Magnussen, Elisabeth B. MD1,3; Vatten, Lars J. MD, PhD1; Smith, George Davey MD, PhD2; Romundstad, Pål R. PhD1
Large population studies have shown that hypertensive disorders in pregnancy, ie, preeclampsia and gestational hypertension, are markers for future risk of cardiovascular disease.1–4 These pregnancy conditions may share common risk factors with cardiovascular disease, and prepregnancy risk factors for hypertensive disorders in pregnancy include high blood pressure, dyslipidemia, and glucose intolerance,5,6 factors that are known to increase cardiovascular risk. It has been suggested that pregnancy could act as a stress test that either provokes metabolic and vascular changes, or amplifies the effect of underlying cardiovascular risk factors.6,7 Although studies on recurrent hypertension in pregnancy are sparse,8–10 some have reported that recurrence is more strongly associated with later cardiovascular disease than hypertension in a single pregnancy.9
We investigated the hypothesis that hypertension in pregnancy may uncover modifiable cardiovascular risk factors before disease,8 thereby addressing the potential for primary prevention among women with high risk of premature heart disease. We linked data from the Medical Birth Registry of Norway to a large population-based health survey in Norway and prospectively examined the association of hypertensive disorders in pregnancy with cardiovascular risk factors measured several years later.
MATERIALS AND METHODS
Data from the Medical Birth Registry of Norway were linked to the Nord-Trøndelag Health (HUNT) Study; a population-based health survey conducted in Nord-Trøndelag County in Norway.11,12 This population is ethnically homogeneous and representative for Norway with respect to demography, population mobility, socioeconomic profile and cause-specific mortality.12 All residents 20 years and older were invited to participate in the second wave of the HUNT Study (1995–1997),12 and a total of 34,882 women (75%) accepted the invitation and attended a clinical examination that included standardized measurements of height, weight, waist circumference, blood pressure, and nonfasting measurements of serum lipids and glucose. The participants also completed a comprehensive health-related questionnaire that, among other items, included history of diabetes and cardiovascular disease, smoking habits, social security benefits, and educational attainment. Further details of the HUNT Study have been described elsewhere.12
Since 1967, there has been compulsory notification of all deliveries to the Medical Birth Registry of Norway.11 For each birth, midwives or doctors at the delivery units fill in a standardized form that includes information related to maternal health before and during pregnancy, complications in pregnancy, and comprehensive information on the newborn.
All women who participated in the HUNT Study were linked to the Medical Birth Registry to obtain information on births that had occurred from 1967 until the HUNT Study (1995–1997). A total of 21,867 participating women were registered in Medical Birth Registry. For the analyses of this study, we excluded 1,600 women who had their first birth subsequent to the HUNT Study, 775 women who were pregnant at baseline of the HUNT Study, and 4,181 women who were not primiparous when they were first registered in the Medical Birth Registry. We also excluded 46 women with pregnancies of less than 22 weeks of gestation, 157 women with multiple births, 23 with chronic hypertension, and 20 women with known diabetes before pregnancy. This left a total of 15,065 women for the statistical analysis. Among these women, 13,310 were registered with a second birth, and 6,576 had a third birth before participation in the HUNT Study. Among the eligible women, 23 were registered with both preeclampsia and gestational hypertension in the first pregnancy, 13 women were registered with both conditions in the second, and six women were registered with preeclampsia and hypertension in the third pregnancy. In the statistical analyses, these cases were coded as only having preeclampsia in the respective pregnancies.
In the HUNT Study, clinical examinations were conducted by specially trained nurses or technicians. Measurements included height, weight, waist and hip circumference, blood pressure, and a nonfasting blood sample was drawn. Blood pressure was measured using an automatic oscillometric method (Dinamap 845 XT; Criticon, Tampa, FL) after a minimum of 2 minutes rest in the sitting position. Measurements were made three times at 1-minute intervals, and the mean of the second and third reading was registered and used in the analyses. Cuff size was adjusted according to the measured arm circumference.12
Serum concentrations of total cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, and glucose were determined subsequent to blood sampling.13 Serum lipids were analyzed using a Hitachi 911 Auto analyzer (Hitachi, Mito, Japan), applying reagents from Boehringer Mannheim (Mannheim, Germany). Total serum cholesterol and HDL cholesterol were measured after precipitation with phosphor tungsten and magnesium ions, and triglycerides were measured with an enzymatic calorimetric method. Glucose was measured using an enzymatic hexokinase method. Day-to-day coefficients of variation were 1.3–1.9 % for total cholesterol, 2.4% for HDL cholesterol, 0.7–1.3 % for triglycerides, and 1.3–2.0% for glucose.
