Review Article

Esophageal Atresia: Future Directions for

Research on the Digestive Tract
Maissa Rayyan1 Nathalie Rommel2,3 Jan Tack3,4 Jan Deprest5,6 Karel Allegaert6,7

1 Neonatal Intensive Care Unit, University Hospital Leuven, Address for correspondence Maissa Rayyan, MD, Neonatal Intensive
Leuven, Belgium Care Unit, University Hospital Leuven, Herestraat 49, Leuven 3000,
2 ExpORL, Department of Neurosciences, KU Leuven, Leuven, Belgium Belgium (e-mail: maissa.rayyan@uzleuven.be).
3 Disorders of Neurogastroenterology and Motility, Department of
Gastroenterology, Universitaire Ziekenhuizen Leuven,
Leuven, Belgium
4 Translational Research Center for Gastrointestinal Disorders
(TARGID), Department of Clinical and Experimental Medicine,
Katholieke Universiteit Leuven, Leuven, Belgium
5 Department of Obstetrics and Gynaecology, University Hospital
Gasthuisberg, Leuven, Belgium
6 Department of Development and Regeneration, Katholieke
Universiteit Leuven, Leuven, Belgium
7 Intensive Care and Department of Pediatric Surgery, Erasmus Medical
Center-Sophia Children’s Hospital, Rotterdam, The Netherlands

Eur J Pediatr Surg

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Abstract
Keywords
► esophageal atresia
► esophageal motility
► doxorubicin rodent
model
► translational research
Esophageal atresia (EA) is a congenital malformation defined by the discontinuity of the
esophagus occurring in 2.4 in 10,000 births. As survival rates are high, the significant
medical morbidity became more relevant. Short-term and long-term morbidities
involve the respiratory and gastrointestinal system in the majority of the patients.
The impact of this morbidity seems large enough to inspire researchers to develop
experimental animal models that may help understanding the pathogenesis and
pathophysiology. These models can also be used to explore potential surgical therapies.
We reviewed the clinical and experimental literature focusing on esophageal morbidity
in EA. Although the consequences of esophageal motility disorders are very relevant in
the clinical setting, research remains largely underexplored. Consequently, we suggest
integrating motility function assessment in the existing research models.

Introduction
Esophageal atresia (EA) is a congenital anomaly of the esophagus.
This anomaly arises from a developmental disruption with faulty
separation of the embryogenic foregut into the trachea and
esophagus during early gestation. The prevalence is 2.4 in 10,000
births.1 Gastrointestinal problems as well as respiratory prob-
lems are very common in young infants, but remain common in
adults.2–5 Many patients suffer from severe gastroesophageal
reflux (GER), esophagitis, dysphagia, and poor weight gain.
Young children may present with respiratory problems such
as tracheomalacia, chronic respiratory infections, and decreased
maximal exercise tolerance.2,6 Some adults still present with a
chronic (barking) cough and wheezing.5
Because of the complexity of this medical condition, the
medical approach remains a challenge for every clinician
treating EA patients. It is still not clear what the best surgical
strategy is for long-gap EA and how we should deal with
motility disorders of the esophagus. Many researchers have
tried to fill these gaps in knowledge by developing experi-
mental models. Doxorubicin and molecular experimental
models are very useful models to study organogenesis of
EA. Organogenesis of the esophagus as well as from the

