Development and mechanisms of fetal hypoxia in severe fetal growth restriction.

Severe fetal growth restriction (FGR) is often associated with hypoxia. We studied FGR hypoxia in an experimental model which is produced by exposing pregnant ewes to a hyperthermic environment. The study utilized simultaneous measurements of several relevant factors, e.g., uterine and umbilical blood flows and O(2) uptakes. Sixteen ewes were divided equally into control (C) and hyperthermic (HT) groups. Hyperthermia (40 degrees C for 12h/35 degrees C for 12h; approximately 35% relative humidity, RH) was maintained for 80 days commencing at approximately 38 days gestational age (dGA term 147+/-3 days). All ewes were then placed in a control environment ( approximately 21 degrees C, 24h; approximately 30% RH) and studied at approximately 134 dGA. Mean HT placental and fetal weights were 39% and 45% of C, respectively (p<0.0001), umbilical O(2) uptake/kg fetus was 76% of C (p<0.01) and umbilical venous PO(2) was reduced (20.2 vs. 29.7 Torr, p<0.001). Contrary to the hypothesis that FGR hypoxia is due to maternal placental hypoperfusion, uterine flow was not reduced in relation to O(2) uptake. The uterine-umbilical venous PO(2) difference was enlarged (38 vs. 23 Torr, p<0.0001). This difference is the expression of a balance between developmental changes in placental structure and oxidative metabolism, which have opposite effects in terms of fetal oxygenation. We postulate that FGR hypoxia results from disproportionate underdevelopment of those changes which allow for a progressive increase in umbilical O(2) uptake.

Umbilical threonine uptake during maternal threonine infusion in sheep.

OBJECTIVE: The infusion into the maternal circulation of amino acid solutions failed to increase umbilical threonine (THR) uptake above normal even when THR was present in the infusate at a relatively high concentration. The purpose of the present study was to determine whether umbilical THR uptake can be increased by infusing a THR solution that does not contain any other amino acids. STUDY DESIGN: Five pregnant sheep (130+/-1.0 days after conception) were infused for 2h with a threonine solution (4.4+/-0.2 micromol.kg(-1).min(-1)). Plasma amino acids, glucose and lactate, hematocrit, blood O(2) content in maternal arterial, uterine venous, umbilical arterial and venous blood were measured. Uterine and umbilical blood flows were measured before and during the infusion and were used to calculate uterine and umbilical uptakes. Maternal and foetal plasma insulin and glucagon concentrations were also measured. RESULTS: The THR infusion increased maternal plasma THR (904 vs 236 microM, P< 0.001), foetal plasma THR (539 vs 334 microM, P< 0.01), and both uterine (20.4 vs 4.7 micromol.min(-1).kg(-1)(fetalweight), P< 0.05) and umbilical (8.6 vs 3.8 micromol.min(-1).kg(-1)(fetalweight), P< 0.001) THR uptakes. The uterine-umbilical THR uptake difference increased significantly (11.8 vs 0.9 micromol.min(-1).kg(-1)(fetalweight), P< 0.05). There were significant (P< 0.001) decreases in the foetal arterial plasma concentrations of tyrosine and the branched chain amino acids, as well as in isoleucine umbilical uptake (P< 0.05). There was a significant increase in maternal plasma glucagon (P< 0.01). CONCLUSION: A maternal THR infusion that causes a 3.8-fold increase in maternal plasma THR concentration above normal, with no significant increase in the concentration of other amino acids, leads to a 2.3-fold increase in umbilical THR uptake. This contrasts with the absence of a significant increase in umbilical THR uptake when THR was infused as part of an amino acid mixture in previous studies. The evidence supports the hypothesis that, in vivo, THR flux from placenta to foetus is mediated by a saturable, rate limiting transport system which is subject to inhibition by other neutral amino acids.

Effects of branched-chain amino acids on placental amino acid transfer and insulin and glucagon release in the ovine fetus.

