Hypertensive disorders of pregnancy, maternal cardiovascular disease mortality and the role of familial predisposition: a Norwegian population-based sibling-comparison, sibling-spillover and negative-control cohort study

Hypertensive disorders of pregnancy (HDP) are associated with increased maternal cardiovascular disease (CVD) mortality, with risks varying by HDP subtypes and subsequent pregnancy outcomes. The contribution of shared familial factors given this heterogeneity is unclear. We conducted a population-based study using Norwegian registries (1967-2020) including 1,106,658 women with complete pregnancy histories, of whom 628,345 had at least one full sibling. Women with HDP were classified into low-risk (gestational hypertension or term preeclampsia followed by no HDPs) and high-risk (all other patterns) trajectories. CVD mortality before age 70 was assessed using population-level and sibling-based models: sibling-comparison (discordant-sisters), sibling-spillover (by sister's HDP history), and negative-control models (by sister-in-law's HDP history). CVD mortality among women with HDP varied by trajectory (population-level adjusted hazard ratios [aHR]low-risk 1.03 [95% confidence intervals 0.89-1.20]; aHRhigh-risk 1.89 [1.74-2.06]). These differences persisted when compared to sisters without HDP (sibling-comparison aHRlow-risk 0.66 [0.44-1.01]; aHRhigh-risk 1.51 [1.16-1.97]). Women without HDP had slightly elevated CVD mortality if sisters had HDP (sibling-spillover aHRlow-risk 1.28 [1.03-1.60]; aHRhigh-risk 1.25 [1.06-1.49]), but not if sisters-in-law had HDP (negative-control aHRlow-risk 1.10 [0.85-1.40]; aHRhigh-risk 1.01 [0.83-1.22]). Individual-specific factors drive the CVD mortality heterogeneity among women with HDP. Shared familial factors modestly elevate CVD mortality in women without HDP.