received © Georg Thieme Verlag KG DOI http://dx.doi.org/

March 4, 2016 Stuttgart · New York 10.1055/s-0036-1587330.
accepted after revision ISSN 0939-7248.
July 6, 2016
EA: Future Directions for Research on the Digestive Tract
respiratory tract in EA models have been described in
research articles.7–10 In this review, the focus lies on esoph-
ageal problems in EA, and therefore only research articles
involving the esophagus are included. First, clinical aspects of
esophageal morbidity are discussed, followed by clinical
esophageal motility testing. Finally, we will discuss relevant
ongoing research that may create opportunities to translate
new-gained knowledge into applicable, evidence-based,
clinical approaches.
Gastroesophageal Morbidity
Gastroesophageal Morbidity Is Common, Persistent,
but Poorly Understood
GER and dysphagia are the two most reported symptoms in
patients with EA, even after successful surgical repair. Chronic
GER can lead to severe peptic esophagitis, and Barrett esophagus.
The incidence of esophagitis ranges between 27 and
46%,3,11,12 but unlike the spontaneous improvement observed
in normal infants, the GER incidence increases in EA cases till
the age of 1 year11 and usually persists in later life.13,14 Two
mechanisms are essential to protect the esophagus from GER:
a normal esophagogastric junction and the clearing capacity of
the esophagus.15,16 The latter seems to play a determinant role,
particularly because the lack of distal esophageal contractions
correlates with the development of GER disease in EA cases.17
Chronic GER and associated esophagitis increase the risk for
development of gastric metaplasia (15%) and Barrett esopha-
gus (intestinal metaplasia in 1–2%), both premalignant con-
ditions.4,12 Barrett esophagus is known to be a risk factor for
esophageal adenocarcinoma.18
Dysphagia is also very common in patients with EA.
Depending on the definition, its incidence varies from 15 to
52% and is present in all the age groups.2,8,19–21 Dysphagia is
usually defined as difficulties in the oral pharyngeal and
esophageal phases of swallowing, but dysphagia is also
used for the sensation of a food bolus lodged in the esophagus.
Dysphagia seems to be less frequent in infants compared with
children and adults, probably because of the ingestion of less
solid food and because of the inability of a young child to
describe the symptom of the sensation of blocked food.19–21
The surgical approach of long-gap EA also remains a real
challenge. Besides esophageal mechanical lengthening by
traction,22,23 esophageal replacement strategies can be
used for long-gap EA. Current strategies include gastric
transposition (gastric pull-up),24 colon interposition,25 and
jejunal interposition.26 The effect of mechanical traction and
of a shortened esophagus on motility remains underexplored.
It is obvious that many patients with EA need long-term
medical care.4,27 Recently, the focus has shifted from a pure
surgical and gastrointestinal approach to the multidisciplinary
long-term evaluation of EA patients.28 Despite all acquired
knowledge, many questions still remain to be explored. Studies
on esophageal dysmotility and its contributing factors—includ-
ing surgical techniques—in former EA patients may improve our
knowledge and clinical management. Animal models have the
