Cervical pessary for preventing preterm birth in singleton pregnancies

Hany Abdel-Aleem; Omar M Shaaban; Mahmoud A Abdel-Aleem; Ahmed Aboelfadle Mohamed

doi:10.1002/14651858.CD014508

. 2022 Dec 1;2022(12):CD014508. doi: 10.1002/14651858.CD014508

Cervical pessary for preventing preterm birth in singleton pregnancies

Hany Abdel-Aleem ^1,^✉, Omar M Shaaban ¹, Mahmoud A Abdel-Aleem ¹, Ahmed Aboelfadle Mohamed ²

Editor: Cochrane Pregnancy and Childbirth Group

PMCID: PMC9713761 PMID: 36453699

Abstract

Background

Preterm birth (PTB), defined as birth prior to 37 weeks of gestation, occurs in ten percent of all pregnancies. PTB is responsible for more than half of neonatal and infant mortalities and morbidities. Because cervical insufficiency is a common cause of PTB, one possible preventive strategy involves insertion of a cervical pessary to support the cervix. Several published studies have compared the use of pessary with different management options and obtained questionable results. This highlights the need for an up‐to‐date systematic review of the evidence.

Objectives

To evaluate the benefits and harms of cervical pessary for preventing preterm birth in women with singleton pregnancies and risk factors for cervical insufficiency compared to no treatment, vaginal progesterone, cervical cerclage or bedrest.

Search methods

We searched Cochrane Pregnancy and Childbirth’s Trials Register, ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform to 22 September 2021. We also searched the reference lists of included studies for additional records.

Selection criteria

We included published and unpublished randomised controlled trials (RCTs) comparing cervical pessary with no treatment, vaginal progesterone, cervical cerclage or bedrest for preventing PTB. We excluded quasi‐randomised trials. Our primary outcome was delivery before 34 weeks' gestation. Our secondary outcomes were 1. delivery before 37 weeks' gestation, 2. maternal mortality, 3. maternal infection or inflammation, 4. preterm prelabour rupture of membranes, 5. harm to woman from the intervention, 6. maternal medications, 7. discontinuation of the intervention, 8. maternal satisfaction, 9. neonatal/paediatric care unit admission, 10. fetal/infant mortality, 11. neonatal sepsis, 12. gestational age at birth, 13. harm to offspring from the intervention 14. birthweight, 15. early neurodevelopmental morbidity, 15. late neurodevelopmental morbidity, 16. gastrointestinal morbidity and 17. respiratory morbidity.

Data collection and analysis

Two review authors independently assessed trials for eligibility and risk of bias, evaluated trustworthiness based on criteria developed by the Cochrane Pregnancy and Childbirth Review Group, extracted data, checked for accuracy and assessed certainty of evidence using the GRADE approach.

Main results

We included eight RCTs (2983 participants). We included five RCTs (1830 women) in the comparison cervical pessary versus no treatment, three RCTs (1126 pregnant women) in the comparison cervical pessary versus vaginal progesterone, and one study (13 participants) in the comparison cervical pessary versus cervical cerclage. Overall, the certainty of evidence was low to moderate due to inconsistency (statistical heterogeneity), imprecision (few events and wide 95% confidence intervals (CIs) consistent with possible benefit and harm), and risk of performance and detection bias.

Cervical pessary versus no treatment

Cervical pessary compared with no treatment may reduce the risk of delivery before 34 weeks (risk ratio (RR) 0.72, 95% CI 0.33 to 1.55; 5 studies, 1830 women; low‐certainty evidence) or before 37 weeks (RR 0.68, 95% CI 0.44 to 1.05; 5 studies, 1830 women; low‐certainty evidence). However, these results should be viewed with caution because the 95% CIs cross the line of no effect. Cervical pessary compared with no treatment probably has little or no effect on the risk of maternal infection or inflammation (RR 1.04, 95% CI 0.87 to 1.26; 2 studies, 1032 women; moderate‐certainty evidence).

It is unclear if cervical pessary compared with no treatment has an effect on neonatal/paediatric care unit admission (RR 0.96, 95% CI 0.58 to 1.59; 3 studies, 1332 infants; low‐certainty evidence) or fetal/neonatal mortality (RR 0.93, 95% CI 0.58 to 1.48; 5 studies, 1830 infants; low‐certainty evidence) because the 95% CIs are compatible with a wide range of effects that encompass both appreciable benefit and harm.

Cervical pessary versus vaginal progesterone

Cervical pessary may reduce the risk of delivery before 34 weeks (RR 0.72, 95% CI 0.52 to 1.02; 3 studies, 1126 women; moderate‐certainty evidence) or before 37 weeks (RR 0.89, 95% CI 0.73 to 1.09; 3 studies, 1126 women; moderate‐certainty evidence), but we are uncertain of the results because the 95% CI crosses the line of no effect. The intervention probably has little or no effect on maternal infection or inflammation (RR 0.95, 95% CI 0.81 to 1.12; 2 studies, 265 women; moderate‐certainty evidence).

It is unclear if cervical pessary compared with vaginal progesterone has an effect on the risk of neonatal/paediatric care unit admission (RR 0.98, 95% CI 0.49 to 1.98; low‐certainty evidence) or fetal/neonatal mortality (RR 1.97, 95% CI 0.50 to 7.70; 2 studies; 265 infants; low‐certainty evidence) because the 95% CIs are compatible with a wide range of effects that encompass both appreciable benefit and harm.

Cervical pessary versus cervical cerclage

Only one very small study of 13 pregnant women contributed data to this comparison; the results were unclear.

Authors' conclusions

In women with a singleton pregnancy, cervical pessary compared with no treatment or vaginal progesterone may reduce the risk of delivery before 34 weeks or 37 weeks, although these results should be viewed with caution due to uncertainty around the effect estimates. There is insufficient evidence with regard to the effect of cervical pessary compared with cervical cerclage on PTB.

Due to low certainty‐evidence in many of the prespecified outcomes and non‐reporting of several other outcomes of interest for this review, there is a need for further robust RCTs that use standardised terminology for maternal and offspring outcomes. Future trials should take place in a range of settings to improve generalisability of the evidence. Further research should concentrate on comparisons of cervical pessary versus cervical cerclage and bed rest. Investigation of different phenotypes of PTB may be relevant.

Keywords: Female; Humans; Pregnancy; Cerclage, Cervical; Cervix Uteri; Pessaries; Pessaries/adverse effects; Premature Birth; Premature Birth/prevention & control; Progesterone

Plain language summary

Vaginal cervical support device to prevent delivery of a single baby before 37 weeks

What is preterm birth?

Preterm birth means birth before 37 weeks of pregnancy. It is the leading cause of death in newborn babies. Often, preterm birth is caused by weakness of the cervix (the lower, narrow end of the womb).

How can cervical weakness be treated to prevent preterm birth?

Methods used to treat cervical weakness include cervical cerclage (tightening the cervix with a stitch to prevent its premature opening), expectant management (monitoring without intervention until problems arise), medical treatment with the female sex hormone progesterone (administered vaginally) or a cervical pessary (a silicone ring used to close the cervix). The cervical pessary is inserted in the upper vagina at between 12 and 24 weeks of pregnancy and is removed at 37 weeks. It is a simple, minimally invasive procedure that does not require anaesthesia and may replace cervical cerclage.

What did we want to find out?

We wanted to find out if cervical pessary was better than any other treatment, or no treatment, for preventing preterm birth in women who were pregnant with a single baby (singleton pregnancy) and who were at risk of having cervical weakness.

What did we do?

We searched for studies that examined cervical pessary compared with any other treatment, or no treatment, in women with singleton pregnancy who were at risk of having cervical weakness. We compared and summarised the results of the studies and rated our confidence in the evidence, based on factors such as study methods and sizes.

What did we find?

We found eight randomised studies (where participants were randomly assigned to their treatment group) involving 2983 pregnant women. We were able to extract data for three comparisons: cervical pessary versus no treatment, cervical pessary versus progesterone, and cervical pessary versus cervical cerclage. The studies took place in 15 high‐income countries.

In women with singleton pregnancy, the use of cervical pessary may decrease the risk of preterm birth compared to no treatment or vaginal progesterone, although the evidence around this was not robust. It is unclear if cervical pessary has an effect on maternal infection or other outcomes related to the baby for all comparisons.

What are the limitations of the evidence?

We have little confidence in the evidence because the results varied widely between studies and there were not enough studies. Future studies are needed to confirm the beneficial effect of cervical pessary on preterm birth. They should include lower‐income settings so that the findings can be applied to a wider population.

How up to date is this evidence?

This evidence is up to date to September 2021.

Summary of findings

Summary of findings 1. Cervical pessary compared to no treatment for preventing preterm birth in singleton pregnancies .

Cervical pessary compared to no treatment for preventing preterm birth in singleton pregnancies
Patient or population: women with singleton pregnancies at risk of cervical insufficiency Setting: hospital  Intervention: cervical pessary Comparison: no treatment
Outcomes	*Anticipated absolute effects (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with no treatment (singleton pregnancy)	Risk with Cervical pessary
Delivery before 34 weeks' gestation	Study population		RR 0.72 (0.33 to 1.55)	1830 (5 RCTs)	⊕⊕⊝⊝ Low^a	—
	218 per 1000	157 per 1000 (72 to 338)
Delivery before 37 weeks' gestation	Study population		RR 0.68 (0.44 to 1.05)	1830 (5 RCTs)	⊕⊕⊝⊝ Low^a	—
	304 per 1000	207 per 1000 (134 to 319)
Maternal infection or inflammation	Study population		RR 1.04 (0.87 to 1.26)	1032 (2 RCTs)	⊕⊕⊕⊝ Moderate^b	—
	289 per 1000	301 per 1000 (251 to 364)
Neonatal/paediatric care unit admission	Study population		RR 0.96 (0.58 to 1.59)	1332 (3 RCTs)	⊕⊕⊝⊝ Low^d	—
	118 per 1000	113 per 1000 (68 to 188)
Fetal/infant mortality	Study population		RR 0.93 (0.58 to 1.48)	1830 (5 RCTs)	⊕⊕⊝⊝ Low^c	—
	34 per 1000	31 per 1000 (20 to 50)
Harm to offspring from the intervention	Not reported		Not reported			—
Birthweight	Not reported		Not reported			—
*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; RCT: randomised controlled trial; RR: risk ratio.
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: 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 certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

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^aDowngraded one level for serious inconsistency (substantial unexplained statistical heterogeneity) and one level for serious imprecision (wide 95% CI consistent with possible benefit and possible harm). ^bDowngraded one level for serious risk of bias due to lack of blinding. ^cDowngraded two levels for very serious imprecision (few events and wide 95% CI consistent with possible benefit and possible harm). ^dDowngraded one level for serious inconsistency (substantial unexplained statistical heterogeneity) and one level for serious imprecision (few events).

Summary of findings 2. Cervical pessary compared to vaginal progesterone for preventing preterm birth in singleton pregnancies.

Cervical pessary compared to vaginal progesterone for preventing preterm birth in singleton pregnancies
Patient or population: women with singleton pregnancies at risk of cervical insufficiency Setting: hospital Intervention: cervical pessary Comparison: vaginal progesterone
Outcomes	*Anticipated absolute effects (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with vaginal progesterone	Risk with cervical pessary
Delivery before 34 weeks' gestation	Study population		RR 0.72 (0.52 to 1.02)	1126 (3 RCTs)	⊕⊕⊕⊝ Moderate^a	—
	125 per 1000	90 per 1000 (65 to 127)
Delivery before 37 weeks' gestation	Study population		RR 0.89 (0.73 to 1.09)	1126 (3 RCTs)	⊕⊕⊕⊝ Moderate^a	—
	264 per 1000	235 per 1000 (193 to 288)
Maternal infection or inflammation	Study population		RR 0.95 (0.81 to 1.12)	265 (2 RCTs)	⊕⊕⊕⊝ Moderate^b	—
	687 per 1000	653 per 1000 (556 to 769)
Neonatal/paediatric care unit admission	Study population		RR 0.98 (0.49 to 1.98)	254 (1 RCT)	⊕⊕⊝⊝ Low^e	—
	111 per 1000	109 per 1000 (54 to 220)
Fetal/infant mortality	Study population		RR 1.97 (0.50 to 7.70)	265 (2 RCTs)	⊕⊕⊝⊝ Low^c	—
	23 per 1000	45 per 1000 (11 to 176)
Harm to offspring from the intervention	Study population		Not estimable	11 (1RCT)	⊕⊕⊝⊝ Low^d	—
	0 per 1000	0 per 1000 (0 to 0)
Birthweight	Not reported		Not reported			—
*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; RCT: randomised controlled trial; RR: risk ratio.
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: 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 certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

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^aDowngraded one level for serious imprecision as we derived the data from subgroup analysis (study included both singleton and twin pregnancies, and we only included the subgroup of data on singletons). ^bDowngraded one level for serious risk of bias due to lack of blinding. ^cDowngraded two levels for very serious imprecision (wide CI, two small studies and few events). ^dDowngraded two levels for very serious imprecision (one very small study with no events). ^eDowngraded two levels for very serious imprecision (wide CI, one small study and few events).

Summary of findings 3. Cervical pessary compared to cervical cerclage for preventing preterm birth in singleton pregnancies.

Cervical pessary compared to cervical cerclage for preventing preterm birth in singleton pregnancies
Patient or population: women with singleton pregnancies at risk of cervical insufficiency Setting: hospital Intervention: cervical pessary Comparison: cervical cerclage
Outcomes	*Anticipated absolute effects (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with cervical cerclage	Risk with cervical pessary
Delivery before 34 weeks' gestation	Study population		Not estimable	13 (1 RCT)	⊕⊕⊝⊝ Low^a	—
	0 per 1000	0 per 1000 (0 to 0)
Delivery before 37 weeks' gestation	Study population		RR 5.71 (0.33 to 99.97)	13 (1 RCT)	⊕⊕⊝⊝ Low^b	—
	0 per 1000	0 per 1000 (0 to 0)
Maternal infection or inflammation	Study population		RR 0.23 (0.01 to 4.00)	13 (1 RCT)	⊕⊝⊝⊝ Very low^c	—
	286 per 1000	66 per 1000 (3 to 1000)
Neonatal/paediatric care unit admission	Not reported		Not reported			—
Fetal/infant mortality	Study population		RR 0.38 (0.02 to 7.93)	13 (1 RCT)	⊕⊕⊝⊝ Low^d	—
	143 per 1000	54 per 1000 (3 to 1000)
Harm to offspring from the intervention	Study population		Not estimable	13 (1 RCT)	⊕⊕⊝⊝ Low^a	—
	0 per 1000	0 per 1000 (0 to 0)
Birthweight	Not reported		Not reported			—
*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; RCT: randomised controlled trial; RR: risk ratio.
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: 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 certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

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^aDowngraded two levels for very serious imprecision (one very small study with no events). ^bDowngraded two levels for very serious imprecision (one very small study with few events and very wide CI). ^cDowngraded two levels for very serious imprecision (one very small study with few events and very wide CI) and one level for serious risk of bias due to lack of blinding. ^dDowngraded two levels for very serious imprecision (one very small study with very few events).

Background

An earlier Cochrane Review on cervical pessary for preventing preterm birth (PTB) included both singleton and multiple pregnancy (Abdel‐Aleem 2013). That review was split into two new reviews to cover the populations in separate analyses (women with singleton pregnancy (this review) and women with multiple pregnancy).

Description of the condition

PTB, defined as birth before 37 weeks of gestation, occurs in around 10% of all births (Institute of Medicine 2011), and is one of the leading causes of infant mortality (70%; Blencowe 2012; Bolbocean 2022; Ngoc 2006; Office of National Statistics 2012). Indeed, perinatal morbidity and mortality are inversely related to gestational age at delivery (D'Onofrio 2013; Saigal 2008). Premature neonates represent a large economic burden (Liu 2012).

Cervical insufficiency is a common cause of PTB, but it is difficult to diagnose, owing to the multifactorial aetiology of second trimester miscarriage and spontaneous PTB. Diagnosis is often based on medical history, clinical examination or ultrasound examination during pregnancy. Typical risk factors include having two or more second‐trimester pregnancy losses, having prelabour rupture of membranes before 32 weeks' gestation, a history of cervical trauma caused by cone biopsy, forced dilation or intrapartum cervical lacerations or congenital uterine anomalies (Lo 2009; Wie 2021). Other possible risk factors are clinical findings during pregnancy of short cervix, dilated cervix, protruding membranes or cervical tear; and ultrasound findings of short cervical length, defined as less than 25 mm at 20 weeks' gestation (Owen 2004; Wie 2021), or funnelling of the cervix during the second or early third trimester of pregnancy (Ayers 1988).

Cervical cerclage is one strategy aimed at preventing premature opening of the cervix (Anthony 1997; Gibb 1995; McDonald 1957; Shirodkar 1955). All operations carry risks, and cervical cerclage is an invasive technique that requires anaesthesia and is associated with complications including haemorrhage, infection and miscarriage (McDonald 1957; Shirodkar 1955). One Cochrane Review (15 trials, 3490 women) concluded that cervical cerclage reduces the risk of PTB in high‐risk women and probably reduces the risk of perinatal death. Whether cerclage is more or less effective than other preventive treatments remains unclear (Alfirevic 2017).

Administration of progesterone has been also advocated for preventing PTB in singleton pregnancy (Jarde 2019) One Cochrane Review on this topic included 36 randomised controlled trials (RCTs) with 8523 women and 12,515 infants, and found that in women with a history of spontaneous PTB, progesterone reduces the risk of perinatal mortality (risk ratio (RR) 0.50, 95% confidence interval (CI) 0.33 to 0.75) and delivery before 34 weeks (average RR 0.31, 95% CI 0.14 to 0.69) compared to placebo (Dodd 2013).

The strategy of using cervical pessaries for managing cervical insufficiency was introduced in the 1950s (Arabin 2003); however, support for this approach has been inconsistent over the subsequent decades (Acharya 2006; Antczak‐Judycka 2003; Arabin 2003; Quaas 1990).

Description of the intervention

The cervical pessary is a specially made silicone device that is inserted into the upper vagina to support the cervix and prevent PTB (Goya 2012; Hui 2012; Nicolaides 2016; Saccone 2017). Most studies investigating this device have used the Arabin pessary, which is a flexible, ring‐like pessary available in different sizes (outer diameter 65 mm or 70 mm, inner diameter 32 mm or 35 mm, height of the curvature 21 mm or 25 mm). A clinician examines the cervix using a speculum to determine the appropriate pessary dimensions. The pessary is inserted with its curvature upwards so that the larger diameter is supported by the pelvic floor. The smaller inner diameter should encompass the cervix. After inserting the pessary, the clinician should ensure the pregnant woman has no uterine activity, discomfort or vaginal bleeding (Arabin 2003; Saccone 2017).

How the intervention might work

The mechanism by which the pessary can prevent cervical insufficiency (also called incompetent cervix) is not exactly known. In 1961, Vitsky suggested that the incompetent cervix is aligned centrally, with no support except the non‐resistant vagina (Vitsky 1961). A lever pessary, however, would change the inclination of the cervical canal, directing it posteriorly. Thus, the weight of the pregnancy would be more on the anterior lower segment (Arabin 2003). Another postulated mechanism is that the pessary supports the immunological barrier between the chorioamnion‐extraovular space and the vaginal microbiological flora; cerclage may work in the same way (Goya 2012; Nicolaides 2016; Saccone 2017).

Why it is important to do this review

Cervical pessary is a minimally invasive intervention for preventing PTB. Non‐randomised trials have shown that treating women with a short cervix with cervical pessary prolonged the pregnancy compared to expectant management. In such trial, mean gestational age at delivery was 38 weeks (range 36 weeks 6 days to 41 weeks) in the pessary group and 33 weeks (range 26 weeks 4 days to 38 weeks) in the control group, with a P value of 0.02 between the groups (Arabin 2003).

