REPEATED IMPLANTATION FAILURE AND WINDOW OF IMPLANTATION TESTING: A WINNING DUET TO IMPROVE LIVE BIRTH RATE

Outcome benefits on live birth rate in patients with repeated implantation failure (RIF) after customized embryo transfer based upon identification of endometrial receptivity window by transcriptomic approach. This is a french prospective multicenter trial. Endometrial biopsies were performed during the implantation window 7-9 days after the LH surge in natural cycle or 5-9 days after progesterone administration under HRT. According to transcriptomic testing result of the biopsy, blastocysts were transferred in the subsequent frozen embryo transfer cycle (FRET), at the specific day where endometrium was identified as receptive. For cleavage stage D2/D3 embryos transfers were performed 72/48 hours before the specific cycle day where endometrium was identified as receptive. From 2015 to 2018 a total of 217 RIF patients (4.4±1.9 failed fresh/frozen transfers of 6.4±3.6 embryos) were enrolled. Genomic testing of endometrial biopsies was performed under natural/HRT cycles and mRNA expression of genes predictive of receptivity was established by RT-qPCR. Customized embryo transfer (n=157 patients) was performed in a subsequent FRET cycle based upon these results. Clinical pregnancy and live birth rates (LBR) were compared to control RIF patients with standard FRET in natural/HRT cycles (n=60 patients). Customized embryo transfer using the genomic testing strategy yielded spectacular increase in outcome for 157 RIF patients (age 37.2±4.3 years). Comparison of the results between the study group and the control group showed significantly higher rates for implantation (22.7% vs 7.2%, p=0.0001), clinical pregnancy (38.8% vs 15.0%, p=0.0006), ongoing pregnancy (36.3% vs 8.3%, p=0.00002) and live birth rates (31.8% vs 8.3%, p=0.0002). Analyses of endometrial receptivity status revealed mostly a delay both in natural and HRT cycles, between 1 to 3 days. Most patients achieved pregnancy after the first customized FRET (70%). Better clinical pregnancy and live birth rates were obtained with blastocyst transfer compared to cleavage stage transfers (respectively 36.3% vs 22.5% and 29.5% vs 14.0%). Whatever the day of transfer, results were significantly higher in the study group compared to the control group, with ongoing pregnancy rate for transfer of cleavage-stage embryos of 21.1% compared to 4.5% in the control group (p=0.03). In blastocyst transfer group ongoing pregnancy rate of 33.9% was significantly higher than 8.6% in the control group (p=0.003). In RIF patients customized embryo transfer according to endometrial transcriptomic testing improves dramatically the clinical outcome by increasing almost four-fold the LBR. In our study, the majority of RIF patients displayed a delay in their receptivity window of 1 to 3 days, revealing a potential cause for their previous implantation failures. The transcriptomic window of implantation testing alone, and without any embryo genetical testings for aneuploidy, is able to enhance significantly the clinical outcome and should be advised to rescue LBR for patients with multiple RIF.