Associations of Maternal Androgen-Related Conditions With Risk of Autism Spectrum Disorder in Progeny and Mediation by Cardiovascular, Metabolic, and Fertility Factors

Abstract

Abstract Fetal exposure to elevated androgens is thought to contribute to autism spectrum disorder (ASD) risk. However, data rely heavily on in utero androgens measurements, which also reflect fetal secretions. Thus, in utero hyperandrogenemia might indicate adverse autism-related neurogenesis that has already occurred affecting fetal androgen homeostasis, rather than being a cause of the disorder. Associations between maternal androgen-related conditions and ASD could more directly implicate androgens’ etiological role. We examined the association between maternal hyperandrogenemia-related conditions, focusing primarily on polycystic ovarian syndrome (PCOS), and progeny ASD, in an Israeli cohort of 437,222 children born in 1999–2013. Odds ratios and 95% confidence intervals were estimated using generalized estimating equations. Multiple mediation analyses using natural effect models were conducted to evaluate combined mediation of the PCOS effect by androgen-related cardiovascular, metabolic, and fertility factors. Results indicated that children of mothers with PCOS had higher ASD odds compared with children of mothers without PCOS (odds ratio = 1.42, 95% confidence interval: 1.24,1.64), and this effect was only partly mediated by the factors considered. Elevated odds were also observed for other hyperandrogenemia-related conditions. Findings provide support for direct involvement of maternal hyperandrogenemia in ASD etiology. Alternatively, findings might reflect shared genetic and/or environmental factors independently affecting maternal androgen homeostasis and fetal neurodevelopment.