Cerclage for Short Cervix on Ultrasound in Singleton Gestations without Prior

Spontaneous Preterm Birth: a Systematic Review and Meta-analysis of Trials using

individual patient-level data

Vincenzo Berghella,1 Andrea Ciardulli,2 Orion A. Rust,3 Meekai To,4 Katsufumi Otsuki,5 Sietske
Accepted Article
Althuisius,6 Kypros Nicolaides,7 Amanda Roman,1 Gabriele Saccone8

1
Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Sidney

Kimmel Medical College of Thomas Jefferson University, Philadelphia, PA, USA

2
Department of Obstetrics and Gynecology, Catholic University of Sacred Heart, Rome, Italy
3
Department of Obstetrics and Gynecology, Lehigh Valley Health Network, Allentown, PA,

USA
4
Kings College Hospital, London, UK
5
Department of Obstetrics and Gynecology, Showa University Koto Toyosu Hospital, Tokyo,

Japan
6
Department of Obstetrics and Gynecology, Dr. Horacio E. Oduber Hospital, Oranjestad, Aruba
7
Harris Birthright Research Centre for Fetal Medicine, Kings College Hospital, London, UK
8
Department of Neuroscience, Reproductive Sciences and Dentistry, School of Medicine,

University of Naples Federico II, Naples, Italy

Correspondence: Vincenzo Berghella, MD, Department of Obstetrics and Gynecology, Division

of Maternal-Fetal Medicine, Thomas Jefferson University, 833 Chestnut, Philadelphia, PA

19107, USA. E-mail: vincenzo.berghella@jefferson.edu

This article has been accepted for publication and undergone full peer review but has not
been through the copyediting, typesetting, pagination and proofreading process, which
may lead to differences between this version and the Version of Record. Please cite this
article as doi: 10.1002/uog.17457

This article is protected by copyright. All rights reserved.

 Disclosure: The authors report no conflict of interest

Financial Support: No financial support was received for this study

Key word: ultrasound-indicated cerclage, prematurity, transvaginal ultrasound, cervical length,

Accepted Article
intensive care, preterm birth

Running title: Cerclage in singletons with no prior preterm birth and short cervical length

ABSTRACT

Objective: The aim of this systematic review and meta-analysis was to quantify the efficacy of

cervical cerclage in preventing preterm birth (PTB) in asymptomatic singleton pregnancies with

a mid-trimester short transvaginal ultrasound cervical length (TVU CL) and without prior

spontaneous PTB.

Methods: Electronic databases were searched from inception of each database until February

2017. No language restrictions were applied. We included all randomized controlled trials

(RCTs) of asymptomatic singleton pregnancies without prior spontaneous PTB screened with

TVU CL, found to have a midtrimester short CL <25mm, and then randomized to management

with either cerclage (i.e. intervention group) or no cerclage (i.e. control group). We contacted

corresponding authors of all the included trials to request access to the data and perform a meta-

analysis of individual patient data. Data provided by the investigators were merged into a master

database specifically constructed for the review. The primary outcome was PTB <35 weeks. The

summary measures were reported as relative risk (RR) with 95% confidence interval (CI). The

quality of the evidence was assessed using the GRADE approach.

Results: Five RCTs, including 419 asymptomatic singleton gestations with TVU CL <25mm

and without prior SPTB, were analyzed. No statistically significant differences were found in

PTB <35 (21.9% vs 27.7%; RR 0.88, 95% CI 0.63 to 1.23; I2=0%; 5 studies, 419 participants),

This article is protected by copyright. All rights reserved.

 <34, <32, <28, and <24 weeks, mean gestational age at delivery, preterm premature rupture of

membranes, and neonatal outcomes, comparing women who were randomized in the cerclage

group with those who were randomized in the control group, respectively. Planned subgroup
Accepted Article
analyses revealed a significant decrease in PTB <35 weeks in women with TVU CL <10mm

(39.5% vs 58.0%; RR 0.68, 95% CI 0.47 to 0.98; I2=0%; 5 studies, 126 participants), in women

who received tocolytics (17.5% vs 25.7%; RR 0.61, 95% CI 0.38 to 0.98; I2=0%; 5 studies, 154

participants), and in those who received antibiotics (18.3% vs 31.5%; RR 0.58, 95% CI 0.33 to

0.98; I2=0%; 3 studies, 163 participants). The quality of evidence was downgraded two levels

because of serious imprecision and serious indirectness, and therefore was judged as low.

Conclusions: In women with singleton gestation, without prior spontaneous PTB but with TVU

CL <25mm in the second trimester, cerclage does not prevent preterm delivery or improve

neonatal outcome. Cerclage, in singletons without prior spontaneous PTB, seems to be possible

efficacious at lower CLs, such as <10mm, and when tocolytics or antibiotics were used as

additional therapy, requiring further studies in these subgroups. Given the low quality of

evidence, further well-designed RCT is necessary to confirm the findings of this study.

This article is protected by copyright. All rights reserved.

 INTRODUCTION

Preterm birth (PTB) is a major cause of perinatal morbidity and mortality.1 Worldwide, about 15

million babies are born too soon every year, causing 1.1 million deaths, as well as short- and
Accepted Article
long-term disability in countless survivors.2,3

Few prognostic tests are available to predict PTB.4,5 A short transvaginal ultrasound cervical

length (TVU CL) has been shown to be a good predictor of spontaneous PTB, in both singletons

and twins.4-8

Different strategies have been adopted for prevention of PTB,9-24 including progesterone,

cerclage, cervical pessary, as well as lifestyle modification, such as smoking cessation, diet,

aerobic exercise, and nutritional supplements. The evidence supports the use of vaginal

progesterone in singleton pregnancies with short cervix,9 while cervical cerclage seems to be

beneficial only in the subgroup of singleton gestations with both prior spontaneous PTB and

TVU CL 25mm,10 and not in singletons without prior PTB,11 nor in multiple gestations.24

Cervical pessary is relatively non-invasive, easy to use, does not require anesthesia, can be used

in an outpatient clinic setting, and it is easily removed when necessary. However, data published

are contradictory, and meta-analyses have shown no efficacy in prevention of PTB in both

singleton,13 and multiple pregnancies.23

Interestingly, only 235 women have been included in randomized controlled trials (RCTs) on

cerclage for TVU CL <25mm for singleton pregnancies without prior spontaneous PTB,11 while

504 for singleton pregnancies with prior spontaneous PTB.10 Indeed, Berghella et al. in an

individual patient data (IPD) meta-analysis of four RCTs found a non-significant 16% reduction

in PTB <35 weeks in singletons without prior spontaneous PTB but with a TVU CL <25mm who

were randomized to cerclage compared to no cerclage.11

This article is protected by copyright. All rights reserved.

