• Ashley M Eskew, Bronwyn S Bedrick, Angela Hardi, Stoll Carolyn R T CRT, Graham A Colditz, Methodius G Tuuli, and Emily S Jungheim.
• Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology, the Department of Library Sciences, and the Department of Surgery, Public Health Sciences Division, Washington University School of Medicine, St. Louis, Missouri; and the Department of Obstetrics and Gynecology, Division of Maternal Fetal Medicine, Indiana University, Indianapolis, Indiana.
• Obstet Gynecol. 2019 Mar 1; 133 (3): 437-444.

ObjectiveTo estimate the clinical effectiveness, as determined by positive pregnancy test, of letrozole compared with clomiphene citrate for ovarian stimulation in patients with unexplained infertility.Data SourcesWe conducted a systematic review and meta-analysis of data from electronic databases including Ovid-MEDLINE, EMBASE, Scopus, Cochrane Database of Systematic Reviews, Cochrane Register of Controlled Trials, Database of Abstracts of Reviews of Effects, and ClinicalTrials.gov.MethodsWe searched for concepts of unexplained infertility, letrozole, clomiphene citrate, and clinical outcomes including pregnancy and live birth. Studies were included if they were randomized controlled trials (RCTs) comparing clomiphene citrate with letrozole in patients with unexplained infertility. Eight RCTs including 2,647 patients with unexplained infertility were included. Primary outcome was positive pregnancy test per patient. Secondary outcomes included positive pregnancy test per cycle, clinical pregnancy, live birth, spontaneous miscarriage, twin gestation, mean serum estradiol (E2), endometrial thickness, and number of dominant follicles. The Cochrane Q test and Higgin's I were used to assess heterogeneity. Random effects models were used to obtain pooled relative risks (RR) and 95% CIs.Tabulation, Integration, And ResultsIn analysis per patient, there was no significant difference in positive pregnancy test between patients treated with letrozole compared with clomiphene citrate (24% vs 23%, pooled RR 1.08, 95% CI 0.85-1.36). Significant heterogeneity was noted between studies (I=60.8%). There were no significant differences in clinical pregnancy (pooled RR 1.15, 95% CI 0.71-1.85), live birth (pooled RR 0.94, 95% CI 0.83-1.08), spontaneous miscarriage (pooled RR 0.92, 95% CI 0.61-1.38), or twin gestation (pooled RR 0.81, 95% CI 0.39-1.68). Mean serum E2 was significantly lower in the letrozole group than in the clomiphene citrate group.ConclusionAlthough limited by heterogeneity, studies of ovarian stimulation in women with unexplained infertility show no difference in clinical outcomes between letrozole and clomiphene citrate.

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