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Glucocorticoids are vital for lung maturation. We previously showed that cortisol is lower in obese pregnancy. Whether this is maintained at delivery is unknown but is clinically relevant as maternal and cord blood cortisol levels are correlated and offspring of obese are more likely to need neonatal respiratory support. We hypothesized that glucocorticoids are lower in maternal and cord blood at delivery in obese pregnancies. Glucocorticoids (cortisol and corticosterone) and their inactive versions (cortisone and 11-dehydrocorticosterone) were measured by LC-MS/MS in maternal and cord plasma from 259 Caucasian women at delivery (BMI 18–55 kg/m2). Analyses adjusted for labour status, delivery mode, offspring gender, birthweight and gestational age. Cortisol and corticosterone were significantly higher in maternal than cord blood. Inactive versions were significantly higher in cord than maternal blood. Increased maternal BMI associated with lower maternal cortisol, corticosterone and 11-dehydrocorticosterone. Despite significant positive correlations between maternal and cord blood glucocorticoid levels, increased maternal BMI was not associated with lower cord blood glucocorticoid levels. Conditions at delivery may overcome any potential negative effects of low maternal glucocorticoids on the fetus in the short-term. This may not preclude the longer-term effects of fetal exposure to lower glucocorticoid levels during obese pregnancy.

Objective: Hypothalamic-pituitary-adrenal axis (HPA) activity is decreased in obese pregnancy and associates with increased foetal size. Pulsatile release of glucocorticoid hormones regulates their action in target tissues. Glucocorticoids are essential for normal foetal growth, but little is known about glucocorticoid pulsatility in pregnancy. We aimed to investigate the ultradian rhythm of glucocorticoid secretion during obese and lean pregnancy and nonpregnancy. Design: Serum cortisol, cortisone, corticosterone and 11-dehydrocorticosterone were measured by LC-MS/MS from samples obtained at 10-minute intervals between 08.00-11.00 hours and 16.00-19.00 hours, from 8 lean (BMI 2) and 7 obese (BMI > 35 kg/m2) pregnant women between 16-24 weeks gestation and again at 30-36 weeks), and nonpregnant controls (lean n = 3, obese n = 4) during the luteal phase of their menstrual cycle. Interstitial fluid cortisol was measured by ELISA, from samples obtained using a portable microdialysis and automated collection device at 20-minute intervals over 24 hours. Results: Serum cortisol AUC, highest peak and lowest trough increased significantly with gestation in lean and obese pregnant compared with nonpregnant subjects. Pulsatility of cortisol was detected in interstitial fluid. In pregnant subjects, interstitial fluid pulse frequency was significantly lower with advancing gestation in obese, but not in lean. Conclusions: We demonstrate cortisol pulsatility in interstitial fluid. Pulse frequency is altered with increased gestation and BMI. This may be a novel mechanism to explain decreased HPA activity in obese pregnancy.

Context: Fetal overexposure to glucocorticoids in utero is associated with fetal growth restriction and is postulated to be a key mechanism linking suboptimal fetal growth with cardiovascular disease in later life. Objective: To develop a model to predict maternal-fetal glucocorticoid transfer. We hypothesized placental 11-β-hydroxysteroid dehydrogenase-type 2 (11β-HSD2) would be the major rate-limiting step in maternal cortisol transfer to the fetus. Design: We used a deuterated cortisol tracer in the ex vivo placental perfusion model, in combination with computational modeling, to investigate the role of interconversion of cortisol and its inactive metabolite cortisone on transfer of cortisol from mother to fetus. Participants: Term placentas were collected from five women with uncomplicated pregnancies, at elective caesarean delivery. Intervention: Maternal artery of the isolated perfused placenta was perfused with D4-cortisol. Main Outcome Measures: D4-cortisol, D3-cortisone, and D3-cortisol were measured in maternal and fetal venous outflows. Results: D4-cortisol, D3-cortisone, and D3-cortisol were detected and increased in maternal and fetal veins as the concentration of D4-cortisol perfusion increased. D3-cortisone synthesis was inhibited when 11-β-hydroxysteroid dehydrogenase (11β-HSD) activity was inhibited. At the highest inlet concentration, only 3.0% of the maternal cortisol was transferred to the fetal circulation, whereas 26.5% was metabolized and 70.5% exited via the maternal vein. Inhibiting 11β-HSD activity increased the transfer to the fetus to 7.3% of the maternal input, whereas 92.7% exited via the maternal vein. Conclusions: Our findings challenge the concept that maternal cortisol diffuses freely across the placenta and confirm that 11β-HSD2 acts as a major “barrier” to cortisol transfer to the fetus., Placental cortisol metabolism and transfer was studied using tracers and computational modeling. This indicated that the placenta presents both metabolic and physical barriers to cortisol transfer.

Context: Fetal overexposure to glucocorticoids in utero is associated with fetal growth restriction and is postulated to be a key mechanism linking suboptimal fetal growth with cardiovascular disease in later life. Objective: To develop a model to predict maternal-fetal glucocorticoid transfer. We hypothesised placental 11β-HSD2 would be the major rate-limiting step in maternal cortisol transfer to the fetus. Design: We used a deuterated cortisol tracer in the ex vivo placental perfusion model, in combination with computational modelling, to investigate the role of interconversion of cortisol and its inactive metabolite cortisone on transfer of cortisol from mother to fetus.Participants: Term placentas were collected from five women with uncomplicated pregnancies, at elective caesarean delivery. Intervention: Maternal artery of the isolated perfused placenta was perfused with D4-cortisol.Main Outcome Measures: D4-cortisol, D3-cortisone and D3-cortisol were measured in maternal and fetal venous outflows.Results: D4-cortisol, D3-cortisone and D3-cortisol were detected and increased in maternal and fetal veins as the concentration of D4-cortisol perfusion increased. D3-cortisone synthesis was inhibited when 11β-HSD activity was inhibited. At the highest inlet concentration only 3.0% of the maternal cortisol was transferred to the fetal circulation, while 26.5% was metabolised and 70.5% exited via the maternal vein. Inhibiting 11β-HSD activity increased the transfer to the fetus to 7.3% of the maternal input, while 92.7% exited via the maternal vein. Conclusions: Our findings challenge the concept that maternal cortisol diffuses freely across the placenta and confirm that 11β-HSD2 acts as a major ‘barrier’ to cortisol transfer to the fetus.

Laura I Stirrat,1,2 Rebecca M Reynolds2,3 1Medical Research Council Centre for Reproductive Health, Queens Medical Research Institute, University of Edinburgh, Edinburgh, UK; 2Tommy's Centre for Maternal and Fetal Health, Queens Medical Research Institute, University of Edinburgh, Edinburgh, UK; 3Endocrinology Unit, University/British Heart Foundation Centre for Cardiovascular Science, Queens Medical Research Institute, University of Edinburgh, Edinburgh, UK Abstract: The prevalence of maternal obesity has increased significantly in recent years, and obesity is currently the most common comorbidity of pregnancy. Pregnancies of obese women are often defined as "high-risk" for the purposes of clinical care, with many well documented risks to the mother and developing baby. Maternal physiology and metabolism is dysregulated in the context of obesity, which may contribute to some of the adverse outcomes during pregnancy. Furthermore, maternal obesity has been hypothesized to cause harmful effects for the developing baby through "early life programming." This review will examine evidence from human studies for outcomes of offspring from obese women during pregnancy, during labor, during the neonatal period, and later in life. Keywords: pregnancy, short-term, physiology, metabolism, early life programming, neonatal complications, adverse intrauterine environment