Preeclampsia, a disorder characterized by hypertension and proteinuria, complicates roughly 5–8% of pregnancies and is associated with an array of adverse maternal and fetal outcomes.1–3 Although the etiology of preeclampsia remains obscure, endothelial cell dysfunction is thought to be one of the mechanisms through which the condition manifests.3–5 Consistently reported risk factors for preeclampsia include nulliparity, advanced maternal age, nonwhite race, multifetal gestation, pregnancy weight gain, chronic hypertension, renal disease, short and long interpregnancy intervals, and change in partner.6–9 Women with a previous preeclampsia are most susceptible to developing preeclampsia in a subsequent pregnancy.7
The prevalence of overweight and obesity have been increasing, with approximately half of white women and a staggering 70% of African-American women aged 20–39 years in the United States reported as being overweight or obese.10 Studies have shown that elevated prepregnancy body mass index (BMI) is associated with increased risk of preeclampsia.11,12 Despite these important associations, the relationship between changes in prepregnancy BMI between pregnancies and risk of preeclampsia has not been adequately studied. Furthermore, whether a racial disparity exists in the association between these changes in BMI across pregnancies and risk of preeclampsia in a subsequent pregnancy remains undetermined. Therefore, we hypothesized that the risk of preeclampsia in the second pregnancy will be associated with changes in prepregnancy BMI between pregnancies and that this association may be modified by maternal race or ethnicity.
MATERIALS AND METHODS
The data for this study were derived from the Missouri 1989–1997 live birth and fetal and infant death data files. These files were linked longitudinally to biological mothers using unique identifiers. Details of the methods and algorithm used in the linkage process and the validation of the linked data have been reported in detail elsewhere.13
The study was restricted to women without preeclampsia in the first pregnancy. Preeclampsia was defined as hypertension accompanied by proteinuria beyond the 20th week of gestation in a woman who was normotensive before the pregnancy. Self-reported maternal prepregnancy weight (kilograms) and height (meters) was used to derive BMI (weight/height2; kg/m2), and was categorized as underweight (less than 18.5), normal weight (18.5–24.9), overweight (25.0–29.9) and obese (30 or greater). Maternal race was grouped as non-Hispanic white, non-Hispanic black (African-American), and other races. Factors considered as potential confounders included maternal age (less than 25, 25–34, and 35 or more years), maternal education (less than 12, 12, and 13 or more years of completed schooling), marital status (married or unmarried), prenatal care (care initiated in the first trimester or no or late care began), smoking during pregnancy (yes or no), and interpregnancy interval defined as the interval between the end of the first pregnancy and estimated conception of the second pregnancy (categorized as less than 1, 1.0–1.5, 1.6–2.0, 2.1–2.5, 2.6–3.0, 3.1–3.5, and 3.6 or more years).
A total of 711,015 live births and fetal deaths were recorded between 1989 and 1997 in Missouri. Of these births, we excluded the following: births to women with only one pregnancy during the study years, women with a pregnancy before 1989, multiple births, records with missing or incomplete maternal weight or height data, women with reported chronic hypertension and pregestational or gestational diabetes in either pregnancy, preeclampsia in the first pregnancy, and births at less than 20 weeks of gestation. After all exclusions, a total of 136,884 women who had their first two consecutive singleton pregnancies remained for analysis (Fig. 1).
We performed a retrospective cohort analysis to assess whether a change in prepregnancy BMI is associated with preeclampsia in the second pregnancy. Because race disparity in body mass composition may influence preeclampsia risk, we repeated the analyses after stratifying the data for maternal race. We used multivariable logistic regression analysis to estimate adjusted odds ratio (OR) with 95% confidence interval (CI) to examine associations between changes in prepregnancy BMI between the first two pregnancies and preeclampsia in the second pregnancy. In all analyses, women with normal BMI in both pregnancies served as the reference group. A racial disparity in preeclampsia risk in relation to changes in BMI between pregnancies was determined by including an interaction term between maternal race and BMI groups in the regression models. Several factors were adjusted in the multivariable regression models, including maternal age, education, marital status, prenatal care, smoking, chronic hypertension, and interpregnancy interval. Some factors (smoking during pregnancy, marital status, and prenatal care) may have changed between pregnancies. To account for complete confounder adjustment, we created a four-level variable for each time-varying confounder: 1) absence of factor in both pregnancies (reference); 2) presence of factor in the first but not in the second pregnancy; 3) presence of factor in the second but not in the first pregnancy; and 4) presence of factor in both pregnancies.
