Cervical stitch (cerclage) for preventing preterm birth in singleton pregnancy

Zarko Alfirevic; Tamara Stampalija; Nancy Medley

doi:10.1002/14651858.CD008991.pub3

Sutura cervical (cerclaje) para la prevención del parto prematuro en embarazos de feto único

Declaraciones de intereses de los autores

Versión publicada: 06 junio 2017 Historial de versiones

https://doi.org/10.1002/14651858.CD008991.pub3

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Resumen

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Antecedentes

El cerclaje cervical es un procedimiento quirúrgico conocido que se realiza durante el embarazo. Incluye la colocación de una sutura alrededor del cuello del útero, con el fin de proporcionarle un apoyo mecánico y, de ese modo, reducir el riesgo de parto prematuro. La efectividad y seguridad de este procedimiento aún son controversiales. Ésta es una actualización de una revisión publicada por última vez en 2012.

Objetivos

Evaluar si el uso de la sutura cervical en el embarazo con feto único y alto riesgo de pérdida del embarazo, según los antecedentes de la mujer o en el resultado de la ecografía de “cuello uterino corto” o el examen físico, mejora la atención obstétrica posterior y el resultado fetal.

Métodos de búsqueda

Se hicieron búsquedas en el registro de ensayos del Grupo Cochrane de Embarazo y Parto (30 de junio 2016) y en las listas de referencias de los estudios recuperados.

Criterios de selección

Se incluyeron todos los ensayos aleatorizados de sutura cervical en embarazos únicos. La sutura del cuello uterino se realizó cuando se consideró que el embarazo tenía un riesgo suficientemente alto debido a los antecedentes de la mujer, al hallazgo de un cuello uterino corto en la ecografía o a otra indicación determinada por el examen físico. Se incluyó cualquier estudio que comparó el cerclaje con ningún tratamiento o con cualquier intervención alternativa. Se planificó incluir estudios aleatorizados grupales, pero no ensayos cruzados (cross‐over). Se excluyeron los estudios cuasialeatorizados. Se incluyeron estudios informados solo en forma de resumen.

Obtención y análisis de los datos

Tres autores de la revisión evaluaron de forma independiente los ensayos para su inclusión. Dos autores de la revisión evaluaron de forma independiente el riesgo de sesgo y extrajeron los datos. Las discrepancias se resolvieron mediante discusión. Se verificó la exactitud de los datos. La calidad de la evidencia se evaluó mediante los criterios GRADE.

Resultados principales

Esta revisión actualizada incluye 15 ensayos (3490 mujeres); se agregaron tres ensayos para esta actualización (152 mujeres).

Cerclaje versus ningún cerclaje

En general, el cerclaje probablemente conlleva un menor riesgo de muerte perinatal en comparación con ningún cerclaje, aunque el intervalo de confianza (IC) cruza la línea de ningún efecto (RR 0,82; IC del 95%: 0,65 a 1,04; diez estudios, 2927 mujeres; evidencia de calidad moderada). Cuando se consideraron los mortinatos y las muertes neonatales por separado, se redujo el número de eventos y el tamaño de la muestra. Aunque el efecto relativo del cerclaje es similar, las estimaciones fueron menos fiables con menos datos y se evaluaron como de calidad baja (mortinatos RR 0,89; IC del 95%: 0,45 a 1,75; cinco estudios, 1803 mujeres; evidencia de calidad baja; muertes neonatales antes del alta RR 0,85; IC del 95%: 0,53 a 1,39; seis estudios, 1.714 mujeres; evidencia de calidad baja). La morbilidad neonatal grave fue similar con y sin cerclaje (RR 0,80; IC del 95%: 0,55 a 1,18; seis estudios, 883 mujeres; evidencia de calidad baja). Las embarazadas con y sin cerclaje tuvieron la misma probabilidad de tener un recién nacido sano al momento del alta (RR 1,02; IC del 95%: 0,97 a 1,06; cuatro estudios, 657 mujeres; evidencia de calidad moderada).

Las embarazadas con cerclaje tuvieron menos probabilidades de tener partos prematuros en comparación con los controles antes de las 37, 34 (RR promedio 0,77; IC del 95%: 0,66 a 0,89; nueve estudios, 2415 mujeres; evidencia de calidad alta) y 28 semanas completas de gestación.

Cinco subgrupos según la indicación clínica proporcionaron datos para el análisis (indicado por los antecedentes; cuello uterino corto basado en una sola ecografía en mujeres de alto riesgo; cuello uterino corto encontrado mediante exploraciones en serie en mujeres de alto riesgo; indicado por el examen físico; y cuello uterino corto encontrado mediante exploración en poblaciones de bajo riesgo o mixtas). Hubo muy pocos ensayos en estos subgrupos clínicos para establecer conclusiones significativas y no hay evidencia de efectos diferenciales.

Cerclaje versus progesterona

Dos ensayos (129 mujeres) compararon el cerclaje con la prevención con progesterona vaginal en mujeres de alto riesgo con cuello uterino corto en la ecografía; estos ensayos fueron demasiado pequeños para detectar diferencias fiables y clínicamente importantes para cualquier resultado de la revisión. Un ensayo incluido comparó el cerclaje con la progesterona intramuscular (75 mujeres), y no tuvo poder estadístico para detectar diferencias de grupo.

Cerclaje indicado por los antecedentes versus cerclaje indicado por la ecografía

La evidencia de dos ensayos (344 mujeres) fue demasiado limitada para establecer diferencias para resultados clínicamente importantes.

Conclusiones de los autores

El cerclaje cervical reduce el riesgo de parto prematuro en las mujeres con alto riesgo de parto prematuro y probablemente reduce el riesgo de muertes perinatales. No hubo evidencia de un efecto diferencial del cerclaje según los antecedentes obstétricos o por indicaciones de un cuello uterino corto, pero los datos fueron limitados para todos los grupos clínicos. La cuestión de si el cerclaje es más o menos efectivo que otros tratamientos preventivos, en particular la progesterona vaginal, aún sigue sin respuesta.

PICO

Population

Intervention

Comparison

Outcome

El uso y la enseñanza del modelo PICO están muy extendidos en el ámbito de la atención sanitaria basada en la evidencia para formular preguntas y estrategias de búsqueda y para caracterizar estudios o metanálisis clínicos. PICO son las siglas en inglés de cuatro posibles componentes de una pregunta de investigación: paciente, población o problema; intervención; comparación; desenlace (outcome).

Para saber más sobre el uso del modelo PICO, puede consultar el Manual Cochrane.

Resumen en términos sencillos

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¿Puede la inserción de un punto cervical prevenir los partos prematuros de fetos únicos?

¿Cuál es el problema?

El cerclaje cervical es un procedimiento quirúrgico que se realiza durante el embarazo para colocar un punto de sutura alrededor del cuello del útero (cérvix). El punto de sutura tiene como objetivo apoyar el cuello del útero y reducir el riesgo de un parto prematuro.

¿Por qué es esto importante?

El cuello del útero se mantiene bien cerrado hasta el final de los embarazos normales, antes de comenzar a acortarse y ablandarse gradualmente para prepararse para el trabajo de parto y el parto. Sin embargo, en ocasiones el cuello uterino comienza a acortarse y ensancharse demasiado pronto, lo que provoca un aborto espontáneo tardío o un parto prematuro. La inserción de un punto cervical puede reducir la posibilidad de un aborto tardío o un parto prematuro.

¿Qué evidencia se encontró?

Se buscó evidencia hasta el 30 de junio 2016. Esta revisión incluye 15 estudios con 3490 mujeres (para esta actualización se agregaron tres estudios con 152 mujeres).

Las mujeres con un punto de sutura tienen menos probabilidades de tener un recién nacido demasiado pronto. Los recién nacidos a cuyas madres se les colocó una sutura también tienen menos probabilidades de morir durante la primera semana de vida. No está claro si una sutura cervical puede prevenir el parto de un mortinato o mejorar la salud del recién nacido.

¿Qué significa esto?

La inserción de un punto de sutura ayuda a las mujeres embarazadas de alto riesgo a evitar los partos prematuros, en comparación con ningún punto de sutura. La inserción de un punto de sutura también puede mejorar las posibilidades de supervivencia del recién nacido. Se encontraron muy pocos ensayos clínicos para determinar si la sutura cervical es más efectiva que otros tratamientos para prevenir los partos prematuros, como la progesterona (un fármaco hormonal utilizado para prevenir los partos prematuros). Se encontraron muy pocos datos para determinar si es mejor insertar un punto de sutura al principio del embarazo (según los antecedentes de la madre) o esperar a realizar una ecografía más tarde en el embarazo para ver si el cuello del útero se ha acortado.

Authors' conclusions

Implications for practice

Cervical cerclage prevents preterm births, but so does the natural progesterone given vaginally to women with a short cervix, without an increased risk of caesarean section (Romero 2012). However, transvaginal sonography and prolonged treatment with progesterone may not be affordable for all. Also, the progesterone option may be unacceptable to women who have already had a successful pregnancy with cervical cerclage. Therefore, the decision on how best to minimise the risk of recurrent preterm birth in women at risk, either because of poor history or a short or dilated cervix, has to be personalised and based on the clinical circumstances, the skill and expertise of the clinical team and, most importantly, the woman's informed choice.

Implications for research

Women with a short cervix on transvaginal sonography should be randomised to either cervical cerclage, natural progesterone, neither, or both. It would be important to report separately results for women who had routine transvaginal sonography screening (low risk) and for those who had serial ultrasound scans because of previous preterm birth or other risk factors.
Further randomised data that includes women with a dilated cervix found on physical examination (digital/speculum) would be welcome.
We need definitive studies to ascertain whether it is better for women at particularly high risk of preterm birth to have cervical cerclage early (as prophylaxis), or to have serial transvaginal scanning.

All future studies should have neonatal morbidity as the primary outcome on which sample size calculations should be based. Such studies will have more than adequate power to address the impact on preterm births and most safety aspects. Studies that use gestational age as the primary outcome do so primarily to justify the smaller (more feasible) sample size. It is unlikely that these will have adequate power to answer the key question of whether there is a benefit for mother and baby.

Summary of findings

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Summary of findings for the main comparison. Cerclage versus no cerclage

Cerclage versus no cerclage
Patient or population: preventing preterm birth in women with singleton pregnancy Setting: Belgium, Brazil, Canada, Chile, France, Greece, Hungary, Iceland, Ireland, Italy, Netherlands, Norway, South Africa, Slovenia, UK, USA, Zimbabwe Intervention: cerclage Comparison: no cerclage
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Quality of the evidence (GRADE)	Comments
	Risk with no cerclage (SoF outcomes)	Risk with cerclage
All perinatal losses	Study population		RR 0.82 (0.65 to 1.04)	2927 (10 RCTs)	⊕⊕⊕⊝ MODERATE¹
	92 per 1000	75 per 1000 (60 to 96)
Serious neonatal morbidity	Study population		RR 0.80 (0.55 to 1.18)	883 (6 RCTs)	⊕⊕⊝⊝ LOW ²
	116 per 1000	93 per 1000 (64 to 136)
Baby discharged home healthy	Study population		RR 1.02 (0.97 to 1.06)	657 (4 RCTs)	⊕⊕⊕⊝ MODERATE³
	912 per 1000	930 per 1000 (885 to 967)
Stillbirths	Study population		RR 0.89 (0.45 to 1.75)	1803 (5 RCTs)	⊕⊕⊝⊝ LOW ²
	19 per 1000	17 per 1000 (9 to 33)
Neonatal deaths before discharge	Study population		RR 0.85 (0.53 to 1.39)	1714 (6 RCTs)	⊕⊕⊝⊝ LOW ²
	35 per 1000	30 per 1000 (19 to 49)
Preterm birth before 34 completed weeks	Study population		average RR 0.77 (0.66 to 0.89)	2415 (9 RCTs)	⊕⊕⊕⊕ HIGH⁴
	238 per 1000	183 per 1000 (157 to 212)
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio; OR: Odds ratio;
GRADE Working Group grades of evidence High quality: We are very confident that the true effect lies close to that of the estimate of the effect Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
¹ Wide confidence interval crossing the line of no effect (‐1). ² Wide confidence interval crossing the line of no effect and small sample size (‐2) ³ Estimate based on small sample size (‐1). 4 Random effects model retained from primary analysis; there is no substantive difference in the risk estimate or the confidence intervals with fixed or random effects.

Background

Description of the condition

During normal pregnancy the neck of the womb (cervix) stays tightly closed, allowing the pregnancy to reach full term. Towards the end of pregnancy, the cervix starts to shorten and progressively becomes softer (more favourable) ‐ these changes are physiological preparations for normal labour and delivery.

Sometimes, the cervix starts to shorten and dilates too early, causing either late miscarriage or preterm birth. In the absence of uterine contractions, the cause of this pathological condition is considered to be cervical insufficiency (sometimes also called incompetence). The condition has been described as early as the 17th century (Riverius 1658). It has been suggested that cervical insufficiency complicates about 1% of an obstetric population (McDonald 1980) and 8% of a recurrent miscarriage population who have experienced mid‐trimester pregnancy losses (Drakeley 1998). There is however, no consistent definition of cervical insufficiency (Berry 1995) which hampers any attempt to establish the true incidence.

Some researchers have defined cervical insufficiency as "the history of painless dilatation of the cervix resulting in second or early third trimester delivery and the passage, without resistance, of size nine Hegar dilator (an instrument which is used to measure the size of cervical dilatation in millimetres)" (Berry 1995). Other descriptions include: recurrent second trimester or early third trimester loss of pregnancy caused by the inability of the uterine cervix to retain a pregnancy until term (Althuisius 2001) and a physical defect in the strength of the cervical tissue that is either congenital (inherited) or acquired, i.e. caused by previous damage (Rust 2000).

Description of the intervention

Cervical cerclage is one of the best known surgical procedures in obstetrics. It involves the positioning of a suture (stitch) around the neck of the womb (cervix), aimed to provide mechanical support to the cervix and keep the cervix closed during the pregnancy.

