Evidence based approach to unexplained infertility A systematic review

The available literature on the treatment of unexplained infertility reflects the heterogeneity of clinical practice. Adequately powered, randomized trials are needed to directly compare the efficacy of these treatments.

Deidre D. Gunn, M.D., G. Wright Bates, M.D.

Volume 105, Issue 6, Pages 1565-1574


To summarize the available evidence for the efficacy of various treatments for unexplained infertility.

Systematic review.

Randomized, controlled trials in the English language literature from 1989 to present.

Patients aged 18–40 years with unexplained infertility.

Clomiphene citrate, letrozole, timed intercourse, IUI, gonadotropins, IVF, and IVF–intracytoplasmic sperm injection.

Main Outcome Measure(s):
Clinical pregnancy rate, ongoing pregnancy rate, and live birth rate.

Thirteen studies with a total of 3,081 patients were identified by systematic search and met inclusion criteria. The available literature demonstrates that expectant management may be comparable to treatment with clomiphene and timed intercourse or IUI. Clomiphene may be more effective than letrozole, and treatment with gonadotropins seems more effective, albeit with significantly higher risk of multiple gestations than either oral agent. On the basis of current data, IVF, with or without intracytoplasmic sperm injection, is no more effective than gonadotropins with IUI for unexplained infertility.

Adequately powered, randomized controlled trials that compare all of the available treatments for unexplained infertility are needed. Until such data are available, clinicians should individualize the management of unexplained infertility with appropriate counseling regarding the empiric nature of current treatment options including IVF.

  • “Unexplained infertility” is one of the most common diagnoses we encounter as REIs- most of us probably on a daily basis. This systematic review contains many important learning points, and potentially alters the counseling process of couples with this diagnosis, arguably making it more complex. I have been using the term “subfertility” for quite some time in this patient population, given the relatively high success rate of expectant management. With respect to the relative efficacy of the available treatments, our practice (and probably many others) have been using the results of RMN multi-center trials as a core element for counseling (references 7, Guzick 1999 and 16, Diamond 2015 in this review). The Guzick trial was excluded from this review because it included male-factor patients without separate data reporting. The Diamond trial compared oral agents+IUI with injectables+IUI (and did not have an IVF arm). Data from the FASTT trial are also very helpful in counseling (reference 23).
    Based on this review, patients should potentially be counseled 1) that expectant management is as effective as some of the first-line empiric treatments; and 2) that IVF may not be more effective that gonadotropins with IUI.
    The challenge to 1) is that once a couple seeks consultation, they are usually eager to pursue “active treatment”. The major footnote to 2) is that the reduction in multiple pregnancy and the faster time to pregnancy are huge benefits of IVF when compared to FSH+IUI.
    I am looking forward to well-designed multi-center trial comparing all approaches, even though it may be difficult to randomize patients to the “expectant” arm.

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