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Original ArticleFree Preview

Randomized Trial of Fetal Surgery for Severe Left Diaphragmatic Hernia

List of authors.
  • Jan A. Deprest, M.D., Ph.D.,
  • Kypros H. Nicolaides, M.D.,
  • Alexandra Benachi, M.D., Ph.D.,
  • Eduard Gratacos, M.D., Ph.D.,
  • Greg Ryan, M.D.,
  • Nicola Persico, M.D., Ph.D.,
  • Haruhiko Sago, M.D., Ph.D.,
  • Anthony Johnson, M.D.,
  • Miros?aw Wielgo?, M.D., Ph.D.,
  • Christoph Berg, M.D., Ph.D.,
  • Ben Van Calster, Ph.D.,
  • and Francesca M. Russo, M.D., Ph.D.
  • for the TOTAL Trial for Severe Hypoplasia Investigators*

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.)

Funding and Disclosures

Supported by a grant (EuroSTEC FP6-LIFESCIHEALTH CT 2006-37409, to Dr. Deprest) from the European Commission for the initial trial setup; a grant (C32/17/054, to Dr. Deprest) from KU Leuven; grants (WT101957) from the Wellcome Trust and (NS/A000027/1) from the Engineering and Physical Sciences Research Council of the United Kingdom for the Image-Guided Intrauterine Minimally Invasive Fetal Diagnosis and Therapy study (both to Drs. Deprest and Nicolaides); and grants (to Dr. Benachi) from the Unit de Recherche Clinique Paris Assistance PubliqueCH?pitaux de Paris Center, Universit de Paris NeckerCCochin, and from Assistance PubliqueCH?pitaux de Paris for data management and monitoring.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

This article was published on June 8, 2021, at NEJM.org.

A data sharing statement provided by the authors is available with the full text of this article at NEJM.org.

Author Affiliations

From the Department of Obstetrics and Gynecology, KU Leuven (J.A.D., F.M.R.) and Academic Department of Development and Regeneration, Biomedical Sciences, University Hospitals KU Leuven, Leuven, Belgium (J.A.D., B.V.C., F.M.R.); Kings College Hospital (K.H.N.) and the Institute for Womens Health, University College London Hospital (J.A.D.) both in London; Hospital AntoineCBclre, Universit ParisCSaclay, Clamart, France (A.B.); Hospital Clinic and Sant Joan de Du, Barcelona (E.G.); Mount Sinai Hospital, Toronto (G.R.); Hospital Maggiore Policlinico, Milan (N.P.); the National Center for Child Health and Development, Tokyo (H.S.); Childrens Memorial Hermann Hospital, Houston (A.J.); the Medical University of Warsaw, Warsaw, Poland (M.W.); and University Hospital Bonn, Bonn, Germany (C.B.).

Address reprint requests to Dr. Deprest at the Academic Department of Obstetrics and Gynecology, University Hospitals KU Leuven, and Department of Development and Regeneration, Biomedical Sciences, KU Leuven, Herestraat 49, B-3000 Leuven, Belgium, or at .

The TOTAL Trial for Severe Hypoplasia Investigators are listed in the Supplementary Appendix, available at NEJM.org.