Infertility
Unexplained infertility
When all tests are normal: assessment and treatment according to the ESHRE guideline
In about 30% of couples with infertility, the basic assessment shows no cause. In 2023, the European Society of Human Reproduction and Embryology (ESHRE) published a dedicated guideline for these couples. Doctors make the diagnosis by exclusion. Infertility is called unexplained when, in a woman up to the age of 40, the ovaries seem to work normally and the tubes, uterus, cervix and pelvis are normal, when the couple has sex often enough, and when the man's testicles, anatomy and semen analysis are normal.
The assessment starts after at least 12 months of regular intercourse without contraception. The guideline recommends intercourse about every two to three days in the fertile window, adapted to the couple's wishes. There is a clear reason for the age limit of 40. According to one calculation, after two years of trying, the diagnosis “unexplained” is wrong in about 10% of cases in women under 35, but in about 80% in women over 40. In older women, age itself is usually the explanation.
The diagnosis does not mean that there is no cause. It means that the cause lies in steps that the usual tests do not check: in egg quality, in fertilization, in the function of the fallopian tubes or in implantation. Nor does it mean that pregnancy is impossible. The chance of a pregnancy remains and changes over time.
What comes before the diagnosis?
The diagnosis “unexplained” only makes sense after a proper basic assessment. Behind “unexplained” infertility there is often something nobody looked for: irregular ovulation, mild endometriosis with typical symptoms, a thyroid disorder, a borderline semen analysis that was not repeated, or a change in the uterus that was not visible on a simple ultrasound. More in the article “Endometriosis and infertility”.
At the same time, ESHRE warns against too many tests. Many tests that are often offered have no value for the diagnosis or for the choice of treatment. The guideline therefore sets out exactly, for each test, whether it is recommended or not. The skill lies in telling apart what each couple needs and what they do not.
Unexplained infertility is a diagnosis of exclusion. The doctor makes it only when all causes of infertility in the woman and in the man have already been tested for and ruled out. The article “Infertility” describes which tests are needed and which are not.
What is the outlook?
The outlook depends mainly on the woman's age, the duration of infertility and whether there has already been a pregnancy. In young couples who have been trying for a short time, the chance of a natural pregnancy in the following year remains considerable. With each further year without pregnancy, it falls.
ESHRE recommends basing the decision to start active treatment on the couple's outlook. The benefit of a treatment is the chance of a live birth with treatment minus the chance without treatment. For this assessment there are prediction models. They calculate the chance of a natural pregnancy in the next twelve months, and the calculation can be repeated over time. A treatment that helps a couple with a poor outlook often brings no additional benefit to a couple with a good outlook.
Which treatment helps?
Expectant management with timed intercourse. For couples with a good outlook, the first step is a period of trying naturally at the right time. If there is no pregnancy after more than six months, the doctor moves on to the next step.
Insemination with ovarian stimulation. According to ESHRE, insemination (IUI) with mild ovarian stimulation is the first choice of active treatment, with a strong recommendation. Insemination without stimulation showed no clear benefit compared with waiting. For stimulation, the guideline recommends low-dose hormone injections with adequate ultrasound monitoring, to avoid multiple pregnancies and ovarian hyperstimulation syndrome. Couples with a poor outlook have three to six cycles, followed by IVF.
IVF. As a first treatment, IVF is probably not better than insemination with stimulation, according to ESHRE. After unsuccessful inseminations, however, IVF is clearly superior. The decision for IVF is individual and depends on the woman's age, the duration of infertility, previous treatments and previous pregnancies. Starting directly with IVF makes sense only in special cases, for example in an older woman. The guideline does not recommend ICSI in this group, because it is not better than conventional IVF.
Flushing the fallopian tubes. Imaging the tubes with an oil-based contrast medium can increase the chance of a pregnancy in the following months. ESHRE therefore sees oil-based contrast as a better choice than water-based contrast. The risk of contrast entering the blood vessels, however, is higher with oil-based contrast, so the doctor always discusses benefits and risks with the woman.
What else is not recommended? ESHRE does not recommend endometrial scratching or hysteroscopy with a normal ultrasound. According to the guideline, antioxidants for the woman or the man, acupuncture and inositol probably bring no benefit and are not recommended.
Lifestyle and psychological support. ESHRE recommends a healthy diet and regular exercise, with support for changing behavior when needed. It also recommends psychological support, up to psychotherapy, when the couple needs it. The uncertainty of having no visible cause is especially hard for many couples.
What are the treatment steps?
Not recommended
How can treatment be part of the diagnosis?
Treatments also have diagnostic value. The response of the ovaries to stimulation, egg quality and fertilization in the laboratory provide information that no test can give in advance. In this way, an “unexplained” infertility often becomes an infertility with a recognizable cause over time.
Why does time matter?
In unexplained infertility, the doctor weighs every decision against time. Waiting makes sense for a young woman who has been trying for a short time. For a woman in her mid-thirties or older, or after a long time of trying, waiting quickly loses its value. Clear time limits for each step prevent valuable months from passing without a plan.
What about mental strain and quality of life?
Unexplained infertility is especially hard for many couples. Without a cause, there is nothing specific to “fix”, and the uncertainty remains. Many couples wonder whether they did something wrong or whether the tests missed something. This emotional exhaustion often leads couples to stop treatment before their chances are used up. Knowing that the outlook in unexplained infertility is often good, and a plan with clear time limits, help the couple cope.
The practice's approach
Before a diagnosis of unexplained infertility, the practice reviews the whole history once more from a hormonal and reproductive point of view. The tests follow the ESHRE guideline, and the practice does not recommend tests without benefit.
The goal of the practice is to find what has been missed, to avoid pointless tests and to plan a strategy based on each couple's outlook, with clear time limits for each step.
Sources: ESHRE – Evidence-based guideline: Unexplained infertility (Unexplained Infertility Guideline Development Group, 2023); Romualdi D et al., Human Reproduction 2023. WHO – Guideline for the prevention, diagnosis and treatment of infertility (2025). WHO laboratory manual for the examination and processing of human semen, 6th edition (2021). Zegers-Hochschild F et al., The International Glossary on Infertility and Fertility Care (ICMART), Human Reproduction 2017. Gameiro S et al., ESHRE guideline: routine psychosocial care in infertility and medically assisted reproduction, Human Reproduction 2015. Gameiro S et al., Why do patients discontinue fertility treatment? A systematic review of reasons and predictors of discontinuation, Human Reproduction Update 2012.