Unexplained Infertility: Is IUI With Ovarian Stimulation Effective?

Peter Kovacs, MD, PhD


October 31, 2018

Unexplained Infertility

A woman's maximum monthly chance of becoming pregnant after unprotected intercourse is about 30%.[1] Infertility is diagnosed after 1 year of unsuccessful attempts to become pregnant. A basic infertility evaluation consists of assessing ovarian function, semen parameters, and tubal status. If no problems are found, a diagnosis of unexplained infertility is made. In such cases, the likelihood of becoming pregnant during subsequent months is, at best, only a few percent.

Further attempts to achieve pregnancy can be successful, however, so expectant management still has a role. Alternatively, various forms of assisted reproductive technology can be offered. Timed intercourse, ovarian stimulation—with or without intrauterine insemination (IUI) or even in vitro fertilization (IVF)—can be considered. Recently, Farquhar and colleagues[1] conducted a randomized controlled trial to compare stimulation with IUI versus expectant management for the care of unexplained infertility.

Women under the age of 42, with a body mass index below 35 kg/m2 and a diagnosis of unexplained infertility, were eligible to participate. According to the Hunault prediction model,[2] a woman's chance for natural conception was predicted to be less than 30% in the next year.

Participants were randomly assigned to either three stimulated cycles (clomiphene citrate or letrozole) of IUI (n = 101) or three cycles of expectant management (n = 100). Couples in the expectant management group were advised to be sexually active around the time of ovulation. The primary outcome was cumulative live birth rate (CLBR).

The CLBR (intention-to-treat) was significantly higher in the IUI group (31% vs 9%; risk ratio [RR], 3.41; 95% confidence interval [CI], 1.71-6.79). When the analysis was limited to those pregnancies that were conceived per protocol, the CLBR in the IUI group was still significantly higher (27% vs 7%; RR, 3.89; 95% CI, 1.66-9.11).

The miscarriage rate was 16% in the IUI group and 9% in the expectant management group, and the mean birthweights were comparable between the two groups. The study authors concluded that for women with unexplained infertility and a predicted poor prognosis for natural conception, ovarian stimulation combined with IUI increases the chance of pregnancy by threefold over expectant management.


For each year of a woman's life beyond age 30, the chance of natural pregnancy declines by 9%. Furthermore, a specific cause for unexplained infertility cannot be identified in 30%-40% of infertility evaluations. It has been proposed that in addition to the standard infertility evaluation, further testing (genetic, immunologic, surgical evaluation, etc.) could identify abnormalities that might be reducing the chance of pregnancy. Such testing, however, increases costs as well. Others propose treatment rather than expanding the evaluation.[3] Instead of expectant management, the use of ovarian stimulation with or without insemination has been suggested.[4,5,6] However, previous studies have not shown improved live birth rates.[4,5,6]

A 2016 Cochrane review[7] found no difference in live birth rates when stimulation combined with IUI was compared with expectant management (OR, 0.82; 95% CI, 0.45-1.49). Furthermore, IUI has been compared with IVF as therapy for unexplained infertility, and the findings are conflicting. Although IUI was more cost-effective, the clinical efficacy of several cycles of IUI versus a single round of IVF has not been found to be superior.[8,9,10]

Unexplained infertility can be managed with one of several protocols. Expectant management is a logical approach when the duration of infertility is relatively short, the couple is young, and the semen parameters are normal. When the decision is made to start treatment, however, the use of controlled ovarian stimulation combined with IUI is a reasonable first-line option. It can be repeated multiple times if needed before one would consider an even more invasive option, such as IVF.


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