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Fetal Development, Physiology, and Effects on Long-Term Health
Key Abbreviations
| 2,3-Diphosphoglycerate | 2,3-DPG |
| α-Melanocyte–stimulating hormone | α-MSH |
| Adrenocorticotropic hormone | ACTH |
| Angiotensin II | AII |
| Angiotensin-converting enzyme | ACE |
| Arginine vasopressin | AVP |
| Atrial natriuretic factor | ANF |
| Bisphenol A | BPA |
| Carbon dioxide | CO 2 |
| Combined ventricular output | CVO |
| Corticotrophin-releasing factor | CRF |
| Corticotropin-like intermediate lobe peptide | CLIP |
| Cyclic adenosine monophosphate | cAMP |
| Epidermal growth factor | EGF |
| Epidermal growth factor receptor | EGF-R |
| Glomerular filtration rate | GFR |
| Insulin-like growth factor | IGF |
| Large for gestational age | LGA |
| Low birthweight | LBW |
| Nonalcoholic fatty liver disease | NAFLD |
| Oxygen | O 2 |
| Small for gestational age | SGA |
| Thyroid-stimulating hormone | TSH |
| Thyrotropin-releasing hormone | TRH |
| Thyroxine | T 4 |
| Triiodothyronine | T 3 |
| Vascular endothelial growth factor | VEGF |
Placental and fetal physiology provide the foundation for understanding pathophysiology and thus mechanisms of disease. Much of our knowledge of fetal physiology derives from observations in mammals other than humans, although we included only observations applicable to the human fetus. The early development and physiology program and predict offspring phenotype. The newborn and adult body contain approximately 2.1 × 10 12 and 3.7 × 10 13 human cells, respectively. Beginning with a fertilized ovum, it would require more than 41 cell division cycles to form a newborn and a total of 45 cycles for an adult. Thus more than 90% of lifetime cell divisions for body growth occur by the time of birth. Therefore it should not be surprising that the maternal/fetal environment may alter cell signaling, epigenetic regulation, and organ development, with nutrient environment alterations specifically impacting energy-regulating organs.
Fetal Metabolism and Growth
Substrates
Fetal nutrient utilization provides for energy production and tissue accretion. Glucose, important for fetal oxidative metabolism, derives from the placenta rather than endogenous glucose production. However, umbilical vein–umbilical artery glucose and oxygen (O 2 ) concentration differences indicate 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. Fetal uptake for some amino acids actually exceeds their accretion into fetal tissues, indicating that amino acids also support fetal aerobic metabolism. In addition, glutamate taken up from the fetal circulation is metabolized by the placenta. In sheep and likely human fetuses, lactate is a substrate for fetal oxygen consumption. Thus glucose, amino acids, and lactate essentially provide the approximately 87 kcal/kg required daily for fetal growth.
Metabolic requirements depend on fetal growth rate and tissue type. Fetal fat content is low at 26 weeks; fat acquisition increases gradually up to 32 weeks and rapidly thereafter (approximately 82 g [dry weight] of fat per week). Because the fetus expresses enzymes necessary for carbohydrate to lipid conversion, fat acquisition reflects both glucose utilization and placental fatty acid uptake. In contrast, fetal nonfat tissue acquisition is linear from 32 to 39 weeks and may decrease to 30% of the fat-acquisition rate in late gestation.
Hormones
Fetal Growth Hormone
Fetal growth hormones influence fetal growth through metabolic and mitogenic effects. Although growth hormone secretion and receptors are present in the fetus, growth hormone has minimal impact on fetal growth. Instead, insulin-like growth factor (IGF), together with IGF-binding proteins (IGFBPs) and IGF receptors, are most important. IGF-I and IGF-II are present in human fetal tissue extracts after 12 weeks’ gestation, and levels begin to increase by 32 to 34 weeks’ gestation. IGF-I levels correlate with fetal size, and reduced IGF-I levels are associated with growth restriction. In contrast, serum IGF-II levels and fetal growth do not correlate. However, IGF-II may regulate placental growth and nutrient permeability. IGFBPs modulate IGF-I and II serum concentrations, where IGFBP1 is inhibitory and IGFBP3 is stimulatory. Diminished fetal IGFBP3 and enhanced IGFBP1 levels are associated with smaller fetal size. Notably, IGF-II is a paternally imprinted gene, indicating that paternal factors can regulate fetal growth. Abnormalities in imprinted gene expression often result in fetal overgrowth or undergrowth.
