In this webinar, Dr Harry Karpouzis, Founder & Scientific Director of Pelargos Fertility Group, discusses one of the most controversial topics in reproductive immunology: natural killer (NK) cells and their role in IVF success, implantation failure, and recurrent miscarriage.
Hosted by Barbara Scott, Chair of the Association of Reproductive Reflexologists and founder of Seren Natural Fertility.
Many fertility patients are told they have “high NK cells” — but what does that actually mean? Do elevated NK cells reduce implantation rates? Should you test for them before IVF? And when, if ever, is immune treatment justified?
Dr Harry Karpouzis explains the latest scientific evidence behind NK cells, fertility immune testing, embryo implantation, and IVF treatment decisions.
For some patients with repeated failed transfers or recurrent miscarriages, reproductive immunology may help explain what standard testing does not. But immune testing is presented as something for selected cases, not a routine add-on for everyone starting IVF.
These cells are lymphocytes that belong to the body’s innate immune system, and inside the uterus, they are not simply attacking tissue or threatening a pregnancy. In fact, uterine natural killer cells are a normal and necessary part of implantation.
Within the endometrium, these cells make up about 70% to 80% of immune cells. Their job is not just immune surveillance. They help prepare the uterus for pregnancy by supporting placental development, releasing growth factors and cytokines, and helping remodel small arteries into low-resistance channels so blood can flow properly to the placenta. They also contribute to maternal-fetal immune tolerance, the process that helps the mother’s body recognise and accept the embryo.
In other words, the key question is not just whether natural killer cells are present, but how they behave, where they are active, and when.
Many patients assume a blood test gives the full picture. Still, peripheral natural killer cells in the bloodstream and uterine natural killer cells inside the womb are different populations with different roles.
This distinction matters because many patients are told they have “high NK cells” based on bloodwork alone. Blood testing can be useful, especially when a biopsy is not feasible, and it may also reveal a broader autoimmune background, such as Hashimoto, thyroid issues, or ANA positivity. But it does not directly show what is happening in the uterine lining.
Peripheral blood natural killer cells are usually checked on the second to the third day of the cycle. Uterine natural killer cells are better assessed through an endometrial biopsy in the luteal phase, usually around the 17th to 21st day of the cycle, depending on the woman’s cycle.
The timing is important because implantation is evaluated within a defined window.
Immune factors are usually not the first place to look in IVF. In a first cycle or in patients without a history of repeated failure, broad immune workups can lead to overtreatment. The more common causes still need to be considered first.
That is especially true in recurrent implantation failure, where embryo quality, endometrial factors, and immunology may all play a role. Even after investigation, about 28% of recurrent implantation failure cases remain unexplained. Immunology may be part of that unexplained group, but it is not the default explanation.
Before moving to immune-based treatment, the article’s message is to exclude more common problems first, including embryo issues, uterine factors, and other obvious causes of failed implantation or miscarriage. In older patients, chromosome problems may be the more likely reason.
Patients often hear about “overactive” immunity, but the more useful framework is balance. According to the biopsy-based systems used here, the endometrium may show a hyperactivated immune system, a hypoactivated immune system, or a mixed profile.
If immune activity is too high, implantation may be disrupted. Elevated natural killer cell activity has been linked to poor arterial remodeling and impaired maternal-fetal tolerance.
But low activity can also be a problem. Reduced uterine natural killer cells may mean the lining is not providing enough support for placental development and blood flow. In other words, suppressing the immune system is not automatically helpful. If the immune system is already underworking, adding steroids may push it further in the wrong direction.
Differences like these help explain why one-size-fits-all immune protocols are hard to justify. A treatment that helps one person may be unhelpful, or even counterproductive, in another.
When the goal is to understand the uterine environment, the clinic relies on biopsy-based approaches linked to the studies of LeDee, with testing referred to as MatriceLab in France and IMAP in other countries. These tests assess immune markers in an endometrial biopsy taken during the implantation window.
That information can shape treatment in very different directions. A hyperactivated profile may lead to treatment with corticosteroids, intralipids, and Plaquenil. A hypoactivated profile calls for a different strategy. In that setting, higher doses of progesterone and estradiol are usually preferred, and luteal support may include Ovitrelle injections. Endometrial scratching may sometimes be used to help mobilise uterine natural killer cells.
The point is to base immune treatment on what the lining shows at the time of embryo transfer. Otherwise, treatment risks targeting a label instead of the underlying biology.
