Randomized Trial of Fetal Surgery for Moderate Left Diaphragmatic Hernia

Jan A Deprest, Alexandra Benachi, Eduard Gratacos, Kypros H Nicolaides, Christoph Berg, Nicola Persico, Michael Belfort, Glenn J Gardener, Yves Ville, Anthony Johnson, Francesco Morini, Mirosław Wielgoś, Ben Van Calster, Philip L J DeKoninck, TOTAL Trial for Moderate Hypoplasia Investigators, Jan A Deprest, Alexandra Benachi, Eduard Gratacos, Kypros H Nicolaides, Christoph Berg, Nicola Persico, Michael Belfort, Glenn J Gardener, Yves Ville, Anthony Johnson, Francesco Morini, Miroslaw Wielgos, Ben Van Calster, Philip L J DeKoninck, Paul Lewi, Tim Van Mieghem, Francesca Russo, Hugo Devlieger, Michael Harrison, Francois I Luks, Angélique Rezer, Kris Dierickx, Beverley Power, Dick Tibboel, Thomas Schaible, Laurent Storme, Liesbeth Lewi, Roland Devlieger, Anne Debeer, Herbert De Caluwe, Anne-Gael Cordier, Nolwenn Le Sache, Virginie Fouquet, Jacques Jani, Josep Maria Martinez, Olga Gomez, Rogelio Cruz-Martinez, Africa Pertierra, Ramona Cazacu, Theodore Dassios, Shailesh Patel, Ewelina Litwinska, Brigitte Strizek, Andreas Müller, Andreas Heydweiller, Isabella Fabietti, Fabio Mosca, Ernesto Leva, Alireza A Shamshirsaz, Joseph A Garcia-Prats, Timothy Lee, Scott Petersen, Lucy Cooke, Craig Mcbride, Julien Stirneman, Elsa Kermorvant-Duchemin, Naziha Ken-Dunlop, Mary Austin, Suzanne M Lopez, Kuojen Tsao, Anita Romiti, Irma Capolupo, Laura Valfre, Przemyslaw Kosinski, Pawel Krajewski, Andrzej Kaminski, Mallory Woiski, Willem P de Boode, Horst Daniels-Scharbatke, Jonathan Rosenblatt, Michael Levy, Elisabeth Carricaburu, Franck Perrotin, Antoine Bouissou, Hubert Lardy, Alex J Eggink, Rene M H Wijnen, Loic Sentilhes, Olivier Brissaud, Frederic Lavrand, Philipp Klaritsch, Berndt Urlesberger, Holger Till, Jean-Marie Jouannic, Julia Guilbert, Sabine Irtan, Arthur Foulon, Pierre Tourneux, Philippe Buisson, Jean-Marc Biard, Catheline Hocq, Catherine De Magnée, Guillaume Benoist, Valerie Datin-Dorriere, Thierry Petit, Thierry Rousseau, Stephanie Litzler-Renault, Emmanuel Sapin, Krzysztof Preis, Iwona Janczewska, Andrzej Golebiewski, Veronique Houfflin-Debarge, Dyuti Sharma, Eugenia Antolin Alvarado, Belen Bernardo Atienza, Juan Carlos de Agustín Asensio, Stefan Kane, Rodney Hunt, Peter Muller, Jodie Dodd, Catherine Cord-Udy, Erin E Perrone, Makrina Savvidou, Shu-Ling Chuang, Simon Clarke, Amelie Delabaere, Karen Coste, Maguelonne Pons, Kurt Hecher, Basky Thilaganathan, Nigel Kennea, Bruce Okoye, Katrin Zahn, Christiane Otto, Florent Fuchs, Odile Pidoux, Dominique Forgues, Alexis Maatouk, Mahmoud Rouabah, Jean-Louis Lemelle, Ladislav Krofta, Zbynek Stranak, Michal Rygl, Gwenaelle Le Bouar, Alain Beuchée, Alexis Arnaud, Marie-Noelle Varlet, Caroline Paricio, Fabienne Prieur, Brigitte Heiberg Kahrs, Øystein Drivenes, Nicole Ochsenbein-Kölble, Ueli Möhrlen, Ranjit Akolekar, Shakuntala Kalla, Elke Sleurs, Rezan Abdul-Kadir, Karolina Adam, Margarita Alvarez de la Rosa, Bill Atkinson, Alfred Bacherer, Susan L Baker, Laetitia Begue, Florence Biquard, Christian Briery, Phil Bullen, Maria José Canto Rivera, Frederic Chantraine, Anne Marie Coady, Perrine Coste-Mazeau, Mónica Echevarria Telleria, Alberto Galindo Izquierdo, Ingo Gottschalk, Timothy J Hurley, Lawrence Impey, Yves Jacquemyn, Sangeeta Jain, Frans J C M Klumper, Shlomo Lipitz, Eva López Quesada, Juan Luis Delgado Marin, Jérome Massardier, Ralf Menkhaus, Ana Modroño Blanco, Nicolas Mottet, Eve Mousty, Antonella Nahom, Monica Notermans, Jos Offermans, Juan Parra Roca, Aparna Reddy, Ricardo Rosell Polo, Colete Sparey, Mauricio Tajada Duaso, Pascal Vaast, Ellen Vercammen, Patrizia Vergani, Jan A Deprest, Alexandra Benachi, Eduard Gratacos, Kypros H Nicolaides, Christoph Berg, Nicola Persico, Michael Belfort, Glenn J Gardener, Yves Ville, Anthony Johnson, Francesco Morini, Mirosław Wielgoś, Ben Van Calster, Philip L J DeKoninck, TOTAL Trial for Moderate Hypoplasia Investigators, Jan A Deprest, Alexandra Benachi, Eduard Gratacos, Kypros H Nicolaides, Christoph Berg, Nicola Persico, Michael Belfort, Glenn J Gardener, Yves Ville, Anthony Johnson, Francesco