cerclage journal pubmed- 2007
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Systematicreview:Cervicalstitch(cerclage)forpreventingpregnancyloss:individualpatientdatametaanalysisARTICLEinBJOGANINTERNATIONALJOURNALOFOBSTETRICS&GYNAECOLOGYNOVEMBER2007ImpactFactor:3.86DOI:10.1111/j.1471-0528.2007.01515.xSource:PubMed
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Cervical stitch (cerclage) for preventing pregnancyloss: individual patient data meta-analysisAL Jorgensen,a Z Alfirevic,b C Tudur Smith,a PR Williamsona; on behalf of the cerclage IPD
Meta-analysis Groupa Centre for Medical Statistics and Health Evaluation, University of Liverpool, Liverpool, UK b Department of Obstetrics and Gynaecology,
University of Liverpool, Liverpool Womens Hospital, Liverpool, UK
Correspondence: Mrs AL Jorgensen, Centre for Medical Statistics and Health Evaluation, University of Liverpool, Shelleys Cottage,
Brownlow Street, Liverpool L69 3GS, UK. Email [email protected]
Accepted 6 August 2007. Published OnlineEarly 28 September 2007.
Background Several observational studies have claimed high
success rates for cerclage in women with cervical insufficiency. A
recent Cochrane review found no conclusive evidence of benefit,
although significant heterogeneity was present for some of the
important clinical outcomes.
Objectives We undertook an individual patient data (IPD) meta-
analysis to examine effect of cerclage on neonatal and maternal
outcomes. In an attempt to explain the heterogeneity, we
investigated whether obstetric factors including multiple gestation
are associated with effectiveness.
Search strategy Search methods described in the original
Cochrane review were adopted and updated to December 2005.
Selection criteria This IPD systematic review and meta-analysis
was of randomised trials comparing cervical cerclage during
pregnancy with expectant management or no cerclage in women
with confirmed or suspected as having cervical insufficiency.
Analysis Multilevel logistic regression models stratified by trial
with random treatment effects were fitted to investigate the impact
of obstetric factors and multiple gestation on treatment effect.
Primary outcome measures were pregnancy loss or death before
discharge from hospital and absence of neonatal morbidity.
Main results The meta-analysis included seven trials and 2091
randomised women. In singleton pregnancies, the reduction in
pregnancy loss or death before discharge from hospital following
cerclage failed to reach statistical significance (OR 0.81; 95% CI
0.601.10). Cerclage was found to have a detrimental effect on the
outcome of pregnancy loss or death before discharge from hospital
in multiple gestations (OR 5.88; 95% CI 1.1430.19), although
only a small number of multiple pregnancies were included in the
analysis. Neither indication for cerclage nor obstetric history was
found to have a statistically significant impact on the effect
of cerclage.
Conclusions Cerclage may reduce the risk of pregnancy loss or
neonatal death before discharge from hospital in singleton
pregnancies thought to be at risk of preterm birth, but further
large trials are needed to elucidate the risk-benefit ratio precisely.
Cerclage in multiple pregnancies should be avoided. The efficacy of
cerclage was not influenced by either indication for cerclage or
mothers obstetric history.
Keywords Cervical cerclage, cervical stitch, individual patient
data meta-analysis, neonatal death, neonatal morbidity, neonatal
mortality, preterm delivery, pregnancy loss, randomised
clinical trials.
Please cite this paper as: Jorgensen A, Alfirevic Z, Tudur Smith C, Williamson P; on behalf of the cerclage IPD Meta-analysis Group. Cervical stitch (cerclage) for
preventing pregnancy loss: individual patient data meta-analysis. BJOG 2007;114:14601476.
Introduction
Cervical cerclage is a surgical procedure involving suturing
the neck of the womb (cervix) with a purse type stitch to keep
the cervix closed during pregnancy. This has been used widely
in the management of pregnancies considered at high risk of
preterm birth.
Several observational studies in the past 50 years have
claimed high rates of successful pregnancy outcome in
women with poor obstetric history attributed to cervical
insufficiency in whom cerclage was used. A recent Cochrane
review of randomised trials analysing outcomes includ-
ing miscarriage, perinatal loss, maternal infection, maternal
morbidity, antepartum haemorrhage and preterm birth
found no conclusive evidence of such benefit.1 However,
significant statistical heterogeneity was present for some of
the important clinical outcomes. This heterogeneity was
attributed to the inconsistency in clinical definitions
1460 2007 The Authors Journal compilation RCOG 2007 BJOG An International Journal of Obstetrics and Gynaecology
DOI: 10.1111/j.1471-0528.2007.01515.x
www.blackwellpublishing.com/bjogSystematic review
-
employed in the trials (e.g. varying cutoff points for defining
preterm birth) and in the different patient populations stud-
ied, however, neither meta-regression nor subgroup analyses
was undertaken.
Practically, methods of undertaking meta-analyses involve
collecting either aggregate data or data on each woman indi-
vidually. The advantages of the latter approach, known as an
individual patient data (IPD) meta-analysis and described as
the yardstick,2 include the potential to ensure a more con-
sistent definition of outcomes across trials, as well as a more
powerful analysis of whether treatment is more or less effec-
tive in particular subgroups.3 Although previous subgroup
analyses4 suggested that cerclage would be of benefit to the
subgroup of women with three or more second trimester
miscarriages or preterm births, the number of women con-
tributing to each obstetric history subgroup, and hence the
power to detect treatment effect within each, was small.
An IPD meta-analysis investigating the effects of cervical
cerclage has previously been published.5 This analysis included
only women found to have short cervix on ultrasound and did
not investigate the effect of cerclage on neonatal morbidity.
The data were analysed as although obtained from a single
large trial recruiting from the same population, and an
assumption of homogeneity of treatment effect between trials
was made. Our work includes methods of random-effects
meta-regression and multilevel logistic regression models to
detect and allow for heterogeneity of effect. Widening our
inclusion criteria to include trials that recruited based on
obstetric history and using the aforementioned analysis tech-
niques enabled us to not only examine the effect of cervical
cerclage in the general population of women at risk of pre-
term birth but also to investigate the impact that previous
obstetric history or cervical length may have on this effect.
Methods
We undertook an IPD meta-analysis to examine the effect
of cerclage on our prespecified neonatal and maternal
outcomes.6
SearchingThe search methods described in the original Cochrane
review1 were adopted and updated to December 2005.
Selection and study characteristicsThe types of studies considered for inclusion in the analysis
were randomised trials comparing cervical cerclage during
pregnancy (Shirodkar technique, McDonald technique, trans-
abdominal and transvaginal methods), with expectant
management or no cerclage in women with confirmed or
suspected as having cervical insufficiency. Quasi-randomised
studies in which allocation was transparent (e.g. use of alter-
native allocation or medical record numbers) were excluded.
Data abstraction and validity assessmentTwo reviewers independently assessed inclusion eligibility of
trials with any difference of opinion being resolved through
discussion. The methodological quality of each trial was
assessed in terms of method of generating randomisation
sequence, method of allocation concealment and potential
impact of losses to follow up. For each eligible trial, we requested
data on trial methods, treatment allocation, patient character-
istics and outcome data. The data provided were cross-checked
against any published report of the trial, and where possible, the
chronological randomisation sequence was reviewed, as was the
balance of prognostic factors at baseline. Any queries were fol-
lowed up with a nominated individual.
