Background
Randomized controlled trials that have assessed the efficacy of cervical pessary to prevent preterm birth in asymptomatic high-risk women have reported conflicting results.
Objective
To evaluate the efficacy and safety of cervical pessary to prevent preterm birth and adverse perinatal outcomes in asymptomatic high-risk women.
Data Sources
MEDLINE, EMBASE, POPLINE, CINAHL, and LILACS (from their inception to October 31, 2019), Cochrane databases, Google Scholar, bibliographies, and conference proceedings.
Study Eligibility Criteria
Randomized controlled trials that compared cervical pessary with standard care (no pessary) or alternative interventions in asymptomatic women at high risk for preterm birth.
Study Appraisal and Synthesis Methods
The systematic review was conducted according to the Cochrane Handbook guidelines. The primary outcome was spontaneous preterm birth <34 weeks of gestation. Secondary outcomes included adverse pregnancy, maternal, and perinatal outcomes. Pooled relative risks with 95% confidence intervals were calculated. Quality of evidence was assessed using the GRADE methodology.
Results
Twelve studies (4687 women and 7167 fetuses/infants) met the inclusion criteria: 8 evaluated pessary vs no pessary in women with a short cervix, 2 assessed pessary vs no pessary in unselected multiple gestations, and 2 compared pessary vs vaginal progesterone in women with a short cervix. There were no significant differences between the pessary and no pessary groups in the risk of spontaneous preterm birth <34 weeks of gestation among singleton gestations with a cervical length ≤25 mm (relative risk, 0.80; 95% confidence interval, 0.43−1.49; 6 trials, 1982 women; low-quality evidence), unselected twin gestations (relative risk, 1.05; 95% confidence interval, 0.79−1.41; 1 trial, 1177 women; moderate-quality evidence), twin gestations with a cervical length <38 mm (relative risk, 0.75; 95% confidence interval, 0.41−1.36; 3 trials, 1128 women; low-quality evidence), and twin gestations with a cervical length ≤25 mm (relative risk; 0.72, 95% confidence interval, 0.25−2.06; 2 trials, 348 women; low-quality evidence). Overall, no significant differences were observed between the pessary and no pessary groups in preterm birth <37, <32, and <28 weeks of gestation, and most adverse pregnancy, maternal, and perinatal outcomes (low- to moderate-quality evidence for most outcomes). There were no significant differences in the risk of spontaneous preterm birth <34 weeks of gestation between pessary and vaginal progesterone in singleton gestations with a cervical length ≤25 mm (relative risk, 0.99; 95% confidence interval, 0.54−1.83; 1 trial, 246 women; low-quality evidence) and twin gestations with a cervical length <38 mm (relative risk, 0.73; 95% confidence interval, 0.46−1.18; 1 trial, 297 women; very low-quality evidence). Vaginal discharge was significantly more frequent in the pessary group than in the no pessary and vaginal progesterone groups (relative risks, ∼2.20; high-quality evidence).
Conclusion
Current evidence does not support the use of cervical pessary to prevent preterm birth or to improve perinatal outcomes in singleton or twin gestations with a short cervix and in unselected twin gestations.
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Why was this study conducted?
To determine whether the placement of a cervical pessary in asymptomatic women at risk for preterm delivery (with a singleton or a multiple gestation) prevents preterm birth and improves perinatal outcome.
Key findings
- •
The placement of a cervical pessary did not reduce the risk of preterm birth (<37, <34, <32, and <28 weeks of gestation) or adverse perinatal outcome in women with:
- ○
A singleton gestation and a cervical length ≤25 mm
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An unselected twin gestation
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A twin gestation and a cervical length <38 mm
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A twin gestation and a cervical length ≤25 mm
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There were no significant differences in the risk of spontaneous preterm birth <34 weeks of gestation between pessary and vaginal progesterone in women with a singleton gestation and a cervical length ≤25 mm and in women with a twin gestation and a cervical length <38 mm
What does this add to what is known?