potential to provide new insights into the mechanisms involved
and can be used to evaluate surgical interventions.
European Journal of Pediatric Surgery
Rayyan et al.
Esophageal Dysmotility Data from Human Research
GER and dysphagia can both—at least partially—be
explained by dysmotility of the esophagus. The etiology
of esophageal dysmotility is still debated, yet is usually
classified as either primary, that is, due to intrinsic factors
or secondary, that is, due to external factors. Primary
dysmotility disorders include intrinsic factors related to
the abnormal development of the esophageal smooth
muscle and (intrinsic and extrinsic) innervation of the
esophagus.18 Preoperative manometry (before surgical
anastomosis) performed in newborns already showed
disturbed esophageal motility.29 Similar, dysmotility has
been described in patients with tracheoesophageal fistula
without atresia.30 In addition, abnormal gastric motility
has also been described in patients with EA.31 Histopatho-
logical data hereby support the role of abnormal intrinsic
and extrinsic innervation of the esophagus with neuronal
abnormalities of the esophagus.10,32,33 These neuronal
defects can—at least partially—explain the esophageal dys-
motility often described in patients with EA.
On the contrary, esophageal motility can be secondary or
caused by external factors such as surgery and GER.34,35
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During surgery, extensive mobilization can cause myoneural
damage and/or worsen preexisting esophageal motility.35
Comparing esophageal motility before and after surgery in
a single human case, Shono et al documented worsening
esophageal dysmotility after surgery.36
Four more recent studies reported on esophageal motility
using high-resolution manometry (HRM) in patients with
EA.37–40 Details are summarized in ►Table 1. Abnormal
patterns such as aperistalsis or failed peristalsis according
to the Chicago Classification are most common.41 Hence,
there was no correlation between symptoms and esophageal
motor patterns. These abnormal esophageal motor patterns
were present in symptomatic as well as asymptomatic pa-
tients, which are similar to the findings in adults.42 Bogte et al
suggested that symptoms are more likely to relate to bolus
flow. Therefore, the yield of pressure analysis needs to be
expanded by adding impedance. Pressure-flow analysis has
the potential to linking motility studies and symptoms by not
only describing flow and pressure, but also by describing the
interaction between bolus flow and pressure.43 This might be
crucial in the diagnosis of esophageal dysmotility in patients
with EA.
Delayed gastric emptying and gastric dysmotility can also
occur in patients who have repaired EA.31,44 This has been
documented with scintigraphy as well as with manometry.
An extremely long lag phase and slow emptying rates seem to
be associated with reflux symptoms and abdominal
complaints.44
Esophageal Dysmotility: Linking Studies in Humans to
Animal Models with EA
Current research on patients with EA as well as in experi-
mental animal models (teratogen-induced, knockout, and
surgical models) study (1) organogenesis, pathophysiology,
and histopathology, (2) esophageal motility, or (3) surgical
approaches to the condition and its consequences.
 EA: Future Directions for Research on the Digestive Tract Rayyan et al.