 Recently, Otsuki et al. reported data from a new RCT on cerclage in women with short TVU CL,

including also singleton gestations without prior spontaneous PTB.24 They showed that for

women with TVU CL <25 mm between 16 and 26 weeks of gestation, cerclage might be
Accepted Article
considered to reduce the occurrence of threatened preterm labor.25

Our objective was to update and expand the previous IPD meta-analysis,11 and to quantify the

efficacy of cervical cerclage in preventing PTB and perinatal morbidity and mortality in

asymptomatic singleton pregnancies with a mid-trimester sonographic short TVU CL and

without prior spontaneous PTB.

METHODS

Search strategy

The review protocol was established by two investigators (VB, GS) prior to commencement and

was registered with the PROSPERO International Prospective Register of Systematic Reviews

(registration No. CRD42016048269).

MEDLINE, ClinicalTrials.gov, the PROSPERO International Prospective Register of Systematic

Reviews, and the Cochrane Central Register of Controlled Trials were searched for the following

terms: cerclage, cervical cerclage, salvage cerclage, rescue cerclage, emergency

cerclage, ultrasound-indicated cerclage, short cervix, cervical length, ultrasound, and

randomized trial, from inception of each database until February 2017. All manuscripts were

reviewed for pertinent references. No language restrictions were applied.

This article is protected by copyright. All rights reserved.

 Study Selection

We included all RCTs of asymptomatic singleton pregnancies without prior spontaneous PTB

screened with TVU CL, found to have a midtrimester CL <25mm, and then randomized to
Accepted Article
management with either cerclage (i.e. intervention group) or no cerclage (i.e. control group)..

Quasi-randomized trials (i.e. trials in which allocation was done on the basis of a pseudo-random

sequence, e.g. odd/even hospital number or date of birth, alternation), studies on multiple

pregnancies and studies on symptomatic women were excluded. Trials evaluating history-

indicated cerclage (placed for the sole indication of prior spontaneous PTB),27 or ultrasound-

indicated (placed for a short TVU CL) in women with also a prior spontaneous PTB,10,11 or

physical-exam indicated cerclage (placed for second trimester cervical dilatation detected on

physical exam),27 as well as studies on technical aspects of cerclage,27 were also excluded.

Therefore, eligible RCTs had to include women with singleton gestations, without prior

spontaneous PTB, found to have upon TVU screening a short CL in the second trimester, who

were randomized to cerclage versus no cerclage, and were followed for the primary outcome of

PTB.

Data extraction and risk of bias assessment

The risk of bias in each included study was assessed by using the criteria outlined in the

Cochrane Handbook for Systematic Reviews of Interventions.29 Seven domains related to risk of

bias were assessed in each included trial since there is evidence that these issues are associated

with biased estimates of treatment effect: 1) random sequence generation; 2) allocation

concealment; 3) blinding of participants and personnel; 4) blinding of outcome assessment; 5)

This article is protected by copyright. All rights reserved.

 incomplete outcome data; 6) selective reporting; and 7) other bias. Review authors judgments

were categorized as low risk, high risk or unclear risk of bias.29

We contacted corresponding authors of all the included RCTs to request access to the data and
Accepted Article
perform a meta-analysis of IPD. Authors were asked to supply anonymized data (without

identifiers) about patient baseline characteristics, experimental intervention, control intervention,

co-interventions, and pre-specified outcome measures for every randomly assigned subject and

were invited to become part of the collaborative group with joint authorship of the final

publication. Data provided by the investigators were merged into a master database specifically

constructed for the review. Data were checked for missing information, errors, and

inconsistencies by cross-referencing the publications of the original trials. Quality and integrity

of the randomization processes were assessed by reviewing the chronological randomization

sequence and pattern of assignment, as well as the balance of baseline characteristics across

treatment groups. Inconsistencies or missing data were discussed with the authors and

corrections were made when deemed necessary.

Quality of evidence

For this review, the quality of the evidence was assessed using the GRADE approach in order to

assess the quality of the body of evidence relating to the primary and secondary outcomes.

GRADEpro Guideline Development Tool was used to import data from Review Manager 5.3

(Copenhagen: The Nordic Cochrane Centre, Cochrane Collaboration, 2014) in order to create

Summary of findings tables. A summary of the intervention effect and a measure of quality for

each of the above outcomes was produced using the GRADE approach. The evidence can be

downgraded from 'high quality' by one level for serious (or by two levels for very serious)

This article is protected by copyright. All rights reserved.

 limitations, depending on assessments for risk of bias, indirectness of evidence, serious

inconsistency, imprecision of effect estimates or potential publication bias.29

Accepted Article
Outcomes

Primary and secondary outcomes were established a priori. The primary outcome was PTB <35

weeks. Secondary outcomes were: PTB <37, <34, <32, <28 and <24 weeks, mean gestational

age at delivery in weeks, mean of latency in days (i.e. time from randomization to delivery),

incidence of preterm premature rupture of membranes (PPROM), and neonatal outcomes

including birth weight, low birth weight (LBW) (i.e. birth weight <2500 grams), very LBW

(VLBW) (i.e. birth weight <1500 grams), respiratory distress syndrome (RDS), intraventricular

hemorrhage (IVH) grade 3 or 4, sepsis, necrotizing enterocolitis (NEC), admission to neonatal

intensive care unit (NICU), mean of length of stay (LOS) in NICU in days, and neonatal death

(i.e. death of a live-born baby within the first 28 days of life). We planned to assess the primary

outcome (i.e. PTB <35 weeks) according to different TVU CL cutoffs (i.e. 20, 15, <10, <5

mm), according to race, according to type of cerclage, and according to additional therapy used.