The primary outcomes were pregnancy loss or death before
discharge from hospital and absence of neonatal morbidity,
and secondary outcomes were preterm delivery (PTD) and
maternal morbidity. The impact of obstetric history and cer-
vical length on the effect of cervical cerclage was also assessed.
We asked trialists to provide all outcome data collected and
not just those reported in publications to avoid bias due to
within-study selective reporting.7
Standardising pregnancy loss or death beforedischarge from hospital outcome across trialsThe primary outcome was pregnancy loss or neonatal death
before discharge from hospital. This outcome includes all mis-
carriages, stillbirths and neonatal deaths before discharge, and
the IPD available for each trial were standardised as summar-
ised in Table 1. The use of a composite outcome appeared
justifiable here on the grounds that all events lead to the loss
of a baby, the prevention of which is the ultimate goal of using
cervical cerclage. The composite outcome was defined in accor-
dance with ICH E9 guidelines since analysing the outcomes
separately would not be addressing the primary question of
interest.14 It was not possible to analyse the outcome pregnancy
loss or neonatal death at any time since most trials4,8,9,11,13
followed up to hospital discharge only. For trials where length
of follow up was unclear,10 we assumed that follow up was to
hospital discharge only. Furthermore, it was confirmed that
although follow up continued after hospital discharge, all
deaths in the trial of Rust et al.12 occurred before discharge.
In the trials of To et al.,13 Berghella et al.,9 MRC,4 Rust
et al.,12 Rush et al.11 and Althuisius et al.8 only viable preg-
nancies were included. This could not be directly confirmed
for the trial of Ezechi et al.,10 and so an assumption had to be
made that this was indeed the case.
Standardising neonatal morbidity outcomeacross trialsDiffering neonatal morbidity outcomes were recorded in the
trials, and so an alternative outcome of baby healthy when
discharged from hospital was chosen, representing the absence
Cervical cerclage for preventing pregnancy loss
2007 The Authors Journal compilation RCOG 2007 BJOG An International Journal of Obstetrics and Gynaecology 1461
-
Table
1.Stan
dardisingoutcomemeasuresacross
trials
Althuisiusetal.8
Berghellaetal.9
Ezechietal.10
MRC4
Rush
etal.11
Rust
etal.12
Toetal.13
Neo
natal
mortality
Intrau
terinefetal
deaths(IU
Fs)
andneo
natal
deathswere
recorded
.No
inciden
cesofIUFs.
Neo
natalmortality
therefore
included
anyneo
nataldeaths
Neo
nataldeaths
wererecorded
.Th
is
included
miscarriages,
stillbirths
anddeathsafter
birth.Weclassified
as:miscarriages:
neo
nataldeathsat
,24weeks1
noNICU;
stillbirths:neo
natal
deathsat
24weeks
1noNICU;neo
natal
deaths:neo
natal
death1
NICU
Stillbirthsonly
wererecorded
.
Apparen
t
from
published
pap
erthat
totalp
erinatal
deathseq
ual
tototal
stillbirths.We
classified
as:miscarriages:
stillbirth
at,24
weeks;stillbirths:
stillbirth
at2
4
weeks;neo
natal
deaths:none
Liveborn,viab
le;
liveb
orn,dead
andstillbirth/
abortionwere
recorded
.We
classified
as:miscarriages:
stillbirth/abortion
at,24weeks;
stillbirths:
stillbirth/abortion
at2
4weeks;
neo
nataldeaths:
liveb
orn,dead
Miscarriages,stillbirths
andneo
nataldeaths
allw
ererecorded
specifically
withsame
classificationas
forthis
meta-an
alysis
Perinataldeaths
wererecorded
.
Notpossible
toclassify
into
subcategories
of
miscarriages,
stillbirthsan
d
neo
nataldeaths
butthiscomposite
outcomewas
sufficien
tfor
ourprimary
outcome
Stillbirthsan
dwhether
bab
ywas
alive
atfollow
uprecorded
.
Weclassified
as:
miscarriages:stillbirth
at,24weeks;
stillbirths:stillbirth
at
24weeks;neo
natal
death:notastillbirth
andnotaliveat
follow
up
Neo
natal
morbidity
Necrotising
enterocolitis,
RDS,
IVHan
d
neo
natalsepsis
wererecorded
.
Trialistsconfirm
ed
notnecessarily
case
that
bab
y
was
healthyat
dischargeifall
thesepathologies
reported
neg
ative.
Hen
ce,trialexcluded
from
analysisof
thisoutcome
IVH,RDS,
NEC
andsepsiswere
recorded
.Trialists
confirm
edthat
ifall
thesemarked
neg
ative,
can
assumebab
ywas
healthyat
discharge
Notavailable
Notrecorded
Anyserious
complicationsof
prematurity
wererecorded
,an
d
soifnone
was
recorded
,
canassume
bab
ywas
healthy
atdischarge
Perinatalmorbidity
was
recorded
in
term
sof
seriousnessof
complications.
Bab
ycountedas
healthy
atdischargeifit
did
notsuffer
from
anyserious
complicationsof
prematurity
IVH,positive
bloodcultures,
retinopathyof
prematurity
andBPD
wererecorded
.
Trialistsconfirm
ed
that
ifallthesemarked
neg
ative,
canassume
bab
ywas
healthy
atdischarge
Spontaneo
us
labour
Notrecorded
Dataonindication
fordeliverywere
collected
.Allwomen
markedspecifically
as
spontaneo
uslabour
werecountedas
having
spontaneo
uslabour
Unclearif
recorded
ornot
Spontaneo
us
labourstatus
was
recorded
directlyin
trial
Spontaneo
us
labourstatus
was
recorded
directlyin
trial
Notrecorded
Typeoflabour
was
recorded
directly.
Allwomen
marked
asspontaneo
us
countedas
having
spontaneo
uslabour
(continued
)
Jorgensen et al.
1462 2007 The Authors Journal compilation RCOG 2007 BJOG An International Journal of Obstetrics and Gynaecology
-
Table
1.(Continued
)
Althuisiusetal.8
Berghellaetal.9
Ezechietal.10
MRC4
Rush
etal.11
Rust
etal.12
Toetal.13
Pyrexia
Notrecorded
Notrecorded
Unclearif
recorded
ornot
Whether
woman
had
temperature
of.38recorded
directly
Temperature
of
mother
recorded
.
If.38,we
classified
aspyrexia.
Datadoes
notmatch
published
report
(onemore
ineach
treatm
entgroup).
Analysisisbased
onIPDdataheld
Notrecorded
Whether
mother
had
feverornotwas
recorded
directly
Chorioam
nionitis
Recorded
directly
Notrecorded
Unclearif
recorded
ornot
Recorded
only
incerclagegroup
asad
verseeven
t
from
interven
tion.