The effects of first and second prepregnancy BMI on preeclampsia risk in the second pregnancy, with BMI considered as a continuous variable, were also examined. To account for nonlinearity in the effects of BMI on preeclampsia risk, restricted cubic spline transformation was applied using 3–6 knots for BMI in the first and second pregnancy.14 Nested models were compared based on likelihood ratio deviance statistics, and models with 4 knots provided the best fit. These knots were positioned at 18, 21, 24, and 34 in the first and at 18, 21, 25, and 35 in the second pregnancy for white women and at 18, 22, 25, and 38 in the first and at 18, 22, 26, and 39 in the second prepregnancy BMI for African-American women.
All analyses were performed with SAS 9.1 (SAS institute, Cary, NC). The study was approved by the ethics committee of the Institutional Review Board of the UMDNJ-Robert Wood Johnson Medical School, New Brunswick, New Jersey.
The prevalence of underweight, overweight, and obesity were 7.8%, 19.5%, and 13.2%, respectively. The rate of preeclampsia in the second pregnancy was 2.0% (white 1.8% and African-American 3.0%). The distributions of maternal characteristics in relation to preeclampsia in the second pregnancy are shown in Table 1.
An increase or decrease in prepregnancy BMI between the first two pregnancies from normal weight to overweight or obese and vice versa was associated with increased risk of preeclampsia in the second pregnancy (Table 2). The greatest risk was observed among obese women. Being overweight or obese in both pregnancies between pregnancies was associated with increased risk of preeclampsia in the second pregnancy.
Table 3 compares race-specific associations between changes in BMI and risk for preeclampsia. Among both white and African-American women, compared with those with normal BMI in both pregnancies, any increase in BMI from normal weight to overweight or obese between pregnancies was associated with increased preeclampsia risk in a dose-dependent fashion. Although a decrease in prepregnancy BMI from obese or overweight to normal weight between pregnancies was not associated with preeclampsia among white women, it was associated with increased risk of preeclampsia among African-American women.
The adjusted rate of preeclampsia in the second pregnancy in relation to changes in prepregnancy BMI between the first and second pregnancies among white (panel A) and African-American (panel B) women are shown in Figure 2. Among white women, the rate of preeclampsia increased in the second pregnancy proportional to BMI in the first pregnancy. However, when the second prepregnancy BMI was 30 or more, the influence of BMI in the first pregnancy was greater (ie, when second prepregnancy BMI was 30 or more, the first prepregnancy BMI had a stronger influence on preeclampsia in the second pregnancy). Among African-American women, changes in prepregnancy BMI had less influence on preeclampsia when the second prepregnancy BMI was 25 or more, especially when women were obese before their first pregnancy.
Despite the strong associations between increased maternal body mass and preeclampsia risk,11,12,15 there are few data regarding the effect of changes in prepregnancy BMI between a woman’s first two pregnancies and risk of preeclampsia in the second pregnancy. Among normotensive women in their first pregnancy, our study shows that the risk of developing preeclampsia in the second pregnancy depends not only on BMI in the index pregnancy, but also on BMI in the previous pregnancy.