Table 1 HRM studies performed in patients with EA

Author HRM Retrospective/ Number of patients Median age Correlation

Type of catheter prospective with symptoms
Tong HRM 36Pa Retrospective 8 EA Not specified N/A
et al (2015) Solid state 6 Postfundoplication
Lemoine HRM 12P/36P Prospective 40 EA 8y No
et al (2013) Solid state 14 Postfundoplication
Pedersen HRM 36P Prospective 48 EA 10.2 y No
et al (2013) Solid state 24 Controls 12.3 y
van Wijk HRM 7P/8P Prospective 16 EA 7 Children (0.23–3.42 yb) No
et al (2013) Water perfused 9 Adults (18.1–31.3 yc)
þ sleeve

Abbreviations: EA, esophageal atresia; HRM, high-resolution manometry; N/A, not available.
a
P is the number of pressure channels on catheter; two different types of catheters are mentioned when two different sizes were used for small
children versus adults.
b
Total number of infants included in this study; age of infants with HRM study not further specified.
c
Total number of adults included in this study; age of adults with HRM study not further specified.

Organogenesis, Pathophysiology, and Histopathology medical condition (although very rarely) associated with,
among other conditions, EA.53,54 We already know that there

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Doxorubicin and Molecular Experimental Models to Study
Organogenesis of EA
The first focus of research relates to organogenesis, patho-
physiology, and histopathology. The causes of EA
(
tracheoesophageal fistula) during human development
are not (fully) elucidated. Adriamycin (doxorubicin; Farm-
iblastina Pharmacia, Madrid, Spain) induces EA in rodents
with many similarities to human infants.45,46 This is a terato-
genic model as doxorubicin induces a spectrum of foregut
anomalies and other VACTERL malformations (vertebral
defects, anal atresia, cardiac defects, tracheoesophageal
fistula, renal anomalies, and limb abnormalities) in fetuses
from pregnant mice and rats.9,45,47 Around 10% of doxorubi-
cin-exposed rodents develop EA. This model is nowadays
frequently used to study organogenesis and gene expression
regulation.48 Doxorubicin causes an abnormal notochord
which is a crucial structure during organogenesis.7 It regu-
lates cell organization of dorsoventral, anteroposterior, and
right–left orientation. It expresses signaling molecules,
including sonic hedgehog (Shh).49 Candidate genes for esoph-
ageal development have been identified, such as NKX2.1,
Sox2, Foxf1, and Shh. The absence of the NKX2.1expression
on the ventral foregut and the absent or altered Sox2 expres-
sion in the dorsal foregut leads to incomplete separation of
the esophagus and trachea.50 Doxorubicin interferes with
DNA replication and inhibits DNA and RNA synthesis, and
therefore affects many tissues and organ systems. Doxorubi-
cin is also likely to be involved in Shh-Gli receptor signaling
pathways and/or in Shh-target genes (Foxf1) resulting in
disruption of the normal development of the foregut.51
Alterations in Shh, Foxf1, Sox2, and Tbx1 genes have been
identified in animal models as well as in patients with EA.52
Altered Tbx1 expression in the dorsal foregut in the doxoru-
bicin-exposed mice suggests that Tbx1 gene disruption plays a
role in the organogenesis of the esophagus and trachea. Tbx1
gene mutation has been linked to 22q11 deletion syndrome, a
is definitely a genetic contribution to EA and VACTERL-
associated defects.52,55 However, many genetic defects and
predisposing factors remain unknown.
Neuronal Histopathology of the Esophagus
Neuronal abnormalities of the esophagus have been described
in clinical as well as experimentally induced EA.10,32,33 These
abnormalities include intrinsic innervation as well as extrinsic
neuronal defects. Qi et al were the first to demonstrate
extrinsic neuronal defects in the doxorubicin-induced rat EA
model.10 The course and branching pattern of the vagal nerve
from the thorax till the extrinsic nerve fiber plexus in the lower
esophagus was affected in rat fetuses with EA. Qi et al also
described fewer branches from both recurrent laryngeal
nerves. In a comparable rat model, Cheng et al demonstrated
smaller cross-sectional diameters of the esophageal wall
mainly attributable to a thinner submucosa.56 The elevated
S100 level in the atretic esophagus was attributed to reactive
hypertrophy of glial cells secondary to neuronal damage. Those
researchers speculated that normal esophageal tissue is
required for the branching process of nerve fibers.57 Similar
histopathological findings were reported in humans. In
neonates with EA, the distal end of the proximal esophageal
segment displays hypoganglionosis and immature ganglion
cells in the myenteric plexus.32 This was partially attributed to
reduced glial cell line-derived neurotrophic factor (GDNF)
immunoreactivity in the myenteric plexus and in the muscular
layer. GDNF is a “survival factor” for central and peripheral
neurons. An abnormal expression of GDNF could at least
partially explain a defective intrinsic neuronal innervation of
the atretic esophagus. The same authors described hypertro-
phic glial tissue as compensation for this defective neuronal
tissue. Another study investigated the imbalance of the excre-
tion of neurotransmitters observed in patients with EA.58 The
authors suggested that this could also contribute to an abnor-
mal intrinsic innervation and thus, to hypocontractility of the

