Metabolic disorders mediate the relation of miscarriage with cardiovascular diseases

Aims The extent to which the contribution of pregnancy loss to cardiovascular diseases (CVDs) can be explained by metabolic disorders is poorly elucidated but holds insights for reducing long-term cardiovascular risk. The aim of this study is to investigate the mediating effects of hypertension, diabetes mellitus (DM), and lipoprotein metabolism disorders on the association of miscarriage and stillbirth with coronary heart disease (CHD), stroke, heart failure, atrial fibrillation, and composite outcomes.Methods and results A total of 163 283 ever-gravid women (age 55.3 +/- 7.9 years) from the UK Biobank cohort without established metabolic disorders and CVDs were included and followed from 2007 to 2010 baseline until December 2020. Causal mediation analyses were used to estimate the proportion mediated. Hypertension mediated 11.1% (95% confidence interval, 3.7-18.5%) of the association between a history of miscarriage and incident CHD. Approximately, 9.5% (4.1-14.8%) of the effect of recurrent miscarriages on incident CHD was via hypertension, 8.4% (2.5-14.3%) of the effect was via lipoprotein metabolism disorders, 1.7% (0.5-2.9%) of the effect was via DM, and 10.7% (0.2-21.1%) of the effect of recurrent miscarriages on incident stroke was via hypertension. Hypertension mediated the largest proportion of effect for the atherosclerotic cardiovascular event (15.5% for a history of miscarriage and 9.4% for recurrent miscarriages), followed by lipoprotein metabolism disorders and DM.Conclusion Hypertension, DM, and lipoprotein metabolism disorders mediated the association between miscarriage and various cardiovascular outcomes in later life. In particular, hypertension mediated a large proportion of the relationship between miscarriage and atherosclerotic CVD. Hypertension, diabetes, and lipoprotein metabolism disorders mediated the association between miscarriage and various cardiovascular outcomes in later life. Hypertension mediated the largest proportion of effect for the atherosclerotic cardiovascular event (15.5% for a history of miscarriage and 9.4% for recurrent miscarriages). Women who have experienced miscarriage should be regularly monitored for possible required interventions on blood pressure, blood lipids, and glucose to reduce their long-term cardiovascular risk.Our findings contribute to ongoing research efforts to better understand the pathogenesis of pregnancy loss leading to CVD. In particular, we identified metabolic disorders processes as potential mediators.Implications: Our findings warrant early monitoring and intensive (preventive) treatment of hypertension and lipoprotein metabolism disorders among women who experience miscarriage(s) to lower their burden of later-life clinical cardiovascular events. Graphical Abstract