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%.2AJOG 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.