Effect of metformin on maternal and fetal outcomes in obese pregnant women (EMPOWaR): a randomised, double-blind, placebo-controlled trial.
Effect of metformin on maternal and fetal outcomes in obese pregnant women (EMPOWaR): a randomised, double-blind, placebo-controlled trial.
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DOI：
10.1016/s2213-8587(15)00219-3
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发表时间：
2015-10
期刊：
影响因子：
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通讯作者：
Norman JE
中科院分区：
文献类型：
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作者：
Chiswick C;Reynolds RM;Denison F;Drake AJ;Forbes S;Newby DE;Walker BR;Quenby S;Wray S;Weeks A;Lashen H;Rodriguez A;Murray G;Whyte S;Norman JE
母亲肥胖与出生体重增加以及成年后代的肥胖和过早死亡有关。孕产妇肥胖导致这些结果的机制尚不清楚，但孕产妇高血糖和胰岛素抵抗都与此有关。我们的目的是确定胰岛素增敏药物二甲双胍是否可以改善不患有糖尿病的肥胖孕妇的母婴结局。我们在英国 15 家国家卫生服务医院的产前诊所进行了这项随机、双盲、安慰剂对照试验。妊娠 12 至 16 周、BMI 为 30 kg/m2 或以上且糖耐量正常的孕妇（年龄≥16 岁）通过基于网络的计算机生成的分组随机化程序（分组大小为 2 至 4 个）被随机分配（1:1），从 12 至 16 周每天接受口服二甲双胍 500 mg（增加至最大 2500 mg）或匹配的安慰剂妊娠直至分娩。随机分组按研究地点和 BMI 范围（30-39 vs ≥40 kg/m2）进行分层。参与者、护理人员和研究人员不知道治疗分配情况。主要结果是 Z 评分，对应于妊娠 24 周或以上分娩的活产婴儿的胎龄、产次和性别标准化出生体重百分位。我们通过修改意向治疗进行了分析。该试验已注册，ISRCTN 编号为 51279843。在 2011 年 2 月 3 日至 2014 年 1 月 16 日（含）期间，我们将 449 名女性随机分配到安慰剂 (n=223) 或二甲双胍 (n=226) 组，其中 434 名 (97%) 被纳入最终修改的意向治疗分析中。安慰剂组的平均出生体重为 3463 克（SD 660），二甲双胍组的平均出生体重为 3462 克（548）。二甲双胍对主要结局的估计效应大小不显着（调整后平均差 -0·029，95% CI -0·217 至 0·158；p=0·7597）。二甲双胍组 (n=7) 与安慰剂组 (n=2) 报告流产、终止妊娠、死产或新生儿死亡等综合不良结果的妇女人数差异不显着（比值比 3·60，95% CI 0·74–17·50；p=0·11）。二甲双胍对肥胖孕妇的出生体重百分位没有显着影响。 EMPOWaR 研究中对母亲所生婴儿的进一步随访将确定二甲双胍在该人群中的长期结果；同时，二甲双胍不应用于改善未患糖尿病的肥胖女性的妊娠结局。功效和机制评估 (EME) 计划是医学研究委员会和国家健康研究所的合作伙伴关系。
Maternal 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. We 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. Between 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). Metformin 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. The Efficacy and Mechanism Evaluation (EME) Programme, a Medical Research Council and National Institute for Health Research partnership.