European Journal of Obstetrics & Gynecology and Reproductive Biology 260 (2021) 137–149

Contents lists available at ScienceDirect

European Journal of Obstetrics & Gynecology and

Reproductive Biology
journal homepage: www.elsevier.com/locate/ejogrb

Review article

Cervical cerclage in twin pregnancies: An updated systematic

review and meta-analysis
Yijun Liua , Meng Chena,b , Tiantian Caoa , Shuai Zenga , Ruixin Chena , Xinghui Liua,b,*
a
West China Second Hospital, Sichuan University, Department of Gynecology and Obstetrics, Chengdu, 610041, China
b
West China Second Hospital, Sichuan University, Key Laboratory of Obstetrics and Gynecologic and Pediatric Diseases and Birth Defects of Ministry of
Education, Chengdu, 610041, China

A R T I C L E I N F O A B S T R A C T

Article history: Objective: Data on the prevention of preterm birth in twin pregnancies with cervical cerclage remain
Received 27 January 2021 inconsistent. Thus, this study aimed to comprehensively evaluate the value of cervical cerclage as a
Received in revised form 3 March 2021 treatment strategy to prevent preterm birth in twin pregnancies with regard to both maternal and
Accepted 8 March 2021
neonatal outcomes.
Study design: In this systematic review and meta-analysis, the PubMed, Cochrane Library, Medline,
Keywords: EMBASE, and Web of Science databases were searched for relevant studies and trials from their inception
Cervical cerclage
up to December 2020. Outcomes were expressed as risk ratios and standardized mean differences in a
Cervical length
Meta-analysis
meta-analysis model using STATA 15.0 software.
Preterm birth Results: The search included 944 studies, 15 of which were eligible for inclusion, representing 726
Twin pregnancies patients treated with cervical cerclage and 8578 non-cerclage treatment controls. When the cervical
length was <15 mm, the risk ratio of preterm birth at <37 weeks (0.77, p = 0.01), <34 weeks (0.58, p =
0.002), and <32 weeks (0.61, p = 0.024) of gestation in the cerclage group was significantly lower than that
in the non-cerclage group.
Conclusion: For twin pregnancies with a cervical length <15 mm, cervical cerclage was associated with
significant reduction in preterm birth.
© 2021 Elsevier B.V. All rights reserved.

Contents

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .......... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138

Materials and methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .......... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138
Search strategy and study design . . . . . . . . . . . . . . . . . . . .......... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138
Inclusion and exclusion criteria . . . . . . . . . . . . . . . . . . . . .......... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138
Quality assessment and data extraction . . . . . . . . . . . . . . .......... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138
Measured outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .......... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140
Statistical analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .......... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140
Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .......... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140
Selection and characteristics of studies . . . . . . . . . . . . . . .......... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140
Quality assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .......... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140
Measured outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .......... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140
Primary outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .......... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141
PTB at <37, <34, <32, and <28 weeks of gestation . .......... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141
Secondary outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .......... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142
Latency period from diagnosis of cervical shortening to delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142
PPROM . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .......... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142

Abbreviations: CI, confidence interval; CL, cervical length; NICU, neonatal intensive care unit; PPROM, premature rupture of membrane; PTB, preterm birth; RCT,
randomized controlled trial; RR, risk ratio; SMD, standardized mean difference.
* Corresponding author at: West China Second University Hospital, Sichuan University, Department of Gynecology and Obstetrics, Chengdu, China.
E-mail address: xinghuiliu@163.com (X. Liu).

https://doi.org/10.1016/j.ejogrb.2021.03.013
0301-2115/© 2021 Elsevier B.V. All rights reserved.
Y. Liu, M. Chen, T. Cao et al. European Journal of Obstetrics & Gynecology and Reproductive Biology 260 (2021) 137–149

GA at delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142
Cesarean delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142
Clinical chorioamnionitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142
Neonatal outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142
Test of publication bias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142
Sensitivity analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143
Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144
Main findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144
Strengths and limitations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147
Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148
Author contributions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149

