Fetal Sex-Dependent Associations Between Gestational Hormone Concentrations and Adverse Birth Outcomes

Abstract 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. The aim of this study was to evaluate associations between hormones at two times points during mid-gestation and adverse birth outcomes, and to assess effect modification by fetal sex. Repeated gestational hormone measurements (at 18 and 26 weeks) and birth outcomes were assessed among 976 women in PROTECT, a longitudinal prospective birth cohort in northern Puerto Rico, from 2011 to 2018. Birth outcomes assessed included preterm and spontaneous preterm birth (PTB), preeclampsia, gestational diabetes mellitus (GDM), small/large for gestational age (SGA, LGA), birthweight z-score, and gestational age at birth. Multivariate logistic and linear regressions were fit using visit-specific concentrations of hormones. We also conducted sensitivity analyses assessing impacts of fetal sex on observed associations. All models were adjusted for maternal age and education, and other confounders were assessed separately between birth outcomes based on a priori knowledge and observed associations with exposure and outcome measures. We observed increased odds of spontaneous PTB with IQR increases in progesterone (OR: 2.12, 95% CI: 1.29, 3.47), fT4 (OR: 1.73, 95% CI: 1.04, 2.86), and the ratio of progesterone to estriol (OR: 1.63, 95% CI: 1.05, 2.54) at 26 weeks. Elevated estriol was protective against preeclampsia at 26 weeks (OR: 0.42, 95% CI: 0.17, 0.99). Increases in TSH and T3 conferred greater risk of GDM at 18 weeks. Many associations were modified by fetal sex, with hormone alterations during male pregnancies conferring greater risk of PTB, spontaneous PTB, and GDM. In conclusion, 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.