Key Abbreviations
2,3-Diphosphoglycerate 2,3-DPG
α-Melanocyte–stimulating hormone α – MSH
Adrenocorticotropic hormone ACTH
Angiotensin-converting enzyme ACE
Angiotensin II AII
Arginine vasopressin AVP
Atrial natriuretic factor ANF
Carbon dioxide CO 2
Corticotropin-like intermediate lobe peptide CLIP
Corticotrophin-releasing factor CRF
Cyclic adenosine monophosphate cAMP
Epidermal growth factor EGF
Epidermal growth factor receptor EGF-R
Glomerular filtration rate GFR
Insulin-like growth factor IGF
Oxygen O 2
Thyrotropin-releasing hormone TRH
Thyroid-stimulating hormone TSH
Thyroxine T 4
Triiodothyronine T 3
Vascular endothelial growth factor VEGF
In obstetric practice, recognition of normal fetal growth, development, and behavior often suggests an expectant management plan. However, abnormalities may require clinical strategies for fetal assessment and intervention. The basic concepts of placental and fetal physiology provide the building blocks necessary for understanding pathophysiology and thus mechanisms of disease. Throughout this chapter, we have reviewed the essential tenets of fetal physiology and have related this information to normal and abnormal clinical conditions.
Much of our knowledge of fetal physiology derives from observations made in mammals other than humans. We have attempted to include only those observations reasonably applicable to the human fetus and in most instances have not detailed the species from which the data were obtained. Should questions arise regarding the species studied, the reader is referred to the extensive bibliography.
Umbilical Blood Flow
Fetal blood flow to the umbilical circulation represents approximately 40% of the combined output of both fetal ventricles . Over the last third of gestation, increases in umbilical blood flow are proportional to fetal growth so that umbilical blood flow remains constant when normalized to fetal weight. Human umbilical venous flow can be estimated through the use of triplex ultrasonography. Although increases in villous capillary number represent the primary contributor to gestation-dependent increases in umbilical blood flow, the factors that regulate this change are unknown; however, a number of important angiogenic peptides and factors, including vascular endothelial growth factor (VEGF), have been identified. Short-term changes in umbilical blood flow are primarily regulated by perfusion pressure. The relationship between flow and perfusion pressure is linear in the umbilical circulation . As a result, small (2 to 3 mm Hg) increases in umbilical vein pressure evoke proportional decreases in umbilical blood flow. Because both the umbilical artery and vein are enclosed in the amniotic cavity, pressure changes caused by increases in uterine tone are transmitted equally to these vessels without changes in umbilical blood flow. Relative to the uteroplacental bed, the fetoplacental circulation is resistant to vasoconstrictive effects of infused pressor agents, and umbilical blood flow is preserved unless cardiac output decreases. Thus despite catecholamine-induced changes in blood flow distribution and increases in blood pressure during acute hypoxia, umbilical blood flow is maintained over a relatively wide range of oxygen tensions. Endogenous vasoactive autacoids have been identified; nitric oxide may also be important. Endothelin-1, in particular, is associated with diminished fetoplacental blood flow.
Amniotic Fluid Volume
Mean amniotic fluid volume (AFV) increases from 250 to 800 mL between 16 and 32 weeks of gestation. Despite considerable variability, the average volume remains stable up to 39 weeks and then declines to about 500 mL at 42 weeks ( Fig. 2-1 ). Amniotic fluid index (AFI) values across gestation are found in Chapter 35 . The origin of amniotic fluid during the first trimester of pregnancy is uncertain. Possible sources include a transudate of maternal plasma through the chorioamnion or a transudate of fetal plasma through the highly permeable fetal skin before keratinization. The origin and dynamics of amniotic fluid are better understood beginning in the second trimester, when the fetus becomes the primary determinant. AFV is maintained by a balance of fetal fluid production (lung liquid and urine) and fluid resorption (fetal swallowing and flow across the amniotic and/or chorionic membranes to the fetus or maternal uterus; Fig. 2-2 ).
