Results
Our analysis identified 2,110 patients with M-RIF and 488 with S-RIF.
The general and clinical features of the cycles and patients included in
the study are shown in Table 1. Table 2 summarizes the parameters of the
test-guided IVF cycles among the different groups of patients. The
retrospective nature of our study resulted in the differential
distribution of some relevant variables, as shown in Tables 1 and 2. To
avoid bias, we included those parameters with statistically significant
differences and/or clinical relevance within a multivariate analysis
model by using generalized estimating equations.
Some patients included in the M-RIF and S-RIF groups had infertility
associated with uterine factors (Table S1). Patients who had the ERA had
a higher percentage of uterine pathologies than control patients or
those undergoing PGT-A (Table S1). Table S2 shows the number of patients
scheduled for personalized ET after the ERA. The percentage of
personalized ET (pET) was 25.7% and 39.3% in the S-RIF and M-RIF
groups, respectively. Hence, a large percentage of patients had an
asynchronous or displaced WOIs, particularly in the M-RIF group.
Univariate ANOVA of the M-RIF group revealed a statistically significant
difference in the overall mean implantation rates of the subgroups
(P = 0.0053). The use of PGT-A yielded a better implantation rate
(45.9%) than standard IVF (35.89%) with an OR of 1.34, 95% CI:
1.17-1.55, P < 0.001. Implantation rates were not
improved over standard rates by ERA. Significant differences were not
detected between subgroups subjected to different tests (ERA vs PGT-A,
ERA vs. PGT-A+ERA, PGT-A vs. PGT-A+ERA). Logistic regression models
adjusted for control variables confirmed that within the M-RIF group,
only the PGT-A test yielded significant improvement (AdjOR 1.22, 95%
CI: 1.14-1.30, P < 0.001) over standard treatment. When
comparing the other subgroups after adjusting for control variables, we
found a statistically significant difference between the ERA and PGT-A
subgroups (OR 0.84, 95% CI: 0.77-0.92, P < 0.001), but
no other subgroup comparison reached significance.
Univariate ANOVA of the implantation rate as calculated by the number of
gestational sacs per number of embryos transferred revealed
statistically significant differences between the M-RIF subgroups
(P = 0.005). The highest implantation rate was in PGT-A (47.2%)
versus the control group (35.8%), ERA (35.6%), and ERA+PGT-A
(31.82%). For M-RIF patients, the implantation rate was higher after
PGT-A testing than after standard IVF (OR 1.61, 95% CI: 1.24-2.11,P = 0.002). There were no statistically significant differences
between other subgroups. When the ORs were adjusted by logistic
regression models for control variables, the PGT-A subgroup was found to
significantly differ from the control subgroup (AdjOR 2.69, 95% CI:
1.99-3.66, P < 0.001). In addition, the ERA subgroup
was found to significantly differ from the PGT-A subgroup (AdjOR 0.40,
95% CI: 0.26-0.62, P < 0.001).
Table 3 shows the rates of ongoing
pregnancy for all study groups based on the number of embryos
transferred. Univariate ANOVA
revealed statistically significant differences between M-RIF subgroups
(P = 0.05). Post-hoc testing between M-RIF subgroups revealed
that, again, only the PGT-A subgroup differed from the control group
(1.51, 95% CI: 1.12-2.05, P = 0.029). There were no significant
differences between other subgroups. When the multivariate analysis was
applied to adjust for control variables, the PGT-A group was found to
differ from the control group (AdjOR 2.19, 95% CI: 1.55-3.07, P< 0.0001). The ERA group was detrimental to the ongoing
pregnancy rate compared to the PGT-A group (AdjOR 0.51, 95% CI:
0.31-0.83, P < 0.0284). No statistically significant
differences emerged in the comparisons between other subgroups.
Univariate analysis of the mean implantation rate of the S-RIF subgroups
revealed no statistically significant differences. The implantation rate
per patient was 34.2% (95% CI: 30.68-37.81) for the control, 40%
(95% CI: 25.40-54.60) for the ERA, 38.2% (95% CI: 28.02-48.37) for
the PGT-A, and 33.3% (95% CI: 0-68.59) for the PGT-A+ERA groups.
Logistic regression models with adjusted OR for control variables
revealed no statistically significant differences between test and
control groups or for multiple comparisons between subgroups.
Univariate analysis did not detect any statistically significant
differences in the implantation rate calculated per S-RIF subgroup
considering the number of gestational sacs and the number of embryos
transferred. The implantation rates were 34.8% (95% CI: 31.63-37.99)
for control, 37% (95% CI: 23.21-52.45) for ERA, 39.8% (95%CI
29.78-50.46) for PGT-A, and 33.3% (95%CI 4.33-77.72) for PGT-A+ERA
patients. A logistic regression model with adjusted OR for any control
variables revealed no statistically significant difference for any group
or the multiple comparisons between all groups. No statistical
significance was detected when comparing ERA vs PGT-A, ERA vs ERA+PGT-A,
or PGT-A vs PGT-A+ERA.
Table 3 shows the rates of ongoing pregnancy for all study groups based
on the number of embryos transferred. Univariate analysis was not
statistically significant for contrasts between S-RIF subgroups. The
multivariate analysis did not detect statistically significant
differences between treatments (PGT-A, ERA, or PGT-A+ERA) and the
control group or in the multiple comparisons between the subgroups.