Randomized Trial of Fetal Surgery for Severe Left Diaphragmatic Hernia

Jan A Deprest, Kypros H Nicolaides, Alexandra Benachi, Eduard Gratacos, Greg Ryan, Nicola Persico, Haruhiko Sago, Anthony Johnson, Mirosław Wielgoś, Christoph Berg, Ben Van Calster, Francesca M Russo, TOTAL Trial for Severe Hypoplasia Investigators, Jan A Deprest, Kypros H Nicolaides, Alexandra Benachi, Eduard Gratacos, Greg Ryan, Nicola Persico, Haruhiko Sago, Anthony Johnson, Miroslaw Wielgos, Christoph Berg, Ben Van Calster, Francesca M Russo, Paul Lewi, Tim Van Mieghem, Philip L J DeKoninck, Hugo Devlieger, Michael Harrison, Francois I Luks, Angélique Rezer, Kris Dierickx, Beverley Power, Dick Tibboel, Thomas Schaible, Laurent Storme, Roland Devlieger, Karel Allegaert, Herbert Decaluwé, Ramona Cazacu, Theodore Dassios, Shailesh Patel, Anne-Gael Cordier, Mostafa Mokhtari, Jérome Nevoux, Joseph Maria Martinez, Olga Gomez, Jordi Prat, Nimrah Abbasi, Karel O'Brien, Priscilla P L Chiu, Isabella Fabietti, Fabio Mosca, Ernesto Leva, Seiji Wada, Yushi Ito, Masayuki Endo, Mary Austin, Suzanne M Lopez, Kuojen Tsao, Przemyslaw Kosinski, Bozena Kociszewska-Najman, Andrzej Kaminski, Brigitte Strizek, Andreas Müller, Andreas Heydweiller, Veronique Houfflin-Debarge, Dyuti Sharma, Alex J Eggink, Rene M H Wijnen, Nicolas Sananes, Pierre Kuhn, François Becmeur, Basky Thilaganathan, Nigel Kennea, Bruce Okoye, Mallory Woiski, Willem P de Boode, Horst Daniels-Scharbatke, Anita Romiti, Irma Capolupo, Laura Valfre, Jean-Marc Biard, Catheline Hocq, Catherine de Magnée, Nicole Ochsenbein-Kölble, Ueli Möhrlen, Florent Fuchs, Odile Pidoux, Dominique Forgues, Lucie Morin, Anne-Monique Nuyt, Dickens St Vil, Jerome Massardier, Sebastien Blanc, Frederic Hameury, Amelie Delabaere, Karen Coste, Maguelonne Pons, Marion Groussolles, Marie-Odile Marcoux, Olivier Abbo, Jean-Marie Jouannic, Julia Guilbert, Sabine Irtan, Jonathan Rosenblatt, Michael Levy, Elisabeth Carricaburu, Ranjit Akolekar, Jacqueline Bamfo, Jennifer Brewster, Sarah Chissel, Simona Cicero, Kelly Cohen, Mark Denbow, Elena Greco, Lawrence Impey, Tomomi Kotani, Pranav Pandya, Nicky Roberts, Mandeep Singh, Stephen Sturgiss, Devi Subramanian, Noriaki Usui, Inge Van