Oral anti‐diabetic agents for women with established diabetes/impaired glucose tolerance or previous gestational diabetes planning pregnancy, or pregnant women with pre‐existing diabetes

Joanna Tieu, Suzette Coat, William Hague, Philippa Middleton, Emily Shepherd

While most guidance recommends the use of insulin in women whose pregnancies are affected by pre-existing diabetes, oral anti-diabetic agents may be more acceptable to women. The effects of these oral anti-diabetic agents on maternal and infant health outcomes need to be established in pregnant women with pre-existing diabetes or impaired glucose tolerance, as well as in women with previous gestational diabetes mellitus preconceptionally or during a subsequent pregnancy. To investigate 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, on maternal and infant health. The use of oral anti-diabetic agents for the management of gestational diabetes in a current pregnancy is evaluated in a separate Cochrane Review. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 October 2016) and reference lists of retrieved studies. Randomised controlled trials (RCTs) and quasi-RCTs assessing the effects of oral anti-diabetic agents in women with established diabetes, impaired glucose tolerance or previous gestational diabetes who were planning a pregnancy, or pregnant women with pre-existing diabetes. Cluster-RCTs were eligible for inclusion, but none were identified. Two review authors independently assessed study eligibility, extracted data and assessed the risk of bias of the included RCTs. Review authors checked the data for accuracy, and assessed the quality of the evidence using the GRADE approach. We identified six RCTs (707 women), eligible for inclusion in this 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.