’ Systematic review and/or Meta-analysis

Risk factors for Hirschsprung disease-associated

enterocolitis: a systematic review and meta-analysis
a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8K2+Ya6H515kE= on 08/26/2023

Xintao Zhang, MSca, Dong Sun, MDa, Qiongqian Xu, MDa, Han Liu, MDb, Yunfeng Li, MDa, Dongming Wang, MDa,
Downloaded from http://journals.lww.com/international-journal-of-surgery by BhDMf5ePHKav1zEoum1tQfN4

Jian Wang, MDa, Qiangye Zhang, MDa, Peimin Hou, MSca, Weijing Mu, MSca, Chunling Jia, MDc, Aiwu Li, MDa,*

Background: The incidence of Hirschsprung disease (HSCR) is nearly 1/5000 and patients with HSCR are usually treated through
surgical intervention. Hirschsprung disease-associated enterocolitis (HAEC) is a complication of HSCR with the highest morbidity
and mortality in patients. The evidence on the risk factors for HAEC remains inconclusive to date.
Methods: Four English databases and four Chinese databases were searched for relevant studies published until May 2022. The
search retrieved 53 relevant studies. The retrieved studies were scored on the Newcastle–Ottawa Scale by three researchers. Revman
5.4 software was employed for data synthesis and analysis. Stata 16 software was employed for sensitivity analysis and bias analysis.
Results: A total of 53 articles were retrieved from the database search, which included 10 012 cases of HSCR and 2310 cases of HAEC. The
systematic analysis revealed anastomotic stenosis or fistula [I2 = 66%, risk ratio (RR) = 1.90, 95% CI 1.34–2.68, P< 0.001], preoperative
enterocolitis (I2 = 55%, RR = 2.07, 95% CI 1.71–2.51, P< 0.001), preoperative malnutrition (I2 = 0%, RR = 1.96, 95% CI 1.52–2.53, P< 0.001),
preoperative respiratory infection or pneumonia (I2 = 0%, RR = 2.37, 95% CI 1.91–2.93, P< 0.001), postoperative ileus (I2 = 17%, RR = 2.41,
95% CI 2.02–2.87, P< 0.001), length of ganglionless segment greater than 30 cm (I2 = 0%, RR = 3.64, 95% CI 2.43–5.48, P< 0.001),
preoperative hypoproteinemia (I2 = 0%, RR = 1.91, 95% CI 1.44–2.54, P< 0.001), and Down syndrome (I2 = 29%, RR = 1.65, 95% CI
1.32–2.07, P< 0.001) as the risk factors for postoperative HAEC. Short-segment HSCR (I2 = 46%, RR = 0.62, 95% CI 0.54–0.71, P< 0.001)
and transanal operation (I2 = 78%, RR = 0.56, 95% CI 0.33–0.96, P = 0.03) were revealed as the protective factors against postoperative
HAEC. Preoperative malnutrition (I2 = 35%,RR = 5.33, 95% CI 2.68–10.60, P< 0.001), preoperative hypoproteinemia (I2 = 20%, RR = 4.17,
95% CI 1.91–9.12, P< 0.001), preoperative enterocolitis (I2 = 45%, RR = 3.51, 95% CI 2.54–4.84, P< 0.001), and preoperative respiratory
infection or pneumonia (I2 = 0%, RR = 7.20, 95% CI 4.00–12.94, P< 0.001) were revealed as the risk factors for recurrent HAEC, while short-
segment HSCR (I2 = 0%, RR = 0.40, 95% CI 0.21–0.76, P = 0.005) was revealed as a protective factor against recurrent HAEC.
Conclusion: The present review delineated the multiple risk factors for HAEC, which could assist in preventing the development of HAEC.
Keywords: Enterocolitis, hirschsprungs disease, meta-analysis, risk factor, systematic review

Introduction Its main pathogenesis is a developmental disorder of the enteric

Hirschsprung disease (HSCR), also referred to aganglionosis, is a
congenital disorder of the intestinal tract[1]. The incidence
of HSCR is ~1 in 5000 with a female-to-male ratio of ~1/4[2].
Departments ofaPediatric surgery, bGastroenterology and cStomatology, Qilu
Hospital of Shandong University, Jinan, China
Sponsorships or competing interests that may be relevant to content are disclosed at
the end of this article.
*Corresponding author. Address: Department of Pediatric surgery, Qilu Hospital of
Shandong University, Wenhua West Road 107#, Jinan, 250012, China.
Tel.: +86 18560086388. E-mail address: liaiwu@qiluhospital.com (A. Li); Department
of Stomatology, Qilu Hospital of Shandong University, Wenhua West Road 107#,
Jinan, 250012, China. Tel.: +86 18560083736. E-mail address: dtjeanne68@126.com
(C. Jia).
Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. This is an
open access article distributed under the Creative Commons Attribution License 4.0
(CCBY), which permits unrestricted use, distribution, and reproduction in any
medium, provided the original work is properly cited.
International Journal of Surgery (2023) 109:2509–2524
Received 5 March 2023; Accepted 8 May 2023
Supplemental Digital Content is available for this article. Direct URL citations are
provided in the HTML and PDF versions of this article on the journal’s website,
www.lww.com/international-journal-of-surgery.
Published online 5 June 2023
http://dx.doi.org/10.1097/JS9.0000000000000473
nervous system, which leads to intestinal motility disorders, and
the main pathological manifestation is the absence of ganglion
cells in the diseased intestine, which usually extend over specific
distances[3]. HSCR is one of the first multi-gene genetic disorders
to be identified, and so far, over 25 genes have been confirmed to
be associated with HSCR[4–6]. However, not all cases of HSCR
are reported to have genetic mutations, and in a large proportion
of patients, HSCR presents with no associated mutations and is
thought to be caused mainly due to environmental factors[2,7,8].
Hirschsprung disease-associated enterocolitis (HAEC) is the
most serious and common complication of HSCR[9], and is also
the leading cause of morbidity and mortality in patients with
HSCR[10,11]. The clinical characteristics of HAEC include
abdominal distention, diarrhoea, fever, and subsequent sepsis[12].
The incidence of HAEC ranges approximately from 17 to 50%,
with the incidence of preoperative HAEC ranging from 5.7 to
50% and that of postoperative HAEC ranging from 2 to 25%.
Recurrent HAEC occurs in 5.2–56% of HSCR patients[13]. These
data demonstrate that HAEC is an important disease affecting the
general well-being of patients with HSCR.
The pathogenesis of HAEC involves a complex interaction of
dysfunction of the enteric nervous system, abnormal mucin
secretion, inadequate immunoglobulin secretion, and imbalance
of the intestinal microflora[14,15]. In addition, several controllable
environmental factors are thought to be associated with the

2509
 Zhang et al. International Journal of Surgery (2023)
development of HAEC[16,17]. The genetic aspects[18] such as
Gfra1, microRNA-18a-5p, and OSMR[19–21] are also being gra-
dually revealed to be relevant to the development of HAEC.
An effective approach to prevent the development of HAEC
remains to be discovered so far[22,23]. Identification of the risk
factors for HAEC could assist in better prevention of the
disease[13,24]. In this context, the present study aimed to system-
a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8K2+Ya6H515kE= on 08/26/2023
atically analyze the risk factors for HAEC.
Downloaded from http://journals.lww.com/international-journal-of-surgery by BhDMf5ePHKav1zEoum1tQfN4
Materials and methods
The present systematic review and meta-analysis followed the
recommendations of the Cochrane Handbook for Systematic
Reviews of Interventions and was complied with the Preferred
Reporting Items for Systematic Reviews and Meta-Analyses
(PRISMA, Supplemental Digital Content 1, http://links.lww.com/
JS9/A626, Supplemental Digital Content 2, http://links.lww.com/
JS9/A627)[25,26] statement and A MeaSurement Tool to Assess
systematic Reviews 2 (AMSTAR2, Supplemental Digital Content
3, http://links.lww.com/JS9/A628)[27].
Inclusion and exclusion criteria
The inclusion criteria were as follows: (1) The duration of follow-
up of the HAEC-related study was sufficiently long, at least over
2 years, to allow for a sufficient duration for the development of
symptoms. (2) The pathological diagnosis of HSCR was estab-
lished distinctly at the relevant hospital. (3) HSCR has a clear
pathological diagnosis at the relevant hospital. (4) A minimum of
one risk factor for HAEC was studied. (5) The study reported
original data.
The exclusion criteria were: (1) Reviews, meta-analyses and
articles without specific data. (2) Data replication in different
studies. (3) Chinese non-core journals.
Data sources
Three researchers searched PubMed, Web of Science, Embase,
Cochrane Library, CNKI, Wanfang database, China Science and
Technology Journal Database (VIP), and China Biomedical
Literature Database (SinoMed) for relevant studies published
until May 2022. The following terms were used for Hirschsprung
disease: Hirschsprung disease, HSCR, HD, congenital mega-
colon, and aganglionosis. The keywords used for risk factors
Figure 1. Flow chart of risk factors for HAEC study search and screening.
HAEC, Hirschsprung disease-associated enterocolitis.
2510
International Journal of Surgery
HIGHLIGHTS
• Hirschsprung disease-associated enterocolitis (HAEC) is
the most serious and common complication of
Hirschsprung disease and is the leading cause of death in
Hirschsprung disease patients.
• Through the analyses we derived a series of risk factors
for HAEC.
• The incidence of preoperative, postoperative, and recur-
rent HAEC was 23.31%, 23.10%, and 8.01%.
• This is the first and largest meta-analysis of HAEC-related
risk factors.
were: risk factor, related factors, influence factor, predictors,
environmental factors, and every specific factor. The key search
terms used for enterocolitis were: enterocolitis, coloenteritis,
intestinal colitis, enteritis, enteronitis, esoenteritis, and HAEC.
The detailed search strategy is presented in Appendix I,
Supplemental Digital Content 4, http://links.lww.com/JS9/A629.
Study selection
Three authors first selected all studies independently of each other
and then met to review their choices to reach a consensus. Any
inconsistencies were resolved through discussion to reach a
common consensus.
Data extraction
Data from all retrieved articles were extracted by three reviewers
independently of each other. Any disagreements were resolved by
a fourth reviewer. The data extracted from the articles included
authors, the journal of publication, the year of publication, the
study location, the type of study, the exposure cases, and the
total cases.
Risk/protective factor definition
In the present study, a risk factor was defined as follows: that
characteristic, variable, or hazard preceding the outcome of
interest, which, if present for a given individual, renders it further
probable that this individual, rather than someone else selected
from the general population, would develop a given disorder[28].
Similarly, protective factors were defined as those factors that led
to reduced risk of morbidity. It was assumed that the risk/pro-
tective factors had occurred prior to HAEC.
The following are the definitions of the factors investigated in
the present study:
Technical factors
Staged surgery was divided into two groups based on whether it
was a one-stage procedure or a multiple-staged procedure.
Intestinal preparation duration of less than 2 weeks was defined
as less than two weeks of bowel preparation prior to surgery.
Dietary control and dilatation were divided into two groups
based on whether diet control and dilation were adopted or not.
Patient factors
Preoperative malnutrition and preoperative hypoproteinemia
implied that the HSCR patients were diagnosed with
 Zhang et al. International Journal of Surgery (2023)

