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

Downloaded by: Cornell. Copyrighted material.

Abstract 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
Keywords experimental animal models that may help understanding the pathogenesis and
► esophageal atresia pathophysiology. These models can also be used to explore potential surgical therapies.
► esophageal motility We reviewed the clinical and experimental literature focusing on esophageal morbidity
► doxorubicin rodent in EA. Although the consequences of esophageal motility disorders are very relevant in
model the clinical setting, research remains largely underexplored. Consequently, we suggest
► translational research integrating motility function assessment in the existing research models.

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

respiratory tract in EA models have been described in Esophageal Dysmotility Data from Human Research
research articles.7–10 In this review, the focus lies on esoph- GER and dysphagia can both—at least partially—be
ageal problems in EA, and therefore only research articles explained by dysmotility of the esophagus. The etiology
involving the esophagus are included. First, clinical aspects of of esophageal dysmotility is still debated, yet is usually
esophageal morbidity are discussed, followed by clinical classified as either primary, that is, due to intrinsic factors
esophageal motility testing. Finally, we will discuss relevant or secondary, that is, due to external factors. Primary
ongoing research that may create opportunities to translate dysmotility disorders include intrinsic factors related to
new-gained knowledge into applicable, evidence-based, the abnormal development of the esophageal smooth
clinical approaches. muscle and (intrinsic and extrinsic) innervation of the
esophagus.18 Preoperative manometry (before surgical
anastomosis) performed in newborns already showed
Gastroesophageal Morbidity
disturbed esophageal motility.29 Similar, dysmotility has
Gastroesophageal Morbidity Is Common, Persistent, been described in patients with tracheoesophageal fistula
but Poorly Understood without atresia.30 In addition, abnormal gastric motility
GER and dysphagia are the two most reported symptoms in has also been described in patients with EA.31 Histopatho-
patients with EA, even after successful surgical repair. Chronic logical data hereby support the role of abnormal intrinsic
GER can lead to severe peptic esophagitis, and Barrett esophagus. and extrinsic innervation of the esophagus with neuronal
The incidence of esophagitis ranges between 27 and abnormalities of the esophagus.10,32,33 These neuronal
46%,3,11,12 but unlike the spontaneous improvement observed defects can—at least partially—explain the esophageal dys-
in normal infants, the GER incidence increases in EA cases till motility often described in patients with EA.
the age of 1 year11 and usually persists in later life.13,14 Two On the contrary, esophageal motility can be secondary or
mechanisms are essential to protect the esophagus from GER: caused by external factors such as surgery and GER.34,35

Downloaded by: Cornell. Copyrighted material.

