Strategies for improving outcome of assisted reproduction in women with polycystic ovary syndrome: systematic review and

1. UOG Journal Club: December 2016 Strategies for improving outcome of assisted reproduction in women with polycystic ovary syndrome: systematic review and meta-analysisM. Kollmann, W. P. Martins, M. L. Lima, L. Craciunas, C. O. Nastri, A. Richardson, N. Raine-Fenning Volume 48, Issue 6, Date: December, Pages 709–718 Journal Club slides prepared by Dr Joel Naftalin (UOG Editor for Trainees)

2. Strategies for improving outcome of assisted reproduction in women with polycystic ovary syndrome: systematic review and meta-analysis M. Kollmann et al UOG 2016 Background • Polycystic ovary syndrome (PCOS) affects 2–13% of women of reproductive age and is the most common cause of anovulatory infertility. • Women with PCOS are more likely to be subfertile, with 26% struggling to conceive compared with 17% of women without signs of PCOS. • Assisted reproductive techniques (ART) are the third line of treatment for PCOS-related infertility, after lifestyle modification and the use of drugs to induce monofollicular ovulation.

3. Strategies for improving outcome of assisted reproduction in women with polycystic ovary syndrome: systematic review and meta-analysis M. Kollmann et al UOG 2016 Background • Women with PCOS are typically more difficult to stimulate in a controlled manner and are more likely to demonstrate resistance to stimulation and/or an exaggerated response. • Recent developments have seen the introduction of various measures to reduce the risks of ovarian hyperstimulation syndrome (OHSS) and cycle cancellation and to improve oocyte quality. • It remains unclear how these new approaches have impacted on ART outcomes in women with PCOS.

4. Strategies for improving outcome of assisted reproduction in women with polycystic ovary syndrome: systematic review and meta-analysis M. Kollmann et al UOG 2016 Objective To examine the efficacy of all strategies aimed at improving ART outcomes in women with PCOS

5. Strategies for improving outcome of assisted reproduction in women with polycystic ovary syndrome: systematic review and meta-analysis M. Kollmann et al UOG 2016 Methods – eligibility criteria • The review protocol was registered at the international prospective register of systematic reviews (PROSPERO): CRD42014007304. • The review included randomized controlled trials evaluating interventions aimed at improving the effectiveness of, or reducing the complications of, ART in women diagnosed with PCOS. • Only studies published in English and reporting one of the following outcomes were included: live birth/ongoing pregnancy, OHSS, clinical pregnancy or miscarriage.

6. Strategies for improving outcome of assisted reproduction in women with polycystic ovary syndrome: systematic review and meta-analysis M. Kollmann et al UOG 2016 Results

7. Strategies for improving outcome of assisted reproduction in women with polycystic ovary syndrome: systematic review and meta-analysis M. Kollmann et al UOG 2016 Results 41 studies reporting live birth/ongoing pregnancy • Evidence from 10 studies (n=856) showed metformin had a positive effect on live birth/ongoing pregnancy compared with placebo or no metformin (RR = 1.28 (95% CI, 1.01–1.63), I2 = 22%). • Evidence from 12 studies (n=1525) showed no difference in using antagonist or agonist protocols for ovarian stimulation (RR = 0.95 (95% CI, 0.84–1.08), I2 = 0%) • There was no clinical difference between ovulation induction and estradiol for endometrial preparation for frozen embryo transfer (FET).

8. Strategies for improving outcome of assisted reproduction in women with polycystic ovary syndrome: systematic review and meta-analysis M. Kollmann et al UOG 2016 Results 61 studies reporting clinical pregnancy • Evidence from 12 studies (n=1004) suggested metformin has a positive effect on clinical pregnancy compared with placebo or no metformin (RR = 1.26 (95% CI, 1.04–1.53), I2 = 24%). • Evidence from 13 studies (n=1551) showed no significant difference in using antagonist or agonist protocols for ovarian stimulation (RR = 1.02 (95% CI, 0.91–1.15), I2 = 7%). • There was no clinical difference between ovulation induction and estradiol for endometrial preparation for FET.

9. Strategies for improving outcome of assisted reproduction in women with polycystic ovary syndrome: systematic review and meta-analysis M. Kollmann et al UOG 2016 • Results40 studies reporting miscarriage • Evidence for all comparisons were of very low quality, not allowing meaningful conclusions to be drawn. • Results • 41 studies reporting OHSS • Evidence suggested that antagonist protocols were associated with a lower risk for developing OHSS than agonist protocols. • There was evidence of a benefit for administration of mannitol

10. Strategies for improving outcome of assisted reproduction in women with polycystic ovary syndrome: systematic review and meta-analysis M. Kollmann et al UOG 2016 Conclusion • There was moderate-quality evidence that there is no clinically relevant difference in live birth/ongoing pregnancy or clinical pregnancy rates when comparing antagonist and agonist protocols for controlled ovarian stimulation. • There was low-quality evidence that starting gonadotropin releasing hormone antagonists early or late has no benefit on clinical pregnancy. • There was low-quality evidence that there is no clinically relevant difference in live birth/ongoing pregnancy and clinical pregnancy rates when comparing human menopausal gonadotropin for inducing ovulation and artificial endometrial preparation with estradiol before FET. • Low-quality evidence suggests that mannitol administration and antagonist protocols reduce rates of OHSS.

11. GnStrategies for improving outcome of assisted reproduction in women with polycystic ovary syndrome: systematic review and meta-analysis M. Kollmann et al UOG 2016 Strengths • A high number of records were screened (n=1021), completely assessed (n=173) and included (n=66) in the analysis. • A random-effects model was incorporated into the results to account for heterogeneity. Limitations • The overall quality of the studies included was low, which means that the true effect may be substantially different from that reported. • Definitions of PCOS differed across the studies and there was some variation in the investigated interventions.

12. Strategies for improving outcome of assisted reproduction in women with polycystic ovary syndrome: systematic review and meta-analysis M. Kollmann et al UOG 2016 Discussion points • Is it justifiable to change clinical practice on the basis of meta-analyses in which the evidence is largely of low quality? • How should we counsel women/couples about the lack of high-quality evidence available to guide their care? • As an academic community, should we try to raise the quality of individual studies to ensure that more useful conclusions can be drawn from subsequent meta-analyses? If so, how might this be done?