Published online before print March 26, 2007, doi: 10.1161/HYPERTENSIONAHA.107.087528
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(Hypertension. 2007;49:1056.)
© 2007 American Heart Association, Inc.
Original Articles |
Previous Hypertensive Disease of Pregnancy Is Associated With Alterations of Markers of Insulin Resistance
From the CHUQ (J.G., Y.G., J-C.F.), Hôpital St-François d’Assise, Faculté de Médecine, Université Laval, Québec City, Québec, Canada; and Centre hospitalier universitaire de Sherbrooke (J-M.M.), Pavillon Fleurimont, Sherbrooke, Québec, Canada.
Correspondence to Jean-Claude Forest, Centre hospitalier universitaire de Québec, Centre de Recherche de L’hôpital St-François d’Assise, Unité de Périnatalogie, 10 rue de l’Espinay, Québec, Québec, Canada G1L 3L5. E-mail jean-claude.forest{at}bcx.ulaval.ca
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Abstract |
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Insulin resistance syndrome has been observed in women with hypertensive disease of pregnancy, but few studies evaluated the presence of the syndrome a few years after delivery. The objective of this study was to evaluate the presence of insulin resistance and its metabolic alterations in these women compared with those who had a normal pregnancy. We performed an observational study in 168 women with previous hypertensive disease of pregnancy and 168 control subjects with normal pregnancy contacted, on average, 7.8 years after their first delivery (mean age: 34.8 years). Complete blood lipid profile, insulin, glucose, homocysteine, adipokins, and markers of inflammation were measured. Also, an oral glucose tolerance test was performed in 146 case and 135 control subjects. Case subjects were more overweight compared with control subjects. We found significantly lower high-density lipoprotein cholesterol and adiponectin levels and higher apolipoprotein (apo) apoB/apoA1 ratio, homocysteine, leptin, and insulin levels among case subjects compared with control subjects (P
0.004). Also, case subjects were more insulin resistant in the basal state estimated by homeostasis assessment model 2, as well as in the nonbasal state as estimated by insulin sensitivity indices calculated from the oral glucose tolerance test. Finally, in a multivariate regression model, leptin, apoB/apoA1 ratio, waist circumference, adiponectin, and free fatty acids explained 40% of homeostasis assessment model 2 variance. Young women with previous hypertensive disease of pregnancy show signs of insulin resistance within the first decade after delivery. These findings suggest that insulin resistance may be the link between hypertensive disease of pregnancy and increased cardiovascular risk later in life.
Key Words: hypertension • insulin resistance • obesity • preeclampsia • gestational hypertension • cardiovascular diseases • dyslipidemia
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Introduction |
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Hypertensive disease of pregnancy (HDP) appears after the 20th week of gestation in women and is classified into 2 main groups: the nonproteinuric group, including gestational hypertension (GH) and transient hypertension, and the preeclampsia (PE) group characterized by proteinuria, returning to normal values in the postpartum period. All together, they occur in
8% of pregnancies.1 Epidemiological data suggest that women with previous HDP are at increased risk of cardiovascular disease (CVD) later in life.2–4 Also, review articles proposed that insulin resistance could play a role bridging HDP to long-term CVD, but data are lacking to validate the hypothesis.5,6 During normal pregnancy, insulin resistance progresses until the third trimester to facilitate the transfer of glucose to the fetus, and insulin returns to a normal level after delivery. However, in women suffering from HDP, recent data indicate that insulin resistance and the associated metabolic disturbances, such as dyslipidemia and hyperinsulinemia, are more pronounced compared with pregnant women without this complication.7,8 Also, insulin resistance has been reported in women with previous HDP a few months to many years after delivery in a few small studies.9–11
Estimates of insulin resistance using the homeostasis model assessment (HOMA2) have been well documented and performed in several epidemiological studies, especially in nondiabetic populations, such as ours.12 The HOMA2 represents a reliable estimate of basal insulin resistance and correlates well with the euglycemic hyperinsulinemic clamp usually recognized as the gold standard to evaluate insulin sensitivity.13
In addition, several markers have been associated recently with the insulin resistance syndrome, including tumor necrosis factor (TNF)-
, IL (IL)-6, platelet activator inhibitor (PAI)-1, C-reactive protein (CRP), leptin, adiponectin, and homocysteine.14 These markers have been studied in women during pregnancy, but few studies compared these markers of insulin resistance a few years after delivery between women with and without HDP.
