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Treatment Strategies for Women with WHO Group II Anovulation: BMJ: First Published As 10.1136/Bmj.J138 on 31 January 2017

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Treatment Strategies for Women with WHO Group II Anovulation: BMJ: First Published As 10.1136/Bmj.J138 on 31 January 2017 RESEARCH OPEN ACCESS Treatment strategies for women with WHO group II anovulation: BMJ: first published as 10.1136/bmj.j138 on 31 January 2017. Downloaded from systematic review and network meta-analysis Rui Wang,1,2 Bobae V Kim,1 Madelon van Wely,3 Neil P Johnson,1,4 Michael F Costello,5 Hanwang Zhang,2 Ernest Hung Yu Ng,6 Richard S Legro,7 Siladitya Bhattacharya,8 Robert J Norman,1,9,10 Ben Willem J Mol1,11 For numbered affiliations see ABSTRACT 1.55, 1.02 to 2.36; respectively). Letrozole led to higher end of article. OBJECTIVE live birth rates when compared with clomiphene alone Correspondence to: R Wang, To compare the effectiveness of alternative first line (1.67, 1.11 to 2.49). Both letrozole and metformin led to University of Adelaide, North Adelaide, Australia, treatment options for women with WHO group II lower multiple pregnancy rates compared with [email protected] anovulation wishing to conceive. clomiphene alone (0.46, 0.23 to 0.92; 0.22, 0.05 to Cite this as: BMJ 2017;356:j138 DESIGN 0.92; respectively). http://dx.doi.org/10.1136/bmj.j138 Systematic review and network meta-analysis. CONCLUSIONS Accepted: 29 December 2016 DATA SOURCES In women with WHO group II anovulation, letrozole and Cochrane Central Register of Controlled Trials, Medline, the combination of clomiphene and metformin are and Embase, up to 11 April 2016. superior to clomiphene alone in terms of ovulation and pregnancy. Compared with clomiphene alone, STUDY SELECTION letrozole is the only treatment showing a significantly Randomised controlled trials comparing eight higher rate of live birth. ovulation induction treatments in women with WHO group II anovulation: clomiphene, letrozole, SYSTEMATIC REVIEW REGISTRATION metformin, clomiphene and metformin combined, PROSPERO CRD42015027579. tamoxifen, gonadotropins, laparoscopic ovarian drilling, and placebo or no treatment. Study quality Introduction was measured on the basis of the methodology and Infertility affects one in seven couples, and ovulation categories described in the Cochrane Collaboration disorders account for a quarter of all cases.1 Normogo- Handbook. Pregnancy, defined preferably as clinical nadotrophic anovulation, also classified as World http://www.bmj.com/ pregnancy, was the primary outcome; live birth, Health Organization group II anovulation, is the most ovulation, miscarriage, and multiple pregnancy were secondary outcomes. common category of anovulatory infertility. Within this group, polycystic ovary syndrome (PCOS) is by far the RESULTS most prevalent cause.2 Of 2631 titles and abstracts initially identified, 57 trials PCOS was first described in 1935 by Stein and reporting on 8082 women were included. All Leventhal.3 Previously described in several different pharmacological treatments were superior to placebo ways, the diagnostic criteria for PCOS, agreed jointly on 23 September 2021 by guest. Protected copyright. or no intervention in terms of pregnancy and ovulation. by the European Society of Human Reproduction Compared with clomiphene alone, both letrozole and and Embryology and the American Society for Repro- the combination of clomiphene and metformin showed ductive Medicine, are known as the Rotterdam crite- higher pregnancy rates (odds ratio 1.58, 95% ria.4 5 These criteria are also endorsed by the confidence interval 1.25 to 2.00; 1.81, 1.35 to 2.42; 6 respectively) and ovulation rates (1.99, 1.38 to 2.87; Endocrine Society and are used by a wide range of medical professionals, and not just obstetricians and gynaecologists. The clinical manifestations of PCOS include oligomenorrhoea or amenorrhoea, hir- WHat IS ALREADY KNOWN ON THIS TOPIC sutism, and frequently infertility.7 From conception, Clomiphene is the longstanding first line treatment for WHO group II anovulation women with PCOS and their infants are at increased Existing pairwise meta-analyses are limited to comparisons of two treatments risk of perinatal complications, including gesta- tional diabetes, pre-eclampsia, preterm labour, and WHat THIS stUDY ADDS neonatal morbidity.8-10 This study compares all of the most common regimens of ovulation induction with Safe and effective ovulation induction is important each other, using direct and indirect means for women with WHO group II anovulation who wish to All pharmacological ovulation inductions were superior to placebo or no treatment conceive, to avoid premature exposure to in vitro fertil- in terms of ovulation and pregnancy in women with WHO group II anovulation isation, which is invasive, expensive, and associated Letrozole was the most effective treatment in terms of live birth, and