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Keywords:

  • Cervical cerclage;
  • cervical stitch;
  • individual patient data meta-analysis;
  • neonatal death;
  • neonatal morbidity;
  • neonatal mortality;
  • preterm delivery;
  • pregnancy loss;
  • randomised clinical trials

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Implications for practice
  8. Implications for research
  9. Conflicts of interest
  10. Contribution to authorship
  11. Acknowledgements
  12. References

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 0.60–1.10). 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 1.14–30.19), 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 mother’s obstetric history.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Implications for practice
  8. Implications for research
  9. Conflicts of interest
  10. Contribution to authorship
  11. Acknowledgements
  12. References

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 including 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 employed in the trials (e.g. varying cutoff points for defining preterm birth) and in the different patient populations studied, 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 individually. 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 consistent definition of outcomes across trials, as well as a more powerful analysis of whether treatment is more or less effective 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 contributing 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 techniques enabled us to not only examine the effect of cervical cerclage in the general population of women at risk of preterm birth but also to investigate the impact that previous obstetric history or cervical length may have on this effect.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Implications for practice
  8. Implications for research
  9. Conflicts of interest
  10. Contribution to authorship
  11. Acknowledgements
  12. References

We undertook an IPD meta-analysis to examine the effect of cerclage on our prespecified neonatal and maternal outcomes.6

Searching

The search methods described in the original Cochrane review1 were adopted and updated to December 2005.

Selection and study characteristics

The types of studies considered for inclusion in the analysis were randomised trials comparing cervical cerclage during pregnancy (Shirodkar technique, McDonald technique, transabdominal 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 alternative allocation or medical record numbers) were excluded.

Data abstraction and validity assessment

Two 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 characteristics 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 followed 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 cervical 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 before discharge from hospital’ outcome across trials

The primary outcome was ‘pregnancy loss or neonatal death before discharge from hospital’. This outcome includes all miscarriages, stillbirths and neonatal deaths before discharge, and the IPD available for each trial were standardised as summarised 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 accordance 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.

Table 1.  Standardising outcome measures across trials
 Althuisius et al.8Berghella et al.9Ezechi et al.10MRC4Rush et al.11Rust et al.12To et al.13
  1. BPD, broncho pulmanary dysplasia; IVH, intraventricular haemorrhage; NEC, nectrotising enterocolitis; NICU, neonatal intensive care unit; RDS, respiratory distress syndrome.

Neonatal mortalityIntrauterine fetal deaths (IUFs) and neonatal deaths were recorded. No incidences of IUFs. Neonatal mortality therefore included any neonatal deathsNeonatal deaths were recorded. This included miscarriages, stillbirths and deaths after birth. We classified as: miscarriages: neonatal deaths at <24 weeks + no NICU; stillbirths: neonatal deaths at ≥24 weeks + no NICU; neonatal deaths: neonatal death + NICUStillbirths only were recorded. Apparent from published paper that total perinatal deaths equal to total stillbirths. We classified as: miscarriages: stillbirth at <24 weeks; stillbirths: stillbirth at ≥24 weeks; neonatal deaths: noneLiveborn, viable; liveborn, dead and stillbirth/abortion were recorded. We classified as: miscarriages: stillbirth/abortion at <24 weeks; stillbirths: stillbirth/abortion at ≥24 weeks; neonatal deaths: liveborn, deadMiscarriages, stillbirths and neonatal deaths all were recorded specifically with same classification as for this meta-analysisPerinatal deaths were recorded. Not possible to classify into subcategories of miscarriages, stillbirths and neonatal deaths but this composite outcome was sufficient for our primary outcomeStillbirths and whether baby was alive at follow up recorded. We classified as: miscarriages: stillbirth at <24 weeks; stillbirths: stillbirth at ≥24 weeks; neonatal death: not a stillbirth and not alive at follow up
Neonatal morbidityNecrotising enterocolitis, RDS, IVH and neonatal sepsis were recorded. Trialists confirmed not necessarily case that baby was healthy at discharge if all these pathologies reported negative. Hence, trial excluded from analysis of this outcomeIVH, RDS, NEC and sepsis were recorded. Trialists confirmed that if all these marked negative, can assume baby was healthy at dischargeNot availableNot recordedAny serious complications of prematurity were recorded, and so if none was recorded, can assume baby was healthy at dischargePerinatal morbidity was recorded in terms of seriousness of complications. Baby counted as healthy at discharge if it did not suffer from any serious complications of prematurityIVH, positive blood cultures, retinopathy of prematurity and BPD were recorded. Trialists confirmed that if all these marked negative, can assume baby was healthy at discharge
Spontaneous labourNot recordedData on indication for delivery were collected. All women marked specifically as ‘spontaneous labour’ were counted as having spontaneous labourUnclear if recorded or notSpontaneous labour status was recorded directly in trialSpontaneous labour status was recorded directly in trialNot recordedType of labour was recorded directly. All women marked as ‘spontaneous’ counted as having spontaneous labour
PyrexiaNot recordedNot recordedUnclear if recorded or notWhether woman had temperature of >38° recorded directlyTemperature of mother recorded. If >38°, we classified as pyrexia. Data does not match published report (one more in each treatment group). Analysis is based on IPD data heldNot recordedWhether mother had fever or not was recorded directly
ChorioamnionitisRecorded directlyNot recordedUnclear if recorded or notRecorded only in cerclage group as adverse event from intervention. As not recorded in control group also data excluded from analysisNot recordedDirectly recordedNot recorded
PPROMRecorded directlyRecorded directlyUnclear if recorded or notRecorded only in cerclage group as adverse event from intervention. As not recorded in control group also data excluded from analysisRecorded directly. The data does not match published report (one less in cerclage group in data than in published report). Analysis is based on IPD heldRecorded directlyRecorded directly
Need for induction and/or need for planned caesareanMethod of delivery was recorded but type of labour not so trial excluded from analysis of this outcomeIndication for delivery and method of delivery were recorded; however, no distinction was made between elective and emergency caesarean section. Therefore, trial excluded from analysis of this outcomeUnclear if recorded or notSpontaneous labour and method of delivery were recorded. Women classed as not having spontaneous labour or having spontaneous labour followed by emergency or elective caesarean classified as ‘yes’ for this analysisSpontaneous labour, induced labour, emergency caesarean and elective caesarean were recorded. Women having either induced labour, emergency caesarean or elective caesarean classified as ‘yes’ for this analysisMethod of delivery was recorded but type of labour not so trial excluded from analysis of this outcomeIndication for delivery and method of delivery were recorded; however, no distinction was made between elective and emergency caesarean section. Therefore, trial excluded from analysis of this outcome

