Centromeric AA motif in KIR as an optimal surrogate marker for precision definition of alloimmune reproductive failure.

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.

Uterine natural killer cells in patients with idiopathic recurrent miscarriage.

PROBLEM: Uterine natural killer (uNK) cells are major players during implantation and early pregnancy. The aim of our study was to analyze uNK cell concentration in the endometrium of idiopathic recurrent miscarriage (iRM) patients and fertile controls. METHOD OF STUDY: Out of n=130 couples with ≥3 consecutive, clinical RM screened according to a standardized diagnostic protocol, n=58 patients with iRM were identified. Endometrial biopsies were investigated in patients and n=17 fertile women (controls) via immunohistochemistry. RESULTS: Compared to controls, the concentration of uNK cells was significantly higher in iRM patients (257±212 vs. 148±73 uNK cells/mm², P=.04). IRM patients showed a higher prevalence of >300 uNK cells/mm² than controls (34.5% vs. 5.9%, P=.02). In 88% of controls and 62% of iRM patients, uNK cells were detected within the range of 40-300/mm². CONCLUSION: Idiopathic recurrent miscarriage patients showed higher uNK cell levels than controls supporting the possible impact of uNK cells in the pathophysiology of miscarriage. Our cutoff levels might help to select RM patients which may benefit from immunomodulatory treatment.

Where and when should natural killer cells be tested in women with repeated implantation failure?

The aim of this study was to identify the candidates for natural killer (NK) testing and to define the best methodology. For this purpose a prospective study was performed on 73 women with repeated implantation failure (RIF). RIF was considered to exist in patients not achieving clinical pregnancy after three transfers with at least one good-quality embryo. Idiopathic RIF was considered to exist in patients in whom thrombophilia, hysteroscopy and endometrial culture were normal, and no chromosomal factor was suspected. Thirty-two of the 73 patients were considered to have idiopathic RIF, and 17 fertile women with children were taken as controls. Immunohistochemical staining for endometrial CD56+ and blood CD56+ or CD16+ NK cells measured using flow cytometry were compared during the mid-luteal phase in both patients and controls. Seventeen out of the 32 patients with idiopathic RIF and only one of the controls had >250 CD56 cells per high power field 400× in endometrial biopsy (p<0.001). The percentage of blood NK cells out of the total lymphocyte population was higher in women with idiopathic RIF (13.4±1.2%; range, 2.63-29.01) than in controls (8.4±0.7%; range, 5.72-13.28; p=0.026). There was a positive correlation between blood and endometrial CD56 cells (ρ=0.707; p<0.001). No significant differences were found between patients with other types of RIF and controls. This study suggested that testing for NK cells might be useful in women with idiopathic RIF during the mid-luteal phase.

Experience in IVIg therapy for selected women with recurrent reproductive failure and NK cell expansion.

PROBLEM: Recurrent reproductive failure (RRF) has been associated with expansion of circulating NK cells, key cells for maternal tolerance, decidual vasculogenesis and embryo growth. This study reports our experience in intravenous immunoglobulin (IVIg) therapy of a large cohort of women with RRF with expanded circulating NK and/or NKT-like cells (blood NKT cells are a heterogeneous subset of T cells that share properties of both T cells and NK cells). METHOD OF STUDY: Observational study of RRF women with NK or NKT-like expansion (>12% or 10% cutoff levels of total lymphocytes, respectively), treated with IVIg for the next gestation. RESULTS: By multivariant logistic regression analysis after adjusting for age, NK cells subsets and other therapies, IVIg significantly improved the live birth rate to 96.3% in women with recurrent miscarriage (RM) compared with 30.6% in case not receiving IVIg (P < 0.0001). In women with recurrent implantation failure (RIF), in comparison with women not receiving IVIg, treatment increased the pregnancy rate from 26.2 to 93.8% (P ≤ 0.0001) and the live birth rate from 17.9 to 80.0% in RIF (P ≤ 0.0001). CONCLUSIONS: Immunomodulation with IVIg in our selected group of RRF patients with immunologic alterations enhanced clinical pregnancy and live birth rates. Our results may facilitate the design of future clinical trials of IVIg in this pathology.

Rotura de vasa previa: comunicación de un caso y revisión de la literatura / Rupture of vasa previa: case report and review of the literature

La vasa previa es una situación que se produce cuando vasos fetales intramembranosos aberrantes, procedentes de la placenta o del cordón umbilical, atraviesan el orificio cervical interno y se sitúan por delante de la presentación fetal. Su incidencia es de 1/2.000-1/3.000 embarazos, y la mortalidad perinatal asociada es del 52-66%, aproximadamente. La reducción de esta elevada mortalidad se basa en su diagnóstico prenatal. Exponemos a continuación el caso clínico de una gestante, con controles obstétricos correctos, que acude a urgencias a las 34,5 semanas por rotura prematura de membranas, objetivándose un líquido amniótico hemático y bradicardia fetal severa, por lo que se realiza una cesárea urgente, naciendo una niña con anemia severa, que ingresa en la unidad de neonatología, presentando buena evolución posterior. Presentamos también una revisión de la literatura de los años 1980 al 2008, a través de Medline, usando las palabras «vasa previa» (AU)

Vasa previa is a condition in which the intramembranous fetal blood vessels within the placenta or umbilical cord cross the internal os and become trapped between the fetus and the opening of the birth canal. The incidence of this entity varies from 1/2000 to 1/3000 pregnancies and the associated perinatal mortality rate has been reported to be as high as 52-66%. Reduction of this high perinatal mortality depends on prenatal diagnosis. We report the case of a pregnant woman with no abnormalities in antenatal visits who presented to the emergency service at 34.5 weeks of pregnancy due to premature rupture of membranes, at which time blood-stained amniotic fluid and severe fetal bradycardia were noted. An emergency cesarean section was performed. A female neonate was delivered with severe anemia. The neonate was admitted into the neonatology unit and subsequent outcome was favorable. We also provide a review of the literature published between 1980 and 2008 using Medline, with the key words "vasa previa" (AU)

Linfoma secundario de mama / Secondary lymphoma of the breast

Se presenta el caso de una recidiva en la mama izquierda de un linfoma no Hodgkin B del centro folicular de grado I en una paciente de 59 años. La afectación de la mama por un linfoma puede ser primaria o aparecer en el contexto de una enfermedad diseminada. Entre los primeros, el más frecuente es el linfoma no Hodgkin B difuso de células grandes, seguido del linfoma folicular y los linfomas MALT

We report a case of non-Hodgkin follicular B lymphoma (grade I) relapse in the left breast in a 59-year-old woman. Lymphomas of the breast may be either primary or may develop in the context of disseminated disease. The most common types of lymphoma in the first group are large cell lymphoma, follicular lymphoma and MALT lymphoma