The insulin resistance syndrome could play a role in the pathophysiology of HDP (GH and/or PE) and may be the underlying mechanism linking HDP to CVD later in life in women who suffered from HDP. We have shown recently that the prevalence of the metabolic syndrome based on published criteria is 3- to 5-fold higher among women with previous HDP.15 We are further reporting here an observational study evaluating metabolic alterations associated with the metabolic syndrome 7.8 years, on average, after the index pregnancy from a cohort of nulliparous women. This large-scale study should help to better refine the link between the insulin resistance syndrome in women with previous GH or PE and long-term risk of CVD.
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Methods |
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Study Population
Our research group performed 3 prospective studies examining biochemical and sonographic markers for the early detection of PE in nulliparous women between 1989 and 1997.16,17 For these studies, >4000 pregnant women were recruited between the 11th and the 27th week of gestation. Multiparous women and women with known renal diseases, diabetes mellitus, or CVD were excluded from these studies. The diagnosis of hypertensive complications during pregnancy was assessed prospectively by a single senior obstetrician using the diagnostic criteria of the National High Blood Pressure Education Program Working Group18; blood pressure
140/90 on 2 occasions 6 hours apart before labor was considered as GH. In addition, women who had proteinuria 0.3 g per 24 hours or a urinary protein qualitative dipstick result of "+" or more (300 mg/L) were classified as PE. To fully ascertain the diagnosis of GH or PE, normalization of blood pressure was assessed 6 weeks postpartum. From the initial studies described above, 341 women with previous GH or PE were eligible for the present study. Between January 2001 and December 2003, we were able to contact 244 (71.5%) of the 341 eligible women, of whom 169 (69.3%) agreed to participate, and 71 (29.1%) refused (not interested or lack of time).15 Women enrolled in this study and those who did not agree to participate or were lost because of lack of contact were comparable for body mass index (BMI), age at the index pregnancy, gestational age at delivery, and infant birth weight (P>0.05). Pregnant women and women who had delivered within 6 months of the contact date were excluded or scheduled for a later visit. Each woman with previous HDP at the index pregnancy was matched to 1 control subject from the same cohort for maternal age and year of delivery of the index pregnancy (within 1 year). All of the participants gave written and informed consent, and the study protocol was accepted by the Ethics Committee of the "Centre Hospitalier Universitaire de Québec."
Study Protocol
Women who accepted to participate in this study were scheduled for a visit with a research nurse. An oral glucose tolerance test (OGTT) with blood specimens drawn at 0, 60, and 120 minutes was proposed to each woman when first contacted by telephone call. Each participant had to fill a questionnaire on sociodemographic data, family history (diabetes, chronic hypertension, early CVD, and HDP), personal history (diabetes, hypertension, and CVD), and life habits. During the visit, OGTT was performed for those who had accepted the test. Anthropometric variables (height, weight, and waist and hip circumferences) were measured, and 2 series of 3 measures of blood pressure in a seated position were recorded 2 hours apart using the Korotkoff V sound as the indication of the diastolic pressure. Blood specimens were collected for measurement of biochemical variables. They were centrifuged within an hour, decanted, and stored at –20°C until analyzed.
