Fetal Surgery for Moderate Left Sided Congenital Diaphragmatic Hernia.

NCT00763737 | Completed DMC

• 3 other identifiers: B322200845402008-4634ML4999- B32220084540
• Study Type: interventional
• Target: 196
• Locations: 10 countries
• Sites: 13

Brief Summary

Isolated Congenital Diaphragmatic Hernia (CDH) can be diagnosed in the prenatal period, and remains associated with a 30 % chance of perinatal death and morbidity mainly because of pulmonary hypoplasia and pulmonary hypertension. In addition, in the survivors there is a high rate of morbidity with evidence of bronchopulmonary dysplasia in more than 70% of cases. The risk for these can be predicted prenatally by the ultrasonographic measurement of the observed/expected lung area to head circumference ratio (O/E LHR) which is a measure of pulmonary hypoplasia. Also position of the liver is predictive of outcome. The proposing consortium has developed a prenatal therapeutic approach, which consists of percutaneous fetoscopic endoluminal tracheal occlusion (FETO) with subsequent removal of the balloon. Both procedures are performed percutaneously, there is now experience with more than 150 cases and it has been shown to be safe for the mother. We have witnessed an improvement of survival in fetuses with a predicted chance of survival of less than 30% (referred to as fetuses with severe pulmonary hypoplasia; O/E LHR \<25% and liver herniation) to 55% on average. Also there is an apparent reduction in morbidity with the rate of bronchopulmonary dysplasia decreasing from the estimated rate of more than 70% to less than 40% in the same severity group. Further we have shown that results of FETO are predicted by LHR measurement prior to the procedure, so that better results can be expected in fetuses with larger lung size. Therefore we now aim to offer FETO to fetuses with moderate CDH (=O/E LHR 25-34.9%, irrespective of the liver position as well as O/E LHR 35-44.9% with intrathoracic herniation of the liver). When managed expectantly the estimated rate of postnatal survival is 55%. This trial will test whether temporary fetoscopic tracheal occlusion rather than expectant management during pregnancy, both followed by standardized postnatal management increases survival or decrease oxygen dependency at 6 months of age. The balloon will be placed between 30 and 31+6 weeks, and will be removed between 34 and 34+6 weeks.

Conditions

Congenital Diaphragmatic Hernia; Fetal Surgery; Pulmonary Hypoplasia

Keywords

congenital diaphragmatic hernia; fetal surgery; pulmonary hypoplasia; observed/expected lung to head ratio; liver position; feto; fetoscopic endoluminal tracheal occlusion; standardized neonatal care

Outcome Measures

Primary Outcomes (2)

• Survival at discharge

  at the time of discharge from NICU, approximately 2 months

• Supplemental oxygen at 6 months of age

  at 6 months of age

Secondary Outcomes (16)

• Grading of oxygen dependency

  between 28 and 56 days of life if born >32 weeks; at 36 weeks postmenstrual age if born <32 weeks

• Pulmonary hypertension

  during NICU admission

• Use of extracorporeal membrane oxygenation

  during NICU admission

• Change in O/E LHR after FETO

  prior to unplug

• NICU days

  during NICU admission

Study Arms (2)

FETO

EXPERIMENTAL

prenatal FETO at 30-31+6 weeks and removal at 34-34+6 wks, followed by standardized postnatal care

Procedure: Fetoscopic Endoluminal Tracheal Occlusion

Expectant management

NO INTERVENTION

expectant management during pregnancy followed by standardized neonatal care

Interventions

Fetoscopic Endoluminal Tracheal Occlusion PROCEDURE

prenatal balloon placement at 30-31+6 weeks and removal at 34-34+6 wks

FETO

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients aged 18 years or more, who are able to consent
• Singleton pregnancy
• Anatomically and chromosomally normal fetus
• Left sided diaphragmatic hernia
• Gestation at randomization prior to 31 wks plus 5 d (so that occlusion is done at the latest on 31 wks plus 6 d)
• Estimated to have moderate pulmonary hypoplasia, defined prenatally as:
• O/E LHR 25-34.9% (included; irrespective of the position of the liver)
• O/E LHR 35-44.9% (included) with intrathoracic liver herniation as determined by ultrasound or MRI
• Acceptance of randomization and the consequences for the further management during pregnancy and thereafter.
• The patients must undertake the responsibility for either remaining close to, or at the FETO center, or being able to travel swiftly and within acceptable time interval to the FETO center until the balloon is removed.
• Intended postnatal treatment center must subscribe to suggested guidelines for "standardized postnatal treatment".
• Provide written consent to participate in this RCT

