Fetal Endoscopic Tracheal Occlusion (FETO) Trial for Congenital Diaphragmatic Hernia
Phase: NA
Conditions: Congenital Diaphragmatic Hernia
Sponsor: University of California, Davis

PROTOCOL TITLE: Fetal Endoscopic Tracheal Occlusion (FETO) Trial for Congenital 
Diaphragmatic Hernia (CDH) 
 
 
 
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1) Protocol Title 
Fetal Endoscopic Tracheal Occlusion (FETO) Trial for Congenital Diaphragmatic Hernia (CDH) 
Protocol Version Date: 01-08-2021 
2) Objectives 
The purpose of this phase 2 study is to assess the feasibility and safety of treating severe CDH with Fetal 
Endoscopic Tracheal Occlusion at the UC Davis Medical Center. 
Primary Objectives:  
1. Successful placement of the balloon 
2. Successful retrieval of the balloon 
Secondary Objectives:  
1. Fetal lung volume growth on prenatal imaging measured by observed-to-expected total 
fetal lung volume (o/e TFLV)  
2. Fetal lung growth on prenatal ultrasound measured by observed-to-expected lung to 
head ratio (o/e/ LHR) 
3. Full Term Gestational age at delivery 
4. Survival to hospital discharge or up to 180 days of life 
5. Avoid, Limit, or Reduce Maternal complications (preterm labor, preterm rupture of 
membranes (PROM), 
premature 
preterm 
rupture 
of membranes (PPROM), 
oligohydramnios, placental abruption, chorioamniotic separation, chorioamnionitis, and 
other infection) 
 
3) Background 
 
Congenital diaphragmatic hernia (CDH) affects 1 in 2,200 to 5,000 live births per year (1, 2).  The defect 
in the fetal diaphragm allows abdominal organs (intestine, stomach, liver, spleen) to migrate into the 
thorax, hindering normal lung development.  The herniated contents place pressure on the developing 
lungs and this may result in varying degrees of pulmonary hypoplasia and associated pulmonary 
hypertension; both of which may be lethal.  In an attempt to prenatally quantify the impact of the 
herniated organs on underlying lung development, prognostic tools have been developed.  The most 
widely used prognostic indicator is the lung-to-head ratio (LHR) as measured by prenatal ultrasound (3-
5).  The lung contralateral to the diaphragmatic defect is measured in a transverse plane at the level of 
the four-chamber heart and its area is divided by the fetal head circumference (LHR).  The LHR is tracked 
through the pregnancy but seems to be most strongly correlated with outcomes in the early third 
trimester.  An observed-to-expected LHR (o/e LHR) can be calculated and may be more predictive than 
an isolated LHR as this percentage should not change throughout gestation (6).  Fetuses with severe 

PROTOCOL TITLE: Fetal Endoscopic Tracheal Occlusion (FETO) Trial for Congenital 
Diaphragmatic Hernia (CDH) 
 
 
 
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pulmonary hypoplasia (defined as o/e LHR <25%) and those with moderate hypoplasia (o/e LHR 25-
<30%) complicated by liver up in the thorax have survival rates under 30% (7).  
 
Fetal intervention for CDH began in the 1990s with open fetal surgical repair of the diaphragmatic defect 
(8, 9). Open repair of liver-down CDH was successful but found no difference in survival, compared to 
postnatal repair, primarily due to increased rates of prematurity in the fetal repair group and the fact 
that liver-down CDH was less severe and postnatal management improved for this group of patients 
(10).  Refinement in prenatal prognostication revealed that in addition to low LHR, it was the subset of 
liver-up patients that were most severe and the best candidates for fetal surgery. Open repair of liver-up 
CDH was plagued with high risk of fetal death during repair due to kinking of the umbilical vein when the 
liver was acutely reduced (9).  As such, a new prenatal strategy was required for liver-up CDH patients.  
It was noted that patients with congenital high airway obstruction syndrome (CHAOS) had hyperplastic 
lungs due to tracheal occlusion.  This strategy was adapted to treat fetal CDH, and research has shown 
that fetal tracheal occlusion results in fetal lung growth with return of the herniated organs into the 
fetal abdomen (11).  A fetal lamb model of CDH with subsequent tracheal occlusion has demonstrated 
this to be an effective way to improve lung volume as well as functional improvement in the lung (12-
14).  These favorable results in an animal model prompted a clinical translation of fetal tracheal 
occlusion to be used as a prenatal intervention for CDH patients while reducing maternal risks 
associated with open repair. 
 
In the past 20 years since the abandonment of hysterotomy for tracheal clip placement, multiple 
techniques have been attempted (15-18). Multi-port fetoscopic clip placement was abandoned due to 
technique associated morbidity, premature delivery, and the difficulty of removing the tracheal clips to 
establish an airway at the time of delivery (19).  The development of the detachable balloon allows a 
fetoscopic approach, which markedly reduces maternal morbidity, and allows removal of the balloon late 
in gestation prior to the delivery, facilitating establishment of the neonatal airway with limited damage to 
the fetal trachea (20, 21).  The GOLDBAL2 detachable balloon from Balt Extrusion (Montmorency, France) 
is currently being used in the international fetal community with successful balloon placement and 
retrieval for fetal CDH.  However, the impact on survival in CDH is still being evaluated.  International 
studies in different fetal centers have mixed results with some centers showing benefit of FETO for 
improved survival and others showing no benefit (17, 18, 22).  Currently, there is insufficient evidence to 
recommend FETO as the standard of care (23).  Investigations are still ongoing with multiple institutions 
in the United States, Europe, and South America participating in the Tracheal Occlusion to Accelerate Lung 
Growth (TOTAL) trial (ClinicalTrials.gov, NCT01240057).  
 
JUSTIFICATION FOR INVESTIGATION 
 
The Fetal Care and Treatment Center (FCTC) at the UC Davis Medical Center has been offering a range of 
fetal interventions since 2016, including open fetal surgery, fetoscopic fetal surgery, and fetal cardiac 
valvuloplasty and septostomy.  The skill set needed to perform FETO is present with our mature team at 
UC Davis. Dr. Shinjiro Hirose performed and helped develop the FETO procedure with Dr. Michael Harrison 
at UCSF for 11 years.  Additionally, Dr. Hirose has participated in other fetal endoscopic tracheal occlusion 
trials. The remainder of the UC Davis surgery team has experience and training with fetoscopy as well as 

PROTOCOL TITLE: Fetal Endoscopic Tracheal Occlusion (FETO) Trial for Congenital 
Diaphragmatic Hernia (CDH) 
 
 
 
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other surgical procedures involving fetal intervention. To ensure the team is adequately prepared to 
perform the FETO procedure, the team will conduct dry runs in the simulation center, which is done 
routinely before beginning any new procedure. Patients are requesting consideration of this experimental 
treatment with increasing frequency when diagnosed with CDH prenatally. The FCTC team desires to be 
able to offer this procedure to patients that meet criteria.  
 
4) Inclusion and Exclusion Criteria 
 
INCLUSION CRITERIA 
 
In order to be eligible to participate in this study, an individual must meet all of the following criteria: 
1. Provision of signed and dated informed consent form 
2. Stated willingness to comply with all study procedures and availability (meets psychosocial criteria 
below) for the duration of the study  
3. Pregnant women, age 18 years and older 
4. Singleton pregnancy 
5. No pathogenic variants on microarray or pathologic findings on karyotype 
6. Fetal echocardiogram with changes expected with CDH and no major structural cardiac defects 
7. Fetal CDH (left or right) with severe pulmonary hypoplasia, defined as o/e LHR <25% with liver up  
8. Gestational age at FETO procedure:  if o/e LHR <25%  will be done at 27 weeks plus 0 days to 29 
weeks plus 6 days 
9. Meets psychosocial criteria  
● Willing to reside within 30 minutes of UC Davis Medical Center and ability to maintain 
follow up appointments  
● Patient has a support person (e.g. spouse, partner, friend, parent) that is available to stay 
with her for the duration of the pregnancy near the UC Davis Medical Center. 
● Willing to comply with restrictions of daily living including inability to exercise, have 
intercourse, or return to work 
 
EXCLUSION CRITERIA  
 
An individual who meets any of the following criteria will be excluded from participation in this study: 
1. Adults unable to consent 
2. Prisoners 
3. Multi-fetal pregnancy 
4. History of latex allergy 
5. History of preterm labor or incompetent cervix (requiring cerclage), short cervix (<20mm), or 
uterine anomaly predisposing to preterm labor 
6. Psychosocial ineligibility 
● Inability to reside within 30 minutes of UC Davis Medical Center or inability to maintain 
follow up appointments  

PROTOCOL TITLE: Fetal Endoscopic Tracheal Occlusion (FETO) Trial for Congenital 
Diaphragmatic Hernia (CDH) 
 
 
 
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● Social work will meet with each patient to evaluate the social situation and support 
system.  Identifiable issues of social instability or compliance with the protocol will 
exclude her as a potential candidate. 
7. Bilateral CDH, unilateral CDH with o/e LHR > 25% or unilateral CDH with o/e LHR <25%  but liver 
completely down in abdomen  
8. Additional fetal or genetic abnormalities that would impact care after delivery or be known to 
have an impact on outcome  
9. Maternal contraindications to elective fetoscopic surgery 
10. Significant placental abnormalities (abruption, chorioangioma, accreta) known at time of 
enrollment and/or surgery 
11. Maternal isoimmunization or neonatal alloimmune thrombocytopenia 
12. Maternal HIV, Hepatitis B with positive surface antigen, Hepatitis C with presence of virus in 
maternal blood due to risk of fetal transmission during the procedure 
13. No safe or feasible fetoscopic approach to balloon placement   
 
Screen failures are defined as participants who consent to be evaluated for the clinical trial but do not 
meet inclusion and/or exclusion criteria.  A minimal set of screen failure information is required to ensure 
transparent reporting of screen failure participants, to meet the Consolidated Standards of Reporting 
Trials (CONSORT) publishing requirements and to respond to queries from regulatory authorities. Minimal 
information includes demography, screen failure details, eligibility criteria, and any serious adverse event 
(SAE). 
 
