Oxygen Consumption and General Carbohydrate Metabolism of the Fetus

Introduction

This chapter reviews a number of factors that are involved in control of fetal metabolism, with reference to relationships between fetal energy balance and substrate uptake during the last trimester. This information relies heavily upon research data obtained from a variety of experiments in animals as well as some theoretical considerations. Data from human studies are now also becoming more available than in previous years and are incorporated here when applicable. Because hospitalization of neonates younger than 30 weeks gestation who were very recently in utero is common in newborn intensive care units, understanding of those factors involved in determining fetal metabolic needs may be of use in these settings. The term metabolism (derived from the Greek metabole , a change) is used in this context to describe a number of biochemical reactions that illustrate chemical processes in the fetus that alter carbon-containing substrates to synthesize tissue (accretion/growth) or provide energy needed for basic homeostasis (fuel/energy).

History and Fetal Energy Requirements

The consumption of oxygen is closely tied to the resting metabolic rate, which, as we will see later, varies with mass in nongrowing adult mammals but not in the fetus or newborn. The first individual who gained insight into the process of metabolism was John Mayow (1640–1679), who noted that the consumption of an undefined substance in air was similar when measured in breathing mammals in a sealed container or during combustion of inert materials. It was not until almost 100 years later that the substance consumed was discovered and named. The discovery of oxygen is attributed to Carl Wilhelm Scheele in 1771 (“fire air”), although both Joseph Priestly (1774, “extra pure air”) and Antoine Lavosier (1775) are also credited. However, it was Lavoisier who named the gas oxygen (from the Greek oxys [sharp acid] and gène [produces]) and demonstrated that in human respiration, oxygen was taken up and converted into another substance he called “fixed air” as part of the metabolism of nutrients. Joseph Black (1775) is credited with the discovery of carbon dioxide shortly thereafter. The fetus was not thought to have any independent metabolism of its own, but in 1786 the surgeon and scientist John Hunter showed that fetal and maternal circulations within the placenta were distinct from each other. Shortly thereafter, Erasmus Darwin, Charles Darwin’s grandfather, surmised correctly in his text Zoonomia (1794) that at least one of the functions of the placenta was to supply the fetus with this newly discovered gas, oxygen, for its own separate metabolic demands.

However, it was not until the late 1800s that fetal blood was demonstrated to contain oxygen derived from mother’s blood, ^, and only in the 1930s did it become possible for the fetal blood oxygen content and hemoglobin saturation to be accurately measured. Fetal oxygen consumption was found to be similar to that of the newborn animal and a maternofetal gradient for oxygen was demonstrated. Even so, mammalian fetuses were thought to live in hypoxic environments ^, because human and animal umbilical venous blood had significantly lower partial pressures than adult arterial blood. This finding led to the “Mount Everest in utero” concept attributed to Sir Joseph Barcroft, and attempts were then made to understand how the fetus adapted to such conditions. Because of the leftward shift in the oxyhemoglobin dissociation curve, ^, elevated levels of fetal (vs. adult) hemoglobin, and increased circulating red cell mass, relatively normal umbilical venous oxygen content (measured by the standard of milliliter or millimole of oxygen per milliliter of blood) was found to be the case.

Parenthetically, it has been demonstrated that acquiring hemoglobin concentrations of 16 to 18 g/dL, similar to those found in the fetus, also appears to confer significant survival advantage for some adults living at high altitude (i.e., 3800 m), another condition placing constraints on arterial blood oxygen tension, although no shifts in the hemoglobin-oxygen dissociation curve have been found in these populations. This predominantly genetic adaptation is also likely to spare cardiac work (i.e., obviating the need to increase cardiac output, which is somewhat limited in the fetus). In addition, it has recently been shown that in these high-altitude populations, presumably due to genetic adaptation, pregnancy induces increases in uterine artery diameter and uteroplacental blood flow and thus oxygen delivery to the fetoplacental unit.

