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.