The efficacy and safety of metformin alone or as an add-on therapy to insulin in pregnancy with GDM or T2DM: A systematic review and meta-analysis of 21 randomized controlled trials

What is known and objective: Pregnant women are increasingly being exposed to metformin for conditions including gestational diabetes mellitus and type 2 diabetes mellitus. Metformin has been found to exhibit maternal to foetal transfer, and the long-term influence is uncertain. We conducted a meta-analysis to compare the efficacy and safety of metformin alone or as add-on therapy to insulin and insulin in pregnancy with gestational diabetes mellitus or type 2 diabetes mellitus. Methods: We performed a comprehensive literature search of PubMed, Embase, Cochrane Library and ClinicalTrials.gov for randomized controlled trials (RCTs) that compared metformin to insulin in pregnancy. Risk ratios (RRs) and mean differences (MDs) with 95% confidence intervals (CIs) were used to synthesize the results. Two authors independently extracted the data, evaluated study quality and calculated pooled estimates. Results: Twenty-one studies involving 4,545 patients were included in this meta-analysis. Compared with insulin, metformin significantly reduced the risks of maternal weight gain [MD -1.51 kg, 95%CI (-1.90 kg, -1.12 kg), P < 0.00001], gestational age at birth [MD -0.12 week, 95%CI (-0.21 week, -0.02 week), P = 0.02], gestational hypertension [RR 0.63, 95%CI (0.48, 0.82), P = 0.0006], maternal hypoglycaemia [RR 0.33, 95%CI (0.15, 0.73), P = 0.006], birthweight [MD -0.13 kg, 95%CI (-0.20 kg, -0.07 kg), P < 0.0001], neonatal hypoglycaemia [RR 0.56, 95%CI (0.49, 0.64), P < 0.00001], neonatal intensive care unit admission [RR 0.73, 95%CI (0.64, 0.83), P < 0.00001], birthweight >= 4000 g [RR 0.70, 95%CI (0.59, 0.83), P < 0.0001], and large for gestational age [RR 0.83, 95%CI (0.72, 0.97), P = 0.02] and significantly increased the risk of small for gestational age [RR 1.43, 95%CI (1.08, 1.89), P = 0.01] in pregnancy. What is new and conclusion: Metformin may have potential benefits for pregnant women and newborns in terms of maternal and foetal outcomes. More studies with long-term follow-up of offspring exposed to metformin in utero are needed to provide evidence for the future use of metformin in pregnancy.