Infertility, miscarriage, and stillbirth are correlated with an increased risk for stroke, with the strongest association observed in women with recurrent miscarriages and stillbirth, according to study findings published in The British Medical Journal.

Previous studies have shown that the relationship between infertility, miscarriage, and stillbirth in relation to risk for stroke has been inconclusive. Additionally, the evidence for associations between infertility and adverse pregnancy outcomes (miscarriage and stillbirth) and the different types of stroke (nonfatal and fatal) has been limited.

The objective of this study was to demonstrate the relationship between adverse pregnancy outcomes and the risk for first nonfatal and fatal stroke, further assessed by subtype.


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Researchers collected data across 7 countries (Australia, China, Japan, the Netherlands, Sweden, the United Kingdom, and the United States) that participated in the International Collaboration for a Life Course Approach to Reproductive Health and Chronic Disease Events (InterLACE) consortium. The studies in this consortium ran from 1990 to the early 2000s, with the exception of the British cohort, where participant data was collected from 1946. Reproductive information and covariates were collected through questionnaires at baseline, with some studies collecting follow-up survey information.

Miscarriages were categorized into 4 categories (0, 1, 2, ≥3) and stillbirths were categorized into 3 categories (0, 1, ≥2).  Recurrent miscarriages were defined as at least 3 miscarriages and recurrent stillbirths were defined as at least 2 stillbirths.

Researchers identified first nonfatal stroke events through self-reported questionnaires and through hospital documentation. Strokes were classified using the International Classification of Diseases (ICD)-9 and ICD-10.

Researchers generated Kaplan-Meier survival curves to represent the probability of stroke in women without infertility, miscarriage, or stillbirth. Survival time models were adjusted for a history of oral contraceptive use and hormone replacement therapies at baseline. Cox proportional hazards survival time models were used to estimate associations between infertility, adverse pregnancy outcomes, and stroke outcomes (first nonfatal stroke, fatal stroke, or stroke subtypes).

The study included 618,851 participants with a history of infertility, adverse pregnancy outcomes, and at least 1 stroke outcome. The ages of participants ranged from 32 to 73 years at the start of the study and a majority of participants were White (81.66%).

The median follow-up for nonfatal stroke was 13 years (interquartile range, 12-14) and for fatal stroke was 9.4 years (interquartile range, 7.6-13). First nonfatal stroke was documented in 9265 (2.8%) participants and 4003 (0.7%) participants experienced a fatal stroke.

Researchers found an association between infertility and increased risk for nonfatal stroke (hazard ratio [HR], 1.14; 95% CI, 1.08-1.20). They also observed an association between miscarriages and increased risk for nonfatal stroke (HR, 1.35; 95% CI, 1.27-1.44) and fatal stroke (HR, 1.82; 95% CI, 1.58-2.10). 

The researchers found that women with stillbirths were at a 31% higher risk for nonfatal stroke (HR, 1.31; 95% CI, 1.10-1.5) and that women who had recurrent stillbirths had a 26% greater chance of higher risk for fatal stroke (HR, 1.26; 95% CI, 1.15-1.39).

A single stroke subtype (nonfatal ischemic stroke or fatal hemorrhagic stroke, respectively) was strongly associated with infertility and recurrent stillbirths. In contrast, both types of stroke (nonfatal or fatal) were associated with a risk for recurrent miscarriages.

The study had several limitations, the researchers acknowledged. There is the potential of a recall bias — data on infertility, miscarriage, and stillbirth were collected via questionnaires. Furthermore, the studies may have included different definitions of infertility, miscarriage, and stillbirth, leading women to report their reproductive history based on their understanding of these definitions. Also, there was limited data on the different causes or treatments related to each woman’s reproductive history, the researchers stated.

They concluded, “A history of recurrent miscarriages and death or loss of a baby before or during birth should be considered a female specific risk factor for stroke. Early monitoring of women with recurrent miscarriages or stillbirths and tailored healthy lifestyle interventions are recommended to lower the risk of stroke.”

Reference

Liang C, Chung HF, Dobson AJ, et al. Infertility, recurrent pregnancy loss, and risk of stroke: pooled analysis of individual patient data of 618 851 women. BMJ. Published online June 22, 2022. doi:10.1136/bmj-2022-070603