STUDY INTERVENTION COMPLIANCE 
Enrolled participants will be expected to reside within 30 minutes of UC Davis Medical Center for the 
remainder of the pregnancy.  They will be expected to maintain weekly follow up appointments while the 
balloon is in place and until delivery.  At each visit, an ultrasound will be done to assess for balloon 
visualization, amniotic fluid volume, and observed-to-expected lung to head ratios (o/e LHRs) as well as 
overall status of the fetus.  Women will need to have a support person (e.g. spouse, partner, friend, 
parent) that is available to stay with her during the duration of the pregnancy and to follow up visits.  She 
will be unable to carry on normal daily activities including exercise and intercourse and would be unable 
to return to work after the balloon was placed until after delivery. Compliance to study restrictions will 
be assessed at each visit via discussion with the patient and her support person.  We will then document 
these responses on an electronic Case Report Form (eCRF). 
 
5) Study Timelines 
 
Study Duration: 
 
48-60 months is estimated to enroll up to 10 patients.  Data will be 
analyzed after delivery of the 10th patient for primary outcomes.  Analysis 
of all secondary outcomes will require that the infants are discharged from 
the hospital or 180 days post-delivery if still hospitalized.   
 
 

PROTOCOL TITLE: Fetal Endoscopic Tracheal Occlusion (FETO) Trial for Congenital 
Diaphragmatic Hernia (CDH) 
 
 
 
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Participant Duration: 
The FETO balloon will ideally be in place 4-8 weeks depending on maternal 
safety for those that meet inclusion criteria.  Mothers will need to 
participate in weekly evaluations during this time and up to delivery.  
Mothers will be followed until their postpartum discharge appointment.  
Infants will be followed through hospital discharge, death, or 180 days of 
life (whichever occurs first).   
 
Study Date Completion 
December 31, 2027 
 
6) Study Endpoints 
Endpoints: 
Primary Endpoints: 
1. Successful placement of the balloon at gestational age 27w0d – 
29w6d; success will be defined as completion with direct visual 
placement above the carina and confirmation on ultrasound done 
during the procedure 
2. Retrieval will ideally be at gestational age of 34w0d + 1 week but 
success will be defined by retrieval prior to delivery, including safe 
retrieval during an ex-utero intrapartum therapy (EXIT) procedure 
 
Secondary Endpoints:  
1. Fetal MRI prior to balloon placement and 2nd fetal MRI at + 2 weeks 
of balloon retrieval 
2. Fetal ultrasound o/e LHR before balloon placement and 
immediately prior to balloon removal 
3. Delivery (preterm) and associated morbidities 
4. Gestational age at delivery 
5. Days neonate is on ventilator 
6. Oxygen dependency at discharge and how much 
7. Type of ECMO needed and how many days  
8. Neonatal discharge from hospital or up to 180 days post-delivery if 
still hospitalized 
9. Maternal postpartum discharge and follow-up to determine 
maternal complications 
 
 
 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR ENDPOINTS 
Primary 
 
 
1. Successful placement of 
the GOLDBAL2 balloon 
1. Placement:  
Gestational 
1. This timing optimizes lung 
growth in the late canalicular 

PROTOCOL TITLE: Fetal Endoscopic Tracheal Occlusion (FETO) Trial for Congenital 
Diaphragmatic Hernia (CDH) 
 
 
 
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2. Successful retrieval of 
GOLDBAL2 balloon 
 
 
 
 
 
age of 27w0d 
– 29w6d 
 
2. Retrieval:  
Gestational 
age of 34w0d 
+ 1 week 
 
 
and early saccular phases of 
fetal lung growth. 
 
2. Removal of the balloon prior 
to delivery is important in 
order to avoid an EXIT 
procedure or airway 
emergency at birth.  Ideally 
this occurs around the 34th 
week of gestation to optimize 
lung growth but have the 
balloon removed prior to 
delivery. Furthermore, studies 
demonstrate enhanced lung 
development when the 
balloon is removed prior to 
birth. 
 
Secondary 
 
 
1. Fetal lung volume growth 
on prenatal MRI 
 
 
 
 
 
 
 
 
 
2. Fetal lung growth on 
prenatal ultrasound 
 
 
 
 
 
 
 
 
 
3. Delivery (preterm) and 
associated morbidities 
1. Fetal MRI 
done prior to 
balloon 
placement 
and again 
done +2 
weeks of 
balloon 
retrieval 
 
 
2. Fetal 
ultrasound 
done before 
balloon 
placement 
and 
immediately 
prior to 
balloon 
retrieval 
 
3. Type of 
delivery and 
1. Fetal MRI will measure the o/e 
TFLV at each MRI.  Fetal lung 
growth (difference between 
1st and 2nd MRIs will be 
calculated).  
 
 
 
 
 
 
2. Prenatal ultrasound will 
measure the o/e LHR at 
weekly visits while the balloon 
is in place.  Fetal lung growth 
will be calculated as the 
difference between the o/e 
LHR pre-balloon placement 
and the o/e LHR immediately 
prior to balloon removal 
 
 
3. Preterm delivery is a known 
risk of the FETO procedure. 

PROTOCOL TITLE: Fetal Endoscopic Tracheal Occlusion (FETO) Trial for Congenital 
Diaphragmatic Hernia (CDH) 
 
 
 
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4. Gestational age at delivery 
 
 
 
 
 
5.  Number of days neonate 
is on ventilator 
 
 
 
 
 
 
 
 
 
6.  Oxygen dependency at 
discharge  
 
 
 
 
 
 
 
 
7. ECMO need 
 
 
 
 
 
 
 
 
associated 
morbidities 
 
 
 
 
 
4. Delivery 
 
 
 
 
 
5. Short-term 
duration on 
ventilator or 
no ventilator 
required. 
 
 
 
 
6. Oxygen 
dependency at 
discharge and 
how much 
 
 
 
 
 
 
7. Type of ECMO 
needed and 
for how long 
 
 
 
 
 
8. Discharge 
from hospital 
The type of delivery and any 
associated morbidities will be 
analyzed. 
 
 
4. Preterm delivery is a known 
risk of FETO.  Gestational age 
at delivery will be an 
important marker in this trial 
of safety and feasibility. 
 
5. A ventilator is often needed 
for babies with the most 
severe cases of CDH. We will 
log and analyze the baby’s 
need for a ventilator and 
compare the duration of that 
need to the historical 
duration, with the goal being 
to reduce the need for a 
ventilator. 
 
 
6. Babies with severe CDH often 
require oxygen upon 
discharge. We will assess each 
baby’s oxygen dependency 
and the amount, with the goal 
being to reduce the baby’s 
need for oxygen upon 
discharge. 
 
 
7. ECMO is a routine treatment 
for babies diagnosed with a 
severe CDH. If ECMO is used, 
the type (VA/VV) and the 
number of days on the ECMO 
treatment will be analyzed, 
with the goal being to reduce 
the need of ECMO. 
 
 

PROTOCOL TITLE: Fetal Endoscopic Tracheal Occlusion (FETO) Trial for Congenital 
Diaphragmatic Hernia (CDH) 
 
 
 
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8. Survival to hospital 
discharge or 180 days 
 
 
 
 
 
9. Maternal complications 
(preterm labor, PROM, 
PPROM, oligohydramnios, 
polyhydramnios, placental 
abruption, chorioamniotic 
separation, 
chorioamnionitis, and 
other infection)  
or 180 days of 
life 
 
 
 
 
9. Maternal 
postpartum 
discharge and 
follow-up (4-6 
weeks after 
delivery) 
8. Survival to hospital discharge 
will be important as this is a 
proposed benefit of FETO.  We 
will analyze survival at 180 
days for those still hospitalized 
at that time point. 
 