There are a number of proposed surgical methods designed to keep the cervix closed until the expected time of birth. All interventions require at least regional anaesthesia in the form of a spinal or epidural block. Shirodkar 1955 reported the insertion of a cervical stitch (suture) at around 14 weeks of pregnancy. The anterior vaginal wall is cut and the bladder reflected (pushed) back and upwards allowing an access close to the level of the internal cervical os by the vaginal route. A stitch, usually silk, tape, or other non‐absorbable material, is inserted around the cervix, enclosing it. McDonald 1957 described a simpler purse string stitch technique, whereby the stitch is inserted around the body of the cervix visible in the vagina in three or four bites. Athough the internal os is often not reached, the procedure is easier to perform with less bleeding. These techniques were described as elective (planned) procedures.

Total cervical occlusion is another proposed variation where, in addition to the standard cerclage, the external cervical os is closed with continuous nylon (Saling 1984; Secher 2007). The rationale for this technique is based on the observation that the mucous plug has a double role in preventing preterm labour. The plug is a mechanical barrier between the vagina and uterus, but its intrinsic richness in immune components also makes it a very important element in defending the fetal compartment from ascending infections. Intuitively, protective nylon could keep the plug in situ, thereby increasing the innate defence of the cervical canal.

There has been some suggestion recently that suture material may have an important influence on the outcome of pregnancy. However, the surgical methods for cerclage, including the choice of material, are beyond the scope of this review.

Stitches are normally inserted via the vaginal route, but transabdominal cerclage has also been proposed. This approach is used for women when vaginal stitches have failed, or when a woman has a short, scarred cervix making vaginal stitch insertion technically difficult (Anthony 1997; Gibb 1995). Initally, cerclage procedures have been carried out in early pregnancy around 12 weeks of gestation, but are increasingly being scheduled before pregnancy. Either way, during laparotomy, the bladder is reflected downwards away from the uterus and the cervical stitch is placed at the level of the internal cervical os. Vaginally inserted cervical stitches are either taken out at 37 weeks' gestation, or when the woman presents in labour, usually without an anaesthetic. Abdominal cervical stitches are left in place and the baby is delivered by caesarean section.

Cervical cerclage, by whichever technique employed, carries risks for the pregnancy. Surgical manipulation of the cervix can cause uterine contractions, bleeding or infection which may lead to miscarriage or preterm labour. These risks must be carefully balanced against the benefit from mechanical support of the cervix.

Cervical cerclage can either be inserted as a planned procedure based on previous history (history‐indicated), because of a short cervical length detected on transvaginal ultrasound (ultrasound‐indicated), or as an emergency procedure when women with threatened miscarriage present at the hospital (physical exam‐indicated) (Chanrachakul 1998; Wong 1993). Ultrasound‐ and physical exam‐indicated cerclages tend to be performed later in pregnancy; history‐indicated procedures are usually planned around 14 weeks.

How the intervention might work

Intuitively, in the presence of a short cervix at ultrasound, or history of recurrent spontaneous mid‐trimester losses, reinforcing the cervix by positioning a mechanical support should prolong pregnancy and reduce the risk of preterm birth and its sequelae.

Why it is important to do this review

Controversies concerning cervical cerclage include effectiveness, safety and risk/benefit to both mother and unborn baby. The avoidance of surgical trauma to the cervix may be as effective as intervention. Grant 1989 reviewed the evidence for the benefits and hazards of treatment by cervical cerclage to prolong pregnancy and suggested that cervical cerclage in women with a previous mid‐trimester loss (or preterm delivery) may help to prevent one delivery before 33 weeks for every 20 stitches inserted (Grant 1989). Since 1989 there have been a number of randomised and non‐randomised studies published, however, the issues surrounding effectiveness in preventing neonatal sequelae of prematurity, timing of cerclage and optimal techniques have not been addressed adequately. The evidence on which to base practice for physical exam‐indicated cerclage is even less robust. A meta‐analysis estimated the effectiveness of physical examination‐indicated cerclage versus expectant management in the setting of second‐trimester cervical dilatation (14 to 27 gestational weeks) (Ehsanipoor 2015). The physical examination‐indicated cerclage was associated with a significant increase in neonatal survival and prolongation of pregnancy. However, as well as including randomised controlled trials, Ehsanipoor 2015 also included retrospective and prospective cohort studies in the meta‐analysis. A previous Cochrane Review on this topic did not find clear benefit, although heterogeneity was high for some important obstetric outcomes. In their meta‐analysis of individual patient data, Berghella 2005 concluded that cerclage could be beneficial in women with singleton pregnancies, short cervix and experience of prior preterm birth. In a similar meta‐analysis, no statistical significance was found for singleton pregnancies (Jorgensen 2007). Both meta‐analyses showed no benefit for multiple gestation pregnancies. In an indirect comparison meta‐analysis of randomised controlled trials, Conde‐Agudelo 2013 et al found that either cerclage or vaginal progesterone are equally efficacious in the prevention of preterm birth in women with sonographic short cervix in the mid trimester, singleton gestation and previous preterm birth.

A Cochrane Review investigating cervical cerclage for preventing preterm birth in multiple gestation pregnancies has been published (Rafael 2014).

Objectives

To assess whether the use of cervical stitch in singleton pregnancy at high risk of pregnancy loss based on woman's history and/or ultrasound finding of 'short cervix' and/or physical exam improves subsequent obstetric care and fetal outcome.

Methods

Criteria for considering studies for this review

Types of studies

All randomised trials comparing cervical stitch in singleton pregnancies of women considered to be at high risk of pregnancy loss. We planned to include cluster‐randomised studies but not cross‐over trials. We excluded quasi‐randomised studies. We included studies reported in abstract form only.

Types of participants

Women with singleton pregnancies considered to be at high risk for pregnancy loss based any of the following: woman's history (e.g. previous preterm birth); prior cervical surgery (loop excision, cone biopsy, surgical termination of pregnancy); short cervix on ultrasound scanning; or physical exam‐detected cervical changes (including emergency or rescue cerclage). Cervical cerclage for multiple pregnancies was investigated in another Cochrane Review (Rafael 2014).

Types of interventions

Cervical stitch in singleton pregnancies considered for women to be at high risk for pregnancy loss.

Comparisons

Cervical stitch (cerclage) versus no stitch according to clinical subgroups (history‐ versus ultrasound‐ versus physical exam‐indicated cerclage).
Cervical stitch (cerclage) versus any alternative preventative treatment (e.g. progesterone or pessary).
Any comparison of different cerclage protocols (history‐ versus ultrasound‐ versus physical exam‐indicated cerclage).

Types of outcome measures

We selected outcome domains based on consensus work undertaken to define core outcome measures for clinical research and evidence synthesis for pregnancy and childbirth generally (Devane 2007) and for preterm birth prevention specifically (van 't Hooft 2016).

Primary outcomes

Perinatal loss: all losses including miscarriages, stillbirth and neonatal deaths.
Serious neonatal morbidity (as defined by trialists).
Baby discharged home healthy (without obvious pathology ‐ as defined by trialists).

It may seem unusual to not include preterm birth rates as the primary outcome. In the context of this review, preterm births should be regarded as a surrogate for mortality and morbidity. More importantly, there is a real possibility that prolongation of pregnancy may be misinterpreted as benefit, when in fact, an early birth in a setting with adequate neonatal care resources may be better for the infant.

Secondary outcomes

Neonatal

Stillbirth: intra‐uterine death at 24 weeks or more weeks; or greater than 500 g fetal weight or reaching viability as defined by trialist.
Neonatal death before discharge.
Miscarriages: perinatal loss before 24 weeks.
Preterm birth (birth before 28, 34 and 37 completed weeks of pregnancy).
Serious intracranial pathology, e.g. intraventricular haemorrhage or periventricular leukomalacia (as defined by trialists).
Serious respiratory morbidity, e.g. respiratory distress syndrome or oxygen dependency after 28 days of life.
Necrotising enterocolitis requiring surgery.
Retinopathy of prematurity.
Apgar less than seven at five minutes.

Maternal

Caesarean section (elective and emergency).
Maternal infection requiring intervention, e.g. antibiotics or delivery.
Maternal side effects (vaginal discharge, bleeding, pyrexia not requiring antibiotics).

We also planned to report non‐prespecified outcomes if they were reported by more than one included trial.

Not prespecified outcomes

Any intravenous, oral or combined tocolysis.
Preterm premature rupture of the membranes (PPROM).
Chorioamnionitis.

Search methods for identification of studies

The following methods section of this review is based on a standard template used by Cochrane Pregnancy and Childbirth.

Electronic searches

We searched Cochrane Pregnancy and Childbirth’s Trials Register by contacting their Information Specialist (30 June 2016).

The Register is a database containing over 22,000 reports of controlled trials in the field of pregnancy and childbirth. For full search methods used to populate Pregnancy and Childbirth’s Trials Register including the detailed search strategies for CENTRAL, MEDLINE, Embase and CINAHL; the list of handsearched journals and conference proceedings, and the list of journals reviewed via the current awareness service, please follow this link to the editorial information about the Cochrane Pregnancy and Childbirth in the Cochrane Library and select the ‘Specialized Register’ section from the options on the left side of the screen.

Briefly, Cochrane Pregnancy and Childbirth’s Trials Register is maintained by their Information Specialist and contains trials identified from:

monthly searches of the Cochrane Central Register of Controlled Trials (CENTRAL);
weekly searches of MEDLINE (Ovid);
weekly searches of Embase (Ovid);
monthly searches of CINAHL (EBSCO);
handsearches of 30 journals and the proceedings of major conferences;
weekly current awareness alerts for a further 44 journals plus monthly BioMed Central email alerts.

Search results are screened by two people and the full text of all relevant trial reports identified through the searching activities described above is reviewed. Based on the intervention described, each trial report is assigned a number that corresponds to a specific Pregnancy and Childbirth review topic (or topics), and is then added to the Register. The Information Specialist searches the Register for each review using this topic number rather than keywords. This results in a more specific search set which has been fully accounted for in the relevant review sections (Included studies; Excluded studies; Studies awaiting classification; Ongoing studies).

Searching other resources

We searched the reference lists of the studies identified. We did not apply any language or date restrictions.

Data collection and analysis

Methods used in the previous version of this review are presented in Alfirevic 2012. The following methods were used for this update to assess records identified as a result of the 2016 search.

Selection of studies

Two review authors independently assessed all potential studies identified as a result of the search for inclusion. We resolved any disagreement through discussion or, if required, we consulted the third review author.

Data extraction and management

We designed a data extraction form. Two review authors extracted data from eligible studies using the form. We resolved discrepancies through discussion or, if required, we consulted the third review author. Data were entered into Review Manager software (RevMan 2014) and checked for accuracy.

When information was unclear, we planned to contact authors of the original reports to provide further details.

Assessment of risk of bias in included studies

Two review authors independently assessed risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). Any disagreement was resolved by discussion or by involving a third assessor.

(1) Random sequence generation (checking for possible selection bias)

We described for each included study the method used to generate the allocation sequence in sufficient detail to allow an assessment of whether it should produce comparable groups.

We assessed the method as:

low risk of bias (any truly random process, e.g. random number table; computer random number generator);
high risk of bias (any non‐random process, e.g. odd or even date of birth; hospital or clinic record number);
unclear risk of bias.

(2) Allocation concealment (checking for possible selection bias)

We described for each included study the method used to conceal allocation to interventions prior to assignment and assessed whether intervention allocation could have been foreseen in advance of, or during recruitment, or changed after assignment.

We assessed the methods as:

low risk of bias (e.g. telephone or central randomisation; consecutively numbered sealed opaque envelopes);
high risk of bias (open random allocation; unsealed or non‐opaque envelopes, alternation; date of birth);
unclear risk of bias.

(3.1) Blinding of participants and personnel (checking for possible performance bias)

We described for each included study the methods used, if any, to blind study participants and personnel from knowledge of which intervention a participant received. We considered that studies were at low risk of bias if they were blinded, or if we judged that the lack of blinding unlikely to affect results. We assessed blinding separately for different outcomes or classes of outcomes.

We assessed the methods as:

low, high or unclear risk of bias for participants;
low, high or unclear risk of bias for personnel.

(3.2) Blinding of outcome assessment (checking for possible detection bias)

We described for each included study the methods used, if any, to blind outcome assessors from knowledge of which intervention a participant received. We assessed blinding separately for different outcomes or classes of outcomes.

We assessed methods used to blind outcome assessment as:

low, high or unclear risk of bias.

(4) Incomplete outcome data (checking for possible attrition bias due to the amount, nature and handling of incomplete outcome data)

We described for each included study, and for each outcome or class of outcomes, the completeness of data including attrition and exclusions from the analysis. We stated whether attrition and exclusions were reported and the numbers included in the analysis at each stage (compared with the total randomised participants), reasons for attrition or exclusion where reported, and whether missing data were balanced across groups or were related to outcomes. Where sufficient information was reported, or could be supplied by the trial authors, we planned to re‐include missing data in the analyses which we undertook.

We assessed methods as:

low risk of bias (e.g. no missing outcome data; missing outcome data balanced across groups);
high risk of bias (e.g. numbers or reasons for missing data imbalanced across groups; ‘as treated’ analysis done with substantial departure of intervention received from that assigned at randomisation);
unclear risk of bias.

(5) Selective reporting (checking for reporting bias)

We described for each included study how we investigated the possibility of selective outcome reporting bias and what we found.

We assessed the methods as:

low risk of bias (where it is clear that all of the study’s pre‐specified outcomes and all expected outcomes of interest to the review have been reported);
high risk of bias (where not all the study’s pre‐specified outcomes have been reported; one or more reported primary outcomes were not pre‐specified; outcomes of interest are reported incompletely and so cannot be used; study fails to include results of a key outcome that would have been expected to have been reported);
unclear risk of bias.

(6) Other bias (checking for bias due to problems not covered by (1) to (5) above)

We described for each included study any important concerns we had about other possible sources of bias.

(7) Overall risk of bias

We made explicit judgements about whether studies were at high risk of bias, according to the criteria given in the Handbook (Higgins 2011). With reference to (1) to (6) above, we planned to assess the likely magnitude and direction of the bias and whether we considered it is likely to impact on the findings. In future updates, we will explore the impact of the level of bias through undertaking sensitivity analyses ‐ seeSensitivity analysis.

