Available via license: CC BY 4.0
Content may be subject to copyright.
STUDY INFORMATION
Title
Fetoscopic Endoluminal Tracheal Occlusion with Smart-TO balloon: efficacy of
removal and safety.
Authors
Nicolas Sananès 1,2,*, David Basurto 3,*, Anne-Gaël Cordier 4, Caroline Elie 5, Francesca
Russo3,6, Alexandra Benachi 4,* and Jan Deprest 3,6,7,*
1 Department of Maternal Fetal Medicine, Strasbourg University Hospital, France
2 INSERM 1121 'Biomaterials and Bioengineering', Strasbourg University, France
3 MyFetUZ Fetal Research Center, Department of Development and Regeneration, Cluster
Woman and Child, Biomedical Sciences, KU Leuven, Belgium
4 Department of Maternal fetal Medicine, Antoine–Béclère Hospital - Paris–Saclay University,
Clamart, France
5 Clinical Research Unit / Clinical Investigation Center, Necker-Enfants malades Hospital,
Paris, France
6 Clinical Department of Obstetrics and Gynaecology, University Hospitals Leuven, Belgium
7 Institute for Women's Health, University College London, UK.
* shared first and last authorship.
Corresponding author:
Nicolas Sananès
Department of Obstetrics and Gynecology
Strasbourg University Hospital
Avenue Molière, 67200 Strasbourg
. CC-BY 4.0 International licenseIt is made available under a
perpetuity.
is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint The copyright holder for thisthis version posted August 22, 2022. ; https://doi.org/10.1101/2022.08.17.22278918doi: medRxiv preprint
NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.
Tel: +33 3 69 55 33 97
Email: Nicolas.sananes@chru-strasbourg.fr
ORCID list:
Nicolas SANANÈS: 0000-0002-0461-8428
David BASURTO: 0000-0002-2022-9027
Anne-Gaël CORDIER: 0000-0002-6006-8408
Francesca RUSSO: 0000-0002-5029-7899
Alexandra BENACHI: 0000-0001-6045-0765
Jan DEPREST: 0000-0002-4920-945X
Disclosure statement: Nicolas Sananès is the primary co-inventor of the Smart-TO balloon.
None of the authors has any financial interest in BS‐Medical Tech Industry, manufacturing the
balloon. There are no other conflicts of interest.
Funding: DB is funded by the Erasmus + Programme of the European Union (Framework
Agreement number: 2013-0040). This publication reflects the views only of the authors, and
the Commission cannot be held responsible for any use which may be made of the information
contained therein. JD is funded by the Great Ormond Street Hospital Charity Fund. In Paris,
the present clinical protocol is funded by a grant from Assistance Publique – Hôpitaux de Paris
(CRC19). In Leuven, the study is funded by the Klinisch Onderzoeks- en Ontwikkelingsfonds
of the UZ Leuven (S65423).
. CC-BY 4.0 International licenseIt is made available under a
perpetuity.
is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint The copyright holder for thisthis version posted August 22, 2022. ; https://doi.org/10.1101/2022.08.17.22278918doi: medRxiv preprint
Acknowledgements:
The Smart-TO balloon is the result of several years of research and development within a
consortium of the following institutions: BS‐Medical Tech Industry (manufacturer), Strasbourg
University Hospital, University of Strasbourg, INSERM Unit 1121 "Biomaterials and
Bioengineering", Institut Hospitalo-Universitaire de Strasbourg, Institute for Research Against
Cancers of the Digestive System, SATT-Conectus Alsace, Simian Laboratory Europe, and the
KU Leuven.
The authors thank URC-CIC Paris Centre (Adèle Bellino), the DRCI (Shoreh Azimi) and UZ
Leuven Clinical Trial Centre (Veerle Doozen) for the implementation, monitoring and data
management of the study.
. CC-BY 4.0 International licenseIt is made available under a
perpetuity.
is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint The copyright holder for thisthis version posted August 22, 2022. ; https://doi.org/10.1101/2022.08.17.22278918doi: medRxiv preprint
ABSTRACT
Introduction
One of the drawbacks of fetoscopic endoluminal tracheal occlusion (FETO) for congenital
diaphragmatic hernia is the need for a second invasive intervention to reestablish airway
patency. The “Smart-TO” (Strasbourg University-BSMTI, France) is a new balloon for FETO,
which spontaneously deflates when positioned near a strong magnetic field, e.g., generated
by a magnetic resonance image (MRI) scanner. Translational experiments have demonstrated
its efficacy and safety. We will now use the Smart-TO balloon for the first time in humans. Our
main objective is the efficacy of prenatal deflation of the balloon by the magnetic field
generated by an MRI scanner.
Material and methods
This is a phase-I study conducted in the fetal medicine units of Antoine–Béclère Hospital,
France, and UZ Leuven, Belgium. Conceived in parallel, protocols were amended by the local
Ethics Committees, resulting in some minor differences. This trial is a single-arm interventional
feasibility study. Twenty (France) and 25 (Belgium) participants will have FETO with the Smart-
TO balloon. Balloon deflation will be scheduled at 34 weeks or earlier if clinically required. The
primary endpoint is the successful deflation of the Smart-TO balloon after exposure to the
magnetic field of an MRI, assessed through ultrasound immediately after MRI-exposure. The
secondary objective is to report on the safety of the balloon. The percentage of fetuses in
whom the balloon is deflated after exposure will be calculated with its 95% confidence interval.
Safety will be evaluated by reporting the nature, number, and percentage of serious
unexpected or adverse reactions.
Conclusion
This phase-I study may provide the first evidence of the potential to reverse the occlusion by
Smart-TO and free the airways non-invasively, as well a safety data.
