Keywords
esophageal atresia with tracheoesophageal fistula - pediatric surgery - follow-up
- management - consensus conference
Introduction
Since the first successful primary repair of esophageal atresia (EA) in 1941, improvements
in operative and perioperative care have led to better outcomes and have shifted the
focus from mortality to morbidity and quality-of-life-issues.[1]
[2]
[3]
[4]
[5]
[6]
[7]
[8]
[9] Esophageal atresia is no more just a neonatal surgical challenge, but rather a lifelong
issue for the patient.[1]
[6]
[7]
[10] It appears that respiratory, nutritional, and gastroenterological issues are the
most prevalent sequelae—not only in the first years of life, but also in adolescence
and adulthood[6]
[7] requiring constant long-term follow-up following standardized protocols in specialized
centers including interdisciplinary transition programs.
However, precisely formulated guidelines on the follow-up of patients with EA are
scarce.[10]
[11]
In 2016, the gastrointestinal working group of the International Network on Esophageal Atresia (INoEA) comprising members from The European Society for Pediatric Gastroenterology Hepatology and Nutrition (ESPGHAN) and The North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) published guidelines for the management of gastrointestinal and nutritional
complications in children with EA with (TEF) tracheoesophageal fistula.[1]
In 2017, the European Reference Network on Rare Inherited and Congenital Anomalies
(ERNICA) has been established in response to the European Commission's call for the
setup of European Reference Networks for rare diseases.[12] The mission of ERNICA is to promote optimal patient care for rare inherited and
congenital digestive track-related disorders from pediatric age to adulthood providing
high quality and accessible education, supporting research, improving clinical standards
and services and reducing health inequalities in Europe.[13]
[14]
[15]
[16]
[17]
During recent ERNICA meetings, participants agreed to establish consensus on all relevant
aspects of the surgical management of patients with EA including Follow-up as an urgent objective of ERNICA.
In this first ERNICA consensus conference focusing on the management of patients with
EA and TEF, two priorities were addressed: The recently published results of the first
part of the ERNICA consensus conference focused on Diagnostics, Preoperative, Operative and Postoperative Management.[18] The second part of the conference mainly dealt with Follow-up and Framework from a surgical perspective which will be presented in the following.
Materials and Methods
The general methodological approach has been recently published when presenting the
first part of the ERNICA consensus conference on Diagnostics, Preoperative, Operative and Postoperative Management.[18] The second part which is reported in this manuscript differed from the first part
in details. Therefore, the two parts are presented separately.
The conference, which dealt exclusively with the management of patients with EA with
TEF who undergo primary anastomosis, took place in Berlin on the October 25th and
26th, 2018. In total, 14 pediatric surgeons, one pediatric gastroenterologist, three
representatives of patient support groups acting under the umbrella of the Federation
of Esophageal Atresia and Tracheo-Esophageal Fistula Support Groups (EAT),[19] and one non-surgeon pediatric surgery academic took part in all steps of the preparation
and the conference itself. All participants were members of the ERNICA Workstream
Congenital Malformations and Diseases of the Esophagus.
The preparation and implementation of the conference included the following steps:[18] (1) generation of a list of items; (2) prioritization of the items using the online
REDCap electronic data capture tools;[20] (3) discussion of all items during the conference, formulation of statements; (4)
anonymous voting via the internet-based system VoxVote.[21]
The items of this second part of the conference focused on the domains Follow-up and Framework. For the domain Follow-up, the ESPGHAN-NASPGHAN guidelines[1] were reviewed to identify matches or similarities in both lists as both focused
on patients with EA with TEF—from a pediatric gastrointestinal and from a pediatric
surgical perspective. It has been consciously decided not to adopt the entire list
of ESPGHAN-NAPGHAN guidelines including 36 statements. Only items of surgical relevance
were finally included.
With regard to literature search, publications with the highest grade of evidence
according to the CEBM (center for evidence-based medicine) classification were suggested
to be preferred[22] as previously reported.[18] Literature was distributed and made available to all participants via a DropBox
(Dropbox Inc., San Francisco, California, United States, 2007) link prior to the conference.