Introduction Materials and methods

With assisted reproductive technology, the incidence of twin Search strategy and study design
pregnancies has increased annually, accounting for 3 % of all
pregnancies [1]. The rates of preterm birth (PTB) in twin PubMed, Cochrane Library, Medline, EMBASE, and Web of
pregnancies are approximately 50 % (<37 weeks of gestation) Science databases were searched for relevant studies and trials
and 14 % (<33 weeks of gestation) [2]. In addition, the rates of early from their inception up to December 2020. The following terms
PTB (<32 weeks of gestation) are eight times higher than those of were used for the initial literature search: “cerclage” or “cervical
singletons [3]. The incidence of short- and long-term neonatal cerclage” or “cerclage of cervix” or “uterine cervix cerclage” or
complications and deaths has substantially increased, resulting in “cerclage of uterine cervix” AND “twin pregnancy” or “twin
a huge burden to countries and families. Therefore, preventing PTB pregnancies” AND “premature birth” or “premature births” or
and improving neonatal outcomes are issues of great significance “preterm births.” Two investigators independently reviewed the
to obstetricians. titles and abstracts initially and subsequently performed full text
At present, conclusions of international research on the reviews. All contradictions were resolved by a third investigator.
prevention of PTB in twin pregnancies with cervical cerclage Ethical approval and patient consent were not required for this
remain inconsistent. The guidelines developed by the Ameri- study.
can College of Obstetricians and Gynecologists (ACOG) [4] in
2014 did not recommend cervical cerclage for twin pregnan- Inclusion and exclusion criteria
cies and pointed out that cervical cerclage may increase the
risk of PTB when the cervical length (CL) measured by vaginal Randomized controlled trials (RCTs), prospective studies, and
ultrasound examination was <25 mm. However, Gordon et al. retrospective studies conducted in humans were included if they
[5] indicated that the incidence of PTB at <35 weeks of met all of the following criteria: 1) enrolled at least two patient
gestation was considerably decreased in the cerclage group groups, including patients who underwent McDonald’s cervical
compared with the non-cerclage group. Levin et al. [6] showed cerclage and patients who underwent non-cerclage treatment; 2)
that rescue cervical cerclage can effectively prolong gesta- included twin pregnancies without intrauterine infection, fetal
tional age at delivery. In summary, the indications and congenital malformations, and PPROM before cerclage; and 3)
effectiveness of cervical cerclage in twin pregnancies remain included at least one of the following outcomes: PTB, PPROM,
unclear. cesarean delivery, latency period from the diagnosis of cervical
Regarding the evaluation of cervical cerclage, a meta-analysis shortening to delivery, GA at delivery, neonatal outcomes, and
in 2014 that included only five small sample size studies reported clinical chorioamnionitis. Data on neonatal outcomes were
no evidence that cervical cerclage prevented PTB in twin extracted: neonatal mortality, admission to the neonatal intensive
pregnancies or decreased neonatal mortality [7]. In 2017, a care unit (NICU), length of stay in the NICU, birth weight, Apgar
meta-analysis on the use of progesterone, a pessary, or cervical score at 5 min, and presence of respiratory distress syndrome,
cerclage to prevent preterm birth pointed out that cerclage did necrotizing enterocolitis, intraventricular hemorrhage, sepsis,
not prevent preterm birth in twin pregnancies [8]. In that meta- retinopathy of prematurity, or bronchopulmonary dysplasia.
analysis, only four studies were selected comparing cervical Duplicated trials, unrelated topics, case reports, reviews,
cerclage with non-cerclage, and the sample size of these old abstracts, single-arm studies, studies not reporting outcomes,
original studies was small. Regrettably, previous meta-analyses studies on twin pregnancies with iatrogenic PTB, studies whose
omitted a larger sample study comparing the cerclage group of control groups included singletons, and publications not in English
146 twin pregnancies with the non-cerclage group of 8,072 twin were excluded.
pregnancies [9]. Moreover, previous studies did not classify and
analyze adverse neonatal outcomes. In the past two years, the Quality assessment and data extraction
United States and China have conducted new original research,
and one randomized controlled trial (RCT) has been incorporated The risk of bias for RCTs was assessed using the modified Jadad
[10]. scale in four domains: random sequence production, allocation
Here, we performed a systematic review and meta-analysis to concealment, blinding method, and withdrawal. For each domain,
evaluate the value of cervical cerclage as a treatment strategy in each item was classified as adequate, unclear, or inadequate. The
terms of PTB, preterm premature rupture of membranes (PPROM), modified Jadad scale has a total score of 7, and 4–7 points are
cesarean delivery, clinical chorioamnionitis, latency period from considered to indicate high quality. The Newcastle–Ottawa scale
diagnosis of cervical shortening to delivery, gestational age (GA) at was used for cohort trials and was dependent on three subscales:
delivery, and neonatal outcomes. selection (four items), comparability (one item), and outcome

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(three items). A study can be awarded a maximum of one star for
each numbered item within the selection and outcome categories.
A maximum of two stars can be given for comparability. A study
with 6 stars is considered to be of high quality, whereas those
with 5 stars are regarded to be of low quality. This meta-analysis
was based on the Preferred Reporting Items for Systematic reviews
and Meta-Analyses statement.
Quality assessment and data extraction using a designed
spreadsheet form were performed independently by two inves-
tigators. All data were discussed, and disputes were resolved by a
third investigator. Data extracted included the first author,
published date, study type, inclusion criteria, interventions,
controls, number of patients, patient age, GA, CL, and cervical
dilatation.

Fig. 1. Flow diagram of study selection.

Table 1
Study characteristics. Age, GA and CL are given as mean  standard deviation.

