Background

Two randomized controlled trials compared the neonatal and infant outcomes after fetoscopic endoluminal tracheal occlusion with expectant prenatal management in fetuses with severe and moderate isolated congenital diaphragmatic hernia, respectively. Fetoscopic endoluminal tracheal occlusion was carried out at 27⁺⁰ to 29⁺⁶ weeks’ gestation (referred to as “early”) for severe and at 30⁺⁰ to 31⁺⁶ weeks (“late”) for moderate hypoplasia. The reported absolute increase in the survival to discharge was 13% (95% confidence interval, −1 to 28; P=.059) and 25% (95% confidence interval, 6–46; P=.0091) for moderate and severe hypoplasia.

Objective

Data from the 2 trials were pooled to study the heterogeneity of the treatment effect by observed over expected lung-to-head ratio and explore the effect of gestational age at balloon insertion.

Study Design

Individual participant data from the 2 trials were reanalyzed. Women were assessed between 2008 and 2020 at 14 experienced fetoscopic endoluminal tracheal occlusion centers and were randomized in a 1:1 ratio to either expectant management or fetoscopic endoluminal tracheal occlusion. All received standardized postnatal management. The combined data involved 287 patients (196 with moderate hypoplasia and 91 with severe hypoplasia). The primary endpoint was survival to discharge from the neonatal intensive care unit. The secondary endpoints were survival to 6 months of age, survival to 6 months without oxygen supplementation, and gestational age at live birth. Penalized regression was used with the following covariates: intervention (fetoscopic endoluminal tracheal occlusion vs expectant), early balloon insertion (yes vs no), observed over expected lung-to-head ratio, liver herniation (yes vs no), and trial (severe vs moderate). The interaction between intervention and the observed over expected lung-to-head ratio was evaluated to study treatment effect heterogeneity.

Results

For survival to discharge, the adjusted odds ratio of fetoscopic endoluminal tracheal occlusion was 1.78 (95% confidence interval, 1.05–3.01; P=.031). The additional effect of early balloon insertion was highly uncertain (adjusted odds ratio, 1.53; 95% confidence interval, 0.60–3.91; P=.370). When combining these 2 effects, the adjusted odds ratio of fetoscopic endoluminal tracheal occlusion with early balloon insertion was 2.73 (95% confidence interval, 1.15–6.49). The results for survival to 6 months and survival to 6 months without oxygen dependence were comparable. The gestational age at delivery was on average 1.7 weeks earlier (95% confidence interval, 1.1–2.3) following fetoscopic endoluminal tracheal occlusion with late insertion and 3.2 weeks earlier (95% confidence interval, 2.3–4.1) following fetoscopic endoluminal tracheal occlusion with early insertion compared with expectant management. There was no evidence that the effect of fetoscopic endoluminal tracheal occlusion depended on the observed over expected lung-to-head ratio for any of the endpoints.

Conclusion

This analysis suggests that fetoscopic endoluminal tracheal occlusion increases survival for both moderate and severe lung hypoplasia. The difference between the results for the Tracheal Occlusion To Accelerate Lung growth trials, when considered apart, may be because of the difference in the time point of balloon insertion. However, the effect of the time point of balloon insertion could not be robustly assessed because of a small sample size and the confounding effect of disease severity. Fetoscopic endoluminal tracheal occlusion with early balloon insertion in particular strongly increases the risk for preterm delivery.

中文翻译：

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先天性膈疝胎儿手术的随机气管阻塞加速肺生长（TOTAL）试验：使用汇总数据进行再分析

背景

两项随机对照试验分别比较了重度和中度孤立性先天性膈疝胎儿在胎儿镜腔内气管阻塞与期待产前管理后的新生儿和婴儿结局。^{在妊娠 27 +0}至 29 ^{+ 6}周（称为“早期”）进行胎儿镜腔内气管封堵（称为“早期”），对于中度发育不全，在 30 ⁺⁰至 31 ^{+6周（“晚期”）进行。}报告的中度和重度出院生存率的绝对增加分别为 13%（95% 置信区间，-1 至 28；P =.059）和 25%（95% 置信区间，6-46；P =.0091）发育不全。

客观的

将 2 项试验的数据合并，通过观察到的超预期肺与头部比率来研究治疗效果的异质性，并探索插入球囊时胎龄的影响。

学习规划

重新分析了 2 项试验的个体参与者数据。2008 年至 2020 年期间，在 14 个经验丰富的胎儿镜腔内气管阻塞中心对女性进行了评估，并以 1:1 的比例随机分配到期待治疗或胎儿镜腔内气管阻塞组。均接受标准化产后管理。综合数据涉及 287 名患者（196 名中度发育不全，91 名严重发育不全）。主要终点是从新生儿重症监护室出院的存活率。次要终点是存活至 6 个月大、存活至 6 个月（不补充氧气）和活产胎龄。惩罚回归与以下协变量一起使用：干预（胎儿腔内气管阻塞 vs 期待）、早期球囊插入（是 vs 否）、观察到超过预期的肺头比、肝疝（是与否）和试验（严重与中度）。评估干预与观察到的超预期肺头比之间的相互作用，以研究治疗效果的异质性。

结果

对于生存至出院，胎儿镜腔内气管阻塞的调整优势比为 1.78（95% 置信区间，1.05-3.01；P =.031）。早期球囊插入的附加效果高度不确定（调整优势比，1.53；95% 置信区间，0.60-3.91；P=.370）。当结合这两种效应时，胎儿镜腔内气管阻塞与早期球囊插入的调整优势比为 2.73（95% 置信区间，1.15-6.49）。生存至 6 个月和无氧依赖生存至 6 个月的结果具有可比性。胎儿镜下气管腔内封堵术后胎龄平均提前 1.7 周（95% 置信区间，1.1-2.3），胎儿镜下气管腔内封堵术提前 3.2 周（95% 置信区间，2.3-4.1）插入与期待管理相比。没有证据表明胎儿镜腔内气管阻塞的效果取决于观察到的任何终点的超预期肺与头部比率。

结论

该分析表明，胎儿镜腔内气管阻塞可增加中度和重度肺发育不全的存活率。气管阻塞加速肺生长试验的结果之间的差异，当分开考虑时，可能是由于球囊插入时间点的差异。然而，由于样本量小和疾病严重程度的混杂效应，无法有力地评估球囊插入时间点的影响。胎儿镜腔内气管阻塞和早期球囊插入尤其会大大增加早产的风险。