新鲜IVF/ICSI周期中，最佳的黄体支持方案是什么？

Study question

研究问题

What is the optimal LPS in fresh cycles in agonist and antagonist cycles?

在鲜胚移植的拮抗剂和激动剂周期中，最佳的黄体支持方案是什么？

Summary answer

最终结论

Vaginal progesterone, with the addition of SCGnRH-a results in improved clinical pregnancy and live birth events in both GnRH-agonist and antagonist ovarian stimulation protocols.

阴道塞孕酮制剂联合皮下注射GnRH-a可以提高拮抗剂和激动剂下卵巢刺激方案的临床妊娠率和活产率。

What is known already

我们已知的是

Despite the proven superiority of various Luteal Phase Support protocols (LPS) over placebo in view of improved pregnancy rates in fresh cycles of IVF (in vitro fertilization) and ICSI (intracytoplasmic sperm injection) cycles, there is ongoing controversy over specific LPS protocol selection, dosage, and duration.

尽管大量研究都证明了黄体支持可以提高IVF(体外受精)和ICSI(胞浆内单精子注射)鲜胚移植周期中妊娠率，但关于最佳黄体支持方案的选择、剂量和持续时间一直存在争议。

Study design, size, duration

研究设计、规模、持续时间

Network Meta-analysis. Twelve databases, namely Embase (OVID), MEDLINE (R) (OVID), GlobalHealth (Archive), GlobalHealth, Health and Psychosocial Instruments, Maternity & Infant Care Database (MIDIRS), APA PsycTests, ClinicalTrials.gov, HMIC Health Management Information Consortium, CENTRAL, Web of Science, Scopus and two prospective registers, MedRxiv, Research Square were searched from inception to Aug.1st, 2023.The study was prospectively registered under the PROSPERO database.

网络荟萃分析。通过检索12个数据库，即Embase (OVID)、MEDLINE (R) (OVID)、GlobalHealth (Archive)、全球健康，健康和社会心理仪器，产妇和婴儿护理数据库(MIDIRS)，APA心理测试，ClinicalTrials.gov, HMIC Health、Management Information Consortium、CENTRAL、Web of Science、Scopus和两个前瞻性注册库MedRxiv、Research Square，检索时间为成立至2023年8月1日。该研究已提前登记在PROSPERO数据库中。

Participants/materials, setting, methods

参与者/材料、设置、方法

Only RCTs were included. Primary outcomes included clinical pregnancy and live birth events, while secondary outcomes included biochemical pregnancy, miscarriage, multiple pregnancy and OHSS events. Bayesian network meta-analysis (NMA) model was employed for outcome analysis, presenting fixed effects, odds ratios (ORs) with 95% credibility intervals (CrIs). Vaginal Progesterone (VP) was considered the reference LPS for the purposes of the NMA given its’ clinical relevance.

仅纳入随机对照试验。主要结局包括临床妊娠和活产事件，次要结局包括生化妊娠、流产、多胎妊娠和OHSS事件。结果分析采用贝叶斯网络元分析(NMA)模型，呈现固定效应，优势比(ORs)为95%可信区间(CrIs)。鉴于荟萃分析给出的临床相关性建议，阴道塞孕酮制剂被作为黄体支持的基本方案。

