] This streaming minimizes mixing of highly oxygenated IVC blood (approximately 70% saturated) with the lower-oxygenated SVC blood (about 40% saturated), ensuring that the brain and heart receive blood with higher oxygen content.^[34] The foramen ovale, a flap-like opening in the interatrial septum, facilitates shunting of this streamed IVC blood from the right atrium to the left atrium, bypassing the pulmonary circulation. Approximately 33% of the total cardiac output passes through the foramen ovale, driven by a pressure gradient created by the directed IVC flow and the relatively lower compliance of the right atrium compared to the left.^[28] This shunt accounts for about one-third of the IVC return being directed to the left side of the heart, with the valve-like structure of the foramen ovale preventing significant backflow under normal fetal pressures.^[34] From the ventricles, the right ventricle ejects blood primarily into the pulmonary artery, but due to high pulmonary vascular resistance, only a small fraction—around 11% of the total cardiac output—flows to the lungs, with the remainder shunted via the ductus arteriosus to the aorta.^[28] The right ventricle contributes about 59% of the combined ventricular output, compared to 41% from the left ventricle, reflecting the parallel nature of fetal circulation.^[28] Meanwhile, the left ventricle pumps blood from the left atrium directly into the ascending aorta, supplying the coronary arteries and brachiocephalic vessels to the head and upper body with relatively oxygenated blood (approximately 60% saturation).^[34] The ductus arteriosus, a vascular connection between the pulmonary artery and the descending aorta, shunts the majority of right ventricular output—about 78%—directly into the systemic circulation, allowing blood to bypass the non-functional lungs.^[28] This vessel's smooth muscle is maintained in a dilated state by low oxygen tension and circulating prostaglandins, such as PGE2, ensuring efficient right-to-left shunting.^[33] Overall, these mechanisms result in pulmonary blood flow comprising only 8-11% of the total cardiac output, with the shunts prioritizing oxygenated blood to the upper body and heart while directing less saturated blood to the lower body and placenta.^[28]^[34] This arrangement sustains fetal oxygenation, which originates from placental gas exchange.^[34]

Arterial outflow to placenta and body

The arterial outflow from the fetal heart occurs primarily through the aorta, which branches to supply both the fetal body and the placenta via the umbilical arteries. The ascending aorta delivers blood to the coronary arteries, providing the myocardium with the highest oxygen content in the fetal circulation due to the relatively oxygenated output from the left ventricle. This segment also gives rise to the brachiocephalic trunk and left common carotid artery, directing approximately 25% of the combined cardiac output to the brain and upper body, where oxygen saturation is around 55%.^[35] The descending aorta continues this distribution, receiving a significant portion of right ventricular output through the ductus arteriosus, which shunts blood from the pulmonary trunk to supply the lower trunk and limbs via the iliac arteries. The internal iliac arteries (also known as hypogastric arteries) give rise to the paired umbilical arteries, which carry deoxygenated blood back to the placenta for gas exchange and nutrient replenishment. This blood in the umbilical arteries has a partial pressure of oxygen (PO₂) of approximately 18 mmHg and an oxygen saturation of about 25%, reflecting the mixed, lower-oxygen venous return from fetal tissues.^[36]^[37]^[35] The combined ventricular output in the late-gestation fetus is approximately 400–500 mL/min/kg, with roughly 30% directed to the placenta through the umbilical arteries to facilitate reoxygenation before returning via the umbilical vein.^[28]^[27] This distribution is enabled by the cardiac shunts that preferentially route more oxygenated blood to vital organs like the heart and brain. Fetal tissues adapt to the resulting hypoxic conditions through reliance on anaerobic metabolism and the presence of fetal hemoglobin (HbF), which has a higher oxygen affinity than adult hemoglobin, enhancing oxygen unloading in low-PO₂ environments. The prioritization of cerebral perfusion, accounting for about 25% of cardiac output, underscores the brain-sparing effect that protects neurological development despite systemic hypoxia.^[38]^[35]

