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.