one of the top with potentially higher chances of perinatal complica- 11-14 three treatments in terms of pregnancy and ovulation tions and congenital abnormalities. Several medical options are used to treat ovulation disorders and infer- Clomiphene and metformin combined was the most effective treatment in terms of tility, including oestrogen receptor modulators (such as pregnancy but not live birth; the potential higher chances of side effects should clomiphene and tamoxifen), aromatase inhibitors also be taken into account in decision making (such as letrozole), insulin sensitising drugs (such as Metformin and letrozole were associated with the lowest rates of multiple pregnancy metformin), and direct hormonal stimulation of the the bmj | BMJ 2017;356:j138 | doi: 10.1136/bmj.j138 1 RESEARCH ovaries (gonadotropins), with laparoscopic ovarian only compared different doses of the same treatment BMJ: first published as 10.1136/bmj.j138 on 31 January 2017. Downloaded from drilling being a surgical alternative. option or compared the effects of adding medical Traditional pairwise meta-analysis only allows adjuncts such as dexamethasone. Authors were con- the comparison of two interventions for ovulation tacted for further information if necessary. induction.15-20 However, many of these treatment strat- egies have not been compared directly in previous ran- Patient involvement domised controlled trials. Therefore, it is difficult to There was no patient involvement in framing the identify the most effective treatment based on direct research question, choosing the outcome measures, or evidence. Network meta-analysis, also known as multi- conducting the research. We plan to involve Fertility ple treatment comparison meta-analysis, compares Network UK, PCOS Challenge, RESOLVE, and Access multiple treatments in one statistical model,21-23 and Australia's National Infertility Network in the dissemi- provides a hierarchy of effectiveness of these treatments nation of the research results by means of short, easy to that can guide decision making.24 25 The application of read summaries of key results, infographics, and audio network meta-analysis is crucial in areas where multi- or video interviews that can be used by patients and ple interventions are available, such as in WHO group II caregivers. anovulation. We therefore performed a systematic review and net- Data extraction and assessment of risk of bias work meta-analysis to compare the effectiveness of dif- Two reviewers (RW and BVK) independently assessed ferent treatment options, including clomiphene, the eligibility of all identified citations, and extracted letrozole, metformin, clomiphene and metformin com- data from original trial reports using a specifically bined, tamoxifen, gonadotropins, laparoscopic ovarian designed form that captured information on study drilling, and placebo or no treatment, in women with design, trial setting, patient characteristics (inclusion WHO group II anovulation, and to identify the best criteria, age, body mass index, duration of infertility, strategy for first line treatment. history of ovulation induction), sample sizes, details of ovulation induction options, and outcomes. Disagree- Methods ments were referred to a third reviewer (BWJM) to reach Search strategy and selection criteria consensus. We conducted and reported the study according to the We chose pregnancy, defined preferably as clinical preferred reporting items for systematic reviews and pregnancy, as the primary outcome. Clinical pregnancy meta-analyses (PRISMA) extension statement for net- was defined as pregnancy diagnosed by ultrasono- http://www.bmj.com/ work meta-analyses.26 We performed an extensive elec- graphic visualisation of one or more gestational tronic search of the Cochrane Central Register of sacs.27 28 Comparing the effectiveness of a treatment Controlled Trials (CENTRAL), Medline, and Embase for based on either clinical pregnancy or live birth rate as randomised controlled trials. The search strategies endpoints often results in comparable conclusions.29 were based on combinations of ovulation induction and Therefore, we used data on live birth or pregnancy (pos- anovulation (or PCOS), using both free words and index itive blood or urine test for human chorionic gonadotro- terms (appendix 1). We sought further trial details or pin) as an outcome when data on clinical pregnancy on 23 September 2021 by guest. Protected copyright. protocols to establish eligibility of potential trials. We were not available. Secondary outcomes were live birth, also searched previous published Cochrane systematic ovulation, miscarriage, and multiple pregnancy. reviews on ovulation induction for additional studies. Study quality was assigned by two reviewers (RW and No language restrictions were applied. Our latest search BVK) using the methodology and categories described was completed on 11 April 2016. in the
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