Preeclampsia identifies women at risk of cardiovascular disease at a young age, making them eligible for preventive strategies.1 The risk of ischemic heart disease, thrombosis, and stroke is doubled in women with a history of preeclampsia.2 The presence of one or more metabolic risk factors, including obesity, hypertension, insulin resistance, dyslipidemia, and microalbuminuria, is frequently observed postpartum in women with a history of preeclampsia.3–5 This suggests that these women may benefit from lifestyle interventions aimed to reduce their risk of cardiovascular disease.
Hypertension itself is a major predictor of cardiovascular disease in the general population with an attributable risk to myocardial infarction of approximately 30% in women.6 Chronic hypertension may be an important mediator for the development of cardiovascular disease in women with a history of preeclampsia. Approximately 25% develop hypertension after preeclampsia in contrast to only 7% after uncomplicated pregnancies.2 We postulate that metabolic and obstetric risk factors are associated with the development of hypertension after preeclampsia. This study aims to identify risk factors that coincide with hypertension at postpartum screening and predispose patients to the development of hypertension during a median follow-up period of 6 years in a cohort of primiparous women with a history of mainly early-onset preeclampsia.
MATERIALS AND METHODS
In Maastricht University Medical Center, we routinely screen women with a recent history of preeclampsia for underlying disorders to increase the efficacy of counseling with respect to a possible future pregnancy and cardiovascular health. For this study, we analyzed the data of all primiparous women with a history of preeclampsia (n=683) who have visited this clinic between 1996 and 2010. These women had mainly early-onset preeclampsia (before 37 weeks of gestation) or preeclampsia complicated by fetal growth restriction or fetal death. All women were white and participated at least 4 months postpartum after they stopped breastfeeding. Oral contraceptives were discontinued 4 weeks before the measurement. Exclusion criteria were pre-existing hypertension, kidney disease, or diabetes mellitus. The Medical Ethical Committee board of Maastricht University Medical Center approved this study (MEC 0-4-049).
At the postpartum screening, we recorded blood pressure for a period of 30 minutes using a semiautomatic oscillometric device in half-sitting position and median values were used for analysis. Blood was collected for fasting plasma lipid profile, glucose, and insulin. We determined fasting triglycerides, total cholesterol, high-density lipoprotein cholesterol, and glucose using standard automated laboratory techniques. Low-density lipoprotein (LDL) cholesterol was calculated by the Friedewald equation. Plasma insulin concentrations were measured using AutoDelfia time-resolved fluoroimmunoassay. We estimated insulin resistance based on the homeostasis model assessment of insulin resistance using the following formula: homeostasis model assessment of insulin resistance=[fasting serum insulin (mU · L−1)×fasting plasma glucose (mmol · L−1)]/22.5.7 Microalbuminuria was measured by turbidometry and since 2007 by nephelometry.
Preeclampsia was defined according to the criteria of the Report of the National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy.8 Small for gestational age was defined as a birth weight below the 10th percentile according to the birth weight reference curves of the Perinatal Registry in The Netherlands. Family history was evaluated using a standard form and for this analysis only, first-degree relatives were taken into account. The metabolic score consisted of components of the metabolic syndrome as defined by the Third Adult Treatment Panel (updated version) and included, elevated glucose, low high-density lipoprotein cholesterol, and elevated triglycerides.9 A high-normal blood pressure was defined as a blood pressure of 130–139 mm Hg systolic, 85–89 mm Hg diastolic,10 or both and was only used to predict the development of hypertension at follow-up. Cutoff values for other metabolic risk factors such as total cholesterol, LDL cholesterol, and microalbuminuria were defined according to the criteria of the European Society of Hypertension10; for plasma insulin and homeostasis model assessment of insulin resistance, we used the 75th percentile in our population as the cutoff point.
The main outcome measure of this study was hypertension after preeclampsia, which was evaluated at postpartum screening and during follow-up. We considered women hypertensive at postpartum screening when automated blood pressures were 140 mm Hg or greater systolic, 90 mm Hg or greater diastolic, or both or when using antihypertensive drugs. We evaluated the development of hypertension by a short health questionnaire sent out every 2 years to all women who had had a diagnostic work-up at least 18 months ago. We used self-reported antihypertensive treatment to define hypertension at follow-up in the groups of women who were normotensive at postpartum screening.
