The National Institute of Child Health and Human Development Maternal-Fetal Medicine Unit Network randomised clinical trial in progress

Department of Obstetrics, Ohio State University, Columbus, Ohio 43210-1228, USA.
Diabetes care (Impact Factor: 8.42). 08/2007; 30 Suppl 2(Supplement 2):S194-9. DOI: 10.2337/dc07-s215
Source: PubMed


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.

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    ABSTRACT: Mothers with gestational diabetes mellitus (GDM) are at high lifetime risk of developing type 2 diabetes mellitus. The magnitude of risk for cardiovascular disease after GDM is less well established. Recently, intervention trials using lifestyle modification or medications used to treat type 2 DM have successfully prevented/delayed development of DM in women after GDM. Offspring of mothers with GDM are at risk for development of obesity and abnormal glucose metabolism during childhood, adolescence, and adulthood. Factors responsible for these risks are not fully understood. Having fetal hyperinsulinism is a risk factor for development of both obesity and abnormal glucose metabolism, and might be implicated in pathophysiology. It remains to be established whether the long-term effects of exposure to diabetes mellitus during intrauterine development can be prevented.
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    ABSTRACT: The incidence of gestational diabetes has duplicated in the last decade, which is attributable to increased obesity and its association with the metabolic syndrome and DM2. Gestacional diabetes occurs mainly in women with risk factors that can be easily identified and those whose normal pregnancy changes increase insulin resistance and glucose, rates which affects the evolution of her product and may result in macrosomia. Maternal physiologic changes during the first half of pregnancy accounts for a higher storing of energy, more evident at fat tissue level near the end of the third trimester adjustments take place to set this energy free and to be sent to her product at an intrauterine level. At this time a number of substances produced in the placenta can be identified. These substances act at the intracellular level blocking insulin effects. Treatment is based on diet, exercise and insulin. If normal glycemia is obtained, the risk for the mother and her child is redued, although not to the levels of non diabetics. Gestacional diabetes per se doesn't alter organogenesis, since hyperglycemia becomes evident at the end of the second trimester of pregnancy, on the contrary, the risk of teratogenesis is associated with pregestacional diabetes, both type 1 and type 2, which can only be identified in the stages of pregnancy when the child could be already affected.
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    ABSTRACT: For the 23,316 participants with blinded data, we calculated adjusted odds ratios for adverse pregnancy outcomes associated with an increase in the fasting plasma glu- cose level of 1 SD (6.9 mg per deciliter (0.4 mmol per liter)), an increase in the 1-hour plasma glucose level of 1 SD (30.9 mg per deciliter (1.7 mmol per liter)), and an in- crease in the 2-hour plasma glucose level of 1 SD (23.5 mg per deciliter (1.3 mmol per liter)). For birth weight above the 90th percentile, the odds ratios were 1.38 (95% confidence interval (CI), 1.32 to 1.44), 1.46 (1.39 to 1.53), and 1.38 (1.32 to 1.44), respectively; for cord-blood serum C-peptide level above the 90th percentile, 1.55 (95% CI, 1.47 to 1.64), 1.46 (1.38 to 1.54), and 1.37 (1.30 to 1.44); for primary cesar- ean delivery, 1.11 (95% CI, 1.06 to 1.15), 1.10 (1.06 to 1.15), and 1.08 (1.03 to 1.12); and for neonatal hypoglycemia, 1.08 (95% CI, 0.98 to 1.19), 1.13 (1.03 to 1.26), and 1.10 (1.00 to 1.12). There were no obvious thresholds at which risks increased. Sig- nificant associations were also observed for secondary outcomes, although these tended to be weaker. CONCLUSIONS Our results indicate strong, continuous associations of maternal glucose levels below those diagnostic of diabetes with increased birth weight and increased cord-blood se- rum C-peptide levels.
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