Fetal Uptake Research Articles

Fetal Secretory IgA Delivery via Transamniotic Fetal Immunotherapy (TRAFIT) in a Rodent Model

PurposeWe sought to determine the feasibility and routing kinetics of transamniotic fetal delivery of secretory immunoglobulin-A (SIgA), in a rodent model. MethodsFetuses (n = 94) from seven time-dated pregnant dams received intra-amniotic injections on gestational day 17 (E17, term = E21–22) of either saline (n = 15) or a solution of 1 mg/mL of ≥95% homogeneous human SIgA (n = 79). Animals were euthanized daily at E18–E21 for quantification of the IgA component by ELISA at gestational membranes, placenta, and select fetal anatomical sites against saline controls procured at term. Statistical analysis was by Mann–Whitney U-test. ResultsNone of the saline-injected animals had detectable human IgA. SIgA-injected fetuses showed human IgA in the stomach aspirate, intestinal wall, lungs, liver, and serum at all time points. IgA levels were significantly higher in the gastric aspirate and in the intestine than in all other sites (p < 0.001 for both), with intestinal levels remaining stable through E18–E21 (p = 0.09–0.62 pairwise). Serum and placental levels were consistently low throughout, reaching near zero levels by E21. ConclusionsThe chronology of exogenous secretory-IgA kinetics after intra-amniotic injection is suggestive of fetal uptake by ingestion, leading to consistent levels in the gastrointestinal tract. Transamniotic fetal immunotherapy (TRAFIT) with secretory-IgA may become a novel strategy for enhancing early mucosal immunity. Level of EvidenceN/A (animal and laboratory study). Type of StudyAnimal and laboratory study.

Uteroplacental versus fetal use of glucose in healthy pregnancies at term. A human in vivo study

IntroductionFetal glucose is thought to originate from maternal glucose driven across the placenta by a maternal-fetal glucose gradient. Still, there is no correlation between the mass of glucose taken up by the uteroplacenta and the fetal uptake. We propose a hypothesis that the uteroplacenta's own treatment of glucose affects the net mass of glucose taken up by the fetus, independent of the maternal-fetal gradient. MethodsWe performed a human in vivo study of term uncomplicated pregnancies including seventy healthy women delivered by scheduled cesarean delivery. We measured uterine and umbilical blood flow by Doppler ultrasonography, and glucose concentrations in the maternal radial artery, uterine vein, umbilical artery and vein. We calculated Spearman's correlations between uteroplacental and fetal glucose uptake within tertiles of placental glucose consumption. ResultsThere were significant correlations between uteroplacental uptake and fetal uptake of glucose when determined within each tertile (Spearman's rho 0.76, (p < 0.001); 0.94 (p < 0.001) and 0.49 (p = 0.029) from lowest to highest tertile, respectively). The median (Q1, Q3) uteroplacental glucose consumption in each tertile was −88.8 (−140.3, 56.7), 29.7 (9.2, 47.4) and 174.7 (87.8, 226.1) (μmol/min). The corresponding median (Q1, Q3) fetal glucose uptake was 152.9 (94.2, 162.7), 110.8 (54.7, 167.2) and 66.6 (8.5, 122.1) (μmol/min). DiscussionThe maternal fetal glucose gradients were similar in the tertiles of placental glucose consumption. Still, the net mass of glucose taken up by the fetus was markedly different between the tertiles. Placental treatment of glucose exhibited a large variation from apparent production to consumption.

248 Maternal Nutrient Restriction During Mid-gestation Decreases Uteroplacental Release and Fetal Uptake of Essential Amino Acids in Sheep

