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Division of Endocrinology, Diabetes, and Hypertension (S.M.H., N.S.-O, E.W.S.), Divisions of General Internal Medicine and Women’s Health (C.G.S.), Brigham and Women’s Hospital, and Harvard Medical School, Boston, Massachusetts 02115; and Cardiovascular Engineering, Inc. (G.F.M.), Holliston, Massachusetts 01746
Address all correspondence and requests for reprints to: Shannon Heitritter, M.D., Division of Endocrinology, Diabetes, and Hypertension, 221 Longwood Avenue, Boston, Massachusetts 02115. E-mail: sheitritter{at}partners.org.
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Abstract |
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Objective: The aim of this study was to compare biochemical and hemodynamic surrogate markers of CVD in nondiabetic women with and without a history of GDM who were at least 1 yr post delivery.
Design: This was a single center cross-sectional study.
Setting: The study was performed in an academic referral center.
Subjects: Forty-eight premenopausal healthy women with a history of GDM (n = 25) or a history of normal pregnancy (n = 23) were studied in the follicular phase of the menstrual cycle.
Main Outcome Measures: The main outcome measures were: 1) inflammatory markers associated with CVD including C-reactive protein, IL-6, and plasminogen activator inhibitor-1; 2) the adipokine adiponectin; and 3) conduit vessel stiffness.
Results: When compared to normal controls, women with prior GDM had higher mean levels of C-reactive protein (3.58 ± 3.86 vs. 0.52 ± 0.16 mg/liter; P < 0.001), IL-6 (1.81 ± 1.04 vs. 0.99 ± 0.52 pg/ml; P = 0.001), plasminogen activator inhibitor-1 (29.6 ± 17.6 vs. 16.5 ± 14.0 ng/ml; P = 0.001), and lower levels of adiponectin (8.9 ± 3.9 vs. 15.9 ± 7.3 µg/ml; P = 0.001). Women with prior GDM also had significantly (P 
0.04) increased peripheral vascular resistance (1658 ± 290 vs. 1462 ± 340 dyne·sec/cm5), decreased stroke volume (65 ± 13 vs. 75 ± 14 ml/beat), and decreased cardiac output (70 ± 12 vs. 74 ± 13 ml/sec) when compared to controls, after adjusting for body mass index.
Conclusions: Nondiabetic women with prior GDM have evidence of subclinical inflammation, hypoadiponectinemia, and early vascular dysfunction; this population may be at increased risk of developing CVD.
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Introduction |
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Several lines of epidemiological and experimental evidence have established the association of markers of subclinical inflammation with CVD, DM2, and the metabolic syndrome (7, 8, 9). Increased levels of the inflammatory biomarkers C-reactive protein (CRP) (10), plasminogen activator inhibitor-1 (PAI-1) (11), and IL-6 (12) are significant independent predictors of future DM2 or CVD (13). Conversely, the adipokine adiponectin, a peptide with antiinflammatory properties, is associated with a decreased risk of developing DM2 (14) or CVD (15).
Emerging evidence suggests that mediators of inflammation may be pathogenic by inducing vascular dysfunction, thus leading to many of the diverse effects of the insulin resistance syndrome (hypertension, dyslipidemia, and impaired fibrinolysis) (16). Noninvasive assessment of conduit vessel stiffness by arterial tonometry is associated with endothelial dysfunction (17) and with increased risk for CVD (18).
We postulated that women with a history of GDM may be at increased risk for future CVD. The aim of this study was to compare biochemical and hemodynamic surrogate markers of CVD in women with and without a history of GDM who were at least 1 yr post delivery.
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Subjects and Methods |
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Forty-eight women with a history of GDM (n = 25) or a history of normal pregnancy (n = 23) were studied in the General Clinical Research Center (GCRC) at the Brigham and Women’s Hospital (BWH). Subjects were recruited using flyers distributed in the primary care and obstetric clinics associated with the BWH and using advertisements in local newspapers.
