The fetus is surrounded by amniotic fluid ( liquor amnii ), a complex fluid that changes as the pregnancy progresses. Amniotic fluid serves a number of vital roles, including the facilitation of fetal growth, the provision of a microgravity environment that cushions the fetus, and the generation of a defense mechanism against invading microbes. The formation and maintenance of amniotic fluid is an intricate process that depends on fetal maturation, maternal hydration, hormonal status, and uteroplacental perfusion.

Amniotic fluid during early embryogenesis is principally derived from maternal plasma by the passage of water and solutes through aquaporin water channels expressed in the fetal-maternal membranes (amnion and chorion). The expression of aquaporins changes as gestation advances and with certain pathologic states, such as polyhydramnios. Between 10 and 20 weeks’ gestation, the volume of amniotic fluid increases in a predictable and linear manner from approximately 25 to 400 mL. During this period, the composition of amniotic fluid is similar to fetal extracellular fluid, owing to the absence of keratin in the fetal skin. Beyond 20 weeks’ gestation, the volume of amniotic fluid is determined by the difference between production, from fetal urine and respiratory tract, and removal, through fetal swallowing. The volume of amniotic fluid is also influenced by intramembranous (between amniotic fluid and fetal blood within the placenta) and transmembranous (between amniotic fluid and maternal blood within the uterus) pathways in both physiologic and pathophysiologic states. Finally, the status of maternal hydration and the amount of decidual prolactin may alter the transfer of amniotic fluid through fetal and maternal tissues. Amniotic fluid volume plateaus at 800 to 1000 mL at around 28 weeks’ gestation, after which it declines to approximately 400 mL at term.

The composition of amniotic fluid undergoes more marked variation than its volume throughout gestation. During the first trimester, amniotic fluid consists mostly of water and electrolytes and contains minimal protein. Keratinization of the fetal skin is complete by 25 weeks’ gestation and decreases the permeability of fetal tissues to water and solutes. The impact of this process, coupled with the ability of the fetal kidneys to produce urine, results in increased amniotic fluid concentrations of urea and creatinine, decreased concentrations of sodium and chloride, and reduced osmolality. A variety of carbohydrates, proteins, lipids, electrolytes, enzymes, and hormones, which vary in concentration depending on the gestational age, are also present; some of these elements, particularly the amino acids taurine, glutamine, and arginine, serve a nutritive function for mitotic cells involved in trophoblastic growth and placental angiogenesis. Many growth factors are found in amniotic fluid, many of which play an important role in fetal intestinal development.

Antimicrobial defenses within the amniotic fluid are primarily composed of humoral mediators such as alpha-defensins, which are released from neutrophils, especially in the setting of preterm labor and/or chorioamnionitis. Other humoral mediators include lactoferrin, calprotectin, leukocyte protease inhibitor, and cathelicidin, which have significant activity against bacteria, viruses, and fungi. Cellular mediators of the immune response are poorly characterized in amniotic fluid, and it remains unclear if the macrophages that are present serve a scavenging or an antimicrobial role. Neutrophils are usually absent from the amniotic fluid of a healthy fetus, and their presence typically signifies an inflammatory or infectious process.

Biochemical and cellular analysis of amniotic fluid provides valuable information on chromosomal abnormalities, neural tube defects, prenatal infections, and most inborn errors of metabolism. Several amniotic fluid-based indices, including the lecithin-sphingomyelin ratio, the phosphatidylglycerol level, lamellar body count, surfactant-to-albumin ratio, and electrical conductivity, can be used to assess fetal lung maturity. Bilirubin levels can be determined by measuring the optical density of amniotic fluid, which assists in the monitoring of fetal hemolysis. Estimation of the amniotic fluid levels of S100-beta (a protein released from injured astrocytes) and cell-free fetal nucleic acids may serve as early screening tests for perinatal neurologic damage and fetal development, respectively. Finally, amniotic fluid is a valuable reservoir for cell types of multiple lineages at different maturational ages; approximately 1% of these cells are pluripotent, thereby representing a novel source of stem cells. Loss of amniotic fluid is one contributor to impaired lung development, and its most extreme form, pulmonary hypoplasia.

