Fetoscopic Endoluminal Tracheal Occlusion (FETO) for Severe Left Diaphragmatic Hernia (CDH)

Study Overview
=================
Brief Summary
-----------------
Despite advances in prenatal diagnosis and postnatal therapies, including extracorporeal membrane oxygenation (ECMO), inhaled nitric oxide therapy, and ventilator strategies that minimize ventilator-induced lung injury, morbidity and mortality rates for babies with congenital diaphragmatic hernia (CDH) remain high. The survival relates to the degree of prenatal lung compression and the subsequent impairment of pulmonary function following delivery. Prenatal assessment by ultrasound or magnetic resonance imaging allows to estimate the severity by relating the circumference of the lung contralateral to the hernia to the fetal head circumference lung to head ratio (LHR) and by noting the degree of upward herniation of the liver. Based on the observed to expected lung to head ratio (O/E LHR), prenatally diagnosed congenital diaphragmatic hernia can be prognostically assessed. While overall survival of congenital diaphragmatic hernia is approximately 60%, an O/E LHR <25% is associated with survival between 11-24%. The rationale for fetal therapy in severe congenital diaphragmatic hernia is to restore adequate lung growth for neonatal survival. Prenatal tracheal occlusion obstructs the normal egress of lung fluid during pulmonary development leading to increased lung tissue stretch, increased cell proliferation, and accelerated lung growth. European colleagues have developed intrauterine endoscopic techniques (fetoscopy) to position and remove endoluminal tracheal balloons in utero (fetoscopic endotracheal occlusion = FETO). Recently, the Belgium group published summary results of FETO showing an improved survival in 175 patients with isolated left CDH from 24% to 49%. We hypothesize that FETO can be performed and may increase survival and decrease morbidity when compared to standard prenatal care for the treatment of severe CDH in the most severe group of fetuses with left CDH (O/E LHR < 30%). FETO therapy will be considered in two subgroups: those with and O/E LHR <25% (severe group) and those with an O/E between 25 to <30% (less severe group).

Detailed Description
-----------------
Comprehensive fetal evaluations will be completed at the Johns Hopkins Center for Fetal Therapy to confirm eligibility. This includes an ultrasound, magnetic resonance imaging, a fetal echocardiogram and fetal genetic studies to identify cases with isolated CDH. Participant must be willing to remain under supervision of the Center for Fetal Therapy at the Johns Hopkins Hospital while the fetal airway is occluded. Participants will undergo FETO with standardized preoperative, intraoperative, post-operative care, and delivery. The FETO will be timed between 27+0 to 29+6 weeks gestation for fetuses with an O/E LHR <25% and between 30+0 to 31+6 weeks gestation for fetuses with an O/E LHR between 25% to <30%. Fetal analgesia and immobilization will consist of fentanyl, atropine and vecuronium. A 10 Fr cannula, 1.3 mm fetoscope within a 3.3 mm sheath (Karl Storz, Tuttlingen, Germany), and a detachable balloon occlusion (BALTACCI-BDPE, Balt, Montmorency, France) system will be used. Serial ultrasound measurements of lung volume and LHR will begin within 24-48 hours following surgery and continue weekly. Amniotic fluid level and membrane status will also be monitored at weekly intervals. Ultrasonography for fetal growth will be performed every 4 weeks. All discharged participants and their support person need to remain within 30 minutes of the surgery center until delivery to permit standardized postoperative management. The social worker at the Center for Fetal Therapy will serve as the participant advocate and assist families in identifying subsidized appropriate accommodation as required. Participants will be on modified bed rest for the first 2 weeks post discharge, but subsequently allowed to graduate to moderate activity if the uterus is quiescent. At 34+0 weeks to 34 + 6 weeks, participants will undergo removal of the tracheal balloon. Balloon retrieval can be either by in utero puncture by ultrasound-guided percutaneous needling or fetoscopic retrieval. In the event there is a need for emergent balloon removal prior to 34 weeks due to the development of preterm labor, shortening of the cervix, preterm rupture of membranes, abnormally vigorous lung response, or development of fetal hydrops, delivery by EXIT or cesarean section will be performed. If percutaneous puncture of balloon is unsuccessful prior to delivery, immediate bronchoscopy and establishment of airway will be performed. Maternal corticosteroids (betamethasone 12 mg intramuscularly and repeated once at 24 hours) will be administered 48 hours prior to fetoscopic balloon removal (due to risks of preterm delivery associated with instrumentation) or for impending preterm delivery. Timing for induction of labor at 37 weeks to 39 weeks will depend upon favorable status of the cervix. Cesarean section will be based upon standard obstetrical indications. In regards to postnatal care, a resuscitation team from neonatology and pediatric surgery will be present at delivery. A standardized protocol will be utilized for postnatal care, using lung protection strategy. Continued follow-up of children until age 2 is planned as the current standard of care. These follow-ups may include bronchoscopy, brain imaging, audiology exam, pulmonary function testing, chest radiograph and developmental assessment. The study duration per mother and child will be up to 877 days, with up to 82 days screening, up to 55 days in the intervention phase, and 744 days in delivery and follow-up. Follow-up will be conducted from birth to 24 months of age at which time the study will conclude.