Asnotrecorded
incontrolg
roup
also
dataexcluded
from
analysis
Notrecorded
Directlyrecorded
Notrecorded
PPROM
Recorded
directly
Recorded
directly
Unclearif
recorded
ornot
Recorded
only
incerclagegroup
asad
verseeven
t
from
interven
tion.
Asnotrecorded
incontrolg
roup
also
dataexcluded
from
analysis
Recorded
directly.
Thedatadoes
notmatch
published
report(oneless
in
cerclagegroupin
datathan
inpublished
report).Analysisis
based
onIPDheld
Recorded
directly
Recorded
directly
Needfor
induction
and/orneed
forplanned
caesarean
Methodof
deliverywas
recorded
but
typeoflabour
notso
trial
excluded
from
analysisofthis
outcome
Indicationfordelivery
andmethodof
deliverywere
recorded
;however,
nodistinctionwas
mad
ebetween
elective
and
emergen
cy
caesareansection.
Therefore,
trialexcluded
from
analysisofthis
outcome
Unclearif
recorded
ornot
Spontaneo
uslabour
andmethodof
deliverywere
recorded
.Women
classedas
not
havingspontaneo
us
labourorhaving
spontaneo
uslabour
followed
by
emergen
cyor
elective
caesarean
classified
asyes
forthisan
alysis
Spontaneo
uslabour,
inducedlabour,
emergen
cy
caesareanan
d
elective
caesarean
wererecorded
.
Women
having
either
induced
labour,em
ergen
cy
caesareanorelective
caesareanclassified
as
yesforthisan
alysis
Methodofdelivery
was
recorded
but
typeoflabournotso
trialexcluded
from
analysisofthis
outcome
Indicationfor
deliveryan
dmethod
ofdeliverywere
recorded
;however,
nodistinctionwas
mad
ebetweenelective
andem
ergen
cy
caesareansection.
Therefore,trial
excluded
from
analysisofthis
outcome
BPD
,bronchopulm
anarydysplasia;
IVH,intraven
tricularhaemorrhag
e;NEC
,nectrotisingen
terocolitis;NICU,neo
natal
intensive
care
unit;RDS,
respiratory
distresssyndrome.
Cervical cerclage for preventing pregnancy loss
2007 The Authors Journal compilation RCOG 2007 BJOG An International Journal of Obstetrics and Gynaecology 1463
-
of any detectable neonatal morbidity at discharge. Table 1
summarises the data recorded on this outcome in each trial,
and how these were classified for the purposes of this analysis.
The lead author for the trials of To et al.,13 Berghella et al.,9
Rust et al.12 and Rush et al.11 confirmed that if a baby had
suffered from any morbidity at all then this would have been
recorded. For the trial of Althuisius et al.,8 only neonatal diag-
noses specifically requested were recorded if present. It does
not automatically follow that a baby with none of these specific
diagnoses was necessarily healthy at discharge; therefore, the
data from this trial were excluded. Neonatal morbidity data
were not collected in the trial of MRC,4 and confirmation
either way has not been obtained for the trial of Ezechi
et al.,10 hence these two trials have also been excluded.
As the outcome of interest was baby healthy when dis-
charged from hospital, for the trials where it was certain or
there was a possibility that follow up continued after
discharge (Rust et al.),12 we made the assumption that any
neonatal morbidity recorded first occurred prior to discharge
from hospital.
The analysis was two-fold: first, a composite outcome was
analysed, the event of interest being defined as not suffering
from any of the following: miscarriage, stillbirth, neonatal
death before discharge from hospital or some pathology
recorded. As well as making sense clinically, this approach
ensured our analysis included all women randomised, thus
the balance achieved from randomisation was preserved. Sec-
ond, an analysis was undertaken where all miscarriages, still-
births and neonatal deaths prior to discharge were omitted.
Hence, in this second analysis, only babies still alive at dis-
charge were included and so enabled conclusions to be drawn
relating to neonatal morbidity conditional on survival.
Standardisation of maternal morbidity andother outcomes across trialsThe maternal morbidity outcomes of pyrexia and chorio-
amnionitis were analysed. Preterm prelabour rupture of
membranes (PPROM), spontaneous labour and need for
induction or a planned caesarean were also examined. Table 1
summarises the data recorded on these outcomes.
Treatmentcovariate interactionsAs mentioned above, one of the aims of our study was to inves-
tigate whether a womans obstetric history influenced the effect
of cervical cerclage. For this purpose, women were categorised
into one of the following mutually exclusive categories:
1 No previous PTD or second-trimester loss (STL) and no
previous cervical surgery.
2 One previous PTD or STL and no previous cervical surgery.
3 Two previous PTDs or STLs and no previous cervical surgery.
4 Three or more previous PTDs or STLs and no previous
cervical surgery.
5 Previous cervical surgery.
These categories were chosen to reflect the subgroup analy-
ses undertaken in the MRC trial4 since this trial had found
a significant treatment effect (P < 0.05) on the outcome of
PTD before 33 weeks of gestation in a subgroup of women
with no previous cervical surgery but with three or more
previous PTDs or STLs.
It was possible to undertake this categorisation in five4,8,1113
out of the seven included trials. For the trial of Ezechi et al.,10
cervical surgery history was not recorded and the numbers of
previous PTDs or STLs were not recorded separately in the
database available from the trial of Berghella et al.9 Hence,
these two trials were excluded from the analyses of interaction
between obstetric history and cerclage.
We were also interested in investigating whether a womans
cervical length influenced the effect of cerclage, and this was
possible again for five8,9,1113 of the seven included trials.
Statistical analysisA study protocol6 and detailed statistical analysis plan (avail-
able on request from first author) were prepared in advance.
All analyses were conducted according to the analysis plan,
and the intention-to-treat principle was applied as far as
possible.
Clinical heterogeneity was assessed by reviewing differences
across trials in characteristics of randomised women. Statis-
tical heterogeneity was assessed using forest plots, the I2 sta-
tistic and chi-square test as set out in the analysis plan. The I2
statistic estimates the proportion of total variability in effect
estimates that can be explained by heterogeneity. Pooled odds
ratios were calculated using Petos method.15 Since the trials
could be partitioned into two distinct groups with respect to
what the main indication was for intervention of cerclage
(either short cervix on ultrasound or obstetric history),
meta-regression incorporating a trial-level covariate repre-
senting main indication was also undertaken to investigate
whether this accounted for any observed heterogeneity.
To examine the impact that a womans obstetric history
and cervical length may have on the effect of cerclage, in
addition to accounting for some of the observed heterogene-
ity, regression models were built stratified by trial. These were
two-level logistic regression models16 as explained in greater
detail in the analysis plan, and the models were fitted using
version 2.02 of the MLwiN software package for multilevel
modelling. In summary, the models included a fixed-effects
indicator variable for each trial to account for any trial-
specific characteristics. An indicator variable was also included
to represent treatment group; however, this was a random-
effects variable since it is assumed that treatment effect will be
similar, although not identical, across trials. Fixed-effect indi-
cator variables to represent both treatmentobstetric history
and treatmentcervical length interaction effects were also
introduced to the models to examine the impact of these
two obstetric factors on treatment effect. To assess the effect
Jorgensen et al.