a normal esophagogastric junction and the clearing capacity of During surgery, extensive mobilization can cause myoneural
the esophagus.15,16 The latter seems to play a determinant role, damage and/or worsen preexisting esophageal motility.35
particularly because the lack of distal esophageal contractions Comparing esophageal motility before and after surgery in
correlates with the development of GER disease in EA cases.17 a single human case, Shono et al documented worsening
Chronic GER and associated esophagitis increase the risk for esophageal dysmotility after surgery.36
development of gastric metaplasia (15%) and Barrett esopha- Four more recent studies reported on esophageal motility
gus (intestinal metaplasia in 1–2%), both premalignant con- using high-resolution manometry (HRM) in patients with
ditions.4,12 Barrett esophagus is known to be a risk factor for EA.37–40 Details are summarized in ►Table 1. Abnormal
esophageal adenocarcinoma.18 patterns such as aperistalsis or failed peristalsis according
Dysphagia is also very common in patients with EA. to the Chicago Classification are most common.41 Hence,
Depending on the definition, its incidence varies from 15 to there was no correlation between symptoms and esophageal
52% and is present in all the age groups.2,8,19–21 Dysphagia is motor patterns. These abnormal esophageal motor patterns
usually defined as difficulties in the oral pharyngeal and were present in symptomatic as well as asymptomatic pa-
esophageal phases of swallowing, but dysphagia is also tients, which are similar to the findings in adults.42 Bogte et al
used for the sensation of a food bolus lodged in the esophagus. suggested that symptoms are more likely to relate to bolus
Dysphagia seems to be less frequent in infants compared with flow. Therefore, the yield of pressure analysis needs to be
children and adults, probably because of the ingestion of less expanded by adding impedance. Pressure-flow analysis has
solid food and because of the inability of a young child to the potential to linking motility studies and symptoms by not
describe the symptom of the sensation of blocked food.19–21 only describing flow and pressure, but also by describing the
The surgical approach of long-gap EA also remains a real interaction between bolus flow and pressure.43 This might be
challenge. Besides esophageal mechanical lengthening by crucial in the diagnosis of esophageal dysmotility in patients
traction,22,23 esophageal replacement strategies can be with EA.
used for long-gap EA. Current strategies include gastric Delayed gastric emptying and gastric dysmotility can also
transposition (gastric pull-up),24 colon interposition,25 and occur in patients who have repaired EA.31,44 This has been
jejunal interposition.26 The effect of mechanical traction and documented with scintigraphy as well as with manometry.
of a shortened esophagus on motility remains underexplored. An extremely long lag phase and slow emptying rates seem to
It is obvious that many patients with EA need long-term be associated with reflux symptoms and abdominal
medical care.4,27 Recently, the focus has shifted from a pure complaints.44
surgical and gastrointestinal approach to the multidisciplinary
long-term evaluation of EA patients.28 Despite all acquired Esophageal Dysmotility: Linking Studies in Humans to
knowledge, many questions still remain to be explored. Studies Animal Models with EA
on esophageal dysmotility and its contributing factors—includ- Current research on patients with EA as well as in experi-
ing surgical techniques—in former EA patients may improve our mental animal models (teratogen-induced, knockout, and
knowledge and clinical management. Animal models have the surgical models) study (1) organogenesis, pathophysiology,
potential to provide new insights into the mechanisms involved and histopathology, (2) esophageal motility, or (3) surgical
and can be used to evaluate surgical interventions. approaches to the condition and its consequences.

European Journal of Pediatric Surgery

 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

Downloaded by: Cornell. Copyrighted material.

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

European Journal of Pediatric Surgery

EA: Future Directions for Research on the Digestive Tract Rayyan et al.

esophageal body. Nakazato et al described abnormal Auerbach tension group described can model for esophageal dysmotil-
plexi in five esophagus specimens at autopsy.33 The Auerbach ity in EA patients with anastomosis under traction. The
plexus was more deficient in the distal esophagus than in the difference in the effect of electrical stimulation on the striated
proximal esophagus. The fundus of the stomach was also and smooth muscle may not only be linked to the type of
showing abnormal Auerbach plexi, mainly larger ganglia and stimulation but may also be influenced by the type of
thicker interganglionic fibers in a looser network. Finally, the musculature being striated versus smooth muscle.
interstitial cells of Cajal (ICC) seem to play a role in dysmotility, Montedonico et al investigated the effect on the esoph-
acting as an intestinal pacemaker and facilitating propagation ageal function of an anastomosis on the esophagus under
of the intestinal peristalsis. They are less numerous in the tension compared with an anastomosis without tension in
esophagus of patients with EA.59 In addition, a craniocaudal rats exposed to doxorubicin.62 The group with tension un-
distribution of these cells was hereby noticed, since the ICC derwent esophageal transection and resection of 15 mm
were more present in the upper esophagus and in the proximal proximal esophagus, whereas the group without tension
pouch compared with the distal esophagus and fistula. More- underwent transection of the esophagus without resection.
over, the aboral migration of neural crest-derived cells leaves They compared the resting pressure at the lower esophageal
the distal part of the atretic esophagus with a lower concen- sphincter (LES) in both groups using a pull through perfusion
tration of neuronal cells. The lower concentration of the neural manometry. They found that the pressure at the LES was
crest-derived cells in the control of maturation of ICC may significantly lowered postoperatively in the tension group. Of
explain the delayed maturation of their target cells. All these note, the baseline pressures at the LES were higher in the
neuronal defects could explain the esophageal dysmotility of esophageal resection group (44.9 mm Hg) versus the esoph-
patients with EA. ageal transection group (32.7 mm Hg). The length of the
intra-abdominal esophagus in the resection group was also
Experimental Esophageal Motility Studies in Relation to significantly lowered after surgery compared with the tran-

