Metabolic dysfunction causes substantial morbidity and mortality among women. Among women, pregnancy complications predict metabolic disease risk. Women with gestational diabetes have a 17% to 63% risk of development of noninsulin-dependent diabetes mellitus within 5 to 16 years of the index pregnancy,1 and recent studies have linked a history of gestational diabetes with cardiovascular risk.2,3
The diagnosis of gestational diabetes presumes a threshold value above which women are at increased risk for pregnancy complications; however, recent work shows that adverse pregnancy outcomes increase continuously with increasing fasting glucose Recent studies have linked gestational impaired glucose tolerance (IGT) with subsequent diabetes and cardiovascular disease risk.3,5 – 9 However, it is not known whether IGT during pregnancy predicts metabolic dysfunction independent of clinical risk factors such as body mass index (BMI, calculated as weight (kg)/[height (m)]2) and family history.
The aim of our study was to determine whether a history of gestational diabetes or gestational IGT is predictive of maternal metabolic dysfunction, independent of recognized clinical risk factors. We hypothesized that we would find a monotonic relationship between degree of gestational glucose in tolerance and metabolic dysfunction at 3 years postpartum. To test this hypothesis, we compared measures of metabolic dysfunction at 3 years postpartum among women with normal glucose tolerance, abnormal glucose challenge test results but normal glucose tolerance test (GTT) values, gestational IGT, or gestational diabetes in Project Viva, a prospective cohort study of maternal and infant health.
MATERIALS AND METHODS
We performed an unplanned secondary analysis of participants in Project Viva, a longitudinal cohort study of maternal and child health.10 Women were recruited for Project Viva at their first prenatal visit at one of eight obstetrical offices of a multispecialty group practice in Eastern Massachusetts from 1999 to 2002. To be eligible for the study, potential participants were required to be fluent in English, less than 22 weeks of gestation at study entry, and to have a singleton pregnancy All participants provided written informed consent, and the Institutional Review Board of Harvard Pilgrim Health Care approved all procedures.
Obstetrical care providers assessed gestational glucose tolerance among women in our cohort according to the following guidelines. At 26 to 28 weeks of gestation, all women underwent a nonfasting 50-g oral glucose challenge test. Women with a result of 140 mg/dL or more underwent a 100-g oral GTT administered the morning after an overnight fast. Normal results were defined by Carpenter-Coustan criteria: fasting, less than 95 mg/dL; 1 hour, less than 180 mg/dL; 2 hours, less than 155 mg/dL; and 3 hours, less than 140 mg/dL. Gestational glucose tolerance was categorized as normal (glucose challenge test less than 140 mg/dL), abnormal glucose challenge test, normal GTT (glucose challenge test 140 mg/dL or more, GTT with no abnormal results), gestational IGT (glucose challenge test 140 mg/dL or more, GTT with only one abnormal result),8,11 or gestational diabetes (glucose challenge test 140 mg/dL or more and GTT with two or more abnormal results).
Women returned at 3 years postpartum for a physical examination that included anthropometric measurements and a blood sample. Methodology for anthropometric measures has been previously described elsewhere.12 We tested all blood samples (N=537) for hemoglobin A1c, sex hormone-binding globulin, C-reactive protein (CRP), and the adipokines leptin13 and adiponectin.14 We identified as fasting those participants who did not eat or drink anything other than water for 8 hours before blood samples were obtained (n=166). We tested fasting blood samples for insulin, glucose, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, interleukin (IL)-6, ghrelin15 and Peptide YY (PYY).16 When we compared women who provided fasting samples with those who provided nonfasting samples, we found no differences in age, race, parity, family history of diabetes mellitus, gestational glucose tolerance, or in any outcome variables measured in both fasting and nonfasting participants. Laboratory methods for assessment of metabolic markers in this study have been previously described.12,17
Participants reported sociodemographic variables including parity, race or ethnicity, and personal history of type 1 or noninsulin-dependent diabetes mellitus at the initial study visit during prenatal care. They reported parental history of noninsulin-dependent diabetes mellitus at 3-year follow-up visit. Women missing data on study covariates were excluded.