In case of available ESPGHAN-NASGPHAN statements, the previously presented literature
was applied and supplemented with recent literature where appropriate. All participants
were aware of the ESPGHAN-NASPGHAN statements. The wordings of the statements on items
were updated during the discussion by the participants of the conference and prepared
for voting by the non-surgical academic (S.E.) who did not vote himself. In the majority
of items, the final wording of the statements somehow differed from the wording of
the ESPGHAN-NASPGHAN guidelines although both dealt with the same topic (see [Supplementary Material], available in the online version).
Consensus was defined as ≥75% of those voting scored 6, 7, 8, or 9, excluding those
who declared no relevant expertise on that statement.[18]
Results and Consensus Statements
Results and Consensus Statements
Item Generation and Prioritization
The systematic literature search and the discussion of the members of the ERNICA Workstream
Congenital Malformations and Diseases of the Esophagus during the ERNICA conference in Stockholm on the 18th to 20th April 2018 resulted
in a total of 16 items.
After the online prioritization phase, two items were excluded. Following the participants'
suggestions, 12 items were added as new items. Consequently, the list included 26
items prior to the conference, for which literature was obtained and circulated.
As a result of the presentations by the domain leaders and discussion during the conference,
six items were excluded, and nine items were added as new items as some items were
split into several separate questions. Finally, 29 items were confirmed for voting
and included 25 items in the domain Follow-up ([Table 1]), and four items in the domain Framework ([Table 2]).
Table 1
Consensus statements on the follow-up of patients with esophageal atresia and tracheoesophageal
fistula
|
No
|
Statement
|
ESPGHAN-NASPGHAN Statement available[8]
|
Consensus
|
%
|
Votes
|
Median
|
|
1
|
There should be a structured schedule for life-long follow-up.
|
–
|
+
|
100
|
18/18
|
9 (8–9)
|
|
2
|
There should be an interdisciplinary follow-up program including surgery, gastroenterology,
pulmonary, nutrition counselling, otolaryngology, and others, with one specialist
leading.
|
+
|
+
|
100
|
18/18
|
9 (8–9)
|
|
3
|
Antacid medication should be routinely administered to all patients after correction
of EA.
|
+
|
+
|
88.9
|
16/18
|
9 (2–9)
|
|
4
|
Proton pump inhibitors should be used for antacid prophylaxis in EA patients.
|
+
|
+
|
100
|
16/16
|
8 (6–9)
|
|
5
|
Antacid medication should be routinely administered for 12 mo after correction of
EA, although it is noted that the evidence base is limited.
|
+
|
−
|
66.7
|
12/18
|
7 (1–9)
|
|
6
|
Antacid therapy should be tapered at the end of prophylaxis.
|
−
|
+
|
94.4
|
17/18
|
9 (4–9)
|
|
7
|
Anastomotic stricture should be diagnosed by either contrast study and/or endoscopy
|
+
|
+
|
94.4
|
17/18
|
8.5 (3–9)
|
|
8
|
Anastomotic stricture should be managed by balloon or semirigid dilatation.
|
+
|
+
|
100
|
15/15
|
9 (6–9)
|
|
9
|
The definition of recurrent anastomotic stricture is three anastomotic stricture relapses
requiring dilatation.
|
+
|
+
|
94.4
|
17/18
|
9 (4–9)
|
|
10
|
The maximum number of esophageal dilatations for recurrent anastomotic strictures
until a fundoplication should be considered is five.
|
−
|
+
|
83.3
|
15/18
|
8 (1–9)
|
|
11
|
Topical application of mitomycin C should be recommended as an option in patients
with recurrent strictures.
|
+
|
−
|
26.7
|
4/15
|
3 (1–9)
|
|
12
|
Intralesional/systemic steroids should be recommended as an option in patients with
recurrent strictures.
|
+
|
−
|
46.2
|
6/13
|
5 (3–9)
|
|
13
|
Customized stents /indwelling balloons should be recommended as an option in patients
with recurrent strictures.
|
+
|
+
|
100
|
14/14
|
8 (6–9)
|
|
14
|
24-h-pH- or pH-impedance monitoring should be routinely used for monitoring children
and adolescents with EA according a specific schedule.
