Abstract
Background and Aims:
The lifelong risk of stroke following adverse pregnancy outcomes, and potential causality, are unknown. This study examined 5 major adverse pregnancy outcomes and long-term risk of stroke in a large population-based cohort.
Methods:
A national cohort study was conducted of all 2,201,393 women with a singleton delivery in Sweden during 1973–2015, followed up for stroke through 2018. Cox regression was used to determine hazard ratios (HRs) for stroke associated with preterm delivery, small for gestational age, preeclampsia, other hypertensive disorders, and gestational diabetes, adjusting for other maternal factors. Co-sibling analyses assessed for potential confounding by shared familial (genetic or environmental) factors.
Results:
In 48 million person-years of follow-up, 667,774 (30%) women experienced an adverse pregnancy outcome and 35,824 (1.6%) women were diagnosed with stroke. All 5 adverse pregnancy outcomes were independently associated with long-term increased risks of stroke. With up to 46 years of follow-up, adjusted HRs for stroke associated with specific adverse pregnancy outcomes were: gestational diabetes, 1.86 (95% CI, 1.69–2.04); other hypertensive disorders, 1.82 (1.67–1.98); preterm delivery, 1.40 (1.36–1.45); preeclampsia, 1.36 (1.31–1.41); and small for gestational age, 1.26 (1.22–1.29). All HRs remained significantly elevated (1.2- to 2.5-fold) even 30–46 years after delivery. These findings were only partially explained by shared familial factors.
Conclusions:
In a large national cohort, women with any of 5 adverse pregnancy outcomes had increased risks of stroke up to 46 years after delivery. Women with adverse pregnancy outcomes need early preventive actions and long-term follow-up to reduce their lifelong risk of stroke.
Keywords: cerebrovascular disorders, gestational diabetes, hypertensive disorders of pregnancy, preeclampsia, pregnancy complications, preterm delivery, small for gestational age, stroke
Graphical Abstract.
Adjusted hazard ratios (and 95% CIs) for associations between adverse pregnancy outcomes and stroke by time since delivery, Sweden, 1973–2018.
INTRODUCTION
Stroke is the third leading cause of death worldwide1 and has a higher burden of disease in women than in men.2 Most strokes occur in women,3 and they tend to be more severe and more likely to be fatal than strokes in men.4–6 In addition to lifestyle risk factors,3 certain adverse pregnancy outcomes7,8 such as preterm delivery9 and hypertensive disorders of pregnancy10–12 have been associated with higher future risk of stroke. During their reproductive years, up to 30% of all women experience a major adverse pregnancy outcome (preterm delivery, small for gestational age, preeclampsia, other hypertensive disorders of pregnancy, or gestational diabetes).13–16 However, the independent effects of specific adverse pregnancy outcomes on long-term risk of stroke, and their potential causality, are unknown. Such knowledge is needed to improve risk stratification and facilitate earlier interventions in high-risk women to reduce their lifelong risk of stroke.
Few studies have examined multiple adverse pregnancy outcomes in the same cohort in relation to future stroke risk. A study of 144,306 women in Finland reported that stroke risk in midlife was increased 1.3-fold in women with one adverse pregnancy outcome and 1.4-fold in those with recurrent adverse pregnancy outcomes.7 In a US study of 45,971 women, those who self-reported “any adverse pregnancy outcome” had >2-fold odds of stroke before age 60 years.8 However, to our knowledge, the comparative effects of adverse pregnancy outcomes on long-term risk of stroke have not been assessed using prospectively ascertained data in a large population-based cohort. In addition, previously reported associations could potentially be explained by familial factors that are shared determinants of adverse pregnancy outcomes and stroke. Family-based designs that control for unmeasured shared familial (genetic or environmental) factors are needed to further elucidate potential causality.
To address these knowledge gaps, we conducted a national cohort study of over 2 million women in Sweden. Our goals were to: (1) determine the risks of stroke and its subtypes associated with 5 major adverse pregnancy outcomes (preterm delivery, small for gestational age, preeclampsia, other hypertensive disorders, and gestational diabetes) using prospectively ascertained data in a large national cohort; (2) assess changes in such risks across the life course with up to 46 years of follow-up after delivery; and (3) assess for potential confounding by unmeasured shared genetic and environmental factors in families using co-sibling analyses. We hypothesized that women who experienced any of these 5 major adverse pregnancy outcomes would have long-term increased risks of stroke, and that such risks would be only partially explained by shared familial factors.
METHODS
Study Population
The Swedish Medical Birth Register contains prenatal and birth information for nearly all deliveries in Sweden since 1973. We identified 2,201,393 women in this register who had a singleton delivery during 1973–2015 and no prior stroke (based on International Classification of Diseases [ICD] codes, as described below). To improve internal comparability, only singleton deliveries were included, given the higher prevalence of adverse pregnancy outcomes and their different underlying causes in multiple gestation pregnancies. This study was approved by the Regional Ethical Review Board in Lund, Sweden (No. 2008/471 and later amendments). Participant consent was not required because this study used only pseudonymized registry-based secondary data.
Adverse Pregnancy Outcome Ascertainment
Five major adverse pregnancy outcomes were identified from prenatal and birth records in the Swedish Medical Birth Register.15,16 Preterm delivery (gestational age <37 completed weeks) was based on maternal report of last menstrual period in the 1970s and ultrasound estimation starting in the 1980s and onward (>70% of the cohort). Small for gestational age was defined by infant birth weight <10th percentile for gestational age. Preeclampsia, other hypertensive disorders of pregnancy, and gestational diabetes were identified from diagnostic codes in the Medical Birth Register (Supplementary Table 1). Gestational age and birth weight in this register have been found to be highly reliable.17,18 Most chronic disorders in the Swedish registries also have high validity, with positive predictive values in the 85% to 95% range,19 although to our knowledge maternal diagnoses in the Medical Birth Register have not been formally validated.
Stroke Ascertainment
The study cohort was followed up for stroke from first delivery through December 31, 2018 (maximum follow-up time, 46 years; median, 25). To exclude immediate effects of the index delivery on stroke incidence, the outcome was defined as any stroke diagnosis occurring >6 months postpartum. Stroke was identified using ICD codes in the Swedish Hospital and Outpatient Registers (Supplementary Table 1). “Any stroke” was examined as the primary outcome. Ischemic or hemorrhagic stroke (and major subtypes of hemorrhagic stroke: intracerebral hemorrhage and aneurysmal subarachnoid hemorrhage) were examined separately as secondary outcomes. The Swedish Hospital Register contains all primary and secondary hospital discharge diagnoses from six populous counties in southern Sweden starting in 1964 and with >99% nationwide coverage starting in 1987.19 Diagnoses of first-time stroke in this register have been reported to have both a positive predictive value and sensitivity >90%.19–21 In addition, the Swedish Outpatient Register contains all diagnoses from specialty clinics with approximately 87% nationwide coverage starting in 2001.22
Covariates
Other maternal characteristics that may be associated with adverse pregnancy outcomes and stroke were identified using the Swedish Medical Birth Register and national census and diagnosis data, which were linked using a pseudonymous serial number. Maternal age was adjusted for in all analyses as the Cox model time scale (as described below). Covariates included the following maternal factors, with all time-varying factors updated for each delivery: calendar year of delivery (continuous and categorical in 5-year groups to allow for potential non-linearity), parity (1, 2, 3, 4, ≥5), education level at delivery (≤9, 10–12, >12 years), employment status (yes/no) and income (quartiles) in the year prior to delivery, country of origin (Sweden, other European, non-European); maternal body mass index (BMI; continuous and categorical [<18.5, 18.5–24.9, 25.0–29.9, ≥30.0 kg/m2] to allow for potential non-linearity) and smoking (0, 1–9, ≥10 cigarettes/day) at the first prenatal visit; and pre-pregnancy history of hypertension, diabetes, hyperlipidemia, atrial fibrillation, or sleep disorders identified from nationwide diagnoses (Supplementary Table 1).
