In summary, the evidence available from clinical studies does not support the use of glyburide in GDM, especially if metformin or insulin is available.
Short-term effects of metformin Since 2007, evidence for the efficacy and safety of metformin use in pregnancy has been reinforced by the results of several RCTs and meta-analyses.74,76–80 In 2013, the first meta-analysis was conducted by Gui etal.76;this study included fiveRCTs81–85 that compared the effects of metformin with those of insulin therapy in terms of glycemic control and maternal and neonatal outcomes in GDM. Although Gui et al.76 reported no differences between metformin and insulin in terms of glycemic control and neonatal outcomes (birth weight, LGA neonates, hypoglycemia, shoulder dystocia, and cesarean delivery), rates of preterm birth were found to be increased for metformin. Conversely, compared with insulin therapy, metformin was associated with less maternal weight gain and lower rates of pregnancyinduced hypertension, the latter thought to be explained by insulin-mediated sodium retention.76 Recently, five other meta-analyses have been published comparing metformin and insulin therapy in GDM.74,77–80 The meta-analyses by Poolsup et al.,77 Balsells et al.,74 and Gui et al.76 included the same RCTs and found comparable results. The main difference between these meta-analyses was that Poolsup et al.77 and Balsells et al.74 included an additional RCT86; they also did not address exactly the same outcomes: Poolsup et al.77 had no information on maternal weight gain and Balsells et al.74 added additional outcomes, including severe neonatal hypoglycemia and maternal total weight gain. In this respect, Balsells et al.74 reported lower occurrence of severe neonatal hypoglycemia and a lower maternal total weight gain in the metformin group. The other three meta-analyses78–80 included the aforementioned RTCs as well as additional RCTs.87–89 On the basis of current evidence, it seems that metformin may have some benefits with short-term neonatal outcomes similar to those for insulin therapy. However, the higher risk of preterm birth in metformin treatment is a point of concern that should be addressed in further studies.
Long-term effects of metformin Unfortunately, little is known about the long-term effects of metformin in GDM. To date, several studies
have investigated the long-term effects of metformin use in pregnancy on the subsequent growth and development of the children.90–93 In 2011, the results of a 2-year follow-up study of offspring were reported by the Metformin in Gestational Diabetes (MiG) Trial. The aim of that study was to compare the results of metformin and insulin treatment in terms of body composition and measures of adiposity in the children of women who participated in the MiG trial.83,92 Children who were exposed to metformin in utero had larger subscapular and biceps skin folds than the offspring of mothers who received insulin. The study suggests that metformin use is associated with more fat being stored in subcutaneous sites and perhaps less accumulation of ectopic or visceral fat.92 The study found no difference in total or percentage body fat between the children exposed to metformin or insulin.92 One other follow-up study found that children exposed to metformin were heavier at the age of 12months and were both taller and heavier at 18months.90 However, in the multivariate regression analysis, maternal body mass index (BMI) was the only risk factor predicting a child being overweight or obese at the age of 18months. Compared with insulin exposure, the study found no adverse effects of prenatal metformin exposure on motor, linguistic, or social development of the offspring during the first 18months of life.90 Another two follow-up studies of offspring and their mothers were from an RCT conducted in women with polycystic ovary syndrome who had been treated with metformin or placebo during pregnancy.91,93 The first study,93 with a 1-year follow-up, showed that women who received a placebo during their pregnancy had lost more weight and had a lower BMI 1year after delivery than women who received metformin during their pregnancy. However, the women in the metformin group gained less weight during their pregnancy. The offspring exposed to metformin in utero had a higher body weight at 1year of age than those exposed to placebo.93 In another study,91 the same authors performed a small follow-up study of the offspring at the age of 8years. At that age there were no differences in height, weight, body composition, and insulin resistance. However, the children exposed to metformin in utero had higher fasting glucose levels, higher systolic blood pressure, and lower low-density lipoprotein cholesterol.91 There appears to be an urgent need for longer followup studies assessing the true effect of metformin in a larger offspring cohort at least until adolescence or adulthood. Studies on the effects of metformin during pregnancy in humans have reported no harmful effects or teratogenicity.94,95 However, animal studies have shown that