Kamp, Christine Willekes, Pensee Wu, Jan A Deprest, Kypros H Nicolaides, Alexandra Benachi, Eduard Gratacos, Greg Ryan, Nicola Persico, Haruhiko Sago, Anthony Johnson, Mirosław Wielgoś, Christoph Berg, Ben Van Calster, Francesca M Russo, TOTAL Trial for Severe Hypoplasia Investigators, Jan A Deprest, Kypros H Nicolaides, Alexandra Benachi, Eduard Gratacos, Greg Ryan, Nicola Persico, Haruhiko Sago, Anthony Johnson, Miroslaw Wielgos, Christoph Berg, Ben Van Calster, Francesca M Russo, Paul Lewi, Tim Van Mieghem, Philip L J DeKoninck, Hugo Devlieger, Michael Harrison, Francois I Luks, Angélique Rezer, Kris Dierickx, Beverley Power, Dick Tibboel, Thomas Schaible, Laurent Storme, Roland Devlieger, Karel Allegaert, Herbert Decaluwé, Ramona Cazacu, Theodore Dassios, Shailesh Patel, Anne-Gael Cordier, Mostafa Mokhtari, Jérome Nevoux, Joseph Maria Martinez, Olga Gomez, Jordi Prat, Nimrah Abbasi, Karel O'Brien, Priscilla P L Chiu, Isabella Fabietti, Fabio Mosca, Ernesto Leva, Seiji Wada, Yushi Ito, Masayuki Endo, Mary Austin, Suzanne M Lopez, Kuojen Tsao, Przemyslaw Kosinski, Bozena Kociszewska-Najman, Andrzej Kaminski, Brigitte Strizek, Andreas Müller, Andreas Heydweiller, Veronique Houfflin-Debarge, Dyuti Sharma, Alex J Eggink, Rene M H Wijnen, Nicolas Sananes, Pierre Kuhn, François Becmeur, Basky Thilaganathan, Nigel Kennea, Bruce Okoye, Mallory Woiski, Willem P de Boode, Horst Daniels-Scharbatke, Anita Romiti, Irma Capolupo, Laura Valfre, Jean-Marc Biard, Catheline Hocq, Catherine de Magnée, Nicole Ochsenbein-Kölble, Ueli Möhrlen, Florent Fuchs, Odile Pidoux, Dominique Forgues, Lucie Morin, Anne-Monique Nuyt, Dickens St Vil, Jerome Massardier, Sebastien Blanc, Frederic Hameury, Amelie Delabaere, Karen Coste, Maguelonne Pons, Marion Groussolles, Marie-Odile Marcoux, Olivier Abbo, Jean-Marie Jouannic, Julia Guilbert, Sabine Irtan, Jonathan Rosenblatt, Michael Levy, Elisabeth Carricaburu, Ranjit Akolekar, Jacqueline Bamfo, Jennifer Brewster, Sarah Chissel, Simona Cicero, Kelly Cohen, Mark Denbow, Elena Greco, Lawrence Impey, Tomomi Kotani, Pranav Pandya, Nicky Roberts, Mandeep Singh, Stephen Sturgiss, Devi Subramanian, Noriaki Usui, Inge Van Kamp, Christine Willekes, Pensee Wu

