Association between Gestational Diabetes and Pregnancy-induced Hypertension

Chris L. Bryson1,2 , George N. Ioannou1,3, Stephen J. Rulyak3 and Cathy Critchlow4

1 VA Puget Sound Health Services Research and Development, Seattle, WA.
2 Division of General Internal Medicine, Department of Medicine, University of Washington, Seattle, WA.
3 Division of Gastroenterology, Department of Medicine, University of Washington, Seattle, WA.
4 Department of Epidemiology, University of Washington School of Public Health, Seattle, WA.

Received for publication March 24, 2003; accepted for publication June 18, 2003.


    ABSTRACT
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Gestational diabetes and pregnancy-induced hypertension are common, and their relation is not well understood. The authors conducted a population-based case-control study using 1992–1998 Washington State birth certificate and hospital discharge records to investigate this relation. Consecutive cases of pregnancy-induced hypertension were divided into four groups based on International Classification of Diseases, Ninth Revision codes: eclampsia (n = 154), severe preeclampsia (n = 1,180), mild preeclampsia (n = 5,468), and gestational hypertension (n = 8,943). Cases were compared with controls who did not have pregnancy-induced hypertension (n = 47,237). Gestational diabetes was more common in each case group (3.9% in eclamptics, 4.5% in severe preeclamptics, and 4.4% in both mild preeclamptics and those with gestational hypertension) than in controls (2.7%). After adjustment for body mass index, age, ethnicity, parity, and prenatal care, gestational diabetes was associated with increased risk of severe preeclampsia (odds ratio (OR) = 1.5, 95% confidence interval (CI): 1.1, 2.1), mild preeclampsia (OR = 1.5, 95% CI: 1.3, 1.8), and gestational hypertension (OR = 1.4, 95% CI: 1.2, 1.6). Gestational diabetes was more strongly associated with pregnancy-induced hypertension among women who received less prenatal care (OR = 4.2 for eclampsia and OR = 3.1 for severe preeclampsia, p < 0.05 for both) and among Black women (OR for eclampsia and preeclampsia together = 3.9, p < 0.05).

diabetes, gestational; eclampsia; ethnic groups; hypertension; pre-eclampsia; pregnancy complications; pregnancy complications, cardiovascular; prenatal care

Abbreviations: Abbreviations: CI, confidence interval; ICD-9, International Classification of Diseases, Ninth Revision; OR, odds ratio.


    INTRODUCTION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Hypertensive disorders of pregnancy complicate 5–10 percent of all pregnancies and can result in a variety of maternal and fetal complications, including seizures, stroke, hepatic failure, renal failure, intrauterine growth retardation, fetal distress, premature delivery, and death (1). The pathophysiology of pregnancy-induced hypertension is poorly understood, but it is likely multifactorial; several lines of evidence suggest that glucose intolerance and insulin resistance have a role in the etiology of these diseases (2). Like pregnancy-induced hypertension, gestational diabetes mellitus is also relatively common and affects 3–5 percent of pregnancies, resulting in a variety of complications that primarily affect the fetus, including macrosomia, stillbirth, jaundice, and respiratory distress syndrome (3). The relation between pregnancy-induced hypertension and gestational diabetes is not well understood (410); several studies suggest an association between these diseases (47, 10, 11), but others do not (8, 9). Whether the association between gestational diabetes and the various subtypes of pregnancy-induced hypertension is the same or varies between types of pregnancy-induced hypertension is also largely unknown. To our knowledge, there have been no large, population-based studies with sufficient power to delineate the relation between gestational diabetes and each subtype of pregnancy-induced hypertension in the same study or to investigate interactions between gestational diabetes and known predictors of pregnancy-induced hypertension.

A better understanding of the association between these conditions may lead to more effective strategies for prenatal care and may ultimately allow for a better understanding of their pathophysiology. Therefore, we conducted a population-based case-control study to better define the relation between gestational diabetes and the subtypes of pregnancy-induced hypertension (eclampsia, severe preeclampsia, mild preeclampsia, and gestational hypertension) in a sample of women delivering infants in Washington State.


