The embryo looked good. The transfer went ahead. Yet the pregnancy test was negative.
After repeated unsuccessful transfers, being told that the embryos were “good quality” can leave you with more questions than answers. What else needs to happen for implantation to succeed? Could the uterine lining be part of the explanation? And where does the immune system fit in?
Implantation depends on communication between the embryo and the endometrium—the lining of the uterus. Embryo development, hormonal signals and the local tissue environment all matter. Immune cells are part of that environment, with roles that extend well beyond defending the body against infection.
Research into uterine natural killer cells is helping us understand this interaction. Interpreting that research, however, requires a distinction between a finding that is biologically interesting and a test that can reliably guide treatment.
What does “good-quality embryo” actually mean?
An embryo grade usually describes its appearance and development under the microscope. It helps embryologists assess which embryos may have a better chance of resulting in pregnancy.
A good morphological grade does not establish that an embryo is chromosomally normal. Appearance and chromosome status are different aspects of embryo assessment.
This matters when investigating unsuccessful transfers. If chromosomal information is unavailable, embryo-related factors cannot be excluded simply because the embryos looked reassuring.
Equally, embryo quality alone cannot describe the conditions in which implantation takes place. The endometrium and its response to hormonal signals also deserve attention.
When do unsuccessful transfers become recurrent implantation failure?
Recurrent implantation failure, or RIF, describes repeated embryo transfers that have not resulted in pregnancy often enough to warrant considering further investigation.
There is no single number of failed transfers that carries the same meaning for everyone. Age, embryo characteristics and the expected chance of implantation affect how the history should be interpreted.
ESHRE therefore recommends an individualised approach rather than defining RIF solely by a fixed number of unsuccessful attempts.
Implantation failure also needs to be distinguished from recurrent pregnancy loss. A negative pregnancy test after transfer, a biochemical pregnancy and a later miscarriage describe different outcomes. They should be recorded separately when reviewing previous treatment.
What do uterine NK cells do?
Despite their name, uterine natural killer cells are a normal part of the reproductive environment.
They participate in processes involved in early pregnancy, including blood vessel development, the remodelling of spiral arteries and interactions with trophoblast cells, which contribute to the developing placenta. Their presence does not mean that the immune system is attacking an embryo.
Uterine NK cells also differ from most NK cells circulating in the blood. They occupy a different tissue environment and have different functional characteristics.
A blood NK cell result cannot be used as a direct picture of immune activity inside the uterine lining.
What did the recent study find?
A retrospective study published in BMC Immunology in September 2026 examined endometrial samples from 94 women with repeated unsuccessful frozen embryo transfers.
Biopsies were taken during a hormone-prepared mock cycle, five days after progesterone was started, known as P+5. Researchers used CD56 staining to measure uterine NK cell density relative to stromal cells.
| Previous unsuccessful frozen embryo transfers | Number of women | Median uterine NK cell density |
|---|---|---|
| Two | 24 | 1.8% |
| Three | 34 | 1.8% |
| Four or more | 36 | 3.9% |
The group with four or more unsuccessful transfers had a significantly higher median density.
The comparison was between groups with different numbers of previous failures. It did not establish a diagnostic threshold separating fertile from infertile women, or prove that a higher count caused implantation failure.
Does a higher NK cell count explain why a transfer failed?
Not by itself. The study identifies an association. It cannot establish whether a higher density contributes to implantation difficulties, reflects another process within the endometrium, or accompanies those difficulties without directly causing them.
Individual results also overlapped between groups. A group-level difference does not necessarily allow a clinician to predict what will happen for one patient.
Another limitation was the absence of available embryo chromosomal data. That makes it difficult to separate embryo-related factors from the possible contribution of the endometrial environment.
The findings therefore should not be extended to every unsuccessful IVF cycle—or interpreted as evidence that every patient with repeated failures has an immune disorder.
Cell number and cell function are different questions
Counting CD56-positive cells tells us about their abundance in a tissue sample. It does not fully describe what those cells are doing.