. CC-BY 4.0 International licenseIt is made available under a
perpetuity.
is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint The copyright holder for thisthis version posted August 22, 2022. ; https://doi.org/10.1101/2022.08.17.22278918doi: medRxiv preprint
INTRODUCTION
Background
Congenital diaphragmatic hernia (CDH) is a birth defect characterized by failed closure of the
diaphragm. This enables abdominal viscera to herniate into the thoracic cavity, leading to
hypoplastic lungs and impaired lung vasculature [1]. Fetoscopic Endoluminal Tracheal
Occlusion (FETO) increases fetal lung volume and therefore can improve survival in selected
fetuses with CDH. Recently two parallel randomized controlled trials in fetuses with isolated
left-sided CDH with severe and moderate pulmonary hypoplasia respectively were concluded
[2, 3]. In severe hypoplasia the balloon was inserted early (27+0 to 29+6 weeks’ gestation) and
FETO improved survival from 15% to 40% (Table 1) [3]. A comparable improvement in survival
(20% to 42%) was achieved in fetuses with severe right-sided CDH [4]. In moderate
hypoplasia, the balloon was inserted later (30+0 to 31+6 weeks’ gestation) in an effort to reduce
the risks of very preterm birth. In that study, FETO improved survival from 50% to 63%, but
the difference in survival was not statistically significant [2]. Analysis of the pooled data from
the two randomized trials demonstrated that FETO increases survival in both severe and
moderate disease (Table 1), but the observed lesser effect in the moderate group is most likely
a mere consequence of the delayed insertion of the balloon in moderate hypoplasia[5].
An adverse side-effect of FETO is that it increases the risk for iatrogenic preterm
membrane rupture and preterm birth [6, 7]. In the TOTAL trials, that risk was inversely related
to the gestational age at the insertion of the balloon [5]. Although the trials did not demonstrate
any obvious differences between the FETO and control groups in prematurity-related
complications, they were not powered to study differences in these secondary outcomes.
Long-term outcomes will have to further elucidate that, but it would seem logical to expect a
measurable effect of prematurity when large numbers are available.
A second disadvantage of the current procedure is the need for a second intervention
to reverse the occlusion and re-establish airway patency. Balloon removal is scheduled
electively at 34 weeks, or earlier if required. Reversal of the occlusion is preferentially
. CC-BY 4.0 International licenseIt is made available under a
perpetuity.
is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint The copyright holder for thisthis version posted August 22, 2022. ; https://doi.org/10.1101/2022.08.17.22278918doi: medRxiv preprint
performed at least 24 hours before birth, as that seems associated with an increased survival
[2, 8-10]. Reversal is at present an invasive procedure that can be performed by either
ultrasound-guided puncture, fetoscopy, or, less ideal, while the fetus is maintained on
placental circulation or at birth after vaginal delivery [10]. Airway re-establishment requires a
specialist team familiar with the procedure and that is available 24/7 [10]. In a large series,
28% of balloon removals were in an emergency setting [10]. The only neonatal deaths that
occurred, were when balloon reversal was attempted in centers without experience or that
were unprepared [10]. Even in experienced centers balloon removal can fail, as observed in
the TOTAL trial [2]. Also, patients may be non-compliant and move away from the fetal surgery
center [2]. The second procedure inherently adds risks for the mother and fetus. These can
be directly procedure-related, but also indirectly, by increasing the risk for membrane rupture
later on [10]. In conclusion, the occlusion period is a serious burden on patients who are
requested to stay close to the FETO center until balloon removal, as well as for the fetal
surgery centers because of the need for permanently available staff. All these conditions, limit
the acceptability of FETO as being practiced today.
The University of Strasbourg, France, in partnership with BS Medical Tech Industry
(BS-MTI), Niederroedern, France, developed an alternative occlusion device, referred to as
"Smart-TO" [11]. Compared to the currently used Goldbal2® (Balt, Montmorency, France)
balloon, the Smart-TO balloon has identical dimensions in its inflated state and is made of the
same material (latex). Around the balloon neck, there is a metallic cylinder and inside a
magnetic ball, which together act as a valve. Deflation occurs under the influence of a strong
magnetic field, which is present around any clinical MRI machine. For that, it is sufficient for
the pregnant woman to walk around the MRI machine. This enables non-invasive, externally
controlled balloon deflation. The Smart-TO balloon been tested preclinically by BS-MTI (the
manufacturer), University of Strasbourg, Simian Laboratory Europe and the KU Leuven. In-
vitro tests including permeability, occlusion, and deflation in a simulated environment were
performed by BS-MTI (unpublished data). Deflation tests were performed using a mannequin
. CC-BY 4.0 International licenseIt is made available under a
perpetuity.
is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint The copyright holder for thisthis version posted August 22, 2022. ; https://doi.org/10.1101/2022.08.17.22278918doi: medRxiv preprint
in a simulated “in-utero” environment, with the fetus and the mother in different positions and
heights. In that experiment, deflation was successfully achieved regardless of the fetal position
and the exact level of the fetus from the ground [12]. In vivo animal tests included the
demonstration of similar lung growth and short-term tracheal side effects as the Goldbal 2
balloon in fetal lambs [12] [13]. In the latter experiment, fetal lambs expelled the Smart-TO
balloon following exposure to the fringe field of a 3T MRI. Finally, feasibility of balloon insertion,
persisting occlusion until reversal, and spontaneous expulsion of the Smart-TO balloon was
confirmed in non-human primates [11]. Therefore, this novel medical device should now be
evaluated in a phase I or first-in-human study. For that purpose we designed two parallel
studies, one at Antoine–Béclère Hospital Paris–Saclay University, Clamart, France referred to
as “Smart-FETO”, and one at the University Hospitals Leuven (UZ Leuven), Belgium, referred
to as “Smart-Removal”. Conceived in parallel, protocols were amended by the local Ethics
Committee on Clinical Studies or its equivalent, resulting in a limited number of differences
(Table 2).
