Accepted Manuscript

Impact of single- vs double-layer closure on adverse outcomes and uterine scar

defect: a systematic review and meta-analysis
Stphanie Roberge , MSc Suzanne Demers , MD Vincenzo Berghella , MD Nils
Chaillet , PhD Lynne Moore , PhD Emmanuel Bujold , MD, MSc
PII:

S0002-9378(14)00575-4

DOI:

10.1016/j.ajog.2014.06.014

Reference:

YMOB 9874

To appear in:

American Journal of Obstetrics and Gynecology

Received Date: 14 March 2014

Revised Date:

28 May 2014

Accepted Date: 5 June 2014

Please cite this article as: Roberge S, Demers S, Berghella V, Chaillet N, Moore L, Bujold E, Impact of
single- vs double-layer closure on adverse outcomes and uterine scar defect: a systematic review and
meta-analysis, American Journal of Obstetrics and Gynecology (2014), doi: 10.1016/j.ajog.2014.06.014.
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ACCEPTED MANUSCRIPT

Impact of single- vs double-layer closure on adverse outcomes

and uterine scar defect: a systematic review and meta-analysis
Stphanie

ROBERGE,

MSc1,

Suzanne

DEMERS,

MD1,2,

Vincenzo

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BERGHELLA, MD3, Nils CHAILLET, PhD4, Lynne MOORE, PhD1, Emmanuel

BUJOLD, MD, MSc1,2
1

Department of Social and Preventive Medicine, Faculty of Medicine, Universit

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Laval, Quebec, QC, Canada

2

Department of Obstetrics and Gynecology, Faculty of Medicine, Universit

Laval, Quebec, QC, Canada

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Department of Obstetrics and Gynecology, Jefferson Medical College, Thomas

Jefferson University, Philadelphia, PA, USA

Department of Obstetrics and Gynecology, Universit de Sherbrooke,

Sherbrooke, QC, Canada

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Corresponding author:

Emmanuel Bujold, MD, MSc, FRCSC

Professor, Department of Obstetrics and Gynecology,

Faculty of Medicine, Universit Laval,

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2705 boulevard Laurier, Qubec, QC, Canada G1V 4G2;

email: emmanuel.bujold@crchul.ulaval.ca

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Word count:

Abstract: 240

Manuscript: 2,114

Disclosure statement
All authors report that they have no potential conflicts of interest.

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Short title: Uterine closure and adverse maternal outcomes

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Condensation: This review estimates the effect of single- vs double-layer

uterine closure at cesarean on the risk of postoperative complications and uterine
scar defect.

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Abstract
A systematic review and meta-analysis were performed through electronic

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database searches to estimate the effect of uterine closure at cesarean on the

risk of adverse maternal outcome and on uterine scar evaluated by ultrasound.
Randomized controlled trials, that compared single vs double layers and locking
vs unlocking sutures for uterine closure of low transverse cesarean, were

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included. Outcomes were short-term complications (endometritis, wound

infection, maternal infectious morbidity, blood transfusion, duration of surgical

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procedure, length of hospital stay, mean blood loss), uterine rupture or

dehiscence at next pregnancy and uterine scar evaluation by ultrasound. Twenty
out of 1,278 citations were included in the analysis. We found that all types of
closure were comparable for short-term maternal outcomes, except for single-

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layer closure that had shorter operative time (-6.1 minutes, 95% confidence
interval (CI) -8.7 to -3.4, p<0.001) than double-layer closure. Single-layer (-2.6
mm, 95% CI -3.1 to -2.1, p<0.001) and locked first layer (mean difference: -2.5

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mm, 95% CI -3.2 to -1.8, p<0.001) were associated with lower residual
myometrial thickness. Two studies reported no significant difference between

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single- vs double-layer closure for uterine dehiscence (relative risk; 1.86, 95% CI
0.44-7.90, p=0.40) or uterine rupture (no case). In conclusion, current evidence
based on randomized trials does not support a specific type of uterine closure for
optimal maternal outcomes and is insufficient to conclude about the risk of
uterine rupture. Single-layer closure and locked first layer are possibly coupled
with thinner residual myometrium thickness.
Keywords: cesarean; uterine scar defect; uterine closure; ultrasound evaluation

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Introduction
Cesarean is one of the most frequent surgical procedures around the world,
constituting the delivery method in up to 30% of births.1 While it allows safe