Measurement of routine biochemical parameters (total cholesterol, high-density lipoprotein [HDL] cholesterol, triglycerides, and blood glucose) were performed on a Hitachi 917 chemistry analyzer (Roche Diagnostics), and low-density lipoprotein (LDL) cholesterol was calculated using the Friedewald formula.19 Insulin was measured with a radioimmunoassay kit (Linco Research Inc). Apolipoprotein (apo) A and B and high sensitive CRP were measured by immunonephelometry on a BN100 nephelometer analyzer (Dade Behring). Homocysteine was measured on an Abbott Axsym (Abbott Diagnostics). Free fatty acids (FFAs) and glycerol were measured on the Advia Centur immunoassay system (Bayer Health Care). All of the biochemical analyses mentioned above were performed in a clinical laboratory of a tertiary care center by skilled laboratory technicians. PAI-1 (TintElize kit from Biopool International), TNF-, IL-6, leptin, and adiponectin (Quantikine high-sensitivity human kits, R&D Systems) analysis were performed by our research team scrupulously following the manufacturer instructions. Coefficient of variations (interassay) of these analyses were 15.8% for PAI-1, 13.3% for TNF-, 26.7% for IL-6, 10% for leptin, and 16.0% for adipokin. LDL particle size was characterized after performing a nondenaturing polyacrylamide gradient gel electrophoresis by the research team who developed this method. Their reported coefficient of variation is <2%.20 The insulin resistance index was assessed using the HOMA2 from an Excel template12 (http://www.dtu. ox.ac.uk). We also calculated insulin sensitivity indices (ISIs) using results of the OGTT as described previously.13,21
Statistical Analyses
Continuous variables are expressed by their mean and SD. Continuous variables that were not normally distributed (kurtosis or skewness >2) are expressed by their median with interquartile range. Comparisons between women with previous HDP (GH, PE, and GH+PE combined) and the control group were performed using unpaired Student’s t tests, Mann-Whitney U test, 
2 tests, or Fisher’ exact tests when appropriate. Logistic regressions were performed to control for BMI (calculated from self-reported prepregnancy weight) at the index pregnancy (as the covariate) to estimate the BMI-independent association between a history of previous HDP and the risk of developing insulin resistance syndrome. From the data obtained from the OGTT, we calculated the area under the curve (AUC) of glucose and insulin concentrations as suggested by Matthews et al.22 We also performed stepwise regressions to find out which variables best predicted the presence of insulin resistance estimated with the HOMA2 (as the dependent variable). The variables included in the regression analysis were chosen based on univariate correlations with HOMA2 and also on their potential role in insulin resistance. Two-sided P<0.05 was considered statistically significant.
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Results |
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Over a 2-year period, we evaluated 168 women with previous HDP (105 with GH and 63 with PE) and 168 control subjects. All but 3 of the women were white. On average, 7.8 years had elapsed (range: 5.1 to 13.0 years) from the index pregnancy to the scheduled visit for the current study. General characteristics of the study subjects appear in Table 1. At the beginning of the index pregnancy, women who developed HDP had a significantly higher BMI compared with control subjects. Those who suffered from PE had smaller babies and delivered earlier compared with the control group, although the proportion of deliveries before 35 weeks of gestation was similar (data not shown).
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We evaluated BMI progression from 18 years of age to the scheduled visit among study subjects (Figure 1). This graph was obtained from self-reported BMI at age 18, prepregnancy weight (mean age: 26 years), and the measured BMI from the actual study (mean age: 35 years). Interestingly, the major difference between women with previous HDP and those in the control group was the increased rate of BMI between age 18 years and their first full pregnancy after adjustment for the number of years elapsed. The prevalence of obesity (BMI 30 kg/m2) in the study groups was 27.4% in women with previous HDP (29.5% for GH and 23.8% for PE) compared with 13.1% in the control group (P=0.001).
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), PE (
), and GH (
).The metabolic profile usually associated with the syndrome of insulin resistance was evaluated, on average, 7.8 years after the index pregnancy (Table 2). Blood lipid profile showed similar total cholesterol between the groups, but among women with previous HDP, we found significantly lower HDL cholesterol values (P<0.001) and slightly higher levels of triglycerides (P=0.02). Higher apoB/apoA1 ratios were observed among case subjects compared with control subjects (P<0.001). However, there were no differences for glycerol, FFA, and LDL particle size between the groups.
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Levels of markers of inflammation, such as IL-6 and CRP, were higher among case subjects (P=0.005 and 0.006, respectively) compared with control subjects, but PAI-1 levels were similar between the study groups (Table 2). Surprisingly, TNF- was higher in the control than in the HDP groups (P<0.001). Leptin and homocysteine concentrations were higher in the HDP groups compared with control subjects (P=0.004 and P<0.001 respectively), whereas adiponectin concentration was lower in case subjects (P=0.004). We calculated the HOMA2 from the fasting blood glucose and insulin levels to compare insulin sensitivity between case and control subjects. We found significantly higher median HOMA2 values in women with previous HDP compared the control group (1.8 versus 1.5; P<0.001). Moreover, based on an HOMA2 >1.9 (corresponding with the 75th percentile of the control group), 41.1% of case subjects (GH: 41.0%; PE: 41.3%) would have insulin resistance compared with 20.8% in the control group (P<0.001).