A woman was eligible for enrollment if she was 1) at least 18 yr of age, 2) premenopausal (documented by a history of regular periods), 3) at least 1 yr past her most recent pregnancy, and 4) less than 20 yr past her index pregnancy. Only women with pregnancies resulting from spontaneous conception were enrolled. Exclusion criteria included diagnosis of diabetes mellitus or hypertension, use of medications (including oral contraceptive pills), and tobacco use.
All subjects underwent a telephone screen, and if they were eligible and signed a medical release form, their prenatal records were obtained to confirm their pregnancy history. Women were defined as having a history of GDM using the 1979 National Diabetes Data Group criteria (19). These criteria require subjects to have at least two values equaling or exceeding the following cutoff points after administration of a 100-g glucose load: fasting glucose, 100 mg/dl; 1-h glucose, 190 mg/dl; 2-h glucose, 165 mg/dl; and 3-h glucose, 145 mg/dl. Women were defined as having normal glucose tolerance in pregnancy if they had undergone a 50-g glucose-loading test with a 1-h value less than 140 mg/dl. All subjects were studied during the follicular phase of the menstrual cycle (d 1–10).
All subjects fasted after midnight and presented the following morning to the GCRC at BWH. Weight, height, and waist circumference were measured. Noninvasive hemodynamic studies were performed (see below). After these studies, an indwelling iv catheter was placed. Thirty minutes after placement of the iv catheter, blood was obtained for insulin, glucose, and lipid profile analysis [total cholesterol, triglycerides, high-density lipoprotein (HDL), and low-density lipoprotein (LDL)]. Additional aliquots were frozen at –70 C until the time of assay [for CRP, IL-6, PAI-1, free fatty acids (FFA), and adiponectin]. Samples were then run in batches. After the baseline blood was drawn, a 75-g oral glucose load was administered. Blood was then drawn for glucose and insulin measurements at 30, 60, 90, and 120 min post load. Two of the 48 women (both in the previous GDM group) were found to have a new diagnosis of diabetes mellitus when the oral glucose tolerance test (OGTT) was performed; their data were, therefore, excluded from the analysis. The study protocol was approved by the BWH Institutional Review Board, and each subject gave written informed consent before enrollment.
Assays
Glucose was measured by the hexokinase glucose-6-phosphate dehydrogenase method (Olympus Diagnostica, Melville, NY). Insulin was measured by a chemiluminescent immunoassay (Beckman Coulter, Fullerton, CA). All lipids were measured by enzymatic reactions (Olympus Diagnostica). The concentration of FFA was determined using an enzymatic colorimetric assay on the Hitachi 917 (Roche Diagnostics, Indianapolis, IN) using reagents from Wako Chemicals USA (Richmond, VA). IL-6 was measured by ELISA (R&D Systems Inc., Minneapolis, MN); the sensitivity was 0.039 pg/ml. Adiponectin was measured by an ELISA method (R&D Systems). The sensitivity was 0.25 ng/ml, and the interassay coefficient of variation was less than 7%. CRP was measured by an ELISA (American Laboratory Products Co., Windham, NH). The sensitivity was 0.124 ng/ml, and the interassay coefficient of variation was less than 9%. PAI-1 was measured by an ELISA (Diagnostica Stago, Parsippany, NJ). The sensitivity was 1.0 ng/ml, and the interassay coefficient of variation was less than 7%.
Hemodynamic studies
Subjects were studied in the supine position after 30 min of rest. Auscultatory blood pressure (BP) was obtained three to five times at 2-min intervals with a goal of obtaining three sequential readings that agreed to within 5 mm Hg for systolic and diastolic BP using a semiautomated computer-controlled device. Arterial tonometry and simultaneous electrocardiographic recordings were obtained from the brachial, radial, femoral, and carotid arteries with a custom pulse transducer. Subjects were then placed in the left lateral decubitus position to image the left ventricular outflow tract in a parasternal long-axis view. Next, duplicate acquisitions of simultaneous tonometry of the carotid artery and pulsed Doppler of the left ventricular outflow tract from an apical five-chamber view were obtained. Body surface measurements were assessed from suprasternal notch to brachial, radial, femoral, and carotid recording sites. All data were digitized during the primary acquisition, transferred to CD-ROM, and shipped to the Core Laboratory at Cardiovascular Engineering Inc. for analysis.
