Fetal Endotracheal Occlusion (FETO) in the Resolution of Pulmonary Hypertension in Fetuses With Severe CDH

Study Overview
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Brief Summary
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Congenital diaphragmatic hernia (CDH) occurs when the diaphragm fails to fully fuse and leaves a portal through which abdominal structures can migrate into the thorax. In the more severe cases, the abdominal structures remain in the thoracic cavity and compromise the development of the lungs. Infants born with this defect have a decreased capacity for gas exchange; mortality rates after birth have been reported between 40-60%. Now that CDH can be accurately diagnosed by mid-gestation, a number of strategies have been developed to repair the hernia and promote lung tissue development. Fetal tracheal occlusion (FETO), using a fetoscopically delivered and removed balloon device, has been used to temporarily occlude the trachea and increase lung distension in CDH to allow the lungs to develop and has been shown to increase survival at birth. The role of FETO in the resolution of pulmonary hypertension in fetuses with severe left- and right- sided CDH remains unclear. Our recent observation that FETO is associated with a higher proportion of infants who resolve their pulmonary hypertension by the age of 1 year as compared with those who have not had FETO, is based on a retrospective cohort study, which, as with any such design, has some intrinsic limitations. Thus, a prospective cohort study that is appropriately powered to confirm or disprove this encouraging observation is needed. If our preliminary observation is confirmed, resolution of PH by the age of 1 year could be added to the benefits of the FETO procedure in severe left and right-sided CDH cases. The investigators will perform 40 FETO procedures on fetuses diagnosed prenatally with severe right- or left-sided CDH, and outcome data will be compared with that of a control group of severe right- or left-sided CDH who will not undergo the FETO procedure because of medical or social issues. Because the prevalence of left-sided CDH is higher than right-side CDH, the investigators will perform 25 FETO procedures in left sided CDH and 15 in right-sided CDH, and these outcomes will be compared to a cohort of 40 non FETO cases.

Detailed Description
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Enrollment Women carrying a fetus with severe CDH and a normal karyotype will undergo routine clinical evaluation. The fetus will be 28+0/7 to 31+6/7 weeks of gestational age and have severe CDH. These patients will have ultrasound and/or MRI evaluation to rule out other anomalies, calculation of the LHR from ultrasound measurements, calculation of observed/expected total lung volume and percentage of liver herniation from fetal MRI studies, echocardiography, and detailed obstetric/perinatal consultation. Patients who meet the eligibility criteria will be extensively counseled, and those who wish to participate will provide written, informed consent for the study. Procedure The procedure will be performed under spinal anesthesia or local anesthesia with intravenous sedation. The technique of fetal endoscopic tracheal occlusion has been described. Using standard technique, a cannula will be inserted into the amniotic cavity and a fetoscope or flexible operating endoscope will be passed through the cannula into the amniotic fluid. If, upon evaluation, the fetal trachea cannot be entered as described above, the uterus will be accessed through an incision in the belly (called a laparotomy). A laparotomy is a surgical technique tin which an incision is made in the abdomen. After the incision has been made, the uterus will be temporarily repositioned externally. The baby will then be accessed using the fetoscope and ultrasound, as described above. The laparotomy will only be performed if the baby cannot be reached and repositioned to a more favorable one by doing external maneuvers (called external version) for the FETO procedure. The scope will be guided into the fetal larynx, and then through the fetal vocal cords with the aid of both direct vision through the scope and cross-sectional ultrasonographic visualization. A detachable latex balloon will be placed in the fetal trachea midway between the carina and the vocal cords. The balloon will be inflated with isosmotic contrast material so that it fills the fetal trachea. Postoperative The mothers will be discharged once stable. Serial measurements of sonographic lung volume and LHR will begin within 24-48 hours following surgery and continue weekly by targeted ultrasound evaluation. Amniotic fluid level and membrane status will also be monitored at weekly intervals. Comprehensive ultrasonography for fetal growth will be performed every four weeks (+/- 1 wk). All discharged patients will stay within 30 minutes of TCH to permit standardized postoperative management and emergent retrieval of the balloon in the event of preterm labor or premature rupture of membranes prior to the scheduled removal. After the FETO surgery, prior to leaving the hospital, the mother will be given a medical alert bracelet identifying her as a patient with a baby with blocked airways. She will be encouraged to wear the bracelet at all times so that in case of emergency, she and others will know who to contact. She will also be given a pamphlet with instructions for medical personnel describing how to remove the balloon in case of an emergency. She should carry it with her at all times. Balloon retrieval will be planned for no later than 36+6/7 weeks, at the discretion of the FETO center. The patient will need to commit to remaining in 30 minutes of Texas Children's Hospital Pavilion for Women until the balloon is retrieved. In the event of a patient relocating after having the balloon placed, despite having committed to remain in the area during consent process, she will be asked to return for the removal. Every effort to make arrangements for her to be managed by the nearest center capable of an EXIT procedure or balloon retrieval will be made. After removal of the balloon, patients will have the choice of delivering at Texas Children's Hospital - Women's Pavilion with the CDH managed and repaired at TCH, or returning to their obstetrician for delivery with subsequent repair of the CDH by the pediatric surgeons at their referring facility. Given the severity of the CDH, the baby will need to be delivered in a facility that has the capability of immediate pediatric surgery services. The investigators will need to monitor the baby at regular intervals (at 6 weeks, 3 months, 6 months, 1 year, and 2 years) after delivery to see how well the baby is breathing and how well the baby is developing. These check - ups may be at Texas Children's Hospital - Pavilion for Women or can be coordinated with doctors from the hospital of the participant's choosing. If the child continues care at another institution, the investigators will attempt to follow up with a review of the child's medical records.

