Unexplained infertility is one of the most challenging conditions in the field of reproductive medicine. In this situation, despite conducting complete examinations including: hormonal tests, ovulation assessment, fallopian tube examination and sperm analysis, no specific cause for infertility can be found.
In such situations, choosing the right path for treating infertility in couples is of great importance in order to avoid unnecessary interventions and increase the chances of pregnancy in a logical and stepwise manner.
The World Health Organization (WHO) recommends a three-step approach for treating infertility in couples with unexplained infertility, which is fully explained below.
At this stage of treatment for couples with unexplained infertility, the World Health Organization recommends that expectant management be substituted for unstimulated intrauterine insemination (U-IUI).
Recommendation type: Conditional
Evidence level: Low
What is expectant management?
Expectant management means that couples are monitored for a period of time, but no active medical intervention is performed. During this time:
In the studies that have informed this recommendation, expectant management has typically been considered to be between 3 and 6 months.
This approach suggests that in many cases, even without drug intervention, pregnancy is possible and there may be no need to immediately begin more aggressive treatments in the course of treating couples’ infertility.
If pregnancy does not occur after the expectant management period, the second stage of infertility treatment for couples begins.
At this stage, the World Health Organization recommends the use of intrauterine insemination with ovarian stimulation (S-IUI).
Type of recommendation: Conditional
Level of certainty of evidence: Low
Recommended medications:
For ovarian stimulation in this method: Two medications are recommended:
When choosing between these two drugs, national regulations regarding off-label use of letrozole should be considered.
How many treatment cycles are required?
The optimal number of S-IUI cycles is still not definitively known. In various studies, between 1 and 6 cycles have been reported, but in more recent research, 3 to 6 cycles are usually performed.
Importantly, WHO recommends that gonadotropins not be used at this stage and that S-IUI be performed only with clomiphene or letrozole.
Type of recommendation regarding the non-use of gonadotropins: Conditional
Level of certainty of evidence: Very low
This stage is considered one of the most important steps in the scientific and stepwise approach to treating couples’ infertility, as it provides an appropriate balance between effectiveness and invasiveness of the treatment.
If S-IUI is also unsuccessful, we enter the third stage of infertility treatment for couples.
In these situations, the World Health Organization recommends that IVF be used instead of expectant management.
Type of recommendation: Conditional
Level of certainty of evidence: Low
IVF is an advanced assisted reproductive technology in which eggs and sperm are combined in a laboratory environment and, after the embryo is formed, they are transferred to the uterus. This method significantly increases the chances of pregnancy in many cases of infertility without a clear cause.
Should ICSI be used?
For couples who are challenged with IVF after S-IUI failure, WHO recommends that IVF be performed alone and that ICSI (intracytoplasmic sperm injection) not be used unless there is a specific indication.
Recommendation Type: Certain
Evidence Level: Low
This recommendation suggests that in unexplained infertility, routine use of ICSI is not necessary and the choice of method should be based on the specific circumstances of each couple.
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