Table 1
Characteristics of the studies included in the meta-analysis.
Study ID District Country Type of study Journal Case/total cases
Gunnarsdóttir [32] Lund Sweden Cohort study European Journal of Pediatric Surgery 4/29
Nasr et al.[33] Toronto Canada Cohort study Journal of Pediatric Surgery 8/54
Yokoi et al.[34] Hyogo Japan Cohort study Journal of Pediatric Surgery 27/89
a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8K2+Ya6H515kE= on 08/26/2023

Kubota et al.[35] Osaka Japan Cohort study Journal of Pediatric Surgery 11/41
Pini Prato et al.[36] Genoa Italy Cohort study Pediatric Surgery International 25/112
Downloaded from http://journals.lww.com/international-journal-of-surgery by BhDMf5ePHKav1zEoum1tQfN4

Pini Prato et al.[37] Genoa/Alessandria Italy Cohort study Journal of Pediatric Surgery 87/324
Aliev[38] Tashkent Uzbekistan Cohort study European Journal of Molecular & Clinical Medicine 17/138
Tannuri[39] São Paulo Brazil Cohort study Journal of Pediatric Surgery 8/64
Kim et al.[40] Multicenter American Cohort study Journal of Pediatric Surgery 105/281
Le-Nguyen et al.[41] Montreal Canada Cohort study Journal of Pediatric Surgery 58/282
Morabito et al.[42] Manchester United kingdom Cohort study Pediatric Surgery International 19/173
Zheng[43] Xi an China Cohort study Chinese Journal of Pediatric Surgery 8/65
Hackam[44] Toronto Canada Cohort study Journal of Pediatric Surgery 35/105
Hackam[45] Toronto Canada Case-control study Journal of Pediatric Surgery 33/105
Lu et al.[46] Nan jing China Cohort study Journal of Pediatric Surgery 76/415
Shi[47] Shang hai China Cohort study Chinese Journal of Pediatric Surgery 16/103
Shen et al.[48] Shang hai China Cohort study Journal of Pediatric Surgery 9/29
Hackam et al.[49] Pittsburgh American Cohort study Pediatric Surgery International 19/173
Roorda et al.[12] Amsterdam Netherlands Cohort study Journal of Pediatric Surgery 31/146
Mo[50] Nanning China Case-control study Master degree thesis of Guangxi Medical University 43/131
Teitelbaum[51] Columbus, Ohio American Cohort study Annals of surgery 19/80
Teitelbaum et al.[52] multicenter American Cohort study Annals of surgery 55/181
Yulianda[53] Yogyakarta Indonesia Case-control study BMC Proceedings 11/61
Travassos[54] Utrecht Netherlands Cohort study Surgical Endoscopy 12/55
Gunadi[55] Yogyakarta Indonesia Cohort study BMC Research Notes 6/33
Gunadi et al.[56] Yogyakarta Indonesia Cohort study BMC Pediatrics 14/83
Parahita[57] Yogyakarta Indonesia Cohort study Journal of Pediatric Surgery 15/100
Minford et al.[58] Liverpool England Cohort study Journal of Pediatric Surgery 14/70
Sulkowski et al.[59] Ohio American Cohort study Journal of Pediatric Surgery 430/1555
Li,[60] Shang hai China Case-control study Journal of Shanghai Jiao Tong University (Medical Science) 28/67
Pruitt et al.[61] national American Cohort study Journal of Pediatric Surgery 265/2030
Santos[62] Johnson City American Cohort study Journal of Pediatric Surgery 11/65
Menezes[63] Dublin Ireland Cohort study Pediatric Surgery International 74/259
Taylor et al.[64] Salt Lake City American Cohort study European Journal of Pediatric Surgery 140/299
Nakamura et al.[65] Tokyo Japan Cohort study Pediatric Surgery International 7/64
Kwendakwema et al.[66] Salt Lake City American Cohort study Journal of Pediatric Surgery 79/207
Ishikawa et al.[67] Osaka Japan Cohort study Pediatric Surgery International volume 12/49
Aworanti et al.[68] Dublin Ireland Cohort study European Journal of Pediatric Surgery 19/73
Liang[69] Xin Jiang China Cohort study Master degree thesis of Xinjiang Medical University 18/60
Romero et al.[70] Manheim Germany Cohort study Langenbeck’s Archives of Surgery 5/53
Dong[71] Guangzhou China Cohort study Journal of Pediatric Surgery 61/133
Surana[72] Dublin Ireland Cohort study Pediatric Surgery International 41/135
Singh et al.[73] Ontario Canada Cohort study Journal of Pediatric Surgery 10/77
Agarwala[74] New Delhi India Cohort study Department of Pediatric Surgery 2/50
Tang[75] Wuhan China Cohort study Chinese Journal of Pediatric Surgery 34/141
Zhang et al.[76] Shengyang China Cohort study Journal of Pediatric Surgery 3/58
Chia et al.[77] Taiwan China Cohort study Pediatrics & Neonatology 169/629
Kim[78] Daegu Korea Cohort study Journal of the Korean Surgical Society 6/36
Giuliani et al.[79] Los Angeles American Cohort study Journal of Laparoendoscopic & Advanced Surgical 10/140
Sakurai[80] Sendai Japan Case-control study Pediatric Surgery International volume 12/66
Saleh et al.[81] Riyadh Saudi Arabia Cohort study Pediatric Surgery International 3/38
Huang et al.[82] Shenyang China Cohort study Journal of Gastrointestinal Surgery 52/181
Wang[83] Nanning China Cohort study Master degree thesis of Guangxi Medical University 73/163

malnutrition or hypoproteinemia prior to surgery. Preoperative
respiratory infection or pneumonia was defined as the occurrence
of respiratory infection or pneumonia in HSCR patients within 2
weeks prior to surgery. Operative age was defined as the age of
the patient at the time of surgery, and because most of the
retrieved studies had classified patients as older than 1 month or
1 year, this was used as a factor in the present study. The objective
was to study the age factor as a continuous variable or to study
the operative age less than 3 months; however, sufficient data to
support this were not available in the literature.
Disease factors
Anastomotic stricture or fistula and postoperative ileus are the
stenosis or fistula located at the anastomosis or ileus that occur

2511
 Zhang et al. International Journal of Surgery (2023) International Journal of Surgery

Table 2
Quality evaluation of the case-control studies included in meta-analysis.
Selection Comparability Outcome

Is the case Selection Definition Comparability of cases and Same method of Non- Quality
definition Representativeness of of controls on the basis of the Ascertainment ascertainment for response assessment
a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8K2+Ya6H515kE= on 08/26/2023

Study ID adequate of the cases Controls Controls design or analysis of exposure cases and controls rate score
Hackam[45] ★ ★ ★ ★ ★ ★ ★ 7
Mo[50] ★ ★ ★ ★ ★ ★
Downloaded from http://journals.lww.com/international-journal-of-surgery by BhDMf5ePHKav1zEoum1tQfN4

