Placental Respiratory Gas Exchange and Fetal Oxygenation

Transport of Atmospheric Oxygen to Fetal Tissues

The transport of oxygen (O ₂ ) from the atmosphere to fetal tissues can be visualized as a sequence of six steps that alternate bulk transport with transport by diffusion ( Fig. 14.1 ). This chapter addresses the last four steps of this process. In steps 3 and 5, O ₂ is transported by maternal and fetal blood, respectively.

Oxygen is transported by blood in two forms: free and bound to hemoglobin. In any blood sample, these two forms are in reversible equilibrium. The terminology that is used in describing the components of this equilibrium is summarized in Table 14.1 .

Measurement of Uterine and Umbilical Oxygen Uptakes

The study of fetal physiology in sheep has led to the development of a method for measuring simultaneously, under normal steady-state conditions, uterine and umbilical blood flows and the concentrations of metabolites in maternal arterial, uterine venous, umbilical venous, and umbilical arterial blood. This method allows the calculation of uterine and umbilical oxygen uptakes as two separate entities. The rationale for this calculation, commonly known as the Fick principle, is as follows. In passing through the pregnant uterus, each milliliter of maternal blood gives up a certain amount of oxygen, which can be calculated by measuring the difference in oxygen content between maternal arterial and uterine venous blood. The quantity of oxygen lost by each milliliter of blood is then multiplied by the milliliters of blood flowing through the pregnant uterus to obtain the uterine oxygen uptake. To calculate the rate at which the umbilical circulation takes up oxygen, exactly the same reasoning is applied to the umbilical blood data.

In mathematical terms, uterine O ₂ uptake (μmol•min ⁻¹ ) is given by the following equation:

where F is uterine blood flow (mL•min ⁻¹ ) and (AO ₂ − VO ₂ ) is the arterial-venous difference in O ₂ content across the uterine circulation (μmol•ml ⁻¹ ).

Similarly,

where f is umbilical blood flow, and (γ o ₂ − α o ₂ ) is the difference in O ₂ content between umbilical venous and arterial blood. The instruments that can measure blood O ₂ content directly are rarely used. Instead, measurements of blood O ₂ saturation, O ₂ capacity, and partial pressure of oxygen (P o ₂ ) are commonly used to calculate O ₂ content.

Because oxygen solubility in blood is very low, it is important to note that ordinarily the concentration of free O ₂ is much smaller than the product of O ₂ saturation and O ₂ capacity. Table 14.2 gives a numeric example of these calculations in a near-term ewe breathing atmospheric air. It shows that setting the solubility coefficient of O ₂ in blood to zero would reduce the uterine oxygen uptake estimate by about 3% (1591 versus 1694 μmol•min ⁻¹ ) and the umbilical oxygen uptake estimate by less than 1% (1020 versus 1027 μmol•min ⁻¹ ).

The uterine-umbilical oxygen uptake difference defines the oxygen consumption rate of a tissue mass that includes, in addition to the placental villous tree, the myometrium and the endometrial glands. This tissue mass is called the uteroplacenta .

Umbilical Oxygen Uptake

Measurements of umbilical oxygen uptake define the rate of fetal oxygen consumption. From midgestation to term, fetal O ₂ consumption increases exponentially, correlating with the exponential increase in fetal weight. However, the consumption does not increase in exact proportion to weight. As shown in Table 14.3 , the fetal lamb at midgestation has an oxygen consumption rate per unit of body mass that is about 30% higher than at near term.

The relationship between oxygen consumption and body weight of adult mammals at rest is described fairly accurately by the Brody-Kleiber equation :

where V. o ₂ is the O ₂ consumption rate (μmol•min ⁻¹ ) and BW is the body weight (in kilograms). This equation summarizes three important aspects of mammalian physiology. First, adult mammals of similar body size, such as sheep and humans, have similar basal oxygen consumption rates despite major differences in body composition. Second, small mammals have an enormously higher oxygen consumption per unit of body weight than large mammals. For example, the resting oxygen consumption rate of a 20-g mouse and that of a 600-kg cow are approximately 1100 and 85 μmol•min ⁻¹ •kg ⁻¹ , respectively. Third, at comparable body weight and temperature, homeotherms consume about five times more oxygen than poikilotherms. This information provides a basis for exploring the physiologic meaning of fetal oxygen consumption.