The fetal lung secretes fluid at a rate of 300 to 400 mL/day near term. Chloride is actively transferred from alveolar capillaries to the lung lumen, and water follows the chloride gradient. Thus lung fluid represents a nearly protein-free transudate with an osmolarity similar to that of fetal plasma. Fetal lung fluid does not appear to regulate fetal body fluid homeostasis, just as fetal intravenous volume loading does not increase lung fluid secretion. Rather, lung fluid likely serves to maintain lung expansion and facilitate pulmonary growth. Lung fluid must decrease at parturition to provide for the transition to respiratory ventilation. Notably, several hormones that increase in fetal plasma during labor (i.e., catecholamines, arginine vasopressin [AVP]) also decrease lung fluid production. With the reduction of fluid secretion, the colloid osmotic gradient between fetal plasma and lung fluid results in lung fluid resorption across the pulmonary epithelium and clearance via lymphatics. The absence of this process explains the increased incidence of transient tachypnea of the newborn, or “wet lung,” in infants delivered by cesarean section in the absence of labor.
Fetal urine is the primary source of amniotic fluid, and outputs at term vary from 400 to 1200 mL/day. Between 20 and 40 weeks’ gestation, fetal urine production increases about tenfold in the presence of marked renal maturation. The urine is normally hypotonic, and the low osmolarity of fetal urine accounts for the hypotonicity of amniotic fluid in late gestation relative to maternal and fetal plasma. Numerous fetal endocrine factors that include AVP, atrial natriuretic factor (ANF), angiotensin II (AII), aldosterone, and prostaglandins can alter fetal renal blood flow, glomerular filtration rate, and urine flow rates. In response to fetal stress, endocrine-mediated reductions in fetal urine flow may explain the association between fetal hypoxia and oligohydramnios. The regulation of fetal urine production is discussed further under “Fetal Kidney” later in this chapter.
Fetal swallowing is believed to be a major route of amniotic fluid resorption, although swallowed fluid contains a mixture of amniotic and tracheal fluids. Human fetal swallowing has been demonstrated by 18 weeks’ gestation, with daily swallowed volumes of 200 to 500 mL near term. Similar to fetal urine flow, daily fetal swallowed volumes (per body weight) are markedly greater than adult values. With the development of fetal neurobehavioral states, fetal swallowing occurs primarily during active sleep states associated with respiratory and eye movements. Moderate elevations in fetal plasma osmolality increase the number of swallowing episodes and volume swallowed, indicating the presence of an intact thirst mechanism in the near-term fetus.
Because amniotic fluid is hypotonic with respect to maternal plasma, there is a potential for bulk water removal at the amniotic-chorionic interface with maternal or fetal plasma. Although fluid resorption to the maternal plasma is likely minimal, intramembranous flow from amniotic fluid to fetal placental vessels may contribute importantly to amniotic fluid resorption. Thus intramembranous flow may balance fetal urine and lung-liquid production with fetal swallowing to maintain normal AFVs .
The mechanisms by which water is transferred across the amnion into fetal vessels remains uncertain, but evidence implicates the presence of water channels within the amnion and, as discussed previously, the placental trophoblast and fetal endothelium. Aquaporins 1, 3, 8, and 9 are found within the placenta and fetal membranes. Mice deficient in aquaporin 1 develop polyhydramnios, which suggests an important role for this protein in intramembranous water transfer. Aquaporins 1 and 3, important in transplacental water flow, are regulated by AVP and by cyclic adenosine monophosphate (cAMP), and they show changes in expression throughout gestation.
Fetal Growth and Metabolism
Substrates
Nutrients are utilized by the fetus for two primary purposes: oxidation for energy and tissue accretion. Under normal conditions, glucose is an important substrate for fetal oxidative metabolism. The glucose utilized by the fetus derives from the placenta rather than from endogenous glucose production. However, based on umbilical vein–umbilical artery glucose and oxygen (O 2 ) concentration differences, glucose alone cannot account for fetal oxidative metabolism. In fact, glucose oxidation accounts for only two thirds of fetal carbon dioxide (CO 2 ) production. Thus fetal oxidative metabolism depends on substrates in addition to glucose. A large portion of the amino acids taken up by the umbilical circulation are used by the fetus for aerobic metabolism instead of protein synthesis. Fetal uptake for a number of amino acids actually exceeds their accretion into fetal tissues. In addition, other amino acids—notably glutamate—are taken up by the placenta from the fetal circulation and are metabolized within the placenta. In fetal sheep, and likely in the human fetus as well, lactate also is a substrate for fetal oxygen consumption. Thus the combined substrates—glucose, amino acids, and lactate—essentially provide the approximately 87 kcal/kg required daily by the growing fetus.
