RESUMEN

Throughout pregnancy, the decidua is predominantly populated by NK lymphocytes expressing Killer immunoglobulin-like receptors (KIR) that recognize human leukocyte antigen-C (HLA-C) ligands from trophoblast cells. This study aims to investigate the association of KIR-HLA-C phenotypes in couples facing infertility, particularly recurrent pregnancy loss (RPL) and recurrent implantation failure (RIF), in comparison to a reference population and fertile controls. This observational, non-interventional retrospective case-control study included patients consecutively referred to our Reproductive Immunology Unit from 2015 to 2019. We analyzed the frequencies of KIR and HLA-C genes. As control groups, we analyzed a reference Spanish population for KIR analysis and 29 fertile controls and their male partners for KIR and HLA-C combinations. We studied 397 consecutively referred women with infertility and their male partners. Among women with unexplained RPL (133 women) and RIF (176 women), the centromeric (cen)AA KIR genotype was significantly more prevalent compared to the reference Spanish population (p = 0.001 and 0.02, respectively). Furthermore, cenAA was associated with a 1.51-fold risk of RPL and a 1.2-fold risk of RIF. Conversely, the presence of BB KIR showed a lower risk of reproductive failure compared to non-BB KIR (OR: 0.12, p < 0.001). Women and their partners with HLA-C1C1/C1C1 were significantly less common in the RPL-Group (p < 0.001) and RIF-Group (p = 0.002) compared to the control group. Moreover, the combination of cenAA/C1C1 in women with C1C1 partners was significantly higher in the control group than in the RPL (p = 0.009) and RIF (p = 0.04) groups, associated with a 5-fold increase in successful pregnancy outcomes. In our cohort, the cenAA KIR haplotype proved to be a more accurate biomarker than the classic AA KIR haplotype for assessing the risk of RPL and RIF, and might be particularly useful to identify women at increased risk among the heterogeneous KIR AB or Bx population. The classification of centromeric KIR haplotypes outperforms classical KIR haplotypes, making it a better indicator of potential maternal-fetal KIR-HLA-C mismatch in patients.

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RESUMEN

Siempre se debe garantizar un asesoramiento genético apropiado a la pareja, tanto antes como después del estudio genético. Las pruebas genéticas se han clasificado como pruebas altamente recomendables, recomendables u opcionales, según su resultado modifique el pronóstico. La indicación de las pruebas genéticas en la mujer con alteraciones en la reproducción se ha clasificado sobre la base de la historia clínica personal y familiar y puede abarcar el cariotipo en sangre periférica, el estudio molecular del gen CFTR (cystic fibrosis transmembrane conductance regulator), de X frágil, del factor II, del factor V y de metilentetrahidrofolatoreductasa (MTHFR). Respecto a los varones con alteraciones en la reproducción, cualquier estudio genético debe ir precedido por un estudio andrológico, que debe incluir al menos una historia clínica personal, familiar y el análisis de semen. Se puede indicar el cariotipo en sangre periférica, el estudio molecular de CFTR, las microdeleciones en el cromosoma Y, la hibridación fluorescente in situ (FISH, por sus siglas en inglés) en espermatozoides, el estudio de meiosis en tejido testicular y la fragmentación del ADN (AU)

In order to improve the care and follow up of couples with impaired reproduction, several scientific societies and experts have established specific recommendations for genetic testing in the evaluation of reproductive disorders in couples with impaired reproduction. Appropriate genetic counselling must be given to the couple before and after the genetic testing. Genetic tests have been classified as “highly recommended,” “recommended” or “optional” depending on whether the results have changed the prognosis of the corresponding pathology. The indication for genetic testing in women with impaired reproduction is classified on the basis of personal and family medical history and can include the karyotype in peripheral blood, the molecular study of CFTR, Fragile X, factor II, factor V and MTHRF. As regards men with impaired reproduction, every genetic study should be preceded by an andrological study, which must include at least the personal and family history and a semen analysis. A medical indication can be made for the karyotype in peripheral blood, the molecular study of CFTR, microdeletions on the Y chromosome, FISH sperm FISH, meiosis in testicular tissue studies, and DNA fragmentation (AU)

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