Maternal BMI and smoking were assessed at the beginning of prenatal care starting in 1982 and were available for 56% and 67% of women, respectively. Data were >99% complete for all other variables. Missing data were multiply imputed with 20 imputations using all other covariates and stroke as predictors. As alternatives to multiple imputation, sensitivity analyses were performed that (1) restricted to women with complete data (N=1,201,390), or (2) coded missing data for each variable as a separate category.
Statistical Analysis
Cox proportional hazards regression was used to compute hazard ratios (HRs) and 95% confidence intervals (CIs) for subsequent risk of stroke associated with specific adverse pregnancy outcomes. These associations were examined across the maximum possible follow-up time (up to 46 years after delivery) and within narrower intervals of follow-up (<10, 10–19, 20–29, 30–46 years) among women still living in Sweden without a prior stroke at the beginning of the respective interval. All adverse pregnancy outcomes were modeled as time-dependent variables based on “ever” experiencing the respective outcome. For example, if a woman’s first delivery had no adverse pregnancy outcomes and her second was preterm with preeclampsia, she entered the preterm and preeclampsia exposure categories at the date of her second delivery. If a woman’s first and second deliveries were both preterm, she entered the preterm delivery exposure category at the date of her first delivery.15,16
Maternal age was used as the Cox model time axis with age at each delivery as “time zero” (i.e., each singleton delivery was included as a separate observation, with exposures updated for each delivery). Women were censored at death as identified in the Swedish Death Register (n=43,966; 2%) or at emigration as determined by absence of a Swedish residential address in census data (n=92,774; 4%). For each adverse pregnancy outcome, two adjusted Cox models were performed that (1) adjusted for maternal sociodemographic factors, parity, and traditional stroke risk factors, and (2) further adjusted for all other adverse pregnancy outcomes. The proportional hazards assumption was assessed by examining log-log survival plots, and no substantial departures were found. Incidence rate differences and 95% CIs, attributable fraction in the exposed (AFe), and population attributable fraction (PAF) were computed for each adverse pregnancy outcome.
Co-sibling analyses were performed to assess for potential confounding by unmeasured familial (genetic and environmental) factors that may be shared determinants of adverse pregnancy outcomes and stroke. Shared environmental factors in families may include lifestyle factors such as diet and physical activity, or ambient exposures such as passive smoking and air pollution. These analyses included all 1,191,316 (54%) women with at least one full sister who had a singleton delivery (regardless of adverse pregnancy outcome status), and the same analysis was performed as the main analyses except for stratifying on sets of sisters. In the stratified Cox models, each stratum included a unique set of sisters identified by their biological mother’s and father’s pseudonymous serial numbers, modeled with their own baseline hazard function that reflects their shared genetic and environmental factors. Thus, these analyses examined associations between adverse pregnancy outcomes and stroke within each family, controlling for shared familial factors.9,15,16,23–26 In addition, these analyses were further adjusted for the same covariates as in the main analyses.
Other secondary analyses were performed to examine: (1) associations between adverse pregnancy outcomes and risk of stroke after stratifying by maternal age at delivery; (2) risk of stroke associated with spontaneous or medically indicated preterm delivery, which was systematically recorded starting in 1990 (N=2,656,196 births among 1,452,167 women; maximum 29 years of follow-up); (3) associations between the total number of adverse pregnancy outcomes (0, 1, 2, or ≥3 in the same or different pregnancies) and stroke risk, adjusting for parity and other covariates; and (4) potential mediation of the association between gestational diabetes and stroke risk by type 2 diabetes, which was explored by repeating the main analyses while censoring for post-pregnancy diagnosis of type 2 diabetes. In addition, sensitivity analyses were performed to examine associations between adverse pregnancy outcomes and risk of stroke while accounting for death as a competing event using competing risks models. All statistical tests were two-sided and used a significance level of 0.05. All analyses were conducted using Stata version 16.1.
RESULTS
A total of 667,774 (30%) women experienced at least 1 adverse pregnancy outcome, and 181,783 (8%) experienced at least 2 adverse pregnancy outcomes (not necessarily in the same pregnancy). The most common adverse pregnancy outcomes were small for gestational age (affecting 14% of women across all deliveries) and preterm delivery (9% of women). Table 1 shows characteristics of women with specific adverse pregnancy outcomes. Women with preterm or small for gestational age delivery were more likely to be younger at first delivery, have low education level or income, and/or to smoke. Women with preeclampsia were more likely to have low education level or income, high BMI, and/or to smoke. Women with other hypertensive disorders or gestational diabetes were more likely to be older at first delivery, have higher income or BMI, and/or to be a nonsmoker.