Metabolic requirements for new tissue accretion depend on the growth rate and the type of tissue acquired. Although the newborn infant has relatively increased body fat, fetal fat content is low at 26 weeks. Fat acquisition increases gradually up to 32 weeks and rapidly thereafter (about 82 g [dry weight] of fat per week). Because many of the necessary enzymes for conversion of carbohydrate to lipid are present in the fetus, fat acquisition reflects glucose utilization in addition to placental fatty acid uptake. In contrast, fetal acquisition of nonfat tissue is linear from 32 to 39 weeks and may decrease to only 30% of the fat-acquisition rate in late gestation (about 43 g [dry weight] per week).
Hormones
The roles of select hormones in the regulation of placental growth are discussed in Chapter 1 . Fetal hormones influence fetal growth through both metabolic and mitogenic effects. Although growth hormone and growth hormone receptors are present early in fetal life, and growth hormone is essential to postnatal growth, growth hormone appears to have little role in regulating fetal growth. Instead, changes in insulin-like growth factor (IGF), IGF-binding proteins, or IGF receptors explain the apparent reduced role of growth hormone on fetal growth. Most if not all tissues of the body produce IGF-I and IGF-II, and both are present in human fetal tissue extracts after 12 weeks’ gestation. Fetal plasma IGF-I and -II levels begin to increase by 32 to 34 weeks’ gestation. The increase in IGF-I levels directly correlates with increase in fetal size, and a reduction in IGF-I levels is associated with growth restriction. In contrast, no correlation has been found between serum IGF-II levels and fetal growth. However, a correlation has been noted between small offspring and genetic manipulations that result in decreased IGF-II messenger RNA production. IGF-II knockout mice are small, and knockout of the IGF-II receptor results in fetal overgrowth. Thus tissue IGF-II concentrations and localized IGF-II release may be more important than circulating levels in supporting fetal growth.
IGF binding proteins (IGFBPs) modulate IGF-I and II concentrations in serum, with IGFBP1 having an inhibitory and IGFBP3 a comparatively stimulatory effect. As such, diminished fetal concentrations of IGFBP3 and enhanced concentrations of IGFBP1 have been associated with smaller fetal size.
A role for insulin in fetal growth is suggested from the increases in body weight and in heart and liver weights in infants of diabetic mothers. Insulin levels within the high physiologic range increase fetal body weight, and increases in endogenous fetal insulin significantly increase fetal glucose uptake. In addition, fetal insulin secretion increases in response to elevations in blood glucose, although the normal rapid insulin response phase is absent. Plasma insulin levels sufficient to increase fetal growth also may exert mitogenic effects, perhaps through insulin-induced IGF-II receptor binding. Separate receptors for insulin and IGF-II are expressed in fetal liver cells by the end of the first trimester. Hepatic insulin receptor numbers (per gram tissue) triple by 28 weeks, whereas IGF-II receptor numbers remain constant. Thus, although infants of diabetic mothers are at increased risk of cardiac defects, the growth patterns of these infants indicate that insulin levels may be most important in late gestation (see Chapter 40 ). Although less common, equally dramatically low birthweights are associated with the absence of fetal insulin. Experimentally induced hypoinsulinemia causes a 30% decrease in fetal glucose utilization and decreases fetal growth.
As in the adult, β-adrenergic receptor activation increases fetal insulin secretion, whereas β-adrenergic activation inhibits insulin secretion. Fetal glucagon secretion also is modulated by the β-adrenergic system. However, the fetal glycemic response to glucagon is blunted, probably caused by a relative reduction in hepatic glucagon receptors.
Corticosteroids are essential for fetal growth and maturation, and levels in the fetus rise near parturition in step with maturation of fetal organs such as the lung, liver, kidneys, and thymus and with slowing of fetal growth. Exogenous maternal steroid administration during pregnancy also has the potential to diminish fetal growth in humans and in a variety of other species, perhaps via suppression of the IGF axis. In addition to the insulin-like growth factors, a number of other factors—including epidermal growth factor (EGF), transforming growth factor (TGF), fibroblast growth factor (FGF), and nerve growth factor (NGF)—are expressed during embryonic development and appear to exert specific effects during morphogenesis; for example, EGF has specific effects on lung growth and on differentiation of the secondary palate, and normal sympathetic adrenergic system development is dependent on NGF. However, the specific role of these factors in regulating fetal growth remains to be defined. Similarly, the fetal thyroid also is not important for overall fetal growth but is important for central nervous system development.
