Ultrasound Obstet Gynecol 2012; 39: 20–27
Published online 14 December 2011 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/uog.10142
A randomized controlled trial of fetal endoscopic tracheal
occlusion versus postnatal management of severe isolated
congenital diaphragmatic hernia
R. RUANO*†, C. T. YOSHISAKI*, M. M. DA SILVA‡, M. E. J. CECCON§, M. S. GRASI§,
U. TANNURI‡ and M. ZUGAIB*
*Department of Obstetrics and Gynecology, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil; †Texas Children’s Fetal
Center and the Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, TX, USA; ‡Department of Pediatric
Surgery, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil; §Department of Neonatology, Faculdade de Medicina,
Universidade de São Paulo, São Paulo, Brazil
K E Y W O R D S: congenital diaphragmatic hernia; fetal abnormalities; fetal surgery; FETO; fetoscopy; prenatal diagnosis;
pulmonary hypertension; pulmonary hypoplasia
ABSTRACT
Objective Severe pulmonary hypoplasia and pulmonary
arterial hypertension are associated with reduced survival in congenital diaphragmatic hernia (CDH). We
aimed to determine whether fetal endoscopic tracheal
occlusion (FETO) improves survival in cases of severe
isolated CDH.
Methods Between May 2008 and July 2010, patients
whose fetuses had severe isolated CDH (lung-to-head
ratio < 1.0, liver herniation into the thoracic cavity and
no other detectable anomalies) were assigned randomly
to FETO or to no fetal intervention (controls). FETO
was performed under maternal epidural anesthesia supplemented with fetal intramuscular anesthesia. Tracheal
balloon placement was achieved with ultrasound guidance
and fetoscopy between 26 and 30 weeks of gestation.
All cases that underwent FETO were delivered by the
EXIT procedure. Postnatal therapy was the same for
both treated fetuses and controls. The primary outcome
was survival to 6 months of age. Other maternal and
neonatal outcomes were also evaluated.
Results Twenty patients were enrolled randomly to
FETO and 21 patients to standard postnatal management.
The mean gestational age at randomization was similar
in both groups (P = 0.83). Delivery occurred at 35.6 ±
2.4 weeks in the FETO group and at 37.4 ± 1.9 weeks in
the controls (P < 0.01). In the intention-to-treat analysis,
10/20 (50.0%) infants in the FETO group survived,
while 1/21 (4.8%) controls survived (relative risk (RR),
10.5 (95% CI, 1.5–74.7), P < 0.01). In the receivedtreatment analysis, 10/19 (52.6%) infants in the FETO
group and 1/19 (5.3%) controls survived (RR, 10.0 (95%
CI, 1.4–70.6) P < 0.01).
Conclusion FETO improves neonatal survival in cases
with isolated severe CDH. Copyright  2011 ISUOG.
Published by John Wiley & Sons, Ltd.
INTRODUCTION
Congenital diaphragmatic hernia (CDH) can be diagnosed
accurately by second-trimester ultrasound examination1 .
Despite all efforts, morbidity and mortality in cases
diagnosed prenatally remain high and are thought to
be related to the severity of pulmonary hypoplasia
and pulmonary arterial hypertension (PAH)2 . Many
studies have shown that a complicated neonatal course
and/or mortality are related to decreased fetal lung size
observed on ultrasound or magnetic resonance imaging,
the presence of herniated liver and decreased pulmonary
vascularity3 – 12 . For severe forms, fetal tracheal occlusion
has been suggested as a therapeutic option, since this
procedure has been shown to stimulate fetal lung growth
in both animal models and humans13 – 15 . Harrison et al.16
published a randomized study in human fetuses with
CDH, in which fetal tracheal occlusion was performed,
by means of maternal laparotomy followed by fetoscopy
using standard laparoscopic instrumentation. Patients in
the tracheal occlusion arm of the study experienced a high
Correspondence to: Dr R. Ruano, Universidade de São Paulo, Faculdade de Medicina, Obstetrics Department, São Paulo, Brazil, Av. Dr.
Enéias de Carvalho Aguiar, 255, 10◦ andar, Obstetrı́cia, São Paulo, Brazil, CEP 05403-900 (e-mail: rodrigoruano@usp.br)
Accepted: 4 October 2011
Copyright  2011 ISUOG. Published by John Wiley & Sons, Ltd.
