CURRENT STATUS REVIEWS
Early Versus Late Preventive Ileostomy Closure
Following Colorectal Surgery: Systematic Review
and Meta-analysis With Trial Sequential Analysis
of Randomized Controlled Trials
Zhiqiang Cheng, M.D., Ph.D. • Shuohui Dong, M.D. • Dongsong Bi, M.D., Ph.D.
Yanlei Wang, M.D., Ph.D. • Yong Dai, M.D., Ph.D. • Xiang Zhang, M.D., Ph.D.
Department of General Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, China
Downloaded from http://journals.lww.com/dcrjournal by BhDMf5ePHKbH4TTImqenVA+lpWIIBvonhQl60EtgtdlLYrLzSPu+hUapVK5dvms8 on 01/05/2021
BACKGROUND:  Most preventive ileostomy following
colorectal surgery requires a closure procedure. The
intervals between primary surgery and ileostomy closure
remain controversial.
OBJECTIVE:  This study aimed to compare early versus
late closure of preventive ileostomy following colorectal
surgery.
DATA SOURCE:  A systematic literature search was
performed in conference papers, MEDLINE, EMBASE,
the Cochrane Library, and the Clinicaltrials.gov database.
STUDY SELECTION:  Randomized clinical trials published
through October 2019 comparing early versus late closure
of ileostomy following colorectal surgery were selected.
MAIN OUTCOME MEASURES:  Morbidity, leak of the
primary anastomosis, reoperation, surgical site infection,
small-bowel obstruction/postoperative ileus, total
operative time, and postoperative length of hospital stay
were measured. Results were synthesized using meta-
analysis and were rated as firm or weak evidence by trial
sequential analysis.
Supplemental digital content is available for this article. Direct URL ci-
tations appear in the printed text, and links to the digital files are pro-
vided in the HTML and PDF versions of this article on the journal’s Web
site (www.dcrjournal.com).
Funding/Support: None reported.
Financial Disclosures: None reported.
Corresponding author: Xiang Zhang, M.D., Ph.D., Department of Gene-
ral Surgery, Qilu Hospital of Shandong University, 107#, West Wenhua Rd,
Jinan, 250012, Shandong, China. E-mail: xiang.zhang02@hotmail.com
Dis Colon Rectum 2021; 64: 128–137
DOI: 10.1097/DCR.0000000000001839
© The ASCRS 2020
DISEASES OF THE COLON & RECTUM VOLUME 64: 1 (2021)
Copyright © The American Society of Colon & Rectal Surgeons, Inc. Unauthorized reproduction of this article is prohibited.
RESULTS:  A total of 6 randomized controlled trials were
included. Firm evidence from trial sequential analysis
demonstrated that the early closure of ileostomy after
colorectal surgery reduced the incidence of small-bowel
obstruction/postoperative ileus and required less total
operative time, but increased the incidence of surgical
site infection, compared with late closure of ileostomy;
postoperative length of hospital stay tended to be longer
with early versus late closure of ileostomy. Weak evidence
showed that there was no difference between early and
late closure in morbidity, reoperation, or leak of the
primary anastomosis.
LIMITATIONS:  The study was limited by some evidence
rated as weak from trial sequential analysis, combined
analysis of small-bowel obstruction and postoperative
ileus, and exclusion of the influence of chemo- or
radiotherapy.
CONCLUSIONS:  In selected patients, early closure of
ileostomy after colorectal surgery can be considered,
with a lower incidence of postoperative small-bowel
obstruction/postoperative ileus and less total operative
time, but a relatively high surgical site infection rate.
PROSPERO registration number: CRD42020160989
KEY WORDS:  Loop ileostomy; Colorectal surgery;
Meta-analysis; Early closure.
A
nastomotic leak remains a major complication fol-
lowing colorectal surgery, particularly in cases of
low pelvic anastomosis, with an incidence of 2.0%
to 10.3%.1 Ileostomy has been treated as a protective fac-
tor with the advantages of alleviating severe systemic sep-
sis, reducing the reoperation rate in cases of anastomotic
leak,2–4 and possibly reducing the anastomotic leak rate.5
Therefore, preventive ileostomy has been recommended to
128
 DISEASES OF THE COLON & RECTUM VOLUME 64: 1 (2021)
protect high-risk anastomoses.1 When the protective func-
tion of the stoma has been achieved, patients require stoma
closure. Most surgeons choose to perform closure ileos-
tomy at 8 to 12 weeks following the primary surgery once
the integrity of the primary anastomosis is ensured.6 How-
ever, recent reports have proposed a challenge: early ileos-
tomy closure might be feasible and safe and feature reduced
stoma-related complications as well as economic burden.7,8
Here we performed a systematic review and meta-analysis
with a trial sequential analysis (TSA) of randomized con-
trolled trials (RCTs) to compare early versus late closure of
preventive ileostomy following colorectal surgery.
MATERIALS AND METHODS
Literature Search and Screening
The present meta-analysis was conducted according to
the Preferred Reporting Items for Systematic Reviews and
Meta-Analyses guidelines. A systematic review of the lit-
erature published through October 2019 was performed
by searching abstracts in conference papers as well as the
MEDLINE, EMBASE, Cochrane Library, and Clinicaltri-
als.gov databases. Original studies reporting the timing
of preventive and temporary loop ileostomy closure were
included. Medical subject headings and keywords used in
the search were: “ileostomy closure,” “ileostomy reversal,”
“timing,” “early,” and “colorectal surgery.” The reference
lists of the retrieved reviews and meta-analyses were also
screened to identify additional eligible studies.
The inclusion criteria were: 1) studies that compared
early stoma closure (defined as ≤30 days after primary
surgery in which the preventive loop ileostomy was cre-
ated) versus late stoma closure (defined as ≥60 days after
primary surgery); 2) studies that reported perioperative
outcomes and postoperative complications; 3) patients
without signs of anastomotic leak confirmed by digital
and/or radiological examination; and 4) RCTs.
The exclusion criteria were as follows: 1) emergency
ileostomy in case of anastomotic leak; and 2) ileostomy
performed during other types of surgery other than colo-
rectal surgery.
Data Extraction and Quality Assessment
Baseline characteristics included number of patients, age,
sex, BMI, nationality, primary bowel disease, and interval
between the primary surgery and the ileostomy closure.
Morbidity (number of patients with at least 1 complica-
tion) and leak of the primary anastomosis (intra-abdom-