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delivery in many situations, it remains associated with a risk of adverse

outcomes.2 Short-term complications of cesarean include hemorrhage, wound
disruption, infection, and venous thromboembolism. In subsequent pregnancies,

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a previous cesarean significantly increases the risk of 2 major obstetrical

complications: uterine rupture and placenta accreta.3,4 Moreover, long-term

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adverse outcomes include pain, abnormal uterine bleeding, intraperitoneal

adhesions, infertility and additional risk of complications from future abdominal
surgeries, including cesareans and hysterectomies.4-8

A growing body of evidence suggests that the surgical technique for uterus

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closure influences uterine scar healing, but there is still no consensus about
optimal uterus closure.6,9-13 Some techniques seem to have the potential to
decrease the risk of short-term complications, while others have long-term

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benefits, such as reduced risk of uterine rupture.9,10,14 Recently, interest has

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grown in the impact of single- vs. double-layer closure of hysterotomy on the risk
of uterine rupture.9,10 Our recent meta-analysis of observational studies, including
randomized and non-randomized trials, suggested that locked, single-layer
closure was associated with a significantly increased risk of uterine rupture in the
next pregnancy compared to double-layer closure (odds ratio (OR) 4.96, 95%
confidence intervals (CI) 2.58-9.52, p<0.001),15 but unlocked single-layer closure
was not (OR 0.49, 95% CI 0.21-1.16, p=0.10). However, most studies were
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retrospective, and the meta-analyses included only 160 cases of uterine rupture.
Therefore, we believe that additional evidence-based literature is required before
recommending one technique over another. With growing interest in uterine scar

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evaluation by ultrasound, and numerous publications showing a relationship

between uterine scar defects, adverse gynecological outcomes, and uterine
rupture.5,16-22 this review and meta-analysis could provide additional evidence

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regarding optimal uterine closure technique for short-term outcomes and scar

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defects in addition to long-term outcomes, such as uterine rupture.

Our objective was to compare the effect of single- versus double-layer and
locked versus unlocked closure of low transverse cesarean on the risk of adverse
maternal outcomes, including uterine rupture and uterine scar defect evaluated

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by ultrasound.

Source

A systematic review and meta-analyses were performed. Only randomized

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controlled trials (RCTs) that compared number of layers (single vs double layers)

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and the use of locking vs unlocking sutures for uterus closure at the time of low
transverse cesarean were included. However, there was no other restriction
about type of skin incision, abdominal opening, or closure of other layers (fascia,
peritoneum or skin). A list of keywords and medical subject headings were
combined to search the electronic databases PubMed, Web of Science, Embase,
and Cochrane Central Register: uterus, uterine, dehiscence, rupture,
separation, scar, VBAC, vaginal birth after cesarean, closure, cesarean,
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and cesarean from 1980 to September 2013. References from other selected
articles, reviews or meta-analysis were searched for additional relevant articles.
Titles, abstracts and full texts were screened by 2 independent reviewers (S.R.,

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E.B.) for inclusion. No language restriction was applied. Disagreement was

resolved by discussion with a third reviewer (S.D.). The quality of studies was
evaluated by Cochrane Handbook criteria for judging risk of bias, and studies

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with high risk of bias were evaluated by sensitivity analysis.23,24 The quality and
integrity of this review were validated with PRISMA: preferred reporting items for

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systematic reviews and meta-analyses.25

We collected information on the following outcomes: 1) maternal infectious

morbidity defined as combination of wound infection, endometritis and post-

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operative febrile morbidity or equivalent; 2) endometritis; 3) wound infection; 4)

blood transfusion; 5) mean blood loss; 6) duration of surgical procedure, and 7)
length of hospital stay. We collected data regarding long-term adverse outcomes

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during subsequent pregnancies, such as uterine rupture or dehiscence. Uterine

rupture is defined as complete separation of the uterine scar with visceral
disruption

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peritoneum

or

bladder

rupture,

necessitating

an

emergency

intervention (or equivalent definition).26,27 Uterine dehiscence is defined as partial

opening of the uterus with intact visceral peritoneum (or an equivalent
definition).26,27

We

collected

all

information

regarding

post-cesarean

ultrasonographic evaluation of uterine scar, including the presence of uterine

scar defect (defined as the observation of myometrical loss or deformity at the

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cesarean scar site), residual myometrial thickness (in mm) or residual

myometrical thickness less than a specific cut-off determined by the author. In
case of multiple ultrasound measures in time, available data or those who were

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close to 6-month evaluation, were analyzed.

