One-year cumulative live birth rate associated with the number of oocytes in ovarian stimulation with follitropin delta: a pooled analysis of four randomized controlled trials.

study questionWhat number of oocytes retrieved is associated with the highest cumulative live birth rates (CLBRs) in the fresh and subsequent frozen cycles following ovarian stimulation with follitropin delta? SUMMARY ANSWER: The CLBR increased with the number of oocytes retrieved, plateauing at 21-25 oocytes. WHAT IS KNOWN ALREADY: Live birth rate (LBR) per fresh cycle is the conventionally reported outcome of IVF; however, the marked increase in cryopreserved cycles in recent years suggests that the CLBR has emerged as a more relevant outcome. In the fresh cycle, the number of oocytes retrieved is regarded as a prognostic factor for LBR, and a similar association has been shown for CLBR. STUDY DESIGN, SIZE, DURATION: Pooled analysis including 1746 patients from four randomized controlled trials. Trials were identified from clinical trials available in the Ferring Pharmaceuticals database up to June 2023. Selected trials used follitropin delta for ovarian stimulation and collected outcome data from both fresh and frozen cycles. Follitropin delta dose-response trials, as well as trials investigating follitropin delta in repeated ovarian stimulation cycles, were excluded. Patients included in the analysis underwent ovarian stimulation with follitropin delta and had at least one oocyte retrieved. The outcome of CLBR in the fresh and subsequent frozen cycles was evaluated in relation to the number of oocytes retrieved. CLBR was calculated as the number of patients with at least one live birth divided by the number of all patients included in the analysis. PARTICIPANTS/MATERIALS, SETTING,

methodsTrial participants were women, 18-42 years of age, who were undergoing their first or second IVF/ICSI cycle in a GnRH antagonist/agonist protocol. Triggering was performed with hCG or GnRH agonist, and insemination was performed by IVF or ICSI. Single or double blastocyst transfer was performed on Day 5 in the fresh cycle, and all viable surplus blastocysts were cryopreserved on Day 5 or Day 6. All pregnancies from the fresh cycle and frozen cycles initiated within 1 year after the start of stimulation were followed until birth. The association between the number of oocytes retrieved and CLBR was assessed using a logistic regression analysis with fractional polynomials to obtain predicted CLBR. Subgroup analyses were performed based on age, anti-Müllerian hormone (AMH), and number of oocytes retrieved. MAIN RESULTS AND THE ROLE OF CHANCE: Overall, 15 trials with follitropin delta were identified in the database. Of those, 11 trials were not eligible, and the remaining 4 trials were included. In total, 1746 patients were included in the analysis. The mean age was 33.8 years (range 21-42 years), and the median AMH level was 17.0 pmol/l (range 0.3-164.2 pmol/l). The vast majority of patients (1645 patients, 94.2%) were treated with a GnRH antagonist protocol, while 101 patients (5.8%) were treated with a GnRH agonist protocol. Overall, 1541 patients (88.3%) received hCG triggering, and 205 patients (11.7%) received GnRH agonist triggering. Frozen cycles (maximum of six) were initiated by 740 patients (42.4%). The study population underwent a total of 2948 cycles: 1746 fresh cycles (referring to ovarian stimulation cycles, with or without transfer) and 1202 frozen cycles (initiated cycles, with or without transfer). The mean number of oocytes retrieved was 12.4 (range 1-72), the fresh cycle LBR was 29.1%, and the CLBR was 51.4%. The CLBR increased with the number of oocytes retrieved up to a plateau starting at 21-25 oocytes. The CLBR reached above 60% at >15 oocytes and above 70% at >20 oocytes. The CLBR decreased with increasing age (57.1%, 51.6%, and 35.8% at <35, 35-37, and ≥38 years), while it was similar for AMH <15 and ≥15 pmol/l (52.0% and 50.9%, respectively). A continued increase in predicted CLBR from 15 oocytes retrieved was observed in older patients (≥38 years); from 41.3% to 53.4% to 58.7% at 15-19, 20-24, and ≥25 oocytes. No equivalent benefit was observed in younger patients (<38 years), where corresponding rates were 72.5%, 68.0%, and 78.8% in patients <35 years and 70.3%, 73.1%, and 71.5% in patients 35-37 years. The fresh cycle LBR decreased beyond 14 oocytes, while the CLBR continued to increase by the number of oocytes retrieved. LIMITATIONS, REASONS FOR CAUTION: A limited number of patients included in the analysis had ≥20 oocytes retrieved (249 patients, 14.3%). WIDER IMPLICATIONS OF THE

findingsThis analysis suggests an increase in CLBR with the number of oocytes retrieved up to a plateau starting at 21-25 oocytes following ovarian stimulation cycles with follitropin delta and subsequent frozen cycles. An increase in CLBR from 20 oocytes was evident in older but not in younger patients. STUDY FUNDING/COMPETING INTEREST(S): The study was funded by Ferring Pharmaceuticals A/S, Copenhagen, Denmark. S.S.-R. has received research funding from Organon/MSD, Theramex, and Gedeon-Richter, consulting fees from Organon/MSD, Ferring Pharmaceuticals, Merck Serono, and IBSA, payment or honoraria from Organon/MSD, Besins and Gedeon-Richter, support for attending meetings from Gedeon-Richter and Besins, is an advisory board member for TTRANSPORT and Deputy of the ESHRE SQART SIG, and owns stocks of IVI Lisboa, Clinica de Reprodução assistida Lda. A.P. has received grants from Cryos, grants and payments from Gedeon Richter, Ferring Pharmaceuticals and Merck A/S, payments from Organon, consulting fees from IBSA, Ferring Pharmaceuticals, Gedeon Richter, Cryos, and Merck A/S, and travel support from Gedeon Richter. N.S.M. has received speaker and consultancy fees from Ferring Pharmaceuticals, IBSA, Merck, Freya, and Gedeon Richter, and is a shareholder in Verso Biosense. K.M. has been a scientific advisor for Calla Lily Clinical Care, Evvy, and AutoIVF. R.L., A.F., K.M., and I.E.J. are employees of Ferring Pharmaceuticals. REGISTRATION NUMBER: N/A.