The fetus has almost no oxygen reserve and depends on maternal sources of oxygen delivery via the placenta. Acute hypoxemia can have immediate, severe consequences, such as perinatal death, hypoxic-ischemic encephalopathy, and long-term consequences including cognitive impairment and cerebral palsy. Chronic reductions of oxygen supply may lead to fetal growth restriction (also known as intrauterine growth restriction) and may have long-term consequences for brain, heart, and kidney function through epigenetic changes. When tissue hypoxia occurs during critical periods of heart development, apoptosis of cardiomyocytes can result, potentially leading to a myocardium that is less resilient to ischemic insults in later life. In addition, chronic hypoxia can influence fetal development of brain and kidney function and metabolism, subsequently leading to problems in adulthood.

Oxygenation of fetal tissues depends principally on the partial pressure of oxygen (P o ₂ ) gradient between maternal and fetal blood, uteroplacental perfusion, and the different types of hemoglobin in maternal and fetal blood. The presence of fetal hemoglobin (hemoglobin F), with its higher concentration (approximately 18 g/dL) and greater affinity for oxygen than adult hemoglobin (see later discussion), results in a fetal arterial blood oxygen content that is similar to the adult, despite a lower oxygen tension and a similar rate of oxygen extraction. The fetus grows and thrives in a hypoxemic environment; specifically, the umbilical vein is the most oxygenated vessel in the fetal circulation and has a P o ₂ of approximately 30 to 40 mm Hg (4.0 to 5.3 kPa). Tissue hypoxia, however, occurs when the demand for oxygen exceeds the available supply. In adult tissues, hypoxia typically occurs at P o ₂ < 20 mm Hg (2.7 kPa; normal, approximately 40 mm Hg [5.3 kPa]). By contrast, in fetal tissues hypoxia occurs at P o ₂ < 17 mm Hg (2.3 kPa; normal, approximately 20 to 25 mm Hg [2.7 to 3.3 kPa]). This implies that the environment for fetal development exhibits a smaller margin of safety before reaching a state of oxygen insufficiency and highlights the importance of maintaining adequate uteroplacental perfusion and fetal cardiac output to ensure fetal oxygen delivery.

Placental oxygen concentration changes with gestation. In early pregnancy, the placental intervillous space is free of maternal blood cells, thereby requiring the embryo to rely on endometrial secretions and maternal plasma for its energy requirements. During the first trimester the placenta has (1) a P o ₂ of approximately 20 mm Hg (2.7 kPa); (2) only a few capillaries, which are located mainly in the center of the mesenchymal core; and (3) a trophoblastic layer that is twice the thickness of that in the second trimester. Moreover, the fetal red blood cells are nucleated, and the exocoelomic cavity contains antioxidant molecules instead of an oxygen transport system. These anatomic and physiologic features, which limit the transfer of oxygen and the creation of free radicals, protect the highly sensitive embryo from the effects of oxidative stress and keep the embryonic cells in their pluripotent state. At the end of the first trimester, an exponential increase in fetal growth creates a significant rise in the demand for oxygen and nutrients ( Fig. 5.1 ). In response, cytotrophoblastic cells interact with the smooth muscle of maternal spiral arteries, resulting in vessel dilation and the provision of oxygen-rich maternal blood flow to the placenta ( Fig. 5.2 ).

The mean oxygen partial pressure (P o ₂ ) throughout gestation in the human intervillous space.

Data from Jauniaux E, Kiserud T, Ozturk O, et al. Amniotic gas values and acid-base status during acute maternal hyperoxemia and hypoxemia in the early fetal sheep. Am J Obstet Gynecol . 2000;182:661–665; Rodesch F, Simon P, Donner C, Jauniaux E. Oxygen measurements in endometrial and trophoblastic tissues during early pregnancy. Obstet Gynecol . 1992;80:283–285; and Schaaps JP, Tsatsaris V, Goffin F, et al. Shunting the intervillous space: new concepts in human uteroplacental vascularization. Am J Obstet Gynecol . 2005;192:323–332.

Invasion and Remodeling of the Spiral Arteries by Endovascular and Interstitial Extravillous Trophoblasts .

(A) In the first trimester, the terminal portion of the spiral artery is blocked by a plug of endovascular trophoblast. Early placental and embryonic development occurs in a state of low oxygen tension, and nutrition at this early stage is derived from secretions from maternal endometrial glands. (B) After 10 to 12 weeks’ gestation, the endovascular trophoblast plug dissolves and the endovascular trophoblast migrates into the myometrium, replacing endothelial cells, which undergo apoptosis. Maternal blood is now able to enter the intervillous space, the oxygen tension increases to 60 mm Hg (8 kPa), and nutrition changes from histotrophic to hemotrophic.