Downloaded by: Cornell. Copyrighted material.

EA section group. They concluded that this might partly explain
The second focus of research is the esophageal pathophysiol- why postoperative patients with EA have more GER. It is yet
ogy at the base of EA. Capeto et al evaluated the in vitro unclear if postoperative patients with traction on the anasto-
contractile profile of esophageal and gastric fundal strips in mosis have more problems. Patients with a long gap are at risk
fetuses of doxorubicin-exposed rats.60 Strips from the distal for developing strictures,27 but it remains unclear if patients
esophagus were exposed to carbamylcholine chloride (CCh) with traction on the anastomosis have more dysmotility and
and to potassium chloride (KCl) in increasing concentrations GER symptoms compared with patients with no/less traction
while mounted on a myograph. The contractility of the on the anastomosis.
esophagus was inhibited in response to CCh, but not in
response to KCl. This effect was also present in offsprings Potential Opportunities to Improve Surgical Approach
from dams exposed to doxorubicin but without EA. Strips of EA
from the gastric fundus did not show any altered contractility The third focus of current research lies on the surgical
to cholinergic stimulation. Esophageal contractility is dis- approach. The surgical approach remains very challenging,
turbed in rat fetuses exposed to doxorubicin but gastric especially in patients with long-gap atresia.23,63 Foker et al
motility seems to remain intact. described a technique in which external traction is used to
In an experiment with normal rats, two segments of the promote esophageal growth in humans.22 The esophagus of
esophagus measuring 1 cm were excised to study the effect of these postsurgical children was evaluated by Khan et al by
acute tension on the esophagus. The first segment was using high-resolution ultrasound. They reported a preserved
dissected from the proximal segment of the esophagus, the thickness of mural layers after traction of the esophagus.64
second from the distal segment just above the gastroesopha- Animal studies were performed in rodents to investigate
geal junction.61 In response to electrical field stimulation, the the influence of esophageal mechanical lengthening, but
authors demonstrated higher isometric contractile responses recently a larger animal model (miniature pig) was
in the proximal segment of an esophagus under traction used.60,61,65,66 In this porcine surgical EA model a polycap-
compared with the distal segment. This response was higher rolactone spring device was inserted in the distal esophagus
in segments under minimal tension compared with a control after dividing the esophagus 2 cm above the gastroesopha-
esophagus without tension. Nevertheless, the observed in- geal junction instead of using external traction.66 After
creased contractility response became less apparent with 4 weeks, they recreated an anastomosis. The distal esoph-
increasing esophageal tension. Similarly, in response to cho- ageal pouch increased significantly in length (doubled to
linergic stimulation the control esophagus showed less con- 4.5 cm). Remarkably, there was no difference in thickness of
tractile amplitudes compared with the esophagus under muscularis mucosa or muscularis propria, nor in the number
tension, but the esophageal contractility was not different of myenteric or submucosal ganglia. The lengthening by a
between the proximal and distal segments. Additionally, spring device does not seem to alter the normal structures,
serotonin-induced esophageal body relaxation was signifi- but was accompanied by a mild-to-moderate degree of
cantly lower in the esophageal segments under tension inflammation and fibrosis. It is yet unclear whether this
compared with esophageal segments without tension. The reflects an increased risk for development of anastomotic
latter research can be linked to clinical practice as the high- strictures.

