ESHRE 2023 guidelines on managing unexplained infertility

Researchers in 2023 provide evidence-based guidelines for managing patients with unexplained infertility, as prepared by ESHRE.

These are official recommendations by the European Society of Human Reproduction and Embryology (ESHRE), based on existing data.

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ESHRE defines unexplained infertility as infertility with:

• Normal ovarian and testicular function.
• No anatomical issues (ie. normal uterus, cervix, etc.)
• Normal ejaculate (above the lower 95% CI limit of the 5th percentile of the WHO reference — see below)
• Age 40 or below with good frequency of sex.

Below you can see the lower limit of the 95% CI for the 5th percentile of semen parameter results from fertile men, from the WHO (6th edition).

I’ll list the recommendations here as a quick overview, but you can check out the full version of these guidelines here (link to pdf). The full version includes all the supporting evidence and explanations that were used as a basis for their recommendations. In this post, I’ll include the page numbers where a particular recommendation is referenced in the full version, so you can refer back.

Now let’s look at their recommendations! They have three types of recommendations:

• Strong recommendations are ones that ESHRE agrees should apply to most patients.
• Conditional recommendations should only apply after discussion between the patient and doctor.
• Research only recommendations mean that the test should only be used in a research setting.

An additional recommendation that you’ll see in the full guide and not in this post is “GPP,” which stands for “good practice points.” These are additional points brought up by the ESHRE group that relate to a particular recommendation, which I’ll incorporate here.

Remember, these guidelines are based primarily on studies that look at unexplained infertility, so other studies that look at other patient groups may not be considered. In many cases, there aren’t many studies on patients with unexplained infertility, so more work needs to be done.

Strong recommendations

These are recommendations that apply to most patients — not all! Some patients may have indications that require these tests. Remember, these apply to patients with unexplained infertility as defined above — normal ovarian function and normal semen ejaculate.

Recommended:

• For fallopian tube patency, hysterosalpingography (HSG) and hysterosalpingo-contrast-sonography (HyCoSy) are comparable vs laparoscopy and chromopertubation (pg. 29-40).
• Ultrasound (preferably 3D) should be used to confirm normal uterine anatomy (pg. 41-44).
• Unexplained infertility treatment should start with ovarian-stimulated IUI, while considering low-dose gonadotropins to avoid OHSS and multiple pregnancies (pg. 79-81).

Not recommended:

• Endometrial biopsy for histological examination (pg. 20-22).
• Ovarian reserve testing to identify the cause of infertility or chance of spontaneous conception (pg. 23-28).
• For identifying uterine abnormalities, the use of MRI as a first-line test (pg. 42-44).
• After normal uterine pathology by ultrasound, further testing by hysteroscopy isn’t needed (pg. 42-44).
• Routine laparoscopy (pg. 45-46).
• Postcoital test (pg. 47-49).
• Testicular imaging (pg. 50).
• Anti-sperm antibodies (pg. 51-60).
• Sperm DNA fragmentation (pg. 53-60).
• Sperm chromatin condensation test (pg. 54-60).
• Sperm aneuploidy screening (pg. 55-60).
• Male serum hormonal testing (pg. 55-60).
• Male human papilloma virus (HPV) testing (pg. 56-60).
• Microbiology testing of semen (pg. 56-60).
• Anti-sperm antibodies in males and females (pg. 61-76).
• Testing for autoimmune conditions (ie. thyroid antibodies) besides celiac disease (pg. 61-76).
• If TSH levels are normal, no additional thyroid testing is needed (pg. 63-76).
• Thrombophilia testing (pg. 64-76).
• Oxidative stress testing in women (ie. malondialdehyde, total antioxidant capacity, etc.) (pg. 66-76).
• Genetic testing of mutations/polymorphisms in various genes (ie. FSH, MTHFR) (pg. 68-76).
• Vitamin D deficiency testing (pg. 70-76).
• Prolactin testing (pg. 71-76).
• ICSI over conventional IVF (pg. 85-86).
• Hysteroscopy to detect uterine abnormalities after normal routine imaging (pg. 87-92).
• Endometrial scratching (pg. 90-92).

Conditional (weak) recommendations

These are recommendations that need to be discussed between the patient and doctor.

• For confirming ovulation (though women with regular menstrual cycles don’t normally need this), urinary LH, ultrasound or mid-luteal progesterone can be used (pg. 16-19).
• Testing for mid-luteal serum progesterone (pg. 20-22).
• For fallopian tube patency, testing for chlamydia antibodies may help in identifying those at risk, although visualization is necessary (pg. 35-40).
• Celiac disease testing for auto-immunity (pg. 61-76).
• IUI should be used first over IVF, although patient specifics may direct the use of IVF (pg. 83-86).
• Oil-soluble contrast medium over water-soluble for HSG may be considered, with an explanation of the risks (pg. 88-92).
• Male and female supplements are “probably not recommended” (pg. 93-96).
• Acupuncture is “probably not recommended” (pg. 93-96).
• Inositol supplementation is “probably not recommended” (pg. 94-96).

