IVF Outperforms IUI in Cumulative Live-Birth Outcomes for Unexplained Infertility: NEJM

A randomized controlled trial that compared the reproductive effectiveness and safety of first-line IUI with ovarian stimulation with that of first-line complete-cycle IVF was undertaken. It involved 737 couples suffering from unexplained infertility and underwent randomization on a 1:1 basis to undergo either initial IUI with ovarian stimulation (up to four cycles; n = 365) or first-line complete-cycle IVF (n = 372). The Stage 1 trial involved the evaluation of the noninferiority of IUI (up to four cycles) in comparison with IVF (one complete cycle) within a period of 7 months using a noninferiority margin of 10 percentage points.

Couples, which failed to become pregnant or gave birth in stage 1 were eligible to be enrolled in stage 2, where the IUI (up to four cycles) group had access to two more IVF cycles and the IVF (one cycle) group, to one more IVF cycle, with overall period being extended to 20 months.ouples having undergone stage 1 under the conditions of the COVID-19 lockdowns were not included in the primary stage 1 analysis.

Key findings:

• Primary and secondary statistical analyses across 737 randomized couples (585 included in the primary Stage 1 per-protocol analysis) established distinct efficacy and safety profiles.
• In the primary analysis of 585 couples (288 in the IUI group and 297 in the IVF group), the cumulative live-birth rate resulting from stage 1 was 31% (89 live births among 288 couples) in the IUI with ovarian stimulation group versus 55% (164 live births among 297 couples) in the primary IVF group.
• This demonstrated an adjusted risk difference of −24 percentage points (95% CI, –31 to –16), failing the 10-percentage point noninferiority threshold.
• Across the total randomized population followed through stage 2 (365 couples in the IUI group and 371 eligible couples in the IVF group), cumulative live-birth rates reached 70% (257 births among 365 couples) and 71% (265 births among 371 couples), respectively (adjusted risk difference, 0 percentage points; 99% CI, −9 to 8).
• Serious adverse events occurred in 6 couples assigned to initial IUI with ovarian stimulation compared to 14 couples in the primary IVF group, with the majority of serious events in both cohorts related to oocyte retrieval procedures or ovarian hyperstimulation syndrome (OHSS).

Overall, the randomized trial evidence proves that four cycles of IUI with ovarian stimulation do not have noninferior cumulative pregnancy rates when compared with one full cycle of IVF in cases of unexplained infertility. Importantly, the authors conclude that while the long-term outcomes show similarities when the patient eventually proceeds to the IVF option, starting from IVF is better at shorter terms.

Reference:

Prentice, L. R., Sadler, L. C., Anderson, K. L., Wilkinson, J. D., Vercoe, M. A., Lensen, S. F., Glanville, E. J., Wakeman, S. A., Searle, L. M., & Farquhar, C. M. (2026). In vitro fertilization or intrauterine insemination in unexplained infertility. New England Journal of Medicine, NEJMoa2602728. https://doi.org/10.1056/nejmoa2602728