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 pregnancies 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 outcome across trials

Differing 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 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 diagnoses 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 discharged 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. Second, an analysis was undertaken where all miscarriages, stillbirths and neonatal deaths prior to discharge were omitted. Hence, in this second analysis, only babies still alive at discharge were included and so enabled conclusions to be drawn relating to neonatal morbidity conditional on survival.

Standardisation of maternal morbidity and other outcomes across trials

The maternal morbidity outcomes of pyrexia and chorioamnionitis 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.

Treatment–covariate interactions

As mentioned above, one of the aims of our study was to investigate whether a woman’s 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 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 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 five4,8,11–13 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 woman’s cervical length influenced the effect of cerclage, and this was possible again for five8,9,11–13 of the seven included trials.

Statistical analysis

A study protocol6 and detailed statistical analysis plan (available 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. Statistical heterogeneity was assessed using forest plots, the I2 statistic 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 Peto’s 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 representing main indication was also undertaken to investigate whether this accounted for any observed heterogeneity.

To examine the impact that a woman’s obstetric history and cervical length may have on the effect of cerclage, in addition to accounting for some of the observed heterogeneity, 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 indicator variables to represent both treatment–obstetric history and treatment–cervical 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 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 pregnancies

Twin 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 mother’s level, a binary covariate representing multiple gestation and also a treatment–multiple 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 once

It 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 contributed with more than one pregnancy.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Implications for practice
  8. Implications for research
  9. Conflicts of interest
  10. Contribution to authorship
  11. Acknowledgements
  12. References

Description of studies

The search identified 17 potential trials, and overall agreement 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 quality. For the trials where randomisation procedure was explicitly clarified,4,8,9,11–13,19 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.

