BMC Pregnancy and Childbirth BioMed Central

Study protocol Open Access

Individual patient data meta-analysis : Cervical stitch (cerclage) for
preventing pregnancy loss in women
Catrin Tudur-Smith1, Andrea L Jorgensen*1, Zarko Alfirevic2 and
Paula R Williamson1

Address: 1Centre for Medical Statistics and Health Evaluation, University of Liverpool, Liverpool, L69 3BX, UK and 2University Department of
Obstetrics and Gynaecology, Liverpool Women's Hospital, Liverpool, UK
Email: Catrin Tudur-Smith - [email protected]; Andrea L Jorgensen* - [email protected]; Zarko Alfirevic - [email protected];
Paula R Williamson - [email protected]
* Corresponding author

Published: 23 February 2005 Received: 19 January 2005

Accepted: 23 February 2005
BMC Pregnancy and Childbirth 2005, 5:5 doi:10.1186/1471-2393-5-5
This article is available from: http://www.biomedcentral.com/1471-2393/5/5
© 2005 Tudur-Smith et al; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0),
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Abstract
Background: Cervical cerclage is a surgical procedure involving suturing the cervix with a purse
type stitch to keep it closed during pregnancy. This procedure has been used widely in the
management of pregnancies considered at high risk of preterm delivery. Several observational
studies into the efficacy of cervical cerclage have claimed high rates of successful pregnancy
outcome in women with a poor obstetric history attributed to cervical incompetence. However, a
recent aggregate data Cochrane review found no such conclusive evidence from seven included
randomised studies. Current data suggests that cervical cerclage is likely to benefit women
considered to be 'at very high risk' of a second trimester miscarriage due to a cervical factor,
however identifying such women remains elusive and many women may be treated unnecessarily.
Undertaking an individual patient data (IPD) meta-analysis of the studies will allow us to investigate
whether treatment is more effective in particular subgroups. Such an analysis will also provide a
more powerful analysis of the predictors of preterm delivery and pregnancy loss, including
ultrasound measurement of cervical length, and will allow a more complete analysis of 'time to
event' outcomes.
Methods/Design: The analysis will include data from randomised trials comparing the
intervention of elective cerclage versus no cerclage or bedrest to prevent miscarriage or pre-term
labour. A specific list of data will be requested for each trial, including demographic and obstetric
history data. The primary outcomes of interest will be neonatal mortality/morbidity. Attention will
also be given to secondary outcomes such as time from randomisation to delivery, preterm delivery
before 32 weeks and maternal morbidity. An intention to treat analysis will be performed, with
attention paid to assessing clinical and statistical heterogeneity. Multilevel models with patients and
trials as the two levels will be explored to investigate treatment effect on various outcomes.
Patient-level covariates will be incorporated into the models in an attempt to account for statistical
heterogeneity as well as to investigate interactions with treatment effect.
Discussion: Predictive models generated from our analysis should lead to more effective
counselling of women at risk and a more cost effective use of cerclage.

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Background treated unnecessarily. The use of IPD will allow us to

Cervical cerclage is a surgical procedure carried out during investigate predictors of preterm delivery including ultra-
pregnancy. The operation involves suturing the neck of sound measurement of cervical length and other woman-
the womb (cervix) with a purse type stitch to keep the cer- cerclage interactions.
vix closed. This surgical procedure has been used widely in
the management of pregnancies considered to be at high IPD meta-analysis will allow an investigation of the
risk of preterm delivery. hypothesis that the effect of cerclage is greater on extreme
preterm delivery. In addition, an IPD meta-analysis has
Several observational studies in the last 50 years have greater power than a single trial for examining subgroups.
claimed high rates of successful pregnancy outcome in The efficacy of a treatment may depend on several factors.
women that had a poor obstetric history attributed to cer- For aggregate data, a meta-analysis stratifying by the abso-
vical incompetence. However, a recent Cochrane review lute risk in the control group may be the only method pos-
found no conclusive evidence from seven included ran- sible for accounting for these multiple factors
domised studies that inserting a cervical stitch in women simultaneously. This analysis is 'flawed and produces seri-
perceived to be at risk of preterm birth or second trimester ously misleading results' (Sharp 1996)[7]. A regression
pregnancy loss attributed to cervical factors, reduces the analysis of IPD allows the relation between treatment
risk of pregnancy loss, preterm delivery or morbidity asso- effect and risk score, derived from these multiple risk fac-
ciated with preterm delivery (Drakeley 2003)[1]. tors, to be investigated thereby avoiding these problems.