Abstract To examine the effects of maternal nutrient restriction on net uteroplacental flux during mid-gestation, 14 singleton ewes (48.2 ± 4.0 kg body weight) were fed 100% (control; CON; n = 7) or 60% of nutrient requirements (restricted; RES; n = 7) from day 50–90 (mid-gestation). On day 90, uteroplacental blood flow was measured via Doppler ultrasonography and blood samples were collected from the femoral artery, uterine vein, umbilical artery, and umbilical vein. Blood vessel glucose and amino acids (AA) concentrations were measured and arterial-venous (uterine, AV; fetal, va) differences and net fluxes were calculated. Data were analyzed using the GLM procedure of SAS for effects of treatment. Nutrient restriction during mid-gestation did not influence (P ≥ 0.17) uterine or umbilical blood flows. Uterine AV and fetal va differences of total, essential, and nonessential AA were not influenced (P &amp;gt; 0.10) by nutrient restriction. Nutrient restriction decreased (P ≤ 0.05) uterine and uteroplacental release of total AA and tended to decrease (P = 0.07) total AA uptake by the fetus. Uteroplacental release and fetal uptake of essential AA were decreased (P = 0.03) with RES by 53.4% and 45%, respectively. Uterine and uteroplacental release of nonessential AA were decreased (P = 0.03) with RES but, fetal uptake was not affected (P = 0.14). Nutrient restriction decreased (P ≤ 0.04) fetal uptake of methionine, phenylalanine, threonine, and valine and tended to decrease (P ≤ 0.10) fetal uptake of isoleucine, leucine, and tryptophan. Umbilical artery glucose concentrations were 32% lesser (P = 0.01) with RES and RES tended to increase (P = 0.08) fetal glucose uptake. Nutrient restriction during mid-gestation altered uteroplacental and fetal flux of AA in the current study. The results may indicate that fetal metabolism shifts to adapt to reduced AA supply which results in greater glucose utilization.

Endocrine regulation of fetal metabolism towards term

Hormones have an important role in regulating fetal metabolism in relation to the prevailing nutritional conditions both in late gestation and during the prepartum period as the fetus prepares for birth. In particular, the pancreatic, thyroid and adrenal hormones all affect fetal uptake and utilization of nutrients for oxidative metabolism, tissue accretion and fuel storage. These hormones also influence the fetal metabolic preparations for the nutritional transition from intra- to extra-uterine life. This review discusses the role of insulin, glucagon, thyroxine, tri-iodothyronine, cortisol and the catecholamines in these processes during normal intrauterine conditions and in response to maternal undernutrition with particular emphasis on the sheep fetus. It also considers the metabolic interactions between these hormones and their role in the maturation of key tissues, such as the liver, skeletal muscle and adipose tissue, in readiness for their new metabolic functions after birth. Endocrine regulation of fetal metabolism is shown to be multifactorial and dynamic with a central role in optimizing metabolic fitness for survival both in utero and at birth.

The challenge of using nanotherapy during pregnancy: Technological aspects and biomedical implications

During the period of pregnancy, several processes and physiological adaptations occur in the body and metabolism of pregnant woman. These physiological adaptations in pregnant woman end up leading to a suppression in immune system favoring obstetric complications to the mother, fetus and placental tissue. An effective pharmacological therapy for these complications is still a challenge, since some drugs during pregnancy can have deleterious and teratogenic effects. An emerging alternative to pharmacological therapy during pregnancy is drugs encapsulated in nanoparticles (NP), recent area called nano-obstetrics. NP have the advantage of drug targeting and reduction of side effects. Then, maternal, placental or fetal uptake can be expected, depending on the characteristics of NP. Inorganic NP, crossing placental barrier effectively, but have several nanotoxicological effects. While organic NP appear to have a better targeting capacity and have few toxicological effects, but the studies are still scarce. Thus, in this review, were examined questions related to use and impact of physicochemical aspects of inorganic and organic NP during pregnancy.

