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Relative Glucose Tolerance and Subsequent Development of Hypertension in Pregnancy

From the Department of Preventive Medicine and Biometrics, University of Colorado Health Sciences Center, Denver, Colorado, the Department of Clinical Sciences, Colorado State University, Fort Collins, Colorado, and the Department of Obstetrics and Gynecology, Kaiser Permanente, Denver, Colorado.

Address reprint requests to: Kim E. Innes, MSPH, PhD Department of Preventive Medicine and Biometrics University of Colorado Health Sciences Center 4200 East 9th Avenue Campus Box C245 Denver, CO 80262 E-mail: kim.innes{at}uchsc.edu

	Abstract

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Objective: To test the hypothesis that relative carbohydrate tolerance, an indicator of insulin resistance, predicts subsequent risk for hypertension of pregnancy among previously normoglycemic, normotensive women.

Methods: We conducted a nested case-control study in women enrolled at a large Colorado urban health maintenance organization. Subjects were previously healthy pregnant women who tested abnormal on their initial 50-g glucose screens and subsequently completed 3-hour, 100-g oral glucose tolerance tests. Cases were 54 previously normotensive women who subsequently developed hypertension and controls were 51 subjects with normotensive pregnancies, matched to cases on parity. Subjects diagnosed with gestational diabetes (17 cases, six controls) were excluded from the main analyses.

Results: Among the 82 normoglycemic women (45 controls, 37 cases, 13 preeclampsia, 24 gestational hypertension), mean post-load glucose levels and total glucose area under the curve were significantly higher in cases than in controls (P .04) and were positively correlated with peak mean arterial pressure. After adjustment for potential confounders, 2-hour post-load glucose levels remained strongly related to risk for hypertension (adjusted odds ratios = 1.48; 95% confidence interval 1.13, 1.92, per 10 mg/dL increase) and to peak mean arterial blood pressure (r = .23, P = .04), as did total glucose area under the curve (P .04). Cases were also more likely to have had one abnormal glucose tolerance test (28% versus 5%, P = .004). Stratifying analyses by case severity (preeclampsia and gestational hypertension) yielded similar results. Among all subjects, more cases than controls were also diagnosed with gestational diabetes (31% versus 12%, P = .008).

Conclusion: These findings are consistent with the hypothesis that insulin resistance precedes the clinical onset of hypertension in pregnancy, and may be important in the etiology of hypertension.

There is growing evidence that hypertension of pregnancy is related to insulin resistance and carbohydrate intolerance.¹ Both proteinuric and non-proteinuric hypertension of pregnancy predict future essential hypertension and diabetes, disorders strongly related to glucose intolerance and insulin resistance.¹ The increased incidence of de novo hypertension among pregnant women with preexisting diabetes is well established.^2–4 Most,^2,4,5 but not all,⁶ studies have also indicated a significantly elevated incidence of hypertension among women with gestational diabetes mellitus (GDM).

Recent research suggests that reduced glucose tolerance and relative insulin resistance are associated with hypertension of pregnancy among normoglycemic women as well. Several controlled cross-sectional studies of women in their third trimester of pregnancy indicate that women with hypertension are relatively hyperinsulinemic and glucose intolerant and that this association is independent of maternal age, weight, gestational period, and other potentially confounding factors.^7–9 In addition, findings from recent case-control¹⁰ and prospective studies^11–14 indicate that relative insulin resistance and carbohydrate intolerance precede the onset of hypertension, suggesting that these factors may be important in the etiology of hypertension of pregnancy. However, the results of other studies have been conflicting,^15,16 and the connection of hypertension in pregnancy to glucose tolerance and other indicators of insulin resistance is not yet established. More population-based studies are needed to clarify the relationship of abnormalities in glucose tolerance and insulin action to subsequent risk for hypertension in pregnancy. In this study, we examined the relationship of relative glucose tolerance to the later development of hypertension in a population of previously healthy pregnant women enrolled at a large urban health maintenance organization.