Table 2.  Characteristics of included studies
StudyRandomisation procedure/allocation concealmentResults of checking randomisation procedureBlinding?Follow up after hospital discharge?Location of studyInclusion criteriaInterventionPrimary outcomes
Althuisius et al.8Balanced blocks stratified for different inclusion criteria and two participating hospitals. Allocation by telephoneNot possible—date of randomisation/randomisation number not providedNoNoThe NetherlandsSingleton pregnancies; considered at high risk of PTD because cervical length <25 mm before 27 weeks of gestationMcDonald type suture with bedrest vs bedrest alonePTD <34 weeks of gestation; neonatal survival; neonatal morbidity
Berghella et al.9Computer-generated balanced blocks. Allocation by sequentially numbered opaque, sealed envelopesFirst block imbalanced. Authors confirmed an overlooked errorNoNoUSAEither at high risk of PTD based on previous obstetric history and identified during ultrasound screening between 14 and 23 weeks 6 days of gestation as having funnelling or a short cervix; or at low risk but found incidentally to have short cervixMcDonald type suture with bedrest vs bedrest alonePreterm birth <35 weeks
Ezechi et al.10Not statedNot possible—date of randomisation/randomisation number not providedNoNot statedNigeriaOne + previous PTDMcDonald’s type suture vs no interventionGestational age at delivery; PTD
MRC4Balanced blocks generated by randomisation service. Allocation by telephone or postNot possible to checkNoNoUK, France, Hungary, Norway, Italy, Belgium, Zimbabwe, South Africa, Iceland, Ireland, Netherlands and CanadaObstetrician uncertain whether or not to use cervical cerclage because of previous: two or more second-trimester miscarriages/PTDs, cervical surgery, termination of pregnancy or first-trimester miscarriage; or current cervical/uterine abnormality; or twin pregnanciesSuture vs controlled management. More than one type of suture was usedLength of pregnancy; vital status of baby following delivery
Rush et al.11Computer-generated random allocation. Allocation in opaque, sealed envelopes opened by clinicianNot possible—date of randomisation/randomisation number not providedNoNot statedSouth AfricaTwo, three or four previous pregnancies ended spontaneously before 37 weeks as well as one or more previous pregnancy ended spontaneously between 14 and 36 weeks of gestationMcDonald type suture vs no sutureGestational age at delivery; delivery before 37 weeks
Rust et al.12Computer-generated random allocation. Allocation in opaque envelopes opened at patients’ bedsideNot possible—date of randomisation/randomisation number not providedNoYes in some casesUSADemonstrable dilation of internal os and either prolapse of membranes of >25% total cervical length or distal cervical length of <2.5 cm between 16 and 24 weeks of gestationMcDonald type suture vs no interventionGestational age at delivery, neonatal morbidity
To et al.13Balanced blocks stratified by centre. Allocation by telephoneNot possible—randomisation number not providedNoNoUK, Brazil, South Africa, Slovenia, Greece and ChileSingleton pregnancies; cervical length of 15 mm or less at between 22 weeks and 24 weeks 6 daysShirodkar suture vs expectant managementDelivery before 33 weeks
Dor et al.18Not statedNot possible to checkNoNot specifiedIsraelConception after induction of ovulation; twin pregnanciesMcDonald type suture vs no sutureDuration of pregnancy
Lazar et al.19Randomisation procedure not stated. Allocation by way of sealed envelopesNot possible to checkNoNot specifiedFranceScore based on obstetric history, previous cervical surgery history and other cervical factors is within a prespecified rangeMcDonald type suture vs no sutureObstetric management; duration of pregnancy
Table 3.  Comparing baseline characteristics across trials
 Althuisius et al.8Berghella et al.9Ezechi et al.10MRC4Rush et al.11Rust et al.12To et al.13
CerclageNo cerclageCerclageNo cerclageCerclageNo cerclageCerclageNo cerclageCerclageNo cerclageCerclageNo cerclageCerclageNo cerclage
  1. BMI, body mass index.