Cervical pessary insertion is an outpatient procedure that does not require anaesthesia, surgery or medications. In one multicentre RCT conducted in Spain, the only reported side effects of this intervention were increased vaginal discharge and expulsion of the pessary (Goya 2012). In this and other studies, there were no serious infectious complications reported during or after removal of the pessary (Goya 2012; Quaas 1990; Jin 2017).

Previous Cochrane Reviews of cervical pessaries included studies on singleton and multiple pregnancies (Abdel‐Aleem 2010; Abdel‐Aleem 2013). The results of meta‐analysis conducted by Jin and colleagues in 2017 showed that the available evidence did not support the use of cervical pessary in singleton pregnancy with short cervix, and they recommended more RCTs on this topic (Jin 2017).

In 2018, Cochrane published an overview of all systematic reviews addressing interventions during pregnancy to prevent PTB (Medley 2018). The overview found no clinical evidence that interventions like cervical pessary and vaginal progesterone can prevent PTB, and recommended that the relevant Cochrane Reviews be updated to include newly published RCTs. In addition, the editorial board of Cochrane Pregnancy and Childbirth recommended splitting the original review into two; one dealing with singleton pregnancy and the other dealing with multiple pregnancy. This review focused on singleton pregnancy.

Objectives

Methods

Criteria for considering studies for this review

Types of studies

We considered only RCTs, including cluster‐RCTs but excluding quasi‐RCTs. We included studies published as abstracts if they contained enough information to assess eligibility and if they met the criteria for scientific integrity.

Types of participants

Inclusion criteria

Pregnant women with singleton viable fetus before 34 weeks' gestation with risk factors for PTB due to cervical insufficiency. Relevant risk factors included:

history of second‐trimester abortion or preterm labour (excluding those resulting from induced preterm labour or placental abruption);
history of prelabour rupture of membranes before 32 weeks' gestation;
short cervical length (25 mm or less at 18 to 24 weeks of gestation), determined by transvaginal ultrasound examination;
history of cervical trauma caused by cone biopsy, forced dilation or intrapartum cervical lacerations; and
congenital uterine anomalies.

Exclusion criteria

Cervical cerclage in current pregnancy
Multiple gestation
Known major fetal abnormalities
Presence of cervical dilation (any dilated cervical os discovered during speculum examination)
Active vaginal bleeding
Painful uterine contractions
Ruptured membranes

Types of interventions

We planned the following comparisons:

cervical pessary versus no treatment;
cervical pessary versus vaginal progesterone;
cervical pessary versus cervical cerclage; and
cervical pessary versus bed rest (at hospital or at home as reported by study authors).

Types of outcome measures

The outcomes below are adapted from a core outcome set (van 't Hooft 2016).

Primary outcomes

Delivery before 34 weeks' gestation (including spontaneous and induced labour)

Secondary outcomes

Maternal

Delivery before 37 weeks' gestation (including spontaneous and induced labour)
Maternal mortality
Maternal infection or inflammation (genital or urinary tract infection requiring treatment at any time after randomisation)
Preterm prelabour rupture of membranes
Harm to woman from the intervention (e.g. pregnancy bleeding, displacement of the pessary, pelvic discomfort)
Maternal medications (e.g. antibiotics, tocolytic drugs, corticosteroids)
Discontinuation of the intervention
Maternal satisfaction (as defined by the study authors)

Offspring

Neonatal/paediatric care unit admission (for any reason)
Fetal/neonatal mortality
Neonatal sepsis (within 72 hours of birth, confirmed by positive blood, cerebrospinal fluid, or urine (catheterised or suprapubic) cultures with or without suspicious clinical findings of infection on physical examination)
Gestational age at birth
Harm to offspring from the intervention (e.g. evidence of congenital fetal or neonatal infection, evidence of direct mechanical pressure from the device)
Birthweight
Early neurodevelopmental morbidity (periventricular leukomalacia grade 3 or 4, based on the classification of de Vries and colleagues (de Vries 1992); intraventricular haemorrhage grade 3 or 4; intraventricular haemorrhage with ventricular dilation or parenchymal extension, confirmed by magnetic resonance imaging (MRI), sonogram or computed tomography (CT); retinopathy of prematurity requiring treatment)
Late neurodevelopmental morbidity (at two years or later)
Gastrointestinal morbidity (necrotising enterocolitis, Bell stage 2 or above)
Respiratory morbidity (chronic lung disease in babies born before 32 weeks: need for more than 30% oxygen, with or without positive pressure ventilation or continuous positive pressure, at 36 weeks postmenstrual age or discharge; or chronic lung disease in babies born after 32 weeks: need for more than 30% oxygen, with or without positive pressure ventilation or continuous positive pressure, at 56 days postnatal age or discharge)

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 in collaboration with the Group's Information Specialist (22 September 2021).

The Register is a database containing over 32,000 reports of controlled trials in the field of pregnancy and childbirth. It represents over 30 years of searching. For full current 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, see the Review Group's website (pregnancy.cochrane.org/pregnancy-and-childbirth-groups-trials-register).

Briefly, Cochrane Pregnancy and Childbirth's Trials Register is maintained by the Group's 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; and
weekly current awareness alerts for a further 44 journals plus monthly BioMed Central email alerts.

Two people screened the search results and review the full‐text articles of all relevant trial reports. 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 that has been fully accounted for in the relevant review sections (Included studies; Excluded studies; Studies awaiting classification; Ongoing studies).

In addition, we searched ClinicalTrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) for unpublished, planned and ongoing trial reports (22 September 2021) using the search methods detailed in Appendix 1.

Searching other resources

We searched the reference lists of retrieved studies.

We applied no language or date restrictions.

Data collection and analysis

Selection of studies

Two review authors independently assessed all potential studies identified by the Information Specialist. In case of discrepancies, they consulted a third review author.

We created a study flow diagram to map the number of records identified, included and excluded.

Screening eligible studies for scientific integrity/trustworthiness

Two review authors independently evaluated all studies meeting our inclusion criteria to select those that, based on available information, were sufficiently trustworthy to include in the analysis. To do this, the review authors answered the following questions.

Research governance

Are there any retraction notices or expressions of concern listed on the Retraction Watch Database relating to this study (retractiondatabase.org)?
Was the study prospectively registered (for those studies published after 2010)? If not, was there a plausible reason?
When requested, did the trial authors provide/share the protocol or ethics approval letter, or both?
Did the trial authors engage in communication with the Cochrane Review authors within the agreed timelines?
Did the trial authors provide individual participant data upon request? If not, was there a plausible reason?

Baseline characteristics

Is the study free from participant characteristics that appear too similar (e.g. distribution of the mean and standard deviation (SD) excessively narrow or excessively wide, as noted by Carlisle 2017).

Feasibility

Is the study free from characteristics that could be implausible (e.g. large numbers of women with a rare condition such as severe cholestasis recruited within 12 months)? In cases with (close to) zero losses to follow‐up, is there a plausible explanation?

Results

Is the study free from implausible results (e.g. massive risk reduction for main outcomes with small sample size)?
Do the numbers randomised to each group suggest that the study authors used adequate randomisation methods? For example, is the study free from issues such as unexpectedly even numbers of women randomised or a mismatch between the numbers and methods?

We attempted to contact the authors of studies considered untrustworthy to address any concerns or request missing information. If we could not obtain contact details for the study authors, or if adequate information remained unavailable, we did not include the study but recorded all relevant details in the Characteristics of studies awaiting classification table, describing in detail the reasons and communications with the study author (or lack thereof).

Abstracts

We included data from abstracts only if the study authors confirmed in writing that the data to be included in the review came from the final analysis and would not change. If such information were unavailable, we did not include the study but recorded all relevant details in the Characteristics of studies awaiting classification table.

Data extraction and management

Review authors extracted data from the included studies using a data extraction form adapted from'Good practice templates' developed by the Cochrane Editorial Resources Committee (including trial dates, sources of trial funding and trial authors' declarations of interest). We resolved disagreement through discussion. We entered data into Review Manager 5 software (RevMan 5) and checked for accuracy (RevMan 2014). We followed Cochrane Methodological Expectations of Cochrane Intervention Reviews (MECIR) Standards (Higgins 2022).

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). We resolved any disagreement by discussion or by involving a third review author.

Random sequence generation (selection bias)

We described for each included study the method used to generate the allocation sequence in sufficient detail to assess whether it should produce comparable groups. We judged the methods at 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) or unclear risk of bias.

Allocation concealment (selection bias)

We described for each included study the method used to conceal allocation to interventions prior to assignment and also assessed whether intervention allocation could have been foreseen before or during recruitment, or changed after assignment. We judged the methods at low risk of bias (e.g. telephone or central randomisation, consecutively numbered sealed opaque envelopes), high risk of bias (e.g. open random allocation; unsealed or non‐opaque envelopes, alternation, date of birth) or unclear risk of bias.

Blinding of participants and personnel (performance bias)

We described for each included study, and for each outcome or class of outcome, the methods used, if any, to blind study participants and personnel to the treatment allocation. We judged studies at low risk of bias if they were blinded, or if we considered the lack of blinding would be unlikely to affect results. We judged the methods at low, high or unclear risk of bias for participants; and low, high or unclear risk of bias for personnel.

Blinding of outcome assessment (detection bias)

We described for each included study, and for each outcome or class of outcome, the methods used, if any, to blind outcome assessors to the treatment allocation. We judged the methods at low, high or unclear risk of bias.

Incomplete outcome data (attrition bias)

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 study authors had reported attrition and exclusions, 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 trial reports or trial authors provided sufficient information relating to participants with missing data, we included the data that had been reported for those participants in our analyses. We judged the methods at 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 with substantial departure from assigned interventions) or unclear risk of bias.

Selective reporting (reporting bias)

We described for each included study how we investigated the possibility of selective outcome reporting bias and what we found. We judged the methods at low risk of bias (where it was clear that all the study's prespecified outcomes were reported), high risk of bias (where not all the study's prespecified outcomes were reported, outcomes of interest were reported incompletely and so could not be used, or the study failed to include results of a key expected outcome) or unclear risk of bias.

Risk of bias from other sources

We described for each included study any important concerns we had about other possible sources of bias, judging each study at low, high or unclear risk of other bias.

Overall risk of bias

We made explicit judgements about whether studies were at high risk of bias, according to the criteria set out in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We assessed the likely magnitude and direction of types of bias described above and whether they were likely to have affected the findings. We also explored the impact of the level of bias through sensitivity analyses (see Sensitivity analysis).

Measures of treatment effect

For dichotomous data, we presented results as summary risk ratios (RRs) with 95% confidence intervals (CIs). For continuous data, we used mean differences (MDs) if outcomes were measured in the same way between trials, or standardised mean differences (SMDs) to combine trials that measured the same outcome with different methods.

Unit of analysis issues

Cluster‐randomised trials

We identified no eligible cluster‐randomised trials. If we identify any such trials in updates of this review, we will include them in our analyses along with individually randomised trials. We will use intracluster correlation coefficients (ICCs) from other sources and document our decisions. We will also consider it reasonable to combine the results from both cluster‐ and individually randomised trials if there is little heterogeneity between the study designs and we consider the choice of randomisation unit is unlikely to have affected the results of the intervention.

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

Dealing with missing data

For included studies, we noted the levels of attrition. We had planned to explore the impact of including studies with high levels of missing data in the overall assessment of treatment effect through a sensitivity analysis.

For all outcomes, we carried out intention‐to‐treat analyses wherever possible. This means we attempted to include all randomised participants in the analyses, in the group to which they were allocated, regardless of whether they received the allocated intervention. The denominator for each outcome in each trial was the number randomised minus any participants with missing data.

We excluded from the analysis trials with high risk of bias (high levels of missing data or a large number of participants analysed in the wrong group).

Assessment of heterogeneity

We assessed statistical heterogeneity in each meta‐analysis using the Tau², I² and Chi² statistics. We regarded heterogeneity as substantial if the I² value was greater than 30% and either the Tau² value was greater than zero or the Chi² test P value was below 0.10.

Assessment of reporting biases

In updates of this review, if we include 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 this visual assessment suggests asymmetry, we will perform exploratory analyses.

Data synthesis

We carried out statistical analysis using RevMan 5 (RevMan 2014). We used fixed‐effect meta‐analysis to combine data where it was reasonable to assume that studies estimated the same underlying treatment effect (i.e. where trials examined the same intervention, and the populations and methods were judged sufficiently similar). We used random‐effects meta‐analysis if we found sufficient clinical heterogeneity to suggest differing underlying treatment effects between trials, or substantial statistical heterogeneity. We treated the random‐effects summary as the average of the range of possible treatment effects, and we 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, we presented the results as the average treatment effect with 95% CIs, and the estimates of Tau² and I².

Subgroup analysis and investigation of heterogeneity

Where we identified substantial heterogeneity, we investigated it through subgroup analyses. We considered whether an overall summary was meaningful, and if it was, we used random‐effects analysis to produce it.

We divided studies into subgroups by type of cervical pessary (Arabian pessary versus other pessaries). We had planned to add a subgroup for unspecified types of pessary.

We used the primary outcome of the review in the subgroup analysis (delivery before 34 weeks' gestation).

We assessed subgroup differences using interaction tests available within RevMan 5 (RevMan 2014), and we reported the results of subgroup analyses quoting the Chi² statistic and P value, and the interaction test I² value.

Sensitivity analysis

We had planned to carry out sensitivity analyses for aspects of the review that might affect the results, for example, where there was risk of bias associated with the quality of some included trials. We may also have considered sensitivity analysis to explore the impact of fixed‐ or random‐effects analyses for outcomes with statistical heterogeneity and the impact of any assumptions made, such as ICC value used for cluster‐randomised trials. We performed a sensitivity analysis for the primary outcome where we removed trials in which participants received progesterone as a cointervention, as progesterone could affect outcomes.

Summary of findings and assessment of the certainty of the evidence

We assessed the certainty of the evidence using the GRADE approach for the following key outcomes:

delivery before 34 weeks' gestation;
delivery before 37 weeks' gestation;
maternal infection or inflammation (genital or urinary tract infection requiring treatment at any time after randomisation);
neonatal/paediatric care unit admission (for any reason);
fetal/infant mortality;
harm to offspring from the intervention (e.g. evidence of congenital fetal or neonatal infection, evidence of direct mechanical pressure from the device); and
birthweight.

We assessed these seven key outcomes for each of the following comparisons:

cervical pessary versus no treatment;
cervical pessary versus vaginal progesterone treatment; and
cervical pessary versus cervical cerclage.

We used GRADEpro GDT to import data from Review Manager 5 (RevMan 2014) and create summary of findings tables. Using the GRADE approach, we produced a summary of the intervention effect and a measure of certainty for each key outcome. The GRADE approach includes five considerations (study limitations, consistency of effect, imprecision, indirectness and publication bias) to assess the certainty of the body of evidence for each outcome. Evidence from RCTs can be downgraded from 'high certainty' by one level for serious limitations (or by two levels for very serious limitations) related to any of these five considerations. For presenting and reporting of the results within the context of GRADE assessment, we referred to Table 1 of the GRADE guidelines 26 (Santesso 2020).

Results

Description of studies

Results of the search

The search retrieved 78 records, of which four were duplicates. After eliminating five records in the title and abstract screen, we assessed 39 studies (69 reports) for eligibility. We excluded 14 studies and identified sixteen ongoing studies at this stage. Two review authors evaluated the remaining nine studies that met the inclusion criteria against Cochrane Pregnancy and Childbirth's set of predefined criteria to identify studies that, based on available information, were sufficiently trustworthy to be included in the analysis (the criteria include questions related to research governance, baseline characteristics, feasibility and results). One trial (Karbasian 2016) was not registered prospectively, and the protocol was not published. We attempted to contact the study authors (via Cochrane Pregnancy and Childbirth) with our queries but received no response. Karbasian 2016 will remain awaiting classification until we update this review. We included eight studies (24 reports), involving 2983 pregnant women (Care 2021; Cruz‐Melguizo 2018; Dugoff 2018; Goya 2012; Hui 2013; Nicolaides 2016; Pacagnella 2022; Saccone 2017). Figure 1 summarises the flow of studies.

Included studies

See the Characteristics of included studies table for full details.

Methods, settings and study dates

Seven studies were two‐arm RCTs (Cruz‐Melguizo 2018; Dugoff 2018; Goya 2012; Hui 2013; Nicolaides 2016; Pacagnella 2022; Saccone 2017) and one was a three‐arm RCT (Care 2021). Nicolaides 2016 was a multicentre trial conducted in England, Slovenia, Portugal, Chile, Australia, Italy, Albania, Germany and Belgium. Pacagnella 2022 was conducted in 17 sites in Brazil. The others took place in Spain (Cruz‐Melguizo 2018; Goya 2012), the USA (Dugoff 2018), Hong Kong (Hui 2013), Italy (Saccone 2017) and the UK (Care 2021).

Five studies took place between 2010 and 2019 (Care 2021, Cruz‐Melguizo 2018 Dugoff 2018; Pacagnella 2022; Saccone 2017), two studies took place between 2000 and 2009 (Goya 2012; Nicolaides 2016) and the remaining study took place from 2008 to 2011 (Hui 2013).

Participants

All studies only included women with cervical length of 25 mm or less. Gestational age at recruitment varied between studies (16 weeks 0 days to 24 weeks 6 days in Care 2021, 18 weeks to 23 weeks in Dugoff 2018 and Pacagnella 2022, 19 weeks to 22 weeks in Cruz‐Melguizo 2018 and Goya 2012, 20 weeks to 24 weeks in Hui 2013 and Nicolaides 2016, and 18 weeks 0 days to 23 weeks 6 days in Saccone 2017). All studies included women with singleton pregnancies except Pacagnella 2022, which included both singleton and twin pregnancies (we only included data from the singleton pregnancy subgroup in our analysis).

Interventions and comparisons

We included five trials in the comparison cervical pessary versus no treatment (Dugoff 2018; Goya 2012; Hui 2013; Nicolaides 2016; Saccone 2017). In three of these trials, women in both groups with cervical length less than 15 mm received additional vaginal progesterone until 36 weeks and 6 days of gestation (Dugoff 2018; Nicolaides 2016; Saccone 2017). We included three trials in the comparison cervical pessary versus vaginal progesterone (Cruz‐Melguizo 2018; Care 2021; Pacagnella 2022). Finally, we included one study in the comparison cervical pessary versus cervical cerclage (Care 2021). No studies compared cervical pessary to bed rest.

Outcomes

Only two of our 19 outcomes of interest were reported in all included studies (delivery before 34 weeks and delivery before 37 weeks). No study reported more than 10 of our review outcomes.

Sources of trial funding

Public sources funded three studies (Care 2021; Cruz‐Melguizo 2018; Goya 2012), and not‐for‐profit organisations funded another three (Dugoff 2018; Nicolaides 2016; Pacagnella 2022). Two studies provided no information about their sources of funding (Hui 2013; Saccone 2017).

Trial authors' declarations of interest

Two studies made no mention of potential conflicts of interest (Dugoff 2018; Hui 2013).

The remaining six studies reported that no authors had any conflicts of interest to declare (Care 2021; Cruz‐Melguizo 2018; Goya 2012; Nicolaides 2016; Pacagnella 2022; Saccone 2017).

Ongoing studies

We identified 16 ongoing RCTs, with two or three arms. Ten studies are investigating cervical pessary compared with progesterone (Hezelgrave 2016; IRCT201603109568N15; NCT02470676; NCT02511574; NCT02901626; NCT03052270; NCT03227705; NCT03637062; NCT04300322; van Zijl 2017); four studies are investigating cervical pessary compared with no treatment (IRCT20180302038914N1; JPRN‐UMIN000015465; NCT03418012; NCT04147117); three studies are investigating cervical pessary compared with cervical cerclage (IRCT20180302038914N1; Koullali 2017; NCT02405455); and one study is investigating vaginal progesterone plus cervical pessary versus vaginal progesterone alone (NCT03052270).

