Abstract 40: Causal Aspects of Preeclampsia and Gestational Hypertension for Risk of Future Cardiovascular Diseases

Introduction: Preeclampsia is a multifactorial disease and a cause of maternal and neonatal morbidity and mortality. Observational studies show that women with preeclampsia have increased risk of cardiovascular diseases later in life. Whether this association is causal is however uncertain. Hypothesis: We assessed the hypothesis that preeclampsia and gestational hypertension are causal risk factors for future cardiovascular diseases, including ischemic heart disease, myocardial infarction, stroke, ischemic stroke, atrial fibrillation, and heart failure. Methods: For this purpose, we performed one-sample Mendelian randomization (MR) analyses using individual level data from 202,876 white British women from the UK Biobank. Subsequently, two-sample MR analyses were performed using summary level data from FinnGen and from the to date largest consortia for each endpoint individually and then pooled in fixed-effects meta-analyses. Genetic instruments for preeclampsia and gestational hypertension were from the most updated genome-wide association study (n=20,064 preeclampsia cases; n=703,117 controls; n=11,027 gestational hypertension cases; n=412,788 controls). Results: In one-sample MR analyses, the odds ratios (95% CI) for preeclampsia were 1.26 (1.11-1.43) for ischemic heart disease, 1.26 (0.99-1.60) for myocardial infarction, 1.28 (1.04-1.57) for stroke, and 1.37 (1.08-1.74) for ischemic stroke; for gestational hypertension the odds ratios (95% CI) were 1.17 (1.07-1.28) for ischemic heart disease, 1.16 (0.98-1.36) for myocardial infarction, 1.35 (1.17-1.56) for stroke, 1.36 (1.15-1.60) for ischemic stroke, 1.16 (1.04-1.29) for atrial fibrillation, and 1.22 (1.04-1.43) for heart failure. The two-sample MR analyses confirmed all associations from one-sample MR analyses with similar results from multiple sensitivity analyses. The MR-Egger results did not suggest pleiotropy. Conclusion: Genetic predisposition to preeclampsia or gestational hypertension was associated with increased risk of cardiovascular diseases later in life, suggesting preeclampsia as a likely causal factor.