Infants of diabetic mothers exhibit increases in body, heart, and liver weights, suggesting an insulin role in fetal growth. High insulin levels increase fetal body weight, and increased fetal insulin significantly increases glucose uptake. In addition, fetal insulin secretion increases with elevations in blood glucose, although the normal rapid insulin response phase is absent. Insulin also may exert mitogenic effects, perhaps through insulin-induced IGF-II receptor binding. Hepatic insulin receptor numbers (per gram tissue) are expressed by the end of the first trimester and triple by 28 weeks, whereas IGF-II receptor numbers remain constant. The growth patterns for infants of diabetic mothers indicate insulin may be most important in late gestation (see Chapter 45 ). In contrast, low birthweights (LBWs) are associated with fetal insulin absence, and experimentally induced hypoinsulinemia decreases fetal glucose utilization and fetal growth.
α-Adrenergic and β-adrenergic receptor activation inhibits and increases, respectively, both adult and fetal insulin secretion. The β-adrenergic system also modulates fetal glucagon secretion. However, the fetal glycemic response to glucagon is blunted, probably due to reduced hepatic glucagon receptors.
Corticosteroids are essential for fetal growth and maturation, and fetal levels rise near parturition, contributing to fetal organ maturation (lung, liver, kidneys, and thymus) and slowing fetal growth. Exogenous maternal steroid administration diminishes human fetal growth, perhaps via IGF axis suppression.
Like IGFs, other growth factors, including epidermal growth factor (EGF), transforming growth factor, fibroblast growth factor, and nerve growth factor, are expressed during embryonic development and morphogenesis. EGF affects lung growth and secondary palate differentiation, while sympathetic adrenergic system development is nerve growth factor dependent. Similarly, the fetal thyroid is not important for overall fetal growth but is important for central nervous system development. These growth factors and their receptors are essential to placental growth and function.
Placental growth is also regulated by growth factors as well as cytokines which exert local effects, promoting proliferation and differentiation through autocrine and/or paracrine actions. EGF promotes cell proliferation, invasion, or differentiation, depending on gestational age. Hepatocyte growth factor and vascular endothelial growth factor (VEGF) stimulate trophoblast DNA replication, whereas transforming growth factor beta suppresses cytoplast invasion and endocrine differentiation. Growth factor receptors and intracellular signaling proteins and transcription factors are expressed in the placenta. Alterations in growth factors or their receptors correlate with placental and fetal growth restriction.
The complexity of fetal/placental growth regulation has been elucidated from studies of transgenic and mutant mice. One example is EGF, a potent mitogen in human placenta. EGF mediates implantation, stimulates syncytiotrophoblast differentiation, and modulates human chorionic gonadotropin (hCG) and human placental lactogen secretion. EGF effects are mediated by EGF receptor (EGF-R), and EGF-R is expressed on apical microvillus plasma membrane fractions from early, middle, and term placentas. 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 parallels intrauterine growth restriction, targeted EGF-R disruption causes fetal death due to placental defects, and EGF-R overexpression causes placental enlargement .
Fetal Cardiovascular System
Development
The heart begins as a simple contractile tube early in the fourth week. During weeks 5 to 8, the single-lumen heart tube is converted into the four-chambered heart through a process of cardiac looping (folding), remodeling, and partitioning. However, an opening in the interatrial septum is retained as the foramen ovale and serves as a right-to-left shunt during fetal life.
During the fourth embryonic week, three primary circulations characterize the vascular system. The aortic/cardinal circulation contributes to the fetal circulatory system, including the left sixth aortic (pulmonary) arch that connects the pulmonary trunk to the aorta as the ductus arteriosus. The ductus arteriosus functions as a right-to-left shunt for right ventricular (RV) output to the aorta and fetal and placental circulations. The vitelline circulation develops with the yolk sac and contributes to the gastrointestinal (GI) tract, spleen, pancreas, and liver vasculature. The allantoic circulation forms the placental circulation, composed 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 typically retained. Rearrangement of the liver vascular plexus forms the ductus venosus, a venous shunt that allows at least half of the umbilical blood to bypass the liver and enter the inferior vena cava.