RANDOMIZED CONTROLLED TRIAL
Fetoscopic tracheal occlusion in severe CDH
rate of preterm premature rupture of the membranes and
preterm delivery, which probably influenced the lack of
benefit reported. Furthermore, CDH cases of moderate
severity were included in the trial, which may similarly
have affected findings.
More recently, a minimal access approach to tracheal
occlusion was performed, with the introduction of a
smaller diameter fetoscope placed percutaneously under
ultrasound guidance, a procedure called ‘fetal endoscopic
tracheal occlusion’ (FETO)13,16,17 . A European group
published the results of the first 210 cases of severe CDH
that underwent FETO using a 1.2-mm fetoscope. Their
findings suggested that this technique may be associated
with a substantial improvement in perinatal survival,
with a low rate of complications14 . Our group recently
published a pilot study of 17 fetuses that underwent FETO
using a 1.0-mm fetoscope, and described the feasibility
and probable benefit of this fetal intervention for severe
CDH18 . However, there has been no randomized trial that
confirms the benefits of FETO for severe isolated CDH.
In the present randomized trial, we investigated the efficacy of FETO for the treatment of severe isolated CDH.
PATIENTS AND METHODS
21
Figure 1 Fetoscope insertion prior to fetal endoscopic tracheal
occlusion. (a) Percutaneous insertion of the slightly curved 2.7-mm
sheath into the amniotic cavity under ultrasound guidance.
(b) Insertion of the 1.0-mm fetoscope inside the cannula after
removing the trocar.
Study design
Between May 2008 and July 2010, a randomized controlled trial was conducted in a tertiary center at the
University of São Paulo in São Paulo, Brazil. The protocol was approved by the Institutional Review Board
of the University of São Paulo (CAPPesq 1087/07) and
followed the CONSORT Statement19 . Women presenting
with a singleton pregnancy between 22 and 26 weeks’
gestation and with fetal CDH were considered for the
trial. Patients were evaluated with comprehensive fetal
ultrasound, magnetic resonance imaging and echocardiography and underwent amniocentesis for karyotyping. Those meeting the following inclusion criteria were
offered enrolment in the trial: no detectable fetal anomalies other than CDH; normal karyotype; fetal lung-to-head
ratio (LHR) < 1.020,21 ; and at least one third of the
fetal liver herniated into the thoracic cavity as estimated by ultrasound4,22,23 . Other fetal ultrasonographic
characteristics recorded were: observed/expected LHR
(o/e-LHR) < 0.2524 ; observed/expected total lung volume (o/e-TotFLV) < 0.3510 and contralateral pulmonary
vascular index < 25%7 .
All patients underwent extensive counseling, and
those who met the inclusion criteria and agreed to
participate provided written informed consent for both
randomization and treatment. Patients who agreed to
participate in the study were assigned randomly to receive
FETO or prenatal expectant management in a ratio of
1 : 1 using a computer-generated randomization scheme.
Fetal endoscopic tracheal occlusion (FETO)
FETO was performed under maternal epidural anesthesia
between 26 and 30 weeks’ gestation by one of three operators (R.R., C.T.Y., M.M.S.), following a well-established
Copyright  2011 ISUOG. Published by John Wiley & Sons, Ltd.
protocol. Adjunct fetal anesthesia involved fentanyl
(15 µg/kg) and pancuronium (2 mg/kg) administration
according to the sonographic estimated fetal weight. Medications were administered intramuscularly into the fetal
arm using a 22-gauge needle under ultrasound guidance18 .