Official Title
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A Prospective Study on the Role of Fetal Endotracheal Occlusion (FETO) in the Resolution of Pulmonary Hypertension Among Fetuses With Severe Congenital Diaphragmatic Hernia

Conditions
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Congenital Diaphragmatic Hernia

Intervention / Treatment
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* Device: Goldbal Detachable Balloon and delivery microcatheter


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient is a pregnant woman between 18 and 45 years of age Singleton pregnancy The fetuses will be 28+0/7 to 31+6/7 weeks of gestational age Confirmed diagnosis of severe left- or right-sided CDH of the fetus: Observed/expected total lung volume equal to or less than 0.32 with more than 21% of liver herniated into the hemithorax. (Ideally calculated between 28+0/7 and 31+6/7 weeks' gestation.) Normal fetal echocardiogram or echocardiogram with a minor anomaly (such a small VSD) that in the opinion of the pediatric cardiologist will not affect postnatal outcome Normal fetal karyotype or microarray The mother must be healthy enough to have surgery Patient and father of the baby provide signed informed consent that details the maternal and fetal risks involved with the procedure Patient willing to remain in Houston for the duration following balloon placement until delivery. Exclusion Criteria: Contraindication to abdominal surgery, fetoscopic surgery, or general anesthesia Allergy to latex Allergy or previous adverse reaction to a study medication specified in this protocol Preterm labor, preeclampsia, or uterine anomaly (e.g., large fibroid tumor) in the index pregnancy. Fetal aneuploidy, known structural genomic variants, other major fetal anomalies that may impact the fetal/neonatal survival or known syndromic mutation Suspicion of major recognized syndrome (e.g. Fryns syndrome) on ultrasound or MRI Maternal BMI >40 High risk for fetal hemophilia