You may not qualify if:

• Maternal contraindication to fetoscopic surgery or severe medical condition in pregnancy that make fetal intervention risk full
• Technical limitations precluding fetoscopic surgery, such as severe maternal obesity, uterine fibroids or potentially others, not anticipated at the time of writing this protocol.
• Preterm labour, cervix shortened (\<15 mm at randomization) or uterine anomaly strongly predisposing to preterm labour, placenta previa
• Patient age less than 18 years
• Psychosocial ineligibility, precluding consent
• Patient refusing randomization or to comply with return to FETO center during the time period the airways are occluded or for elective removal of the balloon

Sponsors & Collaborators

• University Hospital, Gasthuisberg: lead
• King's College Hospital NHS Trust (UK): collaborator
• Hospital Clinic of Barcelona: collaborator
• Hopital Antoine Beclere: collaborator
• Hôpital Necker-Enfants Malades: collaborator
• University Hospital, Bonn: collaborator
• Mater Mothers' Hospital: collaborator
• Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico: collaborator
• Ospedale Pediatrico Bambino Gesù, Rome (IT): collaborator
• Mount Sinai Hospital, Canada: collaborator
• Baylor College of Medicine: collaborator
• The University of Texas Health Science Center, Houston: collaborator
• Medical University of Warsaw: collaborator

Study Sites (13)

Baylor College of Medicine/Texas Children's Hospital

Houston, Texas, 77030, United States

Location

University of Texas Health Science Center

Houston, Texas, 77030, United States

Location

Mater Mother's Hospital

Brisbane, Queensland, 4101, Australia

Location

University Hospitals Leuven

Leuven, 3000, Belgium

Location

Mount Sinai Hospital

Toronto, Ontario, M5G 1X5, Canada

Location

Hôpital Antoine Béclère

Clamart, 92141, France

Location

Hôpital Necker - Enfants Malades

Paris, 75743, France

Location

University Hospital of Bonn

Bonn, 53105, Germany

Location

Ospedale Maggiore Policlinico

Milan, 20122, Italy

Location

Ospedale Pediatrico Bambino Gesù

Rome, 00123, Italy

Location

1st Department of Obstetrics and Gynecology, Medical University of Warsaw

Warsaw, Poland

Location

Hospital Clinic Barcelona

Barcelona, Catalonia, 08028, Spain

Location

King's College Hospital

London, SE5 9RS, United Kingdom

Location

Related Publications (19)

• Jani J, Nicolaides KH, Keller RL, Benachi A, Peralta CF, Favre R, Moreno O, Tibboel D, Lipitz S, Eggink A, Vaast P, Allegaert K, Harrison M, Deprest J; Antenatal-CDH-Registry Group. Observed to expected lung area to head circumference ratio in the prediction of survival in fetuses with isolated diaphragmatic hernia. Ultrasound Obstet Gynecol. 2007 Jul;30(1):67-71. doi: 10.1002/uog.4052.

  PMID: 17587219 BACKGROUND

• Done E, Gucciardo L, Van Mieghem T, Jani J, Cannie M, Van Schoubroeck D, Devlieger R, Catte LD, Klaritsch P, Mayer S, Beck V, Debeer A, Gratacos E, Nicolaides K, Deprest J. Prenatal diagnosis, prediction of outcome and in utero therapy of isolated congenital diaphragmatic hernia. Prenat Diagn. 2008 Jul;28(7):581-91. doi: 10.1002/pd.2033.

  PMID: 18634116 BACKGROUND

• Deprest J, Jani J, Gratacos E, Vandecruys H, Naulaers G, Delgado J, Greenough A, Nicolaides K; FETO Task Group. Fetal intervention for congenital diaphragmatic hernia: the European experience. Semin Perinatol. 2005 Apr;29(2):94-103. doi: 10.1053/j.semperi.2005.04.006.

