Metformin as adjuvant therapy to IVF in women with PCOS: when is intention-to-treat unintentional?

نویسنده

  • Richard S Legro
چکیده

More than 15 years have passed since metformin was hailed as a possible treatment for infertility in women with polycystic ovary syndrome (PCOS) (Velazquez et al., 1994). Though a recent Cochrane Systematic review examining metformin for ovulation induction concludes that ‘the use of metformin in improving reproductive outcomes in women with PCOS appears to be limited’ (Tang et al., 2010), the debate over metformin’s role in infertility continues passionately. A systematic review is only as good as the studies contributing to it, and there have been multiple critiques of previous randomized trials of metformin in women with PCOS, including an over-representation of obese women, a too short pretreatment period with metformin, possible differences between immediate release and extended release preparations of metformin, and failure to recognize its benefit as an adjuvant therapy for other infertility treatments, for example, IVF/ICSI. Another Cochrane Systematic review of metformin for IVF/ICSI in women with PCOS noted no benefit of metformin on pregnancy rates, but stated ‘The risk of ovarian hyperstimulation syndrome (OHSS) in women with PCOS and undergoing IVF or ICSI cycles was reduced with metformin’ and recommended further multi-center trials (Costello et al., 2006). In this issue of Human Reproduction Kjøtrød et al. (2011) have answered the call to provide a multi-center double-blind randomized controlled trial of the use of metformin as an adjuvant to PCOS, as well as identify a population (thin) and a treatment regimen (immediate release metformin given 3 months prior to IVF) that may further increase live birth. This is a well-designed trial, and the best of its kind to date. This tantalizing trial suggests a benefit to metformin in this adjuvant role, but the design and analysis raise as many questions as the study answers. These questions include the use of intention to treat (ITT) analysis for a multi-tiered intervention, the role of IVF in treating anovulatory infertility and the feasibility of randomized trials for a widely popular but unproven adjuvant therapy. The study of Kjøtrød et al. (2011) randomized thin or mildly overweight women (BMI , 28 kg/m) with PCOS to either metformin or placebo for 12 weeks before or during IVF/ICSI, and focused on clinical pregnancy rate as the primary outcome. The sample size was well justified based on a pilot trial which had showed a significant benefit to metformin on clinical pregnancy rate (Kjotrod et al., 2004). An ITT analysis was planned; i.e. everyone is analyzed according to their initial randomized treatment assignment, whether they receive all of the intended treatment (e.g. IVF) or not. On the basis of the ITT analysis, the addition of metformin significantly improved clinical pregnancy rates. There were 62 pregnancies in 149 subjects, 37/74 (50.0%) in the metformin group and 25/75 (33.3%) in the placebo group. The clinical pregnancy rate was significantly higher in the metformin versus the placebo group, with a difference of 16.7% (95% CI: 1.1–32.3; P 1⁄4 0.0391). At first glance, this is a stunning outcome, and one likely to change clinical practice. However, further analysis shows that the benefit accrued only in the period prior to assisted reproduction; i.e. women assigned to metformin conceived clinical pregnancies prior to assisted reproduction techniques (ART) at about twice the rate compared with placebo (65 versus 35%), whereas clinical pregnancy rates were identical in the subjects who made it to IVF/ICSI (50% in each group). Both clinicians and the tabloids could have a field day with these results depending on how they wanted to spin it. While a spontaneous conception on metformin without a whiff of IVF in this ITT analysis may count towards an IVF benefit, does it count in the world of common sense? Certainly the post hoc poor man’s sensitivity analysis (analyzing pregnancies with and without IVF/ICSI), suggests there was no benefit to metformin on IVF/ICSI pregnancy outcomes. The rules in real-time for determining ART pregnancies are often confusing. For example, in the USA, reporting methods for pregnancy rates are mandated by the Society of Reproductive Technology (SART) and overseen by the Centers for Disease Control and Prevention (which is required as a result of the 1992 Fertility Clinic Success Rate and Certification Act to publish the annual ART success rates at U.S. fertility clinics). According to these methods, a pregnancy that occurs in an IVF cycle after start of a GnRH agonist, but before start of gonadotrophins does not count as an ART pregnancy. However, an IVF cycle that is converted to intrauterine insemination and results in pregnancy counts as an ART success. Neither of course involved IVF. In the case of the article of Kjøtrød et al. (2011), I do not see the pretreatment period as a continuum to IVF/ICSI, I see it as a separate treatment.

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عنوان ژورنال:
  • Human reproduction

دوره 26 8  شماره 

صفحات  -

تاریخ انتشار 2011