Cardiovascular Risk Factors Mediate the Long-Term Maternal Risk Associated With Hypertensive Disorders of Pregnancy

Abstract

Background: Hypertensive disorders of pregnancy (HDP), including gestational hypertension and preeclampsia, are associated with an increased risk of CVD.

Objectives: The purpose of this study was to evaluate associations between HDP and long-term CVD and identify the proportion of the association mediated by established CVD risk factors.

Methods: Parous participants without CVD in the Nurses' Health Study II (n = 60,379) were followed for incident CVD from first birth through 2017. Cox proportional hazards models estimated HRs and 95% CIs for the relationship between HDP and CVD, adjusting for potential confounders, including prepregnancy body mass index, smoking, and parental history of CVD. To evaluate the proportion of the association jointly accounted for by chronic hypertension, hypercholesterolemia, type 2 diabetes, and changes in body mass index, we used the difference method.

Results: Women with HDP in first pregnancy had a 63% higher rate of CVD (95% CI: 1.37-1.94) compared with women with normotensive pregnancies. This association was mediated by established CVD risk factors (proportion mediated = 64%). The increased rate of CVD was higher for preeclampsia (HR: 1.72; 95% CI: 1.42-2.10) than gestational hypertension (HR: 1.41; 95% CI: 1.03-1.93). Established CVD risk factors accounted for 57% of the increased rate of CVD for preeclampsia but 84% for gestational hypertension (both P < 0.0001).

Conclusions: Established CVD risk factors arising after pregnancy explained most (84%) of the increased risk of CVD conferred by gestational hypertension and 57% of the risk among women with preeclampsia. Screening for chronic hypertension, hypercholesterolemia, type 2 diabetes, and overweight/obesity after pregnancy may be especially helpful in CVD prevention among women with a history of HDP.

Keywords: cardiovascular disease; cardiovascular disease risk factors; preeclampsia; pregnancy.

Conflict of interest statement

Funding Support and Author Disclosures This research was funded by the following grants from the National Institutes of Health: U01 CA176726, R01 HL088521, R01 HL34594, and U01 HL145386. This work was supported by awards from the American Heart Association (12PRE9110014, 13GRNT17070022). Dr Stuart was supported by Training Grant T32HL098048 from the National Heart, Lung, and Blood Institute and by Training Grant T32HD060454 from the National Institute of Child Health and Human Development. Dr Tanz was supported by F31HL131222 from the National Heart, Lung, and Blood Institute under the Ruth L. Kirschstein National Research Service Award. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1:. Flow diagram for the primary, mediation, and secondary analyses.

* Women reporting chronic hypertension within one year after first birth (n=115) were excluded to prevent misclassification of exposure (undetected chronic hypertension before pregnancy may be incorrectly captured as incident chronic hypertension directly following pregnancy) and since the exact date of diagnosis was unknown, which prevented definitive determination as to whether the chronic hypertension arose before, during, or after pregnancy.

Figure 2:. Nurses’ Health Study II data collection timeline and analytic follow-up.

Ascertainment of exposure and assignment of pre-pregnancy covariate information for participants with their first birth before cohort enrollment and for those with their first birth during active follow-up.

Figure 3:. Multivariable-adjusted cumulative incidence of cardiovascular disease.

Curves were obtained at the mean and mode values of the following continuous and categorical covariates, respectively: age at first birth, age at NHSII enrollment, race/ethnicity, parental education, physical activity at ages 18–22, parental history of CVD

Central Illustration:. Differential associations by hypertensive disorder of pregnancy and cardiovascular disease subtypes.

Hazard ratios and 95% confidence intervals (CI) were obtained from fully adjusted Cox proportional hazards models (Table 2, Model 2). The overall association between having a hypertensive disorder in first pregnancy and long-term maternal cardiovascular disease appeared to be driven by underlying associations between preeclampsia and coronary artery disease and between gestational hypertension and stroke.