Physiological Mechanisms

Pressure gradients and flow rates

In fetal circulation, cardiac pressures are relatively low compared to postnatal values, with the mean right atrial pressure measuring approximately 3 to 4 mmHg and the left atrial pressure slightly lower at 2 to 3 mmHg, creating a small gradient that maintains the patency of the foramen ovale.^[39] Systolic pressures in both ventricles are similar, ranging from 60 to 70 mmHg, reflecting the parallel arrangement of the pulmonary and systemic circulations. Vascular resistances play a critical role in directing blood flow away from the non-functional lungs toward the placenta and body. The pulmonary vascular resistance is approximately 10 times higher than the systemic vascular resistance, largely attributable to hypoxic vasoconstriction in the underdeveloped pulmonary vasculature.^[40] In contrast, placental vascular resistance is about half that of the systemic circulation, facilitating high-volume exchange with the maternal blood.^[28] The ductus venosus exhibits low resistance, allowing efficient streaming of oxygenated blood from the umbilical vein toward the heart.^[1] Flow rates in the fetal circulation are substantial relative to body weight, supporting rapid growth and oxygenation needs. The combined cardiac output averages around 450 mL/min/kg fetal weight, with the right ventricle contributing about 55% and the left ventricle 45%.^[28] Umbilical vein flow constitutes approximately 110-120 mL/min/kg, representing over one-third of the cardiac output directed toward the placenta.^[27] Pulmonary blood flow is minimal at about 45 mL/min/kg, or roughly 10% of the total output, due to the elevated pulmonary resistance.^[41] Specific pressure gradients and hemodynamic principles govern shunting and overall flow distribution. Flow across the foramen ovale is primarily propelled by the inertial momentum of the oxygen-rich stream from the inferior vena cava, rather than a large pressure differential between atria.^[1] Shunting through the ductus arteriosus occurs due to the equivalence of systolic pressures in both ventricles, directing deoxygenated blood from the pulmonary artery to the descending aorta. The higher viscosity of fetal blood, with a hematocrit of approximately 50%, influences flow dynamics according to Poiseuille's law, where resistance is proportional to blood viscosity, necessitating adaptations in vessel dimensions and flow velocities to maintain adequate perfusion.^[28] Hemodynamic stability in the fetus is regulated by integrated physiological mechanisms. Baroreceptors in the great vessels and chemoreceptors in the carotid and aortic bodies respond to changes in pressure and oxygen levels, modulating heart rate and vascular tone to preserve circulation. Prostaglandins, particularly prostaglandin E2, maintain the patency of the ductus arteriosus by relaxing vascular smooth muscle throughout gestation.^[1]

Oxygen transport and saturation

Fetal hemoglobin (HbF), the predominant form of hemoglobin in the fetus, consists of two alpha and two gamma polypeptide chains (α₂γ₂). This structure confers HbF a higher affinity for oxygen than adult hemoglobin (HbA, α₂β₂), enabling efficient extraction of oxygen from maternal blood across the placenta. The higher affinity arises from reduced binding to 2,3-bisphosphoglycerate (2,3-BPG), which is present at lower concentrations in fetal erythrocytes, resulting in a leftward shift of the oxygen dissociation curve and a less pronounced Bohr effect. HbF accounts for 70-90% of total hemoglobin during late gestation and gradually declines after birth, reaching approximately 20-50% by 3 months.^[42]^[42]^[43]^[44] Oxygen saturation in fetal circulation exhibits distinct gradients due to shunting and mixing of blood streams. Blood in the umbilical vein, freshly oxygenated by placental diffusion, reaches saturations of approximately 80%. After partial diversion through the ductus venosus and mixing with deoxygenated hepatic venous blood in the inferior vena cava, saturation drops to around 65%. In contrast, superior vena cava blood from the upper body and head, which is highly desaturated, has only about 25% saturation. Following cardiac mixing and shunting, the descending aorta carries blood at roughly 55% saturation, while the umbilical arteries returning to the placenta have the lowest levels at 25%.^[45]^[1]^[1]^[1]^[1] The oxygen transport capacity of fetal blood is adapted to the relatively hypoxic intrauterine environment. Hemoglobin concentration in fetal blood is 16-18 g/dL, yielding an oxygen content of approximately 15 vol% in the umbilical vein—lower than the 20 vol% typical of adult arterial blood due to lower partial pressures of oxygen despite the higher HbF affinity. Preferential streaming directs the most oxygenated blood from the inferior vena cava across the foramen ovale to the left heart, ensuring that the ascending aorta supplies the brain and heart with blood exceeding 60% saturation, thereby prioritizing these vital organs. The reduced 2,3-BPG levels further support this by minimizing oxygen unloading in peripheral tissues until necessary.^[46]^[42]^[47]^[43] Measurements of these saturation gradients and transport parameters are primarily derived from animal models, such as instrumented fetal lambs, which provide direct sampling data, and non-invasive techniques like Doppler ultrasound in human pregnancies. These methods allow estimation of regional oxygen levels and are essential for identifying abnormalities, such as reduced saturations in intrauterine growth restriction that signal placental insufficiency.^[48]^[49]