7
Yulianda[53] ★ ★ ★ ★ ★ ★ 6
Li[60] ★ ★ ★ ★ ★ ★ ★ 7
Sakurai[80] ★ ★ ★ ★ ★ ★ ★ 7

after an HSCR surgery. Preoperative enterocolitis is the Results

enterocolitis that occurs in HSCR patients prior to surgery.
Pathological type refers to the pathological type of HSCR, and
in the present study, patients were classified into short-segment
type and other types. The length of the aganglionosis segment
greater than 30 cm was selected as its length of the patholo-
gically confirmed aganglionosis bowel over than 30 cm in
HSCR patients.
Quality assessment
The quality of the cohort and case-control studies was assessed
using the Newcastle–Ottawa Scale scale[29,30]. The cohort studies
assessed outcomes using the following three approaches: (1)
representativeness of the exposure cohort. (2) comparability. (3)
assessment of the time to outcome.
The quality of case-control studies was assessed by the fol-
lowing three approaches: (1) selection of the case and control
groups; (2) comparability; (3) exposure[31]. The total score for the
assessment was nine, and the inclusion criteria in the present
meta-analysis were six or more.
Search results and study characteristics
The search for the risk factors of HAEC retrieved 1757
studies (303 from PubMed, 735 from Web of Science, 235
from Embase, and 484 from CNKI, VIP, Wanfang, and
Sinomed). Among the retrieved studies, 511 studies were
excluded due to duplication, while 1032 studies were exclu-
ded due to irrelevant and non-core journals. The remaining
214 studies were read in detail, and eventually, 53 studies
were retained. The literature screening process is illustrated in
Figure 1, and the characteristics of these studies are listed in
Table 1.
Quality assessment of the studies
Among the included studies, the Newcastle–Ottawa Scale score
was eight for six studies, seven for twenty-eight studies, and six
for the remaining studies. Among the studies included in the
present meta-analysis, forty-eight were cohort studies, and five
were case-control studies (forty-seven were in English, and six
were in Chinese). Further details of the quality assessment are
provided in Table 2 and Table 3.

Statistical analysis Quantitative synthesis

Analyses were initially completed by one author and subse- Incidence

quently reviewed by another author. RevMan 5.4 (Review
manager) was employed to calculate the effect sizes and
generate forest plots. The χ2 test was performed to analyze
the statistical heterogeneity between studies, with P less than
0.05 indicating statistical significance. The Q tests were per-
formed to quantitatively assess whether this heterogeneity
would affect the results. According to the Cochrane review
guidelines, fixed-effects models were used when the hetero-
geneity was small (I2 < 50%); otherwise, a random-effects
model was used for analysis. The original data on the pre-
viously published risk factors extracted from the retrieved
studies were analyzed using dichotomous, relative risk (RR),
95% CI, and the calculations were performed using the
Mantel Haenszel method (fixed or random model). Stata 16.0
(Stata Corp LP) was employed for sensitivity analysis and
publication bias. Publication bias was determined using
Egger’s test and funnel plot. P less than 0.05 was considered
statistically significant.
In total, the 53 studies on HAEC contained 2310 cases of HAEC
and 10 012 cases of HSCR[12,32–83]. The proportion of post-
operative incidence of HAEC cases in these studies (HAEC
cases > 10) ranged from 10.98 to 46.82% of the HSCR patients,
with a total incidence of 23.10%.The incidence of preoperative
HAEC ranged from 10.77 to 46.15%, with a total incidence of
21.31%.The incidence of recurrent HAEC ranged from 6.80 to
18.05%, with a total incidence of 8.01%.
Risk factors for postoperative HAEC
Patient factors
Sex. Sex[12,41,45,47,50,56,57,60,64,69,71,72,75,80,82,83] (I2 = 0%, RR = 1.06,
95% CI 0.91–1.24, P = 0.42) (Fig. 2) was not a risk factor for HAEC,
as determined based on the analysis of the data from 4 case-control
studies and 12 cohort studies with 2045 HSCR and 646 HAEC cases.
The analysis of the case-control studies (I2 = 0%, RR = 0.90, 95% CI
0.65–1.26, P = 0.55) or cohort studies(I2 = 0%, RR = 1.11, 95% CI
0.93–1.31, P = 0.25) alone did not change the above finding. Detailed

2512
 Zhang et al. International Journal of Surgery (2023)

Table 3
Quality evaluation of the cohort studies included in meta-analysis.
Selection Comparability Exposure

Comparability
Selection Demonstration that of exposed Was the
a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8K2+Ya6H515kE= on 08/26/2023

of non- Ascertainment outcome of interest and non- Method for follow-up Completeness Quality
Representativeness exposed of exposure was not present at exposed determination time long of follow-up assessment
Study ID of exposure cohort cohort cohort start of study cohorts of results enough cohort score
Downloaded from http://journals.lww.com/international-journal-of-surgery by BhDMf5ePHKav1zEoum1tQfN4

Gunnarsdóttir[32] ★ ★ ★ ★ ★ ★ 6
Nasr et al.[33] ★ ★ ★ ★ ★ ★ ★ 7
Yokoi et al.[34] ★ ★ ★ ★ ★ ★ ★ 7
Kubota et al.[35] ★ ★ ★ ★ ★ ★ 6
Pini Prato ★ ★ ★ ★ ★ ★ ★ 7
et al.[36]
Pini Prato ★ ★ ★ ★ ★★ ★ ★ 8
et al.[37]
Aliev[38] ★ ★ ★ ★ ★ ★ 6
Tannuri[39] ★ ★ ★ ★ ★ ★ ★ 7
Kim et al.[40] ★ ★ ★ ★ ★ ★ 6
Nguyen et al.[41] ★ ★ ★ ★ ★ ★ 6
Morabito ★ ★ ★ ★ ★ ★ ★ 7
et al.[42]
Zheng[43] ★ ★ ★ ★ ★ ★ ★ 7
Hackam[44] ★ ★ ★ ★ ★ ★ ★ 7
Lu et al.[46] ★ ★ ★ ★ ★ ★ ★ 7
Shi[47] ★ ★ ★ ★ ★ ★ 6
Shen et al.[48] ★ ★ ★ ★ ★ ★ 6
Hackam et al.[49] ★ ★ ★ ★ ★ ★ 6
Roorda et al.[12] ★ ★ ★ ★ ★ ★ ★ ★ 8
Teitelbaum[51] ★ ★ ★ ★ ★ ★ ★ ★ 8
Teitelbaum ★ ★ ★ ★ ★ ★ ★ 7
et al.[52]
Travassos[54] ★ ★ ★ ★ ★ ★ ★ 7
Gunadi[55] ★ ★ ★ ★ ★ ★ 6
Gunadi et al.[56] ★ ★ ★ ★ ★ ★ ★ 7
Parahita[57] ★ ★ ★ ★ ★ ★ ★ 7
Minford et al.[58] ★ ★ ★ ★ ★ ★ 6
Sulkowski ★ ★ ★ ★ ★★ ★ ★ 8
et al.[59]
Pruitt et al.[61] ★ ★ ★ ★ ★★ ★ ★ 8
Santos[62] ★ ★ ★ ★ ★ ★ ★ 7
Menezes[63] ★ ★ ★ ★ ★ ★ 6
Taylor et al.[64] ★ ★ ★ ★ ★ ★ ★ 7
Nakamura ★ ★ ★ ★ ★ ★ 6
et al.[65]
Kwendakwema ★ ★ ★ ★ ★ ★ ★ 7
et al.[66]
Ishikawa ★ ★ ★ ★ ★ ★ ★ 6
et al.[67]
Aworanti ★ ★ ★ ★ ★ ★ ★ 7
et al.[68]
Liang[69] ★ ★ ★ ★ ★ ★ ★ 7
Romero et al.[70] ★ ★ ★ ★ ★ ★ ★ 7
Dong[71] ★ ★ ★ ★ ★ ★ ★ 7
Surana[72] ★ ★ ★ ★ ★ ★ ★ 7
Singh et al.[73] ★ ★ ★ ★ ★ ★ 6
Agarwala[74] ★ ★ ★ ★ ★ ★ 6
Tang[75] ★ ★ ★ ★ ★ ★ ★ 7
Zhang et al.[76] ★ ★ ★ ★ ★ ★ 6
Chia et al.[77] ★ ★ ★ ★ ★★ ★ ★ 8
Kim[78] ★ ★ ★ ★ ★ ★ 6
Giuliani et al.[79] ★ ★ ★ ★ ★ ★ ★ 7
Saleh et al.[81] ★ ★ ★ ★ ★ ★ ★ 7
Huang et al.[82] ★ ★ ★ ★ ★ ★ ★ 7
Wang[83] ★ ★ ★ ★ ★ ★ 6

2513
 Zhang et al. International Journal of Surgery (2023) International Journal of Surgery
a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8K2+Ya6H515kE= on 08/26/2023
Downloaded from http://journals.lww.com/international-journal-of-surgery by BhDMf5ePHKav1zEoum1tQfN4

Figure 2. Forest plot of sex for postoperative HAEC. HAEC, Hirschsprung disease-associated enterocolitis.

