Rui Wang, PhD candidate and gynaecologist1 2, Bobae V Kim, postgraduate student1, Madelon van Wely, clinical epidemiologist3, Neil P Johnson, professor1 4, Michael F Costello, senior lecturer5, Hanwang Zhang, professor2, Ernest Hung Yu Ng, professor6, Richard S Legro, professor7, Siladitya Bhattacharya, professor8, Robert J Norman, professor1 9 10, Ben Willem J Mol, professor

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, 57 trials reporting on 8082 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 1.58, 95% confidence interval 1.25 to 2.00; 1.81, 1.35 to 2.42; respectively) and ovulation rates (1.99, 1.38 to 2.87; 1.55, 1.02 to 2.36; respectively). Letrozole led to higher live birth rates when compared with clomiphene alone (1.67, 1.11 to 2.49). Both letrozole and metformin led to lower multiple pregnancy rates compared with clomiphene alone (0.46, 0.23 to 0.92; 0.22, 0.05 to 0.92; respectively).

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

Systematic review registration PROSPERO CRD42015027579.

BMJ