The syncytiotrophoblast (SCT) at the maternal-fetal interface has been presumed to be the primary driver of placental metabolism, and the underlying progenitor cytotrophoblast cells (CTB) an insignificant contributor to placental metabolic activity. However, we now show that the metabolic rate of CTB is much greater than the SCT. The oxygen consumption and extracellular acidification rate, a measure of glycolysis, are both greater in CTB than in SCT in vitro (CTB: 96 ± 16 vs SCT: 46 ± 14 pmol O 2 × min −1 × 100 ng DNA −1 , p < 0.001) and (CTB: 43 ± 6.7 vs SCT 1.4 ± 1.0 ∆mpH × min −1 × 100 ng DNA −1 , p < 0.0001). Mitochondrial activity, as determined by using the mitochondrial activity-dependent dye Mitotracker CM-H 2 TMRosa, is higher in CTB than in SCT in culture and living explants. These data cast doubt on the previous supposition that the metabolic rate of the placenta is dominated by the SCT contribution. Moreover, differentiation into SCT leads to metabolic suppression. The normal suppression of metabolic activity during CTB differentiation to SCT is prevented with a p38 MAPK signaling inhibitor and epidermal growth factor co-treatment. We conclude that the undifferentiated CTB, in contrast to the SCT, is highly metabolically active, has a high level of fuel flexibility, and contributes substantially to global metabolism in the late gestation human placenta.The primary function of the human placenta is to ensure that the fetus it serves continuously receives maternally-derived nutrients that are necessary for optimal growth. The placenta is a powerful organ that produces hormones, alters nutrients biochemically as needed, and transports them to the developing fetus. Each of these processes exacts a metabolic cost. Thus, the placenta has an extraordinarily high metabolic rate, consuming approximately 40% of the oxygen used by the entire conceptus while accounting for less than 20% of its mass [1][2][3][4] . The metabolic status of the placenta is evidently important because several maternal disorders including pre-eclampsia and gestational diabetes mellitus, are associated with metabolic abnormalities [5][6][7] .The materno-placental barrier is composed of a monolayer of terminally differentiated trophoblast cells, the syncytialized trophoblast (SCT), the underlying layer of progenitor cells, the cytotrophoblast (CTB) and the endothelium of the fetal vasculature. Throughout gestation, the SCT is continually repaired by CTB cells 8 . The SCT has been presumed to account for the largest proportion of placental metabolic activity because it is in direct contact with maternal blood, synthesizes and secretes large quantities of protein and steroid hormones, and is the primary transport organ for all nutrients acquired by the fetus. Furthermore, it has been assumed that because the CTB layer gradually disappears with gestational age, it plays an increasingly diminished biological role as term approaches 9 .Freshly isolated CTB and SCT can be studied in vitro. Isolated CTB are known to differentiate and fuse over...

Use of oral agents to treat gestational diabetes mellitus remains controversial. Recent recommendations from the Society for Maternal-Fetal Medicine assert that metformin may be a safe first-line alternative to insulin for gestational diabetes mellitus treatment and preferable to glyburide. However, several issues should give pause to the widespread adoption of metformin use during pregnancy. Fetal concentrations of metformin are equal to maternal, and metformin can inhibit growth, suppress mitochondrial respiration, have epigenetic modifications on gene expression, mimic fetal nutrient restriction, and alter postnatal gluconeogenic responses. Because both the placenta and fetus express metformin transporters and exhibit high mitochondrial activity, these properties raise important questions about developmental programming of metabolic disease in offspring. Animal studies have demonstrated that prenatal metformin exposure results in adverse long-term outcomes on body weight and metabolism. Two recent clinical randomized controlled trials in women with gestational diabetes mellitus or polycystic ovary syndrome provide evidence that metformin exposure in utero may produce a metabolic phenotype that increases childhood weight or obesity. These developmental programming effects challenge the conclusion that metformin is equivalent to insulin. Although the Society for Maternal-Fetal Medicine statement endorsed metformin over glyburide if oral agents are used, there are few studies directly comparing the 2 agents and it is not clear that metformin alone is superior to glyburide. Moreover, it should be noted that prior clinical studies have dosed glyburide in a manner inconsistent with its pharmacokinetic properties, resulting in poor glycemic control and high rates of maternal hypoglycemia. We concur with the American Diabetes Association and American Congress of Obstetricians and Gynecologists, which recommend insulin as the preferred agent, but we believe that it is premature to embrace metformin as equivalent to insulin or superior to glyburide. Due to the uncertainty of the long-term metabolic risks of either metformin or glyburide, we call for carefully controlled studies that optimize oral medication dosing according to their pharmacodynamic and pharmacokinetic properties in pregnancy, appropriately target medications based on individual patterns of hyperglycemia, and follow the offspring long-term for metabolic risk.