|
+
|
+
|
93.8
|
15/16
|
9 (5 − 9)
|
|
15
|
24-h-pH- or pH-impedance monitoring should be routinely performed at time of discontinuation
of antacid therapy.
|
+
|
+
|
83.3
|
15/18
|
8.5 (2–9)
|
|
16
|
At least two additional pH studies should be routinely performed until transition.
|
−
|
−
|
55.6
|
10/18
|
6 (1–9)
|
|
17
|
Endoscopies of the upper gastrointestinal tract should be routinely used for monitoring
children and adolescents with EA according to a specific schedule.
|
+
|
+
|
94.4
|
17/18
|
9 (2–9)
|
|
18
|
Endoscopies of the upper gastrointestinal tract should be routinely performed at 1
y.
|
+
|
+
|
83.3
|
15/18
|
9 (2–9)
|
|
19
|
At least two additional endoscopies of the upper gastrointestinal tract should be
routinely performed until transition.
|
+
|
+
|
100
|
18/18
|
9 (6–9)
|
|
20
|
Lung function tests should be routinely used for monitoring children and adolescents
with EA according to a specific schedule.
|
−
|
+
|
77.8
|
14/18
|
8 (1–9)
|
|
21
|
Contrast study of the upper gastrointestinal tract should be routinely used for monitoring
children and adolescents with EA according to a specific schedule.
|
−
|
−
|
27.8
|
5/18
|
3.5 (1 − 9)
|
|
22
|
Bronchoscopy should be routinely used for monitoring children and adolescents with
EA according to a specific schedule.
|
−
|
−
|
11.8
|
2/17
|
2 (1–7)
|
|
23
|
The following are potential indications for fundoplication: (1) recurrent anastomotic
strictures, (2) poorly controlled GERD despite maximal PPI therapy, (3) long-term
dependency on transpyloric feeding, (4) cyanotic spells.
|
+
|
+
|
94.4
|
17/18
|
8.5 (1–9)
|
|
24
|
Adult EA patients need surveillance as per ESPGHAN guidelines: (1) routine endoscopy
(with biopsies in four quadrants at gastroesophageal junction and anastomotic site)
at time of transition into adulthood and every 5–10 y, (2) additional endoscopy if
new or worsening symptoms develop, (3) in presence of Barrett as per consensus recommendations.
|
+
|
+
|
100
|
18/18
|
9 (6–9)
|
|
25
|
Quality of life assessment using a validated instrument should be offered during follow-up
in children.
|
−
|
+
|
94.4
|
17/18
|
9 (1–9)
|
Abbreviations: EA, esophageal atresia; ESPGHAN, European Society for Pediatric Gastroenterology
Hepatology and Nutrition; GERD, gastroesophageal reflux disease; NASPGHAN, The North
American Society for Pediatric Gastroenterology, Hepatology and Nutrition; PPI, proton
pump inhibitors.
Table 2
Consensus statements on framework conditions in the management of patients with esophageal
atresia with tracheoesophageal fistula
|
No
|
Statement
|
Consensus
|
%
|
Votes
|
Median (range)
|
|
1
|
When EA is suspected, referral to antenatal multidisciplinary counselling in a specialized
center should be made.
|
+
|
100
|
18/18
|
9 (8–9)
|
|
2
|
There should be a minimum average caseload of five new EA per year to meet the requirement
of a specialized center.
|
+
|
100
|
18/18
|
9 (6–9)
|
|
3
|
EA patients should be operated on and treated in specialized centers with a multidisciplinary
team with follow-up including transition.
|
+
|
100
|
18/18
|
9 (6–9)
|
|
4
|
Parents of EA patients should be recommended to be involved in parent and patient
support groups as early as possible.
|
+
|
100
|
18/18
|
9 (6–9)
|
Abbreviation: EA, esophageal atresia.