inal abscess, enterocutaneous fistula, and anastomotic
insufficiency) were extracted as primary outcomes. Reop-
eration, surgical site infection (SSI), small-bowel obstruc-
tion (SBO)/postoperative ileus (POI), total operative time,
and postoperative length of hospital stay were extracted
as secondary outcomes. Two reviewers independently
extracted the data, and a third reviewer was consulted in
Copyright © The American Society of Colon & Rectal Surgeons, Inc. Unauthorized reproduction of this article is prohibited.
129
cases of disagreement. The data were recorded in an Excel
spreadsheet. The quality assessment of the selected studies
was based on the Cochrane Risk of Bias tool,9 and a sum-
mary of findings table was generated using GRADEpro
GDT (GRADEpro Guideline Development Tool [Soft-
ware]. McMaster University, 2015 (developed by Evidence
Prime, Inc)).
Statistical Analysis
The statistical analyses were performed using Review Man-
ager 5.3 software (Cochrane Collaboration, Oxford, UK).
A fixed-effects model was used if there was no evidence
of heterogeneity; otherwise, a random-effects model was
used. Heterogeneity was assessed using the inconsistency
index (I2), with values of 0% to 25%, 25% to 75%, and
75% to 100% representing low, moderate, and substan-
tial heterogeneity. The Mantel-Haenszel (M-H) OR, or
Peto OR, where appropriate, was calculated for each de-
fined dichotomous variable, and 95% CIs were calculated.
Continuous variables reported as median and range in the
original publications were transformed to mean and SD as
described previously.10 The DerSimonian-Laird mean dif-
ference (MD) and the corresponding 95% CIs were calcu-
lated. The p value for the overall effect was calculated using
the Z test, and significance was set at p < 0.05.
A leave-one-out sensitivity analysis was performed to
evaluate the key studies that demonstrated a substantial
impact on the interstudy heterogeneity.11 Publication bias
was assessed by visual inspection of the funnel plot gener-
ated by Review Manager 5.3 software (Cochrane Collabo-
ration, Oxford, UK) and the Egger test12 using Stata V.15.1
(Stata Corp, College Station, TX).
Trial Sequential Analysis
Cumulative meta-analyses are at risk of random errors due
to repetitive statistical testing and a small sample size. Trial
sequential analysis can provide optimal information size, a
threshold for a statistically significant treatment effect, and
a threshold for futility. In the present analysis, a TSA was
performed to evaluate whether CIs and p values in meta-
analyses were sufficient to show the anticipated effects us-
ing TSA software (0.9.5.10 Beta, Copenhagen Trial Unit,
Denmark; http://www.ctu.dk/tsa). The required informa-
tion size (IS) was calculated for each variable based on a
value of 5% for α and 20% for β (equal to 80% power):
for dichotomous variables, the required IS was based on
the incidence of low risk of bias studies, whereas, for con-
tinuous data, the IS was estimated based on D2 as 50%,
MD, and variance based on empirical assumptions, which
were autogenerated by the software. Trial sequential moni-
toring boundaries (TSMBs) and futility boundaries (FBs)
were simultaneously constructed to eliminate early posi-
tive findings and reach more reliable conclusions.13 If the
cumulative Z curve exceeded the IS or crossed the TSMB
or FB, the difference between the 2 interventions (early
 130
closure [EC] vs late closure [LC]) showed firm evidence.
Otherwise, the evidence was rated as weak.
RESULTS
Literature Search and Study Characteristics
We identified 424 relevant publications in the initial
search; of them, 12 were duplicates and 370 were not re-
lated to ileostomy closure secondary to colorectal surgery.
Four additional publications were identified in the refer-
ence lists of the retrieved studies. Thus, a total of 46 studies
were subjected to full-text review. Five reviews, 10 retro-
spective studies, 5 prospective studies, 8 meta-analyses,
and 12 other studies did not meet the inclusion criteria
and were excluded. Thus, 6 studies were included in the
final analysis (Fig. 1).7,14–18
All 6 studies were RCTs; of them, 3 studies7,14,17 were
registered at ClinicalTrial.gov. The nationality of patients
was reported in 5 studies and included French,14 Dane and
Swedish,7 Russian,18 Lithuanian,17 and British.15 Baseline
characteristics were well matched among the studies, with
the exception of one that included a larger proportion of
females.7 One study was prematurely terminated for safety
reasons after 86 patients were randomly assigned, of which
Initial search identified
Identification relevant publications
(n = 424)
Screening Potentially eligible full tests
(n = 42)
Eligibility Total full tests reviewed
(n = 46)
Finally included
Included in the meta-analysis
(n = 6)
FIGURE 1.  Flow chart of literature search.
Copyright © The American Society of Colon & Rectal Surgeons, Inc. Unauthorized reproduction of this article is prohibited.
CHENG ET AL: EARLY CLOSURE OF ILEOSTOMY
5 patients (sex not reported) did not undergo ileostomy
closure and were excluded from the final analysis.17 One
study was written in Russian and was translated (Table 1).
A quality assessment showed that study quality was gener-
ally good. A summary of findings with GRADE evidence is
shown in Table S1 http://links.lww.com/DCR/B401.
Results of Meta-analysis
Morbidity Rate
All 6 studies including 527 patients reported the morbidity
rate for ileostomy closure: 20.1% (54/269) in the EC group
versus 20.0% (49/258) in the LC group.7,14–18 A meta-anal-
ysis using the M-H fixed-effects model showed no signifi-
cant difference in morbidity rates between the EC and LC
groups (OR, 1.05; 95% CI, 0.67–1.64; p = 0.84). Moder-
ate heterogeneity was found (χ2 = 7.11, df = 5, p = 0.21;
I2 = 30%; Fig. 2A).
Leak Rate of Primary Anastomosis
Three of the 6 studies (n = 378 patients) reported leak
rates of the primary anastomosis: 8.8% (17/193) in the
EC group versus 7.0% (13/185) in the LC group.7,14,17
A meta-analysis using the Peto fixed-effects model showed
no significant difference in the leak rate of the primary
Duplicated (n = 12)
Discarded because not related to ileostomy closure
secondary to colorectal surgery (n = 370)
Publications identified from reference lists (n = 4)
Review (n = 5)
Retrospective study (n = 10)
Prospective study (n = 5)
Meta-analysis (n = 8)
Colostomy included (n = 8)
Ileostomy secondary to other types of surgery (n = 4)
 DISEASES OF THE COLON & RECTUM VOLUME 64: 1 (2021) 131

