The National Institute of Child Health and Human Development Maternal-Fetal Medicine Unit Network randomized clinical trial in progress: Standard therapy versus no therapy for mild gestational diabetes

There is apparent widespread acceptance of universal laboratory screening for GDM in the U.S., despite both the 2001 ACOG Technical Bulletin on Gestational Diabetes and the Fourth International Workshop-Conference on Gestational Diabetes failing to endorse this practice (4,18). The clinical dilemma of GDM was summarized during the Fourth International Workshop-Conference, which concluded that "although there is a general consensus that prevalence of GDM is increasing globally, there is considerable controversy about the clinical importance of GDM and the magnitude of its impact on mother and offspring" (14,18). Similarly, the Canadian Task Force on Periodic Health Examination stated that "further research is needed to establish the relative risk of neonatal and perinatal illness in relation to various degrees of sub-diabetic elevations in maternal blood glucose levels. The quality of available evidence cannot support a recommendation to include universal screening for gestational diabetes" (15). Instead, this panel suggested that a decision to proceed with screening for this diagnosis must be made on other nonspecific grounds. This vague recommendation was accompanied by an admission that the Task Force recognized that a proportion of women with various degrees of carbohydrate intolerance during pregnancy will have adverse outcomes and might benefit from screening. In 2003, the U.S. Preventative Services Task Force acknowledged that no well-conducted randomized controlled trial existed that provided direct evidence for the health benefits of screening for GDM (2). Whereas insulin therapy may decrease the incidence of fetal macrosomia in those pregnancies complicated by significant hyperglycemia, the magnitude of any effect on maternal and neonatal health remains uncertain. Moreover, the Task Force report noted that insufficient evidence exists to determine if a health benefit accompanies treatment for the large number of women with GDM with milder degrees of hyperglycemia. A randomized controlled trial is necessary to answer this question (2). With mild GDM affecting 1-3% of pregnancies, ∼50-100,000 women annually are being identified and treated for this diagnosis, making this an important clinical issue. Most recently, Crowther et al. (19) reported results on a 10-year multicenter randomized trial designed to determine whether treatment of GDM reduces the risk of perinatal complications. The primary outcome of this study was a composite of perinatal morbidity and mortality (stillbirth, shoulder dystocia, bone fractures, nerve palsy, neonatal intensive care unit admission, and jaundice). The authors found the composite rate of "serious" perinatal complications was lower among the infants of the 490 treated women compared with the 510 infants in the routine care group (1 vs. 4%). This study represents the first large-scale randomized treatment trial for GDM. The sample size is remarkably similar to the ongoing MFMU trial; however, the Crowther study is different with respect to design and analysis of outcome data. Most importantly, the criteria used for the Crowther study include women with more significant hyperglycemia than the MFMU trial. Thus, our study should provide additional information regarding the effect of treatment of women with milder GDM. The perinatal outcome composite in Crowther's study includes shoulder dystocia, a subjective diagnosis, which in turn weighed heavily on the composite difference observed among study groups. An increased rate of admission to the neonatal intensive care unit was observed in the treatment group; however, no difference was observed in the rate of hypoglycemia (secondary outcome) requiring intravenous therapy. Finally, details regarding several antepartum stillbirths suggest these may not have been related to untreated GDM such that the overall conclusion of a reduction in "serious" perinatal complications in treated GDM must be interpreted with caution. In contrast to the Crowther study, the MFMU Network trial primary outcome includes two markers of fetal response to maternal hyperglycemia: neonatal hypoglycemia and cord C-peptide levels. These outcomes should allow for a meaningful interpretation of any treatment effect in the subset of GDM with mild disease. To date, few additional studies have examined the effectiveness of intensive treatment among women with mild GDM. A summary of four trials including 612 women with mild GDM found no benefit in dietary treatment in preventing adverse health outcomes (20). The ongoing population-based Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study is designed to determine levels of carbohydrate intolerance during pregnancy associated with adverse perinatal outcomes. Specifically, at what level of maternal glycemia is there fetal and/or maternal risk? A continuum of risk is anticipated as a likely result in the Hyperglycemia and Adverse Pregnancy Outcome study. The previously cited Crowther study and the ongoing MFMU trial address whether treatment of GDM is effective at reducing perinatal risk. Given that the MFMU Network trial considers only women with normal fasting glucose levels, it should help clarify whether a benefit exists to treatment of mild GDM. The trial should also complement the Hyperglycemia and Adverse Pregnancy Outcome study data in arriving at some consensus for selecting thresholds for diagnosis and treatment of carbohydrate intolerance during pregnancy.