The other major factor not often considered in discussions of maternofetal oxygen transport is the effect of the Bohr effect on both oxygen loading (fetal umbilical venous blood) and unloading (maternal uterine arterial to venous blood). Zhang and colleagues studied the theoretical shifts in hemoglobin affinity for oxygen in five mammalian species. Their study concluded that oxygen delivery to fetal tissues by fetal hemoglobin was found to be more efficient than that of adult hemoglobin, as was the theoretical ability of hemoglobin to load oxygen at the placental level, due to the Bohr effect on pH ( Fig. 37.1 ). The developmental and species-specific differences in hemoglobin gene regulation have been reviewed elsewhere. ^, Thus, overall, in both human cord blood and umbilical venous samples from fetuses of a number of species, fetal oxygen delivery as measured by blood oxygen content (not Po ₂ [i.e., the partial pressure of oxygen in blood]) is adequate for aerobic metabolic needs.

Fig. 37.1, Enhanced efficiency of oxygen delivery of fetal versus maternal blood in five mammalian species. Efficiency is calculated as the ratio of the arteriovenous saturation difference (Δ S ) associated with the observed arteriovenous partial pressure difference (Δ P ) for an oxyhemoglobin dissociation curve at physiologic P 50 to the maximum saturation change achievable for the same Δ P for dissociation curves for which P 50 is allowed to vary arbitrarily. Efficiency–that is, ( ΔSP(a−v)O2(PhysP50)/maxΔSP(a−v)O2 ΔSP(a−v)O2(PhysP50)/maxΔSP(a−v)O2 )—is then plotted as a function of the arteriovenous partial pressure difference for oxygen ( ΔP(a−v)O2 ΔP(a−v)O2 ) . Values much closer to 1 for fetal blood indicate that the physiologic P 50 for fetal blood is more nearly optimal for oxygen delivery at physiologic arterial and venous oxygen tensions. Brown symbols: fetal, blue symbols: maternal.

It follows that fetal mammals, under steady-state, or unstressed, conditions, ought to achieve adequate oxygen delivery (the product of umbilical venous blood oxygen content and umbilical venous blood flow) and should not exhibit evidence of hypoxia (low tissue oxygen availability), unless specific organ or total blood flow falls dramatically or fetal blood oxygen content declines below a critical level. Studies of fetal acid-base or lactate balance indirectly test this hypothesis. The consensus is that no evidence exists to support a hypoxic fetal milieu because (1) umbilical cord blood pH values of unstressed fetal humans, pigs, monkeys, and sheep are all similar to one another and to the normal adult range of 7.35 to 7.45; (2) venoarterial H ⁺ concentration differences in cord blood of these species are only modest, suggesting relatively small fetomaternal H ⁺ transfer, inconsistent with hypoxia-induced lactic acid production; (3) both in vitro and in vivo, the placenta has been shown to deliver lactate into the fetal circulation, where it is taken up, particularly by the fetal liver, for purposes of accretion and oxidation ; and (4) experimental production of maternal and relative fetal hyperoxia in the sheep is not associated with an increase in fetal oxygen consumption.

Thus, in the unstressed fetus, energy processes use oxidative pathways, and estimation of fetal oxygen consumption may be used as a direct indicator of the fetal metabolic rate. ^, ^, Although rates of substrate uptake and carbon dioxide production provide alternate measurements of fetal metabolic activity, the calculation of each requires a significant number of assumptions. In the case of substrate utilization, the relative partitioning of carbon uptake by the fetus for use as fuel (oxidative needs) or growth (accretion needs) must be considered. Measurement of CO ₂ production must also take into account the relative contributions of carbon from the oxidative metabolism of carbohydrates, amino acids, and fats toward carbon dioxide generation, which may be less than equimolar depending upon the fetal diet. ^,

Fetal Oxygen Consumption

Measurement

Fetal oxygen consumption ( $\dot{V} O_{2}$ $\dot{V} O_{2}$ ) has been estimated using a variety of techniques. Two methods have been used to gauge fetal oxygen consumption in vivo. Because the fetus has little stored oxygen, the vast majority of fetal requirement for oxidative metabolism of substrate is met by transfer of oxygen to the fetus via the placenta and umbilical venous circulation. Negligible transfer is thought to occur across the fetal membranes. The earliest known method for measuring fetal $\dot{V} O_{2}$ $\dot{V} O_{2}$ accurately in the intact animal was that derived by Christian Bohr (circa 1900). By measuring $\dot{V} O_{2}$ $\dot{V} O_{2}$ before and after intermittent umbilical occlusion in pregnant guinea pigs (or in subsequent studies by others before and after delivery of other fetal mammals), fetal $\dot{V} O_{2}$ $\dot{V} O_{2}$ could be calculated as follows:

