BACKGROUND Intrauterine insemination with ovarian stimulation (IUI-OS) is a first-line treatment for unexplained infertility. Gonadotrophins, letrozole and clomiphene citrate (CC) are commonly used agents during IUI-OS and have been compared in multiple aggregate data meta-analyses, with substantial heterogeneity and no analysis on time-to-event outcomes. Individual participant data meta-analysis (IPD-MA) is considered the gold standard for evidence synthesis as it can offset inadequate reporting of individual studies by obtaining the IPD, and allows analyses on treatment-covariate interactions to identify couples who benefit most from a particular treatment. OBJECTIVE AND RATIONALE We performed this IPD-MA to compare the effectiveness and safety of ovarian stimulation with gonadotrophins, letrozole and CC and to explore treatment-covariate interactions for important baseline characteristics in couples undergoing IUI. SEARCH METHODS We searched electronic databases including MEDLINE, EMBASE, CENTRAL, CINAHL, and PsycINFO from their inception to 28 June 2021. We included randomized controlled trials (RCTs) comparing IUI-OS with gonadotrophins, letrozole and CC among couples with unexplained infertility. We contacted the authors of eligible RCTs to share the IPD and established the IUI IPD-MA Collaboration. The primary effectiveness outcome was live birth and the primary safety outcome was multiple pregnancy. Secondary outcomes were other reproductive outcomes, including time to conception leading to live birth. We performed a one-stage random effects IPD-MA. OUTCOMES Seven of 22 (31.8%) eligible RCTs provided IPD of 2495 couples (62.4% of the 3997 couples participating in 22 RCTs), of which 2411 had unexplained infertility and were included in this IPD-MA. Six RCTs (n = 1511) compared gonadotrophins with CC, and one (n = 900) compared gonadotrophins, letrozole and CC. Moderate-certainty evidence showed that gonadotrophins increased the live birth rate compared to CC (6 RCTs, 2058 women, RR 1.30, 95% CI 1.12-1.51, I2 = 26%). Low-certainty evidence showed that gonadotrophins may also increase the multiple pregnancy rate compared to CC (6 RCTs, 2058 women, RR 2.17, 95% CI 1.33-3.54, I2 = 69%). Heterogeneity on multiple pregnancy could be explained by differences in gonadotrophin starting dose and choice of cancellation criteria. Post-hoc sensitivity analysis on RCTs with a low starting dose of gonadotrophins (≤75 IU) confirmed increased live birth rates compared to CC (5 RCTs, 1457 women, RR 1.26, 95% CI 1.05-1.51), but analysis on only RCTs with stricter cancellation criteria showed inconclusive evidence on live birth (4 RCTs, 1238 women, RR 1.15, 95% CI 0.94-1.41). For multiple pregnancy, both sensitivity analyses showed inconclusive findings between gonadotrophins and CC (RR 0.94, 95% CI 0.45-1.96; RR 0.81, 95% CI 0.32-2.03, respectively). Moderate certainty evidence showed that gonadotrophins reduced the time to conception leading to a live birth when compared to CC (6 RCTs, 2058 women, HR 1.37, 95% CI 1.15-1.63, I2 = 22%). No strong evidence on the treatment-covariate (female age, BMI or primary versus secondary infertility) interactions was found. WIDER IMPLICATIONS In couples with unexplained infertility undergoing IUI-OS, gonadotrophins increased the chance of a live birth and reduced the time to conception compared to CC, at the cost of a higher multiple pregnancy rate, when not differentiating strategies on cancellation criteria or the starting dose. The treatment effects did not seem to differ in women of different age, BMI or primary versus secondary infertility. In a modern practice where a lower starting dose and stricter cancellation criteria are in place, effectiveness and safety of different agents seem both acceptable, and therefore intervention availability, cost and patients' preferences should factor in the clinical decision-making. As the evidence for comparisons to letrozole is based on one RCT providing IPD, further RCTs comparing letrozole and other interventions for unexplained infertility are needed.

