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Original ArticleFree Preview

Randomized Trial of Fetal Surgery for Moderate Left Diaphragmatic Hernia

List of authors.
  • Jan A. Deprest, M.D., Ph.D.,
  • Alexandra Benachi, M.D., Ph.D.,
  • Eduard Gratacos, M.D., Ph.D.,
  • Kypros H. Nicolaides, M.D.,
  • Christoph Berg, M.D., Ph.D.,
  • Nicola Persico, M.D., Ph.D.,
  • Michael Belfort, M.D., Ph.D.,
  • Glenn J. Gardener, M.D., Ph.D.,
  • Yves Ville, M.D., Ph.D.,
  • Anthony Johnson, M.D.,
  • Francesco Morini, M.D., Ph.D.,
  • Miros?aw Wielgo?, M.D., Ph.D.,
  • Ben Van Calster, Ph.D.,
  • and Philip L.J. DeKoninck, M.D., Ph.D.
  • for the TOTAL Trial for Moderate Hypoplasia Investigators*

Abstract

Background

Fetoscopic endoluminal tracheal occlusion (FETO) has been associated with increased postnatal survival among infants with severe pulmonary hypoplasia due to isolated congenital diaphragmatic hernia on the left side, but data are lacking to inform its effects in infants with moderate disease.

Methods

In this open-label trial conducted at many centers with experience in FETO and other types of prenatal surgery, we randomly assigned, in a 1:1 ratio, women carrying singleton fetuses with a moderate isolated congenital diaphragmatic hernia on the left side to FETO at 30 to 32 weeks of gestation or expectant care. Both treatments were followed by standardized postnatal care. The primary outcomes were infant survival to discharge from a neonatal intensive care unit (NICU) and survival without oxygen supplementation at 6 months of age.

Results

In an intention-to-treat analysis involving 196 women, 62 of 98 infants in the FETO group (63%) and 49 of 98 infants in the expectant care group (50%) survived to discharge (relative risk , 1.27; 95% confidence interval [CI], 0.99 to 1.63; two-sided P=0.06). At 6 months of age, 53 of 98 infants (54%) in the FETO group and 43 of 98 infants (44%) in the expectant care group were alive without oxygen supplementation (relative risk, 1.23; 95% CI, 0.93 to 1.65). The incidence of preterm, prelabor rupture of membranes was higher among women in the FETO group than among those in the expectant care group (44% vs. 12%; relative risk, 3.79; 95% CI, 2.13 to 6.91), as was the incidence of preterm birth (64% vs. 22%, respectively; relative risk, 2.86; 95% CI, 1.94 to 4.34), but FETO was not associated with any other serious maternal complications. There were two spontaneous fetal deaths (one in each group) without obvious cause and one neonatal death that was associated with balloon removal.

Conclusions

This trial involving fetuses with moderate congenital diaphragmatic hernia on the left side did not show a significant benefit of FETO performed at 30 to 32 weeks of gestation over expectant care with respect to survival to discharge or the need for oxygen supplementation at 6 months. FETO increased the risks of preterm, prelabor rupture of membranes and preterm birth. (Funded by the European Commission and others; TOTAL ClinicalTrials.gov number, NCT00763737.)

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, University Hospitals KU Leuven (J.A.D., P.L.J.D.) and Academic Department of Development and Regeneration, Biomedical Sciences, KU Leuven, Leuven, Belgium (J.A.D., B.V.C., P.L.J.D.); Hospital AntoineCBclre, Universit ParisCSaclay, Clamart (A.B.), and NeckerCEnfants Malades Hospital, Paris (Y.V.) both in France; Hospital Clinic and Sant Joan de Du, Barcelona (E.G.); Institute for Womens Health, University College London Hospital (J.A.D.) and Kings College Hospital(K.H.N.) both in London; the University Hospital Bonn, Bonn, Germany (C.B.); Hospital Maggiore Policlinico, Milan (N.P.), and Bambino Ges Childrens Hospital, Rome (F.M.) both in Italy; Baylor College of Medicine and Texas Childrens Hospital (M.B.) and Childrens Memorial Hermann Hospital (A.J.) all in Houston; Mater Mothers Hospital, Brisbane, QLD, Australia (G.J.G.); the Medical University of Warsaw, Warsaw, Poland (M.W.); and Erasmus MCCUniversity Medical Center Rotterdam, Rotterdam, the Netherlands (P.L.J.D.).

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

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