Study Type Inclusion criteria Intervention (Cerclage) Control (Non–cerclage) Jaded/NOS

score
n Age (y) GA (w) CL (cm) n Age (y) GA (w) CL (cm)
Saltzman 2013 [9] Retro. GA < 28 w 146 32.7  5.2 23.3  2.4 NA 8,072 30.3  5.6 24.7  2.2 NA 8
Roman 2020 [10] RCT GA 16–24 w; 17 31.6  4.4 20.7  1.7 1.8  0.8 13 28.2  5.1 19.4  1.5 2.1  0.7 6
Abbasi 2018 [11] Retro. GA  25 w; 27 33.6  5.6 21.5  2.6 2.6  1.3 9 33.3  5.5 23.2  2.5 3.0  1.5 9
Adams 2017 [12] Retro. GA  24 w; 43 32.9  4.7 20.6  1.8 1.6  1.2 39 29.8  5.8 22.4  1.8 1.3  1.0 7
Eskandar 2007 [13] Pro. Twin pregnancy 76 NA NA 1.5 100 NA NA 1.5 7
Han 2018 [14] Retro. GA 14–26 w; 96 35 (24–51) NA NA 39 32 (17–45) NA NA 8
Houlihan 2016 [15] Retro. GA 16–24 w; 40 31.0 21.9 1.2 40 34.9 22.9 1.2 8
(28.0–34.8) (16.1–24.9) (0.5–2.3) (31.4–37.4) (16.6–24.9) (0.5–2.4)
Newman 2002 [16] Pro. GA 18–26 w; 21 NA 22.3  3.1 NA 12 NA 26.0  6.5 NA 9
Pan 2020 [17] Retro. GA 14–26 w; 31 29.4  3.6 23.6 2.3  1.7 31 29.5  3 22.6 2.0  1.0 9
(19.2–25.1) (18.7–24.3)
Qureshey 2019 [18] Retro. GA 15–25 w; 29 29.2  6.7 20.6  1.7 1.18  0.7 18 29.2  7.6 22.2  2.9 1.56  0.7 8
Roman 2015 [19] Retro. GA 16–24 w; 57 31.8  5.8 19.5  1.8 1.53  0.57 83 31.4  6.0 21.4  1.6 1.62  0.65 9
Roman 2016 [20] Retro. GA 16–24 w; 38 31.5  5.8 20.7  1.6 2.0  1.1 38 30.0  6.6 20.6  1.9 2.1  0.9 9
ROTTENSTREICH 2018 [21] Retro. Twin pregnancy 41 33 (27 36) 26 (24 30) NA 41 33 (30 35) 28 (25 30) NA 9
Rust 2000 [22] RCT GA 16–24 w; 31 NA 20.2  2.1 2.1  1.1 30 NA 21.2  2.1 2.1  1.1 5
Wu 2020 [23] Retro. CL  25 mm 33 34.1  3.3 22.59  4.79 1.39  0.57 13 34.7  2.9 23.77  3.17 1.34  0.52 9

NOS, Newcastle–Ottawa scale; GA, gestational age; CL, cervical length; CD, cervical dilation; RCT, randomized control trial; Retro., retrospective; Pro., prospective.

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Measured outcomes Table 2

Assessment of bias risk of cohort studies.

The primary outcome was PTB at <37, <34, <32, and <28 weeks Study The Newcastle–Ottawa Scale
of gestation. The secondary outcomes were the latency period from Selection Comparability Outcome Total
the diagnosis of cervical shortening to delivery, PPROM, GA at
Nimrah Abbasi 2018 $ $ $ $ $$ $$$ 9
delivery, cesarean delivery, clinical chorioamnionitis, and neonatal Tracy M Adams 2017 $ $ $ $ $$$ 7
outcomes. M. Eskandar 2007 $ $ $ $ $ $$ 7
Michelle N. Han 2018 $ $ $ $ $ $$$ 8
Christopher Houlihan 2016 $ $ $ $ $ $$$ 8
Statistical analysis
Roger B. Newman 2002 $ $ $ $ $$ $$$ 9
Mian Pan 2020 $ $ $ $ $$ $$$ 9
The meta-analysis was performed using STATA software version Emma J. Qureshey 2019 $ $ $ $ $ $$$ 8
15.0 (StataCorp, College Station, TX). The Q test (I2 value) was used Amanda Roman 2015 $ $ $ $ $$ $$$ 9
to evaluate the heterogeneity of the included studies. A fixed- Amanda Roman 2016 $ $ $ $ $$ $$$ 9
Amihai ROTTEN. 2018 $ $ $ $ $$ $$$ 9
effects model was adopted if there was no significant heterogene-
Ashley S. Roman 2013 $ $ $ $ $ $$$ 8
ity (p > 0.1, when I2  50 %); otherwise, a random-effects model Fang-Tzu Wu 2020 $ $ $ $ $$ $$$ 9
was used. Risk ratio (RR) was calculated using dichotomous data.
The standardized mean difference (SMD) with 95 % confidence
interval (CI) was calculated for continuous values. Subgroup
patients and 13 cohort trials that compared 8,535 patients, were
analyses were conducted according to different CLs; p < 0.05 was
included in this meta-analysis. The characteristics of these 15
defined as statistically significant. Publication bias was examined
studies are shown in Fig. 1 and Table 1 [9–23].
in funnel plots by performing Begg–Mazumdar tests. In addition,
we performed a sensitivity analysis to test the robustness of the
Quality assessment
results.
The risk of bias of the two RCTs [15,19] was assessed using the
Results
modified Jadad scale in four domains. For cohort trials, the
Newcastle–Ottawa scale was used. All included studies scored >7
Selection and characteristics of studies
points, with a maximum of 9 points (Table 2).

