Department of Gynecology, Universidade Federal de São Paulo, São Paulo, Brazil.
Division of Obstetrics & Gynaecology, School of Women's and Children's Health, UNSW and Royal Hospital for Women and IVF Australia, Sydney, Australia.
Cochrane Database Syst Rev. 2020 Dec 21;12(12):CD006105. doi: 10.1002/14651858.CD006105.pub4.
The use of insulin-sensitising agents, such as metformin, in women with polycystic ovary syndrome (PCOS) who are undergoing ovulation induction or in vitro fertilisation (IVF) cycles has been widely studied. Metformin reduces hyperinsulinaemia and suppresses the excessive ovarian production of androgens. It is suggested that as a consequence metformin could improve assisted reproductive techniques (ART) outcomes, such as ovarian hyperstimulation syndrome (OHSS), pregnancy, and live birth rates.
To determine the effectiveness and safety of metformin as a co-treatment during IVF or intracytoplasmic sperm injection (ICSI) in achieving pregnancy or live birth in women with PCOS.
We searched the Cochrane Gynaecology and Fertility Group Specialised Register, CENTRAL via the Cochrane Register of Studies Online (CRSO), MEDLINE, Embase, PsycINFO, LILACS, the trial registries for ongoing trials, and reference lists of articles (from inception to 13 February 2020).
Types of studies: randomised controlled trials (RCTs) comparing metformin treatment with placebo or no treatment in women with PCOS who underwent IVF or ICSI treatment.
women of reproductive age with anovulation due to PCOS with or without co-existing infertility factors. Types of interventions: metformin administered before and during IVF or ICSI treatment.
live birth rate, incidence of ovarian hyperstimulation syndrome.
Two review authors independently selected the studies, extracted the data according to the protocol, and assessed study quality. We assessed the overall quality of the evidence using the GRADE approach.
This updated review includes 13 RCTs involving a total of 1132 women with PCOS undergoing IVF/ICSI treatments. We stratified the analysis by type of ovarian stimulation protocol used (long gonadotrophin-releasing hormone agonist (GnRH-agonist) or short gonadotrophin-releasing hormone antagonist (GnRH-antagonist)) to determine whether the type of stimulation used influenced the outcomes. We did not perform meta-analysis on the overall (both ovarian stimulation protocols combined) data for the outcomes of live birth and clinical pregnancy rates per woman because of substantial heterogeneity. In the long protocol GnRH-agonist subgroup, the pooled evidence showed that we are uncertain of the effect of metformin on live birth rate per woman when compared with placebo/no treatment (risk ratio (RR) 1.30, 95% confidence interval (CI) 0.94 to 1.79; 6 RCTs; 651 women; I = 47%; low-quality evidence). This suggests that if the chance for live birth following placebo/no treatment is 28%, the chance following metformin would be between 27% and 51%. Only one study used short protocol GnRH-antagonist and reported live birth rate. Metformin may reduce live birth rate compared with placebo/no treatment (RR 0.48, 95% CI 0.29 to 0.79; 1 RCT; 153 women; low-quality evidence). This suggests that if the chance for live birth following placebo/no treatment is 43%, the chance following metformin would be between 13% and 34% (short GnRH-antagonist protocol). We found that metformin may reduce the incidence of OHSS (RR 0.46, 95% CI 0.29 to 0.72; 11 RCTs; 1091 women; I = 38%; low-quality evidence). This suggests that for a woman with a 20% risk of OHSS without metformin, the corresponding risk using metformin would be between 6% and 14%. Using long protocol GnRH-agonist stimulation, metformin may increase clinical pregnancy rate per woman compared with placebo/no treatment (RR 1.32, 95% CI 1.08 to 1.63; 10 RCTs; 915 women; I = 13%; low-quality evidence). Using short protocol GnRH-antagonist, we are uncertain of the effect of metformin on clinical pregnancy rate per woman compared with placebo/no treatment (RR 1.38, 95% CI 0.21 to 9.14; 2 RCTs; 177 women; I = 87%; very low-quality evidence). We are uncertain of the effect of metformin on miscarriage rate per woman when compared with placebo/no treatment (RR 0.86, 95% CI 0.56 to 1.32; 8 RCTs; 821 women; I = 0%; low-quality evidence). Metformin may result in an increase in side effects compared with placebo/no treatment (RR 3.35, 95% CI 2.34 to 4.79; 8 RCTs; 748 women; I = 0%; low-quality evidence). The overall quality of evidence ranged from very low to low. The main limitations were inconsistency, risk of bias, and imprecision.
AUTHORS' CONCLUSIONS: This updated review on metformin versus placebo/no treatment before or during IVF/ICSI treatment in women with PCOS found no conclusive evidence that metformin improves live birth rates. In a long GnRH-agonist protocol, we are uncertain whether metformin improves live birth rates, but metformin may increase the clinical pregnancy rate. In a short GnRH-antagonist protocol, metformin may reduce live birth rates, although we are uncertain about the effect of metformin on clinical pregnancy rate. Metformin may reduce the incidence of OHSS but may result in a higher incidence of side effects. We are uncertain of the effect of metformin on miscarriage rate per woman.