Research only

• Vaginal microbiota testing (pg. 48-49).
• Oxidative stress testing in men (ie. DNA fragmentation, reactive oxygen species, total antioxidant capacity, etc.) (pg. 66-76)

What evidence did ESHRE use to establish these guidelines?

You might want to look into the details of how ESHRE formed their recommendation for certain topics. I’ll walk you through the process with the example of acupuncture.

First, let me point you to the right resources. They can be found on this page:

1. Full ESHRE recommendation guide – link to pdf
2. Annex 6 – Literature study – link to pdf
3. Annex 7 – Evidence tables – link to pdf

There’s also an Annex 8 – Summary of evidence tables, but I don’t think it’s needed.

So for acupuncture, you can find it on pages 93-96 of the full guidelines document. There you’ll find the data they used for their recommendation and their justification. Annex 7 will give a more detailed look at the studies they included in their recommendation.

If you look at Annex 6, you can also see a list of rejected studies that weren’t considered, along with the reason why they weren’t used. I feel like they also consider these studies when forming their recommendation, because if there are a lot of studies that are low quality/poorly designed they may be more likely to not recommend a treatment.

Anyways, for acupuncture there were four studies they considered, with one being accepted and three being rejected. They all looked at acupuncture in women with unexplained infertility:

1. Effectiveness of acupuncture on pregnancy success rates for women undergoing in vitro fertilization: A randomized controlled trial (accepted)
2. Acupuncture Enhances Chances of Pregnancy in Unexplained Infertile Patients Who Undergo A Blastocyst Transfer in A Fresh-Cycle (rejected because it was very low quality).
3. Unexplained infertility treated with acupuncture and herbal medicine in Korea (rejected because it combined two interventions).
4. Analysis of the application value of dakundan combined with acupuncture in patients with infertility (rejected because it involved multiple treatments; I think for this study they implied it was unexplained infertility based on the patient characteristics, or maybe they contacted the author — I’m not sure)

Conclusions

Overall, the quality of evidence was mostly low to very-low, with limited high-quality randomized controlled trials and a large amount of study variability. As a result, many treatments/tests are not recommended. These guidelines can change as further evidence is collected.

The authors point out that there is a lack of research relating to male tests for unexplained infertility in particular, with many having serious issues. For example, sperm DNA fragmentation lacks a standardized threshold, features a number of tests that aren’t interchangeable, and shows inconsistency in results.

Additionally, a number of research gaps were identified for patients with unexplained infertility, such as SDF, the vaginal microbiota, lifestyle interventions, oxidative stress markers and removal of endometrial polyp and intrauterine adhesion removal.

As mentioned, these guidelines are based primarily on studies that look at unexplained infertility, so other studies that look at other patient groups may not be considered. A problem with unexplained infertility, as mentioned by a user on Instagram who commented on this post, is that it may just truly be unexplored infertility. It’s possible that there is an underlying factor that would explain the infertility, such as silent or mild endometriosis.

There is evidence that laparoscopy can benefit women with unexplained infertility in detecting endometriosis (Nakagawa et al. (2007)).

The authors of these guidelines point out that routine laparoscopy was debated at great length, particularly in its ability to detect mild endometriosis. However, because there’s a lack of good quality evidence to support its routine use, and combined with the surgical/anaesthesiological risks, they didn’t recommend it.

As additional reading, you might want to look at the reviewer comments on these guidelines, which can be found here (link to pdf).

Reference

Guideline Group on Unexplained Infertility; Romualdi D, Ata B, Bhattacharya S, Bosch E, Costello M, Gersak K, Homburg R, Mincheva M, Norman RJ, Piltonen T, Dos Santos-Ribeiro S, Scicluna D, Somers S, Sunkara SK, Verhoeve HR, Le Clef N. Evidence-based guideline: unexplained infertility†. Hum Reprod. 2023 Oct 3;38(10):1881-1890. doi: 10.1093/humrep/dead150. PMID: 37599566; PMCID: PMC10546081.

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About Embryoman

Embryoman (Sean Lauber) is a former embryologist and the founder of Remembryo, an IVF research and fertility education website. After working in an IVF lab in the US, he returned to Canada and now focuses on making fertility research more accessible. He holds a Master’s in Immunology and launched Remembryo in 2018 to help patients and professionals make sense of IVF research. Sean shares weekly study updates on Facebook, Instagram, and Reddit regularly. He also answers questions on Reddit or in his private Facebook group.

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