OBJECTIVE: Competition for placental amino acid transporters can affect the fetal supply of amino acids. Specifically, the branched-chain amino acids-isoleucine, leucine, and valine-may inhibit the transfer of other amino acids. This study was undertaken to determine the effect of branched-chain amino acids on the umbilical uptake of amino acids. STUDY DESIGN: Six late-gestation ewes were infused sequentially for 2 hours with 3 different mixtures of amino acids: (1) one that was comparable to commercial parenteral nutrition preparations, (2) the same solution without branched-chain amino acids, and (3) branched-chain amino acids alone. Maternal and fetal blood samples were collected simultaneously for the determination of uterine and umbilical uptake values of amino acids, and for concentrations of arterial insulin, glucagon, glucose, and lactate before (control) and during (experimental) infusion. RESULTS: Umbilical uptake of branched-chain amino acids increased significantly when they were present in the infusates. The fetal uptake of several other amino acids could be increased by increasing their maternal concentrations. Inhibition of umbilical uptake by branched-chain amino acids could be shown for threonine and methionine. The infusion of branched-chain amino acids alone did not affect maternal and fetal insulin or glucagon concentrations. CONCLUSIONS: In late-gestation sheep, an increase in maternal plasma concentration of branched-chain amino acids led to increased branched-chain amino acid umbilical uptake, but branched-chain amino acids can also inhibit the transport of some amino acids to the fetus. Changes in fetal plasma concentration and uptake of branched-chain amino acid appear to have no significant effect on fetal insulin or glucagon.

An in vivo study of ovine placental transport of essential amino acids.

Under normal physiological conditions, essential amino acids (EA) are transported from mother to fetus at different rates. The mechanisms underlying these differences include the expression of several amino acid transport systems in the placenta and the regulation of EA concentrations in maternal and fetal plasma. To study the relation of EA transplacental flux to maternal plasma concentration, isotopes of EA were injected into the circulation of pregnant ewes. Measurements of concentration and molar enrichment in maternal and fetal plasma and of umbilical plasma flow were used to calculate the ratio of transplacental pulse flux to maternal concentration (clearance) for each EA. Five EA (Met, Phe, Leu, Ile, and Val) had relatively high and similar clearances and were followed, in order of decreasing clearance, by Trp, Thr, His, and Lys. The five high-clearance EA showed strong correlation (r(2) = 0.98) between the pulse flux and maternal concentration. The study suggests that five of the nine EA have similar affinity for a rate-limiting placental transport system that mediates rapid flux from mother to fetus, and that differences in transport rates within this group of EA are determined primarily by differences in maternal plasma concentration.

Elizabeth M. Ramsey and the evolution of ideas of uteroplacental blood flow and placental gas exchange.

During the past century a number of investigators have contributed to an understanding of the regulation of uteroplacental blood flow and its influence on placental respiratory gas exchange and fetal oxygenation. Among these, Elizabeth M. Ramsey is noteworthy for her contributions to embryology and placental development. In addition, with several colleagues she performed pioneering cineangiographic studies on the patterns of blood flow in the primate placenta.

Effect of dexamethasone on fetal hepatic glutamine-glutamate exchange.

Intravenous infusion of dexamethasone (Dex) in the fetal lamb causes a two- to threefold increase in plasma glutamine and other glucogenic amino acids and a decrease of plasma glutamate to approximately one-third of normal. To explore the underlying mechanisms, hepatic amino acid uptake and conversion of L-[1-(13)C]glutamine to L-[1-(13)C]glutamate and (13)CO(2) were measured in six sheep fetuses before and in the last 2 h of a 26-h Dex infusion. Dex decreased hepatic glutamine and alanine uptakes (P < 0.01) and hepatic glutamate output (P < 0.001). Hepatic outputs of the glutamate (R(Glu,Gln)) and CO(2) formed from plasma glutamine decreased to 21 (P < 0.001) and 53% (P = 0.009) of control, respectively. R(Glu,Gln), expressed as a fraction of both outputs, decreased (P < 0.001) from 0.36 +/- 0.02 to 0.18 +/- 0.04. Hepatic glucose output remained virtually zero throughout the experiment. We conclude that Dex decreases fetal hepatic glutamate output by increasing the routing of glutamate carbon into the citric acid cycle and by decreasing the hepatic uptake of glucogenic amino acids.

Contribution of branched-chain amino acids to uteroplacental ammonia production in sheep.