Table 1.
Baseline maternal characteristics by ever occurrence of an adverse pregnancy outcome, Sweden, 1973–2015.
| All women | Preterm delivery | Small for gestational age infant | Preeclampsia | Other hypertensive disorders | Gestational diabetes | |
|---|---|---|---|---|---|---|
| N=2,201,393 (100.0%) | N=194,751 (8.9%) | N=314,605 (14.3%) | N=132,543 (6.0%) | N=34,186 (1.6%) | N=36,269 (1.7%) | |
| n (%) | n (%) | n (%) | n (%) | n (%) | n (%) | |
| Age at first delivery (yrs) | ||||||
| <20 | 118,875 (5.4) | 16,329 (8.4) | 20,027 (6.4) | 6,759 (5.1) | 1,418 (4.2) | 1,859 (5.1) |
| 20–24 | 603,182 (27.4) | 58,301 (29.9) | 90,898 (28.9) | 36,879 (27.8) | 7,966 (23.3) | 8,797 (24.2) |
| 25–29 | 792,501 (36.0) | 64,634 (33.2) | 109,077 (34.7) | 46,754 (35.3) | 11,662 (34.1) | 11,856 (32.7) |
| 30–34 | 486,508 (22.1) | 38,379 (19.7) | 66,712 (21.2) | 28,479 (21.5) | 8,519 (24.9) | 8,595 (23.7) |
| 35–39 | 167,306 (7.6) | 14,009 (7.2) | 23,307 (7.4) | 11,017 (8.3) | 3,639 (10.6) | 4,020 (11.1) |
| ≥40 | 33,021 (1.5) | 3,099 (1.6) | 4,584 (1.5) | 2,655 (2.0) | 982 (2.9) | 1,142 (3.2) |
| Year of first delivery | ||||||
| 1973–1979 | 528,334 (24.0) | 42,646 (21.9) | 92,125 (29.3) | 51,021 (38.5) | 1,817 (5.3) | 6,031 (16.6) |
| 1980–1989 | 446,442 (20.3) | 46,315 (23.8) | 65,695 (20.9) | 27,365 (20.6) | 6,926 (20.3) | 5,060 (14.0) |
| 1990–1999 | 447,323 (20.3) | 42,426 (21.8) | 58,355 (18.5) | 19,738 (14.9) | 8,668 (25.4) | 7,625 (20.0) |
| 2000–2009 | 462,293 (21.0) | 40,717 (20.9) | 57,180 (18.2) | 20,278 (15.3) | 9,601 (28.1) | 10,380 (28.6) |
| 2010–2015 | 317,001 (14.4) | 22,647 (11.6) | 41,250 (13.1) | 14,141 (10.7) | 7,174 (21.0) | 18,557 (20.8) |
| Education (yrs) | ||||||
| ≤9 | 305,953 (13.9) | 30,401 (15.6) | 54,082 (17.2) | 21,391 (16.1) | 2,938 (8.6) | 6,472 (17.8) |
| 10–12 | 974,540 (44.3) | 91,177 (46.8) | 144,549 (45.9) | 62,838 (47.4) | 15,085 (44.1) | 15,990 (44.1) |
| >12 | 920,900 (41.8) | 73,173 (37.6) | 115,974 (36.9) | 48,314 (36.5) | 16,163 (47.3) | 13,807 (38.1) |
| Employed | 1,899,802 (86.3) | 165,857 (85.2) | 264,748 (84.2) | 119,997 (90.5) | 31,121 (91.0) | 28,609 (78.9) |
| Income (quartile) | ||||||
| 1st (highest) | 550,558 (25.0) | 44,134 (22.7) | 67,748 (21.5) | 26,942 (20.3) | 12,531 (36.7) | 10,545 (29.1) |
| 2nd | 548,633 (24.9) | 46,520 (23.9) | 75,756 (24.1) | 33,549 (25.3) | 8,520 (24.9) | 8,587 (23.7) |
| 3rd | 552,878 (25.1) | 49,411 (25.4) | 84,955 (27.0) | 39,390 (29.7) | 6,696 (19.6) | 7,552 (20.8) |
| 4th (lowest) | 549,324 (25.0) | 54,686 (28.1) | 86,146 (27.4) | 32,662 (24.6) | 6,439 (18.8) | 9,585 (26.4) |
| Country of origin | ||||||
| Sweden | 1,807,031 (82.1) | 160,656 (82.5) | 251,510 (79.9) | 114,766 (86.6) | 29,952 (87.6) | 25,929 (70.8) |
| Other European | 206,405 (9.4) | 17,076 (8.8) | 29,948 (9.5) | 11,652 (8.8) | 2,394 (7.0) | 3,526 (9.6) |
| Non-European | 187,947 (8.5) | 17,019 (8.7) | 33,147 (10.6) | 6,125 (4.6) | 1,840 (5.4) | 6,814 (18.6) |
| Body mass index (kg/m2) | ||||||
| <18.5 | 52,933 (2.4) | 5,730 (2.9) | 10,816 (3.4) | 1,509 (1.1) | 477 (1.4) | 542 (1.5) |
| 18.5–24.9 | 847,376 (38.5) | 68,996 (35.4) | 112,544 (35.8) | 32,402 (24.5) | 13,081 (38.3) | 11,010 (30.4) |
| 25.0–29.9 | 244,355 (11.1) | 20,876 (10.7) | 27,176 (8.6) | 15.127 (11.4) | 6.971 (20.4) | 6,558 (18.1) |
| ≥30.0 | 92,519 (4.2) | 9,194 (4.7) | 10,474 (3.3) | 8,962 (6.8) | 4,442 (13.0) | 5,116 (14.1) |
| Unknown | 964,210 (43.8) | 89,955 (46.2) | 153,595 (48.8) | 74,543 (56.2) | 9,215 (27.0) | 13,043 (36.0) |
| Smoking (cigarettes/day) | ||||||
| 0 | 1,256,995 (57.1) | 106,397 (54.4) | 150,527 (47.7) | 60,699 (45.6) | 26,701 (77.7) | 23,423 (64.2) |
| 1–9 | 154,119 (7.0) | 16,158 (8.3) | 29,052 (9.2) | 5,971 (4.5) | 2,390 (7.0) | 2,614 (7.2) |
| ≥10 | 70,495 (3.2) | 8,498 (4.3) | 15,518 (4.9) | 2,575 (1.9) | 994 (2.9) | 1,243 (3.4) |
| Unknown | 719,584 (32.7) | 63,698 (33.0) | 119,508 (38.2) | 63,298 (47.9) | 4,101 (12.4) | 8,989 (25.2) |
| Hypertension | 2,967 (0.1) | 718 (0.4) | 685 (0.2) | 884 (0.7) | 1,212 (3.5) | 351 (1.0) |
| Diabetes | 10,046 (0.5) | 3,058 (1.6) | 745 (0.2) | 1,907 (1.4) | 517 (1.5) | 6,119 (16.8) |
| Hyperlipidemia | 1,827 (0.1) | 296 (0.2) | 211 (0.1) | 203 (0.2) | 114 (0.3) | 415 (1.1) |
| Atrial fibrillation | 251 (<0.1) | 28 (<0.1) | 31 (<0.1) | 10 (<0.1) | 3 (<0.1) | 5 (<0.1) |
| Sleep disorders | 4,246 (0.2) | 280 (0.2) | 525 (0.2) | 262 (0.2) | 93 (0.4) | 106 (0.6) |
In 48 million person-years of follow-up, 35,824 (1.6%) women were diagnosed with stroke. The median age at first delivery was 27 (interquartile range [IQR], 23 to 30), at stroke diagnosis was 55 (IQR, 46 to 63), and at end of follow-up was 49 (IQR, 39 to 60) years. The median follow-up time in women who did not die was 27 (IQR, 14 to 39) years. Stroke incidence rates by specific adverse pregnancy outcomes and follow-up time are reported in Table 2, and cumulative hazards of stroke are shown in Figure 1. The 30-year and total cumulative incidence rates, respectively, were 1.3% and 2.1% in women with preterm delivery, 1.3% and 2.2% in women with small for gestational age delivery, 1.8% and 3.1% in women with preeclampsia, 1.5% and 1.8% in women with other hypertensive disorders, and 1.3% and 1.9% in women with gestational diabetes, compared with 0.9% and 1.6% in the entire cohort.
Table 2.
Associations between adverse pregnancy outcomes and subsequent risk of stroke.
