Original Research
Obstetrics
The randomized Tracheal Occlusion To Accelerate Lung growth (TOTAL)-trials on fetal surgery for congenital diaphragmatic hernia: reanalysis using pooled data

https://doi.org/10.1016/j.ajog.2021.11.1351Get rights and content

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.

Introduction

Congenital diaphragmatic hernia (CDH) is associated with impaired fetal lung development, leading to neonatal respiratory failure and pulmonary hypertension, which can cause neonatal death. In isolated cases, the survival chances can be predicted prenatally by the measurement of the lung size and the presence of intrathoracic herniation of the liver.1 The lung area contralateral to the defect is measured on a standardized 4-chamber view of the heart and is divided by the head circumference to obtain the observed lung-to-head ratio (LHR); the LHR is then expressed as a percentage of what is expected in a normal fetus of the same gestational age (GA) to obtain the observed/expected lung-to-head-ratio (o/e LHR).2 Fetuses with a left-sided CDH and an o/e LHR <25% are considered to have severe pulmonary hypoplasia, because their survival chances are <25%.2 When the o/e LHR is 25.0% to 34.9% irrespective of the liver position or 35.0% to 44.9% with intrathoracic liver herniation, the hypoplasia is moderate, and the estimated survival chances are around 55%.2

AJOG at a Glance

Two randomized controlled trials on fetoscopic endoluminal tracheal occlusion (FETO) for isolated fetal congenital diaphragmatic hernia reported a statistically significant improvement in survival in severe hypoplasia but not in moderate hypoplasia.

This reanalysis on the basis of pooled data suggests that FETO increases survival and prematurity in both the severity groups.

The discrepancy in the results between the 2 trials is more likely because of performing FETO at an earlier gestational age in severe hypoplasia than in moderate hypoplasia; there was no evidence that the effect of FETO depends on the disease severity.

Fetoscopic endoluminal tracheal occlusion (FETO) with a balloon can stimulate lung growth and improve neonatal survival.3 In a large observational study in fetuses with left-sided severe hypoplasia, FETO at a median GA of 27 weeks resulted in a 49% survival, where survival was only 24% in historic controls who did not have fetal therapy.4 The significant predictors of survival were GA at delivery and lung size at the time of FETO.4 Therefore, along the spectrum of severe hypoplasia, those with the highest o/e LHR were the most likely to survive.5 However, FETO also increased the risk for preterm birth, in turn compromising survival chances.4,6 Because randomized data were lacking, we designed the Tracheal Occlusion to Accelerate Lung growth (TOTAL)-trials, wherein fetuses were randomized to either FETO or expectant prenatal management, both followed by standardized neonatal care.7,8 In fetuses with severe lung hypoplasia, the balloon was inserted at 27+0 to 29+6 weeks gestation, this time point being further referred to as “early”9. In moderate cases, insertion was at 30+0 to 31+6 weeks (“late”) to reduce the risks for very preterm birth and considering the higher survival rate when comparing with severe hypoplasia.10 In both trials, balloon removal was scheduled at 34+0 to 34+6 weeks or earlier if clinically indicated.11 In the trial for moderate hypoplasia, survival to discharge from the neonatal unit was 63% (62/98) in the FETO group and 50% (49/98) in the expectant management group (P=0.059; risk difference, 13%; 95% confidence interval [CI], −1 to 28; relative risk [RR], 1.27; odds ratio [OR], 1.72).10 In the trial for severe hypoplasia, survival to discharge was 40% (16/40) in the FETO group and 15% (6/40) in the expectant management group (P=.0091; risk difference, 25%; 95% CI, 6–46; RR, 2.67; OR, 3.78).9 A reductionist interpretation of these results, in terms of statistical significance, suggests that there is evidence of improved survival when the FETO is <25%, but not when FETO is ≥25%. Alternative interpretations may be that first, there is an overall beneficial effect of FETO that decreases with increasing o/e LHR, and second, that the beneficial effect of FETO is primarily dependent on earlier balloon insertion rather than on o/e LHR. The objective of this study is to use the pooled data from the 2 TOTAL trials to examine the heterogeneity of the treatment effect by o/e LHR. Despite the strong confounding of the timing of balloon insertion with o/e LHR, we also aim to gain insight into the effect of GA at balloon insertion.

Section snippets

Study design, setting, and procedures

This is a reanalysis of pooled individual participant data from 2 multicenter trials in which women were randomized in a 1:1 ratio (without stratification factors) to either expectant prenatal management or FETO. The patients were recruited between 2008 and 2020 at 14 experienced FETO centers in 11 countries (Supplemental Table 1). Both trials had a group-sequential design with 5 preplanned interim analyses for superiority. The primary endpoint was survival to discharge from the neonatal unit;

Results

Table 1 summarizes the baseline characteristics and endpoints (Supplemental Tables 2 and 3 provide trial-specific results). In fetuses randomized to FETO, survival to discharge from the neonatal unit was 54% compared with 39% in those randomized to expectant management. Supplemental Figure 1 displays the GAs at which balloon insertion was done as a function of the o/e LHR at randomization. The adjusted odds ratio (aOR) of FETO with late balloon insertion for survival to discharge was 1.78 (95%

Principal findings

There are 4 main findings of this individual patient analysis from the 2 TOTAL trials. First, this study suggests that in both moderate and severe lung hypoplasia, FETO has a beneficial effect on the survival to discharge from the NICU. Second, there is some support for a positive additional effect of early insertion. However, caution is required because of considerable uncertainty in the effects and the strong confounding with disease severity. Third, an adverse consequence of FETO is an

Acknowledgments

We thank all the participants and the multidisciplinary teams of all postnatal management centers that make the Tracheal Occlusion To Accelerate Lung growth trials a success.

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    The authors report no conflict of interest.

    The setup of the Tracheal Occlusion To Accelerate Lung growth (TOTAL)-trials was funded by the European Commission through its sixth framework program in Life Sciences & Health (CT2006-37409) and later, by the KU Leuven (Belgium; C32/17/054) (both to J.A.D.), the Wellcome Trust (WT101957) and from the Engineering and Physical Sciences Research Council (NS/A000027/1) of the United Kingdom for the “Image-Guided Intrauterine Minimally Invasive Fetal Diagnosis and Therapy” study (both to J.A.D. and K.H.N.), and the Unité de Recherche Clinique Paris APHP Centre, Université de Paris, France (to A.B.) for data management and monitoring. B.V.C. was supported by Internal Funds KU Leuven (C24M/20/064). The funding sources had no role in the study design; collection, analysis, and interpretation of data; writing of the report; or the decision to submit the article for publication.

    The TOTAL trials were registered at www.clinicaltrials.gov, for the severe trial as ClinicalTrials.gov Identifier: NCT01240057, on November 15, 2010, enrolling the first patient on February 11, 2011 and last on February 16, 2020, and for the moderate trial as ClinicalTrials.gov Identifier: NCT00763737, on October 1, 2008, enrolling the first patient on October 10, 2008 and last on May 2, 2019.

    Cite this article as: Van Calster B, Benachi A, Nicolaides KH, et al. The randomized Tracheal Occlusion To Accelerate Lung growth-trials on fetal surgery for congenital diaphragmatic hernia: reanalysis using pooled data. Am J Obstet Gynecol 2022;226:560.e1-24.

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