在接受排卵诱导或体外受精 (IVF) 周期的多囊卵巢综合征 (PCOS) 女性中，广泛研究了使用胰岛素增敏剂（如二甲双胍）。二甲双胍可降低高胰岛素血症并抑制卵巢过度产生雄激素。据认为，二甲双胍可改善辅助生殖技术 (ART) 的结果，如卵巢过度刺激综合征 (OHSS)、妊娠和活产率。
确定二甲双胍作为 PCOS 女性 IVF 或卵胞浆内单精子注射 (ICSI) 过程中的辅助治疗，对实现妊娠或活产的有效性和安全性。
我们检索了 Cochrane 妇科和生殖学组专业注册库、Cochrane 对照试验注册库、MEDLINE、Embase、PsycINFO、LILACS、正在进行的试验注册库以及文章参考文献列表（从开始到 2020 年 2 月 13 日）。
类型的研究：比较二甲双胍治疗与安慰剂或无治疗在接受 IVF 或 ICSI 治疗的 PCOS 女性中的随机对照试验 (RCT)。
有排卵障碍的生育年龄妇女，原因是 PCOS，伴有或不伴有共存的不孕因素。干预措施类型：在 IVF 或 ICSI 治疗前和期间给予二甲双胍。
活产率、卵巢过度刺激综合征发生率。
两名综述作者独立选择研究、根据方案提取数据并评估研究质量。我们使用 GRADE 方法评估证据的总体质量。
本更新综述包括 13 项 RCT，共纳入 1132 名接受 IVF/ICSI 治疗的 PCOS 女性。我们根据所用卵巢刺激方案的类型（长促性腺激素释放激素激动剂 (GnRH-激动剂) 或短促性腺激素释放激素拮抗剂 (GnRH-拮抗剂)）进行分析，以确定使用的刺激方案是否会影响结局。由于存在很大的异质性，我们未对活产和每个妇女临床妊娠率的总体（两种卵巢刺激方案合并）数据进行荟萃分析。在长方案 GnRH-激动剂亚组中，综合证据表明，与安慰剂/无治疗相比，我们不确定二甲双胍对每个妇女活产率的影响（风险比 (RR) 1.30，95%置信区间 (CI) 0.94 至 1.79；6 项 RCT；651 名妇女；I = 47%；低质量证据）。这表明，如果安慰剂/无治疗后活产的机会为 28%，则使用二甲双胍后活产的机会在 27%至 51%之间。只有一项研究使用短方案 GnRH 拮抗剂并报告了活产率。与安慰剂/无治疗相比，二甲双胍可能降低活产率（RR 0.48，95%CI 0.29 至 0.79；1 项 RCT；153 名妇女；低质量证据）。这表明，如果安慰剂/无治疗后活产的机会为 43%，则使用二甲双胍后活产的机会在 13%至 34%之间（短 GnRH 拮抗剂方案）。我们发现二甲双胍可能降低 OHSS 的发生率（RR 0.46，95%CI 0.29 至 0.72；11 项 RCT；1091 名妇女；I = 38%；低质量证据）。这表明，对于没有二甲双胍的 20% OHSS 风险的妇女，使用二甲双胍的相应风险在 6%至 14%之间。使用长方案 GnRH-激动剂刺激时，与安慰剂/无治疗相比，二甲双胍可能增加每个妇女的临床妊娠率（RR 1.32，95%CI 1.08 至 1.63；10 项 RCT；915 名妇女；I = 13%；低质量证据）。使用短方案 GnRH 拮抗剂，我们不确定二甲双胍对每个妇女临床妊娠率的影响与安慰剂/无治疗相比（RR 1.38，95%CI 0.21 至 9.14；2 项 RCT；177 名妇女；I = 87%；极低质量证据）。我们不确定二甲双胍与安慰剂/无治疗相比对每个妇女流产率的影响（RR 0.86，95%CI 0.56 至 1.32；8 项 RCT；821 名妇女；I = 0%；低质量证据）。与安慰剂/无治疗相比，二甲双胍可能导致副作用增加（RR 3.35，95%CI 2.34 至 4.79；8 项 RCT；748 名妇女；I = 0%；低质量证据）。证据的总体质量从低到极低不等。主要限制因素是不一致性、偏倚风险和不精确性。
本更新综述关于二甲双胍与安慰剂/无治疗在接受 PCOS 女性的 IVF/ICSI 治疗前或期间的比较，没有确凿的证据表明二甲双胍可以提高活产率。在长 GnRH 激动剂方案中，我们不确定二甲双胍是否可以提高活产率，但二甲双胍可能会提高临床妊娠率。在短 GnRH 拮抗剂方案中，二甲双胍可能会降低活产率，尽管我们不确定二甲双胍对临床妊娠率的影响。二甲双胍可能会降低 OHSS 的发生率，但可能会导致副作用发生率增加。我们不确定二甲双胍对每个妇女流产率的影响。