中文翻译：

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不明原因不孕夫妇宫内授精的卵巢刺激策略：系统评价和个体参与者数据荟萃分析。

背景技术卵巢刺激宫腔内人工授精 (IUI-OS) 是不明原因不孕症的一线治疗方法。促性腺激素、来曲唑和克罗米芬 (CC) 是 IUI-OS 期间常用的药物，并已在多项汇总数据荟萃分析中进行了比较，具有很大的异质性，并且没有对事件发生时间结果进行分析。个体参与者数据荟萃分析 (IPD-MA) 被认为是证据合成的黄金标准，因为它可以通过获得 IPD 来弥补个体研究报告的不足，并允许对治疗协变量相互作用进行分析，以确定从特定项目中受益最多的夫妇治疗。目标和基本原理 我们进行了 IPD-MA 以比较促排卵与促性腺激素的有效性和安全性，来曲唑和 CC 并探索治疗 - 协变量相互作用在接受 IUI 的夫妇中的重要基线特征。搜索方法 我们搜索了包括 MEDLINE、EMBASE、CENTRAL、CINAHL 和 PsycINFO 在内的电子数据库，从它们开始到 2021 年 6 月 28 日。我们纳入了比较 IUI-OS 与促性腺激素、来曲唑和 CC 对不明原因不孕症夫妇的随机对照试验 (RCT)。我们联系了符合条件的 RCT 的作者分享 IPD 并建立了 IUI IPD-MA 协作。主要有效性结果是活产，主要安全性结果是多胎妊娠。次要结局是其他生殖结局，包括导致活产的受孕时间。我们进行了单阶段随机效应 IPD-MA。结果 22 条中的 7 条 (31. 8%) 符合条件的 RCT 提供了 2495 对夫妇的 IPD（参与 22 项 RCT 的 3997 对夫妇中的 62.4%），其中 2411 对有不明原因的不孕症，并被纳入本 IPD-MA。六项 RCT（n = 1511）比较了促性腺激素与 CC，一项（n = 900）比较了促性腺激素、来曲唑和 CC。中等质量证据表明，与 CC 相比，促性腺激素增加了活产率（6 项 RCT，2058 名女性，RR 1.30，95% CI 1.12-1.51，I2 = 26%）。低质量证据表明，与 CC 相比，促性腺激素也可能增加多胎妊娠率（6 项 RCT，2058 名女性，RR 2.17，95% CI 1.33-3.54，I2 = 69%）。多胎妊娠的异质性可以通过促性腺激素起始剂量和取消标准的选择来解释。对低促性腺激素起始剂量（≤75 IU）的 RCT 进行事后敏感性分析证实，与 CC 相比，活产率增加（5 项 RCT，1457 名女性，RR 1.26，95% CI 1.05-1.51），但仅对 RCT 进行分析更严格的取消标准显示关于活产的不确定证据（4 项 RCT，1238 名女性，RR 1.15，95% CI 0.94-1.41）。对于多胎妊娠，两项敏感性分析均显示促性腺激素和 CC 之间的不确定性结果（RR 0.94，95% CI 0.45-1.96；RR 0.81，95% CI 0.32-2.03）。中等确定性证据表明，与 CC 相比，促性腺激素减少了导致活产的受孕时间（6 项 RCT，2058 名女性，HR 1.37，95% CI 1.15-1.63，I2 = 22%）。没有发现关于治疗协变量（女性年龄、BMI 或原发性与继发性不孕症）相互作用的有力证据。更广泛的影响 在接受 IUI-OS 的不明原因不孕夫妇中，与 CC 相比，促性腺激素增加了活产的机会并缩短了受孕时间，但代价是更高的多胎妊娠率，如果不区分取消标准或开始的策略剂量。不同年龄、BMI 或原发性与继发性不孕症的女性的治疗效果似乎没有差异。在采用较低起始剂量和更严格取消标准的现代实践中，不同药物的有效性和安全性似乎都可以接受，因此干预可用性、成本和患者偏好应作为临床决策的考虑因素。由于与来曲唑比较的证据是基于一项提供 IPD 的 RCT，