The uteroplacental tissues are a principal site of ammonia production for the conceptus. The goal of this study was to examine the effect of the composition of maternal amino acid (AA) infusate on uteroplacental ammonia production. Seven pregnant ewes (126 +/- 1. 4 days gestation) were infused through the maternal femoral vein (duration 3.5 h, rate 240 ml per hour) with three solutions of AAs. The first infusate was comparable to commercial parenteral nutrition preparations, the second infusate contained the same solution without branched-chain AAs (BCAAs), and the third infusate contained only BCAAs. Blood samples were simultaneously collected from the maternal artery, uterine vein, fetal artery, and umbilical vein to determine plasma AA concentrations and whole blood ammonia concentrations, before (control) and 2 h after (experimental) the start of infusion. Uterine and umbilical blood flows were measured using the ethanol steady-state diffusion method. Results showed that fetal arterial and venous ammonia concentrations increased significantly after infusions with all AAs or only BCAAs, but not without BCAAs. Uteroplacental ammonia production increased in response to each of the three infusates. However, this increase was much greater when the BCAAs were present in infusates. We conclude that there is a significant contribution of BCAAs to the uteroplacental ammonia production. Maternal AA infusions containing BCAAs can result in increased fetal blood ammonia concentrations.

Fetal supply of amino acids and amino nitrogen after maternal infusion of amino acids in pregnant sheep.

OBJECTIVE: The objective of the study was to determine whether a prolonged maternal infusion of amino acids would increase the umbilical uptake of amino acids and uteroplacental ammonia production. STUDY DESIGN: Six pregnant sheep (134.5 2.3 days after conception) were infused for 12 hours overnight with an amino acid solution. Uterine and umbilical blood flows were measured with the ethanol steady-state diffusion technique before (control) and during (experimental) infusion. Plasma amino acid and whole-blood ammonia concentrations were measured. RESULTS: After infusion, despite an increase in maternal arterial amino acid concentration, umbilical uptakes increased significantly only for branched-chain amino acids. Fetal ammonia concentrations and uteroplacental ammonia production increased moderately. Fetal nitrogen supply did not increase. Uterine nitrogen uptake represented 36% of the maternal nitrogen intake in the control period and 14% in the experimental period. CONCLUSION: Prolonged maternal infusion of an amino acid solution was a relatively ineffective method of increasing fetal amino acid supply.

Relationship of fetal alanine uptake and placental alanine metabolism to maternal plasma alanine concentration.

Uterine and umbilical uptakes of alanine (Ala) were measured in 10 ewes before (control) and during intravenous infusion of Ala, which increased maternal arterial Ala concentration from 115 +/- 14 to 629 +/- 78 microM (P < 0.001). In 8 of these ewes, placental Ala fluxes were traced by constant intravenous infusion of L-[3,3,3-2H3]Ala in the mother and L-[1-13C]Ala in the fetus. Rates are reported as micromoles per minute per kilogram fetus. Ala infusion increased uterine uptake (2.5 +/- 0.6 to 15.6 +/- 3.1, P < 0.001), umbilical uptake (3.1 +/- 0.5 to 6.9 +/- 0.8, P < 0.001), and net uteroplacental utilization (-0.7 +/- 0.8 to 8.6 +/- 2.7, P < 0.01) of Ala. Control Ala flux to fetus from mother (Rf,m) was much less than the Ala flux to fetus from placenta (Rf,p) (0.17 +/- 0.04 vs. 5. 0 +/- 0.6). Two additional studies utilizing L-[U-13C]Ala as the maternal tracer confirmed the small relative contribution of Rf,m to Rf,p. During maternal Ala infusion, Rf,m increased significantly (P < 0.02) but remained a small fraction of Rf,p (0.71 +/- 0.2 vs. 7.3 +/- 1.3). We conclude that maternal Ala entering the placenta is metabolized and exchanged for placental Ala, so that most of the Ala delivered to the fetus is produced within the placenta. An increase in maternal Ala concentration increases placental Ala utilization and the fetal uptake of both maternal and placental Ala.

Uptake and transport by the ovine placenta of neutral nonmetabolizable amino acids with different transport system affinities.

Placental uptake and transport of three nonmetabolizable amino acids with different reactivities for transport systems were studied in sheep under normal physiologic conditions. Methylaminoisobutyric acid (MeAIB), which has specific affinity for the sodium-dependent A system transporters, demonstrated placental concentrative uptake from the uterine and the umbilical circulations, but virtually no transport from mother to fetus. By contrast, aminoisobutyric acid (AIB) and aminocyclopentane-1-carboxylic acid (ACP), which have affinity for both sodium-dependent and sodium-independent transporters, demonstrated both concentrative uptake and transport from mother to fetus. ACP transport rate to the fetus was approximately twice the AIB transport rate. It is concluded that a neutral amino acid which interacts almost exclusively with the weakly reversible system A transporters may be transported rapidly into the placenta and may attain high concentrations within this organ but cannot escape from placenta to fetus down its own concentration gradient because the exit route is controlled by reversible amino acid transporters at the fetal surface of the placenta. Conversely, high affinity for reversible Na-independent transporters may be a necessary condition for the rapid transport of an amino acid from placenta to fetus.