See Characteristics of ongoing studies table.

Studies awaiting classification

Karbasian 2016 is awaiting classification pending information from the study authors and subsequent screening by the review authors.

Excluded studies

We excluded 14 studies from this review. Five had an inappropriate design: non‐RCT (Barinov 2017; Mendoza 2017; Ples 2021), quasi‐RCT (Von Forster 1986), or simulation study (Willan 2016). One study was not registered prospectively and reported only the results of an interim analysis (Daskalakis 2013). We contacted the study authors but received no response. In eight studies, the participants did not meet out eligibility criteria: four included women with placenta praevia (Barinov 2020; Gmoser 1991; Hermans 2016; Stafford 2019), and four included women with threatened PTB (NCT02484820 2015; Mastantuoni 2021; Naeiji 2021; Pratcorona 2019).

Risk of bias in included studies

Figure 2 and Figure 3 summarise the results of our risk of bias assessment.

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

Allocation

We judged all studies at low risk of bias for random sequence generation and allocation concealment.

Blinding

Blinding of participants and personnel (performance bias)

We considered seven studies at high risk of performance bias (Care 2021; Cruz‐Melguizo 2018; Dugoff 2018; Goya 2012; Nicolaides 2016; Pacagnella 2022; Saccone 2017) because blinding of participants and personnel was not possible. We judged Hui 2013 at unclear risk of performance bias because all participants had a digital vaginal examination (in an attempt to simulate insertion of a pessary in the control group), but it is unclear whether personnel were blinded.

Blinding of outcome assessment (detection bias)

We considered six studies at high risk of detection bias (Care 2021; Cruz‐Melguizo 2018; Dugoff 2018; Goya 2012; Nicolaides 2016; Pacagnella 2022). We judged Hui 2013 at unclear risk of detection bias because the trial report stated that data were obtained from hospital records. We judged Saccone 2017 at low risk of detection bias because the outcome assessors and personnel involved in data collection and analysis were blinded.

Incomplete outcome data

We considered all studies at low risk of attrition bias because loss to follow‐up ranged from 0% to 5%.

Selective reporting

Because all studies adhered to their preregistered protocols, we considered them at low risk of reporting bias (Figure 2).

Other potential sources of bias

We judged six studies at low risk of other bias (Care 2021; Cruz‐Melguizo 2018; Dugoff 2018; Goya 2012; Pacagnella 2022; Saccone 2017). We considered Hui 2013 and Nicolaides 2016 to have high risk of other bias because they were terminated before reaching their calculated sample sizes.

Effects of interventions

See: Table 1; Table 2; Table 3

The first comparison (cervical pessary versus no treatment) included data from five studies (Dugoff 2018; Goya 2012; Hui 2013; Nicolaides 2016; Saccone 2017). The second comparison (cervical pessary versus vaginal progesterone) included data from three studies (Cruz‐Melguizo 2018; Care 2021; Pacagnella 2022). A single study evaluated cervical pessary versus cervical cerclage (Care 2021), and no studies evaluated cervical pessary versus bed rest.

Cervical pessary versus no treatment

Five studies provided data for this comparison (Dugoff 2018; Goya 2012; Hui 2013; Nicolaides 2016; Saccone 2017).

Primary outcome

Delivery before 34 weeks' gestation

Five studies measured delivery before 34 weeks' gestation (Dugoff 2018; Goya 2012; Hui 2013; Nicolaides 2016; Saccone 2017). Cervical pessary compared with no treatment may reduce the risk of delivery before 34 weeks (RR 0.72, 95% CI 0.33 to 1.55; 5 studies, 1830 women; low‐certainty evidence; Analysis 1.1). However, we are very uncertain about the results because the upper limit of the 95% CI indicates substantial harm (i.e. an increase in PTB before 34 weeks' gestation with cervical pessary). Due to substantial heterogeneity between studies, we used the random‐effects model for this meta‐analysis (Tau² = 0.65, I²= 90%).

1.1 — Comparison 1: Cervical pessary versus no treatment (singleton pregnancy), Outcome 1: Delivery before 34 weeks' gestation

Subgroup analysis and sensitivity analysis

We divided the studies into two subgroups according to type of pessary: Arabin (Goya 2012; Hui 2013; Nicolaides 2016; Saccone 2017) and Bioteque (Dugoff 2018). The test for subgroup differences did not suggest a difference in effect between Arabin and Bioteque (Chi² = 1.07, P = 0.30, I² = 6.2%), although the number of studies was insufficient for valid subgroup analysis. Three studies used progesterone as a cointervention (Dugoff 2018; Nicolaides 2016; Saccone 2017). The sensitivity analysis that excluded these studies did not change the point estimate substantially but made the 95% CI considerably wider (RR 0.58, 95% CI 0.09 to 3.84).

Secondary outcomes (maternal)

Delivery before 37 weeks' gestation

Five studies measured delivery before 37 weeks' gestation (Dugoff 2018; Goya 2012; Hui 2013; Nicolaides 2016; Saccone 2017). Cervical pessary compared with no treatment may reduce the risk of delivery before 37 weeks compared with no treatment (RR 0.68, 95% CI 0.44 to 1.05; 5 studies, 1830 women; low‐certainty evidence; Analysis 1.2; Table 1). However, the 95% CI crosses the line of no effect, so we cannot rule out a slight increase in PTB. We used the random‐effects model for this analysis because of substantial heterogeneity between studies (Tau² = 0.19, I² = 83%).

1.2 — Comparison 1: Cervical pessary versus no treatment (singleton pregnancy), Outcome 2: Delivery before 37 weeks' gestation

Maternal mortality

No studies reported maternal mortality.

Maternal infection or inflammation

Two studies reported vaginal infection (Hui 2013; Nicolaides 2016). Cervical pessary probably results in little or no difference in the risk of vaginal infection compared with no treatment (RR 1.04, 95% CI 0.87 to 1.26; 2 studies, 1032 women; moderate‐certainty evidence; Analysis 1.3; Table 1).

1.3 — Comparison 1: Cervical pessary versus no treatment (singleton pregnancy), Outcome 3: Maternal infection or inflammation

We identified two additional outcomes that were not included in the definition of maternal infection and inflammation but that were of clinical importance: vaginal discharge and chorioamnionitis. Four studies showed increased vaginal discharge in the pessary arm (Dugoff 2018; Goya 2012; Nicolaides 2016; Saccone 2017), and three studies showed no significant difference between cervical pessary and no treatment in risk of chorioamnionitis (Dugoff 2018; Goya 2012; Saccone 2017).

Preterm prelabour rupture of membranes

Four studies reported preterm prelabour rupture of membranes (Dugoff 2018; Goya 2012; Nicolaides 2016; Saccone 2017). It is unclear if cervical pessary compared to no treatment decreases the risk of preterm prelabour rupture of membranes because the 95% CIs are compatible with a wide range of effects that encompass both appreciable benefit and harm (RR 0.67, 95% CI 0.27 to 1.65; 4 studies, 906 women; Analysis 1.4). Because of substantial heterogeneity, we used the random‐effects model (Tau² = 0.52, I² = 66%).

1.4 — Comparison 1: Cervical pessary versus no treatment (singleton pregnancy), Outcome 4: Preterm prelabour rupture of membranes

Harm to woman from the intervention

Goya 2012 reported pregnancy bleeding in 7/190 (3.6%) women in the cervical pessary group and 9/190 (4.7%) in the no treatment group, with no clear difference between the groups (RR 0.78, 95% CI 0.30 to 2.05; 380 women; Analysis 1.5).

1.5 — Comparison 1: Cervical pessary versus no treatment (singleton pregnancy), Outcome 5: Harm to woman from the intervention

Data from Hui 2013 and Nicolaides 2016 suggested an increase in the risk of pelvic discomfort in the pessary group (RR 3.15, 95% CI 1.88 to 5.29; I² = 0%;² studies, 1033 women; Analysis 1.5).

Maternal medications

This outcome included three types of medications; tocolytic treatment (reported by Goya 2012), corticosteroid treatment for fetal maturation (reported by Goya 2012; Hui 2013) and antibiotics following positive swabs (reported by Nicolaides 2016). Compared to no treatment, cervical pessary may reduce the need for tocolytic treatment (RR 0.63, 95% CI 0.50 to 0.81; 1 study, 380 women; Analysis 1.6), and corticosteroid treatment (RR 0.69, 95% CI 0.57 to 0.84; 2 studies, 488 women; Analysis 1.6), but may increase antibiotic use (RR 1.51, 95% CI 1.13 to 2.02; 1 study, 924 women; Analysis 1.6).

1.6 — Comparison 1: Cervical pessary versus no treatment (singleton pregnancy), Outcome 6: Maternal medications (e.g. tocolytics, corticosteroids)

Discontinuation of the intervention

We did not analyse the data for discontinuation of the intervention because it applied to only the cervical pessary arms of the studies. Three of the five studies reported varying rates of discontinuation of pessary use: half of participants (51.7%) in Dugoff 2018, one quarter (24.7%) in Nicolaides 2016, and only 1/192 in Goya 2012. Reported causes of discontinuation were preterm labour, prelabour rupture of membranes, iatrogenic delivery and participant request.

Maternal satisfaction

Only Goya 2012 reported maternal satisfaction, stating that all pessary users would recommend the intervention to other people.

Secondary outcomes (offspring)

Neonatal/paediatric care unit admission

Three studies reported neonatal/paediatric care unit admission (Hui 2013; Nicolaides 2016; Saccone 2017). It is unclear if cervical pessary compared with no treatment has an effect on the risk of neonatal/paediatric care unit admission because the 95% CI is compatible with a wide range of effects that encompass both appreciable benefit and harm (RR 0.96, 95% CI 0.58 to 1.59; 3 studies, 1332 infants; low‐certainty evidence; Analysis 1.7; Table 1). Because of substantial heterogeneity, we used the random‐effects model (Tau² = 0.13, I² = 66%).

1.7 — Comparison 1: Cervical pessary versus no treatment (singleton pregnancy), Outcome 7: Neonatal/paediatric care unit admission

Fetal/infant mortality

All five studies reported fetal/infant mortality (Dugoff 2018; Goya 2012; Hui 2013; Nicolaides 2016; Saccone 2017). It is unclear if cervical pessary compared with no treatment has an effect on the risk of fetal/infant mortality because the 95% CI is compatible with a wide range of effects that encompass both appreciable benefit and harm (RR 0.93, 95% CI 0.58 to 1.48; 5 studies, 1830 infants; low‐certainty evidence; Analysis 1.8; Table 1).

1.8 — Comparison 1: Cervical pessary versus no treatment (singleton pregnancy), Outcome 8: Fetal/infant mortality

Neonatal sepsis

Three studies measured neonatal sepsis (Goya 2012; Hui 2013; Nicolaides 2016). It is unclear if cervical pessary compared with no treatment has an effect on the risk of neonatal sepsis (RR 0.67, 95% CI 0.23 to 1.96; Tau² = 0.61; I² = 69%; 3 studies, 1412 infants; Analysis 1.9). Because of substantial heterogeneity, we used the random‐effects model (Tau² = 0.52, I² = 69%).

1.9 — Comparison 1: Cervical pessary versus no treatment (singleton pregnancy), Outcome 9: Neonatal sepsis

Gestational age at birth

Two studies reported gestational age at birth as means and SDs (Goya 2012; Hui 2013). It is unclear if cervical pessary compared with no treatment has an effect on gestational age at birth (MD 1.63 weeks, 95% CI −0.82 to 4.07; I² = 90%; 2 studies, 488 infants; Analysis 1.10). Because of substantial heterogeneity, we used the random‐effects model (Tau² = 0.52, I² = 90%).

1.10 — Comparison 1: Cervical pessary versus no treatment (singleton pregnancy), Outcome 10: Gestational age at birth (weeks)

Nicolaides 2016 reported gestational age at birth as median and range, showing no difference between cervical pessary and no treatment. Dugoff 2018 reported this outcome as median and interquartile range (IQR), and found no significant difference between the two groups: 37.2 weeks (IQR 30.0 to 39.1) in the pessary group versus 38.1 weeks (IQR 27.8 to 39.4) in the expectant management group.

Harm to offspring from the intervention

No studies reported harm to offspring from the intervention.

Birthweight

Only Hui 2013 reported mean birthweight, showing no effect of the intervention compared to the control (2.84 (SD 0.59) kg in the pessary group compared with 2.95 (SD 0.74) kg in the no treatment group). Three studies reported birthweight in two categories, less than 2500 g and less than 1500 g. (Goya 2012; Nicolaides 2016; Saccone 2017). These individual studies showed no significant difference between the groups in terms of birthweight categories.

Early neurodevelopmental morbidity

Two studies reported intracranial haemorrhage grade 3 or 4 (Dugoff 2018; Saccone 2017). It is unclear if cervical pessary compared to no treatment has an effect on intracranial haemorrhage (RR 0.33, 95% CI 0.01 to 9.53; Tau² = 5.38; I² = 92%; 2 studies, 418 infants; Analysis 1.11).

1.11 — Comparison 1: Cervical pessary versus no treatment (singleton pregnancy), Outcome 11: Early neurodevelopmental morbidity

Four studies reported fetal retinopathy (Dugoff 2018; Goya 2012; Nicolaides 2016; Saccone 2017). It is unclear if cervical pessary compared to no treatment has an effect on fetal retinopathy (RR 0.51, 95% CI 0.10 to 2.60; Tau² = 1.53; I² = 56%; 4 studies, 1722 infants; Analysis 1.11).

Late neurodevelopmental morbidity

No studies reported late neurodevelopmental morbidity.

Gastrointestinal morbidity: necrotising enterocolitis

Four studies reported necrotising enterocolitis (Dugoff 2018; Goya 2012; Nicolaides 2016; Saccone 2017). It is unclear if cervical pessary compared to no treatment has an effect on necrotising enterocolitis (RR 1.09, 95% CI 0.48 to 1.51; I² = 0%; 4 studies, 1722 infants; Analysis 1.12).

1.12 — Comparison 1: Cervical pessary versus no treatment (singleton pregnancy), Outcome 12: Gastrointestinal morbidity: necrotising enterocolitis

Respiratory morbidity

Two studies reported bronchopulmonary dysplasia (Dugoff 2018; Saccone 2017). It is unclear if cervical pessary compared to no treatment has an effect on the risk of bronchopulmonary dysplasia (RR 0.76, 95% CI 0.38 to 1.52; I² = 0%; 2 studies, 418 infants; Analysis 1.13).

1.13 — Comparison 1: Cervical pessary versus no treatment (singleton pregnancy), Outcome 13: Respiratory morbidity: bronchopulmonary dysplasia

All five studies in this comparison reported respiratory distress syndrome (RDS). No study provided evidence of an effect of the intervention on RDS, but we did not meta‐analyse these data, as RDS was not among our secondary outcomes.

Cervical pessary versus vaginal progesterone

Three studies provided data for this comparison (Care 2021; Cruz‐Melguizo 2018; Pacagnella 2022).

Primary outcome

Delivery before 34 weeks' gestation

Three studies reported delivery before 34 weeks' gestation (Care 2021; Cruz‐Melguizo 2018; Pacagnella 2022). Cervical pessary compared with vaginal progesterone probably reduces the risk of delivery before 34 weeks (RR 0.72, 95% CI 0.52 to 1.02; 3 studies, 1126 women; moderate‐certainty evidence; Analysis 2.1; Table 2). However, as the 95% CI crosses the line of no effect, we cannot rule out a slight increase in this outcome.

2.1 — Comparison 2: Cervical pessary versus vaginal progesterone (singleton pregnancy), Outcome 1: Delivery before 34 weeks' gestation

Secondary outcomes (maternal)

Delivery before 37 weeks' gestation:

Three studies reported delivery before 37 weeks' gestation (Care 2021; Cruz‐Melguizo 2018; Pacagnella 2022). Cervical pessary compared with vaginal progesterone probably reduces the risk of delivery before 37 weeks (RR 0.89, 95% CI 0.73 to 1.09; 3 studies, 1126 women; moderate‐certainty evidence; Analysis 2.2; Table 2). However, as the 95% CI crosses the line of no effect, we cannot rule out a slight increase in this outcome.

2.2 — Comparison 2: Cervical pessary versus vaginal progesterone (singleton pregnancy), Outcome 2: Delivery before 37 weeks' gestation

Maternal mortality

No studies reported maternal mortality.

Maternal infection or inflammation

Two studies reported maternal infection or inflammation (Care 2021; Cruz‐Melguizo 2018). Cervical pessary compared with vaginal progesterone probably has little or no effect on the risk of vaginal infection (RR 0.95, 95% CI 0.81 to 1.12; 2 studies, 265 women; moderate‐certainty evidence; Analysis 2.3; Table 2).

2.3 — Comparison 2: Cervical pessary versus vaginal progesterone (singleton pregnancy), Outcome 3: Maternal infection or inflammation

Preterm prelabour rupture of membranes

Two studies reported preterm prelabour rupture of membranes (Care 2021; Cruz‐Melguizo 2018). It is unclear if cervical pessary compared to vaginal progesterone has an effect on preterm prelabour rupture of membranes because the 95% CI is compatible with a wide range of effects that encompass both appreciable benefit and harm (RR 1.02, 95% CI 0.53 to 1.97; 2 studies, 265 women; I² = 0%; Analysis 2.4).

2.4 — Comparison 2: Cervical pessary versus vaginal progesterone (singleton pregnancy), Outcome 4: Preterm prelabour rupture of membranes

Harm to woman from the intervention

No studies reported harm to women from the intervention.

Maternal medications

This outcome included tocolytic treatment, corticosteroid administration for lung maturity and antibiotics for positive vaginal swab. Data from Care 2021 and Cruz‐Melguizo 2018 showed no clear difference between cervical pessary and vaginal progesterone as regards tocolytic treatment (RR 0.71, 95% CI 0.34 to 1.49; 2 studies, 265 women; I² = 0%; Analysis 2.5) or corticosteroid treatment (RR 0.81, 95% CI 0.51to 1.28; 2 studies, 265 women; Analysis 2.5). Only Care 2021 reported antibiotic use for positive vaginal swab, showing no difference between the groups (RR 0.29, 95% CI 0.01 to 5.79; 1 study, 11 women; Analysis 2.5)

2.5 — Comparison 2: Cervical pessary versus vaginal progesterone (singleton pregnancy), Outcome 5: Maternal medications (e.g. tocolytics, corticosteroids)

Discontinuation of the intervention

Cruz‐Melguizo 2018 reported discontinuation in 4/128 cervical pessary users. Reported reasons were significant vaginal discomfort in two woman, intense vaginal bleeding in one woman and repeated expulsion of the pessary in one multiparous women (Analysis 2.6).

2.6 — Comparison 2: Cervical pessary versus vaginal progesterone (singleton pregnancy), Outcome 6: Discontinuation of the intervention

Maternal satisfaction

No studies reported maternal satisfaction.

Secondary outcomes (offspring)

Neonatal/paediatric care unit admission

Only Cruz‐Melguizo 2018 reported neonatal/paediatric care unit admission. Cervical pessary compared to vaginal progesterone may have little or no effect on the risk of neonatal/paediatric care unit admission (RR 0.98, 95% CI 0.49 to 1.98; low‐certainty evidence; Analysis 2.7; Table 2).

2.7 — Comparison 2: Cervical pessary versus vaginal progesterone (singleton pregnancy), Outcome 7: Neonatal/paediatric care unit admission

Fetal/infant mortality

Care 2021 and Cruz‐Melguizo 2018 reported fetal/neonatal mortality. It is unclear if cervical pessary compared to vaginal progesterone has an effect on the risk of fetal/neonatal mortality (RR 1.97, 95% CI 0.50 to 7.70; 2 studies, 265 infants; low‐certainty evidence; Analysis 2.8; Table 2).

