Gestational diabetes mellitus (GDM) occurs in 1–14% of pregnancies in the United States.1 Up to 60% of women with a history of GDM will develop type 2 diabetes mellitus (DM) within 5–10 years postpartum.2 Identifying women with GDM at the highest risk of progressing to type 2 DM, impaired fasting glucose, or impaired glucose tolerance and providing them with appropriate tools for healthy lifestyle changes can reduce the incidence of type 2 DM.3
Hemoglobin A1c (HbA1c), a hemoglobin variant, is an accepted and standardized measure of glycemic control. Compared with plasma glucose, HbA1c has less intraindividual variability,4 is easily measured with a single blood test, and does not require fasting, consumption of a concentrated glucose beverage; or multiple blood draws. Reasons for reluctance in adopting HbA1c during pregnancy as a measure of maternal glycemic control include the scarcity of published reports that account for the effect of pregnancy-associated metabolic and hematologic changes on the interpretation of HbA1c values in pregnant patients.5,6
Previously, some studies of women with GDM reported that higher HbA1c is associated with postpartum type 2 DM, impaired fasting glucose, or impaired glucose tolerance,7–10 but at least one study did not find such an association.11 We conducted a retrospective cohort study of patients with GDM to determine the extent to which, if at all, higher HbA1c values, determined at the time of GDM diagnosis, are associated with an increased risk of postpartum impaired fasting glucose, impaired glucose tolerance, or any glucose abnormality, including type 2 DM.
MATERIALS AND METHODS
This study was conducted in a large diabetes and pregnancy program located in Charlotte, North Carolina, which is a consortium of two clinics. Clinic A, housed within the main medical center, provides comprehensive education and care for women with type 1 DM, type 2 DM, and GDM and serves a primarily white, privately insured population. Clinic B provides obstetric care for women with and without diabetes in pregnancy. The majority of patients at clinic B are racial or ethnic minorities and are enrolled in Medicaid or lack insurance. These two clinics, located within 1 mile of each other, use a common GDM clinical management protocol developed by the Medical Director, a board-certified endocrinologist (E.M.). The program serves all of Mecklenburg County and the nine surrounding counties.
Typically women are referred to one of the two diabetes and pregnancy program clinics at 24–28 weeks of gestation after a positive 50-g oral glucose challenge and a positive 3-hour 100-g oral glucose tolerance test (OGTT).12 Hemoglobin A1c and other laboratory tests are performed at or near the first appointment at clinic A and at or near the time of GDM diagnosis at clinic B. At both clinics women considered at particularly high risk for GDM may be referred earlier in their pregnancy with or without GDM screening. Additionally, women may be diagnosed with GDM and referred to the diabetes and pregnancy program at any point in their pregnancy after an extremely elevated glucose challenge test or random blood glucose. Women are encouraged to undergo a postpartum 2-hour 75-g OGTT approximately 6 weeks after delivery in keeping with guidelines published by multiple organizations.1,13 Orders for the postpartum OGTT are usually written at the patient's final antepartum visit to the diabetes and pregnancy program or while hospitalized in the immediate postpartum period.
Women treated for GDM who delivered a live singleton neonate between November 15, 2000, and April 15, 2010, were eligible for inclusion in the study. Additional inclusion criteria were: diagnosed with GDM at 24 weeks of gestation or greater by a 3-hour 100-g OGTT, a glucose challenge test 200 mg/dL or higher, or a random blood glucose 160 mg/dL or higher and completion of a postpartum 2-hour 75-g OGTT. Study exclusion criteria were: established type 1 or type 2 DM, GDM diagnosis at less than 24 weeks of gestation, untreated endocrinopathies (hyperadrenalism, hypoadrenalism, hyperthyroidism, hypothyroidism, and acromegaly), hemoglobin variants (HbS, HbC, HbF, and HbE) or conditions (uremia, thalassemia) that impair interpretation of HbA1c, first HbA1c measurement more than 4 weeks after the initial visit to the diabetes and pregnancy program, use of medications at the time of postpartum OGTT that affect glucose tolerance (metformin, glyburide, steroids, hydrochlorothiazide), and pregnant at the time of the postpartum OGTT. The institutional review boards of the University of Washington and Carolinas HealthCare System approved the protocol for this study.