Risk ratios (RR) with 95% CI compared binary outcomes (uterine rupture,

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infectious morbidity, endometritis, wound infection, blood transfusion, scar

defect) between the 2 closure types, and mean difference with 95% CI compared

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continuous outcomes (duration of procedure, length of hospital stay, mean blood

loss, residual myometrial thickness). Heterogeneity between studies was
assessed according to Higgins I2 criteria.28 Pooled RR were calculated with fixed
effects or with DerSimonian and Laird random effects in the absence and

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presence of heterogeneity (I2 >50%), respectively.29 Sensitivity analysis was

conducted to investigate robustness of the findings and to explain heterogeneity
between studies, comparing suture type (locked or unlocked), thread type

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(yes or no).

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(synthetic or chromic), region (North America or other), and primary cesarean

Results

Our systematic search identified 1,278 articles which were first screened by title
and abstract, including 176 that were kept for further evaluation, 39 that were
considered potentially eligible, and 20 (13,086 women) meeting all inclusion
criteria (Figure 1).11,30-47 Out of them, 16 (41%) studies reported post-operative

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outcomes, including maternal infectious morbidity, the result encountered most

frequently (in 11 trials). Six randomized trials detailed uterine scar evaluation with
ultrasound,34,36,38,39,41,47 including 3 that reported the rate of uterine scar defect

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and 3 that observed residual myometrial thickness, but raw data could not be
extracted from 1 of them and, consequently, could not be included in the
analysis.39 Only 2 studies reported follow-up at the next pregnancy and the risk of

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uterine scar dehiscence or uterine rupture (Table 1).13,47

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We undertook sensitivity analysis for maternal infectious morbidity that was

examined in 11 trials. We found no significant difference in any subgroup
analysis. The number of studies that evaluated uterine scar defects and uterine

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rupture was too small to allow sensitivity analyses.

Moderate-to-high heterogeneity was observed for most outcomes so random

effect analysis was undertaken (Table 1). Accurate evaluation of study

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heterogeneity was not possible for uterine scar defect and uterine rupture
because of their small number. Two studies were considered at high risk of bias,

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one for the quality of randomization, and the other for unclear reporting of some
outcomes (Figure 2).32,36 Removing both of them from the analysis did not
significantly change the results so they were conserved for analyses.

Single- vs double-layer closure

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No difference was observed between single- and double-layer closure for the
presence of maternal infectious morbidity, endometritis, wound infection, blood
transfusion and hospital stay (Table 2). Nonetheless, single-layer closure was

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associated with shorter operative time (4,722 patients, -6.1 minutes, 95% CI -8.7
to -3.4, p<0.001).

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Single-layer closure was not linked with a significant risk of uterine scar
dehiscence (187 patients, RR; 2.38, 95% CI 0.63-8.96, p=0.20) or uterine rupture

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(no case) compared to double-layer closure (Table 3).13,40,47 No trials reported

the impact of uterus closure on pelvic adhesion or long-term adverse gynecologic
outcomes.

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We observed no significant difference in the risk of uterine scar defect with

single-layer closure (193 patients, RR: 0.53, 95% CI 0.24-1.17, p=0.12),
compared to double-layer closure, (Table 3). However, we noted lower residual

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myometrial thickness in women with single-layer than in those with double-layer

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closure (240 patients, -2.6 mm, 95% CI -3.1 to -2.2, p<0.001) (Table 3).

Locked vs unlocked sutures

We identified 2 randomized trials that compared locked to unlocked sutures.47,48
The first study reported no difference in the risk of uterine scar dehiscence at
next cesarean delivery for double-layer suture with the first layer locked (29
participants, RR 2.14, 95% CI 0.22-21.10, p=0.51) compared to double-layer

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suture with unlocked first layer.47 However, it showed decreased myometrial

thickness (60 patients, mean difference -2.5, 95% CI -3.2 to -1.8, p<0.001) and
increased blood loss (60 patients, mean difference 45.0 ml, 95% CI 21.6-68.4,

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p<0.001) with locking of the first layer.47 The second study reported no difference
in terms of proportion of scar defect at ultrasound 6-12 months after cesarean
(55 patients, RR 1.16, 95% CI 0.97-1.40, p=0.11), using continuous locked