European Journal of Pediatric Surgery

 EA: Future Directions for Research on the Digestive Tract Rayyan et al.

Besides esophageal mechanical lengthening by trac- In terms of diagnostic progress of patients with EA, HRM
tion,22,23 esophageal replacement strategies can be used for has been proposed as the state-of-the-art test for esophageal
long-gap EA. Current strategies include gastric transposition function. However, currently, normative values for neonates
(gastric pull-up),24 colon interposition,25 and jejunal interpo- and pediatrics are lacking due to ethical constraints.68 More
sition.26 Many researchers looked at alternative approaches for so, the link between symptoms and esophageal motor pat-
esophageal replacement using tubular acellular scaffolds terns as assessed by HRM remains unclear. Therefore, novel
derived from animal and human settings.67 To reduce com- methodologies combining HRM with objective measurement
plications, tissue engineering approaches using cell-seeded of bolus flow have been suggested to increase the diagnostic
grafts have recently been explored.67 Although this technique yield.43
is promising, there are still some issues on the poor regenera- Current esophageal motility methodologies have a high
tion of the muscular layer. Adding to the challenge is that sensitivity and potential to elucidate the difference between
peristaltic contractility needs to be regenerated by electrical congenital and postsurgical dysmotility patterns. So far, only
stimulation or by enhanced neural regeneration. The authors two old studies looked preoperatively at esophageal motility
suggested that enhanced neural regeneration might play a role patterns in humans using water perfused, low-resolution
and that the contribution of neural crest cells is essential for sensors.29,36 Therefore, comparing pre- and postoperative
functional peristalsis. 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
Future Perspectives: From Anatomic
patterns in patients with EA.41,69,70
Continuation to Improved Functional Repair
In conclusion, we reviewed the existing clinical and
Patients with EA suffer—among other issues—from long-term experimental literature focusing on esophageal morbidity
gastrointestinal symptoms. Although more insights in its in EA. Although the consequences of esophageal motility

Downloaded by: Cornell. Copyrighted material.

pathophysiology have been gained over the last decade, there disorders are very relevant in the clinical setting, research
is still a large gap in the understanding of esophageal remains largely underexplored. Consequently, we suggest
dysmotility. To narrow this gap of knowledge, research is integrating objective motility function assessment in the
ongoing in humans and in animal models.64–66 Most interest existing experimental and human research.
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
Conflict of Interest
further integrating the objective motility function assess-
None.
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 References
stretching techniques are already used in clinical prac- 1 Pedersen RN, Calzolari E, Husby S, Garne E; EUROCAT Working

