Preeclampsia - a risk factor for later-life incident stroke among women: JAMA

Preeclampsia can result in acute cerebrovascular complications, including stroke and intracranial vasculopathy, and has been associated with an increase in the risk of stroke in later life. However, existing research has not fully accounted for time-varying midlife risk factors that could bias the association between preeclampsia and later-life stroke.

To address this limitation, Adam de Havenon and team used data from the Framingham Heart Study (FHS), which enrolled 2873 women who had up to 32 follow-up visits every other year published in Obstetrics and Gynecology JAMA Open Network.

This population-based cohort study was a secondary analysis of data from the Framingham Heart Study, which was conducted from 1948 to 2016. Women were included in the analysis if they were stroke free at enrollment and had a minimum of 3 study visits and 1 pregnancy before menopause, hysterectomy, or age 45 years.

Data on vascular risk factors, history of preeclampsia, and stroke incidence were collected biannually. Participants were followed up until incident stroke or censorship from the study. Marginal structural models were used to evaluate the relative risk of incident stroke among participants with and without a history of preeclampsia after accounting for time-varying covariates. Data were analyzed from May 2019 to December 2020.

• A total of 1435 women (mean [SD] age, 44.4 [7.7] years at the beginning of the study; 100% White) with 41,422 person-years of follow-up were included in the analytic sample. Of those, 169 women had a history of preeclampsia, and 231 women experienced strokes during follow-up.

• Stroke events occurred in 30 of 169 women (17.8%) with a history of preeclampsia and in 201 of 1266 women (15.9%) without a history of preeclampsia.

• At baseline, women with preeclampsia were more likely to be younger, to be receiving cholesterol lowering medications, to have lower cholesterol and higher diastolic blood pressure, and to currently smoke.
• The association between preeclampsia and stroke in the marginal structural model was only evident when adjustment was made for all vascular risk factors over the life course, which indicated that women with a history of preeclampsia had a higher risk of stroke in later life compared with women without a history of preeclampsia (relative risk, 3.79; 95% CI, 1.24-11.60).

• After adjustment for time-varying confounders and censoring, the reasearchers found that preeclampsia among White women was associated with significant increases in the long-term risk of incident stroke.

Biomarkers of impaired vascular health, including increased cerebral small vessel disease and carotid intima-media thickness, have been observed years to decades after preeclampsia. The Stroke Prevention in Young Women study reported that a history of preeclampsia had an OR of 1.63 for ischemic stroke among a sample of 682 women; however, the study lacked data on vascular risk factors during midlife. The Million Women Study reported that women with a history of a hypertensive disorder of pregnancy had a relative risk of 1.18 to 1.86 for ischemic stroke, but the study lacked longitudinal data.

The most substantial confounder in this analysis was participant age, with weight and blood pressure also being notable confounders. However, adjusting for age alone was insufficient to establish an association between preeclampsia and stroke. Establishing this association requires additional adjustment for vascular risk factors, including blood pressure, cholesterol level, blood glucose level, smoking status, and weight. Thus, it is the interplay of increasing age and the accumulation of vascular risk factors that likely creates the association between preeclampsia and stroke.

Although age cannot be altered, the study results suggest that improved midlife control of hypertension, hyperlipidemia, hyperglycemia, and other vascular risk factors has the potential to mitigate the later-life risk of stroke among women with a history of preeclampsia.

Based on analysis using the MSM model specification, there may be a complex interplay between preeclampsia and the accumulation of comorbidities throughout one's life that factors into the risk of subsequent stroke. This study illustrates the ways in which MSMs can be properly used to estimate the association between an exposure and an outcome (ie, preeclampsia and stroke) when there is high likelihood of bias induced by time-varying covariates.

The original FHS cohort only enrolled White participants, which limits the generalizability of the findings. The researchers did not have detailed or consistent data on additional vascular risk factors, most importantly physical activity and diet. Despite these limitations, the strengths of the study are notable, primarily the extensive data on vascular risk factor control through midlife, which is a distinct attribute when evaluating this association. The study also used a statistical model that was capable of analyzing the granular data in the FHS.

The researchers concluded, "In this cohort study, White women with a history of preeclampsia had more than 3 times the risk of later-life stroke compared with those without a history of preeclampsia. Because the FHS enrolled only White participants, these results are not generalizable to other racial or ethnic groups. The stroke events occurred at a mean of more than 3 decades after the exposure, suggesting that aggressive medical management of vascular risk factors during midlife has the potential to reduce the risk of stroke."

Research is needed to explore the practical implications of this association, particularly regarding the implementation of additional monitoring of vascular health among women with a history of preeclampsia and the use of lower thresholds for medical and lifestyle interventions to improve vascular health.

Source: Adam de Havenon; Alen Delic; Eric Stulberg; JAMA Network Open. 2021;4(4):e215077.

doi:10.1001/jamanetworkopen.2021.5077