Fetal nutrition after placentation is established

The main fetal substrates for oxidative metabolism are glucose, lactate and amino acids, with free fatty acids also crossing the placenta in variable amounts (Table 1.1) (Figure 1.3).66 The amounts of these substrates taken up by the fetus can be calculated in experimental paradigms, such as the sheep, using the Fick principle. Blood flow is measured using the diffusion of an inert substance (such as ethanol, deuterium, tritiated water or antipyrine) across the placenta during steady state.67-69 As these substances are essentially inert, their loss due to metabolism, accumulation etc. is minimal (usually < 5%) and can usually be ignored. Once blood flow is determined, substrate uptakes canbe calculated from arteriovenous differences across the maternal and fetal sides of the placenta. The technique can be further refined using radioactively labeled tracers to determine substrate utilization.70 The potential contribution of each metabolite to total fetal oxidation can be calculated by comparing the amounts of the metabolite consumed with the amount of oxygen consumed, and taking into account the moles of oxygen required for the complete oxidation of one mole of substrate (the constant, k). Thus, the substrate:oxygen quotient = (k x Asubstrate) / Aoxygen, where A represents the arterio-venous concentration difference across the organ/fetus/uteroplacental unit. However, it is important to remember that this quotient gives the maximum possible contribution of the substrate in question to oxidative metabolism, as it does not allow for carbon incorporation into tissue.

Oxygen consumption

Fetal oxygen consumption varies little between mammalian species and is about 300 |imol Kg-1 • min-1.71 The fetal carcass (skeleton, muscle and skin) accounts for approximately 50% of fetal oxygen consumption, although the heart utilizes the most oxygen per unit weight.71,72

Table 1.1. Nutrient transfer by the placenta

Substrate

Mechanism

Transporters

Regulation of fetal uptake

Glucose

Facilitated diffusion

GLUT-1 and 3

Concentration gradient Uterine and umbilical blood flow Insulin, IGF-I Placental metabolism

Lactate

Active transport

Proton-dependent, Na+ independent lactate transporter

Bi-directional Placental metabolism IGF-I

Amino acids

Active transport

Many different amino acid transporters

Concentration gradient Uterine and umbilical blood flow Insulin, IGF-I and -II Placental metabolism

Fatty acids

Facilitated diffusion

Fatty acid binding protein

Concentration gradient Uterine and umbilical blood flow Hormones? Placental metabolism

Oxygen

Simple diffusion

Extraction fraction by tissues Redistribution ofblood flow Prior exposure to episodes of reduced oxygen tension

Oxygen consumption remains fairly constant with changes in nutritional state and with hyperoxia,73 although consumption can be increased by provision of excess nutrients such as glucose or amino acids,74 or by increased levels of metabolic hormones such as thyroxine.75 Hypothyroidism reduces fetal oxygen consumption,76,77 but in sheep there is little reduction in oxygen consumption if glucose supply is restricted by fasting the ewe.74 Fetal oxygen supply is determined by maternal oxygenation, and thence by uterine and umbilical blood flows. The fetus operates at the upper end of the cardiac function curve and thus has limited capacity for increasing tissue oxygen supply by increasing cardiac output. However, the fetus can adapt to a limitation in oxygen supply by extracting more oxygen from hemoglobin,78,79 increasing oxygen-carrying capacity by increasing hemoglobin and by making cardiovascular adaptations. Studies in sheep have demonstrated that when fetal oxygen supply is reduced below a critical level, there is redistribution of cardiac output away from "non-essential" organs, such as the carcass, to essential organs, such as the brain.80,81 Ultrasound studies in humans suggest that similar changes occur.82,83 If oxygen deprivation is severe or prolonged, fetal oxygen consumption falls and becomes proportional to oxygen delivery.69,84 Interestingly, it appears that the fetal response to an acute episode of hypoxemia in late gestation can be altered by the presence of an earlier mother placenta fetus mother placenta fetus

