Metformin in women with polycystic ovary syndrome for improving fertility

Review question: The aim of this Cochrane review was to determine the effectiveness and safety of metformin, an insulin-sensitising agent, for improving ART outcomes, especially, live birth and clinical pregnancy rates, in women with PCOS undergoing in vitro fertilisation (IVF) treatment.

Background: Polycystic ovary syndrome (PCOS) is a condition characterised by chronic failure or absence of ovulation (anovulation) and excessive production of male hormones (hyperandrogenism). The main symptoms of this disorder are irregular menstrual cycles, infertility, hirsutism (excessive hair growth) and acne. This condition is the most common endocrine disorder in women, affecting approximately 5% to 10% of all women of reproductive age.

Study characteristics: The review included nine randomised controlled trials involving a total of 816 women who were randomised to receive metformin (411) versus placebo or no treatment (405). The trials were conducted in the Czech Republic, Italy, Jordan, Norway, Turkey and the United Kingdom. The evidence is current to October 2014.

Key results: When metformin was compared with placebo or no treatment, there was no conclusive evidence of a difference between the groups in live birth rates, but pregnancy rates were higher in the metformin group, and the risk of OHSS was lower. We estimated that for a woman with a 32 % chance of achieving a live birth using placebo, the corresponding chance using metformin would be between 28% and 53%. For a woman with a 31% chance of achieving a clinical pregnancy without metformin, the corresponding chance using metformin would be between 32% and 49%. For a woman with a 27% risk of ovarian hyperstimulation syndrome (OHSS) without metformin, the corresponding chance using metformin would be between 6% and 15%. Side effects (mostly gastrointestinal) were more common in the metformin group, though only four studies reported this outcome.

Quality of the evidence: The overall quality of the evidence was moderate for the outcomes of clinical pregnancy, OHSS and miscarriage, and low for other outcomes. The main limitations in the evidence were imprecision and inconsistency.

Conclusion: We found no conclusive evidence that metformin treatment before or during ART cycles improved live birth rates in women with PCOS. However, the use of this insulin-sensitising agent increased clinical pregnancy rates and decreased the risk of OHSS.

Authors' conclusions: 

This review found no conclusive evidence that metformin treatment before or during ART cycles improved live birth rates in women with PCOS. However, the use of this insulin-sensitising agent increased clinical pregnancy rates and decreased the risk of OHSS.

Read the full abstract...
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. As a consequence, it is suggested that 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 Menstrual Disorders and Subfertility Group Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library), MEDLINE, EMBASE, LILACS, the metaRegister of Controlled Trials and reference lists of articles (up to 15 October 2014).

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.

Types of outcome measures: live birth rate, clinical pregnancy rate, miscarriage rate, incidence of ovarian hyperstimulation syndrome , incidence of participant-reported side effects, serum oestradiol level on the day of trigger, serum androgen level, and fasting insulin and glucose levels.

Data collection and analysis: 

Two review authors independently selected the studies, extracted the data according to the protocol and assessed study quality. The overall quality of the evidence was assessed using GRADE methods.

Main results: 

We included nine randomised controlled trials involving a total of 816 women with PCOS. When metformin was compared with placebo there was no clear evidence of a difference between the groups in live birth rates (OR 1.39, 95% CI 0.81 to 2.40, five RCTs, 551 women, I2 = 52%, low-quality evidence). Our findings suggest that for a woman with a 32 % chance of achieving a live birth using placebo, the corresponding chance using metformin treatment would be between 28% and 53%.

When metformin was compared with placebo or no treatment, clinical pregnancy rates were higher in the metformin group (OR 1.52; 95% CI 1.07 to 2.15; eight RCTs, 775 women, I2 = 18%, moderate-quality evidence). This suggests that for a woman with a 31% chance of achieving a clinical pregnancy using placebo or no treatment, the corresponding chance using metformin treatment would be between 32% and 49%.

The risk of ovarian hyperstimulation syndrome was lower in the metformin group (OR 0.29; 95% CI 0.18 to 0.49, eight RCTs, 798 women, I2 = 11%, moderate-quality evidence). This suggests that for a woman with a 27% risk of having OHSS without metformin the corresponding chance using metformin treatment would be between 6% and 15%.

Side effects (mostly gastrointestinal) were more common in the metformin group (OR 4.49, 95% CI 1.88 to 10.72, for RCTs, 431 women, I2=57%, low quality evidence)

The overall quality of the evidence was moderate for the outcomes of clinical pregnancy, OHSS and miscarriage, and low for other outcomes. The main limitations in the evidence were imprecision and inconsistency.

Share/Save