Placental gas exchange provides well-oxygenated blood to the umbilical vein that delivers blood to the ductus venosus, small branches to the left lobe of the liver, and a major branch to the right lobe ( Fig. 2.1 ). Although ductus venosus blood and hepatic portal/fetal trunk bloods enter the inferior vena cava and right atrium, little mixing occurs. This stream of well-oxygenated ductus venosus blood is preferentially directed across the interatrial septum via the foramen ovale into the left atrium ( Fig. 2.2 ; see also Fig. 2.1 ). Thus left atrial filling results from umbilical vein–ductus venosus blood, with a small contribution from pulmonary venous flow. As a result, blood with the highest oxygen content is delivered to the left atrium, left ventricle (LV), and ultimately the carotid and vertebral circulations and the brain. The remaining mixed inferior vena cava blood is directed through the tricuspid valve (see Fig. 2.1 ) into the RV (see Fig. 2.2 ), accompanied by venous return from the superior vena cava and coronary sinus. The high pulmonary vascular resistance and pulmonary artery pressure directs most of the RV output through the ductus arteriosus and into the aorta and fetal and placental circulations.
Fetal Heart
In the adult the cardiovascular system includes an RV-driven low-pressure pulmonary circuit and an LV-driven high-pressure pulmonary circuit with the two ventricles working in series. Equal volumes of blood are delivered into the pulmonary and systemic circulations with contraction of each ventricle. Cardiac output is a function of stroke volume and heart rate, and for a 70-kg adult man averages 72 mL/min/kg. Cardiac output also varies with changes in stroke volume, determined by venous return (preload), pulmonary artery and aortic pressures (afterload), and contractility.
In the fetus, unique vascular 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 RV and LV function as two pumps in parallel, rather than in series, and cardiac output is described as the combined ventricular output (CVO). RV output exceeds 60% of biventricular output and is directed through the ductus arteriosus to the descending aorta (see Fig. 2.2 ). Fetal LV output averages 120 mL/min/kg body weight and thus total fetal cardiac output greater than 300 mL/min/kg. Hepatic blood flow derives principally from the umbilical vein and, to a lesser extent, the portal vein and represents approximately 25% of the total venous return to the heart.
The placenta receives approximately 40% of the CVO. Third-trimester umbilical blood flow increases proportionate to fetal growth as increases in villous capillary number and angiogenic peptides such as vascular endothelial growth factor (VEGF) contribute to gestation-dependent increases in umbilical blood flow. Short-term changes in umbilical blood flow are regulated by perfusion pressure, and there is a linear relationship between flow and perfusion pressure. Small (2 to 3 mm Hg) increases in umbilical vein pressure evoke proportional decreases in umbilical blood flow but increases in uterine tone affect both vessels without changing umbilical blood flow. The fetoplacental circulation is resistant to vasoconstrictive effects of infused pressor agents, although endogenous vasoactive autacoids including nitric oxide and endothelin-1 may be important. Thus, despite changes in fetal blood flow distribution and increases in blood pressure during acute hypoxia, umbilical blood flow is maintained over a wide range of oxygen tensions unless cardiac output decreases.
Umbilical vein blood, hepatic portal blood, and blood returning from the lower body contribute approximately 69% of the cardiac output entering the right atrium from the inferior vena cava. Due to the high pulmonary vascular resistance, pulmonary venous return to the left atrium is low (approximately 7% of CVO). Thus foramen ovale flow is the primary source of left atrial filling or approximately one-third (27%) of the CVO. The left atrium accounts for approximately 34% (27% + 7%) of the CVO. Inferior vena cava venous return (69% of CVO) minus the portion shunted across the foramen ovale (27%) leaves 42% in the right atrium and contributes to RV output. With 21% from the superior vena cava and 3% from the coronary circulation, RV output is 66% of the CVO. Only 7% of RV output enters the pulmonary circulation, leaving 59% entering the aorta via the ductus arteriosus, with 10% from the LV. Thus 69% of the CVO reaches the descending aorta, and 40% accounts for placental flow, with the remainder distributed to the fetal abdominal organs and lower body.