Placenta Transfer Nutrients
Figure 1.3. Placental transfer and metabolism of nutrients. CO2 = carbon dioxide, NH3 = ammonia, ser = serine, gly = glycine, CH3 = methyl group, TG = triglyceride, LDLR = low density lipoprotein receptor, NEFA = non-esterified fatty acid, FFA = free fatty acid, FABP = fatty acid binding protein.

insult. Fetal sheep exposed to reversible umbilical cord compression which reduced umbilical blood flow by 30% for 3 days then failed to increase oxygen and glucose extraction and blood lactate levels in response to a later acute hypoxemic insult.85 Gardner et al. propose that this adaptation may be a protective mechanism against elevated lactate levels during hypoxic stress.

Glucose metabolism

Glucose is the major fetal oxidative substrate in utero. Glucose crosses the placenta by facilitated diffusion down a concentration gradient from mother to fetus. Thus fetal glucose concentration is always directly related to but lower than that of the mother, although the ratio of maternal:fetal glucose concentrations varies between species. Inhumans, fetal glucose concentrations are 60-70% of maternal levels, and the glucose:oxygen quotient is about 0.8. In sheep, fetal levels are only 25-30% of maternal levels, and the glucose:oxygen quotient is about 0.55.

In the ovine fetus glucose utilization is between 20-40 |imol Kg-1 • min-1, but this can double when extra glucose is provided experimentally, demonstrating that utilization is probably limitedbysupplyrather than by the capacity of the fetus to metabolize glucose. Although the glucose:oxygen quotient in mammals varies between 0.5 and 0.8, not all the glucose entering the fetal circulation is oxidized.86 The amount that is oxidized increases with increasing glucose concentration, suggesting that when glucose is in plentiful supply, other substrates are spared from oxidation. Non-oxidized glucose is used in other metabolic pathways. Thus glucose oxidation only accounts for about 30% of oxygen consumption in the sheep fetus.86 In late gestation the fetal liver is capable of gluconeogenesis from substrates such as lactate and alanine,87,88 but it appears that the contribution of endogenous gluconeogenesis to fetal glucose supply is normally negligible.25,88,89

The supply of glucose across the placenta appears to be limited by its diffusion characteristics rather than by blood flow. The main factors affecting these diffusion characteristics are the transplacental concentration gradient, placental utilization of glucose and capacity of the glucose transporters (GLUT) to transport the substrate. In the sheep, placental glucose transfer capacity increases 10fold over the second half of pregnancy, maintaining glucose supply to the fetus as the fetus grows. This increase arises in part due to an increase in placental transfer capacity, presumably due to the increase in numbers of glucose transporters,90-92 and in part to a fall in fetal glucose concentration, thus increasing the maternal-fetal glucose concentration gradient.93 A similar fall in fetal glucose concen trations in late gestation, with an increase in the maternal-fetal glucose concentration gradient has been reported in human pregnancies.94 The placenta has a high metabolic rate of its own, and extracts 60-75% of the glucose taken up from the uterine artery for its own metabolism. Thus placental glucose uptake has an important influence on fetal glucose supply (see below). If uterine glucose supply from the mother is reduced by decreasing uterine blood flow, the placenta may even take up glucose from the fetus to maintain its own metabolic requirements.95 Some of the glucose taken up by the placenta is recycled to the fetus as lactate or fructose, but as placental glucose uptake increases with further reductions in uterine blood flow there is a net loss of glucose from the fetus to the placenta.

