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ORIGINAL RESEARCH |
From the University of Pittsburgh and Magee-Womens Research Institute, Pittsburgh, Pennsylvania.
Address reprint requests to: Roberta B. Ness, MD, MPH, University of Pittsburgh, Graduate School of Public Health, Room A527 Crabtree Hall, 130 DeSoto Street, Pittsburgh, PA 15261; E-mail: repro{at}pitt.edu.
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ABSTRACT |
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METHODS: Of 2211 women delivering live births after enrollment in a pregnancy cohort study, 85 (3.8%) developed preeclampsia (antepartum systolic blood pressure greater than 140 or diastolic blood pressure greater than 90 plus proteinuria) and 142 (6.4%) developed transient hypertension of pregnancy (antepartum blood pressure elevation without proteinuria). At a mean of 10.2 weeks’ gestation, women were asked about first-degree family members with heart disease or stroke, hypertension, diabetes, renal disease, or any of these, which defined familial cardiovascular risk.
RESULTS: After adjustment for age and body size, having two or more family members, versus no family members, with cardiovascular risk imparted a 1.9-fold (95% confidence interval [CI] 1.1, 3.2) elevated risk for developing preeclampsia and a 1.7-fold (95% CI 1.1, 2.6) risk for developing transient hypertension of pregnancy. Having two or more family members with hypertension also imparted a significant, two-fold elevation in risk of preeclampsia and transient hypertension of pregnancy, and having two or more family members with heart disease or stroke imparted a 3.2-fold (95% CI 1.4, 7.7) elevation in the risk for preeclampsia.
CONCLUSION: A strong family history of aggregate cardiovascular risk increased the likelihood for developing preeclampsia and transient hypertension of pregnancy. These findings support the theory that a preexisting tendency to cardiovascular risk, and particularly hypertension, increases a women’s susceptibility to developing hypertension in pregnancy.
Hypertension in pregnancy, comprising preeclampsia and transient hypertension of pregnancy, is associated with increased rates of hypertension and coronary heart disease later in life.1–6 Whether preeclampsia and transient hypertension of pregnancy initiate vascular changes that later become clinically evident or whether a predisposition to cardiovascular disease increases the risk of developing hypertension in pregnancy is not clear. Evidence for the latter explanation includes the fact that women who are overweight or have a personal history of hypertension before becoming pregnant are more likely to develop preeclampsia and transient hypertension of pregnancy.7–11 Women who develop preeclampsia also have antepartum and intrapartum evidence of hyperlipidemia,12–15 glucose intolerance,16–19 elevated blood pressure,20 and renal dysfunction,21–23 whereas metabolic aberrations are not consistently found among women with transient hypertension of pregnancy.9,24
One way to distinguish between these two notions—that predisposition to cardiovascular disease is linked to hypertension in pregnancy and that these pregnancy conditions cause cardiovascular damage—is to assess the relationship between preeclampsia and family history. Family history represents the shared genetic or environmental influences that women carry into their pregnancies. Several previous studies have demonstrated that preeclampsia is more common among the mothers, sisters, and monozygotic twins of women who develop preeclampsia.25–29 To the best of our knowledge, however, only a handful of retrospective studies have assessed the relationship between family history of cardiovascular risk (hypertension and diabetes) and preeclampsia,7,30,31 and none have examined family history in relation to transient hypertension of pregnancy.
We asked women enrolled in a prospective observational study of hypertension in pregnancy about their first-degree family history of cardiovascular disease, including hypertension, heart disease, stroke, diabetes, and renal disease to determine whether family history predicted the onset of preeclampsia or transient hypertension of pregnancy.
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MATERIALS AND METHODS |
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ABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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All women entering the Pregnancy Exposures and Preeclampsia Prevention study underwent a standardized interview at their first prenatal visit (mean 10.2 weeks’ gestation) administered by trained, professional interviewers. Women were asked about the following diseases among first-degree family members: diabetes, hypertension, heart disease, stroke, and kidney disease. An aggregate category of cardiovascular risk was created, comprising a family history of any of these. For each disease, women were asked to recall the number of each type of relative experiencing that condition. Because a family history of heart disease and of stroke yielded similar results, and because of small cell sizes, these exposures were combined into a single category.
Preeclampsia was defined as an elevation of blood pressure plus proteinuria. The blood pressure criteria consisted of a mean blood pressure on repeated prelabor measurements of greater than 140 systolic and/or greater than 90 diastolic. The proteinuria criteria were greater than 1+ on a catheterized, greater than 2+ on a voided, and greater than 300 mg on a 24-hour urine specimen, or a protein/creatinine ratio of 0.3. The same elevations in blood pressure in the absence of proteinuria defined transient hypertension of pregnancy.
Covariate information was also obtained by interview, on maternal age, race (white versus nonwhite), education (less than high school, high school graduate, post–high-school attainment), gravidity and parity, smoking since the woman suspected she might be pregnant, recalled prenatal weight and height (combined into body mass index: weight/height2), prepregnancy diabetes, and prepregnancy hypertension.
