Have you been given a diagnosis of unexplained infertility? You may have faced countless negative pregnancy sticks before turning to fertility screening for answers – only to be told the tests can’t find anything wrong. You may have even completed unsuccessful rounds of IVF, or experienced recurrent miscarriage. After heartbreak like that, a non-explanation feels like a door slammed in your face. Surely, there must be a reason I can’t get pregnant or carry a baby.
Here’s the thing: Unexplained infertility doesn’t necessarily mean there is no explanation. It means no explanation has yet been found. And for some patients with a diagnosis of unexplained infertility, advanced screening methods at elite clinics have given greater clarity and a path forward, by studying the immune system.
Read on to learn about reproductive immunology: what it is and how it may provide solutions for some couples facing unexplained infertility.
What does unexplained infertility mean?
Unexplained infertility is the name given when routine fertility testing hasn’t identified any problem that explains why you can’t conceive or sustain a viable pregnancy.
Standard fertility tests should check for:
- Low egg count
- Problems with your ovulation
- Imbalances in your reproductive hormones
- Structural problems or other abnormalities with your womb
- Obstructions in your fallopian tubes
- The sperm health of the male partner (sperm count and motility level, sperm shape, semen volume)
Dr Gorgy, Fertility Consultant, says: “If all the standard fertility tests look fine, you will be given a diagnosis of unexplained infertility. But unexplained infertility doesn’t necessarily mean there is no underlying issue – it means the testing provided hasn’t identified what the issue is.”
Not every clinic offers it, but further screening does exist.
What can be done for unexplained infertility?
After a diagnosis of unexplained infertility, it is often recommended that patients proceed with any appropriate lifestyle adjustments, sometimes in combination with assisted reproduction techniques like fertility drugs, intrauterine insemination (IUI) or even IVF.
Assisted conception techniques can indeed prove successful for some patients with unexplained infertility. However, other patients with undiagnosed fertility issues will then experience recurrent IVF failure or recurrent miscarriage. After these heartbreaking experiences, some of those patients have gone on to achieve success through reproductive immunology.
Unexplained infertility can be emotionally exhausting. Not having a clear diagnosis can sometimes make the experience even harder, because there is no obvious problem to “fix”.
A fertility consultation should give you the opportunity to understand your results, discuss your options and ask questions about treatments – including newer or less-established approaches such as immune therapy.
Read on to learn more.
What is reproductive immunology?
Reproductive immunology is an area of medicine that investigates the relationship between the immune system and reproductive system during conception and pregnancy.
The immune system has an important role in reproduction. During a healthy pregnancy, the mother’s immune system needs to interact with the developing embryo and placenta in a carefully regulated way. Implantation involves a complex communication between the embryo and the lining of the uterus, including immune cells and inflammatory signals.
Reproductive immunology is a highly specialised and even somewhat controversial area of medicine because the science is complex and research is still ongoing. Due to the complexity and specificity of individual patient cases and treatment regimens, large-scale randomised controlled trials (the research gold standard) are difficult to conduct and still lacking. However, many doctors dedicated to helping the specific patients that may benefit from reproductive immunology, have achieved success. And many patients who had all but given up hope of a family have finally gotten that baby of their own.
Please note: HFEA view on immune testing. You can also find further information on the British Fertility Society website.
How might your immune system affect fertility?
The immune system plays a key governing role when it comes to human reproduction and can affect multiple stages from conception to bringing a baby to term. Issues with the immune system can interfere with fertility, conception, and pregnancy in a number of different ways, as the Global Autoimmune Institute acknowledges. For example through chronic inflammation, inappropriate targeting of reproductive cells, and interference with essential hormonal messages.
Immune problems frequently go undiagnosed and immune-associated fertility problems are no exception. Often patients with hidden immune issues are told their inability to achieve a successful pregnancy is down to ‘bad luck’. Indeed in a 2025 review of diagnostics for immune-driven infertility in Biomolecules, researchers Kicińska et al point out that a variety of autoantibodies frequently show up in women suffering problems like unexplained infertility, recurrent miscarriage, and repeated IVF failure, even though those patients appear otherwise healthy. They also point out that patients with immune issues are frequently told their fertility problems are without apparent cause (in other words ‘unexplained infertility’).