 
9. Known maternal 
complications can occur 
during the pregnancy and/or 
at delivery.  Upon discharge 
post-delivery and at post-
partum visit, all potential 
complications will be assessed. 
 
 
7) Procedures Involved 
OVERALL DESIGN 
 
This is a single site, single arm, non-randomized pilot trial to assess the feasibility and safety of treating 
severe CDH with Fetal Endoscopic Tracheal Occlusion (FETO) at the UC Davis Medical Center.    
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
 
A feasibility and safety trial is chosen as the GOLDBAL2 detachable balloon is not FDA approved and its 
use in the FETO procedure is investigational.  Although tracheal balloon placement has not been 
previously performed at the UC Davis Medical Center, our FCTC team has extensive experience in 
fetoscopy for multiple other fetal interventions.  This would be an additional procedure that could be 
offered to our patients with a life-threatening disease. 
 
SCREENING AND STUDY PROCEDURES 
Candidates for the trial will be identified from the investigator’s clinic practice or may be referred from 
other clinicians.  All screening examination procedures will be performed by the investigator or trained 
personnel working under the investigator’s supervision.  EMR will be used to collect data about subjects. 
Screening  
● Maternal demographics 
● Inclusion/Exclusion criteria reviewed 
 

PROTOCOL TITLE: Fetal Endoscopic Tracheal Occlusion (FETO) Trial for Congenital 
Diaphragmatic Hernia (CDH) 
 
 
 
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Please refer to the Schedule of Activities (SoA) of the protocol for standard of care activities that will 
be performed or obtained from the patients’ medical record in order to determine eligibility and 
obtain baseline data. 
 
The following screening examination and procedures will be completed during the screening period as 
per standard of care for women carrying a fetus diagnosed with CDH: 
● Maternal medical history and physical exam  
● Maternal vital signs (temp, pulse, respirations, blood pressure), height and weight 
● Maternal clinical laboratory tests, including complete blood count, blood type and screen, 
antibody screen, HIV, Hepatitis B, and Hepatitis C  
● Fetal karyotype or microarray  
● Confirmation of CDH diagnosis with comprehensive US including observed to expected Lung to 
Head ratio (o/e LHR) 
● Fetal Echocardiogram 
● Fetal MRI with calculated observed to expected total fetal lung volume (o/e TFLV) 
● Extensive counseling with multidisciplinary team  
● Maternal screening for substance abuse and depression  
 
Patients who meet all enrollment criteria and who, after receiving appropriate study information, provide 
their informed consent (as evidenced by a signed informed consent document), will be enrolled in the 
study and have the FETO procedure for balloon placement performed at 27+0 to 29+6 weeks gestation. 
Follow up procedures will occur as listed in the Schedule of Activities table. 
 
DESCRIPTION OF FETO PROCEDURE  
 
The procedure for deployment of the fetal tracheal balloon will take place between 27 weeks 0 days and 
29 weeks 6 days’ gestation as per protocol above, after adequate counseling and signed informed consent. 
The pregnant mother will come with her support person on the day of surgery.  She will be admitted to 
the hospital and, after confirmation of fetal viability, she will have a spinal/epidural placed.  Once in the 
operating room and positioned, ultrasound assessment for fetal positioning will be confirmed.  Maternal 
IV sedation may be given if required.  The fetus will receive an intramuscular injection of Fentanyl (5mcg), 
Atropine (80mcg), and Rocuronium (3mg). The fetal medications can be redosed every 30 minutes as 
needed during the procedure to ensure minimal fetal movement and adequate fetal anesthesia.  After 
adequate maternal anesthesia, a uterine trocar will be inserted into the uterus. After the uterine trocar is 
in place, the fetoscope will be inserted through the trocar into the fetus’ mouth and the balloon will be 
deployed once in the correct position in the fetal trachea.  The balloon will be inflated with isotonic fluid 
and detached into the fetal trachea.  This will complete the placement portion and the fetoscope will be 
withdrawn.  Ultrasound verification of the balloon placement above the carina will be done prior to 
procedure completion.  Amnioreduction will be done if required and the uterine trocar will be removed.  
The skin will be closed with an absorbable suture and/or surgical skin glue. 
 

PROTOCOL TITLE: Fetal Endoscopic Tracheal Occlusion (FETO) Trial for Congenital 
Diaphragmatic Hernia (CDH) 
 
 
 
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Balloon placement attempt will be defined as trocar placement into the uterus with attempt to gain access 
into the fetal trachea.  We will allow a single uterine trocar placement for each patient for attempted 
initial placement.  If our team fails to place the balloon (surgical failure), this will not be attempted a 
second time.  However, if the balloon is successfully placed and later deflates or is expelled from the fetal 
trachea (balloon failure), a second attempt will be allowed to maximize benefit to the fetus if this occurs 
within 10 days of initial insertion and this timing is up to and including 29 weeks and 6 days’ gestation.  
Therefore, a maximum number of balloon placement attempts are:  1 for cases of surgical failure and 2 
for cases of balloon failure.  There may be cases where the patient is taken to the operating room and, 
due to suboptimal fetal positioning, uterine access is not attempted.  Attempts will be made to externally 
rotate the fetus into position however if on ultrasound the fetus remains in poor position for balloon 
placement, uterine access will not proceed.  This will not count as a placement attempt and the patient 
would return to the operating room on subsequent days an unlimited number of times up to 29 weeks 
and 6 days with the goal of uterine access.  
 
Balloon retrieval will ideally take place between 34 weeks 0 days + 1 week.  This may occur earlier in select 
cases for maternal or fetal indications for delivery.  All women will receive a course of antenatal 
betamethasone (12mg intramuscularly every 24 hours for 2 doses) to promote fetal lung development 
prior to balloon retrieval due to the known risk of preterm delivery.  The pregnant mother will again have 
a spinal/epidural placed. Maternal IV sedation may be given if required.  Once in the operating room and 
positioned, the fetus will receive an intramuscular injection of Fentanyl (5mcg), Atropine (80mcg), and 
Rocuronium (3mg).  Redosing can be done every 30 minutes as needed during the procedure to ensure 
minimal fetal movement.  A uterine trocar will be inserted into the uterus. The fetoscope will be inserted 
into the fetus’ mouth and the balloon will be punctured and retrieved from the fetal trachea.  
Amnioreduction will be done if required and the uterine trocar will be removed.  The skin will be closed 
with an absorbable suture and/or surgical skin glue.  In select cases where fetoscopic intervention is 
deemed higher risk (e.g. symptomatic polyhydramnios with premature contractions or preterm labor), 
attempts may be made to puncture the balloon under ultrasound guidance in order to avoid trocar 
placement into the uterus.  The reason for utilizing the percutaneous route secondarily is that the needle 
decompression is done via ultrasound guidance and not direct visualization.  With the percutaneous 
approach, the needle passes through the fetal neck risking injury to vital structures (carotid artery, internal 
jugular vein, nerves, etc.).  Also, the balloon is not removed and depends on fetal expulsion from the 
trachea without assurance that balloon remnants do not remain in the fetal airway.  Lastly, if the balloon 
is unable to be retrieved prior to delivery, an EXIT procedure will be planned for safe removal of the 
balloon prior to birth.  These decisions will be made by members of the FCTC team with a multi-disciplinary 
approach. Potential scenarios requiring EXIT include failure to remove the balloon under other usual 
means or preterm labor with eminent delivery and inability to remove the balloon by fetoscopic or 
percutaneous approaches. 
 
After each intervention, subjects will be admitted post-operatively for observation, pain control, and 
continuous uterine monitoring for contractions. Indomethacin (100mg per rectum preoperatively and 
then 50mg every 6 hours for 24 hours) will be given with the first fetoscopy to mitigate risk of premature 
contractions.  Prophylactic preoperative antibiotics will also be administered intravenously to mother at 
the both balloon placement and retrieval to minimize infectious risk (cefazolin 2 grams is preferred; 

PROTOCOL TITLE: Fetal Endoscopic Tracheal Occlusion (FETO) Trial for Congenital 
Diaphragmatic Hernia (CDH) 
 
 
 
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allergies will be discussed with pharmacy for appropriate substitutions). Maternal pain control will include 
Tylenol as needed with narcotic medications reserved for breakthrough pain in addition to the 
spinal/epidural.  Length of postoperative stay will be individualized to the patient but is expected to be a 
1 night stay for the majority of patients.  Upon discharge, the mother and fetus will be followed on an out-
patient basis as further described in Schedule of Activities.  While the balloon is in place, mothers will be 
followed at least weekly as per standard of care. Weekly ultrasounds will assess for fetal growth, amniotic 
fluid volume, LHR, o/e LHR, and balloon visualization (when the balloon is in place). After balloon removal, 
mothers will be monitored weekly for signs of labor.  Route of delivery will be based on obstetric 
indications with vaginal delivery being the preferred approach. 
 