Maternal Red Blood Cell Catabolism as a Source of Fetal Iron

Abstract Objectives The developing fetus is reliant on maternal iron (Fe) supply across gestation. Fetal Fe may be obtained from maternal red blood cell (RBC) catabolism, dietary sources or maternal stores. Relative use of these Fe pools has not been explored in humans. The objective of this study was to label the maternal RBC pool in early gestation and evaluate determinants of RBC enrichment across. A second objective was to compare fetal uptake of Fe from RBC catabolism vs recent maternal diet. Methods Fifteen women (age 17–34 y) were dosed with an oral stable ,57Fe isotope during the early second trimester of pregnancy (wk 15 ± 0.7) to label the maternal RBC pool. Enrichment of ,57Fe in maternal RBCs was monitored at regular intervals across pregnancy and in neonatal RBC's at birth. All women ingested an additional stable isotope (,58Fe) in late gestation (wk 34 ± 0.7) to quantify rapid transfer of dietary Fe to the fetus. The net amounts of each isotope in the mother and neonate were calculated using hemoglobin (Hb) concentration, body weight and estimated blood volumes. Hb, serum ferritin (SF), soluble transferrin receptor (sTfR), hepcidin and erythroferrone (ERFE) were assessed in maternal and cord blood. Results In this population, 25% of women were anemic at delivery (Hb &amp;lt; 11 g/dL), and 36% of the newborns were anemic at birth (wk 39 ± 1.8) (Hb &amp;lt; 13 g/dL). During the third trimester of pregnancy, 25% of women were Fe deficient (SF &amp;lt; 12 mg/L). In the group as a whole, RBC ,57Fe enrichment decreased (b = −0.2, P = 0.06) on average by 2% across the 22 wk study interval (from 13.1% to 9.6%). Of the net amount of ,57Fe released from RBC catabolism, 25.4% [95% CI: 10.0%–64.4%] was transferred to the neonate. Neonatal RBC ,57Fe enrichment was significantly inversely associated with maternal and neonatal SF, which captured 87% of the variance in neonatal RBC ,57Fe enrichment (P &amp;lt; 0.01). Maternal SF was significantly inversely associated with neonatal RBC ,58Fe enrichment from the dietary source in late gestation. Maternal SF captured 55% of the variance in neonatal RBC ,58Fe enrichment (P = 0.01). Conclusions Women with low Fe stores exhibited a greater loss of RBC enrichment across gestation and a higher transfer of Fe from both catabolized RBC's and dietary sources to the fetus. More research on the determinants of placental Fe trafficking of different sources of maternal Fe is needed. Funding Sources Work funded by the NIH/NIDDK.

Fetal Oxygen and Glucose Consumption in Human Pregnancy Complicated by Fetal Growth Restriction.

In healthy pregnancy, glucose and oxygen availability are essential for fetal growth and well being. However, how substrate delivery and fetal uptake are affected in human pregnancy complicated by fetal growth restriction (FGR) is still unknown. Here, we show that the human FGR fetus has a strikingly reduced umbilical uptake of both oxygen and glucose. In 30 healthy term and 32 FGR human pregnancies, umbilical volume flow (Qumb) and parallel umbilical vein (uv) and artery (ua) blood samples were obtained at elective Cesarean section to calculate fetal glucose and oxygen uptake as Qumb · Δ (uv-ua) differences. Umbilical blood flow was significantly lower in FGR pregnancy (-63%; P<0.001) but not when normalized for fetal body weight. FGR pregnancy had significantly lower umbilical oxygen delivery and uptake, both as absolute values (delivery: -78%; uptake: -78%) and normalized (delivery: -50%; uptake: -48%) for fetal body weight (all P<0.001). Umbilical glucose absolute delivery and uptake were significantly reduced (delivery: -68%; uptake: -72%) but only glucose uptake was decreased when normalized for fetal body weight (-30%; P<0.05). The glucose/oxygen quotient was significantly increased (+100%; P<0.05) while glucose clearance was significantly decreased (71%; P<0.001) in FGR pregnancy (both P<0.05). The human fetus in FGR pregnancy triggers compensatory mechanisms to reduce its metabolic rate, matching the proportion of substrate consumption relative to oxygen delivery as a survival strategy during complicated pregnancy.