| Stroke cases | Ratea | Reduced modelb | Full modelc | Incidence rate difference (95% CI)d | AFee | PAFf | |
|---|---|---|---|---|---|---|---|
| HR (95% CI) | HR (95% CI) | ||||||
| Up to 46 years after delivery | |||||||
| Preterm delivery | 4,142 | 103.7 | 1.46 (1.41, 1.51) | 1.40 (1.36, 1.45) | 35.1 (31.8, 38.4) | 33.8% | 5.6% |
| Small for gestational age | 6,877 | 93.9 | 1.27 (1.23, 1.30) | 1.26 (1.22, 1.29) | 22.7 (20.3, 25.0) | 24.1% | 4.6% |
| Preeclampsia | 4,168 | 122.0 | 1.42 (1.37, 1.46) | 1.36 (1.31, 1.41) | 50.9 (47.1, 54.7) | 41.7% | 4.9% |
| Other hypertensive disorders | 609 | 123.4 | 1.95 (1.79, 2.12) | 1.82 (1.67, 1.98) | 49.2 (39.4, 59.0) | 39.9% | 0.7% |
| Gestational diabetes | 697 | 193.8 | 1.98 (1.79, 2.18) | 1.86 (1.69, 2.04) | 120.0 (105.6, 134.4) | 61.9% | 1.2% |
| <10 years after delivery | |||||||
| Preterm delivery | 370 | 26.1 | 1.79 (1.60, 2.01) | 1.67 (1.48, 1.87) | 13.6 (10.9, 16.3) | 52.1% | 10.1% |
| Small for gestational age | 512 | 18.5 | 1.38 (1.25, 1.52) | 1.33 (1.20, 1.47) | 4.8 (3.1, 6.5) | 25.8% | 4.8% |
| Preeclampsia | 286 | 23.8 | 1.81 (1.60, 2.06) | 1.61 (1.42, 1.83) | 10.0 (7.2, 12.8) | 42.0% | 4.4% |
| Other hypertensive disorders | 109 | 50.6 | 2.32 (1.89, 2.86) | 2.15 (1.76, 2.64) | 36.6 (27.1, 46.1) | 72.3% | 2.9% |
| Gestational diabetes | 56 | 35.2 | 0.86 (0.61, 1.23) | 0.79 (0.56, 1.12) | 21.0 (11.7, 30.2) | 59.5% | 1.2% |
| 10–19 years after delivery | |||||||
| Preterm delivery | 861 | 67.7 | 1.66 (1.53, 1.79) | 1.57 (1.45, 1.69) | 29.1 (24.4, 33.8) | 42.9% | 8.8% |
| Small for gestational age | 1,182 | 55.5 | 1.30 (1.22, 1.39) | 1.28 (1.20, 1.36) | 13.4 (10.1, 16.8) | 24.2% | 4.6% |
| Preeclampsia | 637 | 65.8 | 1.54 (1.42, 1.68) | 1.41 (1.29, 1.53) | 23.2 (18.0, 28.5) | 35.3% | 3.6% |
| Other hypertensive disorders | 196 | 118.3 | 2.18 (1.87, 2.53) | 2.00 (1.72, 2.32) | 75.1 (58.5, 91.7) | 63.4% | 2.0% |
| Gestational diabetes | 144 | 128.7 | 1.67 (1.35, 2.06) | 1.56 (1.26, 1.92) | 85.3 (64.2, 106.3) | 66.3% | 1.5% |
| 20–29 years after delivery | |||||||
| Preterm delivery | 1,382 | 158.7 | 1.38 (1.30, 1.46) | 1.32 (1.24, 1.40) | 45.3 (36.5, 54.1) | 28.6% | 4.9% |
| Small for gestational age | 2,292 | 150.5 | 1.27 (1.21, 1.33) | 1.25 (1.19, 1.31) | 31.8 (25.2, 38.4) | 21.1% | 4.1% |
| Preeclampsia | 1,452 | 193.9 | 1.52 (1.44, 1.61) | 1.45 (1.37, 1.54) | 76.1 (65.9, 86.4) | 39.3% | 4.8% |
| Other hypertensive disorders | 214 | 235.0 | 1.83 (1.58, 2.11) | 1.69 (1.47, 1.95) | 112.3 (80.7, 143.9) | 47.8% | 0.9% |
| Gestational diabetes | 263 | 432.3 | 2.18 (1.85, 2.57) | 2.05 (1.75, 2.41) | 310.5 (258.2, 362.8) | 71.8% | 1.6% |
| 30–46 years after delivery | |||||||
| Preterm delivery | 1,529 | 351.6 | 1.36 (1.29, 1.44) | 1.33 (1.26, 1.40) | 82.5 (64.0, 100.9) | 23.5% | 3.3% |
| Small for gestational age | 2,891 | 317.8 | 1.23 (1.18, 1.28) | 1.23 (1.18, 1.29) | 44.5 (32.0, 57.1) | 14.0% | 2.7% |
| Preeclampsia | 1,793 | 359.4 | 1.26 (1.20, 1.32) | 1.23 (1.17, 1.29) | 86.7 (69.4, 104.0) | 24.1% | 2.9% |
| Other hypertensive disorders | 90 | 417.5 | 1.69 (1.36, 2.09) | 1.60 (1.29, 1.97) | 137.3 (50.9, 223.7) | 32.9% | 0.2% |
| Gestational diabetes | 234 | 834.7 | 2.64 (2.26, 3.10) | 2.51 (2.15, 2.93) | 556.8 (449.8, 663.9) | 66.7% | 1.0% |
Stroke incidence rate per 100,000 person-years in women with the respective adverse pregnancy outcome.
Adjusted for maternal age, year of delivery, parity, education, employment, income, country of origin, body mass index, smoking, and prior history of hypertension, diabetes, hyperlipidemia, atrial fibrillation, or sleep disorders.
Adjusted for the same covariates as above and all other adverse pregnancy outcomes.
Incidence rate difference per 100,000 person-years in women with vs. without the respective adverse pregnancy outcome.
Attributable fraction among the exposed.
Population attributable fraction.
Figure 1.
Cumulative hazard of stroke at 0–46 years of follow-up associated with specific adverse pregnancy outcomes.
Adverse Pregnancy Outcomes and Risk of Stroke
Across the entire follow-up (up to 46 years after delivery), all 5 adverse pregnancy outcomes were independently associated with increased risk of stroke. After adjusting for all other adverse pregnancy outcomes and covariates, HRs for stroke associated with specific adverse pregnancy outcomes were: gestational diabetes, 1.86 (95% CI, 1.69–2.04); other hypertensive disorders, 1.82 (1.67–1.98); preterm delivery, 1.40 (1.36–1.45); preeclampsia, 1.36 (1.31–1.41); and small for gestational age, 1.26 (1.22–1.29).
Adjusted HRs for stroke associated with other hypertensive disorders, preterm delivery, preeclampsia, or small for gestational age were highest in the first 10 years after delivery, then subsequently declined but remained significantly elevated at 30–46 years after delivery: other hypertensive disorders, 1.60 (95% CI, 1.29–1.97); preterm delivery, 1.33 (1.26–1.40); preeclampsia, 1.23 (1.17–1.29); and small for gestational age, 1.23 (1.18–1.29) (Table 2). In contrast, adjusted HRs associated with gestational diabetes increased with additional follow-up time (e.g., 30–46 years: 2.51; 95% CI, 2.15–2.93). Figure 2 shows adjusted HRs for stroke by time since delivery for specific adverse pregnancy outcomes.
Figure 2.
Adjusted hazard ratios (and 95% CIs) for associations between adverse pregnancy outcomes and stroke by time since delivery.
Incidence rate differences (i.e., excess stroke risk) associated with each adverse pregnancy outcome increased with longer follow-up to older ages (Table 2). Gestational diabetes was associated with the most excess risk (557 per 100,000 person-years at 30–46 years after delivery). Across the entire follow-up, preterm delivery accounted for the largest percentage (5.6%) of strokes in this population of women, compared with nearly 5% for preeclampsia or small for gestational age and <2% for gestational diabetes or other hypertensive disorders (Table 2, PAFs).
In analyses of stroke subtypes, all 5 adverse pregnancy outcomes were associated with increased risks of both ischemic and hemorrhagic stroke (Table 3). However, risks were higher for ischemic than for hemorrhagic stroke among all adverse pregnancy outcomes except other hypertensive disorders. For example, gestational diabetes was associated with more than a 2-fold risk of ischemic stroke (adjusted HR, 2.14; 95% CI, 1.89–2.42) and a ~1.3-fold risk of hemorrhagic stroke (1.36; 1.15–1.61) (Table 3). Analyses of hemorrhagic stroke subtypes yielded similar adjusted HRs except that other hypertensive disorders were more strongly associated with intracerebral hemorrhage than with aneurysmal subarachnoid hemorrhage (Table 3).
Table 3.
