Early Pregnancy Immune Signatures May Distinguish Aneuploid Miscarriage from Euploid Pregnancy Loss and Live Birth

Pregnancy loss affects ~15% of couples and often results from embryonic chromosomal abnormalities. Early peripheral biomarkers that signal abnormal development could improve counseling and clinical decision-making. Here, we analyzed early-pregnancy peripheral blood from patients who conceived via assisted reproduction without preimplantation aneuploidy testing. Samples were collected ≤12 weeks' gestation for complete blood counts with differentials and multiparameter flow cytometry to quantify major lymphocyte subsets (total T, B, cytotoxic T cells, T helpers (Th), Th1, Th2, Th9, Th17, and regulatory T cells (Treg)). Participants were followed until pregnancy resolution (live birth, euploid or aneuploid miscarriage), and immune profiles were compared by outcome using the Kruskal-Wallis test. Exploratory discriminative analyses were performed with significantly different immune cell quantities. Basophils were highest in the aneuploid miscarriage group (n = 26), distinguishing them from both euploid miscarriage (n = 27) and live birth (n = 91). Th9 cells were lower in aneuploid miscarriages compared to euploid miscarriages. Th17 levels were higher in live births compared with both miscarriage groups. Additional aneuploidy-type-specific immune differences were observed. These alterations may reflect maternal immune recognition of a non-viable conceptus and localized immune activation at the fetal-maternal interface. If validated in larger cohorts, these early peripheral markers may help identify pregnancies at risk for miscarriage, particularly those involving chromosomal abnormalities.