Use of metformin to treat pregnant women with polycystic ovary syndrome (PregMet2): a randomised, double-blind, placebo-controlled trial
Use of metformin to treat pregnant women with polycystic ovary syndrome (PregMet2): a randomised, double-blind, placebo-controlled trial
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DOI：
10.1016/s2213-8587(19)30002-6
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发表时间：
2019-04-01
影响因子：
44.5
通讯作者：
Vanky, Eszter
中科院分区：
文献类型：
--
作者：
Lovvik, Tone S.;Carlsen, Sven M.;Vanky, Eszter
背景多囊卵巢综合征（PCOS）的妇女有妊娠并发症的风险增加。既往两项随机对照试验比较了二甲双胍与安慰剂在PCOS女性妊娠期间的疗效，Epi分析显示二甲双胍组晚期流产和早产显著减少。这第三个随机试验（PregMet 2）的目的是测试二甲双胍预防晚期流产和早产的妇女PCOS.Methods PregMet 2的假设是一个随机，安慰剂对照，双盲，多中心试验在挪威，瑞典和冰岛的14家医院完成。年龄在18-45岁的PCOS单胎妊娠女性有资格入选。在第一次产前检查或从互联网上获得有关这项研究的信息后，妇女们单独报名参加这项研究。通过计算机生成的随机数字将参与者随机分配（1：1）接受二甲双胍或安慰剂。每个国家和研究中心的随机分组为10个区组;第一个区组的随机大小为1 - 10，以确保设盲。参与者被分配在治疗的第一周接受口服二甲双胍500 mg每日两次或安慰剂，从第2周起增加至1000 mg每日两次或安慰剂，直至分娩。安慰剂片剂和二甲双胍片剂相同，受试者和研究人员对治疗分配设盲。主要结局是在意向治疗人群中分析的晚期流产（第13周至第22周和6天之间）和早产（第23周至第36周和6天之间）的复合发生率。次要终点包括妊娠期糖尿病、先兆子痫、妊娠高血压和新生儿入住新生儿重症监护室的发生率。我们还对妊娠结局进行了事后个体参与者数据分析，将先前两项试验的数据与本研究合并。该研究已在ClinicalTrials注册。gov，编号NCT 01587378和EudraCT，编号2011-002203- 15。结果该研究于2012年10月19日至2017年9月1日进行。我们将487名女性随机分配至二甲双胍组（n=244）或安慰剂组（n=243）。在意向性治疗分析中，二甲双胍组238例女性中有12例（5%）发生晚期流产和早产，安慰剂组240例女性中有23例（10%）发生晚期流产和早产（比值比[OR] 0.50，95%CI 0.22- 1.08; p = 0.08）。我们发现次要终点无显著差异，包括妊娠期糖尿病的发生率（二甲双胍组238例女性中60例[25%] vs安慰剂组240例女性中57例[24%]; OR 1.09，95%CI 0.69-1.66; p=0.75）。我们注意到母亲或后代的严重不良事件没有实质性的组间差异，并且主要研究者认为没有严重不良事件与药物相关。在对本试验和之前两项试验的个体受试者数据进行事后汇总分析时，二甲双胍组397名妇女中有18名（5%）发生晚期流产或早产，而安慰剂组399名妇女中有40名（10（OR 0.43，95%CI 0.23-0.79; p=0.004）.解释在患有PCOS的孕妇中，二甲双胍治疗从妊娠早期晚期直到分娩可能降低晚期流产和早产的风险，但不能预防妊娠期糖尿病。(C)2019爱思唯尔有限公司版权所有。
Background Women with polycystic ovary syndrome (PCOS) have an increased risk of pregnancy complications. Epi-analysis of two previous randomised controlled trials that compared metformin with placebo during pregnancy in women with PCOS showed a significant reduction in late miscarriages and preterm births in the metformin group. The aim of this third randomised trial (PregMet2) was to test the hypothesis that metformin prevents late miscarriage and preterm birth in women with PCOS.Methods PregMet2 was a randomised, placebo-controlled, double-blind, multicentre trial done at 14 hospitals in Norway, Sweden, and Iceland. Singleton pregnant women with PCOS aged 18-45 years were eligible for inclusion. After receiving information about the study at their first antenatal visit or from the internet, women signed up individually to participate in the study. Participants were randomly assigned (1: 1) to receive metformin or placebo by computer-generated random numbers. Randomisation was in blocks of ten for each country and centre; the first block had a random size between one and ten to assure masking. Participants were assigned to receive oral metformin 500 mg twice daily or placebo during the first week of treatment, which increased to 1000 mg twice daily or placebo from week 2 until delivery. Placebo tablets and metformin tablets were identical and participants and study personnel were masked to treatment allocation. The primary outcome was the composite incidence of late miscarriage (between week 13 and week 22 and 6 days) and preterm birth (between week 23 and week 36 and 6 days), analysed in the intention-to-treat population. Secondary endpoints included the incidence of gestational diabetes, preeclampsia, pregnancy-induced hypertension, and admission of the neonate to the neonatal intensive care unit. We also did a post-hoc individual participant data analysis of pregnancy outcomes, pooling data from the two previous trials with the present study. The study was registered with ClinicalTrials. gov, number NCT01587378, and EudraCT, number 2011-002203-15.Findings The study took place between Oct 19, 2012, and Sept 1, 2017. We randomly assigned 487 women to metformin (n=244) or placebo (n=243). In the intention-to-treat analysis, our composite primary outcome of late miscarriage and preterm birth occurred in 12 (5%) of 238 women in the metformin group and 23 (10%) of 240 women in the placebo group (odds ratio [OR] 0.50, 95% CI 0.22- 1.08; p = 0.08). We found no significant differences for our secondary endpoints, including incidence of gestational diabetes (60 [25%] of 238 women in the metformin group vs 57 [24%] of 240 women in the placebo group; OR 1.09, 95% CI 0.69-1.66; p=0.75). We noted no substantial between-group differences in serious adverse events in either mothers or offspring, and no serious adverse events were considered drug-related by principal investigators. In the post-hoc pooled analysis of individual participant data from the present trial and two previous trials, 18 (5%) of 397 women had late miscarriage or preterm delivery in the metformin group ]compared with 40 (10%) of 399 women in the placebo group (OR 0.43, 95% CI 0.23-0.79; p=0.004).Interpretation In pregnant women with PCOS, metformin treatment from the late first trimester until delivery might reduce the risk of late miscarriage and preterm birth, but does not prevent gestational diabetes. (C) 2019 Elsevier Ltd. All rights reserved.