Preeclampsia and the Long-Term Risk of Developing Neurological Disorders Requiring Hospital Admission

Preeclampsia is linked with cardiovascular and renal morbidity later in life [1], but the risk of developing neurological disease is less clear. Preeclampsia is a hypertensive disorder of pregnancy associated with placental and endothelial cell dysfunction after 20 weeks of gestation [2]. Preeclampsia has neurological implications during pregnancy, ranging from relatively minor symptoms such as headache to more concerning sequelae such as seizures, cerebral venous sinus thrombosis, and ischemic or hemorrhagic stroke [3]. The acute effect of preeclampsia on cerebral vasculature is thought to resolve once pregnancy ends [3]. However, the potential for preeclampsia to increase the risk of neurological morbidity after pregnancy has received limited attention, despite emerging evidence that endothelial dysfunction associated with preeclampsia can persist in the long term [4].

A number of studies are beginning to suggest that preeclampsia may be associated with adverse neurological outcomes after pregnancy, although the overall findings are mixed [5‒12]. A prospective cohort study of 1.2 million women from Denmark found that preeclampsia was associated with an increased risk of vascular dementia and possibly Alzheimer’s disease up to 37 years after pregnancy [5]. However, a study of 300,000 women from Sweden found that hypertensive disorders of pregnancy were not associated with the risk of dementia in the 35 years following delivery [6]. Studies of preeclampsia and cognitive function after pregnancy, including cognitive impairment, cerebral white and gray matter volume, and brain atrophy, have been contradictory [7‒11]. More recently, a retrospective analysis of 1.6 million births from Canada found that women with a history of preeclampsia or eclampsia were 2–6 times more likely to develop a seizure disorder after pregnancy [12]. Our objective was to determine if preeclampsia was associated with the risk of developing neurological morbidity up to three decades after pregnancy.

We carried out a longitudinal cohort study of 1,452,689 pregnant women with and without preeclampsia who gave birth in Quebec, Canada, between April 1, 1989, and March 31, 2022. We identified pregnant women in the Maintenance and Use of Data for the Study of Hospital Clientele Registry, which has discharge abstracts for 98% of deliveries in Quebec [13]. The registry contains all patients admitted for neurological conditions during the study period, and includes data for up to 40 morbidities coded using the International Classification of Diseases, 9th and 10th revisions.

We began follow-up at the first delivery for all patients in the cohort. We determined if there was a diagnosis of preeclampsia during the first or any subsequent pregnancy, and used unique patient identifiers to identify neurological admissions any time after pregnancy. We had data until March 31, 2023, for a maximum follow-up period of 34 years. We did not include patients whose pregnancies lasted less than 20 weeks of gestation and patients with a history of neurological disorders in their prenatal chart or during pre-pregnancy hospitalizations. Most patients with preexisting neurological disorders had a history of epilepsy, cerebrovascular disorders, or demyelinating disease.

The main exposure was preeclampsia defined as hypertension (140/90 mm Hg) with new onset of proteinuria or end organ dysfunction after 20 weeks of gestation in any pregnancy [2, 14]. We considered women without any record of preeclampsia as unexposed. We included the severity of preeclampsia (mild, severe, superimposed) as a secondary exposure measure. Mild preeclampsia was defined as hypertension not reaching the threshold of 160/110 mm Hg [15]. Severe preeclampsia was defined as hypertension above this threshold with associated signs of end organ insufficiency [14]. We included eclampsia and HELLP syndrome (hemolysis, elevated liver enzymes, low platelets) in the definition of severe preeclampsia [14]. Superimposed preeclampsia consisted of new onset proteinuria or other end organ dysfunction among women with preexisting chronic hypertension.

We further categorized preeclampsia as early versus late onset. Early onset consisted of preeclampsia occurring before 34 weeks of gestation. Early onset preeclampsia is considered more severe than late onset preeclampsia [16]. We also determined whether preeclampsia recurred in more than one pregnancy. In multiparous women, recurrent preeclampsia is generally more severe than nonrecurrent preeclampsia [1].

We included neurologic outcomes occurring outside of pregnancy (online suppl. Table S1; for all online suppl. material, see https://doi.org/10.1159/000543087): cerebrovascular disorders (transient cerebral ischemic attacks, ischemic or hemorrhagic stroke, nonruptured aneurysm, occlusion and stenosis of cerebral and precerebral arteries, cerebral atherosclerosis, moyamoya disease); epilepsy (generalized, focal, unspecified); other isolated seizures and unspecified convulsion disorders that were not classified as epilepsy; Guillain-Barré syndrome and other neuroimmune disorders; multiple sclerosis and other demyelinating disorders; motor neuron disease; cerebellar ataxia; extrapyramidal disorders; and Alzheimer’s and other neurodegenerative conditions (not including vascular dementia).