A specially designed, slightly curved operating sheath,
with a diameter of 2.7 mm, a working channel 1.3 mm
in diameter and a lower channel 1.2 mm in diameter
for the fetoscope, was introduced percutaneously into
the amniotic cavity under guidance by conventional twodimensional ultrasound (Figure 1a). Inside the amniotic
cavity, the trocar was withdrawn and the 1.0-mm fetoscope (11 510 A, Karl Storz, Tuttlingen, Germany) was
inserted (Figure 1b)15 . The cannula with the fetoscope
was advanced through the fetal mouth, over the epiglottis
(Figure 2a) and finally through the vocal cords (Figure 2b)
into the trachea. After identifying the carina, a catheter
loaded with a detachable balloon (GOLDBALL 4, Balt
Extrusion, Montmorency, France) was positioned just
proximal to the bifurcation of the main stem bronchi
(Figure 2c). The balloon was inflated with 0.8 mL saline
solution and detached from the catheter (Figure 2d) and
its position inside the fetal trachea was confirmed by
ultrasonography. Prophylactic tocolysis in the form of
intravenous Atosiban (Tractocile, Antocin, Ferring Pharmaceuticals, Malmo, Sweden) was administered according to our institution’s standard protocol: 6.75 mg (one
ampule) was administered immediately before the procedure, over a 1-min period; followed by two ampules
(13.50 mg) diluted in 90 mL saline solution administrated at a rate of 24 mL/h in the first 3 h, then 8 mL/h for
3.5 h25 . A prophylactic 2-g dose of intravenous cephalotin
(a first-generation cephalosporin) was given to the patients
Ultrasound Obstet Gynecol 2012; 39: 20–27.
22
Ruano et al.
Figure 2 Fetal endoscopic tracheal occlusion. Advancement of the cannula with the fetoscope over the epiglottis (a) and the vocal cords
(b) to the fetal trachea and positioning of the balloon just proximal to the bifurcation of the main stem bronchi (c). (d) Balloon inflation
inside the fetal trachea. This is followed by confirmation of its location by ultrasonography.
every 6 h for 24 h. All patients stayed in the city for further monitoring until the time of delivery. Ultrasound
examination was performed every 2 weeks until delivery.
Perinatal management
All fetuses in the FETO group were delivered by EXIT
(ex-utero intrapartum therapy) procedure to allow for
the controlled removal of the tracheal balloon at a
planned gestational age of 38 weeks. Briefly, maternal
general anesthesia was initiated and a hysterotomy
was performed, taking care to minimize maternal
bleeding. After delivery of the fetal head and while
the fetus remained on placental bypass, bronchoscopy
was performed to remove the balloon and to insert an
endotracheal tube. The umbilical cord was then cut.
Controls were delivered by planned Cesarean section
at 38 weeks’ gestation in order to avoid bias from the
method of delivery, which could interfere with neonatal
outcome.
All neonates were treated according to the same
protocol26,27 . Briefly, in the delivery room they were
intubated immediately, with placement of a nasogastric
tube, and then admitted to the neonatal intensive care
unit. Immediate ventilator support was started, with
Copyright  2011 ISUOG. Published by John Wiley & Sons, Ltd.
the fraction of inspired oxygen (FiO2 ) progressively
adjusted to achieve a preductal saturation > 80%. Central
venous access was obtained in all cases. Sedation was
not used routinely. High-frequency oscillatory ventilation
was started if persistent hypoxemia and hypercapnia
were observed on conventional ventilation. The treatment
protocol did not include extracorporeal membrane
oxygenation (ECMO), either pre- or postoperatively, as
this treatment modality is not available at our institution.
Surfactant was not used routinely. Inhaled nitric oxide
(iNO) was administered in cases of PAH verified by
a pre- to postductal saturation difference > 10% and
confirmed by echocardiography. Hemodynamic support
was achieved by volume expansion and administration
of dobutamine (10–20 µg/kg/min) and norepinephrine,
when necessary (0.5–2 µg/kg/min). CDH repair was
only performed after preoperative respiratory and
hemodynamic stabilization. Stabilization was defined
by the following criteria: (a) normal hemodynamic
variables (mean blood pressure > 40 mmHg, urine output
> 2 mL/kg/h), without inotropic agents; (b) absence of
pre- to postductal saturation difference and signs of
PAH during echocardiography, without iNO; and (c) a
switch to conventional mechanical ventilation that was
well-tolerated, with moderate values of peak inspiratory
Ultrasound Obstet Gynecol 2012; 39: 20–27.
Fetoscopic tracheal occlusion in severe CDH
23
pressure (15–20 cmH2 O) and adequate oxygenation,
achieved with FiO2 ≤ 40%.
57 patients referred for evaluation
14 not eligible
2 did not provide consent
Outcomes and statistical analysis
The primary outcome was survival to 6 months of age.
Additional outcomes were maternal complications, the
presence of postnatal severe PAH and length of time to
surgical repair of the diaphragmatic defect. Severe PAH
was defined when elevated pulmonary pressure (judged
by right to left or bidirectional shunting) was verified by
echocardiography or a there was a persistent difference in
pre- to postductal saturation gradient > 20%28,29 .