Official Title
-----------------
Study of Fetoscopic Endoluminal Tracheal Occlusion (FETO) in Fetuses With Severe Left Congenital Diaphragmatic Hernia (CDH)

Conditions
-----------------
Congenital Diaphragmatic Hernia

Intervention / Treatment
-----------------
* Device: 11540KE and Balt Goldbal 2 balloon


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Pregnant women age 18 years and older, who are able to consent. Singleton pregnancy. Anatomically and chromosomally normal fetus. Left sided diaphragmatic hernia with liver up. SEVERE pulmonary hypoplasia with O/E LHR < 30%. In patients with O/E LHR 25% to <30%, enrollment prior to gestational age 30 weeks+0 days to 31 weeks+6 days. In patients with O/E LHR <25%, enrollment prior to gestational age 27 weeks+0 days to 29 weeks+6 days. Exclusion Criteria: Pregnant women < 18 years. Maternal contraindication to fetoscopic surgery or severe maternal medical condition in pregnancy. Technical limitations precluding fetoscopic surgery. Women with history of natural rubber latex allergy. Preterm labor, cervix shortened <15 mm within 24 hours prior to the FETO balloon insertion or uterine anomaly strongly predisposing to preterm labor, placenta previa. Diaphragmatic hernia: right-sided or bilateral, major associated anomalies, isolated left-sided with the O/E LHR ≥ 30%.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 11540KE and Balt Goldbal 2 balloon<br>Patients meeting inclusion criteria will receive fetoscopic tracheal occlusion using the fetoscopy sheath 11540 KE and the Balt Goldbal2 detachable balloon. Participants with an O/E LHR <25% (severe group) will have FETO completed at 27 weeks + 0 days to 29 weeks + 6 days gestation. Balloon removal is 4-5 weeks after that. Participants with an O/E LHR 25 to <30% (less severe group) will have FETO completed at 30 weeks + 0 days to 31 weeks + 6 days gestation. Balloon removal is 3 - 4 weeks after that. | Device: 11540KE and Balt Goldbal 2 balloon<br>* Fetoscopic tracheal occlusion will be performed using above devices and reversed after 4-5 weeks.<br>* Other names: BALT COAX delivery catheter (BALTACCIBDPE100);|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Successful balloon insertion and removal | The feasibility of performing the procedure, managing the pregnancy during the period of tracheal occlusion, and removal of the device prior to delivery at Johns Hopkins Hospital. | 4 to 7 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Survival | The neonatal survival of participants receiving FETO expressed as a percentage of the total number of participants undergoing the procedure. | 28 days after delivery | 
| Percentage of lung growth | The percentage of size increase in the contralateral fetal lung as related to the pre-procedure lung size | 4 to 7 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
FETO