Timing may determine the benefit of stimulated IUI in unexplained infertility


Conflicting results from earlier RCTs may be explained by patient prognosis and the likelihood of natural conception, according to a new cohort study. Laurentiu Craciunas reports.

Intrauterine insemination with ovarian stimulation (IUI-OS) remains a controversial treatment for couples with unexplained infertility because of conflicting evidence from RCTs. Now, new evidence from a prospective cohort study suggests that the benefit of IUI-OS is variable and depends on the natural prognosis of the couple diagnosed with unexplained infertility.

And this, according to a review in Barcelona, is not always consistently defined. Briefly, unexplained infertility includes couples who failed to achieve a pregnancy within 12 months of trying despite having regular ovulations, patent tubes and normal semen parameters in the absence of any other plausible explanation. In this context, one my rightly ask what is the benefit of IUI in the first place and then why stimulate the ovaries? Two important trials have tried to answer these questions.(1,2) However, they found conflicting evidence for the benefit of IUI-OS in unexplained infertility.

Rik van Eekelen in an invited session in Barcelona assessed the potential causes behind the positive results reported recently by Farquar as opposed to negative results reported by Steures back in 2006 (each in The Lancet) and suggested their conflicting results are triggered by the inclusion of two different populations in terms of prognosis for natural conception: ie, poor prognosis (Farquar) vs intermediate or good prognosis (Steures). Ven Eekelen also suggested that a cohort study may be able to address this shortcoming by performing subgroup analyses.

Thus, Van Eekelen’s prospective cohort included Dutch registry data for 1896 couples diagnosed with unexplained infertility or mild male factor infertility. There were 800 couples who received at least one IUI-OS cycle and they were compared with couples aiming for natural conception from "expectant management".

The difference in IUI-OS benefit observed in the RCTs persisted in van Eekelen’s cohort. Couples who had a good prognosis for natural conception derived no benefit from IUI-OS. And there was uncertain benefit for couples with intermediate prognosis for a natural conception.

Only couples who suffered from unexplained infertility and had poor prognosis of achieving a natural conception derived any real benefit from IUI-OS. For a couple with a 20% prognosis of natural conception, the chance for ongoing pregnancy within six months increased from 12% with expectant management (natural conception) to 24% (95% confidence interval 15-31%) with IUI-OS.

As the prognosis for natural conception decreases over time, Eekelen suggested that this new evidence may guide clinicians in choosing the timing of IUI-OS, but he agreed that further external validation is required.

1. Farquhar CM, Liu E, Armstrong S, et al. Intrauterine insemination with ovarian stimulation versus expectant management for unexplained infertility (TUI): a pragmatic, open-label, randomised, controlled, two-centre trial. Lancet 2018; 391: 441-450.
2. Steures P, van der Steeg JW, Hompes PG, et al. Intrauterine insemination with controlled ovarian hyperstimulation versus expectant management for couples with unexplained subfertility and an intermediate prognosis: a randomised clinical trial. Lancet 2006; 368: 216-221.