The sample size for the study was calculated considering
the primary outcome (infant survival rate) based on our
pilot study18 . An infant survival rate of 5–10% in cases
with severe CDH receiving standard neonatal care and an
infant survival rate of 40–60% in cases with severe CDH
treated with FETO were used for this calculation. A twotailed type I error of 5% and a power of 90% were used
to determine that a sample size of 19 fetuses per group
would be necessary. The trial was monitored regularly
after delivery of each case by an independent data safety
committee. Since we had performed a previous pilot study,
no interim analysis was planned during the trial due to
the small sample size. Analyses were performed using the
intention-to-treat principle. The data were analyzed using
Student’s t, Mann–Whitney U, chi-square and Fisher’s
exact tests and Kaplan–Meier survival analysis with Cox
proportional hazard model. Relative risks (RR) were also
calculated. Differences were considered to be statistically
significant when P < 0.05.
RE SULTS
During the study period, a total of 57 women with fetal
CDH were referred for evaluation, of whom 41 met
the inclusion criteria and gave written informed consent
(Figure 3). Twenty patients were assigned randomly to
the FETO group and 21 to postnatal care alone. Three
41 underwent randomization
20 assigned to FETO
(intention-to-treat
analysis)
21 assigned to no fetal
intervention
(intention-to-treat analysis)
1 declined
planned treatment based
on randomization
19 included in FETO group
(received-treatment
analysis)
2 declined
planned treatment based
on randomization
19 included in no fetal
intervention group
(received-treatment analysis)
Figure 3 Flow diagram of patients with severe isolated congenital
diaphragmatic hernia enrolled into the study. FETO, fetal
endoscopic tracheal occlusion.
patients (one in the FETO group and two in the standard
neonatal treatment group) declined planned treatment
based on randomization. These three patients did not
receive the same antenatal and neonatal management
as the remaining patients in the trial. They had limited
follow-up, including infant survival – all three died in
the neonatal period. Thus, 19 fetuses with severe CDH
successfully underwent FETO and 19 fetuses received the
standard care (controls).
For the intention-to-treat analysis, in the FETO group
there were 15 left-sided CDH cases and five right-sided
cases; in the control group there were 15 left-sided and
six right-sided cases. The two groups did not differ in this
or any other characteristic (Tables 1 and S1).
In this series, the mean duration of the FETO procedure
was 17.3 ± 8.3 min, which was significantly shorter than
that of our previous series18 (27.7 ± 8.3 min; P < 0.01).
Table 1 Sample characteristics of study groups: fetuses with severe isolated congenital diaphragmatic hernia randomized to receive fetal
endoscopic tracheal occlusion (FETO) or to no prenatal intervention (controls) in the intention-to-treat analysis
Characteristic
GA at randomization (weeks)
Maternal age (years)
Parity
Nulliparous
Parous
LHR
o/e-LHR
o/e-TotFLV
Contralateral VI (%)
Laterality of diaphragmatic defect
Left-sided
Right-sided
FETO group (n = 20)
Controls (n = 21)
P
25.3 ± 3.8 (21–26)
29.5 ± 6.6 (18–41)
25.5 ± 3.5 (21–26)
30.3 ± 6.4 (20–38)
0.83
0.85
0.76
12 (60.0)
8 (40.0)
0.80 ± 0.11
0.18 ± 0.02
0.26 ± 0.05
11.3 ± 4.5
12 (57.1)
9 (42.9)
0.79 ± 0.10
0.17 ± 0.06
0.27 ± 0.04
12.3 ± 4.5
15 (75.0)
5 (25.0)
15 (71.4)
6 (28.6)
0.77
0.85
0.39
0.60
0.99
Data given as mean ± SD (range), mean ± SD or n (%). GA, gestational age; LHR, lung-to-head ratio; o/e, observed/expected; TotFLV, total
fetal lung volume; VI, pulmonary vascular index.
Copyright  2011 ISUOG. Published by John Wiley & Sons, Ltd.
Ultrasound Obstet Gynecol 2012; 39: 20–27.
Ruano et al.