 
 
SCHEMA 
 
 
Informed 
Consent 
 
 
Screening          
  
 
 
 
Enrollment 
 
 
 
 
Balloon 
Placement 
27w0d-29w6d 
 
 
 
 
Weekly 
Monitoring 
While balloon  
Is in place 
 
Screen potential participants (all pregnant women carrying a fetus complicated by CDH) by 
inclusion and exclusion criteria; obtain history and physical exam; discuss FETO availability as 
a potential therapy for qualifying fetuses. 
 
Complete screening as per Schedule of Activities (SOA) 
If a patient qualifies, we will discuss all risks and benefits of the procedure, and willingness 
of individual to have treatment.. 
Procedure will be done in the operating room with both pediatric surgery and maternal fetal 
medicine (MFM) faculty present. 
GOLDBAL2 Detachable Balloon will be deployed into the fetal trachea via a fetoscopic 
approach using the Delivery Microcatheter. 
Weekly maternal assessment with fetal ultrasound and a one time repeat fetal MRI as 
described in Schedule of Activities  
Informed consent will be obtained from the participant. 

PROTOCOL TITLE: Fetal Endoscopic Tracheal Occlusion (FETO) Trial for Congenital 
Diaphragmatic Hernia (CDH) 
 
 
 
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Balloon 
Retrieval  
34w0d+ 1 week 
 
 
 
 
 
 
 
Delivery 
 
 
 
 
Hospital Discharge 
and Follow-Up 
Discharge exam  
and visit within  
4-6 weeks 
of delivery (mom) 
and at hospital  
discharge or 180  
days of life (baby) 
 
 
 
Schedule of Activities (SOA) 
 
Prenatal Plan 
 
Screening 
Enrollment 
(within 1 
week of 
balloon 
placement) 
Balloon 
Placement 
(27w0d to 
29w6d) 
Monitoring  
(placement 
to retrieval) 
Balloon 
Retrieval 
(34w0d  
+ 1 week) 
Monitoring 
(retrieval to  
delivery) 
Delivery 
Maternal 
Demographics* 
X 
 
 
 
 
 
 
Confirmation of 
diagnosis with 
comprehensive US 
including o/e LHR* 
X 
 
 
 
 
 
 
The fetal tracheal balloon will be removed by repeat fetoscopy and retrieval or via 
percutaneous needle decompression of the balloon under ultrasound guidance (select cases 
where operative intervention would ensure more risk) 
 
Early retrieval (and percutaneous needle decompression) will be considered for significant 
polyhydramnios and premature uterine contractions 
 
An EXIT procedure at the time of delivery will be planned if all above fails 
Delivery will be determined by MFM faculty regarding best time for delivery of 
infants with CDH and will be cared for in the NICU with standard therapy given to all CDH 
babies. 
Chart Review and Documentation of all outcomes (primary and secondary) 

PROTOCOL TITLE: Fetal Endoscopic Tracheal Occlusion (FETO) Trial for Congenital 
Diaphragmatic Hernia (CDH) 
 
 
 
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Inclusion/Exclusion 
Criteria Reviewed 
X 
X 
 
 
 
 
 
Maternal History* 
X 
 
 
 
 
 
 
Interval Maternal 
History* 
 
X 
 
Weekly 
 
X 
X 
Maternal Exam* 
X 
 
 
 
 
 
 
Interval Maternal 
Exam* 
 
X 
 
Weekly 
 
X 
X 
Counseling with 
MFM, CGC* 
X 
 
 
 
 
 
 
Invasive testing* 
(Microarray, 
Karyotype) 
X 
 
 
 
 
 
 
Fetal MRI* 
X 
 
 
 
 
 
 
Fetal 
Echocardiogram* 
X 
 
 
 
 
 
 
Evaluation 
with multi-
disciplinary team* 
X 
 
 
 
 
 
 
Maternal screening 
for substance abuse 
and depression*  
X 
 
 
 
 
 
 
Maternal labs:  CBC, 
type and screen, 
antibody screen, 
HIV, HBV, HCV* 
X 
 
 
 
 
 
 
Informed Consent 
(Study 
Participation) 
X 
 
 
 
 
 
 
Surgical Consent* 
 
X 
 
 
X 
 
 
FETO (balloon 
placement) 
 
 
X 
 
 
 
 
US for fetal 
assessment 
including amniotic 
fluid, membrane 
status, fetal well-
being, o/e LHR* 
 
X 
 
Weekly for 
remainder of 
pregnancy 
(including 
balloon 
visualization) 
 
Weekly for 
remainder 
of 
pregnancy 
 

PROTOCOL TITLE: Fetal Endoscopic Tracheal Occlusion (FETO) Trial for Congenital 
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US includes growth 
and anatomy 
overview* 
 
 
 
Every 3  
weeks 
 
Every 3 
weeks 
 
2nd Fetal MRI 
(measure lung 
growth)** 
 
 
 
+2 weeks of 
balloon 
retrieval 
 
 
 
Additional fetal 
antenatal 
surveillance* 
 
 
 
Weekly  
 
Weekly  
 
Balloon retrieval 
 
 
 
 
X 
 
 
Delivery* 
 
 
 
 
 
 
X 
* Standard of Care 
 
CBC = complete blood count; CGC = certified genetic counselor; FETO = fetal endoscopic tracheal 
occlusion; HBV = Hepatitis B Virus; HCV = Hepatitis C Virus; HIV = Human Immunodeficiency Virus; o/e 
LHR = observed-to-expected lung to head ratio; MFM = maternal fetal medicine; MRI = magnetic 
resonance imaging  
**Ideally 2nd Fetal MRI will be done prior to balloon retrieval.  In select cases, it may not be able to be 
completed prior to retrieval and may be done up to 2 weeks after retrieval. 
Postnatal Plan 
 
Infant Birth 
Postpartum 
Maternal 
Discharge 
Postpartum 
Maternal  
Follow-up  
Infant 
Discharge or 
180 Days of 
Life 
Maternal Exam* 
 
X 
X 
 
Evaluation for maternal 
complications* 
 
X 
X 
 
Neonatal History* 
X 
 
 
X 
Infant Demographics* 
X 
 
 
 
Infant Exam* 
X 
 
 
X 
* Standard of Care 
 
DEVICES 
 
Intended Use: 

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The Fetal Endoscopic Tracheal Occlusion (FETO) procedure using the Goldballoon Detachable Balloon 
(GOLDBAL2) along with the Delivery Microcatheter (BALTACCI-BDPE100) is being investigated to treat 
fetuses with severe Congenital Diaphragmatic Hernia (CDH). 
 
FETO Procedure description: 
The procedure for deployment of the fetal tracheal balloon will take place between 27 weeks 0 days and 
29 weeks 6 days’ gestation as per protocol above.  Balloon retrieval will ideally take place between 34 
weeks 0 days + 1 week.   
 
 
 
Device Descriptions: 
General Fetoscopic Equipment: 
● Karl Storz Trocar (11650 TG) for uterine access and introduction of cannula (K943713) 
● Cook Cannula RCF-10.0 Check-Flo Performer Set (K142829) 
● Fetoscopy equipment currently being used at UC Davis per standard of care will also be used  
 
Device and components for balloon placement: 
● Karl Storz Fetal tracheoscopic sheath with 3 side ports (11540 KE)  
● Karl Storz Fetal tracheoscope (11540 AA) (K951343) 
● BALT Goldballoon Detachable Balloon (GOLDBAL2) 
● BALT Delivery Microcatheter (BALTACCI-BDPE100) 
 
Device and components for balloon retrieval: 
● Karl Storz Fetal tracheoscopic sheath with 3 side ports (11540 KE)  
● Karl Storz Fetal tracheoscope (11540 AA) (K951343) 
● Karl Storz Retrieval forceps (11510 C) (K951343) 
● Karl Storz Puncture Needle (11540 KD)  
● Karl Storz Disposable Puncture Needle (11506 P) 
 
The Goldballoon Detachable Balloon (GOLDBAL2) along with the Delivery Microcatheter 
(BALTACCIBMPE100) will be provided by the manufacturer, Balt Extrusion (Montmorency, France).   It will 
be opened under sterile conditions at the time of procedure. 
 
All use of the Goldballoon Detachable Balloon (GOLDBAL2) will be under the direct supervision of the 
principal investigator or her designee. The investigational devices will be clearly labeled as investigational 
use only. The devices will be stored in the office of the Surgical Care Coordinator in the FCTC at UC Davis 
Medical Center, with access limited to the study team. 
All records of receipt, use, and disposition of the devices will be maintained by the study team. At the 
completion of the study, there will be a final reconciliation by study personnel of devices shipped, used, 

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and devices remaining. Any discrepancies noted will be investigated, resolved, and documented prior to 
return or destruction of unused devices.  
 