Objectives and hypotheses
The main objective of the study is to demonstrate the ability to consistently deflate the balloon
prenatally by the magnetic fringe field generated by a clinical MRI scanner, and that it will be
expelled from the airways. Secondary objective is to report on the safety of the balloon. We
hypothesize that there will not be any serious adverse effects directly related to the Smart-TO
balloon itself. Other objectives include assessment of prematurity, preterm premature rupture
of membranes, lung growth, neonatal survival, and the need for oxygen supplementation at
discharge from the hospital.
DESIGN PLAN
Study type
. CC-BY 4.0 International licenseIt is made available under a
perpetuity.
is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint The copyright holder for thisthis version posted August 22, 2022. ; https://doi.org/10.1101/2022.08.17.22278918doi: medRxiv preprint
This clinical trial is a single-arm interventional feasibility study. Eligible consecutive
consenting women will have FETO with the Smart-TO balloon.
Setting
The trial is conducted at two centers i.e., the Antoine–Béclère Hospital - Paris–Saclay
University, Clamart, France, and the University Hospitals Leuven, Belgium
SAMPLING PLAN
Existing data
Both trials have been registered prior to their inception (ClincalTrial.gov NCT04931212 and
NCT05100693). The first inclusion in France was on August 4th,2021, and in Belgium on
September 10th,2021.
Recruitment
Recruitment of participants will be at the latest one day before planned balloon placement.
Inclusion Criteria:
- Patient aged 18 years or more and who can consent,
- Singleton pregnancy with a fetus with an isolated congenital diaphragmatic hernia (i.e., no
additional major structural malformation nor genetic abnormality)
-Eligible for FETO, i.e. having severe pulmonary hypoplasia defined as, in left-sided cases, an
observed-to-expected 'lung-to-head ratio' (O/E LHR) <25% irrespective of the liver position, or
moderate pulmonary hypoplasia defined as O/E LHR 25-34.9% irrespective of the liver position
or O/E LHR 35-44.9% with liver herniation, and, in UZ Leuven, fetuses with right-sided CDH
with severe hypoplasia (O/E LHR < 50%).
. CC-BY 4.0 International licenseIt is made available under a
perpetuity.
is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint The copyright holder for thisthis version posted August 22, 2022. ; https://doi.org/10.1101/2022.08.17.22278918doi: medRxiv preprint
Exclusion Criteria:
- Maternal contraindication to fetoscopy
- Preterm premature rupture of the membranes (PPROM) or any condition strongly
predisposing to PPROM or premature delivery
- Patient does not consent to stay close to the FETO center during the occlusion period.
Sample size
Independent sample size calculation has been performed in both centers. In Paris (France) we
hypothesized that for a 100% deflation and expelling rate, the estimated number of patients is
20 patients in order to achieve a 95% confidence interval (CI) with a lower boundary of 83%
(calculation of the CI of a proportion using the exact method) [14]. In Leuven (Belgium), the
estimated number is 23 patients, in order to achieve a 95% CI with a lower boundary of 85%
[14]. The theoretical possibility of spontaneous balloon deflation, or the impossibility to expose
the patient to MRI at the time of balloon removal (e.g., in an emergency requiring removal on
placental circulation) was considered as possible (n=2), so that a total of 25 patients are to be
recruited.
VARIABLES
Measured variables
These include administrative data, data on the index pregnancy, characteristics of the fetus,
on the FETO procedure, follow-up ultrasound measurements, balloon removal, delivery, and
the neonatal follow-up period until discharge from the neonatal intensive care unit (NICU)
(Table 3).
. CC-BY 4.0 International licenseIt is made available under a
perpetuity.
is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint The copyright holder for thisthis version posted August 22, 2022. ; https://doi.org/10.1101/2022.08.17.22278918doi: medRxiv preprint
Primary endpoint
The primary endpoint is the successful deflation of the Smart-TO balloon after exposure to the
fringe field of the MRI, assessed through ultrasound immediately after MRI exposure. For
France, a co-primary endpoint is the expelling of the Smart-TO balloon from the airways, as
documented by a X-ray of the neonatal chest at birth.
Secondary endpoints are displayed in table 2.
STATISTICAL ANALYSIS PLAN
Quantitative data will be expressed as median and inter-quartile-range (IQR), qualitative data
will be expressed as numbers and percentages. The percentage of fetuses in whom the
balloon deflated at exposure and the percentage of fetuses that expelled the balloon from the
fetal airways will be calculated with its 95% confidence interval using the binomial method [14].
Safety will be evaluated by reporting the nature, number, and percentage of serious
unexpected or adverse reactions. We expect there will be no missing data for the primary
outcome variable. There will be no imputation of missing data for secondary outcomes. A
sensitivity analysis will be performed assuming the worst possible outcome for missing data.
INTERVENTION
FETO
The FETO procedure will be performed as earlier described [15]. Regarding the Smart TO use:
-The catheter system is introduced in the sheath of the endoscope and back loaded with
the Smart-TO balloon. The balloon is then tested by inflation with 0.7 mL of sterile saline
and deflated with its proper stylet, following which the latter is withdrawn.
. CC-BY 4.0 International licenseIt is made available under a
perpetuity.
is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint The copyright holder for thisthis version posted August 22, 2022. ; https://doi.org/10.1101/2022.08.17.22278918doi: medRxiv preprint
-The balloon is positioned between the carina and the vocal cords, inflated with 0.7 mL
sterile saline, and detached by the combination of gentle traction of the delivery system
and counter pressure with the endoscope.
Reestablishment of the fetal airways
The Smart-TO deflation protocol is displayed in Supplementary Video 1.
-The patient is positioned in front of the MRI, her abdomen facing the front of the tunnel of
the machine.
-The patient walks (or is strolled) around the machine while staying as close as possible to
the machine.
-When approaching the rear of the tunnel, the patient positions herself in the middle of it,
facing the tunnel and makes a short stop.
