The human placenta is a dynamic organ with vast changes from initial implantation in the uterine wall until birth. The human embryo initially implants into the uterus at the blastocyst stage. The human placenta grows initially in a low-oxygen environment, with PO₂ <20 mm Hg, following the historical development of species from the pre-oxygen atmosphere epoch. Prior to 10 weeks gestation, the uterine spiral arteries are blocked by extravillous trophoblasts, with an absence of blood flow on Doppler and in vivo oxygen tension <20 mm Hg (1). The placenta and burgeoning fetus are supplied by secretions from the endometrial glands, and perhaps should be described as deciduochorial during this time period (2). The low-oxygen milieu stimulates placental angiogenesis via hypoxia inducible factor-1α and its effect on vascular endothelial growth factor and placental growth factor protects against damage and congenital abnormalities during organogenesis by reactive oxygen species (ROS). ROS are highly reactive oxygen-based molecules with an unpaired valence shell electron that damage DNA, lipids, proteins, and enzymes. The endometrial endovascular trophoblastic plugs are normally lost at 10 to 12 weeks gestation with maternal blood flow occurring peripherally, and then centrally on the placenta. The remodeling results in high volume, low-resistance maternal blood flow within the intervillous space. Improper remodeling at this secondary invasion stage is a precursor of preeclampsia. Intervillous oxygen tension rises to 40 to 80 mm Hg, with higher oxygen tension in the central part of the placental lobule and lower at the periphery of the placenta (Fig. 2-1). The placenta adapts to changes in maternal blood flow and increased oxygen tension. The placenta increases the antioxidant enzymes catalase, glutathione peroxidase, and superoxide dismutase within the placenta to deal with the increase of ROS and oxidative stress of the increased blood flow and increased PO₂. Insufficient trophoblast invasion and lack of proper vascular remodeling in early pregnancy produces premature blood flow and increased oxygenation in the intervillous space, which actually reduces maternal blood flow later in pregnancy (3).

The human placenta is classically described as a villous haemomonochorial type with only one layer of syncytiotrophoblast intervening between maternal and fetal circulation. The villi are projections of fetal tissue surrounded by chorion that are exposed to circulating maternal blood. The chorion is the outermost fetal tissue layer. At term, the human placenta weighs about 500 g and is disc shaped, with a diameter of approximately 20 cm and a thickness of 3 cm. The normal fetal-to-placental-weight ratio is approximately 6:1 at term. Before this, the placenta is relatively heavier and the ratio is less (e.g., 3:1 at 30 weeks of gestation).

Circulation of blood through the placenta is illustrated in Figure 2-2. The maternal blood is carried by the uterine arteries, which divide into spiral arteries in the basal plate. Blood is spurted from these arteries into the intervillous space. It traverses upward toward the chorionic plate, passing fetal villi where exchange takes place, and finally drains back to veins in the basal plate.

The fetal circulation within the placenta is quite different. Blood is carried into the placenta by two umbilical arteries that successively divide into smaller vessels within the fetal villi. Ultimately, capillaries traverse the tips of the fetal villi where exchange occurs with maternal blood within the intervillous space. The maternal–fetal blood flow pattern and vascular geometry consist more like a cross-current exchanger than the more efficient counter-current exchange mechanism. The blood is finally collected into a single umbilical vein in the umbilical cord, and this carries the oxygen, nutrient-rich and waste-poor blood to the fetus.

Fetal and maternal blood streams are separated by three microscopic tissue layers in the human placenta. The first layer is the fetal trophoblast, which consists of cytotrophoblast and syncytiotrophoblast. The syncytiotrophoblast is the metabolically active part of the placenta, where much of the endocrine function of the placenta occurs. The other tissue layers are fetal connective tissue, which serves to support the villi, and the endothelium of fetal capillaries (Fig. 2-3). As the placenta and fetus grow, the diffusion distance decreases as the rate of fetal capillary growth in the villi exceeds the trophoblast growth; thus placental oxygen diffusive conductance is matched to fetal weight (demand), which is also true for other species (4). At term, the ratio of cytotrophoblast to syncytiotrophoblast is significantly lower than earlier in pregnancy.