The immunological alterations required for successful pregnancy in eutherian placental mammals have remained a scientific enigma since the discovery of MHC haplotype diversity and unique immune signatures among individuals. Within the past 10 years, accumulating data suggest immune suppressive regulatory T cells (Tregs) confer essential protective benefits in sustaining tolerance to the semi-allogeneic fetus during pregnancy – along with their more established roles in maintaining tolerance to self and “extended self” commensal antigens that averts autoimmunity. Reciprocally, many human pregnancy complications stemming from inadequacies in fetal tolerance have been associated with defects in maternal Tregs. Thus, further elucidating the immunological shifts during pregnancy not only have direct translational implications for improving perinatal health, but also enormous potential for unveiling new clues for how Tregs work in other biological contexts. Herein, epidemiological data in human pregnancy and complementary animal studies implicating a pivotal protective role for maternal Tregs are summarized.

The placenta is a key organ in programming the fetus for later disease. This review outlines eight of many structural and physiological features of the placenta which are associated with adult onset chronic disease. 1) Placental efficiency relates the placental mass to the fetal mass. Ratios at the extremes are related to cardiovascular disease risk later in life. 2) Placental shape predicts a large number of disease outcomes in adults but the regulators of placental shape are not known. 3) Non-human primate studies suggest that at about mid-gestation, the placenta becomes less plastic and less able to compensate for pathological stresses. 4) Recent studies suggest that lipids have an important role in regulating placental metabolism and thus the future health of offspring. 5) Placental inflammation affects nutrient transport to the fetus and programs for later disease. 6) Placental insufficiency leads to inadequate fetal growth and elevated risks for later life disease. 7) Maternal height, fat and muscle mass are important in combination with placental size and shape in predicting adult disease. 8) The placenta makes a host of hormones that influence fetal growth and are related to offspring disease. Unfortunately, our knowledge of placental growth and function lags far behind that of other organs. An investment in understanding placental growth and function will yield enormous benefits to human health because it is a key player in the origins of the most expensive and deadly chronic diseases that humans face.

The degree that maternal glycemia affects placental metabolism of trophoblast cell types [cytotrophoblast (CTB) and syncytiotrophoblast (SCT)] in pregnant persons with gestational diabetes mellitus (GDM) is unknown. We tested the hypotheses that (a) hyperglycemia suppresses the metabolic rates of CTB and SCT; and (b) low placental metabolic activity from GDM placentas is due to decreased oxygen consumption of CTB. Trophoblast cells isolated from GDM and non‐GDM term placentas were cultured for 8‐hour (CTB) and following syncytialization at 72‐hour (SCT) in 5 mM of glucose or 25 mM of glucose. Oxygen consumption rates, glycolysis, ATP levels, and lipid droplet morphometries were determined in CTB and SCT. In CTB from GDM placentas compared to control CTB: (a) oxidative phosphorylation was decreased by 44% (41.8 vs 74.2 pmol O2/min/100 ng DNA, P = .002); (b) ATP content was 39% lower (1.1 × 10−7 vs 1.8 × 10−7 nM/ng DNA, P = .046); and (c) lipid droplets were two times larger (31.0 vs 14.4 µm2/cell, P < .001) and 1.7 times more numerous (13.5 vs 7.9 lipid droplets/cell, P < .001). Hyperglycemia suppressed CTB glycolysis by 55%‐60% (mean difference 20.4 [GDM, P = .008] and 15.4 [non‐GDM, P = .029] mpH/min/100 ng DNA). GDM SCT was not metabolically different from non‐GDM SCT. However, GDM SCT had significantly decreased expression of genes associated with differentiation including hCG, GCM1, and syncytin‐1. We conclude that suppressed metabolic activity by the GDM placenta is attributable to metabolic dysfunction of CTB, not SCT. Critical placental hormone expression and secretion are decreased in GDM trophoblasts.