-Then she continues to walk (or being strolled) around the MRI while staying as close as
possible to the machine
-Once she has completed the turn, she can leave the MRI room.
Ultrasound is then performed independently by two experienced sonographers, to assess
balloon deflation. When inflated, the balloon is easily visible on ultrasound as an anechoic
structure. Balloon deflation will be indicated by visualization of the balloon on ultrasound
before MRI exposure and its disappearance immediately after MRI exposure. In the case
of deflation failure, a second or third MRI exposure will be attempted, again followed by
ultrasound confirmation of balloon deflation.
Conventional reestablishment of the fetal airways
In the case of failure to deflate, balloon removal will be done as currently done with the
conventional balloon, either ultrasound-guided puncture, fetoscopy, or in an emergency during
. CC-BY 4.0 International licenseIt is made available under a
perpetuity.
is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint The copyright holder for thisthis version posted August 22, 2022. ; https://doi.org/10.1101/2022.08.17.22278918doi: medRxiv preprint
abdominal delivery while the fetus is on placental circulation, or after birth by puncture above
the manubrium sterni[15].
ETHICS AND REGULATORY CONSIDERATIONS
In France, approval was provided by the committee for the protection of persons concerned
(CPP “Ile de France VIII”) in January 2021 (# 21 01 01), and the French medicines controls
authorities (ANSM) in March (2020-A02834-35-A). In Belgium, approval was given by the
Ethics Committee on Clinical Studies of the University Hospitals Leuven in July 2021 (S65423).
The study was registered at the Federal Agency for Medicines and Health Products
(FAGG/80M0892).
DISCUSSION
Based on robust clinical evidence, one should consider the option of FETO in selected fetuses
with CDH [2-5]. One of the major concerns about FETO is the potential problems related to
balloon removal [10]. The Smart-TO balloon addresses this issue by allowing a noninvasive,
easily triggered, and externally controlled reversal of occlusion [16]. After extensive
translational research, the time has come to assess the efficacy of reversal of the occlusion
and the safety of this new device in a first-in-woman study.
The main objective of this study is to demonstrate the ability to successfully deflate the Smart-
TO balloon by the magnetic fringe field generated by an MRI scanner. The present trial also
aims to demonstrate the Smart-TO balloon is no longer within the airways. Non-visualization
of the balloon will provide evidence for airway permeability. In the Belgian site, the E.C. also
required to positively identify the localization of the balloon following deflation, either within the
amniotic fluid, membranes, or placenta (at delivery), and exclude its persistence in the uterus
by postpartum ultrasound. Additional objectives of this study include the evaluation of safety,
even though no serious adverse effects directly related to the Smart-TO balloon are
anticipated.
. CC-BY 4.0 International licenseIt is made available under a
perpetuity.
is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint The copyright holder for thisthis version posted August 22, 2022. ; https://doi.org/10.1101/2022.08.17.22278918doi: medRxiv preprint
The dimensions of the Smart-TO balloon and material (latex) are the same as the Goldbal2®
balloon. For this reason, it is anticipated that the Smart-TO will induce similar lung growth
compared to the Goldbal2® balloon, as previously demonstrated in preclinical studies [12, 17].
Additional outcome measurements include the occurrence of membrane rupture and preterm
delivery, which is consistently reported in all FETO series. We will also report on the
consequence of the above.
The limitations of our study will be that this is a non-comparative trial. However, including a
second arm, where controls would have FETO by means of the Goldbal2® balloon, appears
to be unethical, since this will not provide new data and there is sufficient data on file on
outcomes when using the standard balloon.
In conclusion, this first in-woman study aims to demonstrate the ability of Smart-TO balloon to
be prenatally deflated by the magnetic fringe field generated by an MRI scanner, its expelling
from the airways, as well as the safety of its use.
. CC-BY 4.0 International licenseIt is made available under a
perpetuity.
is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint The copyright holder for thisthis version posted August 22, 2022. ; https://doi.org/10.1101/2022.08.17.22278918doi: medRxiv preprint
. CC-BY 4.0 International licenseIt is made available under a
perpetuity.
is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint The copyright holder for thisthis version posted August 22, 2022. ; https://doi.org/10.1101/2022.08.17.22278918doi: medRxiv preprint
Figure 1: SPIRIT schedule. Abbreviations: FETO, Fetoscopic Endoluminal Tracheal
Occlusion; O/E LHR, observed-to-expected lung-to-head ratio; MRI, Magnetic Resonance
Image.
. CC-BY 4.0 International licenseIt is made available under a
perpetuity.
is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint The copyright holder for thisthis version posted August 22, 2022. ; https://doi.org/10.1101/2022.08.17.22278918doi: medRxiv preprint
Table 1: Outcomes of fetuses diagnosed with isolated congenital diaphragmatic hernia
(CDH) in the prenatal period, either left or right-sided, expectantly managed during
pregnancy or having tracheal occlusion within the “Tracheal Occlusion to Accelerate
Lung Growth” (TOTAL) trial or and a large study on right-sided CDH under the same
management protocol.
Abbreviations: RR, risk ratio; CI, confidence interval; O/E LHR, observed-to-expected lung-
to-head ratio; A, adjusted; OR, odds ratio.