Associations between adverse pregnancy outcomes and subsequent risk of ischemic or hemorrhagic stroke and its subtypes.
| Ischemic stroke | Hemorrhagic stroke | P for diff. in HRsb | Intracerebral hemorrhage | Aneurysmal subarachnoid hemorrhage | P for diff. in HRsb | |||||
|---|---|---|---|---|---|---|---|---|---|---|
| Cases | HR (95% CI)a | Cases | HR (95% CI)a | Cases | HR (95% CI)a | Cases | HR (95% CI)a | |||
| Up to 46 years after delivery | ||||||||||
| Preterm delivery | 2,376 | 1.50 (1.44, 1.57) | 1,667 | 1.31 (1.24, 1.38) | <0.001 | 595 | 1.37 (1.26, 1.50) | 903 | 1.35 (1.26, 1.46) | 0.80 |
| Small for gestational age | 3,838 | 1.30 (1.25, 1.35) | 2,873 | 1.21 (1.16, 1.26) | 0.01 | 1,003 | 1.22 (1.14, 1.31) | 1,577 | 1.26 (1.19, 1.33) | 0.48 |
| Preeclampsia | 2,526 | 1.45 (1.39, 1.51) | 1,512 | 1.22 (1.16, 1.27) | 0.001 | 609 | 1.33 (1.22, 1.45) | 768 | 1.22 (1.13, 1.32) | 0.15 |
| Other hypertensive disorders | 317 | 1.83 (1.63, 2.05) | 282 | 1.92 (1.70, 2.16) | 0.58 | 127 | 2.95 (2.45, 3.56) | 139 | 1.70 (1.43, 2.03) | <0.001 |
| Gestational diabetes | 424 | 2.14 (1.89, 2.42) | 214 | 1.36 (1.15, 1.61) | <0.001 | 84 | 1.56 (1.18, 2.06) | 98 | 1.25 (0.98, 1.60) | 0.24 |
| <10 years after delivery | ||||||||||
| Preterm delivery | 165 | 1.91 (1.59, 2.29) | 213 | 1.58 (1.35, 1.84) | 0.12 | 65 | 1.88 (1.41, 2.50) | 143 | 1.74 (1.44, 2.09) | 0.66 |
| Small for gestational age | 191 | 1.35 (1.15, 1.59) | 326 | 1.35 (1.19, 1.53) | 0.99 | 86 | 1.34 (1.05, 1.71) | 224 | 1.45 (1.25, 1.69) | 0.59 |
| Preeclampsia | 134 | 2.00 (1.65, 2.42) | 163 | 1.47 (1.24, 1.73) | 0.02 | 62 | 2.14 (1.61, 2.84) | 105 | 1.40 (1.14, 1.73) | 0.02 |
| Other hypertensive disorders | 53 | 2.80 (2.09, 3.74) | 56 | 1.89 (1.41, 2.51) | 0.06 | 21 | 2.97 (1.84, 4.80) | 35 | 2.01 (1.40, 2.91) | 0.20 |
| Gestational diabetes | 27 | 0.89 (0.52, 1.53) | 28 | 0.80 (0.50, 1.27) | 0.77 | 6 | 0.41 (0.15, 1.16) | 17 | 0.86 (0.48, 1.55) | 0.22 |
| 10–19 years after delivery | ||||||||||
| Preterm delivery | 436 | 1.86 (1.66, 2.08) | 451 | 1.42 (1.28, 1.58) | <0.001 | 147 | 1.68 (1.39, 2.03) | 282 | 1.42 (1.24, 1.61) | 0.15 |
| Small for gestational age | 504 | 1.29 (1.17, 1.42) | 707 | 1.29 (1.19, 1.41) | 0.99 | 197 | 1.28 (1.09, 1.50) | 488 | 1.38 (1.25, 1.53) | 0.44 |
| Preeclampsia | 324 | 1.56 (1.38, 1.75) | 329 | 1.29 (1.15, 1.45) | 0.02 | 118 | 1.52 (1.25, 1.85) | 216 | 1.31 (1.13, 1.51) | 0.23 |
| Other hypertensive disorders | 93 | 2.03 (1.63, 2.52) | 102 | 2.04 (1.66, 2.50) | 0.97 | 43 | 3.51 (2.54, 4.85) | 61 | 1.96 (1.50, 2.56) | 0.007 |
| Gestational diabetes | 95 | 1.97 (1.49, 2.60) | 47 | 1.15 (0.82, 1.62) | 0.02 | 23 | 1.49 (0.86, 2.57) | 23 | 1.13 (0.71, 1.80) | 0.45 |
| 20–29 years after delivery | ||||||||||
| Preterm delivery | 771 | 1.40 (1.29, 1.51) | 554 | 1.19 (1.08, 1.30) | 0.003 | 202 | 1.22 (1.05, 1.42) | 299 | 1.23 (1.09, 1.40) | 0.94 |
| Small for gestational age | 1,290 | 1.36 (1.27, 1.44) | 972 | 1.16 (1.08, 1.25) | 0.001 | 341 | 1.15 (1.02, 1.29) | 522 | 1.16 (1.06, 1.28) | 0.91 |
| Preeclampsia | 866 | 1.58 (1.47, 1.70) | 558 | 1.31 (1.20, 1.44) | 0.002 | 250 | 1.59 (1.38, 1.82) | 266 | 1.19 (1.05, 1.35) | 0.002 |
| Other hypertensive disorders | 112 | 1.60 (1.31, 1.94) | 95 | 1.90 (1.53, 2.33) | 0.24 | 49 | 2.84 (2.10, 3.84) | 32 | 1.26 (0.88, 1.81) | 0.001 |
| Gestational diabetes | 168 | 2.59 (2.12, 3.16) | 75 | 1.35 (1.00, 1.82) | <0.001 | 36 | 2.07 (1.35, 3.17) | 36 | 1.11 (0.72, 1.72) | 0.05 |
| 30–46 years after delivery | ||||||||||
| Preterm delivery | 1,004 | 1.39 (1.30, 1.49) | 449 | 1.22 (1.10, 1.35) | 0.04 | 181 | 1.21 (1.04, 1.42) | 179 | 1.22 (1.04, 1.43) | 0.94 |
| Small for gestational age | 1,853 | 1.26 (1.19, 1.32) | 868 | 1.14 (1.05, 1.22) | 0.03 | 379 | 1.23 (1.10, 1.38) | 343 | 1.12 (0.99, 1.26) | 0.27 |
| Preeclampsia | 1,202 | 1.30 (1.22, 1.38) | 462 | 1.03 (0.93, 1.13) | <0.001 | 179 | 0.93 (0.80, 1.08) | 181 | 1.09 (0.93, 1.27) | 0.15 |
| Other hypertensive disorders | 59 | 1.59 (1.21, 2.06) | 29 | 1.80 (1.24, 2.61) | 0.60 | 14 | 2.28 (1.32, 3.94) | 11 | 1.55 (0.85, 2.83) | 0.35 |
| Gestational diabetes | 134 | 2.30 (1.88, 2.83) | 64 | 2.25 (1.65, 3.06) | 0.89 | 19 | 1.78 (1.03, 3.05) | 22 | 2.43 (1.48, 3.98) | 0.41 |
Adjusted for maternal age, year of delivery, parity, education, employment, income, country of origin, body mass index, smoking, prior history of hypertension, diabetes, hyperlipidemia, atrial fibrillation, or sleep disorders, and all other adverse pregnancy outcomes.
Cochran’s Q test.
Co-Sibling Analyses
Co-sibling analyses to control for unmeasured shared familial (genetic and environmental) factors resulted in moderate attenuation of some but not all risk estimates (Table 4). Across the entire follow-up period (up to 46 years after delivery), the adjusted HR for stroke associated with preterm delivery was 1.40 (95% CI, 1.40–1.45) in the primary analysis vs. 1.39 (1.27–1.43) in the co-sibling analysis, with small for gestational age was 1.26 (1.22–1.29) vs. 1.17 (1.09–1.26), with preeclampsia was 1.36 (1.31–1.40) vs. 1.21 (1.11–1.32), with other hypertensive disorders was 1.82 (1.67–1.98) vs. 1.39 (1.11–1.72), and with gestational diabetes was 1.86 (1.69–2.05) vs. 1.85 (1.37–2.48).
Table 4.
