Sebastian Franik, Stephanie M Eltrop, Jan AM Kremer, Ludwig Kiesel, Cindy Farquhar

Polycystic ovary syndrome (PCOS) is the most common cause of infrequent periods (oligomenorrhoea) and absence of periods (amenorrhoea). It affects about 4% to 8% of women worldwide and often leads to anovulatory subfertility. Aromatase inhibitors (AIs) are a class of drugs that were introduced for ovulation induction in 2001. Since about 2001 clinical trials have reached differing conclusions as to whether the AI letrozole is at least as effective as the first-line treatment clomiphene citrate (CC). To evaluate the effectiveness and safety of aromatase inhibitors for subfertile women with anovulatory PCOS for ovulation induction followed by timed intercourse or intrauterine insemination (IUI). We searched the following sources from inception to November 2017 to identify relevant randomised controlled trials (RCTs): the Cochrane Gynaecology and Fertility Group Specialised Register, the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, PsycINFO, Pubmed, LILACS, Web of Knowledge, the World Health Organization (WHO) clinical trials register and Clinicaltrials.gov. We also searched the references of relevant articles. We did not restrict the searches by language or publication status. We included all RCTs of AIs used alone or with other medical therapies for ovulation induction in women of reproductive age with anovulatory PCOS. Two review authors independently selected trials, extracted the data and assessed risks of bias. We pooled studies where appropriate using a fixed-effect model to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for most outcomes, and risk differences (RDs) for ovarian hyperstimulation syndrome (OHSS). The primary outcomes were live birth and OHSS. Secondary outcomes were clinical pregnancy, miscarriage and multiple pregnancy. We assessed the quality of the evidence for each comparison using GRADE methods. This is a substantive update of a previous review. We identified 16 additional studies for the 2018 update. We include 42 RCTs (7935 women). The aromatase inhibitor letrozole was used in all studies.Letrozole compared to clomiphene citrate (CC) with or without adjuncts followed by timed intercourseLive birth rates were higher with letrozole (with or without adjuncts) compared to clomiphene citrate (with our without adjuncts) followed by timed intercourse (OR 1.68, 95% CI 1.42 to 1.99; 2954 participants; 13 studies; I2 = 0%; number needed to treat for an additional beneficial outcome (NNTB) = 10; moderate-quality evidence). There is high-quality evidence that OHSS rates are similar with letrozole or clomiphene citrate (0.5% in both arms: risk difference (RD) -0.00, 95% CI -0.01 to 0.00; 2536 participants; 12 studies; I2 = 0%; high-quality evidence). There is evidence for a higher pregnancy rate in favour of letrozole (OR 1.56, 95% CI 1.37 to 1.78; 4629 participants; 25 studies; I2 = 1%; NNTB = 10; moderate-quality evidence). There is little or no difference between treatment groups in the rate of miscarriage by pregnancy (20% with CC versus 19% with letrozole; OR 0.94, 95% CI 0.70 to 1.26; 1210 participants; 18 studies; I2 = 0%; high-quality evidence) and multiple pregnancy rate (1.7% with CC versus 1.3% with letrozole; OR 0.69, 95% CI 0.41 to 1.16; 3579 participants; 17 studies; I2 = 0%; high-quality evidence). However, a funnel plot showed mild asymmetry, indicating that some studies in favour of clomiphene might be missing.Letrozole compared to laparoscopic ovarian drillingThere is low-quality evidence that live birth rates are similar with letrozole or laparoscopic ovarian drilling (OR 1.38, 95% CI 0.95 to 2.02; 548 participants; 3 studies; I2 = 23%; low-quality evidence). There is insufficient evidence for a difference in OHSS rates (RD 0.00, 95% CI -0.01 to 0.01; 260 participants; 1 study; low-quality evidence). There is low-quality evidence that pregnancy rates are similar (OR 1.28, 95% CI 0.94 to 1.74; 774 participants; 5 studies; I2 = 0%; moderate-quality evidence). There is insufficient evidence for a difference in miscarriage rate by pregnancy (OR 0.66, 95% CI 0.30 to 1.43; 240 participants; 5 studies; I2 = 0%; moderate-quality evidence), or multiple pregnancies (OR 3.00, 95% CI 0.12 to 74.90; 548 participants; 3 studies; I2 = 0%; low-quality evidence).Additional comparisons were made for Letrozole versus placebo, Selective oestrogen receptor modulators (SERMS) followed by intrauterine insemination (IUI), follicle stimulating hormone (FSH), Anastrozole, as well as dosage and administration protocols. There is insufficient evidence for a difference in either group of treatment due to a limited number of studies. Hence more research is necessary. Letrozole appears to improve live birth and pregnancy rates in subfertile women with anovulatory polycystic ovary syndrome, compared to clomiphene citrate. There is high-quality evidence that OHSS rates are similar with letrozole or clomiphene citrate. There is high-quality evidence of no difference in miscarriage rates or multiple pregnancy rates. There is low-quality evidence of no difference in live birth and pregnancy rates between letrozole and laparoscopic ovarian drilling, although there were few relevant studies. For the 2018 update, we added good-quality trials, upgrading the quality of the evidence.