This systematic review and meta-analysis does not support the use of cervical pessary to prevent preterm birth in asymptomatic women with a singleton or a twin gestation at risk for preterm delivery.
Introduction
Complications of preterm birth are the leading cause of death among children younger than 5 years worldwide, accounting for approximately 18% of all deaths, and 35% of deaths among newborns. In 2014, preterm birth affected 10.6% of livebirths globally, equating to about 14.84 million liveborn preterm neonates. In the United States, the rate of preterm birth has been rising since 2014, and increased significantly from 9.93% in 2017 to 10.02% in 2018.
Preterm neonates who survive are at greater risk for experiencing short-term complications such as respiratory distress syndrome (RDS), bronchopulmonary dysplasia, necrotizing enterocolitis, sepsis, intraventricular hemorrhage, periventricular leukomalacia, and retinopathy of prematurity, than neonates born at term. Furthermore, children born preterm have lower cognitive, motor, and academic performance scores, and are more likely to be diagnosed with cerebral palsy, visual and hearing impairments, attention-deficit/hyperactivity disorder, and behavioral problems than children born at term. Systematic reviews of observational studies and recent large longitudinal follow-up studies strongly suggest that preterm birth is associated with a significantly higher risk of developing chronic diseases in adulthood such as metabolic syndrome, diabetes mellitus, lung function impairment, venous thromboembolism, sleep-disordered breathing, ischemic heart disease, , , and chronic kidney disease.
Importantly, in a recent nationwide cohort study of more than 4 million people, preterm birth was associated with a significantly increased mortality at all attained ages from birth to 45 years. This outcome could not be attributed to sociodemographic factors, or shared genetic/environmental factors in families, but rather to the consequences of preterm birth. , ,
The burden of preterm birth on health services and other sectors of the economy, for families and caregivers, and more broadly, for society, is substantial. , Moreover, preterm birth has a major impact on the quality of life of parents and families. ,
Preterm labor is a syndrome associated with multiple etiologic processes such as infection/inflammation, vascular disorders, , decidual senescence, uterine overdistention, decline in progesterone action, cervical disease, breakdown of maternal-fetal tolerance, premature activation of the fetal immune system, , and maternal stress, , , among others. Genetic and environmental factors contribute to each etiology of the preterm labor syndrome. A logical consequence of the complexity of the preterm labor syndrome is that there is not a single biomarker to identify the patient at risk or a single intervention to prevent all, or even most, cases. ,
In recent years, several interventions have been proposed for the prevention of preterm birth in asymptomatic high-risk women, including progestogens (17α-hydroxyprogesterone caproate, vaginal progesterone, , , , , , and oral progesterone , ), omega−3 long-chain polyunsaturated fatty acids supplementation, cervical cerclage, , , , , and cervical pessary. , , , , High-quality evidence indicates that vaginal progesterone is effective for preventing preterm birth and improving neonatal outcomes in asymptomatic women with a singleton gestation and a midtrimester sonographic short cervix, regardless of the history of spontaneous preterm birth, without any demonstrable deleterious effects on childhood neurodevelopment or maternal health. , Cervical cerclage has been shown to be effective in reducing the risk of preterm birth and adverse perinatal outcomes in women with a singleton gestation, previous spontaneous preterm birth, and a midtrimester sonographic short cervix. The efficacy of the administration of 17α-hydroxyprogesterone caproate, oral progesterone, and omega−3 long-chain polyunsaturated fatty acids to prevent preterm birth remains inconclusive. , ,
Several systematic reviews regarding the efficacy of cervical pessary for preventing preterm birth in women at high risk have reported conflicting results ; consequently, a thorough examination of the currently available evidence on the efficacy of this intervention is justified. We performed a systematic review and meta-analysis of aggregate data to evaluate the efficacy and safety of cervical pessary for the prevention of preterm birth and perinatal morbidity and mortality in asymptomatic high-risk women.
