Gonadotrophins Versus Clomifene Citrate With or Without Intrauterine Insemination in Women With Normogonadotropic Anovulation and Clomifene Failure (M-OVIN): A Randomized, Two-by-Two Factorial Trial

Abstract

Clomifene citrate has long been used as a first-line ovulation induction agent for women wishing to conceive who have normogonadotropic anovulation (absent or irregular ovulation). Women who ovulate but do not conceive after several cycles with clomifene citrate are usually switched to ovulation induction with gonadotrophins, with or without intrauterine insemination. However, no randomized clinical trials have investigated the effectiveness of a switch to gonadotrophins and intrauterine insemination compared with continued treatment with clomifene citrate. TheModified Ovulation Induction (M-OVIN) study was a 2-by-2 factorial multicenter randomized clinical trial conducted in 48 Dutch hospitals between December 8, 2008, and December 16, 2015. The aim of the study was to determine whether switching to gonadotrophins is more effective than continuing clomifene citrate and whether addition of intrauterine insemination is more effective than intercourse. Subjects were women aged 18 years and older who had normogonadotropic anovulation and were not pregnant after 6 ovulatory cycles of clomifene citrate (maximum of 150 mg daily for 5 days). Using a central password-protected, Internet-based randomization program, women received one of the following: (1) 6 cycles with gonadotrophins plus intrauterine insemination, (2) 6 cycles with gonadotrophins plus intercourse, (3) 6 cycles with clomifene citrate plus intrauterine insemination, or (4) 6 cycles with clomifene citrate plus intercourse. Dosages of clomifene citrate varied from 50 to 150 mg daily orally and gonadotrophins were administered subcutaneously with a starting dose of 50 or 75 IU daily. The primary study outcome was conception leading to live birth within 8 months defined as any baby born alive with a gestational age of more than 24 weeks. Primary analysis was according to intention-to-treat. Two comparisons were made: gonadotrophins compared with clomifene citrate and intrauterine insemination compared with intercourse. A total of 666women were randomized: 166 to ovulation induction with gonadotrophins combined with intrauterine insemination, 165 to ovulation induction with gonadotrophins, 163 to ovulation induction with clomifene citrate combined with intrauterine insemination, and 172 to continued ovulation induction with clomifene citrate. Women receiving gonadotrophins had significantly more live births than women receiving clomifene citrate (52% [167/ 327] vs 41% [138/ 334]; the relative risk [RR] was 1.24, with a 95% confidence interval [CI] of 1.05 to 1.46; P = 0.0124). Adding intrauterine insemination did not increase live birth rates compared with intercourse (49% vs 43%; RR, 1.14; 95% CI, 0.97-1.35; P = 0.1152). Multiple pregnancy rates were low for the 2 comparisons and not different. Three adverse events were noted: 1 woman treated with clomifene citrate conceived a child with congenital abnormalities, 1 woman treated with gonadotrophins delivered at a gestational age of 20 weeks due to cervical insufficiency, and 1 woman treated with clomifene citrate had a stillbirth. These data show that for normogonadotropic anovulatory women with clomifene citrate failure, switching to gonadotrophins increases the live birth rate over continued treatment with clomifene citrate. There is no evidence that the addition of intrauterine insemination increases live birth rates. A randomized trial and network meta-analyses have reported that letrozole is associated with higher live birth rates than clomifene citrate. The authors suggest that future studies investigate whether letrozole is also effective and safe for women who have not conceived within the first 6 months of treatment.