Fetal \dot{V} O_{2} = Predelivery maternal \dot{V} O_{2} - Postdelivery maternal \dot{V} O_{2}

$Fetal \dot{V} O_{2} = Predelivery maternal \dot{V} O_{2} - Postdelivery maternal \dot{V} O_{2}$

Fetal $\dot{V} O_{2}$ $\dot{V} O_{2}$ is usually expressed as either mL or mmol O ₂ /kg/min. As shown in Table 37.1 , estimates for fetuses of several species, including humans, are available.

Table 37.1

Fetal Oxygen Consumption in Various Species.

Species	Measurement	$\dot{V} O_{2}$ $\dot{V} O_{2}$ (mL/kg/min)
Human at term	B	6.8
Rhesus monkey	F	7.0
Sheep	F	7.9
Cow	F	6.7
Horse	F	7.0
Guinea pig	B	8.8

B, Bohr principle measurement; F, Fick principle measurement.

The major assumption in these studies is that the act of delivery (or cord occlusion) does not measurably alter maternal, uterine, or placental $\dot{V} O_{2}$ $\dot{V} O_{2}$ . Such assumptions are likely not entirely accurate due to parturition-induced changes in fetal, placental, and maternal rates of metabolism and/or blood flow, but the results of these studies provide a framework for estimates obtained using other methods.

The second technique for measuring fetal $\dot{V} O_{2}$ $\dot{V} O_{2}$ relies on the principle originally derived by Adolf Fick (circa 1870), whereby uptake of substrates or oxygen for the whole organism can be calculated as the product of cardiac output and the arteriovenous difference in substrate or oxygen content. In the case of specific fetal organ uptake (or in this case, the whole fetus), the product may be transposed as organ or whole fetal blood flow multiplied by the arteriovenous or venoarterial concentration difference of the substance in question across the organ or umbilical circulation, respectively. (See review by Carter. )

Thus, for oxygen consumption of the mammalian fetus, the principle may be restated according to Eq. 37.2 :

Fetal \dot{V} O_{2} = F_{umb} \times C_{(v - a) O_{2}}

$Fetal \dot{V} O_{2} = F_{umb} \times C_{(v - a) O_{2}}$

where F _umb = umbilical blood flow (mL/min or mL/kg/min) and $C_{(v - a) O_{2}}$ $C_{(v - a) O_{2}}$ = the venoarterial difference in O ₂ content (mL or mmol of O ₂ /100 mL blood) across the umbilical circulation. The advantages of the Fick method over the original Bohr technique include (1) the ability to perform serial studies in the same animal during late gestation, (2) the ability to measure uptake and excretion of potential fetal metabolites simultaneously with the uptake of oxygen, and (3) the ability to observe changes in metabolic rate before and after experimental manipulation.

Noninvasive methods for determination of animal and human fetal $\dot{V} O_{2}$ $\dot{V} O_{2}$ are being developed, such as blood oxygenation level–dependent (BOLD) magnetic resonance imaging (MRI), ^, near-infrared spectroscopy (NIRS), and intensity-modulated optical spectroscopy (IMOS; a modification of NIRS). Fig. 37.2 demonstrates the use of BOLD to assess oxygenation in placenta, brain, and liver of two groups of fetuses (normal [AGA] and growth restricted [SGA]) during maternal normoxia and hyperoxia. Changes in signal intensity (R2∗, a measure of hemoglobin saturation in tissues) did not differ between groups in the study, but responses to hyperoxia varied among those organs. These techniques make use of the differences observed in either image density or spectroscopic patterns between saturated and desaturated hemoglobin and may be particularly useful for assessing specific organ (i.e., liver, brain, placenta) oxygen requirements or abnormalities of metabolic function due to maternal or fetal disease states.

