Lobo Rita, Santos-Ribeiro Samuel, Falahati Ali, Moley Kelle, Pinborg Anja, Macklon Nick S, Jepsen Ida E
Ferring Pharmaceuticals, Global Research and Medical, Copenhagen, Denmark.
IVI Lisbon, Department of Obstetrics and Gynaecology, Faculty of Medicine, University of Lisbon, Lisbon, Portugal.
Hum Reprod. 2025 Aug 1;40(8):1526-1534. doi: 10.1093/humrep/deaf111.
What 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?
The CLBR increased with the number of oocytes retrieved, plateauing at 21-25 oocytes.
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, METHODS: Trial 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.
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%).
This 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.
N/A.
在使用注射用曲普瑞林进行卵巢刺激后的新鲜周期及随后的冷冻周期中，获取多少枚卵母细胞与最高累积活产率（CLBR）相关？
CLBR随着获取的卵母细胞数量增加而上升，在获取21 - 25枚卵母细胞时趋于平稳。
新鲜周期的活产率（LBR）是体外受精（IVF）传统报告的结果；然而，近年来冷冻周期的显著增加表明，CLBR已成为更具相关性的结果。在新鲜周期中，获取的卵母细胞数量被视为LBR的一个预后因素，并且CLBR也显示出类似的关联。
研究设计、规模、持续时间：汇总分析，纳入来自四项随机对照试验的1746例患者。试验是从辉凌制药数据库中截至2023年6月的临床试验中识别出来的。选定的试验使用注射用曲普瑞林进行卵巢刺激，并收集新鲜周期和冷冻周期的结局数据。排除注射用曲普瑞林剂量反应试验以及在重复卵巢刺激周期中研究注射用曲普瑞林的试验。纳入分析的患者接受了注射用曲普瑞林的卵巢刺激且至少获取了一枚卵母细胞。根据获取的卵母细胞数量评估新鲜周期及随后冷冻周期的CLBR结局。CLBR的计算方法是，至少有一次活产的患者数量除以纳入分析的所有患者数量。
参与者/材料、设置、方法：试验参与者为18 - 42岁的女性，她们正在接受首次或第二次IVF/ICSI周期治疗，采用GnRH拮抗剂/激动剂方案。使用hCG或GnRH激动剂进行扳机注射，并通过IVF或ICSI进行授精。在新鲜周期的第5天进行单胚胎或双胚胎囊胚移植，所有存活的多余囊胚在第5天或第6天进行冷冻保存。对新鲜周期以及刺激开始后1年内启动的冷冻周期中的所有妊娠进行随访直至分娩。使用带有分数多项式的逻辑回归分析评估获取的卵母细胞数量与CLBR之间的关联，以获得预测的CLBR。根据年龄、抗苗勒管激素（AMH）和获取的卵母细胞数量进行亚组分析。
总体而言，数据库中识别出15项使用注射用曲普瑞林的试验。其中，11项试验不符合条件，其余4项试验被纳入。总共1746例患者纳入分析。平均年龄为33.8岁（范围21 - 42岁），AMH水平中位数为17.0 pmol/l（范围0.3 - 164.2 pmol/l）。绝大多数患者（1645例患者，94.2%）接受GnRH拮抗剂方案治疗，而101例患者（5.8%）接受GnRH激动剂方案治疗。总体而言，1541例患者（88.3%）接受hCG扳机注射，205例患者（11.7%）接受GnRH激动剂扳机注射。740例患者（42.4%）启动了冷冻周期（最多六个）。研究人群共进行了2948个周期：1746个新鲜周期（指卵巢刺激周期，无论是否进行移植）和1202个冷冻周期（启动的周期，无论是否进行移植）。获取的卵母细胞平均数量为12.4（范围1 - 72），新鲜周期LBR为29.1%，CLBR为51.4%。CLBR随着获取的卵母细胞数量增加而上升，直至从21 - 25枚卵母细胞开始趋于平稳。获取>15枚卵母细胞时CLBR达到60%以上，获取>20枚卵母细胞时CLBR达到70%以上。CLBR随着年龄增加而下降（<35岁、35 - 37岁和≥38岁时分别为5个7.1%、51.6%和35.8%），而AMH<15和≥15 pmol/l时CLBR相似（分别为52.0%和50.9%）。在年龄较大的患者（≥38岁）中，观察到从获取15枚卵母细胞开始预测的CLBR持续增加；获取15 - 19枚、20 - 24枚和≥25枚卵母细胞时，分别从41.3%增至53.4%再增至58.7%。在较年轻的患者（<38岁）中未观察到同等益处，<35岁患者相应的比例为72.5%、68.0%和78.8%，35 - 37岁患者相应的比例为七个0.3%、73.1%和71.5%。新鲜周期LBR在获取超过14枚卵母细胞后下降，而CLBR随着获取的卵母细胞数量继续增加。
局限性、谨慎理由：分析中纳入获取≥20枚卵母细胞的患者数量有限（249例患者，14.3%）。
该分析表明，在使用注射用曲普瑞林进行卵巢刺激周期及随后的冷冻周期后，CLBR随着获取的卵母细胞数量增加而上升，直至从21 - 25枚卵母细胞开始趋于平稳。从20枚卵母细胞开始CLBR增加在年龄较大的患者中明显，而在较年轻的患者中不明显。
研究资金/利益冲突：该研究由丹麦哥本哈根的辉凌制药公司资助。S.S.-R. 已从欧加农/默克、梯瓦制药、吉德昂 - 里奇特获得研究资金，从欧加农/默克、辉凌制药、默克雪兰诺和IBSA获得咨询费，从欧加农/默克、贝西恩斯和吉德昂 - 里奇特获得报酬或酬金，从吉德昂 - 里奇特和贝西恩斯获得参加会议的支持，是TTRANSPORT的顾问委员会成员以及ESHRE SQART SIG的副主席，并且拥有IVI里斯本、辅助生殖诊所Lda的股票。A.P. 已从Cryos获得资助金，从吉德昂 - 里奇特、辉凌制药和默克A/S获得资助金和报酬，从欧加农获得报酬，从IBSA、辉凌制药、吉德昂 - 里奇特、Cryos和默克A/S获得咨询费，从吉德昂 - 里奇特获得差旅支持。N.S.M. 已从辉凌制药、IBSA、默克、芙瑞雅和吉德昂 - 里奇特获得演讲费和咨询费，并且是Verso Biosense的股东。K.M. 曾是Calla Lily临床护理、Evvy和AutoIVF的科学顾问。R.L.、A.F.、K.M. 和I.E.J. 是辉凌制药的员工。
无。