CONCOMITANT THERAPY 
 
Polyhydramnios is expected while the balloon is in place due to the occlusion of the fetal trachea.  This 
polyhydramnios may cause symptoms of respiratory distress or preterm contractions in the mother.  If 
the polyhydramnios is causing maternal respiratory compromise, without contractions, the FCTC team 
would evaluate for an amnioreduction in order to improve maternal symptoms.  If preterm labor were to 
occur, steroids may be administered with consideration of tocolysis with or without amnioreduction if 
indicated. If preterm, premature rupture of membranes (PPROM) occurs, hospitalization for the 
remainder of pregnancy would be recommended and antibiotics would be considered for prolongation of 
latency period. 
 
There are cases where the balloon would need to be removed prior to scheduled removal at 34 weeks + 
1 week.  Cases will be evaluated on an individual basis but scenarios that are most likely to require 
premature removal are related to imminent delivery.  Maternal reasons for imminent delivery would 
include medical complications of pregnancy (e.g. pre-eclampsia with severe features or preterm labor not 
responsive to treatment). Fetal reasons for imminent delivery may include fetal distress. Finally, 
symptomatic polyhydramnios that is not responsive to amnioreduction or unable to be treated with 
amnioreduction may be an indication for early balloon removal.   
 
In the extremely rare case of inability to remove the balloon and need for urgent delivery, the FCTC team 
would plan an ex-utero intrapartum therapy (EXIT) procedure for safe delivery of the fetus. This procedure 
involves a maternal hysterotomy under general anesthesia with partial delivery of the fetal head and neck. 
The fetus remains on placental circulation for oxygenation and the balloon will be removed prior to full 
delivery and removal of the fetus from placental bypass. The FCTC team has experience with this 
procedure. If an EXIT procedure was unable to be completed or the fetus was unable to be maintained on 
placental bypass, an emergency airway team is available at all times at UC Davis Medical Center. 
Emergency bronchoscopy equipment is available to our PCAT (Pediatric Critical Airway Team), and the 
emergency airway team will be trained in neonatal balloon removal.  Emergent neonatal balloon removal 
will be completed using real time video-endoscopy to remove the balloon and any fragments, suction and 
clear the airways, and intubate to start ventilation while the cord remains attached to the placenta.  The 
emergency airway team will be taught that if the endoscope is in contact with the inflated balloon, the 
mucosa may appear flattened and the trachea is being stretched.  This will require slight retraction of the 
endoscope to avoid tracheal injury and allow for balloon decompression and removal. Intent will be for 
delay of the cord clamping until signs of open and functional airways are present.  
 
8) Data and/or Specimen Management and Confidentiality  

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 I understand that if this study involves the use of the UC Davis Health Electronic Health Record 
(EMR/EPIC) also contains the clinical data for Marshall Medical Center (MMC). I understand that MMC 
patient data cannot be accessed for research purposes and that I must take the necessary steps to 
ensure that MMC data is not accessed, used, or disclosed for UC Davis Health research purposes. 
 
 I understand that if this study involves use of UC Davis students’ educational records (including 
records    in the PI’s own possession such as course exams/assignments), I must consult with the 
Registrar’s office to see if all requirements of the Family Educational Rights and Privacy Act (FERPA) are 
satisfied.   
 
The trial will be conducted in accordance with Good Clinical Practice and applicable United States (US) 
Code of Federal Regulations (CFR). The Principal Investigator will assure that no deviation from, or 
changes to the protocol will take place without prior agreement from the Investigational Device 
Exemption (IDE) sponsor and documented approval from the Institutional Review Board (IRB), except 
where necessary to eliminate an immediate hazard(s) to the trial participants. All personnel involved in 
the conduct of this study have completed CITI training for Human Subjects Protection and ICH GCP, 
protocol training, and have been delegated by the Primary Investigator (PI) to conduct protocol 
activities.  
The PI and Co-Investigators (Co-I) will coordinate study activities, identify patients, collect study data, 
report study results, and ensure the overall safety of the patient. Adequate personnel in the Division of 
Pediatric Surgery are available to support the conduct of this research. Our Pediatric surgeons and nurses 
all have extensive research experience in addition to support through the Department of Surgery. The 
Clinical Research Coordinators and Research Assistants will assist with screening, consenting, enrolling 
and collecting data for the study. They will assist the PI in adherence to study protocol and deadlines and 
perform regulatory management. The PI and Co-Is are responsible for proposing and explaining the 
protocol treatment to the patient for the consent process, performs physical examinations, and monitors 
test results.  
Adequate records will be maintained for the study including subject medical and surgical records, signed 
ICFs, and device use records. Information collected will be on paper CRFs (Case Report Forms) and will be 
deidentified, and each patient will have a code that will link them to a separate enrollment excel sheet. 
This separate excel sheet will contain identifiers that will be password protected and stored on UC Davis 
encrypted computers.  
Protected health information to be accessed for this study includes name, date of births of both patient 
and baby, medical record numbers for both patient and baby, city and state where patient lives, current 
hospital medications, outpatient medications, past medical history, diagnoses, test and lab results, all 
imaging dates (Ultrasounds, MRI, etc.), date of balloon placement and retrieval, dates for when steroids 
were given, delivery date, and date of baby discharge.  

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The database that will be used to analyze data is the Research Electronic Data Capture (REDCap) 
database. The REDCap database will contain information on deidentified patients. REDCap is a secure 
web application for building and managing online databases for research and for electronic data capture 
and is HIPAA compliant for data storage. The data received from this trial will be stored indefinitely and 
banked for future research. The data, after being stripped of any identifiers and coded, will be stored on 
UC Davis encrypted computers. This data will be downloaded from REDCap once the study is completed, 
therefore ensuring that it is de-identified, anonymous and accurate. 
Only approved researchers to this project will currently have access to the data. The data does not have 
any patient identifiers. The data set is stored on UC Davis encrypted computers in a secure folder that 
only approved research personnel for this study has access to. 
If this data is needed in the future for a new project, it will only be utilized with a future IRB approved 
study that appropriately identifies this data set. The PI will send the file through the secure UC Davis 
email system when the IRB approval for the new study is furnished.  
STATISTICAL ANALYSIS AND SAMPLE SIZE 
This pilot study sample will include 10 patients who successfully undergo balloon placement.   We may 
need to enroll additional patients in the case of screen failures and those that have failed balloon 
placement due to fetal positioning.  As this is a pilot study, a sample size calculation will not be performed. 
GENERAL STATISTICAL CONSIDERATIONS 
Descriptive tabular and graphical summaries of data will be used to characterize primary and secondary 
endpoints.  For categorical variables, frequencies and percentages will be presented.  For continuous 
variables, the number of subjects, mean, standard deviation, median, minimum and maximum values will 
be reported. 
SAFETY ANALYSES 
As this is a pilot study with a very small number of planned subjects, there will be no internal statistical 
analysis of safety.  Analyses will include descriptive statistics on all safety measures (expected and 
unexpected complications) and adverse events.  
 
9) Data and/or Specimen Banking 
All data received from this trial will be stored indefinitely and banked for future research. The data, after 
being stripped of any identifiers and coded, will be stored on UC Davis encrypted computers. This data 
will be downloaded from REDCap once the study is completed, therefore ensuring that it is de-
identified, anonymous and accurate. A separate enrollment spreadsheet will contain the patient’s 
identifiers and will be stored on encrypted and password protected computers.  
Protected health information to be accessed for this study includes name, date of births of both patient 
and baby, medical record numbers for both patient and baby, city and state where patient lives, current 

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hospital medications, outpatient medications, past medical history, diagnoses, test and lab results, all 
imaging dates (Ultrasounds, MRI, etc.), date of balloon placement and retrieval, dates for when steroids 
were given, delivery date, and date of baby discharge. 
Only approved researchers to this project will currently have access to the data. The data set is stored 
on UC Davis encrypted computers in a secure folder that only approved research personnel for this 
study has access to. 
If this data is needed in the future for a new project, it will only be utilized with a future IRB approved 
study that appropriately identifies this data set. The PI will send the file through the secure UC Davis 
email system when the IRB approval for the new study is furnished. If shared with outside institutions, 
we will only share deidentified data, and only when a data use agreement has been executed. Requests 
for data will be made to the PI of this trial, and approval must be given before data can be released.  
 