Fig. 37.2, Changes in R2∗ (an indicator of regional hemoglobin saturation) relative to baseline in placentas and organs of AGA (green) and SGA (red) twin pairs (mean and standard deviation), before, during, and after maternal hyperoxia. (A) placentas, (B) fetal livers, (C) fetal brain.

Experimental Data

The difficulties involved in obtaining Fick principle estimates of fetal $\dot{V} O_{2}$ $\dot{V} O_{2}$ include the necessity of obtaining samples of umbilical venous and umbilical or distal aortic blood for oxygen content analysis, which requires use of a relatively large fetus (i.e., sheep, cow, pig) for catheter placement, or in humans, sampling from the umbilical cord at the time of delivery (usually cesarean section) and the requirement of a reliable estimate of umbilical blood flow. The former problem in animal experiments has been overcome by the implantation of fetal catheters for serial measurements under nonstressed conditions. The latter problem in animals has been overcome by the development of several methods for the accurate measurement of umbilical blood flow, which include the use of laser-Doppler, ultrasonic, or electromagnetic flow transducers; radiolabeled microspheres; or steady-state diffusion of substances such as antipyrine, ethanol, or tritiated water across the placenta. For human studies, F _umb has been estimated using ultrasound and Doppler as the product of the umbilical vein cross-sectional diameter and umbilical vein blood flow velocity. However, technical difficulties in obtaining consistent measurement of both of these parameters have produced published estimates of F _umb varying by more than 20%. ^,

As can be seen in Table 37.1 , when corrected for fetal weight, fetal $\dot{V} O_{2}$ $\dot{V} O_{2}$ as measured in a variety of animal species is remarkably consistent, with a range of 6.7 to 8.8 mL O ₂ /kg/min. Despite the aforementioned caveats regarding F _umb , in recent studies of fetal $\dot{V} O_{2}$ $\dot{V} O_{2}$ obtained in term human fetuses, values of 5.4 to 6.9 mL/kg/min fit well within the range observed for other species. As an example, a noninvasive study of human fetuses near term using MRI/Doppler flow determined $\dot{V} O_{2}$ $\dot{V} O_{2}$ to be 6.9 ± 1.7 mL/kg/min with O ₂ extraction of 34 ± 8%.

Determining Factors

Factors that control fetal energy expenditure are not fully understood, but one main tenet is that there is a relatively consistent relationship between mass and metabolic rate across species in the adult. Although it had been known for many years that body weight correlates with metabolic rate, Kleiber formulated the seminal allometric scaling relationship in comparative physiology:

Metabolic rate \propto {Mass}^{3 / 4}

$Metabolic rate \propto {Mass}^{3 / 4}$

In this relationship, it is important to point out that metabolic rate is expressed in kcal/day (not kcal/kg/day, which would be nonallometric), so daily energy expenditure is proportional to (mass) ^3/4 . Since Eq. 37.3 was first formulated, this basic principle has been extended and is reasonably predictive of the aerobic metabolic rates not only for a variety of mammals and other vertebrates, but also for the metabolic rates of single cells, mitochondria, and even for the turnover rate for substrates in the respiratory enzyme chain within mitochondria. However, newer work suggests that the actual scaling ratio between mass (M) and metabolic rate (Rm) may be somewhat greater or less, depending on the species ( Fig. 37.3 ). Factors that might alter this relationship have been explored by several recent research groups, and the reader is directed there for further review. ^,

Fig. 37.3, Estimates of empirical scaling exponents of R m for a range of species measured at rest (circles), while free living (squares) or during intense activity (diamonds), shown±95% confidence intervals. Groups that are predominantly endothermic are colored red, while groups that are predominantly ectothermic are colored blue. The vertical dashed line represents the scaling exponent of ¾ predicted by several metabolic theories.

The aforementioned general relationship may be predicted theoretically due to the basic limitations of nutrient and oxygen transport placed on respiring cells that relates to the geometry of branching networks, such as blood vessels or mitochondrial cristae. The caveats in such a relationship are that the metabolic rate is measured (classically as $\dot{V} O_{2}$ $\dot{V} O_{2}$ ) (1) in the resting state and (2) in nongrowing adults (i.e., not in subjects that are actively growing, such as the fetus or newborn).