For a subset of patients with recurrent implantation failure or recurrent miscarriages, the issue may involve not just immune activity but also immune recognition. Uterine natural killer cells carry receptors called KIR, while the embryo may carry HLA-C antigens inherited from both parents.
One combination has drawn particular attention: maternal AA receptors together with an embryo carrying HLA-C2. This pairing has been associated with higher rates of recurrent implantation failure, miscarriage, and preeclampsia. The risk for recurrent implantation failure was described here as about 2 and a half times higher.
That does not mean every patient needs this testing. But in selected cases, HLA and KIR compatibility may be checked as part of a broader workup for repeated failure or loss.
The treatment approach in this setting is not about changing genetics. Diet and lifestyle were not described as ways to alter HLA-C or KIR, because these are genetic factors. Instead, the strategy is to reduce exposure where possible and support implantation more carefully. GCSF, also referred to as new progen, was described as showing good results in helping avoid miscarriage or implantation failure in this context.
When testing suggests an overactive immune environment, treatment may include steroids, prednisolone, clexane, intralipid infusion, or IVIG. These are not interchangeable in every case, and they are not used simply because a patient has had a bad IVF experience.
Some of these treatments are aimed at immune modulation rather than blanket suppression. Clexane, for example, was described as having both anticoagulant and immunomodulatory effects.
IVIG was described as effective but more expensive, harder to obtain, and carrying a less safe profile than intralipids. Some studies were said to show equal or very similar results between IVIG and intralipids, especially when combined with steroids.
Still, none of this should be mistaken for settled science. There is ongoing controversy in this field, and not all treatments have conclusive evidence behind them. At the same time, the clinic believes there is good data for HLA-C genotyping incompatibility and for some treatments used when the immune system is overactive.
For patients, this does not mean immune treatment is proven for everyone. It suggests there may be a role for it in carefully selected cases, especially when testing identifies a specific problem.
Immune-based treatment is often discussed in the context of IVF, but the same questions can arise in patients trying to conceive naturally. Here too, the answer depends on the diagnosis rather than the desire to “boost” implantation.
If intralipid infusion is needed and the woman is already pregnant, it may also be used after proper evaluation when the problem is known.
That does not mean natural killer cells are always the reason a pregnancy is not happening or not continuing. They are one possible factor in a much larger picture.
Immune findings rarely exist in isolation. Autoimmune disease, thyroid disease, and endometriosis may all shape the endometrial environment. Endometriosis in particular was described as being associated with immune conditions, though it may also affect egg quality, which can be more relevant in some patients than immunology itself.
That is why a low blastocyst rate would not automatically be blamed on immune issues. Sperm factors, including DNA fragmentation, may also need careful evaluation. If a good chromosomally normal embryo exists, especially after PGTA, then immunity may become a more useful area to investigate for implantation planning.
Even some immune test results need perspective. A low LAD result, for example, was not considered a strong cause on its own, since women with low or high LAD can still become pregnant. It has to be interpreted in the context of the full clinical picture rather than treated as a standalone explanation.
Natural killer cells are not villains in IVF. They are part of the normal biology of implantation, and problems can arise when their activity is too high, too low, or mismatched with the embryo in specific genetic ways. The challenge is that immune testing can easily be overused, and immune treatment can be misapplied if more common causes of failure have not been ruled out first.
In patients with recurrent implantation failure or recurrent miscarriage, particularly after good-quality embryos and standard evaluations, a targeted immune workup may provide useful answers. For everyone else, the wiser path may be restraint. The most credible approach is not to treat every failed cycle as an immune disorder, but to investigate carefully, test at the right time, and match treatment to the biology rather than to fear.
Yes. It is important to know whether the immune system is overworking or underworking before starting treatment. If the immune system is already underworking and steroids are given, they may cause more harm than benefit. Treatment should be personalised and based on what is happening at the time of embryo transfer. If immune activity is lower and uterine natural killer cell mobilisation is reduced, more support may be needed, and steroids might further suppress the system.
It depends on whether there are other reasons for needing IVF. Natural killer cells are not always the only reason for not getting pregnant or for miscarriage. If there are recurrent miscarriages and proper assessment has been done, steroids may sometimes help in natural conception as well, or when already pregnant, to reduce the risk of miscarriage. If intralipid infusion is needed and pregnancy has already occurred, it could be used after proper evaluation and when the problem is known.
Peripheral blood natural killer cells are usually checked in the first phase of the cycle, in the first days of the cycle. Uterine natural killer cells are better assessed by biopsy in the luteal phase, usually around day 17 to day 21 of the cycle depending on the cycle.