	Materials and Methods

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All procedures were approved by Kaiser Permanente and the Colorado Institutional Review Board. To examine the association of relative glucose tolerance to the subsequent development of hypertension in pregnancy, we conducted a nested case-control study in a population of pregnant women enrolled at Kaiser Permanente, a group model health maintenance organization in metropolitan Denver. Subjects were drawn from previously healthy, normotensive enrollees with singleton pregnancies who delivered at a single urban Kaiser Permanente hospital between April 1, 1997, and April 1, 1999, and who were enrolled with Kaiser Permanente throughout their pregnancies. Eligible subjects were defined as women who tested abnormal in their initial 50-g oral glucose screen (at least 140 mg/dL 1 hour post-load) at 24–28 weeks’ gestational age, and who subsequently completed the 3-hour oral 100-g glucose tolerance test (GTT). Using information available on the computerized hospital database, enrollees who were Rh-negative, changed insurance carriers during the pregnancy, were diagnosed with or had a history of a chronic disease condition (including hypertension, diabetes, collagen disease, kidney disease, or thyroid disease), had any serious medical or psychiatric illness other than hypertension of pregnancy that required treatment or monitoring, or experienced serious trauma during pregnancy were excluded. Following computerized selection of cases and controls from the remaining subject pool, medical charts of these patients were then reviewed to confirm diagnosis and further assess subject eligibility. In this step, enrollees with a report of prenatal drug use or significant alcohol consumption (at least one drink per week or more than one drink at a sitting), who had missing data on first trimester blood pressure, or who developed hypertension before undergoing the GTT were excluded.

Cases comprised the first 60 eligible subjects who developed hypertension in pregnancy, defined as hypertension (blood pressure at least 140 mmHg systolic or 90 mmHg diastolic) developing after 20 weeks of gestation in previously normotensive women and measured at least twice, 6 hours apart. Preeclampsia was defined as de novo hypertension with proteinuria (defined as at least 300 mg/24-hour period, or dipstick at least 1+ on at least two occasions at least 4 hours apart or at least 2+ on one occasion). Gestational hypertension was defined as de novo hypertension without significant proteinuria (under 300 mg/24 hours or dipstick less than 1+ ). Sixty controls were selected randomly from eligible subjects with normotensive pregnancies and frequency matched to cases on parity (nulliparous versus non-nulliparous). To generate the stratified random sample of controls, we used a custom random sampling program designed to select a specified number of eligible, normotensive subjects using a random number generating scheme (with each random number corresponding to a previously assigned subject number).

From our initial sample of 60 cases and 60 controls, three subjects with reports of illicit drug or significant alcohol use during their pregnancy (one case, two controls), 11 subjects for whom a baseline blood pressure (during the first 12 weeks of gestation) could not be documented (four cases, seven controls), and one case who developed hypertension at 29 weeks but before her GTT were excluded from the study. In addition, 23 subjects (17 cases, six controls) who were diagnosed with GDM were excluded from the main analyses, leaving a total of 82 nondiabetic subjects (37 cases, 45 controls). GDM was diagnosed if two or more values on the 3-hour GTT were elevated, according to standard criteria outlined by the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus.¹⁷ Of the 37 normoglycemic women who developed hypertension, 13 met the criteria for preeclampsia and 24 for gestational hypertension.

Data on all outcome and explanatory variables included in our analyses were gathered from original patient medical and obstetric charts. Outcome measures included peak antepartum blood pressures and presence/absence of hypertension, combined and broken down by severity (gestational hypertension versus preeclampsia). The major explanatory variable, glucose tolerance, was measured as glucose levels at baseline and at 60, 120, and 180 post-load (mg/dL), total glucose area under the curve (estimated by linear integration, ie, by summing the numerical integration values of successive linear segment approximations of the glucose curve for 0–60, 60–120, and 120–180 minutes post-load), and number of abnormal test results (0 versus 1). In addition, information was collected on first trimester blood pressure, maternal age, race/ethnicity, parity/gravidity, gestational age at the GTT, height, prepregnancy weight, and body mass index (BMI, defined as weight in kg/height in m²), pregnancy weight gain, and smoking status.

