Investigating the association of fetal sex and hypertensive pregnancy outcomes across varying conception types: a retrospective cohort study

Objective(s) . Infertility impacts 17.5% of couples worldwide, and many of those struggling rely on assisted reproductive technology (ART) to aid in conception. Although ART techniques are invasive and known to increase risk of pregnancy complications, no studies have considered the relationship between ART, sex, and hypertension developed during pregnancy. Study Design . In this retrospective cohort study, we analyzed 19,727,414 live births between 2016-2021 in the US, stratified by presence of chronic hypertension (yes or no) and further by conception type (spontaneous, non-IVF assisted conception, ART). Modified Poisson regression models were fit to estimate risk ratios (RRs) and 95% confidence intervals (CIs) for hypertensive disorders of pregnancy among fetal male vs fetal female pregnancies across each conception strata, and further by gestational age stratified groups. Results Among individuals without chronic hypertension, we identified a greater rate of hypertensive disorders of pregnancy in the non-IVF-assisted and ART strata compared with spontaneous conception, with slightly higher crude rates of hypertensive disorders of pregnancy in fetal male pregnancies across all conception strata. Fetal males in the spontaneous conception group displayed a slightly greater risk ratio of hypertensive disorders of pregnancy overall (aRR 1.010, 95% CI 1.007, 1.013). Among gestational age stratified analyses in the spontaneous conception population, fetal females were more strongly associated with hypertensive disorders of pregnancy among early preterm (22-26 weeks; aRR 0.823, 95% CI 0.797, 0.850) and late preterm (27-36 weeks; aRR 0.938, 95% CI 0.932, 0.944) births, whereas fetal males demonstrated a modest excess risk at term (≥37 weeks; 1.016, 95% CI 1.012, 1.019). Similar trends were observed across conception strata. Results were consistent in a sensitivity analysis of only nulliparous patients. No difference by fetal sex was observed among individuals with chronic hypertension overall. Stratification by gestational age revealed an increased fetal female risk for hypertensive disorders of pregnancy among preterm pregnancies in the spontaneous conception strata only (aRR 0.884, 95% CI 0.796, 0,980). Conclusion(s) . These results further inform the importance of considering fetal sex in obstetric outcomes, as assessing mixed-sex populations across all gestational ages at delivery may mask heterogeneity driven by sexual dimorphism. Irrespective of sex, these findings also provide insight on the risks of assisted reproductive technology in the context of maternal health outcomes.