2.8 — Comparison 2: Cervical pessary versus vaginal progesterone (singleton pregnancy), Outcome 8: Fetal/infant mortality

Neonatal sepsis

Only Care 2021 measured neonatal sepsis, reporting no cases among 11 infants (Analysis 2.9).

2.9 — Comparison 2: Cervical pessary versus vaginal progesterone (singleton pregnancy), Outcome 9: Neonatal sepsis

Gestational age at birth

No studies reported gestational age at birth.

Harm to offspring from the intervention

Only Care 2021 measured harm to offspring from the intervention, reporting no cases among 11 infants (low‐certainty evidence; Analysis 2.10; Table 2).

2.10 — Comparison 2: Cervical pessary versus vaginal progesterone (singleton pregnancy), Outcome 10: Harm to offspring from the intervention

Birthweight

No studies reported birthweight.

Early neurodevelopmental morbidity

In Cruz‐Melguizo 2018, 2/128 infants in the cervical pessary group had early neurodevelopmental morbidity (retinopathy), compared with 1/126 in the vaginal progesterone group (Analysis 2.11).

2.11 — Comparison 2: Cervical pessary versus vaginal progesterone (singleton pregnancy), Outcome 11: Early neurodevelopmental morbidity: retinopathy

Late neurodevelopmental morbidity

No studies reported late neurodevelopmental morbidity.

Gastrointestinal morbidity

In Cruz‐Melguizo 2018, 2/128 infants in the cervical pessary group had necrotising enterocolitis, compared with 0/126 in the vaginal progesterone group (Analysis 2.12).

2.12 — Comparison 2: Cervical pessary versus vaginal progesterone (singleton pregnancy), Outcome 12: Gastrointestinal morbidity: necrotising enterocolitis

Respiratory morbidity

In Cruz‐Melguizo 2018 7/128 infants in the cervical pessary group had respiratory morbidity, compared with 6/126 in the vaginal progesterone group (Analysis 2.13).

2.13 — Comparison 2: Cervical pessary versus vaginal progesterone (singleton pregnancy), Outcome 13: Respiratory morbidity

Cervical pessary versus cervical cerclage

Only Care 2021 provided data for this comparison.

Primary outcome

Delivery before 34 weeks' gestation

Care 2021 reported no cases of delivery before 34 weeks in either arm of the study (low‐certainty evidence; Analysis 3.1; Table 3).

3.1 — Comparison 3: Cervical pessary versus cervical cerclage (singleton pregnancy), Outcome 1: Delivery before 34 weeks' gestation

Secondary outcomes (maternal)

Delivery before 37 weeks' gestation

Care 2021 reported 2/6 deliveries before 37 weeks in the cervical pessary group versus 0/7 in the control group (low‐certainty evidence; Analysis 3.2; Table 3).

3.2 — Comparison 3: Cervical pessary versus cervical cerclage (singleton pregnancy), Outcome 2: Delivery before 37 weeks' gestation

Maternal mortality

Care 2021 did not report maternal mortality.

Maternal infection or inflammation

In Care 2021, 2/6 women in the cervical pessary group had vaginal infection versus 2/7 in the cervical cerclage group (very low‐certainty evidence; Analysis 3.3; Table 3).

3.3 — Comparison 3: Cervical pessary versus cervical cerclage (singleton pregnancy), Outcome 3: Maternal infection or inflammation

Preterm prelabour rupture of membranes

In Care 2021, 3/6 women in the cervical pessary group and 1/7 in the cervical cerclage group had prelabour rupture of membranes (Analysis 3.4).

3.4 — Comparison 3: Cervical pessary versus cervical cerclage (singleton pregnancy), Outcome 4: Preterm prelabour rupture of membranes

Harm to woman from the intervention

Care 2021 did not report harm to women from the intervention.

Maternal medications

One woman in each arm of Care 2021 received tocolytic treatment. Corticosteroid stimulation of lung maturity was administered to 3/6 women in the cervical pessary group and 1/7 women in the cervical cerclage group. No women in the cervical pessary group received antibiotics due to a positive vaginal swab, compared with 2/7 women in the cervical cerclage group (Analysis 3.5).

3.5 — Comparison 3: Cervical pessary versus cervical cerclage (singleton pregnancy), Outcome 5: Maternal medications

Discontinuation of the intervention

Care 2021 reported that 0/6 women in the pessary group discontinued the intervention, while one of the seven women with cervical cerclage had it removed when she progressed to active preterm labour at 25 weeks' gestation.

Maternal satisfaction

Care 2021 did not report maternal satisfaction.

Secondary outcomes (offspring)

Neonatal/paediatric care unit admission

Care 2021 did not report neonatal/paediatric care unit admission.

Fetal/neonatal mortality

Care 2021 reported no deaths among the six infants in the cervical pessary group, and one death among the seven infants in the cervical cerclage group (low‐certainty evidence; Analysis 3.7; Table 3).

3.7 — Comparison 3: Cervical pessary versus cervical cerclage (singleton pregnancy), Outcome 7: Fetal/infant mortality

Neonatal sepsis

There were no reported cases of neonatal sepsis in either group (Analysis 3.8).

3.8 — Comparison 3: Cervical pessary versus cervical cerclage (singleton pregnancy), Outcome 8: Neonatal sepsis

Gestational age at birth

Care 2021 did not report gestational age at birth.

Harm to offspring from the intervention

There were no reported cases of harm to offspring from the intervention in either group (Analysis 3.9).

3.9 — Comparison 3: Cervical pessary versus cervical cerclage (singleton pregnancy), Outcome 9: Harm to offspring from the intervention

Birthweight

Care 2021 did not report birthweight.

Early neurodevelopmental morbidity

Care 2021 did not report early neurodevelopmental morbidity.

Late neurodevelopmental morbidity

Care 2021 did not report late neurodevelopmental morbidity.

Gastrointestinal morbidity

Care 2021 did not report late neurodevelopmental morbidity.

Respiratory morbidity

Care 2021 did not report late neurodevelopmental morbidity.

Discussion

Summary of main results

We included eight RCTs in this review; one was a three‐arm study that contributed data to more than one comparison. Five RCTs compared cervical pessary to no treatment, three studies compared cervical pessary to vaginal progesterone, and one study compared cervical pessary to cervical cerclage. All studies took place in high‐income countries and met the criteria for trustworthiness according to the Pregnancy and Childbirth scientific integrity checklist. Risk of bias assessment showed low risk of bias in all domains except for performance and detection biases, as most studies were open‐label. We also identified 16 registered ongoing RCTs evaluating cervical pessary in pregnant women with a short cervix for prevention of PTB in singleton pregnancy (see Characteristics of ongoing studies table). We will assess these ongoing studies for inclusion in the first update of this review.

Cervical pessary versus no treatment

The current evidence suggests that cervical pessary compared with no treatment may reduce the risk of delivery before 34 weeks or before 37 weeks compared with no treatment (low‐certainty evidence), although these results should be viewed with caution because the 95% CIs cross the line of no effect.

Cervical pessary compared with no treatment probably results in little or no difference in the risk of vaginal infection. Vaginal discharge and chorioamnionitis were not among our prespecified outcomes; however, it seems that cervical pessary compared with no treatment probably increases the risk of vaginal discharge, and may make little or no difference to the risk of chorioamnionitis, although the wide 95% CI indicates the possibility of either increased risk or reduced risk.

Regarding outcomes related to offspring, it is unclear if cervical pessary compared with no treatment has an effect on neonatal/paediatric care unit admission, fetal/neonatal mortality or neonatal sepsis, because the 95% CIs are compatible with a wide range of effects that encompass both appreciable benefit and harm. In addition, the use of cervical pessary did not affect the birthweight of the newborns in individual studies.

Cervical pessary versus progesterone treatment

The evidence suggests that cervical pessary use compared with vaginal progesterone may reduce the risk of preterm delivery before 34 weeks and before 37 weeks (moderate‐certainty evidence), although these results should be viewed with caution because the 95% CIs cross the line of no effect. Cervical pessary compared with vaginal progesterone probably has little or no effect on the risk of vaginal infection. Only one study reported neonatal/paediatric care unit admission and infant mortality, providing uncertain evidence.

Cervical pessary versus cerclage

Only one study with a very small sample size was eligible for inclusion in this comparison. It was a feasibility study with few events, and the evidence is insufficient to generate any conclusions.

Overall completeness and applicability of evidence

In the protocol for this review, we stated that we aimed to compare cervical pessary with four comparators: no treatment, vaginal progesterone, cervical cerclage and bed rest (Abdel‐Aleem 2019). We reviewed the search results against explicit criteria. We included eight RCTs, which provided data for three comparisons: cervical pessary versus no treatment (five studies), vaginal progesterone (three studies) and cervical cerclage (one study).

Among the five studies that evaluated cervical pessary versus no treatment, we observed substantial heterogeneity for the primary outcome (delivery before 34 weeks' gestation; Analysis 1.1). However, the evidence suggested that the pessary use may decrease the risk of delivery before 34 weeks (low‐certainty evidence; Table 1). The studies provided data for only some of our prespecified outcomes: no studies reported maternal satisfaction, and between one and four studies reported the remaining maternal outcomes. No studies reported the offspring outcomes of harm to offspring from the intervention or late neurodevelopmental morbidity. The remaining eight outcomes were variably reported in one to four of the studies, although we could not meta‐analyse the data on birthweight (Analysis 1.7; Analysis 1.8; Analysis 1.9; Analysis 1.10; Analysis 1.11; Analysis 1.12; Analysis 1.13). In the key outcomes, the certainty of evidence varied from low to moderate (Table 1).

We observed substantial heterogeneity among primary outcome data from the three studies that evaluated cervical pessary versus vaginal progesterone, though the evidence suggested that the intervention may reduce the rate preterm delivery before 34 weeks (Analysis 2.1; Table 2). Between one and three studies provided data for five of eight maternal secondary outcomes and seven of 10 offspring secondary outcomes (Analysis 2.2; Analysis 2.3; Analysis 2.4; Analysis 2.5; Analysis 2.6; Analysis 2.7; Analysis 2.8; Analysis 2.9; Analysis 2.10; Analysis 2.11; Analysis 2.12; Analysis 2.13). In the key outcomes, the certainty of evidence varied from low to moderate (Table 2).

We met our objective of assessing the effect of cervical pessary in prevention of preterm labour in high‐risk cases, specifically in comparison to no treatment and progesterone treatment. However, we were unable to reach any conclusions on the effects of cervical cerclage, and we identified no studies using bed rest as a comparator.

Certainty of the evidence

All included studies had low risk of selection bias because they used computer‐generated random tables for sequence generation, and either sealed opaque envelopes or web‐based systems for allocation concealment. All had low risk of attrition bias, with 1% to 2% loss to follow‐up, which is to be expected in a sample of pregnant women. Seven studies were considered at high risk of performance and detection biases because they were open‐label. The authors of one study, tried to blind the participants in the control group by simulating pessary insertion during a digital examination (Hui 2013). However, we do not consider this complete blinding because women can feel the pessary in their vagina. Two studies were terminated before reaching the calculated sample size (Hui 2013; Nicolaides 2016). All studies followed preregistered protocols, so had low risk of reporting bias (Figure 2).

We produced an additional table with further details of the studies included in the first comparison (cervical pessary versus no treatment); it shows marked diversity between the populations, interventions, outcomes reported and previous and current risk of PTB (Table 4). It seems that the included studies examined different phenotypes of PTB, which could help to explain the heterogeneity among the results.

1. Clinical diversity (heterogeneity) among the included studies in the first comparison (cervical pessary versus no treatment).

Clinical diversity (heterogeneity) among the included studies in the first comparison (cervical pessary versus no treatment)
Item		Dugoff 2017	Goya 2012	Hui 2012	Nicolaides 2016	Saccone 2017
Population	Mean^aage of participants, years	CP: 27.7 NT: 29.5	CP: 30.3 NT: 29.6	CP: 31.6 NT: 31.8	CP: 30.1 (median) NT: 29.5 (median)	CP: 28.5 NT: 28.9
	Mean BMI, kg/m²	CP: 25.6 NT: 24.6	CP: 24.9 NT: 24.5	CP: 21.9) NT: 21.7	CP: 23.5 NT: 23.8	CP: 26.7 NT: 26.4
	Smokers, n (%)	CP: 5 (9) NT: 3 (5)	CP: 37 (19) NT: 38 (20)	CP: 1 (1.9) NT: 3 (5.5)	CP: 61 (13.1) NT: 68 (14.6)	CP: 19 (12.7) NT: 20 (13.3)
	Ethnicity	Black, white, others	White, Latin American, others	Chinese	White, Black, South Asian, East Asian, Mixed	White, Black, Asian
	Previous cervical surgery, n (%)	Not reported	Not reported	CP: 0 (0) NT: 1 (1.8)	CP: 74 (16) NT: 85 (18.2)	CP: 7 (4.6) NT: 5 (3.4)
	Prior PTB, n (%)	Not reported	CP: 21 (11%) NT: 0 (11%)	CP: 3 (5.7) NT: 6 (10.9)	CP: 70 (15.1) NT: 84 (18)	Not included
	Mean gestational age at randomisation, weeks	CP: 20.9 NT: 20.7	CP: 22.2 NT: 22.4	CP: 21.9 NT: 21.9	CP: 23.4 (median). NT: 23.6 (median).	CP: 22.3 NT: 22.4
	Mean^aCL at randomisation, mm	CP: 17.6 NT: 19	CP: 19 NT: 19	CP: 19.6 NT: 20.5	CP: 20 (median). NT: 20 (median).	CP: 11.5 NT: 12.5
	Vaginal infection requiring treatment, n (%)	Not reported	Not reported	CP: 13 (24.5) NT: 14 (25.5)	CP: 95 (20.4) NT: 69 (14.8)	CP: 122 (81.3) NT: 115 (76.7)
Intervention		Bioteque cup (shorter than Arabin pessary) + vaginal progesterone if CL < 15 mm	Arabin pessary	Arabin pessary	Arabin pessary + vaginal progesterone if CL < 15 mm	Arabin pessary + vaginal progesterone if CL < 20 mm
Comparator		No treatment + vaginal progesterone if CL < 15 mm	No treatment	No treatment	No treatment + vaginal progesterone if CL < 15 mm	No treatment + vaginal progesterone if CL < 20 mm
No. of outcomes reported in study/prespecified outcomes of this review		9/19	14/19	12/19	13/19	10/19
PTB before 34 weeks, n (%)		CP: 19 (32) NT: 15 (26)	CP: 12 (6) NT: 51 (27)	CP: 5 (9.4) NT: 3 (5.5)	CP: 60 (12.9) NT: 53 (11.3)	CP: 11 (7.3) NT: 23 (15.3)
Risk of bias		High risk of performance bias and detection bias	High risk of performance bias and detection bias	Unclear risk of performance bias and detection bias Premature termination of th study	High risk of performance bias and detection bias Premature termination of the study	High risk of performance bias

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^aUnless otherwise specified BMI: body mass index; CL: cervical length; CP: cervical pessary; NT: no treatment; PTB: preterm birth.

We included seven key outcomes in our summary of findings tables. In the first comparison (cervical pessary versus no treatment), we downgraded the certainty of four key outcomes (delivery before 34 weeks, delivery before 37 weeks, neonatal/paediatric care unit admission, fetal/infant mortality) by two levels to low, and we downgraded the certainty of the evidence for maternal infection and inflammation by one level to moderate (Table 1). No studies reported harm to offspring or birthweight in this comparison. In the second comparison (cervical pessary versus vaginal progesterone), we downgraded the three maternal outcomes (delivery before 34 weeks and 37 weeks and maternal infection or inflammation) by one level to moderate‐certainty evidence, and we downgraded three neonatal outcomes (neonatal/paediatric care unit admission, fetal/infant mortality, harm to offspring) by two levels to low‐certainty evidence (Table 2). No studies reported birthweight in this comparison. With regard to the third comparison (cervical pessary versus cervical cerclage, based on only one study), we downgraded the certainty of the evidence for delivery before 34 weeks and 37 weeks, fetal/infant mortality and harm to offspring by two levels to low, and we downgraded the certainty of the evidence for maternal infection and inflammation by three levels to very low (Table 3). The single study in this comparison did not report neonatal/paediatric care unit admission or birthweight.

Potential biases in the review process

We used predefined criteria to assess the scientific integrity/trustworthiness of the studies. Although nine studies met our eligibility criteria, we moved one of them to studies awaiting classification after this trustworthiness assessment (Karbasian 2016). This decision was based on lack of prospective registration and ethics committee approval. We attempted to contact the study authors via Cochrane Pregnancy and Childbirth, but received no response. If we obtain the necessary data, we will include Karbasian 2016 in the first update of this review.

The available data covered three comparisons (cervical pessary versus no treatment, vaginal progesterone and cervical cerclage); we identified no studies for the comparison of cervical pessary versus bed rest.

In the first comparison (cervical pessary versus no treatment) we found substantial heterogeneity between included studies. In Goya 2012 and Saccone 2017, the pessary helped to prevent PTB, while Dugoff 2018, Hui 2013 and Nicolaides 2016 found no benefit. We attempted to explain the heterogeneity among the included studies through subgroup analysis (by type of pessary, as prespecified in the protocol) and sensitivity analyses (repeating the analyses after excluding studies with progesterone cointervention). Neither approach explained the heterogeneity. We examined the clinical diversity of the studies included in the first comparison, in terms of the populations, interventions and outcome reporting in relation to the prespecified outcomes (Table 4). We detected marked clinical diversity in all domains, which could explain part of the heterogeneity.

We noticed extreme degrees of variability in the incidence of the primary outcome (delivery before 34 weeks) between the included RCTs in both study arms. The overall percentage of PTB was as high as 35% in Goya 2012 and 31% in Dugoff 2018; but was much lower in Saccone 2017 (11%), Nicolaides 2016 (12%) and Hui 2013 (7%). This may reflect a difference in the background risk of PTB in the participants.

Other reasons for clinical heterogeneity may be ethnic differences in the participants of the different studies, or history of cervical surgery (an exclusion criterion of Goya 2012 and Dugoff 2018 but not Nicolaides 2016 and Saccone 2017). Additionally, women with prior PTB were excluded from Dugoff 2018 and Saccone 2017 but not the other studies. Vaginal infection requiring treatment was very high in Saccone 2017, much lower in Hui 2013 and not reported in Goya 2012 or Nicolaides 2016. The diversity of results may be related to the fact that some studies included women who were receiving cointerventions (pessary plus progesterone) at the time of randomisation (Dugoff 2018; Nicolaides 2016; Saccone 2017). Four studies used Arabin pessaries, while Dugoff 2018 used the Bioteque cup. However, the subgroup analysis suggested that type of pessary had no effect on the primary outcome. Moreover, the exclusion of studies with the progesterone cointervention did not seem to make any difference in the sensitivity analysis (Table 4). Since we included fewer than 10 studies in this comparison, we did not perform meta‐regression to explain heterogeneity.

Another limitation of the review is that the definitions of the outcomes were mainly based on CROWN consensus and do not exactly match those defined in the included studies (van 't Hooft 2016). This limited the number of reported outcomes in relation to prespecified outcomes. Moreover, outcomes such as chorioamnionitis, vaginal discharge or neonatal RDS, which were not prespecified in the CROWN consensus, are of clinical importance in this population. In addition, some studies reported outcomes in units other than those specified in the review and could not be included in the analysis.

In the second comparison (cervical pessary versus vaginal progesterone), we found substantial heterogeneity among studies for the primary outcome. While Pacagnella 2022 reported a reduction in delivery before 34 weeks in the pessary group, Care 2021 and Cruz‐Melguizo 2018 did not. The reasons outlined above for the first comparison could explain the heterogeneity between studies.

We identified 16 registered ongoing studies. The publication of results has been delayed in many cases, which reflects the difficulty of conducting RCTs in this area (Characteristics of ongoing studies).