tice,23,63 crucial elements to determine the clinical gain of group. Oesophageal atresia: prevalence, prenatal diagnosis and
associated anomalies in 23 European regions. Arch Dis Child 2012;
the novel methodologies are still lacking. First, the role of
97(3):227–232
molecular mechanisms of esophageal tissue lengthening 2 Little DC, Rescorla FJ, Grosfeld JL, West KW, Scherer LR, Engum SA.
needs further study. Second, the physiology of mechanically Long-term analysis of children with esophageal atresia and
induced esophageal growth needs to differentiate whether tracheoesophageal fistula. J Pediatr Surg 2003;38(6):852–856
real growth is achieved or whether the esophageal muscula- 3 Castilloux J, Noble AJ, Faure C. Risk factors for short- and long-term
morbidity in children with esophageal atresia. J Pediatr 2010;
ture is only elongated due to stretch. Third, the impact of
156(5):755–760
stretching on inflammation, fibrosis, and risk for anastomotic
4 Sistonen SJ, Koivusalo A, Nieminen U, et al. Esophageal morbidity
strictures and the clinical implications need to be explored. and function in adults with repaired esophageal atresia with
More so, in-depth esophageal motility testing is essential to tracheoesophageal fistula: a population-based long-term follow-
define the impact of stretching on esophageal function and up. Ann Surg 2010;251(6):1167–1173
thereby the clinical surplus value and safety of this treatment 5 Sistonen S, Malmberg P, Malmström K, et al. Repaired oesophageal
atresia: respiratory morbidity and pulmonary function in adults.
strategy. Finally, recent experiments suggest that tissue
Eur Respir J 2010;36(5):1106–1112
engineering of the esophagus may be the future for patients 6 Gischler SJ, van der Cammen-van Zijp MH, Mazer P, et al.
with long-gap EA. It is important to realize that not only the A prospective comparative evaluation of persistent respiratory
morphology of this newly engineered esophagus is crucial for morbidity in esophageal atresia and congenital diaphragmatic
the long-term success in EA patients. Seen the current hernia survivors. J Pediatr Surg 2009;44(9):1683–1690
comorbidities of esophageal dysmotility in EA patients it is 7 Possoegel AK, Diez-Pardo JA, Morales C, Tovar JA. Notochord
involvement in experimental esophageal atresia. Pediatr Surg
obvious that the motor function of the new esophagus will be
Int 1999;15(3–4):201–205
determining the therapeutic gain of tissue engineering. 8 Liu XM, Aras-Lopez R, Martinez L, Tovar JA. Abnormal develop-
Therefore, the main focus should be the growth of functional ment of lung innervation in experimental esophageal atresia. Eur J
muscle.67 Pediatr Surg 2012;22(1):67–73

European Journal of Pediatric Surgery

EA: Future Directions for Research on the Digestive Tract Rayyan et al.

9 Merei J, Hasthorpe S, Farmer P, Hutson JM. Relationship between 31 Romeo C, Bonanno N, Baldari S, et al. Gastric motility disorders in