Data analysis

The data analysis was completed independently by two authors (VB, GS) using Review Manager

5.3 (Copenhagen: The Nordic Cochrane Centre, Cochrane Collaboration, 2014). The completed

analyses were then compared, and any difference was resolved with review of the entire data and

independent analysis. IPD were analyzed using the so-called two-stage approach. In this

approach, the IPD are first analyzed separately in each study to produce study-specific estimates

of relative treatment effect. A combined estimate is then obtained in the second step by

This article is protected by copyright. All rights reserved.

 calculating a weighted average (inverse error-variance-based) of the individual estimates using

methods analogous to meta-analyses of aggregate data. Between-study heterogeneity was

explored using the I-squared, which represents the percentage of between-study variation that is
Accepted Article
due to heterogeneity rather than chance. Meta-analysis was performed using the random effects

model of DerSimonian and Laird, to produce summary treatment effects in terms of either a RR

or a mean difference (MD) with 95% confidence interval (CI).

Potential publication biases were assessed statistically by using Beggs and Eggers tests.30 Two-

tailed p-value<0.05 was considered statistically significant.

Characteristics of the included women obtained in the merged database were analyzed using

Statistical Package for Social Sciences (SPSS) v. 19.0 (IBM Inc., Armonk, NY, USA). Data are

shown as means standard deviation (SD), or as number (percentage). Univariate comparisons

of dichotomous data were performed with the use of the chi-square or Fisher exact test.

Comparisons between groups were performed with the use of the T-test to test group means with

SD. Two sided p-values <0.05 were considered statistically significant.

All review stages were conducted independently by two reviewers (VB, GS). The two authors

independently assessed electronic search, eligibility of the studies, inclusion criteria, risk of bias,

data extraction and data analysis. Disagreements were resolved by discussion with a third

reviewer (AC).

The meta-analysis was reported following the Preferred Reporting Item for Systematic Reviews

and Meta-analyses (PRISMA) statement.31

This article is protected by copyright. All rights reserved.

 RESULTS

Study selection and population characteristics

Figure 1 shows the flow diagram (PRISMA template) of information derived from reviewing of
Accepted Article
potentially relevant articles. Five RCTs,25,32-35 including 419 asymptomatic singleton gestations

with short mid-trimester TVU CL and without prior spontaneous PTB, were included in the

meta-analysis.

The overall risk of bias of the included trials was low (Figure 2). All studies had a low risk of

bias in random sequence generation, incomplete outcome data, and selective reporting.

Adequate methods for allocation of women were used. All randomized women were included in

an intention-to-treat analysis. Given the intervention, double-blinding was not feasible and all

trials were judged as high risk of bias in performance bias.

Publication bias, assessed using Beggs and Eggers tests, showed no significant bias (P=0.39

and P=0.51, respectively). The statistical heterogeneity between the studies was low with no

inconsistency (I2=0%) in the primary and most of the secondary outcomes.

Table 1 shows the characteristics of the included trials. All the included trials enrolled also

women with prior spontaneous PTB which were excluded from the IPD. Multiple gestations

were also excluded. Therefore, the IPD was used in order to include only singleton gestations

without prior spontaneous PTB.

Out of the 419 women analyzed, 224 (53.5%) were included in the cerclage group (i.e. study

group), and 195 (46.5%) in the control group. Only singleton gestations without prior

spontaneous PTB and with short cervix <25mm were analyzed. Most of the included studies (4

out of the 5),25,32,33,35 defined short cervix as TVU CL <25 mm; while To et al.34 defined as TVU

CL 15 mm. Three trials used only McDonald cerclage,32,33,35 To et al.34 only Shirodkar, while

This article is protected by copyright. All rights reserved.

 Otsuki et al.25 randomized women into three arms: McDonald cerclage, Shirodkar cerclage, or no

cerclage. All studies used the transvaginal approach for cerclage. None of the 419 women

received progesterone (Table 1).

Accepted Article
In the Berghella et al. study,35 indomethacin (100 mg perioperative loading dose per rectum

followed by postoperative 50 mg orally every 6 hours for 48 hours) was left to the discretion of

the obstetrician; while antibiotics were not used. In Althuisius et al.33 all women in the cerclage

group received perioperative antibiotics (amoxicillin/clavulanic acid 1 gr IV qid and

metronidazole 500 mg IV tid for 24 hours followed by 6 days of amoxicillin/clavulanic acid 500

mg qid orally and metronidazole 500 mg tid orally) and indomethacin suppository (100 mg, two

hours before and 6 hours after the operation). In Rust et al.32 before randomization, all women

were placed at inpatient bed rest for 48 to 72 hours and were treated identically with an

amniocentesis, multiple urogenital cultures, and 48 to 72 hours of therapy with indomethacin

(100 mg loading dose per rectum followed by 50 mg orally every 6 hours) and clindamycin (900

mg IV every 8 hours). In To et al.34 no interventions, including tocolytics, antibiotics, and bed

rest, were routinely recommended. In Otsuki et al.25 all women randomized in the cerclage group

received tocolytic agents (usually ritodrine 100mcg/min IV) until the next day after operation

and no longer than two days; women in the cerclage group also received ampicillin 2g/day for

two days. In this trial,25 bed rest was recommended in both groups at least for 7 days and all

patients were permitted to discharge from hospital after two weeks from admission or operation.

Rust et al.32 Althuisius et al.33 Otsuki et al.25 and Berghella et al.35 routinely recommended some

similar activity restriction for both women in the study and in the control group.

The women who received the cervical suture had it removed at 36 0/7 - 37 6/7 weeks of gestation

unless spontaneous onset of labor, rupture of the membranes, or need for early delivery arose.

This article is protected by copyright. All rights reserved.

 The gestational age at randomization was about 22 weeks (22.5 vs 22.2 weeks), and the mean

TVU CL about 12 mm (12.6 vs 12.7 mm), in both groups (Table 2)

Accepted Article
Synthesis of results

No statistically significant differences were found in PTB <35 weeks (Figure 3) and in the

secondary outcomes (Table 3, Figure 4) comparing women who were randomized to the cerclage

group with those who were randomized to the control group.

Planned subgroup revealed a significant decrease in PTB <35 weeks in women with TVU CL

<10mm (39.5% vs 58.0%; RR 0.68, 95% CI 0.47 to 0.98), in white women, and in women who

received tocolytics or antibiotics as additional therapy to cerclage (Table 4, Figure 5, Figure 6).

The quality of evidence was downgraded (Table 3) because of serious imprecision. Outcomes

were imprecise because studies included relatively few patients and few events and thus had

wide CIs around the estimate of the effect and because the optimal information size was not

reached. The quality of the evidence was also downgraded another one level because of serious

indirectness because of the different study design.