1464 2007 The Authors Journal compilation RCOG 2007 BJOG An International Journal of Obstetrics and Gynaecology
-
of a variable on outcome, models both with and without that
variable were compared using the likelihood ratio test.
Where IPD were not available, the reason was assessed for
the potential of bias. Results using aggregate data from these
trials were then compared with results using aggregate data
from trials where IPD had been supplied. The analysis plan
was reviewed in light of the availability of IPD but prior to any
comparative analyses.
Multiple pregnanciesTwin or triplet pregnancies have been excluded from the main
analyses because: (a) the prognosis for PTD and associated
health problems is considered to be different among twins/
triplets and (b) outcomes for such babies are not deemed to
be independent of one another. However, to investigate the
impact of multiple gestation on treatment effect for neonatal
outcomes, data on all babies (from singleton, twin and triplet
pregnancies) were used to fit three-level logistic regression
models. These models included treatment effect assumed to
be random at both the trial and the mothers level, a binary
covariate representing multiple gestation and also a treat-
mentmultiple gestation interaction term. Similar models
but these times limited to two levels with treatment assumed
random only at the trial level were also fitted to assess the
impact of multiple gestation on maternal outcomes. For each
outcome, a Wald test to assess the statistical significance of
including the interaction term was undertaken to assess
whether the effect of cerclage on outcome is indeed different
in multiple pregnancies.
Data for multiple gestation were available for 66 mothers
and 138 babies (Berghella et al.9: 4 twin pregnancies, MRC4:
28 twin pregnancies, Rust et al.12: 28 twin pregnancies and
6 triplet pregnancies).
Women entered into the trials more than onceIt was apparent that women were entered more than once into
two trials (Rust et al.12: three women entered twice, MRC4:
exact number entered more than once unknown), and there
was a possibility that some women in the trial of Rush et al.11
were also entered more than once. No woman was entered
more than once into the trials of To et al.,13 Berghella et al.9
and Althuisius et al.,8 and we have not obtained confirmation
either way regarding the trial of Ezechi et al.10 Since it was not
always clear which women were entered more than once, we
have assumed that all pregnancies are independent regardless
of the fact that in some instances the same woman contrib-
uted with more than one pregnancy.
Results
Description of studiesThe search identified 17 potential trials, and overall agree-
ment between reviewers on eligibility was good. There was
some debate between reviewers regarding the eligibility of the
trial of Kassanos et al.17 However, since women randomised
to the no cerclage group in this trial were initially followed
up weekly with vaginal ultrasonograms with the possibility of
cerclage if a short cervix was found, it was decided that these
control women were not comparable with those in other
included trials, and the trial was excluded on this basis.
In total, nine trials were identified as being eligible for
inclusion, all published. Table 2 describes these trials and
summarises the results of assessing their methodological qual-
ity. For the trials where randomisation procedure was explic-
itly clarified,4,8,9,1113,19 the methods described were robust,
although for the majority of these trials we did not have
sufficient information to check that the methods had been
applied correctly. On inspecting key baseline characteristics
(Table 3), however, these appeared well balanced between the
two treatment groups for all trials. Due to the nature of the
intervention, it was not possible to blind patients or clinicians
to treatment for any of the trials.
Although the cerclage intervention varied with seven trials
using a McDonald type suture,812,18,19 one trial using a
Shirodkar type13 and one trial using a combination of more
than one type of suture4 undertaking a meta-analysis was
deemed appropriate. For two of the eligible trials, the authors
subsequently confirmed that IPD were no longer available,
and hence these trials have been excluded from our IPD
analyses (Lazar et al.,19 Dor et al.18).
Of the seven trials for which IPD were available, the main
indication for cerclage was the detection of short cervix on
ultrasound in four trials (Althuisius et al.,8 Berghella et al.,9
Rust et al.12 and To et al.13) and obstetric history in the
remaining three trials (Ezechi et al.,10 MRC4 and Rush
et al.11) For ease of interpretation, the forest plots have been
ordered such that the four trials where main indication was
ultrasound appear at the top, with the remaining three trials
appearing at the bottom.
Details of the eight excluded trials can be seen in the Quorum
diagram, Figure 1. A further three trials have been identi-
fied as continuing and therefore have not been included in
this analysis (Shennan A., pers. comm.; CIRCLE trial;26 Owen,
www.clinicaltrials.gov/;27 Silver, www.enh.org/).28
Baseline characteristicsA summary of baseline characteristics for the two treatment
groups in each trial can be seen in Table 3. Generally, most
characteristics were well balanced between the two interven-
tion groups within trials, and any small imbalances observed,
as well as those between trials, were given consideration when
accounting for any observed statistical heterogeneity.
Replicating published results from IPDThe IPD analysis replicated the published data by Althuisius
et al.,8 Berghella et al.,9 MRC4 and To et al.13 For the trial of
Cervical cerclage for preventing pregnancy loss
2007 The Authors Journal compilation RCOG 2007 BJOG An International Journal of Obstetrics and Gynaecology 1465
-
Table
2.Characteristicsofincluded
studies
Study
Randomisation
procedure/allocation
concealm
ent
Resultsofchecking
randomisation
procedure
Blinding?
Follow
upafter
hospital
discharge?
Location
ofstudy
Inclusioncriteria
Intervention
Primary
outcomes
Althuisiuset
al.8
Balan
cedblocks
stratified
fordifferent
inclusioncriteriaan
d
twoparticipating
hospitals.Allocation
bytelephone
Notpossibledate
ofrandomisation/
randomisation
number
not
provided
No
No
TheNetherlands
Singletonpregnan
cies;
considered
athigh
risk
ofPTDbecau
se
cervicallength
,25mm
before
27
weeks
ofgestation
McD
onaldtype
suture
with
bed
restvs
bed
restalone
PTD,34weeks
ofgestation;
neo
natalsurvival;
neo
natalmorbidity
Berghellaet
al.9
Computer-gen
erated
balan
cedblocks.
Allocationby
sequen
tially
numbered
opaq
ue,
sealed
envelopes
Firstblock
imbalan
ced.Authors
confirm
edan
overlookederror
No
No
USA
Either
athigh
risk
ofPTDbased
onpreviousobstetric
history
andiden
tified
duringultrasound
screen
ingbetween14
and23weeks
6days
ofgestationas
having
funnellingorashort
cervix;orat
low
risk
butfoundinciden
tally
tohaveshortcervix
McD
onaldtype
suture
with
bed
restvs
bed
restalone
Preterm
birth
,35weeks
Ezechietal.10
Notstated
Notpossibledate
ofrandomisation/
randomisation
number
not
provided
No
Notstated
Nigeria
One1
previousPTD
McD
onaldstype
suture
vsno
interven
tion
Gestational
ageat
delivery;PTD
MRC4
Balan
cedblocks
gen
erated
by
randomisation
service.