Agreements and disagreements with other studies or reviews

Despite the diversity of data included in our meta‐analysis, overall there is evidence of a possible reduction in the risk of delivery before 34 weeks or 37 weeks with the use of cervical pessary compared with no treatment or vaginal progesterone, although the results of all of these meta‐analysis do not rule out the possibility of no effect or a small increase in PTB. One previous Cochrane Review on this topic included both singleton and twin pregnancy and identified only one eligible study (Goya 2012); the evidence suggested that cervical pessary may reduce PTB compared no treatment, in line with our results (Abdel‐Aleem 2013).

However, our findings contradict those of Jin 2017, a review that included three RCTs in the comparison of cervical pessary versus no treatment and showed no benefit of the pessary (Goya 2012; Hui 2013; Nicolaides 2016). Our results also differ from those of Correa 2019, which included five RCTs and found that cervical pessary was not superior to no treatment (Goya 2012; Hui 2013; Karbasian 2016; Nicolaides 2016; Saccone 2017). Additionally, a network meta‐analysis by Jarde and colleagues included four RCTs (Goya 2012; Hui 2013; Nicolaides 2016; Saccone 2017), and found that there was insufficient evidence to reach conclusions for the comparisons of cervical pessary versus cervical cerclage, vaginal progesterone and bed rest (Jarde 2019). Regarding the comparison with no intervention or treatment as usual, Jarde 2019 found that cervical pessary had little or no effect on prevention of delivery before 34 weeks, but may have reduced delivery before 37 weeks. Our systematic review showed a potential protective effect of cervical pessary compared to no treatment in prevention of delivery before 34 weeks or 37 weeks, but with very marked heterogeneity and wide CIs that crossed the line of no effect. Another meta‐analysis by Perez‐Lopez and colleagues included only three studies (Goya 2012; Nicolaides 2016; Saccone 2017), and found that cervical pessary compared with no treatment did not reduce delivery before 34 weeks but did reduce delivery before 37 weeks (Perez‐Lopez 2019). The difference with our review is that Perez‐Lopez 2019 did not include two studies that showed no effect of cervical pessary on PTB (Dugoff 2018; Hui 2013).

The diversity of results on the effectiveness of cervical pessary may be related to different phenotypes of PTB. One retrospective study found that in women with short cervix and previous preterm prelabour rupture of membranes, cervical pessary may be a less effective option (Care 2019). This study highlighted the importance of the phenotype of previous PTB for predicting the treatment effect. Future clinical trials should take this information into account.

Regarding the second comparison (cervical pessary versus vaginal progesterone), our results differ from those of one meta‐analysis by Liu and colleagues (Liu 2019). It included three RCTS (Karbasian 2016; Nicolaides 2016; Saccone 2017), and found that combined treatment (pessary plus progesterone) was not superior to progesterone alone in prevention of delivery before 34 weeks (RR 0.91, 95% CI 0.47 to 1.77). Differences in the phenotypes of PTB and ethnic background of participants may explain the differing results.

Authors' conclusions

Implications for practice.

In women with singleton pregnancy and risk factors for cervical insufficiency, cervical pessary compared to no treatment or vaginal progesterone may reduce the risk of delivery before 34 weeks or 37 weeks of gestation, although these results should be viewed with caution due to uncertainty around the effect estimates. There is insufficient evidence with regard to the effect of cervical pessary versus cervical cerclage.

Implications for research.

Due to the low certainty of evidence in most of the prespecified outcomes and non‐reporting of other outcomes, there is a need for further robust randomised clinical trials that use standardised terminology for maternal and offspring outcomes. There is also a need for data from lower‐income countries to ensure generalisability. Further research should concentrate on comparisons of cervical pessary versus cervical cerclage and bed rest. Investigation of different phenotypes of preterm birth could be of importance.

Notes

The original review, 'Cervical pessary for preventing preterm birth' (Abdel‐Aleem 2013), was split into two reviews:

Cervical pessary for preventing preterm birth in singleton pregnancies (this review).
Cervical pessary for preventing preterm birth in multiple pregnancies (vacant title).

Acknowledgements

As part of the prepublication editorial process, several people provided comments on this review: three peers (an editor and two referees who are external to the editorial team), a member of Cochrane Pregnancy and Childbirth's international panel of consumers, and the Group's Statistical Adviser. The authors are grateful to the following peer reviewers for their time and comments: Dr Vicky Hodgetts Morton, Clinical Lecturer, University of Birmingham, UK; Begoña Martinez de Tejada, University Hospitals of Geneva and Faculty of Medicine, University of Geneva, Switzerland.

The National Institute for Health Research (NIHR) supported this project via Cochrane Infrastructure funding to Cochrane Pregnancy and Childbirth. The views and opinions expressed herein are those of the authors and do not necessarily reflect those of the Evidence Synthesis Programme, the NIHR, the National Health Service (NHS) or the Department of Health and Social Care.

We thank Julia Turner for her help in copy editing the review.

Appendices

Appendix 1. Search methods for ICTRP and ClinicalTrials.gov

ICTRP

pessary AND preterm

pessary AND premature

ClinicalTrials.gov

Interventional Studies | Preterm Labor | pessary

Data and analyses

Comparison 1. Cervical pessary versus no treatment (singleton pregnancy).

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 Delivery before 34 weeks' gestation	5	1830	Risk Ratio (M‐H, Random, 95% CI)	0.72 [0.33, 1.55]
1.1.1 Arabin pessary	4	1712	Risk Ratio (M‐H, Random, 95% CI)	0.64 [0.25, 1.65]
1.1.2 Bioteque subgroup	1	118	Risk Ratio (M‐H, Random, 95% CI)	1.14 [0.67, 1.94]
1.2 Delivery before 37 weeks' gestation	5	1830	Risk Ratio (M‐H, Random, 95% CI)	0.68 [0.44, 1.05]
1.3 Maternal infection or inflammation	2	1032	Risk Ratio (M‐H, Fixed, 95% CI)	1.04 [0.87, 1.26]
1.4 Preterm prelabour rupture of membranes	4	906	Risk Ratio (M‐H, Random, 95% CI)	0.67 [0.27, 1.65]
1.5 Harm to woman from the intervention	3		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
1.5.1 Pregnancy bleeding	1	380	Risk Ratio (M‐H, Fixed, 95% CI)	0.78 [0.30, 2.05]
1.5.2 Pelvic discomfort	2	1033	Risk Ratio (M‐H, Fixed, 95% CI)	3.15 [1.88, 5.29]
1.6 Maternal medications (e.g. tocolytics, corticosteroids)	3		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
1.6.1 Tocolytic treatment	1	380	Risk Ratio (M‐H, Fixed, 95% CI)	0.63 [0.50, 0.81]
1.6.2 Corticosteroid treatment for fetal maturation	2	488	Risk Ratio (M‐H, Fixed, 95% CI)	0.69 [0.57, 0.84]
1.6.3 Antibiotics for positive vaginal swab	1	924	Risk Ratio (M‐H, Fixed, 95% CI)	1.51 [1.13, 2.02]
1.7 Neonatal/paediatric care unit admission	3	1332	Risk Ratio (M‐H, Random, 95% CI)	0.96 [0.58, 1.59]
1.8 Fetal/infant mortality	5	1830	Risk Ratio (M‐H, Fixed, 95% CI)	0.93 [0.58, 1.48]
1.9 Neonatal sepsis	3	1412	Risk Ratio (M‐H, Random, 95% CI)	0.67 [0.23, 1.96]
1.10 Gestational age at birth (weeks)	2	488	Mean Difference (IV, Random, 95% CI)	1.63 [‐0.82, 4.07]
1.11 Early neurodevelopmental morbidity	4		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
1.11.1 Intraventricular haemorrhage grade 3 or 4	2	418	Risk Ratio (M‐H, Random, 95% CI)	0.33 [0.01, 9.53]
1.11.2 Retinopathy	4	1722	Risk Ratio (M‐H, Random, 95% CI)	0.51 [0.10, 2.60]
1.12 Gastrointestinal morbidity: necrotising enterocolitis	4	1722	Risk Ratio (M‐H, Fixed, 95% CI)	1.09 [0.48, 2.51]
1.13 Respiratory morbidity: bronchopulmonary dysplasia	2	418	Risk Ratio (M‐H, Fixed, 95% CI)	0.76 [0.38, 1.52]

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Comparison 2. Cervical pessary versus vaginal progesterone (singleton pregnancy).

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
2.1 Delivery before 34 weeks' gestation	3	1126	Risk Ratio (M‐H, Fixed, 95% CI)	0.72 [0.52, 1.02]
2.2 Delivery before 37 weeks' gestation	3	1126	Risk Ratio (M‐H, Fixed, 95% CI)	0.89 [0.73, 1.09]
2.3 Maternal infection or inflammation	2	265	Risk Ratio (M‐H, Fixed, 95% CI)	0.95 [0.81, 1.12]
2.4 Preterm prelabour rupture of membranes	2	265	Risk Ratio (M‐H, Fixed, 95% CI)	1.02 [0.53, 1.97]
2.5 Maternal medications (e.g. tocolytics, corticosteroids)	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
2.5.1 Tocolytics	2	265	Risk Ratio (M‐H, Fixed, 95% CI)	0.71 [0.34, 1.49]
2.5.2 Corticosteroids	2	265	Risk Ratio (M‐H, Fixed, 95% CI)	0.81 [0.51, 1.28]
2.5.3 Antibiotics for positive vaginal swab	1	11	Risk Ratio (M‐H, Fixed, 95% CI)	0.29 [0.01, 5.79]
2.6 Discontinuation of the intervention	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
2.7 Neonatal/paediatric care unit admission	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.8 Fetal/infant mortality	2	265	Risk Ratio (M‐H, Fixed, 95% CI)	1.97 [0.50, 7.70]
2.9 Neonatal sepsis	1	11	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
2.10 Harm to offspring from the intervention	1	11	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
2.11 Early neurodevelopmental morbidity: retinopathy	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.12 Gastrointestinal morbidity: necrotising enterocolitis	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.13 Respiratory morbidity	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

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Comparison 3. Cervical pessary versus cervical cerclage (singleton pregnancy).

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
3.1 Delivery before 34 weeks' gestation	1	13	Risk Ratio (M‐H, Random, 95% CI)	Not estimable
3.2 Delivery before 37 weeks' gestation	1	13	Risk Ratio (M‐H, Random, 95% CI)	5.71 [0.33, 99.97]
3.3 Maternal infection or inflammation	1	13	Risk Ratio (M‐H, Random, 95% CI)	0.23 [0.01, 4.00]
3.4 Preterm prelabour rupture of membranes	1	13	Risk Ratio (M‐H, Random, 95% CI)	3.50 [0.48, 25.43]
3.5 Maternal medications	1	39	Risk Ratio (M‐H, Fixed, 95% CI)	1.16 [0.35, 3.79]
3.5.1 Tocolytic treatment	1	13	Risk Ratio (M‐H, Fixed, 95% CI)	1.17 [0.09, 14.92]
3.5.2 Corticosteroid treatment for fetal maturation	1	13	Risk Ratio (M‐H, Fixed, 95% CI)	3.50 [0.48, 25.43]
3.5.3 Antibiotics for positive vaginal swab	1	13	Risk Ratio (M‐H, Fixed, 95% CI)	0.23 [0.01, 4.00]
3.6 Discontinuation of the intervention	1	13	Risk Ratio (M‐H, Fixed, 95% CI)	0.38 [0.02, 7.93]
3.7 Fetal/infant mortality	1	13	Risk Ratio (M‐H, Fixed, 95% CI)	0.38 [0.02, 7.93]
3.8 Neonatal sepsis	1	13	Risk Ratio (M‐H, Random, 95% CI)	Not estimable
3.9 Harm to offspring from the intervention	1	13	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable

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3.6 — Comparison 3: Cervical pessary versus cervical cerclage (singleton pregnancy), Outcome 6: Discontinuation of the intervention

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Care 2021.

*Study characteristics*
Methods	Parallel, randomised feasibility study
Participants	Setting: 2 specialist sPTB prevention clinics in large teaching hospitals in the UK Women randomised: 18 (intervention: 6; control (cerclage): 7; control (progesterone): 5) Inclusion criteria Singleton pregnancy, 16 + 0–24 + 6 weeks of gestation History of sPTB or PPROM between 16 + 0 weeks and 33 + 6 weeks of gestation or previous significant cervical surgery, defined as 2 large loop excision of the transformation zone (LLETZ) procedures, or a single knife cone biopsy (KCB) CL < 3rd centile for gestational age Treating clinician in equipoise as to best treatment Age ≥ 18 years Exclusion criteria Known or suspected chromosomal fetal abnormality Inability to give informed consent Treatment with history‐indicated cerclage Treatment with vaginal progesterone within 2 weeks of randomisation Peanut allergy in participant or partner (contraindication to use of progesterone preparation) Known, past or suspected mammary or genital tract carcinoma Severe hepatic dysfunction Porphyria Thrombophlebitis Thromboembolic disorder Cerebral haemorrhage
Interventions	Intervention: Arabin pessary (CE 0482/EN ISO 13485: 2003 annexe III of the council Directive 93/42 EEC) Control: cervical cerclage or vaginal progesterone Cointerventions: none Follow‐up schedule Semi‐structured interview conducted 1 week after randomisation to evaluate participant experience of the trial Study visit to the clinic 2 weeks after randomisation to review CL following treatment Any further visits to PTB clinic at the discretion of the treating clinician Postnatal visit 6 weeks after birth arranged as part of qualitative study to evaluate women's experience
Outcomes	Recruitment rate, measured as number of women recruited in 1‐year period. Willingness of women to be randomised, measured as rate of screening failures in each hospital. Adherence to protocol by doctors and women, measured as number of protocol deviations as defined by the trial monitoring plan Preliminary piloting of appropriate measures of outcome and procedures for definitive trial Participant and clinician acceptability of treatment, measured by number of participant withdrawals or changes of treatment Safety outcomes: incidence of adverse events, PTB and PPROM Participant satisfaction with proposed current trial model (qualitative methods) Expected relative resource impact of using cervical cerclage, Arabin pessary, or vaginal progesterone for the prevention of PTB (nested health economics study) Clinical outcomes: Quote: "We collected data in accordance with the international clinical consensus on minimal data collection for pessary trials as outlined by international consortium PROspective meta‐analysis for pessary trials (PROMPT Collaborative) and to reflect a primary outcome of birth less than 34 weeks and markers of neonatal morbidity and mortality"
Notes	Registration number: EudraCT no. 2014‐003112‐36 Trial dates: 6 October 2015–19 October 2016 Funding sources: funded by the National Institute for Health Research (Research for Patient Benefit Programme, three‐arm randomized trial of Arabin pessary, cervical cerclage, and progesterone to prevent spontaneous preterm birth in an asymptomatic high‐risk cohort: a feasibility study, PB‐PG‐0213‐30106) Conflicts of interest: none declared
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated random sequence.
Allocation concealment (selection bias)	Low risk	Centralised web‐based service used to randomly allocate women to treatment arms.
Blinding of participants and personnel (performance bias) All outcomes	High risk	Open‐label.
Blinding of outcome assessment (detection bias) All outcomes	High risk	No blinding.
Incomplete outcome data (attrition bias) All outcomes	Low risk	No loss to follow‐up in either group.
Selective reporting (reporting bias)	Low risk	Outcomes in protocol included in final report.
Other bias	Low risk	Baseline study characteristics were homogeneous.

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Cruz‐Melguizo 2018.

*Study characteristics*
Methods	Open‐label, multicenter, randomised, non‐inferiority clinical trial
Participants	Setting: 27 hospitals in Spain Women randomised: 254 (intervention: 128; control: 126) Inclusion criteria Singleton pregnancy Gestational age 19–22 weeks CL ≤ 25 mm Exclusion criteria Maternal age < 18 years Major fetal or uterine abnormality Cervical cerclage in place Placenta praevia History of cone biopsy or a loop electrosurgical excision procedure ≥ 3 previous PTBs Painful regular uterine contractions Active vaginal bleeding Ruptured membranes Abnormal physical findings before randomisation that disproportionately increased risk of very early delivery (e.g. prolapsing membranes)
Interventions	Intervention: Arabin cervical pessary (perforated cerclage‐type pessary, hypoallergenic silicon medical device certified by European conformity (CE0482, MED/CERT ISO 9003/EN 46003; Dr Arabin) Control: vaginal progesterone (200 mg micronised progesterone/day by vaginal route, commercial progesterone (Progeffik)). Cointerventions: progesterone (intervention arm: 6; control arm: 5) and cervical cerclage (intervention arm: 1; control arm: 2) Follow‐up schedule Every for weeks until 37 weeks' gestation for: transvaginal ultrasonographic measurement of CL; transabdominal ultrasonography for assessment of fetal well‐being; and assessment of adverse events.
Outcomes	Primary outcome Spontaneous delivery before 34 weeks Secondary outcomes Spontaneous delivery before 37 weeks Spontaneous delivery before 28 weeks PROM before 34 weeks and 37 weeks of gestation Tocolytic treatment Corticosteroids treatment for fetal lung maturation Vaginal side effects Chorioamnionitis Symptomatic vaginal or urinary infections Number of visits to the emergency department during treatment period Proportion of participants with adverse events Mean birthweight < 2500 g and < 1500 g Perinatal (fetal and neonatal) mortality Composite of major neonatal adverse events (admission to NICO, mechanical ventilation, any grade of intraventricular haemorrhage, RDS, retinopathy of prematurity, necrotising enterocolitis)
Notes	Registration number: NCT01643980. Trial dates: August 2012–April 2016 Funding sources: Quote: "This study was fully funded with public funds obtained in competitive calls: grant EC11/086 of the Ministry of Health Call for Independent Clinical Research in year 2011 and grant PI12/02240 from the Institute of Health Carlos III. The study was performed and monitored with the support of the Spanish Clinical Research Network, funded by grant PT13/0002/0005 from the National R+D+I 2013‐2016 Plan of the Institute of Health Carlos III (AES 2013)." Conflicts of interest: Quote: "The authors did not report any potential conflicts of interest"
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated sequence.
Allocation concealment (selection bias)	Low risk	Allocation to assigned treatment through independent unit (central telephone).
Blinding of participants and personnel (performance bias) All outcomes	High risk	Open‐label study.
Blinding of outcome assessment (detection bias) All outcomes	High risk	Open‐label study.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Loss to follow‐up 1%–2%.
Selective reporting (reporting bias)	Low risk	Study authors adhered to study protocol.
Other bias	Low risk	Baseline study characteristics were homogeneous.

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Dugoff 2018.

*Study characteristics*
Methods	Parallel, open‐label RCT
Participants	Setting: 5 hospitals in USA Women randomised: 122 (intervention: 61; control: 61) Inclusion criteria: Age 18‐50 years Asymptomatic Singleton pregnancy Gestational age 18–23 weeks CL ≤ 25 mm No prior sPTB Exclusion criteria: Multiple gestations Prior sPTB at 16 + 0–36 + 6 weeks Ruptured membranes Lethal fetal structural anomaly Fetal chromosomal abnormality Present or planned cerclage Vaginal bleeding Suspicion of chorioamnionitis Ballooning of membranes outside the cervix into the vagina or TVU‐CL of 0 mm Painful regular uterine contractions Placenta praevia
Interventions	Intervention: Bioteque cup cervical pessary (designed for treatment of mild uterine prolapse; very similar to Arabin pessary) Control: no treatment Cointerventions: vaginal progesterone recommended to all women with CL ≤ 20 mm prior to enrolment (intervention arm: 38; control arm: 34) Follow‐up schedule Every 4 weeks until 37 weeks' gestation for: hospital or office visits; and assessment of potential complications or symptoms related to cervical pessary.
Outcomes	Primary outcome PTB before 37 weeks Secondary outcomes PTB before 34 weeks, 28 weeks and 24 weeks sPTB before 37 weeks, 34 weeks, 28 weeks and 24 weeks Gestational age at delivery Birthweight Chorioamnionitis Genitourinary infections Intrauterine fetal demise Caesarean delivery PROM Maternal adverse effects: heavy vaginal bleeding; injury to vagina, cervix, bladder (e.g. erosion or fistula); uterine rupture; maternal intolerance to pessary (request for removal secondary to discomfort or discharge) Neonatal death (birth–28 days) Composite adverse neonatal outcome consisting of necrotising enterocolitis, intraventricular haemorrhage (grade 3 or 4), RDS, bronchopulmonary dysplasia (BPD), retinopathy, blood‐culture proven sepsis and neonatal death
Notes	Registration number: NCT0205665. Trial dates: March 2014–July 2016 Funding sources: Quote: "Financial Support was provided by the Pennsylvania Chapter of the March of Dimes." Conflicts of interest: not reported
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated sequence.
Allocation concealment (selection bias)	Low risk	Allocation to assigned treatment through independent unit (web‐based system).
Blinding of participants and personnel (performance bias) All outcomes	High risk	Open‐label study.
Blinding of outcome assessment (detection bias) All outcomes	High risk	Open‐label study.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Loss to follow‐up 0/61 in intervention group and 3/61 in control group.
Selective reporting (reporting bias)	Low risk	Study authors adhered to study protocol.
Other bias	Low risk	Baseline study characteristics were homogeneous.