Data analysis
Averaged systolic and diastolic cuff pressures were used to calibrate the signal-averaged brachial pressure waveform. Mean arterial pressure was calculated digitally by integrating the calibrated brachial pressure waveform. Diastolic and mean brachial pressures were then used to calibrate the carotid, radial, and femoral pressure tracings. Pulse wave velocity to each peripheral arterial site was calculated from the delay between the appearance of the pressure waveform foot in the carotid and peripheral sites as previously described (20). Left ventricular flow velocity, characteristic impedance of the aorta, and total arterial compliance were calculated as described previously (17). The techniques used for measuring arterial stiffness parameters have been validated, and they demonstrate high reproducibility (21).
Statistical analysis
Data are presented as means ± SD. The data from the two groups were compared using paired t tests for normally distributed data or by using the Mann-Whitney U test for nonnormally distributed data. Logistic regression analysis was carried out to control for the effect of body mass index (BMI). Associations between continuous variables were described by correlation coefficients (Spearman). Partial correlation analysis was used to adjust for the effect of BMI on the relationship between the inflammatory parameters and the hemodynamic parameters. Statistical power calculations performed to detect a difference in triglyceride levels of 45.8 mg/dl with a SD of 50.3 mg/dl revealed the need for 20 subjects per group to achieve a power of 0.80 with 
= 0.05 (22). Statistical significance was defined as a two-sided P value < 0.05. SPSS version 12.0.1 (SPSS Inc., Chicago, IL) was used for all computations.
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Results |
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Characteristics of the subjects are presented in Table 1
. Subjects with a history of GDM and normal subjects did not differ in mean age or number of years postpartum. By design, none of the subjects enrolled were hypertensive. There was no difference in brachial systolic BP. The subjects with a history of GDM had higher diastolic BP (P = 0.002) and mean arterial pressure (MAP) (P = 0.004). As expected, both the prepregnancy BMI and the current BMI were higher in the women with a history of GDM (P = 0.002). The weight gain from the time of the prepregnancy BMI to the time of the research study did not differ between the GDM and the normal groups (4.9 ± 6.6 vs. 3.3 ± 2.9 kg; P = 0.416). In our study where hypertensive subjects were excluded, two women in the GDM group compared with no women in the normal group met Adult Treatment Panel III criteria for the metabolic syndrome (23). Ten (43%) women in the GDM group and one woman (4%) in the control group had impaired glucose tolerance (IGT) (2-h plasma glucose of 140–199 mg/dl; P = 0.01). Eleven (48%) women with previous GDM had a positive family history of DM2 (defined as having at least one first-degree relative with DM2). Seven (30%) normal controls had a positive family history of DM2. This difference was not statistically significant.
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The women with a history of GDM had higher fasting glucose (P = 0.015) and triglyceride (P < 0.0001) levels than women with a history of normal pregnancy; homeostasis model assessment (HOMA) was also higher (P = 0.051) in the GDM group (Table 2). After adjusting for BMI, fasting triglycerides levels remained significantly higher in the prior GDM group (P = 0.007). Postload glucose, insulin, area under the curve for glucose (AUCglucose), and AUCinsulin were all higher in the women with a history of GDM than in the control group (Table 3). After adjusting for BMI, 2-h postload glucose (P = 0.004) and AUCglucose (P = 0.015) were both higher in the women with a history of GDM. The 2-h postload insulin also tended to be higher in this group (P = 0.061) (Table 3). Despite the presence of higher postload insulin levels in the GDM group, postload FFA levels remained higher at both 60 and 120 min when compared with the control group; this difference was attenuated after adjusting for BMI (Table 3).
