Maternal Testosterone and Offspring Birth Weight: A Mendelian Randomization Study

Abstract Context Evidence has shown maternal androgen levels in both the general population and populations with hyperandrogenic disorders are inversely associated with offspring birth weight. Context We aimed to investigate the causal effect of maternal testosterone levels in the general population on offspring birth weight and preterm delivery risk using a two-sample Mendelian randomization (MR) method. Methods We obtained independent genetic instruments from a sex-specific genome-wide association study with up to 230 454 females of European descent from the UK Biobank. Genetic instruments with consistent testosterone effects but no aggregate effect on sex hormone–binding globulin were used to perform the main analysis. Summary-level data of offspring birth weight adjusted for genotype were obtained from a study with 210 406 females of European descent. Summary-level data of preterm delivery were obtained from the FinnGen study (6736 cases and 116 219 controls). Results MR analysis showed that each SD (0.62 nmol/L) increase in testosterone levels could reduce the offspring birth weight by 37.26 g (95% CI, 19.59-54.94 g; P = 3.62 × 10-5). Each SD increase in testosterone levels was also associated with an increased risk of preterm delivery (odds ratio = 1.329; 95% CI, 1.161-1.520; P = 3.57 × 10-5). Similar results were found using different MR methods and multivariable MR analyses. Conclusion This two-sample MR study showed genetically determined higher circulating testosterone levels in females from the general population were associated with low birth weight of offspring and increased risk of preterm delivery.