The clinics measured HbA1c and plasma glucose, the laboratory measures for this study using different methods. Using point-of-care instruments, clinic A measured HbA1c with a DCA 2000 and measured whole blood glucose with a HemoCue B-Glucose Analyzer. All glucose values measured by the HemoCue B-Glucose Analyzer were converted from whole blood to plasma glucose before glucose status determination. The HemoCue B-Glucose Analyzer is highly accurate, with a Pearson correlation of 0.98 to standard laboratory measures14 and is considered appropriate for diagnosis of diabetes in epidemiologic studies.15,16 Clinic B sends all samples to the main laboratory for analysis; at the main laboratory, HbA1c was measured by high-performance liquid chromatography using a Diabetes Complications and Control Trial aligned method, and plasma glucose was measured by an oxygen rate method using the SYNCHRON System. The laboratory method and point-of-care method for HbA1c measurement are highly correlated with a reported Pearson correlation of greater than 0.9 and the DCA 2000 has been certified by the National Glycohemoglobin Standardization program to conform to the results of the Diabetes Complications and Control Trial.17–20
The primary exposure was the first HbA1c, measured and recorded at one of the two diabetes and pregnancy program clinics, within 4 weeks of GDM diagnosis. Key covariates included variables related to maternal demographics; medical and obstetric history; and pregnancy, delivery, and postpartum characteristics. Demographic variables included: clinic (clinic A, clinic B), maternal age at GDM diagnosis, parity (parous, nulliparous), insurance (private insurance, self-pay, or Medicaid), maternal race or ethnicity (white, nonwhite race or ethnicity), and prepregnancy overweight or obesity based on body mass index (BMI, calculated as weight (kg)/[height (m)]2) as calculated from height, measured by clinic staff, and patient-reported prepregnancy weight (BMI less than 25, BMI 25 or greater).21,22 Medical and obstetric history variables included: history of GDM, history of preeclampsia or eclampsia, history of polycystic ovary syndrome, history of spontaneous abortion, and history of intrauterine fetal demise. Pregnancy, delivery, and postpartum variables included: gestational week at first HbA1c as recorded on the medical chart based either on ultrasonography or on last menstrual period, method of GDM diagnosis (OGTT, glucose challenge test 200 mg/dL or higher, or random blood glucose 160 mg/dL or higher), treatment for management of GDM (diet only; insulin, glyburide, insulin, metformin, or combination), gestational week at delivery (calculated from date of delivery, gestational week at last clinic visit, and date of last clinic visit), preterm delivery (delivery at less than 37 weeks of gestation), and breastfeeding (yes, no).
The primary outcomes were postpartum impaired fasting glucose (with or without impaired glucose tolerance), impaired glucose tolerance (with or without impaired fasting glucose), and any postpartum abnormal glucose, including type 2 DM, as diagnosed by a 2-hour 75-g OGTT test according to the 1997 American Diabetes Association criteria.12 Women were considered to have normal glucose if fasting plasma glucose was less than 100 mg/dL and 2-hour plasma glucose was less than 140 mg/dL. Women with fasting plasma glucose 100 mg/dL or greater and less than 126 mg/dL were categorized as impaired fasting glucose and women with 2-hour plasma glucose 140 mg/dL or greater and less than 200 mg/dL were categorized as impaired glucose tolerance. Women with fasting plasma glucose 126 mg/dL or greater or 2-hour plasma glucose 200 mg/dL or greater were categorized as type 2 DM.
A parametric survival time model23 with an exponential distribution and robust standard errors was used to analyze the association between increasing HbA1c quartile and risk of postpartum abnormal glucose. The exponential distribution assumes a constant hazard over time. All analyses were completed using STATA 9 software24 and a user-defined module for interval censored data that fits distributions to data by maximum likelihood.23 The time scale was weeks since delivery. All women had a start time of date of delivery. Women who did not have impaired fasting glucose, impaired glucose tolerance, or type 2 DM at the time of postpartum testing were censored at the time of their postpartum OGTT. Women with impaired fasting glucose, impaired glucose tolerance, or type 2 DM at the time of the postpartum OGTT could have developed abnormal glucose tolerance at any time between delivery and postpartum OGTT and therefore their time to event was left-censored and fell between the date of delivery and postpartum OGTT.
Women were grouped according to HbA1c quartiles based on the distribution of HbA1c among all eligible women regardless of whether or not they completed a postpartum OGTT. The outcomes of impaired fasting glucose, impaired glucose tolerance, and any postpartum abnormal glucose were examined separately and as a combined outcome of any postpartum abnormal glucose. The primary measure was a test for trend25 in risk of postpartum abnormal glucose across increasing quartiles of HbA1c, which was conducted by assigning HbA1c quartiles values in ascending order from 1–4 and entering HbA1c quartile into the regression model as a continuous variable.25,26 Potential confounders were retained in the final model if their inclusion resulted in a greater than 10% change in estimate or if they were a priori considered important. Adjusted and unadjusted hazard ratios are reported along with their 95% confidence intervals and statistical significance was defined at the two-sided α level of .05.