anastomosis between the EC and LC groups (Peto OR,

ileostomy closure (day)
1.28; 95% CI, 0.61–2.72; p = 0.52). Low heterogeneity was
primary surgery and

278.6 ± 89.1 (250)d
Intervals between

92 (80–157)b
148 (64–665)a

148 (64–265)a
17.3 ± 1.5 (17)d
found (χ2 = 2.54, df = 2, p = 0.28; I2 = 21%; Fig. 2B).

34 (29–47)b
66 (62–69)a

11 (8–152)a
8 (8–10)a

11 (8–21)a
57 (38)b
8 (2)b
Reoperation Rate
All 6 studies (n = 527 patients) reported reoperation rates
for ileostomy closure: 6.3% (17/269) in the EC group ver-
sus 4.7% (12/258) in the LC group.7,14–18 The reasons for
reoperation are listed in Table S2 http://links.lww.com/
Rectal cancer, IBD, FAP,
and endometriosis

DCR/B402. A meta-analysis using the Peto fixed-effects

Rectal cancer and
benign disease
Primary bowel

model showed no significant difference in the reoperation

Rectal cancer

Rectal cancer

Rectal cancer

Rectal cancer
disease

rate between the EC and LC groups (Peto OR, 1.40; 95%

CI, 0.66–2.98; p = 0.38). Low to moderate heterogeneity
was found (χ2 = 3.99, df = 3, p = 0.26; I2 = 25%; Fig. 2C).