A total of 944 studies were found following the electronic

Measured outcomes
database search. A total of 810 trials were excluded, and the
remaining 134 studies were subjected to further evaluations, from
The evaluated results of primary and secondary outcomes are
which 69 studies were further excluded according to the exclusion
shown concisely in Table 3.
criteria. Finally, 15 studies, including two RCTs that compared 91

Table 3
All evaluated results of primary and secondary outcomes. RR, risk ratio; SMD, standardized mean difference; CI, confidence interval; PTB, preterm birth; CL, cervical length;
PPROM, preterm premature rupture of membranes; GA, gestational age; NICU, neonatal intensive care unit.

Outcomes Studies Patients RR/SMD I2 (%) Ph Z P

(95 %CI)

Maternal
PTB
<37 weeks 6 640 0.86 (0.69–1.07) 51.4 0.068 1.34 0.179
<34 weeks 12 8,999 0.76 (0.58–1.00) 85.1 <0.001 1.94 0.053
<32 weeks 12 9,525 0.71 (0.48–1.03) 86.8 <0.001 1.8 0.072
<28 weeks 11 8,913 0.71 (0.46–1.12) 82.3 <0.001 1.47 0.141

PTB (CL < 15 mm)

<37 weeks 3 154 0.77 (0.63–0.94) 29.2 0.244 2.56 0.01
<34 weeks 2 106 0.58 (0.41–0.81) <0.1 0.435 3.14 0.002
<32 weeks 3 154 0.61 (0.40–0.94) <0.1 0.575 2.26 0.024
<28 weeks 2 119 0.53 (0.26–1.08) <0.1 0.815 1.74 0.081
Latency period from cervical shortening 7 464 0.85 (0.50–1.21) 66.7 0.006 4.68 <0.001
diagnosis to delivery
PPROM 10 646 0.80 (0.66,0.97) <0.1 0.48 2.24 0.025
GA at delivery 13 8,984 0.48 (0.14–0.81) 85.8 <0.001 2.8 0.005
Cesarean delivery 9 8,667 1.46 (1.14–1.86) 72.9 <0.001 3.03 0.002
Clinical chorioamnionitis 5 323 1.38 (0.81–2.35) <0.1 0.992 1.42 0.155

Neonatal
Neonatal mortality 11 17,604 0.62 (0.38–1.04) 69.1 <0.001 1.81 0.071
Admission to the NICU 10 17,609 0.78 (0.65–0.92) 82 <0.001 2.83 0.005
Length of stay in the NICU 6 684 –0.55 (–1.11–0.01) 89.8 <0.001 1.92 0.055
Birth weight 13 18018 0.47 (0.10–0.83) 94.2 <0.001 2.50 0.013
Apgar score <7 at 5 min 7 905 0.45 (0.35–0.56) 29.1 0.206 6.85 <0.001
Respiratory distress syndrome 7 688 0.73 (0.16–0.57) 69.8 0.037 0.43 0.667
Necrotizing enterocolitis 5 547 0.29 (0.16–0.54) <0.1 0.497 3.93 <0.001
Intraventricular hemorrhage 6 603 0.37 (0.14–0.96) 59.6 0.03 2.004 0.041
Sepsis 6 524 0.38 (0.23–0.62) <0.1 0.416 3.81 <0.001
Retinopathy of prematurity 5 552 0.60 (0.12–3.05) 70.8 0.008 0.61 0.539
Bronchopulmonary dysplasia 2 254 0.90 (0.12–6.53) 79.4 0.027 0.11 0.914

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Fig. 2. Comparison between groups at different gestational age. A forest plot comparing the cerclage group with the non-cerclage group in the incidence of preterm births at
<37 weeks, <34 weeks, <32 weeks, and <28 weeks of gestation. CI, confidence interval; RR, risk ratio.

Primary outcomes
PTB at <37, <34, <32, and <28 weeks of gestation
No significant differences were observed in the reduction of PTB
at <37 weeks (RR 0.86, 95 % CI 0.69–1.07, p = 0.17), <34 weeks (RR
0.76, 95 % CI 0.58–1.00, p = 0.05), <32 weeks (RR 0.71, 95 % CI 0.48–
1.03, p = 0.07), and <28 weeks (RR 0.71, 95 % CI 0.46–1.12, p = 0.14)
of gestation between the cerclage and non-cerclage groups.
However, for twin pregnancies with a CL <15 mm, cervical
cerclage was beneficial in reducing PTB at <37 weeks (RR 0.77, 95 %
CI 0.63–0.94, p = 0.01), <34 weeks (RR 0.58, 95 % CI 0.41–0.81, p =
0.002), and <32 weeks (RR 0.61, 95 % CI 0.40–0.94, p = 0.02) of
gestation with significant differences. No statistical difference was
found in PTB at <28 weeks (RR 0.53, 95 % CI 0.26–1.08, p = 0.08). The
fixed-effects model was similarly adopted when the p value was
>0.1. The results are shown in Figs. 2 and 3.

