BACKGROUND IVF and IUI with ovarian stimulation (IUI-OS) are widely used in managing unexplained infertility. IUI-OS is generally considered first-line therapy, followed by IVF only if IUI-OS is unsuccessful after several attempts. However, there is a growing interest in using IVF for immediate treatment because it is believed to lead to higher live birth rates and shorter time to pregnancy. OBJECTIVE AND RATIONALE Randomized controlled trials (RCTs) comparing IVF versus IUI-OS had varied study designs and findings. Some RCTs used complex algorithms to combine IVF and IUI-OS, while others had unequal follow-up time between arms or compared treatments on a per-cycle basis, which introduced biases. Comparing cumulative live birth rates of IVF and IUI-OS within a consistent time frame is necessary for a fair head-to-head comparison. Previous meta-analyses of RCTs did not consider the time it takes to achieve pregnancy, which is not possible using aggregate data. Individual participant data meta-analysis (IPD-MA) allows standardization of follow-up time in different trials and time-to-event analysis methods. We performed this IPD-MA to investigate if IVF increases cumulative live birth rate considering the time leading to pregnancy and reduces multiple pregnancy rate compared to IUI-OS in couples with unexplained infertility. SEARCH METHODS We searched MEDLINE, EMBASE, CENTRAL, PsycINFO, CINAHL, and the Cochrane Gynaecology and Fertility Group Specialised Register to identify RCTs that completed data collection before June 2021. A search update was carried out in January 2023. RCTs that compared IVF/ICSI to IUI-OS in couples with unexplained infertility were eligible. We invited author groups of eligible studies to join the IPD-MA and share the deidentified IPD of their RCTs. IPD were checked and standardized before synthesis. The quality of evidence was assessed using the Risk of Bias 2 tool. OUTCOMES Of eight potentially eligible RCTs, two were considered awaiting classification. In the other six trials, four shared IPD of 934 women, of which 550 were allocated to IVF and 383 to IUI-OS. Because the interventions were unable to blind, two RCTs had a high risk of bias, one had some concerns, and one had a low risk of bias. Considering the time to pregnancy leading to live birth, the cumulative live birth rate was not significantly higher in IVF compared to that in IUI-OS (4 RCTs, 908 women, 50.3% versus 43.2%, hazard ratio 1.19, 95% CI 0.81–1.74, I2 = 42.4%). For the safety primary outcome, the rate of multiple pregnancy was not significantly lower in IVF than IUI-OS (3 RCTs, 890 women, 3.8% versus 5.2% of all couples randomized, odds ratio 0.78, 95% CI 0.41–1.50, I2 = 0.0%). WIDER IMPLICATIONS There is no robust evidence that in couples with unexplained infertility IVF achieves pregnancy leading to live birth faster than IUI-OS. IVF and IUI-OS are both viable options in terms of effectiveness and safety for managing unexplained infertility. The associated costs of interventions and the preference of couples need to be weighed in clinical decision-making.

中文翻译：

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IVF 与卵巢刺激 IUI 治疗不明原因不孕症：一项协作个体参与者数据荟萃分析


背景 IVF 和卵巢刺激 IUI （IUI-OS） 广泛用于治疗不明原因的不孕症。IUI-OS 通常被认为是一线治疗，只有在多次尝试后 IUI-OS 不成功时，才进行 IVF。然而，人们对使用 IVF 进行即时治疗的兴趣越来越大，因为据信它可以提高活产率和缩短怀孕时间。目标和基本原理 比较 IVF 与 IUI-OS 的随机对照试验 （RCT） 具有不同的研究设计和结果。一些 RCT 使用复杂的算法将 IVF 和 IUI-OS 相结合，而另一些 RCT 的组间随访时间不相等或基于每个周期比较治疗，这引入了偏倚。在一致的时间范围内比较 IVF 和 IUI-OS 的累积活产率对于公平的头对头比较是必要的。先前对 RCT 的荟萃分析没有考虑怀孕所需的时间，而使用汇总数据是不可能的。个体受试者数据荟萃分析（individual participant data meta-analysis， IPD-MA）允许对不同试验中的随访时间和事件发生时间分析方法进行标准化。我们进行了这项 IPD-MA 以研究考虑到怀孕时间，IVF 是否会增加累积活产率，并与 IUI-OS 相比，在不明原因的不孕症夫妇中降低多胎妊娠率。检索方法我们检索了MEDLINE、EMBASE、CENTRAL、PsycINFO、CINAHL和Cochrane妇科和生育组专业注册库（Cochrane Gynaecology and Fertility Group Specialised Register），以确定在2021年6月之前完成数据收集的随机对照试验。2023 年 1 月进行了检索更新。在不明原因不孕症夫妇中比较 IVF/ICSI 与 IUI-OS 的 RCT 符合条件。 我们邀请符合条件的研究的作者组加入 IPD-MA 并分享其 RCT 的去识别化 IPD。IPD 在合成前进行了检查和标准化。使用Risk of Bias 2工具评估证据质量。结果 在 8 项可能符合条件的 RCT 中，2 项被认为正在等待分类。在其他 6 项试验中，4 项共有 934 名女性的 IPD，其中 550 名被分配到 IVF 组，383 名被分配到 IUI-OS。由于干预措施无法盲法，因此两项RCTs具有高偏倚风险，一项存在一些担忧，一项具有低偏倚风险。考虑到导致活产的怀孕时间，与 IUI-OS 相比，IVF 的累积活产率并不显著高（4 项 RCT，908 名女性，50.3% 对 43.2%，风险比 1.19,95% CI 0.81-1.74，I2 = 42.4%）。对于安全主要结局，IVF 中的多胎妊娠率并不显著低于 IUI-OS（3 项随机对照试验，890 名女性，3.8% 对 5.2% 随机分组，比值比 0.78,95% CI 0.41-1.50，I2 = 0.0%）。更广泛的影响 没有强有力的证据表明，在不明原因的不孕症夫妇中，IVF 比 IUI-OS 更快地怀孕导致活产。IVF 和 IUI-OS 在治疗不明原因不孕症的有效性和安全性方面都是可行的选择。在临床决策中需要权衡干预的相关成本和夫妇的偏好。