Abstract
Background:
Early fetal demise (EFD), defined as the absence of cardiac activity in a visible fetus, represents a severe form of pregnancy loss with incompletely understood mechanisms. While genetic factors constitute the primary etiology, emerging evidence implicates maternal immune dysregulation in EFD pathogenesis, though the specific cellular and molecular pathways remain undefined.
Materials and methods:
We performed single-cell RNA sequencing (scRNA-seq) on peripheral blood mononuclear cells (PBMCs) from a 20-subject cohort comprising EFD patients, healthy pregnant women, and non-pregnant controls. Parallel murine studies involved GFP-labeled monocyte transfer into E8.5 pregnant mice, with subsequent embryonic viability assessment. Human villous tissues from EFD and control pregnancies were analyzed alongside functional characterization using primary neonatal rat cardiomyocytes exposed to IFN-α1.
Results:
ScRNA-seq revealed significant CD14+ monocyte accumulation in EFD patients versus controls. In murine models, adoptively transferred maternal monocytes breached the placental barrier, inducing 25.7% embryonic lethality. EFD villous tissues exhibited CD14+ monocyte infiltration with selective IFN-α1 elevation (absent in IFN-α2). Cardiomyocyte functional assays demonstrated IFN-α1-mediated contractile impairment through significant reduction in beating frequency.
Conclusion:
These findings establish maternal CD14+ monocytes as key mediators of EFD via IFN-α1-dependent cardiac dysfunction, revealing a targetable immune axis for pregnancy preservation. The study provides the first direct evidence linking monocyte trafficking with embryonic viability, offering new therapeutic paradigms for miscarriage prevention.
Supplementary Information:
The online version contains supplementary material available at 10.1186/s12967-025-07230-7.