Co-sibling analyses of adverse pregnancy outcomes and subsequent risk of stroke.
| Stroke cases | HR (95% CI)a | |
|---|---|---|
| Up to 46 years after delivery | ||
| Preterm delivery | 2,467 | 1.39 (1.27, 1.43) |
| Small for gestational age | 3,858 | 1.17 (1.09, 1.26) |
| Preeclampsia | 2,222 | 1.21 (1.11, 1.32) |
| Other hypertensive disorders | 375 | 1.39 (1.11, 1.72) |
| Gestational diabetes | 377 | 1.85 (1.37, 2.48) |
| <10 years after delivery | ||
| Preterm delivery | 640 | 2.20 (1.36, 3.57) |
| Small for gestational age | 832 | 0.97 (0.65, 1.46) |
| Preeclampsia | 393 | 2.02 (1.16, 3.50) |
| Other hypertensive disorders | 151 | 1.19 (0.42, 3.41) |
| Gestational diabetes | 101 | 1.30 (0.20, 8.57) |
| 10–19 years after delivery | ||
| Preterm delivery | 670 | 1.23 (0.95, 1.59) |
| Small for gestational age | 910 | 1.22 (0.98, 1.52) |
| Preeclampsia | 467 | 1.09 (0.81, 1.47) |
| Other hypertensive disorders | 154 | 1.15 (0.68, 1.94) |
| Gestational diabetes | 85 | 1.89 (0.76, 4.65) |
| 20–29 years after delivery | ||
| Preterm delivery | 734 | 1.20 (1.00, 1.45) |
| Small for gestational age | 1,187 | 1.20 (1.04, 1.39) |
| Preeclampsia | 783 | 1.17 (0.97, 1.41) |
| Other hypertensive disorders | 61 | 1.36 (0.87, 2.12) |
| Gestational diabetes | 130 | 2.75 (1.51, 5.01) |
| 30–46 years after delivery | ||
| Preterm delivery | 423 | 1.35 (1.09, 1.66) |
| Small for gestational age | 929 | 1.16 (1.00, 1.35) |
| Preeclampsia | 579 | 1.07 (0.87, 1.32) |
| Other hypertensive disorders | 9 | 1.50 (0.64, 3.43) |
| Gestational diabetes | 61 | 1.73 (0.88, 3.40) |
Adjusted for shared familial (genetic and/or environmental) factors, and additionally for maternal age, year of delivery, parity, education, employment, income, country of origin, body mass index, smoking, prior history of hypertension, diabetes, hyperlipidemia, atrial fibrillation, or sleep disorders, and all other adverse pregnancy outcomes.
Other Secondary Analyses
Associations between adverse pregnancy outcomes and risk of stroke, stratified by maternal age at delivery, are shown in Supplementary Table 2. Among women who experienced adverse pregnancy outcomes, >98% of all strokes occurred in those aged ≥25 years at delivery. In women aged <25 years at delivery, long-term risk of stroke was significantly increased only among those with a small for gestational age delivery.
Both spontaneous and medically indicated preterm delivery were associated with increased risks of stroke compared with full-term delivery (adjusted HR, spontaneous preterm: 1.55; 95% CI, 1.39–1.73; medically indicated: 1.82; 1.64–2.01; P=0.03 for difference in HRs) (Supplementary Table 3).
Women who experienced multiple adverse pregnancy outcomes had further increases in risk (Supplementary Table 4). For example, across the entire follow-up period, adjusted HRs for any stroke associated with 1, 2, or ≥3 adverse pregnancy outcomes were 1.30 (95% CI, 1.27–1.33), 1.86 (1.78–1.95), and 2.57 (2.34–2.82), respectively, compared with women who never experienced an adverse pregnancy outcome.
When the main analyses were repeated while censoring for post-pregnancy type 2 diabetes, the association between gestational diabetes and stroke risk was attenuated, consistent with substantial mediation by type 2 diabetes (Supplementary Results). In sensitivity analyses that assessed alternative approaches for missing data or accounted for death as a competing event as an alternative to censoring at death, all results were similar to the main findings and the conclusions were unchanged (Supplementary Results).
DISCUSSION
This study examined 5 major adverse pregnancy outcomes for the first time in a large national cohort, thus enabling a well-powered assessment of the magnitude of their associations with future stroke risk. The findings indicate that all 5 major adverse pregnancy outcomes are independently associated with long-term increased risks of stroke. With up to 46 years of follow-up after delivery, stroke risk was elevated ~1.8-fold in women with either gestational diabetes or other hypertensive disorders, and 1.2- to 1.4-fold in those with preterm delivery, preeclampsia, or small for gestational age, after adjusting for all other adverse pregnancy outcomes and other maternal factors. All risks remained significantly elevated even 30–46 years after delivery, particularly in women with gestational diabetes (2.5-fold). Co-sibling analyses showed that these findings were only partially explained by familial (genetic or environmental) factors that may be shared determinants of adverse pregnancy outcomes and stroke, and thus were consistent with potential causal relationships. Risks were significantly increased for both ischemic and hemorrhagic stroke (and both intracerebral hemorrhage and aneurysmal subarachnoid hemorrhage), but were higher for ischemic stroke among all adverse pregnancy outcomes except other hypertensive disorders.
These findings build on a previous study with an overlapping cohort in Sweden that showed that women with preterm delivery had a 1.5-fold increased risk of ischemic stroke and a 1.3-fold increased risk of hemorrhagic stroke after up to 43 years of follow-up.9 A Finnish study of 144,306 women suggested that preterm delivery, hypertensive disorders of pregnancy, and small for gestational age were associated with moderately increased risks of stroke in midlife (HRs 1.2–1.5), and women with more than one affected pregnancy had earlier onset of stroke.7 A US study of 45,971 women found that women with self-reported “any adverse pregnancy outcome” had >2-fold odds of stroke before age 60, but no significantly increased odds across all ages.8 Most other studies have focused on a single adverse pregnancy outcome. In a meta-analysis of 24 studies with a total of 10.6 million women, both gestational hypertension and preeclampsia were associated with increased risks of ischemic stroke (adjusted risk ratios, 1.35 and 1.75, respectively) and hemorrhagic stroke (2.66 and 2.77, respectively).10 Consistent with those findings, we found that preeclampsia and other hypertensive disorders were associated with elevated risks of both ischemic and hemorrhagic stroke. The few prior comparisons of relative risks for ischemic and hemorrhagic stroke have yielded inconsistent findings10 and may warrant further elucidation in other large cohort studies.
In the present study, the 30-year cumulative incidence of stroke associated with each of the 5 major adverse pregnancy outcomes was <2%. However, the number of excess strokes associated with each adverse pregnancy outcome increased with additional follow-up time to older ages. The public health impact of our findings may thus be expected to rise as women with a history of adverse pregnancy outcomes reach older ages. Gestational diabetes was associated with the most excess risk (i.e., incidence rate differences), whereas preterm delivery was associated with the largest proportion of strokes in this population (i.e., population attributable fraction).
We also found that the relative rate of stroke in women with gestational diabetes increased with additional follow-up time, including a 2.5-fold risk at 30–46 years after delivery. Gestational diabetes is associated with a higher risk of type 2 diabetes later in life,27 which is a strong risk factor for stroke,28 particularly in women.29,30 The association we found between gestational diabetes and subsequent risk of stroke appeared largely mediated by the development of type 2 diabetes. These findings underscore the need for lifelong clinical follow-up of women with gestational diabetes for timely detection and treatment of type 2 diabetes and other cardiovascular risk factors to reduce their long-term risk of stroke.
In co-sibling analyses, most associations persisted after controlling for unmeasured familial (genetic and environmental) exposures that may be shared determinants of adverse pregnancy outcomes and stroke, and thus were consistent with potential causal relationships. The underlying pathophysiology by which adverse pregnancy outcomes may lead to future stroke is not established. Adverse pregnancy outcomes have common features that suggest shared pathogenesis, including abnormal placentation, systemic inflammation, endothelial dysfunction, oxidative stress, and vascular damage.31,32 Preterm delivery, for example, has been associated with endothelial-specific inflammation that was undetectable prior to pregnancy.33 Both preeclampsia34,35 and gestational diabetes36,37 also are associated with long-term endothelial dysfunction and vascular damage. Microvascular structural changes that emerge during pregnancy may sometimes progress or fail to resolve postpartum,31 increasing future susceptibility to stroke. Interventions to interrupt these subclinical processes soon after an adverse pregnancy outcome may be key to reducing the long-term risk of stroke.