Coronary blood flow to the myocardium reflects the greater stroke volume of the RV, RV free wall and septal blood flows are higher than in the LV, and fetal ventricular wall thickness is greater on the right side relative to the left. Fetal ventricular output depends on heart rate, pulmonary artery and aortic pressures, and contractility. The steep ascending limb represents the length–active tension relationship for RV cardiac muscle. Normally, fetal right atrial pressure resides at the ascending limb break point, and pressure increases do not increase stroke volume. Thus Starling mechanisms are limited and decreases in venous return and right atrial pressure decrease stroke volume. The fetal RV has a greater radius/wall thickness ratio and produces increased wall stress in systole as compared to the LV. Because stroke volume decreases when afterload increases, the RV is sensitive to afterload, characterized by a linear inverse relationship between stroke volume and pulmonary artery pressure.
The relationship between atrial pressure and stroke volume in the LV is similar to the RV, although some preload reserve remains. However, the fetal LV is not sensitive to afterload. Newborn increases in systemic blood pressure do not limit LV stroke volume, and LV output increases to meet the needs of the newborn circulation. Although Starling mechanism–related increases in stroke volume are limited, late-gestation fetal heart β-adrenergic receptor numbers are similar to the adult, and circulating catecholamine–induced increases in contractility may increase stroke volume by 50%.
The fetal heart rate (FHR) averages more than twofold greater than resting adult heart rates , although analysis confined to episodes of low heart rate variability shows mean heart rate decreases from 30 weeks to term. Mean heart rate variability over 24 hours includes a nadir between 2 am and 6 am and a peak between 8 am and 10 am . Most FHR accelerations occur simultaneously with limb movement, which primarily reflects central brainstem output, although movement-related decreases in venous return and a reflex tachycardia may also contribute to heart rate accelerations. Because ventricular stroke volumes decrease with increasing heart rate, fetal cardiac output remains constant over a heart rate range of 120 to 180 beats/min.
Coincident with the first breath, alveolar expansion and increased alveolar capillary oxygen tension decreases pulmonary microvascular resistance, pulmonary artery pressure, right atrial afterload, and right atrial pressure. In addition, the increase in pulmonary flow and venous return increases left atrial pressure. The combined decreased right atrial pressure and increased left atrial pressure evoke physiologic foramen ovale closure. The return of the highly oxygenated blood from the lungs to the left atrium, LV, and aorta and the decrease in pulmonary vascular resistance, and hence pulmonary trunk pressure, allows backflow of oxygen-rich blood into the ductus arteriosus. This increase in ductus arteriosus oxygen tension alters the ductus response to prostaglandins and causes a localized vasoconstriction. Concurrent spontaneous constriction (or clamping) of the umbilical cord stops placental blood flow, reduces venous return, and perhaps augments the decrease in right atrial pressure.
Regulation of Cardiovascular Function
Autonomic Regulation
The sympathetic and parasympathetic systems regulate FHR, cardiac contractility, and vascular tone. The fetal sympathetic system develops early, followed by the parasympathetic system. By the third trimester, increasing parasympathetic tone decreases FHR and FHR increases during parasympathetic blockade with atropine. Opposing sympathetic and parasympathetic inputs to the fetal heart contribute to R-R interval variability and to basal heart rate variability. However, even when sympathetic and parasympathetic inputs are removed, a level of variability remains.
Fetal sympathetic innervation is not essential for blood pressure maintenance when circulating catecholamines are present. Nevertheless, fine control of blood pressure and FHR requires an intact sympathetic system. Adrenergic innervation absence negates expected hypoxia-induced increases in peripheral, renal, and splanchnic bed vascular resistances and blood pressure. However, hypoxia-related changes in pulmonary, myocardial, adrenal, and brain blood flows occur in the absence of sympathetic innervation, indicating both local and endocrine effects contribute to blood flow regulation in these organs.
Fetal baroreflex sensitivity is blunted relative to the adult. However, fetal baroreflex sensitivity more than doubles in late gestation. Although the FHR set point does not depend on intact baroreceptors, FHR variability increases in arterial baroreceptor absence, similar to fetal blood pressure. Thus fetal arterial baroreceptors buffer variations in fetal blood pressure during body or breathing movements, and changes in baroreceptor tone account for the late gestation increase in fetal mean blood pressure. In the absence of functional chemoreceptors, mean arterial pressure is maintained while peripheral blood flow increases. Thus peripheral arterial chemoreceptors may contribute to resting peripheral vascular tone. Peripheral arterial chemoreceptors also are important components in fetal reflex responses to hypoxia because the initial hypoxia-induced bradycardia is absent without functional chemoreceptors.