The oxygen consumption rates of near-term bovine and guinea pig fetuses have been estimated to be 300 and 392 μmol•min ⁻¹ •kg ⁻¹ , respectively. Because the guinea pig fetus weighs much less than the bovine fetus (approximately 0.08 versus 25 kg), the Brody-Kleiber equation predicts a four times greater oxygen consumption per unit of fetal body weight in the guinea pig. Clearly, however, this is not the case. This type of evidence has led to the conclusion that, among mammals of different body size, oxygen consumption per unit of body weight is much less variable in prenatal than in postnatal life. Data on fetal heart rate agree with this conclusion. Heart rate is a correlate of O ₂ consumption per unit of body weight. The heart rates of immature fetuses are virtually equal among mammals, irrespective of large differences in body weight.

These data imply a fundamental difference in comparative physiology between small-, medium-, and large-size mammals. In small mammals (adult body weight <1 kg), adaptation to postnatal life requires an increase in oxygen consumption per unit of body weight; in medium- and large-size mammals it requires a decrease. The fetus represents a rate of relatively low energy metabolism within the maternal body of small animals and a rate of relatively high energy metabolism in the maternal body of medium- and large-size animals.

It is not clear why adaptation to postnatal life requires small-size mammals to increase the intensity of resting oxygen consumption to well above the fetal value. By contrast, there is some understanding of why in mammals with greater body size this adaptation entails a decrease in the oxygen consumption per kilogram of body weight. The postnatal environment requires medium- and large-size mammals to develop a heavy bone and muscle structure. In fetal life, the development of this structure is delayed in favor of developing the internal organs. The internal organs have a much higher oxygen consumption rate per unit of weight than do bones and resting muscle. The data in Table 14.4 demonstrate that this organ-specific difference in intensity of oxidative metabolism is already present in fetal life. According to this evidence, one of the reasons the fetuses of medium- and large-size mammals have a higher oxygen consumption per unit of weight than the resting adult is that in the fetus the internal organs are a larger fraction of body weight.

A difference in body composition is the explanation that is generally given for the fact that oxygen consumption per unit of body weight in a newborn baby at rest in a thermoneutral environment is about twice the adult value (approximately 300 versus 150 μmol•min ⁻¹ •kg ⁻¹ ). As a percentage of body weight, the brain is about 12% in the newborn and 2% in the adult human. Note that this figure for oxygen consumption in a newborn human (300 μmol•min ⁻¹ •kg ⁻¹ ) is within the range of values for fetal oxygen consumption that have been measured in experimental animals. This indicates that, in humans, the transition from prenatal to postnatal life is not associated with any immediate and large change in the rate of energy metabolism.

Included in the rate of fetal energy metabolism is the energy cost of growth. The energy cost of protein turnover and accretion in the fetal lamb has been estimated to account for about 18% of oxygen consumption. In a study of severely hypoxic, growth-restricted fetal lambs, umbilical oxygen uptake per kilogram of body weight was reduced only 24% below normal, despite evidence that at the time of measurement the growth rate was virtually zero. Among fetal organs, there is no correlation between oxygen consumption and growth rate (see Table 14.4 ). These findings indicate that the energy cost of growth represents a relatively small fraction of fetal oxidative metabolism. Most of the oxygen consumed by the fetus is used to fuel the rapid ionic and metabolic fluxes that characterize the life of homeotherms.

Normal Fetal Oxygenation

An important aspect of fetal physiology is that during the last third of gestation the fetal organs are perfused by blood having much lower oxygen saturation and P o ₂ values than in postnatal life. At sea level, the O ₂ saturation and P o ₂ of maternal arterial blood are approximately 96% and 100 mm Hg, respectively. By contrast, the blood that carries oxygen to the third-trimester human fetus via the umbilical vein has mean normal O ₂ saturation and P o ₂ values equal to about 81% and 35 mm Hg, respectively. Similarly low values characterize the mean normal oxygenation of umbilical venous blood in sheep ( Table 14.5 ). Furthermore, the structure of the fetal vascular tree is such that fetal arterial blood is formed by mixing the oxygenated blood that flows into the fetal circulation via the umbilical vein with the venous effluent of fetal organs. The only exception is the left hepatic lobe, which is perfused almost exclusively by umbilical venous blood.

In the near-term ovine fetus, the normal mean umbilical arterial oxygen saturation is approximately 55% (see Table 14.5 ). Umbilical arterial oxygenation is identical to that of the blood that supplies oxygen to all the organs perfused via the fetal abdominal aorta.

