Results of global cardiovascular disease risk assessment using the five independent risk factors predictive of a first cardiovascular event (age, diabetes, smoking, systolic and diastolic blood pressures, total cholesterol, and HDL cholesterol) included in the Framingham risk score algorithm22 are shown in Figure 1. In comparison with controls, the distribution of Framingham risk score values in women with previous early-onset preeclampsia showed a shift toward higher estimated global risk (Fig. 1). Mean estimated 10-year cardiovascular disease risk by the Framingham risk score was 1.08% (95% CI 1.04--1.12) in women with previous early-onset preeclampsia compared with 1.01% in the reference population (95% CI 1.00--1.01; P<.001) by comparison with univariable logistic regression analysis.
In this study of apparently healthy primiparous women with a history of early-onset preeclampsia, we found high rates of multiple modifiable risk factors for cardiovascular disease after delivery when compared with a population-based reference group of women of the same age. Women with previous early-onset preeclampsia more often showed marked dyslipidemia, high blood pressure, high BMI, and other components of the metabolic syndrome. Our results demonstrate that more than half of women with previous early-onset preeclampsia exhibit two or more independent risk factors predictive of cardiovascular disease. Based on risk factor profiles obtained within the first few years postpartum, overall predicted risk of cardiovascular events as estimated by the Framingham risk score was low (less than 5%) for all women. However, mean estimated global cardiovascular disease risk scores were already altered among women with previous early-onset preeclampsia when compared with a reference cohort of women of the same age, and risk is expected to increase rapidly with age.
Large-scale cohort studies have consistently shown a link between preeclampsia and future cardiovascular disease. After preeclampsia, women have an increased risk of fatal and nonfatal coronary heart disease, stroke, hypertension, and venous thromboembolism in later life.11 The strongest cofactor for long-term increased incidence of ischemic heart disease and cardiovascular death appears to be early onset of disease with delivery before 34 weeks of gestation, but factors underlying this association are unclear.10,11 Findings from our study support the involvement of traditional cardiovascular disease risk factors and include proatherogenic lipid profile, high blood pressure, and markers of insulin resistance. After early-onset preeclampsia, 15% of women met the criteria for metabolic syndrome compared with less than 5% of the reference group, which may contribute to the long-term risk of noninsulin-dependent diabetes mellitus and enhances atherosclerosis progression.4,15
In line with previous studies, we observed a linear positive association between higher BMI and history of early-onset preeclampsia.30–32 However, differences in maternal weight after early-onset preeclampsia could only partly explain the observed associations with other cardiovascular disease markers, because odds ratios for blood pressure, lipid parameters, and markers of insulin sensitivity were only marginally attenuated after adjustment for BMI. Mean systolic and diastolic blood pressures were higher in women with previous early-onset preeclampsia and mild hypertension (ie, systolic blood pressure more than 130 mm Hg, diastolic blood pressure more than 85 mm Hg, or both) and present in one out of two women compared with one out of five age-matched population-based control group participants. Mild blood pressure elevation may precede the onset of chronic hypertension and is a likely contributor to overall cardiovascular risk in these women.32 However, similar to BMI, clustering of multiple risk factors was not exclusive to hypertensive women.
Our data support the recent recommendation that women with a history of early-onset preeclampsia are eligible for structured cardiovascular screening programs aimed at reducing lifetime cardiovascular disease risk.5 Women with previous early-onset preeclampsia will probably benefit most from lifestyle intervention strategies, including regular exercise, consuming a healthy diet, maintaining a desirable body weight, and discontinuing smoking.1,33 However, we appreciate that more research is needed to provide definitive answers about the appropriate risk markers, algorithms for global risk estimation, and optimal timing of risk assessment for this particular group of young women. Further, adherence to and effectiveness of risk factor reduction programs in women with previous early-onset preeclampsia are presently unknown and await evaluation of appropriately designed intervention studies.33
There are some limitations to this study. First, our study was cross-sectional in design and women were included several months to years after delivery. It is not known whether maternal adaptation to pregnancy itself leads to temporary metabolic, cardiovascular, and inflammatory changes in the postpartum period that may attenuate over time.34 Because inclusion in the study was performed after delivery (and not before pregnancy), from our data, it is not possible to determine whether cardiovascular disease risk factors were already present before conception, might have appeared during or soon after pregnancy, or both. Magnussen et al35 found an association between prepregnancy cardiovascular disease risk factors and subsequent development of preeclampsia; however, only 15 women in this study had early-onset disease. For most cardiovascular disease risk factors, a permanent shift in risk factor levels after early-onset preeclampsia is not very likely because most traditional cardiovascular disease risk factors have a high heritable component, are expected to return to baseline soon after delivery, and are relatively stable over time.36,37 In an attempt to exclude any temporary effects, we enrolled women at least 6 months after delivery. Also, levels of cardiovascular disease risk factors were not influenced by the interval between delivery and assessment, suggesting that biomarker levels have returned to baseline at the time of inclusion to allow for optimal timing of global cardiovascular disease risk assessment. Second, we examined only data on traditional major risk factors for cardiovascular disease based on their independent contribution to global cardiovascular disease risk.18 Recent studies, however, have demonstrated that for women, up to 20% of coronary events occur in the absence of these major risk factors.38 Therefore, it is likely that additional nontraditional risk factors such as C-reactive protein,39,40 interleukin-6,26,41 fibrinogen,26,41 family history of premature cardiovascular disease,40,42 dietary patterns, and physical activity2,43 also may contribute to the link between early-onset preeclampsia and future cardiovascular disease. Third, our study was designed to include only primiparous women with previous early-onset preeclampsia who delivered before 34 weeks of gestation. Our data may not be extrapolated to multiparous women or women with a history of late-onset preeclampsia, near-term preeclampsia, or other hypertensive disorders of pregnancy.15 In addition, we cannot fully exclude a potential confounding by the association between cardiovascular disease risk and parity itself,44 which was unselected for the reference group, although adjustment for parity in the multivariate models revealed no differences in the observed associations. Also, during the observational period for case group participants, prevalence of cardiovascular risk factors, disease management, and outcome theoretically may have changed over time. We estimate this effect to be small, because no major changes in definition, management, and outcome of preeclampsia have been introduced since the onset of this study, background cardiovascular disease risk for young women in the Dutch population has been relatively stable over time, and no additional cardiovascular disease screening or intervention program was performed during the study interval.
In summary, we found evidence that first pregnancy early-onset preeclampsia is associated with a high prevalence of multiple modifiable risk factors predictive of cardiovascular disease after delivery, but with a low estimated 10-year risk of cardiovascular events. We propose that all women with a history of early-onset preeclampsia are eligible for routine assessment of cardiovascular risk factor profile, including blood pressure, glucose intolerance, weight, smoking, and lipid profile from the first years after delivery, aimed at identification of those whose risk for cardiovascular disease is expected to increase rapidly with age. However, the clinical effectiveness and cost-effectiveness of this policy, taking into account the optimal timing and frequency of testing, remain to be established.
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