Fetal Hemoglobin
The fetus exists in a state of aerobic metabolism, despite arterial blood PO 2 values in the 20 to 35 mm Hg range. Adequate fetal tissue oxygenation occurs by several mechanisms. Higher fetal cardiac output and organ blood flows are primary, but higher hemoglobin concentration and increased oxygen-carrying capacity of fetal hemoglobin (HgbF) contribute. The leftward shift in the fetal oxygen dissociation curve ( Fig. 2.3 ) shows increased fetal blood oxygen saturation relative to oxygen tension. At a partial pressure of 26.5 mm Hg, adult blood oxygen saturation is 50%, whereas fetal oxygen saturation is 70%.
The basis for HgbF increased oxygen affinity is the effect of organic phosphate 2,3-diphosphoglycerate (2,3-DPG). The HgbF tetramer contains two α-chains (identical to adult) and two γ-chains, which differ from the β-chains of adult hemoglobin (HgbA) in 39 of 146 amino acid residues. Differences include substitution of serine in the HgbF γ-chain for histidine at the HgbA β-143 position near the entrance to the hemoglobin tetramer central cavity. In adults the positively charged histidine imidazole group binds the negatively charged 2,3-DPG, stabilizing the deoxyhemoglobin tetramer. In contrast, serine is nonionized, minimally interacts with 2,3-DPG, and the resulting increase in HgbF oxygen affinity shifts the dissociation curve to the left. The oxygen affinities for HgbA or HgbF are similar if stripped of organic phosphates, whereas 2,3-DPG addition decreases HgbA oxygen affinity to a greater extent than HgbF. Thus, despite similar overall oxygen affinities, differences in 2,3-DPG interaction increases HgbF oxygen affinity.
After 26 weeks’ gestation, fetal HgbF decreases linearly from 100% to approximately 70% and HgbA increases to 30% at term. Although the basis for this switch from γ- to β-globin synthesis is not clear, understanding human globin gene regulation has provided important insights into several HgbF disorders, including the thalassemias and sickle cell anemia.
Amniotic Fluid Volume
Amniotic fluid volume (AFV) increases from 250 to 800 mL between 16 and 32 weeks’ gestation, remains stable up to 39 weeks, and declines to 500 mL at 42 weeks (see Fig. 28.1 ). The initial amniotic fluid source is uncertain. Possibilities include a transudate of maternal plasma through the chorioamnion or a transudate across fetal skin before keratinization. In the second trimester the fetus becomes the primary determinant of amniotic fluid dynamics, and AFV is maintained by fetal fluid production (lung liquid and urine) and fluid resorption (fetal swallowing and flow across the amniotic and/or chorionic membranes) ( Fig. 2.4 ).
The fetal lung secretes 300 to 400 mL/day of fluid near term. Chloride is secreted by alveolar capillary endothelial cells into the alveolar lumen and water follows. Thus lung fluid represents a protein-free transudate isosmotic with fetal plasma. Changes in fetal body fluid homeostasis do not affect lung fluid secretion, but lung fluid maintains lung expansion and facilitates pulmonary growth. Lung fluid resorption occurs at parturition to facilitate alveolar gas exchange , and fetal hormones that increase during labor (i.e., catecholamines, arginine vasopressin [AVP]) also decrease lung fluid production. Absent lung fluid reabsorption may explain transient tachypnea of the newborn, or “wet lung,” in infants delivered by cesarean section without labor.
Fetal urine is the primary source of amniotic fluid between 20 and 40 weeks’ gestation, with values of 400 to 1200 mL/day at term. The normally hypotonic fetal urine accounts for amniotic fluid hypotonicity in late gestation. Numerous fetal hormones, including AVP, atrial natriuretic factor (ANF), angiotensin II (AII), aldosterone, and prostaglandins, can alter fetal renal blood flow, glomerular filtration rate (GFR), and urine flow. Fetal stress-induced endocrine-mediated reductions in fetal urine flow may connect fetal hypoxia and oligohydramnios. Fetal kidney regulation is discussed under “Fetal Kidney” later in this chapter.
Fetal swallowing is a major route of amniotic fluid resorption, although swallowed fluid contains a mixture of amniotic and tracheal fluids. Human fetal swallowing occurs by 18 weeks’ gestation, with daily swallowed volumes of 200 to 500 mL near term. Similar to fetal urine flow, daily swallowed volumes (per body weight) are markedly greater than adult values. Fetal swallowing occurs during active sleep states associated with respiratory and eye movements. Swallowing frequency and volume swallowed increase with fetal plasma hypertonicity, indicating an intact thirst mechanism.
