Obstetrics & Gynecology:
Cardiovascular Disease Risk Factors in Women With a History of Early-Onset Preeclampsia
van Rijn, Bas B. MD, PhD; Nijdam, Marie-Elise MD; Bruinse, Hein W. MD, PhD; Roest, Mark PhD; Uiterwaal, Cuno S. MD, PhD; Grobbee, Diederick E. MD, PhD; Bots, Michiel L. MD, PhD; Franx, Arie MD, PhD
Division of Perinatology and Gynecology, the Laboratory for Clinical Chemistry and Hematology, and the Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands; and the Division of Human Development and Health, University of Southampton, Southamptom, United Kingdom.
Corresponding author: Bas B. van Rijn, MD, PhD, Division of Human Development and Health, University of Southampton, Princess Anne Hospital, Coxford Road, Southampton SO16 5YA, UK; e-mail: B.Van-Rijn@soton.ac.uk.
Dr. van Rijn was supported by grant 920-03-230 from the Netherlands Organisation for Health Research (ZonMW).
Financial Disclosure The authors did not report any potential conflicts of interest.
OBJECTIVE: To assess the prevalence of established cardiovascular disease risk factors and to estimate 10-year absolute risk of cardiovascular disease after early-onset preeclampsia.
METHODS: We assessed major cardiovascular disease risk factors in 243 primiparous women with a history of early-onset preeclampsia (delivery at less than 34 weeks of gestation) at least 6 months after delivery; 374 healthy nonpregnant women of similar age served as a reference group.
RESULTS: After adjustment for age, we observed significantly higher means for body mass index, blood pressure, total and low-density lipoprotein cholesterol, triglycerides, glucose, and lower mean high-density lipoprotein cholesterol (all P<.01) in women with previous early-onset preeclampsia compared with the reference group. Prevalence of the metabolic syndrome was 15.2% compared with 4.3% (P<.001), two or more major cardiovascular disease risk factors were present in 51.0% compared with 26.5%, and three or more risk factors were present in 18.9% compared with 6.4%, respectively. Mean estimated 10-year cardiovascular disease risks by the Framingham Risk Score were 1.08% (95% confidence interval 1.04–1.12) and 1.01% (95% CI 1.00–1.01; P<.001) for the difference.
CONCLUSION: Women with a history of early-onset preeclampsia have a high prevalence of several major cardiovascular disease risk factors. Although the estimated 10-year cardiovascular disease risk is low (less than 5%) after delivery, cardiovascular disease risk is expected to increase rapidly with increasing age.
LEVEL OF EVIDENCE: II
Cardiovascular disease is the number one cause of death in women, with mortality rates for women exceeding those for men.1 Evidence continues to grow indicating that most cardiovascular disease is preventable and largely dependent on modifiable risk factors.2,3 Because a considerable number of women who experience a first cardiac event either die or become severely impaired, there is a strong imperative to prevent the first episode of cardiovascular disease by early identification of women at high risk.3
Common hypertensive disorders of pregnancy, such as preeclampsia, are now increasingly recognized as early-life reproductive manifestations of increased cardiovascular disease risk.4–6 Many features of preeclampsia resemble changes closely related to atherosclerosis, including dyslipidemia, insulin resistance,7 hypercoagulability, and inflammation.8 Although major clinical signs usually cease within days after delivery, mothers with previous preeclampsia are at increased risk for atherosclerosis,9 coronary heart disease,10 and stroke later in life.11 Lifetime cardiovascular disease risk is especially high for women who experienced early-onset disease (before 34 weeks of gestational age), in whom long-term follow-up studies revealed sevenfold to eightfold increased cardiovascular mortality compared with twofold increase in women with a history of late-onset preeclampsia.10,11 Despite this difference in long-term prognosis, previous studies of postpartum cardiovascular disease risk assessment after preeclampsia mainly have included women with late-onset disease.12 Limited data are available regarding the prevalence of cardiovascular disease risk factors after early-onset preeclampsia, and previous studies have numbers that are too small to include cut-off values for clinically relevant risk factors,13–15 lack an appropriate reference group,16 and do not allow for an integrated approach to estimate global cardiovascular disease risk.12–16 The latter is important because the estimate for absolute cardiovascular disease risk is recommended in current prevention guidelines as the main driver for the initiation of cardiovascular risk factor management.3,17
To provide more information, we assessed major cardiovascular disease risk factors (age, systolic and diastolic blood pressures, body mass index (BMI, calculated as weight (kg)/[height (m)]2), lipid levels, markers of glucose intolerance, smoking, and diabetes) and measured levels of traditional cardiovascular biomarkers that have independent associations with future cardiovascular events18 (total cholesterol, high-density lipoprotein [HDL], low-density lipoprotein, fasting glucose and triglycerides) in a single-center tertiary referral cohort of nonpregnant primiparous women after early-onset preeclampsia included at least 6 months after delivery and compared data with an unselected population-based reference group of healthy women of similar age.