Data were analyzed using SPSS version 6.0 (SPSS Inc., Chicago, IL). Mean case-control differences in continuous variables were evaluated using the Student t test for independent samples. Chi-square analysis was used to examine case-control differences involving dichotomous variables. We assessed the relationship of blood pressure to glucose levels and other continuous variables using the Pearson product moment correlation coefficient. Logistic regression was used to relate glucose tolerance to subsequent risk for developing hypertension and to assess the potentially confounding or modifying influence of other maternal factors.

	Results

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Table 1 gives the case-control distribution of demographic, anthropometric, lifestyle, and obstetric characteristics of the study subjects. Subjects with preeclampsia did not differ from those with gestational hypertension in the distribution of these characteristics, nor did case categories differ in mean glucose levels, in total glucose area under the curve (see Table 2) or in the association of glucose levels to blood pressure. Hypertension categories were thus collapsed for final analyses. Women who developed hypertension were heavier and tended to be shorter than normotensive controls. Baseline (first trimester) blood pressures were also significantly higher in cases than in controls [mean arterial blood pressure (MAP) 89.46 ± 1.54 versus 81.93 ± 1.19 mmHg]. Cases were similar to controls in parity, gravidity, racial/ethnic background, smoking status during pregnancy, maternal age, pregnancy weight gain, 50-g glucose screen values, and gestational age at the GTT (Table 1).

Glucose levels at 60 minutes post-load (r = .21, P = .05), 120 minutes post-load (r = .26, P = .02), and 180 minutes post-load (r = .22, P = .05) were correlated significantly with peak MAP. Total glucose area under the curve was also strongly correlated with peak MAP (r = .26, P = .002). Stratifying correlation analyses by outcome category (cases and controls) did not appreciably change these associations. Likewise, glucose levels at 60, 120, and 180 minutes post-load were associated positively with increased risk for the subsequent development of hypertension, with glucose levels 120 minutes post-load exhibiting the strongest relation (OR 1.45, CI 1.15, 1.84, per 10 mg/dL increase in plasma glucose) (Table 3). Total glucose area under the curve was also a significant positive predictor of hypertension (Table 3). Adjustment for prepregnancy weight reduced the association of 60 minute post-load glucose, but did not alter the relation of hypertension to 120 and 180 minute post-load glucose levels, nor that to total glucose area under the curve. Even after adjustment for baseline blood pressure, 2-hour post-load glucose remained a significant independent predictor of hypertension, as did total glucose area under the curve (Table 3). Further adjustment for pregnancy weight gain, race, parity, age, and other factors did not materially alter these associations, nor did stratification by parity (nulliparous versus parous), age (under 30 versus 30 years or older), or BMI (up to 25 versus more than 25). Stratifying analyses by case outcome category (preeclampsia and gestational hypertension) also yielded similar results. After adjustment for prepregnancy weight, odds ratios for 120 minute post-load glucose levels (per 10-mg/dL increase) were 1.52 (CI 1.04, 2.23) and 1.35 (CI 1.02, 1.81), respectively, for preeclampsia and gestational hypertension. Likewise, total glucose area under the curve remained significantly related to MAP (r = .23, P = .04) and the risk for both preeclampsia (adjusted ² = 3.96, P < .05) and gestational hypertension (adjusted ² = 4.67, P = .03) after controlling for prepregnancy weight.

Among the study group as a whole (N = 54 cases, 51 controls, excluding those with a pregnancy history of alcohol or illicit drug use and those for whom a baseline blood pressure could not be documented), women who developed hypertension were also more likely to have GDM than were their normotensive counterparts (31% versus 12%, ² = 7.1, P = .008). Adjustment for prepregnancy weight did not materially alter this association (² = 6.8, P = .009).

	Discussion

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In this nested case-control study of previously healthy women who tested abnormal on their initial oral glucose screen, relative glucose intolerance at 26–31 weeks’ gestation predicted the subsequent development of both preeclampsia and gestational hypertension among normoglycemic subjects. After adjusting for prepregnancy weight and other potentially confounding factors, post-load glucose levels, and particularly 2-hour post-load glucose level and total glucose area under the curve, were positively associated with hypertension risk and peak blood pressure, as was one abnormal value of the GTT test. In addition, among all subjects, a strikingly higher percentage of cases were diagnosed with GDM than were controls. These results suggest that relative glucose intolerance is positively associated with the subsequent development of pregnancy-induced hypertension in normoglycemic, previously healthy women, and that this association is independent of prepregnancy weight, baseline blood pressure, pregnancy weight gain, age, race, or other factors. These results are consistent with the hypothesis that insulin resistance precedes the onset of hypertension in pregnancy, and may play an etiologic role in the development of this disorder.