Figure 3. Forest plot of age of surgery more than 1 month for postoperative HAEC. HAEC, Hirschsprung disease-associated enterocolitis.

Figure 4. Forest plot of age of surgery more than 1 year for postoperative HAEC. HAEC, Hirschsprung disease-associated enterocolitis.

2514
 Zhang et al. International Journal of Surgery (2023)
a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8K2+Ya6H515kE= on 08/26/2023
Downloaded from http://journals.lww.com/international-journal-of-surgery by BhDMf5ePHKav1zEoum1tQfN4

Figure 5. Forest plot of preoperative malnutrition for postoperative HAEC. HAEC, Hirschsprung disease-associated enterocolitis.

Figure 6. Forest plot of preoperative hypoproteinemia for postoperative HAEC. HAEC, Hirschsprung disease-associated enterocolitis.

Figure 7. Forest plot of preoperative respiratory infection or pneumonia for postoperative HAEC. HAEC, Hirschsprung disease-associated enterocolitis.

Figure 8. Forest plot of transanal operation for postoperative HAEC. HAEC, Hirschsprung disease-associated enterocolitis.

2515
 Zhang et al. International Journal of Surgery (2023) International Journal of Surgery
a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8K2+Ya6H515kE= on 08/26/2023
Downloaded from http://journals.lww.com/international-journal-of-surgery by BhDMf5ePHKav1zEoum1tQfN4

Figure 9. Forest plot of anastomotic stenosis or fistula for postoperative HAEC. HAEC, Hirschsprung disease-associated enterocolitis.

Figure 10. Forest plot of preoperative enterocolitis for postoperative HAEC. HAEC, Hirschsprung disease-associated enterocolitis.

Figure 11. Forest plot of short-segment HSCR for postoperative HAEC. HAEC, Hirschsprung disease-associated enterocolitis; HSCR, Hirschsprung disease.

2516
 Zhang et al. International Journal of Surgery (2023)
a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8K2+Ya6H515kE= on 08/26/2023
Downloaded from http://journals.lww.com/international-journal-of-surgery by BhDMf5ePHKav1zEoum1tQfN4

Figure 12. Forest plot of postoperative ileus for postoperative HAEC. HAEC, Hirschsprung disease-associated enterocolitis.

Figure 13. Forest plot of Down syndrome for postoperative HAEC. HAEC, Hirschsprung disease-associated enterocolitis.

Figure 14. Forest plot of length of ganglionless segment for postoperative HAEC. HAEC, Hirschsprung disease-associated enterocolitis.

Figure 15. Forest plot of preoperative enterocolitis for recurrent HAEC. HAEC, Hirschsprung disease-associated enterocolitis.

2517
 Zhang et al. International Journal of Surgery (2023)
a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8K2+Ya6H515kE= on 08/26/2023
Downloaded from http://journals.lww.com/international-journal-of-surgery by BhDMf5ePHKav1zEoum1tQfN4
Figure 16. Forest plot of short-segment HSCR for recurrent HAEC. HAEC, Hirschsprung disease-associated enterocolitis; HSCR, Hirschsprung disease.
results of the analyses conducted for all factors separately for the case-
control study or the cohort study, along with the forest plots, are
presented in Appendix II, Supplemental Digital Content 4, http://
links.lww.com/JS9/A629.
Operative age. No statistical significance was revealed for the
age of surgery more than 1 month[45,46,51,75] (I2 = 89%,
RR = 1.20, 95% CI 0.38–3.79, P = 0.75) (Fig. 3) and the age of
surgery more than 1 year[47,50,64,75,76,83] (I2 = 0%, RR = 0.91,
95% CI 0.74–1.12, P = 0.37) (Fig. 4) in the analysis of the data
from three cohort studies and one case-control study, and five
cohort studies and one case-control study, respectively.
Analysis of the case-control studies or cohort studies alone did
not change the above results.
Preoperative malnutrition. Preoperative malnutrition (I2 = 0%,
RR = 1.96, 95% CI 1.52–2.53, P < 0.001) (Fig. 5) was revealed as
a risk factor for HAEC in the analysis of the data from one cohort
study and two case-control studies with 331 HSCR and 132
HAEC cases. The analysis of case-control studies[60,84] [I2 = 0%,
odds ratio (OR) = 2.86, 95% CI 1.48–5.51, P = 0.002] or cohort
studies[71 ](I2 = 0%, RR = 4.41, 95% CI 2.08–9.34, P < 0.001)
alone did not change the above finding.
Preoperative respiratory infection or pneumonia. Preoperative
respiratory infection or pneumonia[50,60,71,75] (I2 = 0%,
RR = 2.37, 95% CI 1.91–2.93, P < 0.001) (Fig. 6) was revealed as
a risk factor for HAEC in the analysis of the data from two cohort
studies and two case-control studies with 472 HSCR and
166 HAEC cases. The analysis of case-control studies[50,60]
(I2 = 0%, OR = 7.00, 95% CI 3.09–15.84, P < 0.001) or cohort
Figure 17. Forest plot of preoperative malnutrition for recurrent HAEC. HAEC, Hirschsprung disease-associated enterocolitis.
2518
International Journal of Surgery
studies[71,75] (I2 = 0%, RR = 2.22, 95% CI 1.66–2.96, P < 0.001)
alone did not change the above finding.
Preoperative hypoproteinemia. The analysis of data from two
studies revealed that preoperative hypoproteinemia[60,71]
(I2 = 0%, RR = 1.91, 95% CI 1.44–2.54, P < 0.001) (Fig. 7)
was a risk factor for postoperative HAEC.
Technical factors
Surgical methods and access. The analysis of data for 253
HAEC and 782 HSCR from eight cohort studies and one case-
control study revealed that compared with transabdominal,
transanal[35,38,40,41,67,69,70,73,83] (I2 = 78%, RR = 0.56, 95% CI
0.33–0.96, P = 0.03) (Fig. 8) is a protective factor for HAEC.
Moreover, comparisons of Soave and Duhamel[45,48,
56,57,63–65,71,72,78,80,82]
(nine cohort studies and two case-control
studies, I2 = 37%, RR = 0.95, 95% CI 0.69–1.30, P = 0.75),
Swenson and Soave[38,45,63,64,72,82] (five cohort studies and one
case-control study, I2 = 88%, RR = 1.31, 95% CI 0.70–2.48,
P = 0.40), Duhamel and transanal endorectal pull-through
(TEPT)[32,39,50,55,63,79] (six cohort studies, I2 = 0%, RR = 0.93,
95% CI 0.59–1.45, P = 0.74), Swenson and Duhamel[45,63,64,72]
(three cohort studies and one case-control study, I2 = 0%,
RR = 0.95, 95% CI 0.67–1.33, P = 0.75), laparotomy and
laparoscope[12,34,41,54,69,71,79,82,83] (nine cohort studies,
I2 = 23%, RR = 1.14, 95% CI 0.87–1.49, P = 0.35) did not reveal
statistically significant differences.
Other technical factors. The analysis of the data from seven
cohort studies and one case-control study revealed no statistical
significance for staged surgery[43,44,52,58,59,62,75] (I2 = 75%,
 Zhang et al. International Journal of Surgery (2023)
a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8K2+Ya6H515kE= on 08/26/2023
Downloaded from http://journals.lww.com/international-journal-of-surgery by BhDMf5ePHKav1zEoum1tQfN4
Figure 18. Forest plot of preoperative respiratory tract infection or pneumonia for recurrent HAEC. HAEC, Hirschsprung disease-associated enterocolitis.
RR = 1.19, 95% CI 0.75–1.90, P = 0.46). The data from two
cohort studies were analyzed, and no statistical significance was
revealed for the intestinal preparation time of less than 2
week[69,82] (I2 = 88%, RR = 1.31, 95% CI 0.38–4.48, P = 0.67)
and dietary control[69,82] (I2 = 77%, RR = 0.42, 95% CI
0.14–1.27, P = 0.12). No statistical significance was revealed
for anal dilatation[68,69,82,83] (I2 = 0%, RR = 1.21, 95% CI
0.92–1.60, P = 0.17) in the analysis of data from four cohort
studies.
Disease factors
Anastomotic stricture or fistula. The analysis of the data from
five cohort studies and three case-control studies containing 1004
HSCR and 360 HAEC cases revealed that anastomotic stenosis
or fistula[45,47,50,64,68,71,75,80] (I2 = 66%, RR = 1.90, 95% CI
1.34–2.68, P < 0.001) (Fig. 9) was a risk factor for HAEC. The
analysis of the case-control studies[45,50,80] (I2 = 0%, OR = 5.56,
95% CI 2.33–13.28, P < 0.001) or cohort studies[47,64,68,71,75]
(I2 = 70%, RR = 1.69, 95% CI 1.02–2.79, P = 0.04) separately
did not change the above finding.
Preoperative enterocolitis. Preoperative enterocolitis[12,41,45,47,50,
57,60,64,69,71,75,77,80,82,83] 2
(I = 55%, RR = 2.07, 95% CI 1.71–2.51,
P < 0.001) (Fig. 10) was revealed as a risk factor for HAEC in the
analysis of the data of 2446 HSCR and760 HAEC cases from
eleven cohort studies and four case-control studies. The analysis of
the case-control studies[45,50,60,80] (I2 = 59%, OR = 2.89, 95% CI
1.14–7.33, P = 0.03) or cohort studies[12,41,47,57,64,69,71,75,77,82,83]
(I2 = 60%, RR = 2.12, 95% CI 1.70–2.65, P < 0.001) alone did not
change the above finding.
Pathological type. Short-segment HSCR[12,41,47,50,51,56,57,60,63,64,
69,71,72,75,80,82,83]
(I2 = 46%, RR = 0.62, 95% CI 0.54–0.71,
Figure 19. Forest plot of preoperative hypoproteinemia for recurrent HAEC. HAEC, Hirschsprung disease-associated enterocolitis.
2519
P < 0.001) (Fig. 11) was revealed as a protective factor for HAEC
in the analysis of the data on 2246 HSCR and 687 HAEC cases
from fourteen cohort studies and three case-control studies. The
analysis of the case-control studies[50,60,80] (I2 = 70%, RR = 0.55,
95% CI 0.36–0.83, P = 0.004) or cohort studies[12,41,47,51,56,57,63,
64,69,71,72,75,82,83]
(I2 = 43%, RR = 0.63, 95% CI 0.55–0.72,
P < 0.001) alone did not change the above finding.
Postoperative ileus. Postoperative ileus[41,45,50,71,75,83]
2
(I = 17%, RR = 2.41, 95% CI 2.02–2.87, P < 0.001) (Fig. 12)
was revealed as a risk factor for HAEC in the analysis of the
data on 822 HSCR and 277 HAEC cases from four cohort
studies and two case-control studies. The analysis of the
case-control studies[45,50] (I2 = 0%, OR = 6.42, 95% CI
2.25–18.34, P < 0.001) or cohort studies[41,71,75,83] (I2 = 49%,
RR = 2.40, 95% CI 1.96–2.95, P < 0.001) alone did not
change the above finding.
Down syndrome. Down syndrome[37,41,42,49,51,63,66,72,75,80] (I2 =
29%, RR = 1.65, 95% CI 1.32–2.07, P < 0.001) (Fig. 13) was
revealed a risk factor for HAEC in the analysis of the data on 158
Down syndrome, 400 HAEC, and 1668 HSCR cases from nine
cohort studies and a case-control study. This finding did not change
when the cohort studies[37,41,42,49,51,63,66,72,75] (I2 = 37%,
RR = 1.65, 95% CI 1.31–2.08, P < 0.001) were analyzed indivi-
dually.
Length of the ganglionless segment. The analysis of the data
from three studies and two studies revealed that the length of the
ganglionless segment greater than 30 cm[69,76,82] (I2 = 0%,
RR = 3.64, 95% CI 2.43–5.48, P < 0.001) (Fig. 14) was a risk
factor for postoperative HAEC.
 a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8K2+Ya6H515kE= on 08/26/2023
Downloaded from http://journals.lww.com/international-journal-of-surgery by BhDMf5ePHKav1zEoum1tQfN4

