Abstract: We identified six RCTs (707 women), eligible for inclusion in this updated review, however, three RCTs had mixed populations (that is, they included pregnant women with gestational diabetes) and did not report data separately for the relevant subset of women for this review. Therefore we have only included outcome data from three RCTs; data were available for 241 women and their infants. The three RCTs all compared an oral anti-diabetic agent (metformin) with insulin. The women in the RCTs that contributed data had type 2 diabetes diagnosed before or during their pregnancy. Overall, the RCTs were judged to be at varying risk of bias. We assessed the quality of the evidence for selected important outcomes using GRADE; the evidence was low- or very low-quality, due to downgrading because of design limitations (risk of bias) and imprecise effect estimates (for many outcomes only one or two RCTs contributed data). For our primary outcomes there was no clear difference between metformin and insulin groups for pre-eclampsia (risk ratio (RR) 0.63, 95% confidence interval (CI) 0.33 to 1.20; RCTs = 2; participants = 227; very low-quality evidence) although in one RCT women receiving metformin were less likely to have pregnancy-induced hypertension (RR 0.58, 95% CI 0.37 to 0.91; RCTs = 1; participants = 206; low-quality evidence). Women receiving metformin were less likely to have a caesarean section compared with those receiving insulin (RR 0.73, 95% CI 0.61 to 0.88; RCTs = 3; participants = 241; low-quality evidence). In one RCT there was no clear difference between groups for large-for-gestational-age infants (RR 1.12, 95% CI 0.73 to 1.72; RCTs = 1; participants = 206; very low-quality evidence). There were no perinatal deaths in two RCTs (very low-quality evidence). Neonatal mortality or morbidity composite outcome and childhood/adulthood neurosensory disability were not reported. For other secondary outcomes we assessed using GRADE, there were no clear differences between metformin and insulin groups for induction of labour (RR 1.42, 95% CI 0.62 to 3.28; RCTs = 2; participants = 35; very low-quality evidence), though infant hypoglycaemia was reduced in the metformin group (RR 0.34, 95% CI 0.18 to 0.62; RCTs = 3; infants = 241; very low-quality evidence). Perineal trauma, maternal postnatal depression and postnatal weight retention, and childhood/adulthood adiposity and diabetes were not reported. There are insufficient RCT data to evaluate the use of oral anti-diabetic agents in women with established diabetes, impaired glucose tolerance or previous gestational diabetes who are planning a pregnancy, or in pregnant women with pre-existing diabetes. Low to very low-quality evidence suggests possible reductions in pregnancy-induced hypertension, caesarean section birth and neonatal hypoglycaemia with metformin compared with insulin for women with type 2 diabetes diagnosed before or during their pregnancy, and no clear differences in pre-eclampsia, induction of labour and babies that are large-for-gestational age. Further high-quality RCTs that compare any combination of oral anti-diabetic agent, insulin and dietary and lifestyle advice for these women are needed. Future RCTs could be powered to evaluate effects on short- and long-term clinical outcomes; such RCTs could attempt to collect and report on the standard outcomes suggested in this review. We have identified three ongoing studies and four are awaiting classification. We will consider these when this review is updated.

Plain-language summary: We searched for evidence from randomised controlled trials (RCTs) on 31 October 2016 and included six RCTs (707 women). Three RCTs included women with current gestational diabetes and did not report data separately for the population of women relevant to this review. Therefore we have only included outcome data from three RCTs, involving 241 pregnant women and their infants. The quality of the evidence was assessed as being low or very low and the overall risk of bias of the RCTs was varied. The three RCTs all compared an oral anti-diabetic agent (metformin) with insulin in pregnant women with pre-existing (type 2) diabetes. There was no clear difference in the development of pre-eclampsia (high blood pressure and protein in the urine) for women who received metformin compared with insulin (2 RCTs; 227 women; very low-quality evidence), though women receiving metformin were less likely to have pregnancy-induced high blood pressure in one RCT (206 women; low-quality evidence). Women who received metformin were less likely to have a caesarean section birth (3 RCTs; 241 women; low-quality evidence), though no difference was observed in induction of labour (2 RCTs; 35 women; very low-quality evidence). There was no clear difference between groups of infants born to mothers who received metformin or insulin for being large-for-gestational age (1 RCT; 206 infants; very low-quality evidence), though infants born to mothers who received metformin were less likely to have low blood sugar (hypoglycaemia) (3 RCTs; 241 infants; very low-quality evidence). There were no infant deaths (before birth or shortly afterwards) (2 RCTs; very low-quality evidence). The RCTs did not report on many important short- and long-term outcomes, including perineal trauma and a combined outcome of infant death or morbidity, postnatal depression and weight retention for mothers, and adiposity or disability in childhood or adulthood for infants. There is not enough evidence to guide us on the effects of oral anti-diabetic agents in women with established diabetes, impaired glucose tolerance or previous gestational diabetes who are planning a pregnancy, or pregnant women with pre-existing diabetes. Further large, well-designed, RCTs are required and could assess and report on the outcomes suggested in this review, including both short- and long-term outcomes for mothers and their infants.