COMMENT

Main findings

This IPD meta-analysis from five low risk of bias RCTs, including 419 women, showed that

transvaginal cervical cerclage did not reduce the rate of PTB or improve neonatal outcome in

asymptomatic singleton pregnancies with midtrimester TVU CL <25mm and without prior

spontaneous PTB. Planned subgroup analyses revealed a significant decrease in PTB <35 weeks

This article is protected by copyright. All rights reserved.

 in women with TVU CL <10mm, and when tocolytics or antibiotics were used as additional

therapy.

The quality level of summary estimates was judged low as assessed by GRADE, indicating that
Accepted Article
the true effect may, or is even likely to, be substantially different from the estimate of the effect.

Comparison with existing literature

Our data supports earlier findings of a prior meta-analysis.11 This prior review showed that

cerclage did not prevent preterm delivery in the overall population of singletons without prior

spontaneous PTB, but with short TVU CL.11

Strengths and limitations

Our study has several strengths. This meta-analysis included all RCTs published so far on the

topic, studies of high quality and with a low risk of bias according to the Cochrane risk of bias

tools. To our knowledge, no prior meta-analysis on this issue is as large, up-to-date or

comprehensive. Statistical tests showed no significant potential publication biases. Intent-to-treat

analysis was used. The statistical heterogeneity within the studies was very low. We also used

patient-level data to explore for heterogeneity and maternal factors, reported in Table 2, and to

perform subgroup analyses (Table 4).

Limitations of our study are inherent to the limitations of the included RCTs. The TVU CL

cutoff for intervention was different in the RCT by To et al.34 Different techniques for cerclage

were used, but there is no definitive data proving superiority of one versus another technique,

and the subgroup analysis on this issue failed to reveal any significant differences. Progesterone,

which is currently recommended for women with short TVU CL,36 was not used in any of the

This article is protected by copyright. All rights reserved.

 included trials. The use of pericerclage tocolytics or antibiotics was not uniform in the included

RCTs. Furthermore, most of the included RCTs routinely recommended bed rest, in both

cerclage group and control group. So far there is no evidence supporting the use of bed rest at
Accepted Article
home or in hospital to prevent preterm delivery.37 Grobman et al., in a secondary analysis of a

RCT of 17- hydroxyprogesterone caproate among nulliparous women with singleton gestations

and TVU CL <30 mm by midtrimester ultrasonography, showed that activity restriction

increased the risk of PTB <37 weeks.38 In one trial,25 women with genital tract infection were

excluded, and the design of the study allowed rescue cerclage for all arms, when bulging

membrane was noted. The high number of subgroup analyses and secondary outcomes may lead

to high risk of false positive results. We also acknowledge that only one trial25 was added in this

meta-analysis compared to our prior review.11 However, in this new review, IPD were used. An

IPD has several distinct advantages over aggregate data meta-analysis (ADMA). IPD involves

the synthesis of individual-level data from the individual trials, and therefore allows for the

verification of published results. As IPD are available, an IPD meta-analysis allows for more

flexibility regarding the inclusion and exclusion of individuals, and the choice of end points and

subgroups, compared with ADMA. These subgroups showed potential benefit when the CL is

<10mm and when tocolytics or antibiotics were used with cerclage. Given the low number of

included trials, while no differences were found in patient characteristics available in the

databases, unknown confounders cannot be ruled out.

This article is protected by copyright. All rights reserved.

 Interpretation

Our findings provide evidence that cerclage does not prevent PTB in all singleton gestations

without prior spontaneous PTB but with short TVU CL. In subgroup analysis of women who had
Accepted Article
TVU CL <10mm, or received additional therapy, such as tocolytics or antibiotics, cerclage may

reduce PTB, and well-powered trials should be carried out in this group of patients. Notably,

there is evidence in the literature that adjunctive perioperative tocolytics and/or antibiotics might

increase the efficacy of the cervical cerclage.39 Biologic plausibility would support these results,

as pathways to PTB are several, and involve mechanical weakness to the cervix from prior

surgical procedures40 or other factors which could be treated with cerclage, infection which could

be treated by antibiotics, and uterine contractions which could be treated by tocolytics.

Conclusions

In summary, based on this level-1 data, at least as used so far in these trials, there is not a

significant association between cervical cerclage and a lower incidence of PTB in asymptomatic

singleton gestations with short TVU CL and without prior spontaneous PTB. Cerclage seems to

be possibly efficacious at lower CLs, such as <10mm, and when tocolytics or antibiotics were

used as additional therapy, requiring further studies in these subgroups. Indeed, with a low

number of included women in these subgroup analyses, the ability to discern differences in

preterm delivery is impaired by type II error. We observed that with an a of 0.05 and 80% power,

a sample size of 103 patients in each group, for a total of 206 singleton gestations without prior

spontaneous PTB but short TVU CL <25mm, is required to detect a reduction in PTB <37 weeks

from a 34% baseline risk of women given vaginal progesterone,40 based on the RR of 0.54 with

indomethacin, antibiotics, and cerclage versus no tocolysis, no antibiotics, and no cerclage. We

are starting this new RCT.

This article is protected by copyright. All rights reserved.

 REFERENCES

1. Hamilton BE, Martin JA, Osterman MJ, Curtin SC, Matthews TJ. Births: final data for

2014. Natl Vital Stat Rep, 2015; 64:1-64.

Accepted Article
2. Rysavy MA, Li L, Bell EF, Das A, Hintz Sr, Stoll BJ, Vohr BR, Carlo WA, Shankaran S,

Walsh MC, Tyson JE, Cotten CM, Smith PB, Murray JC, Colaizy TT, Brumbaugh JE,

Higgins RD; Eunice Kennedy Shriver National Institute of Child Health and Human

Development Neonatal Research Network. B etween-hospital variation in treatment and

outcomes in extremely preterm infants. New Engl J Med, 2015; 372:1801-11.

3. Patel RM, Kandefer S, Walsh MC, Bell EF, Carlo WA, Laptook AR, Snchez PJ,

Shankaran S, Van Meurs KP, Ball MB, Hale EC, Newman NS, Das A, Higgins RD, Stoll

BJ; Eunice Kennedy Shriver National Institute of Child Health and Human Development

Neonatal Research Network.. Causes and timing of death in extremely premature infants

from 2000 through 2011. New Engl J Med, 2015; 372:331-40.