Zhang et al. International Journal of Surgery (2023)

Table 4
Risk factors of postoperative HAEC, preoperative HAEC and recurrent HAEC.
Factors studied Exposure/case Non-exposed/ control I2, (%) P for heterogeneity Model RR/OR 95% CI P
Risk factors for postoperative HAEC.
Anal dilatation[68,69,82,83] 285 192 0 0.450 Fixed 1.21 0.92–1.60 0.170
Anastomotic stricture or fistula[45,47,50,64,68,71,75,80] 103 901 66 0.004 Random 1.63 1.34–2.00 < 0.001
Preoperative enterocolitis[12,41,45,47,50,57,60,64,69,71,75,77,80,82,83] 438 2008 55 0.005 Random 2.07 1.71–2.51 < 0.001
Sex[12,41,45,47,50,56,57,60,64,69,71,72,75,80,82,83] 1575 470 0 0.730 Fixed 1.06 0.91–1.24 0.420
Pathological type (Short-segment HSCR)[12,41,47,50,51,56,57,60,63,64,69,71,72,75,80,82,83] 1786 470 46 0.020 Fixed 0.62 0.54–0.71 < 0.001
Preoperative malnutrition[50,60,71] 103 228 0 0.700 Fixed 3.46 2.12–5.66 < 0.001
Preoperative respiratory infection or pneumonia[50,60,71,75] 101 371 0 0.900 Fixed 2.37 1.91–2.93 < 0.001
Postoperative ileus[41,45,50,71,75,83] 91 731 17 0.300 Fixed 2.41 2.02–2.87 < 0.001
Operative age > 1 mo[45,46,51,75] 192 533 89 < 0.001 Random 1.20 0.38–3.79 0.750
Operative age > 1 y[47,50,64,75,76,83] 374 519 0 0.460 Fixed 0.91 0.74–1.12 0.370
Staging operation (one-stage operation)[43,44,52,58,59,62,75] 1479 703 75 < 0.001 Random 1.19 0.75–1.90 0.460
Intestinal preparation time > 2 wk[69,82] 144 97 88 0.004 Random 1.31 0.38–4.48 0.670
Dietary control[69,82] 155 86 77 0.040 Random 0.42 0.14–1.27 0.120
Length of ganglionless segment > 30cm[69,76,82] 74 225 0 0.770 Fixed 3.64 2.43–5.48 < 0.001
Preoperative hypoproteinemia[60,71] < 0.001
2520

44 156 0 0.480 Fixed 1.91 1.44–2.54

Down syndrome[37,41,42,49,51,63,66,72,75,80] 158 1510 29 0.180 Fixed 1.65 1.32–2.07 < 0.001
Comparison of Soave and Duhamel[45,48,56,57,63–65,71,72,78,80,82] 647 369 36 0.110 Fixed 0.97 0.78–1.20 0.750
Comparison of Swenson and Soave[38,45,63,64,72,82] 258 592 88 < 0.001 Random 1.31 0.70–2.48 0.400
Comparison of Duhamel and TEPT[32,39,50,55,63,79] 222 184 0 0.450 Fixed 0.93 0.59–1.45 0.740
Comparison of Swenson and Duhamel[45,63,64,72] 224 136 0 0.920 Fixed 0.95 0.67–1.33 0.750
Comparison of laparotomy and laparoscope[12,34,41,54,69,71,79,82,83] 393 287 23 0.240 Fixed 1.14 0.87–1.49 0.350
Comparison of transanal and transabdominal[35,38,40,41,67,69,70,73,83] 473 447 78 < 0.001 Random 0.56 0.33–0.96 0.030
Risk factors for preoperative HAEC.
Age of surgery > 1 mo[49,53,77] 232 589 92 < 0.001 Random 0.95 0.18–4.96 0.950
Sex[41,53] 176 56 24 0.250 Fixed 1.30 0.61–2.80 0.490
Pathological type (Short-segment HSCR)[41,53] 184 42 0 0.430 Fixed 0.66 0.33–1.33 0.240
Risk factors for recurrent HAEC.
Sex[60,61,71] 1706 524 0 0.870 Fixed 1.04 0.74–1.46 0.830
Pathological type (Short-segment HSCR)[60,71] 126 74 0 0.450 Fixed 0.40 0.21–0.76 0.005