Circulatory Transition at Birth

Triggers and immediate adaptations

The transition from fetal to neonatal circulation is initiated primarily by the newborn's first breath, which expands the lungs and dramatically reduces pulmonary vascular resistance (PVR) by approximately 8- to 10-fold.^[50] This reduction occurs through a combination of mechanical stretch of the pulmonary vasculature, the release of surfactant, which stabilizes alveoli and facilitates lung inflation, and nitric oxide release from endothelium, thereby increasing pulmonary blood flow (PBF) to accommodate gas exchange.^[51]^[50] Concurrently, the onset of breathing alters gas composition in the blood, with arterial partial pressure of oxygen (PaO₂) rising from about 25 mmHg in the fetus to around 100 mmHg in the neonate, while partial pressure of carbon dioxide (PaCO₂) falls, promoting vasodilation in the pulmonary circulation.^[52]^[51] Clamping of the umbilical cord serves as a critical mechanical trigger, abruptly removing the low-resistance placental circulation and increasing systemic vascular resistance (SVR).^[1] This elevates mean arterial pressure and redirects the entire cardiac output away from the placenta, boosting left atrial pressure as pulmonary venous return increases.^[51] The rise in PaO₂ and fall in PaCO₂ further contribute to these adaptations by inducing vasoconstriction in the ductus arteriosus, shifting flow from right-to-left to left-to-right within minutes.^[1] Hormonal factors amplify these changes, with a surge in catecholamines—triggered by the stress of labor—enhancing vascular tone, supporting blood pressure elevation, and aiding metabolic adaptations.^[53] As a result, PBF rapidly increases to 100% of cardiac output within minutes of birth, allowing the left ventricle to assume the full systemic workload previously shared with the right ventricle and placenta.^[51]

Closure of fetal shunts

At birth, the fetal circulatory shunts undergo a series of functional and anatomical changes to adapt to the independent pulmonary and systemic circulations of the newborn. These shunts—the foramen ovale, ductus arteriosus, and ductus venosus—close primarily due to alterations in pressure gradients, oxygen levels, and hormonal influences following the initiation of breathing and umbilical cord clamping. Functional closure occurs rapidly to prevent mixing of oxygenated and deoxygenated blood, while anatomical closure involves tissue remodeling over weeks to years.^[1] The foramen ovale, an interatrial communication, achieves functional closure shortly after birth (within minutes to hours) as pulmonary blood flow increases, elevating left atrial pressure above right atrial pressure and pressing the septum primum against the septum secundum.^[1] Anatomical fusion of these septa typically completes within 1-2 years, though incomplete fusion results in a patent foramen ovale (PFO) in approximately 25% of adults.^[54] The ductus arteriosus, connecting the pulmonary artery to the aorta, undergoes functional closure in 10-15 hours through oxygen-induced contraction of its smooth muscle cells and a decline in circulating prostaglandins, which had previously maintained patency.^[55] Anatomical remodeling into the ligamentum arteriosum follows within 2-3 weeks.^[55] Meanwhile, the ductus venosus, which shunts oxygenated blood from the umbilical vein to the inferior vena cava, closes immediately upon umbilical cord clamping due to contraction of its muscular sphincter and cessation of umbilical venous flow.^[31] This functional closure leads to anatomical obliteration into the ligamentum venosum over 1-3 months.^[31] Failure of these shunts to close can lead to persistent patency, with patent ductus arteriosus (PDA) occurring in 20–60% of preterm infants, with rates up to 50–80% in those with birth weights under 1000 grams, increasing risks of pulmonary overcirculation and heart failure.^[55]^[56] PFO, while often asymptomatic, persists in 25% of adults and may contribute to paradoxical emboli or migraines in select cases.^[57] Echocardiography serves as the primary tool for assessing shunt closure, visualizing residual flows and chamber enlargements to guide management.^[55] For symptomatic PDA, particularly in preterm neonates, indomethacin—a nonsteroidal anti-inflammatory drug—inhibits prostaglandin synthesis to promote closure, achieving success in 66-70% of cases when administered in multiple doses.^[55]