Treatment allocated19 (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%)
Compliant with treatment allocated: yes19 (100%)14 (88%)27 (87%)28 (93%)Not statedNot stated586 (92%)581 (92%)95 (99%)97 (99%)104 (100%)103 (100%)122 (96%)124 (98%)
Bedrest: yes19 (100%)16 (100%)28 (100%)29 (100%)Not statedNot stated227 (36%) (21 missing)168 (27%) (24 missing)9 (9%)3 (3%)104 (100%)103 (100%)0 (0%)0 (0%)
Previous cerclage: yes4 (21%)2 (13%)Not statedNot statedNot statedNot stated134 (21%) (1 missing)116 (19%) (2 missing)0 (0%)0 (0%)Not statedNot stated2 (2%)2 (2%)
Previous cervical surgery: yes3 (16%)2 (13%)3 (11%)2 (7%)Not statedNot stated193 (30%)179 (28%)0 (0%)0 (0%)16 (15%)25 (24%)7 (6%)9 (7%)
Funnelling: yes10 (53%)11 (69%)Not statedNot statedNot statedNot statedNot statedNot statedNot statedNot statedNot statedNot stated121 (95%)117 (93%)
Ethnic origin: Non-Caucasian: yes9 (47%)8 (50%)25 (89%)23 (79%)Not statedNot statedNot statedNot stated96 (100%)98 (100%)35 (34%)31 (30%)68 (54%)78 (62%)
Smoker: yes2 (11%)0 (0%)9 (32%)8 (28%)Not statedNot statedNot statedNot statedNot statedNot stated24 (25%) (7 missing)25 (26%) (7 missing)10 (8%)17 (13%)
Fetal fibronectin: yesNot statedNot statedNot statedNot statedNot statedNot statedNot statedNot statedNot statedNot stated29 (28%)31 (30%)7 (6%) (1 missing)8 (6%)
Bacterial vaginosis: yes6 (32%)4 (25%)Not statedNot statedNot statedNot statedNot statedNot statedNot statedNot stated19 (18%)20 (19%)13 (10%) (2 missing)12 (10%) (2 missing)
Chlamydia: yesNot statedNot statedNot statedNot statedNot statedNot statedNot statedNot statedNot statedNot stated1 (1%)1 (1%)Not statedNot stated
Bishop score >4: yesNot statedNot statedNot statedNot stated12 (31%)10 (24%)Not statedNot statedNot statedNot statedNot statedNot statedNot statedNot stated
Mean age at 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)Not statedNot stated28.03 (6.10)28.88 (6.79)29.85 (6.06)29.30 (5.90)
Mean gestational age at cerclage procedure (SD)20.95 (2.93)N/ANot statedN/ANot statedN/ANot statedN/A20.00.(1.41)N/A20.67 (2.12)N/A23.85 (0.71)N/A
Mean cervical length (SD)19.90 (2.87)19.56 (4.29)15.69 (9.20)16.67 (8.01)Not statedNot statedNot statedNot stated16.47 (3.71)18.42 (2.92)16.11 (7.72)17.59 (6.24)9.60 (3.46)9.33 (3.57)
Mean BMI (SD)Not statedNot statedNot statedNot statedNot statedNot statedNot statedNot statedNot statedNot statedNot statedNot stated26.45 (5.49)25.96 (5.60)
Mean gestational age at entry (SD)Not statedNot stated19.61 (2.40)19.03 (2.2)Not statedNot stated14.63 (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)
Primigravida: yes10 (53%)9 (56%)7 (23%)12 (40%)0 (0%)0 (0%)Not statedNot stated0 (0%)0 (0%)14 (13%)13 (13%)32 (25%)33 (26%)
Previous delivery at greater than 37 weeks: yes8 (42%)3 (19%)Not statedNot statedNot statedNot statedNot statedNot stated44 (46%)37 (38%)40 (38%)34 (33%)57 (45%)49 (39%)
Previous STL: yesNot statedNot stated15 (54%)13 (45%)Not statedNot stated285 (45%) (1 missing)260 (41%) (2 missing)78 (81%)79 (81%)33 (32%)19 (18%)Not statedNot stated
Previous early spontaneous loss: yes4 (21%)5 (31%)20 (71%)20 (69%)Not statedNot stated201 (32%) (1 missing)193 (31%) (2 missing)47 (49%)61 (62%)40(38%)42 (41%)54 (43%)61 (48%) (2 missing)
Previous PTD: yesNot statedNot stated19 (68%)16 (55%)39 (100%)42 (100%)277 (44%) (1 missing)258 (41%) (2 missing)40 (42%)32 (33%)Not statedNot stated69 (54%)76 (61%)

Although the cerclage intervention varied with seven trials using a McDonald type suture,8–12,18,19 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 identified 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

image

Figure 1. Quorum diagram.

Download figure to PowerPoint

Baseline characteristics

A 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 intervention 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 IPD

The 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 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 numbers 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, sometimes difficult to read. It was, therefore, not possible to replicate published results for some of the variables. Data on 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 discharge from hospital

Singleton pregnancies only

The 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 (obstetric history versus short cervical length) was not statistically significant (P = 0·61).

image

Figure 2. Forest plot comparing cerclage with no cerclage for outcome of pregnancy loss of death before discharge from hospital.

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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).

Table 4.  Results from undertaking logistic regressions
OutcomeTreatment–obstetric history interaction*Treatment–cervical length interaction**Treatment–multiple gestation interaction
P valueP valueOR (95% CI)P value
  • *

    The P values here are those obtained from undertaking a likelihood ratio test comparing a logistic regression model including treatment–obstetric 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 treatment–cervical 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 treatment–multiple 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 treatment–multiple 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.