Allocation
bytelephoneorpost
Notpossible
tocheck
No
No
UK,Fran
ce,
Hungary,Norw
ay,
Italy,Belgium,
Zimbab
we,
South
Africa,
Icelan
d,
Irelan
d,Netherlands
andCan
ada
Obstetrician
uncertainwhether
ornotto
use
cervical
cerclagebecau
seof
previous:tw
oormore
second-trimester
miscarriages/PTD
s,
cervicalsurgery,
term
inationof
pregnan
cyorfirst-
trim
estermiscarriage;
orcurren
tcervical/
uterineab
norm
ality;
or
twin
pregnan
cies
Suture
vs
controlled
man
agem
ent.
More
than
one
typeofsuture
was
used
Length
of
pregnan
cy;vital
statusofbab
y
followingdelivery
(continued
)
Jorgensen et al.
1466 2007 The Authors Journal compilation RCOG 2007 BJOG An International Journal of Obstetrics and Gynaecology
-
Table
2.(Continued
)
Study
Randomisation
procedure/allocation
concealm
ent
Resultsofchecking
randomisation
procedure
Blinding?
Follow
upafter
hospital
discharge?
Location
ofstudy
Inclusioncriteria
Intervention
Primary
outcomes
Rush
etal.11
Computer-gen
erated
random
allocation.
Allocationin
opaq
ue,
sealed
envelopes
open
ed
byclinician
Notpossibledate
ofrandomisation/
randomisation
number
not
provided
No
Notstated
South
Africa
Two,three
orfourprevious
pregnan
cies
ended
spontaneo
usly
before
37weeks
aswellasoneormore
previous
pregnan
cyen
ded
spontaneo
usly
between14an
d36
weeks
ofgestation
McD
onaldtype
suture
vsno
suture
Gestationalag
e
atdelivery;
deliverybefore
37weeks
Rustet
al.12
Computer-gen
erated
random
allocation.
Allocationin
opaq
ueen
velopes
open
edat
patients
bed
side
Notpossibledate
ofrandomisation/
randomisation
number
not
provided
No
Yes
insome
cases
USA
Dem
onstrable
dilationofinternal
osan
deither
prolapse
of
mem
branes
of
.25%
total
cervicallength
or
distalcervicallength
of,2.5
cmbetween
16an
d24weeks
ofgestation
McD
onaldtype
suture
vsno
interven
tion
Gestational
ageat
delivery,
neo
natal
morbidity
Toet
al.13
Balan
cedblocks
stratified
bycentre.
Allocationby
telephone
Notpossible
randomisation
number
not
provided
No
No
UK,Brazil,
South
Africa,
Slovenia,Greece
andChile
Singletonpregnan
cies;
cervicallength
of
15mm
orless
atbetween
22weeks
and
24weeks
6days
Shirodkarsuture
vsexpectant
man
agem
ent
Deliverybefore
33weeks
Doret
al.18
Notstated
Notpossible
tocheck
No
Notspecified
Israel
Conceptionafter
inductionofovulation;
twin
pregnan
cies
McD
onaldtype
suture
vsno
suture
Durationof
pregnan
cy
Lazaret
al.19
Ran
domisation
procedure
not
stated
.Allocation
byway
ofsealed
envelopes
Notpossible
tocheck
No
Notspecified
Fran
ceScore
based
onobstetrichistory,
previouscervicalsurgery
history
andother
cervicalfactorsiswithin
aprespecified
range
McD
onaldtype
suture
vsno
suture
Obstetric
man
agem
ent;
durationof
pregnan
cy
Cervical cerclage for preventing pregnancy loss
2007 The Authors Journal compilation RCOG 2007 BJOG An International Journal of Obstetrics and Gynaecology 1467
-
Table
3.Comparingbaselinecharacteristicsacross
trials
Althuisiusetal.8
Berghellaetal.9
Ezechietal.10
MRC4
Rush
etal.11
Rust
etal.12
Toetal.13
Cerclage
Nocerclage
Cerclage
Nocerclage
Cerclage
Nocerclage
Cerclage
Nocerclage
Cerclage
Nocerclage
Cerclage
Nocerclage
Cerclage
Nocerclage
Treatm
ent
allocated
19(54%)
16(46%)
28(49%)
29(51%)
39(48%)
42(52%)
635(50%)
629(50%)
96(49%)
98(51%)
104(50%)
103(50%)
127(50%)
126(50%)
Compliantwith
treatm
ent
allocated:yes
19(100%)
14(88%)
27(87%)
28(93%)
Notstated
Notstated
586(92%)
581(92%)
95(99%)
97(99%)
104(100%)
103(100%)
122(96%)
124(98%)
Bed
rest:yes
19(100%)
16(100%)
28(100%)
29(100%)
Notstated
Notstated
227(36%)
(21missing)
168(27%)
(24missing)
9(9%)
3(3%)
104(100%)
103(100%)
0(0%)
0(0%)
Previous
cerclage:
yes
4(21%)
2(13%)
Notstated
Notstated
Notstated
Notstated
134(21%)
(1missing)
116(19%)
(2missing)
0(0%)
0(0%)
Notstated
Notstated
2(2%)
2(2%)
Previouscervical
surgery:yes
3(16%)
2(13%)
3(11%)
2(7%)
Notstated
Notstated
193(30%)
179(28%)
0(0%)
0(0%)
16(15%)
25(24%)
7(6%)
9(7%)
Funnelling:yes
10(53%)
11(69%)
Notstated
Notstated
Notstated
Notstated
Notstated
Notstated
Notstated
Notstated
Notstated
Notstated
121(95%)
117(93%)
Ethnicorigin:
Non-Cau
casian
:
yes
9(47%)
8(50%)
25(89%)
23(79%)
Notstated
Notstated
Notstated
Notstated
96(100%)
98(100%)
35(34%)
31(30%)
68(54%)
78(62%)
Smoker:yes
2(11%)
0(0%)
9(32%)
8(28%)
Notstated
Notstated
Notstated
Notstated
Notstated
Notstated
24(25%)
(7missing)
25(26%)
(7missing)
10(8%)
17(13%)
Fetalfi
bronectin:
yes
Notstated
Notstated
Notstated
Notstated
Notstated
Notstated
Notstated
Notstated
Notstated
Notstated
29(28%)
31(30%)
7(6%)
(1missing)
8(6%)
Bacterialvaginosis:
yes
6(32%)
4(25%)
Notstated
Notstated
Notstated
Notstated
Notstated
Notstated
Notstated
Notstated
19(18%)
20(19%)
13(10%)
(2missing)
12(10%)
(2missing)
Chlamydia:yes
Notstated
Notstated
Notstated
Notstated
Notstated
Notstated
Notstated
Notstated
Notstated
Notstated
1(1%)
1(1%)
Notstated
Notstated
Bishopscore
.4:yes
Notstated
Notstated
Notstated
Notstated
12(31%)
10(24%)
Notstated
Notstated
Notstated
Notstated
Notstated
Notstated
Notstated
Notstated
Meanag
eat
randomisation
(SD)
30.53(4.57)34.50(4.93)
27.81(6.4)
29.93(6.85)24.56(4.81)25.79(4.81)
27.69(5.07)
27.72(4.98)
Notstated
Notstated
28.03(6.10)
28.88(6.79)
29.85
(6.06)
29.30(5.90)
Meangestational
ageat
cerclage
procedure
(SD)
20.95(2.93)
N/A
Notstated
N/A
Notstated
N/A
Notstated
N/A
20.00.(1.41)
N/A
20.67(2.12)
N/A
23.85
(0.71)
N/A
Meancervical
length
(SD)
19.90(2.87)19.56(4.29)15.69(9.20)16.67(8.01)
Notstated
Notstated
Notstated
Notstated
16.47(3.71)18.42(2.92)
16.11(7.72)
17.59(6.24)
9.60(3.46)
9.33(3.57)
MeanBMI(SD
)Notstated
Notstated
Notstated
Notstated
Notstated
Notstated
Notstated
Notstated
Notstated
Notstated
Notstated
Notstated
26.45(5.49)
25.96(5.60)
Meangestational
ageat
entry(SD)
Notstated
Notstated
19.61(2.40)
19.03(2.2)
Notstated
Notstated
14.63(4.83)
14.89(5.10)
17.56(3.59)14.87(5.14)
20.67(2.12)
21.15(2.25)
23.52(0.69)
23.49(0.73)
Prim
igravida:
yes
10(53%)
9(56%)
7(23%)
12(40%)
0(0%)
0(0%)
Notstated
Notstated
0(0%)
0(0%)
14(13%)
13(13%)
32(25%)
33(26%)
(continued
)
Jorgensen et al.