An oral glucose tolerance test was performed in 146 women in the HDP group (85 with GH and 61 with PE) and 135 control subjects (Figure 2). Women with previous HDP showed diminished tolerance for glucose compared with control subjects. The AUC for blood glucose was higher for the GH and PE groups, but only the former reached statistical significance compared with control subjects. Fasting insulin and insulin AUC were higher in each HDP subgroup compared with control subjects, although the insulin AUC in the GH subgroups showed only a trend. Both calculated ISIs showed decrease insulin sensitivity among case subjects (Table 3).
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), PE (•) and GH (
).
We performed stepwise regression analysis to assess the magnitude of the independent effect of different variables (adiponectin, leptin, waist circumference, FFAs, high sensitive CRP, IL-6, LDL density [peak particle diameter], systolic and diastolic blood pressure, triglyceride, apoB/apoA1 ratio, and TNF-) with insulin resistance estimated by HOMA2. Table 4 shows the variables that were significantly associated with HOMA2 in the final model. The best multivariate model could explain 40% of HOMA2 variance for which leptin, apoB/apoA1 ratio, waist circumference, adiponectin, and FFA were the 5 main statistically significant contributors in decreasing order of magnitude (based on standardized coefficient). We also performed stepwise regression in the subgroup of patient who had the OGTT, and the 4 major variables (leptin, apoB/apoA1 ratio, waist circumference, and adiponectin) were included in the final model (data not shown).
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Discussion |
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In this observational study, we compared indices of insulin resistance and levels of emerging markers of insulin resistance between women with previous HDP and those who had a normal index pregnancy. Women eligible for this study had initially been recruited prospectively between 1989 and 1997 for a study on detection of early markers of PE and recontacted for the present study 7.8 years, on average, after the index pregnancy (mean age: 34.8 years). Recent epidemiological studies have suggested that women with a past history of HDP could be at increased risk of CVD later in life.2,3 In a recent study, we observed that women with previous HDP could be at increased risk of CVD based on an unfavorable risk profile and a high prevalence of metabolic syndrome.15
Obesity, particularly central obesity, is predominant in individuals with the insulin resistance syndrome.23 Women with a history of HDP in our study were more obese than the control subjects based on BMI and waist circumference. From the self-reported weight at age 18 years and from measurements in our study records (weight before first term pregnancy and weight from the current study), we were able to draw the evolution of the BMI for each patient. Results from Figure 1 suggest that an increased weight gain in women who will develop HDP (GH or PE) takes place in early adulthood before the first term pregnancy when compared with the control group. Although self-reported data are prone to bias, this finding suggests that predisposition to metabolic disturbances precedes the occurrence of HDP. In a retrospective study, Barden et al24 showed that women who suffered from PE had higher BMI and higher blood pressure before pregnancy than normotensive control subjects, suggesting a predisposition to metabolic syndrome.