Assessment of the quality of the evidence using the GRADE approach

For this update, we assessed evidence quality using the GRADE approach as outlined in the GRADE handbook relating to the following outcomes:

perinatal loss: all losses including miscarriages, stillbirth and neonatal deaths;
serious neonatal morbidity (as defined by trialists);
baby discharged home healthy (without obvious morbidity, as defined by trialists);
Stillbirth: intra‐uterine death at 24 or more weeks or more than 500 g fetal weight or reaching viability as defined by trialists;
neonatal death before discharge; and
preterm birth before 34 completed weeks of pregnancy.

GRADEpro GDT was used to import data from Review Manager 5.3 (RevMan 2014) to create ’Summary of findings’ tables. A summary of the intervention effect and a measure of quality for each of the above outcomes was produced using the GRADE approach. The GRADE approach uses five considerations (study limitations, consistency of effect, imprecision, indirectness and publication bias) to assess the quality of the body of evidence for each outcome. The evidence can be downgraded from 'high quality' by one level for serious (or by two levels for very serious) limitations, depending on assessments for risk of bias, indirectness of evidence, serious inconsistency, imprecision of effect estimates or potential publication bias.

Measures of treatment effect

Dichotomous data

We presented results as summary risk ratio with 95% confidence intervals for dichotomous data.

Continuous data

No continuous data were analysed in this review. In future updates, if applicable, we will use the mean difference if outcomes are measured in the same way between trials. We will use the standardised mean difference to combine trials that measure the same outcome, but use different methods.

Unit of analysis issues

Cluster‐randomised trials

For this update, we did not include any cluster‐randomised trials. If in future updates of the review we find cluster‐randomised trials, we will include these trials in the analyses along with individually randomised trials. We will adjust their sample sizes or standard errors using the methods described in the Handbook (Section 16.3.4 or 16.3.6) (Higgins 2011) using an estimate of the intracluster correlation co‐efficient (ICC) derived from the trial (if possible), from a similar trial, or from a study of a similar population. If we use ICCs from other sources, we will report this and conduct sensitivity analyses to investigate the effect of variation in the ICC. If we identify both cluster‐randomised trials and individually‐randomised trials, we plan to synthesise the relevant information. We will consider it reasonable to combine the results from both if there is little heterogeneity between the study designs and the interaction between the effect of intervention and the choice of randomisation unit is considered to be unlikely.

We will also acknowledge heterogeneity in the randomisation unit and perform a sensitivity analysis to investigate the effects of the randomisation unit.

Cross‐over trials

Cross‐over trials are not feasible for the population of interest or for interventions relevant to this systematic review.

Other unit of analysis issues

Multiple pregnancy was not eligible for inclusion in this review. Where trials reported both singleton and multiple pregnancy, we used data for women with singleton pregnancies.

Dealing with missing data

Levels of attrition were noted for included studies. In future updates, if more studies are included, the impact of including studies with high levels of missing data in the overall assessment of treatment effect will be explored in sensitivity analyses.

Analyses for all outcomes were carried out, as far as possible, on an intention‐to‐treat basis, i.e. we attempted to include all participants randomised to each group in the analyses. The denominator for each outcome in each trial was the number randomised minus any participants whose outcomes were known to be missing.

Assessment of heterogeneity

We assessed statistical heterogeneity in each meta‐analysis using the Tau², I² and Chi² statistics. We regarded heterogeneity as substantial if I² was greater than 30% and either Tau² was greater than zero, or there was a low P value (less than 0.10) in the Chi² test for heterogeneity. If we identified substantial heterogeneity (above 30%), we explained in the text possibly sources of clinical heterogeneity between trials. See also Data synthesis.

Assessment of reporting biases

In future updates, if there are 10 or more studies in the meta‐analysis, we will investigate reporting biases (such as publication bias) using funnel plots. We will assess funnel plot asymmetry visually. If asymmetry is suggested by a visual assessment, we will perform exploratory analyses to investigate.

Data synthesis

We carried out statistical analysis using Review Manager software (RevMan 2014). We used fixed‐effect meta‐analysis for combining data where it was reasonable to assume that studies were estimating the same underlying treatment effect: i.e. where trials were examining the same intervention, and the trials’ populations and methods were judged sufficiently similar.

If there was clinical heterogeneity sufficient to expect that the underlying treatment effects differed between trials, or if substantial statistical heterogeneity was detected, we used random‐effects meta‐analysis to produce an overall summary if an average treatment effect across trials was considered clinically meaningful. The random‐effects summary was treated as the average range of possible treatment effects. We also discussed the clinical implications of treatment effects differing between trials. If the average treatment effect was not clinically meaningful, we did not combine trials. If we used random‐effects analyses, the results were presented as the average treatment effect with 95% confidence intervals, and the estimates of Tau² and I².

Within each comparison, analyses for all outcomes are displayed according to clinical groups (history‐indicated, physical‐exam indicated, etc). Subgroup analysis was conducted only for comparison of cerclage versus no cerclage.

Subgroup analysis and investigation of heterogeneity

If we found substantial heterogeneity (I² > 30%) for our primary outcomes, and had adequate numbers of included trials in each relevant subgroup, we planned to investigate sources using subgroup analyses to consider whether an overall summary was meaningful, and if so, to use random‐effects analysis to investigate.

We planned to carry out the following subgroup analyses for the main comparison (cerclage versus no cerclage). Five potential subgroups were examined: history‐indicated cerclage; one‐off ultrasound‐indicated cerclage in high‐risk women, serial ultrasound‐indicated cerclage, physical exam‐indicated cerclage (rescue cerclage) and one‐off ultrasound‐indicated cerclage in low or unspecified risk women. There were too few trials in each subgroup to make meaningful conclusions regarding differences in effect in subgroups. Forest plots show trials within the appropriate subgroup for display only.

If in future updates, if we have adequate numbers of trials, we will assess subgroup differences by interaction tests available within RevMan (RevMan 2014). If evidence of subgroup differences are identified, we plan to report the results of subgroup analyses quoting the Chi² statistic and P value, and the interaction test I² value.

Sensitivity analysis

For primary outcomes only, we carried out sensitivity analyses to explore the impact of trial quality, assessed as high quality if the trial reported adequate methods for sequence generation and allocation concealment and had no other clear markers of poor trial quality (unacceptable attrition, for example). We reported whether or not the exclusion of studies with substantial risks of bias changed the overall effect estimate or its interpretation.

Results

Description of studies

Results of the search

An updated search (June 2016) identified 22 new reports. We also re‐assessed Althuisius 2001, and included Althuisius 2003, which had previously been listed as a report of this study. We also included two new studies (five reports) from the 2016 search (Chandiramani 2010; Ionescu 2012), added five additional reports of two already included studies (MRC/RCOG 1993 (1 report); Owen 2009 (4 reports)). We also identified and excluded another report of a previously excluded study (Secher 2007). We excluded six new studies (Hui 2013;Israfil‐Bayli 2014 (two reports); Ismail 2014; Üçyiğit 2013 (two reports); Zakhera 2015; Zolghadri 2014). There are two ongoing studies (Hezelgrave 2015; Koulalli 2014) and one study (Ragab 2015) awaiting classification. See Figure 1.

Figure 1

Study flow diagram

Included studies

Interventions

Most included studies (n = 10) compared cerclage versus no cerclage (Althuisius 2001; Althuisius 2003; Berghella 2004; Ezechi 2004; Lazar 1984; MRC/RCOG 1993; Owen 2009; Rush 1984; Rust 2000; To 2004). Of these, two studies required women in both the intervention (cerclage) and control (no cerclage) groups to undertake bed rest (Althuisius 2001; Berghella 2004). Three studies incorporated a rescue arm for women randomised to the control group based on physical exam (Owen 2009) or ultrasound‐detected changes of the cervix (Althuisius 2001; Rust 2000).

Two studies compared cerclage versus progesterone for pregnant women with a history of preterm birth undergoing serial ultrasound who developed short cervix (< 25 mm) (Chandiramani 2010; Ionescu 2012). One study compared cervical cerclage versus weekly intramuscular injections of 17 OHP‐C (Keeler 2009).

Two studies compared different management protocols for cervical cerclage: elective cerclage based on previous obstetrical history versus cerclage based on cervical changes on serial transvaginal ultrasound scans (Beigi 2005; Simcox 2009).

Setting

Studies took place in many countries including: USA (4), UK (2), France (2), Netherlands (3), South Africa (2), Brazil, Slovenia, Greece, Chile, Iran, Nigeria, Romania, Hungary, Norway, Italy, Belgium, Zimbabwe, Iceland, Ireland, Belgium and Canada. Two trials took place in multiple countries (MRC/RCOG 1993; To 2004).

Population

Only women at high risk of preterm labour were included in 11 studies. Risk of preterm labour was assessed based on previous obstetrical history (n = 5; Beigi 2005; Ezechi 2004; MRC/RCOG 1993; Rush 1984; Simcox 2009) and serial ultrasound scans (Owen 2009). Lazar 1984 used a mixed scoring system based on obstetrical history, serial ultrasound scans of the cervix and physical exam. Althuisius 2001 assessed risk of preterm labour based on previous obstetrical history in half the population and serial ultrasound scans of the cervix in the other half. Althuisius 2003 assessed women with ultrasound and physical exam. Ionescu 2012 and Chandiramani 2010 included pregnant women with both history of preterm birth and short cervix < 25 mm on serial ultrasound.

To 2004 included an unselected general obstetric population with the need for cerclage assessed using a one‐off ultrasound scan. Three studies included a mixed population, with indication for cerclage based either on serial ultrasound scans of the cervix in women at high risk of preterm birth, or a one‐off ultrasound scan in women at low risk (Berghella 2004; Keeler 2009; Rust 2000).

Nine studies involved singleton pregnancies only (Althuisius 2001; Beigi 2005; Chandiramani 2010; Keeler 2009; Lazar 1984; Owen 2009; Rush 1984; Simcox 2009; To 2004) and four assessed both singleton and multiple pregnancies (Althuisius 2003; Berghella 2004; MRC/RCOG 1993; Rust 2000). Two trials did not state if only singleton pregnancies were included (Ezechi 2004; Ionescu 2012); however, Ezechi 2004 reported individual patient data for singletons only.

We classified trials according to clinical groups for display purposes only: pregnant women with a history of preterm birth (Beigi 2005; Ezechi 2004; Lazar 1984; MRC/RCOG 1993; Rush 1984; Simcox 2009); pregnant women with one‐off ultrasound (To 2004); serial ultrasound (Althuisius 2001; Owen 2009) or using both ultrasound protocols (Berghella 2004; Rust 2000). We included Althuisius 2003 in the physical exam‐indicated subgroup. Three trials compared cerclage with natural progesterone (Chandiramani 2010; Ionescu 2012) or 17 OHP‐C (Keeler 2009).

See Characteristics of included studies.

Excluded studies

We excluded a total of 17 studies; of these, six were excluded based on assessments for the 2016 search. Three studies included only twin pregnancies (Dor 1982; Nicolaides 2001; Rust 2001); six compared different types of cervical cerclage (Broumand 2011; Caspi 1990; Secher 2007; Tsai 2009; Üçyiğit 2013; Zolghadri 2014). We excluded two studies that did not use adequate randomisation procedures (Kassanos 2001; Von Forster 1986). Blair 2002 compared outpatient cerclage with inpatient cerclage. Hui 2013 compared Arabin pessary with no treatment for women with sort cervix at 20 to 24 weeks' gestation. Three trials compared suture materials (Israfil‐Bayli 2014; Ismail 2014). Zakhera 2015 included women for cerclage on the basis of recurrent early bleeding in pregnancy; women did not have a short cervix or history of preterm birth. Varma 1986 is a study protocol, and we doubt that this trial was carried out.

See Characteristics of excluded studies.

Risk of bias in included studies

The overall quality of most studies was good, with adequate reporting of sequence generation, allocation concealment and outcome data. However, several trials had insufficient information in published reports to inform assessment of these key domains. It is not feasible to blind cerclage treatment, and therefore, all trials were assessed at high risk of performance bias due to lack of blinding. We feel that the impact of lack of blinding in trials will vary by outcomes, and we took this into consideration for our GRADE assessments (Characteristics of included studies; Figure 2).

Figure 2

Risk of bias summary: review authors' judgements about each risk of bias item for each included study

Allocation

Six studies reported adequate methods for random sequence generation and concealment allocation (Berghella 2004; Chandiramani 2010; Keeler 2009; Owen 2009; Simcox 2009; To 2004). Allocation concealment was judged as low risk of bias, but sequence generation was unclear in three studies (Althuisius 2001; Althuisius 2003; MRC/RCOG 1993). Six studies had both unclear sequence generation and concealment allocation (Beigi 2005; Ezechi 2004; Ionescu 2012; Lazar 1984; Rush 1984; Rust 2000).

Blinding

Blinding of participants and personnel was not feasible due to the nature of the intervention. Nevertheless, information on attempts to protect against biased assessment of the outcomes (detection bias) was available in one study (Owen 2009). Chandiramani 2010 had adequate blinding for laboratory staff assessing the primary aim of the study (cytokine concentrations).

Incomplete outcome data

Eleven studies adequately addressed the issue of incomplete outcome data assessment (attrition bias) (Althuisius 2001; Althuisius 2003; Berghella 2004; Chandiramani 2010; Ionescu 2012; Keeler 2009; MRC/RCOG 1993; Owen 2009; Rust 2000; Simcox 2009; To 2004). In four studies, the quality of outcome data assessment was judged as unclear (Beigi 2005; Ezechi 2004; Lazar 1984; Rush 1984). Only a few studies provided information on the number of women approached to take part in the study, the number eligible for inclusion, and the overall refusal rate. Although not sources of bias, high exclusion and refusal rates may affect the generalisability of findings and interpretation of results.

Selective reporting

With one exception(To 2004), trial protocols were not available to inform assessment of prespecified primary and secondary outcomes. Despite this, we judged nine studies to be free of selective reporting on the basis that prespecified data extraction forms were provided by the authors (Althuisius 2001; Althuisius 2003; Berghella 2004; Ezechi 2004; MRC/RCOG 1993; Owen 2009; Rush 1984; Rust 2000; To 2004). Selective reporting was judged as unclear in the remaining included studies (Beigi 2005; Chandiramani 2010; Ionescu 2012; Keeler 2009; Lazar 1984; Simcox 2009).

