Liquid Biopsy as a Screening Tool in Recurrent Implantation Failure During IVF: A Narrative Review

Authors

  • Reza Saeedinia Student Research Committee, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
  • Ava Hemmat Department of Nutrition, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
  • Zohreh Heidary Vali-E-Asr Reproductive Health Research Center, Family Health Research Institute, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran

DOI:

https://doi.org/10.18502/jfrh.v20i2.22610

Keywords:

Recurrent Implantation Failure; Liquid Biopsy, Uterine Fluid; Extracellular Vesicles

Abstract

Objective: Recurrent implantation failure (RIF) remains a multifaceted challenge in assisted reproductive technology (ART), affecting a subset of in vitro fertilization (IVF) patients despite transfer of high-quality embryos. Conventional diagnostics often require invasive procedures that may disturb endometrial receptivity. This narrative review critically synthesizes the evidence on liquid-biopsy strategies for RIF screening, emphasizing biofluids such as uterine fluid (UF), spent embryo culture medium (SCM), peripheral blood, cervicovaginal fluid (CVF), and seminal plasma.

Materials and methods: Literature searches covered PubMed, Scopus, and Web of Science through August 2025, with inclusion of pivotal pre-2022 studies. Eligible works included observational studies, clinical trials, multi-omics analyses, and systematic reviews reporting molecular biomarkers relevant to endometrial receptivity or embryo competence.

Results: UF-derived microRNAs (miRNAs) and extracellular vesicle (EV) cargo during the window of implantation (WOI) consistently differentiate receptive from nonreceptive endometrium, with predictive accuracies (AUC 0.75–0.90) in small validation studies. SCM-based noninvasive PGT-A (niPGT-A) shows moderate concordance (~65%) with trophectoderm biopsy PGT-A, constrained by contamination and low cfDNA yield; recent advances include blastocoel fluid integration and methylation-based decontamination. Peripheral blood, CVF, and seminal plasma biomarkers remain exploratory due to lower specificity. Pre-analytical standardization and harmonized outcome definitions are critical for translation.

Conclusion: UF-miRNA/EV profiling holds the strongest promise for noninvasive RIF screening, whereas niPGT-A may serve as an adjunct for embryo competence assessment when biopsy is not feasible. Both approaches require multicenter validation and prospective trials demonstrating improved live-birth rates before routine clinical adoption.

Published

2026-09-12

Issue

Volume (20) issue (2)

Section

Articles