The randomized TOTAL-trials on fetal surgery for congenital diaphragmatic hernia: re-analysis using pooled data.

ABSTRACT Background Two randomized controlled trials compared the neonatal and infant outcomes after fetoscopic endoluminal tracheal occlusion (FETO) with expectant prenatal management in fetuses with moderate and severe isolated congenital diaphragmatic hernia (CDH), respectively. FETO 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. Reported absolute increase in survival to discharge were 13% (95% confidence interval, -1–28; P=.059), and 25% (95% confidence interval, 6–46; P=.0091) for moderate and hypoplasia CDH, respectively. Objectives Data from the two trials were pooled to study the heterogeneity of the treatment effect by observed over expected lung-to-head ratio and explore the effect of the gestational age at balloon insertion. Study design Individual participant data from the two trials were reanalyzed. Women were assessed between 2008 and 2020 at 14 experienced FETO centers, and were randomized in a 1:1 ratio to either expectant management or FETO. All received standardized postnatal management. The combined data involved 287 patients (196 moderate and 91 severe hypoplasia). The primary endpoint was survival to discharge from the neonatal intensive care unit. 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 (FETO 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 observed over expected lung-to-head ratio was evaluated to study treatment effect heterogeneity. Results For survival to discharge, the adjusted odds ratio of FETO was 1.78 (95% confidence interval, 1.05–3.01; P=.031). The additional effect of early balloon insertion was positive but highly uncertain (adjusted odds ratio, 1.53; 95% confidence interval, 0.60–3.91; P=.370). When combining these two effects, the adjusted odds ratio of FETO with early balloon insertion was 2.73 (95% confidence interval, 1.15–6.49). 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% CI, 1.1–2.3) following FETO with late insertion and 3.2 weeks earlier (95% CI, 2.3–4.1) following FETO with early insertion, as compared to expectant management. There was no evidence that the effect of FETO depended on the observed over expected lung-to-head ratio for any of the endpoints. Conclusions This analysis suggests that FETO increases survival both for moderate and severe lung hypoplasia. The difference between the results for the TOTAL trials, when considered apart, may be due to the difference in the time point of balloon insertion. However, the effect of time point of balloon insertion could not be robustly assessed due to small sample size and the confounding effect of disease severity. FETO, in particular with early balloon insertion, strongly increases the risk for preterm delivery.