O-199 Proof of concept: implantation window must be wider than proposed. Report of seven twins after asynchronous double embryo transfer

Study question Can simultaneous transfer of two embryos that were cryopreserved at different stages (D3 and Blastocyst) be appropriate to enhance success in women with more than three failed embryo transfers? Summary answer Double asynchronous embryo transfer offered excellent results in RIF. Unexpectedly high twin rate suggests that embryo-endometrium synchrony is overemphasized. Implantation window must be wider. What is known already Transcriptomic signature of the endometrium has been investigated in the last few years trying to understand the best moment for embryo implantation. Nevertheless, the optimal period has not been well established yet in humans. Simultaneous transfer of two human embryos at different developmental stages (D3 and Blastocyst) on Day 4 was proposed to help couples who have had RIF. Study design, size, duration Observational case-control study. From April 2016 to January 2021, we offered double asynchronous embryo transfer only after Recurrent Implantation Failure (RIF). Two requirements were necessary: 1) Double embryo transfer was acceptable by the couple due to poor reproductive outcome. 2) Availability of two embryos cryopreserved at different stage (D3 and Blastocyst). Results were compared with good prognosis patients (all patients under 35 years in that period who had elected to transfer two day 3 cryopreserved embryos). Participants/materials, setting, methods Forty-five patients accepted to participate in the study. Results were compared with all patients (237) under 35 years where two D3 thawed embryos were transferred. All cases received same protocol (oral estradiol 6mg/d or vaginal estradiol 4mg/d until ultrasound showed endometrial growth) LH, P4 and E2 were monitored in all patients to detect spontaneous LH surge. All cases received transvaginal micronized progesterone 800 mg/d. Embryo transfers were ultrasound guided and Wallace Embryosure catheter was employed. Main results and the role of chance Limitations, reasons for caution Multiple pregnancy rate was unacceptably high. Therefore, it should not be suggested for good prognosis couples where single embryo transfer is clearly advidsed. Our main limitation was the combination of D3 embryos with blastocysts. The retrospective design make the results to be considered as a proof of concept. Wider implications of the findings Double asynchronic embryo transfer can offer new insights in the understanding of human implantation. The concept of implantation window is clearly challenged. Aiming to the center of the window is fine, but we still dońt know how wide is that center. Trial registration number not applicable

O-110 A randomised, controlled, assessor-blind trial assessing clinical outcomes of individualised dosing with follitropin delta in Asian IVF/ICSI patients