4. Berghella V, Baxter JK, Hendrix NV. Cervical assessment by ultrasound for preventing

preterm delivery. Cochrane Database Syst Rev, 2013; CD007235.

5. Berghella V, Saccone G. Fetal fibronectin testing for prevention of preterm birth in

singleton pregnancies with threatened preterm labor: a systematic review and

metaanalysis of randomized controlled trials. Am J Obstet Gynecol. 2016

Oct;215(4):431-8. doi: 10.1016/j.ajog.2016.04.038. Epub 2016 Apr 29.

6. Owen J, Yost N, Berghella V, Thom E, Swain M, Dildy GA 3rd, Miodovnik M, Langer

O, Sibai B, McNellis D; National Institute of Child Health and Human Development,

Maternal-Fetal Medicine Units Network. Mid-trimester endovaginal sonography in

women at high risk for spontaneous preterm birth. JAMA, 2001; 286:1340-8.

This article is protected by copyright. All rights reserved.

 7. Verhoeven CJ, Opmeer BC, Oei SG, Latour V, van der Post JA, Mol BW. Transvaginal

sonographic assessment of cervical length and wedging for predicting outcome of labor

induction at term: a systematic review and meta-analysis. Ultrasound Obstet Gynecol,

Accepted Article
2013; 42:500-8.

8. Saccone G, Simonetti B, Berghella V. Transvaginal ultrasound cervical length for

prediction of spontaneous labour at term: a systematic review and meta-analysis. BJOG,

2016; 123 (1):16-22. doi: 10.1111/1471-0528.13724.

9. Romero R, Nicolaides K, Conde-Agudelo A, Tabor A, O'Brien JM, Cetingoz E, Da

Fonseca E, Creasy GW, Klein K, Rode L, Soma-Pillay P, Fusey S, Cam C, Alfirevic Z,

Hassan SS. Vaginal progesterone in women with an asymptomatic sonographic short

cervix in the midtrimester decreases preterm delivery and neonatal morbidity: a

systematic review and metaanalysis of individual patient data. Am J Obstet Gynecol,

2012; 206:124.e1-19.

10. Berghella V, Rafael TJ, Szychowski JM, Rust OA, Owen J. Cerclage for short cervix on

ultrasonography in women with singleton gestations and previous preterm birth: a meta-

analysis. Obstet Gynecol, 2011; 117:663-71.

11. Berghella V, Odibo AO, To MS, Rust OA, Althuisius SM. Cerclage for short cervix on

ultrasonography: meta-analysis of trials using individual patient-level data. Obstet

Gynecol, 2005; 106:181-9.

12. Arabin B, Halbesma JR, Vork F, Hbener M, van Eyck J. Is treatment with vaginal

pessaries an option in patients with sonographically detected short cervix? J Perinat Med,

2003; 31:122-3.

This article is protected by copyright. All rights reserved.

 13. Saccone G, Ciardulli A, Xodo S, Dugoff L, Ludmir J, Pagani G, Visentin S, Gizzo S,

Volpe N, Maruotti GM, Rizzo G, Martinelli P, Berghella V. Cervical pessary for

preventing preterm birth in singleton pregnancies with short cervical length: a systematic
Accepted Article
review and meta-analysis. Journal of Ultrasound in Medicine, 2017 (in press)

14. Jones G, Clark T, Bewley S. The weak cervix: failing to keep the baby in or infection

out? Br J Obstet Gynaecol, 1998; 105:1214-5.

15. Society for Maternal-Fetal Medicine Publications Committee, with assistance of

Vincenzo Berghella. Progesterone and preterm birth prevention: translating clinical trials

data into clinical practice. Am J Obstet Gynecol, 2012; 206:376-86.

16. Lumley J, Chamberlain C, Dowswell T, Oliver S, Oakley L, Watson L. Interventions for

promoting smoking cessation during pregnancy. Cochrane Database Syst Rev, 2009;

CD001055.

17. Ota E, Hori H, Mori R, Tobe-Gai R, Farrar D. Antenatal dietary education and

supplementation to increase energy and protein intake. Cochrane Database Syst Rev,

2015; CD000032.

18. Saccone G, Saccone I, Berghella V. Omega-3 long-chain polyunsaturated fatty acids and

fish oil supplementation during pregnancy: which evidence? J Matern Fetal Neonatal

Med. 2016;29(15):2389-97. doi: 10.3109/14767058.2015.1086742. Epub 2015 Sep 18.

19. Saccone G, Berghella V, Maruotti GM, Sarno L, Martinelli P. Omega-3 supplementation

during pregnancy to prevent recurrent intrauterine growth restriction: a systematic review

This article is protected by copyright. All rights reserved.

 and meta-analysis of randomized controlled trials. Ultrasound Obstet Gynecol, 2015; 46

(6):659-64. doi: 10.1002/uog.14910

20. Saccone G, Berghella V. Omega-3 supplementation to prevent recurrent preterm birth: a

Accepted Article
systematic review and metaanalysis of randomized controlled trials. Am J Obstet

Gynecol. 2015 Aug;213(2):135-40. doi: 10.1016/j.ajog.2015.03.013.

21. Saccone G, Berghella V. Omega-3 long chain polyunsaturated fatty acids to prevent

preterm birth: a systematic review and meta-analysis. Obstet Gynecol. 2015

Mar;125(3):663-72. doi: 10.1097/AOG.0000000000000668

22. Saccone G, Berghella V. Folic acid supplementation in pregnancy to prevent preterm

birth: a systematic review and meta-analysis of randomized controlled trials. Eur J Obstet

Gynecol Reprod Biol. 2016 Apr;199:76-81. doi: 10.1016/j.ejogrb.2016.01.042

23. Saccone G, Ciardulli A, Xodo S, Dugoff L, Ludmir J, D'Antonio F, Boito S, Olearo E,

Votino C, Maruotti GM, Rizzo G, Martinelli P, Berghella V. Cervical pessary for

preventing preterm birth in twin pregnancies with short cervical length: a systematic

review and meta-analysis. J Matern Fetal Neonatal Med. 2017 Jan 12:1-8. doi:

10.1080/14767058.2016.1268595. [Epub ahead of print]

24. Saccone G, Rust O, Althuisius S, Roman A, Berghella V. Cerclage for short cervix in

twin pregnancies: systematic review and meta-analysis of randomized trials using

individual patient-level data. Acta Obstet Gynecol Scand. 2015 Apr;94(4):352-8. doi:

10.1111/aogs.12600

This article is protected by copyright. All rights reserved.

