Unexplained infertility - a non-clinical diagnosis with unclear guidelines and a heavy psychological impact

Sandy Christiansen
BSc, MSc, HCPC Clinical Embryologist & Fertility Coach

Unexplained Infertility

Infertility is generally defined as not getting pregnant after 12 months of unprotected intercourse. The NHS (national health service) state that 84% of heterosexual couples will conceive within a year if they have regular, unprotected sex, meaning that approximately 1 in 7 couples in the UK may experience problems associated with their fertility¹. For many couples, these are statistics that are completely new to them, until they visit their GP. While we can argue that fertility should be added to the curriculum to educate and empower our younger generations, the fact that it has been lacking has left a gap in our society where people have little understanding of their own fertility and what could be affecting it.

Medical professionals have the knowledge and understanding that infertility may be caused by many different things. In women, common causes of fertility problems may be related to ovulatory factors, tubal disorders or imbalances of reproductive hormones². In men, causes are most often associated with sperm quality like low sperm count, low sperm motility or low sperm morphology³. And in approximately 25% of couples, a cause cannot be identified³, a term known as “unexplained infertility”.

For heterosexual couples trying to conceive, unexplained infertility is a joint issue, however the NICE (National Institute of Health and Care Excellency) guidelines⁴ quote a study stating that unexplained infertility accounts for 40% of female infertility⁵. It’s also been reported that females are more likely to seek help or initial contact for infertility investigations⁶ and is the second most common reason for women to visit their GP⁷. As the female reproductive system accounts for the egg which needs to be fertilised, the fallopian tubes in which the sperm need to swim, and the uterus where a successful implantation should occur, she is more anatomically, biologically and often medically involved than her male counterpart.

If a cause of infertility can not be identified through standard investigations including ovulation, tubal potency and semen analysis, infertility is described as “unexplained”⁸. It is also known as a diagnosis of exclusion, which is a medical term used when a diagnosis is reached by ruling out other conditions, but can it really be called a diagnosis at all⁹? The medical definition of diagnosis is the process of identifying a condition or disease, and “unexplained infertility” is exactly a failure to identify a specific cause.

The terminology is problematic, what about treatment of these couples?

The NICE guidelines for fertility “Fertility: assessment and treatment for people with fertility problems” is a 562 page document. The guidance is meant to cover diagnosis and treatment of fertility problems. It is also meant to assist reduction in practice variation and improve investigations and management of fertility issues. The chapter on unexplained infertility is a mere 10 pages long and its sole purpose is to review the clinical effectiveness of ovarian stimulation for unexplained infertility. The review includes 23 studies, most of which are considered “low quality”, only 4 had sufficient data to be deemed as “moderate” quality, and yet it concludes that ovarian stimulation should not be offered¹⁰. The reason for this being, the low quality studies did not show an improvement in chances of conceiving with fertility drugs, like clomid, compared to trying naturally. So for a couple with unexplained infertility, a heterosexual couple must continue trying to conceive naturally for another full year before any offer of interventions.

The guidelines also quote a Finnish paper that studied 70 couples in a prospective follow up study on obstetric outcomes of patients with unexplained fertility. They report in their findings that around 15% of couples diagnosed with unexplained infertility will conceive without treatment within 1 year and 35% within 2 years¹¹. The NICE guidelines takeaway is that many of the couples will successfully conceive naturally and have a live birth without treatment. However they neglect a conclusion in the quoted study, namely that many couples ultimately will reproduce but over a period of time longer than in the general population and that fertility treatment makes it possible for these couples to complete their families earlier. Essentially a paper that the NICE guidelines use to justify not treating these couples, is suggesting treatment of these couples.

Not only are the guidelines confusing, hospitals within the NHS are providing contradictory information as well. Yeovil Hospital in Somerset argue that the most efficient management of unexplained infertility is in fact treatment with clomid or alternatively treatment with gonadotropins with intrauterine insemination for up to three cycles¹².