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.).

Conflict of interest statement

No potential conflict of interest relevant to this article was reported.

Copyright © 2021 Massachusetts Medical Society.

Figures

Figure 1. Screening, Randomization, and Analysis.
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.
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.

References

    1. Dolk H, Loane M, Garne E. The prevalence of congenital anomalies in Europe. Adv Exp Med Biol. 2010;686:349–64.
    1. Langham MR, Jr, Kays DW, Ledbetter DJ, Frentzen B, Sanford LL, Richards DS. Congenital diaphragmatic hernia: epidemiology and outcome. Clin Perinatol. 1996;23:671–88.
    1. Ameis D, Khoshgoo N, Keijzer R. Abnormal lung development in congenital diaphragmatic hernia. Semin Pediatr Surg. 2017;26:123–8.
    1. Harting MT, Lally KP. The Congenital Diaphragmatic Hernia Study Group registry update. Semin Fetal Neonatal Med. 2014;19:370–5.
    1. American Academy of Pediatrics Section on Surgery, American Academy of Pediatrics Committee on Fetus and Newborn. Lally KP, Engle W. Postdischarge follow-up of infants with congenital diaphragmatic hernia. Pediatrics. 2008;121:627–32.
    1. Raval MV, Wang X, Reynolds M, Fischer AC. Costs of congenital diaphragmatic hernia repair in the United States — extracorporeal membrane oxygenation foots the bill. J Pediatr Surg. 2011;46:617–24.
    1. Metkus AP, Filly RA, Stringer MD, Harrison MR, Adzick NS. Sonographic predictors of survival in fetal diaphragmatic hernia. J Pediatr Surg. 1996;31:148–52.
    1. Jani J, Nicolaides KH, Keller RL, et al. Observed to expected lung area to head circumference ratio in the prediction of survival in fetuses with isolated diaphragmatic hernia. Ultrasound Obstet Gynecol. 2007;30:67–71.
    1. Done E, Debeer A, Gucciardo L, et al. Prediction of neonatal respiratory function and pulmonary hypertension in fetuses with isolated congenital diaphragmatic hernia in the fetal endoscopic tracheal occlusion era: a single-center study. Fetal Diagn Ther. 2015;37:24–32.
    1. Jani JC, Benachi A, Nicolaides KH, et al. Prenatal prediction of neonatal morbidity in survivors with congenital diaphragmatic hernia: a multicenter study. Ultrasound Obstet Gynecol. 2009;33:64–9.
    1. Doné E, Gratacos E, Nicolaides KH, et al. Predictors of neonatal morbidity in fetuses with severe isolated congenital diaphragmatic hernia undergoing fetoscopic tracheal occlusion. Ultrasound Obstet Gynecol. 2013;42:77–83.
    1. Wilson JM, DiFiore JW, Peters CA. Experimental fetal tracheal ligation prevents the pulmonary hypoplasia associated with fetal nephrectomy: possible application for congenital diaphragmatic hernia. J Pediatr Surg. 1993;28:1433–40.
    1. Khan PA, Cloutier M, Piedboeuf B. Tracheal occlusion: a review of obstructing fetal lungs to make them grow and mature. Am J Med Genet C Semin Med Genet. 2007;145C:125–38.
    1. Evrard VA, Verbeken EA, Vandenberghe K, Lerut T, Flageole H, Deprest JA. Endoscopic in utero tracheal plugging in the fetal lamb to treat congenital diaphragmatic hernia. J Am Assoc Gynecol Laparosc. 1996;3(Suppl):S11.
    1. Benachi A, Dommergues M, Delezoide AL, Bourbon J, Dumez Y, Brunnelle F. Tracheal obstruction in experimental diaphragmatic hernia: an endoscopic approach in the fetal lamb. Prenat Diagn. 1997;17:629–34.
    1. Davey M, Shegu S, Danzer E, et al. Pulmonary arteriole muscularization in lambs with diaphragmatic hernia after combined tracheal occlusion/glucocorticoid therapy. Am J Obstet Gynecol. 2007;197(4):381.e1–381.e7.
    1. Flageole H, Evrard VA, Piedboeuf B, Laberge JM, Lerut TE, Deprest JA. The plug-unplug sequence: an important step to achieve type II pneumocyte maturation in the fetal lamb model. J Pediatr Surg. 1998;33:299–303.
    1. Flake AW, Crombleholme TM, Johnson MP, Howell LJ, Adzick NS. Treatment of severe congenital diaphragmatic hernia by fetal tracheal occlusion: clinical experience with fifteen cases. Am J Obstet Gynecol. 2000;183:1059–66.
    1. Deprest J, Gratacos E, Nicolaides KH. Fetoscopic tracheal occlusion (FETO) for severe congenital diaphragmatic hernia: evolution of a technique and preliminary results. Ultrasound Obstet Gynecol. 2004;24:121–6.
    1. Jani JC, Nicolaides KH, Gratacós E, et al. Severe diaphragmatic hernia treated by fetal endoscopic tracheal occlusion. Ultrasound Obstet Gynecol. 2009;34:304–10.