The transport of glucose across the placenta is mediated by glucose transporters. At least six different glucose transporters are now known, and several members of the GLUT family have been described in the human placenta, although only GLUT-1 is found in the syncytium.96 In the rat and the sheep, both GLUT-1 and GLUT-3 are present in the placenta,90-92,97,98 and the levels of both increase with increasing gestation.90-92 However, in the sheep GLUT-1 expression peaks at around 120 days (term = 145 days) whereas GLUT-3 expression continues to increase until term.90 In the rat placenta GLUT-3 expression is polarized to the maternal microvillous membrane (MVM), whereas GLUT-1 is expressed on both the MVM and the fetal-facing basal membrane (BM).97 In the human, the distribution of GLUT-1 in syncytium is also asymmetric, with higher concentrations on the MVM than the BM. When combined with the greater surface area of the MVM (the maternal facing membrane) compared with the BM (the fetal facing membrane), it is likely that GLUT-1 density on the BM is the determinant for the rate of placental glucose transport.99 GLUT-1 concentrations in the MVM of the human placenta do not appear to increase with increasing gestation.100,101 However, GLUT-1 expression and activity in the BM increase significantly in later gestation.101 Placental glucose transport also increases in late gestation.

The regulation of glucose transporter levels has been studied in several tissues, although there is little work specifically looking at regulation in the placenta. In the sheep, hypoglycemia down-regulates placental GLUT-1 levels. Hyperglycemia initially up-regulates placental GLUT-1 levels, although with chronic hyperglycemia there is subsequently a decline in levels.102 No changes in placental GLUT 1 levels were seen in streptozotocin-induced diabetic rats, although hypoglycemia together with hypoxia following uterine artery ligation resulted in a 50% fall in GLUT-1 levels.102 In the human, placental

GLUT-1 levels appear to be inversely related to high glucose concentrations,103,104 although other data suggest that variations in glucose concentration within the physiological range do not affect GLUT-1 levels.105 In both human and animal IUGR no change in placental GLUT-1 levels have been seen,101,106 although down-regulation of GLUT-3 has been reported in the placentae from undernourished rats.107 In diabetic pregnancies a substantial increase in GLUT-1 levels on the BM has been reported with no change in MVM GLUT-1 levels.108,109 Placen-tal glucose transport was increased by between 40 and 60%. It has been proposed that this up-regulation in BM GLUT-1 levels and consequent glucose transport may be involved in macrosomic growth of the fetus in diabetic pregnancies.96

In other tissues, such as brain and muscle, glucose transporters are up-regulated by IGF-I.110-113 Insulin also up-regulates membrane translocation of both GLUT-1 and GLUT-3 in brain and myotubules.111,112 The regulation of the glucose transporters by insulin and IGF-I has not been well studied in placental tissue.

Lactate metabolism

Lactate is also an important fuel for the fetus. In ruminants, such as the sheep andcow, thefetallactate:oxygen quotient is between 0.25 and 0.4, compared with only 0.1 for the human.71 Endogenous production of lactate by the fetus is high even in unstressed fetuses, and most of this is derived from glucose, although some is derived from other carbon sources. The major site of lactate production in the fetus is the carcass, and lactate release from here may provide fuel for other fetal organs in times of substrate deprivation.114 The placenta is also a major source of fetal lactate. A significant proportion of placental glucose utilization in sheep is directed towards lactate production which, in late gestation, is released into both the uterine and umbilical circulations.115,116 Most of the lactate taken up by the sheep fetus is oxidized to CO2, and this CO2 contributes substantially to total fetal CO2 production.117 However some lactate is incorporated into fetal tissue, including hepatic glycogen, non-essential amino acids and lipids.118 Thus, the lactate:oxygen quotient underestimates the proportion of fetal oxygen consumption that is accounted for by lactate oxidation.71 Lactate utilization by the fetus may increase substantially in the face of undernutrition.119

Lactate concentrations in the fetus are higher than in the mother, and fetal pH is lower. Both the MVM and the BM of the placenta express proton-dependent, sodium-independent lactate transporters.1,5,120-122 These transporters appear to be reversible, allowing transport of lactate in either direction.120 Thus, lactate can be provided to the fetus as a fuel, or removed should lactate accumulate in the fetus posing a risk to tissues.