Modified from Pijnenborg R, Vercruysse L, Hanssens M. The uterine spiral arteries in human pregnancy: facts and controversies. Placenta . 2006;27:939–958.

The placenta acts as both a conduit and consumer of oxygen. The placenta is metabolically active and performs important roles in carbohydrate and amino acid metabolism, protein synthesis, and substrate transport. Almost 40% of the oxygen delivered to the pregnant uterus is needed to support the metabolic processes of the placenta. During periods of hypoxia, the placenta appears to alter its metabolism to diminish its consumption of oxygen, most likely by increasing glycolysis. When the oxygen supply is compromised, the fetus shunts blood flow from peripheral tissues to vital organs (see later discussion), converts to greater use of anaerobic pathways, and induces gene expression that enables improved survival in a low-oxygen environment. These processes can acutely maintain fetal oxygen supply but, if hypoxia is ongoing, fetal growth restriction may result.

Glucose is the primary substrate for energy production in the fetus. Under normal conditions, gluconeogenesis is absent in mammalian fetuses and placental transfer is the only source of glucose. Glucose uptake into the fetal tissues is regulated by glucose transporters whose expression varies in response to acute and chronic changes in fetal glucose concentration. Fetal glucose concentration is linearly related to maternal concentration over a range of 3 to 5 mmol/L (54 to 90 mg/dL) ( Fig. 5.3 ); studies in isolated placentas suggest that this relationship continues up to a glucose concentration of 20 mmol/L (360 mg/dL). The placenta uses the majority of glucose delivered to the uterus for oxidation, glycogen storage, and conversion to lactate, with the remainder being transferred to the umbilical venous blood by facilitated, carrier-mediated diffusion.

The Linear Relationship Between Maternal and Fetal Blood Glucose Concentrations During the Third Trimester .

Fetal blood was obtained by percutaneous umbilical cord blood sampling.

From Kalhan SC. Metabolism of glucose and methods of investigation in the fetus and newborn. In: Polin RA, Fox WW, eds. Fetal and Neonatal Physiology . Vol I. WB Saunders; 1992:477–488.

The umbilical cord blood glucose uptake is approximately 5 mg/kg/min at normal maternal arterial plasma glucose concentrations in sheep models. It is estimated that lactate and amino acids provide approximately 25% each of the total fetal energy requirements.

Lactate is produced even in well-oxygenated fetal lambs, with total lactate production being approximately 4 mg/kg/min. Although the exact origin of fetal lactate is unclear, skeletal muscle and bone have been identified as sources of lactate production under resting conditions. Lactate production increases during episodes of acute hypoxemia, although this response may be blunted in fetuses previously exposed to oxidative stress. Lactate consumption occurs in the fetal myocardium and liver.

The fetus uses amino acids for protein synthesis, growth, and oxidation. Most maternal-to-fetal amino acid transfer occurs against a concentration gradient and involves energy-dependent transfer mechanisms. Under conditions in which fetal aerobic metabolism is decreased, amino acid uptake by the placenta and fetus may be reduced because it involves an expenditure of energy. During maternal fasting, fetal amino acid uptake does not change; however, enhanced fetal proteolysis may occur, resulting in amino acid oxidation or gluconeogenesis.

Lipid products are transferred from the mother to the fetus. The fetus requires free fatty acids for growth, brain development, and the deposition of body fat for postnatal life. Fatty acids are transferred across the placenta by simple diffusion. Ketones are also transferred by simple diffusion, and in humans the maternal/fetal ketone ratio is approximately 2.0. The fetus can use ketones as lipogenic substrates or as energy substrates in the brain, kidney, heart, liver, and placenta. Beta-hydroxybutyrate (fatty acid) metabolism can occur in the placenta, brain, and liver during episodes of fetal hypoglycemia that result from maternal fasting.

Intrauterine fetal temperature largely depends on maternal temperature. Owing to the high metabolic rate in the fetus, the net flow of heat is from the fetus to the mother. The fetus produces approximately twice as much weight-adjusted heat as the mother and maintains a temperature 0.5°C higher. This maternal-fetal difference in temperature remains relatively constant and is referred to as the “heat clamp.”