We used analysis of variance and χ2 tests to measure bivariate associations between sociodemographic characteristics and gestational glucose tolerance. We used multiple linear regression to model the relation between gestational glucose tolerance category and metabolic markers at 3 years. Because BMI may have a nonlinear association with metabolic markers, we used linear, quadratic, and three-knot cubic spline models18 to adjust for maternal BMI 3 years postpartum, retaining the more complex model if the log likelihood ratio test had P<.05. Because inclusion of quadratic and three-knot quadratic spline terms did not improve model fit, we modeled BMI as a linear variable. We further adjusted for maternal age, race, parity, and parental history of noninsulin-dependent diabetes mellitus to ascertain the predictive role of gestational glucose tolerance-independent of clinical risk factors for metabolic disease. Adjustment for breastfeeding duration and weight change from prepregnancy to the 3-year visit did not materially change our results; therefore, they were excluded from our model.
The Sharpiro-Wilk test and visual inspection of regression residuals suggested that normality should not be assumed in several cases. Log transformation of Homeostasis Model Assessment of Insulin Resistance (HOMA-IR), insulin, sex hormone-binding globulin, triglycerides, CRP, and IL-6 improved normality of regression residuals. We present P values for the partial F test to assess the joint null hypothesis of equality across all of the glucose tolerance categories.19
To facilitate interpretation of the magnitude and clinical significance of differences among gestational glucose tolerance groups, we present results as predicted means and 95% confidence intervals (CIs) for the mean. We present unadjusted mean values and adjusted predicted mean values for participants of average postpartum BMI (26.2) who were white, aged 35 to younger than 40 years, had two children, and had no parental history of noninsulin-dependent diabetes mellitus. Data analyses were performed using SAS 9.2. Two-tailed P<.05 were considered statistically significant.
Of 5,055 women screened for Project Viva, 4,208 were eligible and 2,670 enrolled (Fig. 1). Among the 2,128 Project Viva participants who gave birth, 1,579 met criteria for a 3-year follow-up examination with their children by virtue of completing a pregnancy dietary questionnaire and consenting for child follow-up. Of these women, 611 met criteria for the current analysis because they attended the 3-year visit, had not delivered another child since the birth of the index child 3 years previously, denied a diagnosis of type 1 or noninsulin-dependent diabetes mellitus early in the index pregnancy, and provided a blood sample. We excluded women with missing data for 3-year laboratory results (n=25), breastfeeding duration at 1 year (n=8), BMI at 3 years postpartum (n=14), or gestational glucose tolerance (n=27), leaving 537 women for analysis. At this 3-year visit, 166 women provided a fasting blood sample.
Glucose challenge test results were normal for 85.9% (n=461, 95% CI 82.9%–88.8%) of women in our cohort. Among the 76 women with a glucose challenge test result of 140 mg/dL or more, 39 had all normal values on the 100-g GTT, 21 had one abnormal value (IGT), and 16 met the diagnostic criteria for gestational diabetes. Maternal age, parity, BMI at 3 years postpartum, and race were similar among the glucose tolerance groups. Women with a parental history of noninsulin-dependent diabetes mellitus were more likely to have had gestational diabetes (Table 1).
Most women in our cohort gained weight from before the index pregnancy to the 3-year visit; the median weight gain was 2.2 kg (interquartile range −0.4 to 5.3 kg), and 26.5% (95% CI 22.8%–30.4%) of women had gained 5 kg or more during this interval. Most participants had normal glucose tolerance at 3 years postpartum by American Diabetes Association criteria.20 Among 535 women for whom HbA1c was obtained, 14 were at increased risk for diabetes (A1c 5.7%–6.4%) and one, with an A1c of 6.58%, met American Diabetes Association criteria for diabetes (A1c 6.5% or more). In addition, one participant self-reported a diagnosis of noninsulin-dependent diabetes mellitus. Among 164 women for whom fasting glucose was obtained, two had impaired fasting glucose (fasting plasma glucose 100–125 mg/dL) and none met criteria for diabetes (fasting plasma glucose more than 126 mg/dL).