Low-density lipoprotein (LDL) cholesterol was calculated using Friedewald’s formula: LDL cholesterol equals total serum cholesterol minus HDL cholesterol minus one fifth of the triglyceride concentration. Low-density lipoprotein cholesterol was only calculated in participants with triglyceride concentrations lower than 4.5 mmol/L.14 Body mass index (BMI) was calculated as body weight (in kg) divided by the squared value of height (in meters). Body weight was measured to the nearest one-half kilogram, and body height, to the nearest centimeter. On the basis of self-reporting of smoking status, participants were classified into three categories, as current smokers, former smokers, or never smokers.
From The Medical Birth Registry of Norway, we retrieved information on parity, plurality, age at child bearing, birth weight (in grams), gestational age (in days), as well as information on maternal diabetes and hypertensive disorders before and during pregnancy. Estimated gestational age at delivery was based on the last menstrual period. Births up to 36 completed pregnancy weeks were defined as preterm, and births at 37 weeks or later were defined as term pregnancies.
In Norway, the diagnostic criteria for preeclampsia follow the 1972 recommendations of the American college of Obstetricians and Gynecologists, which define preeclampsia as a sustained increase in blood pressure to at least 140/90 mm Hg after mid gestation, combined with proteinuria of at least 1+ or more on a semiquantitative dipstick.15 The diagnostic criteria have remained stable since 1967. Clinical criteria for gestational hypertension are also in accordance with the 1972 recommendations of the American college of Obstetricians and Gynecologists. Gestational hypertension is defined as blood pressure of 140/90 mm Hg or more (one or both values exceeded) or increase in systolic blood pressure of 30 mm Hg or more and diastolic blood pressure of 15 mm Hg or more after mid gestation, without concomitant proteinuria.15 The study was approved by the regional committee for Medical Research Ethics in Norway.
We estimated adjusted mean blood pressure and means of lipid concentrations using linear regression analysis, and multiple logistic regression analysis was used to estimate odds ratios (ORs) with 95% confidence intervals (CIs) related to the use of blood pressure medication (never, former compared with current use). All analyses were adjusted for age in 5-year categories from 20 to 75 years. In addition, adjustments were made for time interval (years) between the index delivery and the HUNT Study, smoking status (never, former, current), level of education (less than 9 years, 9–12 years, 12–14 years, and more than 14 years), and requirement of social security benefits (yes or no). In the analyses of serum lipids we also included time since last meal as a covariate. Stata 10.0 for Windows (StataCorp LP, College Station, TX) was used for the statistical analyses.
Table 1 shows demographic characteristics of the 15,065 women who had a first delivery from 1967 until participation in the HUNT Study between 1995 and 1997. Women with a history of hypertensive disorders in pregnancy were similar to women with no such history in age, educational level, and socioeconomic status at follow-up, and mean time from first delivery to participation in the HUNT Study was approximately 16.5 years for both groups. Women with hypertensive disorders in pregnancy were, however, less likely to be current smokers, and more likely to be antihypertensive drug users at follow-up.
Mean age at first, second, and third birth was 23.0 years, 26.4 years, and 29.8 years, respectively. Overall, 661 (4.4%) women had preeclampsia diagnosed in their first pregnancy; 261 (2.0%) had preeclampsia in their second, and 129 (2.0%), in their third pregnancy. The number of women who were diagnosed with gestational hypertension in their first, second, and third pregnancy was 321 (2.1%), 199 (1.5%), and 118 (1.8%), respectively.
We assessed whether hypertensive disorders in pregnancy were related to BMI at follow-up several years later (Table 2). Both preeclampsia and gestational hypertension were associated with higher BMI: Women with a history of hypertensive disorders in pregnancy had approximately two units (kg/m2) higher BMI at follow-up compared with women without this experience. Moreover, the difference in BMI between women with and without a hypertensive pregnancy disorder was larger if the hypertensive disorder occurred in a pregnancy subsequent to the first.