International Journal of Surgery

Preoperative malnutrition[60,71] 69 131 35 0.220 Fixed 5.33 2.68–10.60 < 0.001
Preoperative EC[60,61,71] 204 1913 45 0.160 Fixed 3.51 2.54–4.84 < 0.001
Preoperative respiratory infection or pneumonia[60,71] 38 162 0 0.810 Fixed 7.20 4.00–12.94 < 0.001
Preoperative hypoproteinemia[60,71] 44 156 20 0.260 Fixed 4.17 1.91–9.12 < 0.001
Statistically significant values are in bold.
HAEC, Hirschsprung disease-associated enterocolitis; EC, enterocolitis; HSCR, Hirschsprung disease; OR, odds ratio; RR, risk ratio; TEPT, transanal endorectal pull-through.
 Zhang et al. International Journal of Surgery (2023)
Risk factors for preoperative HAEC
[41,53]
The analyses of the extracted data revealed that sex (two
studies, I2 = 24%, RR = 1.30, 95% CI 0.61–2.80, P = 0.49), type of
pathology[41,53] (two studies, I2 = 0%, RR = 0.66, 95% CI
0.33–1.33, P = 0.24) and age of surgery more than 1 month[49,53,77]
(three studies, I2 = 92%, RR = 0.95, 95% CI 0.18–4.96, P = 0.95)
a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8K2+Ya6H515kE= on 08/26/2023
were not statistically associated with preoperative HAEC.
Downloaded from http://journals.lww.com/international-journal-of-surgery by BhDMf5ePHKav1zEoum1tQfN4
Risk factors for recurrent HAEC
The analysis of the data on 2230 HSCR patients, including 173
recurrent cases, from three studies, revealed preoperative
EC[60,61,71] (I2 = 45%, RR = 3.51, 95% CI 2.54–4.84, P < 0.001)
(Fig. 15) as a risk factor for recurrent HAEC, while sex[60,61,71]
(I2 = 0%, RR = 1.04, 95% CI 0.74–1.46, P = 0.83) was revealed
not to have a statistically significant association with this disease.
The analysis of the data from two studies revealed short-segment
HSCR[60,71] (I2 = 0%, RR = 0.40, 95% CI 0.21–0.76, P = 0.005)
(Fig. 16) as a protective factor, while preoperative
malnutrition[60,71] (I2 = 35%, RR = 5.33, 95% CI 2.68–10.60,
P < 0.001) (Fig. 17), preoperative respiratory tract infection or
pneumonia[60,71] (I2 = 0%, RR = 7.20, 95% CI 4.00–12.94,
P < 0.001) (Fig. 18), and hypoproteinemia[60,71] (I2 = 20%,
RR = 4.17, 95% CI 1.91–9.12, P < 0.001) (Fig. 19) were revealed
as the risk factors for recurrent HAEC. The details of the forest
plots for the non-statistically significant factors are provided in
Appendix III, Supplemental Digital Content 4, http://links.lww.
com/JS9/A629.
Sensitivity analysis and publication bias
Sensitivity remained largely stable after the removal of any of the
studies, with little influence on the outcomes. No significant
asymmetry was detected in the funnel plot. Moreover, no evident
publication bias was detected using Egger’s test (P > 0.05). The
associated funnel plot and Egger’s test results are presented in
Appendix IV, Supplemental Digital Content 4, http://links.lww.
com/JS9/A629.
Discussion
In the present systematic review and meta-analysis, the factors
associated with HAEC were explored, and 31 factors associated
with HAEC were analyzed (Table 4). The results revealed eight
risk factors and two protective factors significantly associated with
postoperative HAEC. In addition, four risk factors and one pro-
tective factor associated with recurrent HAEC were revealed. No
risk factors or protective factors were revealed for preoperative
HAEC.
The debate on the risk factors for HAEC continues to date.
Roorda et al.[12] reported that preoperative EC, short-segment
HSCR, and surgical methods were not associated with the
development of HAEC, while the age of the patient during sur-
gery was associated with HAEC. In contrast, Gao et al.[85] and
certain other scholars[77,80,86] have demonstrated the association
of surgical methods, short-segment HSCR, and preoperative EC
with the development of HAEC. In certain other studies, Soave
was reported as a protective factor for HAEC[57] while some do
not[87]. These factors were analyzed comprehensively in the pre-
sent study, and a number of factors associated with HAEC were
identified. This is expected to have a positive impact on the
2521
relevant clinical work. When a patient presents with multiple risk
factors for HAEC, the possibility of the development of HAEC
must be considered. When a child suffers preoperative mal-
nutrition, preoperative respiratory infection or pneumonia, and
preoperative hypoproteinemia, it is appropriate to postpone the
surgery. After correcting these symptoms without delaying the
disease, the surgery should then be performed.
In addition to the 31 factors analyzed in the present meta-
analysis, a number of other factors are thought to be potentially
associated with HAEC. For instance, oblique anastomosis[88], dis-
tance of the ganglion site from the incision margin[89], low IgA
levels, low birth weight[82], birth Apgar score[12], and milk
allergy[90] could be the risk factors for HAEC. HSCR complications
are reportedly associated with other congenital malformations,
maternal age older than 35 years, preterm birth[53]. However, due
to insufficient data available in the literature, further analysis could
not be conducted in the present study.
In comparison with other similar studies, Mao et al.[91] con-
cluded that the incidence of HAEC was lower in Duhamel com-
pared with TEPT. In contrast, different conclusions were reached
in the present study due to the inclusion of greater literature for
comparison. The results of the present study revealed no differ-
ence in the incidence of HAEC between the two surgical proce-
dures. A meta-analysis by Ruttenstock et al.[92] revealed that
TEPT is a safe and less-invasive procedure with a low incidence of
postoperative HAEC. This was consistent with the findings of the
present study. In addition, three studies[11,22,93] on the associa-
tion of probiotics with HAEC, which were conducted by
Nakamura et al., presented a consistent conclusion that probio-
tics were not statistically correlated with HAEC. Since no new
studies have been published after the literature search process was
completed for the present studying, this factor was not updated
and included as such in the results of the present study.
The major strength of the present study is that it is the first
meta-analysis of the risk factors for HAEC. Moreover, it is the
largest study conducted on HAEC to date. Multiple factors for
preoperative, postoperative, and recurrent HAEC were analyzed
separately. However, as with all research, the present study also
had certain limitations. The diagnostic criteria were not the same
among the different studies, although consistent clinical symp-
toms of HAEC were used in all diagnostic methods. In addition,
only Chinese and English databases were searched, and the data
obtained from the search may not be comprehensive. For certain
factors, such as dietary control, intestinal preparation time, only a
few studies were included, which resulted in a small sample size
for such studies.
Conclusion
The present review discusses the meta-analysis of 53 studies,
which revealed eight risk factors and two protective factors for
postoperative HAEC. Four risk factors and one protective factor
for recurrent HAEC were obtained. No risk factors for pre-
operative HAEC were identified.
Ethical approval
This study is a meta-analysis and ethics statement is not
applicable.
 Zhang et al. International Journal of Surgery (2023)
Funding
This research was funded by the National Natural Science
Foundation of China (Project nos. 81873846 and 82071682).
Author contribution
a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8K2+Ya6H515kE= on 08/26/2023
X.Z.: conceptualization, data curation, formal analysis, investi-
gation, methodology, project administration, validation, writing
Downloaded from http://journals.lww.com/international-journal-of-surgery by BhDMf5ePHKav1zEoum1tQfN4
—original draft and visualization. D.S., MD: data curation, for-
mal analysis, methodology and visualization. Q.X.: data cura-
tion, formal analysis, methodology and visualization. H.L.:
methodology, writing—review and editing. Y.L.: formal analysis,
writing—review and editing. D.W.: formal analysis and investi-
gation. J.W.: formal analysis, investigationand and methodology.
Q.Z.: formal analysis and investigation. P.H.: formal analysis
and methodology. W.M.: investigation and methodology. C.J.:
conceptualization, formal analysis, methodology, project
administration, resources, supervision and writing—review and
editing. A.L.: conceptualization, formal analysis, funding acqui-
sition, methodology, project administration, resources, super-
vision and writing—review and editing. All authors read and
approved the final manuscript.
Conflicts of interest disclosure
None.
Research registration unique identifying number
(UIN)
1. Name of the registry: Prospero.
