Effect of metformin on maternal and fetal outcomes in obese pregnant women (EMPOWaR): a randomised, double-blind, placebo-controlled trial

Abstract

SummaryBackgroundMaternal obesity is associated with increased birthweight, and obesity and premature mortality in adult offspring. The mechanism by which maternal obesity leads to these outcomes is not well understood, but maternal hyperglycaemia and insulin resistance are both implicated. We aimed to establish whether the insulin sensitising drug metformin improves maternal and fetal outcomes in obese pregnant women without diabetes.MethodsWe did this randomised, double-blind, placebo-controlled trial in antenatal clinics at 15 National Health Service hospitals in the UK. Pregnant women (aged ≥16 years) between 12 and 16 weeks' gestation who had a BMI of 30 kg/m2 or more and normal glucose tolerance were randomly assigned (1:1), via a web-based computer-generated block randomisation procedure (block size of two to four), to receive oral metformin 500 mg (increasing to a maximum of 2500 mg) or matched placebo daily from between 12 and 16 weeks' gestation until delivery of the baby. Randomisation was stratified by study site and BMI band (30–39 vs ≥40 kg/m2). Participants, caregivers, and study personnel were masked to treatment assignment. The primary outcome was Z score corresponding to the gestational age, parity, and sex-standardised birthweight percentile of liveborn babies delivered at 24 weeks or more of gestation. We did analysis by modified intention to treat. This trial is registered, ISRCTN number 51279843.FindingsBetween Feb 3, 2011, and Jan 16, 2014, inclusive, we randomly assigned 449 women to either placebo (n=223) or metformin (n=226), of whom 434 (97%) were included in the final modified intention-to-treat analysis. Mean birthweight at delivery was 3463 g (SD 660) in the placebo group and 3462 g (548) in the metformin group. The estimated effect size of metformin on the primary outcome was non-significant (adjusted mean difference −0·029, 95% CI −0·217 to 0·158; p=0·7597). The difference in the number of women reporting the combined adverse outcome of miscarriage, termination of pregnancy, stillbirth, or neonatal death in the metformin group (n=7) versus the placebo group (n=2) was not significant (odds ratio 3·60, 95% CI 0·74–17·50; p=0·11).InterpretationMetformin has no significant effect on birthweight percentile in obese pregnant women. Further follow-up of babies born to mothers in the EMPOWaR study will identify longer-term outcomes of metformin in this population; in the meantime, metformin should not be used to improve pregnancy outcomes in obese women without diabetes.FundingThe Efficacy and Mechanism Evaluation (EME) Programme, a Medical Research Council and National Institute for Health Research partnership.

Os Efeitos Da Metformina Na Obesidade Da Gestante E No Peso Do Recém-Nascido

“…Um estudo com gestantes obesas não diabéticas demonstrou que a metformina não tem efeito significativo no peso da mãe, concluindo, através dos seus dados estatísticos, que o medicamento não deve ser usado na gravidez por mulheres obesas sem diabetes (CHISWICK et al, 2015). Em contraposição, autores, num ensaio clinico randomizado com grupos metformina e placebo, identificaram diferença na média de ganho de peso entre os dois grupos de mães, sendo de 4,6 kg na terapia com metformina e 6,3 kg nas gestantes com placebo, apontando a eficiência da metformina na redução de peso em grávidas não diabéticas (SYNGELAKI et al, 2016).…”

“…Em relação aos desfechos neonatais, as dosagens de 2.500 mg diárias em mulheres grávidas obesas não diabéticas com IMC acima de 30, administrado entre 16 a 18 semanas de gestação até o parto, não demonstraram significância quanto à média de peso dos bebês (CHISWICK et al, 2015). Isso equivale aos achados de Vanky e seus colaboradores, porém com uma dosagem de 800 mg duas vezes ao dia ( VANKY et al, 2010).…”

Metformin in Pregnancy: Mechanisms and Clinical Applications

“…Disappointingly, these changes had no significant effect on the subsequent development of gestational diabetes. The primary outcome, a Z score corresponding to the gestational age, parity, and sex-standardised birthweight percentile of live-born babies was no different in the offspring of metformin treated women compared to controls [21].…”

“…The reduced rate of preeclampsia observed in the MOP trial contrasts with the lack of effect in EMPOWaR. One explanation for this difference is that gestational weight gain was reduced in MOP but not in EMPOWar [22] [21]. Lower maternal weight gain was associated with a reduced rate of preeclampsia in a recent meta-analysis of metformin and risk of preeclampsia [27] .…”

“…Metformin in obese non-diabetic pregnant women Chiswick and colleagues (2015) reported a double blind, placebo controlled trial (EMPOWaR) in non-diabetic (normal glucose tolerance test) obese (BMI of 30kg/m 2 or more) predominantly Caucasian (96%) women receiving metformin 500mg (up to a maximum of 2,500mg/day) or placebo from 12-16 weeks gestation until term [21].…”