    MATERIALS AND METHODS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Study population
Anonymous subject data for this case-control study were drawn from the electronic Washington Birth Events Records Database (BERD) records of mothers who delivered infants in Washington State between 1992 and 1998. This statewide database links more than 95 percent of all Washington State birth certificate data with maternal and infant International Classification of Diseases, Ninth Revision (ICD-9) records of delivery hospitalization from the Comprehensive Hospital Discharge Reporting System (CHARS) (12), providing birth certificate data and ICD-9 discharge diagnosis data. Subjects were excluded from the analysis if they had a history of pregestational hypertension (ICD-9 codes 401–405.9, 642.0, 642.1, 642.2, 642.7), renal disease (ICD-9 codes 582.0–582.9, 585, 587, 588–588.8), or prior diabetes mellitus (ICD-9 codes 250–250.9, 648.0, or reported on the birth certificate). The study was restricted to women for whom body mass index was available for analysis.

Study design and assessment of pregnancy-induced hypertension
Cases of pregnancy-induced hypertension were identified from ICD-9 codes. Four separate case groups were created based on these codes: eclampsia (ICD-9 code 642.6, n = 154), severe preeclampsia (ICD-9 code 642.5, n = 1,180), mild preeclampsia (ICD-9 code 642.4, n = 5,468), and gestational hypertension (ICD-9 code 642.3, n = 8,943). All cases identified during the study period were included. Controls (n = 47,237) were defined as women who did not have any of the above diagnoses. Controls were randomly sampled from each year of the study and were frequency matched to the cases by year of birth. There were 215,897 total possible controls from which this sample was drawn.

Ascertainment of gestational diabetes and other covariates
The presence of gestational diabetes was ascertained from the hospital discharge records (ICD-9 code 648.8). Covariates that were used to adjust for confounding and examine for interaction with gestational diabetes were identified from prior studies (1318) and included age, parity, ethnicity, body mass index, and adequacy of prenatal care. Maternal ethnicity was determined from the birth certificate and was grouped into four categories: White, Black, Hispanic, and other. The "other" category consisted of those listed on the birth certificate as American Indian, Chinese, Japanese, Filipino, Hawaiian, other Asian, other non-White, Asian Indian, Korean, Samoan, Vietnamese, Guamanian, and those who refused classification.

Body mass index was available for approximately 60 percent of mothers giving birth in Washington State during this period. Maternal prepregnancy weight, present on 78 percent of the birth certificates, and maternal height obtained from driver’s license records of the Washington State Department of Licensing (available for 77 percent of those for whom a weight was available) were used to calculate body mass index. Body mass index was categorized into quartiles for the purposes of this analysis.

Adequacy of prenatal care was determined by calculating the Kotelchuck index, as described previously (19). This index is a composite score that summarizes prenatal care based on both the number and timing of prenatal visits. The score was dichotomized for our analysis into either high care ("adequate" and "adequate plus"), representing those who received at least 80 percent of the expected number of visits, or low care ("inadequate" and "intermediate"), representing those who received less than 80 percent of the expected number of prenatal care visits.

Statistical analysis
Unconditional logistic regression was used to simultaneously control for multiple confounders and to model interactions. Each case group was modeled independently of the others with the same control group. We assessed the statistical significance of effect modification between gestational diabetes and each of the covariates by using the likelihood ratio test. Age was modeled as a linear variable, while body mass index, parity, and degree of prenatal care were modeled as indicator variables to allow for either linear or nonlinear effects.


    RESULTS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
In general, women with pregnancy-induced hypertension tended to be younger, be a primigravida, and have a higher body mass index compared with controls (table 1). In addition, they were more likely to receive adequate prenatal care.


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TABLE 1. Characteristics (%){dagger} of mothers by case status, Washington State, 1992–1998
 
Gestational diabetes was more common in each of the pregnancy-induced hypertension case groups than in controls (table 2), with prevalences of 3.9 percent in women with eclampsia, 4.5 percent in women with severe pre-eclampsia, and 4.4 percent in both women with mild pre-eclampsia and women with gestational hypertension compared with 2.7 percent in controls. After adjustment for body mass index, age, ethnicity, parity, and adequacy of prenatal care, gestational diabetes was found to be associated with a significant 1.5-fold increased risk of severe and mild preeclampsia and a 1.4-fold increase in gestational hypertension. Overall, no significant association was found between gestational diabetes and eclampsia (adjusted odds ratio (OR) = 1.27, 95 percent confidence interval (CI): 0.52, 3.15).


