In a large population of women diagnosed with GDM requiring medical therapy, we report that treatment with glyburide is associated with increased risk of undesirable perinatal outcomes, including higher birthweight or macrosomia, neonatal admissions to the intensive care nursery, as well as PTD and IUFD in some subsets of higher-risk populations. While most prior studies which compared oral hypoglycemic agents to subcutaneous insulin have focused on the efficacy of glyburide for glycemic control in women with GDM [11
], the association between glyburide and perinatal outcome has not been examined in depth. Some of these studies have reported higher rates of preeclampsia, neonatal hyperbilirubinemia requiring phototherapy, longer stay in the intensive care nursery [12
], macrosomia, and neonatal hypoglycemia [13
] in women who were treated with glyburide; however, these important findings were not further explored. Our study findings confirmed that the use of glyburide in women with GDM is associated with several undesirable neonatal outcomes.
Although we observed a modest increase in the risk of macrosomia and NICU admissions in women treated with glyburide, we did not have information regarding the occurrence of neonatal hypoglycemia. Besides the short-term implications of macrosomia, it has been reported that children born to women with GDM who were LGA at birth are at significantly increased risk of childhood metabolic syndrome with an onset as early as 6 years of age [19
]. With respect to clinical utility, we attempt to estimate the number needed to treat from the adjusted odds ratios of our regression model for macrosomia. According to this analysis, the baseline frequency of macrosomia was 13%; if women treated with oral agents have 29% greater odds of having infants with macrosomias compared to insulin, the number needed to treat in order to avoid one case of macrosomia is 30. While this estimate may not be generalizable across all population, it is a relatively small number that may potentially have large impact on the long-term health in the children of diabetic mothers.
The American Diabetes Association (ADA) has cautioned that the use of glyburide for the treatment of GDM awaits larger studies to establish its safety [6
], and the most recent ACOG practice guidelines state that subcutaneous insulin remains as the standard of care in women with GDM requiring medical therapy [1
]. Yet, the utilization of oral hypoglycemic agents, particularly glyburide, has become an increasingly common practice [20
]. Nearly one in five women with GDM was treated with glyburide in our cohort. Maternal characteristics associated with higher use of oral hypoglycemic agents included multiparity, Asian race/ethnicity, normal or low BMI, GA at GDM diagnosis between 20 and 32 weeks, less than high school education, and non-English as primary language. Further, in this cohort, we observed that a high proportion (39%) of women who were started on glyburide for treatment of GDM on initial visit was eventually placed on insulin therapy. While the precise reason for this crossover is uncertain, it is likely due to either intolerance of side effect or suboptimal glycemic control as previously reported by other studies [11
]. Thus, it appeared that for the cohort of high-risk women who likely have overt hyperglycemia requiring medical therapy at time of GDM diagnosis, there is a high likelihood of need for insulin therapy.
Likely, treatment allocation is not random and clinicians may be more inclined to prescribe oral hypoglycemic agents to women considered at lower risk of insulin resistance given the reported ‘failure’ rate of glyburide of around 20% [11
]. As our study was not a randomized trial, this difference in treatment allocation made the use of multivariable regression paramount in examining the outcomes associated with glyburide as compared to insulin.
In women who were diagnosed with GDM early in gestation (<24 weeks), glyburide use, compared to insulin, was associated with higher risk of macrosomia/LGA and IUFD. In this high-risk population, we speculate that suboptimal glycemic control and adverse outcomes are more likely with glyburide use.
We observed that the two groups of women who either did not attend high school, or do not speak English as their primary language, were more likely to receive glyburide as opposed to insulin. While it may be that these women were more likely to decline insulin therapy secondary to socio-cultural differences or perceptions regarding insulin, we also speculate that providers may have lacked the resources to adequately teach insulin administration to non-English speakers and/or were concerned about the ability of these women to self-administer insulin injections once appropriately taught. Despite these differences, when the subsets of women with lower education or who did not report English as their primary language were analyzed, those treated with glyburide had worse perinatal outcome compared to those who received insulin.
Our study has limitations. First, treatment for a large proportion of the women in this cohort was designated as ‘oral hypoglycemic agents;’ however, of the women for whom we did have such information, nearly 99% were treated with glyburide. Prior to and during the study period, most studies on oral agents focused on glyburide, as no other agents have been shown to be safe and effective [1
] until a recent large study on metformin use in GDM became available in 2008 [21
]. Therefore, we speculate that nearly all women in this cohort who were treated with oral hypoglycemic agents received glyburide, with very few receiving metformin or other oral hypoglycemic agents. Of note, this limitation would only appear to bias our results toward the null as the most recent randomized controlled trial of metformin versus insulin was adequately powered and demonstrated no differences in outcomes between the two groups. Another limitation of our study is that there are a number of factors and outcomes often associated with diabetes in pregnancy which we could not examine, including prior history of macrosomia, presence of coexisting medical morbidity such as chronic hypertension, details of labor/delivery, and complications often related to hyperglycemia. While preexisting medical condition would have been interesting to examine as potential effect modifiers, we believe that they would not be associated with the exposure of interest (treatment modality of GDM for our study), and thus, by definition of confounding bias, they would likely not have biased our study results. Additionally, we did not have information regarding the degree of glycemic control or whether treatment was changed during pregnancy, since treatment groups were categorized based on treatment modality at the last Sweet Success visit. Thus, a small proportion of women who were initially started on oral hypoglycemic agents but subsequently switched to insulin were analyzed as belonging to the insulin group. Although this misclassification could be bi-directional, likely much fewer women who were started on insulin would be switched to oral agents. In this setting, the misclassification likely should bias our results toward the null. Since we consistently observed that glyburide was associated with undesirable outcomes, our findings are likely valid and may underestimate the true differences.
Our observational study design may be prone to confounding bias. Although we used statistical techniques to control for potential confounders, there may be residual confounding for which we could not observe or did not control for. Ideally, a large, double-blinded, randomized controlled trial would more accurately evaluate the causal association between glyburide for the treatment of GDM and perinatal outcomes. Specifically, assuming a 50% risk reduction, with a probability of event at 10%, the RCT would require 686 women in each arm to achieve 80% power. Until such information is available, the efficacy of glyburide remains debatable and subcutaneous insulin should remain the standard of care for the treatment of women with GDM requiring medical therapy.