Direct and indirect evidence for pyroptosis and immune dysregulation in IVF/ICSI-ET-related early pregnancy loss.

BACKGROUND

Early pregnancy loss(EPL) remains a major obstacle to successful in vitro fertilization/intracytoplasmic sperm injection-embryo transfer(IVF/ICSI-ET). Immune dysregulation at the maternal-fetal interface has been increasingly implicated in implantation failure and early miscarriage, while inflammasome-mediated pyroptosis has emerged as a potential contributor to inflammatory tissue injury. However, the direct evidence linking pyroptosis to IVF/ICSI-ET-related EPL remains limited.

OBJECTIVE

To critically appraise direct and indirect evidence regarding immune dysregulation and the potential role of pyroptosis in IVF/ICSI-ET-related EPL, and to define current translational limitations.

METHODS

A structured review of epidemiological, clinical, and mechanistic studies published between 2020 and 2025 was conducted using literature relevant to EPL, IVF/ICSI-ET, maternal-fetal immune regulation, inflammasome activation, and pyroptosis. Evidence was considered according to its direct relevance to IVF/ICSI-ET-related EPL and interpreted with attention to study design, methodological limitations, and translational applicability.

RESULTS

Established clinical predictors of EPL after IVF/ICSI-ET include maternal age, body mass index, endometrial characteristics, and embryonic or sperm-related factors. Immune abnormalities involving uterine natural killer cells, macrophage polarization, and regulatory T-cell imbalance may contribute to impaired maternal-fetal tolerance. Pyroptosis-related pathways, particularly those involving the NLRP3/ASC/Caspase-1 axis, gasdermin D cleavage, and IL-1β/IL-18 release, provide a biologically plausible framework for both physiological epithelial remodeling during implantation and inflammatory injury when dysregulated. Nevertheless, most pyroptosis-related evidence is indirect and derived from pregnancy-related complications or non-reproductive inflammatory diseases rather than from IVF/ICSI-ET-specific EPL studies.

CONCLUSION

Immune dysregulation is likely contributes to in IVF/ICSI-ET-related EPL, whereas pyroptosis should currently be regarded as a promising but insufficiently validated mechanistic candidate. Future studies should prioritize cell-specific, temporally resolved, and clinically relevant investigations to clarify whether immune-pyroptosis interactions have diagnostic or therapeutic value in this setting.