Sometimes both are done, but a uterine biopsy is usually preferred for uterine natural killer cells. Blood tests can still be useful, especially when a biopsy is not feasible, and they may also provide general autoimmune information such as Hashimoto’s disease, thyroid issues, and ANA. However, blood tests do not directly reflect uterine natural killer cells.
No. Blood testing checks peripheral natural killer cells in the blood, not uterine natural killer cells. Uterine natural killer cells exist only inside the uterus, and the levels are different in the blood and the uterus.
Biopsy-based assessment is usually preferred, although both tests are good. Chicago blood tests are usually sent in the US, while Fertilysis is a Greek brand. Blood tests are useful when a biopsy cannot be done, such as when living abroad. However, blood tests assess peripheral natural killer cells, which do not always correspond to what is happening inside the womb.
Most tests are blood tests, but some are biopsies inside the lining of the womb. Autoimmune conditions such as Hashimoto disease or celiac disease can also place someone in an autoimmune background that may affect natural killer cells in the endometrium. If there is no history of recurrent implantation failure or recurrent miscarriage, and this is a first IVF cycle, there is no reason to check all of these immune factors because that would be overtreatment.
IVIG is a good treatment, but it is more expensive, harder to obtain, and has a less safe profile than intralipids. Some studies show equal or very similar results, especially when combined with steroids, so intralipids are preferred over IVIG.
These treatments should not be used in the wrong setting. It would not be correct to say directly that they cause implantation failure, but they can cause trouble if used in cases where they should not be used.
Immunology is not linked to blastocyst formation. Endometriosis is associated with immune conditions and can affect egg quality, which may be more important in a low blastocyst rate. Sperm can also play a role, so it should be evaluated thoroughly, including DNA fragmentation. If a good chromosomally normal embryo is created, especially with PGTA, then immunity may be checked because of APS and endometriosis, and a specific protocol can be applied for implantation and endometrial preparation.
At age 44 to 46, the most obvious and common reason for failure is chromosomes. Egg quality is usually significantly reduced in this age group. If trying another IVF cycle, embryos should be allowed to grow to day 5, and PGTA should be done before considering immunological testing, because if there is no chromosomally normal embryo, immunology treatment will not lead to implantation.
Yes. Immunity and uterine natural killer cells can change over time. Infection, inflammation, endometriosis, and even pregnancy can change local immunity. These tests usually have a duration of about six months, because otherwise it is not possible to be sure what is happening at the time of embryo transfer.
The full picture is needed before giving advice. There may be overactivity of the natural killer system in relation to the partial DQA, but DQA is not considered strongly supported by the studies. Immunomodulating treatment at embryo transfer, such as steroids and possibly GCSF, might be needed, but this cannot be answered definitively from limited information.
LAD stands for leukocyte antibody detection and is part of some immunology reports. It is not considered a very important reason on its own, because women with low or high LAD can still become pregnant. It should be interpreted in the context of the full picture and other autoimmune reasons, and it is not treated as the sole cause of failure.
No. HLA and KIR are genetic, and genetics do not usually change. In IVF, this incompatibility is usually managed by minimising the antigens involved, such as transferring only one embryo, and by using immunomodulatory treatments like GCSF. Some clinics use LIT, which involves paternal antigens, but it is not used here because it is not considered safe and lacks conclusive evidence.
That cannot be determined without knowing how the immune testing was done and what the actual immune problem was, such as raised natural killer cells, raised cytotoxicity, or HLA-KIR incompatibility. LIT is usually used for HLA and KIR incompatibility. Before attributing the problem to immunology, more common causes should be ruled out, including whether the embryos are PGT-tested healthy embryos, whether there is a uterine problem, and whether hysteroscopy has been done.
The gold standard for diagnosing endometriosis is laparoscopy. However, if there is not a strong clinical suspicion, laparoscopy is not always done because it is invasive. If endometriosis is suspected, downregulation may be used before frozen embryo transfer. There are also genetic tests, through biopsy or even blood, that can predict endometriosis with a high percentage, and these tests are now part of practice.
Endometriosis has a small hereditary factor, but it is not a condition that simply passes from generation to generation like a classic genetic disorder.
Yes. Euploid embryos from a UK clinic can be accepted, the immune system can be checked, treatment can be given, and transfer can be done. Euploid embryos generated by mitochondrial replacement therapy can also be accepted for frozen embryo transfer.