SSI Rate
Lithuanian
Nationality

Five of the 6 studies (n = 462 patients) reported SSI rates:

Dane and
Swedish

Russian
French

British

NR

11.3% (27/238) in the EC group versus 3.6% (8/224) in

the LC group.7,14–17 A meta-analysis using the M-H fixed-
effects model showed that the SSI rate was significantly
greater in the EC group than in the LC group (OR, 3.10;
Female
(n)
51
49
6
5
31
21
11
13

17
13
18
25

95% CI, 1.44–6.66; p = 0.004). No heterogeneity was found

(χ2 = 3.34, df = 4, p = 0.50; I2 = 0%; Fig. 2D).
Male
(n)
44
42
10
5
24
36
18
16

14
21
25
18

SBO/POI Rate
All 6 studies (n = 527 patients) reported SBO/POI rates
Sample

for ileostomy closure: 3.0% (8/269) in the EC group versus

size
(n)

38e
56c
95
91
16
10
55

29
29

31
34
43

7.8% (20/258) in the LC group.7,14–18 A meta-analysis using

the Peto fixed-effects model showed that the SBO/POI rate
65 (56–72)b
66 (60–70)b
55.7 ± 12.2d
56.2 ± 12.5d
a

56 (20–82)a

67 (36–82)a
67 (39–81)a

62 (32–78)a
67 (35–77)a
58 (18–89)
(years)

One patient (sex not reported) did not undergo ileostomy due to metastasis and was excluded in analysis.

was significantly lower in the EC group than in the LC group

63 (24)b
61 (24)b
Age

(Peto OR, 0.37; 95% CI, 0.17–0.79; p = 0.01). No heteroge-

neity was found (χ2 = 4.90, df = 5, p = 0.43; I2 = 0%; Fig. 2E).
Five patients (sex not reported) did not undergo ileostomy closure and were excluded in analysis.
EC = early closure; FAP = familial adenomatous polyposis; LC = late closure; NR = not reported.
Group
EC

EC

EC

EC

EC

EC
LC

LC

LC

LC

LC

LC

Total Operative Time

All 6 studies (n = 527 patients) reported total operative time
2001–2004

2003–2007

2011–2015

2016–2017

2011–2017

for ileostomy closure.7,14–18 A meta-analysis using the ran-

performed
of study
Period

dom effects model showed that the total operative time was
NR

significantly less in the EC group than in the LC group (MD,

–9.68 minutes less in the EC group; 95% CI, –18.55 to –0.81;
NCT00428636

NCT01287637

NCT03796702

p = 0.03). Meanwhile, substantial heterogeneity was found

Registration
TABLE 1.   Main characteristics of included studies

(τ2 = 92.59; χ2 = 31.38, df = 5, p < 0.00001, I2= 84%; Fig. 2F).

NR

NR

NR

Postoperative Length of Hospital Stay

Four of the 6 studies (n = 315 patients) reported the post-
operative length of hospital stay.7,16–18 A meta-analysis us-
Maloinwazyjne
Khirurgiia (Mosk)

Values are median (interquartile range).

ing the fixed effect model showed that the postoperative

World J Surg

J Surg Oncol
Inne Tech

length of hospital stay tended to be longer in the EC group

Wideochir
Ann Surg
Br J Surg
Journal

than in the LC group (MD, 0.4 day longer in the EC group;

95% CI, –0.04 to –0.85; p = 0.07). Moderate heterogeneity
Values are median (range).

was found (χ2 = 4.75, df = 3, p = 0.19; I2 = 37%; Fig. 2G).

Values are mean ± SD.
Lasithiotakis,
14

Kłęk, 201816
Alves, 2008

Gallyamov,
Danielson,

Sensitivity Analysis
201615

201918

201917
20177

Bausys,

In the meta-analysis of total operative time, 2 studies were

Study

key contributors to the substantial interstudy heteroge-

neity by the leave-one-out sensitivity analysis.15,18 After
b

e
a

Copyright © The American Society of Colon & Rectal Surgeons, Inc. Unauthorized reproduction of this article is prohibited.
 132 CHENG ET AL: EARLY CLOSURE OF ILEOSTOMY

EC LC Odds Ratio Odds Ratio

Study or Subgroup Events Total Events Total Weight M–H, Fixed, 95% CI Year M–H, Fixed, 95% CI
Alves, A. 200814 29 95 35 91 66.9% 0.70 [0.38, 1.29] 2008
Lasithiotakis, 201615 4 95 1 10 2.5% 3.00 [0.28, 31.63] 2016
Danielsen, A. K. 20177 4 55 4 56 9.9% 1.02 [0.24, 4.30] 2017
Kłęk, S. 201816 3 29 4 29 9.7% 0.72 [0.15, 3.55] 2018
Gallyamov, E. A. 201918 2 31 2 34 4.8% 1.10 [0.15, 8.35] 2019
Bausys A. 201917 12 43 3 38 6.2% 4.52 [1.17, 17.50] 2019
Total (95% CI) 269 258 100.00% 1.05 [0.67, 1.64]
Total events 54 49
Heterogeneity: Chi2 = 7.11, df = 5 (P = 0.21); I2 = 30%
0.01 0.1 1 10 100
Test for overall effect: Z = 0.21 (P = 0.84) Favours [EC] Favours [LC]
A. morbidity rate
EC LC Peto Odds Ratio Peto Odds Ratio
Study or Subgroup Events Total Events Total Weight Peto, Fixed, 95% CI Year Peto, Fixed, 95% CI
Alves, A. 200814 11 95 11 91 71.6% 0.95 [0.39, 2.31] 2008
Danielsen, A. K. 20177 3 55 2 56 17.7% 1.54 [0.26, 9.20] 2017
Bausys A. 201917 3 43 0 38 10.7% 6.90 [0.69, 68.61] 2019

