PROJECT SUMMARY/ABSTRACT Gestational diabetes (GDM) complicates 10% of pregnancies in the US annually and is rising dramatically as a result of the obesity epidemic. GDM and the resulting maternal hyperglycemia lead to significant maternal and neonatal complications that can be reduced with glycemic control. The extent of treatment needed is based on maternal glycemic response to medical nutrition therapy (MNT) and exercise; yet at least 30-50% of patients will fail the initial trial of MNT and exercise and subsequently require pharmacotherapy. It is crucial to note, that the definition of what constitutes an unsuccessful attempt at MNT and exercise has not been established. Consequently, initiation of pharmacotherapy is at a provider’s discretion with a wide variation in practice. We recently demonstrated this variation in a national survey of 452 Maternal-Fetal Medicine providers (MFMs), with >80% of MFMs requesting evidence-based recommendations to guide initiation of pharmacotherapy. We also showed that earlier pharmacotherapy initiation at 20% elevated glucose values improved composite neonatal outcome. However, such intensified treatment could also increase the risk of a small-for-gestational age and may carry a negative impact on patient reported outcomes such as anxiety, depression and stress. Finally, the lack of standardized guidelines for pharmacotherapy initiation may introduce biases and lead to a variation in healthcare delivery by race and ethnicity. Therefore, there is a critical need to address this major gap in clinical practice of GDM and investigate the efficacy, safety, and patient reported outcomes of earlier pharmacotherapy initiation for GDM. We plan to address this gap with GDM and Pharmacotherapy (GAP) study, a randomized controlled trial of 416 patients with GDM that will compare two thresholds (20% vs. 40%) of elevated glucose values prior to insulin initiation. Our central hypothesis is that initiating insulin earlier, defined as 20% elevated glucose values, compared with controls, defined as 40% elevated glucose values, will result in reduced GDM-related adverse outcomes and disparities in GDM management, without adverse health consequences. Our hypothesis has been formulated based on our pilot data favoring the 20% threshold for clinical outcomes. The active control group chosen to be 40% based on our survey results demonstrating that 75% of MFMs start pharmacotherapy at 40% elevated glucose values. We will pursue the following three specific aims:1) Determine the effect of earlier insulin initiation for GDM management on adverse neonatal and maternal outcomes associated with GDM; 2) Assess the safety of earlier insulin initiation in pregnant patients and their neonates; and 3) Determine the effect of earlier insulin initiation on patient-reported outcomes using standardized measures and qualitative interviews. The GAP study will provide a high-level evidence for pharmacotherapy initiation in GDM and will have a direct impact on clinical practice. If proven effective and safe, earlier pharmacotherapy initiation will improve the health of pregnant patients and their offspring and will promote standardization of GDM management.

PROJECT NARRATIVE Gestational Diabetes and Pharmacotherapy (GAP) study is a randomized controlled trial that will investigate the optimal glycemic threshold for pharmacotherapy addition to medical nutrition therapy in GDM. The GAP study will promote standardization in GDM management and will have direct relevance for clinical practice.