esophageal atresia with tracheoesophageal fistula and vertebral patients operated on for esophageal atresia and tracheoesophageal
anomalies in mammalian embryos. J Pediatr Surg 1998;33(1):58–63 fistula: long-term evaluation. J Pediatr Surg 2000;35(5):740–744
10 Qi BQ, Merei J, Farmer P, et al. The vagus and recurrent laryngeal 32 Boleken M, Demirbilek S, Kirimiloglu H, et al. Reduced neuronal
nerves in the rodent experimental model of esophageal atresia. innervation in the distal end of the proximal esophageal atretic
J Pediatr Surg 1997;32(11):1580–1586 segment in cases of esophageal atresia with distal tracheoesopha-
11 Koivusalo A, Pakarinen MP, Rintala RJ. The cumulative incidence of geal fistula. World J Surg 2007;31(7):1512–1517
significant gastrooesophageal reflux in patients with oesophageal 33 Nakazato Y, Landing BH, Wells TR. Abnormal Auerbach plexus in the
atresia with a distal fistula—a systematic clinical, pH-metric, and esophagus and stomach of patients with esophageal atresia and
endoscopic follow-up study. J Pediatr Surg 2007;42(2):370–374 tracheoesophageal fistula. J Pediatr Surg 1986;21(10):831–837
12 Deurloo JA, Ekkelkamp S, Taminiau JA, et al. Esophagitis and 34 Cucchiara S, Staiano A, Di Lorenzo C, et al. Esophageal motor
Barrett esophagus after correction of esophageal atresia. J Pediatr abnormalities in children with gastroesophageal reflux and peptic
Surg 2005;40(8):1227–1231 esophagitis. J Pediatr 1986;108(6):907–910
13 Lindahl H, Rintala R, Sariola H. Chronic esophagitis and gastric 35 Davies MR. Anatomy of the extrinsic motor nerve supply to
metaplasia are frequent late complications of esophageal atresia. mobilized segments of the oesophagus disrupted by dissection
J Pediatr Surg 1993;28(9):1178–1180 during repair of oesophageal atresia with distal fistula. Br J Surg
14 Deurloo JA, Ekkelkamp S, Bartelsman JF, et al. Gastroesophageal 1996;83(9):1268–1270
reflux: prevalence in adults older than 28 years after correction of 36 Shono T, Suita S, Arima T, et al. Motility function of the esophagus
esophageal atresia. Ann Surg 2003;238(5):686–689 before primary anastomosis in esophageal atresia. J Pediatr Surg
15 Tovar JA, Fragoso AC. Anti-reflux surgery for patients with esoph- 1993;28(5):673–676
ageal atresia. Dis Esophagus 2013;26(4):401–404 37 Lemoine C, Aspirot A, Le Henaff G, Piloquet H, Lévesque D, Faure C.
16 Di Pace MR, Caruso AM, Catalano P, Casuccio A, Cimador M, De Characterization of esophageal motility following esophageal
Grazia E. Evaluation of esophageal motility and reflux in children atresia repair using high-resolution esophageal manometry.
treated for esophageal atresia with the use of combined multi- J Pediatr Gastroenterol Nutr 2013;56(6):609–614
channel intraluminal impedance and pH monitoring. J Pediatr 38 van Wijk M, Knüppe F, Omari T, de Jong J, Benninga M. Evaluation
Surg 2011;46(3):443–451 of gastroesophageal function and mechanisms underlying gastro-