ESPGHAN-NASPGHAN Guidelines
In the domain Follow-up, corresponding ESPGHAN-NASPGHAN statements were available for 17 items (68%). Mapping
of the ERNICA consensus conference items to the ESPGHAN-NASPGHAN statements is shown
in the [Supplementary Material] (available in the online version). The participants of this conference divided two
of the ESPGHAN-NASPGHAN statements into several items and voted separately: three
items (item No 11, 12, 13) referred to a single ESPGHAN-NASPGHAN statement (statement No 28); and two items (item No 18, 19) also referred to a single ESPGHAN-NASPGHAN statement (statement No 7); ([Supplementary Material], available in the online version).
Consensus
In the domain Follow-up, complete agreement, defined as 100% consensus amongst voters, was achieved on seven
items (28%) and general consensus (≥75% of those voting having scored 6–9) on 18 items
(72%). Eight items (32%) were particularly controversial in that the votes ranged
from 1 to 9; in four (50%) of these consensus was not reached. Detailed results are
summarized in [Tables 1] and [3].
Table 3
Summary of the voting results of the first ERNICA consensus conference on the management
of patients with esophageal atresia and tracheoesophageal fistula; Part I was published
elsewhere[18]
|
Part of the consensus conference
|
Domain
|
Complete consensus, 100% consensus
|
General consensus, ≥75% consensus[a]
|
No consensus, <75% consensus
|
Controversial discussion, (range 1–9)
|
Total number of items per domain
|
Total number of items per part
|
|
I
|
Diagnostics
|
3 (50%)
|
3 (50%)
|
3 (50%)
|
3 (50%)
|
6
|
52
|
|
Preoperative management
|
3 (38%)
|
4 (50%)
|
4 (50%)
|
1 (13%)
|
8
|
|
Operative management
|
9 (32%)
|
23 (82%)
|
5 (18%)
|
7 (25%)
|
28
|
|
Postoperative management
|
5 (50%)
|
7 (70%)
|
3 (30%)
|
2 (20%)
|
10
|
|
II
|
Follow-up
|
7 (28%)
|
19 (76%)
|
6 (24%)
|
8 (32%)
|
25
|
29
|
|
Framework
|
4 (100%)
|
4 (100%)
|
0 (0%)
|
0 (0%)
|
4
|
|
|
|
|
|
|
|
81
|
a Including items with complete consensus.
In the domain Framework, complete consensus was achieved on all items with no controversial items (n = 4; 100%). Detailed results are summarized in [Tables 2] and [3].
Abstention
In the domain Follow-up, one or more participants declared “no relevant expertise on this statement” for seven (28%) items; for one (4%) item, one participant abstained; for two (8%)
items, two participants abstained; in two items (8%) three participants abstained;
in one (4%) item, four participants abstained from voting. There was no abstention
from voting in the domain Framework.
Controversial Discussion
Several items were discussed controversially as indicated by a wide range from 1 to
9 ([Tables 1] and [3]). The controversial discussion included eight items (32%) in the domain Follow-up, of which four items (50%) did not reach consensus. There was no controversial discussion
in the domain Framework.
Concordance with ESPGHAN-NASPGHAN Guidelines
The majority (n = 14; 82%) of items that mapped directly to ESPGHAN-NASPGHAN guidelines[1] were voted in consensus, so were in concordance with the ESPGHAN-NASPGHAN recommendations.
Concerning the other three items (18%), consensus was not reached, meaning the votes
of the participants of the conference were not in line with the ESPGHAN-NASPGHAN recommendations,[1] ([Table 1]):
-
Duration of antacid medication.
-
Topical application of mitomycin C as a therapeutic option for recurrent strictures.
-
Administration of intralesional/systemic steroids as a therapeutic option for recurrent
strictures.
Discussion
The ESPGHAN-NASPGHAN guidelines for the evaluation and treatment of gastrointestinal
and nutritional complications in children with EA and TEF[1] provide a major contribution to the development of generally accepted guidelines
for patient care. These guidelines were set up during two consensus meetings using
the nominal voting technique. Expert opinion was used where no randomized controlled
trials were available to support the recommendations.[1] However, the ESPGHAN-NASPGHAN guidelines approach the field of Follow-up from a rather gastroenterological/non-surgical perspective. The medical and surgical
follow-ups of this particular group of patients are undoubtedly similar in many respects.