Survival to discharge
Side, severity
Criteria severity on ultrasound
Expectant
FETO
RR (95% CI)
Isolated left sided CDH – TOTAL trials
TOTAL
severe[3]
O/E LHR <25.0%
Irrespective of liver position
6/40
(15%)
16/40
(40%)
2.67
(1.22-6.11)
TOTAL
moderate[2]
O/E LHR 25.0-34.9%, any liver
position
O/E LHR 35.0-44.9% & liver into
chest
49/98
(50%)
62/98
(63%)
1.27
(0.99-1.63)
Isolated left sided CDH – Pooled analysis TOTAL data
Late
insertion
O/E LHR 0.0-34.9%, any liver
position
O/E LHR 35.0-44.9% & liver into
chest
A OR: 1.78
(1.05-3.01)
Early
insertion
O/E LHR 0.0-34.9%, any liver
position
O/E LHR 35.0-44.9% & liver into
chest
55/142
(39%)
79/145
(54%)
A OR: 2.73
(1.15-6.49)
Isolated right sided CDH
Severe[4]
O/E LHR <50%
Irrespective of liver position
7/34
(20%)
53/125
(42%)
2.84
(1.15-7.01)
. CC-BY 4.0 International licenseIt is made available under a
perpetuity.
is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint The copyright holder for thisthis version posted August 22, 2022. ; https://doi.org/10.1101/2022.08.17.22278918doi: medRxiv preprint
Table 2: Inclusion criteria and outcome measurements in both studies.
Differences are displayed in bold.
Smart-FETO (Paris)
Smart-Removal (Leuven)
Inclusion criteria
- Patient can consent, has 18 years or more, and has
medical insurance
- Singleton pregnancy with a fetus with an isolated
left CDH with severe or moderate lung hypoplasia
- Patient can consent, has 18 years or more
- Singleton pregnancy with a fetus with an isolated
left CDH with severe or moderate lung hypoplasia or
right CDH with severe lung hypoplasia
(Co-)primary endpoint
- Balloon deflation rate after MRI exposure (by
ultrasound).
- Balloon expulsion from the fetal airways (by
postnatal chest X-ray)
- Balloon deflation rate after MRI exposure (by
ultrasound).
Secondary endpoints
Prenatal
- Spontaneous balloon deflation prior to MRI
exposure (by ultrasound)
- Lung growth (O/E LHR).
- Balloon height and width (ultrasound).
- Gestational age at membrane rupture
Postnatal:
- Gestational age at delivery
- Localisation of the balloon by postnatal chest X-
ray of the newborn
Neonatal:
- Survival at discharge from the NICU
-Survival at 6 months
-Need for oxygen supplementation at 6 months
Adverse events:
- Any adverse event, either in the mother or the fetus
or newborn, at whatever time point between insertion
and discharge from the neonatal unit
Prenatal
- Spontaneous balloon deflation prior to MRI
exposure (by ultrasound).
- Lung growth 2 weeks after FETO (O/E LHR).
- Gestational age at membrane rupture
Postnatal:
- Gestational age at delivery
- Balloon expulsion from the fetal airways (by
postnatal chest X-ray)
- Localisation of the balloon either by (1) direct
visualization within the amniotic fluid,
membranes or placenta, (2) postnatal chest X-ray
of the newborn, and (3) ultrasound of the
postpartum uterus.
Neonatal:
- Survival at discharge from the NICU
- Tracheal diameter on first postnatal chest X-ray
- Assessment for any local side effects of the
balloon (signs or symptoms of tracheomegaly
and /or tracheomalacia)
Adverse events:
- Any adverse event, either in the mother or the fetus
or newborn, at whatever time point between insertion
and discharge from the neonatal unit
Sample size
n=20 for a 95% CI with a lower boundary of
83%[14].
n=25 for a 95% CI with a lower boundary of
85%[14] and an expected loss rate of 8% (n=2)
due to the need for removal on placental
circulation or spontaneous balloon deflation.
Abbreviations: CDH, congenital diaphragmatic hernia; MRI, magnetic resonance image; O/E
LHR, observed to expected lung to head ratio; CI, confidence interval.
. CC-BY 4.0 International licenseIt is made available under a
perpetuity.
is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint The copyright holder for thisthis version posted August 22, 2022. ; https://doi.org/10.1101/2022.08.17.22278918doi: medRxiv preprint
Table 3: List of variables from both studies.
Differences are displayed in bold.
Paris (Smart FETO)
Leuven (Smart Removal)
Administrative data
-Last name initial
-First name initial
-Date of birth
-Physician responsible for the inclusion
-Referring center prenatal
-Referring fetal medicine specialist
-Center postnatal care
-Postnatal specialist
Subject number
Date of birth
-Physician responsible for the inclusion
-Referring center prenatal
-Referring fetal medicine specialist
-Center postnatal care
-Postnatal specialist
Selection visit
-Date of selection visit
-Have all inclusion criteria been met? yes; no;
-Date of signature of consent
-Parity
-Conception: spontaneous; assisted;
unknown
-Estimated day of delivery
-Pre-pregnancy weight (kg)
-Height (cm)
-Smoking: 0/d; 1-10/d; 10-20/d; 21 or more/d
-Alcohol use: 0; once a week; 2-4/w; >5/w
-Drugs: yes; no
-Concomitant diseases: yes; no; describe
-Ethnicity: Caucasian; North African; African;
Asian; Other
-Gestational age
-Severity of hernia: moderate; severe
-Method for LHR measurement: tracing;
longest diameter; anteroposterior
diameter and perpendicular
-O/E LHR (%)
-Liver herniation: down; up
-Grading of stomach position according to
Cordier classification: 1; 2; 3; 4
-Cervical length (mm)
-Chorionic membrane separation
-Deepest vertical amniotic fluid pocket (cm)
-Placental position: anterior; posterior; fundal
-Placenta previa: no; yes
-Karyotype performed: no; yes
-CGHarray performed: no; yes
-Date of selection visit
-Have all inclusion criteria been met? yes; no;
-Date of signature of consent
-Parity
-Conception: spontaneous; assisted;
unknown
-Estimated day of delivery
-Pre-pregnancy weight (kg)
-Height (cm)
-Smoking: 0/d; 1-10/d; 10-20/d; 21 or more/d
-Alcohol use: 0; once a week; 2-4/w; >5/w
-Drugs: yes; no
-Concomitant diseases: yes; no; describe
-Ethnicity: Caucasian; North African; African;
Asian; Other
-Gestational age
-Severity of hernia: moderate; severe
-Hernia side; left; right
-O/E LHR (%)
-Liver herniation: down; up
-Grading of stomach position according to
Cordier classification: 1; 2; 3; 4; N/A (right-
CDH)
-Cervical length (mm)
-Chorionic membrane separation
-Deepest vertical amniotic fluid pocket (cm)
-Placental position: anterior; posterior; fundal
-Placenta previa: no; yes
-Karyotype performed: no; yes
-CGHarray performed: no; yes
. CC-BY 4.0 International licenseIt is made available under a
perpetuity.