Total (95% CI) 193 185 100.00% 1.28 [0.61, 2.72]

Total events 17 13
Heterogeneity: Chi2 = 2.54, df = 2 (P = 0.28); I2 = 21%
0.01 0.1 1 10 100
Test for overall effect: Z = 0.65 (P = 0.52) Favours [EC] Favours [LC]
B. leak rate of the primary anastomosis
EC LC Peto Odds Ratio Peto Odds Ratio
Study or Subgroup Events Total Events Total Weight Peto, Fixed, 95% CI Year Peto, Fixed, 95% CI
Alves, A. 200814 8 95 7 91 51.3% 1.10 [0.38, 3.16] 2008
Lasithiotakis, 201615 0 16 0 10 Not estimable 2016
Danielsen, A. K. 20177 5 55 4 56 30.9% 1.30 [0.33, 5.03] 2017
Kłęk, S. 201816 0 29 0 29 Not estimable 2018
Gallyamov, E. A. 201918 0 31 1 34 3.7% 0.15 [0.00, 7.48] 2019
Bausys A. 201917 4 43 0 38 14.2% 7.08 [0.96, 52.39] 2019
Total (95% CI) 269 258 100.00% 1.40 [0.66, 2.98]
Total events 17 13
Heterogeneity: Chi2 = 3.99, df = 3 (P = 0.6); I2 = 25%
Test for overall effect: Z = 0.88 (P = 0.38) 0.01 0.2 0.5 1 2 5 10
Favours [EC] Favours [LC]
C. reoperation rate
EC LC Odds Ratio Odds Ratio
Study or Subgroup Events Total Events Total Weight M–H, Fixed, 95% CI Year M–H, Fixed, 95% CI
Alves, A. 200814 18 95 5 91 49.2% 4.02 [1.42, 11.35] 2008
Lasithiotakis, 201615 2 16 0 10 6.2% 3.62 [0.16, 83.53] 2016
Danielsen, A. K. 20177 2 55 0 56 5.6% 5.28 [0.25, 112.54] 2017
Kłęk, S. 201816 2 29 3 29 33.2% 0.64 [0.10, 4.16] 2018
Bausys A. 201917 3 43 0 38 5.8% 6.65 [0.33, 133.10] 2019
Total (95% CI) 238 224 100.00% 3.10 [1.44, 6.66]
Total events 27 8
Heterogeneity: Chi2 = 3.34, df = 4 (P = 0.50); I2 = 0%
0.01 0.1 1 10 100
Test for overall effect: Z = 2.90 (P = 0.004) Favours [EC] Favours [LC]
D. surgical site infection rate
EC LC Peto Odds Ratio Peto Odds Ratio
Study or Subgroup Events Total Events Total Weight Peto, Fixed, 95% CI Year Peto, Fixed, 95% CI
Alves, A. 200814 3 95 15 91 62.9% 0.22 [0.08, 0.58] 2008
Lasithiotakis, 201615 1 16 1 10 7.0% 0.60 [0.03, 11.02] 2016
Danielsen, A. K. 20177 1 55 1 56 7.6% 1.02 [0.06, 16.49] 2017
Kłęk, S. 201816 1 29 0 29 3.9% 7.39 [0.15, 372.38] 2018
Bausys A. 201917 2 43 2 38 14.8% 0.88 [0.12, 6.51] 2019
Gallyamov, E. A. 201918 0 31 1 34 3.7% 0.15 [0.00, 7.48] 2019
Total (95% CI) 269 258 100.00% 0.37 [0.17, 0.79]
Total events 8 20
Heterogeneity: Chi2 = 4.90, df = 5 (P = 0.43); I2 = 0%
0.01 0.1 1 10 100
Test for overall effect: Z = 2.56 (P = 0.01) Favours [EC] Favours [LC]
E. small bowel ostruction/postoperative ileus rate

EC LC Mean Difference Mean Difference

Study or Subgroup Mean SD Total Mean SD Total Weight IV, Random, 95% CI Year IV, Random, 95% CI
Alves, A. 200814 15 94 18.3 95 95 18.2 91 62.9% –1.00 [–6.25, 4.25] 2008
Lasithiotakis, 2016 20 9.6 16 40 6.7 10 19.9% –20.00 [–26.27, –13.73] 2016
Danielsen, A. K. 20177 50 40.8 55 71 92.5 56 7.4% –21.00 [–47.52, 5.52] 2017
16
Kłęk, S. 2018 83.2 15.9 29 87.1 21.7 29 17.4% –3.90 [–13.69, 5.89] 2018
Gallyamov, E. A. 201918 50 24.8 31 71 25.8 34 15.5% –21.00 [–33.31, –8.89] 2019
Bausys A. 201917 50 18.5 43 50 14.8 38 19.2% 0.00 [–7.26, 7.26] 2019
Total (95% CI) 269 258100.00% –9.68 [–18.55, –0.81]
Heterogeneity: Tau2 = 92.29; Chi2 = 31.38 , df = 5 (P < 0.00001); I2 = 84%
–100 –50 0 50 100
Test for overall effect: Z = 2.14 (P = 0.03) Favours [EC] Favours [LC]
F. total operative time