The quantitative relationship of fetal and maternal blood flow and relative concentrations of substances at any one point in the human placenta are quite complex. The relative rates of blood flow in various areas of the placenta are also quite variable, and there is a continually changing concentration of nutrients and waste materials in various areas of the placenta as exchange occurs (5).

Substances are exchanged across the placental membrane by five mechanisms (Fig. 2-4): Diffusion (passive and facilitated), active transport, bulk flow, pinocytosis/phagocytosis, and barrier breaks (6). The placenta is a dynamic organ throughout pregnancy and these mechanisms of transfer vary at different stages of gestation. Placental stress states such as acidosis may cause placental cell damage, increasing placental permeability of substances (e.g., local anesthetics) (7).

When limitations of placental transfer occur in the human, they usually are first recognized as limitations of those substances that are exchanged by passive diffusion. For example, an acute decrease in placental function limits exchange of oxygen to and carbon dioxide between the fetus and the
mother, resulting in fetal asphyxia. A more chronic decrease in placental function may limit the transfer of substances necessary for growth (e.g., carbohydrates), thus leading to IUGR. Hence, the process of diffusion is examined in some detail.

Fick’s equation describes the physicochemical process of passive diffusion:

Rate of transfer (V_diff) = (concentration gradient × area × permeability)/membrane thickness

Each of the factors determining rate of passage of substances by diffusion is considered in turn. Note that some factors affect the steady state concentrations and while others have an effect predominantly on the immediate-, short-term transfer rates.

Since uterine blood flow is one of the prime determinants of passage of a number of critical substances across the placenta, its characteristics, the factors affecting it, and the effects of anesthesia on uterine blood flow are discussed in the latter portion of this chapter.

Uterine blood flow rises progressively throughout pregnancy from 50 mL/min at 10 weeks to approximately 700 mL/min at term (Fig. 2-7). This represents about 10% of the maternal cardiac output. Approximately 70% to 90% of the uterine blood flow passes through the intervillous space, and the remainder largely supplies the myometrium. About 150 mL blood is in the intervillous space at term.

The uterine vascular bed is thought to be almost maximally dilated under normal conditions, with little capacity to dilate further (18). It is not autoregulated, so flow is proportional to the mean perfusion pressure. However, it is capable of marked vasoconstriction by α-adrenergic action. The uterine blood flow is determined by the following relationship:

Many factors affect uterine blood flow. A number of causes of decreased uterine blood flow are shown in Table 2-1.

Uterine contractions decrease uterine blood flow as a result of increased uterine venous pressure brought about by increased intramural pressure of the uterus. There may also be a decrease in uterine arterial pressure with contractions. Uterine hypertonus or tachysystole (too frequent contractions) causes a decreased uterine blood flow through the same mechanism.

In sheep, if uterine arterial perfusion pressure is altered without changing the resistance of the uterine vascular bed, there is a direct relationship between uterine blood flow and the pressure (18). Hence, hypotension through any of the mechanisms noted in Table 2-1 will cause a decrease in blood flow.

In the case of maternal arterial hypertension, both chronic and acute, there is a concomitant increased vascular resistance by the uterine vascular bed, decreasing uterine blood flow. Either endogenous or exogenous vasoconstriction results in decreased blood flow because of increased uterine vascular resistance.

There are a few useful means of increasing uterine blood flow when it is known to be suboptimal. The most important clinical considerations are the avoidance or correction of factors responsible for an acute decrease in blood flow (e.g., excessive uterine activity or maternal hypotension). Uterine blood flow can generally be increased by decreasing uterine tone (if increased), by increasing maternal BP (if low), decreasing uterine vascular resistance (if increased), and by using hemodynamic alterations which increase cardiac output (see Table 2-2).

