Reproductive Medical Center, International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, China.
Hum Reprod. 2022 Jul 30;37(8):1795-1805. doi: 10.1093/humrep/deac114.
Is a dual ovulation trigger with a combination of GnRH agonist (GnRHa) and hCG superior to single hCG and/or single GnRHa trigger in improving treatment outcomes in advanced-age women (aged ≥ 35 years) undergoing IVF/ICSI treatment?
Co-administration of GnRHa and hCG as a dual trigger increases the number of good-quality embryos but it is not associated with a higher number of oocytes retrieved, compared with single hCG or GnRHa trigger.
Many studies have demonstrated that a dual trigger has positive impact on oocyte maturation, retrieval rate and pregnancy rate without increasing the risk of ovarian hyperstimulation syndrome (OHSS) in some groups of IVF patients, when compared with single hCG trigger. Few studies have however been conducted to compare a dual trigger with a single GnRHa trigger, and insufficient evidence exists to support which trigger can achieve the best outcomes in IVF patients aged ≥35 years.
STUDY DESIGN, SIZE, DURATION: This was an open-label randomized controlled trial of 510 participants conducted at single reproductive medical center from January 2019 to December 2021. After a sample size calculation performed by retrospectively analyzing our previous clinical data, we planned to recruit 170 patients in each group and 510 patients in total for the study.
PARTICIPANTS/MATERIALS, SETTING, METHODS: Women aged ≥35 years undergoing IVF/ICSI treatment, receiving a non-pituitary down-regulation protocol, and with low risk of OHSS, were enrolled in this trial. On the trigger day, patients were randomized into three groups: hCG alone (who received 6000 IU of hCG), GnRHa alone (who received 0.2 mg of triptorelin) and dual trigger (who received 0.2 mg of triptorelin plus 2000 IU of hCG) groups. The primary outcome parameter was the number of retrieved oocytes. The secondary outcome parameters included, among others, the number and rates of mature oocytes, two pronuclei (2PN) embryos and good-quality embryos, as the rates of OHSS, clinical pregnancy, miscarriage and live birth.
There were no significant differences in the baseline demographic characteristics among the three groups. The dual trigger was associated with a higher retrieval rate (87.9% vs 84.1% in the hCG group, P = 0.031; 87.9% vs 83.6% in the GnRHa group, P = 0.014). However, the number of retrieved oocytes in the dual trigger group was comparable with those in the hCG group (4.08 ± 2.79 vs 3.60 ± 2.71, P = 0.080) and the GnRHa group (4.08 ± 2.79 vs 3.81 ± 3.38, P = 0.101); comparable data between the groups were also found when analyzing the number of 2PN embryos and the 2PN rate. In the dual trigger group, the numbers of good-quality embryos and viable embryos were both significantly higher than in the hCG group (1.74 ± 1.90 vs 1.19 ± 1.45, P = 0.016 and 2.19 ± 2.11 vs 1.56 ± 1.66, P = 0.008, respectively) and the GnRHa group (1.74 ± 1.90 vs 1.20 ± 1.67, P = 0.003 and 2.19 ± 2.11 vs 1.45 ± 1.75, P = 0.001, respectively). Pregnancy outcomes after fresh embryo transfer (ET) were comparable between the groups. The live birth rate and ongoing pregnancy rate after frozen ET in the dual trigger group were significantly higher than those in the GnRHa group (32.6% vs 14.1%, P = 0.007 and 34.8% vs 17.6%, P = 0.013, respectively), but not superior to those in the hCG group (32.6% vs 27.9%, P = 0.537 and 34.8% vs 27.9%, P = 0.358, respectively).
LIMITATIONS, REASONS FOR CAUTION: Women of advanced age are quite a heterogeneous population and overlap with poor ovarian responders or patients with diminished ovarian reserve. We therefore could not entirely exclude selection biases or confounding factors. This study was also not a double-blinded trial; the patients in the GnRHa and dual trigger groups could have been affected by the placebo effect.
The results of this study suggest that in advanced-age women with low risk of OHSS, a dual trigger or even a single hCG trigger may be a better choice than a single GnRHa trigger.
STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the Shanghai Municipal Health Commission of Science and Research Fund (20184Y0289). The authors declare no conflict of interest.