Materials and Methods
This systematic review was conducted by following the guidelines outlined in the most recent edition of the Cochrane Handbook for Systematic Reviews of Interventions and reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. The study protocol was registered with PROSPERO, number CRD42019141531. Two of the authors (A.C.-A. and R.R.) independently retrieved and reviewed studies for eligibility and assessed their risk of bias. Any disagreements encountered in the review process were resolved through discussion between the 2 reviewers.
Search strategy
Identification of relevant articles was undertaken through searches in MEDLINE, EMBASE, POPLINE, LILACS, CINAHL, the Cochrane Central Register of Controlled Trials, clinical trial registries (all from their inception to October 31, 2019), and Google Scholar, using a combination of keywords and text words related to cervical pessary and preterm birth . We reviewed proceedings of congresses and scientific meetings on obstetrics, maternal-fetal medicine, and ultrasound in obstetrics, reference lists of retrieved articles, previously published systematic reviews, and review articles for any additional relevant studies. We also contacted investigators in the field to locate unpublished studies. There were no language restrictions.
Eligibility criteria
We included randomized controlled trials comparing cervical pessary to standard care (no pessary) or alternative interventions (such as vaginal progesterone or cervical cerclage) in asymptomatic women at high risk for preterm birth (such as those with a midtrimester sonographic short cervix, history of preterm birth, multiple gestation, and uterine anomalies or excisional cervical procedures) with the aim of preventing preterm birth and/or adverse perinatal outcomes. Trials were excluded if they: (1) were quasi-randomized; (2) assessed cervical pessary in women with arrested preterm labor or placenta previa; or (3) did not report clinical outcomes. Studies published only as abstracts were excluded if additional information on methodological issues and results could not be obtained. Trials with planned co-interventions were eligible for inclusion provided that the co-interventions were permitted equally in each trial arm.
Outcome measures
The prespecified primary outcome was spontaneous preterm birth <34 weeks of gestation. Secondary outcomes included spontaneous preterm birth <37, <32, and <28 weeks of gestation, any preterm birth <37, <34, <32, and <28 weeks of gestation, mean gestational age at delivery, chorioamnionitis, preterm prelabor rupture of membranes (PPROM), vaginal discharge, vaginal infection, vaginal bleeding, pelvic discomfort, use of tocolytic agents, cesarean delivery, maternal death, fetal death, neonatal death, perinatal death, birthweight <1500 and <2500 g, Apgar score <7 at 5 minutes, RDS, necrotizing enterocolitis, intraventricular hemorrhage, neonatal sepsis, retinopathy of prematurity, bronchopulmonary dysplasia, periventricular leukomalacia, any composite adverse neonatal or perinatal outcome, admission to the neonatal intensive care unit (NICU), use of mechanical ventilation, and long-term neurodevelopmental and health outcomes in children.
Data extraction
Using a specially developed data extraction form, 1 investigator (A.C.-A.) extracted the relevant data from eligible studies, which were then verified independently by another investigator (R.R.). Information was extracted on study characteristics (randomization procedure, concealment allocation method, blinding of clinicians, women and outcome assessors, follow-up period, completeness of outcome data for each outcome, including attrition and exclusions from the analysis, and intention-to-treat analysis), participants (inclusion and exclusion criteria, number of women in randomized groups, baseline characteristics, and country and date of recruitment), details of intervention (type of cervical pessary, gestational age at trial entry, scheduled gestational age for pessary removal, frequency of and reasons for early pessary removal, interventions used in the control group, compliance, and use of co-interventions) and outcomes (definition of outcomes, number of outcome events and/or mean ± standard deviation [SD] for each outcome).