Some of the β-mimetic agents that are used as uterine relaxants for preterm labor may increase uterine blood flow, but this effect, if it occurs, is small and may only be a result of decreased uterine tonus. There are a number of experimental means of increasing uterine blood flow, sometimes transiently, but these have no real clinical use. Examples of such treatments include estrogens, acetylcholine, nitroglycerin, cyanide, ischemia, and mild hypoxia, the latter either acute or chronic (19). Antihypertensives such as hydralazine can improve uterine blood flow. Similarly, epidural anesthesia during labor will increase uterine blood flow.

Clinically, it has been known for many years that maternal bed rest may improve the outcome in suspected fetal growth restriction. There is some evidence that bed rest does improve fetal growth, as evidenced by increasing estriol excretion (20).

The umbilical blood flow in the undisturbed fetus at term is about 120 mL/kg/min or 360 mL/min by noninvasive ultrasound techniques (21). Lower values are obtained immediately after birth, but are probably affected by cord manipulation during the birth process. Ultrasound can be used to calculate the peak systolic-to-diastolic (S/D) ratio, which is a reflection of vascular resistance distal to the point of measurement.

The umbilical blood flow in human is considerably less than that of sheep, where it is approximately 200 mL/kg/min (22). The differences may be explained by the somewhat higher metabolic rate of sheep (body temperature 39°C) and differences in hemoglobin concentrations (sheep, 10 g/dL vs. human, 15 g/dL). It is important to recognize this species difference because the bulk of our information regarding fetal circulatory physiology comes from the chronically instrumented sheep fetus. In sheep, the umbilical blood flow is approximately 45% of the combined ventricular output (22), and about 20% of this blood flow is “shunted,” that is, it does not exchange with maternal blood (5).

Umbilical blood flow is unaffected by acute moderate hypoxia but is decreased by severe hypoxia (23). Only the most proximal segment of the umbilical cord is innervated; however, the smooth muscle cells are responsive to paracrine effects and umbilical blood flow decreases with the administration of catecholamines. It is also decreased by acute cord occlusion. There are no known means of increasing umbilical flow in patients in whom it is thought to be decreased chronically. However, certain fetal heart rate patterns (i.e., variable decelerations) have been ascribed to transient umbilical cord compression in the fetus during labor. Manipulation of maternal position either to the lateral or Trendelenburg position can sometimes abolish these patterns, the implication being that cord compression has been relieved.

Most stillbirths and cases of fetal depression are likely the result of inadequate exchange of the respiratory gases. Oxygen has the lowest storage-to-utilization ratio of any nutrient in the fetus. From animal data, it can be calculated that a term fetus has approximately 42 mL of oxygen with a normal oxygen consumption of approximately 21 mL/min (23). In theory, the fetus has a 2-minute supply of oxygen. However, fetuses do not consume the total quantity of oxygen in their body within 2 minutes, nor do they die after this time. In fact, irreversible brain damage does not start to occur until about 10 minutes have elapsed (29). This is because the fetus has a number of important compensatory mechanisms that enable it to survive on a lesser quantity of oxygen for longer periods. Clinical situations in which there is total cessation of oxygen delivery are rare. These include sudden total abruption of the placenta or complete umbilical cord compression, generally after prolapse of the cord.

Animal experiments show that the compensations that occur in the hypoxic fetus are (a) redistribution of blood flow to vital organs, including heart, brain, and placenta; (b) decreased total oxygen consumption (e.g., with moderate hypoxia, the fetal oxygen consumption drops to 50% of the normal level); and (c) dependence of certain vascular beds on anaerobic metabolism. These compensatory mechanisms appear to be initiated with mild hypoxia and result in the maintenance of oxygen supply to vital organs during times of oxygen limitation (23).