Other potential sources of bias

We assessed 10 studies to be free of other sources of bias (Althuisius 2001; Althuisius 2003; Beigi 2005; Chandiramani 2010; MRC/RCOG 1993; Owen 2009; Rush 1984; Rust 2000; Simcox 2009; To 2004); three studies were judged as unclear (Berghella 2004; Ezechi 2004; Ionescu 2012). Two studies were stopped early and considered to be of high risk of bias (Keeler 2009; Lazar 1984).

Sensitivity analyses

To determine which studies to exclude in sensitivity analyses based on their quality, we referred to both adequate (low risk of bias) labelled sequence generation and adequate (low risk of bias) allocation concealment as essential criteria for adequate quality. If there were obvious additional sources of risk of bias, such as unacceptable attrition or the was trial stopped early, we also considered these factors. We assessed five studies (Berghella 2004; Chandiramani 2010; Owen 2009; Simcox 2009; To 2004) to be at overall low risk of bias (Figure 2).

Effects of interventions

See: Summary of findings for the main comparison Cerclage versus no cerclage

Some trial data included in the analyses for all perinatal losses and baby discharged home healthy outcomes were based on individual patient data meta‐analyses published in Jorgensen 2007. Data for some trials may not match the published reports because we obtained data sets from trial authors (see Characteristics of included studies).

The denominator used for the outcomes of neonatal death, baby discharged home healthy and Apgar less than seven at five minutes, was as far as possible, live births (where reported, we subtracted the number of stillbirths and miscarriages from the total number randomised to calculate live births). The denominator for all other outcomes was the total number of participants randomised. The all perinatal losses outcome includes miscarriage, stillbirth and neonatal death events.

Trial effect estimates are reported according to clinical groups based on indication for cerclage (history‐ or physical‐exam indicated) and trial protocol (one‐off or serial ultrasound) for Comparison 1. We pooled effect estimates for all analyses where heterogeneity was not substantial and did not formally discuss subgroup interaction tests. The small number of trials in clinical groups means these interaction tests are not valid. Plausible explanations for sources of substantial heterogeneity are provided.

GRADEpro GDT software is unable to analyse data split into clinical groups. Therefore, we collapsed the clinical groups for summary of findings outcomes from Comparison 1 and assessed these in Comparison 5 (Cerclage versus no cerclage (Summary of findings outcomes)).

Comparison 1. Cerclage versus no cerclage

Several trials in this comparison were split according to clinical groups as shown in the forest plots.

Primary outcomes

1.1 All perinatal losses

Cerclage may lead to reduced risk of perinatal death when compared with no cerclage, although the confidence interval (CI) just crosses the line of no effect (RR 0.82, 95% CI 0.65 to 1.04; 10 studies, 2927 participants; moderate‐quality evidence; Analysis 1.1).

1.2 Serious neonatal morbidity

Treatment groups had similar rates of serious neonatal morbidity (RR 0.80, 95% CI 0.55 to 1.18; 6 studies, 883 participants; low‐quality evidence; Analysis 1.2).

1.3 Baby discharged home healthy

In four trials similar numbers of women with and without cerclage had healthy babies discharged home (RR 1.02, 95% CI 0.97 to 1.06; 4 studies, 657 participants; moderate‐quality evidence; Analysis 1.3).

Secondary outcomes

1.4 Stillbirth and 1.6 Miscarriage

There was no evidence that cerclage had an impact on rates of stillbirth (RR 0.89, 95% CI 0.45 to 1.75; 5 studies, 1803 participants; low‐quality evidence; Analysis 1.4) or miscarriage (RR 0.84, 95% CI 0.58 to 1.22; 7 studies, 2091 participants; Analysis 1.6).

1.5 Neonatal deaths before discharge

There was no clear evidence that cerclage prevented neonatal deaths before discharge (RR 0.85, 95% CI 0.53 to 1.39; 6 studies, 1714 participants; low‐quality evidence; Analysis 1.5).

1.7 Preterm birth < 37 weeks, 1.8 Preterm birth < 34 weeks, 1.9 Preterm birth < 28 weeks

Cerclage was associated with reduced risk of preterm births before 37 weeks, with some heterogeneity noted (average RR 0.80, 95% CI 0.69 to 0.95; 9 studies, 2898 participants; I² = 39%; Analysis 1.7). Pregnant women who underwent cerclage were also less likely to give birth before 34 weeks' gestation (average RR 0.77, 95% CI 0.66 to 0.89; 9 studies, 2415 participants; high‐quality evidence; Analysis 1.8) and also probably less likely to give birth before 28 weeks, although this result was marginal, with the CI meeting the line of no effect (RR 0.80, 95% CI 0.64 to 1.00; 8 studies, 2392 participants; Analysis 1.9).

Reporting of various aspects of neonatal morbidity was inconsistent and meta‐analyses showed no clear evidence of an effect from cerclage. There was marginally more respiratory morbidity in the cerclage group (Analysis 1.11), but less intracranial pathology (Analysis 1.10), less necrotising enterocolitis (Analysis 1.12) and less retinopathy of prematurity (Analysis 1.13) with cerclage. None of these differences reached statistical significance.

One small trial reported similar numbers of babies with Apgar score less than seven at five minutes in both treatment arms (RR 0.68, 95% CI 0.40 to 1.15; 301 participants; Analysis 1.14).

1.15 Caesarean section (emergency and elective)

Women with cerclage were more likely to have caesarean sections, although the CI for this result was marginal (RR 1.19, 95% CI 1.01 to 1.40; 8 studies, 2817 participants; Analysis 1.15).

1.16 Maternal side effects

Cervical cerclage was associated with a higher rate of maternal side effects (vaginal discharge and bleeding and pyrexia) although this result did not reach statistical significance and had substantial heterogeneity (average RR 2.25, 95% CI 0.89 to 5.69; 3 studies, 953 participants; I² = 66%; Analysis 1.16). An increased risk of pyrexia appears to be a particular problem, with three trials reporting significantly higher rates in cerclage groups (6% versus 2.4%) (RR 2.39, 95% CI 1.35 to 4.23; 1245 participants; Analysis 1.17).

Two small trials reported similar numbers of women receiving any intravenous, oral or combined tocolysis in both arms (RR 1.28, 95% CI 0.80 to 2.05; 2 studies, 217 participants; Analysis 1.18).

1.19 Preterm premature rupture of membranes (PPROM) (not prespecified)

There was no evidence of a difference in the rates of PPROM, although this analysis had substantial heterogeneity (average RR 0.96, 95% CI 0.62 to 1.48; 6 studies, 2010 participants; I² = 33%; Analysis 1.19).

1.20 Chorioamnionitis (not prespecified)

There were similar group rates of chorioamnionitis showing no evidence of benefit of cerclage, with the exception of Althuisius 2001. However, Althuisius 2001 contributed to substantial heterogeneity in the analysis (average RR 0.84, 95% CI 0.26 to 2.72; 3 studies, 1506 participants; I² = 58%; Analysis 1.20).

Subgroup analysis

Where possible, five potential subgroups were examined: history‐indicated cerclage; one‐off ultrasound‐indicated cerclage in high risk women, serial ultrasound‐indicated cerclage, physical exam‐indicated cerclage (rescue cerclage) and one‐off ultrasound‐indicated cerclage in low or unspecified risk women. There were too few trials in each subgroup to make meaningful conclusions.

Sensitivity analysis

Three studies were assessed as high quality (Berghella 2004; Owen 2009; To 2004) based on adequate reported methods of sequence generation and allocation concealment. Confidence intervals overlapped for estimates of primary outcomes, and conclusions regarding effect estimates for our primary outcomes did not change when trials of worse quality were removed from analyses (data not shown).

Comparison 2. Cerclage versus vaginal progesterone

Chandiramani 2010 compared cerclage and natural progesterone (Cyclogest) in a small randomised study nested in a larger prospective observational study. All pregnant women underwent serial ultrasound, but only those with a history of preterm birth who developed a short cervix (< 25 mm) at less than 24 weeks' gestation were randomised to receive treatment. Ionescu 2012 randomised pregnant women with short cervix (< 25 mm) at 19 to 24 weeks' gestation; this trial was reported as an abstract only, but received additional information and unpublished data through correspondence with the author. Few data per outcome limit the conclusions that can be made for this comparison.

There was considerable heterogeneity for several outcomes in this comparison. Differences in relative effects may be due to the different trial objectives (the primary outcome in Chandiramani 2010 was cervical cytokines); the dose of progesterone also differed (400 mg/day Chandiramani 2010 and 200 mg/day Ionescu 2012).

There were no group differences detected for any review outcome, apart from greater incidence of PPROM in the cerclage arm in a single small trial (N = 92)(Ionescu 2012).

Primary outcomes

2.1 All perinatal losses

Cerclage and progesterone had similar efficacy to prevent perinatal deaths (RR 0.94, 95% CI 0.36 to 2.48; 2 studies, 108 participants; Analysis 2.1).

2.2 Serious neonatal morbidity

Two small trials reached different conclusions regarding the relative effect of progesterone on serious morbidity (average RR 0.49, 95% CI 0.05 to 4.52; 2 studies, 120 participants; I² = 84%; Analysis 2.2).

2.3 Baby discharged home healthy

There were no clear differences in the number of babies who went home healthy (RR 0.97, 95% CI 0.88 to 1.07; 2 studies, 119 participants; Analysis 2.3).

Secondary outcomes

2.4 Stillbirth

There were no treatment group differences detected in rates of stillbirth (RR 2.70, 95% CI 0.12 to 62.17; 2 studies, 128 participants; Analysis 2.4).

2.5 Neonatal deaths before discharge

There were no treatment group differences detected for rates of neonatal death (RR 2.18, 95% CI 0.34 to 13.86; 2 studies, 120 participants; Analysis 2.5).

2.6 Miscarriages

Similar numbers of pregnant women miscarried in each treatment group (RR 0.58, 95% CI 0.17 to 2.01; 2 studies, 128 participants; Analysis 2.6).

2.7 Preterm birth < 37 weeks, 2.8 Preterm birth < 34 weeks, 2.9 Preterm birth < 28 weeks

Data were sparse, and results for preterm birth at all time points showed no evidence of a difference between treatments: preterm birth < 37 weeks (RR 1.16, 95% CI 0.64 to 2.08; 2 studies, 128 participants; Analysis 2.7); preterm birth < 34 weeks (RR 1.01, 95% CI 0.51 to 2.01; 2 studies, 128 participants; Analysis 2.8); preterm birth < 28 weeks (RR 0.92, 95% CI 0.37 to 2.27; 2 studies, 128 participants; Analysis 2.9).

There was no evidence of group differences for the following review outcomes: serious intracranial pathology (intraventricular haemorrhage or periventricular leukomalacia: RR 0.96, 95% CI 0.17 to 5.28; 2 studies, 128 participants; Analysis 2.10); serious respiratory morbidity (respiratory distress syndrome or oxygen dependency after 28 days of life (average RR 0.48, 95% CI 0.04 to 6.41; 2 studies, 128 participants; I² = 64%; Analysis 2.11); Apgar less than seven at five minutes (RR 1.90, 95% CI 0.37 to 9.80; 2 studies, 120 participants; Analysis 2.14); caesarean section (average RR 0.67, 95% CI 0.18 to 2.47; 2 studies, 128 participants; I² = 70%; Analysis 2.15); and chorioamnionitis (RR 1.53, 95% CI 0.10 to 23.61; 2 studies, 128 participants; I² = 54%; Analysis 2.21).

Ionescu 2012 reported very few events and no group differences for necrotising enterocolitis (RR 3.00, 95% CI 0.13 to 71.78; 92 participants; Analysis 2.12) and retinopathy of prematurity (RR 1.00, 95% CI 0.06 to 15.51; 92 participants; Analysis 2.13).

Ionescu 2012 reported very few maternal side effects (vaginal discharge, bleeding or pyrexia not requiring antibiotics) (RR 3.00, 95% CI 0.32 to 27.79; 92 participants; Analysis 2.17) and no instances of maternal pyrexia in either treatment arm (RR not calculated due to zero events in both arms; 92 participants).

No trials reported maternal infection requiring intervention (antibiotics or delivery).

Progesterone led to fewer women with preterm premature rupture of membranes, although this result was based on a single trial (Ionescu 2012) with few events and small sample size (RR 8.00, 95% CI 1.04 to 61.42; 92 participants; Analysis 2.20).

Sensitivity analysis

There were too few studies in this comparison to conduct sensitivity analysis.

Comparison 3. Cerclage versus intramuscular progesterone

Keeler 2009 (79 participants) compared cerclage with weekly intramuscular injections of 17 α‐hydroxyprogesterone caproate in women with a short cervix detected by transvaginal ultrasound scan. The study was interrupted after three years of recruitment because interim analysis did not reveal any obvious differences in obstetric and neonatal outcomes. Therefore the results of this trial must be interpreted with caution (Keeler 2009).

Primary outcomes

3.1 All perinatal losses

There was no evidence of a difference in prevention of perinatal death (RR 1.12, 95% CI 0.58 to 2.16; Analysis 3.1).

3.2 Serious neonatal morbidity

There were similar rates of neonatal morbidity in treatment groups (RR 1.13, 95% CI 0.47 to 2.74; Analysis 3.2).

3.3 Baby discharged home healthy

Similar numbers of healthy infants were reported in both treatment arms (RR 1.17, 95% CI 0.82 to 1.67; Analysis 3.3).

Secondary outcomes

No trials reported the following secondary outcomes: stillbirth, neonatal death before discharge, preterm birth less than 34 weeks, serious intracranial pathology, serious respiratory morbidity, necrotising enterocolitis, retinopathy of prematurity, Apgar less than seven at five minutes, caesarean section, maternal infection, maternal side effects or maternal pyrexia. Keeler 2009 (79 participants) provided data for the following analyses.

3.6 Miscarriages

There was no clear evidence of an impact on the risk of miscarriage (RR 1.47, 95% CI 0.38 to 5.73; Analysis 3.6).

Data were sparse, and results for preterm birth at all time points showed no evidence of a difference between treatments.

3.7 Preterm birth < 37 weeks

Cerclage and intramuscular progesterone were associated with similar risks of preterm birth (RR 0.88, 95% CI 0.60 to 1.30; Analysis 3.7).

