After repeated IVF failures or miscarriages, immune testing may offer another avenue to investigate—but it is not a first step, and it cannot promise an answer. Featuring Dr Harry Karpouzis, Founder & Scientific Director, IVF Pelargos Fertility Group, this guide examines where immune investigation may fit when other explanations have been explored. The challenge is distinguishing a carefully targeted approach from expensive testing and treatment built on uncertain evidence.
Hosted by Jessica Bourke, Founder of The Fertility Detective, with 20+ years of experience supporting individuals through fertility challenges and pregnancy loss.
The appeal of a new explanation is understandable when embryo transfers keep ending in disappointment. Yet recurrent implantation failure and recurrent miscarriage do not automatically point to an immune problem. Before pursuing that possibility, the investigation needs to return to the embryos, the uterus and the patient’s medical history.
Embryo chromosome problems can remain central, even when attention has shifted toward the immune system. In a woman who is 45 years old and has miscarriages or repeated implantation failures involving embryos that have not undergone PGT-A, chromosome problems are likely to be the most common explanation. Immune therapy would not resolve that underlying issue. A failed transfer involving a euploid embryo, one assessed as having the expected chromosome number, deserves a careful review too—but does not, by itself, establish an immune cause.
The uterine assessment also deserves scrutiny. Hysteroscopy can identify problems that ultrasound may miss, including signs of chronic infection, while assessment for chronic endometritis may form part of the investigation. The details of previous embryos and transfers remain relevant rather than becoming secondary once an immune test produces an abnormal result.
Other investigations depend on the history. Karyotyping can reveal a chromosome rearrangement, such as a translocation, in someone who is otherwise healthy, while thrombophilia, a tendency toward blood clotting, may warrant evaluation when there is a relevant background. The purpose is not to order every available test, but to make sure an immune explanation is not being pursued while another plausible cause remains unaddressed.
Reproductive immunology examines how immune activity may influence implantation and pregnancy. Its difficulty lies partly in interpretation: there is no universal agreement on the appropriate levels of various immune factors in blood or the uterine lining. Different tests use different thresholds, and the evidence remains conflicting.
That uncertainty matters most when a result is labelled “high” or “low.” Such a label does not carry the same meaning across every laboratory or testing approach. A useful consultation should therefore move beyond the label to consider what was measured, where it was measured and how much confidence the result deserves.
Natural killer cells, often shortened to NK cells, illustrate the problem. Despite their alarming name, they may help implantation, which is itself an inflammatory process. Uterine NK cells are also different from those circulating in the blood, so a blood result and a uterine result describe different parts of the immune picture.
Cell numbers are only part of that picture. Cytotoxicity, or cell-killing activity, may matter as much as the number of NK cells, while immune signalling substances called cytokines, including interleukins, may also influence implantation. Disturbances in their balance may contribute to miscarriage, but those possibilities do not translate into a universally accepted test or treatment protocol.
For patients, the practical distinction is between investigating a plausible contributor and identifying a proven explanation. Immune evaluation may be relevant after recurrent unexplained losses or implantation failures, once other causes have been investigated. It is not intended as routine testing before a first IVF cycle.
A test result is most useful when it reflects the circumstances in which treatment will take place. The hormonal environment of the uterine lining changes immune activity, which complicates interpretation. Testing without considering the intended embryo-transfer cycle may leave an important gap between the result and the proposed protocol.
Progesterone supports pregnancy, but it also acts as an immunomodulator, changing immune activity. Higher doses may reduce that activity, and estrogen can influence the uterine environment as well. The timing and preparation of a test therefore deserve attention alongside the result itself.
At IVF Pelargos Fertility Group, the approach is to assess the lining after estrogen and progesterone preparation, aiming to resemble the conditions of embryo transfer. Testing may involve an endometrial biopsy, performed as an outpatient procedure or combined with hysteroscopy. It may also be coordinated with other investigations, such as testing for chronic endometritis.
This is a clinic-specific approach, not a universal standard. Immune testing can be expensive, and the clinic reserves it for patients whose histories suggest a reason to investigate. Before proceeding, patients can ask what decision the test is intended to inform, how its timing relates to their transfer and whether the result would change treatment.