The factors that determine oxygen transfer from mother to fetus are listed in Table 2-3. Since the transfer of oxygen to the fetus depends on rates of blood flow and not limitations to diffusion, the respective blood flow on each side of the placenta assumes major importance for maintenance of fetal oxygenation. Animal studies suggest that in the normal placenta there is a “safety factor” of approximately 50% of the total uterine blood flow. That is, the uterine blood flow will drop to half its normal value before severe fetal acidosis becomes evident (30) and oxygen uptake declines (31). This applies only to the normal situation with normal placental reserve and is unlikely to be the case in pathologic situations, such as in the infant of a hypertensive mother. In such situations, the placental function may be adequate for oxygenation but not for fetal growth, and a growth-restricted infant may result from such a pregnancy. Furthermore, with superimposition of uterine contractions on such a fetus, there may be transient inadequacy of uterine blood flow during the uterine contractions; this may be recognized by responses of the fetal heart rate (i.e., late decelerations).

During labor, uterine contractions reduce uterine blood flow and can lead to episodes of hypoxia–reperfusion stress; increased levels of lipid peroxidation were noted compared to elective cesarean section (2). The increased activity of xanthine oxidase, a marker of hypoxia–reperfusion, and decreased vitamin C levels, which typically scavenge ROS, help compensate. Preeclamptic placentas also show these changes (2). Indeed, the oxidative stress that occurs in preeclampsia leads to release of proinflammatory cytokines and angiogenic factors that affect the maternal endothelial cells. Normal placental tissue exposed to hypoxia showed similar metabolites as preeclamptic placental tissue, supporting the role of hypoxia and oxidative stress, as well as possible future diagnostic testing (32).

Additional important determinants of fetal oxygenation include oxygen tension in maternal arterial and fetal arterial blood. In general, maternal arterial oxygen tension depends on adequate ventilation and pulmonary integrity. Disruptions of this function are relatively rare in obstetrics, although they can occur with pulmonary diseases such as asthma, with congestive heart failure, or in mothers with congenital cardiac defects. The oxygen affinity and oxygen capacity of maternal and fetal blood are also important determinants of fetal oxygen transfer. At a given oxygen tension, the quantity of oxygen carried by blood depends on the oxygen capacity, which depends on the hemoglobin concentration and oxygen affinity. The oxygen affinity of fetal hemoglobin (p50 at 18 mm Hg) is greater than that of maternal hemoglobin (p50 at 27 mm Hg) (Fig. 2-8). That is, the oxygen dissociation curve of the fetus is to the left of that of the mother. In addition, the hemoglobin concentration of fetal blood is approximately 15 g/100 mL in the term fetus, whereas that of the mother is approximately 12 g/100 mL. Both of these factors, an increased oxygen affinity and higher oxygen capacity, confer advantages to the fetus for oxygen uptake across the placenta (Fig. 2-9). During acidosis and increased tissue oxygen demand, fetal hemoglobin was more efficient in delivering oxygen to tissues (33).

Both the Bohr and Haldane effects enhance the exchange of oxygen and carbon dioxide across the placenta (Fig. 2-10). The Bohr effect describes the shift of the hemoglobin dissociation curve to the right by hydrogen ions, which reduces the affinity of hemoglobin for oxygen. The Haldane effect
describes the increased ability of deoxygenated blood to carry more carbon dioxide. The carbon dioxide from the fetal side diffuses into the maternal blood, causing an increase in maternal intervillous hydrogen ion, which reduces the affinity of maternal hemoglobin for oxygen, increasing oxygen transfer to the fetus. At the same time, the relative decrease in carbon dioxide on the fetal side causes the fetal blood to become slightly more alkaline, increasing the fetal hemoglobin uptake of oxygen. Since the Bohr effect occurs on both sides of oxygen delivery/uptake, it has been called the double Bohr effect. Likewise, the double Haldane effect describes maternal and fetal changes in carbon dioxide and oxygen uptake. The fetal hemoglobin becomes oxygenated and releases carbon dioxide, which has increased binding to the maternal hemoglobin that has just deoxygenated. The double Bohr effect occurs functionally by the slight opening and closing of the hemoglobin chain allowing or blocking entry of oxygen to the iron-heme–binding site. Carbon dioxide binding to the sentinel histidine on the hemoglobin chain can block access of oxygen to the heme-binding site (see Fig. 2-10).

