Infertility, pregnancy loss, and stillbirth increased women’s later risk of both nonfatal and fatal stroke, based on data from more than 600,000 women.
“To date, multiple studies have generated an expanding body of evidence on the association between pregnancy complications (e.g., gestational diabetes and preeclampsia) and the long-term risk of stroke, but studies on associations with infertility, miscarriage, or stillbirth have produced mixed evidence,” Chen Liang, a PhD candidate at the University of Queensland, Brisbane, Australia, and colleagues wrote.
In a study published in the BMJ, the researchers reviewed data from eight observational cohort studies across seven countries (Australia, China, Japan, the Netherlands, Sweden, the United Kingdom, and the United States). The participants were part of the InterLACE (International Collaboration for a Life Course Approach to Reproductive Health and Chronic Disease Events) consortium established in 2021. Most observational studies included in the analysis began between 1990 and 2000.
The study population included 618,851 women aged 32-73 years at baseline for whom data on infertility, miscarriage, or stillbirth, were available. The primary outcome was the association of infertility, recurrent miscarriage, and stillbirth with risk of first fatal or nonfatal stroke, and the results were further stratified by subtype. Stroke was identified through self-reports, linked hospital data, national patient registers, or death registry data. Baseline was defined as the first incidence of infertility, miscarriage, or stillbirth. The exception was the National Survey of Health and Development, a British birth cohort started in 1946, that collected data retrospectively.
The median follow-up period was 13 years for nonfatal stroke and 9.4 years for fatal stroke.
Overall, 17.2%, 16.6%, and 4.6% of the women experienced infertility, miscarriage, and stillbirth, respectively.
Women with a history of infertility had a significantly higher nonfatal stroke risk, compared with those without infertility (hazard ratio, 1.14). Further analysis by stroke subtypes showed an increased association between miscarriage and ischemic stroke (HR, 1.15).
Those with a history of miscarriage also had an increased risk of nonfatal stroke, compared with those without miscarriages (HR, 1.11). In the miscarriage group, the risk of stroke increased with the number of miscarriages, with adjusted HRs of 1.07, 1.12, and 1.35 for women with one, two, and three or more miscarriages, respectively. When stratified by stroke subtype, women with three or more miscarriages were more likely than women with no miscarriages to experience ischemic and hemorrhagic nonfatal strokes.
Associations were similar between miscarriage history and fatal stroke risk. Women with one, two, and three or more miscarriages had increased risk of fatal stroke, compared with those with no miscarriages (aHR, 1.08, 1.26, and 1.82, respectively, and women with three or more miscarriages had a higher risk of ischemic and hemorrhagic stroke (aHR, 1.83 and 1.84, respectively).
Women with a history of stillbirth had an approximately 31% increased risk of nonfatal stroke, compared with those with no history of stillbirth, with aHRs similar for single and recurrent stillbirths (1.32 and 1.29, respectively). Ischemic nonfatal stroke risk was higher in women with any stillbirth, compared with those without stillbirth (aHR, 1.77). Fatal stroke risk also was higher in women with any stillbirth, compared with those without, and this risk increased with the number of stillbirths (HR, 0.97 and HR, 1.26 for those with one stillbirth and two or more, respectively).
“The increased risk of stroke associated with infertility or recurrent stillbirths was mainly driven by a single subtype of stroke (nonfatal ischemic stroke or fatal hemorrhagic stroke, respectively), whereas the risk of stroke associated with recurrent miscarriages was driven by both subtypes,” the researchers wrote.
The researchers cited endothelial dysfunction as a potential underlying mechanism for increased stroke risk associated with pregnancy complications. “Endothelial dysfunction might lead to pregnancy loss through placentation-related defects, persist after a complicated pregnancy, and contribute to the development of stroke through reduced vasodilation, proinflammatory status, and prothrombic properties,” and that history of recurrent pregnancy loss might be a female-specific risk factor for stroke.
To mitigate this risk, they advised early monitoring of women with a history of recurrent miscarriages and stillbirths for stroke risk factors such as high blood pressure, blood sugar levels, and lipid levels.
The study findings were limited by several factors including the use of questionnaires to collect information on infertility, miscarriage, and stillbirth, and the potential variation in definitions of infertility, miscarriage, and stillbirth across the included studies, and a lack of data on the effect of different causes or treatments based on reproductive histories, the researchers noted. Other limitations include incomplete data on stroke subtypes and inability to adjust for all covariates such as thyroid disorders and endometriosis. However, the results were strengthened by the large study size and geographically and racially diverse population, extend the current knowledge on associations between infertility, miscarriage, and stillbirth with stroke, and highlight the need for more research on underlying mechanisms.