Letrozole, gonadotropin, or clomiphene for unexplained infertility

The NICHD Reproductive Medicine Network

Research output: Contribution to journalArticle

87 Citations (Scopus)

Abstract

Background: 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. Methods: 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. Results: 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. Conclusions: 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.

Original languageEnglish (US)
Pages (from-to)1230-1240
Number of pages11
JournalNew England Journal of Medicine
Volume373
Issue number13
DOIs
StatePublished - Sep 24 2015

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letrozole
Clomiphene
Gonadotropins
Infertility
Pregnancy
Ovulation Induction
Live Birth
Fetal Heart
Fetal Movement

All Science Journal Classification (ASJC) codes

  • Medicine(all)

Cite this

The NICHD Reproductive Medicine Network. / Letrozole, gonadotropin, or clomiphene for unexplained infertility. In: New England Journal of Medicine. 2015 ; Vol. 373, No. 13. pp. 1230-1240.
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abstract = "Background: 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. Methods: 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. Results: 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. Conclusions: 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.",
author = "{The NICHD Reproductive Medicine Network} and Diamond, {M. P.} and Richard Legro and C. Coutifaris and R. Alvero and Robinson, {R. D.} and P. Casson and Christman, {G. M.} and J. Ager and H. Huang and Hansen, {K. R.} and V. Baker and R. Usadi and A. Seungdamrong and Bates, {G. W.} and Rosen, {R. M.} and D. Haisenleder and Krawetz, {S. A.} and K. Barnhart and Trussell, {J. C.} and D. Ohl and Y. Jin and N. Santoro and E. Eisenberg and H. Zhang",
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Letrozole, gonadotropin, or clomiphene for unexplained infertility. / The NICHD Reproductive Medicine Network.

In: New England Journal of Medicine, Vol. 373, No. 13, 24.09.2015, p. 1230-1240.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Letrozole, gonadotropin, or clomiphene for unexplained infertility

AU - The NICHD Reproductive Medicine Network

AU - Diamond, M. P.

AU - Legro, Richard

AU - Coutifaris, C.

AU - Alvero, R.

AU - Robinson, R. D.

AU - Casson, P.

AU - Christman, G. M.

AU - Ager, J.

AU - Huang, H.

AU - Hansen, K. R.

AU - Baker, V.

AU - Usadi, R.

AU - Seungdamrong, A.

AU - Bates, G. W.

AU - Rosen, R. M.

AU - Haisenleder, D.

AU - Krawetz, S. A.

AU - Barnhart, K.

AU - Trussell, J. C.

AU - Ohl, D.

AU - Jin, Y.

AU - Santoro, N.

AU - Eisenberg, E.

AU - Zhang, H.

PY - 2015/9/24

Y1 - 2015/9/24

N2 - Background: 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. Methods: 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. Results: 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. Conclusions: 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.

AB - Background: 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. Methods: 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. Results: 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. Conclusions: 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.

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U2 - 10.1056/NEJMoa1414827

DO - 10.1056/NEJMoa1414827

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JO - New England Journal of Medicine

JF - New England Journal of Medicine

SN - 0028-4793

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