Arooshi Kumar, MD
It is well established that stroke is a leading cause of mortality and disability around the world. It is more recently accepted that sex-related differences exist for stroke prevalence and outcomes, and that females might carry additional risk factors transcending the traditional vascular risk factors. To that end, pregnancy and childbirth mark a uniquely special experience for females. A growing body of evidence suggests that pregnancy and complications of pregnancy are associated with long-term risk of stroke.1-2 Liang et al. published a comprehensive systematic review on the association between infertility, miscarriage, stillbirth, and stroke.
The authors identified relevant human cohorts or case-control studies of females with a history of infertility (diagnosed or being treated for), miscarriage, or stillbirth who had stroke outcomes monitored, conglomerated the data, and performed a meta-analysis on the studies that passed their stringent review criteria. For the purposes of their analysis, history of miscarriage was reclassified as a single miscarriage vs recurrent miscarriage. The authors compiled all hazard ratios (HR), odds ratios, risk ratios and incidence rate ratios as hazard ratios considering stroke a rare event. Subgroup analysis was performed by region and study quality, as well as exposure ascertainment.
This review ultimately included 18 studies (2 of which were case-control) performed between 2011-2019 for its meta-analysis. The mean age of patients ranged from 23 to 63 years, and the follow up periods ranged from 3.8 to 19.0 years. Meta-analysis for association between infertility and stroke demonstrated a pooled result HR of 1.07 ([95% CI, 0.87 – 1.32] I2 = 79.0%). In leave-one-out sensitivity analysis, heterogeneity from an Asian study, defined by I2 analysis, decreased to less than 40%. Leave-one-out sensitivity analysis is a useful method to discover the influence of each study on the overall effect-size estimate. Of about 2 million women pooled together, females with a history of any miscarriage were associated with a 7% increase in the risk of stroke (HR, 1.07 [95% CI, 1.00 – 1.14]). An even more increased risk of stroke was evident among women with greater than or equal to 3 miscarriages (HR, 1.42 [95% CI, 1.05-1.90]). Regarding association between stillbirth and stroke, a pooled analysis demonstrated a 38% increase in risk of stroke (HR, 1.38 [95% CI, 1.11–1.71]).
This comprehensive review found that women with miscarriage or stillbirth were at higher risk of stroke and highlighted a dose-response increase in stroke risk for repeat miscarriages and stillbirths. Risk factors for infertility, like endometriosis, have been linked to traditional vascular risk factors, like hyperlipidemia and hypertension, which may contribute to elevated risk of stroke. Further, pregnancy loss has been associated with endothelial injury and inflammatory response, both of which could potentiate the risk for thrombotic events. This is an interesting meta-analysis to further identify sex-specific risk factors that could be used to further risk stratify stroke patients, leading to more timely primary prevention. Further studies should elucidate and include sex-specific risk factors.
- Béjot Y, Bailly H, Durier J, Giroud M. Epidemiology of stroke in Europe and trends for the 21st century. Presse Med. 2016;45(12 pt 2):e391–e398. doi: 10.1016/j.lpm.2016.10.003
- Phan HT, Blizzard CL, Reeves MJ, Thrift AG, Cadilhac D, Sturm J, Heeley E, Otahal P, Konstantinos V, Anderson C, et al. Sex differences in long-term mortality after stroke in the INSTRUCT (International Stroke Outcomes Study): a meta-analysis of individual participant data. Circ Cardiovasc Qual Outcomes. 2017;10:e003436. doi: 10.1161/CIRCOUTCOMES.116.003436