EC LC Mean Difference Mean Difference

Study or Subgroup Mean SD Total Mean SD Total Weight IV, Random, 95% CI Year IV, Random, 95% CI
Danielsen, A. K. 20177 4 6.4 55 4 6.5 56 3.4% 0.00 [–2.40, 2.40] 2017
Kłęk, S. 201816 6 1.5 29 6 0.7 29 53.7% 0.00 [–0.60, 0.60] 2018
Bausys A. 201917 7 2.2 43 6 0.7 38 40.4% 1.00 [0.39, 1.69] 2019
Gallyamov, E. A. 201918 4 4.8 31 4 6.5 34 2.6% 0.00 [–2.76, 2.76] 2019
Total (95% CI) 158 157100.00% 0.40 [–0.04, –0.85]
Heterogeneity: Chi2 = 4.75 , df = 3 (P = 0.19); I2 = 37%
Test for overall effect: Z = 1.79 (P = 0.07) –4 –2 0 2 4
Favours [EC] Favours [LC]
G. postoperative length of hospital stay

FIGURE 2.  Meta-analysis results for studies comparing early versus late closure of preventive ileostomy following colorectal surgery.
EC = early closure; LC = late closure; M-H, Mantel-Haenszel.

exclusion of the 2 studies, no heterogeneity was found Publication Bias

(τ2 = 0.00; χ2 = 2.50, df = 3, p = 0.47; I2 = 0%), and the
results were changed without any significant difference be-
tween the EC and LC groups (MD, –1.59; 95% CI, –5.45
to 2.27; p = 0.42). One study reported significantly dif-
ferent total operative times.17 However, the results did
not change after the exclusion of that study (MD, –12.09;
95% CI, –22.56 to –1.62; p = 0.02). In the meta-analysis of
SBO/POI, after the exclusion of 1 study,14 the intergroup
difference was no longer significant (MD, 0.87; 95% CI,
0.25–3.09; p = 0.84).
Visual inspection of the funnel plot (Fig. 3) and Egger test
showed no evidence of publication bias for any of the des-
ignated variables of all included studies (p > 0.05).
Trial Sequential Analysis
Z curves of 4 variables (morbidity rate, leak rate of the
primary anastomosis, reoperation rate, and postoperative
length of hospital stay) did not reach IS or cross TSMB or
FB, suggesting that TSA of the pooled meta-analysis had
weak evidence of the difference between the 2 interven-

Copyright © The American Society of Colon & Rectal Surgeons, Inc. Unauthorized reproduction of this article is prohibited.
 DISEASES OF THE COLON & RECTUM VOLUME 64: 1 (2021) 133

SE(log[OR]) SE(log[OR])
0 0

0.5 0.5

1 1

1.5 1.5

OR Peto OR
2 2
0.01 0.1 1 10 0.01 0.1 1 10 100
Morbidity rate Leak rate of primary anastomosis

SE(log[OR]) SE(log[OR])
0 0

1
0.5

1.5
4

Peto OR OR
5 2
0.1 0.2 0.5 1 2 5 10 0.01 0.1 1 10 100
Reoperation rate Surgical site infection rate

SE(log[OR]) SE(MD)
0 0

1 0.5

2 1

3 1

4 1.zz

Peto OR MD
5 2
0.01 0.1 1 10 100 0.01 0.1 1 10 100
Small bowel obstuction/postoperantice ileus rate Total operative time

SE(MD)
0

0.5

1.5

MD
2
0.01 0.1 1 10 100
Postperative length of hospital stay 450

FIGURE 3.  Funnel plots of each outcome.

Copyright © The American Society of Colon & Rectal Surgeons, Inc. Unauthorized reproduction of this article is prohibited.
 134 CHENG ET AL: EARLY CLOSURE OF ILEOSTOMY

tions (EC vs LC). The Z curve of SSI rate crossed TSMB

EC = early closure; FB = futility boundary; IS = information size; LC = late closure; N/A = IS was ignored due to the limited information used; RRR = relative risk reduction; SBO/POI = small-bowel obstruction/postoperative ileus;
Evidence

Evidence
and exceeded IS, whereas the Z curves of total operative

Weak

Weak
Weak

Weak
Firm
rank

Firm
Firm
rank
time and SBO/POI rate exceeded IS and crossed TSMB,
indicative of firm evidence (Tables 2 and 3; Fig. 4).

Cross

No
No

No
No
No
Cross

FB
No
No
FB
DISCUSSION
To our knowledge, this is the first meta-analysis with TSA

TSMB
Cross
TSMB

Yes
Yes
Cross

No
No

No
No
No
to include only RCTs to investigate the timing of ileos-
tomy closure following colorectal surgery. Firm evidence
demonstrated that EC of ileostomy after colorectal surgery

Exceed
Exceed

Yes
No
No

No

No
Yes
No

IS
IS
reduced the incidence of SBO/POI and required less to-
tal operative time but increased the incidence of SSI com-
pared with LC of ileostomy. The postoperative length of

Actual

Actual
315
527

527
378

527
462
527
hospital stay tended to be longer in EC versus LC of ileos-

IS

IS
tomy. Weak evidence demonstrated no difference between
early and late closure in morbidity, reoperation, or leak of

TSA
Required

Required
the primary anastomosis.