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single-layer compared to interrupted, unlocked, single-layer suture. However,

continuous, locked, single-layer closure was coupled with a larger scar defect

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(p<0.001) on sonographic evaluation.48

Conclusion

Our systematic review and meta-analyses suggest no difference in the risk of

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maternal morbidity or long-term outcomes between single- vs double-layer uterus

closure at low transverse cesarean. Data from randomized trials are actually
insufficient to conclude about the risk of uterine rupture, dehiscence, or

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gynecological outcomes because of insufficient power. On the other hand, when

compared to double-layer, single-layer closure was associated with decreased

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residual myometrial thickness and shorter operative time based on 2 (n=240) and
9 (n=4,722 women) studies, respectively. Few data are available on the impact of
locked vs unlocked sutures that actually favor the use of unlocked sutures to
obtain a thicker myometrium measured by ultrasound.

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Our study has limitations. Based on current evidence, it is very difficult to

recommend 1 or the other type of uterus closure. Single- and double-layer
closures are associated with low and comparable adverse maternal outcomes in

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almost 15,000 randomized participants. On the other hand, only 504 women
underwent ultrasonographic evaluation of uterine scar after cesarean, including
heterogeneous protocols and criteria for uterine scar defect. The fact that

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ultrasonographic evaluation of uterine scar was performed 6 weeks to 6 months

after cesarean could have affected the results, since complete scar healing can

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take up to 6 months or longer.49 Ultrasound was sometimes undertaken via a

transvaginal, sometimes via a transabdominal approach, which could also have
influenced the results. Regarding the type of technique for single- or double-layer
closure, we observed heterogeneity between studies in the use of locked,

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unlocked, continuous and interrupted sutures, making comparison between

studies even more difficult. While the difference was not significant (p=0.12), the
rates of uterine scar defect (single-layer: 25% vs double-layer: 61%) do not seem

respectively,

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to be in agreement with residual myometrium thickness (15.0 mm vs 17.6 mm,

p<0.001).

Finally,

participants

were

randomized

for

other

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procedures (type of incision, type of closure for other layers) in some studies,
while others specifically combined single or double-layer closure with other
specific procedures that could have influenced several outcomes, such as
operative time, making meta-analyses even more difficult to interpret. Our
sensitivity analysis was unable to give us information on robustness of the

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analysis because of the small number of studies available for the primary
outcome.

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Our results are in agreement with the Cochrane Review9 that included 7 RCTs
(1,769 patients) and compared single vs. double-layer closure on short-term
outcomes. The authors did not observe a significant difference between single-

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and double-layer closure in the risk of blood transfusion (1 study, RR 0.80, 95%
CI 0.34-1.92), post-operative febrile morbidity (RR 1.07, 95% CI 0.70-1.64) or

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wound infection (RR 1.27, 95% CI 0.95-1.70).9 However, they found that singlelayer uterus closure was associated with reduction of operative time (4 studies, 7.4 minutes, 95% CI -8.4 to -6.5) and blood loss (3 studies, -70.1 ml, 95% CI 101.6 to -38.6) compared to double-layer closure.9 Relative to the Cochrane

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review, our study added the 2 most recent and large RCTs and provided data
regarding the evaluation of scar-healing.11,30

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Based on current randomized trials, we cannot recommend a specific technique

for uterus closure. However, data from non-randomized or quasi-randomized

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studies strongly suggest that uterine closure techniques can influence uterine
scar healing and the risk of uterine rupture.47,50 Moreover, the presence of uterine
scar defects and residual myometrial thickness, evaluated by ultrasound, have
been associated with gynecologic outcomes, uterine scar dehiscence and uterine
rupture, making them surrogate markers of uterine scar healing.8,21,47,51,52
Therefore, we believe that primary prevention of uterine scar defects and

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optimization of residual myometrial thickness have the potential to improve

womens health after cesarean and to decrease the risk of abnormal uterine
bleeding, secondary infertility, and adverse obstetrical outcomes, including

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ectopic scar pregnancy, abnormal placentation, scar dehiscence and uterine

rupture.7,53

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Currently, there is increasing interest in uterine scar evaluation by ultrasound

after cesarean, and a growing practice of uterine scar surgical repair, even in the

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absence of comparative studies showing the benefits of such procedures.20,54,55

We believe that such enthusiasm should be directed towards the primary
prevention of uterine scar defects that affect up to 59% of women.56 Additional
retrospective and prospective studies could lead to better identification of risk

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factors for scar defects and to future randomized trials.