The aim of this study was to assess major risk factors known to be predictive of cardiovascular disease, to estimate 10-year absolute cardiovascular disease risk after early-onset preeclampsia, and to identify target risk factors that may be relevant for the development of primary prevention programs.
MATERIALS AND METHODS
Between November 1994 and January 2007, all women with a first pregnancy complicated by early-onset preeclampsia referred for tertiary care to the University Medical Center Utrecht, Utrecht, the Netherlands, were eligible to participate in the follow-up study, with a first visit planned at least 6 months after delivery. Details of characteristics of the background population, inclusion criteria, and reproductive follow-up data were recently published elsewhere.19 Preeclampsia was defined as the presence of gestational hypertension and concomitant proteinuria in the second half of pregnancy, based the criteria of the International Society for the Study of Hypertension in Pregnancy.20 According to the International Society for the Study of Hypertension in Pregnancy criteria, gestational hypertension is defined as diastolic blood pressure more than 90 mm Hg, systolic blood pressure more than 140 mm Hg, or both measured on two or more separate occasions at least 4 hours apart; proteinuria was diagnosed when there was more than 300 mg per 24 hours or when dipstick urinalysis was more than 2+. Early-onset preeclampsia was defined as preeclampsia that required delivery before 34 completed weeks of gestation. Coexistent hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome was defined according to previously described criteria21 as hemolysis (defined as serum lactate dehydrogenase more than 600 units/L, haptoglobin 0.3 g/L or less, or both), elevated liver enzymes (serum aspartate aminotransferase more than 70 units/L, serum alanine aminotransferase more than 70 units/L, or both), and a low platelet count (less than 100×109/L). Newborns were considered small for gestational age if birth weight was less than the fifth percentile based on standardized Dutch population charts.22 Diagnostic criteria were unchanged throughout the course of the study. For the purpose of this study, we excluded women with pre-existent chronic hypertension as defined by hypertension that required the use of antihypertensive medication present before pregnancy. The population-based reference group consisted of healthy women recruited for the Atherosclerosis Risk in Young Adults study, a study that comprises an unselected population-based cohort of similar age, demographics, and geographical background.23 In contrast to most previous studies in which data of women with adverse pregnancy outcomes are compared with a control group of women with only uneventful pregnancies, for this study we chose to use an unselected population-based reference group to avoid overestimation of cardiovascular disease risk because normotensive pregnancy itself predicts a high probability of being free from long-term hypertensive and cardiovascular sequelae.15,24 Details of inclusion criteria, recruitment procedures, data, and sample handling were previously described elsewhere.24 At enrollment, demographic, general medical, and obstetric data were recorded, and fasting blood samples were obtained for detection of metabolic, inflammatory, and lipid risk factors. Risk factor assessment was performed at least 6 months after delivery and at least 6 weeks after discontinuation of breastfeeding, and women were required to adhere to a minimum of 6 weeks without taking any vitamin or folic acid supplements. The study was approved by the Institutional Review Board of the University Medical Center Utrecht and participants provided written informed consent.
The presence of diabetes and chronic hypertension was recorded, height and weight were obtained, and BMI was calculated at inclusion. Blood pressure was measured by a trained research nurse using the auscultatory method with a validated aneroid sphygmomanometer using Korotkoff phase V for diastolic pressure as the mean value of two separate measurements.25 Fasting blood samples were collected, immediately centrifuged, and directly analyzed for lipid markers, glucose, and triglyceride levels by standard procedures at the routine Clinical Chemistry Laboratory of our hospital. A detailed description of measurements and laboratory procedures was previously published elsewhere.23,26,27 Briefly, fasting total cholesterol, HDL cholesterol, triglycerides, and glucose were determined using a Vitros950 dry-chemistry analyzer. Low-density lipoprotein cholesterol was calculated using the Friedewald formula. Within-run variation coefficients were 1.7% for total cholesterol, 2.3% for HDL cholesterol, 1.9% for triglycerides, and 4.3% for fasting glucose levels. All analyses were performed by technicians blinded for study group and unaware of the underlying hypothesis.
