Chronic Endometritis, Uterine Natural Killer Level and Celiac Disease Predisposition in Idiopathic Recurrent Pregnancy Loss

Achoimre

ABSTRACT Objective Both chronic endometritis (CE) and high levels of uterine Natural Killer (uNK) have been associated to recurrent pregnancy loss (RPL), but a clear causality has not yet been defined. In addition, an increased prevalence of celiac disease (CD) genetic predisposition, defined by HLA‐DQ2/DQ8 high risk, has been reported in RPL patients, despite negative serological screening for CD. Recent evidence suggested that HLA‐mediated immune mechanisms may contribute to endometrial inflammation. The two main aims of this multicenter retrospective cohort study were to assess the prevalence of CE and high uNK cells level in idiopathic RPL patients with and without HLA‐DQ2/DQ8 haplotypes. Methods Patients with at least two prior first trimester miscarriages and negative standard diagnostic work‐up for RPL and CD underwent HLA‐DQ2/DQ8 genotyping and endometrial biopsy. CE was defined as >5.15 CD 138 positive plasma cells per 10 mm 2 (1/high‐power field). Increased uNK levels were defined as >4.5%. Results In this study, a total of 197 idiopathic RPL patients were included: 92 were HLA‐DQ2/DQ8‐high risk and 105 were HLA‐DQ2/DQ8‐low risk. While the prevalence of CE was not significantly different, increased uNK density was significantly more frequent in HLA‐DQ2/DQ8 high‐risk patients compared to HLA‐DQ2/DQ8 low‐risk patients (50% vs. 29.7%, p = 0.017). In multiple regression analysis, HLA‐DQ2/DQ8 risk was independently associated with high uNK cell levels (aOR 2.25, 95%CI 1.01–5.02, p = 0.049). Conclusions These findings suggest that HLA‐mediated immune mechanisms may increase uNK cell levels, potentially impairing embryo implantation. However, a causal relationship cannot be established.