Randomized Trial of Fetal Surgery for Severe Left Diaphragmatic Hernia

Abstract

BACKGROUNDObservational studies have shown that fetoscopic endoluminal tracheal occlusion (FETO) has been associated with increased survival among infants with severe pulmonary hypoplasia due to isolated congenital diaphragmatic hernia on the left side, but data from randomized trials are lacking. METHODSIn this open-label trial conducted at centers with experience in FETO and other types of prenatal surgery, we randomly assigned, in a 1:1 ratio, women carrying singleton fetuses with severe isolated congenital diaphragmatic hernia on the left side to FETO at 27 to 29 weeks of gestation or expectant care. Both treatments were followed by standardized postnatal care. The primary outcome was infant survival to discharge from the neonatal intensive care unit. We used a group-sequential design with five prespecified interim analyses for superiority, with a maximum sample size of 116 women. RESULTSThe trial was stopped early for efficacy after the third interim analysis. In an intention-to-treat analysis that included 80 women, 40% of infants (16 of 40) in the FETO group survived to discharge, as compared with 15% (6 of 40) in the expectant care group (relative risk, 2.67; 95% confidence interval [CI], 1.22 to 6.11; twosided P = 0.009). Survival to 6 months of age was identical to the survival to discharge (relative risk, 2.67; 95% CI, 1.22 to 6.11). The incidence of preterm, prelabor rupture of membranes was higher among women in the FETO group than among those in the expectant care group (47% vs. 11%; relative risk, 4.51; 95% CI, 1.83 to 11.9), as was the incidence of preterm birth (75% vs. 29%; relative risk, 2.59; 95% CI, 1.59 to 4.52). One neonatal death occurred after emergency delivery for placental laceration from fetoscopic balloon removal, and one neonatal death occurred because of failed balloon removal. In an analysis that included 11 additional participants with data that were available after the trial was stopped, survival to discharge was 36% among infants in the FETO group and 14% among those in the expectant care group (relative risk, 2.65; 95% CI, 1.21 to 6.09). CONCLUSIONSIn fetuses with isolated severe congenital diaphragmatic hernia on the left side, FETO performed at 27 to 29 weeks of gestation resulted in a significant benefit over expectant care with respect to survival to discharge, and this benefit was sustained to 6 months of age. FETO increased the risks of preterm, prelabor rupture of membranes and preterm birth. (Funded by the European Commission and others; TOTAL ClinicalTrials.gov number, NCT01240057.

Congenital Diaphragmatic Hernia: Fetal Therapies to Increase Survival Are Only the Beginning

“…Severe Left Diaphragmatic Hernia using fetoscopic endoluminal tracheal occlusion (FETO) for the treatment of severe left diaphragmatic hernia with promising survival outcome. 2 This was a randomized open label trial conducted at specialized centers with experience using FETO and fetal surgery. FETO procedure involves the placement of a balloon in the trachea of the fetus above the carina to occlude the airway and stimulate lung growth including volume and function.…”

Management of Congenital Diaphragmatic Hernia (CDH): Role of Molecular Genetics

“…In addition, pulmonary hypertension (PHT) causes an increase in the right ventricle (RV) after loading, progressively compromising the RV function. Dysfunction and dilation of the RV, in turn, lead to left ventricular (LV) dysfunction, potentially contributing to adverse clinical outcomes [7,65]. Aggarwal et al in fact demonstrated that LV dysfunction was associated with death and negative outcomes, justifying incorporation of echocardiographic indices as prognostic markers of CDH [66].…”

“…Congenital diaphragmatic defects are variable in size encompassing diaphragm agenesis; well-circumscribed defects or "holes"; and, less often, a thinning or undermuscularization of diaphragmatic tissue. Prenatal ultrasound detection is successful in 50% of CDH cases at a mean gestational age of 24 weeks; fetal magnetic resonance imaging (MRI), fetal echocardiography, and three-dimensional ultrasound imaging also play a role in the study of congenital diaphragmatic hernia, including diagnosis, severity stratification, and prognostic prediction [7,8]. The vast majority of neonates with CDH present with cardiorespiratory distress within the first hours or days of life; however, about 5% to 25% of diaphragmatic hernias present beyond the neonatal period (late-presenting CDH), and clinical manifestations may include respiratory or gastrointestinal symptoms, or a combination of both [9][10][11].…”

“…Despite its high impact on neonatal health, pathogenesis and etiology of CDH remain poorly understood. CDH is thought to be multi-factorial, with genetic, environmental, and nutritional factors playing a role [7,12,13]. The involvement of multiple genetic factors is suggested by recent advances in our understanding of the genetic pathways regulating normal diaphragm development and genetic mutations leading to CDH.…”

Prenatal Molecular Hydrogen Administration Ameliorates Several Findings in Nitrofen-Induced Congenital Diaphragmatic Hernia

“…Currently, a clinical trial of fetoscopic endoluminal tracheal occlusion (FETO) as a prenatal intervention for CDH is ongoing [7]. FETO has been shown to improve survival rate by increasing lung volume but has the risk of premature delivery due to fetoscopy [5,8]. Therefore, prenatal medical therapies should be explored as alternatives [9].…”