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TABLE 2. Risk of pregnancy-induced hypertension associated with gestational diabetes, Washington State, 1992–1998
 
Ethnicity was found to significantly modify the association between gestational diabetes and subtypes of pregnancy-induced hypertension (table 3). Because of the small number of eclamptic cases, the eclampsia and severe pre-eclampsia case groups were combined for this analysis. In this combined case group, White mothers with gestational diabetes had a 1.5-fold increased risk of eclampsia or severe preeclampsia compared with White mothers without gestational diabetes. Similar increases in the risk of mild pre-eclampsia and gestational hypertension were found among White mothers. Black mothers with gestational diabetes had a three- to fourfold higher risk of pregnancy-induced hypertension compared with Black mothers without gestational diabetes. This finding reflected the largest increase in risk among the ethnic groups. The differences in odds ratios between ethnic groups were significant in the eclampsia/severe eclampsia group (p = 0.01), not significant in the mild preeclampsia group (p = 0.12), and of borderline significance in the gestational hypertension group (p = 0.06).


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TABLE 3. Association between gestational diabetes and pregnancy-induced hypertension stratified by ethnicity, Washington State, 1992–1998{dagger}
 
The amount and timing of prenatal care also modified the association between gestational diabetes and the most severe forms of pregnancy-induced hypertension (table 4). Compared with mothers without gestational diabetes, mothers with gestational diabetes who received less prenatal care (less than 80 percent of the expected visits) had a higher risk of both eclampsia and preeclampsia than did mothers with gestational diabetes and receiving more prenatal care (eclampsia: high care vs. low care, 0.61 vs. 4.16, p for difference = 0.07; preeclampsia: high vs. low care, 1.25 vs. 3.13, p for difference = 0.02). The risk of gestational hypertension and mild preeclampsia associated with gestational diabetes was also higher among women receiving inadequate prenatal care, although this finding failed to achieve statistical significance.


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TABLE 4. Association between gestational diabetes and pregnancy-induced hypertension stratified by prenatal care, Washington State, 1992–1998{dagger}
 
We were unable to find any significant interactions between gestational diabetes and body mass index, age, or parity. Furthermore, the results of the study were unchanged when the women who refused classification of ethnicity were excluded from analysis (data not shown).


    DISCUSSION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
In this large, population-based study, we found a significantly increased risk of gestational hypertension, mild pre-eclampsia, and severe preeclampsia among women with gestational diabetes. After adjustment for confounders, the risk of developing these serious disorders was 1.5 times greater among women with gestational diabetes. Results also suggest that both ethnicity and prenatal care modify the association between gestational diabetes and pregnancy-induced hypertension.

Our results are consistent with the findings from several prior studies. One cohort study of 10,666 women in Sweden examined risk factors for gestational hypertension and preeclampsia (6). This study reported a significantly increased risk of preeclampsia among mothers with gestational diabetes (OR = 3.16, 95 percent CI: 1.65, 6.03) compared with mothers without gestational diabetes, but it was unable to demonstrate a statistically significant increased risk of gestational hypertension (OR = 1.34, 95 percent CI: 0.49, 3.71). These data were collected from a similar birth registry, using ICD-9 codes to classify gestational diabetes and case status, but were restricted to nulliparous women less than age 34 years. This study included many fewer cases of gestational hypertension (n = 466) and preeclampsia (n = 557), and it excluded cases of eclampsia. Another large, population-based study (n = 878,680) conducted in Latin America by using a birth event database also demonstrated an association between gestational diabetes and preeclampsia (relative risk = 1.93, 95 percent CI: 1.66, 2.25), although it did not account for either race or body mass index in the analysis (7).

A number of other studies have examined the association between gestational diabetes and pregnancy-induced hypertension, although some have been limited by small sample size or limited descriptive information (4, 5, 9, 10). Nonetheless, three of these studies (4, 5, 10) also found a higher proportion of pregnancy-induced hypertension among women with gestational diabetes compared with women without gestational diabetes. A prospective study of women participating in a calcium supplementation trial for the prevention of preeclampsia also demonstrated that the degree of abnormal glucose tolerance was associated with preeclampsia (11). This study also suggested that women with gestational diabetes have an increased risk of pre-eclampsia (OR = 1.67, 95 percent CI: 0.92, 3.05). A French study of 15 maternity units also found an association between gestational diabetes and a combined outcome including all pregnancy-induced hypertension (OR = 2.86, 95 percent CI: 1.05, 7.83) (20).

We found interactions between ethnicity and gestational diabetes regarding their association with eclampsia and severe preeclampsia; trends were similar for the outcomes of gestational hypertension and mild preeclampsia. The risk of pregnancy-induced hypertension associated with gestational diabetes was highest among mothers of Black ethnicity, followed by Hispanic, White, and "other." Comparisons of environmental or genetic differences between ethnic categories may provide further clues to mechanisms involved in the association between gestational diabetes and pregnancy-induced hypertension and may illuminate other modifiable risks or treatable factors.

