Endometrial Microbiome and Recurrent Implantation Failure After Transfer of PGT-A Euploid Embryos: Is There a Missing Link?

Abstract

Background: Recurrent implantation failure (RIF) remains a challenging problem in assisted reproductive technology (ART). The increasing use of preimplantation genetic testing for aneuploidy (PGT-A) has reduced the contribution of embryo aneuploidy to implantation failure after transfer of euploid blastocysts, increasing interest in maternal endometrial factors. Among these, endometrial receptivity, chronic endometritis, immune regulation, and the endometrial microbiome have received considerable attention. Molecular assays including Endometrial Receptivity Analysis (ERA), Endometrial Microbiome Metagenomic Analysis (EMMA), and Analysis of Infectious Chronic Endometritis (ALICE) have been proposed as tools for individualized evaluation, although their clinical utility remains uncertain.

Methods: A narrative review was conducted using evidence from peer-reviewed studies, systematic reviews, meta-analyses, randomized controlled trials, and contemporary recommendations from the European Society of Human Reproduction and Embryology (ESHRE) and the American Society for Reproductive Medicine (ASRM). Particular attention was given to evidence concerning endometrial microbiota, chronic endometritis, endometrial receptivity, and outcomes following euploid embryo transfer.

Results: The endometrial microbiome is biologically plausible as a component of the implantation environment. Still, current evidence is heterogeneous and limited by low microbial biomass, sampling-related contamination, inconsistent sequencing methodologies, and the absence of standardized definitions of dysbiosis. Although associations between microbial composition and reproductive outcomes have been reported, causality has not been established. Randomized evidence does not support routine ERA-guided embryo transfer, and evidence for EMMA– or ALICE-guided treatment remains insufficient. Patients with repeated implantation failure following euploid embryo transfer represent an important under-studied population.

Conclusion: Current evidence does not support routine microbiome or receptivity testing in IVF. However, after comprehensive evaluation for established causes of implantation failure, selected patients with repeated failure after PGT-A-confirmed euploid embryo transfer may be considered for individualized endometrial assessment, with appropriate counseling that the clinical utility of ERA, EMMA, and ALICE remains unproven. Prospective studies specifically enrolling this population are required.