Interpretation
In some cases, even euploid embryos are unable to implant40, indicating an etiology independent of the embryo’s genetics. Although PGT-A help to select embryos with a higher probability of implanting in these patients, any euploid embryos not implant suggesting that chromosomal status is not the only factor to consider.
In the case of S-RIF, the use of PGT-A was insufficient to improve IVF outcomes, suggesting that different tools may be needed to assess embryo quality and take endometrial factors into account. Even though PGT-A can mitigate maternal age effect in IVF patients, patients in the oldest group (> 42 years) had different implantation rates than those in younger groups (<35–42 years)41.
The temporal window of endometrial receptivity to blastocysts is limited, and most of the histologic criteria using markers of endometrial receptivity are subjective and lack accuracy and predictive value18. The ERA was created for more accurate endometrial dating throughout the luteal phase20. In this study, we found that numerous M-RIF and S-RIF patients had displaced WOIs and qualified for pET. This is consistent with previous studies that report a 25–30% contribution of the endometrial factor to implantation failure42,43. The higher percentage of pET in the M-RIF group could be explained by the higher percentage of uterine pathologies, diagnosed by ultrasound, which could affect ERA results. Unfortunately, the ERA test did not improve implantation or ongoing pregnancy rates in this study and thus cannot be used as a predictor of a healthy WOI. This is consistent with a prior study in which a personalized adjustment of progesterone did not improve pregnancy outcomes in RIF patients receiving euploid embryos (as confirmed by PGT-A)43.
Although PGT-A is considered an important tool for patients with advanced maternal age, the standard use of PGT-A is actively debated44. PGT-A may not improve overall pregnancy outcomes in all women, but there was a significant increase in the ongoing pregnancy rate per ET with the use of PGT-A in women aged 35-40 years with two or more embryos that could be biopsied45. The use of PGT-A should be addressed according to clinical history, as there is not sufficient evidence to recommend PGT-A for all infertile patients46. Moreover, the use of PGT-A in patients with RIF could improve live birth rates in ET compared to patients with no PGT-A at all47.
Demonstrating a healthy embryo is necessary before considering whether the endometrium might contribute to implantation failure, but chromosomal status is not enough. Novel embryo assessment and selection procedures, such as time-lapse imaging and metabolomics, may help to better evaluate embryo quality and viability48. These should be evaluated for their usefulness in RIF as well. In addition, more data on PGT-A in S-RIF could be worth pursuing. After these results, fertility status seems not to be related to endometrial dating by ERA, deep characterization of endometrial pathology is needed to evaluate properly the endometrial factor in IVF cycles.