What's the Best Treatment Approach for Unexplained Infertility?

Peter Kovacs, MD, PhD


August 03, 2016

Evidenced-Based Approach to Unexplained Infertility: A Systematic Review

Gunn DD, Bates GW
Fertil Steril. 2016;105:1566-1574


Couples who are unsuccessful after 1 year of trying to conceive are diagnosed with infertility. This diagnosis involves ordering a basic workup to assess ovarian function, semen quality, and anatomic structures.[1] In about one quarter of the cases, however, there is no clear etiology for the infertility; these cases are better described as subfertile.

Expectant management after proper counseling is one option that can be offered. Alternatively, controlled ovarian stimulation with various medications, insemination, or even in vitro fertilization (IVF) are considered appropriate choices. This systematic review evaluated the published evidence concerning these various approaches.

The Study

Randomized controlled trials (RCTs) compared the following treatment options for unexplained infertility:

  • expectant management;

  • timed intercourse;

  • intrauterine insemination (IUI);

  • intra-cytoplasmic sperm injection;

  • IVF; and

  • controlled ovarian stimulation with clomiphene citrate (CC), aromatase inhibitor (AI), or gonadotropin (hMG)


  • When ovarian stimulation with CC and timed intercourse was compared with expectant management, no difference was found in ongoing pregnancy rates.

  • When expectant management was compared with IUI in a natural cycle or following controlled ovarian stimulation with CC, AI, or hMG stimulation, no significant difference was found in ongoing pregnancy rates.

  • One study found higher ongoing pregnancy rates with ovarian stimulation with AI plus IUI when compared with CC plus IUI, but another, larger, study found no difference.

  • Controlled ovarian stimulation with hMG plus IUI resulted in higher ongoing pregnancy rates when compared with controlled ovarian stimulation with CC plus IUI or controlled ovarian stimulation with AI plus IUI. Two other RCTs, however, found no benefit with hMG. Multiple pregnancy rates were also higher after hMG use.

  • The limited available evidence did not show superior ongoing pregnancy rates with IVF compared with IUI.

The authors concluded that for the management of unexplained infertility, expectant management is as effective as timed intercourse or oral agents plus IUI. Gonadotropin use seems to improve clinical outcome but is associated with more multiples. Finally, on the basis of the limited available evidence, IVF is not more effective than hMG plus IUI. The authors also pointed out that the available evidence is rather limited, and therefore, further RCTs should evaluate treatment options.


Rather than ordering extensive evaluation, a common approach to couples with unexplained infertility is to treat those couples with no major abnormalities. Expectant management is one option but the couple has to be carefully selected for it. A younger couple with a short history of infertility and with no signs of stress over infertility would be the ideal candidate. Those who are older, have been trying for years, and are already stressed by infertility would benefit from treatment.

It is very important to involve the couple in the decision-making process. It also should be explained that if one treatment fails, even if repeated, then the treatment can be taken to the next level (eg, IVF after IUIs). The risks associated with the interventions have to be considered. IVF, for example, is accompanied with more risks when compared with IUI. IUI, on the other hand, could be associated with more multiple pregnancies, which is also undesired. In the current era with both partners likely to work, time-to-pregnancy becomes important, too, and a timely switch from one treatment to another can lower dropout rates.[2] All of these factors must be considered in the decision-making process. Hopefully, further RCTs will compare these treatment options to offer even better guidance to clinicians.



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