Production and utilization of amino acids by ovine placenta in vivo.

Uterine and umbilical uptakes of plasma amino acids were measured simultaneously in eighteen singleton pregnant ewes at 130 +/- 1 days gestation for the purpose of establishing which amino acids are produced or used by the uteroplacenta under normal physiological conditions and at what rates. The branched-chain amino acids (BCAA) had uterine uptakes significantly greater than umbilical uptakes. Net uteroplacental BCAA utilization was 8.0 +/- 2.5 mumol.kg fetus-1.min-1 (P < 0.005) and represented 42% of the total BCAA utilization by fetus plus uteroplacenta. There was placental uptake of fetal glutamate (4.2 +/- 0.3 mumol.kg fetus-1.min-1, P < 0.001) and no uterine uptake of maternal glutamate. Umbilical uptake of glutamine was approximately 61% greater than uterine uptake, thus demonstrating net uteroplacental glutamine production of 2.2 +/- 0.9 mumol.kg fetus-1.min-1 (P < 0.021). In conjunction with other evidence, these data indicate rapid placental metabolism of glutamate, which is in part supplied by the fetus and in part produced locally via BCAA transamination. Most of the glutamate is oxidized, and some is used to synthesize glutamine, which is delivered to the fetus. There was net uteroplacental utilization of maternal serine and umbilical uptake of glycine produced by the placenta. Maternal serine utilization and glycine umbilical uptake were virtually equal (3.14 +/- 0.50 vs. 3.10 +/- 0.46 mumol.kg fetus-1.min-1). This evidence supports the conclusion that the ovine placenta converts large quantities of maternal serine into fetal glycine.

Placental transport of threonine and its utilization in the normal and growth-restricted fetus.

Placental transport and fetoplacental utilization of threonine (Thr) were compared at 130 +/- 1 days gestational age between seven control ewes (C) and six ewes in which intrauterine growth restriction (IUGR) had been induced by exposure to high ambient temperature from 33 +/- 1 to 112 +/- 2 days of gestation. The fluxes were measured using simultaneous intravenous infusions of L-[1-13C]Thr into the mother and L-[U-14C]Thr into the fetus. The IUGR group had less fetal weight (1.27 +/- 0.14 vs. 3.10 +/- 0.10 kg, P < 0.01) and placental weight (120 +/- 17 vs. 295 +/- 14 g, P < 0.01) than the C group. The direct flux of maternal Thr into the fetal systemic circulation was less in the IUGR fetuses, both relative to fetal weight (1.40 +/- 0.19 vs. 2.19 +/- 0.18 mumol.min-1.kg fetus-1, P = 0.0107) and placental weight (1.5 +/- 0.2 vs. 2.3 +/- 0.2 mumol.min-1.100 g placenta-1, P = 0.0187). In both groups, there was excretion of CO2 produced from fetal Thr. The rate of CO2 production from fetal plasma Thr carbon by fetus plus placenta was reduced in the IUGR group (1.50 +/- 0.23 vs. 2.86 +/- 0.32 mumol.min-1.kg fetus-1, P = 0.0065). We conclude that the flux of maternal Thr into the IUGR fetus is markedly reduced because of a reduction in placental mass and because of a weight-specific reduction in Thr placental transport. The reduced flux is routed into fetal Thr accretion via a decrease in fetal Thr oxidation.

Metabolic alterations in the fetal hepatic and umbilical circulations during glucocorticoid-induced parturition in sheep.