The placental circulation is responsible for approximately 85% of the heat exchange between the mother and fetus. The remaining 15% is dissipated through the fetal skin and transferred through the amniotic fluid and the uterine wall to the maternal abdomen. In animal models, fetal temperature may be rapidly affected by changes in umbilical blood flow. In humans, fetal temperature increases during uterine contractions, which may be a result of intermittent obstruction of umbilical cord blood flow. Whether this rise in fetal temperature contributes to acute hypoxic-ischemic brain damage in the setting of umbilical cord prolapse is unknown. However, relatively small increases in temperature increase the sensitivity of the fetal brain to hypoxic injury.

Thermogenic mechanisms are not developed until the end of gestation and are largely inactive in utero . Newborns are at high risk for rapid heat loss due to amniotic fluid evaporation and a sudden decrease in ambient temperature. Because of their small muscle mass, neonates are incapable of significant heat production through shivering. Instead, nonshivering thermogenesis occurs in brown adipose tissue.

Fetal circulation differs significantly from the postnatal circulation. The fetal systemic circulation receives cardiac output from both the left and the right ventricle, with the ventricles working in parallel . In contrast, during postnatal life, the left and right circulations are separated, and the ventricles work in series . The fetal lungs are filled with fluid and do not participate in gas exchange. The pulmonary vascular resistance (PVR) is high.

Fetal blood flow is characterized by three anatomic shunts: the ductus venosus , the foramen ovale , and the ductus arteriosus ( Fig. 5.4 ). Oxygenated blood travels from the placenta through the umbilical vein to the ductus venosus , which connects the umbilical vein with the inferior vena cava, thus bypassing the portal circulation and the liver. At mid-gestation, approximately 30% of the umbilical venous blood is shunted through the ductus venosus. From 30 to 40 weeks’ gestation, this fraction decreases to approximately 20%, although a significant increase may occur in response to hypoxia. Once in the right atrium, oxygenated blood preferentially flows through the foramen ovale and then to the left atrium and left ventricle, preferentially delivering well-oxygenated blood to the brain and the heart rather than the systemic circulation. Only a small amount of desaturated blood returns from the pulmonary veins and drains into the left atrium.

The Fetal Circulation .

Oxygenated blood leaves the placenta via the fetal umbilical vein (1) , enters the liver where flow divides between the portal sinus and the ductus venosus, and then empties into the inferior vena cava (2) . Inside the fetal heart, blood enters the right atrium, where most of the blood is directed through the foramen ovale (3) into the left atrium and ventricle (4) , and then enters the aorta. Blood is then sent to the brain (5) and myocardium, ensuring that these cells receive the highest oxygen content available. Deoxygenated blood returning from the lower extremities and the superior vena cava (6) is preferentially directed into the right ventricle (7) and pulmonary trunk. Most blood passes through the ductus arteriosus (8) into the descending aorta (9) , which in turn supplies the lower extremities (10) and the hypogastric arteries (11) . Blood returns to the placenta via the umbilical arteries for gas and nutrient exchange. A small amount of blood from the pulmonary trunk travels through the pulmonary arteries (12) to perfuse the lungs. Arrows in this figure depict the direction and oxygen content ( white [oxygenated], blue [deoxygenated]) of the blood in circulation.

Illustration by Naveen Nathan, MD, NorthShore University HealthSystem, University of Chicago Pritzker School of Medicine.

Deoxygenated blood from the head and upper extremities enters the right atrium through the superior vena cava and is preferentially directed into the right ventricle and the pulmonary artery. Because fetal PVR is higher than systemic vascular resistance (SVR), most of the pulmonary artery blood flow crosses the ductus arteriosus into the descending aorta, supplying the lower extremities and hypogastric arteries. Deoxygenated blood returns to the placenta via the umbilical arteries for gas and nutrient exchange.

PVR plays an important role in the fetal circulation. The small pulmonary arteries are compressed by fluid-filled alveoli; concomitantly, the lack of rhythmic distension contributes to the mechanical impact on PVR. In the early stages of fetal development, PVR is elevated because of the small cross-sectional area and the lack of pulmonary vessels, and pulmonary blood flow comprises only approximately 13% of the combined cardiac output at 20 weeks’ gestation. As lung development progresses from the canalicular to the saccular stage, there is a rapid proliferation of pulmonary blood vessels with a resultant relative drop in PVR and increase in pulmonary blood flow to approximately 25% to 30% of the combined cardiac output. Towards the third trimester, there is a secondary increase in PVR due to the response of pulmonary vasoconstrictor substances in response to oxygen.