Substantial evidence now exists to support the view that several cell-specific growth factors and their cognate receptors play an essential role in placental growth and function in a number of species. Growth factors identified to date include family members of EGF, TGF-β, NGF, IGF, hematopoietic growth factors, VEGF, and FGF. The expression, ontogeny, and regulation of most but not all of these growth factors have been explored; in addition, a number of cytokines also play a role in normal placental development. In vitro placental cell culture studies support the concept that growth factors and cytokines exert their functions locally, promoting proliferation and differentiation through their autocrine and/or paracrine mode of actions. For example, EGF promotes cell proliferation, invasion, or differentiation depending on the gestational age. Hepatocyte growth factor and VEGF stimulate trophoblast DNA replication, whereas TGF-β suppresses cytoplast invasion and endocrine differentiation. In support of local actions, functional receptors for various growth factors have been demonstrated on trophoblast and other cells. Various intracellular signal proteins and transcription factors that respond to growth factors are also expressed in the placenta. A number of elegant studies have identified alterations in growth factors and growth factor receptors in association with placental and fetal growth restriction. Placental defects in growth factor and receptor pathways, explored through the use of transgenic and mutant mice, have provided potential mechanisms for explaining complications of human placental development. An illustrative example is EGF, a potent mitogen for epidermal and mesodermal cells that is expressed in human placenta. EGF is involved in embryonal implantation, it stimulates syncytiotrophoblast differentiation in vitro, and it modulates production and secretion of human chorionic gonadotropin (hCG) and human placental lactogen (hPL). The effects of EGF are mediated by EGF-receptor (EGF-R), a transmembrane glycoprotein with intrinsic tyrosine kinase activity. EGF-R is expressed on the apical microvillus plasma membrane fractions from early, middle, and term whole placentae. Placental EGF-R expression is regulated by locally expressed parathyroid hormone–related protein, which is important in placental differentiation and maternal-fetal calcium flux. Decreased EGF-R expression has been demonstrated in association with intrauterine growth restriction (IUGR). Targeted disruption of EGF-R has been shown to result in fetal death as a result of placental defects. Overexpression of EGF-R activity results in placental enlargement.
The EGF family now consists of at least 15 members, many of which have been identified in human placenta. Future studies should reveal whether EGF family members play distinct or overlapping functions in mediating placental growth.
Control of fetal growth may occur via the impact of growth factors/hormones on the placenta or may occur as a direct result of action in and on the fetus. It is clear that nutrition may play a role in these processes. However, the number of genes and gene products known to control or affect fetal growth continues to increase. Imprinted genes, expressed primarily from maternally or paternally acquired alleles, play a particularly important role in controlling fetal growth. Abnormalities in the expression of these genes often result in fetal overgrowth or undergrowth. Environmental influences, such as alterations in gene methylation or in modification of histones associated with genes, may further alter gene expression and thus fetal growth, making this a rich area for further exploration.
Fetal Cardiovascular System
Development
The heart and the vascular system develop from splanchnic mesoderm during the third week after fertilization. The two primordial heart tubes fuse to form a simple contractile tube early in the fourth week, and the cardiovascular system becomes the first functional organ system. During weeks 5 to 8, this single-lumen tube is converted into the definitive four-chambered heart through a process of cardiac looping (folding), remodeling, and partitioning. However, an opening in the interatrial septum, the foramen ovale, is present and serves as an important right-to-left shunt during fetal life.
During the fourth embryonic week, three primary circulations characterize the vascular system. The aortic/cardinal circulation serves the embryo proper and is the basis for much of the fetal circulatory system. Of note the left sixth aortic (pulmonary) arch forms a connection between the left pulmonary artery and the aorta as the ductus arteriosus. The ductus arteriosus also functions as a right-to-left shunt by redistributing right ventricular (RV) output from the lungs to the aorta and fetal and placental circulations. The vitelline circulation develops in association with the yolk sac, and although it plays a minor role in providing nutrients to the embryo, its rearrangement ultimately provides the circulatory system for the gastrointestinal (GI) tract, spleen, pancreas, and liver. The allantoic circulation develops in association with the chorion and the developing chorionic villi and forms the placental circulation, comprised of two umbilical arteries and two umbilical veins. In humans, the venous pathways are rearranged during embryonic weeks 4 to 8, and only the left umbilical vein is retained. Subsequent rearrangement of the vascular plexus associated with the developing liver forms the ductus venosus, a venous shunt that allows at least half of the estimated umbilical blood flow (70 to 130 mL/min/kg fetal weight after 30 weeks’ gestation) to bypass the liver and enter the inferior vena cava.
