Fetal Sex-Dependent Associations Between Gestational Hormone Concentrations and Adverse Birth Outcomes: A Cohort Study

Abstract Background: Adverse birth outcomes remain significant public health problems that can have long-lasting impacts on mother and child. Understanding biological mechanisms underlying these outcomes, including altered endocrine function, can inform prevention efforts. Thus, we aimed to explore associations between repeated gestational hormone measurements and birth outcomes. Secondarily, we assessed impacts of fetal sex and timing of hormone measurement on these associations. Methods: We explored associations between repeated gestational hormone measurements and birth outcomes among 976 women in PROTECT, a longitudinal prospective birth cohort in northern Puerto Rico. Birth outcomes assessed included preterm and spontaneous preterm birth (PTB), preeclampsia, gestational diabetes mellitus (GDM), small/large for gestational age (SGA, LGA), birth weight z-score, and gestational age at birth. Multivariate logistic and linear regressions were fit using pregnancy average concentrations of hormones. We also conducted sensitivity analyses assessing impacts of fetal sex and timing of hormone measurement on observed associations. Results: Among male fetuses, spontaneous PTB was associated with increased average corticotropin releasing hormone (CRH) (OR: 2.50, 95% CI: 1.19, 5.24), increased total triiodothyronine (T3) (OR: 1.80, 95% CI: 1.02, 3.16) and decreased testosterone (OR: 0.34, 95% CI: 0.15, 0.74). Odds of GDM increased with average free thyroxine (fT4) (OR: 2.80, 95% CI: 1.06, 7.41), and decreased with average testosterone (OR: 0.23, 95% CI: 0.06, 0.86). Progesterone/estriol ratio was inversely associated with birth weight z-score (b: -0.14, 95% CI: -0.27, -0.01) and gestational age (b: -0.39 weeks, 95% CI: -0.66 , -0.12), and positively associated with odds of SGA (OR: 2.08, 95% CI: 1.36, 3.19). Among females, birth weight z-score was inversely associated with progesterone (b: -0.17, 95% CI: -0.31, -0.02) and total thyroxine (T4) (b: -0.16, 95% CI: -0.30, -0.02), and GDM was inversely associated with progesterone/estriol (OR: 0.34, 95% CI: 0.12, 0.99). Conclusions: Associations between hormones and birth outcomes vary based on timing of hormone measurement and fetal sex. Future studies are needed to understand mechanisms involved in adverse birth outcomes and fetal sex differences.