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Fig. 3. Comparison between groups with cervical length <15 mm. A forest plot comparing the cerclage group and the non-cerclage group in incidence of preterm births at <37
weeks, <34 weeks, <32 weeks, and <28 weeks of gestation with cervical length <15 mm. CI, confidence interval; RR, risk ratio.
Secondary outcomes
Latency period from diagnosis of cervical shortening to delivery
A total of seven studies were included. The cerclage group had a
shorter latency period from the diagnosis of cervical shortening to
delivery than the non-cerclage group, with a statistically signifi-
cant difference (SMD 0.85, 95 % CI 0.50–1.21, p < 0.001) based on
the random-effects model (Fig. 4a).
PPROM
Ten studies reported about PPROM. The cerclage group had a
substantially decreased incidence of PPROM compared with the
non-cerclage group, with a statistically significant difference (SMD
0.80, 95 % CI 0.66–0.97, p = 0.02). The fixed-effects model was
adopted because the p value was >0.1 (Fig. 4b).
GA at delivery
A total of 13 studies reported this outcome. The GA at delivery in
the cerclage group was lower than that in the non-cerclage group,
with a statistically significant difference (SMD 0.48, 95 % CI 0.14–
0.81, p = 0.005) from the random-effects model (Fig. 4c).
Cesarean delivery
Nine studies investigated cesarean delivery. The cerclage group
was more inclined to choose cesarean delivery as the mode of
delivery than the non-cerclage group, with a statistically
European Journal of Obstetrics & Gynecology and Reproductive Biology 260 (2021) 137–149
significant difference (RR 1.46, 95 % CI 1.14–1.86, p = 0.002) from
the random-effects model (Fig. 4d).
Clinical chorioamnionitis
Five studies investigated clinical chorioamnionitis. No statisti-
cal differences were noted in the incidence of clinical chorioam-
nionitis between the cerclage and non-cerclage groups (RR 1.38, 95
% CI 0.81–2.35, p = 0.61) from the random-effects model (Fig. 4e).
Neonatal outcomes
No significant differences were observed in neonatal mortality
(RR 0.62, 95 % CI 0.38–1.04, p = 0.07) and the incidence of
respiratory distress syndrome (RR 0.73, 95 % CI 0.16–0.57, p = 0.66),
retinopathy of prematurity (RR 0.60, 95 % CI 0.12–3.05, p = 0.53),
and bronchopulmonary dysplasia (RR 0.90, 95 % CI 0.12–6.53, p =
0.91), and length of NICU stay (SMD -0.55, 95 % CI 1.11 to 0.01, p
= 0.05) between the cerclage and non-cerclage groups. The cerclage
group had a lower rate of admission to the NICU (RR 0.78, 95 % CI
0.65–0.92, p = 0.91), birth weight (SMD 0.47, 95 % CI 0.10–0.83, p =
0.01), and incidence of an Apgar score <7 at 5 min (RR 0.45, 95 % CI
0.35–0.56, p < 0.001) than the non-cerclage group. The results are
shown in Figs. 5 and 6.
Test of publication bias
The Begg–Murley test was used to obtain funnel plots to assess
publication bias, and all plots reflected basic symmetry (Fig. 6a–h).
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Fig. 4. Comparison between groups in multiple outcomes. Forest plots of outcomes comparing the cerclage group with the non-cerclage group in (a) the latency period from
diagnoses of cervical shortening to delivery, (b) the incidence of preterm premature rupture of membranes, (c) gestational age at delivery, (d) cesarean delivery, and (e)
clinical chorioamnionitis. CI, confidence interval; RR, risk ratio; SMD, standardized mean difference.

No statistically significant publication bias was found in terms of
the selected indicators (all p > 0.05 in Begg–Murley test) (Fig. 7).
Sensitivity analysis
The sample size of the control group is much larger than that
of the intervention group in the study [9]; hence, we conducted a
sensitivity analysis and removing it in this meta-analysis. In the
sensitivity analyses, cervical cerclage was beneficial in reducing
PTB at <34 weeks (RR 0.72, 95 % CI 0.55–0.95, p = 0.022), <32
weeks (RR 0.65, 95 % CI 0.47–0.89, p = 0.007) and <28 weeks (RR
0.62, 95 % CI 0.42–0.91, p = 0.016) of gestation, all with statistically
significant differences. The cerclage group had lower neonatal
mortality than the non-cerclage group (RR 0.54, 95 % CI 0.33–0.88,
p = 0.014). The GA at delivery in the cerclage group was lower than