There is no single immune protocol that fits every patient with repeated IVF failure. Treatment may target an underlying systemic condition or immune activity within the uterine lining. The term “personalised” is meaningful only when each medication has a specific rationale, rather than being added to an increasingly complicated package.
For profiles interpreted as immune overactivity, the clinic uses treatments such as steroids and intralipids. These are part of its approach when testing suggests increased NK-cell activity or an imbalance in certain immune responses. Their use within an individual protocol does not resolve the wider uncertainty around reproductive immunology or establish that they will prevent another loss.
IVIG is another treatment used for immune overactivity, but it brings substantial practical and safety concerns. It is expensive, can be difficult to obtain and may cause anaphylaxis, a severe allergic reaction. The clinic does not use it because of legal and access difficulties and cost.
Other medicines address different findings. The clinic uses G-CSF in selected cases, including certain regulatory immune-cell imbalances, and may also consider it for an unexplained thin uterine lining. G-CSF can alter white blood cell counts, so repeated use may require monitoring with a full blood count, particularly when it is given by injection rather than infusion.
These distinctions are more useful to patients than a long list of possible drugs. A proposed protocol should come with an explanation of the condition being targeted, the uncertainty surrounding benefit and the medication’s safety profile. Where evidence is inconclusive, safety remains part of the decision—not a separate conversation to have after treatment begins.
An autoimmune history can change the context of fertility care. Conditions such as Hashimoto disease, celiac disease and lupus may coexist with other immune-related problems, and an autoimmune background may be associated with pregnancy difficulties or changes within the uterine lining. Identifying and appropriately treating those conditions is different from interpreting an isolated NK-cell result.
Antiphospholipid syndrome is particularly relevant because it involves both the immune system and blood clotting. Diagnosis requires the laboratory findings and the clinical picture to fit together. A blood result alone is not the whole diagnosis.
When antiphospholipid syndrome is confirmed, treatment may include anticoagulant injections and aspirin, with steroids considered in some circumstances. Low molecular weight heparin may be used with aspirin in that setting. This is another reason to ask what each medicine is treating: a prescription for a diagnosed clotting-related condition has a different rationale from an empirical immune add-on.
Lifestyle measures offer something practical to focus on while investigations continue. Proper sleep, daily movement and avoiding smoking and alcohol are supportive foundations for overall health, including immune function. Exercise, including resistance training, may also be relevant to immune function and hormone balance, with the approach tailored to the individual.
Supplements require a more selective conversation. Antioxidants, including vitamin E and vitamin C, are among the supportive measures discussed in this area. But products aimed at increasing NK cells are intended, if used at all, for specific patient categories rather than everyone preparing for IVF.
Vitamin D is a useful example of why testing can be preferable to assumptions. Levels may be deficient or excessively high, so more is not automatically the right answer. These measures belong within an individualised health plan, rather than replacing investigation of repeated loss or the assessment of a proposed medical treatment.
Different clinics may measure immune factors differently and offer different treatment protocols. That variation makes trust essential, but trust should include room for questions about conflicting evidence. Experience in immunology is valuable only alongside a clear explanation of what is known, what remains uncertain and why a particular approach fits the patient’s history.
A focused consultation can help make competing recommendations easier to assess. Bring the discussion back to the unresolved problem rather than the length of the proposed test list. Useful questions include:
A second opinion can be valuable when previous care feels incomplete, or recommendations differ substantially. It can also help review whether the embryo assessment, uterine investigation, medical history and transfer details have been considered together. The goal is a coherent explanation for the next step, not simply a larger treatment package.
Sometimes that review leads to less treatment rather than more. Even after extensive investigation, a case may remain unexplained, and returning to a natural cycle with spontaneous ovulation can sometimes lead to a positive outcome. That possibility is not a guarantee, but it challenges the assumption that every unsuccessful attempt must be followed by an additional medication.