To reiterate, as suggested by Kleiber, if nonallometric basal metabolic rate (kcal/kg/time unit) is used, the relationship between mass and metabolic rate becomes an inverse one, with smaller adult nongrowing animals having relatively larger mass-specific metabolic rates. However, there exists a relative constancy of fetal $\dot{V} O_{2}$ $\dot{V} O_{2}$ across species lines when corrected for fetal weight under standard conditions. Among species whose fetal weights differ by as much as a factor of 300, weight-specific fetal $\dot{V} O_{2}$ $\dot{V} O_{2}$ estimates (mL/kg/min) differ by only 15% with a mean value of 7.4 mL/kg/min (see Table 37.1 ). The most frequently studied steady-state data remain available from the fetal lamb, which, in one review of data from 162 near-term sheep, the mean fetal $\dot{V} O_{2}$ $\dot{V} O_{2}$ was 354 ± 45 μmol/kg/min (7.93 ± 1.01 mL/kg/min).

The observation that the inverse scaling principle does not apply to fetal mammals has led to the speculation that confounding factors such as the rapid rate of growth in late perinatal life and changes in membrane lipid composition may be important. In addition, it has been hypothesized that another reason for the apparent inconsistency is that the fetus is relatively free from the “adult” oxidative demands of temperature homeostasis and, to a lesser extent, gravity and muscular activity, all of which are dependent on body mass and surface area.

During and after the transition from fetus to newborn, there is a gradual increasing ratio between weight and mass-specific metabolic rate. Predominantly due to diminished needs for such metabolic functions as heat control, $\dot{V} O_{2}$ $\dot{V} O_{2}$ in late fetal life is somewhat closer to the weight-specific metabolic rate for the adult ( Fig. 37.4 ). Postnatally, metabolic rate rises significantly greater than that of the adult, with a slow decline thereafter. Studies in human infants have concluded that the relationship between body mass and $\dot{V} O_{2}$ $\dot{V} O_{2}$ declines back to “adult” levels by approximately 18 months of age, or at a body weight of approximately 12 kg.

Fig. 37.4, Left-shift of P o 2 /metabolic rate relationship in neonatal mice as compared with adult tissue. Microcalorimetric data were recorded on mouse heart tissue slices under various oxygenation conditions. The same metabolic adaptation that enables the fetus at low P o 2 to maintain a metabolic rate similar to the adult at high P o 2 (arrow 1) may lead to the metabolic increase with increasing P o 2 at birth (arrow 2) and to “hypometabolism” being observed under hypoxic conditions (arrow 3) .

At the cellular level, the control of metabolic rate has not been clearly elucidated but involves complex interactions between a number of factors, including (1) the concentration of adenosine triphosphate (ATP; the product of mitochondrial oxidative phosphorylation); (2) the ratio of intracellular adenosine diphosphate (ADP) to ATP, (3) rates of intracellular protein synthesis, and (4) the generation of proton (H ⁺ ) gradients by respiratory enzymes across the mitochondrial and cell membranes. ^, It has been estimated that approximately 15% of $\dot{V} O_{2}$ $\dot{V} O_{2}$ of the term fetus might be spent on total active transport processes.