This trial was registered in the Chinese Clinical Trial Registry (ChiCTR-1800016285).
24 May 2018.
DATE OF FIRST PATIENT’S ENROLMENT: 2 January 2019.
在接受体外受精/卵胞浆内单精子注射（IVF/ICSI）治疗的高龄（≥35 岁）妇女中，与单独使用 hCG 或单独使用 GnRH 激动剂（GnRHa）触发相比，联合使用 GnRH 激动剂和 hCG 的双重触发是否能改善治疗结局，提高获卵数？
与单独使用 hCG 或 GnRHa 触发相比，联合使用 GnRHa 和 hCG 作为双重触发可增加优质胚胎数量，但与前者相比，并不与获卵数增加相关。
许多研究表明，在某些 IVF 患者群体中，与单独使用 hCG 触发相比，双重触发对卵母细胞成熟、取卵率和妊娠率有积极影响，而不会增加卵巢过度刺激综合征（OHSS）的风险。然而，与单独使用 GnRHa 触发相比，很少有研究比较双重触发与单一 GnRHa 触发，并且没有足够的证据支持哪种触发可以在年龄≥35 岁的 IVF 患者中获得最佳结局。
研究设计、规模、持续时间：这是一项于 2019 年 1 月至 2021 年 12 月在单一家生殖医学中心进行的开放标签随机对照试验。根据我们之前的临床数据进行样本量计算后，我们计划在每组中招募 170 名患者，总计 510 名患者参加该研究。
参与者/材料、设置、方法：纳入接受非垂体下调方案、低 OHSS 风险且年龄≥35 岁的 IVF/ICSI 治疗的妇女。在触发日，患者随机分为三组：hCG 组（接受 6000IU 的 hCG）、GnRHa 组（接受 0.2mg 的曲普瑞林）和双重触发组（接受 0.2mg 的曲普瑞林加 2000IU 的 hCG）。主要结局参数是获卵数。次要结局参数包括成熟卵母细胞、2 原核（2PN）胚胎和优质胚胎的数量和率，以及 OHSS、临床妊娠、流产和活产的发生率。
三组患者的基线人口统计学特征无显著差异。双重触发与更高的取卵率相关（hCG 组为 87.9%，GnRHa 组为 87.9%，P=0.031；GnRHa 组为 83.6%，P=0.014）。然而，双重触发组的获卵数与 hCG 组（4.08±2.79 vs 3.60±2.71，P=0.080）和 GnRHa 组（4.08±2.79 vs 3.81±3.38，P=0.101）相当；当分析 2PN 胚胎和 2PN 率时，两组之间也发现了相似的数据。在双重触发组中，优质胚胎和可存活胚胎的数量均明显高于 hCG 组（1.74±1.90 vs 1.19±1.45，P=0.016；2.19±2.11 vs 1.56±1.66，P=0.008）和 GnRHa 组（1.74±1.90 vs 1.20±1.67，P=0.003；2.19±2.11 vs 1.45±1.75，P=0.001）。新鲜胚胎移植（ET）后的妊娠结局在各组之间相似。双重触发组冷冻 ET 后的活产率和持续妊娠率明显高于 GnRHa 组（32.6% vs 14.1%，P=0.007；34.8% vs 17.6%，P=0.013），但与 hCG 组无差异（32.6% vs 27.9%，P=0.537；34.8% vs 27.9%，P=0.358）。
局限性、谨慎原因：高龄妇女是一个相当异质的人群，与卵巢反应不良或卵巢储备减少的患者重叠。因此，我们不能完全排除选择偏倚或混杂因素。本研究也不是双盲试验；GnRHa 和双重触发组的患者可能受到安慰剂效应的影响。
该研究结果表明，在低 OHSS 风险的高龄妇女中，双重触发甚至单一 hCG 触发可能比单一 GnRHa 触发更好的选择。
研究资金/利益冲突：本研究由上海市卫生健康委员会科学与研究基金（20184Y0289）资助。作者声明没有利益冲突。
本试验在中国临床试验注册中心（ChiCTR-1800016285）注册。
2018 年 5 月 24 日。
2019 年 1 月 2 日。