Maternal-fetal cholesterol transfer in human term pregnancies

ObjectivesThe extent to which the human term fetus utilizes cholesterol released from the placenta has remained elusive.Our aims were to estimate the net mass of cholesterol taken up by the uteroplacental unit, released by the placenta and taken up by the fetus. Thereby we aimed to explore the maternal-fetal cholesterol transfer and hypothesized that maternal levels and uteroplacental uptake were correlated to the fetal uptake of cholesterol. MethodsA cross-sectional in vivo study of 179 fasting, healthy women with uncomplicated singleton pregnancies. Blood flow in the uterine artery (n = 70) and umbilical vein (n = 125) was measured by Doppler ultrasound. Blood samples from the maternal radial artery, antecubital vein and uterine vein, and the umbilical artery and vein were obtained during cesarean section. Cholesterol was determined enzymatically. ResultsWe found a significant uteroplacental uptake (median [Q1,Q3]) of total (3.50 [-36.8,61.1]) and HDL cholesterol (6.69 [-3.78,17.9]) μmol/min, and a fetal uptake of HDL (8.07 [4.48,12.59]), LDL (5.97 [2.77,8.92]) and total cholesterol (13.2 [8.06,21.58]) μmol/min. Maternal cholesterol levels were not correlated to fetal uptake of cholesterol. There was a correlation between uteroplacental uptake of total (rho 0.35, p 0.003) and LDL cholesterol (rho 0.25, p 0.03) and the fetal uptake of LDL cholesterol from the umbilical circulation. The fetal uptake of cholesterol from HDL was higher than from LDL (p < 0.001). ConclusionFetal cholesterol uptake is independent of maternal cholesterol levels, but related to the uteroplacental uptake of cholesterol from LDL. This suggests that the placenta influences maternal-fetal cholesterol transfer at term.

Clustered villous mineralization: a placental feature of fetal vascular malperfusion in prolonged retained stillbirth

The extent to which the human term fetus utilizes cholesterol released from the placenta has remained elusive.Our aims were to estimate the net mass of cholesterol taken up by the uteroplacental unit, released by the placenta and taken up by the fetus. Thereby we aimed to explore the maternal-fetal cholesterol transfer and hypothesized that maternal levels and uteroplacental uptake were correlated to the fetal uptake of cholesterol.A cross-sectional in vivo study of 179 fasting, healthy women with uncomplicated singleton pregnancies. Blood flow in the uterine artery (n = 70) and umbilical vein (n = 125) was measured by Doppler ultrasound. Blood samples from the maternal radial artery, antecubital vein and uterine vein, and the umbilical artery and vein were obtained during cesarean section. Cholesterol was determined enzymatically.We found a significant uteroplacental uptake (median [Q1,Q3]) of total (3.50 [-36.8,61.1]) and HDL cholesterol (6.69 [-3.78,17.9]) μmol/min, and a fetal uptake of HDL (8.07 [4.48,12.59]), LDL (5.97 [2.77,8.92]) and total cholesterol (13.2 [8.06,21.58]) μmol/min. Maternal cholesterol levels were not correlated to fetal uptake of cholesterol. There was a correlation between uteroplacental uptake of total (rho 0.35, p 0.003) and LDL cholesterol (rho 0.25, p 0.03) and the fetal uptake of LDL cholesterol from the umbilical circulation. The fetal uptake of cholesterol from HDL was higher than from LDL (p < 0.001).Fetal cholesterol uptake is independent of maternal cholesterol levels, but related to the uteroplacental uptake of cholesterol from LDL. This suggests that the placenta influences maternal-fetal cholesterol transfer at term.

Adaptive changes in the maternal pancreas to deal with the demands of the growing fetus

The extent to which the human term fetus utilizes cholesterol released from the placenta has remained elusive.Our aims were to estimate the net mass of cholesterol taken up by the uteroplacental unit, released by the placenta and taken up by the fetus. Thereby we aimed to explore the maternal-fetal cholesterol transfer and hypothesized that maternal levels and uteroplacental uptake were correlated to the fetal uptake of cholesterol.A cross-sectional in vivo study of 179 fasting, healthy women with uncomplicated singleton pregnancies. Blood flow in the uterine artery (n = 70) and umbilical vein (n = 125) was measured by Doppler ultrasound. Blood samples from the maternal radial artery, antecubital vein and uterine vein, and the umbilical artery and vein were obtained during cesarean section. Cholesterol was determined enzymatically.We found a significant uteroplacental uptake (median [Q1,Q3]) of total (3.50 [-36.8,61.1]) and HDL cholesterol (6.69 [-3.78,17.9]) μmol/min, and a fetal uptake of HDL (8.07 [4.48,12.59]), LDL (5.97 [2.77,8.92]) and total cholesterol (13.2 [8.06,21.58]) μmol/min. Maternal cholesterol levels were not correlated to fetal uptake of cholesterol. There was a correlation between uteroplacental uptake of total (rho 0.35, p 0.003) and LDL cholesterol (rho 0.25, p 0.03) and the fetal uptake of LDL cholesterol from the umbilical circulation. The fetal uptake of cholesterol from HDL was higher than from LDL (p < 0.001).Fetal cholesterol uptake is independent of maternal cholesterol levels, but related to the uteroplacental uptake of cholesterol from LDL. This suggests that the placenta influences maternal-fetal cholesterol transfer at term.

