For women with unexplained infertility, treatment with letrozole (Femara), an aromatase inhibitor, for ovarian stimulation yielded lower rates of multiple gestation, but also lower rates of clinical pregnancy than standard infertility therapies, according to the results of a randomized non-inferiority trial.
, of Georgia Regents University in Augusta, Ga., and colleagues found statistically significant differences between letrozole and gonadotropin (Menopur), but not between letrozole and clomiphene (Clomid) for either multiple gestation rates or rates of clinical pregnancy. They published their findings in
Action Points
- In women with unexplained infertility, ovarian stimulation with letrozole resulted in lower frequency of live births and multiple gestation as compared with gonadotropin, but not as compared with clomiphene.
- Maternal serious adverse events were more common in the gonadotropin group compared to the other two groups, but congenital abnormalities and neonatal deaths did not differ among groups.
Multiple gestation rates for the letrozole group were 13% compared to 32% for gonadotropin (P=0.006), and 9% for clomiphene (P=0.44). The difference was also not significant when comparing letrozole to either gonadotropin or clomiphene (22%, P=0.15).
Letrozole was associated with both lower rates of multiple gestation and lower rates of clinical pregnancy. These differences were statistically significant when comparing letrozole to gonadotropin (22.4% vs 35.5%, P<0.001) and letrozole to gonadotropin or clomiphene (P=0.003). However, differences between letrozole and clomiphene (28.3%) were not significant (P=0.10).
The authors note that while pregnancy rates for letrozole were lower than standard therapy, these rates were within the prespecified non-inferiority margin for the trial.
, professor and vice-chair of the department of obstetrics and gynecology at the Keck School of Medicine at the University of Southern California in Los Angeles, said that he currently treats patients with clomiphene, but that it appears that letrozole is a viable alternative to clomiphene in patients with unexplained fertility. In an e-mail to ľֱ, he also added that the patient's age would play a role in the treatment. Paulson was not involved with the study.
"For young patients, the high multiple gestation rate with gonadotropins really makes me want to stick with clomiphene," he said. "But now I feel better about using letrozole in those patients who experience side effects with clomiphene."
"In the older group, where multiple gestations are much less common, gonadotropins may still be a good option, knowing that they produce a higher chance of pregnancy than clomiphene."
Not surprisingly, letrozole was also associated with statistically significant lower rates of live birth compared to gonadotropin (18.7% vs 32.2%, P<0.001). Clomiphene compared to gonadotropin yielded similar differences in birth rates (23.3%, P=0.02).
Examining multiple gestation, letrozole and clomiphene groups had twins only, while the gonadotropin group had 10 triplets in addition to 24 twins. Overall, decreasing gestational age was unsurprisingly associated with increasing number of fetuses (38.6 weeks for singletons, 35.3 weeks for twins, 34.2 weeks for triplets, P<0.001).
, assistant professor, department of obstetrics and gynecology at the University of Rochester Medical Center in Rochester N.Y. mentioned that approximately 10% of couples experience unexplained infertility and that this study provides clinicians important prognostic information for counseling these couples. She did mention the rate of multiple gestation as a factor in how she plans to treat patients in her practice.
"I will continue to recommend letrozole for women with infertility related to polycystic ovary syndrome and will continue to prescribe either clomiphene or letrozole as first line therapy for women with unexplained infertility and reserve gonadotropin therapy as a second line treatment given the risk of multiple gestations," she told ľֱ via e-mail.
Maternal adverse events were more common in the gonadotropin group compared to the other two groups (P=0.009). The gonadotropin group also experienced more frequent abdominal bloating. Jaundice, respiratory distress syndrome, and intrauterine growth restriction were the most common neonatal complications, and incidence was similar across treatment groups. There was one neonatal death (23 weeks gestation) in the letrozole group due to preterm labor and delivery.
(AMIGOS) trial examined three groups of ovulatory women ages 18 to 40 with unexplained infertility in a randomized trial at 12 medical centers. Of the couples providing written informed consent and completing screening, 900 were randomized to one of three groups: gonadotropin (301 women), clomiphene (300), or letrozole (299).
While there were no differences in the frequency of dropouts between the three groups, treatment cycle cancellation rates were statistically significant (6.9% for gonadotropin, 3.3% for clomiphene, and 3.7% for letrozole, P<0.001 for differences among three groups).
The gonadotropin group was not blinded, as it was administered by injection whereas the other two groups had identical coated pills. The authors cite this as a potential limitation, along with the fact that the study was powered for a comparison of letrozole with the other two groups combined, not for individualized group comparisons. Finally, they acknowledge that this study had no placebo group, but state that would be unethical when treating couples with fertility difficulties.
Disclosures
This study was supported by grants from the National Institutes of Health, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Center for Research Resources, the National Center for Advancing Translational Sciences, and the American Recovery and Reinvestment Act.
Diamond reports grant support from the NICHD during the conduct of the study; grant support from EMD Serono, AbbVie, and Bayer, and other support from Advanced Reproductive Care outside the submitted work.
Other co-authors report relevant conflicts of interest, which can be found in the full text of the article.
Primary Source
The New England Journal of Medicine
Diamond MP, et al "Letrozole, gonadotropin, or clomiphene for unexplained infertility" NEJM 2015; DOI: 10.1056/NEJMoa1414827