All major adverse pregnancy outcomes should now be recognized as long-term independent risk factors for stroke. These outcomes should be routinely tracked in electronic health records to facilitate transition of patients from obstetric to primary care clinics where they need early preventive evaluation and long-term clinical follow-up. Adverse pregnancy outcomes may provide an early window for identifying high-risk women long before the development of stroke, thus enabling earlier preventive interventions.38 Such actions should include control of other modifiable risk factors such as hypertension, diabetes, obesity, physical inactivity, and smoking.39,40 Access to high-quality preconception and prenatal care is also a high priority to reduce the prevalence of adverse pregnancy outcomes and their long-term health sequelae.16,23,41
Strengths and Limitations
A key strength of the present study is its large national cohort design with up to 46 years of follow-up. The availability of highly complete nationwide birth and medical registry data, both inpatient and outpatient, helped minimize potential selection and ascertainment biases. The large sample size enabled high statistical power for simultaneous assessment of 5 major adverse pregnancy outcomes and major stroke subtypes. The results were controlled for multiple other maternal factors, as well as unmeasured shared familial factors using co-sibling analyses.
This study also had certain limitations. First, detailed clinical records were unavailable to validate stroke diagnoses, although high positive predictive values have been reported in the Swedish registries.19–21 Information on stroke severity was unavailable. This study will need replication in other countries when feasible, including diverse populations to explore for potential racial/ethnic differences. The public health impacts may potentially be higher in minority populations in the US that have less access to prenatal and postpartum care and higher rates of adverse pregnancy outcomes and stroke.3,31,41
Conclusions
In this large national cohort, women who experienced any of 5 major adverse pregnancy outcomes (preterm delivery, small for gestational age, preeclampsia, other hypertensive disorders, or gestational diabetes) had long-term increased risks for stroke. These risks remained elevated up to 46 years after delivery, particularly in women with gestational diabetes (2.5-fold). All major adverse pregnancy outcomes should now be recognized as long-term independent risk factors for stroke. Women who experience adverse pregnancy outcomes need early preventive actions and long-term clinical care to reduce their lifelong risk of stroke.
Supplementary Material
Key question
What are the lifelong risks of stroke in women with major adverse pregnancy outcomes (preterm delivery, small for gestational age, preeclampsia, other hypertensive disorders, or gestational diabetes)?
Key findings
In a national cohort of 2.2 million women in Sweden, women with any of 5 adverse pregnancy outcomes had long-term increased risks of stroke, which remained significantly elevated (1.2- to 2.5-fold) even 30–46 years after delivery.
Take-home message
Women with adverse pregnancy outcomes need early preventive actions and long-term clinical follow-up to reduce their lifelong risk of stroke.
REFERENCES
- 1.Global Burden of Disease Causes of Death Collaborators. Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet 2018;392:1736–1788. doi: 10.1016/S0140-6736(18)32203-7 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Lundberg GP, Volgman AS. Burden of stroke in women. Trends Cardiovasc Med 2016;26:81–88. doi: 10.1016/j.tcm.2015.04.010 [DOI] [PubMed] [Google Scholar]
- 3.Martin SS, Aday AW, Almarzooq ZI, Anderson CAM, Arora P, Avery CL, et al. 2024 Heart Disease and Stroke Statistics: A Report of US and Global Data From the American Heart Association. Circulation 2024;149:e347–e913. doi: 10.1161/CIR.0000000000001209 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Gargano JW, Reeves MJ, Paul Coverdell National Acute Stroke Registry Michigan Prototype Investigators. Sex differences in stroke recovery and stroke-specific quality of life: results from a statewide stroke registry. Stroke 2007;38:2541–2548. doi: 10.1161/STROKEAHA.107.485482 [DOI] [PubMed] [Google Scholar]
- 5.Gall SL, Tran PL, Martin K, Blizzard L, Srikanth V. Sex differences in long-term outcomes after stroke: functional outcomes, handicap, and quality of life. Stroke 2012;43:1982–1987. doi: 10.1161/STROKEAHA.111.632547 [DOI] [PubMed] [Google Scholar]
- 6.Appelros P, Stegmayr B, Terent A. Sex differences in stroke epidemiology: a systematic review. Stroke 2009;40:1082–1090. doi: 10.1161/STROKEAHA.108.540781 [DOI] [PubMed] [Google Scholar]
- 7.Miller EC, Kauko A, Tom SE, Laivuori H, Niiranen T, Bello NA, et al. Risk of Midlife Stroke After Adverse Pregnancy Outcomes: The FinnGen Study. Stroke 2023;54:1798–1805. doi: 10.1161/STROKEAHA.123.043052 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Miller EC, Bello NA, Davis R, Friedman AM, Elkind MSV, Wapner R, et al. Women with Adverse Pregnancy Outcomes Have Higher Odds of Midlife Stroke: The Population Assessment of Tobacco and Health Study. J Womens Health (Larchmt) 2022;31:503–512. doi: 10.1089/jwh.2021.0184 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Crump C, Sundquist J, Sundquist K. Preterm Delivery and Long-Term Risk of Stroke in Women: A National Cohort and Cosibling Study. Circulation 2021;143:2032–2044. doi: 10.1161/CIRCULATIONAHA.120.052268 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Brohan MP, Daly FP, Kelly L, McCarthy FP, Khashan AS, Kublickiene K, et al. Hypertensive disorders of pregnancy and long-term risk of maternal stroke-a systematic review and meta-analysis. Am J Obstet Gynecol 2023;229:248–268. doi: 10.1016/j.ajog.2023.03.034 [DOI] [PubMed] [Google Scholar]
- 11.Canoy D, Cairns BJ, Balkwill A, Wright FL, Khalil A, Beral V, et al. Hypertension in pregnancy and risk of coronary heart disease and stroke: A prospective study in a large UK cohort. Int J Cardiol 2016;222:1012–1018. doi: 10.1016/j.ijcard.2016.07.170 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Hung SK, Lee MS, Lin HY, Chen LC, Chuang CJ, Chew CH, et al. Impact of Hypertensive Disorders of Pregnancy on the Risk of Stroke Stratified by Subtypes and Follow-Up Time. Stroke 2022;53:338–344. doi: 10.1161/STROKEAHA.121.034109 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Rich-Edwards JW, Fraser A, Lawlor DA, Catov JM. Pregnancy characteristics and women’s future cardiovascular health: an underused opportunity to improve women’s health? Epidemiol Rev 2014;36:57–70. doi: 10.1093/epirev/mxt006 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Fraser A, Nelson SM, Macdonald-Wallis C, Cherry L, Butler E, Sattar N, et al. Associations of pregnancy complications with calculated cardiovascular disease risk and cardiovascular risk factors in middle age: the Avon Longitudinal Study of Parents and Children. Circulation 2012;125:1367–1380. doi: 10.1161/CIRCULATIONAHA.111.044784 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Crump C, Sundquist J, McLaughlin MA, Dolan SM, Govindarajulu U, Sieh W, et al. Adverse pregnancy outcomes and long term risk of ischemic heart disease in mothers: national cohort and co-sibling study. BMJ 2023;380:e072112. doi: 10.1136/bmj-2022-072112 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Crump C, Sundquist J, Sundquist K. Adverse pregnancy outcomes and long-term risk of chronic kidney disease in women: national cohort and co-sibling study. Am J Obstet Gynecol 2023;230:563.e561–563.e520. doi: 10.1016/j.ajog.2023.10.008 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Cnattingius S, Ericson A, Gunnarskog J, Kallen B. A quality study of a medical birth registry. Scand J Soc Med 1990;18:143–148. doi: 10.1177/140349489001800209 [DOI] [PubMed] [Google Scholar]