24
Table 2 Obstetric outcomes in fetuses with severe isolated congenital diaphragmatic hernia randomized to receive fetal endoscopic tracheal
occlusion (FETO) or to no prenatal intervention (controls) in the intention-to-treat analysis
Obstetric outcome
Maternal death
Maternal blood transfusion
Abruption
Maternal infection
PPROM < 37 weeks
PPROM < 32 weeks
Preterm delivery < 37 weeks
Preterm delivery < 32 weeks
GA at delivery (weeks)
FETO group (n = 20)
Controls (n = 21)
0
0
0
1 (5.0)*
7 (35.5)
4 (20.0)
10 (50.0)
3 (15.0)
35.6 ± 2.4 (31–38)
0
0
0
0
5 (23.8)
2 (9.5)
6 (28.6)
0
37.4 ± 1.9 (33–40)
P
—
—
—
—
0.51
0.41
0.21
0.11
< 0.01
Data given as n (%) or mean ± SD (range). *Chorioamnionitis after preterm premature rupture of membranes (PPROM).
Table 3 Infant outcome in cases of severe isolated congenital diaphragmatic hernia which as fetuses were randomized to receive fetal
endoscopic tracheal occlusion (FETO) or to no prenatal intervention (controls) in the intention-to-treat analysis
Infant survival to 6 months
Severe pulmonary arterial hypertension
FETO group (n = 20)
(n (%))
Controls (n = 21)
(n (%))
P
Relative risk
(95% CI)
10 (50.0)
10 (50.0)
1 (4.8)
18 (85.7)
< 0.01
0.02
10.5 (1.5–74.7)
0.6 (0.4–0.9)
The balloon was initially placed successfully inside the
fetal trachea using a single entry into the uterus in all
cases, including the seven patients with anterior placenta,
which did not require a transplacental fetoscopic entry.
Correct placement was confirmed by ultrasound examination. In two cases, the balloon ruptured after introducing
it into the fetal trachea and a second balloon was placed
correctly through the fetoscope without additional entry
into the uterus. Since our cannula had an independent
working channel, the balloon could be replaced without
removing the cannula from its position inside the fetal
trachea. The balloon was identified 6 weeks after FETO
in all 16 cases that delivered more than 6 weeks after the
procedure. The balloon was removed in all infants during
EXIT procedure; in two of these cases reduced inflation
was noted (13.3%).
There were no immediate intraoperative complications. Obstetric outcomes are shown in Tables 2 and S2.
Preterm premature rupture of the membranes < 32 weeks
and < 37 weeks were not significantly different between
FETO and control groups. Patients delivered at an earlier mean gestational age in the FETO group compared
with controls (P < 0.01); however, the frequencies of
prematurity (delivery < 37 weeks) and extreme prematurity (delivery < 32 weeks) were not significantly different
between the two groups. All cases in the FETO group
(received-treatment analysis) were delivered by EXIT procedure; 14 (73.7%) cases were planned procedures (10
at 37–38 weeks and four at 34–36 weeks after PROM)
and five (26.3%) cases were emergency EXIT procedures
due to the onset of preterm contractions. In the control
group, all patients were delivered by Cesarean section; 15
Copyright  2011 ISUOG. Published by John Wiley & Sons, Ltd.
Cumulative proportion surviving
Infant outcome
1.0
0.8
0.6
0.4
0.2
0.0
0
20
40
60
80 100 120 140 160 180
Days of age
Figure 4 Kaplan–Meier survival plot for intention-to-treat analysis,
showing cumulative proportion surviving from birth, in infants
which had undergone fetal endoscopic tracheal occlusion for severe
, n = 20)
isolated congenital diaphragmatic hernia (
compared with controls which received no prenatal intervention
, n = 21) (P < 0.01).
(
(78.9%) cases were planned deliveries and four (21.1%)
cases were emergency sections (P = 0.70).
In the intention-to-treat analysis, 10 of 20 (50.0%)
infants in the FETO group survived, while 1/21
(4.8%) controls survived (P < 0.01; RR, 10.5 (95%
CI, 1.5–74.7)) (Table 3 and Figure 4). The frequency
of severe PAH was significantly lower in the FETO group
compared with controls (50.0% vs. 85.7%, P = 0.02).
In the received-treatment analysis (Table S3), among
the neonates that had postnatal surgical repair (12 in the
FETO group and four in the control group, P = 0.02),
hemodynamic stabilization occurred earlier in the FETO
group than it did in controls (P < 0.01). A prosthetic
Ultrasound Obstet Gynecol 2012; 39: 20–27.
