Infertility, Miscarriage, Stillbirth, and the Risk of Stroke Among Women: A Systematic Review and Meta-Analysis

Background and Purpose: Stroke is one of the leading causes of mortality, and women are impacted more from stroke than men in terms of their absolute number and in having worse outcomes. A growing number of studies have explored the association between pregnancy complications, pregnancy outcomes, and stroke. Limited studies, however, have investigated links involving infertility, miscarriage, and stillbirth, which could plausibly be associated via a background of endocrine conditions, endothelial dysfunction, and chronic systematic inflammation. This review aims to summarize current evidence and provide up-to-date information on the associations of infertility, miscarriage, and stillbirth, with stroke incidence. Methods: A comprehensive literature search was conducted for cohort and case-control studies on associations between infertility, miscarriage, stillbirth, and stroke up to September 26, 2020. Seven databases were searched: PubMed, Embase, Cochrane, CINIHL, PsyclNFO, Wanfang, and CNKI. Random-effects models were used to estimate the pooled hazard ratios (HRs) and 95% CIs. Results: Sixteen cohort studies and 2 case-control studies enrolling 7 808 521 women were included in this meta-analysis. Women who had experienced miscarriage or stillbirth were at higher risk of stroke (miscarriage: HR, 1.07 [95% CI, 1.00-1.14]; stillbirth: HR, 1.38 [95% CI, 1.11-1.71]) than other women. The HRs of stroke for each additional miscarriage and stillbirth were 1.13 (95% CI, 0.96-1.33) and 1.25 (95% CI, 1.06-1.49), respectively. In subgroup analysis, increased risk of stroke was associated with repeated miscarriages and stillbirths (miscarriage >= 3: HR, 1.42 [95% CI, 1.05-1.90]; stillbirth >= 2: HR, 1.14 [95% CI, 1.04-1.26]). Associations between infertility and stroke were inconsistent and inconclusive (HR, 1.07 [95% CI, 0.87-1.32]). Conclusions: Miscarriage and stillbirth are associated with increased risk of stroke among women, which could be used as a contributing risk factor to help identify women at higher risk of stroke.