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Fig. 5. Comparison between groups in neonatal mortality. A forest plot comparing the cerclage group with the non-cerclage group in terms of neonatal mortality. CI,
confidence interval; RR, risk ratio.
that in the non-cerclage group, with a statistically significant
difference (SMD, 0.55; 95 % CI, 0.20–0.90; p = 0.002). The cerclage
group was more inclined to choose cesarean delivery than the
non-cerclage group, with a statistically significant difference (RR
1.52, 95 % CI 1.07–2.15, p < 0.001). The cerclage group had a lower
rate of admission to the NICU (RR 0.74, 95 % CI 0.63–0.88, p <
0.001) and lower birth weight (SMD 0.55, 95 % CI 0.26–0.83,
p < 0.001) than the non-cerclage group. The evaluated results of
outcomes after sensitivity analysis are shown concisely in Table 4.
The forest plots in the sensitivity analysis comparing the cerclage
group with the non-cerclage group based on the incidence of
preterm births at <34 weeks, <32weeks, and <28 weeks of
gestation, as well as neonatal mortality, are shown in Figs. 8 and 9,
respectively.
Discussion
Main findings
Cervical cerclage is a method of preventing PTB and has been
used clinically for many years. Existing RCTs, Cochrane systematic
review articles, and meta-analyses evaluating the role of cerclage
have yielded conflicting results.
Our meta-analysis showed that cervical cerclage is not effective,
compared with non-cerclage treatment, in reducing PTB at <37,
<34, <32, and <28 weeks of gestation. However, when the CL is <15
mm, cervical cerclage is beneficial to reduce PTB at <37, <34, and
<32 weeks of gestation. These findings are consistent with the
conclusions of the included studies, but not exactly the same as the
recommendations of the 2014 ACOG guidelines [12,14,19,20].
Of all articles included in this meta-analysis, only one small-
sample study [11] specifically set the treatment group for rescue
cervical cerclage and concluded that rescue cervical cerclage was
European Journal of Obstetrics & Gynecology and Reproductive Biology 260 (2021) 137–149
associated with the reduction of PTB. Combined with the results of
the meta-analysis, for twin pregnancies, when the CL is shortened
(25 mm), it is not an indication for preventive cervical cerclage,
whereas when the CL is too short (<15 mm), rescue cervical
cerclage may be beneficial. In general, we can try to observe
changes in the length of the cervix. When the CL is progressively
shortened, rescue cervical cerclage should be performed immedi-
ately. However, only a few studies in this meta-analysis mentioned
that the CL was set to 15 mm as the dividing line. Five studies
[10,11,14,17,20] reported that when the cervical dilation is 10
mm, cervical cerclage was effective in reducing PTB. This suggests
that, in the future, we may be able to use CL, in combination with
the degree of cervical dilation (i.e., to observe the cervical
morphology), to predict the occurrence of PTB and reasonably
determine the indications for cervical cerclage surgery. These
conclusions need to be further confirmed by conducting large-
sample prospective studies.
In this meta-analysis, cervical cerclage treatment leads to a
lower incidence of PPROM but a higher incidence of cesarean
delivery than non-cerclage treatment. The reason may be that
PPROM had been ruled out in some patients before cervical
cerclage surgery. The higher rates of cesarean section in twin
pregnancies with cervical cerclage may be due to the increased risk
of cervical laceration and complications such as intrauterine
infection after cervical cerclage. No significant difference was
found in the incidence of clinical chorioamnionitis between the
two treatments (p = 0.15). One of the reasons may be that during
the perioperative period of cervical cerclage, antibiotics will be
conventionally applied in cases of twin pregnancies, which can
effectively reduce the risk of infection. Finally, cervical cerclage
does not show any advantages over non-cerclage for the
prolongation of GA or the period from diagnosing shortened CL
to delivery.
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Fig. 6. Comparison between groups in adverse neonatal outcomes. A forest plot comparing the cerclage group with the non-cerclage group in terms of adverse neonatal
outcomes. CI, confidence interval; RR, risk ratio.
As regards neonatal outcomes, compared with non-cerclage
treatment, cervical cerclage is associated with a higher risk of low
birth weight and an Apgar score of <7 at 5 min, but a lower risk of
admission to the NICU. However, no differences were found in
neonatal mortality or length of NICU stay between the two
treatments. These results may be due to the low birth weight and
poor general condition of newborns when cerclage is used; thus,
European Journal of Obstetrics & Gynecology and Reproductive Biology 260 (2021) 137–149
obstetricians and neonatologists should consider that admission to
the NICU is of little significance for further treatment. Therefore,
some newborns were not admitted to the NICU.
In this meta-analysis, five, six, and six studies have reported on
necrotizing enterocolitis, intraventricular hemorrhage, and sepsis,
respectively. A total of 547, 603, and 524 newborns, respectively,
were included in these studies. Compared with non-cerclage
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Fig. 7. Begg–Murley funnel plots of outcomes. Funnel plots created using the Begg–Murley test to demonstrate (a) preterm birth (PTB) <34 weeks (P = 0.732), (b) PTB <32
weeks (P = 0.373), (c) PTB <28 weeks (P = 0.350), (d) preterm premature rupture of membranes (PPROM) (P = 0.649), (e) gestational age (GA) at delivery (P = 0.100), (f) neonatal
mortality (P = 0.350), (g) admission to the NICU (P = 0.107), and (h) birth weight (P = 0.360). NICU, neonatal intensive care unit.

treatment, cervical cerclage significantly decreased the incidence
of these adverse neonatal diseases. To improve the incidence of
adverse neonatal outcomes, it is crucial to prolong GA at delivery as
much as possible.
Notably, when the study [9] was removed, cervical cerclage was
beneficial in reducing PTB at <34 weeks, <32 weeks, and <28
weeks of gestation. Additionally, the cerclage group had lower
neonatal mortality than the non-cerclage group. It is almost
impossible to conduct large-scale, double-blind, randomized
controlled trials in women pregnant with twins given that it
may violate ethical principle. Hence, mostly prospective or
retrospective cohort studies are conducted. These studies are
not only low-level of evidence but there are also large differences
in study population characteristics between the study subjects.