Downloaded by: Cornell. Copyrighted material.

17 Kawahara H, Kubota A, Hasegawa T, et al. Lack of distal esophageal esophageal reflux in infants and adults born with esophageal
contractions is a key determinant of gastroesophageal reflux atresia. J Pediatr Surg 2013;48(12):2496–2505
disease after repair of esophageal atresia. J Pediatr Surg 2007; 39 Pedersen RN, Markøw S, Kruse-Andersen S, et al. Esophageal
42(12):2017–2021 atresia: gastroesophageal functional follow-up in 5-15 year old
18 Aspirot A, Faure C. Esophageal dysmotility: characterization and children. J Pediatr Surg 2013;48(12):2487–2495
pathophysiology. Dis Esophagus 2013;26(4):405–409 40 Tong S, Mallitt KA, Krishnan U. Evaluation of Gastroesophageal
19 Deurloo JA, Ekkelkamp S, Hartman EE, Sprangers MA, Aronson DC. Reflux by Combined Multichannel Intraluminal Impedance and
Quality of life in adult survivors of correction of esophageal atresia. pH Monitoring and Esophageal Motility Patterns in Children with
Arch Surg 2005;140(10):976–980 Esophageal Atresia. Eur J Pediatr Surg 2016;26(4):322–331
20 Schneider A, Blanc S, Bonnard A, et al. Results from the French 41 Bredenoord AJ, Fox M, Kahrilas PJ, Pandolfino JE, Schwizer W,
National Esophageal Atresia register: one-year outcome. Orphanet Smout AJ; International High Resolution Manometry Working
J Rare Dis 2014;9:206 Group. Chicago classification criteria of esophageal motility dis-
21 Taylor AC, Breen KJ, Auldist A, et al. Gastroesophageal reflux and orders defined in high resolution esophageal pressure topography.
related pathology in adults who were born with esophageal Neurogastroenterol Motil 2012;24(Suppl 1):57–65
atresia: a long-term follow-up study. Clin Gastroenterol Hepatol 42 Bogte A, Bredenoord AJ, Oors J, Siersema PD, Smout AJ. Relation-
2007;5(6):702–706 ship between esophageal contraction patterns and clearance of
22 Foker JE, Kendall TC, Catton K, Khan KM. A flexible approach to swallowed liquid and solid boluses in healthy controls and
achieve a true primary repair for all infants with esophageal patients with dysphagia. Neurogastroenterol Motil 2012;24(8):
atresia. Semin Pediatr Surg 2005;14(1):8–15 e364–e372
23 van der Zee DC, Gallo G, Tytgat SH. Thoracoscopic traction tech- 43 Rayyan M, Allegaert K, Omari T, Rommel N. Dysphagia in Children
nique in long gap esophageal atresia: entering a new era. Surg with Esophageal Atresia: Current Diagnostic Options. Eur J Pediatr
Endosc 2015;29(11):3324–3330 Surg 2015;25(4):326–332
24 Spitz L. Gastric transposition via the mediastinal route for infants with 44 Montgomery M, Escobar-Billing R, Hellström PM, Karlsson KA,
long-gap esophageal atresia. J Pediatr Surg 1984;19(2):149–154 Frenckner B. Impaired gastric emptying in children with repaired
25 Spitz L. Esophageal atresia. Lessons I have learned in a 40-year esophageal atresia: a controlled study. J Pediatr Surg 1998;33(3):
experience. J Pediatr Surg 2006;41(10):1635–1640 476–480
26 Ring WS, Varco RL, L’Heureux PR, Foker JE. Esophageal replace- 45 Diez-Pardo JA, Baoquan Q, Navarro C, Tovar JA. A new rodent
ment with jejunum in children: an 18 to 33 year follow-up. experimental model of esophageal atresia and tracheoesophageal
J Thorac Cardiovasc Surg 1982;83(6):918–927 fistula: preliminary report. J Pediatr Surg 1996;31(4):498–502
27 Kovesi T, Rubin S. Long-term complications of congenital esoph- 46 Ioannides AS, Chaudhry B, Henderson DJ, Spitz L, Copp AJ. Dorso-
ageal atresia and/or tracheoesophageal fistula. Chest 2004;126(3): ventral patterning in oesophageal atresia with tracheo-oesopha-
915–925 geal fistula: Evidence from a new mouse model. J Pediatr Surg
28 Ijsselstijn H, van Beelen NW, Wijnen RM. Esophageal atresia: long- 2002;37(2):185–191
term morbidities in adolescence and adulthood. Dis Esophagus 47 Qi BQ, Merei J, Farmer P, et al. Cardiovascular malformations in rat
2013;26(4):417–421 fetuses with oesophageal atresia and tracheo-oesophageal fistula
29 Romeo G, Zuccarello B, Proietto F, Romeo C. Disorders of the induced by adriamycin. Pediatr Surg Int 1997;12(8):556–564
esophageal motor activity in atresia of the esophagus. J Pediatr 48 Mc Laughlin D, Hajduk P, Murphy P, Puri P. Adriamycin-Induced
Surg 1987;22(2):120–124 Models of VACTERL Association. Mol Syndromol 2013;4(1–2):
30 Lemoine C, Aspirot A, Morris M, Faure C. Esophageal dysmotility is 46–62
present before surgery in isolated tracheoesophageal fistula. 49 Cleaver O, Krieg PA. Notochord patterning of the endoderm. Dev
J Pediatr Gastroenterol Nutr 2015;60(5):642–644 Biol 2001;234(1):1–12

European Journal of Pediatric Surgery

 EA: Future Directions for Research on the Digestive Tract Rayyan et al.