Immune investigation may have a place after recurrent unexplained miscarriage or implantation failure, but it belongs within a broader review rather than at the front of every IVF plan. The most useful next step is one that addresses a specific unanswered question and makes the limits of testing and treatment clear. An abnormal immune result should begin a careful discussion, not end the search for other explanations.
Repeated disappointment does not mean that nothing remains to reconsider. A thorough review, a second opinion or a different transfer approach may help shape a more considered plan. Hope and realism can sit together: continuing to seek answers does not require treating an uncertain explanation as a proven one.
When there is a relevant history, blood testing can check for thrombophilia and other systemic disorders. Immune factors may also be assessed, including TH1, TH2, CD56, natural killer cell cytotoxicity, and other parameters. Testing is preferably performed in the uterus after preparing the lining of the womb. The results can then guide treatment at the time of embryo transfer.
After 6 frozen embryo transfers, four implantation failures, and two early pregnancy losses—including one after transfer of a PGT-A euploid embryo—the first step is to investigate other common causes of failure. This includes hysteroscopy and testing for chronic endometritis. Not all previous embryos were tested, and the quality of the euploid embryo also matters.
A KIR A/B result usually does not cause problems. If immune treatment is still being considered, steroids, intralipids, sometimes Plaquenil, and rarely Tacrolimus may be used, depending on the rest of the history. A healthy embryo should be confirmed before proceeding with an immunological protocol.
The main medications and treatments include steroids, de-clotting injections such as Clexane, intralipids, G-CSF, and sometimes Plaquenil. IVIG is not used in Greece at the clinic, and LIT is not used because it is not considered effective enough relative to its risk.
Steroids are usually started at the beginning of endometrial preparation and continued later. De-clotting injections depend on the diagnosis. They are used from the beginning together with aspirin in antiphospholipid syndrome, and they are also used in homozygous cases of relevant thrombophilia. They are not routinely needed for heterozygous cases unless there is a specific immunologic reason or a very high clot risk, such as obesity.
This pattern is considered immune overactivity. The goal is to suppress it, usually with steroids together with intralipids.
Yes. In cases of immune overactivity, prednisolone is preferred instead of dexamethasone.
Assuming the issue is implantation rather than miscarriage, this is interpreted as unexplained implantation failure. A 4AA euploid embryo should give about a 70% to 75% chance, but further evaluation is still needed. This may include hysteroscopy, immune testing in the uterine lining, natural killer cell testing, TH1/TH2 testing, and assessment for chronic infections, transfer protocol issues, and endometriosis.
If everything has been checked and the problem remains, the failure is still unexplained. Even after obtaining a new euploid embryo, the exact reason may never be found.
These situations are felt very heavily. It is frustrating when every effort is being made to cross everything off the list. It is important to cross-check that all areas have been accounted for and, if possible, create another euploid embryo before moving to the next phase.
Supportive measures include antioxidants, vitamin E, vitamin C, and a healthy lifestyle. Alcohol and smoking should be avoided. Some dietitians check genetics and recommend specific diets that may help the immune system. Some supplements on the market may help increase natural killer cells, and these can be used in specific categories.
Vitamin D should be assessed with a blood test to determine whether there is a deficiency. It is important not to make assumptions, because vitamin D can affect the immune system and levels can also become too high if a patient has been taking it. The level should be checked and brought back into range if necessary.
Patients should trust the doctor they choose. Immunology is complicated, with conflicting evidence, and different clinics may use different protocols, tests, and theories. The simpler and more common causes should be checked first. If something keeps happening repeatedly without explanation, especially miscarriages, immunology may be the answer. Seek a clinic and doctor who believe in and understand immunology.
The issue is not belief so much as logic. Immunology may not have the same level of evidence as some other areas, but there is still a lot of logic behind it. Treatment is personalised, good results are seen in different cases, and people with this history usually trust the approach.
Do not keep repeating the same thing over and over and expecting a different result. After an unsuccessful euploid transfer, do not be afraid to keep pushing for answers. Patients deserve that at the very least.
Do not wait to check everything that can be checked. There is always hope, even when it feels as if there is none. Anyone who wants to contact the team can find them online.
