IVF Beats IUI for Early Live Births in Unexplained Infertility

First-line in vitro fertilization (IVF) produced more live births than intrauterine insemination (IUI) with ovarian stimulation within 7 months among couples with unexplained infertility, according to a randomized trial published October 27, 2026, in the New England Journal of Medicine.¹ Live-birth rates were similar once both groups had access to IVF, and the findings challenge the first-line IUI approach recommended by ASRM and ESHRE.

How the FIIX Trial Compared IUI and IVF

The FIIX trial (ACTRN12619001003167; Fertility and IVF and IUI Trial for Unexplained Infertility) was an open-label, pragmatic, randomized trial conducted at 6 fertility clinics in New Zealand. Investigators randomly assigned 737 couples 1:1 to up to 4 cycles of IUI with oral ovarian stimulation (clomiphene citrate or letrozole) or 1 complete IVF cycle with transfer of all embryos. The Health Research Council of New Zealand and other funders supported the trial.

After 7 months, couples without a live birth or ongoing pregnancy could proceed to stage 2, in which the IUI group could undergo up to 2 IVF cycles and the IVF group 1 additional cycle. The primary outcome was the cumulative live-birth rate from stage 1, meaning the share of couples with a live birth across all treatment cycles. IUI would count as noninferior only if its rate fell no more than 10 percentage points below that of IVF.

Couples had a median infertility duration of 63 months and a median predicted 12-month chance of unassisted conception of 18%.

IVF Produced More Live Births Within 7 Months

The primary analysis included 585 couples after investigators omitted those whose stage 1 treatment fell within COVID-19 lockdown periods. The cumulative live-birth rate was 31% (89 of 288 couples) with IUI and 55% (164 of 297 couples) with IVF, an adjusted risk difference of −24 percentage points (95% CI, −31 to −16). These results excluded noninferiority of IUI.

The time from randomization to the treatment cycle that led to a live birth appeared shorter with IVF, at a restricted mean (an average over the follow-up window) of 143 days vs 174 days with IUI.

The authors noted that the IVF rate exceeded those in earlier trials. They attributed this partly to counting all embryo transfers from a complete IVF cycle, unassisted conceptions (14% of live births in the IVF group), and improvements in IVF success over time.

By the end of both stages, the gap had disappeared. Among all couples who underwent randomization and provided consent, cumulative live-birth rates were 70% (257 of 365) with IUI followed by IVF and 71% (265 of 371) with first-line IVF (adjusted risk difference, 0 percentage points; 99% CI, −9 to 8).

Across both stages, 6 serious adverse events occurred in the IUI group and 14 in the IVF group, mostly related to ovarian hyperstimulation or complications of oocyte retrieval. Ectopic pregnancy occurred in 2% (8 of 365) of couples assigned to IUI and 1% (2 of 371) assigned to IVF in stage 1. Multiple pregnancy occurred in 3% (10 of 365) and 1% (5 of 371), respectively, by 20 months.

Implications for Guidelines and Practice

The American Society for Reproductive Medicine calls 3 or 4 cycles of oral ovarian stimulation with IUI, then IVF if unsuccessful, the best initial therapy for most couples with unexplained infertility.² The European Society of Human Reproduction and Embryology deems IUI with ovarian stimulation first-line.³ In contrast, March 2026 guidance from the UK's National Institute for Health and Care Excellence advises clinicians to consider up to 4 cycles of IUI with gonadotropin stimulation before IVF, or to offer IVF directly.⁴ The FIIX investigators wrote that their finding “calls into question current international guideline recommendations.”¹

Cost-effectiveness, access to care, patient preferences, treatment burden, and safety should also guide the choice of first-line treatment, the authors wrote. Separate analyses of cost-effectiveness and treatment acceptability are planned.

Results may not generalize to couples with shorter infertility durations; the trial's definition of unexplained infertility was broader than the most widely used one, and blinding was not feasible.

References

1. 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
2. American Society for Reproductive Medicine Practice Committee. Evidence-based treatments for couples with unexplained infertility: a guideline. Fertil Steril. 2020;113(2):305-322. doi:10.1016/j.fertnstert.2019.10.014
3. Romualdi D, Ata B, Bhattacharya S, et al. Evidence-based guideline: unexplained infertility. Hum Reprod. 2023;38(10):1881-1890. doi:10.1093/humrep/dead150
4. National Institute for Health and Care Excellence. Fertility problems: assessment and treatment. NICE guideline NG257. Published March 31, 2026. Accessed November 6, 2026. https://www.nice.org.uk/guidance/ng257