Data are presented as mean±standard deviation or median with interquartile range. The rate of missing data ranged from 1% to 8%. Differences between groups were tested using independent t test or Mann-Whitney U test. Proportions were compared by χ2 test. We used logistic regression analysis to test the association between several risk factors and the presence of hypertension at postpartum screening. Cox proportional hazard analysis was used to estimate the hazard to develop hypertension during follow-up. The event was occurrence of hypertension during follow-up (yes or no). Time-to-event was calculated by the time elapsed between year of postpartum screening and year of initiating antihypertensive drugs (16 events) or, if not available, the year halfway in the most recent follow-up interval (11 events). Data were censored for follow-up time if the event had not occurred. A subsequent pregnancy was taken into account only when delivery preceded the event. As a rule of thumb, we determined that we needed at least five cases for each independent variable in the model.11 A P value <.05 was considered statistically significant.
Figure 1 presents a flowchart of the selection of the study population. Exclusion for kidney disease included nine cases of systemic lupus erythematosus and one case of atrophic kidney, kidney aplasia, and Fabry's syndrome. Of the 626 primiparous women with a history of preeclampsia, 107 (17%) were hypertensive and 519 (83%) were normotensive at postpartum screening. A total of 470 women received a follow-up questionnaire; they were all normotensive at the time of postpartum screening and had at least 18 months of follow-up. Of these women, 339 (72%) responded to at least one questionnaire. During a median follow-up of 6 (interquartile range 4–9, mininum–maximum 1–14) years covering 2,095 person-years, we identified 27 cases of new-onset hypertension, an incidence of 13 cases per 1,000 person-years. Five women did develop noninsulin-dependent diabetes mellitus during follow-up.
Table 1 lists the characteristics and clinical variables of the hypertensive and normotensive women with a history of preeclampsia at postpartum screening. The screening was performed approximately 8 (interquartile range 6–18, minimum–maximum 4–92) and 10 (interquartile range 6–19, minimum–maximum 4–166) months postpartum in the hypertensive and normotensive women, respectively. Groups were comparable with respect to age and smoking. Hypertensive women delivered at an earlier gestational age of an neonate with a lower birth weight compared with normotensive women. A family history of hypertension was more often present and hypertensive women had a higher body mass index (BMI, calculated as weight (kg)/[height (m)]2) and elevated fasting plasma levels of insulin, total, LDL cholesterol, and triglycerides compared with normotensive women. Microalbuminuria was present in 22% of hypertensive and in 12% of normotensive women with a history of preeclampsia (P<.01).
Table 2 shows to what extent risk factors at postpartum screening coincided with hypertension after adjustment for maternal age, smoking, and months postpartum with and without adjustment for BMI. The presence of hypertension was associated with obesity (odds ratio [OR] 1.9, 95% confidence interval [CI] 1.1–3.2), elevated levels of insulin (OR 2.2, 95% CI 1.4–3.5), and insulin resistance based on homeostasis model assessment of insulin resistance (OR 1.7, 95% CI 1.0–2.7). Adjustment for BMI attenuated the associations with insulin and homeostasis model assessment of insulin resistance (OR 1.7, 95% CI 1.0–2.9 and OR 1.2, 95% CI 0.7–2.1, respectively). Hypertension related to elevated levels of total and LDL cholesterol and microalbuminuria independent of BMI (OR 1.6, 95% CI 1.0–2.4; OR 1.6, 95% CI 1.1–2.6; and OR 2.3, 95% CI 1.3–4.0, respectively). Hypertension was associated with a family history of hypertension and delivery before 34 weeks of gestation (OR 1.8, 95% CI 1.1–2.8 and OR 2.5, 95% CI 1.6–4.0, respectively) and not with the birth of a small-for-gestational-age neonate.
Table 3 shows to what extent risk factors at postpartum screening were associated with the development of hypertension during a median follow-up of 6 years after adjustment for maternal age, smoking, and months postpartum with and without adjustment for BMI. The hazard rate for the presence of two and three or more components of the metabolic syndrome was 2.9 (95% CI 1.2–7.5) and 8.1 (95% CI 2.8–22.9), respectively (Fig. 2). Obesity and high-normal blood pressure predisposed to the development of hypertension (hazard ratio [HR] 3.1, 95% CI 1.3–7.4 and HR 3.8, 95% CI 1.6–8.8, respectively). Associations of high-density lipoprotein cholesterol and insulin with hypertension during follow-up disappeared after adjustment for BMI. Moreover, glucose, total and LDL cholesterol, triglycerides, and birth of a small-for-gestational-age neonate were not associated with hypertension during follow-up. A family history of hypertension and recurrence of a hypertensive disorder in the next pregnancy were independent of BMI related to the occurrence of hypertension during follow-up (HR 3.7, 95% CI 1.4–10.0 and HR 4.3, 95% CI 1.6–11.5, respectively).