Fetoscopic tracheal occlusion in severe CDH
patch was used in 13 of the 16 (81.3%) infants that
underwent postnatal repair.
In the control group, two infants died after surgery
secondary to heart failure related to severe pulmonary
hypertension and another died secondary to pneumonia.
The sole surviving infant in the control group was discharged home without needing any respiratory support.
In the FETO group, one infant died after postnatal surgical repair due to heart failure caused by severe pulmonary
hypertension. Another infant died due to aspiration pneumonia secondary to megaesophagus caused by severe
esophageal reflux. None of the survivors in the FETO
group needed respiratory support after discharge. In one
case, fundoplication was performed before discharge due
to severe esophageal reflux. The mean age at hospital
discharge among the survivors in the FETO group was
34.7 ± 5.7 (range, 28–48) days.
The laterality of the CDH lesion was not associated
statistically with outcome. The overall infant survival
rates among the left-sided CDH and right-sided CDH
cases in the FETO group were 8/15 (53.3%) and 2/5
(40.0%), respectively (P = 0.38, intention-to-treat analysis). In cases of left-sided CDH, the survival rate in the
FETO group was better than that of the controls (53.3%
vs 6.7%, P < 0.01; RR, 8.0 (95% CI, 1.1–56.3)). In
cases of right-sided CDH, FETO again appeared to be
associated with an increased chance of survival compared
with controls although this difference was not statistically
significant (40.0% vs 0%, P = 0.08; RR, 5.8 (95% CI,
0.3–99.2)).
DISCUSSION
We found that FETO improved survival for fetuses with
severe isolated CDH compared with cases that received
only postnatal intensive care that is standard in our
country (50% vs 4.8%). However, the survival rates in our
present series for both antenatally treated and non-treated
groups were considerably lower when compared to a
previous randomized study16 . This difference could be
explained by the more rigorous criteria of CDH severity
used in the present study. In the previous randomized
study16 , inclusion criteria were LHR < 1.4 and liver
herniation, while in our study only fetuses with LHR
< 1.0 and liver herniation were included. Our results
are very similar to those of a European cohort, which
reported a 50% rate of neonatal survival after FETO13,14 .
The inclusion criteria in that study were similar to those
in our current investigation.
Our previous pilot study18 demonstrated that FETO
was feasible using a fetoscope of smaller diameter (1 mm)
than has been reported previously. In that earlier series,
placental abruption occurred in one case following FETO
and hemorrhage into the amniotic cavity occurred in
another. Both complications occurred in patients in which
there was inadvertent transplacental placement of the trocar. In our current randomized study, we avoided inserting
the trocar through or near the placenta. The duration of
the fetal procedure was significantly reduced compared
Copyright  2011 ISUOG. Published by John Wiley & Sons, Ltd.
25
with our initial series18 . These findings demonstrate a
clear learning curve for the procedure. However, despite
the use of a small-diameter fetoscope and a reduced size
of the trocar, FETO was still associated with a high
incidence of prematurity (50.0%), extreme prematurity
(15.0%) and preterm premature rupture of the membranes (35.0%). The incidence of these complications
was significantly lower compared with a previously published randomized trial that used maternal laparotomy
and 5.0-mm diameter trocars, in which the incidence of
prematurity was 73% and that of preterm rupture of
the membranes was 100%16 . On the other hand, our
incidence of premature complications was very similar to
those reported in the European cohort of 210 cases that
underwent FETO using a 1.2-mm fetoscope and a 3.2-mm
trocar. In that series, the median gestational age at delivery was 35 weeks, the incidence of extreme prematurity
was 17.1% and that of preterm premature rupture of the
membranes was 47.1%14 .
In our present study we used a larger balloon
(GOLDBALL 4) in comparison to our previous pilot
study18 , in which we used the GOLDBALL 2. The main
difference between these two balloons is the diameter
after inflation. The GOLDBALL 2 should be inflated
with 0.6 mL saline solution to reach an inflated diameter
and length of 7 mm and 20 mm, respectively. The
GOLDBALL 4 can be inflated with a maximum 0.8 mL
volume, leading to an inflated diameter and length of
9 mm and 16 mm, respectively. We changed to the largerdiameter balloon after our pilot study based on our
experience with frequent rupture of the smaller-diameter
balloon during inflation as well as a reduced rate of
retention of the inflated balloon after placement. We
noted in our pilot study that the balloon was no longer
inflated after 5–6 weeks in almost two thirds of cases and
hypothesized that a larger balloon would result in a more
occlusive effect and a greater incidence of retention. This
hypothesis was confirmed by our current finding that, after
the prescribed 6-week period of retention, the balloon was
identified in all 16 fetuses that had not already delivered.