3.9 Preterm birth < 28 weeks

There was no clear evidence of group differences for preterm birth less than 28 weeks, although data were few (RR 1.26, 95% CI 0.53 to 2.97; Analysis 3.9).

3.19 Preterm premature rupture of membranes

Pregnant women with cerclage and intramuscular progesterone experienced similar rates of preterm premature rupture of membranes (RR 0.88, 95% CI 0.47 to 1.65; Analysis 3.19).

3.20 Chorioamnionitis

Pregnant women in both treatment groups had similar rates of chorioamnionitis (RR 1.32, 95% CI 0.61 to 2.88; Analysis 3.20).

Sensitivity analysis

There were too few studies in this comparison to conduct sensitivity analysis.

Comparison 4. Cerclage versus pessary

There were no included trials eligible for this comparison and therefore no data for any review outcome.

Comparison 5. Comparisons of different cerclage protocols

Simcox 2009 and Beigi 2005 compared the benefits of two cerclage protocols in women at high risk of preterm birth. In one group, the indication to perform cerclage was based on previous history, in the other women had cerclage only if the cervix was found to be short on transvaginal ultrasound (≤ 20 mm). The trials were not entirely comparable because only 20% of high risk women in Simcox 2009 received cerclage when assigned to elective management (80% were left untreated). Beigi 2005 treated all women; one arm were treated with elective cerclage and the other arm with serial transvaginal sonography followed by ultrasound‐indicated cerclage. Of the women randomised to this second arm, 54% received cerclage.

There was no significant difference in any of the primary and secondary outcomes in either of these trials. Miscarriage rate was the only prespecified outcome reported by both trials (Analysis 5.6).

Sensitivity analysis

Simcox 2009 was assessed as a high‐quality study, but with only two studies included in this comparison, formal sensitivity analysis based on quality was not appropriate.

Comparison 6. Summary of findings outcomes

We include GRADE assessments in our reporting of Comparison 1; the outcomes reported under this comparison are identical to those above in Comparison 1.

Discussion

Summary of main results

The evidence from 15 included randomised trials demonstrated that, compared with expectant management, the placement of cervical cerclage in women at risk of preterm birth reduced risk of preterm birth.

The key issue is whether such prolongation of pregnancy improves the outcome for the baby; there is a distinct possibility that a baby may be better off after an early birth in a setting with adequate neonatal care resources. The difference in all perinatal losses was not established because the upper limit for the 95% confidence interval (CI) for the pooled effect estimate crossed the line of no effect (RR 0.82, 95% CI 0.65 to 1.04; 10 studies, 2927 participants). Women with cerclage and expectant management had a similar rate of serious neonatal morbidity and a similar chance of having a healthy baby at discharge.

The key question regarding long‐term development in terms of neurological and respiratory outcomes was not addressed; most trials did not follow‐up mother and baby after discharge from hospital. Data for short‐term neonatal morbidity are also sparse because of inconsistencies between trials in terms of how this outcome was defined and reported.

In terms of safety, it is clear that cerclage is associated with a higher rate of maternal side effects, especially pyrexia. However, side effects tend to be self‐limiting (vaginal discharge and bleeding) or treatable (pyrexia) and do not appear to put maternal health at risk. The higher rates of caesarean section after cervical cerclage have not been reported previously. This is unsurprising given few participants in primary studies and relatively modest increase in absolute terms (3% absolute risk increase; 95% CI 0.06% to 5.5% increase). The exact mechanism is difficult to establish, but we were mindful that none of the trials was double‐blind. The decision to perform caesarean section is very subjective, and therefore, the knowledge of allocated treatment may have been a significant source of bias. It is possible that cervical cerclage causes damage to the cervix that increases the need for caesarean section. However, we also speculate that increased caesarean section is due to biased (more frequent) diagnosis of failed induction or failure to progress in labour when clinicians know that a woman had cervical cerclage earlier in pregnancy.

We prespecified three clinical scenarios based on the indications for cervical cerclage in current clinical practice:

history‐indicated cerclage ‐ usually because of previous preterm births and sometimes referred to as elective cerclage;
cerclage performed because a short cervix is found on transvaginal sonography (one‐off ultrasound indicated cerclage and serial ultrasound‐indicated cerclage); and
physical exam‐indicated cerclage, also called emergency or rescue cerclage, when symptomatic women are found to have either significant cervical shortening or cervical dilatation detected on vaginal examination (performed digitally or with speculum).

We found four trials of history‐indicated cerclage, five trials of ultrasound‐indicated cerclage and one small trial of physical exam‐indicated cerclage.

Women with previous preterm birth are often extremely anxious in subsequent pregnancies and there are an increasing number of specialist clinics for these women. The issue of prevention is clearly a hot topic, particularly when a cervix is found to be short on transvaginal sonography. Treatment options include daily vaginal pessaries of natural progesterone (Fonseca 2007; Hassan 2011), weekly intramuscular injections of 17 α‐hydroxyprogesterone (Meis 2003), or Arabin pessary (Arabin 2003).

No robust conclusions could be made about cerclage versus alternative interventions such as vaginal and intramuscular progesterone or pessary. Two studies compared cerclage to vaginal progesterone (Chandiramani 2010; Ionescu 2012). These two trials had different objectives (the primary outcome of the Chandiramani 2010 trial was cervical cytokines) and used different dose of progesterone ‐ differences which likely contributed to the significant heterogeneity noted in meta‐analyses.

Only Keeler 2009 attempted to compare ultrasound‐indicated cerclage with 17 α‐hydroxyprogesterone, but this trial was halted prematurely and was too small for any meaningful conclusions to be made. No included trials assessed cerclage versus pessary. These findings underline the necessity of high quality data.

There is also the question of whether it is better to perform a prophylactic procedure electively in early pregnancy, or wait and see if the cervix gets shorter before performing cerclage. Simcox 2009 and Beigi 2005 attempted to answer this question but both studies were quite small and important clinical outcomes were reported inconsistently, precluding meaningful comparisons and conclusions from pooled data. Interestingly, in the Simcox 2009 study only 20% of the women managed without ultrasound scans had cerclage, despite being identified as of high risk. An improved design may have been for women to be randomised only if clinicians were in equipoise whether to perform prophylactic cerclage or wait for ultrasound shortening of the cervix, as was the case in Beigi 2005.

Overall completeness and applicability of evidence

The consistency in the size and direction of effects across all clinical scenarios is reassuring. However, the lack of robust neonatal morbidity data and lack of long‐term follow‐up studies, in particular, are considerable weaknesses. As the data are emerging that natural vaginal progesterone has a more pronounced protective effect for women with a short cervix (Fonseca 2007; Hassan 2011), the role of cervical cerclage in the prevention of preterm birth remains unclear.

There is often a lot of pressure to perform cervical cerclage in early pregnancy as a prophylaxis for women who have experienced late miscarriage in a previous pregnancy. Unfortunately, the results from Simcox 2009 and Beigi 2005 are inconclusive and further similar studies are urgently needed with strict inclusion criteria and firm management protocols.

We were unable to provide what would be considered as definitive evidence regarding benefits, or harms, associated with rescue cerclage, i.e. cerclage performed when women are found to have a dilated cervix in the second trimester of pregnancy. Published observational data are likely to be biased (Pereira 2007), but consenting and randomising this group of patients is very difficult.

Quality of the evidence

Overall, most included trials were at low risk of bias. Selective reporting of the results is always a concern when trial protocols are unavailable for review. We significantly minimised this risk by asking study authors to provide outcome data for prespecified outcomes, including individual patient data if available. It was particularly gratifying that the response was excellent and additional information was provided by Althuisius 2001; Chandiramani 2010; MRC/RCOG 1993; Owen 2009; Rush 1984; Rust 2000 and To 2004.

Performance bias (blinding of personnel and participants) will always be an issue in cerclage trials; it is not practical to blind participants to the type of treatment. However, several key outcomes (perinatal mortality, serious neonatal morbidity) and gestational age at birth are objective and therefore, unlikely to be influenced by lack of blinding.

For the comparison of cerclage versus no cerclage we assessed six primary and secondary outcomes using GRADE methods. Perinatal deaths evidence was assessed as moderate quality (good quality trials and adequate sample size); we downgraded the evidence one level because the confidence interval just crossed 1. We assessed evidence for preterm birth before 34 weeks' gestation to be of high quality. Evidence for baby discharged home healthy was assessed as moderate quality, downgraded one level due to small sample size. Serious neonatal morbidity, neonatal death and stillbirth were all assessed as low quality due to small sample size and wide confidence intervals crossing the line of no effect.

Potential biases in the review process

We followed the proscribed Cochrane methods for reducing bias in the process of writing a systematic review. We conducted a comprehensive search of the literature and have no reason to believe any relevant trials were left out. We completed study selection, appraisal and data extraction in duplicate.

Agreements and disagreements with other studies or reviews

Systematic reviews

An indirect meta‐analysis compared progesterone and cerclage for women with ultrasound‐detected short cervix (< 25 mm), singleton pregnancy and history of preterm birth. Treatments were estimated to be of similar efficacy for preventing preterm birth. Compared with placebo or no cerclage, both interventions reduced the risk of preterm birth before 32 weeks and composite perinatal morbidity and mortality (Conde‐Agudelo 2013).

A recent network meta‐analysis compared use of cerclage, progesterone and pessary. The review included 40 trials and 11,637 women and found pessary ranked best for preterm birth before 37 weeks, followed by progesterone with cerclage not more effective than control. For births before 34 weeks, no single treatment (cerclage, pessary or progesterone) was significantly better than control (Jarde 2016).

An individual patient data meta‐analysis comparing cerclage versus no cerclage in patients at high risk of preterm labour did not demonstrate a statistically significant reduction of perinatal loss in the cerclage group (Jorgensen 2007). Furthermore, the main indication for cerclage (obstetric history versus short cervical length) did not influence the effect estimate for pregnancy loss.

A meta‐analysis by Berghella 2011a compared cerclage versus no cerclage in a subgroup of women with short cervix and previous preterm delivery. Berghella 2011a reported a significant decrease in preterm births in the cerclage group, together with a significant decrease in composite perinatal mortality and morbidity. When considered individually, perinatal mortality and composite morbidity decreased in the cerclage group (perinatal mortality 8.8% versus 13.8% and composite neonatal morbidity 8.2% versus 14.3% respectively), although statistical significance was not achieved. These data were broadly in accordance with our results.

Berghella and colleagues published a separate meta‐analysis comparing history‐indicated cerclage with ultrasound‐indicated cerclage in women at high risk for preterm labour (Berghella 2011b). Berghella 2011b did not identify any differences in terms of preterm birth or perinatal outcomes between management strategies and concluded that women with prior preterm birth may be monitored safely with ultrasound‐indicated cerclage. Berghella 2011b suggested that history‐indicated cerclage should be reserved for women with three prior early preterm births or second‐trimester losses.

Our analysis did not find significant differences in key primary and secondary outcomes; however, we urge caution in interpreting data. Unlike Berghella 2011b, we excluded Kassanos 2001 from our analysis, because this was likely to be a quasi‐randomised study. Data from Althuisius 2001 were not included because primary randomisation was to prophylactic cerclage or no treatment. Two included studies comparing history‐indicated with ultrasound‐indicated cerclage (Beigi 2005; Simcox 2009) are not entirely comparable because in Simcox 2009 only 20% of women randomised to the elective cerclage group received the intervention. For this reason, we feel that it is too premature to conclude that both management strategies are equally safe.

Emergency cerclage

A recent meta‐analysis pooled data on the use of emergency cerclage in pregnant women with singleton pregnancy and cervical dilation of at least 0.5 cm. Evidence comparing cerclage with no cerclage from 10 studies (1 randomised controlled trial and 9 cohort studies) and 757 women showed an association between emergency cerclage and improved neonatal survival as well as prolongation of pregnancy for approximately one month (Ehsanipoor 2015).

A retrospective study of 158 pregnant women receiving emergency cerclage for cervical dilation and bulging membranes (mean gestation 21.45 weeks; SD 2.23) reported that cerclage placement led to live birth for 130/158 women. The study authors compared women with dilation > 3 cm and women with dilation < 3 cm; survival, birthweight and suture‐to‐delivery interval were all greater for women with cervical dilation < 3 cm (Zhu 2015).

Observational evidence

A retrospective, multicentre cohort study examined a specific subset of pregnant women with singleton pregnancy. All included women had a preterm birth before 37 weeks for their first pregnancy. All women had ultrasound‐indicated cerclage for short cervix (< 25 mm) during their second pregnancy. At the third singleton pregnancy, women received either history‐indicated cerclage or transvaginal ultrasound screening. The cohort study compared outcomes from the third pregnancy; 38 women received cervical length screening and 64 women underwent cerclage. Pregnancy outcomes were similar for women managed with either cerclage or ultrasound, but just under half of women receiving ultrasound screening developed short cervix < 25 mm and required cerclage (Suhag 2015).

Khalifeh 2016 argued for a cervical length screening programme for all pregnant women, with cut‐off of < 25 mm as standard; the study authors proposed that such a test is acceptable to women, effective in preventing the prevalent condition of preterm birth, and cost‐effective.

Figure 1

Study flow diagram

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Figure 2

Risk of bias summary: review authors' judgements about each risk of bias item for each included study

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Analysis 1.1

Comparison 1 Cerclage versus no cerclage, Outcome 1 All perinatal losses.

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Analysis 1.2

Comparison 1 Cerclage versus no cerclage, Outcome 2 Serious neonatal morbidity.

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Analysis 1.3

Comparison 1 Cerclage versus no cerclage, Outcome 3 Baby discharged home healthy.

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Analysis 1.4

Comparison 1 Cerclage versus no cerclage, Outcome 4 Stillbirths.

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Analysis 1.5

Comparison 1 Cerclage versus no cerclage, Outcome 5 Neonatal deaths before discharge.

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Analysis 1.6

Comparison 1 Cerclage versus no cerclage, Outcome 6 Miscarriages.

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Analysis 1.7

Comparison 1 Cerclage versus no cerclage, Outcome 7 Preterm birth before 37 completed weeks.

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Analysis 1.8

Comparison 1 Cerclage versus no cerclage, Outcome 8 Preterm birth before 34 completed weeks.

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Analysis 1.9

Comparison 1 Cerclage versus no cerclage, Outcome 9 Preterm birth before 28 completed weeks.