Placental gas exchange provides well-oxygenated blood that leaves the placenta ( Fig. 2-3 ) via the umbilical vein. In addition to the ductus venosus, small branches into the left lobe of the liver and a major branch to the right lobe account for the remainder of the umbilical venous flow. Left hepatic vein blood combines with the well-oxygenated ductus venosus flow as it enters the inferior vena cava. Because right hepatic vein blood combines with the portal vein (only a small fraction of portal vein blood passes through the ductus venosus), right hepatic vein blood is less oxygenated than its counterpart on the left, and a combination of right hepatic/portal drainage with blood returning from the lower trunk and limbs further decreases the oxygen content. Although both ductus venosus blood and hepatic portal/fetal trunk bloods enter the inferior vena cava and the right atrium, little mixing occurs. This stream of well-oxygenated ductus venosus blood is preferentially directed into the foramen ovale by the valve of the inferior vena cava and the crista dividens on the wall of the right atrium. This shunts a portion of the most highly oxygenated ductus venosus blood through the foramen ovale with little opportunity for mixing with superior vena cava/coronary sinus venous return ( Fig. 2-4 ; see also Fig. 2-3 ). As a result, left atrial filling results primarily from umbilical vein–ductus venosus blood, with a small contribution from pulmonary venous flow. Thus blood with the highest oxygen content is delivered to the left atrium and left ventricle and ultimately supplies blood to the upper body and limbs, carotid and vertebral circulations, and the brain. Inferior vena cava flow is greater than the volume that can cross the foramen ovale. The remainder of the oxygenated inferior vena cava blood is directed through the tricuspid valve (see Fig. 2-3 ) into the right ventricle (see Fig. 2-4 ) and is accompanied by venous return from the superior vena cava and coronary sinus. However, the very high vascular resistance in the pulmonary circulation maintains mean pulmonary artery pressure 2 to 3 mm Hg above aortic pressure and directs most of the RV output through the ductus arteriosus and into the aorta and the fetal and placental circulations.
Fetal Heart
The adult cardiovascular system includes a high-pressure (95 mm Hg) system and a low-pressure pulmonary circuit (15 mm Hg) driven by the left and right ventricles working in series. Although the ejection velocity is greater in the left ventricle than in the right, equal volumes of blood are delivered into the systemic and pulmonary circulations with contraction of each ventricle. The stroke volume is the volume of blood ejected by the left ventricle with each contraction, and cardiac output is a function of the stroke volume and heart rate (70 mL/beat × 72 beats/min = 5040 mL/min). For a 70-kg adult man, cardiac output averages 72 mL/min/kg. In addition to heart rate, cardiac output varies with changes in stroke volume, which in turn is determined by venous return (preload), pulmonary artery and aortic pressures (afterload), and contractility.
In contrast to the adult heart, where the two ventricles pump blood in a series circuit, the unique fetal shunts provide an unequal distribution of venous return to the respective atria, and ventricular output represents a mixture of oxygenated and deoxygenated blood. Thus the fetal right and left ventricles function as two pumps that operate in parallel, rather than in series, and cardiac output is described as the combined ventricular output. RV output exceeds 60% of biventricular output and is primarily directed through the ductus arteriosus to the descending aorta (see Fig. 2-4 ). As a result, placental blood flow, which represents approximately 40% of the combined ventricular output, primarily reflects RV output. Because of the high pulmonary vascular resistance, the pulmonary circulation receives only 5% to 10% of the combined ventricular output. Instead, left ventricular (LV) output is primarily directed through the aortic semilunar valve and aortic arch to the upper body and head. Estimates of fetal LV output average 120 mL/min/kg body weight. If LV output is less than 40% of the combined biventricular output, total fetal cardiac output would be above 300 mL/min/kg. The distribution of the cardiac output to fetal organs is summarized in Table 2-1 , with fetal hepatic distribution reflecting only the portion supplied by the hepatic artery. In fact, hepatic blood flow derives principally from the umbilical vein and to a lesser extent the portal vein, and represents about 25% of the total venous return to the heart.
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