Introduction
Infertility is a worldwide problem1 contributing to rising demand for assisted reproductive techniques (ART)2. The European Society of Human Reproduction and Embryology (ESHRE) recently highlighted the expansion of ART treatments in Europe3, and a similar trend was reported by the American Society for Reproductive Medicine (ASRM)4. ART outcomes for struggling couples have improved recently; yet, there are still significant numbers of unresolved cases 5and frequently a significant number of embryos must be transferred for a successful pregnancy even with donated oocytes. Despite advances in ART, the implantation rate and several ’take-home’ babies per initiated treatment or embryo transfer (ET) remain low8. Recurrent implantation failure (RIF) is one of the most common conditions affecting IVF outcomes and is diagnosed after the failure of varying numbers of ET9,10. Both the age of the mother and the type of embryo (cleavage stage or blastocyst) are also considered in the diagnosis11.
The disparity in the definition of RIF likely stems from its multiple compounded etiologies5. Both the endometrium and the quality of embryos impact implantation12. However, objectively and uniformly defining good quality embryos is difficult and there is a lack of consensus on chromosome analysis following embryo biopsy. Regardless, endometrial receptivity and embryo quality may represent as high as ~30% of factors influencing pregnancy success in IVF8. This contribution is unsurprising considering that uterine implantation is an intricate process requiring both a receptive endometrium and a competent embryo13.
If conditions are appropriate, implantation is initiated by attachment of the blastocyst to the epithelial layer of the endometrium14. Attachment and invasion are optimal during an interval in the menstrual cycle termed the “window of implantation” (WOI)15. This window is classically diagnosed by endometrial histology, but this evaluation is subjective16, histological dating through biopsy should not be part of the infertility workup without17,18. The endometrial receptivity array (ERA), based on the expression of 238 endometrial genes, may objectively diagnose receptivity19. The ERA test is superior to endometrial histology in its ability to detect temporal displacement of the WOI20,21 and helped create personalized ET schedules that could result in better pregnancy rates22,23, although no randomized controlled are currently unpublished. In contrast, RIF may result from the displacement of the WOI and/or its disruption by molecular pathologies independent of timing24. There is support for both mechanisms25-27, highlighting the need for defining unique RIF etiologies27.
Different techniques have been proposed to select the best embryos for transfer. Pre-implantation genetic screening (PGT-A) defines a normal embryo based on chromosomal status28. Chromosomal aneuploidies are the major cause of pregnancy loss and implantation failure29. Patients most likely to benefit from PGT-A are infertile women of advanced maternal age with a history of recurrent pregnancy loss or RIF30,31. Considering the multifactorial etiology of RIF, we used a large cohort to retrospectively evaluate the effectiveness of testing for endometrial (using ERA) and embryonic (using PGT-A) quality to improve clinical outcomes.