is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint The copyright holder for thisthis version posted August 22, 2022. ; https://doi.org/10.1101/2022.08.17.22278918doi: medRxiv preprint
-Results karyotype / CGHarray: normal;
abnormal
-Results karyotype / CGHarray: normal;
abnormal
Pre-FETO visit
-Date
-Gestational age
-Severity of hernia: moderate; severe
-Method for LHR measurement: tracing;
longest diameter; anteroposterior
diameter and perpendicular
-O/E LHR (%)
-Liver herniation: down; up
-Grading of stomach position according to
Cordier classification: 1; 2; 3; 4
-Cervical length (mm)
-Chorionic membrane separation
-Deepest vertical amniotic fluid pocket (cm)
-Placental position: anterior; posterior; fundal
-Placenta previa: no; yes
-Date of MRI
-O/E Total lung volume MRI (%)
-Additional anomalies on MRI: yes; no;
describe
-Date
-Gestational age
-Severity of hernia: moderate; severe
-Hernia side; left; right
O/E LHR (%)
-Liver herniation: down; up
-Grading of stomach position according to
Cordier classification: 1; 2; 3; 4; N/A (right-
CDH)
-Cervical length (mm)
-Chorionic membrane separation
-Deepest vertical amniotic fluid pocket (cm)
-Placental position: anterior; posterior; fundal
-Placenta previa: no; yes
-Date of MRI
-O/E Total lung volume MRI (%)
-Additional anomalies on MRI: yes; no;
describe
FETO procedure
-Date
-Operator name
-Anesthesia: local; loco-regional (spinal;
epidural; spinal-epidural); general
-Complications related to anesthesia
-Initial position of fetus: cephalic, breech,
transverse
-Fetal version: no; yes
-Final position of fetus: cephalic, breech,
transverse
-Complications / difficulties related with
balloon preliminary tests: no; yes
-Complications / difficulties related with
connection of balloon with catheter: no; yes
-Complications / difficulties related with
balloon positioning in working channel: no;
yes
-Complications / difficulties related with trocar
insertion: no; yes
-Complications / difficulties related with
tracheoscopy: no; yes
-Date
-Operator name
-Anesthesia: local; loco-regional (spinal;
epidural; spinal-epidural); general
-Complications / difficulties related with
balloon preliminary tests: no; yes
-Complications / difficulties related with
connection of balloon with catheter: no; yes
-Complications / difficulties related with
balloon positioning in working channel: no;
yes
-Complications during FETO procedure: yes;
no describe)
. CC-BY 4.0 International licenseIt is made available under a
perpetuity.
is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint The copyright holder for thisthis version posted August 22, 2022. ; https://doi.org/10.1101/2022.08.17.22278918doi: medRxiv preprint
-Complications / difficulties related with
balloon filling: no; yes
-Complications / difficulties related with
balloon withdrawal: no; yes
-Success positioning of Smart-TO balloon :
no; yes
-Amniodrainage during FETO: no; yes
-Volume of amniodrainage (ml)
-Total in utero time (min)
-Time between beginning of fetoscopy and
balloon withdrawal
-Tocolysis
-Complications / difficulties related with
balloon filling: no; yes
-Complications / difficulties related with
balloon withdrawal: no; yes
-Success positioning of Smart-TO balloon:
no; yes
-Amniodrainage during FETO: no; yes
-Volume of amniodrainage (ml)
-Total in utero time (min)
-Time between beginning of fetoscopy and
balloon withdrawal
Postoperative ultrasound
-Date
-Alive fetus: yes; no
-Balloon in place yes; no
-Balloon length (mm)
-Balloon width (mm)
-Cervical length (mm)
-Chorionic membrane separation
-Deepest vertical amniotic fluid pocket (cm)
-Any additional findings: yes; no; describe
-Did any A/E/SAE occur? Yes, no; describe
Did any device deficiency occur? Yes, no;
describe
-Date
-Alive fetus: yes; no
-Balloon in place yes; no
-Balloon length (mm)
-Balloon width (mm)
-Cervical length (mm)
-Chorionic membrane separation
-Deepest vertical amniotic fluid pocket (cm)
-Any additional findings: yes; no; describe
-Did any A/E/SAE occur? Yes, no; describe
Did any device deficiency occur? Yes, no;
describe
Follow-up visit
-Date
-Alive fetus: yes; no
-Balloon in place yes; no
-Balloon length (mm)
-Balloon width (mm)
-Cervical length (mm)
-Chorionic membrane separation
-Deepest vertical amniotic fluid pocket (cm)
-Any additional findings: yes; no; describe
-Did any A/E/SAE occur? Yes, no; describe
Did any device deficiency occur? Yes, no;
describe
-Method for LHR measurement: tracing;
longest diameter; anteroposterior
diameter and perpendicular
-O/E LHR (%)
-Date
-Alive fetus: yes; no
-Balloon in place yes; no
-Balloon length (mm)
-Balloon width (mm)
-Cervical length (mm)
-Chorionic membrane separation
-Deepest vertical amniotic fluid pocket (cm)
-Any additional findings: yes; no; describe
-Did any A/E/SAE occur? Yes, no; describe
Did any device deficiency occur? Yes, no;
describe
O/E LHR (%)
Balloon removal procedure
-Date for balloon removal
-Removal context: at scheduled date; at
emergency (labor; PROM; other)
-Date for balloon removal
-Removal context: at scheduled date; at
emergency (labor; PROM; other)
. CC-BY 4.0 International licenseIt is made available under a
perpetuity.