In general, women with a history of preeclampsia had higher levels of triglycerides, total serum cholesterol, and LDL cholesterol and lower levels of HDL cholesterol at follow-up compared with women with no history of preeclampsia. Nonfasting glucose was also higher in women with a history of preeclampsia (Tables 3 and 4). Among women who had preeclampsia in both the first and second pregnancy, these differences were more pronounced than for women with preeclampsia only in one pregnancy. However, adjustment for BMI attenuated these differences substantially.
Among women with gestational hypertension in their first pregnancy, the crude differences in serum lipids compared with women without a history of gestational hypertension were of the same magnitude as those observed for preeclampsia. However, adjustment for BMI fully attenuated these differences (Tables 3 and 4).
In women with a history of preeclampsia, the adjusted odds ratio for diabetes was 3.8 (95% CI 2.1–6.6) compared with other parous women, and after further adjustment for BMI, the odds ratio was attenuated to 2.8 (95% CI 1.6–5.0). In relation to gestational hypertension, there was no clear association with later diabetes (adjusted odds ratio, 1.3, 95% CI 0.4–4.0), and after additional adjustment for BMI, the estimated odds ratio changed to 0.9 (95% CI 0.3–3.8).
In women registered with one or more pregnancies, mean adjusted systolic blood pressure was 7.2 mm Hg (95% CI 6.0–8.3) higher in women with preeclampsia in their first pregnancy compared with women who did not have preeclampsia in their first pregnancy. Similarly, mean diastolic blood pressure was 4.8 mm Hg (95% CI 4.4–5.2) higher in this group (data not tabulated).
In women with two or three births, preeclampsia in the second or third pregnancy was associated with higher systolic blood pressure at follow-up than if preeclampsia occurred in the first pregnancy, and the highest mean blood pressure was found if preeclampsia occurred in the third pregnancy (Table 5). For women with preeclampsia in both the first and second pregnancy, systolic blood pressure was substantially higher than in the nonpreeclamptic group and also higher than in women with preeclampsia in either their first or second pregnancy. Adjustment for BMI attenuated these differences only slightly (Table 5), and excluding current users of blood pressure medication from the analysis did not influence these differences.
Similar results were found for diastolic blood pressure and for women with a history of gestational hypertension (Table 5). Thus, women with gestational hypertension in two consecutive pregnancies had substantially higher mean blood pressure at follow-up compared with women without a history of hypertension in pregnancy. In women with gestational hypertension in three consecutive pregnancies, the differences were even stronger, with 27.3 mm Hg (95% CI 17.8–37.0) higher systolic and 12.1 mm Hg (95% CI 4.8–18.5) higher diastolic pressure compared with women with no history of gestational hypertension.
In an effort to disentangle the potentially modifying effect of parity from that of maternal age, we studied the association of hypertension in pregnancy with later blood pressure within strata of maternal age and parity. These analyses suggested that the association became stronger with increasing maternal age and with increasing parity. We also investigated the association of preeclampsia with later cardiovascular risk factors among women with only one registered pregnancy. Among primiparous women with preeclampsia, mean systolic blood pressure was 139.0 mm Hg (95% CI 135.9–142.2) compared with 130.2 mm Hg (95% CI 128.0–132.3) in primiparous women without preeclampsia, and mean diastolic blood pressure was 5.7 mm Hg higher in the preeclampsia group (data not tabulated).
Women with a history of preeclampsia were three times (adjusted odds ratio 3.1, 95% CI 2.2 to 4.3) more likely to use blood pressure medication at follow-up compared with women with no history of preeclampsia. Women with two episodes of preeclampsia were even more likely to use blood pressure medication at follow-up (adjusted odds ratio 11.6, 95% CI 7.1–26.3). Similar, but somewhat weaker results were observed for gestational hypertension, and adjustment for BMI attenuated these results only slightly.
We studied whether preterm and term preeclampsia yielded different associations with blood pressure and serum lipids at follow-up. For systolic blood pressure, we found only a very modest difference between these subtypes of preeclampsia (0.9 mm Hg higher for preterm preeclampsia, 95% CI –1.0 to 1.0). Similarly, there were no differences between preterm and term preeclampsia related to serum lipids (all P>.40).
We found that, several years after pregnancy, women with a history of hypertensive disorders in pregnancy were more likely to have developed diabetes, unfavorable serum lipid levels, and substantially higher blood pressure compared with other parous women. These findings were particularly pronounced in women with repeated hypertensive disorders, or if the hypertensive condition occurred late in their reproductive career.
