Treatment strategies for women with WHO group II anovulation: systematic review and network meta-analysis

Rui Wang, Bobae V Kim, Madelon van Wely, Neil P Johnson, Michael F Costello, Hanwang Zhang, Ernest Hung Yu Ng, Richard S Legro, Siladitya Bhattacharya, Robert J Norman, Ben Willem J Mol, Rui Wang, Bobae V Kim, Madelon van Wely, Neil P Johnson, Michael F Costello, Hanwang Zhang, Ernest Hung Yu Ng, Richard S Legro, Siladitya Bhattacharya, Robert J Norman, Ben Willem J Mol

Abstract

Objective: To compare the effectiveness of alternative first line treatment options for women with WHO group II anovulation wishing to conceive.

Design: Systematic review and network meta-analysis.

Data sources: Cochrane Central Register of Controlled Trials, Medline, and Embase, up to 11 April 2016.

Study selection: Randomised controlled trials comparing eight ovulation induction treatments in women with WHO group II anovulation: clomiphene, letrozole, metformin, clomiphene and metformin combined, tamoxifen, gonadotropins, laparoscopic ovarian drilling, and placebo or no treatment. Study quality was measured on the basis of the methodology and categories described in the Cochrane Collaboration Handbook. Pregnancy, defined preferably as clinical pregnancy, was the primary outcome; live birth, ovulation, miscarriage, and multiple pregnancy were secondary outcomes.

Results: Of 2631 titles and abstracts initially identified, 54 trials reporting on 7173 women were included. All pharmacological treatments were superior to placebo or no intervention in terms of pregnancy and ovulation. Compared with clomiphene alone, both letrozole and the combination of clomiphene and metformin showed higher pregnancy rates (odds ratio 1.69, 95% confidence interval 1.33 to 2.14; 1.71, 1.28 to 2.27; respectively). Letrozole led to higher live birth rates when compared with clomiphene alone (1.67, 1.11 to 2.49). Metformin led to lower multiple pregnancy rates compared with clomiphene alone (0.22, 0.05 to 0.93).

Conclusions: In women with WHO group II anovulation, letrozole and the combination of clomiphene and metformin are superior to clomiphene alone in terms of pregnancy. Compared with clomiphene alone, letrozole is the only treatment showing a significantly higher rate of live birth.

Systematic review registration: PROSPERO CRD42015027579.

Readers' note: This is the second version of this paper. The original version was corrected following the retraction of two studies and removal of another which were ineligible (references 40, 41, and 75 of the original paper). These studies are not shown in this version. A tracked changes version of the original version is attached as a supplementary file to the correction notice, which explains the issue further.

Conflict of interest statement

Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: support from the Australian government research training programme and the Australian National Health and Medical Research Council funded Centre for Research Excellence in Polycystic Ovary Syndrome for the submitted work; NPJ declares having received conference expenses from Bayer Pharma, Merck-Serono, and MSD, research funding from AbbVie, and is a consultant to Vifor Pharma and Guerbet; RSL reports consulting fees from Euroscreen, Kindex, Bayer, and Millendo Pharmaceuticals, and research funding from Ferring, but none of the treatments analysed in the paper conflicted with his consulting or research funding; all other authors declare no financial relationships with any organisations that might have an interest in the submitted work in the previous three years, and no other relationships or activities that could appear to have influenced the submitted work.

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Figures

Fig 1
Fig 1
PRISMA flow diagram of literature search for randomised controlled trials comparing eight ovulation induction treatments in women with WHO group II anovulation. *Full text articles=including abstract only publications
Fig 2
Fig 2
Network meta-analysis of effectiveness of treatment options for pregnancy in women with WHO group II anovulation. Blue squares=estimate summary odds ratios of each comparison; black horizontal lines=confidence intervals; blue horizontal lines (overall length of lines)=predictive intervals (PrI); blue vertical line=line of no effect (odds ratio=1). Odds ratios less than 1 favour the first intervention; odds ratios greater than 1 favour the second intervention

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Source: PubMed

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