The FETO procedure apparently improves survival by
enhancing pulmonary growth as a consequence of fetal
tracheal occlusion30,31 . Some experimental studies suggest
that fetal tracheal occlusion may also improve pulmonary
vascularity32 , which may reduce the risk of severe PAH.
In our present study, the frequency of severe PAH was significantly lower in cases that underwent FETO. However,
further studies are necessary to demonstrate conclusively
the beneficial effects of FETO on pulmonary growth and
vasculature response.
One criticism of this study is related to the fact that
the balloon was removed at the time of delivery through
an EXIT procedure. Other groups have recommended
removal of the balloon prior to delivery to improve neonatal outcome30 . Experimental research in a sheep model for
CDH has revealed that reversal of tracheal occlusion prior
to delivery allows recovery of type II pneumocytes33,34 .
Current guidelines for FETO include placement between
26 and 30 weeks’ gestation, with removal 6 weeks later13 .
Ultrasound Obstet Gynecol 2012; 39: 20–27.
Ruano et al.
26
A recent study suggested that the release of tracheal
occlusion at least 24 h before delivery was associated
with improved neonatal outcome30 . However, there are
insufficient data that provide information on the optimal
duration of tracheal occlusion in humans. Perhaps the
main advantage of removing the tracheal balloon before
delivery is avoidance of the need for an emergency EXIT
procedure, which occurred in 26% of our cases.
Another possible criticism is that our cases were not
managed after birth with ECMO. The use of ECMO in
the management of CDH is controversial and its true
benefits have not been proven conclusively35 – 38 . One
systematic review including 21 retrospective studies and
three randomized controlled trials indicated that ECMO
improves short-term neonatal survival (RR, 0.73 (95% CI,
0.54–0.98), P = 0.04), but not long-term survival (RR,
0.83 (95% CI, 0.66–1.05), P = 0.12)37 . A more recent
Cochrane review found that ECMO improved shortterm neonatal survival (RR, 0.73 (95% CI, 0.55–0.99),
P = 0.03), but not long-term survival (RR, 0.84 (95% CI,
0.67–1.10), P = 0.13)38 . In our study, all infants that survived to discharge were alive at 6 months of age. ECMO
has been associated with other long-term morbidities,
including neurological and respiratory complications37,38 .
Larger studies in centers that provide ECMO are needed
to determine if FETO can reduce the need for ECMO and
its associated morbidities.
We did not use laterality of the diaphragmatic defect
to stratify patients before randomization. In general, right
sided-CDH is considered more severe because these cases
have a greater amount of herniated liver and smaller lung
volumes. However, in our series, the laterality of the CDH
did not appear to influence the survival rate after FETO.
In conclusion, FETO improves infant survival in
isolated severe CDH. However, the risk of prematurity
and preterm premature rupture of membranes was high,
despite the use of small-diameter fetoscopes.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
ACKNOWLEDGMENTS
We thank Dr Kenneth Moise Jr. for his great contribution
to the revision and analysis of the data as well as
editing of the English text. We also thank Dr Michael
A. Belfort for revision and editing of the manuscript.
The present study was funded by the CNPq (Conselho
Nacional de Desenvolvimento de Pesquisa e Tecnologia do
Brasil). SISNEP CAAE - 0926.0.015.000-07 (April 2008)
ClinicalTrials.gov Identifier: NCT01302977 (Feb 2011).
13.
14.
15.
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SUPPORTING INFORMATION ON THE INTERNET
The following supporting information may be found in the online version of this article:
Tables S1–S3 Sample characteristics (Table S1), obstetric outcome (Table S2) and infant outcome
(Table S3) in fetuses with severe isolated congenital diaphragmatic hernia randomized to receive fetal
endoscopic tracheal occlusion (FETO) or to no prenatal intervention (controls) in the received-treatment
analysis.
Copyright  2011 ISUOG. Published by John Wiley & Sons, Ltd.
Ultrasound Obstet Gynecol 2012; 39: 20–27.