Recent insights on the role and regulation of retinoic acid signaling during epicardial development.

The vitamin A metabolite, retinoic acid, carries out essential and conserved roles in vertebrate heart development. Retinoic acid signals via retinoic acid receptors (RAR)/retinoid X receptors (RXRs) heterodimers to induce the expression of genes that control cell fate specification, proliferation, and differentiation. Alterations in retinoic acid levels are often associated with congenital heart defects. Therefore, embryonic levels of retinoic acid need to be carefully regulated through the activity of enzymes, binding proteins and transporters involved in vitamin A metabolism. Here, we review evidence of the complex mechanisms that control the fetal uptake and synthesis of retinoic acid from vitamin A precursors. Next, we highlight recent evidence of the role of retinoic acid in orchestrating myocardial compact zone growth and coronary vascular development.

Placental transport of nutrients and its implications for fetal growth

Placental growth during early and mid-pregnancy has a powerful, constraining influence on fetal growth during late pregnancy. Studies involving surgical and environmental reduction of placental size in sheep have shown an associated reduction in capacity to transport oxygen, glucose and amino acids. Oxygen transport is limited by placental blood flow but transport of glucose and amino acids is determined by the abundance and activity of specific transport proteins. Glucose transporters include the GLUT1 and GLUT3 isoforms previously identified in brain and other tissues; systems for active transport of amino acids have been inferred but not characterized. Placental metabolism of glucose and amino acids has major effects both on the quantity of carbon and nitrogen delivered to the fetus, and on the composition of substrates involved. For example, the uteroplacental tissues consume more than 60% of uterine glucose uptake during late pregnancy, and the placenta substantially modifies the pattern of amino acids delivered to fetal blood. The placenta also participates in the array of metabolic adaptations of maternal and conceptus tissues to altered maternal nutrient supply. Placental capacity for glucose transport in moderately undernourished ewes is upregulated, partly by increased expression of the GLUT3 transport protein. During more severe glucose deprivation, placental transfer and fetal uptake of glucose are constrained in proportion with maternal supply, leading to fetal growth retardation.

A newborn with seizures born to a mother diagnosed with primary carnitine deficiency

BackgroundMaternofetal carnitine transport through the placenta is the main route of fetal carnitine uptake. Decreased free carnitine levels discovered by newborn screening has identified many asymptomatic adult women with systemic primary carnitine deficiency (PCD). Here, we presented amplitude integrated electroencephalogram (aEEG) and magnetic resonance imaging (MRI) findings from a neonate with epilepsy whose mother was carnitine deficient.Case presentationA one-day-old female newborn was admitted after experiencing seizures for half a day; status epilepticus was found on the continuous normal voltage background pattern with immature sleep-wake cycling during aEEG monitoring. On T1-weighted, T2-weighted, FLAIR, and DWI head MRI, there were various degrees of hyperintense signals and diffusion restrictions in the deep white matter of the right hemisphere. Tandem mass spectrometry discovered carnitine deficiency on the second day, which elevated to normal by the 9th day before L-carnitine supplementation was started. The patient was treated with phenobarbital after admission. No further seizures were noted by day 5. It was confirmed that the patient’s mother had a low level of serum-free carnitine. Gene analyses revealed that the newborn had heterozygote mutations on c.1400C > G of the SLC22A5 gene, and her mother had homozygous mutations on c.1400C > G. The patient had a good outcome at the 8-month follow up.ConclusionsMaternal carnitine deficiency that occurs during the perinatal period may manifest as secondary epilepsy with cerebral injury in neonates. The short-term neurodevelopmental outcomes were good. Early diagnosis of asymptomatic PCD in female patients can provide guidance for future pregnancies.