Morini, Miroslaw Wielgos, Ben Van Calster, Philip L J DeKoninck, Paul Lewi, Tim Van Mieghem, Francesca Russo, Hugo Devlieger, Michael Harrison, Francois I Luks, Angélique Rezer, Kris Dierickx, Beverley Power, Dick Tibboel, Thomas Schaible, Laurent Storme, Liesbeth Lewi, Roland Devlieger, Anne Debeer, Herbert De Caluwe, Anne-Gael Cordier, Nolwenn Le Sache, Virginie Fouquet, Jacques Jani, Josep Maria Martinez, Olga Gomez, Rogelio Cruz-Martinez, Africa Pertierra, Ramona Cazacu, Theodore Dassios, Shailesh Patel, Ewelina Litwinska, Brigitte Strizek, Andreas Müller, Andreas Heydweiller, Isabella Fabietti, Fabio Mosca, Ernesto Leva, Alireza A Shamshirsaz, Joseph A Garcia-Prats, Timothy Lee, Scott Petersen, Lucy Cooke, Craig Mcbride, Julien Stirneman, Elsa Kermorvant-Duchemin, Naziha Ken-Dunlop, Mary Austin, Suzanne M Lopez, Kuojen Tsao, Anita Romiti, Irma Capolupo, Laura Valfre, Przemyslaw Kosinski, Pawel Krajewski, Andrzej Kaminski, Mallory Woiski, Willem P de Boode, Horst Daniels-Scharbatke, Jonathan Rosenblatt, Michael Levy, Elisabeth Carricaburu, Franck Perrotin, Antoine Bouissou, Hubert Lardy, Alex J Eggink, Rene M H Wijnen, Loic Sentilhes, Olivier Brissaud, Frederic Lavrand, Philipp Klaritsch, Berndt Urlesberger, Holger Till, Jean-Marie Jouannic, Julia Guilbert, Sabine Irtan, Arthur Foulon, Pierre Tourneux, Philippe Buisson, Jean-Marc Biard, Catheline Hocq, Catherine De Magnée, Guillaume Benoist, Valerie Datin-Dorriere, Thierry Petit, Thierry Rousseau, Stephanie Litzler-Renault, Emmanuel Sapin, Krzysztof Preis, Iwona Janczewska, Andrzej Golebiewski, Veronique Houfflin-Debarge, Dyuti Sharma, Eugenia Antolin Alvarado, Belen Bernardo Atienza, Juan Carlos de Agustín Asensio, Stefan Kane, Rodney Hunt, Peter Muller, Jodie Dodd, Catherine Cord-Udy, Erin E Perrone, Makrina Savvidou, Shu-Ling Chuang, Simon Clarke, Amelie Delabaere, Karen Coste, Maguelonne Pons, Kurt Hecher, Basky Thilaganathan, Nigel Kennea, Bruce Okoye, Katrin Zahn, Christiane Otto, Florent Fuchs, Odile Pidoux, Dominique Forgues, Alexis Maatouk, Mahmoud Rouabah, Jean-Louis Lemelle, Ladislav Krofta, Zbynek Stranak, Michal Rygl, Gwenaelle Le Bouar, Alain Beuchée, Alexis Arnaud, Marie-Noelle Varlet, Caroline Paricio, Fabienne Prieur, Brigitte Heiberg Kahrs, Øystein Drivenes, Nicole Ochsenbein-Kölble, Ueli Möhrlen, Ranjit Akolekar, Shakuntala Kalla, Elke Sleurs, Rezan Abdul-Kadir, Karolina Adam, Margarita Alvarez de la Rosa, Bill Atkinson, Alfred Bacherer, Susan L Baker, Laetitia Begue, Florence Biquard, Christian Briery, Phil Bullen, Maria José Canto Rivera, Frederic Chantraine, Anne Marie Coady, Perrine Coste-Mazeau, Mónica Echevarria Telleria, Alberto Galindo Izquierdo, Ingo Gottschalk, Timothy J Hurley, Lawrence Impey, Yves Jacquemyn, Sangeeta Jain, Frans J C M Klumper, Shlomo Lipitz, Eva López Quesada, Juan Luis Delgado Marin, Jérome Massardier, Ralf Menkhaus, Ana Modroño Blanco, Nicolas Mottet, Eve Mousty, Antonella Nahom, Monica Notermans, Jos Offermans, Juan Parra Roca, Aparna Reddy, Ricardo Rosell Polo, Colete Sparey, Mauricio Tajada Duaso, Pascal Vaast, Ellen Vercammen, Patrizia Vergani

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.).

Copyright © 2021 Massachusetts Medical Society.

Figures

Figure 1. Screening, Randomization, and Analysis.
Figure 1. Screening, Randomization, and Analysis.
Among the women who were excluded from the fetoscopic endoluminal tracheal occlusion (FETO) group after inclusion in the intention-to-treat analysis, four chose expectant care and three had contraindications to FETO (one had a short cervix, one had spontaneous membrane rupture, and in one there was an unfavorable fetal position before FETO was attempted). In another participant who was excluded from the FETO group, the fetal mouth was not accessible after trocar insertion into the amniotic cavity, and a balloon was not inserted. Two fetuses had major congenital abnormalities that were diagnosed after randomization (Simpson–Golabi–Behmel syndrome in one fetus and a mutation in the gene encoding filamin A [FLNA] in the other).

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