 25. Otsuki K, Nakai A, Matsuda Y, Shinozuka N, Kawabata I, Makino Y, Makei Y, Iwashita

M, OKai T. Randomized trial of ultrasound-indicated cerclage in singleton women

without lower genital tract inflammation. J Obstet Gynaecol Res, 2016; 42:148-57.
Accepted Article
26. Suhag A, Reina J, Sanapo L, Martinelli P, Saccone G, Simonazzi G, Giraldo-Isaza M,

Potti S, Hoffman MK, Berghella V. Prior Ultrasound-Indicated Cerclage: Comparison of

Cervical Length Screening or History-Indicated Cerclage in the Next Pregnancy. Obstet

Gynecol. 2015 Nov;126(5):962-8. doi: 10.1097/AOG.0000000000001086.

27. Ehsanipoor RM, Seligman NS, Saccone G, Szymanski LM, Wissinger C, Werner EF,

Berghella. Physical Examination-Indicated Cerclage: A Systematic Review and Meta-

analysis. Obstet Gynecol, 2015; 126:125-35.

28. Berghella V, Ludmir J, Simonazzi G, Owen J. Transvaginal cervical cerclage: evidence

for perioperative management strategies. Am J Obstet Gynecol, 2013; 209:181-92.

29. Higgins JPT, Green S, eds. Cochrane handbook for systematic reviews of interventions,

version 5.1.0 (update March 2011). The Cochrane Collaboration, 2011. Available at:

www.cochrane-handbook.org. (Access on 16 September 2016).

30. Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for

publication bias. Biometrics 1994;50:1088-1101.

31. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic

reviews and meta-analyses: the PRISMA statement. J Clin Epidemiol 2009; 62:1006-12.

32. Rust OA, Atlas RO, Reed J, van Gaalen J, Balducci J. Revisiting the short cervix detected

by transvaginal ultrasound in the second trimester: Why cerclage therapy may not help.

Am J Obstet Gynecol 2001;185: 1098-105.

This article is protected by copyright. All rights reserved.

 33. Althuisius SM, Dekker GA, Hummel P, Bekedam DJ, van Geijn HP. Final results of the

cervical incompetence prevention randomized cerclage trial (CIPRACT): Therapeutic

cerclage with bed rest versus bed rest alone. Am J Obstet Gynecol 2001;185: 1106-12.
Accepted Article
34. To MS, Alfirevic Z, Heath VCF, Cacho AM, Williamson PR, Nicolaides KH. Cervical

cerclage for prevention of preterm delivery in women with short cervix: randomized

controlled trial. Lancet 2004;363: 1849-53.

35. Berghella V, Odibo AO, Tolosa JE. Cerclage for prevention of preterm birth in women

with a short cervix found on transvaginal ultrasound examination: A randomized trial.

Am J Obstet Gynecol 2004;191: 1311-17.

36. Society for Maternal-Fetal Medicine Publications Committee, with assistance of

Vincenzo Berghella. Progesterone and preterm birth prevention: translating clinical trials

data into clinical practice. Am J Obstet Gynecol, 2012; 206: 376-86.

37. Sosa CG, Althabe F, Belizn JM, Bergel E. Bed rest in singleton pregnancies for

preventing preterm birth. Cochrane Database Syst Rev, 2015; 3:CD003581.

38. Grobman WA, Gilbert SA, Iams JD, Spong CY, Saade G, Mercer BM, Tita AT, Rouse

DJ, Sorokin Y, Leveno KJ, Tolosa JE, Thorp JM, Caritis SN, Van Dorsten JP; Eunice

Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Maternal-Fetal Medicine Units (MFMU) Network.. Activity restriction among women

with a short cervix. Obstet Gynecol, 2013; 121:1181-6.

39. Miller ES, Grobman WA, Fonseca L, Robinson BK. Indomethacin and antibiotics in

examination-indicated cerclage: a randomized controlled trial. Obstet Gynecol, 2014;

123:1311-6.

This article is protected by copyright. All rights reserved.

 40. Saccone G, Perriera L, Berghella V. Prior uterine evacuation of pregnancy as

independent risk factor for preterm birth: a systematic review and metaanalysis. Am J

Obstet Gynecol. 2016 May;214(5):572-91. doi: 10.1016/j.ajog.2015.12.044. Epub 2015

Accepted Article
Dec 29.

41. Romero R, Nicolaides KH, Conde-Agudelo A, O'Brien JM, Cetingoz E, Da Fonseca E,

Creasy GW, Hassan SS. Vaginal progesterone decreases preterm birth34weeks of

gestation in women with a singleton pregnancy and a short cervix: an updated meta-

analysis including data from the OPPTIMUM study. Ultrasound Obstet Gynecol, 2016;

48:308-17

This article is protected by copyright. All rights reserved.

 TABLES

Table 1. Characteristics of the included trials

Rust 200132 Althuisius To 200434 Berghella Otsuki

Accepted Article
200133 200435 201625

Study location USA Netherlands Multicenter** USA Japan

Sample size* 105 (51 vs 9 (5 vs 4) 209 (106 vs 21 (9 vs 12) 75 (53 vs 22)

54) 103)

GA at 16-24 14-27 22-24 14-24 16-26

randomization

(weeks)

Definition of <25 mm <25 mm 15 mm <25 mm <25 mm

short TVU CL

Type of McDonald McDonald Shirodkar McDonald McDonald

cerclage (27/53) and

Shirodkar

(26/53)

Cerclage Permanent Braided Tape Braided Tape Braided Tape Braided Tape

suture Monofilament

Definition of 16-36 17-33 16-32 16-34 16-36

prior

spontaneous

PTB (weeks)

Primary PTB <34 PTB <34 PTB <33 PTB <35 GA at

This article is protected by copyright. All rights reserved.

 outcome weeks weeks weeks weeks delivery

Lost to follow- 0% 2.8% 0.4% 0% 0%

up
Accepted Article
*Data are presented as number in the cerclage group vs number in the control group. Data refer

only to singleton pregnancies without prior spontaneous preterm birth

**including UK, Brazil, South Africa, Slovenia, Greece, and Chile.

GA, gestational age; TVU, transvaginal ultrasound; CL, cervical length; PTB, preterm birth

This article is protected by copyright. All rights reserved.

