Prenatal exposure to maternal steroid hormones and child neurodevelopment: evidence for sex-specific effects in a longitudinal birth cohort

Background Neurodevelopmental disorders affect millions of children worldwide, yet their prenatal biological origins remain unclear. Steroid hormones regulate key processes in fetal brain development, but the role of maternal steroid metabolism during pregnancy on children's neurodevelopment remains poorly understood. Methods We report the first comprehensive longitudinal analysis of maternal steroid metabolism in late pregnancy in relation to offspring neurodevelopment. We quantified 50 maternal urinary steroid metabolites and derived 40 indicators of steroid metabolism in third-trimester samples from two Spanish birth cohorts (INMA-Sabadell, n = 500; BiSC, n = 556). In INMA-Sabadell, child cognition, motor development, attention and behaviour were assessed repeatedly from 15 months to 15 years, and associations were estimated using linear mixed-effects models, including sex-stratified analyses. As a secondary analysis, we evaluated cross-cohort consistency by testing whether associations with early-life cognitive and motor outcomes identified in INMA-Sabadell were also observed in BiSC at 18 months using linear regression models. Results In INMA-Sabadell, higher maternal levels of the cortisol metabolite 20α-dihydrocortisol-glucuronide were associated with poorer early cognitive abilities (estimate β = -2.05, 95% confidence interval (CI): [-3.08, -1.02]), whereas indicators of enhanced cortisol inactivation were associated with better attention, as reflected by lower variability in reaction time (β = -12.99, 95% CI: [-20.22, -5.76]). The association with 20α-dihydrocortisol-glucuronide was consistently observed in the BiSC cohort at 18 months (β = -0.29, 95% CI: -0.51, -0.06). Sex-stratified analyses revealed marked sexual dimorphism. Notably, indicators of greater androgen bioavailability were associated with increased externalizing behaviour in females (β = 0.23, 95% CI: [0.11, 0.35]) but better fluid intelligence in males (β = 4.76, 95% CI: [2.02, 7.52]). Conclusions These findings establish maternal steroid metabolism as a determinant of child neurodevelopment, highlight the relevance of including metabolic transformation indicators, and identify both shared and sex-specific in utero biomarkers of neurodevelopmental trajectories.