Pregnancy loss or death before discharge from hospital0.920.785·88 (1·14–30·19)***0.03***
Baby healthy at discharge from hospital (all babies)0.690.710·12 (0·02–0·89)***0.04***
Baby healthy at discharge from hospital (babies alive at discharge only)0.690.370.54 (0.07–0.48)***0.56***
Spontaneous labour0.830.191·08 (0·22–5·44)****0.92****
Pyrexia0.560.8Insufficient data available
Chorioamnionitis0.60.963·65 (0·47–28·17)****0.21****
PPROM0.440.321·57 (0·34–7·28)****0.56****
Need for induction/caesarean section0.680.080.74 (0·16–3·42)****0.70****
Multiple gestations

Including a treatment–multiple gestation interaction effect in a three-level logistic regression model including data on all babies gave a significant result (Table 4), suggesting that cerclage 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 demonstrated 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 morbidity

Singleton pregnancies only

The 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 excluded from the analysis of this outcome. These figures suggested no heterogeneity in treatment effect across trials.

image

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).

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Introducing a covariate representing indication for cerclage in a meta-regression did not have a statistically significant effect (P value including all babies: 0·64; P value excluding babies not alive at discharge: 0·44).

When fitting two-level logistic regression models, introducing a treatment–obstetric history term did not have a statistically significant effect (Table 4). The same applied for a treatment–cervical length interaction (Table 4).

Multiple gestations

Including a treatment–multiple 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 demonstrated 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 substantially. However, the test for an interaction was nonsignificant (Table 4) when excluding babies not alive at discharge from the analysis.

Maternal morbidity

Singleton pregnancies only

The trial-specific odds ratios, together with the pooled odds ratio and corresponding 95% CI for each outcome are displayed in Figure 4. These figures suggested that there was significant 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.

imageimage

Figure 4. Forest plots comparing cerclage with no cerclage for outcomes of maternal morbidity.

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 treatment–obstetric 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 treatment–cervical length interaction (Table 4).

Multiple gestations

The results from including a treatment–multiple gestation interaction term in a two-level logistic regression model are summarised in Table 4. There was insufficient data on multiple pregnancies for which the outcome of pyrexia had been measured to undertake the test for this outcome.

Preterm birth

We 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.

image

Figure 5. Odds ratios of preterm delivery comparing cerclage with no cerclage.

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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 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 pregnancies delivering before each gestational age cutoff to investigate the effect of multiple gestation on treatment effect for this outcome (results not shown).

Comment on studies for which IPD were not obtained

Two 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’, ‘preterm 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

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Implications for practice
  8. Implications for research
  9. Conflicts of interest
  10. Contribution to authorship
  11. Acknowledgements
  12. References

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 pregnancies, 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 confidence intervals for the absence of neonatal morbidity were much wider since only three trials collected sufficient information on this outcome.

In terms of maternal morbidity, a statistically significant increased risk of maternal pyrexia was observed in the cerclage group. It was decided following publication of the protocol,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 pregnancies 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 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 baby’s 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 morbidity. 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 important 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 neonatal 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 gestations, 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 randomisation 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 sometimes occur too late during the pregnancy to have any effect. Gestational age of the cerclage procedure was recorded for women in four trials.8,11–13 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 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 gestation in a subgroup of women with no previous cervical surgery 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 indication 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

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Implications for practice
  8. Implications for research
  9. Conflicts of interest
  10. Contribution to authorship
  11. Acknowledgements
  12. References

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 pregnancies should be avoided.

Implications for research

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Implications for practice
  8. Implications for research
  9. Conflicts of interest
  10. Contribution to authorship
  11. Acknowledgements
  12. References

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

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Implications for practice
  8. Implications for research
  9. Conflicts of interest
  10. Contribution to authorship
  11. Acknowledgements
  12. References

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

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Implications for practice
  8. Implications for research
  9. Conflicts of interest
  10. Contribution to authorship
  11. Acknowledgements
  12. References

A.L.J. organised, cleaned and checked the individual patient data sets, contacted the authors with queries, wrote the statistical 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 guidance 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, provided advice on the statistical analysis plan and the statistical analyses and provided comments on the manuscript.

Cerclage IPD meta-analysis group members

A.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 working party; R.W. Rush (previously from University of Cape Town); O.A. Rust (Lehigh Valley Hospital and Health Network, Pennsylvania); M.S.T. (Fetal Medicine Foundation); K. Nicolaides (Fetal Medicine Foundation).

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Implications for practice
  8. Implications for research
  9. Conflicts of interest
  10. Contribution to authorship
  11. Acknowledgements
  12. References

The authors would like to thank the Fetal Medicine Foundation, 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 various queries raised and providing valuable feedback on the draft paper. They would also like to thank Adrian Grant (MRC/RCOG working party) who provided helpful comments on an earlier draft.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Implications for practice
  8. Implications for research
  9. Conflicts of interest
  10. Contribution to authorship
  11. Acknowledgements
  12. References
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