One general assumption has been that metabolic rate is not influenced by oxygen availability unless the diffusion of oxygen is severely limited. Justification for this view stems from the observation that several mammalian tissues (i.e., heart, liver, and kidney) have similar in vivo and in vitro rates of oxygen consumption, suggesting an intrinsic regulatory mechanism. For example, in exteriorized artificially ventilated premature lambs, mitochondrial respiratory activity in heart, kidney, and muscle was no different from control animals. However, some contradictory in vivo studies in mammals genetically adapted to living at high altitude (the South American Andean llama) and in sheep recently acclimatized to high altitude have shown that prolonged exposure to relative fetal hypoxemia can induce long-standing protective changes. These changes include, in addition to the well-known compensatory increase in hemoglobin concentration, changes in glucocorticoid signaling, depression of cerebral Na ⁺ , K ⁺ -ATPase pump activity, reduced expression of at least two Na channel proteins, decreased cerebral heat production, altered cerebral vasculature anatomy, and decreased cerebral $\dot{V} O_{2}$ $\dot{V} O_{2}$ without apparent biochemical or histologic evidence of brain damage. ^, ^, At least some of these changes appear to be mediated by endothelin-1 and intrinsic nitric oxide (NO), both potent mediators of vascular tone, as well as by vascular endothelial growth factor (VEGF) and endogenously produced carbon monoxide (CO). ^, Studies of two distinct human populations living at high altitude for many centuries (Andeans and Tibetans) suggest that a broad range of genetic adaptations, including divergent hypoxia-inducible factor (HIF)-1 responses (see later), have evolved to deal with the challenge of oxygen delivery under these conditions. ^, Furthermore, the use of microarray genomic techniques are beginning to elucidate even more information about cellular responses to chronic hypoxic stimuli. Such studies have important implications for understanding the manner in which the fetus might be protected against sudden changes in oxygen delivery.

However, at sea level, classic studies have shown the characteristic fetal blood flow (and consequent oxygen) redistribution during graded maternal hypoxia, in which blood flow and oxygen delivery are preferentially shunted to brain and away from carcass. Interestingly, in vitro studies have shown that tissues such as fetal muscle do decrease $\dot{V} O_{2}$ $\dot{V} O_{2}$ in response to change in media Po ₂ . Similar findings have been observed in other fetal organs such as liver and kidney.

A series of studies have also shown that brief fetal hypoxia induces a number of changes in regulatory genes, particularly in the fetal hypothalamus and pituitary. More prolonged hypoxia causes stimulation of HIF-1, 2, and 3, ^, potent gene transcriptional factors. Hypoxic response elements (HREs), which bind HIFs, are intrinsic to a number of genes that are developmentally regulated ^, ^, and control synthesis of several protective proteins such as VEGF, erythropoietin (Epo), platelet-derived growth factor and metabolic enzymes that induce increases in anaerobic ATP production via increased mitochondrial glycolysis.

Furthermore, activation of carotid body chemoreceptors, specifically the adenosine A _2A receptor, plays a significant role in defending against fetal hypoxia by helping to maintain brain blood flow. ^, Activation of specific calcium channel receptors such as RyR1 may act to stimulate local organ intravascular synthesis of the intrinsic vasodilator NO, thereby increasing local blood flow and therefore oxygen delivery during times of relative hypoxemia. Fetal hemoglobin appears to facilitate this change in delivery by at least twice that of adult hemoglobin.

Integration of Fetal Metabolic Rate

Under a wide variety of conditions, changes in O ₂ delivery to the fetus are met by changes in O ₂ extraction to meet metabolic demands. In the fetal sheep, O ₂ extraction may be calculated as the ratio between O ₂ consumption (see Eq. 37.2 ) and O ₂ delivery (the product of umbilical blood flow and umbilical venous O ₂ content). In the steady state, this ratio is usually approximately 0.4 in the fetal sheep, meaning that only 40% of the oxygen delivered to the fetus via the placental circulation is extracted. The ratio during experimental hypoxemia in animals may rise to some extent (to 0.5 to 0.6) without serious adverse effects. Measurements in healthy human fetuses were in this range, but during delivery, extraction ratios of 0.57 to 0.7 have been observed. ^, At high altitude, ratios even higher than these were observed. Confirming earlier work in animals, extraction was inversely related to oxygen delivery.

