Maternal overweight and obesity during pregnancy and sex‐dependent dysregulation of the materno‐fetal stress axis

OBJECTIVE: Maternal obesity and excess gestational weight gain (GWG) are linked to adverse perinatal outcomes, potentially via disruption of the maternal-fetal stress axis. Placental HSD11B2 protects the fetus from excess glucocorticoids and may influence fetal programming during maternal metabolic stress. The present study assessed maternal overweight and GWG effects on stress axis and fetal development. METHODS: We conducted a prospective study of 175 singleton pregnancies at Charité University Berlin, recruited by pre-pregnancy body mass index (BMI: normal, overweight, obese). Maternal weight, hair and serum cortisol, neonatal anthropometrics, and placental HSD11B2 expression and methylation were analyzed during pregnancy, at delivery, and/or 6 months postpartum. Linear regression and correlation analyses were applied. RESULTS: Excessive gestational weight gain (GWG) was more common in obese women, who also showed higher postpartum weight retention. First-trimester hair cortisol and cortisone, reflecting chronic stress, were elevated in overweight and obese groups. While serum cortisol levels were similar, obese women showed a greater increase from the second to third trimester. Neonatal means did not differ consistently, yet macrosomia and small for gestational age rates were higher in offspring of obese mothers. Elevated maternal cortisol in late pregnancy and postpartum correlated with altered infant growth. Placental HSD11B2 was not GWG-dependent but varied by sex and BMI. Promoter methylation was linked to infant body composition and growth. CONCLUSION: Maternal overweight may relate to chronic hypothalamic-pituitary-adrenal (HPA) axis activation and altered placental HSD11B2, with sex-specific placental adaptations affecting fetal glucocorticoid exposure and offspring development. These findings support integrated perinatal strategies targeting nutrition and stress.