In the Cochrane review, the data for important clinical Methods/Design

outcomes including preterm delivery and maternal infec- Objectives
tion showed significant heterogeneity due to inconsist- The aim of this project is to undertake an IPD meta-anal-
ency in clinical definitions used, including the cut off ysis of randomised trials of cervical cerclage. Specific
gestational age defining preterm delivery, and different objectives are as follows.
patient populations studied.
1. To estimate the effect of cervical cerclage on gestational
Practically, methods of undertaking a meta-analysis of age at delivery.
several studies may involve collecting either aggregate
data, or data on each patient individually. The advantages 2. To investigate whether cervical cerclage is more likely to
of the latter approach, described as the 'yardstick' (Chalm- prevent extreme prematurity (<28 weeks) or delivery at
ers 1993)[2] include (i) a more complete analysis of 'time later gestations.
of event' outcomes and (ii) a more powerful analysis of
whether treatment is more or less effective in particular 3. To investigate risk factors for preterm delivery.
subgroups (Stewart 1993)[3].
4. To investigate interactions between risk factors and cer-
One of the main concerns regarding current evidence vical cerclage.
related to cervical cerclage and other interventions for pre-
ventions of preterm delivery is a possibility that the 'pri- 5. To model the effect of cervical cerclage and other risk
mary outcomes' may have been selected to give results in factors on neonatal and maternal morbidity.
greatest accord with the a priori beliefs of the authors. The
evidence to support this phenomenon of within-study Criteria for considering studies for this IPD meta-analysis
selective reporting comes from empirical research, which The types of studies considered for inclusion in the analy-
demonstrates discrepancies between research protocols sis will be all randomised trials comparing cervical cer-
and subsequent publications (Hahn 2002 [4], William- clage with expectant management or no cerclage during
son 2005 [5], Chan 2004 [6]). Individual patient data pregnancy. The previous Cochrane review (Drakeley
(IPD) meta-analysis has the capacity to overcome these 2003) [1] identified eight eligible trials with 2,513 ran-
problems. domised women (Rust 2000 [8], Althuisius 2000 [9],
Althuisius 2001 [10], Rush 1983 [11], Lazar 1984 [12],
Currently available data suggest that cervical cerclage is Dor 1982 [13], MRC/RCOG 1988 [14], Meekai To et al.
likely to be of benefit for women considered 'at very high [15]). We have agreement in principle to provide IPD
risk' of second trimester miscarriage due to a cervical fac- from six of these trials (Meekai To et al. [15], MRC/RCOG
tor e.g. greater than two second trimester losses or progres- 1988 [14], Rust 2000 [8], Althuisius 2000 [9], Althuisius
sive shortening of the cervix on ultrasound. However, 2001 [10], Rush 1983 [11]), accounting for 1919(78%) of
predicting those women who will miscarry due to a cervi- all women randomised. The remaining trialists and trial-
cal factor remains elusive and many women may be ists of any further trials identified as eligible will be

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approached at the start of the project and we anticipate Data collection

their willingness to collaborate. Already, two further trials The following data for each woman/infant pair will be
have been identified (Berghella 2004 [16], Ezechi 2003 requested from all trials: date of randomisation and gesta-
[17]) and the authors have agreed to provide IPD from tional age, maternal demographics and obstetric charac-
these trials. teristics at randomisation including cervical length on
ultrasound, fibronectin and bacterial vaginosis data if
The data collected in the studies will relate to women with available, treatment allocated, complications during preg-
confirmed, or suspected of having, cervical incompetence nancy including ruptured membranes, maternal pyrexia
who desire future pregnancies and women who present as or chorioamnionitis, date of delivery, gestational age at
an emergency and are thought to have a diagnosis of cer- delivery and all neonatal data including birthweight,
vical incompetence. The intervention investigated in the length of stay at NICU and morbidity related to prematu-
studies will be elective cerclage by whichever method rity.
(Shirodkar technique, McDonald technique, transabdom-
inal and transvaginal methods), versus no cerclage or bed The following methodological data will also be requested
rest as interventions to prevent miscarriage or pre-term for all trials: method of generation of randomisation list,
labour as defined in the original Cochrane review (Drake- method of concealment of randomisation, stratification
ley 2003)[1]. factors and blinding methods.