As we hypothesized, women with both IGT and gestational diabetes had more adverse metabolic profiles than women with normal glucose challenge test results or with abnormal glucose challenge test results but normal values on the GTT. These patterns were similar in unadjusted models and in models adjusted for BMI at 3 years postpartum, parity, age, self-reported race, and parental history of diabetes (Tables 2, 3, and 4). Women with gestational diabetes had lower adiponectin and higher HOMA-IR and waist circumference compared with women with IGT or normal glucose tolerance (Fig. 2A; HOMA-IR gestational diabetes 2.7 compared with normal glucose tolerance 1.3; adiponectin gestational diabetes 13.1 ng/mL compared with normal glucose tolerance 21.2 ng/mL; waist circumference gestational diabetes 91.3 cm compared with normal glucose tolerance 86.2 cm; partial F test P<.05 for all models). Women in both the IGT and gestational diabetes groups had lower HDL and higher triglycerides compared with women in the normal glucose tolerance group (Fig. 2B; HDL gestational diabetes 44.7 mg/dL; IGT 45.4 mg/dL compared with normal glucose tolerance 55.8 mg/dL; partial F test P=.07; triglycerides gestational diabetes 136.1 mg/dL; IGT 140.1 mg/dL compared with normal glucose tolerance 78.3 mg/dL; partial F test P<.01). We had hypothesized that we would find a monotonic association between metabolic dysfunction and degree of glucose intolerance; however, we found the highest values for hemoglobin A1c and CRP among women with IGT (Fig. 2C; hemoglobin A1c gestational diabetes 5.1%, IGT 5.3%, normal glucose tolerance 5.1%, partial F test P<.01; high-sensitivity CRP gestational diabetes 1.4 mg/dL, IGT 2.2 mg/dL, normal 1.0 mg/dL, partial F test P<.01). We found no pattern of association between gestational glucose tolerance category and sex hormone-binding globulin, total cholesterol, fasting IL-6, leptin, ghrelin, or PYY (Tables 2, 3).
In this community-based prospective cohort study, we found that both gestational diabetes and gestational IGT were associated with an adverse metabolic profile at 3 years postpartum, independent of BMI and parental history of diabetes.
Strengths of our study include its prospective assessment of gestational glucose tolerance and standardized assessment of 3-year outcomes. Nevertheless, our results must be interpreted within the context of the study design. Our population was healthy, resulting in low rates of gestational diabetes and IGT. Among the 91 women aged 30–39 years for whom we had data on waist circumference, blood pressure, serum lipids, and glucose, only five (5.5%, 95% CI 1.8–12.4%) met criteria for the metabolic syndrome compared with 15% of women in this age range in the general U.S. population.21 In addition, the number of participants with fasting blood samples limited power to detect subtle differences among glucose tolerance groups, and we were not able to define metabolic syndrome in the full cohort. Further studies in larger populations will be needed to validate our findings. Nevertheless, our study size is comparable to several other studies that have assessed metabolic markers among postpartum women with a history of gestational diabetes.2,22 We did not measure postglucose load insulin or glucose in our population; therefore, we were unable to compare indices of glycemia, insulin sensitivity, and β-cell function. Nevertheless, our study included postpartum measures of adiponectin, which is highly correlated with β-cell dysfunction during pregnancy23 and with 2-hour oral GTT in the postpartum period.24
Our results confirm and extend earlier work linking gestational glucose tolerance with an adverse maternal metabolic profile in later life. Several authors have reported an increased risk of IGT and noninsulin-dependent diabetes mellitus among women with abnormal glucose screening results in pregnancy in the setting of both normal oral GTT7 and one abnormal GTT result.5,6,9,25 Moreover, both IGT and gestational diabetes have been associated with the metabolic syndrome at 3 months postpartum.8 Other authors have reported associations between gestational diabetes and markers of metabolic dysfunction after pregnancy. At a mean of 2 years postpartum, Costacou et al22 reported adverse associations between history of gestational diabetes (n=22) and waist circumference, hemoglobin A1c, and HOMA-IR compared with women without a history of pregnancy complications (n=29). Heitritter et al2 similarly compared women with a gestational diabetes history (n=23) with normal controls (n=23) at a mean of 4 years postpartum. Women in the gestational diabetes group had higher diastolic blood pressure, mean arterial pressure, heart rate, fasting glucose, HOMA, triglycerides, CRP, IL-6, and plasminogen activator inhibitor-1 and lower adiponectin than women in the control group.