 Table 2. Characteristics of the included women

Cerclage No cerclage P-value

N = 224 (53.5%) N = 195 (46.5%)

Accepted Article
Age25,32-35

meanSD 29.66.3 29.76.5 0.72

Prior cone33,35

n (%) 3/14 (21.4%) 4/16 (25.0%) 0.58

Race32-35 0.75

White n (%) 95/171 (55.5%) 88/173 (50.9%)

Black n (%) 57/171 (33.4%) 68/173 (39.3%)

Others n (%)* 19/171 (11.1%) 17/173 (9.8%)

Mullerian anomalies33,35

n (%) 1/14 (7.1%) 0/16 0.44

Smoking25,33,34,35

n (%) 18/173 (10.4%) 16/141 (11.3%) 0.70

GA at randomization25,32-35

meanSD

22.52.0 22.22.2 0.27

CL25,32-35

meanSD 12.66.4 12.76.3 0.93

Mode of delivery25,33,34,35 0.08

VD n (%) 135/173 (78.0%) 122/141 (86.5%)

CD n (%) 38/173 (22.0%) 19/141 (13.5%)

This article is protected by copyright. All rights reserved.

 Not all the variables have been registered in every database; results therefore are accompanied

with the number of cases in which the outcomes were registered (n) with the references of the

included trials. Proportions are presented as percentage of n, rather than as percentages of the
Accepted Article
total population.

SD, standard deviation; GA, gestational age; CL, cervical Length; VD, vaginal delivery; CD,

cesarean delivery

*Including Asian, Hispanic

This article is protected by copyright. All rights reserved.

 Table 3. Primary and secondary outcomes in all singleton pregnancies without prior spontaneous

Singleton pregnancies without prior spontaneous PTB and with TVU CL 25 mm

(n=419)
Accepted Article
Outcome Cerclage No RR or MD I2 Q- GRADE

N = 224 cerclage (95% CI) statistic

(53.5%) N = 195

(46.5%)

PTB <35 49/224 54/195 0.88 (0.63 0% 2.09 Low-

weeks25,32-35 (21.9%) (27.7%) to 1.23) quality

of

evidence

PTB <37 81/224 80/195 0.93 (0.73 57% 4.84 Low-

weeks25,32-35 (36.2%) (41.0%) to 1.18) quality

of

evidence

PTB <34 45/224 49/195 0.89 (0.63 0% 0.67 Low-

weeks25,32-35 (20.1%) (25.1%) to 1.27) quality

of

evidence

PTB <32 38/224 39/195 0.96 (0.64 0% 0.62 Low-

weeks25,32-35 (17.0%) (20.0%) to 1.42) quality

of

evidence

This article is protected by copyright. All rights reserved.

 PTB <28 26/224 22/195 1.15 (0.68 0% 0.52 Low-

weeks25,32-35 (11.6%) (11.3%) to 1.93) quality

of
Accepted Article
evidence

PTB <24 5/224 4/195 1.14 (0.36 0% 0.69 Low-

weeks25,32-35 (2.2%) (2.0%) to 3.63) quality

of

evidence

GA at delivery 35.81 35.59 0.22 (-0.58 0% 2.02 Low-

(weeks)25,32-35 to 1.02) quality

of

evidence

Latency 86.68 83.41 3.27 (-3.22 50% 8.14 Low-

(days)25,32-35 to 9.76) quality

of

evidence

PPROM32,34,35 34/166 23/169 1.52 (0.94 0% 1.21 Low-

(20.4%) (13.6%) to 2.46) quality

of

evidence

Birth weight 2,635 2,540 94.65 (- 0% 0.41 Low-

(grams)25,32-35 146.23 to quality

335.53) of

This article is protected by copyright. All rights reserved.

 evidence

LBW25,32-35 42/224 49/195 0.88 (0.44 52% 9.41 Low-

(18.7%) (25.6%) to 1.74) quality

Accepted Article
of

evidence

VLBW25,32-35 22/224 21/195 0.97 (0.57 0% 0.84 Low-

(9.8%) (10.8%) to 1.68) quality

of

evidence

RDS33,35 2/14 2/16 1.33 (0.23 0% 1.34 Low-

(14.3%) (12.5%) to 7.74) quality

of

evidence

IVH33,35 1/14 (7.1%) 0/16 3.90 (0.18 0% 1.27 Low-

to 85.93) quality

of

evidence

Sepsis33,35 2/14 2/16 1.33 (0.23 0% 0.67 Low-

(14.3%) (12.5%) to 7.74) quality

of

evidence

NEC33,35 0/14 0/16 Not Not Not Low-

estimable applicable applicable quality

This article is protected by copyright. All rights reserved.

 of

evidence

NICU25,33,35 3/67 (4.5%) 4/38 0.80 (0.26 31% 6.41 Low-

Accepted Article
(10.5%) to 2.47) quality

of

evidence

LOS in NICU 25,2 14,9 10.30 days 0% 2.34 Low-

(days)33,35 (-27.35 to quality

47.95) of

evidence

Neonatal 7/118 6/92 1.08 (0.41 0% 1.21 Low-

death25,32,33,35 (5.9%) (6.5%) to 2.86) quality

of

evidence

Data are presented as number (percentage) or as mean difference standard deviation.

Not all the variables have been registered in every database; results therefore are accompanied

with the number of cases in which the outcomes were registered (n) with the references of the

included trials. Proportions are presented as percentage of n, rather than as percentages of the

total population.

PTB, preterm birth; TVU, transvaginal ultrasound; CL, cervical length; RR, relative risk; MD,

mean difference; CI, confidence interval; GA, gestational age; PPROM, preterm premature

rupture of membranes; LBW, low birth weight; VLBW, very low birth weight; RDS, respiratory

This article is protected by copyright. All rights reserved.

 distress syndrome; IVH, intraventricular hemorrhage; NEC, necrotizing enterocolitis; NICU,

neonatal intensive care unit; LOS, length of stay;

Accepted Article

This article is protected by copyright. All rights reserved.