In conclusion, data from randomized trials that evaluated types of uterine closure

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at cesarean are limited and do not allow us to recommend a specific suture.

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Acknowledgments: Emmanuel Bujold holds a Clinician Scientist Award from the

Canadian Institutes of Health Research (CIHR) and Stphanie Roberge is the
recipient of a PhD Study Award from Fonds de recherche du Qubec Sant

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(FRQS). Suzanne Demers received a MSc Study Award from FRQS and the
CIHR. This study was supported by the Jeanne and Jean-Louis Lvesque

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Perinatal Research Chair at Universit Laval, Quebec, QC, Canada.

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Caesarean section surgical techniques (CORONIS): a fractional, factorial,

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19

ACCEPTED MANUSCRIPT

Table 1: Characteristics of included studies

N

Inclusion criteria

CORONIS, 2013

8,516

Primary or secondary CS through a planned

transverse abdominal incision

Any method

El-Gharib & Awara,

201336

150

Primary CS

Continuous locked

Guyot-Cottrel,
38
2011

70

18 years, 37 weeks, near 1 of 2 hospitals

Continuous
unlocked

Yasmin et al., 201147

90

Repeat CS in a singleton pregnancy.

Continuous locked

CAESAR, 201011

2,727

Primary CS planned
through LUS

Continuous, locked
or unlocked

Continuous, locked
or unlocked

Nabhan, 200842

600

LUS CS

nr

nr

Borowski et al.,
200734

64

Primary CS

nr

Hamar et al., 200739

30

Non-urgent primary CS

Banad, 200631

100

Poonam et al.,
200643
Batioglu et al.,
199832
Sood, 200558

Double layer

Outcomes

Any method

Maternal infectious morbidity, endometritis, wound

infection, blood transfusion, operative time, hospital
stay
RMT

RI
PT

1st layer continuous

locked, 2nd
imbricating
Continuous
unlocked
Continuous, locked
(group B) or
continuous unlocked
(group C)

SC

Single layer

M
AN
U

57

Scar defect, blood transfusion

RMT, operative time, uterine dehiscence

Transvaginal US at 6
weeks post-CS

Continuous locked

1st layer continuous

locked, 2nd
imbricating

Operative time

US at 48 h, 2 weeks
and 6 weeks post-CS

LUS CS

nr

nr

400

CS after 37 weeks gestation

nr

118

LTCS

208

LTCS

nr

Continuous
unlocked
Continuous
unlocked

Continuous locked
for the 1st layer
Continuous
unlocked

Continuous

Continuous

Continuous locked
Continuous locked

nr
Continuous

nr

nr

Maternal infectious morbidity, endometritis, wound

infection
Maternal infectious morbidity, blood transfusion,
operative time, hospital stay
Maternal infectious morbidity, endometritis, operative
time, hospital stay
Maternal infectious morbidity, endometritis, wound
infection, operative time, hospital stay
Maternal infectious morbidity, endometritis, wound
infection, operative time, hospital stay
Duration of cesarean
Duration of cesarean, hospital stay
Maternal infectious morbidity, wound infection,
operative time, hospital stay
Maternal infectious morbidity, endometritis, wound
infection, blood transfusion

LTCS
Primary CS
Primary CS after 30 weeks gestation

339

CS after 37 weeks gestation

Wallin & Fall, 199945

72

Elective CS without prior abdominal surgery

Interrupted

Interrupted

Lal & Tsomo, 1998

100

LUS CS

Interrupted

Interrupted

Scar defect

Hauth et al., 199240

Chapman et
al.,199713

906
145

LTCS

Continuous locked

1st layer continuous

locked, 2nd
imbricating

Maternal infectious morbidity, endometritis, blood

transfusion, operative time, hospital stay, uterine
dehiscence

47

AC
C

EP

146
200
158

Yasminet al., 2011

Transabdominal US
at 6 weeks post-CS

Scar defect

Chitra et al., 200435

Ferrari et al., 200137
Bjorklund et al.,
200033

Ceci et al., 201248

Transabdominal US
at 48 h, 2 weeks and
6 weeks post-CS
Transvaginal US at 6
weeks post-CS

Maternal infectious morbidity, endometritis, wound

infection, blood transfusion, operative time, hospital
stay
Maternal infectious morbidity, wound infection, blood
transfusion

Xavier et al., 200546

41

Scar evaluation

nr

TE
D

Study

Locked sutures

Unlocked
sutures

60

Non-urgent LUS CS in singleton pregnancy

at 38 weeks

Locked continuous
excluding decidua

Interrupted suture
excluding decidua

Scar defect

90

Repeat CS in a singleton pregnancy.