  PMID: 16050527 BACKGROUND

• Deprest J, Gratacos E, Nicolaides KH; FETO Task Group. Fetoscopic tracheal occlusion (FETO) for severe congenital diaphragmatic hernia: evolution of a technique and preliminary results. Ultrasound Obstet Gynecol. 2004 Aug;24(2):121-6. doi: 10.1002/uog.1711.

  PMID: 15287047 BACKGROUND

• Jani JC, Nicolaides KH, Gratacos E, Valencia CM, Done E, Martinez JM, Gucciardo L, Cruz R, Deprest JA. Severe diaphragmatic hernia treated by fetal endoscopic tracheal occlusion. Ultrasound Obstet Gynecol. 2009 Sep;34(3):304-10. doi: 10.1002/uog.6450.

  PMID: 19658113 BACKGROUND

• Deprest JA, Gratacos E, Nicolaides K, Done E, Van Mieghem T, Gucciardo L, Claus F, Debeer A, Allegaert K, Reiss I, Tibboel D. Changing perspectives on the perinatal management of isolated congenital diaphragmatic hernia in Europe. Clin Perinatol. 2009 Jun;36(2):329-47, ix. doi: 10.1016/j.clp.2009.03.004.

  PMID: 19559323 BACKGROUND

• Deprest JA, Hyett JA, Flake AW, Nicolaides K, Gratacos E. Current controversies in prenatal diagnosis 4: Should fetal surgery be done in all cases of severe diaphragmatic hernia? Prenat Diagn. 2009 Jan;29(1):15-9. doi: 10.1002/pd.2108. No abstract available.

  PMID: 19125386 BACKGROUND

• Gregoir C, Engels AC, Gomez O, DeKoninck P, Lewi L, Gratacos E, Deprest JA. Fertility, pregnancy and gynecological outcomes after fetoscopic surgery for congenital diaphragmatic hernia. Hum Reprod. 2016 Sep;31(9):2024-30. doi: 10.1093/humrep/dew160. Epub 2016 Jul 4.

  PMID: 27378767 BACKGROUND

• Snoek KG, Reiss IK, Greenough A, Capolupo I, Urlesberger B, Wessel L, Storme L, Deprest J, Schaible T, van Heijst A, Tibboel D; CDH EURO Consortium. Standardized Postnatal Management of Infants with Congenital Diaphragmatic Hernia in Europe: The CDH EURO Consortium Consensus - 2015 Update. Neonatology. 2016;110(1):66-74. doi: 10.1159/000444210. Epub 2016 Apr 15.

  PMID: 27077664 BACKGROUND

• Nawapun K, Eastwood MP, Diaz-Cobos D, Jimenez J, Aertsen M, Gomez O, Claus F, Gratacos E, Deprest J. In vivo evidence by magnetic resonance volumetry of a gestational age dependent response to tracheal occlusion for congenital diaphragmatic hernia. Prenat Diagn. 2015 Nov;35(11):1048-56. doi: 10.1002/pd.4642. Epub 2015 Sep 29.

  PMID: 26135752 BACKGROUND

• Deprest J, Brady P, Nicolaides K, Benachi A, Berg C, Vermeesch J, Gardener G, Gratacos E. Prenatal management of the fetus with isolated congenital diaphragmatic hernia in the era of the TOTAL trial. Semin Fetal Neonatal Med. 2014 Dec;19(6):338-48. doi: 10.1016/j.siny.2014.09.006. Epub 2014 Nov 11.

  PMID: 25447987 BACKGROUND

• Done E, Debeer A, Gucciardo L, Van Mieghem T, Lewi P, Devlieger R, De Catte L, Lewi L, Allegaert K, Deprest J. Prediction of neonatal respiratory function and pulmonary hypertension in fetuses with isolated congenital diaphragmatic hernia in the fetal endoscopic tracleal occlusion era: a single-center study. Fetal Diagn Ther. 2015;37(1):24-32. doi: 10.1159/000364805. Epub 2014 Nov 8.

  PMID: 25402437 BACKGROUND

• DeKoninck P, Gomez O, Sandaite I, Richter J, Nawapun K, Eerdekens A, Ramirez JC, Claus F, Gratacos E, Deprest J. Right-sided congenital diaphragmatic hernia in a decade of fetal surgery. BJOG. 2015 Jun;122(7):940-6. doi: 10.1111/1471-0528.13065. Epub 2014 Sep 17.