1468 2007 The Authors Journal compilation RCOG 2007 BJOG An International Journal of Obstetrics and Gynaecology
-
Ezechi et al.,10 the numbers randomised to the cerclage and
no cerclage groups have been reported in the paper as 38 and
43, respectively, whereas in the IPD, the corresponding num-
bers in each group are 39 and 42 and the data have been
analysed as such. The IPD obtained for the trial of Rush
et al.11 were handwritten in pencil and, due to its age, some-
times difficult to read. It was, therefore, not possible to rep-
licate published results for some of the variables. Data on
Table
3.(Continued
)
Althuisiusetal.8
Berghellaetal.9
Ezechietal.10
MRC4
Rush
etal.11
Rust
etal.12
Toetal.13
Cerclage
Nocerclage
Cerclage
Nocerclage
Cerclage
Nocerclage
Cerclage
Nocerclage
Cerclage
Nocerclage
Cerclage
Nocerclage
Cerclage
Nocerclage
Previousdelivery
atgreater
than
37
weeks:yes
8(42%)
3(19%)
Notstated
Notstated
Notstated
Notstated
Notstated
Notstated
44(46%)
37(38%)
40(38%)
34(33%)
57(45%)
49(39%)
PreviousSTL:yes
Notstated
Notstated
15(54%)
13(45%)
Notstated
Notstated
285(45%)
(1missing)
260(41%)
(2missing)
78(81%)
79(81%)
33(32%)
19(18%)
Notstated
Notstated
Previousearly
spontaneo
us
loss:yes
4(21%)
5(31%)
20(71%)
20(69%)
Notstated
Notstated
201(32%)
(1missing)
193(31%)
(2missing)
47(49%)
61(62%)
40(38%)
42(41%)
54(43%)
61(48%)
(2missing)
PreviousPTD:yes
Notstated
Notstated
19(68%)
16(55%)
39(100%)
42(100%)
277(44%)
(1missing)
258(41%)
(2missing)
40(42%)
32(33%)
Notstated
Notstated
69(54%)
76(61%)
BMI,bodymassindex.
Potentially eligible studies identified bysearches (duplicates removed) n = 17
Studies excluded sincecomparison of cerclagetechnique only (n =1)
(Caspi et al.22)
Studies excluded sincewomen already included in
another of the included trials(n = 2) (Szeverenyi et al,24
Althuisius et al.20)
Studies retrieved (n =16)
Studies excluded sincecomparison of cerclage vs
pessary (n = 1)(Foster et al.23)
Studies retrieved (n = 15)
Studies retrieved (n = 13)
Studies excluded sincewomen not randomised
(n = 1) ) (Varma T.R., pers.comm.)
Studies retrieved (n = 12)
Studies excluded sincecontrol group
subsequently received elective cerclage (n = 2) )(Kassanos et al.17, Beigi
and Zarrinkoub25)
Studies retrieved (n = 10)
Studies excluded sincecomparison of inpatient vsoutpatient cerclage (n =1)
(Blair et al.21)
Studies included in the review (n = 9)
Figure 1. Quorum diagram.
Cervical cerclage for preventing pregnancy loss
2007 The Authors Journal compilation RCOG 2007 BJOG An International Journal of Obstetrics and Gynaecology 1469
-
such variables have been excluded from the analyses, with the
exception of maternal pyrexia and PPROM for which there
were very small discrepancies (Table 1). We did not attempt
to replicate the results for the trial of Rust et al.12 since the
most recent paper published included only a subset of the
women available for IPD.
Pregnancy loss or death before dischargefrom hospitalSingleton pregnancies onlyThe trial-specific odds ratios, together with the pooled odds
ratio and corresponding 95% CI are displayed in Figure 2.
These figures suggest little heterogeneity in treatment effect
across trials. The result of the meta-regression, introducing
a covariate representing main indication for cerclage (obstet-
ric history versus short cervical length) was not statistically
significant (P = 061).Introducing interaction terms between treatment and
obstetric history in a two-level logistic regression model did
not have a significant effect. The same applies for a treatment
cervical length interaction term (Table 4).
Multiple gestationsIncluding a treatmentmultiple gestation interaction effect in
a three-level logistic regression model including data on all
babies gave a significant result (Table 4), suggesting that cerc-
lage has a detrimental effect on the outcome for such babies.
Calculating risk scores (data not shown) for babies grouped
into four categories depending on both singleton/multiple
pregnancy status and cerclage/no cerclage status demon-
strated that using cerclage in singleton pregnancies decreased
the risk of pregnancy loss or death before discharge from
hospital but that using cerclage in multiple pregnancies
increased the risk substantially.
Absence of neonatal morbiditySingleton pregnancies onlyThe trial-specific odds ratios, together with the pooled odds
ratios and corresponding 95% CI for the two analyses are
displayed in Figure 3. It should be noted, however, that three
trials, representing 66% of randomised women, were ex-
cluded from the analysis of this outcome. These figures sug-
gested no heterogeneity in treatment effect across trials.
Introducing a covariate representing indication for cerclage
in a meta-regression did not have a statistically significant
effect (P value including all babies: 064; P value excludingbabies not alive at discharge: 044).
When fitting two-level logistic regression models, intro-
ducing a treatmentobstetric history term did not have a sta-
tistically significant effect (Table 4). The same applied for
a treatmentcervical length interaction (Table 4).
Multiple gestationsIncluding a treatmentmultiple gestation interaction effect in
a three-level logistic regression model gave a significant result
(Table 4) for the analysis including all babies and this suggests
that cerclage has a detrimental effect on this outcome for
such babies.
Calculating risk scores (data not shown) for babies grouped
into four categories depending on both singleton/multiple
pregnancy status and cerclage/no cerclage status demon-
strated that using cerclage in singleton pregnancies increased
the likelihood of a baby being healthy at discharge but that
using cerclage in multiple pregnancies decreased the likelihood
Figure 2. Forest plot comparing cerclage with no cerclage for outcome of pregnancy loss of death before discharge from hospital.
