Safety and Efficacy of FETO in CDH: a Phase III Trial

Inclusion Criteria:

1. Pregnant women age 18 years and older

2. Singleton pregnancy

3. Normal fetal karyotype with confirmation by culture results, whole exome sequencing (WES), whole genome sequencing (WGS), or chromosomal microarray with non-pathologicvariants. Results by fluorescence in situ hybridization (FISH) will be acceptable ifthe patient is greater than 26 weeks.

4. Gestational age at enrollment is prior to 29 weeks 6 days

5. Liver is intrathoracic

6. Isolated left congenital diaphragmatic hernia (CDH) with observed/expected lung tohead ratio (O/E LHR) of less than 30% at enrollment (18^0 to 29^5 weeks), or:

7. Isolated right CDH with O/E LHR equal to or less than 45% at enrollment (18^0 to 29^5 weeks).

8. Cervical length by transvaginal ultrasound equal to or greater than 20 mm within 24hours of fetoscopic endoluminal tracheal occlusion (FETO) procedure

9. Patient meets psychosocial criteria

10. Informed consent

Exclusion Criteria:

1. Patient is less than 18 years of age

2. Multi-fetal pregnancy

3. History of natural rubber latex allergy

4. Preterm labor, cervix shortened (less than 20 mm at enrollment or within 24 hours ofFETO balloon insertion procedure) or uterine anomaly strongly predisposing topreterm labor, placenta previa

5. Psychosocial ineligibility, precluding consent:

• Inability to reside within 30 minutes of the Children's Hospital ofPhiladelphia (CHOP) and inability to comply with the travel for the follow-uprequirements of the trial

• Patient does not have a support person (e.g. spouse, partner, mother) availableto stay with the patient for the duration of the pregnancy at CHOP

6. Bilateral CDH, isolated left sided CDH with O/E LHR greater than or equal to 30% (measured at 18^0 to 29^5 weeks), isolated right sided CDH with O/E LHR greater than 45% (measured at 180 to 295 weeks), as determined by ultrasound

7. No Liver herniation into thoracic cavity.

8. Additional fetal anomaly by ultrasound, magnetic resonance imaging (MRI), orechocardiogram at the fetal treatment center. Exclude chromosomal abnormalities,associated anomalies recognized to alter survival prognosis (ie. CDH and congenitalheart disease) or presence of an underlying genetic syndrome (ie. Fryns). No caseswill be removed post hoc if abnormalities are discovered in the course ofpost-operative monitoring.

9. Maternal contraindication to fetoscopic surgery or severe maternal medical conditionin pregnancy

10. History of incompetent cervix with or without cerclage

11. Placental abnormalities (previa, abruption, accrete) known at time of enrollment.

12. Maternal-fetal Rh isoimmunization, Kell sensitization or neonatal alloimmunethrombocytopenia affecting the current pregnancy.

13. Maternal HIV, Hepatitis-B, Hepatitis-C status positive because of the increased riskof transmission to the fetus during maternal-fetal surgery. If the patient's HIV orHepatitis status is unknown, the patient must be tested and found to have negativeresults before enrollment.

14. Uterine anomaly such as large or multiple fibroids or mullerian duct abnormality

15. There is no safe or technically feasible fetoscopic approach to balloon placement.

16. Participation in another intervention study that influences maternal and fetalmorbidity and mortality or participation in this trial in a previous pregnancy.