Interplay Between Systemic Immune-Metabolic Signatures and Endometrial Immune Profiles in Women With Recurrent Pregnancy Loss Publisher Pubmed



Kamrani A ; Pourvahdani S ; Pirouzpanah M ; Salamati A ; Hassanzadeh A ; Baharaghdam S ; Aghapour A ; Mehdizadeh A ; Akbari M ; Heris J ; Yousefi M
Source: Naunyn-Schmiedeberg's Archives of Pharmacology Published:2026

Abstract

Recurrent pregnancy loss (RPL) is a complex disorder fundamentally linked to immune dysregulation at the maternal–fetal interface. While endometrial immune profiling provides critical diagnostic insights for managing RPL, its clinical application is limited by the invasive nature of endometrial biopsies. This study aimed to identify non-invasive, serum-based immunological and metabolic markers that accurately reflect local endometrial immune profiles, facilitating a less-invasive risk assessment and patient categorization. The study enrolled 106 participants, including 81 women with RPL and 25 fertile controls. The specimens of endometrium by doing biopsy of IL-15/Fn-14, IL-18/TWEAK, and CD56 expression were analyzed to categorize patients as having balanced, highly dysregulated (over-activated) and lowly dysregulated immune profiles. For each patient, blood samples from the same time frame were processed for immune profile (Th1/Th2 ratio), non-specific immune cell populations (NK), a metabolic profile containing autoantibody levels, and a metabolic screening of adiponectin, prostaglandin E2 (PGE-2), insulin-like growth factor-1 (IGF-1), and total phospholipids. All control subjects exhibited a balanced endometrial immune profile. In contrast, approximately 71% of RPL patients demonstrated immune dysregulation, with 46.9% showing an over-activated profile and 24.7% a low-activated profile. Systemically, the high immune dysregulation group exhibited significantly elevated peripheral NK cell frequencies and Th1/Th2 ratios compared to the balanced group. Furthermore, this over-activated group demonstrated a substantially higher prevalence of serum autoantibodies. Metabolically, high immune dysregulation was associated with significantly decreased serum adiponectin and IGF-1 levels, alongside markedly elevated PGE-2 and total phospholipid concentrations. These findings suggest that systemic metabolic and immune biomarkers may potentially reflect local endometrial immune status in women with RPL. Although these serum markers demonstrate promise as minimally invasive tools for immune profiling, further large-scale validation and predictive studies are required before they can be introduced as reliable alternatives to endometrial biopsy in clinical practice. © The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2026.