Search strategy for identification of studies Data will be accepted either in electronic (floppy disk/
The methods of trial identification described in the origi- CD/internet) or paper form. A desired format and coding
nal Cochrane review (Drakeley 2003)[1] (see below) will will be specified but trialists may supply data in the most
be adopted and updated to December 2004. convenient way open to them, providing details of coding
are sent with the data.
The original review has drawn on the search strategy
developed for the Pregnancy and Childbirth Group. The Data validation strategy
full list of journals and conference proceedings as well as A copy of the original data sent (before checking) will be
the search strategies for the electronic databases, which are held in a separate file. The following procedures will then
searched by the Group on behalf of its reviewers, are be performed and documented for all trial data supplied.
described in detail in the 'Search strategies for the identi- Trial details will be crosschecked against any published
fication of studies section' within the editorial informa- report of the trial. Range and consistency checks will be
tion about the Cochrane Pregnancy and Childbirth applied – missing data, errors and inconsistencies will be
Group. Briefly, the Trials Search Coordinator searches on followed up with a nominated individual. The chronolog-
a regular basis MEDLINE, the Cochrane Controlled Trials ical randomisation sequence will be reviewed. The bal-
Register and reviews the Contents tables of a further 38 ance of prognostic factors will be checked, taking into
relevant journals received via ZETOC, an electronic cur- account of factors stratified for in the randomisation pro-
rent awareness service. cedure.

In addition, handsearches will be performed on congress Outcome measures

proceedings of the International and European society The primary outcome of interest will be neonatal mortal-
meetings of feto-maternal medicine, recurrent miscarriage ity/morbidity. Choice of primary outcome is about what
and reproductive medicine. Whenever possible, investiga- should determine clinical decision-making. However it is
tors will be contacted to ask about any additional studies recognised that trials to date may have insufficient power
potentially eligible for inclusion. and there is a need to consider secondary outcomes of
time from randomisation to delivery, preterm delivery
Trial eligibility and methodological quality assessment before 32 completed weeks (<32+0 weeks) and maternal
Two reviewers will independently assess eligibility of morbidity as defined in the Cochrane Review (Drakeley
identified randomised controlled trials for inclusion in 2003)[1]. We will aim to obtain all neonatal and maternal
the review. Any difference of opinion will be resolved by morbidity outcome data collected in each trial and not
discussion. The methodological quality of each trial will just those reported in publications.
be assessed by summarising the method of generation of
randomisation list, method of allocation concealment, Reporting of these outcomes in the original trial report is
and potential impact of losses to follow-up. Quasi-ran- not an eligibility requirement for this review.
domised studies in which allocation was transparent (e.g.
use of alternative allocation or medical record numbers)
were excluded in the original review.

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Data analysis ence investigated. The analysis plan will be reviewed in

Data on all randomised patients will be requested to per- light of the availability of IPD but prior to any compara-
form an intention-to-treat analysis as far as possible. Clin- tive analyses.
ical heterogeneity will be assessed by reviewing the
differences across trials in characteristics of randomised Discussion
patients. Predictive models generated by our analysis should allow
more effective counselling of women at risk of preterm
Initially, an aggregate data analysis will be undertaken delivery and thus more cost effective use of cerclage.
although treatment effect estimates will be obtained from
the individual patient data. Binary outcomes will be sum- Competing interests
marised in terms of odds ratios or relative risks, depend- ZA and PRW were authors of a paper that will be included
ing on the degree of heterogeneity observed. Time-to- in the IPD meta-analysis (To, 2004). ZA was an author of
event outcomes will be summarised in terms of the log the non-IPD systematic review on this topic (Drakeley,
(hazard ratio). The I square statistic and chi-square test for 2003)[1]. The authors declare that they do not have any
statistical heterogeneity will be applied to these summary other competing interests.
data.
Authors' contributions
Regression models, stratified by trial, will be used to PRW conceived the idea, CTS drafted the initial protocol,
explore the effects of treatment, risk factors and treatment- and all authors commented on and approved this final
covariate interactions on the various outcomes of interest. version.
These will include Cox and accelerated life models for
time-to-event outcomes (Tudur-Smith 2004 [18], Wil- Acknowledgements
liamson 2002 [19]) and logistic regression models with The authors would like to thank the trialists who have kindly agreed to pro-
trial indicator variables for binary outcomes (Whitehead vide IPD data from their trials.
2002) [20]. Factors other than treatment to be investi-
gated are gestational age at randomisation, maternal References
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