European Journal of Pediatric Surgery

EA: Future Directions for Research on the Digestive Tract
esophageal body. Nakazato et al described abnormal Auerbach
plexi in five esophagus specimens at autopsy.33 The Auerbach
plexus was more deficient in the distal esophagus than in the
proximal esophagus. The fundus of the stomach was also
showing abnormal Auerbach plexi, mainly larger ganglia and
thicker interganglionic fibers in a looser network. Finally, the
interstitial cells of Cajal (ICC) seem to play a role in dysmotility,
acting as an intestinal pacemaker and facilitating propagation
of the intestinal peristalsis. They are less numerous in the
esophagus of patients with EA.59 In addition, a craniocaudal
distribution of these cells was hereby noticed, since the ICC
were more present in the upper esophagus and in the proximal
pouch compared with the distal esophagus and fistula. More-
over, the aboral migration of neural crest-derived cells leaves
the distal part of the atretic esophagus with a lower concen-
tration of neuronal cells. The lower concentration of the neural
crest-derived cells in the control of maturation of ICC may
explain the delayed maturation of their target cells. All these
neuronal defects could explain the esophageal dysmotility of
patients with EA.
Experimental Esophageal Motility Studies in Relation to
EA
The second focus of research is the esophageal pathophysiol-
ogy at the base of EA. Capeto et al evaluated the in vitro
contractile profile of esophageal and gastric fundal strips in
fetuses of doxorubicin-exposed rats.60 Strips from the distal
esophagus were exposed to carbamylcholine chloride (CCh)
and to potassium chloride (KCl) in increasing concentrations
while mounted on a myograph. The contractility of the
esophagus was inhibited in response to CCh, but not in
response to KCl. This effect was also present in offsprings
from dams exposed to doxorubicin but without EA. Strips
from the gastric fundus did not show any altered contractility
to cholinergic stimulation. Esophageal contractility is dis-
turbed in rat fetuses exposed to doxorubicin but gastric
motility seems to remain intact.
In an experiment with normal rats, two segments of the
esophagus measuring 1 cm were excised to study the effect of
acute tension on the esophagus. The first segment was
dissected from the proximal segment of the esophagus, the
second from the distal segment just above the gastroesopha-
geal junction.61 In response to electrical field stimulation, the
authors demonstrated higher isometric contractile responses
in the proximal segment of an esophagus under traction
compared with the distal segment. This response was higher
in segments under minimal tension compared with a control
esophagus without tension. Nevertheless, the observed in-
creased contractility response became less apparent with
increasing esophageal tension. Similarly, in response to cho-
linergic stimulation the control esophagus showed less con-
tractile amplitudes compared with the esophagus under
tension, but the esophageal contractility was not different
between the proximal and distal segments. Additionally,
serotonin-induced esophageal body relaxation was signifi-
cantly lower in the esophageal segments under tension
compared with esophageal segments without tension. The
latter research can be linked to clinical practice as the high-
European Journal of Pediatric Surgery
Rayyan et al.
tension group described can model for esophageal dysmotil-
ity in EA patients with anastomosis under traction. The
difference in the effect of electrical stimulation on the striated
and smooth muscle may not only be linked to the type of
stimulation but may also be influenced by the type of
musculature being striated versus smooth muscle.
Montedonico et al investigated the effect on the esoph-
ageal function of an anastomosis on the esophagus under
tension compared with an anastomosis without tension in
rats exposed to doxorubicin.62 The group with tension un-
derwent esophageal transection and resection of 15 mm
proximal esophagus, whereas the group without tension
underwent transection of the esophagus without resection.
They compared the resting pressure at the lower esophageal
sphincter (LES) in both groups using a pull through perfusion
manometry. They found that the pressure at the LES was
significantly lowered postoperatively in the tension group. Of
note, the baseline pressures at the LES were higher in the
esophageal resection group (44.9 mm Hg) versus the esoph-
ageal transection group (32.7 mm Hg). The length of the
intra-abdominal esophagus in the resection group was also
significantly lowered after surgery compared with the tran-
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section group. They concluded that this might partly explain
why postoperative patients with EA have more GER. It is yet
unclear if postoperative patients with traction on the anasto-
mosis have more problems. Patients with a long gap are at risk
for developing strictures,27 but it remains unclear if patients
with traction on the anastomosis have more dysmotility and
GER symptoms compared with patients with no/less traction
on the anastomosis.
Potential Opportunities to Improve Surgical Approach
of EA
The third focus of current research lies on the surgical
approach. The surgical approach remains very challenging,
especially in patients with long-gap atresia.23,63 Foker et al
described a technique in which external traction is used to
promote esophageal growth in humans.22 The esophagus of
these postsurgical children was evaluated by Khan et al by
using high-resolution ultrasound. They reported a preserved
thickness of mural layers after traction of the esophagus.64
