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 IUI 卵巢刺激治疗不明原因不孕症：协作性个体参与者数据荟萃分析


背景 IVF 和 IUI 联合卵巢刺激 (IUI-OS) 广泛用于治疗不明原因不孕症。 IUI-OS 通常被认为是一线治疗，只有在多次尝试后 IUI-OS 不成功的情况下才进行 IVF。然而，人们对使用体外受精进行立即治疗越来越感兴趣，因为它被认为可以提高活产率并缩短怀孕时间。目的和理由 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。一些随机对照试验使用复杂的算法将 IVF 和 IUI-OS 结合起来，而另一些随机对照试验则在各组之间的随访时间不平等或按每个周期比较治疗，从而引入了偏差。为了进行公平的面对面比较，有必要在一致的时间范围内比较 IVF 和 IUI-OS 的累积活产率。之前的随机对照试验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实现这一点的。个体参与者数据荟萃分析 (IPD-MA) 允许对不同试验和事件时间分析方法中的随访时间进行标准化。我们进行了这项 IPD-MA，以调查在不明原因不孕夫妇中，与 IUI-OS 相比，IVF 是否会在考虑怀孕时间的情况下提高累积活产率，并降低多胎妊娠率。检索方法 我们检索了 MEDLINE、EMBASE、CENTRAL、PsycINFO、CINAHL 和 Cochrane 妇科和生育小组专业注册库，以确定 2021 年 6 月之前完成数据收集的 RCT。2023 年 1 月进行了搜索更新。比较 IVF/ICSI 的 RCT患有不明原因不孕症的夫妇有资格接受 IUI-OS。 我们邀请符合条件的研究的作者团体加入 IPD-MA 并分享其 RCT 的去识别化 IPD。合成前对IPD进行检查和标准化。使用偏倚风险 2 工具评估证据质量。结果 在八项可能符合资格的随机对照试验中，有两项被认为正在等待分类。在其他六项试验中，四项共享了 934 名女性的 IPD，其中 550 名分配给 IVF，383 名分配给 IUI-OS。由于干预措施无法盲法，两项随机对照试验具有高偏倚风险，一项存在一些担忧，一项具有低偏倚风险。考虑到怀孕到活产的时间，与 IUI-OS 相比，IVF 的累积活产率并没有显着更高（4 项随机对照试验，908 名女性，50.3% 对比 43.2%，风险比 1.19，95% CI 0.81– 1.74，I2 = 42.4%）。对于安全性主要结局，IVF 中的多胎妊娠率并不显着低于 IUI-OS（3 项随机对照试验，890 名女性，所有随机夫妇中分别为 3.8% 和 5.2%，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，在不明原因不孕的夫妇中，IVF 比 IUI-OS 更快地实现妊娠并实现活产。就治疗不明原因不孕症的有效性和安全性而言，IVF 和 IUI-OS 都是可行的选择。在临床决策中需要权衡干预措施的相关成本和夫妇的偏好。