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Analysis 1.10

Comparison 1 Cerclage versus no cerclage, Outcome 10 Serious intracranial pathology (IVH or periventricular leukomalacia).

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Analysis 1.11

Comparison 1 Cerclage versus no cerclage, Outcome 11 Serious respiratory morbidity (RDS or oxygen dependency after 28 days of life).

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Analysis 1.12

Comparison 1 Cerclage versus no cerclage, Outcome 12 Necrotising enterocolitis.

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Analysis 1.13

Comparison 1 Cerclage versus no cerclage, Outcome 13 Retinopathy of prematurity.

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Analysis 1.14

Comparison 1 Cerclage versus no cerclage, Outcome 14 Apgar < 7 at 5 minutes.

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Analysis 1.15

Comparison 1 Cerclage versus no cerclage, Outcome 15 Caesarean section (elective and emergency).

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Analysis 1.16

Comparison 1 Cerclage versus no cerclage, Outcome 16 Maternal side effects (vaginal discharge, bleeding, pyrexia not requiring antibiotics).

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Analysis 1.17

Comparison 1 Cerclage versus no cerclage, Outcome 17 Pyrexia.

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Analysis 1.18

Comparison 1 Cerclage versus no cerclage, Outcome 18 Any intravenous, oral or combined tocolysis (not prespecified).

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Analysis 1.19

Comparison 1 Cerclage versus no cerclage, Outcome 19 PPROM (not prespecified).

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Analysis 1.20

Comparison 1 Cerclage versus no cerclage, Outcome 20 Chorioamnionitis (not prespecified).

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Analysis 2.1

Comparison 2 Cerclage versus vaginal progesterone, Outcome 1 All perinatal losses.

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Analysis 2.2

Comparison 2 Cerclage versus vaginal progesterone, Outcome 2 Serious neonatal morbidity.

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Analysis 2.3

Comparison 2 Cerclage versus vaginal progesterone, Outcome 3 Baby discharged home healthy.

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Analysis 2.4

Comparison 2 Cerclage versus vaginal progesterone, Outcome 4 Stillbirths.

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Analysis 2.5

Comparison 2 Cerclage versus vaginal progesterone, Outcome 5 Neonatal deaths before discharge.

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Analysis 2.6

Comparison 2 Cerclage versus vaginal progesterone, Outcome 6 Miscarriages.

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Analysis 2.7

Comparison 2 Cerclage versus vaginal progesterone, Outcome 7 Preterm birth before 37 completed weeks.

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Analysis 2.8

Comparison 2 Cerclage versus vaginal progesterone, Outcome 8 Preterm birth before 34 completed weeks.

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Analysis 2.9

Comparison 2 Cerclage versus vaginal progesterone, Outcome 9 Preterm birth before 28 completed weeks.

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Analysis 2.10

Comparison 2 Cerclage versus vaginal progesterone, Outcome 10 Serious intracranial pathology (IVH or periventricular leucomalacia).

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Analysis 2.11

Comparison 2 Cerclage versus vaginal progesterone, Outcome 11 Serious respiratory morbidity (RDS or oxygen dependency after 28 days of life).

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Analysis 2.12

Comparison 2 Cerclage versus vaginal progesterone, Outcome 12 Necrotising enterocolitis.

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Analysis 2.13

Comparison 2 Cerclage versus vaginal progesterone, Outcome 13 Retinopathy of prematurity.

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Analysis 2.14

Comparison 2 Cerclage versus vaginal progesterone, Outcome 14 Apgar < 7 at 5 minutes.

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Analysis 2.15

Comparison 2 Cerclage versus vaginal progesterone, Outcome 15 Caesarean section (elective and emergency).

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Analysis 2.17

Comparison 2 Cerclage versus vaginal progesterone, Outcome 17 Maternal side effects (vaginal discharge, bleeding, pyrexia not requiring antibiotics).

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Analysis 2.18

Comparison 2 Cerclage versus vaginal progesterone, Outcome 18 Pyrexia.

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Analysis 2.19

Comparison 2 Cerclage versus vaginal progesterone, Outcome 19 Any intravenous, oral or combined tocolysis (not prespecified).

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Analysis 2.20

Comparison 2 Cerclage versus vaginal progesterone, Outcome 20 PPROM (not prespecified).

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Analysis 2.21

Comparison 2 Cerclage versus vaginal progesterone, Outcome 21 Chorioamnionitis (not prespecified).

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Analysis 3.1

Comparison 3 Cerclage versus intramuscular progesterone, Outcome 1 All perinatal losses.

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Analysis 3.2

Comparison 3 Cerclage versus intramuscular progesterone, Outcome 2 Serious neonatal morbidity.

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Analysis 3.3

Comparison 3 Cerclage versus intramuscular progesterone, Outcome 3 Baby discharged home healthy.

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Analysis 3.6

Comparison 3 Cerclage versus intramuscular progesterone, Outcome 6 Miscarriages.

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Analysis 3.7

Comparison 3 Cerclage versus intramuscular progesterone, Outcome 7 Preterm birth before 37 completed weeks.

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Analysis 3.9

Comparison 3 Cerclage versus intramuscular progesterone, Outcome 9 Preterm birth before 28 completed weeks.

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Analysis 3.19

Comparison 3 Cerclage versus intramuscular progesterone, Outcome 19 PPROM (not prespecified).

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Analysis 3.20

Comparison 3 Cerclage versus intramuscular progesterone, Outcome 20 Chorioamnionitis (not prespecified).

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Analysis 5.1

Comparison 5 Any comparison of different cerclage protocols, Outcome 1 All perinatal losses.

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Analysis 5.2

Comparison 5 Any comparison of different cerclage protocols, Outcome 2 Serious neonatal morbidity.

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Analysis 5.4

Comparison 5 Any comparison of different cerclage protocols, Outcome 4 Stillbirths.

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Analysis 5.5

Comparison 5 Any comparison of different cerclage protocols, Outcome 5 Neonatal deaths before discharge.

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Analysis 5.6

Comparison 5 Any comparison of different cerclage protocols, Outcome 6 Miscarriages.

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Analysis 5.7

Comparison 5 Any comparison of different cerclage protocols, Outcome 7 Preterm birth before 37 completed weeks.

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Analysis 5.8

Comparison 5 Any comparison of different cerclage protocols, Outcome 8 Preterm birth before 34 completed weeks.

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Analysis 5.10

Comparison 5 Any comparison of different cerclage protocols, Outcome 10 Serious intracranial pathology (IVH or periventricular leucomalacia).

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Analysis 5.11

Comparison 5 Any comparison of different cerclage protocols, Outcome 11 Serious respiratory morbidity (RDS or oxygen dependency after 28 days of life).

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Analysis 5.16

Comparison 5 Any comparison of different cerclage protocols, Outcome 16 Maternal infection requiring intervention(antibiotics or delivery).

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Analysis 5.17

Comparison 5 Any comparison of different cerclage protocols, Outcome 17 Maternal side effects (vaginal discharge, bleeding, pyrexia not requiring antibiotics).

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Analysis 5.18

Comparison 5 Any comparison of different cerclage protocols, Outcome 18 Tocolysis (not prespecified).

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Analysis 6.1

Comparison 6 Cerclage versus no cerclage (Summary of findings outcomes), Outcome 1 All perinatal losses.

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Analysis 6.2

Comparison 6 Cerclage versus no cerclage (Summary of findings outcomes), Outcome 2 Serious neonatal morbidity.

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Analysis 6.3

Comparison 6 Cerclage versus no cerclage (Summary of findings outcomes), Outcome 3 Baby discharged home healthy.

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Analysis 6.4

Comparison 6 Cerclage versus no cerclage (Summary of findings outcomes), Outcome 4 Stillbirths.

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Analysis 6.5

Comparison 6 Cerclage versus no cerclage (Summary of findings outcomes), Outcome 5 Neonatal deaths before discharge.

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Analysis 6.6

Comparison 6 Cerclage versus no cerclage (Summary of findings outcomes), Outcome 6 Preterm birth before 34 completed weeks.

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Summary of findings for the main comparison. Cerclage versus no cerclage

Cerclage versus no cerclage
Patient or population: preventing preterm birth in women with singleton pregnancy Setting: Belgium, Brazil, Canada, Chile, France, Greece, Hungary, Iceland, Ireland, Italy, Netherlands, Norway, South Africa, Slovenia, UK, USA, Zimbabwe Intervention: cerclage Comparison: no cerclage
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Quality of the evidence (GRADE)	Comments
	Risk with no cerclage (SoF outcomes)	Risk with cerclage
All perinatal losses	Study population		RR 0.82 (0.65 to 1.04)	2927 (10 RCTs)	⊕⊕⊕⊝ MODERATE¹
	92 per 1000	75 per 1000 (60 to 96)
Serious neonatal morbidity	Study population		RR 0.80 (0.55 to 1.18)	883 (6 RCTs)	⊕⊕⊝⊝ LOW ²
	116 per 1000	93 per 1000 (64 to 136)
Baby discharged home healthy	Study population		RR 1.02 (0.97 to 1.06)	657 (4 RCTs)	⊕⊕⊕⊝ MODERATE³
	912 per 1000	930 per 1000 (885 to 967)
Stillbirths	Study population		RR 0.89 (0.45 to 1.75)	1803 (5 RCTs)	⊕⊕⊝⊝ LOW ²
	19 per 1000	17 per 1000 (9 to 33)
Neonatal deaths before discharge	Study population		RR 0.85 (0.53 to 1.39)	1714 (6 RCTs)	⊕⊕⊝⊝ LOW ²
	35 per 1000	30 per 1000 (19 to 49)
Preterm birth before 34 completed weeks	Study population		average RR 0.77 (0.66 to 0.89)	2415 (9 RCTs)	⊕⊕⊕⊕ HIGH⁴
	238 per 1000	183 per 1000 (157 to 212)
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio; OR: Odds ratio;
GRADE Working Group grades of evidence High quality: We are very confident that the true effect lies close to that of the estimate of the effect Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
¹ Wide confidence interval crossing the line of no effect (‐1). ² Wide confidence interval crossing the line of no effect and small sample size (‐2) ³ Estimate based on small sample size (‐1). 4 Random effects model retained from primary analysis; there is no substantive difference in the risk estimate or the confidence intervals with fixed or random effects.

Summary of findings for the main comparison. Cerclage versus no cerclage

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Comparison 1. Cerclage versus no cerclage

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 All perinatal losses Show forest plot	10	2927	Risk Ratio (M‐H, Fixed, 95% CI)	0.82 [0.65, 1.04]

1.1 History‐indicated cerclage vs no cerclage	4	2045	Risk Ratio (M‐H, Fixed, 95% CI)	0.82 [0.60, 1.12]
1.2 One‐off ultrasound‐indicated cerclage in high risk for PTL vs no cerclage	1	56	Risk Ratio (M‐H, Fixed, 95% CI)	0.77 [0.14, 4.25]
1.3 Serial ultrasound‐indicated cerclage in high risk for PTL vs no cerclage	4	509	Risk Ratio (M‐H, Fixed, 95% CI)	0.66 [0.41, 1.06]
1.4 Physical exam indicated cerclage vs no cerclage	1	30	Risk Ratio (M‐H, Fixed, 95% CI)	1.97 [0.77, 5.01]
1.5 One‐off ultrasound‐indicated cerclage in low/unspecified risk for PTL vs no cerclage	3	287	Risk Ratio (M‐H, Fixed, 95% CI)	1.01 [0.46, 2.22]
2 Serious neonatal morbidity Show forest plot	6	883	Risk Ratio (M‐H, Random, 95% CI)	0.84 [0.57, 1.25]

2.1 History‐indicated cerclage vs no cerclage	0	0	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
2.2 One‐off ultrasound‐indicated cerclage in high risk for PTL vs no cerclage	1	56	Risk Ratio (M‐H, Random, 95% CI)	0.77 [0.14, 4.25]
2.3 Serial ultrasound‐indicated cerclage in high risk for PTL vs no cerclage	4	510	Risk Ratio (M‐H, Random, 95% CI)	0.77 [0.48, 1.25]
2.4 Physical exam‐indicated cerclage in high risk for PTL vs no cerclage	1	30	Risk Ratio (M‐H, Random, 95% CI)	0.22 [0.03, 1.73]
2.5 One‐off ultrasound‐indicated cerclage in low/unspecified risk for PTL vs no cerclage	3	287	Risk Ratio (M‐H, Random, 95% CI)	1.38 [0.60, 3.17]
3 Baby discharged home healthy Show forest plot	4	657	Risk Ratio (M‐H, Fixed, 95% CI)	1.02 [0.97, 1.06]

3.1 History‐indicated cerclage vs no cerclage	1	183	Risk Ratio (M‐H, Fixed, 95% CI)	1.00 [0.93, 1.07]
3.2 One‐off ultrasound‐indicated cerclage in high risk for PTL vs no cerclage	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.3 Serial ultrasound‐indicated cerclage in high risk for PTL vs no cerclage	2	238	Risk Ratio (M‐H, Fixed, 95% CI)	1.04 [0.94, 1.14]
3.4 Physical exam‐indicated cerclage in high risk for PTL vs no cerclage	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.5 One‐off ultrasound‐indicated cerclage in low/unspecified risk for PTL vs no cerclage	1	236	Risk Ratio (M‐H, Fixed, 95% CI)	1.01 [0.95, 1.08]
4 Stillbirths Show forest plot	5	1803	Risk Ratio (M‐H, Fixed, 95% CI)	0.89 [0.45, 1.75]

4.1 History‐indicated cerclage vs no cerclage	2	1458	Risk Ratio (M‐H, Fixed, 95% CI)	1.00 [0.45, 2.20]
4.2 One‐off ultrasound‐indicated cerclage in high risk for PTL vs no cerclage	1	56	Risk Ratio (M‐H, Fixed, 95% CI)	0.23 [0.01, 4.58]
4.3 Serial ultrasound‐indicated cerclage in high risk for PTL vs no cerclage	2	82	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.4 Physical exam‐indicated cerclage in high risk for PTL vs no cerclage	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.5 One‐off ultrasound‐indicated cerclage in low/unspecified risk for PTL vs no cerclage	2	207	Risk Ratio (M‐H, Fixed, 95% CI)	0.95 [0.20, 4.59]
5 Neonatal deaths before discharge Show forest plot	6	1714	Risk Ratio (M‐H, Fixed, 95% CI)	0.85 [0.53, 1.39]