Expectant management

Since the couples are not being offered active treatment, they should be given advice on lifestyle and successful conception, something known as expectant management. The NICE guidelines explain why expectant management is important, as it can increase the cumulative chances of success, but the description of it is vague. “Expectant management should consist of supportively offering an individual or couple information and advice about the regularity and timing of intercourse and any lifestyle changes which might improve their chances of conceiving”⁴.

It’s possible that expectant management isn’t appealing to couples as it delays treatment and they may feel like it’s delaying the time to conception, however it has been documented that couples with unexplained infertility have a good prognosis of conceiving if given adequate expectant management¹³. This shows the importance of how clear guidance and realistic expectations can help with the emotional aspect of continuing to try naturally. The Dutch College of General Practitioners have developed a tailored expectant management approach¹⁴ that calculates approximate chances of conceiving naturally. General practitioners can use a prognostic score model which can give an indication of good chances of conceiving naturally, moderate chances or low chances which would result in a referral for treatment.

Our current guidelines do not support our general practitioners in tailored expectant management, but more importantly, they fail our patients. A Cochrane review concludes that intrauterine insemination still plays an important role in the treatment of couples with unexplained infertility, particularly if they have a poor prognosis of conceiving naturally¹⁵. With no clear guidelines or reference values, how do we know if the patients with unexplained infertility are good or poor prognosis of natural conception? Intrauterine insemination is often the initial treatment for unexplained infertility in many other countries¹6. The NICE guidelines have been criticised for the lack of support of intrauterine insemination as an intervention by several papers ¹⁷,¹⁸,¹⁹ including one that states that the lack of evidence is a call for concern²⁰.

What can we do?

The NICE guidelines state that they do not overrule the individual responsibility of the healthcare professionals to make decisions that are appropriate to the circumstances and care of the individual patient, but unfortunately our CCGs (Clinical Commissioning Groups) get in the way of that. A study conducted by BPAS (British Pregnancy Advisory Service) reported that for the couples who do get funding for IVF treatment, only 17% of all CCGs offer funding for the full three cycles recommended by the NICE guidelines²¹. So even if healthcare professionals wanted to help, they are limited in the services they may be able to offer. Leaving us with patients concerned about conceiving within a time they feel reasonable, vague expectant management outlines, limited testing and guidelines with insufficient evidence.

The emotional impact that comes with the unexplained infertility “diagnosis” can not be disregarded. Studies have shown that couples with unexplained infertility experience significant distress²², which can arise from perceptions of bodily dysfunction and inability to manage, communicate or get help with their emotions²³. Another aspect which is important to consider is the financial implications. It is argued that expectant management is better in terms of cost and reducing multiple pregnancies⁴, however the evidence suggests that intrauterine insemination can help achieve a pregnancy faster and would be more cost effective if implemented sooner and in some cases would remove the need for IVF²⁰.

The exact cause of unexplained infertility is obviously unknown. Our inability to identify the cause does not mean that there isn’t one. Some may think that it’s due to subtle unmeasurable anomalies in ovulation, egg quality, sperm quality or in the uterus²⁴. Due to our lack of knowledge and limited investigations, couples will sometimes seek out expensive experimental tests to try to find answers to their unexplained infertility diagnosis⁸. With better research and increasing our knowledge we could develop better expectant management, better plans and treatment options for these couples. They deserve it.

References:

  1. National Health Services, Infertility https://www.nhs.uk/conditions/infertility/

  2. The World Health Organisation, Infertility https://www.who.int/news-room/fact-sheets/detail/infertility

  3. National Health Services, Infertility Causes https://www.nhs.uk/conditions/infertility/causes/

  4. National Institute for Health and Clinical Excellence, Fertility https://www.nice.org.uk/guidance/cg156/evidence/full-guideline-pdf-188539453

  5. Cates W, Farley TM, Rowe PJ. Worldwide patterns of infertility: is Africa different? Lancet. 1985 Sep 14;2(8455):596-8. doi: 10.1016/s0140-6736(85)90594-x. PMID: 2863605.

