Abstract：
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.
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.
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.
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.
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.
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.
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.
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.
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.
摘要：
卵巢刺激宫腔内人工授精（IUI-OS）是无法解释的不孕症的一线治疗方法。促性腺激素,来曲唑和柠檬酸氯米芬（CC）是IUI-OS期间常用的药物，并在多个汇总数据荟萃分析中进行了比较，具有实质性异质性，没有对事件发生时间结果的分析。个体参与者数据荟萃分析（IPD-MA）被认为是证据综合的黄金标准，因为它可以通过获得IPD来抵消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，以确定从特定治疗中受益最大的夫妇。
我们进行了这种IPD-MA，以比较促性腺激素与促性腺激素刺激卵巢的有效性和安全性，来曲唑和CC，并探讨IUI夫妇中重要基线特征的治疗-协变量相互作用。
我们搜索了包括MEDLINE在内的电子数据库，EMBASE,中部,CINAHL,和PsycINFO从成立到2021年6月28日。我们纳入了比较IUI-OS与促性腺激素的随机对照试验(RCT)，来曲唑和CC在不明原因不孕症夫妇中的应用。我们联系了符合条件的RCT的作者分享IPD，并建立了IUIIPD-MA合作。主要有效性结局是活产，主要安全性结局是多胎妊娠。次要结果是其他生殖结果，包括导致活产的受孕时间。我们进行了一个阶段的随机效应IPD-MA。
22个符合条件的RCT中有7个（31.8％）提供了2495对夫妇的IPD（参与22个RCT的3997对夫妇中的62.4％），其中2411人患有无法解释的不孕症，并包括在此IPD-MA中。六个RCT（n=1511）比较了促性腺激素与CC，和一个（n=900）比较促性腺激素，来曲唑和CC。中等确定性证据表明，与CC相比，促性腺激素增加了活产率(6个随机对照试验，2058名妇女，RR1.30，95%CI1.12-1.51，I2=26%）。低确定性证据表明，与CC相比，促性腺激素也可能增加多胎妊娠率（6个RCT，2058名妇女，RR2.17，95%CI1.33-3.54，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。对促性腺激素低起始剂量（≤75IU）的RCT进行的事后敏感性分析证实，与CC相比，活产率增加（5个RCT，1457名妇女，RR1.26，95%CI1.05-1.51），但是仅对具有更严格取消标准的随机对照试验的分析显示，关于活产的证据不确定(4个随机对照试验，1238名妇女，RR1.15，95%CI0.94-1.41）。对于多胎妊娠，两项敏感性分析均显示促性腺激素和CC之间的结果不确定(RR0.94,95%CI0.45-1.96;RR0.81,95%CI0.32-2.03).中度确定性证据表明，与CC相比，促性腺激素减少了导致活产的受孕时间（6个RCT，2058名妇女，HR1.37，95%CI1.15-1.63，I2=22%）。没有关于治疗协变量的有力证据(女性年龄，发现BMI或原发性与继发性不孕症）相互作用。
在经历IUI-OS的无法解释的不孕症夫妇中，与CC相比，促性腺激素增加了活产的机会并减少了受孕时间，以更高的多胎妊娠率为代价，当不区分取消标准或起始剂量的策略时。不同年龄女性的治疗效果似乎没有差异，BMI或原发性与继发性不孕症。在现代实践中，较低的起始剂量和更严格的取消标准已经到位，不同药物的有效性和安全性似乎都可以接受，因此，干预的可用性，成本和患者偏好应在临床决策中考虑。因为与来曲唑比较的证据是基于一个提供IPD的RCT，需要进一步的RCT比较来曲唑和其他干预措施对无法解释的不孕症的影响.
我们进行了这种IPD-MA，以比较促性腺激素与促性腺激素刺激卵巢的有效性和安全性，来曲唑和CC，并探讨IUI夫妇中重要基线特征的治疗-协变量相互作用。
我们搜索了包括MEDLINE在内的电子数据库，EMBASE,中部,CINAHL,和PsycINFO从成立到2021年6月28日。我们纳入了比较IUI-OS与促性腺激素的随机对照试验(RCT)，来曲唑和CC在不明原因不孕症夫妇中的应用。我们联系了符合条件的RCT的作者分享IPD，并建立了IUIIPD-MA合作。主要有效性结局是活产，主要安全性结局是多胎妊娠。次要结果是其他生殖结果，包括导致活产的受孕时间。我们进行了一个阶段的随机效应IPD-MA。
22个符合条件的RCT中有7个（31.8％）提供了2495对夫妇的IPD（参与22个RCT的3997对夫妇中的62.4％），其中2411人患有无法解释的不孕症，并包括在此IPD-MA中。六个RCT（n=1511）比较了促性腺激素与CC，和一个（n=900）比较促性腺激素，来曲唑和CC。中等确定性证据表明，与CC相比，促性腺激素增加了活产率(6个随机对照试验，2058名妇女，RR1.30，95%CI1.12-1.51，I2=26%）。低确定性证据表明，与CC相比，促性腺激素也可能增加多胎妊娠率（6个RCT，2058名妇女，RR2.17，95%CI1.33-3.54，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。对促性腺激素低起始剂量（≤75IU）的RCT进行的事后敏感性分析证实，与CC相比，活产率增加（5个RCT，1457名妇女，RR1.26，95%CI1.05-1.51），但是仅对具有更严格取消标准的随机对照试验的分析显示，关于活产的证据不确定(4个随机对照试验，1238名妇女，RR1.15，95%CI0.94-1.41）。对于多胎妊娠，两项敏感性分析均显示促性腺激素和CC之间的结果不确定(RR0.94,95%CI0.45-1.96;RR0.81,95%CI0.32-2.03).中度确定性证据表明，与CC相比，促性腺激素减少了导致活产的受孕时间（6个RCT，2058名妇女，HR1.37，95%CI1.15-1.63，I2=22%）。没有关于治疗协变量的有力证据(女性年龄，发现BMI或原发性与继发性不孕症）相互作用。
在经历IUI-OS的无法解释的不孕症夫妇中，与CC相比，促性腺激素增加了活产的机会并减少了受孕时间，以更高的多胎妊娠率为代价，当不区分取消标准或起始剂量的策略时。不同年龄女性的治疗效果似乎没有差异，BMI或原发性与继发性不孕症。在现代实践中，较低的起始剂量和更严格的取消标准已经到位，不同药物的有效性和安全性似乎都可以接受，因此，干预的可用性，成本和患者偏好应在临床决策中考虑。因为与来曲唑比较的证据是基于一个提供IPD的RCT，需要进一步的RCT比较来曲唑和其他干预措施对无法解释的不孕症的影响.
