In this report, we demonstrate that standard antepartum screening for GDM identifies four metabolically distinct glucose tolerance groups in pregnancy whose differences in insulin sensitivity, β-cell function, and glucose handling persist at 3 months postpartum. Indeed, the prevalence of postpartum glucose intolerance progressively increases across these four groups. Most importantly, any degree of abnormal glucose homeostasis in pregnancy (i.e., not just GDM) independently predicts glucose intolerance at 3 months postpartum. Thus, antepartum GDM screening provides an opportunity to obtain insight into a women's future risk of pre-diabetes and type 2 diabetes.
Women with GDM, who have chronic insulin resistance and a chronic defect in their insulin secretion-sensitivity relationship, are identified on the basis of hyperglycemia on glucose tolerance testing in pregnancy. The current data demonstrate that standard GDM screening can actually identify four distinct groups with differences in insulin sensitivity, β-cell function, and glycemia in pregnancy. Specifically, compared with normal GCT NGT, GDM and GIGT were associated with lower insulin sensitivity, poorer β-cell function, and greater glycemia. In addition, abnormal GCT NGT was associated with greater glycemia (AUCgluc) than normal GCT NGT, although significant differences in insulin sensitivity and β-cell function were not detected with the measures used in this study.
The significance of this readily achievable identification of these four groups (through standard clinical care with GCT and OGTT) becomes apparent when one considers that the metabolic differences between these groups persist into the postpartum period. Importantly, the current data demonstrate that even mild glucose intolerance in pregnancy portends an increased risk of glucose intolerance postpartum. In particular, women with GIGT are clearly distinct from those with normal GCT NGT, on the basis of lower insulin sensitivity, poorer β-cell function, and greater glycemia. Furthermore, as in pregnancy, the abnormal GCT NGT group exhibited greater glycemia (AUCgluc) than the normal GCT NGT group, with no detectable dissimilarity in β-cell function, suggestive of a persistent difference in glucoregulation between these groups (the pathophysiologic basis of which remains unclear). Indeed, the abnormal GCT NGT and GIGT groups exhibited surprisingly high rates of pre-diabetes/diabetes at 3 months postpartum (10.2 and 16.5%, respectively). This relationship has escaped clinical attention to date because it is driven largely by the high prevalence of IGT in these groups. As such, in the absence of systematic evaluation of postpartum glucose intolerance by OGTT, as in this study, the high rates of pre-diabetes would not be detected.
The identification of pre-diabetes is important because up to 70% of affected individuals may eventually develop type 2 diabetes (15
). Thus, the high rates of pre-diabetes in the three categories of abnormal antepartum glucose homeostasis suggest that the young women in these groups have an increased risk of future type 2 diabetes. Although this risk is well established for women with GDM (2
), there has been limited study of this issue in women with lesser degrees of glucose intolerance in pregnancy. Recently, Vambergue et al. (20
) reported that GIGT was independently associated with glucose intolerance at 6.75 years postpartum, with an adjusted OR of 4.57 (95% CI 1.47–14.22), which was similar to that reported herein. Furthermore, based on administrative data, Carr et al. (21
) recently reported that women with a history of GIGT have an increased risk of developing diabetes. Importantly, the current study extends these findings by 1
) careful stratification of subjects into four glucose tolerance groups in pregnancy (with GCT and OGTT in all subjects), 2
) use of a prospective study design with ascertainment of postpartum glucose tolerance status by OGTT in all subjects, 3
) the demonstration of significant differences in insulin sensitivity and β-cell function between the groups, and 4
) the demonstration that even abnormal GCT NGT (i.e., a milder abnormality than GIGT) independently predicts postpartum glucose intolerance.
The significance of our study rests in its illustration of the concept that the spectrum of abnormal glucose homeostasis in pregnancy identifies a continuum of risk for postpartum glucose intolerance and that this spectrum extends to levels of antepartum dysglycemia far less severe than GDM. Interestingly, our demonstration that, compared with their truly normal peers with normal GCT NGT, women with GIGT and even those with abnormal GCT NGT have metabolic perturbations that translate into an increased risk of postpartum glucose intolerance is consistent with an emerging body of literature indicating that these two groups (like women with GDM) have an enhanced risk of adverse obstetrical outcomes (22
). These obstetrical data have posed the question as to whether glucose-lowering treatment in pregnancy, as prescribed for GDM, should be instituted for these groups of women. In the same way, the current data raise the possibility that postpartum follow-up for diabetes surveillance (as is currently recommended after GDM) should be considered for women with GIGT and possibly those with abnormal GCT NGT. The importance of this question is underscored by the fact that the population in question is young women of child-bearing age, in whom early detection and/or prevention of diabetes could have enormous public health implications. Further long-term follow-up will be needed, with a particular emphasis on the cost-benefit implications of any postpartum screening strategies under consideration.
A limitation of the current study is that the CIs surrounding the adjusted ORs in the logistic regression analysis of postpartum glucose intolerance are relatively wide, probably reflecting limitations in power. Nevertheless, our findings are supported by the complete consistency of the associations between each abnormal glucose tolerance group in pregnancy and 1) postpartum glycemia (both glucose intolerance and AUCgluc), 2) insulin resistance, and 3) β-cell dysfunction. Furthermore, although the other independent determinants of postpartum AUCgluc did not persist as significant predictors of the categorical outcome of postpartum glucose intolerance, it should be noted that the three abnormal glucose tolerance groups in pregnancy were the only significant independent predictors of both the continuous and the categorical measure of postpartum glycemia (supplemental Table). A second limitation is that this analysis was performed in the first 487 women who returned for their study visit at 3 months postpartum, representing nearly 70% retention of the originally recruited cohort. Although we cannot fully exclude the possibility that loss-to-follow-up may have biased the study groups in some way, it is encouraging that the women who did not return were similar to the participants who did return with respect to demographic and clinical features, including ethnicity, family history of diabetes, and BMI at 3 months (determined from weight reported on telephone questionnaire follow-up with nonreturners). Furthermore, the retention of a large number of subjects within each of the four baseline glucose tolerance groups also supports the relevance of this analysis.
In summary, standard antepartum screening for GDM identifies four metabolically distinct glucose tolerance groups in pregnancy, whose differences in insulin sensitivity, β-cell function, and glucose tolerance persist at 3 months postpartum. Importantly, any degree of abnormal glucose homeostasis in pregnancy (i.e., not just GDM) independently predicts glucose intolerance at 3 months postpartum. Thus, clinical screening for GDM, as currently practiced, provides an opportunity to obtain insight into a woman's future risk of pre-diabetes and type 2 diabetes, information that may have implications for diabetes surveillance and prevention.