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Fig. 8. Comparison between groups at different gestational ages. A forest plot comparing the cerclage group with the non-cerclage group based on the incidence of preterm
births at <34 weeks, <32 weeks, and <28 weeks of gestation. CI, confidence interval; RR, risk ratio.

This study is retrospective in nature and there is a potential
selection bias in choosing the inclusive period of cerclage
procedures; this led to instability in the results. Therefore, the
results of this meta-analysis should be carefully evaluated.
Strengths and limitations
The articles included in our meta-analysis had a sufficient
sample size, were of high quality, and reached some reasonable
conclusions. However, several important limitations may have
affected the final results. First, because the pooled effects mainly
came from cohort studies and there was a lack of large-sample
RCTs, the conclusions should be interpreted with caution. Second,
all included studies did not explicitly mention twin pregnancies
with a CL of 15–25 mm, so our meta-analysis did not reach any
conclusion. Moreover, none of the current international research
and guidelines gave any significant conclusions. Third, the
indications and protocols of cervical cerclage for preventing PTB
in twin pregnancies were not precise, which lead to clinical
heterogeneity. Briefly, cervical cerclage at different gestational
ages and CL may have affected the final results. In addition, there is
no standard recommendation for the use of progesterone in twin
gestation. In the intervention and control groups of these studies,
some patients may have used vaginal progesterone because they

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Table 4
All evaluated results of outcomes after sensitivity analysis.

Outcomes Studies Patients RR/SMD I2 (%) Ph Z P

(95 %CI)
Maternal
PTB
<34 weeks 11 781 0.72 (0.55–0.95) 77.9 <0.001 2.3 0.022
<32 weeks 11 1,307 0.65 (0.47–0.89) 73.1 <0.001 2.68 0.007
<28 weeks 10 695 0.62 (0.42–0.91) 63.1 <0.001 2.42 0.016
GA at delivery 12 766 0.55 (0.20–0.90) 80.7 0.002 3.05 0.002
Cesarean delivery 8 449 1.52 (1.07–2.15) 74.6 <0.001 2.35 0.019

Neonatal
Neonatal mortality 10 1,168 0.54 (0.33–0.88) 62.7 0.004 2.45 0.014
Admission to the NICU 9 1,173 0.74 (0.63–0.88) 73.7 <0.001 3.43 0.001
Birth weight 12 1,582 0.55 (0.26–0.83) 85.0 <0.001 3.77 <0.001

Fig. 9. Comparison between groups based on neonatal mortality. A forest plot comparing the cerclage group with the non-cerclage group in terms of neonatal mortality. CI,
confidence interval; RR, risk ratio.

may have received assisted reproduction treatment, or were more Conclusions

likely to receive a combination of multiple treatments rather than a
single treatment. History of progesterone treatment and assisted
reproductive technology may affect maternal and neonatal out-
comes. Therefore, the relationship between the history of cervical
injury or surgical, rather than cervical sufficient, and preterm birth
should be considered in future studies. Fourth, despite the
classification of adverse neonatal disease outcomes in this
meta-analysis, few studies still lacked long-term follow-up results
for surviving neonates. Fifth, these studies did not classify the
nature of twins, such as monochorionic or dichorionic. Additional
high-quality studies are needed to confirm whether cervical
cerclage has variable effects on preventing PTB in twin pregnancies
of various natures.
The safety and effectiveness of cervical cerclage on maternal
and neonatal outcomes in twin pregnancies remains inconsistent.
However, for twin pregnancies with a cervical length <15 mm,
cervical cerclage was associated with a significant reduction in PTB.
Author contributions
Y.L and M.C designed the study; Y.L and T.C searched the
literature; Y.L and S.Z performed the statistical analyses; Y.L and R.
C drafted the manuscript; X.L revised important academic content.
All authors interpreted the results, read and approved the final
manuscript.