The relationship between PVR and pulmonary blood flow is inverse in late-gestation fetuses. PVR is the main determinant of the relative proportions of left ventricular filling that are driven by shunting of blood across the foramen ovale or by pulmonary venous return. Ultimately, this relationship is governed by the dynamic interplay between the different modulators of blood flow. For instance, fetal breathing increases pulmonary blood flow by up to fourfold owing to changes in capillary-interstitial transmural pressures, which in turns leads to a transient decrease in PVR. Pulmonary blood flow then increases and the shunt across the foramen ovale decreases. This knowledge is particularly important to the understanding of maternal hypoxia and hyperoxia and the impact on delivery of oxygen to the fetal brain.

Several mechanisms protect the fetus from oxygen toxicity while still guaranteeing that oxygen delivery meets tissue demand. Although the fetal lungs do not participate in gas exchange, the pulmonary vasculature is reactive to oxygen and modulates blood flow to maintain oxygen delivery to the brain within a narrow range. Fetal sheep experiments of maternal hyperoxia demonstrated that significant increases in maternal arterial P o ₂ are buffered by the placenta, resulting in an increase in umbilical vein P o ₂ with little change in the fetal preductal circulation P o ₂ .

Fetal oxygen delivery is regulated in the setting of maternal hypoxia by several mechanisms. Acutely, these include increased umbilical vein flow, dilation of the ductus venosus and the cerebral circulation, and decreased fetal oxygen content, which in turn increases PVR and decreases pulmonary blood flow. These changes, in turn, lead to a limited amount of desaturated blood returning to the left atrium from the pulmonary veins as well as preferential flow of blood coming from the umbilical vein through the foramen ovale and then to the ascending aorta.

At birth, the fetus undergoes a significant and abrupt transition to a state of physiologic independence (see Chapter 9 ). Clamping of the umbilical cord results in a sudden increase in SVR and left ventricular afterload, and a reduction in right atrial preload. In addition, expansion of the lungs and increased alveolar oxygen tension result in decreased PVR. This allows for increased pulmonary blood flow, a decrease in right atrial pressure, and an increase in left atrial pressure, ultimately leading to the functional closure of both the foramen ovale and the ductus arteriosus.

The ductus arteriosus, a vascular connection between the pulmonary artery and the proximal descending aorta, is responsible during fetal life for diverting deoxygenated blood away from the high-resistance pulmonary circuit into the systemic circulation. Of the total combined cardiac output, approximately 65% goes through the right ventricle and only 5% to 10% enters the fetal pulmonary circulation. The remainder is shunted through the ductus arteriosus to the descending aorta. Prostaglandin E2 (PGE2) and prostacyclin I2 (PGI2) maintain the patency of the ductus arteriosus in utero . PGE2 is released from various fetal tissues and the placenta, with a higher circulating level in the fetus than the mother. Stimulation of PGE2 receptors results in an increased concentration of cyclic adenosine monophosphate, which, in turn, inhibits myosin light-chain kinase and results in ductus arteriosus relaxation.

Following birth in term infants, the ductus arteriosus smooth muscle undergoes vasoconstriction, which leads to a functional closure of the lumen within the first couple of hours. This vasoconstriction is triggered primarily by the increase in oxygen tension through several mechanisms, as well as by increased lung catabolism of PGE2 and PGI2 with the removal of the placenta, and decreased ductus arteriosus expression of PGE2 receptors. Reduction in endogenous nitric oxide production also contributes to postnatal ductus arteriosus closure. Following smooth muscle vasoconstriction, ischemia-hypoxia of the muscle media of the ductus arteriosus occurs with an increase in vascular endothelial growth factor production. This is followed by vasa vasorum proliferation into the wall of the ductus arteriosus which, in combination with the attraction of mononuclear cells as well as platelet adhesion, ultimately leads to thrombotic sealing of the vasoconstricted ductus arteriosus, luminal remodeling, and anatomic occlusion.

Human fetal intravascular volume is approximately 110 mL/kg, which is a greater proportion than in postnatal life. Approximately 25% of this blood volume is contained within the placenta; the blood volume within the fetal body is estimated to be approximately 80 mL/kg. Fetal intravascular volume is regulated through a complex interplay between the fetal heart, kidneys, and circulation and the placenta. The fetus can adapt more quickly to changes in intravascular volume than the adult, owing to higher diffusion rates between the different fetal compartments.