There are several strengths to our study. The large sample size, standardized clinical examinations, the high retention of subjects in this longitudinal study, and comprehensive information from self-administered questionnaires secure high precision of the findings and allow adjustment for relevant confounding factors. The wide range of available variables allows mediation and underlying factors to be examined and the prospective design makes recall and selection bias unlikely explanations of the findings. However, it is a limitation that serum lipid measurements were nonfasting. It seems unlikely that the findings in the present study are restricted to the Norwegian population only, because supporting evidence has been reported in several countries.1–4
Results from large cohort studies have suggested that women with a history of hypertensive disorders in pregnancy are at increased risk of subsequent cardiovascular and cerebrovascular diseases.1–4 Previously, three studies have reported a greater risk of future cardiovascular disease after recurrent pregnancies with hypertensive disorders compared with having one pregnancy with hypertension.8–10 Few studies have reported lipid profiles and standardized blood pressure measurements several years after recurrent hypertensive pregnancies.
Several investigators have suggested that early onset preeclampsia (delivery up to 36 completed weeks) may be a different disease from preeclampsia at term (delivery at 37 weeks and beyond).16–18 In our study, however, there was no substantial difference in the cardiovascular risk factor profile between women who had experienced preterm and term preeclampsia.
After adjustment for body mass index, the association with serum lipids was fully attenuated for gestational hypertension, but only partly attenuated for preeclampsia. This suggests that the unfavorable serum lipids associated with hypertensive disorders in pregnancy could be mediated by higher body mass index. However, as a marker of adiposity, body mass index may have some limitations. Maybe a better marker than body mass index could reveal that the associations related to serum lipids are essentially driven by adiposity.
The finding that women with a history of preeclampsia were much more likely to have developed diabetes at follow-up compared with women with normotensive pregnancies has recently been reported by others19,20; however, in the present study we observed no clear association between gestational hypertension and diabetes later in life. This distinction between preeclampsia and gestational hypertension has also been observed by others, suggesting that the long-term associations with preeclampsia may differ from those of gestational hypertension.21,22
Whether the hypertensive pregnancy itself is causally related to risk of later cardiovascular disease is uncertain. One possible explanation for the findings is that the pregnancy disorders share common causes or mechanisms with later cardiovascular disease, but that the pregnancy condition is not a cause in itself. Several studies have suggested that insulin resistance, chronic hypertension, renal dysfunction, and obesity may be linked to gestational hypertension in a previous pregnancy, as well as to future risk of cardiovascular disease, suggesting that both conditions may have common underlying causes.23–27
However, it cannot be excluded that hypertensive disorders in pregnancy may be causally related to later cardiovascular risk, or that the pregnancy condition could play a promotional role for cardiovascular and related diseases.6 A healthy pregnancy involves a range of physiologic and metabolic changes,6,7 and these changes seem to be exaggerated in preeclamptic pregnancies. Systemic endothelial dysfunction is an important characteristic of preeclampsia, with possible long-term effects that, to some extent, may be irreversible.6,7
We found that the cardiovascular risk profile of women with recurrent preeclampsia in the first and second pregnancy was less favorable than in women with only one episode of preeclampsia. This provides some support for a possible causal relation in suggesting a dose–risk effect. Another explanation is that the women who have recurrent preeclampsia might have a more unfavorable metabolic risk profile at baseline, and therefore are at higher risk of recurrent disease due to the more severe perturbations in baseline metabolic function.
In women with three or more pregnancies, we found consistently higher mean blood pressure and unfavorable lipid profiles associated with hypertensive disorders in the second compared with the first pregnancy and also in the third compared with the second pregnancy. Thus, the association of hypertensive disorders in pregnancy and later blood pressure seemed to be relatively stronger in later pregnancies. One possible explanation for this finding could be that baseline levels of cardiovascular risk factors may increase with parity or with maternal age28,29 and that the combination of a late pregnancy and preeclampsia could be particularly unfavorable for cardiovascular health. Another possibility could be that women with severe preeclampsia in the first pregnancy are less likely to become pregnant later.
It has been suggested that there is a gap in knowledge related to cardiovascular prevention and disease management among women.30 A crucial point has been to identify and target high-risk women for early detection and potential intervention.7 In the present study we found that women with recurrent hypertensive disorders in pregnancy are likely to be at substantially higher cardiovascular risk based on their body mass, blood pressure, and lipid levels several years after pregnancy. Based on established knowledge, this excess risk could be substantially reduced by applying available interventions.
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