Using clomiphene citrate for ovarian stimulation led to a higher live birth rate, compared with using letrozole, and a lower multiple gestation rate, compared with using gonadotropins, in a randomized, multicenter trial in 900 women.
The rate of multiple gestations was roughly eight times higher among the 300 women randomized to ovarian stimulation with gonadotropins (10.3%) than among the 301 women who received clomiphene (1.3%) and fourfold higher than among the 299 women who received letrozole (2.7%), Dr. Michael P. Diamond and his associates reported at the 2014 annual meeting of the American Society for Reproductive Medicine.
The rate of conception was significantly lower in the letrozole group (28%), compared with the clomiphene group (35%) or the gonadotropins group (46%). Clinical pregnancies occurred in 22% of patients in the letrozole group, 28% in the clomiphene group, and 36% in the gonadotropin group (Fertil. Steril. 2014;102:e3 [doi:http://dx.doi.org/10.1016/j.fertnstert.2014.07.140]). Live births occurred in 19% of cycles in the letrozole group, 23% of cycles in the clomiphene group, and 32% of cycles in the gonadotropins group.
Dr. Michael P. Diamond
Clomiphene for ovarian stimulation followed by intrauterine insemination “remains a first-line therapy for couples with unexplained fertility wishing to conceive, in that it offers a balance of achieving clinical pregnancies with a lower multiple pregnancy rate,” said Dr. Diamond, professor and the William H. Brooks, M.D., Distinguished Chair in Obstetrics and Gynecology at Georgia Regents University, Augusta.
The investigators had hoped that using letrozole might result in fewer multiple gestations without worsening the live birth rate.
Among women in whom fetal heart rates could be identified, rates of multiple gestations were not significantly different in those who received letrozole (9 of 67, or 13%) and those who got clomiphene (8 of 85, or 9%), although the rates were significantly lower than that seen with gonadotropins (35 of 107, or 32% ).
Stimulation with gonadotropins produced 10 triplet gestations and 24 sets of twins, while all multiples in the letrozole and clomiphene groups were twins. The drugs appeared to be equally safe, with congenital anomalies occurring in 3% of infants in the clomiphene group and 4% in the letrozole and gonadotropins groups. Rates of other adverse events also were similar between groups.
The study included women aged 18-40 years having at least one patent fallopian tube and a minimum of nine spontaneous menstrual periods per year. Standardized protocols for administration and withholding of HCG (human chorionic gonadotropin) were followed in each group. Baseline characteristics of the patients were similar between groups.
Ovarian stimulation started on cycle day 3-5 with an initial cycle dosage of 5.0 mg/day of letrozole, 100 mg/day of clomiphene, or 150 IU/day of gonadotropin. The dosage could be adjusted for subsequent cycles in women who did not conceive in the initial cycle. All women underwent intrauterine insemination within 40 hours of HCG administration.
Patients’ baseline characteristics were similar between groups.
Although the findings support clomiphene as a first-line ovarian stimulation strategy, “revisions to current insurance reimbursement policies in most states will likely be required before couples are willing to reduce use of gonadotropins for ovarian stimulation,” Dr. Diamond said.
The National Institutes of Health and the National Institute of Child Health and Human Development funded the study. Dr. Diamond reported financial associations with Advanced Reproductive Care, Teijin Pharma, Auxogyn, ZSX Medical, Actamax Surgical Materials, AbbVie, and EMD Serono.
On Twitter @sherryboschert