We accounted for age (<25, 25–34, ≥35 years), multiple birth (yes, no), pregnancy comorbidity (preexisting or gestational diabetes, preexisting dyslipidemia, obesity, antiphospholipid syndrome, and alcohol, tobacco, or other substance use disorders), socioeconomic disadvantage (yes, no, unknown), and time period at first pregnancy (1989–1999, 2000–2010, 2011–2022) as these factors could potentially influence the relationship between preeclampsia and neurological diseases. Socioeconomic disadvantage was measured as an index of neighborhood-level income, employment rate, and education levels, with the most deprived quintile corresponding to the highest level of material disadvantage [1].

We began by assessing patient characteristics and the frequency of preeclampsia. We calculated the cumulative incidence of neurological hospitalization over time per 1,000 patients with and without preeclampsia, and estimated the median number of years needed to attain one neurological hospitalization per 10,000 women using Weibull accelerated failure time models adjusted for age, multiple birth, comorbidity, socioeconomic disadvantage, and time period [17].

In primary analyses, we estimated hazard ratios (HR) and 95% confidence intervals (CI) for the association between preeclampsia and subsequent risk of neurological hospitalization. We used Cox proportional hazards regression models adjusted for patient characteristics, with the time scale corresponding to the number of days between the first delivery and the first admission for a neurological disorder. We censored women who were never hospitalized for neurological disorders by the end of the study, and treated death from non-neurological causes as a competing event. We used survival curves and time interaction terms to verify the proportionality of hazards.

We performed the analysis for any preeclampsia compared with no preeclampsia, as well as for preeclampsia severity, onset, and recurrence. In secondary analyses, we used flexible parametric survival models to examine the association between preeclampsia and neurological outcomes at different time points after pregnancy [18]. In sensitivity analyses, we examined if associations differed when we included women with a preexisting history of neurological disorders. We performed the analysis using SAS version 9.4 (SAS Institute Inc., Cary, NC).

Among 1,460,098 women with deliveries between 1989 and 2022, 73,890 (5.1%) developed preeclampsia in at least one pregnancy (online suppl. Table S2). During a total of 27,659,555 person-years of follow-up, 1,443 (1.9%) women with preeclampsia were hospitalized for a neurological disorder, compared with 20,934 (1.5%) women without preeclampsia. Women with preeclampsia were more likely to be younger than 25 or older than 34 years at the time of delivery, have a multiple birth or pregnancy comorbidity, and be socioeconomically disadvantaged compared with women without preeclampsia. By the end of follow-up, women had a median age of 47.0 years, and 25% were 64 years or older.

After 34 years of follow-up, women with preeclampsia had a higher cumulative rate of neurological hospitalization than women without preeclampsia (51.5 vs. 36.4 per 1,000 women) (shown in Fig. 1). Neurological hospitalization rates increased more rapidly among women with preeclampsia than among women without preeclampsia beginning around 10 years after pregnancy.

Preeclampsia was more strongly associated with cerebrovascular disorders and epilepsy than other neurological conditions (Table 1). Compared with no preeclampsia, women with preeclampsia were 1.89 times more likely to be hospitalized for cerebrovascular disorders (95% CI, 1.76–2.03) and 1.39 times more likely to be hospitalized for epilepsy (95% CI, 1.24–1.57). Median time to reach 1 neurological hospitalization per 10,000 women was 0.64 years for preeclampsia compared with 0.82 years for no preeclampsia. Women with preeclampsia had a shorter time to hospitalization for cerebrovascular disorders and epilepsy. However, preeclampsia did not appear to be associated with neuroimmune, demyelinating, extrapyramidal, and other neurodegenerative disorders.

Severe forms of preeclampsia were more strongly associated with the risk of cerebrovascular disorders and epilepsy (Table 2). Compared with no preeclampsia, women with severe (HR 2.07, 95% CI, 1.83–2.34), superimposed (HR 3.58, 95% CI, 2.86–4.47), early onset (HR 3.32, 95% CI, 2.81–3.91), or recurrent preeclampsia (HR 3.43, 95% CI, 2.84–4.14) all had an elevated risk of cerebrovascular hospitalization. Findings were similar for epilepsy, with severe variants of preeclampsia associated with 1.74–2.69 times greater risk of epilepsy hospitalization compared with no preeclampsia.

When we examined specific time points after pregnancy, preeclampsia was associated with cerebrovascular and epilepsy hospitalization consistently throughout follow-up (shown in Fig. 2). Compared with no preeclampsia, preeclampsia was associated with 2.34 times the risk of cerebrovascular hospitalization 1 year after pregnancy (95% CI, 1.92–2.86), 2.07 times the risk 5 years after pregnancy (95% CI, 1.85–2.32), and 1.83 times the risk 20 years after pregnancy (95% CI, 1.69–1.98). Preeclampsia was associated with 1.37 times the risk of epilepsy hospitalization 1 year after pregnancy (95% CI, 1.04–1.79), 1.34 times the risk 5 years after pregnancy (95% CI, 1.13–1.58), and 1.42 times the risk 20 years after pregnancy (95% CI, 1.22–1.65).

