Association of Maternal Preeclampsia With Offspring Risks of Ischemic Heart Disease and Stroke in Nordic Countries

Abstract

Importance: An association between maternal preeclampsia and an increased risk of cardiovascular disease in the offspring is plausible, but evidence in this area is limited.

Objective: To investigate (1) the association between maternal preeclampsia and risks of ischemic heart disease (IHD) and stroke in the offspring, (2) whether the association varies by severity or timing of onset of preeclampsia, and (3) the role of preterm birth and small for gestational age (SGA) birth, both of which are related to preeclampsia and cardiovascular diseases, in this association.

Design, setting, and participants: This multinational population-based cohort study obtained data from Danish, Finnish, and Swedish national registries. Live singleton births from Denmark (1973-2016), Finland (1987-2014), and Sweden (1973-2014) were followed up until December 31, 2016, in Denmark and December 31, 2014, in Finland and Sweden. Data analyses were performed between September 2020 and September 2022.

Exposures: Preeclampsia and its subtypes, including early onset (<34 gestational weeks) and late onset (≥34 gestational weeks), severe and mild or moderate, and with and without SGA birth.

Main outcomes and measures: Diagnoses of IHD and stroke were extracted from patient and cause-of-death registers. Cox proportional hazards regression models and flexible parametric survival models were used to analyze the associations. Sibling analyses were conducted to control for unmeasured familial factors.

Results: The cohort included of 8 475 819 births (2 668 697 [31.5%] from Denmark, 1 636 116 [19.3%] from Finland, and 4 171 006 [49.2%] from Sweden, comprising 4 350 546 boys [51.3%]). Of these offspring, 188 670 (2.2%) were exposed to maternal preeclampsia, 7446 (0.1%) were diagnosed with IHD, and 10 918 (0.1%) were diagnosed with stroke during the median (IQR) follow-up of 19.3 (9.0-28.1) years. Offspring of individuals with preeclampsia had increased risks of IHD (adjusted hazard ratio [HR], 1.33; 95% CI, 1.12-1.58) and stroke (adjusted HR, 1.34; 95% CI, 1.17-1.52). These associations were largely independent of preterm or SGA birth. Severe forms of preeclampsia were associated with a higher stroke risk than less severe forms (severe vs mild or moderate: adjusted HR, 1.81 [95% CI, 1.41-2.32] vs 1.22 [95% CI, 1.05-1.42]; early vs late onset: adjusted HR, 2.55 [95% CI, 1.97-3.28] vs 1.18 [95% CI, 1.01-1.39]; with vs without SGA birth: adjusted HR, 1.84 [95% CI, 1.44-2.34] vs 1.25 [95% CI, 1.07-1.48]). Sibling analyses suggested that the associations were partially explained by unmeasured familial factors.

Conclusions and relevance: Results of this study suggest that offspring born to individuals with preeclampsia had increased IHD and stroke risk that were not fully explained by preterm or SGA birth, and that the associated risks for stroke were higher for severe forms of preeclampsia.

Figure 1.. Adjusted Hazard Ratios (HRs) for Ischemic Heart Disease and Stroke From Flexible Parametric Survival Models

Hazard ratios (orange lines) and 95% CIs (gray lines) for ischemic heart disease (A) and stroke (B) in offspring according to maternal preeclampsia. A spline with 5 degrees of freedom (4 intermediate knots and 2 knots at each boundary, placed at quintiles of the distribution of events) was used for the baseline rate, and a spline with 3 degrees of freedom was used for the time-varying effect. Analyses were adjusted for offspring calendar year of birth; offspring sex; and maternal parity, age, educational level, marital status, and diabetes status before childbirth.

Figure 2.. Hazard Ratios (HRs) for Ischemic Heart Disease (IHD) and Stroke According to Preeclampsia, Preterm Birth, and Small for Gestational Age (SGA)

Offspring born to individuals without any hypertensive disorders of pregnancy were the reference, and analyses were adjusted for offspring calendar year of birth; offspring sex; and maternal parity, age, educational level, marital status, and diabetes status before childbirth. In case of IHD, the P values for interaction were P = .27 between preeclampsia and SGA and P = .31 between preeclampsia and preterm birth. In case of stroke, the P values for interaction were P = .56 between preeclampsia and SGA and P = .11 between preeclampsia and preterm birth.