5.1 History‐indicated cerclage vs no cerclage	2	1350	Risk Ratio (M‐H, Fixed, 95% CI)	0.61 [0.29, 1.27]
5.2 One‐off ultrasound‐indicated cerclage in high risk for PTL vs no cerclage	1	54	Risk Ratio (M‐H, Fixed, 95% CI)	2.15 [0.21, 22.37]
5.3 Serial ultrasound‐indicated cerclage in high risk for PTL vs no cerclage	2	73	Risk Ratio (M‐H, Fixed, 95% CI)	0.79 [0.12, 5.26]
5.4 Physical exam‐indicated cerclage in high risk for PTL vs no cerclage	1	30	Risk Ratio (M‐H, Fixed, 95% CI)	1.97 [0.77, 5.01]
5.5 One‐off ultrasound‐indicated cerclage in low/unspecified risk for PTL vs no cerclage	2	207	Risk Ratio (M‐H, Fixed, 95% CI)	0.63 [0.18, 2.18]
6 Miscarriages Show forest plot	7	2091	Risk Ratio (M‐H, Fixed, 95% CI)	0.84 [0.58, 1.22]

6.1 History‐indicated cerclage vs no cerclage	3	1539	Risk Ratio (M‐H, Fixed, 95% CI)	0.86 [0.57, 1.30]
6.2 One‐off ultrasound‐indicated cerclage in high risk for PTL vs no cerclage	1	56	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
6.3 Serial ultrasound‐indicated cerclage in high risk for PTL vs no cerclage	3	209	Risk Ratio (M‐H, Fixed, 95% CI)	0.65 [0.25, 1.66]
6.4 Physical exam‐indicated cerclage in high risk for PTL vs no cerclage	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
6.5 One‐off ultrasound‐indicated cerclage in low/unspecified risk for PTL vs no cerclage	3	287	Risk Ratio (M‐H, Fixed, 95% CI)	1.72 [0.16, 18.22]
7 Preterm birth before 37 completed weeks Show forest plot	9	2898	Risk Ratio (M‐H, Random, 95% CI)	0.80 [0.69, 0.95]

7.1 History‐indicated cerclage vs no cerclage	4	2045	Risk Ratio (M‐H, Random, 95% CI)	0.86 [0.59, 1.27]
7.2 One‐off ultrasound‐indicated cerclage in high risk for PTL vs no cerclage	1	56	Risk Ratio (M‐H, Random, 95% CI)	0.55 [0.30, 0.99]
7.3 Serial ultrasound‐indicated cerclage in high risk for PTL vs no cerclage	4	510	Risk Ratio (M‐H, Random, 95% CI)	0.78 [0.60, 1.02]
7.4 Physical exam‐indicated cerclage in high risk for PTL vs no cerclage	0	0	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
7.5 One‐off ultrasound‐indicated cerclage in low/unspecified risk for PTL vs no cerclage	3	287	Risk Ratio (M‐H, Random, 95% CI)	0.80 [0.55, 1.16]
8 Preterm birth before 34 completed weeks Show forest plot	9	2415	Risk Ratio (M‐H, Random, 95% CI)	0.77 [0.66, 0.89]

8.1 History‐indicated cerclage vs no cerclage	3	1539	Risk Ratio (M‐H, Random, 95% CI)	0.76 [0.40, 1.46]
8.2 One‐off ultrasound‐indicated cerclage in high risk for PTL vs no cerclage	1	56	Risk Ratio (M‐H, Random, 95% CI)	0.63 [0.27, 1.46]
8.3 Serial ultrasound‐indicated cerclage in high risk for PTL vs no cerclage	4	510	Risk Ratio (M‐H, Random, 95% CI)	0.77 [0.55, 1.10]
8.4 Physical exam‐indicated cerclage in high risk for PTL vs no cerclage	1	23	Risk Ratio (M‐H, Random, 95% CI)	0.56 [0.34, 0.93]
8.5 One‐off ultrasound‐indicated cerclage in low/unspecified risk for PTL vs no cerclage	3	287	Risk Ratio (M‐H, Random, 95% CI)	0.82 [0.55, 1.22]
9 Preterm birth before 28 completed weeks Show forest plot	8	2392	Risk Ratio (M‐H, Fixed, 95% CI)	0.80 [0.64, 1.00]

9.1 History‐indicated cerclage vs no cerclage	3	1539	Risk Ratio (M‐H, Fixed, 95% CI)	0.82 [0.59, 1.13]
9.2 One‐off ultrasound‐indicated cerclage in high risk for PTL vs no cerclage	1	56	Risk Ratio (M‐H, Fixed, 95% CI)	0.69 [0.18, 2.62]
9.3 Serial ultrasound‐indicated cerclage in high risk for PTL vs no cerclage	4	510	Risk Ratio (M‐H, Fixed, 95% CI)	0.71 [0.48, 1.04]
9.4 Physical exam‐indicated cerclage in high risk for PTL vs no cerclage	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
9.5 One‐off ultrasound‐indicated cerclage in low/unspecified risk for PTL vs no cerclage	3	287	Risk Ratio (M‐H, Fixed, 95% CI)	1.01 [0.55, 1.83]
10 Serious intracranial pathology (IVH or periventricular leukomalacia) Show forest plot	5	839	Risk Ratio (M‐H, Random, 95% CI)	0.83 [0.23, 3.09]

10.1 History‐indicated cerclage vs no cerclage	1	194	Risk Ratio (M‐H, Random, 95% CI)	1.02 [0.06, 16.09]
10.2 One‐off ultrasound‐indicated cerclage in high risk for PTL vs no cerclage	1	56	Risk Ratio (M‐H, Random, 95% CI)	0.38 [0.02, 9.01]
10.3 Serial ultrasound‐indicated cerclage in high risk for PTL vs no cerclage	3	382	Risk Ratio (M‐H, Random, 95% CI)	0.96 [0.05, 19.53]
10.4 Physical exam‐indicated cerclage in high risk for PTL vs no cerclage	0	0	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
10.5 One‐off ultrasound‐indicated cerclage in low/unspecified risk for PTL vs no cerclage	2	207	Risk Ratio (M‐H, Random, 95% CI)	0.95 [0.06, 14.98]
11 Serious respiratory morbidity (RDS or oxygen dependency after 28 days of life) Show forest plot	5	839	Risk Ratio (M‐H, Fixed, 95% CI)	1.11 [0.66, 1.88]

11.1 History‐indicated cerclage vs no cerclage	1	194	Risk Ratio (M‐H, Fixed, 95% CI)	3.06 [0.32, 28.93]
11.2 One‐off ultrasound‐indicated cerclage in high risk for PTL vs no cerclage	1	56	Risk Ratio (M‐H, Fixed, 95% CI)	0.58 [0.06, 6.00]
11.3 Serial ultrasound‐indicated cerclage in high risk for PTL vs no cerclage	3	382	Risk Ratio (M‐H, Fixed, 95% CI)	0.98 [0.53, 1.81]
11.4 Physical exam‐indicated cerclage in high risk for PTL vs no cerclage	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
11.5 One‐off ultrasound‐indicated cerclage in low/unspecified risk for PTL vs no cerclage	2	207	Risk Ratio (M‐H, Fixed, 95% CI)	1.63 [0.39, 6.86]
12 Necrotising enterocolitis Show forest plot	3	372	Risk Ratio (M‐H, Fixed, 95% CI)	0.81 [0.16, 4.12]

12.1 History‐indicated cerclage vs no cerclage	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
12.2 One‐off ultrasound‐indicated cerclage in high risk for PTL vs no cerclage	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
12.3 Serial ultrasound‐indicated cerclage in high risk for PTL vs no cerclage	3	362	Risk Ratio (M‐H, Fixed, 95% CI)	0.81 [0.16, 4.12]
12.4 Physical exam‐indicated cerclage in high risk for PTL vs no cerclage	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
12.5 One‐off ultrasound‐indicated cerclage in low/unspecified risk for PTL vs no cerclage	1	10	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
13 Retinopathy of prematurity Show forest plot	2	553	Risk Ratio (M‐H, Fixed, 95% CI)	0.46 [0.14, 1.48]

13.1 History‐indicated cerclage vs no cerclage	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
13.2 One‐off ultrasound‐indicated cerclage in high risk for PTL vs no cerclage	1	56	Risk Ratio (M‐H, Fixed, 95% CI)	0.23 [0.01, 4.58]
13.3 Serial ultrasound‐indicated cerclage in high risk for PTL vs no cerclage	1	300	Risk Ratio (M‐H, Fixed, 95% CI)	0.62 [0.15, 2.53]
13.4 Physical exam‐indicated cerclage in high risk for PTL vs no cerclage	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
13.5 One‐off ultrasound‐indicated cerclage in low/unspecified risk for PTL vs no cerclage	1	197	Risk Ratio (M‐H, Fixed, 95% CI)	0.32 [0.01, 7.69]
14 Apgar < 7 at 5 minutes Show forest plot	1	301	Risk Ratio (M‐H, Fixed, 95% CI)	0.68 [0.40, 1.15]

14.1 History‐indicated cerclage vs no cerclage	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
14.2 One‐off ultrasound‐indicated cerclage in high risk for PTL vs no cerclage	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
14.3 Serial ultrasound‐indicated cerclage in high risk for PTL vs no cerclage	1	301	Risk Ratio (M‐H, Fixed, 95% CI)	0.68 [0.40, 1.15]
14.4 Physical exam‐indicated cerclage in high risk for PTL vs no cerclage	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
14.5 One‐off ultrasound‐indicated cerclage in low/unspecified risk for PTL vs no cerclage	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
15 Caesarean section (elective and emergency) Show forest plot	8	2817	Risk Ratio (M‐H, Fixed, 95% CI)	1.19 [1.01, 1.40]

15.1 History‐indicated cerclage vs no cerclage	3	1964	Risk Ratio (M‐H, Fixed, 95% CI)	1.21 [0.96, 1.52]
15.2 One‐off ultrasound‐indicated cerclage in high risk for PTL vs no cerclage	1	56	Risk Ratio (M‐H, Fixed, 95% CI)	1.35 [0.52, 3.50]
15.3 Serial ultrasound‐indicated cerclage in high risk for PTL vs no cerclage	4	510	Risk Ratio (M‐H, Fixed, 95% CI)	1.10 [0.82, 1.46]
15.4 Physical exam‐indicated cerclage in high risk for PTL vs no cerclage	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
15.5 One‐off ultrasound‐indicated cerclage in low/unspecified risk for PTL vs no cerclage	3	287	Risk Ratio (M‐H, Fixed, 95% CI)	1.31 [0.84, 2.04]
16 Maternal side effects (vaginal discharge, bleeding, pyrexia not requiring antibiotics) Show forest plot	3	953	Risk Ratio (M‐H, Random, 95% CI)	2.25 [0.89, 5.69]

16.1 History‐indicated cerclage vs no cerclage	2	700	Risk Ratio (M‐H, Random, 95% CI)	1.57 [0.76, 3.24]
16.2 One‐off ultrasound‐indicated cerclage in high risk for PTL vs no cerclage	0	0	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
16.3 Serial ultrasound‐indicated cerclage in high risk for PTL vs no cerclage	0	0	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
16.4 Physical exam‐indicated cerclage in high risk for PTL vs no cerclage	0	0	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
16.5 One‐off ultrasound‐indicated cerclage in low/unspecified risk for PTL vs no cerclage	1	253	Risk Ratio (M‐H, Random, 95% CI)	5.95 [1.36, 26.06]
17 Pyrexia Show forest plot	3	1245	Risk Ratio (M‐H, Fixed, 95% CI)	2.39 [1.35, 4.23]

17.1 History‐indicated vs. no cerclage	2	992	Risk Ratio (M‐H, Fixed, 95% CI)	2.22 [1.22, 4.01]
17.2 One‐off ultrasound‐indicated cerclage in high risk for PTL vs no cerclage	1	56	Risk Ratio (M‐H, Fixed, 95% CI)	3.44 [0.15, 81.09]
17.3 One‐off ultrasound‐indicated cerclage in low/unspecified risk for PTL vs no cerclage	1	197	Risk Ratio (M‐H, Fixed, 95% CI)	6.66 [0.35, 127.20]
18 Any intravenous, oral or combined tocolysis (not prespecified) Show forest plot	2	217	Risk Ratio (M‐H, Fixed, 95% CI)	1.28 [0.80, 2.05]

18.1 History‐indicated vs. no cerclage	1	194	Risk Ratio (M‐H, Fixed, 95% CI)	1.53 [0.66, 3.58]
18.2 Physical exam‐indicated cerclage in high risk for PTL versus no cerclage	1	23	Risk Ratio (M‐H, Fixed, 95% CI)	1.06 [0.72, 1.56]
19 PPROM (not prespecified) Show forest plot	6	2010	Risk Ratio (M‐H, Random, 95% CI)	0.96 [0.62, 1.48]

19.1 History‐indicated vs. no cerclage	2	1458	Risk Ratio (M‐H, Random, 95% CI)	1.63 [0.71, 3.70]
19.2 One‐off ultrasound‐indicated cerclage in high risk for PTL vs no cerclage	1	56	Risk Ratio (M‐H, Random, 95% CI)	0.49 [0.14, 1.72]
19.3 Serial ultrasound‐indicated cerclage in high risk for PTL vs no cerclage	3	209	Risk Ratio (M‐H, Random, 95% CI)	0.51 [0.18, 1.45]
19.4 One‐off ultrasound‐indicated cerclage in low/unspecified risk for PTL vs no cerclage	3	287	Risk Ratio (M‐H, Random, 95% CI)	1.32 [0.78, 2.23]
20 Chorioamnionitis (not prespecified) Show forest plot	3	1506	Risk Ratio (M‐H, Random, 95% CI)	0.84 [0.26, 2.72]

20.1 History‐indicated vs. no cerclage	1	1264	Risk Ratio (M‐H, Random, 95% CI)	2.97 [0.12, 72.81]
20.2 Serial ultrasound‐indicated cerclage in high risk for PTL vs no cerclage	2	162	Risk Ratio (M‐H, Random, 95% CI)	0.41 [0.03, 6.21]
20.3 One‐off ultrasound‐indicated cerclage in low/unspecified risk for PTL vs no cerclage	1	80	Risk Ratio (M‐H, Random, 95% CI)	1.29 [0.39, 4.23]