Continuous locked

Continuous
unlocked

RMT, operative time, uterine dehiscence

Hysterography at 3
months post-CS

Transvaginal US at 6,
12 and 24 months
post-CS
Transabdominal US
at 6 weeks post-CS

20

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AC
C

EP

TE
D

M
AN
U

SC

RI
PT

CS: Cesarean section

LUS: Low uterine segment
LTCS: Low transverse cesarean section
US: ultrasound
RMT: Residual myometrial thickness
nr: not reported

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Table 2: Impact of single- vs double-layer closure on the risk of maternal outcome

13,815
13,730
14,313
No. of
participants
1,025

4,722

4,063

Double layer (%)

416/2,937
(14.2)
196/6,907 (2.8)
566/6,856 (8.3)
141/7,149 (2.0)

425/2,931
(14.5)
183/6,908 (2.6)
612/6,874 (8.9)
164/7,164 (2.3)

RI
PT

8
8
7
No. of
trials
6

Single layer (%)

P value

0.92 (0.74, 1.15)

0.48
0.76
0.18
0.19

513

1.04 (0.81, 1.34)

0.93 (0.83, 1.04)
0.86 (0.69, 1.08)
Mean difference
(95% CI)
-40 [-110, 29]

33.5

39.7

-6.1 (-8.7, -3.4)

<0.0001

4.2

4.6

-0.3 (-0.7, 0.0)

0.05

Means
473

SC

5,868

RR (95% CI)

M
AN
U

Mean blood loss (ml)

Duration of cesarean
(minutes)
Hospital stay (days)

10

Prevalence

I2
37%
26%
15%
23%

P value
0.26

95%
94%
85%

TE
D

Endometritis
Wound infection
Blood transfusion

No. of
participants

EP

Maternal infectious morbidity

No. of
trials

AC
C

Outcome

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Table 3: Single- vs double-layer closure on the risk of scar defect and lower uterine segment thickness
No. of
participants

3
2

193
187

Prevalence
Single layer (%)

25/100 (25.0)
4/83 (4.8)

Double layer
(%)

57/93 (61.3)
3/104 (2.9)

Means
2

240

15.0

17.6

0.53 (0.24, 1.17)

2.38 (0.63, 8.96)
Mean difference
(95% CI)
-2.6 mm (-3.1, -2.2)

P value

I2

0.12
0.20

67%
0%

<0.0001

0%

M
AN
U

LUS thickness (mm)

RR (95% CI)

RI
PT

Scar defect evaluated by US

Uterine rupture or dehiscence

No. of
trials

SC

Outcome

AC
C

EP

TE
D

LUS: Lower uterine segment

US: ultrasound

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Figure legends
Figure 1: Study selection process

AC
C

EP

TE
D

M
AN
U

SC

RI
PT

Figure 2: Assessment of risk of bias in studies included following the Cochrane Handbook

24

ACCEPTED MANUSCRIPT

RI
PT

Potentially relevant citation

identified and screened for
research (n=1278)

SC

Citations not relevant excluded

(n=1102)

Trials retrieved for more

detailed evaluation (n=176)

M
AN
U

Citations excluded, with

reasons (n=137)

AC
C

TE
D

EP

Potentially eligible studies

reviewed (n=40)

-Same analysis (6)

-Other study design (29)
-Inappropriate comparison (23)
-Allocation inadequate (1)
-Letters, commentary, editorial (18)
-<1980 (21)
-Review or meta-analysis (24)
-Other (15)

Studies included in the

analysis (n=20)

Citations excluded, with

reasons (n=20)
-Quasi-random studies (3)
-Other comparison (8)
-Not a RCT (4)
-No results available (4)
-Same study (1)

Random sequence allocation

Allocation concealment
Blinding of participant and
Blinding of outcome assessment

TE
D

Incomplete outcome data

M
AN
U

SC

RI
PT

ACCEPTED MANUSCRIPT

Low
Unclear
High

Selective reporting
Other bias

AC
C

EP

0%

20%

40%

60%

80%

100%

Figure 2 Assessment of risk of bias in studies included following the

Cochrane Handbook