High triglycerides, decreased HDL cholesterol, apoA1, increased apoB, small dense LDL particles, and FFAs usually characterize the syndrome of insulin resistance. We observed these trends in women with a past history of HDP, although differences were statistically significant only for HDL cholesterol, apoA1, apoB, apoB/apoA1 ratio, and triglycerides. After adjusting for prepregnancy BMI, HDL cholesterol and apoB/apoA1 ratio remained significant. Of note, it was shown recently in the large-scale INTERHEART Study that the apoB/apoA1 ratio is a major independent predictive marker of myocardial events.25
TNF-, CRP, IL-6, leptin, adiponectin, PAI-1, and homocysteine all have been reported to be increased in women suffering from PE,26–29 and they are associated with insulin resistance syndrome.14,30 We were interested to see whether these anomalies found during pregnancy remained a few years later. CRP showed slight increases in the HDP group as a whole compared with control subjects, but the difference disappeared after controlling for index BMI. IL-6 was higher in women with previous HDP compared with control subjects, especially in the subgroups of women with previous PE, and this difference remained after controlling for index BMI. This contrasts with the only published study that measured IL-6 level after preeclamptic pregnancy, which did not find any difference compared with women with normal pregnancy 20 years after delivery.28 Surprisingly, TNF- was higher among control subjects in both the combined and subgroup analyses. This finding was unexpected, because insulin resistance is usually associated with higher levels of TNF-. Only 1 study reported TNF- levels after HDP and normal pregnancy, and the authors did not find any differences between groups.28 It is probable that the difference that we observed is of no clinical significance (1.9 versus 1.6 pg/mL). In this study, women with previous HDP had increased homocysteine levels independent of obesity. Homocysteine has been associated with endothelial activation31 and atherosclerosis.32
Adipocytes secrete adiponectin and leptin, and these markers have been associated with the insulin resistance syndrome.26 In our study, leptin showed higher levels in women with previous HDP, although differences were linked to obesity as they disappeared after adjustment for index BMI. Adiponectin was decreased in women with previous HDP compared with control subjects, although the reverse has been reported in women suffering of PE.33,34 Our results are consistent with published data showing that adiponectin is inversely correlated with insulin resistance and the metabolic syndrome,35 even after controlling for index BMI. Adiponectin has antiatherogenic and antidiabetic actions, suggesting that low levels may be a marker of increased cardiovascular risk. To our knowledge, this study is the first to evaluated adiponectin levels in women with a past history of HDP.
We also investigated glucose tolerance in a subset of our patients using the OGTT. This test is frequently performed to evaluate prediabetic state characterized by hyperglycemia and hyperinsulinemia in a nonbasal state. Recently, ISIs calculated from the OGTT have been published and validated with euglycemic hyperinsulinemic clamp showing good correlations.13,21 In our cohort, we observed that women with previous HDP tend to have higher AUC for blood glucose and for insulin during the OGTT. These results confirm data published by others in smaller studies.7,9 Also, ISIs obtained from the OGTT tend to show decreased insulin sensitivity among women with a history of HDP. However, after controlling for index BMI, these differences were no longer significant.
In a multivariate regression model, leptin, apoB/apoA1 ratio, waist circumference, adiponectin, and FFAs were the most predictive markers of insulin resistance estimated by HOMA2 in our population (R=0.63; R2=0.404). These findings are very interesting, because they reinforce the role of adipokins, blood lipids metabolism (imbalance between apoB and apoA1 and the FFAs), and, more importantly, adiposity in the syndrome of insulin resistance. Although these observations apply only to the population studied, they corroborated with our previous findings showing a higher prevalence of metabolic syndrome in women with previous HDP.15 We also tested the robustness of our model in the subgroup of women who had OGTT, and the same variables were statistically significant and were included in the final model.
It appears that obesity plays an important role in insulin resistance among the women that we studied, as well as in other populations in general, and it is recognized that obesity is an independent risk factor for HDP.36 Our results suggest that women who developed HDP are at increased risk of obesity later in life and of metabolic aberrations associated with it, such as insulin resistance and glucose intolerance, blood lipid anomalies (especially increased apoB/apoA1 ratio), adipocytes dysregulation (low level of adiponectin and high level of leptin), and hypertension. These factors have all been associated with CVD.37–39 Our results extend those of Paradisi et al40 for carbohydrates and lipid metabolic alterations in women with previous GH. It is possible that these metabolic defects precede the manifestations of HDP, although this hypothesis should be confirmed in a prospective study from a cohort of young women recruited before their first pregnancy.
Perspectives
Young women with previous HDP already show significant manifestations of insulin resistance within the first decade after delivery. A pregnancy complicated by HDP should, thus, prompt the establishment of preventive measures to avoid the long-term consequences of obesity and its associated metabolic dysregulations.
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Acknowledgments |
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We thank Nathalie Bernard and Mylène Badeau for their inestimable help in technical assistance. We also thank Pastelle Ladouceur-Kègle for assistance in statistical analysis.
Sources of Funding
This work was supported by grants to J-C.F. (MPO-37903) and Y.G. (MPO-122236) from the Canadian Institutes of Health Research and Valorisation Recherche Québec.
Disclosures
None.
Received January 13, 2007; first decision January 30, 2007; accepted February 28, 2007.
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