Comparison 1. Cerclage versus no cerclage

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Comparison 2. Cerclage versus vaginal progesterone

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 All perinatal losses Show forest plot	2	108	Risk Ratio (M‐H, Fixed, 95% CI)	0.94 [0.36, 2.48]

2 Serious neonatal morbidity Show forest plot	2	120	Risk Ratio (M‐H, Random, 95% CI)	0.49 [0.05, 4.52]

3 Baby discharged home healthy Show forest plot	2	119	Risk Ratio (M‐H, Fixed, 95% CI)	0.97 [0.88, 1.07]

4 Stillbirths Show forest plot	2	128	Risk Ratio (M‐H, Fixed, 95% CI)	2.7 [0.12, 62.17]

5 Neonatal deaths before discharge Show forest plot	2	120	Risk Ratio (M‐H, Fixed, 95% CI)	2.18 [0.34, 13.86]

6 Miscarriages Show forest plot	2	128	Risk Ratio (M‐H, Fixed, 95% CI)	0.58 [0.17, 2.01]

7 Preterm birth before 37 completed weeks Show forest plot	2	128	Risk Ratio (M‐H, Fixed, 95% CI)	1.16 [0.64, 2.08]

8 Preterm birth before 34 completed weeks Show forest plot	2	128	Risk Ratio (M‐H, Fixed, 95% CI)	1.01 [0.51, 2.01]

9 Preterm birth before 28 completed weeks Show forest plot	2	128	Risk Ratio (M‐H, Fixed, 95% CI)	0.92 [0.37, 2.27]

10 Serious intracranial pathology (IVH or periventricular leucomalacia) Show forest plot	2	128	Risk Ratio (M‐H, Fixed, 95% CI)	0.96 [0.17, 5.28]

11 Serious respiratory morbidity (RDS or oxygen dependency after 28 days of life) Show forest plot	2	128	Risk Ratio (M‐H, Random, 95% CI)	0.48 [0.04, 6.41]

12 Necrotising enterocolitis Show forest plot	1	92	Risk Ratio (M‐H, Fixed, 95% CI)	3.0 [0.13, 71.78]

13 Retinopathy of prematurity Show forest plot	1	92	Risk Ratio (M‐H, Fixed, 95% CI)	1.0 [0.06, 15.51]

14 Apgar < 7 at 5 minutes Show forest plot	2	120	Risk Ratio (M‐H, Fixed, 95% CI)	1.90 [0.37, 9.80]

15 Caesarean section (elective and emergency) Show forest plot	2	128	Risk Ratio (M‐H, Random, 95% CI)	0.67 [0.18, 2.47]

16 Maternal infection requiring intervention(antibiotics or delivery)	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
17 Maternal side effects (vaginal discharge, bleeding, pyrexia not requiring antibiotics) Show forest plot	1	92	Risk Ratio (M‐H, Fixed, 95% CI)	3.0 [0.32, 27.79]

18 Pyrexia Show forest plot	1	92	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]

19 Any intravenous, oral or combined tocolysis (not prespecified) Show forest plot	1	92	Risk Ratio (M‐H, Fixed, 95% CI)	3.75 [1.93, 7.29]

20 PPROM (not prespecified) Show forest plot	1	92	Risk Ratio (M‐H, Fixed, 95% CI)	8.0 [1.04, 61.42]

21 Chorioamnionitis (not prespecified) Show forest plot	2	128	Risk Ratio (M‐H, Random, 95% CI)	1.53 [0.10, 23.61]

Comparison 2. Cerclage versus vaginal progesterone

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Comparison 3. Cerclage versus intramuscular progesterone

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 All perinatal losses Show forest plot	1	79	Risk Ratio (M‐H, Fixed, 95% CI)	1.12 [0.58, 2.16]

2 Serious neonatal morbidity Show forest plot	1	79	Risk Ratio (M‐H, Fixed, 95% CI)	1.13 [0.47, 2.74]

3 Baby discharged home healthy Show forest plot	1	79	Risk Ratio (M‐H, Fixed, 95% CI)	1.17 [0.82, 1.67]

4 Stillbirths	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
5 Neonatal deaths before discharge	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
6 Miscarriages Show forest plot	1	79	Risk Ratio (M‐H, Fixed, 95% CI)	1.47 [0.38, 5.73]

7 Preterm birth before 37 completed weeks Show forest plot	1	79	Risk Ratio (M‐H, Fixed, 95% CI)	0.88 [0.60, 1.30]

8 Preterm birth before 34 completed weeks	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
9 Preterm birth before 28 completed weeks Show forest plot	1	79	Risk Ratio (M‐H, Fixed, 95% CI)	1.26 [0.53, 2.97]

10 Serious intracranial pathology (IVH or periventricular leucomalacia)	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
11 Serious respiratory morbidity (RDS or oxygen dependency after 28 days of life)	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
12 Necrotising enterocolitis	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
13 Retinopathy of prematurity	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
14 Apgar < 7 at 5 minutes	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
15 Caesarean section (elective and emergency)	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
16 Maternal infection requiring intervention(antibiotics or delivery)	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
17 Maternal side effects (vaginal discharge, bleeding, pyrexia not requiring antibiotics)	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
18 Pyrexia	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
19 PPROM (not prespecified) Show forest plot	1	79	Risk Ratio (M‐H, Fixed, 95% CI)	0.88 [0.47, 1.65]

20 Chorioamnionitis (not prespecified) Show forest plot	1	79	Risk Ratio (M‐H, Fixed, 95% CI)	1.32 [0.61, 2.88]

Comparison 3. Cerclage versus intramuscular progesterone

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Comparison 4. Cerclage versus pessary

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 All perinatal losses	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
2 Serious neonatal morbidity	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3 Baby discharged home healthy	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4 Stillbirths	0		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
5 Neonatal deaths before discharge	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
6 Miscarriages	0		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
7 Preterm birth before 37 completed weeks	0		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
8 Preterm birth before 34 completed weeks	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
9 Preterm birth before 28 completed weeks	0		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
10 Serious intracranial pathology (IVH or periventricular leucomalacia)	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
11 Serious respiratory morbidity (RDS or oxygen dependency after 28 days of life)	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
12 Necrotising enterocolitis	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
13 Retinopathy of prematurity	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
14 Apgar < 7 at 5 minutes	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
15 Caesarean section (elective and emergency)	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
16 Maternal infection requiring intervention(antibiotics or delivery)	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
17 Maternal side effects (vaginal discharge, bleeding, pyrexia not requiring antibiotics)	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
18 Pyrexia	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
19 PPROM (not prespecified)	0		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
20 Chorioamnionitis	0		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

Comparison 4. Cerclage versus pessary

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Comparison 5. Any comparison of different cerclage protocols

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 All perinatal losses Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

1.1 History‐indicated cerclage vs ultrasound‐indicated cerclage	1	247	Risk Ratio (M‐H, Fixed, 95% CI)	1.37 [0.63, 2.96]
2 Serious neonatal morbidity Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

2.1 History‐indicated cerclage vs ultrasound‐indicated cerclage	1	247	Risk Ratio (M‐H, Fixed, 95% CI)	1.71 [0.51, 5.69]
3 Baby discharged home healthy	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.1 History‐indicated cerclage vs ultrasound‐indicated cerclage	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.2 History‐indicated cerclage vs physical exam‐indicated cerclage	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4 Stillbirths Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

4.1 History‐indicated cerclage vs ultrasound‐indicated cerclage	1	247	Risk Ratio (M‐H, Fixed, 95% CI)	0.49 [0.04, 5.31]
5 Neonatal deaths before discharge Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

5.1 History‐indicated cerclage vs ultrasound‐indicated cerclage	1	247	Risk Ratio (M‐H, Fixed, 95% CI)	0.24 [0.03, 2.15]
5.2 History‐indicated cerclage vs physical exam‐indicated cerclage	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
6 Miscarriages Show forest plot	2	344	Risk Ratio (M‐H, Random, 95% CI)	1.71 [0.55, 5.30]

6.1 History‐indicated cerclage vs ultrasound‐indicated cerclage	2	344	Risk Ratio (M‐H, Random, 95% CI)	1.71 [0.55, 5.30]
7 Preterm birth before 37 completed weeks Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

7.1 History‐indicated cerclage vs ultrasound‐indicated cerclage	1	97	Risk Ratio (M‐H, Fixed, 95% CI)	0.72 [0.25, 2.05]
8 Preterm birth before 34 completed weeks Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

8.1 History‐indicated cerclage vs ultrasound‐indicated cerclage	1	247	Risk Ratio (M‐H, Fixed, 95% CI)	1.03 [0.57, 1.87]
9 Preterm birth before 28 completed weeks	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
9.1 History‐indicated cerclage vs ultrasound‐indicated cerclage	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
9.2 History‐indicated cerclage vs physical exam‐indicated cerclage	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
10 Serious intracranial pathology (IVH or periventricular leucomalacia) Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

10.1 History‐indicated cerclage vs ultrasound‐indicated cerclage	1	247	Risk Ratio (M‐H, Fixed, 95% CI)	1.95 [0.36, 10.46]
10.2 History‐indicated cerclage vs physical exam‐indicated cerclage	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
11 Serious respiratory morbidity (RDS or oxygen dependency after 28 days of life) Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

11.1 History‐indicated cerclage vs ultrasound‐indicated cerclage	1	247	Risk Ratio (M‐H, Fixed, 95% CI)	1.46 [0.25, 8.61]
11.2 History‐indicated cerclage vs physical exam‐indicated cerclage	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
12 Necrotising enterocolitis	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
12.1 History‐indicated cerclage vs ultrasound‐indicated cerclage	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
12.2 History‐indicated cerclage vs physical exam‐indicated cerclage	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
13 Retinopathy of prematurity	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
13.1 History‐indicated cerclage vs ultrasound‐indicated cerclage	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
13.2 History‐indicated cerclage vs physical exam‐indicated cerclage	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
14 Apgar < 7 at 5 minutes	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
14.1 History‐indicated cerclage vs ultrasound‐indicated cerclage	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
14.2 History‐indicated cerclage vs physical exam‐indicated cerclage	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
15 Caesarean section (elective and emergency)	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
15.1 History‐indicated cerclage vs ultrasound‐indicated cerclage	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
15.2 History‐indicated cerclage vs physical exam‐indicated cerclage	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
16 Maternal infection requiring intervention(antibiotics or delivery) Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

16.1 History‐indicated cerclage vs ultrasound‐indicated cerclage	1	247	Risk Ratio (M‐H, Fixed, 95% CI)	0.33 [0.01, 7.91]
16.2 History‐indicated cerclage vs physical exam‐indicated cerclage	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
17 Maternal side effects (vaginal discharge, bleeding, pyrexia not requiring antibiotics) Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

17.1 History‐indicated cerclage vs ultrasound‐indicated cerclage	1	243	Risk Ratio (M‐H, Fixed, 95% CI)	0.54 [0.21, 1.42]
17.2 History‐indicated cerclage vs physical exam‐indicated cerclage	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
18 Tocolysis (not prespecified) Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

18.1 History‐indicated cerclage vs ultrasound‐indicated cerclage	1	247	Risk Ratio (M‐H, Fixed, 95% CI)	0.44 [0.16, 1.24]

Comparison 5. Any comparison of different cerclage protocols

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Comparison 6. Cerclage versus no cerclage (Summary of findings outcomes)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 All perinatal losses Show forest plot	10	2927	Risk Ratio (M‐H, Fixed, 95% CI)	0.82 [0.65, 1.04]

2 Serious neonatal morbidity Show forest plot	6	883	Risk Ratio (M‐H, Fixed, 95% CI)	0.80 [0.55, 1.18]

3 Baby discharged home healthy Show forest plot	4	657	Risk Ratio (M‐H, Fixed, 95% CI)	1.02 [0.97, 1.06]

4 Stillbirths Show forest plot	5	1803	Risk Ratio (M‐H, Fixed, 95% CI)	0.89 [0.45, 1.75]

5 Neonatal deaths before discharge Show forest plot	6	1714	Risk Ratio (M‐H, Fixed, 95% CI)	0.85 [0.53, 1.39]

6 Preterm birth before 34 completed weeks Show forest plot	9	2415	Risk Ratio (M‐H, Random, 95% CI)	0.77 [0.66, 0.89]

Comparison 6. Cerclage versus no cerclage (Summary of findings outcomes)

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Resumen

Antecedentes

Objetivos

Métodos de búsqueda

Criterios de selección

Obtención y análisis de los datos

Resultados principales

Conclusiones de los autores

PICO

PICO

Population

Intervention

Comparison

Outcome

Resumen en términos sencillos

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Resumen visual

Authors' conclusions

Implications for practice

Implications for research

Summary of findings

Background

Description of the condition

Description of the intervention

How the intervention might work

Why it is important to do this review

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Comparisons

Types of outcome measures

Primary outcomes

Secondary outcomes

Neonatal

Maternal

Search methods for identification of studies

Electronic searches

Searching other resources

Data collection and analysis

Selection of studies

Data extraction and management

Assessment of risk of bias in included studies

(1) Random sequence generation (checking for possible selection bias)

(2) Allocation concealment (checking for possible selection bias)

(3.1) Blinding of participants and personnel (checking for possible performance bias)

(3.2) Blinding of outcome assessment (checking for possible detection bias)

(4) Incomplete outcome data (checking for possible attrition bias due to the amount, nature and handling of incomplete outcome data)

(5) Selective reporting (checking for reporting bias)

(6) Other bias (checking for bias due to problems not covered by (1) to (5) above)

(7) Overall risk of bias

Assessment of the quality of the evidence using the GRADE approach

Measures of treatment effect

Dichotomous data

Continuous data

Unit of analysis issues

Cluster‐randomised trials

Cross‐over trials

Other unit of analysis issues

Dealing with missing data

Assessment of heterogeneity

Assessment of reporting biases

Data synthesis

Subgroup analysis and investigation of heterogeneity

Sensitivity analysis

Results

Description of studies

Results of the search

Included studies

Interventions

Setting

Population

Excluded studies

Risk of bias in included studies

Allocation

Blinding