Letrozole Compared With Clomiphene Citrate for Unexplained Infertility: A Systematic Review and Meta-analysis : Obstetrics & Gynecology

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Contents: Reproductive Endocrinology and Infertility: Review

Letrozole Compared With Clomiphene Citrate for Unexplained Infertility

A Systematic Review and Meta-analysis

Eskew, Ashley M. MD; Bedrick, Bronwyn S. BA; Hardi, Angela MLIS; Stoll, Carolyn R. T. MPH, MSW; Colditz, Graham A. MD, DrPH; Tuuli, Methodius G. MD, MPH; Jungheim, Emily S. MD, MSCI

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Obstetrics & Gynecology 133(3):p 437-444, March 2019. | DOI: 10.1097/AOG.0000000000003105


To estimate the clinical effectiveness, as determined by positive pregnancy test, of letrozole compared with clomiphene citrate for ovarian stimulation in patients with unexplained infertility.


We 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.


We 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 I2 were used to assess heterogeneity. Random effects models were used to obtain pooled relative risks (RR) and 95% CIs.


In 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 (I2=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.


Although limited by heterogeneity, studies of ovarian stimulation in women with unexplained infertility show no difference in clinical outcomes between letrozole and clomiphene citrate.

© 2019 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.

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