However, in human fetuses with intrauterine growth restriction who were excreting significant amounts of lactate (and presumably had relative fetal hypoxia), no increase in extraction was observed, suggesting a relative maximum in extraction efficiency had been reached in that population. ^,

Of those factors influencing fetal $\dot{V} O_{2}$ $\dot{V} O_{2}$ , several are particularly prominent ( Box 37.1 ). “Specific organ metabolism” refers to those various cellular processes common to most tissues. It is, of course, well known that it is chemical energy provided by oxygen and a variety of carbon-containing substrates including glucose that is the actual fuel underpinning all forms of homeostasis. In adults only approximately 20% of this energy is converted to support basal cellular metabolism, with the remainder used to produce heat. ^, Regarding cellular homeostasis, virtually all mitochondrial and plasma membrane ion pumps require energy in the form of ATP and are thus heavily dependent on cellular respiratory activity. Such pumps consist of F-type H ⁺ pumps (mitochondria), V-type H ⁺ pumps (lysosomes, storage granules), or P-type Na ⁺ , K ⁺ , or H ⁺ pumps (plasma membranes). ^, Although it has thus far been difficult to estimate the contribution of such processes to the fetal metabolic rate, it is probable that in many tissues, pump activity is vital in determining intraorgan $\dot{V} O_{2}$ $\dot{V} O_{2}$ . For example, in one estimate, ouabain (via inhibition of Na ⁺ , K ⁺ -ATPase pump activity) caused a decline in fetal sheep liver and placental $\dot{V} O_{2}$ $\dot{V} O_{2}$ , which accounted for 20% and 34% of whole organ $\dot{V} O_{2}$ $\dot{V} O_{2}$ in those organs, respectively. Similarly, in the newborn rat, approximately 50% of liver metabolism was due to activity of the sodium pump, followed by a significant decline in infancy.

Box 37.1

Factors Influencing Fetal Oxygen Consumption

Specific organ metabolism ^a

a Including ion pump activity and other processes necessary for cellular homeostasis.
Activity
Fetal breathing
Fetal limb movement
Fetal cardiac activity
Fetal sleep state
Fetal growth
Substrate uptake
Maternal exercise
Fetomaternal temperature gradient
Fetal hormonal status
Thyroid hormones
Catecholamines
Insulin

Other metabolic processes, such as protein synthesis and attendant energy-dependent chemical reactions such as transamination and decarboxylation, have metabolic costs, but the contributions of these to fetal $\dot{V} O_{2}$ $\dot{V} O_{2}$ have not been determined. Fetal work (i.e., muscle oxidative requirements to perform such activities as fetal breathing and limb movements) also accounts for a significant fraction of the total fetal $\dot{V} O_{2}$ $\dot{V} O_{2}$ . For example, striated muscle activity (excluding cardiac work), as assessed in the fetal sheep, has been estimated to account for as much as 15% of the total fetal $\dot{V} O_{2}$ $\dot{V} O_{2}$ , which agrees with an in vitro measurement of approximately 20 μmol/100 g/min, assuming muscle mass in the term fetal lamb of 25% fetal wet weight. If specific cardiac $\dot{V} O_{2}$ $\dot{V} O_{2}$ , as also measured in the lamb, is added, slightly greater than 20% of the fetal requirement for oxygen is necessary for normal striated muscle activity.

Unfortunately, further information of tissue-specific oxygen needs in the fetus is limited to several accessible organs in animals, predominantly sheep, although some in vitro tissue data from prematurely delivered humans are available for comparison. Lastly, the energy cost of growth (i.e., the energy necessary to synthesize new tissue) has been estimated to be approximately 10% of the caloric value of new tissue, which is equivalent to approximately 6% of the fetal $\dot{V} O_{2}$ $\dot{V} O_{2}$ .

In summary, it can be seen that approximately 50% of the measured fetal $\dot{V} O_{2}$ $\dot{V} O_{2}$ is attributable to metabolism in fetal brain, liver, kidney, and intestine ( Table 37.2 ). In the sheep fetus, approximately 83% of the fetal $\dot{V} O_{2}$ $\dot{V} O_{2}$ can be accounted for in the resting state. It is assumed that measurement of $\dot{V} O_{2}$ $\dot{V} O_{2}$ in other tissues (e.g., bone marrow, lung, adrenal gland, cartilage, skin) and underestimation of fetal tissue pump activity and limited thermogenesis would provide for the remaining 17% of whole fetus oxygen needs.

Table 37.2

Tissue-Specific Oxygen Needs in the Fetus.