While patients with preeclampsia overall did not appear to have an elevated risk of neuroimmune and neurodegenerative conditions, associations tended to be present with severe forms of preeclampsia (Table 3). Superimposed preeclampsia was associated with extrapyramidal disorders (HR 2.21, 95% CI, 1.25–3.89), severe preeclampsia with motor neuron disease (HR 3.45, 95% CI, 1.62–7.36), early onset preeclampsia with Alzheimer’s disease (HR 2.41, 95% CI, 1.20–4.85), and recurrent preeclampsia with neuroimmune disorders (HR 3.01, 95% CI, 1.42–6.37). In sensitivity analyses, preeclampsia was associated with a similar risk of neurological hospitalization when women with a preexisting history of neurological disorders were included in the analysis (HR 1.46, 95% CI, 1.39–1.54).

In this longitudinal cohort study with 27 million person-years of follow-up, preeclampsia was associated with an increased risk of hospitalization for neurological disorders up to 3 decades after pregnancy. Severe variants of preeclampsia, including early onset, recurrent, and superimposed preeclampsia, were more strongly associated with the onset of neurological morbidity. Preeclampsia was primarily linked with cerebrovascular disease and epilepsy. There was also evidence that patients with severe preeclampsia were at risk of developing motor neuron disease. Risk of hospitalization for neurological disorders was greatest within 1 year of pregnancy, but associations persisted throughout follow-up. The findings suggest that patients with preeclampsia, especially severe hypertension during pregnancy, may be at risk of developing subsequent neurological disorders, particularly cerebrovascular disease and epilepsy.

The pathways linking preeclampsia with neurological disorders remain to be established, but may stem from the underlying vascular pathology of hypertensive disorders of pregnancy. In normal pregnancies, remodeling of spiral arteries results in vasodilation and a wider lumen of uterine arteries [19, 20]. In patients with preeclampsia, spiral arteries do not remodel adequately and retain thick walls with narrow lumina. Defective remodeling leads to insufficient placental development, placental vascular lesions, and placental ischemia [20, 21]. Placental stress is associated with maternal endothelial cell dysfunction and a systemic inflammatory response marked by imbalance of circulating biomarkers such as soluble fms-like tyrosine kinase-1 and vascular endothelial growth factor [22, 23]. As vascular dysfunction progresses, the classic syndrome of preeclampsia appears with patients experiencing hypertension and end organ damage, including heart failure, pulmonary edema, acute kidney failure, and neurological dysfunction [14]. In some cases, preeclampsia can lead to seizures, cerebral venous sinus thrombosis, and ischemic or hemorrhagic stroke during pregnancy [3]. The same pathways leading to acute neurologic complications have the potential to contribute to long-term neurologic pathology, although these have received only limited attention in research.

In some patients, endothelial dysfunction and inflammatory biomarker elevation has been found to persist after pregnancy [4]. Endothelial dysfunction that persists at a subclinical level is thought to be responsible for the association between preeclampsia and subsequent development of cardiovascular disease, including cerebrovascular disease [1]. A cohort study of 1,235 women from the USA found that women with a history of preeclampsia were 3 times more likely to have a stroke up to 3 decades after pregnancy [24]. Similarly, a cohort study of 2,227,711 women from France found that preeclampsia was associated with 2 times the risk of cerebrovascular disease up to 10 years postpartum [25]. A study of 31,688 Finnish women reported that severe or recurrent preeclampsia was even more strongly associated with the risk of stroke [26]. Our findings align with these studies and suggest that the most important neurological implication of preeclampsia is cerebrovascular disease.

Women with a history of preeclampsia were also at risk of developing epilepsy after pregnancy. During pregnancy, preeclampsia is known to impact cerebral blood flow and the risk of seizures [27]. Severe cases may progress to eclampsia, with patients experiencing convulsions, status epilepticus, and other acute neurological complications [28]. The risk of seizures is thought to diminish once pregnancy ends and hypertension resolves [2]. However, the decrease in seizure risk has never been verified in quantitative analysis. Emerging reports suggest that the risk of seizures may in fact persist postpartum. A study of 1,565,733 births from Canada found that preeclampsia was associated with an elevated risk of admission for epilepsy in the decade following pregnancy, although the investigators did not examine other types of seizures [12]. We found that women with preeclampsia were at risk of any type of convulsive disorder after pregnancy, whether attributable to epilepsy or not. Preeclampsia was associated with up to 2 times the risk of epilepsy and other types of seizures. Our findings suggest that preeclampsia has the potential to injure the brain and affect electrical function in the long-term, even if there is an immediate reduction in seizure risk once the pregnancy ends. The underlying pathways may relate to the development of subclinical cerebrovascular disease, a potential risk factor for adult-onset epilepsy [29].

