Abstract
We systematically assessed the impact of metformin treatment on maternal pregnancy outcomes. PubMed, Ovid Embase, Medline, Web of Science, ClinicalTrials.gov and Cochrane databases were systematically searched (inception-1st February 2021). Randomised controlled trials reporting pregnancy outcomes in women randomised to metformin versus any other treatment for any indication were included. Outcomes included gestational weight gain (GWG), pre-eclampsia, gestational hypertension, preterm birth, gestational age at delivery, caesarean section, gestational diabetes, glycaemic control, and gastrointestinal side-effects. Two independent reviewers conducted screening, with a third available to evaluate disagreements. Risk-of-bias and GRADE assessments were conducted using Cochrane Risk-of-Bias and GRADE-pro software. Thirty-five studies (n = 8033 pregnancies) met eligibility criteria. GWG was lower in pregnancies randomised to metformin versus other treatments (1.57 kg ± 0.60 kg; I2 = 86%, p < 0.0001), as was likelihood of pre-eclampsia (OR 0.69, 95% CI 0.50–0.95; I2 = 55%, p = 0.02). The risk of gastrointestinal side-effects was greater in metformin-exposed versus other treatment groups (OR 2.43, 95% CI 1.53–3.84; I2 = 76%, p = 0.0002). The risk of other maternal outcomes assessed was not significantly different between metformin-exposed versus other treatment groups. Metformin for any indication during pregnancy is associated with lower GWG and a modest reduced risk of pre-eclampsia, but increased gastrointestinal side-effects compared to other treatments.
Highlights
Metformin, an oral insulin-sensitizing and glucose-lowering drug, is widely prescribed during pregnancy
Given the increasingly high number of women currently being prescribed metformin during pregnancy, we evaluated the impact of metformin treatment in pregnancy on the mother, by synthesizing all available randomised trial data pertaining to common maternal outcomes
When analysis was performed combining all indications for metformin treatment, there was a lower likelihood of delivery by caesarean section in women randomised to metformin versus other treatments (Supplementary Fig. S7f) based on 31 studies including 7053 pregnancies
Summary
This systematic review and meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) g uidelines[22]. Two reviewers (JLA and CEA) independently assessed each study using pre-determined inclusion/exclusion criteria (Supplementary Table S2). Data extraction from eligible studies was conducted independently using a standardised proforma by two authors (JLA and CEA). All outcome measures were defined as per the original study criteria, and we did not apply any exclusion with respect to these. Each study was independently assessed by two authors (JLA and CEA) for quality and validity using the Cochrane Collaboration tool for assessing risk of bias. Where the indication for randomisation was diabetes in pregnancy, the included studies all compared metformin to either insulin or glyburide, further sub-group analyses were performed by comparator group. Where the indication for randomisation was PCOS or obesity, all included studies compared metformin to placebo, no further sub-group analyses were performed. Where p values are reported, an alpha level < 0.05 was considered statistically significant
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