 Table 4. Primary and secondary outcomes in subgroup analyses

Only women with TVU CL 20 mm (n=349)

Outcome Cerclage No cerclage RR (95% CI) I2

Accepted Article
N = 188 N = 161

PTB <35

weeks25,32-35 47 (25.0%) 51 (31.7%) 0.79 (0.56 to 0%

1.10)

Only women with TVU CL 15 mm (n=305)

Outcome Cerclage No cerclage RR (95% CI) I2

N = 159 N = 146

PTB <35

weeks25,32-35 43 (27.0%) 49 (33.6%) 0.81 (0.57 to 0%

1.13)

Only women with TVU CL <10 mm (n=126)

Outcome Cerclage No cerclage RR (95% CI) I2

N = 76 N = 50

PTB <35 0.68 (0.47 to

weeks25,32-35 30 (39.5%) 29 (58.0%) 0.98) 0%

Only women with TVU CL <5 mm (n=48)

Outcome Cerclage No cerclage RR (95% CI) I2

N = 27 N = 21

PTB <35 0.79 (0.50 to

weeks25,32-35 15 (55.5%) 15 (71.4%) 1.23) 0%

This article is protected by copyright. All rights reserved.

 Only white women (n= 183)

Outcome Cerclage No cerclage RR (95% CI) I2

N = 95 N = 88
Accepted Article
PTB <35 0.59 (0.37 to

weeks32-35 21 (22.1%) 33 (37.5%) 0.94) 0%

Only black women (n= 125)

Outcome Cerclage No cerclage RR (95% CI) I2

N = 57 N = 68

PTB <35 1.07 (0.63 to

weeks32-35 18 (31.6%) 20 (29.4%) 1.83) 0%

Shirodkar cerclage (n =257)

Outcome Cerclage No cerclage RR (95% CI) I2

N = 132 N = 125

PTB <35 0.86 (0.55 to

weeks25,34 29 (22.0%) 32 (25.6%) 1.33) 0%

McDonald cerclage (n =185)

Outcome Cerclage No cerclage RR (95% CI) I2

N = 87 N = 98

PTB <35 0.78 (0.48 to

weeks25,32,33,35 20 (23.0%) 29 (29.6%) 1.27) 0%

Tocolytics and cerclage versus no tocolytics and no cerclage (n=254)

Outcome Cerclage+Tocolytics No cerclage and RR (95% CI) I2

N = 114 no tocolytics

This article is protected by copyright. All rights reserved.

 N = 140

PTB <35 20 (17.5%) 40 (25.7%) 0.61 (0.38 to 0%

weeks25,32-35 0.98)
Accepted Article
Tocolytics and cerclage versus tocolytics and no cerclage (n= 169)

Outcome Cerclage+Tocolytics Tocolytics and RR (95% CI) I2

N = 114 no cerclage

N = 55

PTB <35 0.54 (0.31 to

weeks25,32,33,35 20 (17.5%) 18 (32.7%) 0.93) 0%

Antibiotics and cerclage versus no antibiotics and no cerclage (n=249)

Outcome Cerclage+Antibiotics No cerclage and RR (95% CI) I2

N = 109 no antibiotics

N = 140

PTB <35 0.71 (0.44 to

weeks25,32-35 20 (18.3%) 36 (25.7%) 1.66) 0%

Antibiotics and cerclage versus antibiotics and no cerclage (n=163)

Outcome Cerclage+Antibiotics Antibiotics and RR (95% CI) I2

N = 109 no cerclage

N = 54

PTB <35 0.58 (0.33 to

weeks25,32,33 20 (18.3%) 17 (31.5%) 0.98) 0%

Data are presented as number (percentage) or as mean difference standard deviation.

This article is protected by copyright. All rights reserved.

 Not all the variables have been registered in every database; results therefore are accompanied

with the number of cases in which the outcomes were registered (n) with the references of the

included trials. Proportions are presented as percentage of n, rather than as percentages of the
Accepted Article
total population. Boldface data, statistically significant

PTB, preterm birth; TVU, transvaginal ultrasound; CL, cervical length; RR, relative risk; CI,

confidence interval;

This article is protected by copyright. All rights reserved.

 FIGURES

Figure 1. Flow diagram of studies identified in the systematic review. (Prisma template

[Preferred Reporting Item for Systematic Reviews and Meta-analyses]). FFN, fetal fibronectin;
Accepted Article
PPROM, preterm premature rupture of membranes

This article is protected by copyright. All rights reserved.

Accepted Article

This article is protected by copyright. All rights reserved.

 2 Assessmen
Figure 2. nt of risk of bias.
b (A) Sum
mmary of rissk of bias foor each trial; Plus sign: loow

risk of biias; minus sign: high risk

k of bias; qu
uestion mark: unclear riskk of bias. (B
B) Risk of biaas

graph abo
out each risk
k of bias item
m presented as percentagges across alll included sttudies.
Accepted Article

Figure 3. Forest plott for the risk of the primaary outcomee (i.e. incidennce of preterrm birth <355

weeks) in
n the overalll population. CI, confidence interval;
l; M-H, Manntel-Haenszeel; df, degreees of

freedom;; TVU CL, trransvaginal ultrasound

u cervical
c lenggth

This article is protected by copyright. All rights reserved.

 4 Incidence of
Figure 4. o preterm birth
b at differrent cutoffs ccomparing ccerclage grouup (solid barrs)

and no ceerclage grou

up (striped baars). RR, relaative risk; inn parentheses: 95% conffidence intervvals.
Accepted Article

5 Incidence of
Figure 5. o preterm birth
b <35weeeks by transvvaginal ultraasound cerviccal length

subgroup
ps comparing
g cerclage grroup (solid bars)
b and no cerclage grooup (striped bars). RR,

relative risk;
r in paren
ntheses: 95%
% confidencee intervals; **, statisticallyy significantt.

This article is protected by copyright. All rights reserved.

Accepted Article

6 Incidence of
Figure 6. o preterm birth
b <35weeeks by additiion of tocolyysis or not too cerclage (tw
wo

left bars)), and by add

dition of antiibiotics or no
ot to cerclage (two right bars) compaaring cerclagge

group (so
olid bars) and no cerclag
ge group (striiped bars). R
RR, relative risk; in pareentheses: 95%
%

confidence intervals; *, statisticaally significaant.

This article is protected by copyright. All rights reserved.

Accepted Article

This article is protected by copyright. All rights reserved.