To test if the association of HbA1c and postpartum impaired fasting glucose, impaired glucose tolerance, or any abnormal glucose differed by GDM treatment modality, method of GDM diagnosis, or race and ethnicity, interaction terms were introduced between these variables and quartile of HbA1c. The statistical significance of the interaction terms was assessed using the Wald test (z=estimate/SE).26
We reviewed 1,345 charts (clinic A n=701; clinic B n=644) and 536 (40%) met our eligibility criteria (Fig. 1). Among eligible women, 277 (clinic A n=163; clinic B n=114) completed a postpartum OGTT after delivery (median 7.9 weeks, interquartile range 6.6–9.4, range 3–111). Compared with women who did not complete a postpartum OGTT, women who completed a postpartum OGTT were more likely to have required insulin or oral hypoglycemic agents, but the two groups did not differ on any other demographic or clinical characteristics. Two women completed a postpartum OGTT but were missing information on prepregnancy BMI and were excluded from the analysis. The overall prevalence of any postpartum glucose abnormality was 42%: 42 (15%) women had isolated impaired fasting glucose, 28 (10%) had isolated impaired glucose tolerance, 33 (12%) had combined impaired fasting glucose and impaired glucose tolerance, and 15 (5%) had type 2 DM.
Demographic; medical and obstetric history; and pregnancy, delivery, and postpartum characteristics of the study population are described in Table 1. The majority of study participants were privately insured, of nonwhite race or ethnicity, and overweight or obese (BMI 25 or greater). The mean gestational age at first HbA1c was 30 weeks (standard deviation 2.4) and 74% were diagnosed by a 3-hour OGTT. Compared with women treated at clinic A, those treated at clinic B were less likely to be nulliparous or have private insurance but more likely to be of nonwhite race or ethnicity, to be overweight or obese, to have a history of GDM or preeclampsia, have higher HbA1c at GDM diagnosis, and to require insulin or oral hypoglycemics. Similarly, compared with women in the first HbA1c quartile, those in the second, third, and fourth quartiles were less likely to be nulliparous and more likely to be of nonwhite race or ethnicity, to be overweight or obese, and to require insulin or oral hypoglycemics.
As indicated in Table 2, the median time from delivery to postpartum OGTT was 7–8 weeks in all HbA1c quartiles. One woman who was included in the primary analysis had a postpartum OGTT 111 weeks after delivery; excluding her in a subsequent sensitivity analysis did not substantially change our results. Mean fasting plasma glucose increased from 93 mg/dL in the first HbA1c quartile to 103 mg/dL in the fourth HbA1c quartile. Mean 2-hour plasma glucose increased from 119 mg/dL in the first HbA1c quartile to 145 mg/dL in the fourth HbA1c quartile.
After adjustment for clinic, maternal age, parity, prepregnancy BMI 25 or greater, nonwhite race or ethnicity, and gestational week at first HbA1c, higher HbA1c quartile at GDM diagnosis was associated with an increased risk for impaired fasting glucose (P for trend=.01), impaired glucose tolerance (P for trend=.002), and any glucose abnormality (impaired fasting glucose, impaired glucose tolerance, or type 2 DM) (P for trend<.001) (Table 3). Compared with women in the first HbA1c quartile, women in the second quartile had an 1.90 times higher risk for impaired fasting glucose (95% confidence interval [CI] 0.99–3.67), those in the third quartile had a 1.96 times higher risk for impaired fasting glucose (95% CI 0.90–4.27), and those in the fourth quartile had 2.96 times higher risk for impaired fasting glucose (95% CI 1.35–6.46). Compared with women in the first HbA1c quartile, women in the second quartile had a 1.73 times higher risk for impaired glucose tolerance (95% CI 0.78–3.85), those in the third quartile had a 2.68 times higher risk of impaired glucose tolerance (95% CI 1.09–6.60), and those in the fourth quartile 4.05 times higher risk for impaired glucose tolerance (95% CI 1.66–9.89). Finally, compared with women in the first HbA1c quartile, women in the second quartile had a 1.68 times higher risk for any glucose abnormality (95% CI 0.94–2.98), those in the third quartile had a 2.29 times higher risk for any glucose abnormality (95% CI 1.22–4.32), and those in the fourth quartile had a 3.75 times higher risk for any glucose abnormality (95% CI 1.99–7.07). No statistically significant interactions were detected between HbA1c quartile and GDM diagnostic method, treatment modality, or nonwhite race or ethnicity.