3132

6928

5230
232

TSA

N/A

377
679
IS

IS
It remains controversial whether preventive stoma
can reduce the incidence of anastomotic leak after co-
lorectal surgery,19,20 but its effect on alleviating severe

FB = futility boundary; IS = information size; MD = mean difference; TSA = trial sequential analysis; TSMB = trial sequential monitoring boundary.
Estimated

Estimated
systemic sepsis secondary to anastomotic leak has been

49.71%
57%
87%
D2

D2
verified.2,19,20 Compared to colostomy, ileostomy has the

0
0
0
advantages of easy creation and a low occurrence of post-
operative stoma prolapse,21 and it has gained the pref-
Defined

50%
50%

erence of surgeons as a temporary stoma.21 However,

Incidence

4.70%
D2

19.0%
6.5%

3.6%
7.8%
in LC
ileostomy also has its disadvantages. Dehydration or re-
nal failure following ileostomy is reportedly common, in
Variance

particular, in elderly patients, leading to a 17% to 30%

345.89
7.98

readmission rate.22,23 In addition, the vital function of the

8.26%
Incidence

11.15%
20.1%

6.48%

2.95%

SSI = surgical site infection; TSA = trial sequential analysis; TSMB = trial sequential monitoring boundary.
in EC
distal ileum and colon in maintaining metabolic home-
TABLE 3.   Meta-analysis and trial sequential analysis for dichotomous variables

ostasis has recently received more attention.24 Ileostomy

TABLE 2.   Meta-analysis and trial sequential analysis for continuous variables

0.40
–9.68
MD

bypasses this area, leading to microbial dysbiosis,25 and

it may have adverse effects, in particular, in patients with –5.79%
–27.09%

25% –37.77%
0 –209.79%
62.22%
RRR

metabolic disorders. Moreover, prolonged ileostomy may

37%
84%
I2

have a substantially negative impact on patient social and

economic status.26 All of these problems have indicated
30%
21%
I2

0
value

that EC of ileostomy is an important research target for

0.07
0.03
p

further improvement.
p value

0.004
0.84
0.52

0.38

0.01
Meta-analysis

Meta-analysis

Among the 6 RCTs included, 5 supported EC of ile-

–18.55 to –0.81

ostomy. The other RCT reported the opposite conclusion

–0.04 to 0.85
95% CI

0.67–1.64
0.61–2.72

0.66–2.98
1.44–6.66
0.17–0.79

based on a dramatically higher 30-day postoperative mor-

95% CI

bidity rate.17 In the pooled meta-analysis, postoperative

morbidity rate, reoperation rate, and leak rate of the pri-
mary anastomosis did not differ between the EC and LC
1.05
1.28

1.40
3.10
0.37
OR

groups, suggesting the feasibility and safety of EC of ileos-

0.40
–9.68
MD

tomy. Compared to LC, EC has the advantage of requiring

less total operative time. The rationale behind this is intu-
primary anastomosis
Dichotomous variables
Postoperative length

itively understandable, because EC was performed before

Continuous variables
Total operative time

of hospital stay

severe adhesions had formed and peristomal dissection

Reoperation rate
Leak rate of the
Morbidity rate

was technically easy. However, an accompanying increase

SBO/POI rate

in SSI rate was observed. An increased SSI rate was previ-

SSI rate

ously reported in a meta-analysis,8 which was further con-

firmed by the present meta-analysis with firm evidence
from TSA. The underlying mechanisms remain unknown

Copyright © The American Society of Colon & Rectal Surgeons, Inc. Unauthorized reproduction of this article is prohibited.
 DISEASES OF THE COLON & RECTUM VOLUME 64: 1 (2021) 135

Cumulative Cumulative
Z-Score Z-Score
Required information size = 6928
8 8
7 7
6 6
5 5

Favors
Favors

EC
4
EC

4
3 3
2 2
1 1

289 Z-curve 378

Z-curve Number of
-1 Number of -1
patients patients
-2 -2
(Linear scaled) (Linear scaled)
-3 -3

Favors
Favors

LC
-4
LC

-4
-5 -5
-6 -6
-7 -7
-8 -8
Morbidity rate Leak rate of the primary anastomosis

Cumulative
Cumulative Z-Score
Z-Score IS = 377
IS = S230 8
8
7
7
6
6
5

Favors
5
Favors

EC
4
EC

4
3
3
2
2
1
1
323 Number of
443 Number of -1 patients
-1 Z-curve
patients -2 (Linear scaled)
-2 (Linear scaled) Z-curve
-3
Favors