Risk of bias assessment
The risk of bias in each study was assessed through the use of the Version 2 of the Cochrane risk-of-bias tool for randomized trials (RoB 2), , which considers the following domains: bias arising from the randomization process, bias due to deviations from intended interventions, bias due to missing outcome data, bias in measurement of the outcome, and bias in selection of the reported result. For each domain, the tool comprises a series of “signaling questions” aiming to elicit information about features of the trial that are relevant to risk of bias. Once the signaling questions were answered, the next step was to reach a risk-of-bias judgement and assign 1 of 3 levels to each domain: “low risk of bias,” “some concerns,” or “high risk of bias.” Finally, an overall risk of bias judgment was reached for each study as follows: “low risk of bias” (the study is judged to be at low risk of bias for all domains), “some concerns” (the study is judged to raise some concerns in at least 1 domain, but not to be at high risk of bias for any domain), and “high risk of bias” (the study is judged to be at high risk of bias in at least 1 domain or to have some concerns for multiple domains in a way that substantially lowers confidence in the result).
Data synthesis
The data synthesis was performed according to the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions. Outcomes were analyzed on an intent-to-treat basis. The denominator for pregnancy and maternal outcomes was the number of women, whereas for perinatal and child outcomes we used the number of fetuses/neonates and children, respectively. Analyses were undertaken separately for singleton gestations with a midtrimester sonographic cervical length ≤25 mm, unselected multiple gestations, twin gestations with a midtrimester sonographic cervical length <38 mm, and twin gestations with a midtrimester sonographic cervical length ≤25 mm.
A random-effects model was used to calculate the pooled relative risk (RR) for dichotomous outcomes and the mean difference for continuous outcomes with corresponding 95% confidence intervals (CIs). We chose a random-effects model, anticipating heterogeneity between the results of the relevant studies. When the RR was statistically significant, we calculated the number needed to treat (NNT) with 95% CI for an additional beneficial outcome or an additional harmful outcome of cervical pessary.
For perinatal outcomes of multiple gestations, we estimated pooled RRs with 95% CIs assuming independence between fetuses/neonates by using data reported in the studies at the fetal/neonatal level. However, because of the potential of nonindependence of outcomes in fetuses/neonates from multiple gestations, we also planned estimating pooled adjusted RRs with 95% CIs by using an estimate of the intracluster correlation coefficient (ICC) derived from the trial, or from similar trials, as recommended by the Cochrane Handbook. Given that ICCs for perinatal outcomes were not reported in the included studies, we used those that had recently been estimated from randomized controlled trials in women with a twin gestation, which had similar aims and inclusion/exclusion criteria to those of trials included in our systematic review. We considered the adjusted RRs as the main estimates of the pessary’s effect on perinatal outcomes in multiple gestations.
Heterogeneity of treatment effect was assessed with the I 2 statistic. In addition, forest plots were visually inspected for evidence of heterogeneity. If there was evidence of statistical heterogeneity ( I 2 ≥ 30%), we planned to explore the possible sources by using sensitivity and subgroup analyses to search for evidence of bias or methodological differences among trials. We also addressed heterogeneity by calculating 95% prediction intervals for meta-analyses that contained at least 3 studies, which provide a predicted range for the true effect size in future studies.
In singleton gestations with a cervical length ≤25 mm, we performed subgroup analyses for the primary outcome according to concomitant use of vaginal progesterone (yes vs no), cervical length (≤10 mm vs 11−25 mm), and obstetric history (no previous preterm birth vs at least 1 previous preterm birth). In twin gestations with a cervical length ≤25 mm, we performed a subgroup analysis according to cervical length (≤10 mm vs 11−25 mm). An interaction P value ≥ .05 was considered to indicate that the effect of treatment did not differ significantly between subgroups. We also planned to assess publication and related biases if at least 10 studies were included in a meta-analysis; however, these analyses were not performed given the limited number of trials included in the review. Prespecified sensitivity analyses to explore the impact of risk of bias on results were not performed because most trials were judged to be at low risk of bias.
Quality of evidence
The quality of evidence for primary and secondary outcomes was assessed using the GRADE approach, which takes into account 5 domains: risk of bias, inconsistency, indirectness, imprecision, and publication bias. The GRADE approach categorizes the certainty of the evidence into 4 levels: (1) high: we are very confident that the true effect lies close to that of the estimate of the effect, and further research is unlikely to change our confidence in the estimate of the effect; (2) moderate: we are moderately confident in the effect estimate, and the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different; (3) low: our confidence in the effect estimate is limited, and the true effect may be substantially different from the estimate of the effect; and (4) very low: we have very little confidence in the effect estimate, and the true effect is likely to be substantially different from the estimate of effect.