The blood that perfuses the fetal upper body has a greater oxygenation level than umbilical arterial blood. This difference is caused by a preferential streaming of umbilical venous blood into the left ventricle. In near-term fetal lambs, the difference in oxygen content across the aortic isthmus is 0.45 ± 0.02 mM. This means that the oxygen saturation in the fetal ascending aorta is about 63%. At this saturation, the P o ₂ of ovine fetal blood is about 22 mm Hg.

In conclusion, the oxygenation of a third-trimester fetus would define a state of severe hypoxia in postnatal life. How is it possible, then, for the human and the ovine fetus to have an oxygen consumption rate per kilogram that is about twice the basal adult value? The factor that makes this possible is the output of the fetal heart, which, in the near-term human fetus, is about 460 mL•min ⁻¹ •kg ⁻¹ , ^, much higher than that of the adult heart at rest. For example, in a 50-kg adult human, the output of each ventricle would have to be 11.5 L•min ⁻¹ to match the fetal output, rather than the normal resting cardiac output of about 5 L•min ⁻¹ .

Fetal cardiac output compensates for the low level of fetal oxygenation by maintaining a high ratio of blood flow to oxygen consumption through the circulation of individual fetal organs. Table 14.6 compares the fetal and adult values of this ratio for the brain and the hind limbs of sheep. For each of these organs, the blood flow that is used to maintain a normal oxygen consumption rate is about 2.5 times greater in the fetus than in the adult. This difference in blood flow is not caused by differences in oxygen capacity. In near-term ovine pregnancies, the hemoglobin contents of maternal and fetal blood are not significantly different.

In Ovine Pregnancies Umbilical Venous P o ₂ is a Function of Uterine Venous P o ₂

In near-term pregnant ewes, umbilical venous P o ₂ (i.e., the P o ₂ of oxygenated blood that flows into the fetal circulation via the umbilical vein) varies as a function of uterine venous P o ₂ . Umbilical venous P o ₂ is less than uterine venous P o ₂ , and the uterine-umbilical venous P o ₂ difference remains virtually constant in response to wide acute changes in uterine venous P o ₂ . Fig. 14.2 shows the umbilical venous P o ₂ response to variations in uterine venous P o ₂ induced by changing the percentage of oxygen in maternal inspired air or by shifting the oxyhemoglobin dissociation curve of maternal blood to the right via a decrease in the pH of maternal blood. Fig. 14.3 shows the results of experiments in five animals in which the uterine venous P o ₂ was decreased by decreasing uterine blood flow. The two figures demonstrate a similar umbilical-versus-uterine venous P o ₂ relationship despite the different means that were used to vary uterine venous P o ₂ . Changes in the percentage of oxygen in maternal inspired air cause changes in the P o ₂ and oxygen content in maternal arterial blood, but they have virtually no effect on uterine blood flow. In contrast, a decrease of uterine blood flow does not change the oxygenation of maternal arterial blood. A detailed analysis of the P o ₂ versus blood flow experiment can be found in the original publication.

The evidence that in sheep umbilical venous P o ₂ varies as a function of uterine venous P o ₂ is part of a larger study on the transplacental diffusion of molecules that rapidly cross the placental barrier. In addition to studies of O ₂ and carbon dioxide (CO ₂ ), there have been studies on the transplacental diffusion of tritiated water, antipyrine, and ethanol. These studies have led to the conclusion that the ovine placenta is a venous equilibrator. The prototype of this type of exchange is shown in the upper panel of Fig. 14.4 . It consists of a membrane separating two bloodstreams that flow in the same direction. At the arterial end of the exchanger, maternal arterial blood (A) enters the exchanger with a higher P o ₂ than umbilical arterial blood (i.e., 100 versus 21 torr). This P o ₂ difference drives O ₂ into fetal blood. As the two streams flow concurrently past the membrane, diffusion of O ₂ from the maternal to the fetal stream causes a progressive decrease of P o ₂ in the maternal stream and a progressive increase of P o ₂ in the fetal stream, so that the transmembrane P o ₂ difference trends asymptotically toward zero. A venous equilibrator placenta has two basic properties. First, the P o ₂ at the venous end of the fetal stream cannot be higher than the P o ₂ at the venous end of the maternal stream. Second, the P o ₂ of the fetal venous effluent depends directly on the P o ₂ of the maternal venous effluent and has no direct relation to maternal arterial P o ₂ . In addition to the concurrent exchanger, there are several other types of venous equilibrators. According to histologic studies, and one study of artificial placental perfusion, the ovine placenta is a crosscurrent exchanger.