Adult Derivatives

Structural remnants

After birth, the ductus venosus, which shunted oxygenated blood from the umbilical vein directly to the inferior vena cava in the fetus, undergoes obliteration and transforms into the ligamentum venosum, a fibrous cord located within the falciform ligament of the liver.^[4] This remnant extends from the porta hepatis to the inferior vena cava, serving no vascular function in the adult but marking the site of the former shunt.^[31] The foramen ovale, an interatrial communication that directed blood from the right to the left atrium during fetal life, functionally closes shortly after birth due to pressure changes and anatomically fuses in most individuals, leaving the fossa ovalis as its remnant on the interatrial septum.^[4] The fossa ovalis appears as a shallow depression bounded superiorly by the limbus ovalis, representing the edge of the septum secundum.^[58] In some cases, incomplete fusion or redundant tissue from the septum primum can lead to an aneurysmal septum primum, a bulging variant within or adjacent to the fossa ovalis that may be incidental or associated with certain cardiac conditions.^[59] The ductus arteriosus, which connected the pulmonary artery to the descending aorta to bypass the non-functional lungs, constricts postnatally and fibroses into the ligamentum arteriosum, a short fibrous band linking the aortic arch to the left pulmonary artery near the ligamentum pulmonale.^[4] This structure provides structural continuity but no blood flow in the adult circulatory system.^[4] The umbilical vein, responsible for delivering oxygenated blood from the placenta to the fetus, obliterates after birth into the ligamentum teres hepatis, also known as the round ligament of the liver, which runs within the free edge of the falciform ligament from the umbilicus to the porta hepatis.^[4] This fibrous remnant occasionally contains patent segments in pathological states but is typically non-vascular.^[29] The two umbilical arteries, which carried deoxygenated blood to the placenta, persist partially in the adult: their proximal portions remain patent as the superior vesical arteries, supplying the superior bladder and related structures, while the distal portions atrophy and form the medial umbilical ligaments, paired fibromuscular cords extending from the internal iliac arteries along the anterior abdominal wall to the umbilicus.^[4] These ligaments lie within peritoneal folds known as the medial umbilical folds and serve as anatomical landmarks during surgery.^[60]

Clinical significance

Congenital heart defects often arise from disruptions in fetal circulation patterns, leading to significant clinical challenges. Transposition of the great arteries (TGA) exemplifies this by inverting the normal parallel circulations, where the aorta arises from the right ventricle and the pulmonary artery from the left, thereby compromising systemic oxygenation despite intact shunting mechanisms like the foramen ovale and ductus arteriosus.^[61] This malposition results in severe cyanosis postnatally, necessitating urgent arterial switch surgery within the first weeks of life to restore proper outflow.^[62] Similarly, hypoplastic left heart syndrome (HLHS) impairs left ventricular outflow, forcing reliance on right ventricular circulation via the ductus arteriosus for systemic perfusion during fetal life, which fails at birth without intervention.^[63] Fetuses with HLHS exhibit reduced left heart growth and altered flow dynamics, contributing to underdevelopment and requiring staged palliative surgeries like the Norwood procedure.^[64] Perinatal complications can mimic persistent fetal circulatory states, as seen in persistent pulmonary hypertension of the newborn (PPHN), where high pulmonary vascular resistance fails to decrease after birth, sustaining right-to-left shunting through fetal channels.^[65] This condition, often triggered by asphyxia or meconium aspiration, leads to profound hypoxemia and right heart strain.^[66] Treatment typically involves inhaled nitric oxide (iNO) to selectively dilate pulmonary vessels and improve oxygenation, reducing the need for extracorporeal membrane oxygenation (ECMO) in severe cases.^[67] ECMO provides temporary cardiopulmonary support when iNO is insufficient, with survival rates of approximately 65-80% in affected neonates as of recent studies.^[68] In adults, incomplete closure of fetal shunts manifests as clinical issues; patent foramen ovale (PFO) allows right-to-left shunting, facilitating paradoxical emboli that can cause cryptogenic stroke or systemic ischemia.^[69] PFO is also implicated in migraine with aura, potentially via microemboli or vasoreactive changes, with closure devices showing symptom relief in select patients.^[70] Patent ductus arteriosus (PDA), if uncorrected, imposes chronic left-to-right shunting, leading to volume overload, pulmonary hypertension, and eventual heart failure.^[71] Adults with significant PDA often present with dyspnea and fatigue, managed by transcatheter closure to prevent irreversible Eisenmenger syndrome.^[72] Prenatal evaluation is crucial for timely intervention; fetal echocardiography identifies outflow anomalies and shunt patency through real-time imaging of cardiac structures and flows.^[73] Doppler ultrasound assesses umbilical artery systolic/diastolic (S/D) ratios, where elevated values (>3) indicate placental resistance and risk of intrauterine growth restriction (IUGR), often linked to circulatory redistribution favoring the brain.^[74] Recent advances since 2020 include stem cell therapies for congenital heart defects like HLHS, with clinical trials demonstrating feasibility and potential improvements in cardiac growth and function; for example, allogeneic mesenchymal stem cell injections (e.g., laromestrocel) in ongoing trials as of 2025.^[75] AI-assisted imaging enhances shunt prediction by analyzing fetal echocardiograms for subtle flow abnormalities, achieving over 90% accuracy in detecting ventricular septal defects and improving diagnostic precision in resource-limited settings.^[76]