Transplacental transfer of water from mother to fetus depends on hydrostatic and osmotic pressures. The hydrostatic pressure is determined by the difference in pressures between the maternal intervillous space or capillaries and the fetal capillaries. The osmotic pressure is mainly determined by the presence of plasma proteins (i.e., colloid osmotic pressure). Transplacental water transfer is further regulated by angiotensin II. Adamson et al. found that angiotensin II lowered the pressures in fetal placental exchange vessels, thereby promoting fluid transfer from the maternal to the fetal circulation. The production of angiotensin II is under control of the renin-angiotensin-aldosterone system in the fetal kidneys. A reduction in fetal arterial pressure results in an increase in fetal plasma renin activity, which results in subsequent increases in angiotensin I and II. The resulting expansion of intravascular volume augments fetal cardiac output and arterial pressure.

During gestation, the fetal heart grows quickly and adapts to the continuously changing demands. The fetal myocardium grows primarily through hyperplasia, whereas after delivery, cardiac mass increases as a result of cell enlargement/hypertrophy. This growth correlates with a prebirth transition from mononucleated cardiomyocytes to binucleated cardiomyocytes, which contribute to heart growth by hypertrophy. Interruption of the normal process of myocyte hyperplasia will lead to decreased myocardial endowment.

The number of cardiac myofibrils and the transition in the type of cardiac troponins that are present during prenatal development can alter fetal heart contractility. The change from fetal to adult troponin is associated with decreased sensitivity of the contractile apparatus to calcium. A heightened calcium sensitivity is important in the early development of the fetal heart, when the sarcoplasmic reticulum is immature. With advancing gestational age, ejection fraction declines, but cardiac output (per unit of fetal weight) does not change, owing to increasing ventricular volume. The fetal heart rate decreases over the course of gestation from 140 to 150 beats/min at 18 weeks’ gestation to 120 to 140 beats/min at term.

In utero developmental issues can have gestational and long-term heart consequences. Fetuses of mothers with diabetes mellitus were found to have signs of biventricular diastolic dysfunction, right ventricular systolic dysfunction, and septal hypertrophy in the third trimester, compared with control subjects. Human growth-restricted fetuses have smaller, more spherical hearts, impaired systolic longitudinal function, and mild impairment in diastolic function, compared with matched non–growth-restricted fetuses; these alterations have been observed to persist when examined even 10 years later.

In postnatal life, the right and left ventricles operate in series and their output is approximately equal; consequently, cardiac output is defined through measurements of output from either ventricle. However, in the fetus, the systemic circulation receives blood from both the left and right ventricle in parallel (i.e., the sum of the right and left ventricular outputs, except for a proportion of the right ventricular output that is delivered to the fetal lungs). At mid-gestation, the combined ventricular output (CVO) is approximately 210 mL/min, and it increases to approximately 1900 mL/min at 38 weeks’ gestation (500 mL/min/kg). During fetal life, the right ventricular volume is greater than the left ventricular volume during both systole and diastole, but stroke volume does not differ significantly between the two ventricles.

Fetal cardiac output is sensitive to changes in fetal heart rate. As heart rate increases, cardiac output increases. As fetal heart rate decreases, fetal stroke volume increases only slightly, in part because of low fetal myocardial compliance. Although fetal bradycardia results in an extended diastolic filling time, the stiff fetal cardiac ventricles have limited ability to distend. Therefore, fetal bradycardia is associated with a marked drop in fetal cardiac output.

In both fetal and adult animals, approximately equal volumes of blood are delivered to oxygen-uptake organs (i.e., the placenta before delivery, the lungs after delivery) and the oxygen-consuming organs. Earlier studies investigating the organ distribution of CVO in the fetus were based on experiments on instrumented animals. However, significant interspecies differences exist. Recently, Abduljalil et al. collated available published data and applied mathematical physiologically based pharmacokinetic modeling and simulation to estimate the distribution of CVO to different organs and tissues in the human fetus at different gestational ages ( Table 5.1 ). This knowledge is important because fetal organ blood flow delivers not only nutrients but also chemicals and medications to which the pregnant woman may be exposed, intentionally or unintentionally. The distribution of the CVO to fetal organs changes in certain conditions and disease states (e.g., hypoxia, hypovolemia, preeclampsia, diabetes, fetal growth restriction). For example, in human fetuses the brain receives approximately 14% to 18% of CVO, but this fraction may be increased during circumstances of decreased placental perfusion, acidosis, or increased P co ₂ .