Statistical analyses were performed using Review Manager (Version 5.3; The Nordic Cochrane Centre, Copenhagen, Denmark) and StatsDirect (Version 3.2.8; StatsDirect Ltd, Cheshire, UK). The quality of evidence was assessed using GRADEpro GDT (GRADEpro Guideline Development Tool [Software]; McMaster University, Hamilton, ON, Canada).
Results
Selection, characteristics, and risk of bias of studies
Figure 1 summarizes the process of identification and selection of studies. Twelve studies, which included 4687 women and 7167 fetuses/infants, met the inclusion criteria: 8 evaluated pessary vs no pessary in women with a short cervix (6 in singleton gestations and 2 in twin gestations , ), 2 assessed pessary vs no pessary in unselected multiple gestations (1 in twin gestations and another in both twin and triplet gestations ), and 2 compared pessary vs vaginal progesterone in women with a short cervix (1 in singleton gestations and another in twin gestations ). The study by Liem et al did not report outcome data separately for twin and triplet gestations. Data on child neurodevelopmental outcomes for that trial were reported in 2 additional publications. , We obtained additional unpublished data for the 2 largest trials in singleton and twin gestations.
The main characteristics of the studies included in the systematic review are shown in Table 1 . Ten trials were specifically designed to evaluate the use of cervical pessary in women with a short cervix (defined as cervical length ≤25 mm, , , <25 mm, ≤30 mm, and <38 mm ). The remaining 2 studies , tested the effect of cervical pessary in women with unselected multiple gestations but also reported results for subgroups of women with a short cervix (defined as cervical length <38 mm and ≤25 mm ).
| First author, reference, year (country) | Participants | Interventions (sample size) | GA at trial entry, wk | Cervical length at trial entry, mm | Concomitant use of vaginal progesterone | Primary outcome | Main findings |
|---|---|---|---|---|---|---|---|
| Singleton gestations | |||||||
| Goya, 2012 (Spain) | Women with a singleton gestation and a cervical length ≤25 mm | • Arabin pessary (n = 190) • No pessary (n = 190) | 20–23; mean, 22.3 | 19.0 ± 4.8 | Pessary group: 0% No pessary group: 0% | Spontaneous PTB <34 wk | Cervical pessary significantly reduced PTB and adverse perinatal outcomes |
| Hui, 2013 (China) | Women with a singleton gestation and a cervical length <25 mm | • Arabin pessary (n = 53) • No pessary (n = 55) | 20–24; mean, 21.9 | 20.1 ± 0.5 | Pessary group: 0% No pessary group: 0% | PTB <34 wk | There were no significant differences between the study groups in PTB and adverse perinatal outcomes |
| Nicolaides, 2016 (Multicountry a ) | Women with a singleton gestation and a cervical length ≤25 mm | • Arabin pessary (n = 465) • No pessary (n = 467) | 20–24; median, 23.5 | 20.0 (14.0–22.0) b | Pessary group: 44% No pessary group: 47% | Spontaneous PTB <34 wk | There were no significant differences between the study groups in PTB and adverse perinatal outcomes |
| Karbasian, 2016 (Iran) | Women with a singleton gestation and a cervical length ≤25 mm | • Arabin pessary plus vaginal progesterone 400 mg/d (n = 71) • Vaginal progesterone 400 mg/d (n = 73) | 18–22; mean, 19.6 | 22.0 ± 1.7 | Pessary group: 100% No pessary group: 100% | PTB <37 wk | There were no significant differences between the study groups in PTB and adverse perinatal outcomes |