10)  Provisions to Monitor the Data to Ensure the Safety of Subjects 
SAFETY OVERSIGHT 
To protect the interests of research subjects and ensure that they are not exposed to undue risk, this trial 
will be monitored by an independent Data and Safety Monitoring Committee (DSMC). The DSMC will be 
appointed by the Sponsor-Investigator and shall have no formal involvement with the subjects or the 
investigation and function independently of Sponsor-Investigator.  
The DSMC will monitor the progress of the trial with a scheduled meeting or conference call. In addition 
to reviewing Serious Adverse Events (SAEs), the first DSMC meeting will focus on overall safety of the trial 
and study device and will make a determination as to whether or not the study should proceed. 
The DSMC will also serve as the Clinical Events Committee (CEC), and will adjudicate all adverse events for 
clinical accuracy and relatedness to the treatment and will also ensure a unified evaluation by applying 
standardized event criteria. The CEC will perform final adjudication of adverse events. 
A report will be submitted to the FDA following the delivery of each subject enrolled in the study, to ensure 
adequate oversight over the safety outcomes. 
CLINICAL MONITORING 
To assure adequate protection of the rights of human subjects, per 21 CFR 812.40, 812.43 and 812.46,  
Investigators will conduct continuous review of patient safety. Patients will be monitored weekly during 
the study. The PI, Co-Is, clinic nurse, clinical research coordinator (CRC), and research assistants will 
meet at least monthly for protocol specific meetings to discuss patient data and adverse events possibly 
associated with the study procedures. All enrolled patients will be discussed at these team meetings, 
which will be held at the University of California, Davis Medical Center. This meeting will update all 
research staff on the current status of the trial, and any serious adverse events that have occurred will 
be discussed so that appropriate action can be taken. In between these regularly scheduled meetings, 
investigators will review and report any serious adverse events in accordance with data safety and 

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monitoring procedures. All adverse events and serious adverse events will be reported to the UCD IRB 
according to the current policy. 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
All adverse events will be recorded on the EMR and eCRFs during study visits and as reported by the 
participant.  The description of the event, date first observed, any action taken, and ultimate outcome will 
be recorded.  
For all adverse events, sufficient information will be pursued and/or obtained so as to permit  
1) an adequate determination of the outcome of the event (i.e., whether the event should be classified as 
a serious adverse event) and;  
2) an assessment of the causal relationship between the adverse event and the investigational device or, 
if applicable, the other study treatment or diagnostic product(s).    
 
Adverse events felt to be associated with the investigational device or, if applicable, other study treatment 
or diagnostic product(s) will be followed until the event (or its sequelae) or the abnormal test finding 
resolves or stabilizes at a level acceptable to the investigator-sponsor. 
 
The investigator will classify all adverse events as expected or unexpected, and as either not related to 
the investigational device or surgical procedure, unlikely related to the investigational device or surgical 
procedure, potentially related to the investigational device or surgical procedure, probably related to the 
investigational device or surgical procedure, or definitely related to the investigational device or surgical 
procedure.  
 
DEFINITIONS OF ADVERSE EVENTS (AE) 
An adverse event is any undesirable occurrence in a study patient, whether or not it is related to the study 
intervention. Any condition that was recorded as pre-existing is not an AE unless there is a change in the 
nature, severity, or degree of the condition.  
 
Adverse events will be recorded on the appropriate event eCRF.  The date of the event, seriousness 
criteria, relatedness, expectedness and outcome will also be recorded.  Adverse events will be collected 
once the participant has been enrolled in the trial and the subject will be instructed to report any event 
to the Investigator when and/or as it occurs.  Adverse events will be collected for mother up until the time 
of her postpartum visit. Adverse events for the fetus/baby will be collected for 30 days after delivery.     
 
DEFINITION OF SERIOUS ADVERSE EVENTS (SAE) 
 
An adverse event (AE) or suspected adverse reaction is considered "serious" if, in the view of either the 
investigator or sponsor, it results in any of the following outcomes: death, an unanticipated life-
threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization of mother, 
or a persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions after delivery. Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered serious when, based upon appropriate medical judgment, they 

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may jeopardize the participant and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. 
 
 
SEVERITY OF EVENT 
 
For adverse events (AEs) not included in the protocol defined grading system, the following guidelines will 
be used to describe severity.  
 
• 
Mild – Events require minimal or no treatment and do not interfere with the participant’s daily 
activities.  
• 
Moderate – Events result in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning. 
• 
Severe – Events interrupt a participant’s usual daily activity and may require systemic drug 
therapy or other treatment. Severe events are usually potentially life-threatening or 
incapacitating.  Of note, the term “severe” does not necessarily equate to “serious”. 
 
RELATIONSHIP TO STUDY INTERVENTION 
 
All adverse events (AEs) must have their relationship to study intervention assessed by the clinician who 
examines and evaluates the participant based on temporal relationship and his/her clinical judgment. The 
degree of certainty about causality will be graded using the categories below. In a clinical trial, the study 
product must always be suspect.  
 
• 
Definitely Related – There is clear evidence to suggest a causal relationship, and other possible 
contributing factors can be ruled out. The clinical event, including an abnormal laboratory test 
result, occurs in a plausible time relationship to study intervention and cannot be explained by 
concurrent disease or other drugs or chemicals. The response to withdrawal of the study 
intervention should be clinically plausible. The event must be phenomenologically definitive. 
• 
Probably Related – There is evidence to suggest a causal relationship, and the influence of other 
factors is unlikely. The clinical event, including an abnormal laboratory test result, occurs within a 
reasonable time of the study intervention, is unlikely to be attributed to concurrent disease or 
other procedures, other drugs or chemicals.  
• 
Potentially Related – There is some evidence to suggest a causal relationship (e.g., the event 
occurred within a reasonable time after the study intervention). However, other factors may have 
contributed to the event (e.g., the participant’s clinical condition, other concomitant events). 
Although an AE may rate only as “potentially related” soon after discovery, it can be flagged as 
requiring more information and later be upgraded to “probably related” or “definitely related”, 
as appropriate. 
• 
Unlikely to be related – A clinical event, including an abnormal laboratory test result, whose 
temporal relationship to the study intervention makes a causal relationship improbable (e.g., the 
event did not occur within a reasonable time after the study intervention) and in which other 

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procedures, other drugs or chemicals or underlying disease provides plausible explanations (e.g., 
the participant’s clinical condition, other concomitant treatments). 
• 
Not Related – The AE is completely independent of study intervention, and/or evidence exists 
that the event is definitely related to another etiology. There must be an alternative, definitive 
etiology documented by the clinician. 
 
 
 
EXPECTEDNESS 
The study investigator will be responsible for determining whether an adverse event (AE) is expected or 
unexpected.  An AE will be considered unexpected if the nature, severity, or frequency of the event is not 
consistent with the risk information previously described for the study intervention. 
 
TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
 
The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the attention of 
study personnel during study visits and interviews of a study participant presenting for medical care, or 
upon review by a study monitor. 
AEs will be captured on the appropriate electronic case report form (eCRF). Information to be collected 
includes event description, time of onset, clinician’s assessment of severity, relationship to study product 
(assessed only by those with the training and authority to make a diagnosis), and time of 
resolution/stabilization of the event.  
 
Any medical condition that is present at the time that the participant is screened will be considered as 
baseline medical history and not reported as an AE. If the study participant’s condition deteriorates at any 
time during the study, it will be recorded as an AE.  
 
Changes in the severity of an AE will be documented to allow an assessment of the duration of the event 
at each level of severity to be performed. AEs characterized as intermittent require documentation of 
onset and duration of each episode. 
 
All reportable events will be recorded with start dates occurring any time after informed consent is 
obtained until the post-partum visit for the mom and 30 days after delivery for the baby.  At each study 
visit, the investigator will inquire about the occurrence of AE/SAEs since the last visit.  Events will be 
followed for outcome information until resolution or stabilization. 
 
The Clinical Events Committee (CEC) will adjudicate all serious or related (potentially, probably or 
definitely) adverse events for clinical accuracy and relatedness to the treatment and will also ensure a 
unified evaluation by applying standardized event criteria. The CEC will perform final adjudication of 
adverse events.   
 

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ADVERSE EVENT REPORTING  
 
All adverse events that occur will be assessed for expectedness and relatedness. Adverse events will be 
reported to the UC Davis IRB in accordance with their policy.    
Infant adverse events associated with CDH and expected as normal course of the condition will be 
recorded as expected.  Such events include but are not limited to: 
● Death after birth due to CDH disease severity and/or complications of standard of care treatment 
● Pulmonary hypertension with resultant need for medications or need of ECMO 
● All complications associated with ECMO (i.e. bleeding, stroke, etc.) 
● Pulmonary hypoplasia with resultant need for mechanical ventilation  
● Gastrointestinal reflux or other feeding problems (i.e. dysmotility, need for feeding tube, etc.) 
● Increased oxygenation requirements or need for home oxygen 
● Neurodevelopmental delay 
 
 
SERIOUS ADVERSE EVENT REPORTING 
 
An adverse event is considered “serious” if, in the view of either the investigator, it results in any of the 
following outcomes:  
● Maternal death and/or fetal death 
o If death results from (progression of) the disease, the disease should be reported as an 
event (SAE) itself.  
● A life-threatening adverse event  
An adverse event is considered ‘life-threatening’ if, in the view of either the investigator [or sponsor], its 
occurrence places the patient or subject at immediate risk of death. It does not include an adverse event 
that, had it occurred in a more severe form, might have caused death.  
● Inpatient hospitalization or prolongation of existing hospitalization for > 24 hours.  
● A persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions  
● A congenital anomaly/birth defect other than those expected of a baby with CDH 
● Important medical event  
Any event that may not result in death, be life-threatening, or require hospitalization may be considered 
serious when, based upon appropriate medical judgment, they may jeopardize the patient and may 
require medical or surgical intervention to prevent one of the outcomes listed in this definition of “Serious 
Adverse Event”. Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home; convulsions that do not result in inpatient hospitalization 
or the development of drug dependency or drug abuse.  
 