Fetal hepatic amino acid metabolism has unique features in comparison to postnatal life. Thus, it seemed likely that this metabolism might be changed by the endocrine changes which precede birth. To explore the changes in placental and fetal carbohydrate and amino acid metabolism that occur during parturition, labor was induced in six ewes at 131 +/- 1 d gestation with a fetal infusion of dexamethasone. For purpose of chemical analysis, blood was withdrawn before and approximately 3 and 25 h from the start of the infusion from maternal arterial, uterine venous, umbilical venous, fetal arterial, and left hepatic venous catheters. Fetal oxygenation remained normal. At 25 h, both fetal and maternal arterial plasma glucose concentrations increased (p < 0.01 and p < 0.02, respectively) and umbilical glucose uptake decreased (p < 0.05). Fetal glutamate showed a significant reduction in its hepatic output (p < 0.05) with a concomitant reduction in fetal arterial plasma concentration (p < 0.05) and placental uptake (p < 0.01). Fetal plasma concentrations of several other amino acids were markedly increased. The reduction in placental glutamate uptake was temporally associated with a decline in progesterone release by the pregnant uterus. These data suggest the hypothesis that glutamate plays a role in integrating the complex changes in placental and fetal hepatic metabolism that occur during parturition.

Comparison of leucine, serine and glycine transport across the ovine placenta.

To estimate the transport rate of maternal glycine across the placenta [1-13C]glycine and L-[1-13]serine were infused intravenously in pregnant sheep using both continuous and bolus infusions. Each tracer was infused together with L-[1-13C]leucine, to enable a comparison with the placental transport of an essential amino acid. At steady state, fetal plasma leucine enrichment was 40 per cent of maternal enrichment, indicating that approximately 60 per cent of the entry rate of leucine into fetal plasma is derived from protein breakdown in the placenta and fetus. Fetal plasma glycine enrichment was 11 per cent of maternal and there was no detectable fetal serine enrichment. The direct flux of maternal leucine into the fetal circulation was approximately 3.0 (bolus experiments) to 3.6 (continuous infusion experiments) mumol/min (kg fetus) and greater than the estimated 1.4 mumol/min (kg fetus) direct flux of maternal glycine, despite the fact that the net umbilical uptake of glycine exceeds that of leucine. This supports the conclusion that placental glycine production is a quantitatively important contribution to fetal glycine uptake via the umbilical circulation. The fetal glycine supply from the placenta is provided by a relatively small direct maternal glycine transplacental flux and a larger contribution derived from serine utilization within the placenta for glycine production.

Placental transport and fetal utilization of leucine in a model of fetal growth retardation.

Placental transport and fetal utilization of leucine were studied at 130 days of gestation in six control ewes and in seven ewes in which intrauterine growth retardation (IUGR) had been induced by exposure to heat stress. Leucine fluxes were measured during simultaneous intravenous infusion of L-[1-13C]leucine into the mother and L-[1-14C] leucine into the fetus. In the IUGR group, the following leucine fluxes, expressed as micromol/min/kg fetus, were reduced compared with control: net uterine uptake (3.44 vs. 8.56, P<0.01), uteroplacental utilization (0.0 vs. 4.7, P<0.01), fetal disposal rate (6.4 vs. 8.9, P<0.001), flux from placenta to fetus (5.0 vs. 7.1, P<0.01), direct transport from mother to fetus (1.6 vs. 3.4, P<0.01), flux from fetus to placenta (1.5 vs. 3.2, P<0.001), and oxidation of fetal leucine by fetus plus placenta (2.1 vs. 3.2, P<0.02). Uterine uptake, uteroplacental utilization, and direct transport were also significantly reduced per gram placenta. We conclude that maternal leucine flux into the IUGR placenta is markedly reduced. Most of the reduced flux is routed into fetal metabolism via a decrease in placental leucine utilization and a decrease in the leucine flux from fetus to placenta.

Ultrasonographic assessment of fetal growth: comparison between human and ovine fetus.

OBJECTIVE: Our purpose was to evaluate the rate of ovine fetal growth for several body parameters by serial ultrasonographic measurements and to compare them with analogous data in the human fetus. STUDY DESIGN: Forty-three ewes with singleton gestations were studied. Four parameters were measured: biparietal diameter, abdominal circumference, femur length, and tibia length. Ultrasonographic examinations were performed weekly from 50 to 138 days of gestation (term 147 days). Quadratic regression analysis was used to describe each data set. RESULTS: The biparietal diameter showed a significant deceleration of its growth rate. The abdominal circumference showed a linear growth pattern. Both femur and tibia revealed a significant acceleration of the growth rate. CONCLUSION: The ovine fetal growth pattern is different from that observed in the human fetus, in which all four parameters show deceleration of the growth rate in late gestation. In comparison to the ovine, the human fetus reaches similar abdominal circumference and femur length values at term, but in a gestational period that is twice as long. In sharp contrast to abdominal circumference and femur length growth, the biparietal diameter has a similar growth rate in both species. Thus the human fetus has a slower rate of somatic growth and its greater biparietal diameter at term results from the longer gestational period.

