Thyroid function and hypertensive disorders of pregnancy: Insights from a sex‐specific cohort study, Mendelian randomization, and experimental validation

OBJECTIVE: To investigate the association of a history of hypertensive disorders of pregnancy (HDP) and a higher risk of cardiovascular disease using a sex-specific cohort study, bidirectional two-sample Mendelian randomization (MR), and in vitro experiments. METHODS: Multivariable logistic regression was used to assess the association between thyroid function and HDP. We performed bidirectional two-sample MR using summary statistics from genome-wide association study meta-analyses, FinnGen, and UKB to assess the potential association between thyroid function and HDP. In vitro experiments were conducted to explore the potential biologic mechanisms underlying the observed association. RESULTS: In the cohort (n = 119 668), hyperthyroidism was associated with higher HDP risk (odds ratio [OR] 1.79, 95% confidfence interval [CI] 1.10-2.92, P = 0.020; fully adjusted for confounders). MR identified a potential association of genetically predicted thyroid-stimulating hormone (TSH) on HDP (OR 0.92, 95% CI 0.85-0.99, P = 0.018), but no evidence was found to support a causal effect of hypothyroidism, hyperthyroidism, or free thyroxine on HDP. Reverse MR indicated that genetically predicted pre-eclampsia was associated with elevated TSH levels (β 0.12, 95% CI 0.05-0.19, P < 0.001). In vitro experiments confirmed and provided supportive mechanistic evidence that TSH may directly induce vascular endothelial injury and dysfunction. CONCLUSION: This study demonstrates an independent observational association between hyperthyroidism and an increased risk of HDP, and provides supportive genetic evidence for a possible bidirectional association between genetically predicted TSH and HDP. These findings highlight TSH as a potential biomarker for HDP risk stratification.