Amino acid metabolism

Amino acids are utilized by the fetus for protein synthesis and for oxidation, and certain amino acids are also essential components of pathways such as purine and pyrimi-dine synthesis. Essential amino acids must be derived from maternal circulating amino acids, whereas non-essential amino acids could be derived either from de novo synthesis by the fetus, from transplacental transfer or via placental synthesis. As well as the traditionally accepted essential amino acids, arginine is regarded as conditionally essential in the fetus. Total amino-nitrogen concentrations in the fetus are higher than in the mother, and concentrations in the placenta for some amino acids are higher than in either the maternal or fetal circulations.

Calculations of uterine and umbilical uptakes of amino acids in the sheep using the Fick principle123 have demonstrated large uptakes of most basic and neutral amino acids by both the placenta124 and fetus.125 Utero-placental amino acid uptake provides nitrogen in excess of amounts required by the fetus for protein accretion, and the difference is accounted for by ammonia production by the placenta.124,126 The ammonia produced is released into both the maternal and fetal circulations, where it is converted into urea by the fetal liver.127 Most of the ammonia is produced by placental metabolism of the branched chain amino acids leucine, isoleucine and valine.128 Both ovine129,130 and human placentae131 have high branched chain amino acids (BCAA) amino transaminase activities, and significant amounts of the products of BCAA deamination, the branched-chain alpha-keto acids, are released from the ovine placenta into maternal and fetal circulations.132,133 The role of placental metabolism of BCAA may include oxidation as an energy source, conversion to glutamate by transamination and to make nitrogen available for purine synthesis. The proportion of amino acids utilized by the placenta for oxidation increases as glucose availability falls, and in severe conditions BCAA and glutamate may be extracted from the fetal circulation for consumption by the placenta.130,134

Amino acids are transported across the placenta by active transport. Many different classes of amino acid transporter have nowbeen described in the placenta135 and are present on both the MVM and the BM.136 Experiments on isolated human placental cotyledons have demonstrated that the placenta can take up amino acids from both the maternal and fetal circulations against a concentration gradient.137 Thus the amino acid transporters on the MVM probably have a more important effect on net transfer of amino acids from mother to fetus.

Placental levels of amino acid transporters are related to fetal amino acid concentrations and thus to fetal nutrition. For example, levels of the system A amino acid transporter have been related to anthropometric measurements at birth,138 but it is not clear if down-regulation of amino acid transporters follows a reduced growth trajectory, or if the reduced growth is secondary to lower levels of amino acid transporters.139 MVM levels and activity of both system A transporters140-144 and p-amino acid transporters35 are reduced in IUGR, and the activity of the system A transporter is associated with the severity of the IUGR.140 Oxygenation of the uteroplacental unit has also been correlated with levels of systemA and cationic amino acid transporter activity.145,146 Transplacental transfer of the BCAA leucine has been studied in sheep with IUGR induced by heat stress using tracer techniques.147 Net uterine uptake, uteroplacental utilization, flux from placenta to fetus and direct maternal-fetalfluxwere allreducedin IUGR animals.

Further good evidence for a direct role of the amino acid transporters in fetal nutrition and thus growth comes from studies in mice with deletion of a placental-specific transcript (P0) of the Igf2 gene.148 Placental growth was restricted from embryonic day 12 (E12), but the transfer of 14C-methylaminoisobutyric acid (MeAIB) per gram of placenta was significantly increased compared with wild type until E16, resulting in transfer of identical amounts of 14C-MeAIB across the placenta. At this time (E16) fetal weight was also not different between mutant and wild type mice. By E19 the increase in transfer of 14C-MeAIB per gram placenta was reduced and therefore, when combined with the reduced placental size, total transfer was also reduced by 26%. By E19 fetal weight in mutants was reduced by 22% compared with wild type.148

In addition to amino acid transfer, the placenta is also involved in metabolism of amino acids. The most notable examples of placental amino acid metabolism are the glycine-serine and glutamine-glutamate placenta-hepatic shuttles. These appear to be mechanisms by which nitrogen and carbon can be shuttled between the placenta and fetal liver.29 In sheep, there is very little umbilical uptake of serine, with almost all fetal serine arising from hepatic production from placental glycine.149 Serine derived from the fetal pool is used within the placenta for glycine production, some of which is then returned to the fetal circulation. The net effect of such cycling is the transfer of methyl groups derived from glycine oxidation within the liver to the placenta.149,150

