Humoral pregnancy analyses reveal strategies for fetal protection and aberrancy in miscarriage.

The maternal immune system must simultaneously defend against pathogens with tolerance of the antigenically distinct fetus. Despite the central importance of immune modulation during pregnancy, epitope-level analyses of the maternal antibody repertoire remain lacking. Here, we performed high-throughput, multi-isotype longitudinal serology of 119 women from preconception through pregnancy, combining phage display of linear peptides with whole protein-based antigen assays to profile antibody responses to viral and self-antigens. We observed a broad expansion of the maternal IgG repertoire and a relative increase in IgA titers, both tracking with pregnancy progression. These changes may augment transplacental and mucosal immunity in the fetus and newborn, respectively. Notably, pregnancies ending in miscarriage exhibited pronounced IgA titer spikes against both viral and self-antigens unrelated to active infection (sensitivity 14/19, 74%, specificity 95%), indicating an underlying immune perturbation may precede pregnancy loss.