Clinical potential of fluid-based biomarkers for recurrent implantation failure: a systematic review
Mojtaba Moradi1,2, Leilani L Santos1,2, Wei Zhou1,2
1Department of Obstetrics, Gynecology and Newborn Health, University of Melbourne, Parkville, VIC, Australia.
Background:
Recurrent implantation failure (RIF) remains a significant challenge in reproductive medicine, with diagnostic approaches that are limited and widely debated. This systematic review evaluates whether fluid-based biomarkers from blood, uterine fluid, and menstrual fluid can provide more accessible and clinically informative alternatives.
Methods:
A systematic search of MEDLINE, Embase, Scopus, and Web of Science was conducted (2015-2025). Study quality was assessed using QUADAS-2 for diagnostic studies and PROBAST for prognostic studies. Due to substantial methodological heterogeneity, meta-analysis was not performed. Findings were synthesized narratively, and diagnostic performance was summarized using forest plots of reported AUC values without statistical pooling.
Results:
From 3,105 records, 18 studies met the inclusion criteria. The evidence base was dominated by blood-based biomarkers (n = 17). Multi-marker models consistently demonstrated higher diagnostic performance than single analytes, with immune-cell profiling panels and cytokine-clinical parameter models achieving AUC values up to 0.94. In contrast, individual biomarkers generally showed lower performance (e.g., lymphocyte count, AUC = 0.577). Prognostic evidence for blood biomarkers was limited, although plasma D-dimer (AUC ≈ 0.81) and immune-cell profiling models (AUC ≈ 0.72) showed potential for predicting pregnancy outcomes. Only one study evaluated uterine fluid biomarkers, identifying a four-protein panel with promising diagnostic performance, while no eligible studies assessed menstrual fluid.
Conclusion:
Fluid-based biomarkers, particularly multi-marker models, may have diagnostic potential in RIF; however, current evidence remains insufficient to support routine clinical implementation. Future research should prioritize prospective validation of blood-based multi-marker models in standardized, euploidy-controlled cohorts, alongside greater investigation of biologically proximal uterine and menstrual biofluids.
Systematic Review Registration:
https://www.crd.york.ac.uk/PROSPERO/, identifier CRD420251068643.