Amniotic fluid hypotonicity raises the potential for bulk water or intramembranous flow from amniotic fluid to fetal placental vessels. Intramembranous flow may balance fetal urine and lung-liquid production with fetal swallowing to maintain normal AFVs . Although membrane water transfer mechanisms remain undefined, placental and fetal membranes express aquaporins 1, 3, 8, and 9, and mice deficient in aquaporin 1 develop polyhydramnios. Aquaporins 1 and 3, important in transplacental water flow, are regulated by AVP and by cyclic adenosine monophosphate (cAMP), and their expression changes throughout gestation.
Hormonal Regulation of Amniotic Fluid
Adrenocorticotropic hormone (ACTH) and catecholamines are discussed in the sections describing the fetal adrenal and thyroid glands later in this chapter.
Arginine Vasopressin
AVP is present in the human fetal neurohypophysis, and ovine fetal plasma AVP levels increase appropriately in response to changes in fetal plasma osmolality induced directly in the fetus or via changes in maternal osmolality. As in adults, fetal AVP secretion is regulated by osmoreceptor and volume/baroreceptor pathways. Hypoxia-induced AVP secretion responsiveness increases during the last half of gestation. Thus fetal AVP responsiveness to hypoxia is augmented relative to the adult (as much as 40-fold), and hypoxemia is the most potent stimulus known for fetal AVP secretion.
Fetal AVP infusion includes dose-dependent increases in mean blood pressure and decreases in heart rate at plasma levels well below those required for similar effects in adults. Receptors (V 1 ) distinct from those mediating AVP antidiuretic effects in the kidney (V 2 ) mediate AVP-induced fetal circulatory adjustments during hemorrhage, hypotension, and hypoxia. Corticotropin-releasing factor (CRF) effects of AVP may contribute to hypoxia-induced increases in plasma ACTH and cortisol levels. In addition to FHR, cardiac output, and arterial blood pressure, AVP-induced changes in peripheral, placental, myocardial, and cerebral blood flows directly parallel the cardiovascular changes associated with acute hypoxia. Because AVP receptor blockade attenuates these cardiovascular changes, AVP effects on cardiac output distribution may facilitate fetal oxygen availability during hypoxic challenges. However, other hypoxia-related responses, including decreases in renal and pulmonary blood flows and increased adrenal blood flow, are not mediated by AVP.
Renin-Angiotensin II
Fetal plasma renin levels are typically elevated during late gestation. Changes in tubular sodium concentration; reductions in blood volume, vascular pressure, or renal perfusion pressure; and hypoxemia increase fetal plasma renin activity. As in adults, changes in fetal renal perfusion pressure alter plasma renin activity and renal sympathetic nerve activity directly modulates fetal renin gene expression. Although fetal plasma AII levels respond to changes in blood volume and hypoxemia, fetal AII and aldosterone levels do not parallel plasma renin activity. This apparent uncoupling of the fetal renin-angiotensin-aldosterone system may relate to placental AII clearance. In addition, limited pulmonary blood flow and angiotensin-converting enzyme (ACE) availability and ANF-induced inhibition of aldosterone secretion may contribute. Thus reduced AII production and aldosterone responses to AII, augmented AII and aldosterone clearances, and reduced AII and aldosterone feedback inhibition may account for elevated renin secretion.
In contrast to AVP-induced bradycardia, fetal AII infusion increases fetal mean arterial blood pressure and heart rate (after an initial reflex bradycardia) through direct effects on the heart and decreased baroreflex responsiveness. Both hormones increase fetal blood pressure consistent with the levels seen with hypoxemia. However, AII does not reduce peripheral blood flow, perhaps because circulation to muscle, skin, and bone is under maximum response to AII. AII infusions decrease renal blood flow and increase umbilical vascular resistance with no change in placental blood flow. The adult kidney contains both AII-receptor subtypes (AT 1 and AT 2 ), whereas only the AT 2 subtype is present in the human fetal kidney. Maturational differences in AII receptor subtype expression are consistent with earlier studies demonstrating differing AII effects on fetal renal and peripheral vascular beds.
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