Nonetheless, the already existing guidelines needed to be evaluated also by pediatric
surgeons as being not only responsible for a crucial intervention—the esophageal anastomosis[23]—but also taking part in subsequent follow-up. Besides the overlap of certain aspects,
additional items from a surgical angle needed to be addressed supplementary to the
already existing ESPGHAN-NASPGHAN guidelines.
We hereby present for the first time the results of a consensus conference focused
on surgical aspects of the management of patients with EA with TEF. In line with the ESPGHAN-NASPGHAN
guidelines, this conference was based on two keystones: (1) on evidence from literature,
and (2) on expert opinion.
Participants of this conference achieved general consensus (defined by ≥75% of votes
scoring higher 6–9) in 72% of the items in the domain Follow-up and even 100% in the domain Framework suggesting predominantly homogeneous approaches in ERNICA institutions. When comparing
the results in terms of general consensus in the individual domains including the
previously reported domains Diagnostics (50%), Preoperative (50%), Operative (82%), and Postoperative Management (70%),[18] it appears that consistency of expert opinion reaches the highest level in the domains
Operative Management, Follow-up, and Framework.
One-third of the items in the domain Follow-up were discussed controversially, out of which half did not reach consensus:
According to the ESPGHAN-NASPGHAN guidelines, it is recommended that gastroesophageal
reflux should be systematically treated for prevention of peptic complications and
anastomotic stricture up to the first year of life or longer, depending on the persistence
of gastroesophageal reflux disease[1]; ([Supplementary Material], available in the online version). Stenström et al investigated the incidence of
stricture formation, comparing outcomes of 3- and 12-month antacid prophylactic regimens.[24] They demonstrated in their study including 63 patients with EA that the development
of anastomotic stricture in the first year after esophageal reconstruction was not
reduced by prolonged antacid prophylaxis (12 vs. 3 months), but initial balloon dilation
procedures were performed later in infants who were treated longer.[24] In contrast, another study by Donoso and Lilja aimed to assess the efficacy of postoperative
antacid prophylaxis in reducing the incidence of anastomotic strictures in 128 patients
with EA.[25] They concluded that prophylactic antacid treatment does not appear to reduce the
rate of anastomotic strictures at all.[25]
Participants of the conference discussed these details intensively and did not reach
consensus on the item “duration of administration of antacid medication” as they felt
a lack of evidence from the current literature.[1]
There was also controversial discussion on the item “topical application of mitomycin
C as an option in patients with recurrent strictures.” Mitomycin C is an antineoplastic
and antifibroblastic agent which has been described to exert inconsistent results
at different drug concentrations, when used as a topical agent applied to the anastomotic
stricture after dilatation.[26] According to the ESPGHAN-NASPGHAN guidelines, mitomycin C has been recommended as
potential adjuvant treatment for the management of recurrent strictures in EA patients
among other options[1] ([Supplementary Material], available in the online version). Recently, treatment with mitomycin C has been
reported to significantly reduce stricture recurrence after endoscopic dilatation.[27]
[28] In contrast, Chapuy et al postulated that there is no benefit in the resolution
of the stricture when adding mitomycin C treatment compared with repeated esophageal
dilations alone.[29] Madadi-Sanjani et al also failed to demonstrate a beneficial effect of mitomycin
C.[30] Given the fact that there is limited data to prove the beneficial effect of mitomycin
C treatment, it should be carefully considered whether the advantages of this therapy
outweigh the necessity of life-long endoscopic follow-ups. Therefore, participants
of the conference agreed that further randomized controlled studies are mandatory
and did not reach consensus on this item.
During the conference, participants agreed on the routine use of pH-studies for monitoring
patients with EA according to a specific schedule and at time of discontinuation of
antacid therapy. However, due to a lack of evidence in the current literature and
controversial opinions among the participants, no consensus could be achieved on the
frequency of pH studies until transition.
For the same reasons, no consensus could be reached on the routine use of contrast
study of the upper gastrointestinal tract for monitoring patients with EA according
to a specific schedule. As in the previous presented item, participants of the conference
hold very divergent opinions and approaches on these aspects indicating certain heterogeneity
of applied protocols in ERNICA centers.