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Goya 2012.

*Study characteristics*
Methods	Open‐label RCT
Participants	Setting: 5 hospitals in Spain Women randomised: 385 (intervention: 192; control: 193) Inclusion criteria Singleton pregnancy Age 18–43 years CL ≤ 25 mm 18–22 weeks of gestation Exclusion criteria Major fetal abnormalities Painful regular uterine contractions Active vaginal bleeding Ruptured membranes Placenta praevia History of cone biopsy Cervical cerclage in place
Interventions	Intervention: Arabin cervical pessary (CE0482, MED/CERT ISO 9003/EN 46003; Dr Arabin, lower larger diameter 65 mm, height 25 mm, upper smaller diameter 32 mm) Control: no treatment Cointerventions: none Follow‐up schedule Every 4 weeks until 37 weeks' gestation for: ultrasonographic measurement of CL; assessment of adverse effects; and collection of vaginal swabs.
Outcomes	Primary outcome Delivery before 34 weeks' gestation Secondary outcomes Spontaneous delivery before 37 weeks Gestational age at delivery (weeks) Tocolytic treatment Corticosteroid treatment for fetal maturation Chorioamnionitis Pregnancy bleeding PPROM Caesarean delivery Adverse effects (vaginal discharge, pessary repositioning without removal, pessary withdrawal) Perinatal outcome (fetal death, neonatal death, birthweight < 1500 g, birthweight < 2500 g) Neonatal adverse events (necrotising enterocolitis, intraventricular haemorrhage, RDS, retinopathy, treatment for sepsis, composite adverse outcomes)
Notes	Registration number: NCT00706264 Trial dates: June 2007–June 2010 Funding sources: Quote: "this study was supported by a grant (Fondo de Investigaciones Sanitarias number 071086) from the Instituto Carlos III, Madrid, Spain." Conflicts of interest: Quote: "We declare that we have no conflicts of interest. We also declare that we have no conflicts of interest with Dr Arabin."
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated sequence.
Allocation concealment (selection bias)	Low risk	Allocation to assigned treatment through independent unit (central phone randomisation).
Blinding of participants and personnel (performance bias) All outcomes	High risk	Open‐label study.
Blinding of outcome assessment (detection bias) All outcomes	High risk	Open‐label study.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Loss to follow‐up 2/192 in intervention group and 3/193 in control group.
Selective reporting (reporting bias)	Low risk	Study authors adhered to study protocol.
Other bias	Low risk	Baseline study characteristics were homogeneous.

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Hui 2013.

*Study characteristics*
Methods	Single‐centre RCT
Participants	Setting: Department of Obstetrics and Gynecology of Prince of Wales Hospital, the Chinese University of Hong Kong (CUHK) Women randomised: 108 (intervention: 53; control: 55) Inclusion criteria Singleton viable pregnancy CL ≤ 25 mm 20–24 weeks of gestation Exclusion criteria Known history of cervical incompetence Surgical cerclage in current or previous pregnancy Multiple gestation Known major fetal abnormalities Presence of cervical dilation (any dilated cervical os discovered during speculum examination) Painful uterine contractions Ruptured membrane
Interventions	Intervention: cervical pessary (type of pessary not stated in registered protocol or published manuscript) Control: no treatment Cointerventions: 4 doses of dexamethasone 6 mg IM, 12 hours apart, if CL < 10 mm; appropriate treatment for symptoms with abnormal swab results Follow‐up schedule Every 4 weeks until 34 weeks' gestation for: ultrasound scans for fetal growth and CL; and high vaginal swabs.
Outcomes	Primary outcome Delivery before 34 weeks' gestation Secondary outcomes Gestational age at delivery Interval from randomisation to delivery New‐onset vaginal infections Birthweight Miscarriage rate Neonatal death Major adverse outcomes before discharge from the hospital including neonatal jaundice Sepsis Intraventricular haemorrhage RDS
Notes	Registration number: ISRCTN18185477 Trial dates: October 2008–November 2011 Funding sources: not reported Conflicts of interest: not reported
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated random sequence.
Allocation concealment (selection bias)	Low risk	Allocation results concealed in sequentially numbered, identical, opaque, sealed envelopes, kept away from clinic where participants were being assessed. Treatment allocation only revealed to obstetrician in charge after participant gave consent.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Participants blinded to allocation (simulated insertion of pessary during vaginal digital examination in control group). Blinding unclear for personnel.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Data on pregnancy outcomes obtained from hospital records.
Incomplete outcome data (attrition bias) All outcomes	Low risk	All 108 women included in analysis.
Selective reporting (reporting bias)	Low risk	Study authors adhered to study protocol.
Other bias	High risk	No baseline differences between 2 groups, but calculated sample size not achieved (108/1120).

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Nicolaides 2016.

*Study characteristics*
Methods	Open‐label, multicenter RCT
Participants	Setting: 16 maternity hospitals in England, Slovenia, Portugal, Chile, Australia, Italy, Albania, Germany and Belgium Women randomised: 935 (intervention: 466; control: 469) Inclusion criteria Age ≥ 16 years Singleton pregnancy Routine ultrasonographic examination at 20–24 weeks of gestation CL ≤ 25 mm Exclusion criteria Fetal death Major fetal defect Cervical cerclage in place Painful regular uterine contractions Ruptured membranes diagnosed before randomisation
Interventions	Intervention: Arabin cervical pessary (CE0482, MED/CERT ISO 9003/EN 46003; Dr Arabin, Witten, Germany) Control: no treatment Cointerventions: participants in either group with CL ≤ 15 mm at randomisation or follow‐up visits given capsules containing natural progesterone (200 mg) and instructed to introduce 1 capsule into the vagina before going to sleep every night up to 33 + 6 weeks of gestation; antibiotics and corticosteroids given if needed Follow‐up schedule Every 4 weeks until 34 weeks' gestation for: ultrasonographic measurement of CL; assessment of adverse events; and collection of vaginal swabs.
Outcomes	Primary outcome Spontaneous delivery before 34 weeks' gestation Secondary outcomes Mean birthweight Perinatal (fetal or neonatal) death Composite of major adverse events in neonate before hospital discharge (any grade of intraventricular haemorrhage, RDS, any retinopathy of prematurity, necrotising enterocolitis) Composite of indicators of neonatal special care (admission to NICU, mechanical ventilation, phototherapy, treatment for proven or suspected sepsis, blood transfusion) Major maternal complication attributable to pessary (maternal death, serious cervical or vaginal trauma, chorioamnionitis)
Notes	Registration number: ISRCTN01096902. Trial dates: September 2008–January 2013 Funding sources: Quote: "Supported by a grant from the Fetal Medicine Foundation." Conflicts of interest: Quote: "No potential conflict of interest relevant to this article was reported."
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated; no restrictions (e.g. block size or stratification according to site).
Allocation concealment (selection bias)	Low risk	Allocation to assigned treatment through independent unit (web‐based system).
Blinding of participants and personnel (performance bias) All outcomes	High risk	Open‐label study.
Blinding of outcome assessment (detection bias) All outcomes	High risk	Open‐label study.
Incomplete outcome data (attrition bias) All outcomes	Low risk	932/932 women included in analysis.
Selective reporting (reporting bias)	Low risk	Study authors adhered to study protocol.
Other bias	High risk	No baseline differences between groups, but trial terminated before reaching sample size (935/1600).

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Pacagnella 2022.

*Study characteristics*
Methods	Open‐label RCT
Participants	Setting: co‐ordinating centre is the Women's Hospital at the University of Campinas in Brazil. Participating centres are 17 reference obstetric units in different geographic regions of Brazil, including academic and general maternity hospitals and other health facilities such as ultrasound clinics and prenatal care units. Women randomised: 475 (intervention: 225; control: 220) Inclusion criteria Singleton or twin pregnancy No maternal age restriction Gestational age 18 + 0–22 + 6 weeks CL 5 mm–30 mm Exclusion criteria Painful contractions Vaginal bleeding Cerclage during current pregnancy before screening PPROM Severe liver disease, cholestasis during current pregnancy Previous or current thromboembolism Placenta praevia Cervical dilation > 1 cm Monoamniotic twin pregnancy, higher order twin pregnancy (triplets or higher) Major fetal malformation of ≥ 1 fetus Stillbirth
Interventions	Intervention: Arabin pessary registered at the national health surveillance agency of Brazil (Pessário AM® by Ingamed) with the dimensions: inner circle 30 mm, outer circle 70 mm, height 25 mm; plus micronised progesterone 200 mg capsules (commercial Progesterone (Utrogestam)) Control: vaginal progesterone (micronised progesterone 200 mg capsules (commercial Progesterone (Utrogestam)) Cointerventions: described above (intervention arm) Follow‐up schedule: Pessary not removed until week 36 of gestation, except in cases of PROM, active vaginal bleeding, signs of preterm labour (defined as severe discomfort with regular uterine contractions) or medically indicated birth before 36 weeks' gestation
Outcomes	Primary outcome Composite of neonatal adverse events Periventricular leukomalacia (focal periventricular necrotic and diffuse gliosis in the surrounding cerebral white matter that may have cystic lesions secondary to necrotic foci in the white matter) Severe RDS (grunting, retractions, or other typical distress symptoms in a premature infant immediately after birth with a chest radiography showing homogenous opaque infiltrates and air bronchograms) Bronchopulmonary dysplasia (infant requiring treatment with > 21% oxygen for ≥ 28 days) Periventricular haemorrhage grade 2 (haemorrhage is present in a non‐distended lateral ventricle) or higher Necrotising enterocolitis (spectrum of intestinal conditions including feeding intolerance, mild abdominal distention, spontaneous intestinal perforations and intestinal necrosis) Proven sepsis before discharge (generalised bacterial infection occurring within the neonatal period up to 4 weeks beyond expected date of delivery accompanied by a positive blood culture) Stillbirth or neonatal death Secondary outcomes Gestational age at birth Birthweight Adequacy of birth weight for gestational age 1st‐ and 5th‐minute Apgar score Neonatal gestational age Overall, spontaneous and medical induced PTB rate before 28 weeks, 32 weeks, 34 weeks and 37 weeks of gestation PPROM rate NICU admission and length of stay Maternal morbidity and mortality Maternal length of stay in hospital Maternal ICU admission Cost‐benefit analysis of screening programme, treatment cost, maternal inpatient treatment costs, neonatal inpatient treatment costs and pessary use unwanted effects
Notes	Registration number: Brazilian Clinical Trial Registry (ReBec) RBR‐3t8prz, UTN: U1111–1164‐2636, 2014/11/18. Trial dates: 15 July 2015–29 March 2019. Funding sources: Quote: "The study was funded by the Bill & Melinda Gates Foundation and Brazilian National Research Council (CNPq)." Conflicts of interest: Quote: "The authors declare that they have no competing interests."
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated random numbers.
Allocation concealment (selection bias)	Low risk	Allocation performed centrally in online database, using computer‐generated algorithm that was concealed from investigators.
Blinding of participants and personnel (performance bias) All outcomes	High risk	Open‐label study.
Blinding of outcome assessment (detection bias) All outcomes	High risk	Open‐label study.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Loss to follow‐up 12/475 in intervention group and 25/461 in control group.
Selective reporting (reporting bias)	Low risk	No change in protocol from time submitted to registration.
Other bias	Low risk	Similar baseline data.

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Saccone 2017.

*Study characteristics*
Methods	Parallel‐group, non‐blinded RCT
Participants	Setting: single centre at the University of Naples Federico II, Naples, Italy Women randomised: 300 (intervention: 150, control: 150) Inclusion criteria Age 18–50 years Singleton pregnancy CL ≤ 25 mm Gestational age 18 + 0–23 + 6 weeks Exclusion criteria Multiple pregnancies Rupture of membranes at time of randomisation Lethal fetal structural abnormality Cerclage in place Vaginal bleeding at time of randomisation Suspicion of chorioamnionitis Placenta praevia or accreta Ballooning of membranes outside the cervix into the vagina CL 0 mm Painful and regular uterine contractions History of sPTB between 16 + 0 weeks and 36 + 6 weeks of gestation
Interventions	Intervention: cervical pessary (certified by European Conformity) Control: no treatment Cointerventions: for CL ≤ 20 mm, women in both groups prescribed vaginal progesterone 200 mg suppositories daily until 36 + 6 weeks of gestation Follow‐up schedule In the pessary group, digital examination every 4 weeks until delivery to ensure proper pessary placement. Women asked about adherence to progesterone and AEs (vaginal discharge, pelvic discomfort, and pelvic pain). Bleeding or lacerations during insertion and removal of pessary also recorded. For women in both groups who presented after 26 weeks' gestation with symptoms of preterm labour, tocolytic and glucocorticoids administrated for fetal lung maturation and hospitalisation offered.
Outcomes	Primary outcome Spontaneous delivery before 34 weeks' gestation Secondary outcomes Spontaneous PTB before 37 weeks, 32 weeks and 28 weeks of gestation Gestational age at delivery Latency (time from randomisation to delivery) PPROM before 34 weeks' gestation Mode of delivery Maternal AEs (vaginal discharge and pelvic discomfort) Chorioamnionitis (inflammation of the chorion and amnion by histopathological assessment after delivery) Neonatal outcomes including birthweight, admission to NICU, neonatal death (≤ 28 days of life), perinatal death (intrauterine fetal death after 20 weeks' gestation or neonatal death), and composite of adverse perinatal outcomes, defined as ≥ 1 of the following: necrotising enterocolitis; intraventricular haemorrhage grade 3 or 4; RDS; bronchopulmonary dysplasia; retinopathy of prematurity requiring therapy; or blood culture‐proven sepsis or neonatal death. Post hoc exploratory outcomes included PTB (spontaneous and iatrogenic) before 37 weeks, 34 weeks, 32 weeks, and 28 weeks of gestation; iatrogenic PTB before 34 weeks; birthweight < 2500 g or < 1500 g; and the components of the composite of adverse perinatal outcomes.
Notes	Registration number: NCT02716909 Trial dates: March 2016–May 2017 Funding sources: not reported Conflicts of interest: Quote: "All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported."
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomisation sequence prepared by independent statistician and implemented through central telephone number.
Allocation concealment (selection bias)	Low risk	Allocation to assigned treatment through independent unit (web‐based system).
Blinding of participants and personnel (performance bias) All outcomes	High risk	Participants and personnel aware of intervention (vaginal examination each month to ensure proper position of pessary).
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Outcome assessors, data collectors, and data analysts blinded to allocated treatment group. Outcome assessment and outcome collection by clinicians not involved in clinical trial. Outcomes reported in a form with only trial identification as identifier. Data analyst blinded until completion of analysis.
Incomplete outcome data (attrition bias) All outcomes	Low risk	300/300 randomised women included in analysis.
Selective reporting (reporting bias)	Low risk	Study authors adhered to study protocol.
Other bias	Low risk	No baseline differences between groups. Study not terminated prematurely. Sample size achieved.

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CL: cervical length; ICU: intensive care unit; IM: intramuscular; NICO: neonatal intensive care unit; PPROM: preterm prelabour rupture of membranes; PROM: prelabour rupture of membranes; PTB: preterm birth; RCT: randomised controlled trial; RDS: respiratory distress syndrome; sPTB: spontaneous preterm birth; TVU: transvaginal ultrasound.

Characteristics of excluded studies [ordered by study ID]

Study	Reason for exclusion
Barinov 2017	Inappropriate type of study: controlled but non‐randomised trial.
Barinov 2020	Inappropriate type of participants: including women with placenta praevia.
Daskalakis 2013	Inappropriate type of study: interim analysis, final data not published, no ethical approval (after author contact without reply).
Gmoser 1991	Inappropriate type of participants: including women with placenta praevia.
Hermans 2016	Inappropriate type of participants: including women with placenta praevia.
Mastantuoni 2021	Inappropriate type of participants: including women in labour.
Mendoza 2017	Inappropriate type of study: not an RCT.
Naeiji 2021	Inappropriate type of participants: including women in labour.
NCT02484820 2015	Inappropriate type of participants: including women with threatened PTB.
Ples 2021	Inappropriate type of study: not an RCT, women allowed to choose type of intervention.
Pratcorona 2019	Inappropriate type of participants: including women in labour.
Stafford 2019	Inappropriate type of participants: including women with placenta praevia.
Von Forster 1986	Inappropriate type of study: quasi‐randomised.
Willan 2016	Inappropriate type of study: simulation study.

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PTB: preterm birth; RCT: randomised controlled trial.

Characteristics of studies awaiting classification [ordered by study ID]

Karbasian 2016.

Methods	Open‐label RCT
Participants	Setting: university hospital in Iran Women randomised: 146 (intervention: 73; control: 73) Inclusion criteria Singleton pregnancy Gestational age 18–22 weeks CL ≤ 25 mm Exclusion criteria Any medical illness upon enrolment Cervical dilation Urogenital infection Major fetal abnormalities Painful regular uterine contractions Placenta praevia Ruptured membranes Active vaginal bleeding History of cone biopsy Refusal to provide informed consent to participate in study
Interventions	Intervention: Arabin pessary (CE0482, MED/CERT ISO 9003/EN 46003; Dr Arabin GmbH and Co. KG) + vaginal progesterone 400 mg (Cyclogest 400 mg progesterone suppository, LD Collins & Co. Ltd) Control: vaginal progesterone alone (Cyclogest 400 mg progesterone suppository, LD Collins & Co. Ltd) Cointervention: none Follow‐up schedule: Every 4 weeks until 37 weeks of gestation for: routine assessments, including weight and blood pressure measurements, cervicometry, fetal sonography and evaluation of possible AEs of each treatment.
Outcomes	Primary outcome: PTB before 37 weeks' gestation Secondary outcomes Rate of low‐birthweight delivery (defined as birthweight < 2500 g) PROM Chorioamnionitis (diagnosed based on placental pathology after delivery) Requirement for NICU admission Fetal/neonatal death
Notes	Registration number: not found. We contacted the study authors by email, no response yet. Trial dates: August 2014–December 2015 Funding sources: Quote: "This research was funded by the research deputy of our institute." Conflicts of interest: none declared

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CL: cervical length; NICU: neonatal intensive care unit; PROM: prelabour rupture of membranes; RCT: randomised controlled trial.

Characteristics of ongoing studies [ordered by study ID]

Hezelgrave 2016.