Uterine NK cells include populations with different receptors and functional characteristics. Two samples with similar counts may therefore represent different biological situations.
This is one reason reproductive immunology research is moving beyond cell numbers towards more detailed assessment of cell populations, activation and interactions within the endometrium.
That direction is scientifically important. It does not mean that every expanded immune panel already has established clinical value.
Why biopsy timing matters
The immune composition of the endometrium changes throughout the menstrual cycle. Hormonal exposure, particularly progesterone, affects the tissue being sampled.
A result therefore needs to be interpreted alongside the timing of the biopsy, the type of cycle and the laboratory method. In the study described above, sampling at P+5 allowed the researchers to compare women at a defined point in a hormone-prepared cycle. It does not make P+5 the correct timing for every endometrial investigation.
Before arranging a biopsy, the clinical question should be clear: what are we looking for, and how would the result affect the next decision?
A research biomarker is not yet a validated clinical test
A research biomarker may help identify a biological pattern. A clinically useful test must go further. It needs reliable measurement, meaningful interpretation and evidence that using the result improves clinical decisions or outcomes.
For uterine NK testing, important questions remain about methods, reference ranges, the relationship between cell density and function, and which interventions- if any – help patients selected by those results. ESHRE’s recommendations do not support routine peripheral or uterine NK cell testing for recurrent implantation failure. A higher count alone is also insufficient justification for immune treatment.
For a patient deciding what to do before another transfer, the practical question is: will this test provide information that can meaningfully change my care?
Where a reproductive immunology consultation can help
After repeated unsuccessful transfers, the next step may be a careful review of what has already happened. That includes the embryos transferred, the outcomes of each attempt, uterine and endometrial assessments, hormonal preparation, existing diagnoses and previous treatments.
An immunological assessment becomes particularly relevant when the reproductive history overlaps with autoimmune disease, inflammatory symptoms or findings that require specialist interpretation.
The purpose is to assess whether there is a clinically justified immune-related question, which investigations could answer it, and how the findings fit alongside the work of your fertility team.
Sometimes that leads to targeted further assessment. Sometimes it helps clarify why an additional test or proposed treatment is unlikely to provide useful information.
Frequently asked questions
Do elevated NK cells mean my body is rejecting the embryo?
No. Uterine NK cells have normal roles in early pregnancy. An elevated count alone does not demonstrate immune rejection.
Can a blood test tell me whether my uterine NK cells are elevated?
No. Blood and uterine NK cells are different populations. A blood result cannot reliably establish the number or behaviour of NK cells within the endometrium.
Should I have an endometrial biopsy before another transfer?
That depends on your history and the specific question being investigated. Repeated unsuccessful transfers do not automatically justify a biopsy solely to count NK cells.
Does this research show that lowering NK cells improves IVF success?
No. An association between cell density and previous transfer failures does not demonstrate that lowering those cells improves the chance of pregnancy or live birth.
Considering an online reproductive immunology consultation?
If you have had repeated unsuccessful embryo transfers and want a specialist review before deciding on further investigations or treatment, you can request an online consultation with Dr Amira Ćerimagić, specialist in clinical immunology and founder of Immuno Centar.
The consultation brings together your reproductive history, previous investigations and any relevant autoimmune or inflammatory findings. The aim is to identify reasonable next steps and explain the evidence behind them, in the context of your ongoing fertility care.
Online consultations are available to international patients, and medical documentation can be reviewed in English.
Request an online reproductive immunology consultation
References
Yang WJ, Zhang T, Yu S, Zhao Y, Li TC, Hsiao SY. Elevated uterine natural killer cell density is associated with severity of recurrent implantation failure in frozen embryo transfer cycles. BMC Immunology. 2026. Read the study.
ESHRE Working Group on Recurrent Implantation Failure. ESHRE good practice recommendations on recurrent implantation failure. Human Reproduction Open. 2023;2023(3). Read the recommendations.