Jorgensen et al.
1470 2007 The Authors Journal compilation RCOG 2007 BJOG An International Journal of Obstetrics and Gynaecology
-
substantially. However, the test for an interaction was non-
significant (Table 4) when excluding babies not alive at dis-
charge from the analysis.
Maternal morbiditySingleton pregnancies onlyThe trial-specific odds ratios, together with the pooled odds
ratio and corresponding 95% CI for each outcome are dis-
played in Figure 4. These figures suggested that there was sig-
nificant heterogeneity in treatment effect for the outcomes of
chorioamnionitis and PPROM. On inspecting the forest plots
for these outcomes, treatment effect in the trial of Althuisius
et al.8 is noticeably different to the other trials; however, there
is no immediately apparent reason for this difference.
In a meta-regression model, indication for cerclage did not
have a statistically significant effect for any of the outcomes
(P value 0.36 or greater for all outcomes).
Finally, introducing treatmentobstetric history terms to
a logistic regression model did not have a significant effect
on any of the outcomes (Table 4), with similar nonsignificant
results for a treatmentcervical length interaction (Table 4).
Multiple gestationsThe results from including a treatmentmultiple gestation
interaction term in a two-level logistic regression model are
summarised in Table 4. There was insufficient data on mul-
tiple pregnancies for which the outcome of pyrexia had been
measured to undertake the test for this outcome.
Preterm birthWe were interested in investigating the effect of cervical
cerclage on the timing of preterm births. For cutoffs
between 16 and 37 weeks of gestation, pooled odds ratios
were calculated. An increased confidence level of 99% was
used to calculate the intervals for these multiple pooled
odds ratios (Figure 5). The effect estimates favoured no
cerclage for the earlier cutoff points and cerclage for the
later cutoffs, although the results do not reach statistical
significance.
Statistical significance of the impact of obstetric history and
cervical length on treatment effect for the outcome of preterm
births before all these cutoffs was also assessed by way of
logistic regression models. Neither of these two factors was
Table 4. Results from undertaking logistic regressions
Outcome Treatmentobstetric
history interaction*
Treatmentcervical
length interaction**
Treatmentmultiple gestation interaction
P value P value OR (95% CI) P value
Pregnancy loss
or death before
discharge from hospital
0.92 0.78 588 (1143019)*** 0.03***
Baby healthy
at discharge from
hospital (all babies)
0.69 0.71 012 (002089)*** 0.04***
Baby healthy
at discharge from
hospital
(babies alive at discharge only)
0.69 0.37 0.54 (0.070.48)*** 0.56***
Spontaneous labour 0.83 0.19 108 (022544)**** 0.92****Pyrexia 0.56 0.8 Insufficient data available
Chorioamnionitis 0.6 0.96 365 (0472817)**** 0.21****PPROM 0.44 0.32 157 (034728)**** 0.56****Need for induction/caesarean section 0.68 0.08 0.74 (016342)**** 0.70****
*The P values here are those obtained from undertaking a likelihood ratio test comparing a logistic regression model including treatmentobstetric
history interaction terms to a model without the interaction terms.
**The P values here are those obtained from undertaking a likelihood ratio test comparing a logistic regression model including treatmentcervical
length interaction term to a model without the interaction term.
***The odds ratios here are those obtained from fitting a multilevel logistic regression model with trial as the first level, woman as the second
level and baby as the third level. The model includes indicator variables to represent both treatment group (random effect) and multiple gestation
status (fixed effect) and also a treatmentmultiple gestation interaction variable. The P values are those obtained from undertaking a likelihood
ratio test to compare a model with the interaction variable to one without.
****The odds ratios here are those obtained from fitting a multilevel logistic regression model with trial as the first level and woman as the
second level. The model includes indicator variables to represent both treatment group (random effect) and multiple gestation status (fixed effect)
and also a treatmentmultiple gestation interaction variable. The P values are those obtained from undertaking a likelihood ratio test to compare
a model with the interaction variable to one without.
Cervical cerclage for preventing pregnancy loss
2007 The Authors Journal compilation RCOG 2007 BJOG An International Journal of Obstetrics and Gynaecology 1471
-
found to be statistically significant at the 1% level for any of
the gestational age cutoffs investigated.
There was not enough data on women in multiple preg-
nancies delivering before each gestational age cutoff to inves-
tigate the effect of multiple gestation on treatment effect for
this outcome (results not shown).
Comment on studies for which IPD werenot obtainedTwo studies were eligible for inclusion in this meta-analysis for
which the authors confirmed that IPD were no longer available
(Dor et al.18 and Lazar et al.19). The trial of Dor et al.18 included
women with twin pregnancies only and so these women would
not have formed part of our main analysis even if IPD had been
available. For the trial of Lazar et al.,19 the aggregate results for
the outcomes of induced labour or caesarean section, pre-
term delivery before 32 weeks of gestation, preterm delivery
before 36 weeks of gestation and preterm delivery before 37
weeks of gestation were all obtainable from the published
paper and therefore for these four outcomes a comparison
was made between pooled results both excluding and including
the aggregate results from this trial. The results were found to
be almost identical (results not shown).
Discussion
There continues to be considerable controversy about the value
of cervical cerclage in the management of women considered to
be at high risk of PTD. Our IPD review included trials where
main indication for cerclage was based on obstetric history, as
well as trials where the main indication was short cervical
length detected by ultrasound. The availability of IPD enabled
us to standardise outcome definitions across trials, which led to
an increase in the number of women contributing to each
outcome, and hence more precise effect estimates.
Although the overall results suggest that, in singleton preg-
nancies, cervical cerclage may reduce the risk of pregnancy
loss or death before discharge from hospital (OR 0.81), this
result did not reach statistical significance at the 5% level. The
true effect on the outcome of pregnancy loss or death before
discharge from hospital could range from a reduction in odds
of up to 40% in favour of cervical cerclage to an increase in
10% against the intervention. We believe that this trend
towards treatment benefit warrants further study. The confi-
dence intervals for the absence of neonatal morbidity were
much wider since only three trials collected sufficient infor-
mation on this outcome.
Figure 3. Forest plots comparing cerclage with no cerclage for outcome of (A) baby healthy when discharged from hospital (all babies); (B) baby healthy
when discharged from hospital (excluding babies not alive at discharge).
Jorgensen et al.
1472 2007 The Authors Journal compilation RCOG 2007 BJOG An International Journal of Obstetrics and Gynaecology
-
In terms of maternal morbidity, a statistically significant
increased risk of maternal pyrexia was observed in the cerc-
lage group. It was decided following publication of the pro-
tocol,6 but prior to analysis, that onset of labour was also of
interest since we wished to test the hypothesis that cervical
cerclage could damage the cervix and prevent spontaneous
labour or indeed cause morbidity that would force induction
or caesarean section. There was no significant evidence that
the likelihood of induction or caesarean section was higher in
the cerclage group. The data were quite limited because there
have been some difficulties in classifying women in terms of
this outcome for many of the trials (Table 1).
