How to manage recurrent implantation failure after Intracytoplasmic Sperm Injection (ICSI) with normal Preimplantation Genetic Testing for Aneuploidy (PGTA), normal Endometrial Receptivity Array (ERA), and normal endometrium?

Management of Recurrent Implantation Failure with Normal PGTA, ERA, and Endometrium

For patients with recurrent implantation failure despite normal PGTA, ERA, and endometrium, the most effective approach is to combine ERA with endometrial immune profiling to identify and address potential immune dysregulation that may be preventing successful implantation.

Understanding Recurrent Implantation Failure (RIF)

• True RIF is relatively uncommon, occurring in less than 5% of infertility cases, and should only be diagnosed after at least 3 failed euploid blastocyst transfers (or equivalent number of unscreened embryos adjusted for age) 1
• RIF can result from multiple factors including uterine, male, embryonic issues, or specific IVF protocol problems 2
• Despite normal PGTA, ERA, and endometrial assessment, molecular abnormalities at the endometrial level and abnormal embryo-endometrium dialogue may still be responsible for implantation failure 3

Diagnostic Approach for Unexplained RIF

Immunological Assessment

• Evaluate immunological factors including cytokine levels and presence of specific autoantibodies 2
• Consider endometrial immune profiling, as immune dysregulation occurs in approximately 75.3% of RIF cases 4
• Assess for chronic endometritis which may contribute to implantation failure 5

Additional Evaluations

• Rule out infectious organisms in the uterus that could lead to chronic endometritis 2
• Consider vaginal microbiota assessment which may impact implantation 5
• Review sperm analysis parameters even when ICSI is being used 2

Treatment Recommendations

Combined ERA and Immune Profiling Approach

• The combination of ERA and endometrial immune profiling shows significantly higher implantation rates compared to no treatment and is more effective than either test alone 4
• After controlling for confounders, combined ERA and immune profiling treatment is associated with a higher pregnancy rate (adjusted OR 3.412,95% CI 1.387-8.395) 4

Embryo Transfer Strategy

• Continue with single embryo transfer (eSET) as the standard procedure, as there is no evidence showing that cumulative live birth rate with eSET is inferior to double embryo transfer (DET) 6
• Blastocyst transfers should be done as single embryo transfers due to higher monozygotic twin potential and increased risk of complications with multiple embryos 6

Ovarian Stimulation Considerations

• For patients with normal ovarian reserve, use routine stimulation protocols to obtain more oocytes for testing and transfer 7
• Consider alternative protocols such as natural cycle, minimal ovarian stimulation, or luteal phase stimulation for poor responders 7

Potential Pitfalls and Caveats

• Avoid transferring more than one embryo as a solution to RIF, as this increases risks of multiple pregnancy, ectopic pregnancy (up to 20-fold higher risk), and other complications 6
• Be cautious about empirical treatments without sufficient evidence, as many RIF treatments lack robust clinical trial support 1, 5
• Recognize that the displaced window of implantation (84.9% incidence) and endometrial immune dysregulations (75.3% incidence) are highly prevalent in RIF patients and may not be detected by standard ERA alone 4

Follow-up Recommendations

• If combined ERA and immune profiling approach fails, consider re-evaluation of embryo quality and laboratory conditions 5
• Discuss with patients that true RIF is rare and continued conventional therapies with appropriate adjustments based on testing are warranted in most cases 1
• Consider personalized embryo transfer timing based on ERA results, especially when displaced window of implantation is identified 4