  6. J. Datta, M.J. Palmer, C. Tanton, L.J. Gibson, K.G. Jones, W. Macdowall, A. Glasier, P. Sonnenberg, N. Field, C.H. Mercer, A.M. Johnson, K. Wellings, Prevalence of infertility and help seeking among 15 000 women and men, Human Reproduction, Volume 31, Issue 9, September 2016, Pages 2108–2118, https://doi.org/10.1093/humrep/dew123

  7. Nargund G. Why Fertility Education is needed in schools. Facts Views Vis Obgyn. 2015;7(3):189-191.

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  9. Buckett W, Sierra S. The management of unexplained infertility: an evidence-based guideline from the Canadian Fertility and Andrology Society. Reprod Biomed Online. 2019 Oct;39(4):633-640. doi: 10.1016/j.rbmo.2019.05.023. Epub 2019 Jul 11. PMID: 31439397.

  10. National Institute for Health and Clinical Excellence, Unexplained Infertility https://www.nice.org.uk/guidance/CG156/ifp/chapter/Unexplained-infertility

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  12. Yeovil Hospital Healthcare https://yeovilhospital.co.uk/unexplained-infertility/

  13. F.A.M. Kersten, R.P.G.M. Hermens, D.D.M. Braat, E. Tepe, A. Sluijmer, W.K. Kuchenbecker, N. Van den Boogaard, B.W.J. Mol, M. Goddijn, W.L.D.M. Nelen, on behalf of the Improvement study Group, P.G. Hompes, H.R. Verhoeve, J. Gianotten, J.P. de Bruin, C.H. de Koning, C.A. Koks, F.J. Broekmans, A.P. Manger, G.J.J.M. Muijsers, J. Kwee, G.J. Scheffer, J.M. van Rijn, M.J. Pelinck, I.A. van Rooij, A. Hoek, T. Spinder, M.M. van Rumste, D. Boks, J.H. Vollebergh, E. Scheenjes, J.M. van der Ploeg, (2016) Tailored expectant management in couples with unexplained infertility does not influence their experiences with the quality of fertility care, Human Reproduction, Volume 31, Issue 1, January 2016, Pages 108–116, https://doi.org/10.1093/humrep/dev277

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  16. N A Danhof, R Wang, M van Wely, F van der Veen, B W J Mol, M H Mochtar, IUI for unexplained infertility—a network meta-analysis, Human Reproduction Update, Volume 26, Issue 1, January-February 2020, Pages 1–15, https://doi.org/10.1093/humupd/dmz035

  17. Bahadur, G., Ilahibuccus, A., Al-Habib, A., & Okolo, S. (2015). Intrauterine insemination practice and the UK NICE Guidelines. Human Reproduction, 30, 1277–1278. doi: 10.1093/humrep/dev040

  18. Bahadur, G., Homburg, R., Muneer, A., Racich, P., Alangaden, T., Al-Habib, A., & Okolo, S. (2016). First line fertility treatment strategies regarding IUI and IVF require clinical evidence. Human Reproduction, first published online April 12, 2016. doi: 10.1093/humrep/dew075.

  19. Peeraer, K., Debrock, S., De Loecker, P., Tomassetti, C., Laenen, A., Welkenhuysen, M., D’Hooghe, T.M. (2015). Low-dose human menopausal gonadotrophin versus clomiphene citrate in subfertile couples treated with intra- uterine insemination: A randomized controlled trial. Human Reproduction, 30, 1079–1088. doi: 10.1093/humrep/ dev062

  20. Woodward, B., Tomlinson, M., Kirkman-Brown, J. (2016) Replacing IUI with IVF for initial treatment of unexplained infertility: why this NICE recommendation is cause for concern, Human Fertility, 19:2, 80-84, DOI: 10.1080/14647273.2016.1182220

  21. British Pregnancy Advisory Society, BPAS investigation into the IVF postcode lottery: an examination of CCG policy for the provision of fertility services (2020) https://www.bpas.org/media/3369/bpas-fertility-ivf-postcode-lottery-report.pdf

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  23. De D, Roy PK, Sarkhel S. A psychological study of male, female related and unexplained infertility in Indian urban couples. J Reprod Infant Psychol. 2017 Sep;35(4):353-364. doi: 10.1080/02646838.2017.1315632. Epub 2017 Apr 26. PMID: 29517374.

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