No studies to our knowledge have measured associations between IGT and low-density lipoprotein, inflammatory markers, or adipokines, or with other metabolic markers beyond 3 months postpartum. We found that women with IGT during pregnancy had elevations of triglycerides, hemoglobin A1c and CRP, as well as lower HDL, after adjustment for current BMI and parental history of diabetes. Women with a history of gestational diabetes had triglyceride and HDL levels that were similar to those with IGT, but they had higher HOMA-IR and waist circumference, as well as lower adiponectin levels.
These adverse profiles of intermediate markers among women with pregnancy dysglycemia imply increased risk for cardiovascular disease, which is consistent with findings in a recent population-based cohort study.3 In that study, compared with women who did not undergo glucose tolerance testing during pregnancy and therefore were presumed to have had normal glucose challenge test results, women with both IGT and gestational diabetes were more likely to experience cardiovascular events (IGT odds ratio 1.19, 95% CI 1.02–1.39; gestational diabetes odds ratio 1.66, 95% CI 1.30–2.13).
Compared with women with normal glucose testing during pregnancy, we found that women with a history of gestational glucose intolerance had unfavorable markers of glucose and lipid homeostasis and inflammation. These findings persisted with adjustment for current BMI, suggesting that normal or overweight women with a history of IGT may be at risk for metabolic dysfunction at 3 years postpartum. These women therefore may benefit from dietary changes, physical activity, or screening for metabolic syndrome. Current guidelines recommend screening women with a history of gestational diabetes for noninsulin-dependent diabetes mellitus.26,27
In conclusion, in a prospective study of maternal and infant health, we found that maternal gestational glucose intolerance and gestational diabetes were both associated with adverse metabolic profile at 3 years postpartum, independent of other clinical risk factors.
1. Kim C, Newton KM, Knopp RH. Gestational diabetes and the incidence of type 2 diabetes: a systematic review. Diabetes Care 2002;25:1862–8.
2. Heitritter SM, Solomon CG, Mitchell GF, Skali-Ounis N, Seely EW. Subclinical inflammation and vascular dysfunction in women with previous gestational diabetes mellitus. J Clin Endocrinol Metab 2005;90:3983–8.
3. Retnakaran R, Shah BR. Mild glucose intolerance in pregnancy and risk of cardiovascular disease: a population-based cohort study. CMAJ 2009;181:371–6.
4. HAPO Study Cooperative Research Group, Metzger BE, Lowe LP, Dyer AR, Trimble ER, Chaovarindr U, et al.. Hyperglycemia and adverse pregnancy outcomes. N Engl J Med 2008;358:1991–2002.
5. Retnakaran R, Qi Y, Sermer M, Connelly PW, Hanley AJ, Zinman B. Glucose intolerance in pregnancy and future risk of pre-diabetes or diabetes. Diabetes Care 2008;31:2026–31.
6. Retnakaran R, Qi Y, Sermer M, Connelly PW, Zinman B, Hanley AJ. Isolated hyperglycemia at 1-hour on oral glucose tolerance test in pregnancy resembles gestational diabetes mellitus in predicting postpartum metabolic dysfunction. Diabetes Care 2008;31:1275–81.
7. Retnakaran R, Qi Y, Sermer M, Connelly PW, Hanley AJ, Zinman B. An abnormal screening glucose challenge test in pregnancy predicts postpartum metabolic dysfunction, even when the antepartum oral glucose tolerance test is normal. Clin Endocrinol (Oxf) 2009;71:208–14.
8. Retnakaran R, Qi Y, Connelly PW, Sermer M, Zinman B, Hanley AJ. Glucose intolerance in pregnancy and postpartum risk of metabolic syndrome in young women. J Clin Endocrinol Metab 2010;95:670–7.