Previously planned (prior to signing the informed consent form) surgeries should not be reported as SAEs 
unless the underlying medical condition has worsened during the course of the study. Preplanned 
hospitalizations or procedures for preexisting conditions (e.g. CDH in infants) that are already recorded in 

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the patient’s medical history at the time of study enrollment should not be considered SAEs. However, if 
the preexisting condition worsened during the course of the study, it should be reported as an SAE. 
 
UNANTICIPATED ADVERSE DEVICE EFFECTS 
 
An unanticipated adverse device effect (UADE) is defined as “any serious adverse effect on health or safety 
or any life-threatening problem or death caused by, or associated with, a device if that effect, problem, 
or death was not previously identified in nature, severity, or degree of incidence in the investigational 
plan, or any other unanticipated serious problem associated with a device that relates to the rights, safety 
or welfare of subjects.” 
All serious and unanticipated adverse events should be reported to the sponsor investigator 
within 24 hours of first learning of the event. Those that are determined to be serious and 
unanticipated after sponsor investigator review should also be reported to the IRB as required 
according to the reporting requirements of the UC Davis IRB. 
 
The Sponsor-Investigator will report all UADEs to the Food and Drug Administration (FDA) within 10 
working days after being notified of the event. Thereafter, the sponsor investigator shall submit such 
additional reports concerning the effect as FDA requests.  The sponsor investigator shall also report the 
results of such evaluation to the UC Davis IRB in the expected time frame of the institution’s IRB policy. 
All UADEs will be reported to the IRB according to local policies and to the FDA according to the regulations 
found in 21 CFR 812.150.  
 
UNANTICIPATED PROBLEMS 
DEFINITION OF UNANTICIPATED PROBLEMS (UP) 
 
The Office for Human Research Protections (OHRP) considers unanticipated problems involving risks to 
participants or others to include, in general, any incident, experience, or outcome that meets all of the 
following criteria: 
 
• 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures that are 
described in the protocol-related documents, such as the Institutional Review Board (IRB)-
approved research protocol and informed consent document; and (b) the characteristics of the 
participant population being studied; 
• 
Related or possibly related to participation in the research (“possibly related” means there is a 
reasonable possibility that the incident, experience, or outcome may have been caused by the 
procedures involved in the research); and 
• 
Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or recognized. 
 
This definition could include an unanticipated adverse device effect, any serious adverse effect on health 
or safety or any life-threatening problem or death caused by, or associated with, a device, if that effect, 
problem, or death was not previously identified in nature, severity, or degree of incidence in the 

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investigational plan or application (including a supplementary plan or application), or any other 
unanticipated serious problem associated with a device that relates to the rights, safety, or welfare of 
subjects (21 CFR 812.3(s)). 
 
UNANTICIPATED PROBLEM REPORTING 
 
The investigator will report unanticipated problems (UPs) to the reviewing Institutional Review Board 
(IRB). The UP report will include the following information: 
• 
Protocol identifying information: protocol title and number, PI’s name, and the IRB  number; 
• 
A detailed description of the event, incident, experience, or outcome;  
• 
An explanation of the basis for determining that the event, incident, experience, or outcome 
represents an UP;  
• 
A description of any changes to the protocol or other corrective actions that have been taken or 
are proposed in response to the UP. 
 
To satisfy the requirement for prompt reporting, UPs will be reported to the UC Davis IRB in accordance 
with their policy.   
 
 
PROTOCOL DEVIATIONS 
 
The investigator will not deviate from the protocol without prior IRB approval, unless such deviation is 
necessary to manage a medical emergency.  The investigator will notify the IRB of any protocol deviation 
to protect the life, or physical well-being of a subject in an emergency.  Such notice shall be given as soon 
as possible, but in no event any later than 5 working days after the emergency occurred.  All other 
revisions and/or amendments to the protocol that affect subject treatment, study outcome, or subject 
safety should be submitted in writing to the IRB for approval prior to implementation. The investigator 
should maintain a record of all protocol deviations showing the dates of, and the reason for, each protocol 
deviation. 
Changes that affect the scientific soundness of the study or the rights, safety, or welfare of human subjects 
may also require FDA approval, in addition to IRB approval, prior to implementation.  The investigator will 
obtain such approvals, if required. 
 
11) Withdrawal of Subjects 
Participants are free to withdraw from participation in the study at any time upon request. If requested, 
the balloon will be removed prior to scheduled removal at 34 weeks + 1 week.  The balloon may also be 
removed prior to 34 weeks + 1 week if there are maternal or fetal concerns that arise.  If the balloon is 
removed early for maternal or fetal risk reasons, this will not be considered a withdrawal of participation 
but will be listed as an adverse event.   
 

PROTOCOL TITLE: Fetal Endoscopic Tracheal Occlusion (FETO) Trial for Congenital 
Diaphragmatic Hernia (CDH) 
 
 
 
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In the unlikely case that a mother decides to withdraw from the study after balloon placement and before 
scheduled removal, the FCTC team would follow the wishes of the patient after extensive counseling.  She 
would still require weekly OB/MFM follow-up to ensure safe delivery and we would recommend delivery 
in a CDH center as per standard of care.  Although not advised, if she decided to deliver at another 
institution we would take the steps necessary to discuss with the delivery team and pediatric surgery team 
at the accepting center regarding what had been done and what potential complications should be 
evaluated for due to the fetal intervention.  In this case, the participant will not be replaced.  Data from 
the withdrawn patient will be collected but not analyzed in the final analysis.     
 
An investigator may discontinue or withdraw a participant from the study for the following reasons: 
 
● Significant study intervention non-compliance  
● If any clinical adverse event (AE), laboratory abnormality, or other medical condition or situation 
occurs such that continued participation in the study would not be in the best interest of the 
participant 
● Fetal distress (e.g. sustained fetal heart rate changes) which requires discontinuation of the study 
intervention 
● If the participant meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation prior to balloon placement 
● Participant unable to have the balloon placed by 29 weeks and 6 days. 
The reason for participant discontinuation or withdrawal from the study will be recorded on the electronic 
Case Report Form (eCRF). Subjects who sign the informed consent form and are enrolled but do not have 
the balloon placed may be replaced.  Subjects who sign the informed consent form, are enrolled and have 
the balloon placed, but subsequently withdraw or are withdrawn or discontinued from the study, will not 
be replaced.   
LOST TO FOLLOW-UP 
A participant will be considered lost to follow-up if she fails to return for 2 scheduled visits and is unable 
to be contacted by the study site staff.  
 
The following actions must be taken if a participant fails to return to the clinic for a required study visit: 
● The site will attempt to contact the participant and reschedule the missed visit within 1 week and 
counsel the participant on the importance of maintaining the assigned visit schedule and ascertain 
if the participant wishes to and/or should continue in the study. 
● Before a participant is deemed lost to follow-up, the investigator or designee will make every 
effort to regain contact with the participant (where possible, 3 telephone calls and, if necessary, 
a certified letter to the participant’s last known mailing address or local equivalent methods). 
These contact attempts should be documented in the participant’s medical record or study file.  
● Should the participant continue to be unreachable, she will be considered to have withdrawn 
from the study with a primary reason of lost to follow-up.   

PROTOCOL TITLE: Fetal Endoscopic Tracheal Occlusion (FETO) Trial for Congenital 
Diaphragmatic Hernia (CDH) 
 
 
 
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● In the rare case that the mother is completely lost to follow-up, the study team will contact her 
referring physician as there is potential for infant risk if the balloon is in place and not retrieved 
prior to birth or immediately after birth.  Instructions on how to retrieve the balloon postnatally 
will be provided to her home obstetrician.   
● All mothers will be given a wallet-sized emergency card with information regarding the balloon 
and what is to be done in an emergency situation. 
 
12) Risks to Subjects 
Although FETO has shown increase in fetal lung growth with potential for increased neonatal survival, it 
does not occur without risks (24).  A 2016 systematic review and meta-analysis showed that the most 
common complications associated with FETO was increased risk of preterm birth (72.4% born before 37 
weeks and 17.9% born before 32 weeks) and premature rupture of membranes (46.8% PROM).  Less 
frequent complications were reported as chorioamnionitis (2.6%) and placental abruption (1.2%)(23).   
 