We first compared demographic and clinical features among women who developed preeclampsia, transient hypertension of pregnancy, or neither. Baseline differences between groups were analyzed with Fisher exact test for categoric variables and Student t test for continuous variables. The proportion of women reporting one family member and the proportion reporting two or more family members (representing a stronger family aggregation), as compared with none, with each type of cardiovascular risk, were then compared among women developing preeclampsia, women developing transient hypertension of pregnancy, and women with no hypertension in pregnancy. Odds ratios (with 95% confidence intervals [CIs]) were the measure of association. Because the small numbers of exposed women in some categories would not allow the addition of multiple covariates into multivariable models, we instead repeated analyses among more homogeneous groups. First, we excluded women with prepregnancy diabetes and prepregnancy hypertension. Next, we separately analyzed associations among women who were primiparous and those who were multiparous. Finally, logistic regression analyses were performed adjusting for age and body mass index and separately considering each family history variable as the main independent factor.
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RESULTS |
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). Women developing preeclampsia were also more likely to be older, have prepregnancy diabetes, and to deny smoking before conception.
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). After adjustment for age and body mass index, having two or more affected relatives imparted a 1.9-fold excess risk of preeclampsia (95% CI 1.1, 3.2) and a 1.7-fold excess risk of transient hypertension of pregnancy (95% CI 1.1, 2.6). Adjusted relative risks were approximately 2 for the associations between having two or more family members with hypertension and preeclampsia or transient hypertension of pregnancy. Having two or more family members, as opposed to none, with heart disease or stroke was 3.2-fold more likely (95% CI 1.4, 7.7) among women developing preeclampsia and 1.9-fold more likely (95% CI 0.8, 4.5) among women developing transient hypertension of pregnancy. Neither a family history of diabetes nor a family history of renal disease elevated the risk of preeclampsia or transient hypertension of pregnancy. These relationships were not significantly affected by exclusion of women with prepregnancy diabetes and prepregnancy hypertension (data not shown).
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). However, in primiparous women developing transient hypertension of pregnancy, no familial risk was apparent. Among multiparous women, familial cardiovascular risk was associated with both preeclampsia and transient hypertension of pregnancy.
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DISCUSSION |
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Although there is substantial epidemiologic evidence supporting links between hypertension in pregnancy and later cardiovascular risk,1–6 the role for familial cardiovascular risk in predicting preeclampsia has been little examined. Eskanazi et al,7 in a case–control study based on medical record reviews, found that regardless of parity, preeclamptic women were more likely to have a family history of hypertension. More recently, Qiu et al30 found that a first-degree family history of hypertension and a family history of diabetes were associated with preeclampsia cases compared with normotensive controls identified at delivery. Finally, Kobashi et al,31 in examining a Glu298Asp variant of the endothelial nitric oxide synthase gene (NOS3) noted a two-fold elevation in the familial risk of hypertension among women with hypertension in pregnancy (three quarters of whom had preeclampsia). All studies were retrospective, examined a limited set of cardiovascular risk factors among family members, and did not consider transient hypertension of pregnancy. This study, therefore, replicates and extends the previous findings.
Familial aggregation represents shared genetic or environmental commonalities in families, commonalities that would be carried by a woman into her pregnancy. Our data, providing evidence for family aggregation in cardiovascular risk, thus supports the idea that women entering pregnancy with an elevated risk for cardiovascular disease are more likely to develop preeclampsia. Previous observations suggest that blood pressures are higher and endothelial function is impaired, even early in the second trimester, among women bound to develop hypertension in pregnancy.20,24 A question raised by our results is whether the family history of heart disease or stroke associated with hypertension in pregnancy is entirely accounted for by (diagnosed or undiagnosed) hypertension running in the family.
We found some evidence of an association between family history of renal disease and hypertension in pregnancy, although the number of women with affected relatives was small and the estimates therefore did not reach statistical significance. A renal pathology or hematuria is also more common among women with preeclampsia or eclampsia and transient hypertension of pregnancy than among women without these conditions.21–23
Strengths of our study are as follows. Interviewer-administered questionnaires were used to ask women about family history. With the use of such techniques, recall of first-degree family history for cardiovascular risk is excellent.32 Family history information was obtained at the first prenatal visit, before the onset of preeclampsia, and is thus unbiased by knowledge of pregnancy outcome. Preeclampsia and transient hypertension of pregnancy were determined by meticulous chart review for all women and characterized on the basis of antepartum blood pressure and urinary protein measurements, so as to avoid any interference from labor in these determinations.
The greatest weakness in our analysis is the limited number of women with familial cardiovascular risk who developed preeclampsia or transient hypertension of pregnancy. This is not surprising, given their young age and thus the relative youth of their first-degree relatives. Nonetheless, the incidence of preeclampsia (3.8%) in this study is similar to that reported in other, recent studies.33 Furthermore, elimination of women refusing to participate in our study, if they differed both by exposure and outcome from those enrolled, might have biased our results.
In summary, our data suggest that a first-degree family history of cardiovascular risk, particularly when present in two or more relatives, increases the risk of developing preeclampsia and transient hypertension of pregnancy. This finding supports the theory that preexisting cardiovascular risk, and particularly hypertension, increases a woman’s susceptibility to developing hypertension in pregnancy.
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Footnotes |
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The authors thank Cindy Schatzman, RN, and Jennifer Eicher, BS, for Pregnancy Exposures and Preeclampsia Prevention study leadership, coordination, and data collection; and Dr. Richard Day for statistical consultation.
doi:10.1016/j.obstetgynecol.2003.08.011
Received May 20, 2003. Received in revised form July 23, 2003. Accepted August 14, 2003.
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REFERENCES |
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