Cumulative pregnancy rates of two strategies: Day 3 fresh embryo transfer followed by Day 3 or Day 5/6 vitrificationãnd embryo transfer:ã randomized controlled trial

Abstract

STUDY QUESTION: Are cumulative pregnancy rates better if supernumerary embryosãre vitrified on Day 5/6 instead of Day 3? SUMMARY ANSWER: The results do not showã significant difference in cumulative pregnancy rates between the Day 3ãnd Day 5/6 vitrification groups. WHAT IS KNOWN ALREADY: Pregnancyãnd live birth rates following IVF or ICSI treatmentãre higherãfter extended embryo cultureãnd blastocyst transfer (Day 5/6) compared to cleavage-stage (Day 3) transfer. Cumulative pregnancy rates from one oocyte retrieval (OR) cycle show no significant differenceãfter freshãnd frozen embryo transfers, but only one study has used vitrification for the cryopreservation of supernumerary embryos while four studies have usedã slow freezing protocol. STUDY DESIGN, SIZE, DURATION: Our prospective randomized controlled trial was performed inãnãcademic centre between January 2018ãnd August 2020. Patients were randomized into vitrification Day 3 (n 80) or Day 5/6 (n 81) groups. The primary outcome was the cumulative ongoing pregnancy rate (cOPR), considering only the first pregnancy for each couple. The power calculation revealed that 75 patients were required in each group, whenãssumingã 50% cOPR with four embryo transfers in the vitrification Day 3 group vs two transfers in the vitrification Day 5/6 group. PARTICIPANTS/MATERIALS, SETTING, METHODS: Patients <38 years undergoing their first or second OR cycles were randomizedãt the start of the first cycle. Up to two cycles were included in theãnalysis. A fresh embryo transfer was performed on Day 3. Supernumerary embryos (with ≥6 cells, <25% fragmentation,ãnd equal blastomeres) or blastocysts (with expansion grade ≥2 with inner cell massãnd trophectoderm score A/B) were vitrified on Day 3 or Day 5/6, respectively,ãnd then transferredãtã later date. A time-to-eventãnalysis was performed with the patient's first ongoing pregnancyãs the event of interestãnd the number of embryo transfersãs the time component. The statistical comparison was performed byã Cox proportional hazards model. Cumulative costs of vitrification on Day 3 vs Day 5/6 were exploredãnd compared using Mann-Whitney U tests. MAIN RESULTS AND THE ROLE OF CHANCE: By December 2021, 233 transfers (96 freshãnd 137 frozen) in 77 patients were performed in the vitrification Day 3 groupãnd 201 transfers (88 freshãnd 113 frozen) in 77 patients were performed in the vitrification Day 5/6 group. The time-to-eventãnalysis did not showã difference between the twoãrms with regard to the patient's first ongoing pregnancyãs the primary study outcome (hazard ratio [HR] 1.25, 95% CI 0.82; 1.92, P 0.30). The cumulative ongoing pregnancy rateãfter eight transfers (from one or two ORs) was 57% in the vitrification Day 3 group vs 58% in the vitrification Day 5/6 group. The median number of embryo transfers untilã pregnancy wasãchieved was five vs four, respectively, in the vitrification Day 3 group vs the Day 5/6 group. Similar results were found for the secondary study outcome, i.e. clinical pregnancy with foetal heart rate (HR 1.19, 95% CI 0.78; 1.80, P 0.41). The cumulative clinical pregnancy rate (cCPR)ãfter eight embryo transfers was 62% in the vitrification Day 3 group vs 59% in the vitrification Day 5/6 group. The median number of transfers untilã pregnancy wasãchieved was four in both groups. The healthcare consumption pattern differed between the two groupsãnd we observed higher costs for the vitrification Day 3 group compared to the vitrification Day 5/6 group,ãlthough these differences were not statistically significant. LIMITATIONS, REASONS FOR CAUTION: Although our power calculation revealed that only 75 patients were needed in each study group (b 0.87,ã < 0.05), the numbers were low. Also, different numbers of singleãnd double embryo transfers were performed between the two groups, which may haveãffected the results. The costãnalysis was performed onã subset of the patientsãnd is therefore exploratory. WIDER IMPLICATIONS OF THE FINDINGS: Our study shows no difference in the cumulative pregnancy rate nor costsãfter freshãnd frozen embryo transfers ofãt most two sequential OR cycles between the Day 3ãnd Day 5/6 vitrification groups; however, obstetricãnd perinatal outcomes should be taken intoãccount to determine the best strategy. STUDY FUNDING/COMPETING INTEREST(S): This study was fundedãsãn investigator-sponsored study of S.D. by Merck nv/sa Belgium,ãnãffiliate of Merck KGaA, Darmstadt, Germany,ãnd by Gedeon Richter Benelux (PA18-0162). Theãuthors declare no conflict of interest related to this study. TRIAL REGISTRATION NUMBER: NCT04196036. TRIAL REGISTRATION DATE: 15 January 2018. DATE OF FIRST PATIENT'S ENROLMENT: 15 January 2018.