Risk of Midlife Stroke After Adverse Pregnancy Outcomes: The FinnGen Study

Abstract

Background: Adverse pregnancy outcomes (APO) contribute to higher risk of maternal cerebrovascular disease, but longitudinal data that include APO and stroke timing are lacking. We hypothesized that APO are associated with younger age at first stroke, with a stronger relationship in those with >1 pregnancy with APO.

Methods: We analyzed longitudinal Finnish nationwide health registry data from the FinnGen Study. We included women who gave birth after 1969 when the hospital discharge registry was established. We defined APO as a pregnancy affected by gestational hypertension, preeclampsia, eclampsia, preterm birth, small for gestational age infant, or placental abruption. We defined stroke as first hospital admission for ischemic stroke or nontraumatic intracerebral or subarachnoid hemorrhage, excluding stroke during pregnancy or within 1 year postpartum. We used Kaplan-Meier survival curves and multivariable-adjusted Cox and generalized linear models to assess the relationship between APO and future stroke.

Results: We included 144 306 women with a total of 316 789 births in the analysis sample, of whom 17.9% had at least 1 pregnancy with an APO and 2.9% experienced an APO in ≥2 pregnancies. Women with APO had more comorbidities including obesity, hypertension, heart disease, and migraine. Median age at first stroke was 58.3 years in those with no APO, 54.8 years in those with 1 APO, and 51.6 years in those with recurrent APO. In models adjusted for sociodemographic characteristics and stroke risk factors, risk of stroke was greater in women with 1 APO (adjusted hazard ratio, 1.3 [95% CI, 1.2-1.4]) and recurrent APO (adjusted hazard ratio, 1.4 [95% CI, 1.2-1.7]) compared with those with no APO. Women with recurrent APO had more than twice the stroke risk before age 45 (adjusted odds ratio, 2.1 [95% CI, 1.5-3.1]) compared with those without APO.

Conclusions: Women who experience APO have earlier onset of cerebrovascular disease, with the earliest onset in those with more than 1 affected pregnancy.

Keywords: cerebrovascular disorders; hypertension, pregnancy-induced; pregnancy; stroke.

Figure 1.. Flow diagram of analysis sample selection

FinnGen Data Freeze 10 consists of participants from Finnish cohort studies and patients from Finland’s national hospital biobanks. We included all people who gave birth in Finland in 1969 or later, with at least one birth documented in the Medical Birth Register. Out of a total of 430,885 FinnGen participants (male and female), 184,012 women had data as mothers in the birth registries. We excluded those who first gave birth before 1969; those with no recorded births; those who had a stroke before their first birth; those with pregnancy-associated stroke; and those with missing data other than educational status, which was imputed.

Figure 2.. Median age at first stroke in parous women in the FinnGen study.

Stacked histogram plot shows age at the first incident stroke, among people with zero (blue), 1 (green) or 2 or more (red) pregnancies affected by an APO. Overall, median age at first stroke was 57.5 years (dashed line). Median age was 58.3 years (interquartile range [IQR] 46.6-67.6) in those with no APO; 54.8 years (IQR 43.3-64.2) in those with one pregnancy with APO; and 51.6 (IQR 41.6-60.9) years in those with recurrent APO (p<0.001).

Figure 3:. Age at first stroke in women with 0, 1, or ≥2 pregnancies complicated by APO.

Kaplan Meier survival curves show age at time of first hospital admission for stroke, among women with zero (blue), one (green) or two or more (red) pregnancies affected by an adverse pregnancy outcome. Follow up time spanned from first birth until December 31, 2021. Unadjusted model is adjusted for baseline age implicitly, since age is the time axis. Fully adjusted model included education, number of births, age at first birth, year of first birth (cohort effects), hypertension as time-varying covariate, and additional stroke risk factors (obesity, diabetes, hyperlipidemia, ischemic heart disease, atrial fibrillation, heart failure, chronic kidney disease, lupus, and migraine). HR: Hazard ratio. Numbers in parentheses indicate 95% confidence intervals. APO: Adverse pregnancy outcome, defined as any pregnancy complicated by gestational hypertension, preeclampsia/eclampsia, preterm birth, small for gestational age infant, or placental abruption.