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N Engl J Med. 2015 Sep 24;373(13):1230-40. doi: 10.1056/NEJMoa1414827.

Letrozole, Gonadotropin, or Clomiphene for Unexplained Infertility.

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From the Department of Obstetrics and Gynecology, Georgia Regents University, Augusta (M.P.D.); Department of Obstetrics and Gynecology, Wayne State University, Detroit (M.P.D., J.A., S.A.K.); Department of Obstetrics and Gynecology, Pennsylvania State University, Hershey (R.S.L.); Department of Obstetrics and Gynecology, University of Pennsylvania School of Medicine, Philadelphia (C.C., K.B.); Department of Obstetrics and Gynecology, University of Colorado, Denver (R.A., N.S.); Department of Obstetrics and Gynecology, University of Texas Health Science Center at San Antonio, San Antonio (R.D.R.); Department of Obstetrics and Gynecology, University of Vermont, Burlington (P.C.); Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor (G.M.C., D.O.); Department of Biostatistics, Yale University School of Public Health, New Haven, CT (H.H., Y.J., H.Z.); Department of Obstetrics and Gynecology, University of Oklahoma College of Medicine, Oklahoma City (K.R.H.); Stanford University Medical Center, Stanford, CA (V.B.); Carolinas Medical Center, Charlotte, NC (R.U.); University of Medicine and Dentistry of New Jersey, Newark (A.S.); University of Alabama at Birmingham, Birmingham (G.W.B.); Department of Reproductive Endocrinology and Infertility, University of California, San Francisco, San Francisco (R.M.R.); Ligand Core Laboratory, University of Virginia Center for Research in Reproduction, Charlottesville (D.H.); Upstate University Hospital, Syracuse, NY (J.C.T.); and Fertility and Infertility Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Rockville, MD (E.E.).



The standard therapy for women with unexplained infertility is gonadotropin or clomiphene citrate. Ovarian stimulation with letrozole has been proposed to reduce multiple gestations while maintaining live birth rates.


We enrolled couples with unexplained infertility in a multicenter, randomized trial. Ovulatory women 18 to 40 years of age with at least one patent fallopian tube were randomly assigned to ovarian stimulation (up to four cycles) with gonadotropin (301 women), clomiphene (300), or letrozole (299). The primary outcome was the rate of multiple gestations among women with clinical pregnancies.


After treatment with gonadotropin, clomiphene, or letrozole, clinical pregnancies occurred in 35.5%, 28.3%, and 22.4% of cycles, and live birth in 32.2%, 23.3%, and 18.7%, respectively; pregnancy rates with letrozole were significantly lower than the rates with standard therapy (gonadotropin or clomiphene) (P=0.003) or gonadotropin alone (P<0.001) but not with clomiphene alone (P=0.10). Among ongoing pregnancies with fetal heart activity, the multiple gestation rate with letrozole (9 of 67 pregnancies, 13%) did not differ significantly from the rate with gonadotropin or clomiphene (42 of 192, 22%; P=0.15) or clomiphene alone (8 of 85, 9%; P=0.44) but was lower than the rate with gonadotropin alone (34 of 107, 32%; P=0.006). All multiple gestations in the clomiphene and letrozole groups were twins, whereas gonadotropin treatment resulted in 24 twin and 10 triplet gestations. There were no significant differences among groups in the frequencies of congenital anomalies or major fetal and neonatal complications.


In women with unexplained infertility, ovarian stimulation with letrozole resulted in a significantly lower frequency of multiple gestation but also a lower frequency of live birth, as compared with gonadotropin but not as compared with clomiphene. (Funded by the National Institutes of Health and others; number, NCT01044862.).

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