Although we did not detect a statistically significant interaction between HbA1c 5.3% or greater and treatment modality (P=.35), the estimates began to diverge when stratifying by treatment (insulin or oral hypoglycemics: hazard ratio [HR] 2.12, 95% CI 1.16–3.87; diet only: HR 1.08, 95% CI 0.33–3.54). There was little evidence of heterogeneity of the association of HbA1c and postpartum abnormal glucose when stratifying by clinic and using a continuous measure of HbA1c (clinic A: HR 1.87, 95% CI 1.11–3.16; clinic B: HR 2.67, 95% CI 1.48–4.82).
This study found that higher HbA1c at GDM diagnosis is associated with increased risk of abnormal postpartum glucose. The overall prevalence of abnormal postpartum glucose is 42% in our study population. After adjustment, women in the highest HbA1c quartile (greater than 6.1) compared with those in the lowest quartile (less than 5.3) had a nearly fourfold higher risk of any postpartum abnormal glucose.
Our findings largely agree with previously published studies of HbA1c measured at GDM diagnosis and postpartum abnormal glucose.27 Both Oldfield9 and Ogonowski10 found that higher HbA1c at GDM diagnosis was associated with increased risk of postpartum abnormal glucose. More recently Ekelund et al28 found that in a 5-year follow-up study, HbA1c 5.7% or greater at GDM diagnosis was associated with a sixfold increased risk of postpartum diabetes. We also found that when combining women in the highest three HbA1c quartiles, women with HbA1c 5.3% or greater had a twofold increased risk for any abnormal postpartum glucose compared with women with HbA1c less than 5.3%. Use of the 5.7% threshold attenuated these findings (data not shown). Unlike Ekelund et al, we included impaired fasting glucose and impaired glucose tolerance and did not look exclusively at type 2 DM, and this may explain the slightly lower threshold that we found.
Over 62% of women in this study were of nonwhite race or ethnicity. Compared with whites, African Americans and Hispanics have higher average HbA1c.29 However, we did not detect a difference in the association of HbA1c and postpartum abnormal glucose by race or ethnicity.
Although antenatal HbA1c may influence a clinician's decision regarding initiation of insulin or oral hypoglycemic agents, women who require these medications constitute a population with greater underlying disease severity, and the association of HbA1c and postpartum abnormal glucose may differ among those with more severe GDM. Ogonowski et al report a stronger association of HbA1c and postpartum abnormal glucose among women requiring insulin compared with those who were treated with diet alone.10 We did not detect a statistically significant interaction between HbA1c 5.3% or greater and treatment modality, although the estimates began to diverge when stratifying by treatment.
Although impaired fasting glucose is characterized by hepatic insulin resistance and increased endogenous glucose output,30 insulin resistance of muscle tissue and impaired insulin secretion are characteristic of impaired glucose tolerance.31 Therefore, one might expect the association of HbA1c and abnormal postpartum glucose to differ for impaired fasting glucose and impaired glucose tolerance depending on the relative contributions of preprandial and postprandial glucose to HbA1c. However, we observed similar trends of increased risk for impaired fasting glucose and impaired glucose tolerance across quartiles of HbA1c.
Strengths of this study include: size and diversity of the population, detailed information regarding treatment modality, examination of impaired fasting glucose and impaired glucose tolerance as separate outcomes, and statistical analysis that accounted for both left and right censoring. Nevertheless, several limitations should be taken into consideration when interpreting our findings. We were unable to collect detailed information on indicators of socioeconomic status including income and level of education or health behaviors such as physical activity. However, all final models adjusted for clinic, which was strongly correlated to lack of private insurance and increased probability of obesity, both of which are correlated with lower socioeconomic status and unhealthy lifestyle behaviors.32
Adjustment for clinic also accounted for differences in methods used for measurement of both HbA1c and glucose.33,34 Although clinic A relied on capillary glucose, which has lower sensitivity for detecting type 2 DM16 compared with measurements of venous plasma glucose, little to no bias in the HRs would be expected given the high specificity of this method.35 Finally, the generalizability of our findings may have been limited by the failure of women to return for a postpartum OGTT. When we compared the characteristics of women who did and did not complete a postpartum OGTT, we found that compared with women who did not complete a postpartum OGTT, women who completed a postpartum OGTT were more likely to have required insulin or oral hypoglycemics but that the two groups did not differ on any other characteristics.
We found a consistent trend of increased risk of postpartum abnormal glucose across quartiles of HbA1c at GDM diagnosis. Our findings indicate that HbA1c can be a useful and generalizable measure for identifying patients with GDM at highest risk of postpartum abnormal glucose.
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