The presence of hypertension at postpartum screening related to modifiable risk factors such as obesity, hyperinsulinemia, and dyslipidemia. The subsequent development of hypertension in women, who were normotensive at postpartum screening, was three times more likely when obesity was present and four times more likely when the blood pressure at postpartum screening was within the high-normal range. The risk of developing hypertension increased even more when three or more components of the metabolic syndrome were present. These findings support the view that women with a history of preeclampsia are likely to benefit from lifestyle interventions to reduce their long-term cardiovascular disease risk.
The total prevalence of chronic hypertension after preeclampsia in this study of approximately 25% was comparable to previous reports.2 This is higher than the expected prevalence of hypertension in the Dutch population of women of reproductive age of approximately 2.8–5.6%.12 We observed a relatively high proportion of hypertension directly at postpartum screening (17%) and another 8% developed hypertension during a median 6 years follow-up. Hypertension in the early postpartum period may still normalize over the years, because 14 of 74 women who were hypertensive at postpartum screening (and who filled out a questionnaire) did not indicate to use antihypertensive medication during follow-up. We used self-reported antihypertensive treatment to define hypertension during follow-up, because we intended to restrict our outcome to these women who have a confirmed diagnosis of hypertension. Self-reported hypertension underestimates the incidence of new-onset disease but is reliable if reported to be present.13,14
The prevalence of metabolic abnormalities at postpartum screening was high in our study population, which is in line with others.4,5,15 Our study shows that these metabolic risk factors are associated with hypertension after preeclampsia. Whether or not the placental disorder itself contributes to this risk is still under debate. This study gives some direction to this question, suggesting a possible effect of disease severity because women with an earlier onset of preeclampsia (delivery before 34 weeks of gestation) had more often hypertension at postpartum screening. On the other hand, we could not confirm an association between small for gestational age and maternal hypertension.
This study gives further support for the current view that lifestyle interventions may be beneficial to these women. The benefit of a healthy lifestyle is clear from large epidemiologic studies,6,16 but there is a strong need for trials proving the (cost)effectiveness of postpartum lifestyle interventions on long-term cardiovascular disease outcomes such as stroke and myocardial infarction.17 Some preliminary reports suggest that women with a history of preeclampsia are willing to participate in such an intervention program and will have improved weight and lipid profile after 3 months.18,19 Several trials in women with gestational diabetes or obesity suggest that a postpartum lifestyle intervention is feasible.20,21
We want to emphasize that a high-normal blood pressure was a strong predictor of the development of hypertension in the subsequent years. Recent evidence shows that there is a continuous relationship between blood pressure and cardiovascular disease risk; the cutoff level of 140/90 mm Hg for hypertension seems arbitrary.22,23 Some studies suggest that it may be beneficial to treat people with a high-normal blood pressure, especially if concomitant risk factors are present.10,24,25 Whether this also applies to women with a history of preeclampsia requires further research.
There are several limitations of our study. First, the study population consisted of white women only and women with mild preeclampsia were relatively underrepresented. Moreover, it would have been preferably to have a control group of women who had normotensive pregnancies. Second, we identified some differences in the risk profile of responders and nonresponders to the questionnaire. A subanalysis showed that nonresponders delivered at a later gestational age, smoked more often, and had a slightly less favorable lipid profile without differences in BMI (Table 4). Third, first-trimester booking blood pressures of the index pregnancy were unfortunately not available. Some women with hypertension at postpartum screening may have had underlying secondary hypertension instead of essential hypertension, which is less likely to be related to metabolic risk factors and might have led to an underestimation of association estimates.
In conclusion, this study showed that several metabolic risk factors such as obesity, insulin resistance, and dyslipidemia coincided with or predisposed patients to hypertension after preeclampsia. Besides, this study identified several other clinical variables useful in postpartum cardiovascular risk stratification after preeclampsia such as a family history of hypertension, a high-normal blood pressure, and recurrence of a hypertensive disorder in the next pregnancy.
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