It is important to note that, although the trials included in
the review contributed data from over 2000 women in total,
the outcomes and covariates of interest were not recorded for
all women.
A previously published meta-analysis5 suggested that the
intervention of cervical cerclage in women with twin preg-
nancies increased the risk of preterm birth before 35 weeks of
gestation, although the number of women for which data was
available was small. Our analysis suggested that cerclage has
a detrimental effect on the outcome of pregnancy loss or
death before discharge from hospital and our composite
outcome of a baby being healthy at discharge, for multiple
Figure 4. Forest plots comparing cerclage with no cerclage for outcomes of maternal morbidity.
Cervical cerclage for preventing pregnancy loss
2007 The Authors Journal compilation RCOG 2007 BJOG An International Journal of Obstetrics and Gynaecology 1473
-
gestations. These results must be interpreted with caution
due to the relatively small number of women with a multiple
gestation for which data were available.
The focus in studies to date has been on investigating
whether cervical cerclage has the ability to prevent preterm
birth. However, increasing gestational age at delivery does not
necessarily mean an improvement in the babys outcome. For
example, a baby delivered at 35 weeks of gestation may not
necessarily fare better than a baby delivered a few weeks earlier
if spontaneous delivery was artificially delayed. Care should
always be taken to ensure that the gestational age of preterm
birth is not mistaken as a surrogate outcome for pregnancy
loss or death before discharge from hospital/neonatal mor-
bidity. It is for this reason that we chose pregnancy loss or
death before discharge from hospital and neonatal morbidity
as our primary focus. However, the timing of PTD is impor-
tant in its own right for the purpose of investigating other
hypotheses of interest relating to the use of cervical cerclage.
These hypotheses are as follows:
1 That cervical cerclage delays delivery only for a short period
of time.
2 That cervical cerclage is only effective in improving neo-
natal outcome where the risk of preterm birth is during
a specific time interval.
We undertook an exploratory analysis to investigate
whether the effect of cerclage varied according to gestational
age. On inspecting the point estimates for effect, there was
a suggestion of a change from favouring no cerclage to
favouring cerclage at around the 21-week cutoff point,
although the results did not reach statistical significance.
Due to the small number of events occurring at earlier ges-
tations, the confidence intervals are very wide. The analysis
was limited further by the fact that some women were not
recruited until they had reached a gestational age greater than
some of the earlier cutoff points, which meant that they had
to be excluded from the analysis of those cutoffs. Excluding
such women meant that the balance achieved from random-
isation was potentially disrupted. For these reasons, our
results must be treated with caution.
There is also a possibility that the stage of pregnancy at
which the cervical cerclage is administered may play a part in
how effective it will be. Indeed, the intervention may some-
times occur too late during the pregnancy to have any effect.
Gestational age of the cerclage procedure was recorded for
women in four trials.8,1113 We used these data to investigate
whether there was any association between gestational age
of the procedure and the outcome of pregnancy loss or
neonatal death before discharge from hospital by fitting
Figure 4. Continued from previous page.
Jorgensen et al.
1474 2007 The Authors Journal compilation RCOG 2007 BJOG An International Journal of Obstetrics and Gynaecology
-
a two-level logistic regression. No significant association was
found (P = 0.26).
Neither obstetric history nor cervical length was found to
have a significant impact on the effect of cerclage on PTD.
Our five obstetric history categories were purposefully chosen
to reflect the subgroup analyses undertaken in the MRC
trial4 since this trial had found a significant treatment effect
(P < 0.05) on the outcome of PTD before 33 weeks of gesta-
tion in a subgroup of women with no previous cervical sur-
gery but three or more previous PTDs or STLs. This result was
not confirmed in our analysis.
Similar analyses looking at the impact of obstetric history
and cervical length on cerclage effect were also undertaken for
the outcomes of pregnancy loss or death before discharge
from hospital, neonatal morbidity and maternal morbidity,
but no significant results were found.
We also found no evidence that the effect of cerclage in
trials where the main indication was short cervical length on
ultrasound was different from the effect in trials where indi-
cation was based on obstetric history alone.
Although it was apparent that some women were entered
into the trials of Rust et al.,12 Rush et al.11 and MRC4 more
than once, it was not always possible to identify them. For the
purpose of this review, it is therefore assumed that pregnancy
outcomes for the same woman are independent, although this
may have introduced a small amount of over-precision into
the results.
Implications for practice
Although the results for the outcome of pregnancy loss or
death before discharge from hospital in singleton pregnancies
appears promising, further research is required before any
conclusive advice can be provided with regard to the benefits
of using cervical cerclage to improve neonatal outcome.
Women should be advised of the increased risk of maternal
pyrexia and treated accordingly. Cerclage in multiple preg-
nancies should be avoided.
Implications for research
There is an urgent need for further large trials to elucidate the
risk-benefit ratio in singleton pregnancies with precision and
to identify groups most likely to benefit.
Conflicts of interest
Z.A. and P.R.W. were authors of a paper that is included in
the IPD meta-analysis.13 Z.A. was an author of the non-IPD
systematic review on this topic.1 The authors declare that they
do not have any other competing interests.
Contribution to authorship
A.L.J. organised, cleaned and checked the individual patient
data sets, contacted the authors with queries, wrote the sta-
tistical analysis plan, performed data validation checks and
statistical analyses and co-wrote the review.
Z.A. assessed eligibility and methodological quality of
trials, liaised with individual trialists, provided clinical guid-
ance and provided comments on the manuscript.
C.T.S. prepared the protocol, assessed eligibility and
methodological quality of the trials and provided comments
on the manuscript.
P.R.W. conceived the idea for undertaking the IPD meta-
analysis, supervised A.L.J. on all aspects of the review, pro-
vided advice on the statistical analysis plan and the statistical
analyses and provided comments on the manuscript.
Cerclage IPD meta-analysis group membersA.L. Jorgensen (Liverpool); Z. Alfirvec (Liverpool); C. Tudur
Smith (Liverpool); P.R. Williamson (Liverpool); S.M.
Althulsivus (William Harvey Hospital, Kent); V. Berghella
(Thomas Jefferson University, Philadelphia; O.C. Ezechi
(Nigerian Institute of Medical Research); MRC/RCOG work-
ing party; R.W. Rush (previously from University of Cape
Town); O.A. Rust (Lehigh Valley Hospital and Health Net-
work, Pennsylvania); M.S.T. (Fetal Medicine Foundation); K.
Nicolaides (Fetal Medicine Foundation).
Acknowledgements
The authors would like to thank the Fetal Medicine Founda-
tion, a registered UK charity, for providing some financial
support for the project and also the cerclage IPD meta-analysis
group for kindly providing the data, responding to the vari-
ous queries raised and providing valuable feedback on the
Figure 5. Odds ratios of preterm delivery comparing cerclage with no
cerclage.
Cervical cerclage for preventing pregnancy loss
2007 The Authors Journal compilation RCOG 2007 BJOG An International Journal of Obstetrics and Gynaecology 1475
-
draft paper. They would also like to thank Adrian Grant
(MRC/RCOG working party) who provided helpful com-
ments on an earlier draft. j
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