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The placenta: the forgotten essential organ of iron transport - NIH
Transferrin-iron is the major, if not only, maternal iron source for placental transfer, and its uptake is mediated by transferrin receptor 1 (TFR1) (Figure 1).
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These present a surface area of 12–14 m2 at term, and are ... Expression of members of the multidrug resistance protein family in human term placenta.
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Fetal circulation flows from the fetus to the two umbilical arteries (deoxygenated), then to chorionic arteries in the cotyledons, through the capillary beds ...
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Fetal wastes (e.g., urea, creatinine, bilirubin) are rapidly transferred across the placenta from the fetal circulation to the maternal blood bathing the villi.
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Placental CO2 Transfer After Fetal Carbonic Anhydrase Inhibition
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Transport Across the Placenta
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Development and Physiology of the Placenta and Membranes
Fetal surface of term human placenta. Fetal vessels radiate from the cord insertion. The maternal surface of the placenta usually appears to have several major ...
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Sensors for Fetal Hypoxia and Metabolic Acidosis: A Review - PMC
pH. The normal arterial pH of a healthy fetus is about 7.35 and is regulated primarily by gas exchange at the placenta. There is a physiological decrease in pH ...
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Rh incompatibility Information | Mount Sinai - New York
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Volume 3, Chapter 58. Fetal Circulation
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[PDF] Fetal Physiology and the Transition to Extrauterine Life
Blood within the umbilical vein has the highest oxygen saturation (70%–80%, estimated PO2 5 32–35 torr) compared with the rest of the fetal circulation. Because ...
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Embryology, Ductus Venosus - StatPearls - NCBI Bookshelf - NIH
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[PDF] The Fetal Circulation
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Recasting Current Knowledge of Human Fetal Circulation
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Cardiac output and central distribution of blood flow in the human fetus
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Physiology, Fetal Hemoglobin - StatPearls - NCBI Bookshelf
Fetal hemoglobin (HbF) is the dominant form of hemoglobin present in the fetus during gestation. HbF is produced by erythroid precursor cells from 10 to 12 ...Introduction · Cellular Level · Related Testing · Pathophysiology
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Physiology, Oxygen Transport And Carbon Dioxide Dissociation Curve
A rightward shift of the curve indicates that hemoglobin has a decreased affinity for oxygen; thus, oxygen actively unloads.
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Preferential streaming of blood in the inferior vena cava facilitates delivery of well-oxygenated ductus venosus blood to the brain and heart. During fetal ...
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Normal human and sheep fetal vessel oxygen saturations by T2 ...
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Ventilation-induced pulmonary vasodilation at birth is modulated by ...
At birth, pulmonary blood flow rapidly increases 8- to 10-fold, and pulmonary arterial pressure falls by 50% within 24 h. The postnatal adaptation of the ...
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The abrupt increase in PaO2 from approximately 25 to 30 mm Hg in the fetus to 90 to 95 mm Hg just after delivery causes serum erythropoietin to fall, and red ...
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Physiology of Transition from intrauterine to Extrauterine Life - PMC
The transition involves complex adaptations including air breathing, cardiovascular changes, endocrine function, and lung fluid clearance. Cortisol and ...
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Mar 16, 2025 · Transposition of the great arteries (TGA) is a congenital cardiac defect characterized by an embryological discordance of the aorta and pulmonary trunk.
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Persistent Pulmonary Hypertension of the Newborn (PPHN)
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Persistent Pulmonary Hypertension of the Newborn (PPHN ...
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Patent Foramen Ovale: The Known and the To Be Known - JACC
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The Correlation Between Migraine and Patent Foramen Ovale - PMC
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Patent Ductus Arteriosus | Circulation
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Patent ductus arteriosus in adults – indications and possibilities for ...
Left untreated, PDA can lead to pulmonary hypertension, Eisenmenger syndrome, heart failure and endarteritis. We report two adult patients diagnosed with PDA.
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Apr 24, 2014 · Continuous-wave Doppler can be used to assess ventricular systolic pressures ... fetal ventricular rates when <55 bpm has been reported.
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Role of prenatal fetal echocardiography in the assessment of ...
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Gene Therapy in Cardiovascular Disease: Recent Advances and ...
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Application of artificial intelligence in VSD prenatal diagnosis from ...
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