Study name	Rationale and design of SuPPoRT: a multicenter randomised controlled trial to compare 3 treatments: cervical cerclage, cervical pessary and vaginal progesterone, for the prevention of preterm birth in women who develop a short cervix
Methods	RCT
Participants	Setting: as a National Institute for Health Research registered portfolio study, SuPPoRT is open to UK hospitals with the appropriate facilities and experience of PTB surveillance and treatment Sample size: 400 participants Inclusion criteria High‐risk women with singleton pregnancies and CL < 25 mm on TVU between 14 + 0 weeks' gestation (dated by ultrasound or last menstrual period and adjusted for ultrasound‐estimated date of delivery once ultrasound performed if no miscarriage prior to dating ultrasound) until 23 + 6 weeks' gestation with written consent to participate and ≥ 1 of the following risk factors: previous PPROM (before 37 weeks); history of sPTB/second trimester loss (16–37 weeks); or history of any cervical procedure to treat abnormal smears (i.e. large loop excision, laser conization, cold knife conization or radical diathermy). Women with incidental finding of short cervix on ultrasound scan (e.g. at the time of anomaly scan) are also eligible for inclusion. Exclusion criteria: Persistent fresh vaginal bleeding evident on speculum examination Visible membranes evident on speculum examination or open cervix on ultrasound scan Severe abdominal pain/evidence of sepsis (as judged by attending clinician) Known significant congenital or structural or chromosomal fetal abnormality Suspected or proven rupture of fetal membranes at time of recruitment Current use of progesterone pessaries or use of progesterone beyond 18 weeks' gestation Cervical suture in place (vaginal or abdominal) Cervical pessary in place Judgement by attending clinician that 1 treatment modality is better than the other in an individual woman Insufficient understanding of the trial in investigator's opinion Any contraindications or cautions to investigational medicinal product, including known allergy or hypersensitivity to progesterone, hepatic dysfunction, undiagnosed vaginal bleeding, mammary or genital tract carcinoma, thrombophlebitis, thromboembolic disorders, cerebral haemorrhage or porphyria
Interventions	Cervical pessary (Arabin pessary) versus vaginal progesterone (200 mg daily) versus cervical cerclage
Outcomes	Primary outcome Delivery before 37 completed weeks' gestation Secondary outcomes Adverse perinatal outcome, defined as a composite outcome of death (antepartum/intrapartum stillbirths plus neonatal deaths prior to discharge from neonatal services) or ≥ 1 of the following: intraventricular haemorrhage; periventricular leukomalacia; hypoxic Ischaemic encephalopathy; necrotising enterocolitis; bronchopulmonary dysplasia; or sepsis. Delivery before 30 completed weeks and 34 completed weeks' gestation Gestational age at delivery Time between intervention and delivery Requirement for rescue cerclage (bulging fetal membranes) Other maternal and fetal outcomes: clinical course, therapies administered, maternal and fetal morbidity and mortality data until discharge or 28 days postnatal (whichever soonest), AEs related to intervention Participant and clinician's perception of treatment/satisfaction: questionnaires with a selection of participants at 0–2 weeks after procedure Questionnaires at 1 year planned (if funding is obtained) Health costs at 28 days postnatal Biochemical endpoints (on available samples): cervicovaginal swabs will be taken to determine the presence of infection and concentrations of bio markers of PTB, infection and inflammation, and blood samples taken for inflammatory markers and genetic analysis. Results will be correlated with maternal and fetal outcomes.
Starting date	Not reported
Contact information	Rachel M Tribe; rachel.tribe@kcl.ac.uk
Notes	REC (15/LO/0485)

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IRCT201603109568N15.

Study name	The effectiveness of the combined treatment with vaginal progesterone plus cervical pessary compared to vaginal progesterone monotherapy for the prevention of preterm birth: a randomised clinical trial
Methods	RCT
Participants	Setting: University of Medical Sciences, Tehran, Iran Sample size: 144 participants Inclusion criteria Age 18–40 years Singleton gestation 18–22 weeks of gestation CL < 25 mm by TVU No cervical dilation No history of any medical illness Exclusion criteria Any medical illness upon enrolment Having urogenital infection Major fetal abnormalities Painful regular uterine contractions Placenta praevia Ruptured membranes Active vaginal bleeding History of cone biopsy Refusal to provide informed consent to participate in the study
Interventions	Cervical pessary versus vaginal progesterone (400 mg daily)
Outcomes	Primary outcome PTB before 37 weeks' gestation Secondary outcomes Low birthweight delivery PROM Chorioamnionitis Requirement for NICU admission Fetal/neonatal death rate
Starting date	August 2014
Contact information	Niloofar Karbasian; nfkarbasian@gmail.com
Notes	IRCT201603109568N15

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IRCT20180302038914N1.

Study name	Comparing efficacy of cerclage and adjunctive therapy (cerclage and pessary) in prevention of preterm birth in pregnant women with cervical incompetence
Methods	RCT
Participants	Setting: Royan Institute, Tehran, Iran Sample size: 60 participants Inclusion criteria: Age 18–42 years Cervical insufficiency Gestational age 14–26 weeks Singleton pregnancy without vaginal bleeding and vaginal discharge and rupture of membrane Exclusion criteria: Multiple pregnancy Dilation > 4 cm Uterine contraction Cerclage contraindication
Interventions	Cerclage + pins (intervention) versus cerclage alone (control)
Outcomes	Primary outcome Gestational age at delivery > 34 weeks Secondary outcomes Participant satisfaction
Starting date	7 May 2018
Contact information	Mitra Arjmandi Far; Tehran Faculty of Nursing and Midwifery, Mirkhani St (East Nusrat St), Tohid Sq. Tehran, Iran; m‐arjmandifar@razi.tums.ac.ir
Notes	IRCT20180302038914N1

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JPRN‐UMIN000015465.

Study name	Cervical pessary for the prevention of preterm delivery in pregnant woman with a short cervix
Methods	RCT
Participants	Setting: Japan Sample size: 100 participants Inclusion criteria Singleton pregnancy CL < 25 mm Informed consent for participation Exclusion criteria: Multiple pregnancy CL > 26 mm Major fetal anomalies Painful regular uterine contractions Active vaginal bleeding Rupture of membranes Placenta praevia Cervical myoma History of cone biopsy or cervical cerclage in place Non‐eligibility according to study doctors
Interventions	Cervical pessary versus no treatment
Outcomes	Primary outcome Rate of term delivery Secondary outcomes Spontaneous delivery before 28 weeks Spontaneous delivery before 37 weeks Gestational age at delivery Tocolytic treatment PROM Corticosteroids treatment for fetal maturation Chorioamnionitis Hospitalisation Vaginal discharge Pessary withdrawal Bleeding at delivery Cervical laceration Uterus rupture Fetal death Neonatal death Birthweight Adverse outcomes (intra‐ventricular haemorrhage, RDS, retinopathy, necrotising enterocolitis, sepsis) Admission to NICU
Starting date	2015
Contact information	Kyoko Kimagi; og‐nzw@med.nagoya‐cu‐ac.jp
Notes	Not provided

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Koullali 2017.

Study name	A multi‐centre, non‐inferiority, randomised controlled trial to compare a cervical pessary with a cervical cerclage in the prevention of preterm delivery in women with short cervical length and a history of preterm birth – PC study
Methods	RCT
Participants	Setting: Dutch Consortium for Healthcare Evaluation and Research in Obstetrics and Gynaecology – NVOG Consortium 2.0, a collaborative network of all major hospitals in The Netherlands and the Dutch Society of Obstetrics and Gynaecology (NVOG). In addition, international hospitals interested in the trial can participate in this study. Sample size: 400 participants Inclusion criteria: Asymptomatic women with a singleton pregnancy Women with prior sPTB before 34 weeks' gestation are offered the use of progesterone and cervical length measurements before 24 weeks' gestation. Women with CL ≤ 25 mm before 24 weeks' gestation are eligible to participate in the trial as these women would be eligible for a secondary cerclage. Women who are considered for placement of cerclage before 16 weeks' gestation based on their obstetric history of cervical insufficiency (primary cerclage) are eligible. Exclusion criteria Placenta praevia Vasa praevia PPROM CL < 2 mm Cervical dilation ≥ 3 cm Identified major congenital or chromosomal abnormalities Signs of intrauterine infection Maternal age < 18 years Inability to give informed consent
Interventions	Cervical pessary (Arabin) versus cervical cerclage
Outcomes	Primary outcome Delivery before 32 weeks of gestation Secondary outcomes Time from intervention to delivery Gestational age at birth PTB rate before 24 weeks, 28 weeks, 34 weeks and 37 weeks of gestation (overall and stratified by spontaneous or indicated delivery) PROM Use of tocolysis or corticosteroids during pregnancy Mode of delivery Maternal infections Maternal side effects and both neonatal and maternal hospital admissions Perinatal outcomes will be assessed through a composite of adverse perinatal outcome (chronic lung disease, intraventricular haemorrhage > grade II, periventricular leukomalacia > grade I, necrotising enterocolitis > stage I, retinopathy of prematurity, patent ductus arteriosus, treated seizures, early and late onset sepsis, neonatal meningitis, (intrapartum) stillbirth, death before discharge from the nursery).
Starting date	Not reported
Contact information	Bouchra Koullali; b.koullali@amc.nl
Notes	NTR 4415

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NCT02405455.

Study name	Cerclage vs cervical pessary in women with cervical incompetence (CEPEIC)
Methods	Open‐label, pilot, multicentre, prospective RCT
Participants	Setting: not provided Sample size: 60 participants Inclusion criteria Singleton pregnancy Age ≥ 18 years Previous PTB based on cervical insufficiency Exclusion criteria Major fetal abnormalities (requiring surgery or leading to infant death or severe handicap) Threatened preterm labour at time of randomisation Spontaneous rupture of membranes at time of randomisation Chorioamnionitis at time of randomisation Active vaginal bleeding Placenta praevia
Interventions	Cervical pessary versus cervical cerclage
Outcomes	Primary outcome Spontaneous delivery before 34 complete weeks Secondary outcomes Spontaneous delivery before 28 complete weeks Spontaneous delivery before 37 complete weeks Fetal and neonatal death Neonatal morbidity Maternal side effects Maternal morbidity Number of participants with chorioamnionitis infection Hospitalisation for threatened preterm labour
Starting date	June 2015
Contact information	Maria Goya
Notes	NCT02405455

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NCT02470676.

Study name	Cervical pessary vs vaginal progesterone in preventing preterm birth among women presenting with short cervix: an open‐label randomised controlled trial
Methods	RCT
Participants	Setting: Hillel Yaffe Medical Center, Israel Sample size: 430 participants Inclusion criteria ≤ 24 + 0 weeks' gestation CL ≤ 25 mm in a singleton pregnancy or ≤ 38 mm in twins pregnancy Willingness to comply with the protocol for the duration of the study Informed consent Exclusion criteria: Fetal factors: major fetal abnormalities, death of 1 or both fetuses, twin‐to‐twin transfusion syndrome, severe growth retardation Maternal factors: prophylactic cervical cerclage in place, painful regular uterine contractions, active labour, active vaginal bleeding, maternal age < 18, uterine abnormalities (e.g. 2 cervices), severe uterine prolapse Membranes and placental factors: placenta praevia, ruptured membranes
Interventions	Cervical pessary (2 pessary sizes: 65 mm/17 mm/35 mm or 70 mm/17 mm/35 mm) + progesterone 200 mg daily vaginal suppositories (Utrogestan) versus progesterone 200 mg daily vaginal suppositories (Utrogestan) alone
Outcomes	Primary outcomes PTB before 34 weeks of gestation in singleton pregnancies (time frame: up to 20 weeks from recruitment) PTB before 32 weeks of gestation in twin pregnancies (time frame: up to 20 weeks from recruitment) Secondary outcomes Other PTB age before 34 weeks in singleton pregnancies or 28 weeks in twin pregnancies (time frame: up to 20 weeks from recruitment) Neonatal/perinatal complications (time frame: up to 20 weeks from recruitment): RDS, necrotising enterocolitis, intraventricular haemorrhage, proven neonatal sepsis, retinopathy of prematurity, bronchopulmonary dysplasia, periventricular leukomalacia, fetal death, neonatal death, Apgar score < 7 at 5 minutes, birthweight < 1500 g or < 2500 g, use of mechanical ventilation, congenital anomaly Maternal adverse events (time frame: up to 20 weeks from recruitment): vaginal discharge, vaginal pruritus, discontinuation of treatment because of adverse events, threatened preterm labour
Starting date	July 2015
Contact information	Asnat Walfisch, MD; +972 50 4492200; asnatwalfisch@yahoo.com Dvir Reder, MD; +972 52 6131383; dvir.reder@gmail.com
Notes	NCT02470676

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NCT02511574.

Study name	Comparison between natural progesterone and vaginal pessary for the prevention of spontaneous preterm birth (PROPE)
Methods	Prospective RCT
Participants	Setting: not provided Sample size: 200 participants Inclusion criteria Gestational age 20 + 0–23 + 6 weeks Singleton pregnancy Exclusion criteria No confirmation of gestational age Ruptured membranes Painful regular uterine contractions Major fetal abnormalities
Interventions	Cervical pessary versus natural progesterone
Outcomes	Primary outcome PTB before 34 complete weeks of gestation
Starting date	June 2014
Contact information	Mario Henrique Burlacchini de Carvalho
Notes	NCT02511574 Recruitment status unknown

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NCT02901626.

Study name	A randomised trial of pessary in singleton pregnancies with a short cervix (TOPS)
Methods	RCT
Participants	Setting: 12 hospitals in the USA Sample size: 850 participants Inclusion criteria: Singleton gestation. Twin gestation reduced to singleton either spontaneously or therapeutically, is not eligible unless the reduction occurred before 13 + 6 weeks project gestational age. Higher order multifetal gestations reduced to singletons are not eligible. Gestational age at randomisation 16 + 0–23 + 6 weeks based on clinical information and evaluation of earliest ultrasound. CL ≤ 20 mm on transvaginal examination by study‐certified sonographer. There is no lower cervical length threshold. Exclusion criteria Cervical dilation (internal os) ≥ 3 cm on digital examination or evidence of prolapsed membranes beyond the external cervical os either at the time of the qualifying cervical ultrasound examination or at a cervical exam immediately before randomisation Fetal anomaly or imminent fetal demise. This includes lethal anomalies, or anomalies that may lead to early delivery or increased risk of neonatal death (e.g. gastroschisis, spina bifida, serious karyotypic abnormalities). An ultrasound examination from 14 + 0 weeks to 23 + 6 weeks by project estimated date of confinement (EDC) must be performed prior to randomisation to evaluate the fetus for anomalies. Previous sPTB between 16 + 0 weeks and 36 + 6 weeks. This includes induction for PPROM in a prior pregnancy. Planned treatment with intramuscular 17‐α hydroxy‐progesterone caproate Placenta praevia, because of risk of bleeding and high potential for indicated PTB. A low‐lying placenta is acceptable. Active vaginal bleeding greater than spotting at time of randomisation (because of potential exacerbation due to pessary placement) Symptomatic, untreated vaginal or cervical infection (because of potential exacerbation due to pessary placement). Women may be treated and, if subsequently asymptomatic, randomised. However, if it is more than 10 days since CL measurement, a new CL measurement must be obtained. Active, unhealed herpetic lesion on labia minora, vagina, or cervix (due to potential for significant discomfort or increasing genital tract viral spread). Once lesion(s) heal and the woman is asymptomatic, she may be randomised. History of herpes is not an exclusion criterion. Rupture of membranes (due to likelihood of pregnancy loss and preterm delivery as well as the risk of ascending infection which could be increased with pessary placement). > 6 contractions/hour reported or documented prior to randomisation. It is not necessary to place the participant on a tocodynamometer. Known major Mullerian anomaly of the uterus; specifically bicornuate, unicornuate, or uterine septum not resected (due to increased risk of preterm delivery which is unlikely to be affected by progesterone) Any fetal/maternal condition that would require invasive in‐utero assessment or treatment (e.g. significant red cell antigen sensitisation or neonatal alloimmune thrombocytopenia). Major maternal medical illness associated with increased risk for adverse pregnancy outcome or indicated PTB (treated hypertension requiring > 1 agent, treatment for diabetes prior to pregnancy, chronic renal insufficiency defined by creatinine > 1.4 mg/dL, carcinoma of the breast, conditions treated with chronic oral glucocorticoid therapy). Lupus, uncontrolled thyroid disease, and New York Heart Association(NYHA) stage II or greater cardiac disease are also excluded. Participants with seizure disorders, HIV, and other medical conditions not specifically associated with an increased risk of indicated PTB are not excluded. Prior cervical cone/LOOP/loop electrocautery excision procedure (LEEP) is not an exclusion criterion. Planned cerclage or cerclage already in place (since it would preclude placement of a pessary) Planned indicated delivery before 37 weeks Allergy to silicone Participation in another interventional study that influences gestational age at delivery or neonatal morbidity or mortality Participation in this trial in a previous pregnancy. Participants who were screened in a previous pregnancy but not randomised may be included. Prenatal care or delivery planned elsewhere, unless the study visits can be made as scheduled and complete outcome information can be obtained
Interventions	Cervical pessary versus vaginal progesterone
Outcomes	Primary outcome Delivery or fetal demise before 37 + 0 weeks Secondary outcomes Adverse perinatal outcome, defined as a composite outcome of death (antepartum/intrapartum stillbirths)
Starting date	February 2017
Contact information	Rebecca Clifton, PhD 301‐881‐9260; rclifton@bsc.gwu.edu
Notes	NCT02901626

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NCT03052270.

Study name	Arabin pessary combine with vaginal progesterone compare with vaginal progesterone alone to prevent preterm delivery in singleton pregnancies
Methods	RCT
Participants	Setting: University of Illinois at Chicago, USA Sample size: 200 participants Inclusion criteria CL ≤ 20 mm Singleton pregnant women at 18–24 weeks of gestation with no prior history of preterm deliveries Age ≥ 18 years at time of enrolment Consent to participate in the study Exclusion criteria Previous preterm delivery before 37 weeks Major fetal anomalies Multiple pregnancy Cervical cerclage in place for the treatment of incompetent cervix Regular uterine contractions or significantly dilated cervical canal Age < 18 years Refusal to participate in the study
Interventions	Vaginal progesterone plus pessary (Arabin) versus vaginal progesterone alone
Outcomes	Primary outcome Preterm delivery before 37 weeks (time frame: 2 years) Secondary outcomes Preterm delivery before 28 weeks Preterm delivery before 32 weeks Preterm delivery before 34 weeks
Starting date	January 2017
Contact information	Christopher A Enakpene, MD 347 217 5127; cenakpene@gmail.com Micaela Della Torre, MD MS 312 543 8813; micaela@uic.edu
Notes	NCT03052270

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NCT03227705.

Study name	Canadian study on the association of pessary with progesterone (CAPP)
Methods	RCT
Participants	Setting: 9 hospitals in Canada Sample size: 250 participants Inclusion criteria CL ≤ 25 mm by TVU Gestational age 18 + 7–23 + 6 weeks according to results of first trimester, ultrasound or by integrating the date of the last period Informed consent Exclusion criteria Major congenital malformation Regular and painful uterine activity History of PPROM Active vaginal bleeding Complete and incomplete placenta praevia Cervical cerclage in place History of conization Multiple gestation Allergy/intolerance or hypersensitivity to progesterone or any of its ingredients
Interventions	Cervical pessary (Arabin pessary) plus vaginal progesterone (400 mg daily) versus vaginal progesterone (400 mg daily) alone
Outcomes	Primary outcome Recruitment feasibility Secondary outcomes Preterm delivery
Starting date	June 2018
Contact information	Jean‐Charles Pasquier
Notes	NCT03227705

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NCT03418012.