2. Unique Identifying number or registration ID: CRD4202
2353241.
3. Hyperlink to your specific registration (must be publicly
accessible and will be checked): https://www.crd.york.ac.uk/
PROSPERO/display_record.php?RecordID =353241
Guarantor
Aiwu Li.
Data statement
This is a meta-analysis article, data availability is not applicable,
please contact the corresponding author if some data needed.
Provenance and peer review
Not commissioned, externally peer-reviewed.
Acknowledgements
None.
References
[1] Niesler B, Kuerten S, Demir IE, et al. Disorders of the enteric nervous
system - a holistic view. Nat Rev Gastroenterol Hepatol 2021;18:
393–410.
2522
International Journal of Surgery
[2] Tilghman JM, Ling AY, Turner TN, et al. Molecular genetic anatomy and
risk profile of Hirschsprung’s disease. N Engl J Med 2019;380:1421–32.
[3] Heuckeroth RO. Hirschsprung disease—integrating basic science and
clinical medicine to improve outcomes. Nat Rev Gastroenterol Hepatol
2018;15:152–67.
[4] Bahrami A, Joodi M, Moetamani-Ahmadi M, et al. Genetic background
of hirschsprung disease: a bridge between basic science and clinical
application. J Cell Biochem 2018;119:28–33.
[5] Tang CS, Li P, Lai FP, et al. Identification of genes associated with
hirschsprung disease, based on whole-genome sequence analysis, and
potential effects on enteric nervous system development. Gastroenterology
2018;155:1908–922.e1905.
[6] Young HM, Stamp LA, Hofstra RM. Hirschsprung disease and activa-
tion of hedgehog signaling via GLI1-3 mutations. Gastroenterology
2015;149:1672–5.
[7] Heuckeroth RO. Even when you know everything, there is still more to
learn about Hirschsprung disease. Gastroenterology 2018;155:1681–4.
[8] Heuckeroth RO, Schäfer KH. Gene-environment interactions and the
enteric nervous system: Neural plasticity and Hirschsprung disease pre-
vention. Dev Biol 2016;417:188–97.
[9] Jiao C-L, Chen X-Y, Feng J-X. Novel insights into the pathogenesis of
Hirschsprung’s-associated enterocolitis. Chin Med J 2016;129:1491–7.
[10] Gosain A, Frykman PK, Cowles RA, et al. Guidelines for the diagnosis
and management of Hirschsprung-associated enterocolitis. Pediatr Surg
Int 2017;33:517–21.
[11] Mei F, Wu M, Zhao L, et al. Probiotics for the prevention of
Hirschsprung-associated enterocolitis. Cochrane Database Syst Rev
2022;4:Cd013714.
[12] Roorda D, Oosterlaan J, van Heurn E, et al. Risk factors for enterocolitis
in patients with Hirschsprung disease: a retrospective observational
study. J Pediatr Surg 2021;56:1791–8.
[13] Hagens J, Reinshagen K, Tomuschat C. Prevalence of Hirschsprung-
associated enterocolitis in patients with Hirschsprung disease. Pediatr
Surg Int 2022;38:3–24.
[14] Demehri FR, Halaweish IF, Coran AG, et al. Hirschsprung-associated
enterocolitis: pathogenesis, treatment and prevention. Pediatr Surg Int
2013;29:873–81.
[15] Jiao CL, Chen XY, Feng JX. Novel insights into the pathogenesis of
Hirschsprung’s-associated enterocolitis. Chin Med J (Engl) 2016;129:
1491–7.
[16] Sarioğlu A, Tanyel FC, Büyükpamukçu N, et al. Clinical risk factors of
hirschsprung-associated enterocolitis. II: postoperative enterocolitis. The
Turk J Pediatr 1997;39:91–8.
[17] Sarioğlu A, Tanyel FC, Büyükpamukçu N, et al. Clinical risk factors of
Hirschsprung-associated enterocolitis. I: preoperative enterocolitis. The
Turk J Pediatr 1997;39:81–9.
[18] Ahmad H, Levitt MA, Yacob D, et al. Evaluation and management of
persistent problems after surgery for Hirschsprung disease in a child. Curr
Gastroenterol Rep 2021;23:18.
[19] Porokuokka LL, Virtanen HT, Lindén J, et al. Gfra1 underexpression
causes Hirschsprung’s disease and associated enterocolitis in mice. Cell
Mol Gastroenterol Hepatology 2019;7:655–78.
[20] Bachetti T, Rosamilia F, Bartolucci M, et al. The OSMR gene is involved
in Hirschsprung associated enterocolitis susceptibility through an altered
downstream signaling. Int J Mol Sci 2021;22:3831.
[21] Chen Y, Yuan X, Li Y, et al. Circulating exosomal microRNA-18a-5p
accentuates intestinal inflammation in Hirschsprung-associated
enterocolitis by targeting RORA. Am J Translational Res 2021;13:
4182–96.
[22] Nakamura H, Lim T, Puri P. Probiotics for the prevention of
Hirschsprung-associated enterocolitis: a systematic review and meta-
analysis. Pediatr Surg Int 2018;34:189–93.
[23] Teitelbaum DH, Coran AG. Enterocolitis. Semin Pediatr Surg 1998;7:
162–9.
[24] Nakamura H, Lim T, Puri P. Inflammatory bowel disease in patients with
Hirschsprung’s disease: a systematic review and meta-analysis. Pediatr
Surg Int 2018;34:149–54.
[25] Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for
reporting systematic reviews and meta-analyses of studies that evaluate
healthcare interventions: explanation and elaboration. BMJ (Clin Res Ed)
2009;339:b2700.
[26] Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement:
An updated guideline for reporting systematic reviews. Int J Surg
2021;88:105906.
 Zhang et al. International Journal of Surgery (2023)
[27] Shea BJ, Reeves BC, Wells G, et al. AMSTAR 2: a critical appraisal tool
for systematic reviews that include randomised or non-randomised stu-
dies of healthcare interventions, or both. BMJ (Clin Res Ed) 2017;358:
j4008.
[28] Kraemer HC, Kazdin AE, Offord DR, et al. Coming to terms with the
terms of risk. Arch Gen Psychiatry 1997;54:337–43.
[29] Stang A. Critical evaluation of the Newcastle-Ottawa scale for the
assessment of the quality of nonrandomized studies in meta-analyses. Eur
a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8K2+Ya6H515kE= on 08/26/2023
J Epidemiol 2010;25:603–5.
[30] Wells GA, Wells G, Shea B, , et al. The Newcastle-Ottawa Scale (NOS) for
Downloaded from http://journals.lww.com/international-journal-of-surgery by BhDMf5ePHKav1zEoum1tQfN4
Assessing the Quality of Nonrandomised Studies in Meta-Analyses.
2014.
[31] Stroup DF, Berlin JA, Morton SC, et al. Meta-analysis of observational
studies in epidemiologya proposal for reporting. JAMA 2000;283:
2008–12.
[32] Gunnarsdóttir A, Larsson LT, Arnbjörnsson E. Transanal endorectal vs.
Duhamel pull-through for Hirschsprung’s disease. Eur J Pediatr Surg
2010;20:242–6.
[33] Nasr A, Haricharan RN, Gamarnik J, et al. Transanal pullthrough for
Hirschsprung disease: matched case-control comparison of Soave and
Swenson techniques. J Pediatr Surg 2014;49:774–6.
[34] Yokoi A, Satoh S, Takamizawa S, et al. The preliminary study of modified
Swenson procedure in Hirschsprung disease. J Pediatr Surg 2009;44:
1560–3.
[35] Kubota A, Kawahara H, Okuyama H, et al. Clinical outcome of lapar-
oscopically assisted endorectal pull-through in Hirschsprung’s disease:
comparison of abdominal and perineal approaches. J Pediatr Surg
2004;39:1835–7.
[36] Pini Prato A, Gentilino V, Giunta C, et al. Hirschsprung’s disease:
13 years’ experience in 112 patients from a single institution. Pediatr Surg
Int 2008;24:175–82.
[37] Pini Prato A, Arnoldi R, Sgrò A, et al. Hirschsprung disease and Down
syndrome: from the reappraisal of risk factors to the impact of surgery.
J Pediatr Surg 2019;54:1838–42.
[38] Aliev A. Tashkent R. A comparative study of the surgical procedures to
treat hirschsprung disease in children. Europ J Molecular & Clin Med
2020;7.
[39] Tannuri AC, Tannuri U, Romão RL. Transanal endorectal pull-through
in children with Hirschsprung’s disease--technical refinements and com-
parison of results with the Duhamel procedure. J Pediatr Surg 2009;44:
767–72.
[40] Kim AC, Langer JC, Pastor AC, et al. Endorectal pull-through for
Hirschsprung’s disease-a multicenter, long-term comparison of
results: transanal vs transabdominal approach. J Pediatr Surg
2010;45:1213–20.
[41] Le-Nguyen A, Righini-Grunder F, Piché N, et al. Factors influencing the
incidence of Hirschsprung associated enterocolitis (HAEC). J Pediatr
Surg 2019;54:959–63.
[42] Morabito A, Lall A, Gull S, et al. The impact of Down’s syndrome on the
immediate and long-term outcomes of children with Hirschsprung’s
disease. Pediatr Surg Int 2006;22:179–81.
[43] Zheng B. Long-term efficacy of laparoscopic-assisted radical treatment of
long-segment Hirschsprung disease. Chin J Pediatr Surg 2015.
[44] Hackam DJ, Superina RA, Pearl RH. Single-stage repair of
Hirschsprung’s disease: a comparison of 109 patients over 5 years.
J Pediatr Surg 1997;32:1028–31.
[45] Hackam DJ, Filler RM, Pearl RH. Enterocolitis after the surgical treat-
ment of Hirschsprung’s disease: risk factors and financial impact.
J Pediatr Surg 1998;33:830–3.
[46] Lu C, Hou G, Liu C, et al. Single-stage transanal endorectal pull-
through procedure for correction of Hirschsprung disease in neo-
nates and nonneonates: A multicenter study. J Pediatr Surg 2017;52:
1102–7.
[47] Shi C. Enterocolitis after resection of hirschsprung disease. Chin J Pediatr
