The initial step in a successful pregnancy involves the recognition of the embryo, which, being genetically distinct from the mother, necessitates the adaptation of the maternal body to accommodate and create an immunologically privileged environment for the fetus. This transformation establishes active immunological tolerance, shielding the embryo from the maternal immune system. Fetal recognition relies, in part, on identifying paternal HLA markers on embryo cells. However, challenges may arise if partners share common HLA variants (HLA matching or sharing), creating potential difficulties in recognition. "Maternal-fetal immune incompatibility" occurs when the mother and father have similar HLA-DQa alleles, potentially triggering an immune response that hinders implantation or leads to early pregnancy loss. As counterintuitive it may seem, studies suggest that fetuses with HLA haplotypes similar to their mothers' are more likely to be aborted. It seems that the paternally-derived genetic diversity is essential for embryo recognition and initiation of active immunological tolerance by the mother.

T-regulatory cells (Tregs) & uterine NK (uNK) cells:

At the same time, for the pregnancy to initiate and progress, the mother’s regulatory T (Tregs) immune suppressive cells and her uterine natural killer cells (uNKs) are required to help regulate the local uterine immunity and prevent rejection of the embryo. Tregs are essential mediators of the immune tolerance required to initiate pregnancy. It has been suggested that inadequate levels of Tregs may fail to effectively suppress pro-inflammatory responses, compromising the embryo's ability to avoid maternal immune rejection. Low toxicity uNK cells contribute to implantation, vascular modification and placentation. The activation of uNKs is facilitated by killer immunoglobulin-like receptors (KIRs) on their surface, which interact with fetal HLA proteins, expressed by the embryo. The balance between activating and inhibitory KIRs determines the activation or inhibition of uNK cells, crucial for successful pregnancy outcomes. Women with a genetic KIR-HLA-C mismatch characterized by maternal lack of activating KIRs in conjunction with embryo HLA-C2 presence, may face increased risk of uNK cell inactivation, leading to implantation failure, recurrent miscarriage, and serious pregnancy complications. Defective placentation, pre-eclampsia, fetal growth restriction, stillbirth and recurrent spontaneous abortion are associated with higher frequencies of inhibitory KIRs in women.

The FERTILYSIS Reproductive Alloimmunity panel involves 3 main tests:

HLA DQα matching between partners

KIR - HLA-C mismatch

Leukocyte Antibody Detection Panel (LAD)

HLA DQα-1 partner matching

In a healthy pregnancy, the mother's immune system adapts to accept the fetus through active immunological tolerance. This process involves the identification of at least a minimum level of genetic diversity from the father, including diverse human leukocyte antigen (HLA) genes. Studies suggest that fetuses with HLA haplotypes similar to the mother's are more likely to be aborted. Through this test we can predict possible embryo HLA combination and compare to the mother for compatibility.

KIR-HLA-C mismatch

To maintain tolerance, Immune suppressive regulatory T cells (Tregs) and uterine natural killer cells (uNKs) need to regulate the local uterine immunity and prevent rejection of the embryo. The activation of uNKs is facilitated by killer immunoglobulin-like receptors (KIRs), which interact with fetal HLAs. The balance between activating and inhibitory KIRs determines the activation or inhibition of NK cells, crucial for successful pregnancy outcomes. Defective placentation, pre-eclampsia, fetal growth restriction, and recurrent spontaneous abortion are associated with higher frequencies of inhibitory KIRs in women. Specific combinations of maternal KIR and paternal HLA-C genes may indicate a higher risk of infertility. This test allows genotyping of maternal KIR genes and comparison with possible fetal HLA genotypes to predict a possible mismatch.

KIR-HLA-C mismatch

To maintain tolerance, Immune suppressive regulatory T cells (Tregs) and uterine natural killer cells (uNKs) need to regulate the local uterine immunity and prevent rejection of the embryo. The activation of uNKs is facilitated by killer immunoglobulin-like receptors (KIRs), which interact with fetal HLAs. The balance between activating and inhibitory KIRs determines the activation or inhibition of NK cells, crucial for successful pregnancy outcomes. Defective placentation, pre-eclampsia, fetal growth restriction, and recurrent spontaneous abortion are associated with higher frequencies of inhibitory KIRs in women. Specific combinations of maternal KIR and paternal HLA-C genes may indicate a higher risk of infertility. This test allows genotyping of maternal KIR genes and comparison with possible fetal HLA genotypes to predict a possible mismatch.

Lymphocyte Antibody Detection (LAD)

It is a specialized infertility test aimed at assessing immune compatibility between partners. This test is particularly relevant in cases where there are recurrent pregnancy losses or unexplained infertility. During LAD testing, the blood of the female partner is analyzed to detect the presence of antibodies that may react against her partner's lymphocytes. The rationale behind this test is based on the concept of immune-mediated infertility, where the female partner's immune system produces antibodies against the male partner's cells, as a measure of the levels of blocking antibodies and protective antibodies which need to be produced during pregnancy to stop maternal immunological response against the fetus. Overall, LAD interpretation and utility should be evaluated in conjunction with other clinical findings and diagnostic tests.

Lymphocyte Antibody Detection (LAD)

It is a specialized infertility test aimed at assessing immune compatibility between partners. This test is particularly relevant in cases where there are recurrent pregnancy losses or unexplained infertility. During LAD testing, the blood of the female partner is analyzed to detect the presence of antibodies that may react against her partner's lymphocytes. The rationale behind this test is based on the concept of immune-mediated infertility, where the female partner's immune system produces antibodies against the male partner's cells, as a measure of the levels of blocking antibodies and protective antibodies which need to be produced during pregnancy to stop maternal immunological response against the fetus. Overall, LAD interpretation and utility should be evaluated in conjunction with other clinical findings and diagnostic tests.

Maternal HLA-C testing
Until recently, fertility testing only looked at the mother’s KIR genes and the father’s HLA-C type. The mother’s HLA-C was not taken into consideration because it was thought to be a “background factor” with little impact.

But new evidence shows that’s not true. Uterine immune cells react to any HLA-C2 on the embryo — whether it comes from the father or the mother. This means a woman’s own HLA-C type can influence how her immune system interacts with the embryo, especially if she has the inhibitory KIR AA genotype.

By adding maternal HLA-C typing to the evaluation, we get the full picture of compatibility. This matters because:

• It identifies risks that other tests could miss
• It explains why some women experience implantation failure or miscarriage despite “normal” results
• It opens the door to personalized, immune-based treatments that can improve pregnancy outcomes

Including maternal HLA-C makes the test more accurate, more actionable, and more valuable for guiding treatment. At the moment you can add it extra as a single test to include it on the Reproductive Immunology Full panel.