| Saccone, 2017 (Italy) | Women with a singleton gestation, no previous spontaneous PTB, and a cervical length ≤25 mm | • Arabin pessary (n = 150) • No pessary (n = 150) | 18–23; mean, 22.4 | 12.0 ± 5.8 | Pessary group: 89% No pessary group: 83% | Spontaneous PTB <34 wk | Pessary significantly reduced PTB and adverse perinatal outcomes |
| Dugoff, 2018 (United States) | Women with a singleton gestation, no previous spontaneous PTB, and a cervical length ≤25 mm | • Bioteque cup pessary (n = 60) • No pessary (n = 58) | 18–23; mean, 21.1 | Pessary group: 17.6 (10.9–22.0) b No pessary group: 19.0 (11.2–22.9) b | Pessary group: 84% No pessary group: 91% | PTB <37 wk | There were no significant differences between the study groups in PTB and adverse perinatal outcomes |
| Cruz-Melguizo, 2018 (Spain) | Women with a singleton gestation and a cervical length ≤25 mm | • Arabin pessary (n = 125) • Vaginal progesterone 200 mg/d (n = 118) | 19–22; mean, 21.3 | 20.9 ± 4.2 | Pessary group: 5% Progesterone group: 100% | Spontaneous PTB <34 wk | There were no significant differences between the study groups in PTB and adverse perinatal outcomes |
| Multiple gestations | |||||||
| Liem, 2013 (Netherlands) | Women with a multiple gestation (97.8% twins and 2.2% triplets) | • Arabin pessary (n = 401) • No pessary (n = 407) | 12–20, mean 17.0 | 43.9 ± 8.3 | Pessary group: 0% No pessary group: 0% | Composite adverse perinatal outcome c | There were no significant differences between the study groups in PTB and adverse perinatal outcomes |
| Nicolaides, 2016 (Multicountry) d | Women with a twin gestation | • Arabin pessary (n = 588) • No pessary (n = 589) | 20–24; median, 22.7 | 32.0 (27.0–37.0) b | Pessary group: 0% No pessary group: 0.3% | Spontaneous PTB <34 wk | There were no significant differences between the study groups in PTB and adverse perinatal outcomes |
| Goya, 2016 (Spain) | Women with a twin gestation and a cervical length ≤25 mm | • Arabin pessary (n = 68) • No pessary (n = 66) | 20–23; mean, 22.3 | 19.4 ± 3.6 | Pessary group: 0% No pessary group: 0% | Spontaneous PTB <34 wk | Cervical pessary significantly reduced PTB. There was no effect on adverse neonatal outcomes |
| Berghella, 2017 (United States) | Women with a diamniotic twin gestation and a cervical length ≤30 mm | • Bioteque cup pessary (n = 23) • No pessary (n = 23) | 18–27; median, 21.1 | Pessary group: 16.7 (10.7–27.8) b No pessary group: 22.9 (15.9–25.6) b | Pessary group: 4% No pessary group: 9% | PTB <34 wk | There were no significant differences between the study groups in PTB and adverse perinatal outcomes |
| Dang, 2019 (Vietnam) | Women with a twin gestation and a cervical length <38 mm | • Arabin pessary (n = 148) • Vaginal progesterone 400 mg/d (n = 149) | 16–22, mean, 17.8 | 31.3 ± 4.3 | Pessary group: 1% Progesterone group: 100% | PTB <34 wk | There were no significant differences between the study groups in PTB <34 wk. Pessary significantly reduced PTB <37 wk and adverse perinatal outcomes |
a England, Slovenia, Portugal, Chile, Australia, Italy, Albania, Germany, and Belgium
b Median (interquartile range)
c Occurrence of any of the following events: stillbirth, periventricular leukomalacia of grade 2 or worse, severe respiratory distress syndrome of grade 2 or worse, bronchopulmonary dysplasia, intraventricular hemorrhage of grade 2B or worse, necrotizing enterocolitis, proven sepsis, and neonatal death within 6 weeks after the expected term date
d United Kingdom, Spain, Germany, Austria, Slovenia, Portugal, Italy, Belgium, Albania, China, Brazil, and Chile.
