Effects of metformin in women with polycystic ovary syndrome treated with gonadotrophins for in vitro fertilisation and intracytoplasmic sperm injection cycles: a systematic review and meta-analysis of randomised controlled trials.

Metformin is widely used for treating women with polycystic ovary syndrome (PCOS), and many patients with PCOS who are infertile receive gonadotrophins while being treated with metformin. To assess the effects of metformin administration in infertile patients with PCOS who receive gonadotrophins for in vitro fertilisation (IVF) and intracytoplasmic sperm injection (ICSI) cycles. We searched international scientific databases, websites for the registration of trials, and bibliographies of retrieved articles, books, and review articles up to August 2012. Randomised controlled trials (RCTs). Authors independently reviewed and extracted the data. Ten RCTs (with a total of 845 women with PCOS) were included in the final analysis. Metformin administration in IVF/ICSI cycles had no effect on the rates of pregnancy (OR 1.20, 95% CI 0.90-1.61) and live birth (OR 1.69, 95% CI 0.85-3.34). No effect of metformin dose, metformin pretreatment duration, and stopping time of metformin administration was observed on these reproductive end points. Metformin administration reduced the risk of ovarian hyperstimulation syndrome (OHSS; OR 0.27, 95% CI 0.16-0.46) and of miscarriage (OR 0.50, 95% CI 0.30-0.83), while increased that of implantation (OR 1.42, 95% CI 1.24-2.75). In infertile patients with PCOS treated with gonadotrophins for IVF/ICSI cycles, metformin exerts no clinical effect on rates of pregnancy or live birth, but it reduces the risk of OHSS, and improves the rates of miscarriage and implantation. Further RCTs are needed to assess the reproductive effect of metformin in young well-selected patients with PCOS and specific phenotypes and features.

Palomba S ，Falbo A ，La Sala GB 《-》

Metformin treatment before and during IVF or ICSI in women with polycystic ovary syndrome.

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; I2 = 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; I2 = 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; I2 = 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; I2 = 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; I2 = 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; I2 = 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. 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.

Tso LO ，Costello MF ，Albuquerque LET ，Andriolo RB ，Macedo CR ... -  《Cochrane Database of Systematic Reviews》

Metformin treatment before and during IVF or ICSI in women with polycystic ovary syndrome.

Tso LO ，Costello MF ，Albuquerque LE ，Andriolo RB ，Freitas V ... -  《Cochrane Database of Systematic Reviews》

Metformin treatment before and during IVF or ICSI in women with polycystic ovary syndrome.

Tso LO ，Costello MF ，Albuquerque LE ，Andriolo RB ，Macedo CR ... -  《Cochrane Database of Systematic Reviews》

Metformin during ovulation induction with gonadotrophins followed by timed intercourse or intrauterine insemination for subfertility associated with polycystic ovary syndrome.

Bordewijk EM ，Nahuis M ，Costello MF ，Van der Veen F ，Tso LO ，Mol BW ，van Wely M ... -  《Cochrane Database of Systematic Reviews》