Metformin in women with polycystic ovary syndrome (PCOS) for improving fertility

Review question

The aim of this review was to determine if metformin improves live birth and clinical pregnancy rates and whether it reduces the incidence of ovarian hyperstimulation syndrome (OHSS) in women with PCOS undergoing in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI).

Background

In women with PCOS there is a chronic failure or absence of ovulation (anovulation) and excessive production of male hormones (hyperandrogenism). The main symptoms of the disorder are irregular periods, infertility, hirsutism (excessive facial and body hair growth), and acne. PCOS is the most common endocrine disorder in women, affecting 5% to 10% of women of reproductive age. IVF could be an effective treatment option for infertility in women with PCOS who do not respond to ovulation induction treatments. In the first part of IVF treatment, ovarian stimulation using gonadotrophins is necessary to develop more mature oocytes in order to produce more good-quality embryos to be transferred into the uterus. This overstimulation increases the risk of developing a serious complication known as ovarian hyperstimulation syndrome (OHSS). Strategies used during IVF treatments to decrease the risk of OHSS include: low-dose gonadotrophin ovarian stimulation, metformin co-treatment, use of gonadotrophin-releasing hormone (GnRH)-antagonist protocol instead of GnRH-agonist, and use of GnRH-agonist trigger to final oocyte maturation rather than the usual human chorionic gonadotrophin (hCG)-trigger.

Study characteristics

We included 13 randomised controlled trials (a type of study in which participants are assigned to one of two or more treatment groups using a random method) involving a total of 1132 women assigned to receive either metformin (570) or placebo (dummy treatment)/no treatment (563). The evidence is current to 13 February 2020.

Key results

We divided the analysis by type of ovarian stimulation protocol used during the IVF treatment (long GnRH-agonist or short GnRH-antagonist) to determine whether the type of stimulation used influenced the outcomes. We are uncertain of the effect of metformin using long protocol GnRH-agonist on live birth rates compared with placebo or no treatment, but metformin may increase clinical pregnancy rate with this type of ovarian stimulation protocol. Metformin may reduce the incidence of OHSS. We estimated that for a woman with a 28% chance of achieving a live birth (long protocol GnRH-agonist) following placebo or no treatment, the chance following metformin would be between 27% and 51%. For a woman with a 28% chance of achieving a clinical pregnancy in long protocol GnRH-agonist without metformin, the chance using metformin would be between 30% and 45%.

For the short protocol GnRH-antagonist, metformin may reduce live birth rate, and we are uncertain of its effect on clinical pregnancy and OHSS rates compared with placebo/no treatment.

Overall, metformin may reduce the incidence of OHSS when compared with placebo/no treatment. For a woman with a 20% risk of OHSS without metformin, the corresponding risk using metformin would be between 6% and 14%. Side effects (mostly gastrointestinal) may be more common with metformin. We are uncertain of the effect of metformin on miscarriage rates when compared with placebo/no treatment.

Quality of the evidence

The overall quality of evidence for the primary outcomes live birth rate and incidence of OHSS was low. We assessed the evidence as low for the secondary outcomes clinical pregnancy rate (long protocol GnRH-agonist), miscarriage rate, and side effects, and very low for clinical pregnancy rate (short protocol GnRH-antagonist). The main limitations were risk of bias and imprecise results.

Conclusion

This updated review on metformin versus placebo/no treatment before or during IVF/ICSI treatment in women with PCOS found no clear evidence that metformin improves live birth rates: the effect of metformin is uncertain using long protocol GnRH-agonist, but live birth rates may be reduced using short protocol GnRH-antagonist. Metformin may increase clinical pregnancy rates using long protocol GnRH-agonist, but we are uncertain of the effect using short protocol GnRH-antagonist. 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.

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.

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Background: 

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.

Objectives: 

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.

Search strategy: 

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).

Selection criteria: 

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.

Types of participants: 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.

Primary outcome measures: live birth rate, incidence of ovarian hyperstimulation syndrome.

Data collection and analysis: 

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.

Main results: 

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.

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