在ART治疗中，卵巢刺激的最佳GnRH拮抗剂方案是什么？

近期《Human Reproduction Update》杂志发表了一篇题为《What is the optimal GnRH antagonist protocol for ovarian stimulation during ART treatment? A systematic review and network meta-analysis》的文章，在ART治疗中，卵巢刺激的最佳GnRH拮抗剂方案是什么？

BACKGROUND

背景

Several GnRH antagonist protocols are currently used during COS in the context of ART treatments; however, questions remain regarding whether these protocols are comparable in terms of efficacy and safety.

目前ART治疗中，常常用到几种GnRH拮抗剂方案进行超促排卵。但对于这些GnRH拮抗剂方案的有效性和安全性是否具有可比性，目前仍存在争议。

OBJECTIVE AND RATIONALE

目的和原理

A systematic review followed by a pairwise and network meta-analyses were performed. The systematic review and pairwise meta-analysis of direct comparative data according to the PRISMA guidelines evaluated the effectiveness of different GnRH antagonist protocols (fixed Day 5/6 versus flexible, ganirelix versus cetrorelix, with or without hormonal pretreatment) on the probability of live birth and ongoing pregnancy after COS during ART treatment. A frequentist network meta-analysis combining direct and indirect comparisons (using the long GnRH agonist protocol as the comparator) was also performed to enhance the precision of the estimates.

开展了一个系统综述，进行配对和网络荟萃分析。根据PRISMA指南对直接比较数据进行系统回顾性分析和配对荟萃分析，从ART治疗超促排卵后的活产率和持续妊娠率等方面来评价不同拮抗剂方案的有效性（固定D5/6方案 vs. 灵活方案，加尼瑞克vs.西曲瑞克，采用或不采用激素预处理）。还进行了一项结合直接和间接比较的频率学网络荟萃分析（使用GnRH激动剂长方案作为对照组），以提高评估的准确性。

SEARCH METHODS

研究方法

The systematic literature search was performed using Embase (Ovid), MEDLINE (Ovid), Cochrane Central Register of Trials (CENTRAL), SCOPUS and Web of Science (WOS), from inception until 23 November 2021. The search terms comprised three different MeSH terms that should be present in the identified studies: GnRH antagonist; assisted reproduction treatment; randomized controlled trial (RCT). Only studies published in English were included.

检索了2021年11月23日至今，在Embase（Ovid）、MEDLINE（Ovid）、Cochrane Central Register of Trials（Central）、SCOPUS和Web of Science（WOS）发表的文献。搜索关键词包括三个不同的MeSH术语，这些术语可能出现在不同的研究中：GnRH拮抗剂；辅助生殖治疗；随机对照试验（RCT）。只纳入了以英语发表的研究。

OUTCOMES

结果

The search strategy resulted in 6738 individual publications, of which 102 were included in the systematic review (corresponding to 75 unique studies) and 73 were included in the meta-analysis. Most studies were of low quality. One study compared a flexible protocol with a fixed Day 5 protocol and the remaining RCTs with a fixed Day 6 protocol. There was a lack of data regarding live birth when comparing the flexible and fixed GnRH antagonist protocols or cetrorelix and ganirelix. No significant difference in live birth rate was observed between the different pretreatment regimens versus no pretreatment or between the different pretreatment protocols. A flexible GnRH antagonist protocol resulted in a significantly lower OPR compared with a fixed Day 5/6 protocol (relative risk (RR) 0.76, 95% CI 0.62 to 0.94, I2 = 0%; 6 RCTs; n = 907 participants; low certainty evidence). There were insufficient data for a comparison of cetrorelix and ganirelix for OPR. OCP pretreatment was associated with a lower OPR compared with no pretreatment intervention (RR 0.79, 95% CI 0.69 to 0.92; I2 = 0%; 5 RCTs, n = 1318 participants; low certainty evidence). Furthermore, in the network meta-analysis, a fixed protocol with OCP resulted in a significantly lower OPR than a fixed protocol with no pretreatment (RR 0.84, 95% CI 0.71 to 0.99; moderate quality evidence). The surface under the cumulative ranking (SUCRA) scores suggested that the fixed protocol with no pretreatment is the antagonist protocol most likely (84%) to result in the highest OPR. There was insufficient evidence of a difference between fixed/flexible or OCP pretreatment/no pretreatment interventions regarding other outcomes, such as ovarian hyperstimulation syndrome and miscarriage rates.

共检索出6738篇独立报道，其中102篇被纳入系统综述（对应于75项独特的研究），73篇被纳入荟萃分析。大多数研究质量都很低。一项研究比较了灵活方案与第5天固定方案，其余RCT中比较了灵活方案与第6天固定方案。在比较灵活方案和固定方案，以及西曲瑞克和加尼瑞克时缺乏活产率的数据。预处理与未预处理或不同预处理方案之间，活产率没有显著差异。与固定的第5/6天方案相比，灵活GnRH拮抗剂方案可显著降低持续妊娠率（相对风险（RR）0.76，95%CI 0.62-0.94，I2=0%；6项随机对照试验；n=907名参与者；低确定性证据）。没有足够的数据支持来比较西曲瑞克和加尼瑞克的持续妊娠率。与未进行预处理相比，口服避孕药预处理与较低的持续妊娠率相关（RR 0.79，95%CI 0.69-0.92；I 2=0%；5项随机对照试验，n=1318名参与者；低确定性证据）。此外，在网络荟萃分析中，口服避孕药预处理固定方案的持续妊娠率显著低于没有预处理的固定方案（RR 0.84，95%CI 0.71-0.99；中等质量证据）。表面累积排名（SUCRA）评分表明，不进行预处理的固定方案是最有可能产生最高持续妊娠率（84%）的拮抗剂方案。没有足够的证据表明，固定/灵活方案或口服避孕药预处理/不进行预处理在其他结果如卵巢过度刺激综合征和流产率方面存在差异。

WIDER IMPLICATIONS

更广泛意义

Available evidence, mostly of low quality and certainty, suggests that different antagonist protocols should not be considered as equivalent for clinical decision-making. More trials are required to assess the comparative effectiveness of ganirelix versus cetrorelix, the effect of different pretreatment interventions (e.g. progestins or oestradiol) or the effect of different criteria for initiation of the antagonist in the flexible protocol. Furthermore, more studies are required examining the optimal GnRH antagonist protocol in women with high or low response to ovarian stimulation.

现有证据大多是质量和确定性较低，表明在临床决策中，不同的拮抗剂方案可能有所不同。还需要更多的试验来评估加尼瑞克和西曲瑞克的有效性、不同预处理措施（如孕激素或雌二醇）的效果，以及灵活方案中以不同标准开始使用拮抗剂的效果。此外，还需开展更多的研究来评估卵巢高反应或低反应女性最佳的GnRH拮抗剂方案。

文章来源：

Human Reproduction Update, Volume 29, Issue 3, May-June 2023, Pages 307–326, https://doi.org/10.1093/humupd/dmac040