is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint The copyright holder for thisthis version posted August 22, 2022. ; https://doi.org/10.1101/2022.08.17.22278918doi: medRxiv preprint
-Balloon in place yes; no
-Balloon length (mm)
-Balloon width (mm)
-Physician responsible for procedure
-Date and data related to ultrasound scan at
removal, including balloon shape and
measurements
-MRI exposure: no; yes
-MRI type: 1 tesla; 1.5; 2; 3
-MRI Brand and model
-Ultrasound scan after first tour around MRI
including balloon visualization, position,
shape, and measurements
-Successful deflation: no; yes
-Ultrasound scan after additional tour around
MRI including balloon visualization, position,
shape, and measurements
-Balloon removal before birth: no; yes
-Time between unplug and birth less than
24h: no; yes
-Route of removal: MRI; fetoscopic,
ultrasound-guided puncture; on placental
circulation; off placental circulation;
spontaneous deflation
-Balloon in place yes; no
-Physician responsible for procedure
-Date and data related to ultrasound scan at
removal, including balloon shape and
measurements
-MRI exposure: no; yes
-MRI Brand and model
-Ultrasound scan after first tour around MRI
including balloon visualization, position,
shape, and measurements
-Successful deflation: no; yes
-Ultrasound scan after additional tour around
MRI for balloon visualization
-Balloon removal before birth: no; yes
-Time between unplug and birth less than
24h: no; yes
-Route of removal: MRI; fetoscopic,
ultrasound-guided puncture; on placental
circulation; off placental circulation;
spontaneous deflation
Ultrasound scan after balloon deflation
-Alive fetus: yes; no
-Balloon in place yes; no
-Balloon length (mm)
-Balloon width (mm)
-Cervical length (mm)
-Chorionic membrane separation
-Deepest vertical amniotic fluid pocket (cm)
-Any additional findings: yes; no; describe
-Alive fetus: yes; no
-Balloon in place yes; no
-Balloon length (mm)
-Balloon width (mm)
-Cervical length (mm)
-Chorionic membrane separation
-Deepest vertical amniotic fluid pocket (cm)
-Any additional findings: yes; no; describe
Post balloon deflation visit
-Date
-Alive fetus: yes; no
-Cervical length (mm)
-Chorionic membrane separation
-Deepest vertical amniotic fluid pocket (cm)
-Any additional findings: yes; no; describe
-Did any A/E/SAE occur? Yes, no; describe
Did any device deficiency occur? Yes, no;
describe
-Method for LHR measurement: tracing;
longest diameter; anteroposterior
diameter and perpendicular
-O/E LHR (%)
-Date
-Alive fetus: yes; no
-Cervical length (mm)
-Chorionic membrane separation
-Deepest vertical amniotic fluid pocket (cm)
-Any additional findings: yes; no; describe
-Did any A/E/SAE occur? Yes, no; describe
Did any device deficiency occur? Yes, no;
describe
-O/E LHR (%)
. CC-BY 4.0 International licenseIt is made available under a
perpetuity.
is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint The copyright holder for thisthis version posted August 22, 2022. ; https://doi.org/10.1101/2022.08.17.22278918doi: medRxiv preprint
Delivery
-Date of delivery
-Center of delivery
-Premature rupture of membranes: no; yes
(date)
-Indication for birth: elective birth;
spontaneous birth; fetal complications;
maternal complications
-Route of birth: vaginal; assisted vaginal;
primary caesarean; secondary caesarean; on
placental circulation.
-Liveborn: yes; no
-Gender: male; female
-Birthweight (g)
-Apgar at 1’
-Apgar at 5’
-Arterial pH
-Balloon visualization at birth: no; yes
(shape, localization, need for withdrawal
and modalities)
-Did any A/E/SAE occur? Yes, no; describe
-Date of delivery
-Center of delivery
-Premature rupture of membranes: no; yes
(date)
-Indication for birth: elective birth;
spontaneous birth; fetal complications;
maternal complications
-Route of birth: vaginal; assisted vaginal;
primary caesarean; secondary caesarean; on
placental circulation.
-Liveborn: yes; no
-Gender: male; female
-Birthweight (g)
-Apgar at 1’
-Apgar at 5’
-Arterial pH
-Postpartum ultrasound performed: yes;
no
-Date of ultrasound
-Balloon location: not visible;
intracavitary; intramural; cervical;
intraabdominal
-Balloon location: placenta/membranes;
amniotic fluid; uterus; newborn airways;
newborn gastrointestinal tract; not visible;
other (specify).
-Did any A/E/SAE occur? Yes, no; describe
Neonatal outcome
-Postnatal death
-Cause of death
-Signs of symptoms of tracheomalacia: yes;
no (specify)
-Did any A/E/SAE occur? Yes, no; describe
-Date of discharge from the NICU
-Survival at day 28, 56, at discharge from
NICU, at discharge from Hospital, at 6
months: no; yes
-Date of discharge from Hospital
-Date of surgery
-Use of patch at surgery: no; yes
-Defect size: A,B,C,D
-Postnatal death
-Cause of death
-Tracheal diameter at thoracic entry (mm)
-Tracheal diameter 10 mm above the carina
(mm)
-Tracheal diameter at mid-distance (mm)
-Signs of symptoms of tracheomalacia: yes;
no (specify)
-Did any A/E/SAE occur? Yes, no; describe
-Date of discharge from the NICU
. CC-BY 4.0 International licenseIt is made available under a
perpetuity.
