Immune and vascular dysregulation at the maternal-fetal interface in oocyte donation triplet pregnancies: unraveling mechanisms of failed immune tolerance.

[INTRODUCTION] Oocyte donation (OD) pregnancies present the highest level of fetal allogenicity, potentially triggering immune dysregulation at the maternal-fetal interface. Triplet pregnancies represent an extreme physiological challenge, yet the immune and vascular adaptations in OD triplets remain poorly understood. This study evaluated immunovascular profiles in triplet pregnancies conceived via OD compared with non-OD and spontaneous conceptions, exploring mechanisms of maladaptation related to high fetal allogenicity.

[METHODS] We conducted a retrospective case-control study of 115 triplet placentas: 29 conceived by OD and 86 by spontaneous conception, artificial insemination, or assisted reproductive technology without OD. Decidua basalis, chorionic villi, and fetal membranes were assessed by immunohistochemistry for immune and vascular markers. Quantitative immunoreactivity scores, qualitative expression patterns, and vascular morphology were compared between groups.

[RESULTS] OD placentas showed reduced CD163 regulatory macrophages, increased CD68, CD14 macrophages, CD56 NK cells, and HLA-DR immune cells, moderate PD-L1 expression, scanty CD4 regulatory T cells, and only scattered CD8 T cells in decidua basalis. Vascular alterations in OD placentas included muscularized maternal vessels (29.9 %), perivascular immune infiltration, endothelial activation (WT1, CD15), and absence of VEGF expression. C4d deposition on villous basal membranes was more frequent in OD placentas, indicating complement activation.

[DISCUSSION] OD triplet pregnancies exhibit a distinct immunovascular phenotype compatible with a graft-versus-host-like process. Regulatory immune cell depletion, enrichment of antigen-presenting cells, and vascular maladaptation suggest chronic immune dysregulation, contributing to placental insufficiency and adverse outcomes. These findings highlight the need for closer monitoring and may inform targeted interventions in highly allogeneic pregnancies.