Baseline variables were expressed as means and standard deviation or number and percentage when appropriate, and comparisons were made between women with a history of early-onset preeclampsia and the reference group by the independent samples t test and χ2 test, respectively. To account for missing data (less than 5% for all variables) and to avoid potential bias introduced by complete case analysis, a previously published single-conditional imputation method was used. In brief, this method fits an estimated value based on a prediction model for each test with a missing value using a missing value analysis syntax, in which the test with a missing value is the outcome and all the variables in the dataset (ie, all predictors plus outcome pattern) are included as predictors. For dichotomous test results, estimated values were rounded to 0 or 1. For continuous variables, imputed values were constrained to the lowest and highest values actually observed.28,29 The relation between BMI, lipid levels, and early-onset preeclampsia was analyzed by increasing quintiles, with cut-off points based on the distribution of values within the control population; odds ratios and corresponding 95% confidence intervals (CIs) were calculated for each quintile compared with the lowest quintile as a set reference group using multivariable logistic regression models. Trend was evaluated using the quintiles as one independent variable (0--4) in a multivariable logistic regression model. The P value obtained from the quintile variable was used to indicate the presence of a trend. Goodness-of-fit tests for trends were performed using the Hosmer-Lemeshow test when indicated and were considered acceptable at P>.05. Further data analysis included comparisons of multiple risk factors and estimation of 10-year absolute cardiovascular risk by a validated global risk factor algorithm based on the Framingham Heart Study,18 which includes weighted risk scores for age, smoking status, systolic and diastolic blood pressures, diabetes, total cholesterol, and HDL cholesterol. When appropriate, ie, when the variable undergoing study was related to the outcome and the exposure and not considered to be in the causal pathway as evaluated with regression models, relations undergoing study were adjusted for age and further adjusted for other potential confounders. Statistical analyses were performed using IBM SPSS Statistics 20.0.0.
Baseline clinical and outcome characteristics of the study group and the reference population are summarized in Table 1. Compared with the reference group, women with previous early-onset preeclampsia had a small but significant difference in mean age at inclusion of 2.2 years (standard deviation 0.2), which marginally affected all of the other baseline variables and which was adjusted in all subsequent logistic regression models. In our tertiary referral cohort, first pregnancies with early-onset preeclampsia had a mean gestational age at delivery of less than 30 completed weeks and were characterized by high rates of concurrent maternal and fetal complications and included 62% of women who met the criteria for HELLP syndrome and 11% placental abruptions; more than half of newborns were small for gestational age (birth weight less than fifth percentile). At a mean interval of 9.4 months (standard deviation 11.4) after delivery, primiparous women with previous early-onset preeclampsia had higher systolic and diastolic blood pressures, weight, and BMI. In comparison with the reference group, concentrations of total cholesterol, low-density lipoprotein cholesterol, ratio of total cholesterol to HDL cholesterol, triglycerides, and glucose also were higher after early-onset preeclampsia. Women with a history of early-onset preeclampsia were less likely to use oral contraceptives (82% compared with 34% in the reference group). Because of a potential effect of oral contraceptive use on lipid levels, this information was included in subsequent multivariable models to exclude potential bias. No significant differences were observed regarding height, ethnicity, diabetes, and current smoking rates.
We observed the presence of at least one major independent cardiovascular disease risk factor in 88.9% of women with a history of early-onset preeclampsia compared with 65.8% in the reference group (P<.001) according to the American Heart Association and American College of Cardiology Joint Guidelines criteria (Table 2).3 These criteria include current smoking, high blood pressure (140/90 mm Hg or higher), high total cholesterol (200 mg/dL or higher), low HDL cholesterol (less than 40 mg/dL), and diabetes. The presence of two or more cardiovascular disease risk factors was observed in 51.0% of women with previous early-onset preeclampsia compared with 26.5% of controls (P<.001), including 18.9% of formerly preeclamptic women with three or more cardiovascular disease risk factors compared with 6.4% of the reference population (P=.001). Of women with previous early-onset preeclampsia, 15.2% met the criteria for metabolic syndrome (Table 2) compared with 4.3% of the reference group (adjusted odds ratio 4.02, 95% CI 1.93–8.39). Further risk factor stratification showed an incremental increase in odds ratios for previous early-onset preeclampsia with increasing quintiles of BMI, HDL cholesterol, and ratio of total cholesterol to HDL cholesterol in a dose-dependent manner that were unchanged after multivariable adjustment for potential confounding by other cardiovascular disease risk factors (Table 3).
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.
Distribution of valu...Image Tools
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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