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: The investigators will perform 40 FETO procedures on fetuses diagnosed prenatally with severe right- or left-sided CDH and outcome data will be compared with that of a control group of severe right- or left-sided CDH who will not undergo the FETO procedure because of medical or social issues. Because the prevalence of left-sided CDH is higher than right-side CDH, the investigators will perform 25 FETO procedures in left sided CDH and 15 in right-sided CDH, whose outcomes will be compared to a cohort of 40 non FETO cases. The control group will consist of patients who fit the same fetal inclusion/exclusion criteria as our FETO subjects, and will be matched by variables including maternal age, body mass index, gestational age, severity of CDH and site of CDH (left- or right-sided).
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Fetal Endotracheal Occlusion (FETO)<br>Placement and retrieval of the GoldBAL4 or GoldBAL2 Detachable balloon using the plug/unplug method, using BALTACCIDBPE100 Delivery Catheter. | Device: Goldbal Detachable Balloon and delivery microcatheter<br>* Between 28+0/7 - 31+6/7 weeks gestation for severe CDH placement of the detachable balloon. Balloon retrieval will be planned for no later than 36+6/7 weeks at the discretion of the FETO center.<br>* Other names: BALTACCIBDPE100 delivery microcatheter;|
| No Intervention: non-FETO<br>The control group will consist of patients who did not undergo the FETO procedure who fit the same fetal inclusion/exclusion criteria as our FETO subjects and will be matched by variables including maternal age, body mass index, gestational age, severity of CDH and site of CDH (left- or right-sided). | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Resolution of Pulmonary Hypertension - 6 months | To compare the proportion of fetuses with resolution of PH by the age of 6 months in neonates with severe CDH who underwent the FETO procedure and that of a control group composed of neonates who did not have the FETO procedure. | by the age of 6 months | 
| Resolution of Pulmonary Hypertension - 12 months | To compare the proportion of fetuses with resolution of PH by the age of 12 months in neonates with severe CDH who underwent the FETO procedure and that of a control group composed of neonates who did not have the FETO procedure. | by the age of 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 2-year Survival | To assess two-year neonatal survival following FETO. | 2 years after childbirth | 
| Number of participants who undergo a successful completion of surgical procedures/balloon placement | To assess the successful completion of surgical procedures/placement of balloons in fetuses with severe CDH. Case report forms are utilized to record study related data, including any procedural complications such as failed balloon placement or failed balloon retrieval, as well as surgical or anesthesia complications. At least twice a month fetal surveillance will be performed for up to 10 weeks post balloon placement. | Up to 10 weeks | 
| Maternal Outcomes- Maternal Morbidity-incidence of preterm delivery | Case report forms are utilized to record study related data through patient's medical chart review. Maternal morbidity will be assessed in terms of incidence of preterm delivery (spontaneous or indicated). | Up to 6 weeks postpartum | 
| Maternal Outcomes- Maternal Morbidity-incidence of cesarean section | Case report forms are utilized to record study related data through patient's medical chart review. Maternal morbidity will be assessed in terms of incidence of cesarean section rate. | Up to 6 weeks postpartum | 
| Maternal Outcomes- Maternal Morbidity-length of hospitalization | Case report forms are utilized to record study related data through patient's medical chart review. Maternal morbidity will be assessed in terms of length of hospitalization after the FETO procedure. | Up to 6 weeks postpartum | 
| Maternal Outcomes- Maternal Morbidity- length of hospitalization after UNPLUG procedure | Case report forms are utilized to record study related data through patient's medical chart review. Maternal morbidity will be assessed in terms of length of hospitalization after balloon removal (UNPLUG) | Up to 6 weeks postpartum | 
| Maternal Outcomes- Maternal Morbidity- vaginal bleeding | Case report forms are utilized to record study related data through patient's medical chart review. Maternal morbidity will be assessed in terms of incidence of post procedure vaginal bleeding. | Up to 6 weeks postpartum | 
