UOG Journal Club: January 2018 Effect of clomiphene citrate on endometrial thickness, ovulation, pregnancy and live birth in anovulatory women: systematic review and meta-analysis M. A. Gadalla, S, Huang, R. Wang, R. J. Norman, S. A. Abdullah, A. M. El Saman, A. M. Ismail, M. Van Wely, B. W. J. Mol Volume 51, Issue 1, pages 64–76 Journal Club slides prepared by Dr Joel Naftalin (UOG Editor for Trainees)

Background About 25% of infertility is caused by ovulatory disorders. Effect of clomiphene citrate on endometrial thickness, ovulation, pregnancy and live birth in anovulatory women: systematic review and meta-analysis Gadalla et al., UOG 2018 Background About 25% of infertility is caused by ovulatory disorders. The World Health Organization (WHO) classifies ovulatory disorders into three groups: Group I hypothalamic-pituitary-ovarian failure Group II hypothalamic-pituitary-ovarian dysfunction Group III ovarian failure Group II is predominantly made up of women with PCOS.

Effect of clomiphene citrate on endometrial thickness, ovulation, pregnancy and live birth in anovulatory women: systematic review and meta-analysis Gadalla et al., UOG 2018 Background Clomiphene Citrate (CC) is often recommended as the first-line treatment for women with group II anovulation, although many guidelines recommend both CC and letrozole as first-line treatments. While the cost-differences between letrozole and CC are less important in highly resourced countries, the 3-fold greater cost of letrozole is important in low-resourced countries. While it has been hypothesized that CC resistance is related to its anti-estrogenic effects on the endometrium, cervical mucus and uterine blood flow, these effects have not been systematically assessed.

Effect of clomiphene citrate on endometrial thickness, ovulation, pregnancy and live birth in anovulatory women: systematic review and meta-analysis Gadalla et al., UOG 2018 Objective To compare the impact of CC vs other drug regimens on mid-cycle endometrial thickness, ovulation, pregnancy and live birth rates in women with WHO group II ovulatory disorders

MEDLINE, EMBASE, Scopus, Web of Science, Cochrane Central Register of Clinical Trials and the non-MEDLINE subset of PubMed to December 2016 were searched, along with the reference lists of relevant studies. No language restrictions were applied. All published trials studying the impact of CC alone vs other drug regimens on mid-cycle endometrial thickness in women with WHO group II ovulatory disorders were searched for. Flowchart of studies included in systematic and meta-analysis.

Forest plot for comparison of live birth between CC and letrozole Effect of clomiphene citrate on endometrial thickness, ovulation, pregnancy and live birth in anovulatory women: systematic review and meta-analysis Gadalla et al., UOG 2018 Results Forest plot for comparison of live birth between CC and letrozole

Results Forest plot for comparison of mid-cycle endometrial thickness Effect of clomiphene citrate on endometrial thickness, ovulation, pregnancy and live birth in anovulatory women: systematic review and meta-analysis Gadalla et al., UOG 2018 Results Forest plot for comparison of mid-cycle endometrial thickness between CC and letrozole.

Effect of clomiphene citrate on endometrial thickness, ovulation, pregnancy and live birth in anovulatory women: systematic review and meta-analysis Gadalla et al., UOG 2018 Results Forest plot for comparison of ovulation rates between CC and letrozole.

Effect of clomiphene citrate on endometrial thickness, ovulation, pregnancy and live birth in anovulatory women: systematic review and meta-analysis Gadalla et al., UOG 2018 Results Summary of findings on impact of CC vs letrozole on endometrial thickness, ovulation, pregnancy and live birth in women with WHO group II ovulatory disorders.

Effect of clomiphene citrate on endometrial thickness, ovulation, pregnancy and live birth in anovulatory women: systematic review and meta-analysis Gadalla et al., UOG 2018 Key findings CC resulted in lower endometrial thickness and lower pregnancy and live birth rates compared with letrozole, for comparable ovulation rates. CC, when compared with nitric oxide donor or N-acetyl cysteine, resulted in lower endometrial thickness and lower ovulation and pregnancy rates, but the number of studies was limited. There was no statistically significant difference in endometrial thickness, ovulation and pregnancy rates when comparing CC with tamoxifen, raloxifene, recombinant follicle stimulating hormone and phytoestrogens.

Publication bias and quality of evidence Effect of clomiphene citrate on endometrial thickness, ovulation, pregnancy and live birth in anovulatory women: systematic review and meta-analysis Gadalla et al., UOG 2018 Publication bias and quality of evidence The quality of evidence was rated as very low for all outcomes in the main comparison between CC and letrozole. Funnel plots were produced for mid-cycle endometrial thickness, ovulation and pregnancy rates in comparison between CC and letrozole. These suggested a low risk of publication bias for mid-cycle endometrial thickness and a high risk of publication bias for ovulation and pregnancy outcomes.

Effect of clomiphene citrate on endometrial thickness, ovulation, pregnancy and live birth in anovulatory women: systematic review and meta-analysis Gadalla et al., UOG 2018 Strengths The study dealt with a topic that has not been addressed thoroughly in systematic reviews. The study focused on the most commonly recommended first-line treatment for ovulation induction. A high number of records were screened (n = 929). No language restrictions were applied and the search included trials published as abstracts to reduce publication bias.

Limitations The overall quality of the studies included was low. Effect of clomiphene citrate on endometrial thickness, ovulation, pregnancy and live birth in anovulatory women: systematic review and meta-analysis Gadalla et al., UOG 2018 Limitations The overall quality of the studies included was low. Most of the studies were underpowered and there was considerable heterogeneity in the data comparing mid-cycle endometrial thickness. By basing the search strategy on mid-cycle endometrial thickness, it is likely that estimates of ovulation, pregnancy and live birth rates were not based on all available evidence.

Effect of clomiphene citrate on endometrial thickness, ovulation, pregnancy and live birth in anovulatory women: systematic review and meta-analysis Gadalla et al., UOG 2018 Discussion points Is the lower pregnancy and birth rate seen with CC, in comparison with letrozole, secondary to reduced endometrial thickness or other factors? How would one construct a study to test this? Given the difference in the cost of CC and letrozole, do we need a cost-effectiveness analysis to help determine which drug to use in settings which are differently-resourced? How should we counsel women with WHO group II ovulatory disorders about the lack of high-quality evidence available to guide their care? As an academic community, how do we raise the quality of individual studies to ensure that more useful conclusions can be drawn from meta-analyses?