Preeclampsia was not as clearly linked with other neurological disorders in our data, although severe preeclampsia appeared to be associated with motor neuron disease. Motor neuron disease is an atrophic disorder in which progressive degeneration of upper and lower motor neurons leads to eventual paralysis and respiratory failure [30]. The cause of atrophy is unclear but thought to be initiated following subclinical inflammation or injury [31]. Preeclampsia is a proinflammatory state associated with structural changes in white matter and loss of cortical gray matter volume after pregnancy [7, 8, 11, 12, 23]. Preeclampsia-related cortical changes are frequently found in areas of the cortex affected by motor neuron disease [32]. A study of 148 women from the Netherlands found that preeclampsia was associated with a 37% increase in white matter lesions up to 5 years after pregnancy [7]. A Dutch study of 68 patients found that women with eclampsia were twice as likely to have subcortical white matter lesions up to 6 years postpartum [8]. However, more research is needed to verify whether the cerebral changes following preeclampsia are linked with those in motor neuron disease.

Similarly, more data are required to understand how preeclampsia relates to other forms of neurodegeneration. In our analysis, early onset preeclampsia was associated with Alzheimer’s disease and other nonvascular dementias. Other studies tend to present mixed findings for dementia [5, 6]. A study of 1.2 million women from Denmark found that preeclampsia was associated with a 45% greater risk of developing Alzheimer’s disease during a median follow-up time of 21 years [5]. In contrast, a study of nearly 300,000 women from Sweden found no association between hypertensive disorders of pregnancy and the long-term risk of developing nonvascular dementia [6]. The investigators, nevertheless, called for more research as mechanisms linking preeclampsia with neurodegeneration are plausible, and their data may have been underpowered [6]. Endothelial dysfunction and the inflammatory responses involved in preeclampsia are thought to possibly trigger Alzheimer’s disease and other nonvascular dementias [5]. A genetic predisposition is also possible as patients with preeclampsia are more likely to have a specific variant of the STOX1 gene expressed in the placenta and brain. STOX1 is overexpressed in patients with Alzheimer’s disease [5].

This study had limitations. We used administrative hospital data in which miscoding may affect the classification of exposures or outcomes and attenuate the associations to the null. Outcomes may be misclassified for patients who received ambulatory neurological care during follow-up and were never admitted to hospital. Power for Alzheimer’s disease and other disorders that develop later in life may be limited as the cohort consisted of predominantly younger women. We did not have data on postpartum vasculopathy. The prevalence of preeclampsia increased over time, due to either better ascertainment or changes in the demographic characteristics of the obstetric population. However, we could not determine the extent to which such changes may have affected the results, especially for outcomes that are common at older ages. We did not have patient characteristics such as ethnicity and pharmacotherapy, and cannot rule out residual confounding. Certain characteristics, such as obesity and substance-use disorders, may be underreported. As the study was observational, the findings should be interpreted with caution. Although the data are representative of a large Canadian population, it is unclear whether the findings can be generalized to other populations.

In this longitudinal study of a large cohort of women in Canada, preeclampsia was associated with an increased risk of hospitalization for a range of neurological complications up to three decades later, especially cerebrovascular disease and epilepsy. Although preeclampsia was not as clearly linked with other neurological outcomes, severe forms of preeclampsia tended to be associated with the development of motor neuron disease and Alzheimer’s disease over time. Our findings suggest that women with preeclampsia may be at risk of developing cerebrovascular disease, epilepsy, and other neurological disorders later in life. These patients may benefit from closer monitoring after pregnancy to optimize neurologic outcomes.

This study protocol was exempted from review by the University of Montreal Hospital Centre Institutional Review Board. The study was exempted from informed consent by the University of Montreal Hospital Centre Institutional Review Board.

The authors have no conflicts of interest to declare.

This work was supported by the Heart and Stroke Foundation of Canada (Grant No. G-22-0031974) and the Fonds de recherche du Québec-Santé (Grant No. 296785). The funders had no role in the design, data collection, data analysis, and reporting of this study.

N.A., G.P., A.L., and B.J.P. conceived and designed the study. A.M. performed the data analysis. N.A., M.K., V.L., and J.H.-P. helped interpret the results. N.A., J.H.-P., and A.M. drafted the manuscript. G.P., M.K., V.L., A.L., and B.J.P. revised it critically for important intellectual content. All authors approved the version to be published.

The data that support the findings of this study are available from the Institut de la statistique du Québec repository (https://statistique.quebec.ca/recherche/#/accueil).