Immune issues linked to fertility problems include:
Inflammation: Persistent immune overactivity can create chronic inflammation, which can reduce sperm and egg quality, interfere with hormones, and prevent normal fertilisation.
Autoantibodies: Autoantibodies are immune proteins that target the body’s own cells, tissues or proteins instead of foreign aggressors. Frequently, a range of problematic autoantibodies appear in women suffering recurrent miscarriage, recurrent implantation failure, and unexplained infertility, even when they have no other apparent symptoms.
Implantation failure and the immune “switch”: Implantation of the embryo in the womb is a process heavily dependent on an exacting immune “switch”. Early implantation relies upon a vigorous, inflammatory immune effort to enable the embryo to breach the womb lining – but then that immune response needs to be downregulated by other regulatory immune cells (the “switch”). Otherwise the aggression can harm the embryo instead of supporting it to implant.
Ovulation problems: Ovulation itself is an immune-driven process. White blood cells actually drive the tissue breakdown that is necessary for an egg to be released. In some cases, immune problems here can impair ovulation, even while hormone tests appear normal.
Antisperm antibodies: Antisperm antibodies can impair fertility. They are sometimes produced by the immune system in reaction to inflammation or trauma. They can weaken fertility by disturbing sperm motility, function, and general seminal fluid content.
Natural killer cell irregularities in the uterus: Uterine natural killer (NK) cells and fertility are intricately linked. In the womb, natural killer cells (a type of immune cell) help to govern the formation of blood vessels in the placenta. Irregularities in their receptors, activity or numbers are associated with miscarriage, implantation failure, and growth restriction.
What is immune testing for infertility?
Having an immune system that is “too active” is not currently a straightforward explanation for unexplained infertility, and there is no single immune test that can reliably diagnose an immune cause of infertility.
Immune testing for infertility is a series of blood screenings (and in some cases a womb lining biopsy) to establish how your immune cells may be affecting your fertility.
Immune testing for infertility should not be conducted in first-line fertility testing. It is for individuals and couples who have experienced recurrent miscarriage, recurrent IVF implantation failure, or who have known immune conditions impacting fertility.
The Fertility and Gynaecology Academy is one of the UK’s leading fertility clinics for immune testing for infertility, with decades of experience. Frequently, couples come to us from other clinics, asking why does IVF keep failing, or looking to identify their recurrent miscarriage causes. You can read more here about advanced immune testing for infertility.
What are immune treatments for infertility?
The term ‘immune treatment’ can refer to a number of different therapies. Depending on the clinic and the individual circumstances, these may include:
- Corticosteroids such as prednisolone
- Hydroxychloroquine
- Clexane
- Intralipid or other intravenous fat emulsions
- Intravenous immunoglobulin (IVIG)
- G-CSF
- Other medicines intended to modify the immune response
Immune treatments for infertility aim to calm overactive immune responses, lower inflammation in the womb and inhibit blood clotting that may interfere with embryo implantation or early pregnancy. Immune treatments for infertility are for people who have suffered recurrent IVF implantation failure, recurrent miscarriage, or who have immune conditions that can affect fertility. The selection of any immune treatments (and what they are targeting) will depend on issues identified in immune testing. You can read more here about the most common immune treatments for infertility.
Please note: HFEA view on immune treatments. You can also find further information on the British Fertility Society website.
Reproductive immunology is not for everyone – it must be responsibly targeted and offered without false hope. Here at The Fertility and Gynaecology Academy one of our primary areas of expertise is immune treatment for infertility. We have been able to help many couples with a diagnosis of unexplained infertility who have suffered recurrent miscarriage and/or recurrent IVF failure. Many patients who have come to us after treatment has been unsuccessful elsewhere have indeed finally been able to have a baby of their own.
To speak with a consultant or book an initial fertility assessment at our London clinic, contact us by calling 020 7224 1880 or email info@fertility-academy.co.uk.