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Declaration of Competing Interest
The authors declare that the research was conducted in the
absence of any commercial or financial relationships that could be
construed as a potential conflict of interest.
Acknowledgments
We express our gratitude to Lei He for the constructive criticism
to improve the quality of this article and also thank Editage (www.
editage.cn) for English language editing. This research was
supported by funding from the National Key Research and
Development Program of China (2018YFC1004603).
References
[1] Khalil MI, Alzahrani MH, Ullah A. The use of cervical length and change in
cervical length for prediction of spontaneous preterm birth in asymptomatic
twin pregnancies. Eur J Obstet Gynecol Reprod Biol 2013;169:193–6.
[2] Blondel B, Kogan MD, Alexander GR, Dattani N, Kramer MS, Macfarlane A, et al.
The impact of the increasing number of multiple births on the rates of preterm
birth and low birthweight: an international study. Am J Public Health
2002;92:1323–30.
[3] Tsakiridis I, Giouleka S, Mamopoulos A, Athanasiadis A, Dagklis T. Manage-
ment of twin pregnancies: a comparative review of national and international
guidelines. Obstet Gynecol Surv 2020;75:419–30.
[4] American College of Obstetricians and Gynecologists. ACOG Practice Bulletin
No. 142: Cerclage for the management of cervical insufficiency. Obstet Gynecol
2014;123:372–9.
[5] Gordon M, Robbins A, McKenna D, Howard B, Barth W. Cervical length
assessment as a resource to identify twins at risk for preterm delivery (Clarity
study). Am J Obstet Gynecol 2006;195:.
[6] Levine LD, Srinivas SK. Length of second stage of labor and preterm birth in a
subsequent pregnancy. Am J Obstet Gynecol 2016;214:535 e1-e4.
[7] Liu XR, Luo X, Xiao XQ, Qi HB. Cervical cerclage for preventing preterm birth in
twin pregnancies. A systematic review and meta-analysis. Saudi Med J
2013;34:632–8.
[8] Jarde A, Lutsiv O, Park CK, Barrett J, Beyene J, Saito S, et al. Preterm birth
prevention in twin pregnancies with progesterone, pessary, or cerclage: a
systematic review and meta-analysis. BJOG 2017;124:1163–73.
European Journal of Obstetrics & Gynecology and Reproductive Biology 260 (2021) 137–149
[9] Roman AS, Saltzman DH, Fox N, Daniel H, Ashley S, Chad K, et al. Prophylactic
cerclage in the management of twin pregnancies. Am J Perinatol 2013;30:751–
4.
[10] Roman A, Zork N, Haeri N, Schoen CN, Saccone G, Colihan S, et al. Physical
examination-indicated cerclage in twin pregnancy: a randomized controlled
trial. Am J Obstet Gynecol 2020;223:902 e1-.11.
[11] Abbasi N, Barrett J, Melamed N. Outcomes following rescue cerclage in twin
pregnancies. J Matern Fetal Neonatal Med 2018;31:2195–201.
[12] Adams TM, Rafael TJ, Kunzier NB, Mishra S, Calixte R, Vintzileos AM. Does
cervical cerclage decrease preterm birth in twin pregnancies with a short
cervix? J Matern Fetal Neonatal Med 2018;31:1092–8.
[13] Eskandar M, Shafiq H, Almushait MA, Sobande A, Bahar AM. Cervical cerclage
for prevention of preterm birth in women with twin pregnancy. Int J Gynaecol
Obstet 2007;99:110–2.
[14] Han MN, O’Donnell BE, Maykin MM, Gonzalez JM, Tabsh K, Gaw SL. The impact
of cerclage in twin pregnancies on preterm birth rate before 32 weeks. J
Matern Fetal Neonatal Med 2019;32:2143–51.
[15] Houlihan C, Poon LCY, Ciarlo M, Kim E, Guzman ER, Nicolaides KH. Cervical
cerclage for preterm birth prevention in twin gestation with short cervix: a
retrospective cohort study. Ultrasound Obstet Gynecol 2016;48:752–6.
[16] Newman RB, Krombach RS, Myers MC, McGee DL. Effect of cerclage on
obstetrical outcome in twin gestations with a shortened cervical length. Am J
Obstet Gynecol 2002;186:634–40.
[17] Pan M, Zhang J, Zhan W, Ouyang X, Jiang X, Yang D. Physical examination-
indicated cerclage in twin pregnancy: a retrospective cohort study. Arch
Gynecol Obstet 2021;303:665–76.
[18] Qureshey EJ, Quiñones JN, Rochon M, Sarno A, Rust O. Comparison of
management options for twin pregnancies with cervical shortening. J Matern
Fetal Neonatal Med 2019;1–7.
[19] Roman A, Rochelson B, Fox NS, Hoffman M, Fleischer A. Efficacy of ultrasound-
indicated cerclage in twin pregnancies. Am J Obstet Gynecol 2015;212:788 e1-
6.
[20] Roman A, Rochelson B, Martinelli P, Saccone G, Harris K, Zork N, et al. Cerclage
in twin pregnancy with dilated cervix between 16 to 24 weeks of gestation:
retrospective cohort study. Am J Obstet Gynecol 2016;215:98 e1-11.
[21] Rottenstreich A, Levin G, Kleinstern G, Yagel S, Zigron R, Elchalal U, et al.
History-indicated cervical cerclage in management of twin pregnancy.
Ultrasound Obstet Gynecol 2019;54:517–23.
[22] Rust OA, Atlas RO, Jones KJ, Benham BN, Balducci J. A randomized trial of
cerclage versus no cerclage among patients with ultrasonographically
detected second-trimester preterm dilatation of the internal os. Am J Obstet
Gynecol 2000;183:830–5.
[23] Wu FT, Chen YY, Chen CP, Sun FJ, Chen CY. Outcomes of ultrasound-indicated
cerclage in twin pregnancies with a short cervical length. Taiwan J Obstet
Gynecol 2020;59:508–13.
149