Surg 1994;124:488.
[48] Shen C, Song Z, Zheng S, et al. A comparison of the effectiveness of the
Soave and Martin procedures for the treatment of total colonic agan-
glionosis. J Pediatr Surg 2009;44:2355–8.
[49] Hackam DJ, Reblock KK, Redlinger RE, et al. Diagnosis and outcome of
Hirschsprung’s disease: does age really matter? Pediatr Surg Int 2004;20:
319–22.
[50] Mo D. Analysis of risk factors for enterocolitis after hirschsprung disease
surgery. Guangxi Medical University Master’s Thesis 2008;10:1994–
2022.
2523
[51] Teitelbaum DH, Qualman SJ, Caniano DA. Hirschsprung’s disease.
Identification of risk factors for enterocolitis. Ann Surg 1988;207:240–4.
[52] Teitelbaum DH, Cilley RE, Sherman NJ, et al. A decade of experience
with the primary pull-through for hirschsprung disease in the new-
born period: a multicenter analysis of outcomes. Ann Surg 2000;232:
372–80.
[53] Yulianda D, Sati AI, Makhmudi A, et al. Risk factors of preoperative
Hirschsprung-associated enterocolitis. BMC Proc 2019;13(Suppl 11):18.
[54] Travassos DV, Bax NM, Van der Zee DC. Duhamel procedure: a com-
parative retrospective study between an open and a laparoscopic tech-
nique. Surg Endosc 2007;21:2163–5.
[55] Gunadi, Karina SM, Dwihantoro A. Outcomes in patients with
Hirschsprung disease following definitive surgery. BMC Res Notes
2018;11:644.
[56] Gunadi, Sukarelawanto AVR, Ritana A, et al. Postoperative enterocolitis
assessment using two different cut-off values in the HAEC score in
Hirschsprung patients undergoing Duhamel and Soave pull-through.
BMC Pediatr 2020;20:457.
[57] Parahita IG, Makhmudi A, Gunadi. Comparison of Hirschsprung-
associated enterocolitis following Soave and Duhamel procedures.
J Pediatr Surg 2018;53:1351–4.
[58] Minford JL, Ram A, Turnock RR, et al. Comparison of functional outcomes
of Duhamel and transanal endorectal coloanal anastomosis for
Hirschsprung’s disease. J Pediatr Surg 2004;39:161–5; discussion 161-165.
[59] Sulkowski JP, Cooper JN, Congeni A, et al. Single-stage versus multi-
stage pull-through for Hirschsprung’s disease: practice trends and out-
comes in infants. J Pediatr Surg 2014;49:1619–25.
[60] Li Y. Analysis of risk factors for recurrent Hirschsprung-associated
enterocolitis. J Shanghai Jiao Tong Univ (Med Sci) 2016;36:830–4.
[61] Pruitt LCC, Skarda DE, Rollins MD, et al. Hirschsprung-associated
enterocolitis in children treated at US children’s hospitals. J Pediatr Surg
2020;55:535–40.
[62] Santos MC, Giacomantonio JM, Lau HY. Primary Swenson pull-through
compared with multiple-stage pull-through in the neonate. J Pediatr Surg
1999;34:1079–81.
[63] Menezes M, Puri P. Long-term outcome of patients with enterocolitis
complicating Hirschsprung’s disease. Pediatr Surg International 2006;22:
316–8.
[64] Taylor MA, Bucher BT, Reeder RW, et al. Comparison of Hirschsprung
disease characteristics between those with a history of postoperative
enterocolitis and those without: results from the pediatric colorectal and
pelvic learning consortium. Eur J Pediatr Surg 2021;31:207–13.
[65] Nakamura M, Wada M, Fukuzawa T, et al. Treatment of classic-type
Hirschsprung’s disease: rectoplasty with posterior triangular colonic flap
versus transanal endorectal pull-through with rectoanal myotomy.
Pediatr Surg Int 2019;35:203–7.
[66] Kwendakwema N, Al-Dulaimi R, Presson AP, et al. Enterocolitis and
bowel function in children with Hirschsprung disease and trisomy 21.
J Pediatr Surg 2016;51:2001–4.
[67] Ishikawa N, Kubota A, Kawahara H, et al. Transanal mucosectomy for
endorectal pull-through in Hirschsprung’s disease: comparison of
abdominal, extraanal and transanal approaches. Pediatr Surg Int
2008;24:1127–9.
[68] Aworanti O, Hung J, McDowell D, et al. Are routine dilatations neces-
sary post pull-through surgery for Hirschsprung disease? Eur J Pediatr
Surg 2013;23:383–8.
[69] Liang P. Analysis of risk factors for postoperative enterocolitis in
hirschsprung disease. Master ‘s Thesis of Xinjiang Medical University
2021.
[70] Romero P, Kroiss M, Chmelnik M, et al. Outcome of transanal endor-
ectal vs. transabdominal pull-through in patients with Hirschsprung’s
disease. Langenbeck’s Arch Surg 2011;396:1027–33.
[71] Dong Q, Li G, Dong J-q. Identification of risk factors for postoperative
recurrent Hirschsprung associated enterocolitis. J Pediatr Surg
2018;27S0022-3468(18):30477–9.
[72] Surana R, Quinn FMJ, Puri PL. Evaluation of risk factors in the devel-
opment of enterocolitis complicating Hirschsprung’s disease. Pediatr
Surg Int 2004;9:234–6.
[73] Singh R, Cameron BH, Walton JM, et al. Postoperative Hirschsprung’s
enterocolitis after minimally invasive Swenson’s procedure. J Pediatr Surg
2007;42:885–9.
[74] Agarwala S, Bhatnagar V, Mitra DK. Long-term follow-up of
Hirschsprung’s disease: review of early and late complications. Ind
Pediatr 1996;33:382–6.
 Zhang et al. International Journal of Surgery (2023)
[75] Tang S. High risk factors for developing enterocolitis after hirschsprung
disease surgery. Chin J Pediatr Surg 2001;2001:21–23.
[76] Zhang SC, Bai YZ, Wang W, et al. Clinical outcome in children after
transanal 1-stage endorectal pull-through operation for Hirschsprung
disease. J Pediatr Surg 2005;40:1307–11.
[77] Chia ST, Chen SC, Lu CL, et al. Epidemiology of Hirschsprung’s disease
in Taiwanese children: a 13-year nationwide population-based study.
Pediatr Neonatol 2016;57:201–6.
a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8K2+Ya6H515kE= on 08/26/2023
[78] Kim SH, Lee NH. Comparison of transanal one-stage soave procedure to
modified duhamel procedure in Hirschsprung’s disease. J Korean Surg
Downloaded from http://journals.lww.com/international-journal-of-surgery by BhDMf5ePHKav1zEoum1tQfN4
Soc 2009;77:202–6.
[79] Giuliani S, Betalli P, Narciso A, et al. Outcome comparison among
laparoscopic Duhamel, laparotomic Duhamel, and transanal endorectal
pull-through: a single-center, 18-year experience. J Laparoendosc Adv
Surg Tech Part A 2011;21:859–63.
[80] Sakurai T, Tanaka H, Endo N. Predictive factors for the development of
postoperative Hirschsprung-associated enterocolitis in children operated
during infancy. Pediatr Surg Int 2021;37:275–80.
[81] Saleh W, Rasheed K, Mohaidly MA, et al. Management of Hirschsprung’s
disease: a comparison of Soave’s and Duhamel’s pull-through methods.
Pediatr Surg Int 2004;20:590–3.
[82] Huang WK, Li XL, Zhang J, et al. Prevalence, risk factors, and prognosis
of postoperative complications after surgery for Hirschsprung disease.
J Gastrointest Surg 2018;22:335–43.
[83] Wang Y. Study on related factors of enterocolitis after hirschsprung disease
operation. Master Thesis of Guangxi Medical University 2019:1–45.
[84] Dan Mo. Analysis of risk factors for enterocolitis after hirsch-
sprungdisease surgery. Guangxi Medical University Master’s Thesis
2008;10:1994–2022.
2524
International Journal of Surgery
[85] Gao T, Xu W, Sheng Q, et al. Clinical outcomes and risk factors for
postoperative complications in children with Hirschsprung’s disease. Am
J Transl Res 2022;14:4830–7.
[86] Xie C, Yan J, Zhang Z, et al. Risk factors for Hirschsprung-associated
enterocolitis following Soave: a retrospective study over a decade. BMC
Pediatr 2022;22:654.
[87] Gabriela GC, Geometri ET, Santoso GE, et al. Long-term growth out-
comes in children with Hirschsprung disease after definitive surgery: a
cross-sectional study. Ann Med Surg 2012;2020:176–9.
[88] Askarpour S, Peyvasteh M, Droodchi G, et al. Oblique vs. circular ana-
stomosis in the children underwent soave’s pull-through surgery for the
treatment of Hirschsprung’s disease: which is the best? Arquivos brasi-
leiros de cirurgia digestiva: ABCD = Brazilian archives of digestive sur-
gery 2021;33:e1545.
[89] Haricharan RN, Seo JM, Kelly DR, et al. Older age at diagnosis of
Hirschsprung disease decreases risk of postoperative enterocolitis, but resection
of additional ganglionated bowel does not. J Pediatr Surg 2008;43:1115–23.
[90] Umeda S, Kawahara H, Yoneda A, et al. Impact of cow’s milk allergy on
enterocolitis associated with Hirschsprung’s disease. Pediatr Surg Int
2013;29:1159–63.
[91] Mao YZ, Tang ST, Li S. Duhamel operation vs. transanal endorectal pull-
through procedure for Hirschsprung disease: a systematic review and
meta-analysis. J Pediatr Surg 2018;53:1710–5.
[92] Ruttenstock E, Puri P. Systematic review and meta-analysis of enterocolitis
after one-stage transanal pull-through procedure for Hirschsprung’s dis-
ease. Pediatr Surg Int 2010;26:1101–5.
[93] Soh HJ, Nataraja RM, Pacilli M. Prevention and management of recurrent
postoperative Hirschsprung’s disease obstructive symptoms and enterocolitis:
Systematic review and meta-analysis. J Pediatr Surg 2018;53:2423–9.