Paternal HLA‐Derived Epitopes and Live Birth in Secondary Recurrent Pregnancy Loss: New Insights From a Clinical Trial

ABSTRACT Recurrent pregnancy loss (RPL), defined as two or more pregnancy losses before the 24th week of gestation, affects 1%–3% of women worldwide. Approximately, 40% of RPL cases are secondary RPL (sRPL), where women have given birth before facing pregnancy losses. The underlying causes of RPL remain unclear, but immune‐related factors may play a role. Previously, a randomised controlled trial using immunoglobulin (IVIG) in sRPL women with a history of four pregnancy losses performed in our RPL unit did not show significant effects of IVIG treatment overall. Yet, some evidence suggests potential benefits for a subset of sRPL patients. In the cohort used for the randomised controlled trial, we examined the role of maternal HLA class II‐presented fetal HLA‐derived epitopes in sRPL using the predicted indirectly recognisable HLA epitopes (PIRCHE‐II) algorithm. In the placebo group, sRPL mothers with an anti‐HLA antibody response had higher PIRCHE‐II scores when having a live birth compared with sRPL women who experienced another pregnancy loss. This difference was not observed in the IVIG‐treated group. Furthermore, as a proxy for T‐cell memory, the number of overlapping peptides between the two paternal haplotypes in couples having live births without treatment displayed a larger number of overlapping peptides. This effect was primarily driven by class II‐derived peptides. These results suggest that specific combinations of sRPL mothers and fathers, particularly those with an anti‐HLA antibody response, may generate higher PIRCHE‐II scores, which could contribute to successful live births. Understanding these immune interactions may provide insights for personalised diagnostic and therapeutic strategies in sRPL.