Animal studies were performed in rodents to investigate
the influence of esophageal mechanical lengthening, but
recently a larger animal model (miniature pig) was
used.60,61,65,66 In this porcine surgical EA model a polycap-
rolactone spring device was inserted in the distal esophagus
after dividing the esophagus 2 cm above the gastroesopha-
geal junction instead of using external traction.66 After
4 weeks, they recreated an anastomosis. The distal esoph-
ageal pouch increased significantly in length (doubled to
4.5 cm). Remarkably, there was no difference in thickness of
muscularis mucosa or muscularis propria, nor in the number
of myenteric or submucosal ganglia. The lengthening by a
spring device does not seem to alter the normal structures,
but was accompanied by a mild-to-moderate degree of
inflammation and fibrosis. It is yet unclear whether this
reflects an increased risk for development of anastomotic
strictures.
 EA: Future Directions for Research on the Digestive Tract
Besides esophageal mechanical lengthening by trac-
tion,22,23 esophageal replacement strategies can be used for
long-gap EA. Current strategies include gastric transposition
(gastric pull-up),24 colon interposition,25 and jejunal interpo-
sition.26 Many researchers looked at alternative approaches for
esophageal replacement using tubular acellular scaffolds
derived from animal and human settings.67 To reduce com-
plications, tissue engineering approaches using cell-seeded
grafts have recently been explored.67 Although this technique
is promising, there are still some issues on the poor regenera-
tion of the muscular layer. Adding to the challenge is that
peristaltic contractility needs to be regenerated by electrical
stimulation or by enhanced neural regeneration. The authors
suggested that enhanced neural regeneration might play a role
and that the contribution of neural crest cells is essential for
functional peristalsis.
Future Perspectives: From Anatomic
Continuation to Improved Functional Repair
Patients with EA suffer—among other issues—from long-term
gastrointestinal symptoms. Although more insights in its
pathophysiology have been gained over the last decade, there
is still a large gap in the understanding of esophageal
dysmotility. To narrow this gap of knowledge, research is
ongoing in humans and in animal models.64–66 Most interest
has gone to organogenesis, histology, and mechanical length-
ening, but data on functional motility testing of the esopha-
gus and esophagogastric junction are still limited. We suggest
further integrating the objective motility function assess-
ment in the existing research models.
Over the past 5 years, novel morphology treatment op-
tions for EA have been become available, such as mechanical
lengthening and tissue engineering. Although mechanical
stretching techniques are already used in clinical prac-
tice,23,63 crucial elements to determine the clinical gain of
the novel methodologies are still lacking. First, the role of
molecular mechanisms of esophageal tissue lengthening
needs further study. Second, the physiology of mechanically
induced esophageal growth needs to differentiate whether
real growth is achieved or whether the esophageal muscula-
ture is only elongated due to stretch. Third, the impact of
stretching on inflammation, fibrosis, and risk for anastomotic
strictures and the clinical implications need to be explored.
More so, in-depth esophageal motility testing is essential to
define the impact of stretching on esophageal function and
thereby the clinical surplus value and safety of this treatment
strategy. Finally, recent experiments suggest that tissue
engineering of the esophagus may be the future for patients
with long-gap EA. It is important to realize that not only the
morphology of this newly engineered esophagus is crucial for
the long-term success in EA patients. Seen the current
comorbidities of esophageal dysmotility in EA patients it is
obvious that the motor function of the new esophagus will be
determining the therapeutic gain of tissue engineering.
Therefore, the main focus should be the growth of functional
muscle.67
Rayyan et al.
In terms of diagnostic progress of patients with EA, HRM
has been proposed as the state-of-the-art test for esophageal
function. However, currently, normative values for neonates
and pediatrics are lacking due to ethical constraints.68 More
so, the link between symptoms and esophageal motor pat-
terns as assessed by HRM remains unclear. Therefore, novel
methodologies combining HRM with objective measurement
of bolus flow have been suggested to increase the diagnostic
yield.43
Current esophageal motility methodologies have a high
sensitivity and potential to elucidate the difference between
congenital and postsurgical dysmotility patterns. So far, only
two old studies looked preoperatively at esophageal motility
patterns in humans using water perfused, low-resolution
sensors.29,36 Therefore, comparing pre- and postoperative
motility in the proximal as well as in the distal segment
using novel, quantitative HRM impedance technology could
result in the refined characterization of esophageal motor
patterns in patients with EA.41,69,70
In conclusion, we reviewed the existing clinical and
experimental literature focusing on esophageal morbidity
in EA. Although the consequences of esophageal motility
Downloaded by: Cornell. Copyrighted material.
disorders are very relevant in the clinical setting, research
remains largely underexplored. Consequently, we suggest
integrating objective motility function assessment in the
existing experimental and human research.
Conflict of Interest
None.
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