OBJECTIVEMetformin was reported to reduce the risk of gestational diabetes (GD) in women with polycystic ovarian syndrome (PCOS). However, little is known about the mechanisms of action of this drug during pregnancy. In the attempt to fill this gap, we performed a prospective longitudinal study providing a detailed examination of glucose and insulin metabolism in pregnant women with PCOS undergoing metformin therapy.RESEARCH DESIGN AND METHODSWe enrolled 60 women with PCOS who conceived while undergoing metformin treatment. An oral glucose tolerance test and a euglycemic-hyperinsulinemic clamp were performed at each trimester of gestation in 47 ongoing pregnancies.RESULTSTwenty-two of the study subjects had development of GD despite the treatment. At baseline, insulin sensitivity was comparable between women who had development of GD and women who did not. A progressive decline in this parameter occurred in all subjects, independently of the trimester of GD diagnosis. Insulin secretion was significantly higher during the first trimester in patients with an early failure of metformin treatment. Women with third trimester GD and women with no GD exhibited a significant increase in insulin output as gestation proceeded. All newborns were healthy and only one case of macrosomia was observed.CONCLUSIONSWomen with PCOS who enter pregnancy in a condition of severe hyperinsulinemia have development of GD earlier, independently of metformin treatment. The physiologic deterioration of insulin sensitivity is not affected by the drug and does not predict the timing and severity of the glycemic imbalance. Despite the high incidence of GD observed, the drug itself or the intensive monitoring probably accounted for the good neonatal outcome.