is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint The copyright holder for thisthis version posted August 22, 2022. ; https://doi.org/10.1101/2022.08.17.22278918doi: medRxiv preprint
-Occurrence of pulmonary hypertension:
no; yes
-Date of onset pulmonary hypertension
-Need for oxygen at day 28 and 56: no;
yes
-Grade of oxygen dependency at day 28
and 56: 0 (no BPD); I (FiO2 21% or room
air); II (FiO2 22-29%); III (FiO2 >29%, CPAP
or mechanical ventilation)
-Need for ECMO: no; yes
-Duration of ECMO (days)
-Total duration of ventilatory support
(days)
-Age at full enteral feeding (days)
-Periventricular leukomalacia: no; grade I,
grade II; grade III; not applicable
-Intraventricular hemorrhage: no; grade I,
grade II; grade III; not applicable
-Sepsis: no; yes; not applicable
-Necrotizing enterocolitis: no; yes; not
applicable
-Retinopathy of prematurity: yes (grade III
or higher); no (<grade III); not applicable
-Presence of reflux (>1/3 of the esophagus
on clinically indicated radiography); no;
yes; not applicable
-Treatment of reflux: none; medical;
surgical; other
-Oxygen at discharge from Hospital: no;
yes (grade of oxygen dependency)
-Oxygen at 6 months: no; yes (grade of
oxygen dependency)
Abbreviations: LHR; lung-to-head ratio: O/E; observed-to-expected; w; weeks; CDH;
congenital diaphragmatic hernia; FETO, Fetoscopic Endoluminal Tracheal Occlusion; MRI,
magnetic resonance image; A/E, adverse event; SAE, serious adverse event; NICU; neonatal
intensive care unit; ECMO, extracorporeal membrane oxygenation; PROM, premature rupture
of the membranes; EXIT, ex-utero intrapartum treatment.
. CC-BY 4.0 International licenseIt is made available under a
perpetuity.
is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint The copyright holder for thisthis version posted August 22, 2022. ; https://doi.org/10.1101/2022.08.17.22278918doi: medRxiv preprint
REFERENCES
1. Ameis, D., N. Khoshgoo, and R. Keijzer, Abnormal lung development in congenital
diaphragmatic hernia. Semin Pediatr Surg, 2017. 26(3): p. 123-128.
2. Deprest, J.A., et al., Randomized Trial of Fetal Surgery for Moderate Left
Diaphragmatic Hernia. N Engl J Med, 2021. 385(2): p. 119-129.
3. Deprest, J.A., et al., Randomized Trial of Fetal Surgery for Severe Left Diaphragmatic
Hernia. N Engl J Med, 2021. 385(2): p. 107-118.
4. Russo, F.M., et al., Fetal endoscopic tracheal occlusion reverses the natural history
of right-sided congenital diaphragmatic hernia: European multicenter experience.
Ultrasound Obstet Gynecol, 2021. 57(3): p. 378-385.
5. Van Calster, B., et al., The randomized TOTAL-trials on fetal surgery for congenital
diaphragmatic hernia: re-analysis using pooled data. Am J Obstet Gynecol, 2021.
6. Araujo Junior, E., et al., Erratum: Procedure-Related Complications and Survival
Following Fetoscopic Endotracheal Occlusion (FETO) for Severe Congenital
Diaphragmatic Hernia: Systematic Review and Meta-Analysis in the FETO Era. Eur J
Pediatr Surg, 2017. 27(4): p. e1.
7. Araujo Junior, E., et al., Procedure-Related Complications and Survival Following
Fetoscopic Endotracheal Occlusion (FETO) for Severe Congenital Diaphragmatic
Hernia: Systematic Review and Meta-Analysis in the FETO Era. Eur J Pediatr Surg,
2017. 27(4): p. 297-305.
8. Deprest, J., et al., Technical aspects of fetal endoscopic tracheal occlusion for
congenital diaphragmatic hernia. Journal of pediatric surgery, 2011. 46(1): p. 22-32.
9. Done, E., et al., Predictors of neonatal morbidity in fetuses with severe isolated
congenital diaphragmatic hernia undergoing fetoscopic tracheal occlusion. Ultrasound
Obstet Gynecol, 2013. 42(1): p. 77-83.
10. Jimenez, J.A., et al., Balloon removal after fetoscopic endoluminal tracheal occlusion
for congenital diaphragmatic hernia. Am J Obstet Gynecol, 2017.
11. Sananes, N., et al., Evaluation of a new balloon for fetal endoscopic tracheal
occlusion in the nonhuman primate model. Prenat Diagn, 2019.
12. Basurto, D., et al., New device permitting non-invasive reversal of fetal endoscopic
tracheal occlusion: ex-vivo and in-vivo study. Ultrasound Obstet Gynecol, 2020.
56(4): p. 522-531.
13. Basurto, D., et al., Safety and efficacy of the Smart Tracheal Occlusion device in the
diaphragmatic hernia lamb model. Ultrasound Obstet Gynecol, 2020.
14. Vollset, S.E., Confidence intervals for a binomial proportion. Stat Med, 1993. 12(9): p.
809-24.
15. Van der Veeken, L., et al., Fetoscopic endoluminal tracheal occlusion and
reestablishment of fetal airways for congenital diaphragmatic hernia. Gynecol Surg,
2018. 15(1): p. 9.
16. Sananes, N., et al., Evaluation of a new balloon for fetal endoscopic tracheal
occlusion in the non-human primate model. Prenat Diagn, 2019.
17. Basurto, D., et al., Safety and efficacy of smart tracheal occlusion device in
diaphragmatic hernia lamb model. Ultrasound Obstet Gynecol, 2021. 57(1): p. 105-
112.
. CC-BY 4.0 International licenseIt is made available under a
perpetuity.
is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint The copyright holder for thisthis version posted August 22, 2022. ; https://doi.org/10.1101/2022.08.17.22278918doi: medRxiv preprint
. CC-BY 4.0 International licenseIt is made available under a
perpetuity.
is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint The copyright holder for thisthis version posted August 22, 2022. ; https://doi.org/10.1101/2022.08.17.22278918doi: medRxiv preprint