9. Carr DB, Newton KM, Utzschneider KM, Tong J, Gerchman F, Kahn SE, et al.. Modestly elevated glucose levels during pregnancy are associated with a higher risk of future diabetes among women without gestational diabetes mellitus. Diabetes Care 2008;31:1037–9.
10. Gillman MW, Rich-Edwards JW, Rifas-Shiman SL, Lieberman ES, Kleinman KP, Lipshultz SE. Maternal age and other predictors of newborn blood pressure. J Pediatr 2004;144:240–5.
11. Herring SJ, Oken E, Rifas-Shiman SL, Rich-Edwards JW, Stuebe AM, Kleinman KP, et al.. Weight gain in pregnancy and risk of maternal hyperglycemia. Am J Obstet Gynecol 2009;201:61 e1–7.
12. Stuebe AM, Kleinman K, Gillman MW, Rifas-Shiman SL, Gunderson EP, Rich-Edwards J. Duration of lactation and maternal metabolism at 3 years postpartum. J Womens Health (Larchmt) 2010;19:941–50.
13. Schwartz MW, Niswender KD. Adiposity signaling and biological defense against weight gain: Absence of protection or central hormone resistance? J Clin Endocrinol Metab 2004;89:5889–97.
14. Antuna-Puente B, Feve B, Fellahi S, Bastard JP. Adipokines: the missing link between insulin resistance and obesity. Diabetes Metab 2008;34:2–11.
15. Poykko SM, Kellokoski E, Horkko S, Kauma H, Kesaniemi YA, Ukkola O. Low plasma ghrelin is associated with insulin resistance, hypertension, and the prevalence of type 2 diabetes. Diabetes 2003;52:2546–53.
16. Karra E, Chandarana K, Batterham RL. The role of peptide YY in appetite regulation and obesity. J Physiol 2009;587(Pt 1):19–25.
17. Stuebe AM, Mantzoros C, Kleinman K, Gillman MW, Rifas-Shiman S, Gunderson EP, et al.. Duration of lactation and maternal adipokines at 3 years postpartum. Diabetes 2011;60:1277–85.
18. Greenland S. Dose-response and trend analysis in epidemiology: alternatives to categorical analysis. Epidemiology 1995;6:356–65.
19. Neter J, Kutner M, Nachtsheim C, Wasserman W. Applied linear statistical models. 4th ed. Boston (MA): WCB/McGraw-Hill; 1996.
20. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care 2010;33:S62–9.
21. Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome among US adults: Findings from the third National Health and Nutrition Examination Survey. JAMA 2002;287:356–9.
22. Costacou T, Bosnyak Z, Harger GF, Markovic N, Silvers N, Orchard TJ. Postpartum adiponectin concentration, insulin resistance and metabolic abnormalities among women with pregnancy-induced disturbances. Prev Cardiol 2008;11:106–15.
23. Retnakaran R, Hanley AJ, Raif N, Hirning CR, Connelly PW, Sermer M, et al.. Adiponectin and beta cell dysfunction in gestational diabetes: pathophysiological implications. Diabetologia 2005;48:993–1001.
24. Choi SH, Kwak SH, Youn BS, Lim S, Park YJ, Lee H, et al.. High plasma retinol binding protein-4 and low plasma adiponectin concentrations are associated with severity of glucose intolerance in women with previous gestational diabetes mellitus. J Clin Endocrinol Metab 2008;93:3142–8.
25. Vambergue A, Dognin C, Boulogne A, Rejou MC, Biausque S, Fontaine P. Increasing incidence of abnormal glucose tolerance in women with prior abnormal glucose tolerance during pregnancy: DIAGEST 2 study. Diabet Med 2008;25:58–64.
26. American Diabetes Association. Gestational diabetes mellitus. Diabetes Care 2004;27(90001):88S–90.
© 2011 by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.
27. Postpartum screening for abnormal glucose tolerance in women who had gestational diabetes mellitus. ACOG Committee Opinion No. 435. American College of Obstetricians and Gynecologists. Obstet Gynecol 2009;113:1419–21.