| Maternal Outcomes- Maternal Morbidity- Placental abruption | Case report forms are utilized to record study related data through patient's medical chart review. Maternal morbidity will be assessed in terms of incidence of post-procedure placental abruption. | Up to 6 weeks postpartum | 
| Maternal Outcomes- Maternal Morbidity- Rupture of membranes | Case report forms are utilized to record study related data through patient's medical chart review. Maternal morbidity will be assessed in terms of incidence of post-procedure rupture of membranes. Amniotic fluid level and membrane status will also be monitored at weekly intervals by ultrasonography. | Up to 6 weeks postpartum | 
| Maternal Outcomes- Maternal Morbidity- oligohydramnios | Case report forms are utilized to record study related data through patient's medical chart review. Maternal morbidity will be assessed in terms of incidence of post-procedure oligohydramnios.Amniotic fluid level and membrane status will also be monitored at weekly intervals by ultrasonography. | Up to 6 weeks postpartum | 
| Maternal Outcomes- Maternal Morbidity- chorioamnionitis | Case report forms are utilized to record study related data through patient's medical chart review. Maternal morbidity will be assessed in terms of incidence of post-procedure chorioamnionitis. | Up to 6 weeks postpartum | 
| Neonatal/Child outcomes- Pulmonary Morbidity - Number of babies that require ECMO | Case report forms are utilized to record study related data through patient's medical chart. Short-term measures of neonatal pulmonary morbidity, including the need for extracorporeal membrane oxygenation. | Up to 2 years of age | 
| Neonatal/Child outcomes- Pulmonary Morbidity- ventilatory support | Case report forms are utilized to record study related data through patient's medical chart. Short-term measures of neonatal pulmonary morbidity, including the duration of neonatal ventilatory support. | Up to 2 years of age | 
| Neonatal/Child outcomes- Pulmonary Morbidity- Number of participants that require the use of supplemental oxygen | Case report forms are utilized to record study related data through patient's medical chart. Short-term measures of neonatal pulmonary morbidity, including the need for administration of supplemental oxygen. | Up to 2 years of age | 
| Neonatal/Child outcomes- gastrointestinal morbidity | Case report forms are utilized to record study related data through patient's medical chart. Short-term measures of gastrointestinal morbidity. | Up to 2 years of age | 
| Neonatal/Child outcomes-neurologic morbidity | Case report forms are utilized to record study related data through patient's medical chart. Short-term measures of neurologic morbidity. | Up to 2 years of age | 
| Neonatal/Child outcomes- Survival to discharge from the hospital | Case report forms are utilized to record study related data through patient's medical chart. Survival to discharge from the hospital. | Up to 2 years of age | 
| Neonatal/Child outcomes- Duration of hospitalization. | Case report forms are utilized to record study related data through patient's medical chart. Duration of hospitalization after delivery. | Up to 2 years of age | 
| Neonatal/Child outcomes- Number of participants that need supplemental oxygen | Case report forms are utilized to record study related data through patient's medical chart. Assessments of measures of long-term morbidity as the need for supplemental oxygen. | Up to 18 years of age | 
| Neonatal/Child outcomes- recurrent infection | Case report forms are utilized to record study related data through patient's medical chart. Assessments of measures of long-term morbidity as the rates of recurrent infection. | Up to 18 years of age | 
| Neonatal/Child outcomes- repeated hospitalization | Case report forms are utilized to record study related data through patient's medical chart. Assessments measures of long-term morbidity as the need for repeated hospitalization. A general health questionnaire will also be given in the form of an interview, either face to face or over the phone. The questionnaire contains questions regarding the children's health status; including hospitalizations, medications, surgical procedures, medical interventions and additional therapies he/she is receiving, and questions to evaluate his/her behavioral and social development. | Up to 18 years of age | 
| Neonatal/Child outcomes- Neurodevelopmental | Developmental Profile 3 (DP-3) questionnaire will be utilized to record study related data. Assessments of neurodevelopmental outcomes. | Up to 18 years of age | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Fetal Tracheal Occlusion, FETO plug-unplug, Goldvalve balloon, Severe Congenital Diaphragmatic Hernia, Goldbal balloon, FETO