Peculiarities of glucose intake in fetal tissues in chronic hypoxemia

Objective — to investigate fetal blood distribution and glucose metabolism of heart, liver and brain during chronic hypoxaemia. Establishment of a model of real time measurement of the metabolic changes during chronic fetal hypoxaemia using PET-CT measurement in pregnant sheep after iatrogenic induction of chronic fetal hypoxaemia. Laser coagulation of placental vessels was performed in pregnant sheep in order to cause fetal hypoxaemia 14 days before the PET-procedure. The following PET-Scans were performed after 18F-FDG was injected into the jugular vein of the sheep. Fetal glucose uptake was scanned in fetal brain, liver, heart and kidneys during a period of 60 min after injection of the FDG tracer. Glucose uptake of these organs was measured in comparison with placental glucose uptake during the above-called 60 minutes course. Here we present the analysis of the metabolic changes in fetal hypoxaemia in a small series of 8 fetal sheep. It was found that FDG Uptake in the placenta, brain, liver and heart of the fetus was measured at normal oxygenation and in chronic hypoxia in 8 sheep fetuses, between 112 and 135 days of pregnancy (gestational age) 125±4 days (mean±SD). Umbilical cord artery resistance was significantly higher in hypoxemic fetuses compared to normoxemic. Venous duct reactions as a respond to hypoxia was observed. Index of pulsation in the umbilical artery was not significantly increased during hypoxia (1,06±0,18 та 1,67±0,12, р=0,018). PI in venous duct during chronic hypoxia (0,62±0,25) was increased in compare with normoxemic (0,41±0,2), but not significantly. Relative FDG uptake was about 3.8 times higher in brain of hypoxemic fetuses (0.019±0.005) compared to normoxemic (0.005±0.002), (р=0,02). In contrast, hypoxic fetal heart showed no significant difference in absorption of FDG compared to normoxemic fetal brain (p=0.11). Relative FDG uptake in the liver did not differ substantially between the two groups (p=0.97). Thus, it was shown that chronic maternal hypoxemia led to decreased placental and increased brain blood flow, although, glucose metabolism was not decreased in the fetal liver and heart.

Placental release of taurine to both the maternal and fetal circulations in human term pregnancies.

Taurine is regarded as an essential amino acid in utero, and fetal taurine supply is believed to rely solely on placental transfer from maternal plasma. Despite its potential role in intrauterine growth restriction and other developmental disturbances, human in vivo studies of taurine transfer between the maternal, placental, and fetal compartments are scarce. We studied placental transfer of taurine in uncomplicated human term pregnancies in vivo in a cross-sectional study of 179 mother-fetus pairs. During cesarean section, we obtained placental tissue and plasma from incoming and outgoing vessels on the maternal and fetal sides of the placenta. Taurine was measured by liquid chromatography-tandem mass spectrometry. We calculated paired arteriovenous differences, and measured placental expression of the taurine biosynthetic enzyme cysteine sulfinic acid decarboxylase (CSAD) with quantitative real-time polymerase chain reaction and western blot. We observed a fetal uptake (p<0.001), an uteroplacental release (p<0.001), and a negative placental consumption of taurine (p=0.001), demonstrating a bilateral placental release to the maternal and fetal compartments. Increasing umbilical vein concentrations and fetal uptake was associated with the uteroplacental release to the maternal circulation (rs=-0.19, p=0.01/rs=-0.24, p=0.003), but not with taurine concentrations in placental tissue. CSAD-mRNA was expressed in placental tissue, suggesting a potential for placental taurine synthesis. Our observations show that the placenta has the capacity to a bilateral taurine release, indicating a fundamental role of taurine in the human placental homeostasis beyond the supply to the fetus.