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Compared with the control group, women with a history of GDM had higher levels of CRP, IL-6, and PAI-1 and lower levels of adiponectin (all P 0.001) (Fig. 1). After adjusting for BMI, CRP remained higher and adiponectin lower (P < 0.05) in the women with a history of GDM. IL-6 and PAI-1 were also higher in this group, although these differences were not statistically significant (P = 0.064 and 0.110, respectively). Adiponectin was negatively related to the inflammatory markers CRP (r = –0.568; P < 0.0001), IL-6 (r = –0.534; P = 0.001), and PAI-1 (r = –0.528; P = 0.002). IL-6 related positively to CRP (r = 0.474; P = 0.005). After adjusting for BMI, adiponectin remained negatively correlated to CRP (r = –0.423; P = 0.16), IL-6 (r = –0.396; P = 0.023), and PAI-1 (r = –0.427; P = 0.015); IL-6 remained positively related to CRP (r = 0.392; P = 0.029).
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The women with a history of GDM had higher central systolic pressure and MAP than the control women. After adjusting for BMI, the women with a history of GDM had a higher peripheral resistance than the normal controls. The women with prior GDM also had a lower mean stroke volume (P = 0.011) and cardiac output (P = 0.040) (Table 4).
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We compared nonobese (BMI < 30 kg/m2) women in the GDM group (n = 13) with the women in the normal group, all of whom were nonobese (n = 23). When looking at only the nonobese subjects, BMI no longer differed between the two groups (23.2 ± 2.3 kg/m2 in the normal group and 23.7 ± 2.7 kg/m2 in the GDM group; P = 0.596). Diastolic BP and MAP remained higher in the nonobese GDM group, although they were still within normal limits (Table 1
). Fasting triglycerides remained higher in the nonobese GDM group when compared with controls (106 ± 57 vs. 59 ± 22 mg/dl; P = 0.013). Postload glucose (P = 0.001) and insulin (P = 0.025) remained higher in the nonobese GDM group (Table 3). The inflammatory markers all remained higher in the nonobese GDM group: CRP (2.80 ± 2.75 vs. 0.52 ± 0.75; P < 0.001), IL-6 (1.45 ± 0.61 vs. 0.99 ± 0.52; P = 0.028), and PAI-1 (30.9 ± 20.3 vs. 16.5 ± 14.0; P = 0.008); adiponectin remained lower (9.3 ± 4.2 vs. 15.9 ± 7.3; P = 0.007) (Fig. 1). Hemodynamic measurements revealed that central systolic pressure no longer differed between the two groups. Peripheral resistance remained higher (P = 0.044), and peak cardiac flow remained lower (P = 0.042) as did stroke volume (P = 0.007) (Table 4).
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Discussion |
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Our findings that women with prior GDM had higher fasting glucose, fasting triglycerides, post-load glucose, and postload insulin levels are similar to findings in previous studies (5, 24, 25). One report found that fasting insulin levels remain significantly higher in women with prior GDM, even after adjusting for BMI (5). In contrast, Holte et al. (24) found that differences in both fasting and postload insulin levels were significantly attenuated when adjusted for BMI, as we found in the present study. These observations may be explained by the emerging understanding that increased amounts of adipose tissue contribute directly to the pathogenesis of the subclinical inflammation; therefore controlling for adiposity may be adjusting for part of the direct causal pathway in mediating insulin resistance. Similarly, women with a history of GDM had a higher incidence of IGT than normal controls. This study was designed to look at nondiabetic women with or without prior GDM, and it is possible that part of the differences described are attributable to IGT because this may be part of the causal pathway. However, many women with IGT remain undiagnosed because the OGTT is cumbersome and not routinely performed in practice. A history of GDM appears to capture a high-risk population (some of whom have IGT) and offers a simple potential marker of future cardiovascular risk in women.
