IUI With Ovarian Stimulation Not Noninferior to IVF in Unexplained Infertility

A randomized trial published in NEJM found that, among couples with unexplained infertility, up to four cycles of intrauterine insemination (IUI) with ovarian stimulation was not noninferior to a single complete cycle of in vitro fertilization (IVF) for cumulative live births.

The investigators noted that international guidelines recommend IUI with ovarian stimulation as first-line treatment for unexplained infertility, yet few studies have directly compared it with IVF. The sequential, multicenter FIIX trial was funded by the Health Research Council of New Zealand and others.

A total of 737 couples were randomly assigned to IUI with ovarian stimulation (up to four cycles) before IVF or to first-line IVF (one complete cycle, with transfer of all embryos). The primary outcome was the cumulative live-birth rate from stage 1, which covered the 7 months after randomization; the noninferiority margin was a between-group difference of 10 percentage points. Among the 585 couples in the primary analysis, the cumulative live-birth rate was 31% with IUI and 55% with IVF (adjusted risk difference, −24 percentage points; 95% CI, −31 to −16).

Couples without a live birth or ongoing pregnancy after 7 months could proceed to stage 2: up to two IVF cycles for the IUI group and one further IVF cycle for the IVF group. Across both stages, with live births counted through 20 months after randomization, the cumulative live-birth rate was 70% in the IUI group and 71% in the IVF group (adjusted risk difference, 0 percentage points; 99% CI, −9 to 8). Serious adverse events occurred in 6 couples in the IUI group and 14 couples in the IVF group; most were related to oocyte retrieval or hyperstimulation.

Couples who were in stage 1 during COVID-19 lockdowns were omitted from the primary-outcome analysis. The investigators concluded that IUI with ovarian stimulation (four cycles) was not noninferior to a single complete IVF cycle with regard to cumulative live-birth rate.

Source: Prentice LR, Sadler LC, Anderson KL, et al. In vitro fertilization or intrauterine insemination in unexplained infertility. N Engl J Med. Published online October 27, 2026. doi:10.1056/NEJMoa2602728