Vitamin E status and associations in maternal-infant Dyads in the Midwestern United States

Oxidative stress has been associated with adverse neonatal outcomes, and vitamin E has powerful anti-oxidant properties. Vitamin E occurs in several different isoforms which differ in their ability to modulate inflammation and oxidative stress. Therefore, the purpose of this study was to evaluate the status of α-, γ- and δ-tocopherol in maternal-infant pairs, and the impact on maternal-newborn outcomes. Vitamin E status was evaluated in 189 mother-infant pairs. Concentrations of α-, γ- and δ-tocopherol were measured using HPLC. Descriptive statistics were calculated and Spearman coefficients were used to assess correlations between maternal and cord measurements. Linear and logistic regression models were used to adjust for relevant confounders. A p<0.05 was considered statistically significant. Maternal and cord serum tocopherol concentrations were positively correlated for γ-tocopherol (r=0.32, p˂0.001) and δ-tocopherol (r=0.46, p˂0.001) but not for α-tocopherol. After adjustment for confounders, maternal concentrations of tocopherols were positively associated with Apgar scores (p=0.02) and infant growth parameters at birth. Conversely, cord tocopherol levels were inversely associated with Apgar scores (p=0.02) and infant growth. Cord concentrations of α-tocopherol were higher in infants born to mothers with a diagnosis of pre-eclampsia (p=0.04). Maternal-fetal transfer of γ- and δ-tocopherols is higher than α-tocopherol and may be mediated by either different or more efficient methods, conversely tissue uptake of α-tocopherol by the developing fetus may be higher. As serum levels of maternal tocopherols are positively associated with outcomes while higher cord levels show a negative impact, uptake and tissue deposition of vitamin E by the fetus may be crucial in growth and development. More research into the role of maternal diet, placental regulation, and fetal uptake of vitamin E tocopherols in relation to clinical outcomes is warranted.

Ovine uteroplacental and fetal metabolism during and after fetal cortisol overexposure in late gestation.

Cortisol modifies fetal metabolism in preparation for delivery, but whether preterm cortisol exposure programs persisting changes in fetoplacental metabolism remains unknown. This study infused fetal sheep with saline (n = 36) or cortisol (n = 27) to raise fetal plasma cortisol to normal prepartum concentrations for 5 days from day 125 of gestation (term: ≈145 days). Fetal uptake and uteroplacental metabolism of glucose, oxygen, and lactate, together with fetal hepatic glucogenic capacity, were measured on the final day of infusion or 5 days later. Cortisol reduced adrenal weight and umbilical glucose uptake during infusion but increased fetal glucose concentrations, hepatic glycogen content, and hepatic glucogenic enzyme activity (fructose-1,6-bisphosphatase and glucose-6-phosphatase) and gene expression (PC and G6PC) compared with saline infusion. Postcortisol infusion, umbilical glucose uptake, and hepatic glucose-6-phosphatase activity remained low and high, respectively, whereas fetal glucose levels normalized and hepatic glycogen was lower with higher adrenal weights than in controls. Cortisol infusion increased the proportion of total uterine glucose uptake consumed by the uteroplacental tissues, irrespective of age. Placental tracer glucose transport capacity was also increased after, but not during, cortisol infusion, without changes in placental glucose transporter gene expression. Blood lactate concentration and Pco2 were higher, whereas pH and O2 content were lower in cortisol-infused than saline-infused fetuses, although uteroplacental metabolism and fetal uptake of oxygen and lactate were unaltered. The results suggest that preterm cortisol overexposure alters fetoplacental metabolism and adrenal function subsequently with persisting increases in uteroplacental glucose consumption at the expense of the fetal supply.

Uptake and release of amino acids in the fetal-placental unit in human pregnancies.

