Intrauterine insemination (IUI) with or without letrozole for unexplained or mild male factor infertility: a randomized pilot study. [Human Reproduction]

Abstract

Study question: Is a randomized controlled trial (RCT) comparing intrauterine insemination (IUI) with and without letrozole in couples with unexplained or mild male factor infertility feasible? Summary answer: We showed that an RCT comparing IUI with letrozole versus unstimulated IUI in couples with unexplained or mild male factor infertility is feasible. What is known already: IUI is the treatment of first choice for couples with unexplained or mild male factor infertility, but it is unclear whether ovarian stimulation improves fertility outcomes. In our recent retrospective cohort study, we found that in couples undergoing IUI ovarian stimulation with letrozole increased live birth rate as compared to unstimulated IUI without increasing multiple pregnancy rates. There are no RCTs comparing IUI with letrozole versus unstimulated IUI and therefore we plan a large RCT to test the hypothesis. Here, we present the results of our pilot study to evaluate the feasibility of a subsequent RCT. Study design, size, duration: We performed a randomized pilot study in the Reproductive Medicine Centre of Peking University Third Hospital in China. This pilot study included 100 couples with unexplained or mild male infertility. There was no masking. The study was registered under trial number NCT03455426. Participants/materials, setting, methods: Couples with unexplained or mild male factor infertility scheduled for IUI were randomized to IUI with or without ovarian stimulation (letrozole) for up to 3 IUI cycles within a time horizon of 4 months. Women in the letrozole group received letrozole 5 mg oral tablets daily starting from cycle day 3-5 for 5 days. Women in the unstimulated IUI group did not receive ovarian stimulation before IUI. The primary outcome was ongoing pregnancy. Main results and the role of chance: Between March 2018 and January 2019, 158 couples were eligible to participate after initial screening, and 100 (63.3%) couples agreed to participate in this study. Of the 100 recruited couples, 50 were randomly allocated to IUI with letrozole and 50 to unstimulated IUI. The women's mean age was 31.8 years (SD3.3) and 30.3 years (SD3.3) in the letrozole group and unstimulated group, respectively. At the moment, we have follow up data of 81% of the recruited couples (41 in letrozole group and 40 in unstimulated group). Ongoing pregnancy occurred in 29.2% in the letrozole group and 20.0% in the unstimulated group (RR 1.46 (95% CI 0.67 to 3.20)). Clinical pregnancy rates were 34.1% and 22.5% (RR 1.41 (95% CI 0.68 to2.92)). There were no multiple pregnancies. There was one ectopic pregnancy and one miscarriage in the group with letrozole versus one miscarriage in the unstimulated group. Limitations, reasons for caution: This is a pilot study with a limited sample size. Full follow up data will be available before July 2019. Based on these data, we plan a large randomised clinical trial in our centre. Wider implications of the findings: This pilot study confirmed the feasibility of a well powered clinical trial. In couples with unexplained or mild male infertility scheduled for IUI, we hypothesise letrozole results in higher ongoing pregnancy rate without substantially increasing multiple pregnancy rate.