免疫球蛋白+泼尼松龙对ART后反复妊娠丢失患者妊娠率的影响？

Study question

研究问题

Does intravenous immunoglobulin (IVIG) and prednisolone in combination affect ongoing pregnancy rate among patients with recurrent pregnancy loss (RPL) after assisted reproductive technology (ART) treatment?

静脉注射免疫球蛋白（IVIG）和口服泼尼松龙联合使用是否会影响辅助生殖技术 （ART） 治疗后反复妊娠丢失患者的持续妊娠率？

Summary answer

概要回答

The results of this trial will provide important information about whether immunomodulatory treatment to RPL patients undergoing ART treatment can increase clinical pregnancy rate.

该试验的结果将提供对接受ART治疗的反复妊娠丢失患者进行免疫调节治疗是否可以提高临床妊娠率的重要信息。

What is known already

已知信息

Two retrospective cohort studies suggest that IVIG and prednisolone in combination result in a 34-37% live birth rate in RPL patients undergoing ART which is higher than the expected 12% for patients with RPL after ART. A randomized controlled trial (RCT) testing IVIG in RPL patients conceiving naturally indicated that very early administration of IVIG caused more positive effects than late administration, and prospective cohort studies suggest that treatment efficacy depends on presence of immune disturbances. No RCT has tested the IVIG/prednisolone combination starting before implantation and continued in very early pregnancy for RPL patients undergoing ART.

两项回顾性队列研究表明，IVIG和泼尼松龙联合使用可使接受 ART的反复妊娠丢失患者的活产率达到 34%～37%，高于ART治疗反复妊娠丢失患者预期的 12%。一项随机对照试验研究IVIG在自然受孕的反复妊娠丢失患者中的作用表明， 免疫球蛋白早期给药比晚期给药产生更积极的影响，前瞻性队列研究表明，治疗效果取决于免疫紊乱是否存在。（迄今）没有随机对照试验研究过IVIG、（口服）泼尼松龙联合疗法在植入前开始并在极早期继续用于接受 ART的反复妊娠丢失患者。

Study design, size, duration

研究设计、规模、持续时间

In a randomized, double-blinded, placebo-controlled trial, patients undergoing IVF/ICSI/FET were treated with 400mg/kg IVIG and 5-10mg/day oral prednisolone or IV human albumin and oral placebo between January 2021 and March 2024. Oral treatment was administered from day one of menstrual cycle to GW 8 + 4, while IV treatment was given once in a short time interval before or after embryo transfer and repeated three times before GW 8 + 0. Primary outcome was ongoing pregnancy in GW 12

在一项随机、双盲、安慰剂对照试验中，接受 IVF/ICSI/FET 的患者在 2021 年 1 月至 2024 年 3 月期间接受 400mg/kg IVIG 和 5—10mg/天口服泼尼松龙或静脉注射人白蛋白和口服安慰剂治疗。从月经周期的第一天到孕8+4W进行口服治疗，而IVIG治疗在胚胎移植之前或之后短时内进行一次，并在孕8W之前重复三次。主要结果是孕12周内的持续妊娠状况。

Participants/materials, setting, methods

参与者/材料、背景、方法

Seventy-four women <41 years old with ≥2 consecutive biochemical or clinical early pregnancy losses after ART were randomized 1:1 and underwent trial treatment along with their next IVF/ICSI/FET treatment. Patients were followed with weekly ultrasound scans in first trimester, however, if no implantation occurred, trial participation ended, and no re-entry was allowed. Exclusion criteria included antiphospholipid syndrome, BMI >35, uterine malformations, parental chromosomal translocations, AMH <4 pmol/l, drug contraindications, thyroid disease, and prior IVIG treatment.

74名<41 岁、连续2次生化或临床早孕流产的女性在 ART 后以 1:1 的比例随机分配，接受试验治疗以及后续的IVF/ICSI/FET 治疗。在妊娠早期，患者每周接受一次超声扫描，如果没有发生植入，试验参与结束，并且不允许再次进入。排除标准包括抗磷脂综合征、BMI >35、子宫畸形、父母染色体易位、AMH <4 pmol/l、药物禁忌症、甲状腺疾病和既往IVIG治疗。

Main results and the role of chance

主要结果和机会的作用

Seventy-four patients have been randomized, and currently we are awaiting the last two patients to complete the treatment protocol before the code can be disclosed. Blinded interim analysis after inclusion of 38 patients showed no serious adverse events and an ongoing pregnancy rate of 30.0% and 9.5% (RR 1.8, 95% CI 1.0-3.1, Fisher’s exact test: p = 0.13), in the two allocation groups, respectively. Final, unblinded data on ongoing pregnancy rate, miscarriage rate and adverse events will be presented at the Congress if selected for presentation.

74名患者已被随机分配，目前我们正在等待最后两名患者完成治疗后开码，纳入38例患者的盲法中期分析显示，在两组中，没有严重不良事件，持续妊娠率分别为30.0%和9.5%（RR1.8,95%CI1.0-3.1，Fisher确切检验：P=0.13）。最后，如果被选中会议发言，有关持续妊娠率、流产率和不良事件的数据将在大会上公开。

Limitations, reasons for caution

局限性和谨慎的理由

No published study has tested the same treatments in comparable patient groups which could have been the basis for the sample-size calculation, and the study is therefore at risk for being underpowered to evaluate the treatment effect in patients suffering from a combination of infertility, recurrent implantation failure, and RPL.

在相似的患者群体中比较该治疗方法，目前还没有已发表的研究，而这本可以成为样本量计算的基础。因此该研究存在评估该群体（患有不孕症、复发性植入失败和反复妊娠丢失的患者）治疗效果不足的风险。

Wider implications of the findings

研究结果更广泛的影响

Blood samples were collected before first IV treatment and approximately 4 weeks later, which allow analysis for immunological disturbances and searching for biomarkers identifying those who will benefit from the treatment. This treatment could potentially increase success rate in patients undergoing ART after multiple unsuccessful treatment attempts.

在第一次静脉注射治疗之前和大约 4 周后收集血样，这样可以分析免疫紊乱并寻找生物标志物，以确定那些将从治疗中获益的人。在多次治疗尝试失败后，这种治疗可能会提高接受 ART 治疗的患者的成功率。

参考文献：

C Nørgaard-Pedersen, U S Kesmodel, O B Christiansen, M Møller Jørgensen, O-032 Intravenous immunoglobulin and prednisolone to women with unexplained recurrent pregnancy loss undergoing assisted reproductive technology treatment: a randomized, double-blinded, placebo-controlled trial, Human Reproduction, Volume 39, Issue Supplement_1, July 2024, deae108.032, https://doi.org/10.1093/humrep/deae108.032