Regulation of Fetal Circulation

The autonomic nervous system is present early in gestation and plays a critical role in maintaining cardiovascular homeostasis. In the fetal chick heart, evidence of cholinergic innervation occurs as early as 3 days after fertilization (average incubation, 22 days). In the mammalian heart, inotropic and chronotropic responses to adrenergic agents have been measured as early as 4 to 5 weeks’ gestation, and the fetal myocardial pacemaker can be inhibited at this time by the cholinergic agonists carbamylcholine and acetylcholine.

Most studies indicate that the parasympathetic system appears earlier than the sympathetic system (8 weeks’ gestation versus 9 to 10 weeks’ gestation), becomes more dominant as pregnancy progresses, and is more functionally complete at birth ( Fig. 5.5 ). As a result, the baseline fetal heart rate is slower at term than at 26 weeks’ gestation.

The Growing Influence of the Parasympathetic Nervous System on Fetal Heart Rate as Gestation Progresses .

This parasympathetic activity is reversible with administration of atropine.

From Schifferli P, Caldeyro-Barcia R. Effects of atropine and beta-adrenergic drugs on the heart rate of the human fetus. In: Boréus LO, ed. Fetal Pharmacology . Raven Press; 1973:264.

Both parasympathetic and sympathetic systems undergo significant maturation during postnatal life, and full maturation of the vagal response is not observed until 1 to 2 months after delivery. Similarly, although the contractile response of the fetal vasculature is less functional than the adult response, the fetal administration of an alpha-adrenergic receptor agonist can result in the redistribution of blood flow away from the kidneys, skin, and splanchnic organs and toward the heart, brain, placenta, and adrenal glands. At birth, the autonomic nervous system mediates changes in heart rate and peripheral vascular resistance, and a redistribution of blood flow.

Fetal cardiovascular function also adapts to varying metabolic and environmental conditions through regulation by the neurologic and endocrine systems. Most neuroregulation occurs in response to baroreceptor and chemoreceptor afferent input to the autonomic nervous system and through modulation of myocardial adrenergic receptor activity.

Arterial baroreceptor function has been demonstrated in several different fetal animal models. The predominant baroreceptors are located within the vessel walls of the aortic arch and at the bifurcations of the common carotid arteries. These receptors project signals to the vasomotor center in the medulla, from which autonomic responses emanate. The baroreceptors are functional early in fetal development and undergo continuous adaptation to the increases in blood pressure observed over time. A sudden increase in fetal mean arterial pressure—as occurs with partial or complete occlusion of the umbilical arteries—results in cholinergic stimulation and subsequent fetal bradycardia.

Peripheral chemoreceptors are present within the vessel walls of the aortic arch and at the bifurcations of the common carotid arteries. In some animal species, peripheral chemoreceptors are transiently present in the adrenal glands but disappear after birth. The fetal aortic chemoreceptors are responsive even to small changes in arterial oxygenation, which contrasts with the less active fetal carotid chemoreceptors. Dawes et al. concluded that the carotid chemoreceptors are important for postnatal respiratory control, whereas the aortic chemoreceptors are more involved in the control of cardiovascular responses and the regulation of oxygen delivery. Central chemoreceptors, located in the medulla oblongata, appear to play little if any role in fetal circulatory responses.

The neural control of the fetal circulation is far more dependent on chemoreceptor-mediated responses than in the adult circulation. Acute fetal hypotension often stimulates a reflex response, which can include both bradycardia and vasoconstriction. Vasoconstriction is dependent on increases in both sympathetic autonomic activity and the rate of secretion of several vasoactive hormones, including arginine, vasopressin, renin, angiotensin, and aldosterone. Fetal bradycardia is most likely caused by activation of peripheral chemoreceptors.

The fetus starts swallowing at approximately 15 weeks’ gestation, and at term the fetus ingests 500 to 750 mL of amniotic fluid per day. Fetal swallowing plays an important role in amniotic fluid homeostasis, and the swallowed fluid appears to provide nutritional support for mucosal development within the gastrointestinal tract. Intestinal growth occurs by duplication of intestinal crypts, a process that is promoted by the presence of trophic factors in amniotic fluid; these factors include epidermal growth factor, hepatocyte growth factor, transforming growth factor alpha (TGF-α) and beta (TGF-β), insulin-like growth factor-1 (IGF-1) and-2 (IGF-2), erythropoietin, granulocyte colony-stimulating factor, and cytokines. Avila et al. found that surgical obstruction of ingested fluid within the upper gastrointestinal tract resulted in restricted development of the gastrointestinal tract, liver, and pancreas.