Since most measurements have been made in the human fetus during or after labor, the values of oxygen saturation, oxygen tension, and pH are generally decreased compared with those of the mother. In fact, investigations on chronically instrumented animals have shown that the oxygen saturation and content of fetal blood and acid–base status is very close to that of maternal blood; only the Po₂ is lower. Note that the quantity of oxygen delivered or taken up by each 100 mL of circulating blood in the placenta is approximately equal in the mother and fetus. A number of additional miscellaneous factors determine the rate of oxygen transfer across the placenta; they are listed in Table 2-3 as the last six determinants. They appear to be relatively minor compared with the major factors already outlined.

Carbon dioxide crosses the placenta even more readily than does oxygen; the diffusion coefficient is 20 times greater than oxygen. In general, the determinants for oxygen transfer also apply to carbon dioxide transfer across the placenta. It is limited by rate of blood flow and not by resistance to diffusion. The carbon dioxide tension in fetal blood in the undisturbed state is close to 40 mm Hg (5). It is well known that the maternal arterial carbon dioxide tension is approximately 34 mm Hg, and the mother is in a state of compensated respiratory alkalosis (lowered serum bicarbonate by the kidneys). The pH of fetal blood under undisturbed conditions is probably close to 7.4, and the bicarbonate concentration is close to that of maternal blood.

Bicarbonate and the fixed acids cross the placenta much more slowly than does carbon dioxide; that is, equilibration takes a matter of hours rather than seconds. There is a situation analogous to “respiratory acidosis” that occurs in the fetus when blood flow, either uterine or umbilical, is acutely compromised. In such cases, carbon dioxide tension acutely increases causing a drop in pH, but the metabolic acid–base status remains unchanged. This occurs during severe or profound fetal decelerations (called variable decelerations) in association with certain uterine contractions, especially during the second stage of labor. These acid–base changes are generally rapidly resolved with cessation of the contraction and
the bradycardia. However, as noted earlier, if there is a significant oxygen lack that is unrelieved, the fetus will decrease its oxygen consumption, redistribute blood flow, and depend partly on anaerobic metabolism to supply its energy needs, albeit with decreased efficiency. Under these conditions, lactate (an end product of anaerobic metabolism) is produced, resulting in metabolic acidosis. The acidosis may also be aggravated by combined respiratory acidosis because of retained carbon dioxide. Unlike carbon dioxide, lactate is lost slowly from the fetus.

Lactate is transported by specific, pH-dependent carriers, while protons pass to the maternal circulation via channels, lipid diffusion, co-transport, and specific proton-pumping ATPases.

Fetal compromise results from an alteration of normal placental exchange mechanisms. With a knowledge of the components involved in exchange of nutrients and waste materials across the placenta, potential problems can be recognized and corrections made.

The most important components of placental exchange are the rates of blood flow on each side of the placenta and the area available for exchange. Uterine blood flow will decline in the presence of factors causing decreased perfusion pressure or increased uterine vascular resistance. Common clinical occurrences are hypotension, hypertension, endogenous or exogenous vasoconstriction, and severe psychological stress. The uterine vascular bed is not autoregulated and normally has little capacity to dilate further. However, hypertensive states (e.g., preeclampsia) and high catecholamine levels (e.g., stress, pain) can cause increased uterine vascular resistance. During labor, it is most likely that the rate of uterine blood flow is a common limiting factor in cases of fetal compromise because of the intermittent decline in uterine blood flow with each uterine contraction. In addition, transient or persistent umbilical cord compression may cause fetal asphyxia.

Obstetric anesthesia and analgesia may directly affect uterine blood flow or may alter the response of the uteroplacental circulation to noxious stimuli and to various pharmacologic agents (Table 2-4). Uterine blood flow varies directly with the perfusion pressure (i.e., uterine arterial minus

uterine venous pressure) and inversely with uterine vascular resistance. Obstetric anesthesia may affect uterine blood flow by (a) changing the perfusion pressure, that is, altering the uterine arterial or venous pressure; or (b) changing uterine vascular resistance either directly through changes in vascular tone or indirectly by altering uterine contractions or uterine muscle tone; or (c) changing the maternal cardiac output.