- 18.Kallen B, Kallen K. The Swedish Medical Birth Register—A Summary of Content and Quality. Scand J Soc Med 2003;18:143–148. doi: 10.1177/140349489001800209 [DOI] [Google Scholar]
- 19.Ludvigsson JF, Andersson E, Ekbom A, Feychting M, Kim JL, Reuterwall C, et al. External review and validation of the Swedish national inpatient register. BMC Public Health 2011;11:450. doi: 10.1186/1471-2458-11-450 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Koster M, Asplund K, Johansson A, Stegmayr B. Refinement of Swedish administrative registers to monitor stroke events on the national level. Neuroepidemiology 2013;40:240–246. doi: 10.1159/000345953 [DOI] [PubMed] [Google Scholar]
- 21.Merlo J, Lindblad U, Pessah-Rasmussen H, Hedblad B, Rastam J, Isacsson SO, et al. Comparison of different procedures to identify probable cases of myocardial infarction and stroke in two Swedish prospective cohort studies using local and national routine registers. Eur J Epidemiol 2000;16:235–243. doi: 10.1023/a:1007634722658 [DOI] [PubMed] [Google Scholar]
- 22.Swedish National Board of Health and Welfare. Kodningskvalitet i patientregistret: Ett nytt verktyg för att mäta kvalitet. https://www.socialstyrelsen.se/globalassets/sharepoint-dokument/artikelkatalog/statistik/2013-3-10.pdf (November 29, 2023)
- 23.Crump C, Sundquist J, Sundquist K. Preterm delivery and long term mortality in women: national cohort and co-sibling study. BMJ 2020;370:m2533. doi: 10.1136/bmj.m2533 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Crump C, Sundquist J, Howell EA, McLaughlin MA, Stroustrup A, Sundquist K. Pre-Term Delivery and Risk of Ischemic Heart Disease in Women. J Am Coll Cardiol 2020;76:57–67. doi: 10.1016/j.jacc.2020.04.072 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Crump C, Sundquist J, McLaughlin MA, Dolan SM, Sieh W, Sundquist K. Pre-term delivery and long-term risk of heart failure in women: a national cohort and co-sibling study. Eur Heart J 2021:ehab789. doi: 10.1093/eurheartj/ehab789 [DOI] [PubMed] [Google Scholar]
- 26.Crump C, Sundquist J, Sundquist K. Preterm Delivery and Long-term Risk of Hypertension in Women. JAMA Cardiol 2022;7:65–74. doi: 10.1001/jamacardio.2021.4127 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Vounzoulaki E, Khunti K, Abner SC, Tan BK, Davies MJ, Gillies CL. Progression to type 2 diabetes in women with a known history of gestational diabetes: systematic review and meta-analysis. BMJ 2020;369:m1361. doi: 10.1136/bmj.m1361 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Janghorbani M, Hu FB, Willett WC, Li TY, Manson JE, Logroscino G, et al. Prospective study of type 1 and type 2 diabetes and risk of stroke subtypes: the Nurses’ Health Study. Diabetes Care 2007;30:1730–1735. doi: 10.2337/dc06-2363 [DOI] [PubMed] [Google Scholar]
- 29.Peters SA, Huxley RR, Woodward M. Diabetes as a risk factor for stroke in women compared with men: a systematic review and meta-analysis of 64 cohorts, including 775,385 individuals and 12,539 strokes. Lancet 2014;383:1973–1980. doi: 10.1016/S0140-6736(14)60040-4 [DOI] [PubMed] [Google Scholar]
- 30.Gasbarrino K, Di Iorio D, Daskalopoulou SS. Importance of sex and gender in ischaemic stroke and carotid atherosclerotic disease. Eur Heart J 2022;43:460–473. doi: 10.1093/eurheartj/ehab756 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Lane-Cordova AD, Khan SS, Grobman WA, Greenland P, Shah SJ. Long-Term Cardiovascular Risks Associated With Adverse Pregnancy Outcomes: JACC Review Topic of the Week. J Am Coll Cardiol 2019;73:2106–2116. doi: 10.1016/j.jacc.2018.12.092 [DOI] [PubMed] [Google Scholar]
- 32.Sultana Z, Maiti K, Aitken J, Morris J, Dedman L, Smith R. Oxidative stress, placental ageing-related pathologies and adverse pregnancy outcomes. Am J Reprod Immunol 2017;77. doi: 10.1111/aji.12653 [DOI] [PubMed] [Google Scholar]
- 33.Lane-Cordova AD, Gunderson EP, Carnethon MR, Catov JM, Reiner AP, Lewis CE, et al. Pre-pregnancy endothelial dysfunction and birth outcomes: The Coronary Artery Risk Development in Young Adults (CARDIA) Study. Hypertens Res 2018;41:282–289. doi: 10.1038/s41440-018-0017-5 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34.Hausvater A, Giannone T, Sandoval YH, Doonan RJ, Antonopoulos CN, Matsoukis IL, et al. The association between preeclampsia and arterial stiffness. J Hypertens 2012;30:17–33. doi: 10.1097/HJH.0b013e32834e4b0f [DOI] [PubMed] [Google Scholar]
- 35.Rangaswami J, Naranjo M, McCullough PA. Preeclampsia as a Form of Type 5 Cardiorenal Syndrome: An Underrecognized Entity in Women’s Cardiovascular Health. Cardiorenal Med 2018;8:160–172. doi: 10.1159/000487646 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36.Knock GA, McCarthy AL, Lowy C, Poston L. Association of gestational diabetes with abnormal maternal vascular endothelial function. Br J Obstet Gynaecol 1997;104:229–234. doi: 10.1111/j.1471-0528.1997.tb11051.x [DOI] [PubMed] [Google Scholar]
- 37.Lappas M Markers of endothelial cell dysfunction are increased in human omental adipose tissue from women with pre-existing maternal obesity and gestational diabetes. Metabolism 2014;63:860–873. doi: 10.1016/j.metabol.2014.03.007 [DOI] [PubMed] [Google Scholar]
- 38.Sheiner E, Kapur A, Retnakaran R, Hadar E, Poon LC, McIntyre HD, et al. FIGO (International Federation of Gynecology and Obstetrics) Postpregnancy Initiative: Long-term Maternal Implications of Pregnancy Complications-Follow-up Considerations. Int J Gynaecol Obstet 2019;147 Suppl 1:1–31. doi: 10.1002/ijgo.12926 [DOI] [PubMed] [Google Scholar]
- 39.O’Donnell MJ, Chin SL, Rangarajan S, Xavier D, Liu L, Zhang H, et al. Global and regional effects of potentially modifiable risk factors associated with acute stroke in 32 countries (INTERSTROKE): a case-control study. Lancet 2016;388:761–775. doi: 10.1016/S0140-6736(16)30506-2 [DOI] [PubMed] [Google Scholar]
- 40.Grysiewicz RA, Thomas K, Pandey DK. Epidemiology of ischemic and hemorrhagic stroke: incidence, prevalence, mortality, and risk factors. Neurol Clin 2008;26:871–895, vii. doi: 10.1016/j.ncl.2008.07.003 [DOI] [PubMed] [Google Scholar]
- 41.Crump C, Howell EA. Perinatal Origins of Cardiovascular Health Disparities Across the Life Course. JAMA Pediatr 2020;174:113–114. doi: 10.1001/jamapediatrics.2019.4616 [DOI] [PMC free article] [PubMed] [Google Scholar]
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