Increased levels of biomarkers indicative of subclinical inflammation including CRP, IL-6, and PAI-1 predict risk for DM2 and cardiovascular disease (7, 8, 9). Conversely, adiponectin, an adipokine known to have antiinflammatory properties, is associated with a decreased risk of developing DM2 or CVD (15, 26). Subclinical inflammation also appears to be present in pregnancy complicated by GDM. High first-trimester CRP levels and low adiponectin levels predict an increased risk of subsequent GDM (2, 27). However, it has been uncertain whether this inflammatory state persists beyond the postpartum period. One study of the early postpartum period (3 months after delivery) showed that Austrian women with prior GDM have elevated levels of CRP, IL-6, and PAI-1 and lower levels of adiponectin than controls, before adjusting for body fat mass (28). After adjusting for body fat mass, PAI-1 remained higher and adiponectin remained lower in the prior GDM group. Lactation was not an exclusion criterion for this study, and it is not known what effects lactation may have on carbohydrate metabolism. Furthermore, it is not known how perturbations in the baseline hormonal milieu in the initial postpartum period, such as elevated levels of prolactin (29) or amylin (30), may affect biomarkers of inflammation. The present study found that even after the postpartum period (mean 4 yr postpartum), the differences between the two groups in the biomarkers CRP, IL-6, PAI-1, and adiponectin persists and that CRP and adiponectin remain significantly different after adjusting for BMI.
Vascular dysfunction is another independent risk factor for CVD (18). Recent data suggest that women with prior GDM may have impaired vascular function. One study showed that during the postpartum period (3–6 months), women with a history of GDM have impaired endothelial function as assessed by flow-mediated dilatation (6). Another study showed that after the postpartum period (2–4 yr), women with prior GDM have impaired acetylcholine-induced skin vasodilatation assessed by laser Doppler flow, when compared with normal controls (31). However, measures of vascular function may vary with phase of the menstrual cycle (32), which was not controlled for in previous studies. We studied all women in the follicular phase of their cycle. We found that, when compared with controls, women with prior GDM had increased peripheral vascular resistance, heart rate, and MAP, whereas cardiac output and stroke volume were depressed. A reduction in cardiac output and stroke volume could represent either a primary reduction in myocardial contractility or a primary defect in resistance vessel function, both of which would be accompanied by an increase in peripheral resistance. However, MAP was elevated, not decreased, suggesting that the problem is one of abnormal resistance vessel function and inappropriately elevated peripheral vascular resistance causing an increase in MAP and a secondary reduction in cardiac output.
This study has several limitations. First, the sample size in this study may have limited the ability to detect statistical significance of differences between the two groups in some of the metabolic and vascular function assessments. Second, we measured insulin resistance using OGTT and the HOMA calculation. Although HOMA assessments of insulin resistance correlate well with insulin clamp measurements, the latter may have increased our sensitivity for detecting insulin resistance. Third, there are several other correlates of insulin resistance that have been noted such as low SHBG (34), low IGF-I (35), and elevated dense LDL levels (36) that would have been interesting to assess, but we did not have sufficient serum to measure these. Fourth, our study population was recruited from the BWH obstetrical clinics, which are largely composed of Caucasian women, and therefore this study may not be generalizable to other ethnicities.
Women with prior GDM have elevated markers of inflammation and decreased levels of adiponectin. Furthermore, they have increased peripheral resistance, decreased cardiac output, and decreased stroke volumes. These findings suggest that a history of GDM may serve as a marker for increased risk for future cardiovascular disease. Longer-term studies are indicated to confirm that women with prior GDM have increased cardiac morbidity and mortality and to define a potential role for lifestyle and/or pharmacological intervention.
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Footnotes |
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First Published Online April 19, 2005
Abbreviations: AUC, Area under the curve; BMI, body mass index; BP, blood pressure; CRP, C-reactive protein; CVD, cardiovascular disease; DM2, type 2 diabetes mellitus; FFA, free fatty acids; GDM, gestational diabetes mellitus; HDL, high-density lipoprotein; HOMA, homeostasis model assessment; IGT, impaired glucose tolerance; LDL, low-density lipoprotein; MAP, mean arterial pressure; OGTT, oral glucose tolerance test; PAI-1, plasminogen activator inhibitor-1.
Received December 20, 2004.
Accepted April 11, 2005.
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References |
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C polymorphism are associated with the development of cardiovascular disease. Arterioscler Thromb Vasc Biol 22:2066–2071This article has been cited by other articles:
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