  PMID: 25227954 BACKGROUND

• Windrim R, Ryan G, Lebouthillier F, Campisi P, Kelly EN, Baud D, Yoo SJ, Deprest J. Development and use of a high-fidelity simulator for fetal endotracheal balloon occlusion (FETO) insertion and removal. Prenat Diagn. 2014 Feb;34(2):180-4. doi: 10.1002/pd.4284. Epub 2013 Dec 27.

  PMID: 24284906 BACKGROUND

• Engels AC, DeKoninck P, van der Merwe JL, Van Mieghem T, Stevens P, Power B, Nicolaides KH, Gratacos E, Deprest JA. Does website-based information add any value in counseling mothers expecting a baby with severe congenital diaphragmatic hernia? Prenat Diagn. 2013 Nov;33(11):1027-32. doi: 10.1002/pd.4190. Epub 2013 Aug 29.

  PMID: 23813901 BACKGROUND

• Dekoninck P, Gratacos E, Van Mieghem T, Richter J, Lewi P, Ancel AM, Allegaert K, Nicolaides K, Deprest J. Results of fetal endoscopic tracheal occlusion for congenital diaphragmatic hernia and the set up of the randomized controlled TOTAL trial. Early Hum Dev. 2011 Sep;87(9):619-24. doi: 10.1016/j.earlhumdev.2011.08.001.

  PMID: 21907109 BACKGROUND

• Deprest J, Flake A. How should fetal surgery for congenital diaphragmatic hernia be implemented in the post-TOTAL trial era: A discussion. Prenat Diagn. 2022 Mar;42(3):301-309. doi: 10.1002/pd.6091. Epub 2022 Jan 22.

  PMID: 35032132 DERIVED

• Van Calster B, Benachi A, Nicolaides KH, Gratacos E, Berg C, Persico N, Gardener GJ, Belfort M, Ville Y, Ryan G, Johnson A, Sago H, Kosinski P, Bagolan P, Van Mieghem T, DeKoninck PLJ, Russo FM, Hooper SB, Deprest JA. The randomized Tracheal Occlusion To Accelerate Lung growth (TOTAL)-trials on fetal surgery for congenital diaphragmatic hernia: reanalysis using pooled data. Am J Obstet Gynecol. 2022 Apr;226(4):560.e1-560.e24. doi: 10.1016/j.ajog.2021.11.1351. Epub 2021 Nov 19.

  PMID: 34808130 DERIVED

• Deprest JA, Benachi A, Gratacos E, Nicolaides KH, Berg C, Persico N, Belfort M, Gardener GJ, Ville Y, Johnson A, Morini F, Wielgos M, Van Calster B, DeKoninck PLJ; TOTAL Trial for Moderate Hypoplasia Investigators. Randomized Trial of Fetal Surgery for Moderate Left Diaphragmatic Hernia. N Engl J Med. 2021 Jul 8;385(2):119-129. doi: 10.1056/NEJMoa2026983. Epub 2021 Jun 8.

  PMID: 34106555 DERIVED

Related Links

• website on prenatal diagnosis and management of CDH of the FETO consortium
• website of this trial on prenatal management of CDH
• same as www.euroCDH.org
• same as totaltrial.eu

MeSH Terms

Conditions

Hernias, Diaphragmatic, Congenital

Condition Hierarchy (Ancestors)

Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Hernia, Diaphragmatic; Internal Hernia; Hernia; Pathological Conditions, Anatomical; Pathological Conditions, Signs and Symptoms

Study Officials

• Jan A Deprest, MD PhD

  Universitaire Ziekenhuizen KU Leuven

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Jan Deprest, MD PhD, Professor in Obstetrics and Gynaecology

Study Record Dates

• First Submitted: September 30, 2008
• First Posted: October 1, 2008
• Study Start: August 1, 2010
• Primary Completion: March 1, 2020
• Study Completion: March 1, 2020
• Last Updated: December 3, 2020

Record last verified: 2020-11

Locations

ES (1); AU (1); IT (2); US (2); CA (1); FR (2); GB (1); BE (1); DE (1); PL (1)