The mechanism by which prepregnancy BMI in the earlier pregnancy exerts its effect on preeclampsia in the following pregnancy remains unclear. Inflammatory substances secreted by adipose tissues among overweight and obese women may lead to chronic inflammation and adversely affect vascular function. Therefore, chronic inflammation could be a cardinal link between prepregnancy BMI in earlier pregnancy and preeclampsia in the following pregnancy.16,17
The etiology of preeclampsia remains largely unknown. However, there is a consensus that endothelial cell dysfunction resulting from excessive maternal intravascular inflammatory response to pregnancy,4 immunologic maladaptation,18 genetic components to susceptibility,5 and obesity-related inflammatory process11 are believed to be some of the chief mechanisms. Although there is some conflicting evidence about paternal contribution to the risk of preeclampsia,8 most of the evidence suggests that preeclampsia may be an immunologic disease process. A subsequent pregnancy with the same father or a longer period of sexual cohabitation with the same father before a pregnancy may confer a protective effect on preeclampsia.9,19,20 Women with a partner who had a previous relationship in which a pregnancy was complicated by preeclampsia are also at increased risk of preeclampsia.21 Although the etiological mechanisms underlying these associations are largely speculative, abnormal or suboptimal maternal immune adaptation to paternal genes at the maternal-fetal interface may be responsible.
Despite the retrospective design of our study, given the strong associations observed, it is tempting to draw causal inferences. The apparent dose-response relationship of increasing changes in prepregnancy BMI on preeclampsia risk may support the concept that obesity-mediated inflammatory changes may play a role in the pathogenesis of preeclampsia. This concept is further supported by the finding of excessive levels of C-reactive protein in overweight and obese women.11,22 Extrahepatic synthesis of C-reactive protein in response to proinflammatory cytokines, such as interleukin-6 and tumor necrosis factor α, has been recently identified in adipose tissue.23
We showed an association between a decrease in prepregnancy BMI from obese or overweight to normal weight between pregnancies and preeclampsia among African-American, but not among white women. Previous studies have reported that factors such as asthma and psychosocial stress during pregnancy influence risk for preeclampsia, and these factors are more likely to occur among African-American women than white women.24–26 Because the data used in this study does not contain information about maternal asthma and psychosocial stress during pregnancy, these factors were not taken into account in our analysis. Therefore, further study is needed to determine if these and other unaccounted factors may have influenced our findings.
Caution is required in interpreting our results. In this study, some degree of misclassification of preeclampsia is likely, but the extent to which this misclassification, if any, may have affected our findings remains unknown. Women with preeclampsia in their first pregnancies were excluded from this cohort, and maternal weight and height data were ascertained at the first prenatal visit—well before women developed preeclampsia in the second pregnancy. Thus, even if a small proportion of women with preeclampsia were misclassified, the bias would have been nondifferential. Therefore, the reported associations in this study are likely conservative. Residual confounding due to unmeasured factors such as nutritional intake before and during pregnancy may have impacted our study. Observational studies have reported a potential benefit of omega-3 fatty acids in decreasing the incidence of preeclampsia.27,28 We were unable to assess the effects of BMI changes between pregnancies on the risk of mild and severe preeclampsia; the data utilized in this study does not enable distinctions of preeclampsia based on severity. Because data on prepregnancy weight was self-reported, it is possible that the derived BMI may have been underestimated. However, self-reported prepregnancy weight was previously shown to be quite reliable for clinical studies.29
The effect of interpregnancy interval on the associations noted merits some discussion in at least two aspects. First, women who were of normal BMI before their first pregnancy but gained weight before their second pregnancy may have taken longer time to conceive.30 Second, women who changed partners between their first and second pregnancy also have longer intervals.31 Both of these issues have been previously shown to effect preeclampsia risk.30,31 Furthermore, interpregnancy intervals may have been the consequence of selective fertility,32 whereby couples with a previous loss tend to replace their loss more quickly to achieve a desired family size.33 Although all of our associations were indeed adjusted for interpregnancy interval, specifically studying the independent effects of time to conception (of the second pregnancy) and change in paternity on our overall associations may provide interesting clues to understanding etiologies of preeclampsia.
In summary, any increase in prepregnancy BMI from normal weight to overweight or obese between pregnancies is associated with increased risk of preeclampsia compared with normal prepregnancy BMI in both pregnancies. A decrease in prepregnancy BMI from overweight or obese to normal weight between pregnancies attenuated the risk, although the risk is nevertheless high.
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