The findings of this study indicated that blood glucose levels throughout pregnancy of women with GDM were directly related to the risk of developing type 2 DM or prediabetes at 6 weeks postpartum. This association was independent of the glucose levels measured at the time of GDM diagnosis, as assessed by the 100-g OGTT values. Our observation suggests that not merely the presence of GDM, which is a well-known risk factor for type 2 DM [13], but also glycemic control plays an important role in modifying the risk of postpartum DM as well as prediabetes. Pregnant women with GDM should be educated about the benefits and targets of optimal glycemic control to decrease both intra- and postpartum adverse effects. Regular monitoring of plasma glucose levels and timely initiation of insulin therapy should be considered to maintain adequate glycemic control throughout pregnancy.
Furthermore, we found a direct association between the degree of suboptimal glycemic control, as characterized by the pattern of elevated fasting and postprandial glucose levels, and the development of DM or prediabetes postpartum. Risks of postpartum DM or prediabetes were increased by 3.7-fold among women with suboptimal control of either fasting or postprandial glucose and 5.9-fold among women with suboptimal control of both fasting and postprandial glucose compared to women with optimal glycemic control.
Two hypotheses have been proposed to explain the association between suboptimal glycemic control during GDM pregnancy and the development of postpartum type 2 DM or prediabetes. First, this may be related to the severity of chronic β-cell dysfunction and insulin resistance that manifests as hyperglycemia in pregnancy [9, 14, 15] and translates into a continuum of dysglycemia (prediabetes and type 2 DM) in the postpartum period or later in life [14, 15]. Saisho et al. [9], who used the disposition index to evaluate β-cell dysfunction, found an association of the level of β-cell dysfunction with the severity of glucose intolerance (assessed by the fasting and mean daily blood glucose levels) during pregnancy among Japanese women with GDM. Other authors also observed a correlation between the degree of glucose intolerance in pregnancy and the magnitudes of β-cell dysfunction and insulin resistance in Western pregnant women [14, 15]. Given that insulin secretory defects and insulin resistance are well recognized as precursors of type 2 DM and prediabetes [3, 4], the risk of developing either type of glucose intolerance postpartum was therefore higher in women with a more severe degree of suboptimal glycemic control during pregnancy than in those with a lesser extent of suboptimal glycemic control.
The second hypothesis is that chronic exposure of pancreatic islets to elevated glucose levels during pregnancy exerts toxicity on β-cells by oxidative stress, leading to more β-cell dysfunction and cell death and consequent prediabetes or type 2 DM after pregnancy [16, 17]. These cascade events were demonstrated in several studies that found a reduction in β-cell volume among patients with type 2 DM compared to nondiabetic subjects [18–21]. Nevertheless, such prior studies were limited by being a cross-sectional research design and not being conducted in vivo. Further longitudinal studies are therefore needed to compare the changes in β-cell mass over time from antepartum to postpartum among women with GDM who develop and do not develop postpartum DM or prediabetes.
Given that there have been no recommendations from the expert panels regarding plasma glucose thresholds during pregnancy that are related to a reduced risk of postpartum DM or prediabetes, we then adopted the fasting and postprandial glucose targets, as recommended by the ADA and ACOG to reduce the risk of macrosomia [10, 11], to classify the plasma glucose levels of women in this study as indicating optimal or suboptimal glycemic control. Previous studies have reported that intermittent high glucose levels rather than persistent hyperglycemia stimulate reactive oxygen species overproduction, β-cell apoptosis and dysfunction [22–24]. Hence, we focused on high blood glucose levels at different time points in preference over high mean blood glucose levels. With a fasting glucose level of 95 mg/dL or higher and/or 2-h postprandial glucose of 120 mg/dL or higher on at least two occasions, the predictive performance of these glucose thresholds for postpartum DM or prediabetes yielded moderate discriminatory power (an area under the ROC curve of 0.677). Aside from these glucose thresholds, two other studies that used different glucose thresholds to define suboptimal glycemic control during pregnancy also reported an increased risk of postpartum glucose intolerance or future type 2 DM among women with suboptimal glycemic control [7, 8]. When a comparison among the three glucose thresholds was made, we found that the thresholds used in our study yielded the best predictive performance for type 2 DM or prediabetes at 6 weeks postpartum. Our findings suggested that the fasting and 2-h postprandial glucose targets recommended by the ADA and ACOG to reduce the risk of macrosomia could also lessen the risk of developing postpartum DM or prediabetes.
Aside from type 2 DM, we also paid attention to the development of prediabetes because this metabolic state represents an intermediate hyperglycemic state for progression to type 2 DM [25]. As the lifetime risk of progressing from prediabetes to DM has been reported to be high at 74% [26], a reduced risk of postpartum prediabetes should be as important as that of type 2 DM. This study found that both spectra of glucose intolerance were significantly decreased with optimal glycemic control.
Notably, the present study focused specifically on the development of dysglycemia in the early postpartum period. Although data on the long-term impact of glycemic control during pregnancy on glucose intolerance are interesting, we were aware of other factors that may influence the risk of subsequent type 2 DM or prediabetes, such as diet and physical activity. A well-designed prospective study controlling all relevant factors with a long-term follow-up may be able to provide a definite answer regarding an association of glycemic control during pregnancy and the long-term risk of dysglycemia.
The strength of our study included having a large number of pregnant women with multiple fasting and postprandial blood glucose measurements throughout pregnancy. In addition, all blood glucose specimens collected in our institution were measured using the same automated glucose analyzer, which was calibrated regularly to obtain accurate results. Furthermore, the diagnoses of GDM and postpartum DM or prediabetes were made according to the standard guidelines. Nevertheless, there are a few limitations that one should bear in mind when applying our results in clinical practice. Although the mean blood glucose level may be more accurate in representing optimal or suboptimal blood glucose control, most women, especially those in limited-resource settings, may be unable to comply with frequent self-monitoring of their blood glucose levels. We therefore suggest a regular blood glucose measurement in the hospital to define optimal or suboptimal glycemic control. Second, our study was limited by being conducted in a single institution and by the use of Carpenter and Coustan criteria to diagnose GDM. We cannot confirm the generalizability of our results until further prospective studies are carried out in different settings.