FETO Procedure (balloon placement and retrieval) and/or EXIT Procedure 
Maternal risks:  
● Premature rupture of membranes (PROM) 
● Preterm Premature rupture of membranes (PPROM) 
● Preterm labor 
● Polyhydramnios 
● Amniotic fluid leakage into the abdomen with resultant oligohydramnios  
● Chorioamnionitis 
● Chorioamniotic separation 
● Bleeding with possible need of blood transfusion 
● Allergic reaction to latex 
● Complications associated with anesthesia/analgesia 
● Placental abruption 
● Amniotic fluid embolism with resultant respiratory failure 
Fetal Endoscopic Tracheal Occlusion Trial Participant at UC Davis 
Health 
Balloon in fetal trachea. 
Contact Dr. Shinjiro Hirose in case of an emergency at 
916-453-2080 

PROTOCOL TITLE: Fetal Endoscopic Tracheal Occlusion (FETO) Trial for Congenital 
Diaphragmatic Hernia (CDH) 
 
 
 
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● Deep venous thrombosis that may lead to pulmonary embolism and respiratory failure 
● Maternal death 
● Need for EXIT procedure 
 
 Fetal/neonatal risks:  
● Preterm birth with associated complications of prematurity 
● Fetal death associated with the removal procedure (inability to remove the balloon) 
● Adverse tracheal effects from the balloon including epithelial damage, cartilage and/or muscle 
damage, tracheomegaly, tracheomalacia, etc. 
● Morbidity after birth which may be increased by the procedure as it allowed survival or treated 
pulmonary hypoplasia at the expense of complications of prematurity 
● Failure to enter the uterus/trachea or position the balloon adequately 
● Vocal cord injury 
● Injury to fetal neck or trachea from percutaneous balloon puncture 
● Complications associated with anesthesia/analgesia 
● Spontaneous intrauterine fetal demise/death 
● Loss of ECMO eligibility (the baby’s inability to receive ECMO due to prematurity) 
 
Drug Risks 
 
Indomethacin (given at balloon placement) 
 
Maternal Risk 
● Dizziness 
● GI distress including heartburn, nausea, vomiting, and inflamed stomach lining 
 
Fetal/Neonatal risk 
● Early narrowing or closure of ductus arteriosus  
● Decreased responsiveness to postnatal indomethacin for closure of persistent patent ductus 
arteriosus 
● Possible increased risk of necrotizing enterocolitis  
● Possible impact on renal function due to oligohydramnios 
● Possible increased risk of intraventricular hemorrhage or periventricular leukomalacia 
● Oligohydramnios 
 
Betamethasone (given prior to balloon retrieval as this medication is a steroid that will help develop 
the fetus’ lungs due to risk of preterm delivery) 
Maternal Risk 
● Allergic reaction causing wheezing, chest tightness, swelling of face/lips/tongue/throat, or seizure 
● Infection at the injection site 
● Elevated blood glucose 
 
Fetal/Neonatal Risk 
● No known risks with single course 
 

PROTOCOL TITLE: Fetal Endoscopic Tracheal Occlusion (FETO) Trial for Congenital 
Diaphragmatic Hernia (CDH) 
 
 
 
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Since the inception of fetal surgery, there has been concern regarding maternal wellbeing during the index 
pregnancy and with future pregnancies (25).  A recent survey of women who had undergone FETO versus 
expectant management for a CDH pregnancy was completed.  Although the response rate was only 40%, 
there was no evidence of worse outcomes for the fetoscopy group.  Specifically, no one reported 
subsequent fertility problems and subsequent pregnancies had the same rate of congenital anomalies or 
complications as the normal population (26).     
 
Of note, fetoscopic procedures are done during pregnancy for a wide range of indications and there is no 
evidence to date that these procedures, in general, have an adverse impact on subsequent obstetric 
outcomes.  In summary, we expect that FETO will be associated with increased preterm birth and PROM.  
We will monitor for rare complications of chorioamnionitis and placental abruption.  We do not expect 
long term complications with future pregnancies. 
 
13) Potential Benefits to Subjects 
FETO has shown to increase prenatal lung volumes and prenatal lung perfusion (27, 28).  Hypothetically, 
these will counteract the two major problems associated with CDH, namely pulmonary hypoplasia and 
pulmonary hypertension. Although individual studies show mixed results, a 2016 systematic review 
showed increased neonatal survival in severe CDH patients who underwent FETO. Specifically, the relative 
risk comparing FETO to expectant management was 5.8 (1.5-22.9) for 30 day survival and 10.5 (1.5-74.7) 
for 6 month survival (23).   
 
ASSESSMENT OF POTENTIAL RISKS AND BENEFITS 
Although there are known risks of the procedure (preterm labor, PROM, PPROM, oligohydramnios, 
polyhydramnios, placental abruption, chorioamniotic separation, chorioamnionitis, and other maternal 
infection), the potential for increased lung volume and neonatal survival in a condition with such high 
mortality makes complete and transparent counseling extremely important.  Patients will be counseled 
regarding all potential risks and benefits including uncertain benefit of their fetus and the potential 
prematurity to which makes lethality more likely. We will only include patients with severe diaphragmatic 
hernia and we will adhere strictly to inclusion criteria, including excluding patients at increased risk of 
premature delivery or with signs of placental abruption.  Fetal screening will be thorough to exclude 
fetuses with known conditions that would limit survival and, therefore, would have limited benefit from 
the prenatal therapy.  Antibiotics and sterile technique will be used during the procedure to decrease 
infectious risk.  Long-term risks to the mother or her future reproductive potential are not anticipated but 
will be discussed as a hypothetical risk.  There is risk of premature balloon removal for maternal reasons 
or fetal distress which may limit the degree of fetal lung growth. 
 
 
14) Sharing of Results with Subjects 

PROTOCOL TITLE: Fetal Endoscopic Tracheal Occlusion (FETO) Trial for Congenital 
Diaphragmatic Hernia (CDH) 
 
 
 
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The results of this study will not be shared with subjects, during or upon completion of the study outside 
of published data results. 
 
15) Prior Approvals 
N/A 
 
16) Provisions to Protect the Privacy Interests of Subjects 
 Patients will be contacted by a member of the research team in a private setting such as a patient room 
or conference room. The research team will explain the study treatment, procedures, and the timing of 
each to the patient/family and they will be offered the opportunity to ask questions. Patients’ privacy 
interests will be respected at all times and requests for specific privacy requirements will be met if at all 
possible, taking into consideration the study protocol requirements and the patients’ welfare. 
Information about study subjects will be kept confidential and managed according to the requirements 
of the Health Insurance Portability and Accountability Act (HIPAA). Only research personnel approved by 
the IRB to work on this project will have access to this study. 
Access to medical records that contain patient’s personal information for the purpose of this study will 
be limited to the approved research personnel. These personnel already have knowledge of and access 
to identifiable medical information of the current patient populations as part of their daily job functions. 
EMR access PHI is password-protected and no PHI will be reused or disclosed to any other person or 
entity, except as required by law. 
To minimize the risks of breach of confidentiality, we will not include any information that directly 
identifies the subjects on the information we collect, and on the data resulting from the research. 
Instead, we will record a code on the information, and we will keep a link between the code and the 
subject’s identity in a different location. 
 
17) Compensation for Research-Related Injury 
If subjects are injured as a result of being in this study, the University of California will provide 
the necessary medical treatment. Depending on the circumstances, the costs of the treatment  
may be covered by the University or may be billed to the participants insurance company just  
like other medical costs. The University do not normally provide any other form of  
compensation for injury. 
 
18) Economic Burden to Subjects 

PROTOCOL TITLE: Fetal Endoscopic Tracheal Occlusion (FETO) Trial for Congenital 
Diaphragmatic Hernia (CDH) 
 
 
 
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 There will be no cost to the subject for any procedures that are done only for the study such as the 
second MRI. They will have to pay for basic expenses like any childcare, food, parking, or transportation 
related to study activities. The subject or their insurance company may be billed for any standard 
medical care (not part of this study) given. 
 
19) Drugs or Devices 
☐ I confirm that all investigational drugs will be received by the Investigational Drug Service 
(IDS).  The IDS will store, handle, and administer those drugs so that they will be used only on 
subjects and be used only by authorized investigators. 
 
☒ I confirm that all investigational devices will be labelled in accordance with FDA regulations 
and stored and dispensed in such a manner that they will be used only on subjects and be 
used only by authorized investigators. 
20) Review Requirements 
Are there any contractual obligations or other considerations that require IRB review of this research, 
or review at intervals other than those required by the Common Rule or FDA? If yes, check box: 
 
⬜ Yes 
 
 No 
 
 
 
 
 
 
 
 
 

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PROTOCOL TITLE: Fetal Endoscopic Tracheal Occlusion (FETO) Trial for Congenital 
Diaphragmatic Hernia (CDH) 
 
 
 
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PROTOCOL TITLE: Fetal Endoscopic Tracheal Occlusion (FETO) Trial for Congenital 
Diaphragmatic Hernia (CDH) 
 
 
 
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