Main results and the role of chance

主要结果

Seventy-six RCTs, comparing 22 interventions, and including 26536 participants were included in the present NMA.Combinatorial regimens, with subcutaneous GnRH-a (SCGnRH-a) on a vaginal progesterone base and oral oestrogen (OE) appeared to overall improve clinical pregnancy events; VP+OE+SCGnRH-a [OR 1.57 (95% CrI 1.11 to 2.22)], VP+SCGnRH-a [OR 1.28 (95% CrI 1.05 to 1.55)] as well as live pregnancy events, VP+OE+SCGnRH-a [OR 8.81 (95% CrI 2.35 to 39.1)], VP+SCGnRH-a [OR 1.76 (95% CrI 1.45 to 2.15)]. Equally, the progesterone free LPS, intramuscular human chorionic gonadotrophin, [OR 9.67 (95%CrI 2.34, 73.2)] was also found to increase live birth events, however was also associated with an increased probability of ovarian hyperstimulation, [OR 1.64 (95%CrI 0.75, 3.71)]. Of all LPS protocols, VP+SC GnRH-a was found to significantly reduce miscarriage events, OR 0.54 (95% CrI 0.37 to 0.80). Subgroup analysis according to ovarian stimulation (OS) protocol revealed that the optimal LPS across both long and short OS, taking into account increase in live birth and reduction in miscarriage as well as OHSS events, was VP+SCGnRH-a, with an OR 2.89 [95%CrI 1.08, 2.96] and OR 2.84 [95%CrI 1.35, 6.26] respectively.

该网状荟萃分析共纳入76项随机对照研究，包含26536名参与者和22种干预措施。在阴道塞孕酮制剂基础上皮下注射GnRH-a (SCGnRH-a)和口服雌激素(OE)的组合方案似乎提高总体的临床妊娠率：阴道塞孕酮制剂+皮下注射GnRH-a +口服雌激素[OR 1.57 (95% CrI)1.11至2.22)]；阴道塞孕酮制剂+皮下注射GnRH-a [OR 1.28 (95% CrI 1.05 to 1.55)]，同时也提高了临床妊娠率：阴道塞孕酮制剂+皮下注射GnRH-a +口服雌激素 [OR 8.81 (95% CrI 2.35 to39.1)]，阴道塞孕酮制剂+皮下注射GnRH-a [OR 1.76 (95% CrI 1.45 to 2.15)]。此外，不包含孕酮的黄体支持方案如肌注人绒毛膜促性腺激素也可提高活产率[OR 9.67(95%CrI 2.34, 73.2)]，但也会增加卵巢过度刺激综合征的发生率[OR 1.64 (95%CrI 0.75, 3.71)]。在所有的黄体支持方案中，阴道塞孕酮制剂+皮下注射GnRH-a可以显著降低流产率, [OR 0.54 (95% CrI 0.37 to 0.80)]。根据卵巢刺激(OS)方案进行的亚组分析显示，考虑到活产率的增加和流产以及OHSS发生率的下降，长和短OS方案中的最佳黄体支持方案为阴道塞孕酮制剂+皮下注射GnRH-a, [OR2.89 [95%CrI 1.08, 2.96]和[OR2.84 [95%CrI 1.35, 6.26]。

Limitations, reasons for caution

研究的局限性

Given the anticipated diversity of measured outcomes, a Bayesian meta-synthesis approach has been adopted to account for the expected heterogeneity and to incorporate modelling flexibility by allowing for posterior distributions interpreted as SUCRA probabilities with the later enabling crisper communication of the uncertainty in the treatment effects estimates.

考虑到预期测量结果的多样性，采用了贝叶斯综合方法来解释预期的异质性，并通过允许将后向分布解释为SUCRA概率，从而结合建模灵活性，更清晰地交流治疗效果估计中的不确定性。

Wider implications of the findings

更长远的启示

Overall, NMA data suggest that combinatorial treatments, with the addition of SCGnRH-a on a VP base result in improved clinical pregnancy and live birth events in both GnRH-agonist and antagonist ovarian stimulation protocols.

总的来说，网状荟萃分析结果显示阴道塞孕酮制剂联合皮下注射GnRH-a可以提高拮抗剂和激动剂下卵巢刺激方案的临床妊娠率和活产率。

参考文献：

K. Specialty Registrar Obstetrics & Gynaecology, P-396 Comparison of luteal support protocols in fresh IVF/ICSI cycles: A network meta-analysis, Human Reproduction, Volume 39, Issue Supplement_1, July 2024, deae108.105, https://doi.org/10.1093/humrep/deae108.105