	$\dot{V} O_{2}$ $\dot{V} O_{2}$ /100 g Tissue	$\dot{V} O_{2}$ $\dot{V} O_{2}$ /kg Body Weight	% Total $\dot{V} O_{2}$ $\dot{V} O_{2}$
	μmol/100 g Tissue/min	μmol/kg Body Weight/min	% Total $\dot{V} O_{2}$ $\dot{V} O_{2}$
Whole fetus	—	360 (8.0)	100.0
Brain ^, ^,	190	30 (0.7)	8.8
Heart ^, ^,	400	25 (0.6)	7.5
Liver	174	67 (1.5)	18.0
Intestine ^,	100	40 (0.9)	11.3
Kidneys	100	8 (0.2)	2.5
Adrenal	68	2	0.05
Muscle ^a ^, ^, ^,	20	50 (1.1)	14.0
Other Growth	—	20 (0.45)	5.6
Activity ^a ,	—	54 (1.2) a	15.0
Total	—	296 (6.6)	83.0

a Data for muscle (in vitro) and activity (in vivo) must reflect both sedentary and active states of striated muscle respiration.

Several factors may further influence the fetal metabolic rate (see Box 37.1 ). Interestingly, other than active fetal cooling, such potential adverse stimuli such as mild hypoxemia or other experimental manipulations such as maternal exercise or severe maternal starvation do not appear to depress overall fetal metabolic activity. Although not well studied, maternally administered drugs that cross the placenta and have a depressive effect on fetal activity are likely to decrease fetal $\dot{V} O_{2}$ $\dot{V} O_{2}$ . For example, experimental skeletal muscle paralysis in the fetal lamb causes a 10% to 15% decrease in fetal $\dot{V} O_{2}$ $\dot{V} O_{2}$ . Significant depression of fetal respiratory or body movement have been noted after maternal exposure to ethanol, antidepressants, cigarette smoking, hypoxemia, or steroids. ^, The fetal metabolic rate can be stimulated by such factors as change in fetal sleep state, excessive fetal muscular activity, maternal fever, and possibly external stimuli such as sound.

Studies regarding changes in human fetal behavior are now possible using fetal ultrasound to gauge fetal movement and breathing. Using these techniques, it has also been shown that fetal breathing is more prominent after maternal food intake or glucose infusion and by maternal drug abuse (cocaine, methadone). In addition, one recent study using a fetal accelerometer sensor to monitor human fetal movement over longer epochs during maternal sleep showed that gross human fetal movement declines normally during the last trimester of pregnancy from 17% of time studied at 28 weeks to 6% near term.

The hormonal milieu also plays a significant role in setting the background for the fetal metabolic rate at rest and during changes in the fetal environment. The interplay between the hypothalamic-pituitary-adrenal axis, catecholamines, and other fetal hormones also influences cellular respiration and metabolic rate. Fetal concentrations of thyroxine (T ₄ ) and triiodothyronine (T ₃ ) are crucial to accretion of fetal mass and regulation of fetal $\dot{V} O_{2}$ $\dot{V} O_{2}$ . The control of circulating levels of these hormones is a complicated balance between activation of synthesis and endogenous secretion, peripheral conversion of T ₄ to T ₃ , uptake into peripheral tissues, and, in some species including humans, transplacental transfer from mother to fetus. Fetal thyroid ablation has been shown to cause a 20% to 30% reduction in fetal metabolic rate, mostly related to effects on skeletal muscle and fat. These observations may have important implications for such disease states as fetal thyrotoxicosis or maternal diabetes. Other hormones such as insulin and catecholamines also play roles in control of fetal $\dot{V} O_{2}$ $\dot{V} O_{2}$ . For example, although fetal insulin deficiency does not alter resting umbilical $\dot{V} O_{2}$ $\dot{V} O_{2}$ , ^, maternal and subsequent fetal hypoglycemia have been shown to lower $\dot{V} O_{2}$ $\dot{V} O_{2}$ by as much as 30%. As noted in the following sections, both fetal hyperinsulinemia and hyperglycemia appear to have independent effects upon accelerating fetal $\dot{V} O_{2}$ $\dot{V} O_{2}$ .

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