The ovine placenta takes up glutamate from the fetal circulation,126 and also forms glutamate by oxidizing branch chain amino acids taken up from the maternal circulation.151 Amidation of glutamate produces glu-tamine, which is released into the fetal circulation.152 Some of the glutamine delivered to the fetus from the placenta is converted back to glutamate by the fetal liver, which is the main source of glutamate consumed by the placenta.152 Thus a glutamate-glutamine shuttle is established, promoting glutamate amidation by the placenta and allowing hepatic utilization of the amide group of glutamine. This amide group, together with glycine and methylene tetrahy-drofolate (derived from the conversion of serine to glycine) can be used for purine synthesis.

Fatty acid metabolism

The human baby is born with a large proportion of fat, and fat deposition increases exponentially with gesta-tional age. Near term the accretion rate is ~7 g day-1. 153 Early in gestation, the fetus derives most of the fatty acids from the mother, but as gestation progresses there is increased de novo synthesis.74,154,155 Fatty acids are required by the fetus for membrane formation, as precursors of compounds such as prostaglandins, and as a source of energy. All fatty acids can be used as an energy source, but the structural functions are largely performed by the polyunsaturated fatty acids (PUFA). Humans cannot synthesize the «3 and «6 fatty acids, and these essential fatty acids must therefore be provided by the mother. Intrauterine requirements for «3 and «6 fatty acids in late gestation have been calculated to be approximately 400 and 50 mgKg-1 • day-1 respectively.154 In tissues such as the brain, almost half of the lipid content is comprised of long chain polyunsaturated fatty acids (LCPUFA) such as arachidonic acid (AA) anddocosahexanoic acid (DHA). The percentage of fatty acids in fetal circulation composed of LCPUFAis higher than in the mother,156 despite the fact that the human placenta lacks A5- and A6-desaturase activity and is therefore unable to convert y-linolenic acid (18:3, «6) into AA (20:4, «6).157 The placenta must therefore be able to extract LCPUFA from the maternal circulation and deliver them to the fetus.

Free fatty acids (FFA) can directly cross the placenta, probably via facilitated membrane translocation involving a plasma membrane fatty acid-binding protein (FABP). There appears to be a specific placental FABP that has higher affinities and binding capacities for AA and DHA compared with FABPs in other tissues.120,158,159 Placental FABP are found on both the MVM and the BM. Transport of FFA across the placenta via FABP is ATP dependent at the MVM and ATP and Na+ dependent at the BM,160 but appears to occur predominantly as facilitated transport down a concentration gradient. However, FFA represents a very small amount of PUFA in the maternal circulation, as most are esterified and associated with lipoproteins (VLDL and LDL). Unlike FFAs, triglycerides (TG) and glycerol are not able to cross the placenta in any significant amount.161 Transfer of LCPUFAfrom mother to fetus therefore involves placental uptake and metabolism of maternal lipoproteins and TGs. The MVM of trophoblast expresses receptors for both VLDL and LDL,162-164 enabling uptake of circulating maternal lipoproteins into the placenta. The TG are then hydrolyzed by lipoprotein lipase and the FFA diffuse into the fetal circulation, from where they are taken up by the fetal liver and re-esterified into TG before being released back into the circulation.

In other species TG also do not cross the placenta in any appreciable quantities, and most of the fetal FFA are derived from hydrolysis and re-esterification.154,157,165-167 The ovine placenta does express increasing levels of A6-desaturase during late gestation,156,168,169 suggesting that there may be some placental synthesis of AA by the ovine placenta, although there is no direct transfer of TG from mother to fetus.167

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Responses

  • Hamza Jamieson
    What percentage of fetal oxygen delivery requirement is provided by placenta?
    7 years ago
  • Jolanda
    Does sex influence transport of substances across the placenta?
    7 years ago

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