The ingestion and intestinal absorption of nutrient-rich amniotic fluid also appear to play an important role in general fetal growth and development. In the fetal rabbit model, disorders of the upper gastrointestinal tract (e.g., esophageal obstruction, gastroschisis) lead to decreased intestinal nutrient absorption and decreased birth weight and crown-rump length. Similar findings have been reported in human neonates with congenital esophageal atresia.

Meconium—which consists of water, intestinal secretions, squamous cells, lanugo hair, bile pigments, and blood—first appears in the fetal intestine between 10 and 12 weeks’ gestation. By 16 weeks’ gestation, meconium moves into the colon. Between 14 and 22 weeks’ gestation, fetal colonic contents, as indicated by the presence of high levels of intestinal enzymes (e.g., disaccharidases, alkaline phosphatase), appear in the amniotic fluid. After 22 weeks’ gestation, a subsequent decline in the concentration of these gastrointestinal enzymes within the amniotic fluid is observed, which coincides with the development of anal sphincter tone.

Meconium is continually cleared by fetal swallowing, leading to relatively clear amniotic fluid in most pregnancies. The presence of meconium-stained amniotic fluid may therefore represent either decreased clearance or increased passage of meconium, which is observed in the presence of fetomaternal stress factors such as hypoxia and infection, independent of fetal maturation. Meconium-stained amniotic fluid occurs more frequently with advanced gestational age and is common in postterm pregnancies.

Although many fetuses with meconium-stained amniotic fluid are born without adverse sequelae, meconium can have detrimental effects on fetal organs and the placenta. Meconium may cause umbilical cord vessel constriction, vessel necrosis, and the production of thrombi, which can lead to altered coagulation, cerebral palsy, and neonatal seizures. In addition, meconium may reduce the antibacterial properties of amniotic fluid by altering zinc levels. Fetal aspiration of meconium also may neutralize the action of surfactant, promote lung tissue inflammation through the activation of neutrophils, and possibly result in meconium aspiration syndrome (see Chapter 9 ). Finally, in the presence of perinatal hypoxia, meconium also may contribute to pulmonary hypertension.

Primary neuromodulation and neural tube formation occur by 4 weeks’ gestation. By 8 weeks’ gestation, the rostral end of the neural tube gives rise to the prosencephalon (forebrain), the mesencephalon (midbrain), and the rhombencephalon (hindbrain). These three segments further subdivide: the prosencephalon divides into the telencephalon and the diencephalon and the rhombencephalon divides into the metencephalon and myelencephalon. These five subdivisions establish the primary organization of the central nervous system.

The human subplate, the developmental anlage of the cerebral cortex, develops between 13 and 15 postconceptional weeks as a temporary location for synapses with cortical and thalamic projections. The subplate layer disintegrates between 24 and 28 weeks’ gestation. A significant increase in cortical development, organization, and synapse formation begins by 20 weeks’ gestation and continues postnatally; during the third trimester alone, the cerebral cortex volume increases fourfold.

The first fetal movements are witnessed near the end of the first trimester. These initial movements have simple patterns and originate from spontaneous discharges within the spine and brainstem. The fetal movements become more organized and complex as the pregnancy progresses, with higher brain centers modulating the activity of the brainstem and spine.

The exact onset of electrocortical activity is unknown, but electroencephalographic (EEG) activity can be recorded in preterm infants as early as 24 weeks’ gestation. Fetal EEG activity differs from that in adults and is characterized by the presence of intermittent bursts of activity separated by periods of complete suppression. With maturation, these suppressed episodes become shorter and less frequent before completely disappearing in postnatal life. The early electrical activity within the nervous system controls several developmental processes, such as neuronal differentiation, migration, synaptogenesis, and formation of neuronal networks. For example, the initial spontaneous spinal and subcortical discharges are believed necessary for somatosensory development. As they elicit movements in the periphery, afferent signals establish topographic representation on the sensory cortex.

Alterations in fetal brain and nervous system development can lead to major malformations.