Fetal sex influences molecular regulation of human placental vascular development across gestation

Males experience elevated mortality and morbidity during the perinatal period and infancy; however, the biological origins of this vulnerability remain unclear. Emerging evidence suggests that sex-dependent placental development may contribute to differences in fetal growth and outcomes. Vascular networks are central to placental function, established early in the first trimester to support growth and mitigate harmful exposures, and maturing by term to sustain late fetal development. Although these processes are tightly regulated by gene-expression programmes, the role of sex-specific vascular signalling in placental development remains poorly understood. To address this, we analysed raw, publicly available RNA-sequencing transcriptomics data from first trimester and term placental samples. We conducted parallel differential gene expression and functional enrichment analyses across the datasets to ensure direct comparability and to disentangle the specific contribution of sex chromosomes. We identified multiple differentially expressed genes and enriched pathways between male and female placentas. In the first trimester, male placentas exhibited significant enrichment of vascular signalling pathways, particularly Notch signalling, cell adhesion, and migration, consistent with heightened proliferative and remodelling activity. At the end of gestation, sex differences remained detectable; however differentially expressed genes was clearly sex-chromosome driven, with autosomal single-gene sex differences and autosomal-sex-specific pathways markedly reduced. This reflected a mature placental vascular system with minimal sex-based differences outside of the sex chromosome genes. These results reveal gestational stage-dependent sex differences in placental vascular development, with early male fetuses exhibiting increased angiogenic activity and immature vascular signalling, potentially contributing to accelerated growth and increased vulnerability in male neonates.