ObjectivesThe current concepts of human fetal-placental amino acid exchange and metabolism are mainly based on animal-, in vitro- and ex vivo models. We aimed to determine and assess the paired relationships between concentrations and arteriovenous differences of 19 amino acids on the maternal and fetal sides of the human placenta in a large study sample.MethodsThis cross-sectional in vivo study included 179 healthy women with uncomplicated term pregnancies. During planned cesarean section, we sampled blood from incoming and outgoing vessels on the maternal (radial artery and uterine vein) and fetal (umbilical vein and artery) sides of the placenta. Amino acid concentrations were measured by liquid chromatography—tandem mass spectrometry. We calculated paired arteriovenous differences and performed Wilcoxon signed-rank tests and Spearman’s correlations.ResultsIn the umbilical circulation, we observed a positive venoarterial difference (fetal uptake) for 14 amino acids and a negative venoarterial difference (fetal release) for glutamic acid (p<0.001). In the maternal circulation, we observed a positive arteriovenous difference (uteroplacental uptake) for leucine (p = 0.005), isoleucine (p = 0.01), glutamic acid (p<0.001) and arginine (p = 0.04) and a negative arteriovenous difference (uteroplacental release) for tyrosine (p = 0.002), glycine (p = 0.01) and glutamine (p = 0.02). The concentrations in the maternal artery and umbilical vein were correlated for all amino acids except tryptophan, but we observed no correlations between the uteroplacental uptake and the fetal uptake or the umbilical vein concentration. Two amino acids showed a correlation between the maternal artery concentration and the fetal uptake.ConclusionsOur human in vivo study expands the current insight into fetal-placental amino acid exchange, and discloses some differences from what has been previously described in animals. Our findings are consistent with the concept that the fetal supply of amino acids in the human is the result of a dynamic interplay between fetal and placental amino acid metabolism and interconversions.

The 4-vessel Sampling Approach to Integrative Studies of Human Placental Physiology In Vivo.

The human placenta is highly inaccessible for research while still in utero. The current understanding of human placental physiology in vivo is therefore largely based on animal studies, despite the high diversity among species in placental anatomy, hemodynamics and duration of the pregnancy. The vast majority of human placenta studies are ex vivo perfusion studies or in vitro trophoblast studies. Although in vitro studies and animal models are essential, extrapolation of the results from such studies to the human placenta in vivo is uncertain. We aimed to study human placenta physiology in vivo at term, and present a detailed protocol of the method. Exploiting the intraabdominal access to the uterine vein just before the uterine incision during planned cesarean section, we collect blood samples from the incoming and outgoing vessels on the maternal and fetal sides of the placenta. When combining concentration measurements from blood samples with volume blood flow measurements, we are able to quantify placental and fetal uptake and release of any compound. Furthermore, placental tissue samples from the same mother-fetus pairs can provide measurements of transporter density and activity and other aspects of placental functions in vivo. Through this integrative use of the 4-vessel sampling method we are able to test some of the current concepts of placental nutrient transfer and metabolism in vivo, both in normal and pathological pregnancies. Furthermore, this method enables the identification of substances secreted by the placenta to the maternal circulation, which could be an important contribution to the search for biomarkers of placenta dysfunction.

Dietary Reference Values for riboflavin.

Following a request from the European Commission, the EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA) derives dietary reference values (DRVs) for riboflavin. The Panel considers that the inflection point in the urinary riboflavin excretion curve in relation to riboflavin intake reflects body saturation and can be used as a biomarker of adequate riboflavin status. The Panel also considers that erythrocyte glutathione reductase activation coefficient is a useful biomarker, but has limitations. For adults, the Panel considers that average requirements (ARs) and population reference intakes (PRIs) can be determined from the weighted mean of riboflavin intake associated with the inflection point in the urinary riboflavin excretion curve reported in four intervention studies. PRIs are derived for adults and children assuming a coefficient of variation of 10%, in the absence of information on the variability in the requirement and to account for the potential effect of physical activity and the methylenetetrahydrofolate reductase 677TT genotype. For adults, the AR and PRI are set at 1.3 and 1.6 mg/day. For infants aged 7–11 months, an adequate intake of 0.4 mg/day is set by upward extrapolation from the riboflavin intake of exclusively breastfed infants aged 0–6 months. For children, ARs are derived by downward extrapolation from the adult AR, applying allometric scaling and growth factors and considering differences in reference body weight. For children of both sexes aged 1–17 years, ARs range between 0.5 and 1.4 mg/day, and PRIs between 0.6 and 1.6 mg/day. For pregnant or lactating women, additional requirements are considered, to account for fetal uptake and riboflavin accretion in the placenta during pregnancy or the losses through breast milk, and PRIs of 1.9 and 2.0 mg/day, respectively, are derived.