In the vast majority of votes (82%), results from this ERNICA consensus conference
were consistent with the ESPGHAN-NASPGHAN guidelines[1] except in three (18%) votes: The items “administration of antacid medication for
12 months” and “topical application of mitomycin C” have already been discussed above.
The third item with divergent results is on the “administration of intralesional/systemic
steroids as a therapeutic option in patients with recurrent strictures.” The use of
intralesional steroids has been reported with inconsistent improvement of anastomotic
strictures.[28]
[31]
[32] Potential complications such as perforation, infection, pleural effusion, or adrenal
suppression are well known.[1] Side effects have been reported neither for local nor for systemic short-term steroid
treatment.[1] Based on a recently published case series by Ten Kate et al,[33] a multicenter, single-blind randomized controlled trial (STEPS-EA trial; approval number MEC-2018–1586/NL65364.078.18) involving ERNICA centers is currently
being conducted on the use of intralesional steroid injections to prevent refractory
strictures in patients with EA. After extensive discussion, participants of the conference
did not reach consensus on this item.
The domain Framework focuses on centralization, multidisciplinary treatment, and participation of patient
organizations in the management of patients with EA. Particular attention should be
paid to the fact that complete consensus (defined as 100% consensus) was achieved
on all items in this domain. The uniformity of opinions regarding these aspects is
also reflected by the lack of abstention from voting on these items.
Over the last two decades, important contributions were made at national, European,
and international levels to foster collaboration in rare diseases research.[13] The European legislation calls for multidisciplinary centers treating children with
rare diseases and proposes clear and demanding quality criteria.[34] Centralization in surgical patient care is a topic that is increasingly becoming
important due to the growing number of reports that the level of care has improved
and the number of complications, including mortality, have decreased with an elevation
in the number of treated patients per surgeon and center.[14]
[34]
[35]
[36] Pediatric surgery is a specialty of rare cases and low numbers.[35] It is therefore all the more important to pool expertise and corresponding infrastructure
in a specialized center. Thus, participants of this conference strongly believe that
the implementation of a minimum average caseload of new patients with EA per year
per center is mandatory to define the requirements of a “specialized” center.
Until today, the optimal way to concentrate on pediatric surgical experience in each
European country remains undefined and most likely depends on multiple national features,
such as size and distribution of the population, geographical distances, local surgical
expertise, organization of the health care system, and political agendas:[15]
[34]
[37]
[38] The architype for centralization in the United Kingdom, for example, is the management
of biliary atresia being exclusively managed in three centers.[39] All the Nordic countries (Finland, Norway, Sweden, and Denmark) have a relatively
small population making it necessary to concentrate advanced pediatric surgical care
to a few specialized centers to ensure adequate caseload and high-quality care.[15]
[36] In France, the available data strongly suggest that centralization, specialization,
and connections between specialized and routine pediatric surgical departments can
greatly improve management of and outcomes in children.[34]
In this study, it was demonstrated that efforts toward further centralization of pediatric
surgery have already resulted in reduced morbidity and mortality.[34]
[38]
[39] These endeavors should be urgently pursued implementing the mission of ERNICA.
As defined in the European Commission Delegated Decision,[40] European Reference Networks have to demonstrate that they are patient-centered and
empower patients.[13] Patients and patient organizations play a critical role in rare disease European
Reference Networks due to their expertise.[13]
[41]
[42]
[43] Patients and/or their representatives become increasingly involved in addressing
ethical issues, transparency in quality of care, safety standards, and contributing
to research.[13]
[44]
[45] The involvement of representatives of patient support groups in this consensus conference
allowed a unique perspective to all discussed aspects of patient care and management
and emphasizes the benefits of collaboration as already proved in the past.[44]
[46]
Conclusion
Participants of this ERNICA conference reached significant consensus on the follow-up
of patients with EA and TEF who undergo primary anastomosis. Fundamental statements
regarding centralization, multidisciplinary approach, and involvement of patient organizations
were formulated. These consensus statements will provide the cornerstone for uniform
treatment protocols and resultant optimized patient care.