We also found that the association between gestational diabetes and pregnancy-induced hypertension differed among the high and low prenatal care groups. Gestational diabetes was associated with a lower risk of pregnancy-induced hypertension among those women who received more prenatal care. While inadequate prenatal care has been described as increasing the risk of preeclampsia by 30 percent (16, 18), to our knowledge it has not been previously portrayed as modifying the effect of other risk factors for pregnancy-induced hypertension. Other studies and trials have suggested that aggressive early treatment of high-risk mothers might reduce the risk of preeclampsia (2123). Additionally, it has been suggested that the decreasing incidence rate of eclampsia over the past 20 years is due in part to better prenatal care (24).

Alternatively, this association could result from incomplete ascertainment and exclusion of preexisting diabetic and hypertensive disorders or related types of correlated misclassification. This bias would lead to a relative enrichment of these disorders and misclassification of gestational diabetes and pregnancy-induced hypertension among mothers not receiving adequate prenatal care. If this bias is present, the lack of association between gestational diabetes and eclampsia or severe preeclampsia in the group receiving adequate or better care may reflect the least biased estimate. Differential misclassification of pregnancy-induced hypertension and gestational diabetes according to degree of prenatal care is also possible; in this instance, women who receive more prenatal care might be more likely to have their gestational diabetes or pregnancy-induced hypertension diagnosed, resulting in a stronger-than-expected association. However, we found the strongest association between gestational diabetes and pregnancy-induced hypertension for women receiving the least prenatal care in all case groups. Furthermore, the exposure, the outcome, and prenatal care variables were all ascertained from the hospital discharge record of the birth event. This single point of data acquisition may limit errors that occur in large administrative databases compiled at different time points for different persons and makes this population data cross-sectional, reducing the possibility that recording of these variables was influenced by the frequency of preceding prenatal visits. Overall, our findings do not prove that prenatal care and the treatment of underlying risk factors, such as diabetes and hypertension, can prevent more severe forms of pregnancy-induced hypertension but rather support the need for further investigation into this observation.

This study has several other limitations. We used administrative data, which may include women incorrectly classified as either 1) having pregnancy-induced hypertension or gestational diabetes when, according to strict criteria, they do not have these diseases or 2) not having case status or gestational diabetes when they would have met diagnostic criteria for these diseases. Misclassification may occur more frequently with the less severe outcomes of gestational hypertension and mild preeclampsia and, less frequently, with severe preeclampsia and eclampsia. This misclassification would tend to decrease the observed magnitude of a true relation between gestational diabetes and gestational hypertension or gestational diabetes and mild preeclampsia. Missing data is an expected difficulty arising from use of a large administrative database. In this population, we were able to calculate body mass index for the 60 percent of women for whom a prepregnancy weight was available and who obtained a driver’s license before the pregnancy. Women without a driver’s license may have a different socioeconomic status and may vary in other demographic characteristics; it is possible that the relation between gestational diabetes and pregnancy-induced hypertension is different in this cohort. However, although demographic characteristics may vary for these women, there is no reason to suspect that the basic biologic association between gestational diabetes and the pregnancy-induced hypertension case groups is different between those with and without a driver’s license.

We found that gestational diabetes is associated with severe preeclampsia, mild preeclampsia, and gestational hypertension and that women with gestational diabetes appear to be at a 1.5-fold increased risk overall of developing a hypertensive disorder of pregnancy. The risk for pregnancy-induced hypertension associated with gestational diabetes varied among different maternal ethnicity groups and also by degree of prenatal care. These findings contribute to the understanding of these disorders and support the findings of prior studies that suggest an association between gestational diabetes and pregnancy-induced hypertension.


    ACKNOWLEDGMENTS
 
This work was supported in part by resources at VA Puget Sound, Seattle, Washington.

Dr. Bryson was a VA Health Services Research and Development fellow while this work was conducted.

The authors are indebted to Bill O’Brien for donating programming time to extract BERD data for this project.


    NOTES
 
Correspondence Dr. Chris L. Bryson, VA Puget Sound HSR&D, MS 152, 1660 South Columbian Way, Seattle, WA 98108-1597 (e-mail: cbryson{at}u.washington.edu). Back


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 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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