Randomized Trial of Fetal Surgery for Severe Left Diaphragmatic Hernia

Abstract

Background: Observational 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.

Methods: In 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.

Results: The 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; two-sided 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).

Conclusions: In 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.).

Figure 1. Screening, Randomization, and Analysis.

One participant in the fetoscopic endoluminal tracheal occlusion (FETO) group was excluded from the perprotocol analysis because after the FETO procedure was performed, a diagnosis of tetrasomy 12p was made in the fetus, after which the parents opted for palliative care for the infant after birth. Two participants in the expectant care group who requested termination of pregnancy were excluded from the per-protocol analysis. Overrunning participants were those who had undergone randomization after recruitment of the 80 patients required for the third interim analysis and before the results of that analysis became available and recruitment was concluded.

Figure 2. FETO Procedure.

After the administration of local anesthesia to the mother and administration of medication to the fetus, the fetoscope is inserted into the amniotic cavity, into the fetal mouth, and eventually into the fetal trachea. In the fetal trachea, the catheter, which has been loaded with a balloon, is advanced to position the balloon between the vocal cords and the carina (bottom left). Once inflated, the balloon is detached, and the fetoscope is withdrawn (bottom right). Adapted from a drawing by Myrthe Boymans, University Hospitals KU Leuven, Leuven, Belgium.