    1. Reiss I, Schaible T, van den Hout L, et al. Standardized postnatal management of infants with congenital diaphragmatic hernia in Europe: the CDH EURO Consortium consensus. Neonatology. 2010;98:354–64.
    1. Snoek KG, Reiss IKM, Greenough A, et al. Standardized postnatal management of infants with congenital diaphragmatic hernia in Europe: the CDH EURO Consortium consensus — 2015 update. Neonatology. 2016;110:66–74.
    1. Deprest JA, Benachi A, Gratacos E, et al. Randomized trial of fetal surgery for moderate left diaphragmatic hernia. N Engl J Med. 2021;385:119–29.
    1. Dekoninck P, Gratacos E, Van Mieghem T, et al. Results of fetal endoscopic tracheal occlusion for congenital diaphragmatic hernia and the set up of the randomized controlled TOTAL trial. Early Hum Dev. 2011;87:619–24.
    1. Engels AC, DeKoninck P, van der Merwe JL, et al. Does website-based information add any value in counseling mothers expecting a baby with severe congenital diaphragmatic hernia? Prenat Diagn. 2013;33:1027–32.
    1. Van der Veeken L, Russo FM, De Catte L, et al. Fetoscopic endoluminal tracheal occlusion and reestablishment of fetal airways for congenital diaphragmatic hernia. Gynecol Surg. 2018;15:9.
    1. Jiménez JA, Eixarch E, DeKoninck P, et al. Balloon removal after fetoscopic endoluminal tracheal occlusion for congenital diaphragmatic hernia. Am J Obstet Gynecol. 2017;217(1):78.e1–78.e11.
    1. Moher D, Hopewell S, Schulz KF, et al. CONSORT 2010 explanation and elaboration: updated guidelines for reporting parallel group randomised trials. BMJ. 2010;340:c869.
    1. O’Brien PC, Fleming TR. A multiple testing procedure for clinical trials. Biometrics. 1979;35:549–56.
    1. Dimairo M, Pallmann P, Wason J, et al. The Adaptive designs CONSORT Extension (ACE) statement: a checklist with explanation and elaboration guideline for reporting randomised trials that use an adaptive design. BMJ. 2020;369:m115.
    1. Harrison MR, Keller RL, Hawgood SB, et al. A randomized trial of fetal endoscopic tracheal occlusion for severe fetal congenital diaphragmatic hernia. N Engl J Med. 2003;349:1916–24.
    1. Peralta CFA, Cavoretto P, Csapo B, Vandecruys H, Nicolaides KH. Assessment of lung area in normal fetuses at 12-32 weeks. Ultrasound Obstet Gynecol. 2005;26:718–24.
    1. Ruano R, Yoshisaki CT, da Silva MM, et al. A randomized controlled trial of fetal endoscopic tracheal occlusion versus postnatal management of severe isolated congenital diaphragmatic hernia. Ultrasound Obstet Gynecol. 2012;39:20–7.
    1. Jani JC, Nicolaides KH. Fetal surgery for severe congenital diaphragmatic hernia? Ultrasound Obstet Gynecol. 2012;39:7–9.
    1. Al-Maary J, Eastwood MP, Russo FM, Deprest JA, Keijzer R. Fetal tracheal occlusion for severe pulmonary hypoplasia in isolated congenital diaphragmatic hernia: a systematic review and meta-analysis of survival. Ann Surg. 2016;264:929–33.
    1. Grivell RM, Andersen C, Dodd JM. Prenatal interventions for congenital diaphragmatic hernia for improving outcomes. Cochrane Database Syst Rev. 2015;11:CD008925
    1. Araujo Júnior E, Tonni G, Martins WP, Ruano R. Procedure-related complications and survival following fetoscopic endotracheal occlusion (FETO) for severe congenital diaphragmatic hernia: systematic review and meta-analysis in the FETO era. Eur J Pediatr Surg. 2017;27:297–305.
    1. Alfaraj MA, Shah PS, Bohn D, et al. Congenital diaphragmatic hernia: lung-to-head ratio and lung volume for prediction of outcome. Am J Obstet Gynecol. 2011;205(1):43.e1–43.e8.
    1. Snoek KG, Capolupo I, van Rosmalen J, et al. Conventional mechanical ventilation versus high-frequency oscillatory ventilation for congenital diaphragmatic hernia: a randomized clinical trial (the VICI-trial) Ann Surg. 2016;263:867–74.
    1. Gregoir C, Engels AC, Gomez O, et al. Fertility, pregnancy and gynecological outcomes after fetoscopic surgery for congenital diaphragmatic hernia. Hum Reprod. 2016;31:2024–30.
    1. Sacco A, Van der Veeken L, Bagshaw E, et al. Maternal complications following open and fetoscopic fetal surgery: a systematic review and meta-analysis. Prenat Diagn. 2019;39:251–68.

Source: PubMed

Sponsors et collaborateurs

Les conditions médicales

Interventions en matière de drogue

3
S'abonner