-3
Favors

LC

-4
LC

-4
-5
-5
-6
-6
-7
-7
-8
-8 Surgical site infection rate
Reoperation rate

Cumulative Cumulative
Z-Score Z-Score
IS = 679 IS = 232
8 8
7 7
6 6
5 5
Favors

Favors
EC

EC

4 4
3 3
Z-curve Z-curve
2 2
1 1

527 Number of 212 Number of

-1 -1
patients patients
-2 (Linear scaled) -2 (Linear scaled)
-3 -3
Favors

Favors
LC

LC

-4 -4
-5 -5
-6 -6
-7 -7
-8 -8
Small bowel obtruction/postoperative ileus rate Total operative time

Cumulative
Z-Score
8
IS = 3132
7
6
5
Favors
EC

4
3
2
1

-1
315 Number of
Z-curve patients
-2 (Linear scaled)
-3
Favors
LC

-4
-5
-6
-7
-8
Postoperative length of hospital stay

FIGURE 4.  Trial sequential analyses for each outcome. The horizontal dark red solid lines represent traditional boundaries with significant
differences. The sloping red solid lines represent the trial sequential monitoring boundaries (outer) and the futility boundaries (inner). The
solid blue line represents the cumulative Z curve. IS = information size.

Copyright © The American Society of Colon & Rectal Surgeons, Inc. Unauthorized reproduction of this article is prohibited.
 136
but could be related to inflammation around the ileos-
tomy, which was still active within 30 days. To reduce the
SSI rate, a pursestring closure technique was proposed by
a recent meta-analysis, leading to significantly lower SSI
rates as well as favorable cosmetic outcomes.27 However,
the closure technique for ileo-ileal anastomosis and skin
was not reported for any of the RCTs included, which may
represent a confounding factor.
Small-bowel obstruction/postoperative ileus was re-
portedly the most common complication associated with
ileostomy closure in a meta-analysis of 6107 cases.28 The
rate was 7.2%, consistent with our results from the LC
group (7.8%). It is noteworthy that only one-third of the
patients required reoperation; most of the patients expe-
riencing SBO/POI were diagnosed with a functional ob-
struction and were able to recover with only conservative
therapies.28 These phenomena suggest that, rather than
mechanical factors, the defunctionalized gut, character-
ized by a loss of contractility of the muscular layer and
atrophy of the intestinal villi,29 may play a major role in
the incidence of postoperative SBO/POI.
Interstudy heterogeneity is commonly observed in
meta-analyses and requires the exploration of potential
sources. The present meta-analysis showed no to mod-
erate heterogeneity across different outcomes, with the
exception of total operative time, in which substantial
heterogeneity was observed. The 2 studies contributing
to the heterogeneity both reported significantly less total
operative time with EC versus LC,15,18 whereas the other
studies showed no significant difference. However, af-
ter careful review, we were unable to identify the reasons
for the results of these 2 outlier studies versus the others.
It should also be noted that the inclusion criteria of one
study contributing to the heterogeneity of leak rate of the
primary anastomosis (I2 = 21%) had differed from those
of the others. The definition of EC was 30 days after pri-
mary surgery in this study as opposed to 8 to 14 days in
the other 5 studies. However, we agree with this definition.
For patients undergoing ileostomy closure within 8 to 14
days, it is still possible, although not probable, that a de-
layed leak of the primary anastomosis may occur despite
a negative enema contrast examination or CT scan.14 In
addition, a number of patients who did not recover fast e-
nough from the primary surgery were excluded from ran-
domization. Therefore, a wide window of EC may provide
opportunities for patients who are deemed inappropriate
for EC within 8 to 14 days for reasons other than leak of
the primary anastomosis.
A major strength of the present meta-analysis is that
only RCTs were included, increasing the likelihood that
we would reach a reasonable conclusion. In addition, TSA
was introduced, and the rated evidence may better guide
future research. Several limitations should also be noted.
First, some evidence was rated as weak from TSA; thus,
the outcomes should be interpreted carefully. Second, the
Copyright © The American Society of Colon & Rectal Surgeons, Inc. Unauthorized reproduction of this article is prohibited.
CHENG ET AL: EARLY CLOSURE OF ILEOSTOMY
sensitivity test showed that the SBO/POI results were un-
stable. The underlying reason may lie in the combined a-
nalysis of SBO and POI, because some patients more likely
had POI rather than SBO.14 This is also supported by an-
other meta-analysis that the incidence of POI following
ileostomy closure was in proportion to the interval from
ileostomy creation to closure and was related in part to its
definition.30 Third, the influence of postoperative chemo-
or radiotherapy was not considered, which may confound
the results.
In selected patients, the EC of ileostomy after colo-
rectal surgery can be considered because of its lower inci-
dence of postoperative SBO/POI and less total operative
time, but it has a relatively high SSI rate.
ACKNOWLEDGMENTS
The authors thank Dr Sheng (Department of General Sur-
gery, Qilu Hospital of Shandong University) for expert sta-
tistical advice. The authors thank Dr Wang (Department of
Cardiology, Shandong Provincial Hospital), who graduated
from Mitch Nikov Northwest National Medical University,
for professional translation of the Russian article.
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