Cervical length at trial entry was measured in all women enrolled in the trial by Nicolaides et al, and in 76.4% of women in the trial by Liem et al (81.4% in the pessary group vs 71.5% in the no pessary group, P = .0009). The mean or median gestational age at trial entry was 23.5 weeks in 1 study, between 21 and 22 weeks in 8 studies, , , , 19.6 weeks in 1 study, and about 17.4 weeks in 2 studies. , Among studies in singleton gestations, the mean or median cervical length at randomization was about 20 mm in 6 studies , , and 12 mm in the remaining study. Among studies in multiple gestations, the mean or median cervical length at randomization was about 20 mm in 2 studies, , about 32 mm in 2 studies, , and 44 mm in 1 study.
Ten studies used the Arabin pessary , , and 2 used the Bioteque cup pessary. , Pessary removal was scheduled for 37 weeks of gestation in 9 studies , , and 36 weeks of gestation in the remaining 3 studies. , , The main indications for early pessary removal included preterm labor not responding to tocolytic therapy, active vaginal bleeding, PPROM, severe patient discomfort, and patient request ( Supplemental Table 1 ). The frequency of pessary removal before schedule ranged from 0.5% to 51.7% in singleton gestations and from 2.9% to 69.6% in multiple gestations ( Supplemental Table 2 ).
Vaginal progesterone was concomitantly used in 6 of the 10 studies that compared pessary vs no pessary. , , The proportion of patients who received vaginal progesterone simultaneously with a pessary was ≥86% in 3 studies, 45.4% in 1 study, 6.5% in another, and 0.2% in the remaining study. The primary outcome was spontaneous preterm birth < 34 weeks of gestation in 6 trials, , , , , , any preterm birth < 34 weeks of gestation in 3 trials, , , any preterm birth < 37 weeks of gestation in 2 trials, , and a composite adverse perinatal outcome in 1 trial.
Among the 10 studies that compared pessary vs no pessary, 7 (4 in singleton gestations , and 3 in multiple gestations , , ) reported that there were no significant differences between the study groups in the risk of preterm birth and adverse perinatal outcomes. Two studies performed in singleton gestations with a short cervix showed that pessary use was associated with a significant decrease in the risk of preterm birth and adverse perinatal outcomes. , The remaining study, performed in twin gestations with a short cervix, reported that pessary significantly reduced the risk of spontaneous preterm birth <34 weeks but had no effect on neonatal morbidity and mortality. The 2 trials that compared pessary and vaginal progesterone in singleton and twin gestations with a short cervix did not report significant differences in the frequency of the primary outcome between the study groups.
Ten studies were deemed to be at low risk of bias for all domains of the RoB 2 tool ( Figure 2 ). Two studies were judged as having “some concerns” in the domain of bias arising from the randomization process. , In the study by Berghella et al, there was an excess in statistically or marginally significant differences in baseline characteristics between intervention groups, whereas in the study by Dang et al, there was imbalance in some key prognostic factors—this is unlikely to be due to chance. The between-group difference is large enough to result in bias in the intervention effect size estimate. The study by Dang et al was also considered to have “some concerns” in the domain of bias in selection of the reported results, because we detected serious discrepancies between the trial report and the protocol posted on clinicaltrials.gov , which strongly suggest that a subgroup analysis according to cervical length was not prespecified but was conducted post hoc. In addition, it is implausible that no woman enrolled in this trial had a cervical length <18 mm, which suggests that there was a bias in the execution of this study. Overall, this trial was judged to be at high risk of bias.
