Fetal Sex as a Biological Modifier of Maternal Hyperglycemia: Sex-specific Placental Adaptation, Divergent Growth Trajectories, and Perinatal Outcomes – A Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 Systematic Review with a Mechanistic Case Proposal

Introduction: Maternal hyperglycemia, including gestational diabetes mellitus, remains a leading contributor to adverse perinatal outcomes; however, variability in fetal growth and neonatal risk is frequently observed even under comparable glycemic conditions. This inconsistency has prompted consideration of factors beyond maternal glucose exposure alone, including fetal biological characteristics. Fetal sex has been repeatedly associated with differences in pregnancy outcomes, yet it is often treated as a covariate rather than a biologically active modifier. Methods: In this Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020-guided systematic review, we synthesized evidence from clinical, epidemiologic, and mechanistic studies to examine whether fetal sex may influence placental adaptation and downstream outcomes in pregnancies complicated by maternal hyperglycemia. Results: A total of 30 studies, including cohort studies, experimental placental investigations, transcriptomic analyses, and systematic reviews, were included. Across these heterogeneous sources, a broadly consistent – though not uniform – pattern was observed. Male placentas appear more likely to exhibit growth-oriented but metabolically constrained responses, often accompanied by inflammatory activation and reduced adaptive reserve. In contrast, female placentas tend to demonstrate features suggestive of metabolic buffering, immune tolerance, and epigenetic flexibility. These differences may help account for clinically observed divergence in fetal growth and neonatal outcomes under similar glycemic exposure. Importantly, the proposed framework is conceptual and hypothesis-generating, reflecting integration of diverse evidence rather than a confirmed causal model. Conclusion: The findings highlight gaps in sex-stratified data from major studies and suggest potential directions for future research, including the development of sex-aware risk assessment strategies. Taken together, this synthesis supports consideration of fetal sex as a potential biological modifier in diabetic pregnancy while underscoring the need for prospective validation.