Our findings of elevated post-load glucose levels in women who subsequently developed hypertension agree with those of most^11,12,18,19 but not all¹⁵ previously published cohort and case-control studies that have examined this association. Cioffi and coworkers¹⁵ reported no difference in 1-hour glucose levels between women who developed hypertension and those who did not, although these findings were based on only 11 hypertension cases. In contrast, other investigators reported increased glucose levels after a 1-hour 50-g glucose challenge test^12,18,19 and a 3-hour, 100-g oral GTT^10,11 among women who later developed hypertension. In a study of pregnant women who had an abnormal glucose screen but were not subsequently diagnosed with GDM, Solomon and coworkers¹⁰ also found a tendency toward elevated glucose levels 1 and 2 hours post-load among those who later developed hypertension. Postpartum studies have likewise suggested elevated glucose levels in women with a history of preeclampsia.^20,21

In agreement with our findings, several previous studies have reported an increased risk for hypertension among women with GDM,^2,4,5 again supporting a link between glucose intolerance and insulin resistance and the development of hypertension in pregnancy. Our results are also consistent with those of studies assessing the relation between hypertension in pregnancy and other indicators of insulin resistance. These studies have indicated that pregnant women who develop de novo hypertension are relatively hyperinsulinemic^{7,9,10,13,14,20} and have lower insulin sensitivity^22,23 and higher insulin responses after a glucose load,^{8,9,18,21,22,24,25} and that these abnormalities precede the onset of hypertension.^10,13,14,18

There is growing epidemiologic and pathophysiologic evidence that insulin resistance may play an etiologic role in the development of hyperlipidemia, endothelial damage, and other early hallmarks of hypertension in pregnancy, and ultimately, in the pathogenesis of hypertension itself.¹ Evidence supporting a causal link between insulin activity and blood pressure in nonpregnant individuals has been reviewed else-where.^26–28 Recent research in normal pregnant women has also shown plasma insulin levels to be significantly and positively related to blood pressure after controlling for BMI.²⁹ Insulin resistance and ensuing hyperinsulinemia may lead to hypertension by inducing sympathetic nervous system activation,³⁰ renal sodium retention,^31,32 hypertrophy of vascular smooth muscle,^31,33 and changes in the levels of intracellular calcium^34,35 or other cations affecting vascular tone and blood pressure.^31,36 The hyperglycemia associated with reduced glucose tolerance could also itself contribute to endothelial dysfunction and resulting hypertension of pregnancy. Recent research indicates that hyperglycemia after glucose loading suppresses endothelium-dependent vasodilation.^37–39 Endothelial dysfunction has been documented even in early stages of abnormal glucose metabolism, and studies of patients with borderline to mild hypertension have shown 2-hour post-load glucose level to be a strong, independent predictor of endothelial dysfunction.⁴⁰

In this study, women with preeclampsia did not differ from those with gestational hypertension in their glucose profiles, and relative glucose tolerance was a strong predictor of both outcomes. These findings are consistent with those of several,^10,13,18,19 although not all¹² previous studies, and suggest that the etiology of preeclampsia and gestational hypertension, at least with respect to the role of glucose intolerance and insulin resistance, may be similar. Because this study was restricted to women with elevated values on their initial glucose screen, our conclusions could be limited in generalizability to that group. However, women with GDM, preexisting chronic disorders, or other potentially confounding conditions were excluded from the main analyses. Likewise, our results are also consistent with those of other prospective and case-control studies of women who did not test positive on their initial glucose screen.^11,12,18,19

	Footnotes

 
PII S0029-7844(01)01342-4

Received September 18, 2000. Received in revised form December 21, 2000. Accepted January 31, 2001.

	References

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by INNES, K. E. Articles by MCDUFFIE, R. Search for Related Content PubMed PubMed Citation Articles by INNES, K. E. Articles by MCDUFFIE, R.