Fetal sex-specific differences in the placental transcriptome of gestational diabetes

Gestational diabetes mellitus (GDM) affects 14% of pregnancies worldwide with adverse maternal and offspring outcomes. Fetal sex is known to influence pregnancy outcomes and shape placental function. Although the placenta plays a central role in regulating maternal glucose levels, the molecular mechanisms driving GDM pathophysiology—and how they vary by fetal sex—are incompletely understood. We examined fetal sex impact on placental gene programs in GDM using two independent cohorts. In a case-control study (N = 101, 42 with GDM), we assessed expression of eight glycemic/immune regulation genes via qPCR in GDM placentas versus sex-matched controls. In a second prospective cohort of 433 individuals (N = 35 with GDM), we performed sex-stratified transcriptomic analyses of placental RNA-Seq data. Placental expression of genes implicated in glucose metabolism (IGFBP1, RBP4, EPYC, and PRL) was sexually dimorphic in GDM versus sex-matched controls. Transcriptomic analyses revealed enrichment in proinflammatory/glycolytic pathways and dysregulated retinoic acid signaling in male GDM placentas, while female GDM placentas showed enrichment in cell growth and immunoregulatory pathways. GDM elicits sex-specific differences in placental gene programs, highlighting the importance of incorporating fetal sex in pregnancy studies. These findings may inform future sex-tailored strategies for offspring risk prediction and intervention in GDM.