Early ultrasonographic detection of fetal growth retardation in an ovine model of placental insufficiency.

OBJECTIVE: Our aims were as follows: (1) to determine whether fetal growth retardation can be detected noninvasively with ultrasonography in ewes and (2) to establish the time interval between exposure of ewes to environmental stress that causes growth retardation (heat stress) and detection of growth lag for specific fetal body measurements. STUDY DESIGN: Four ewes were exposed to heat stress for 80 days starting at 35 days' gestation. (The duration of pregnancy in sheep is 147 days). Serial ultrasonographic measurements of fetal biparietal diameter, abdominal circumference, and femur and tibia lengths were obtained beginning at 50 days' gestation. Growth curves were calculated for each parameter and compared with growth curves obtained from 43 normal fetuses. RESULTS: Biparietal diameter measurements deviated significantly from normal starting at 90 days' gestation (p < 0.05). Abdominal circumference diverged at 70 days' gestation (p < 0.05), and both femur and tibia length diverged at 80 days (p < 0.05). The regression lines showed significant differences for all the parameters in both slope (p < 0.01) and intercept (p < 0.01). CONCLUSIONS: Fetal growth retardation can be detected noninvasively by ultrasonography after approximately 5 weeks of exposure to heat stress. Fetal growth continues throughout gestation but at a slower rate than normal and according to a pattern similar to that observed in asymmetrically growth-retarded human fetuses. Early detection of stunted fetal growth in an animal model is important for testing intervention strategies in the treatment of fetal growth retardation.

Glutamine-glutamate exchange between placenta and fetal liver.

The hypothesis that glutamine shuttles nitrogen between placenta and fetal liver via interconversion with glutamate was explored by infusing L-[1,2-13C2]glutamine in six fetal sheep chronically catheterized for sampling of the umbilical and hepatic circulations. Fetal plasma glutamine disposal rate was 19.9 +/- 1.3 mumol.min-1.kg fetus-1. Entry of glutamine from the placenta accounted for approximately 60% of the total glutamine entry rate in fetal plasma. Glutamine was taken up by fetal liver, and 45.3 +/- 7.9% of the glutamine taken up was released as glutamate. The fetal liver released large quantities of glutamate, as evidenced by a sixfold increase in plasma glutamate concentration in the blood flowing through the left hepatic lobe and a hepatic glutamate output-to-O2 uptake molar ratio of 0.149 +/- 0.013. In conjunction with a previous study of fetal glutamate metabolism, these data demonstrate that glutamine entering the fetal circulation is converted to glutamate by the fetal liver at a rate of approximately 3-4 mumol.min-1.kg fetus-1.

Main routes of plasma lactate carbon disposal in the midgestation fetal lamb.

The turnover rates of plasma lactate, normalized for O2 consumption rate, are higher in the fetus than in the adult. This occurs despite very low rates of fetal gluconeogenesis which preclude the recycling of lactate carbon into glucose. In an effort to establish the main routes of disposal of fetal plasma lactate, 12 midgestation ovine fetuses (age 74 +/- 1 days) were infused intravenously at constant rate with L-[U-14C]lactate for a 4-hour period. At the end of the infusion, the amounts of 14C retained by the fetus and by the placenta, and the distribution of the retained 14C in free and protein-bound amino acids and in lipids were measured. Of the total 14C infused, 17.0 +/- 1.4% was recovered in the placenta, 4.0 +/- 0.3% in the fetal liver, and 15.0 +/- 0.8% in the extrahepatic fetal tissues. Of the retained radioactive carbon, 45-57% was recovered in the free and protein-bound amino acid fractions and 11-17% in the lipid fractions. Approximately 90% of the 14C in the free amino acid fractions was present as glutamate/glutamine, serine, glycine, and alanine carbon. In conjunction with data on fetal CO2 production from lactate carbon, these results demonstrate that the main routes of fetal lactate disposal are oxidation and synthesis of nonessential amino acids and lipids.