Study question To evaluate the efficacy and safety of individualised dosing with follitropin delta versus conventional dosing with follitropin alfa in an Asian population undergoing ovarian stimulation. Summary answer Individualised dosing with follitropin delta results in significantly higher live birth rate and fewer early OHSS and/or preventive interventions compared to conventional follitropin alfa dosing. What is known already Previous randomised controlled trials conducted in Europe, North- and South America mainly including Caucasian IVF/ICSI patients as well as in Japan have demonstrated that ovarian stimulation with the individualised follitropin delta dosing regimen based on serum AMH level and body weight modulated the ovarian response and reduced the risk of OHSS without compromising pregnancy and live birth rates. Study design, size, duration Randomised, controlled, assessor-blind trial conducted in 1,009 Asian patients from mainland China, South Korea, Vietnam and Taiwan, undergoing their first IVF/ICSI cycle. Randomisation was stratified by age (<35, 35-37, 38-40 years). The primary endpoint was ongoing pregnancy assessed 10-11 weeks after transfer (non-inferiority limit -10.0%; analysis adjusted for age strata). Patients <35 years underwent single embryo transfer if a good-quality embryo was available, otherwise double embryo transfer. Patients ≥35 years underwent double embryo transfer. Participants/materials, setting, methods Follitropin delta (Rekovelle, Ferring Pharmaceuticals) daily treatment consisted of a fixed dose individualised according to each patient’s initial AMH level (<15 pmol/L: 12 μg; ≥15 pmol/L: 0.19 to 0.10 μg/kg; min-max 6-12 μg) and body weight. Follitropin alfa (Gonal-f, Merck Serono) dose was 150 IU/day for the first five days with subsequent potential dose adjustments according to individual response. A GnRH antagonist protocol was applied. OHSS was classified based on Golan’s system. Main results and the role of chance The ongoing pregnancy rate was 31.3% with follitropin delta and 25.7% with follitropin alfa (adjusted difference 5.4% [95% CI: -0.2%; 11.0%]). The live birth rate was significantly higher at 31.3% with follitropin delta compared to 24.7% with follitropin alfa (adjusted difference 6.4% [95% CI: 0.9%; 11.9%]; p < 0.05). Live birth rates per age stratum were as follows for follitropin delta and follitropin alfa; <35 years: 31.0% versus 25.0%, 3537 years: 35.3% versus 26.7%, 38-40 years: 20.0% versus 14.3%. Early OHSS risk, evaluated as the incidence of early OHSS and/or preventive interventions, was significantly (p < 0.01) reduced from 9.6% with follitropin alfa to 5.0% with follitropin delta. The number of oocytes was 10.0±6.1 with follitropin delta and 12.4±7.3 with follitropin alfa. Individualised follitropin delta dosing compared to conventional follitropin alfa dosing resulted in 2 more oocytes (9.6±5.3 versus 7.6±3.5) in potential low responders (AMH <15 pmol/L) and 3 fewer oocytes (10.1±6.3 versus 13.8±7.5) in potential high responders (AMH ≥15 pmol/L). Among patients with AMH ≥15 pmol/L, excessive response occurred less frequently with individualised than conventional dosing (≥15 oocytes: 20.2% versus 39.1%; ≥20 oocytes: 6.7% versus 18.5%). Total gonadotropin dose was reduced from 109.9±32.9 μg with follitropin alfa to 77.5±24.4 μg with follitropin delta. Limitations, reasons for caution The trial only covered the clinical outcome of one treatment cycle with fresh cleavage-stage embryo transfers. Wider implications of the findings The present trial implies that in addition to reducing the early OHSS risk, individualised dosing has the potential to improve the take-home baby rate in fresh cycles across all ages and with a lower gonadotropin consumption. The benefits in outcomes appear to be explained by the modulation of ovarian response. Trial registration number NCT03296527

Effectiveness of elective single versus double frozen embryo transfer in good prognosis IVF patients

Objective: This study aimed to evaluate the effectiveness of elective single embryo transfer (eSET) versus double embryo transfer (DET) in frozen embryo transfer cycles following in vitro fertilization (IVF) treatment in good prognosis patients. The outcome would provide medical data for the multiple pregnancy rate reduction in IVF treatment. Methods: This multicenter retrospective cohort study was performed in patients undergoing the first frozen embryo transfer (FET) cycles at IVF centers which belonged to the IVFMD Group, Vietnam, from January 2018 to May 2020. Patients were divided into four groups, based on the number of embryos transferred, as follows: Group 1: one good quality day-3 embryo (eSET D3), Group 2: one good quality day-5 embryo (eSET D5), Group 3: two good quality day-3 embryos (DET D3), and Group 4: two good quality day-5 embryos (DET D5). The primary outcome of the study was live birth rates (LBR) after the first FET. Secondary outcomes were also analyzed, including pregnancy outcomes (β-hCG positive, clinical pregnancy, miscarriage < 12 weeks, ongoing pregnancy 12 weeks, miscarriage < 20 weeks, and multiple birth rates [MBR]), as well as neonatal outcomes (birth weight and gestational age at birth). Results: There were 819 patients, of which 819 FET cycles were analyzed, including 132 eSET D3, 278 eSET D5, 140 DET D3, and 269 DET D5. LBR and MBR values were significantly lower in the eSET D3 group than in the DET D3 group (LBR: 22.7% vs 39.3%, p = 0.002; MBR: 3.3% vs 29.1%, p < 0.001, respectively). MBR was also significantly lower in eSET D5 compared with DET D5 (9.6% vs 38.3%, p < 0.001), while LBR was comparable between the two groups (41.4% vs 42.8%, p < 0.74). Birth weight and gestational age at birth were similar between eSET and DET, regardless of day-3 or day-5 embryo transfer. Conclusions: Among infertile, good prognosis women undergoing FET, the eSET significantly decreased multiple birth rates compared with double embryo transfer, while still sustaining an acceptable rate of live birth as well as pregnancy and neonatal outcomes.