Study name	Prevention of sPTB with early cervical pessary treatment in women at high risk for PTB (Prometheus)
Methods	RCT
Participants	Setting: Australia, Germany, Greece, Spain Sample size: 310 participants Inclusion criteria Singleton pregnancy History of ≥ 1 previous preterm delivery before 34 + 0 weeks or history of ≥ 1 cervical surgery 12 + 0–16 + 0 weeks of gestation at time of randomisation Age ≥ 18 years Ability to give consent Exclusion criteria: Major fetal abnormalities Uterine malformation, placenta praevia totalis Cerclage prior to randomisation At randomisation: active vaginal bleeding or spontaneous rupture of membranes or painful regular uterine contractions Silicone allergy Current participation in other RCT
Interventions	Cervical pessary (Arabin pessary) versus no treatment
Outcomes	Primary outcome Children's survival without neurodevelopmental disability at age 3 years Secondary outcomes Rate of PTB Time till birth Birthweight of neonate Fetal or neonatal death Need (days) for neonatal special care unit Neonatal morbidity Harm from intervention Maternal death Rate of significant maternal adverse events Infection/inflammation Physical or psychological intolerance to pessary Hospitalisation for threatened preterm labour before 31 + 6 weeks PROM before 31 + 6 weeks
Starting date	December 2019
Contact information	Ioannis Kyvernitakis, MD, PhD; +49 69 1500 ext 5807; i.kyvernitakis@buergerhospital‐ffm.de
Notes	NCT03418012

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NCT03637062.

Study name	Verify the safety and effectiveness of the cerclage pessary in prevention and treatment of high‐risk preterm pregnancy
Methods	RCT
Participants	Setting: not provided Sample size: 300 participants Inclusion criteria Pregnancy and history of ≥ 1 sPTB before 34 + 0 weeks or history of late abortion 12 + 0–8 + 0 weeks of gestation Age ≥ 8 years Informed consent signature Exclusion criteria Iatrogenic preterm delivery Major fetal abnormalities (requiring surgery or leading to infant death or severe handicap) Severe cervical erosion, cervical polyp or haemorrhage Doctor's opinion that cerclage pessary is unsuitable for an individual woman Uterine cervicitis Confirmed premature birth Cerclage prior to randomisation Placenta praevia totalis Active vaginal bleeding at moment of randomisation Spontaneous rupture of membranes at time of randomisation Silicone allergy Painful regular uterine contractions Indication of cervical cerclage operation Current participation in other RCT
Interventions	Cervical pessary (silicone ring) versus progesterone (200 mg)
Outcomes	Primary outcome Child's birth and survival Secondary outcomes PTB before 37 weeks: rate of delivery before 36 + 6 weeks PTB before 34 weeks: rate of delivery before 33 + 6 weeks PTB before 32 weeks: rate of delivery before 31 + 6 weeks PTB before 30 weeks: rate of delivery before 29 + 6 weeks PTB before 28 weeks: rate of delivery before 27 + 6 weeks Birthweight Fetal or neonatal death Neonatal morbidity (intraventricular haemorrhage grade 3–4, retinopathy of prematurity, RDS grade 2–4, need for ventilation (> 72 hours), necrotising enterocolitis, proven or suspected sepsis, antibiotics (> 5 days), need (duration in days) for NICU admission Harm from intervention Maternal death Rate of significant maternal adverse events (bleeding that requires a medical intervention, cervical rupture due to pessary placement, rupture of uterus due to contractions or surgery) Physical or psychological intolerance to pessary for mother (number of cases) Rupture of membranes before 32 weeks Inflammation 3rd stage of chorioamnionitis Hospitalisation for threatened preterm labour before 32 weeks
Starting date	December 2019
Contact information	Not provided
Notes	NCT03637062

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NCT04147117.

Study name	Cervical pessary to prevent preterm singleton birth in high‐risk population
Methods	RCT
Participants	Setting: Hospital Sant Joan de Déu, Barcelona, Spain Sample size: 214 participants Inclusion criteria Asymptomatic singleton pregnancy Age > 18 years Gestational age 18 + 0–23 + 6 weeks ≥ 1 of the following: previous spontaneous preterm delivery or PPROM (23 + 0–34 + 6 weeks); previous spontaneous second trimester miscarriage (16 + 0–22 + 6 weeks); previous surgery on uterine cervix; or uterine malformation. Capacity to sign informed consent form Exclusion criteria Congenital, chromosomal abnormalities or stillbirth in current pregnancy before randomisation Obstetrical history of iatrogenic PTB indicated for maternal or fetal conditions Symptomatic high‐risk pregnancy or PPROM in the current pregnancy Indication of prophylactic cervical cerclage due to obstetrical history Indication of cervical cerclage prior to study inclusion Cerclage in place Active vaginal bleeding
Interventions	Cervical pessary versus no treatment
Outcomes	Primary outcome Spontaneous PTB before 37 weeks' gestation Secondary outcomes PTB before 34 weeks PTB before 28 weeks PPROM before 34 weeks Threatened preterm labour Serious cervical or vaginal trauma Pessary tolerance Infection Progesterone co‐treatment Chorioamnionitis Maternal mortality or morbidity Neonatal birthweight Apgar Umbilical artery pH NICU admission Neonatal respiratory support RDS Intraventricular haemorrhage Necrotising enterocolitis Neonatal death Neonatal sepsis
Starting date	25 October 2017
Contact information	Silvia Irene Ferrero Martínez
Notes	NCT04147117 Recruitment status in 2020: unknown

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NCT04300322.

Study name	Pessary versus progesterone in singletons
Methods	RCT
Participants	Setting: Mỹ Đức Hospital, Ho Chi Minh City, Vietnam Sample size: 804 participants Inclusion criteria Singleton pregnancies CL ≤ 25 mm, measured by TVU in second trimester (16 + 0–22 + 0 weeks of gestation) Not participating in any other study with intervention on maternity or fetus Provision of written informed consent to participate Exclusion criteria Cervical dilation with visible amniotic membranes or amniotic membranes prolapsed into the vagina Major congenital abnormalities of the fetus Presence of severe vaginal discharge Presence of vaginitis or cervicitis Presence of vaginal bleeding PPROM Premature labour without ruptured membrane at time of screening Suspected chorioamnionitis Cervical pessary insertion not possible Cerclage or pessary in place
Interventions	Cervical pessary versus vaginal progesterone
Outcomes	Primary outcome Rate of PTB before 37 weeks' gestation (any cause) Secondary outcomes Gestational age at delivery Time from randomisation to delivery Rate of PTB before 28 weeks' gestation Rate of PTB before 34 weeks' gestation Rate of spontaneous PTB before 28 weeks' gestation Rate of spontaneous PTB before 34 weeks' gestation Rate of spontaneous PTB before 37 weeks' gestation Rate of iatrogenic PTB before 28 weeks' gestation Rate of iatrogenic PTB before 34 weeks' gestation Rate of iatrogenic PTB before 37 weeks' gestation Rate of onset of labour Rate of modes of delivery Rate of all live births at any gestational age Rate of use of antenatal corticosteroids Rate of use of MgSO4 for neuroprotection Rate of PPRO Length of maternal admission for preterm labour (days) Rate of chorioamnionitis Rate of maternal mortality Birthweight (mean) Birthweight < 1500 g Birthweight < 2500 g Rate of congenital anomalies 5‐minute Apgar score 5‐minute Apgar score < 7 Rate of NICU admission Length of NICU admission Rate of death before discharge Rate of neonatal death Rate of perinatal death Rate of stillbirth Rate of composite of poor perinatal outcomes Rate of RDS Rate of periventricular haemorrhage grade 2B or worse Rate of necrotising enterocolitis Rate of proven sepsis Rate of maternal vaginal side effects Vaginal pain score Rate of pessary repositioning Rate of maternal cervical side effect
Starting date	1 May 2020
Contact information	Vinh Q Dang
Notes	NCT04300322 Recruitment status in 2020: recruiting

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van Zijl 2017.

Study name	–Pessary or progesterone to prevent preterm delivery in women with short cervical length: the Quadruple P randomised controlled trial
Methods	Multicenter RCT
Participants	Setting: the Dutch Consortium for Healthcare Evaluation and Research in Obstetrics and Gynaecology – NVOG Consortium 2.0, a collaboration of approximately 70 obstetric practices (academic and non‐academic hospitals) in the Netherlands Sample size: 960 participants Inclusion criteria Age ≥ 18 years Singleton or multiple pregnancy (both twin and higher order) undergoing routine anomaly scan (18–22 weeks for singleton pregnancy and 16–22 weeks for multiple pregnancies) Short cervix, defined as ≤ 35 mm in singletons and < 38 mm in multiples Exclusion criteria Previous sPTB before 34 weeks' gestation Cervical cerclage in this pregnancy Participation in the Quadruple P study in a previous pregnancy Identified major congenital abnormalities Death of 1 or both fetuses Cervical length < 2 mm or cervical dilation < 3 cm
Interventions	Cervical pessary (Arabin) versus vaginal progesterone (vaginal progesterone 200 mg capsules)
Outcomes	Primary outcome Composite adverse perinatal outcome including both morbidity and mortality, specifically: severe RDS, bronchopulmonary dysplasia, intraventricular haemorrhage grade 3 and 4, periventricular leukomalacia > grade I, necrotising enterocolitis > stage I, retinopathy of prematurity and culture‐proven sepsis, patent ductus arteriosus, treated seizures, (intrapartum) stillbirth and death before discharge from the nursery (all measured up to 10 weeks after the expected due date) Secondary outcomes PTB rate before 28 weeks, 32 weeks, 34 weeks and 37 weeks (spontaneous, iatrogenic and total) Birthweight NICU admission PROM Tocolysis (duration), use of corticosteroids, use of magnesium sulphate Mode of delivery Twin‐to‐twin transfusion syndrome Maternal morbidity Maternal admission days for preterm labour
Starting date	Not reported
Contact information	Maud D van Zijl; m.d.vanzijl@amc.nl
Notes	NTR 4414

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CL: cervical length; PPROM: preterm prelabour rupture of membranes; PROM: prelabour rupture of membranes; PTB: preterm birth; RCT: randomised controlled trial; RDS: respiratory distress syndrome; sPTB: spontaneous preterm birth; TVU: transvaginal ultrasound.

Differences between protocol and review

The protocol for this review was published in PROSPERO on 2 July 2019 (Abdel‐Aleem 2019)

We changed the comparator 'placebo/no treatment' to 'no treatment' on the advice of the Contact Editor. Although 'placebo/no treatment' is our standard, there is no real possibility of a placebo vaginal device.

Contributions of authors

HA‐A is the guarantor of this systematic review. He is responsible for conceiving, designing and co‐ordinating the review. OMS extracted and analysed the data and wrote and revised the review. MAA‐A extracted the data, produced the summary of findings tables and revised the review. AAM extracted and analysed the data and revised the review.

Sources of support

Internal sources

Assiut University, Egypt

Assuit University supported the authors who are employees of the University.

External sources

The National Institute for Health Research (NIHR), UK

The National Institute for Health Research (NIHR) supported this project via Cochrane Infrastructure funding to Cochrane Pregnancy and Childbirth.

Declarations of interest

HA‐A is a Professor of Obstetrics and Gynaecology at the Faculty of Medicine, Assuit University, Egypt and reports no conflicts of interest. OMS reports no conflicts of interest. MAA‐A works as a Professor of Obstetrics and Gynaecology at the Women Health Centre, Assiut University, Egypt and reports no conflicts of interest. AAM reports no conflicts of interest.

New

References

References to studies included in this review

Care 2021 {published data only}

Care A, Jackson R, O'Brien E, Leigh S, Cornforth C, Haycox A, et al. Cervical cerclage, pessary, or vaginal progesterone in high-risk pregnant women with short cervix: a randomized feasibility study. Journal of Maternal-Fetal & Neonatal Medicine 2021;34(1):49-57. [DOI] [PubMed] [Google Scholar]
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Cruz‐Melguizo 2018 {published data only}

Cabrera-Garcia L, Cruz-Melguizo S, Ruiz-Antoran B, Torres F, Velasco A, Martinez-Payo C, et al. Evaluation of two treatment strategies for the prevention of preterm birth in women identified as at risk by ultrasound (PESAPRO Trial): study protocol for a randomised controlled trial. Trials 2015;16(1):427. [DOI] [PMC free article] [PubMed] [Google Scholar]
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Cruz-Melguizo S, San-Frutos L, Martinez-Payo C, Ruiz-Antoran B, Adiego-Burgos B, Campillos-Maza JM, et al. Cervical pessary compared with vaginal progesterone for preventing early preterm birth: a randomized controlled trial. Obstetrics and Gynecology 2018;132(4):907-15. [DOI] [PubMed] [Google Scholar]
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Dugoff 2018 {published data only}

Boelig RC, Roman A, Berghella V, Ludmir J, Dugoff L. Predicting asymptomatic cervical dilation in pregnant patients with short mid-trimester cervical length: a secondary analysis of a randomized controlled trial. Acta Obstetricia et Gynecologica Scandinavica 2019;98:761-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
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Dugoff L, Ludmir J, Berghella V, Mackeen AD, Goetzl L. Prevention of preterm birth with pessary in singletons (PoPPS): a randomized controlled trial. American Journal of Obstetrics and Gynecology 2017;216(1 Suppl):S4-S5. [DOI] [PubMed] [Google Scholar]
NCT02056652. Prevention of preterm birth with a pessary in singleton gestations. clinicaltrials.gov/ct2/show/NCT02056652 (first received 6 February 2014).

Goya 2012 {published data only}

Goya M, Pratcorona L, Merced C, Rodo C, Valle L, Romero A, et al. Cervical pessary in pregnant women with a short cervix (PECEP): an open-label randomised controlled trial. Lancet 2012;12(379):1800-6. [DOI] [PubMed] [Google Scholar]
NCT00706264. Prevention of preterm birth using cervical pessary in pregnant women with short cervix (PECEP). clinicaltrials.gov/ct2/show/NCT00706264 (first received 27 June 2008).

Hui 2013 {published data only}

Hui S, Chor C, Lau T, Lao T, Leung T. Cerclage pessary for preventing preterm birth in women with a singleton pregnancy  and a short cervix at 20 to 24 weeks: a randomised controlled trial. American Journal of Perinatology 2013;30(4):283-8. [DOI] [PubMed] [Google Scholar]
ISRCTN18185477. Cerclage pessary for preventing preterm birth in Chinese women with a short cervix in singleton pregnancies: a randomized controlled trial. www.isrctn.com/ISRCTN18185477 (first received 10 April 2012).

Nicolaides 2016 {published data only}

ISRCTN01096902. Randomized study of pessary versus standard management in women with increased chance of premature birth. www.controlled-trials.com/ISRCTN01096902 (first received 5 April 2008).
NCT00735137. Randomized study of pessary vs standard management in women with increased chance of premature birth. clinicaltrials.gov/ct2/show/NCT00735137 (first received 14 August 2008).
Nicolaides KH, Syngelaki A, Poon LC, Picciarelli G, Tul N, Zamprakou A, et al. A randomised trial of a cervical pessary to prevent preterm singleton birth. New England Journal of Medicine 2016;374(11):1044-52. [DOI] [PubMed] [Google Scholar]

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NCT02716909. Pessary in singleton gestations with short cervix without prior preterm birth. clinicaltrials.gov/ct2/show/NCT02716909 (first received 23 March 2016).
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EUCTR2015-000456-15-GB. The prevention of pre-term birth in women who develop a short cervix. A multi-centre randomised controlled trial to compare three treatments; a cervical cerclage, cervical pessary and vaginal progesterone. www.clinicaltrialsregister.eu/ctr-search/search?query=2015-000456-15 (first received 11 March 2015).
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IRCT20180302038914N1. Comparing efficacy of cerclage and adjunctive therapy (cerclage & pessary) in prevention of preterm birth in pregnant women with cervical incompetence. en.irct.ir/trial/30016 (first received 7 May 2018).

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NCT02405455 {published data only}

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NCT02470676 {published data only}

NCT02470676. Cervical pessary vs. vaginal progesterone in preventing preterm birth among women presenting with short cervix: an open-label randomized controlled trial. clinicaltrials.gov/ct2/show/NCT02470676 (first received 12 June 2015).

NCT02511574 {published data only}

NCT02511574. Comparison between natural progesterone and vaginal pessary for the prevention of spontaneous preterm birth (PROPE) [Comparison between natural progesterone and vaginal pessary for the prevention of spontaneous preterm birth in pregnant women with a uterine cervix measuring 25 mm or less in length]. clinicaltrials.gov/show/NCT02511574 (first received 30 July 2015). [CENTRAL: CN-01584361]

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NCT02901626. A randomized trial of pessary in singleton pregnancies with a short cervix. clinicaltrials.gov/ct2/show/NCT02901626 (first received 15 September 2015).

NCT03052270 {published data only}

NCT03052270. Arabin pessary combined with vaginal progesterone compare with vaginal progesterone alone to prevent preterm delivery in singleton pregnancies [Comparison of vaginal progesterone with Arabin cervical pessary and vaginal progesterone alone in the prevention of preterm delivery in singleton pregnancies with incidental premature shortening of cervical length]. clinicaltrials.gov/ct2/show/NCT03052270 (first received 14 February 2017).

NCT03227705 {published data only}

NCT03227705. Canadian study on the association of pessary with progesterone. clinicaltrials.gov/ct2/show/NCT03227705 (first received 24 July 2017).

NCT03418012 {published data only}

NCT03418012. Prevention of sPTB with early cervical pessary treatment in women at high risk for PTB [Effect of history-indicated early treatment with cervical pessary versus expectant management treatment with rescue cerclage in cases with cervical shortening in singleton pregnancies at high-risk for sPTB on children's long-term outcome]. clinicaltrials.gov/ct2/show/NCT03418012 (first received 31 January 2018).

NCT03637062 {published data only}

NCT03637062. Verify the safety and effectiveness of the cerclage pessary in prevention and treatment of high-risk preterm pregnancy. clinicaltrials.gov/show/nct03637062 (first received 17 August 2018).

NCT04147117 {published data only}

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NCT04300322 {published data only}

NCT04300322. Pessary versus progesterone in singletons [The effectiveness of cervical pessary versus vaginal progesterone for the prevention of preterm birth in women with singleton pregnancies and short cervix: a multicenter randomized controlled trial]. clinicaltrials.gov/show/NCT04300322 (first received 9 March 2020). [CENTRAL: CN-02083132]

van Zijl 2017 {published data only}

EUCTR2013-002884-24-NL. Pessary or progesterone to prevent preterm delivery in women with short cervical length – Quadruple P Trial. www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2013-002884-24 (first received 12 May 2013).
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PERMALINK

Cervical pessary for preventing preterm birth in singleton pregnancies

Hany Abdel-Aleem

Omar M Shaaban

Mahmoud A Abdel-Aleem

Ahmed Aboelfadle Mohamed

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Summary of findings

Summary of findings 1. Cervical pessary compared to no treatment for preventing preterm birth in singleton pregnancies .

Summary of findings 2. Cervical pessary compared to vaginal progesterone for preventing preterm birth in singleton pregnancies.

Summary of findings 3. Cervical pessary compared to cervical cerclage for preventing preterm birth in singleton pregnancies.

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

Inclusion criteria

Exclusion criteria

Types of interventions

Types of outcome measures

Primary outcomes

Secondary outcomes

Maternal

Offspring

Search methods for identification of studies

Electronic searches

Searching other resources

Data collection and analysis

Selection of studies

Screening eligible studies for scientific integrity/trustworthiness

Research governance

Baseline characteristics

Feasibility

Results

Abstracts

Data extraction and management

Assessment of risk of bias in included studies

Random sequence generation (selection bias)

Allocation concealment (selection bias)

Blinding of participants and personnel (performance bias)

Blinding of outcome assessment (detection bias)

Incomplete outcome data (attrition bias)

Selective reporting (reporting bias)

Risk of bias from other sources

Overall risk of bias

Measures of treatment effect

Unit of analysis issues

Cluster‐randomised trials

Dealing with missing data

Assessment of heterogeneity

Assessment of reporting biases

Data synthesis

Subgroup analysis and investigation of heterogeneity

Sensitivity analysis

Summary of findings and assessment of the certainty of the evidence

Results

Description of studies

Results of the search

1.

Included studies

Methods, settings and study dates

Participants

Interventions and comparisons

Outcomes

Sources of trial funding

Trial authors' declarations of interest

Ongoing studies