50 Hajduk P, Sato H, Puri P, Murphy P. Abnormal notochord branching induced esophageal atresia. Braz J Med Biol Res 2015;48(5):
is associated with foregut malformations in the adriamycin 458–464
treated mouse model. PLoS ONE 2011;6(11):e27635 61 Soyer T, Kalkışım S, Yalcin S, et al. The effects of acute tension
51 Arsic D, Cameron V, Ellmers L, Quan QB, Keenan J, Beasley S. increase on rat esophageal muscle contractions: An in vitro study.
Adriamycin disruption of the Shh-Gli pathway is associated with J Pediatr Surg 2015;50(10):1691–1694
abnormalities of foregut development. J Pediatr Surg 2004;39(12): 62 Montedonico S, Diez-Pardo JA, Possögel AK, Tovar JA. Effects of
1747–1753 esophageal shortening on the gastroesophageal barrier: an exper-
52 Brosens E, Ploeg M, van Bever Y, et al. Clinical and etiological imental study on the causes of reflux in esophageal atresia.
heterogeneity in patients with tracheo-esophageal malformations J Pediatr Surg 1999;34(2):300–303
and associated anomalies. Eur J Med Genet 2014;57(8):440–452 63 Bairdain S, Hamilton TE, Smithers CJ, et al. Foker process for the
53 Digilio MC, Marino B, Bagolan P, Giannotti A, Dallapiccola B. correction of long gap esophageal atresia: Primary treatment
Microdeletion 22q11 and oesophageal atresia. J Med Genet versus secondary treatment after prior esophageal surgery.
1999;36(2):137–139 J Pediatr Surg 2015;50(6):933–937
54 Kilic SS, Gurpinar A, Yakut T, Egeli U, Dogruyol H. Esophageal 64 Khan KM, Sabati AA, Kendall T, Foker JE. The effect of traction on
atresia and tracheo-esophageal fistula in a patient with Digeorge esophageal structure in children with long-gap esophageal atresia.
syndrome. J Pediatr Surg 2003;38(8):E21–E23 Dig Dis Sci 2006;51(11):1917–1921
55 Dauvé V, McLin VA. Recent advances in the molecular and genetic 65 Inoue S, Kosaka T, Takatsuki M, Kuroki T, Eguchi S. Histological
understanding of congenital gastrointestinal malformations. study of the elongated esophagus in a rat model. J Surg Res 2015;
J Pediatr Gastroenterol Nutr 2013;57(1):4–13 195(2):495–501
56 Cheng W, Bishop AE, Spitz L, Polak JM. Abnormalities of neuro- 66 Sullins VF, Traum PK, French SW, Wu BM, Dunn JC, Lee SL. A novel
peptides and neural markers in the esophagus of fetal rats with method of esophageal lengthening in a large animal model of long
adriamycin-induced esophageal atresia. J Pediatr Surg 1997; gap esophageal atresia. J Pediatr Surg 2015;50(6):928–932
32(10):1420–1423 67 Maghsoudlou P, Eaton S, De Coppi P. Tissue engineering of the
57 Cheng W, Bishop AE, Spitz L, Polak JM. Abnormal enteric nerve esophagus. Semin Pediatr Surg 2014;23(3):127–134
morphology in atretic esophagus of fetal rats with adriamycin- 68 Singendonk MM, Kritas S, Cock C, et al. Applying the Chicago
induced esophageal atresia. Pediatr Surg Int 1999;15(1):8–10 Classification criteria of esophageal motility to a pediatric cohort:

Downloaded by: Cornell. Copyrighted material.

58 Li K, Zheng S, Xiao X, Wang Q, Zhou Y, Chen L. The structural effects of patient age and size. Neurogastroenterol Motil 2014;
characteristics and expression of neuropeptides in the esophagus 26(9):1333–1341
of patients with congenital esophageal atresia and tracheoeso- 69 Kahrilas PJ, Bredenoord AJ, Fox M, et al; International High
phageal fistula. J Pediatr Surg 2007;42(8):1433–1438 Resolution Manometry Working Group. The Chicago Classification
59 Midrio P, Alaggio R, Strojna A, et al. Reduction of interstitial cells of of esophageal motility disorders, v3.0. Neurogastroenterol Motil
Cajal in esophageal atresia. J Pediatr Gastroenterol Nutr 2010; 2015;27(2):160–174
51(5):610–617 70 Conklin JL. Evaluation of Esophageal Motor Function With High-
60 Capeto FA, Lima FJ, Okoba W, et al. Contractile profile of esoph- resolution Manometry. J Neurogastroenterol Motil 2013;19(3):
ageal and gastric fundus strips in experimental doxorubicin- 281–294

European Journal of Pediatric Surgery