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currently unpublished.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.