Pessary vs no pessary in singleton gestations with a cervical length ≤25 mm
Six studies, with a total of 1982 women, compared pessary vs no pessary in singleton gestations with a cervical length ≤25 mm. The placement of a pessary was not associated with a significant reduction in the risk of spontaneous preterm birth <34 weeks (11.3% vs 15.0%; RR, 0.80; 95% CI, 0.43−1.49; P = .48; I 2 = 81%; low-quality evidence; 95% prediction interval of the RR, 0.13−5.00) ( Figure 3 ). There were no significant differences between the pessary and no pessary groups in the risk of spontaneous preterm birth <37, <32, and <28 weeks of gestation, and any preterm birth <37, <34, <32, and <28 weeks of gestation (RRs from 0.71−1.21; low- to moderate-quality evidence for most outcomes) ( Table 2 ). The mean gestational age at delivery did not significantly differ between the study groups (mean difference, 0.87 weeks; 95% CI, −0.52 to 2.26; P = .22; 5 studies, 1864 women; I 2 = 93%; low-quality evidence).
| Outcome | No. of trials | Pessary | No pessary | Relative risk (95% CI) | P value | I 2 , % | Quality of evidence |
|---|---|---|---|---|---|---|---|
| Pregnancy/maternal outcomes | |||||||
| Spontaneous preterm birth <37 wk | 4 , , , | 196/865 (22.7%) | 282/865 (32.6%) | 0.71 (0.41–1.24) | .23 | 91 | Low |
| Spontaneous preterm birth <32 wk | 1 | 41/465 (8.8%) | 34/467 (7.3%) | 1.21 (0.78–1.87) | .39 | NA | Low |
| Spontaneous preterm birth <28 wk | 4 , , , | 44/865 (5.1%) | 52/865 (6.0%) | 0.76 (0.37–1.54) | .44 | 65 | Low |
| Preterm birth <37 wk | 5 , , | 197/799 (24.7%) | 205/803 (25.5%) | 0.95 (0.75–1.19) | .64 | 31 | High |
| Preterm birth <34 wk | 6 | 123/989 (12.4%) | 159/993 (16.0%) | 0.82 (0.46–1.45) | .50 | 81 | Low |
| Preterm birth <32 wk | 3 | 62/686 (9.0%) | 56/690 (8.1%) | 1.11 (0.78–1.58) | .57 | 2 | Moderate |
| Preterm birth <28 wk | 4 , , , | 46/728 (6.3%) | 41/730 (5.6%) | 1.08 (0.71–1.65) | .72 | 5 | Moderate |
| Chorioamnionitis | 5 , | 18/936 (1.9%) | 17/938 (1.8%) | 1.04 (0.54–2.00) | .90 | 0 | Low |
| PPROM | 6 | 103/989 (10.4%) | 103/993 (10.4%) | 0.90 (0.57–1.42) | .65 | 52 | Low |
| Vaginal discharge | 5 , , | 594/891 (66.7%) | 257/895 (28.7%) | 2.15 (1.67–2.78) | <.00001 | 81 | High |
| Vaginal infection | 2 , | 138/458 (30.1%) | 116/405 (28.6%) | 1.04 (0.85–1.28) | .68 | 0 | Moderate |
| Vaginal bleeding | 2 , | 8/243 (3.3%) | 9/245 (3.7%) | 0.87 (0.35–2.21) | .78 | 0 | Low |
| Pelvic discomfort | 3 , , | 59/641 (9.2%) | 18/647 (2.8%) | 3.28 (1.96–5.50) | <.00001 | 0 | High |
| Use of tocolytic agents | 1 | 64/190 (33.7%) | 101/190 (53.2%) | 0.63 (0.50–0.81) | .0002 | NA | Moderate |
| Cesarean delivery | 4 , , , | 198/865 (22.9%) | 192/865 (22.2%) | 1.01 (0.81–1.25) | .96 | 27 | High |
| Maternal death | 3 , , | 0/805 (0.0%) | 0/807 (0.0%) | Not estimable | NA | NA | Low |
| Perinatal outcomes | |||||||
| Fetal death | 6 | 12/989 (1.2%) | 12/993 (1.2%) | 1.01 (0.44–2.31) | .98 | 0 | Low |
| Neonatal death | 6 | 13/989 (1.3%) | 16/993 (1.6%) | 0.83 (0.40–1.72) | .61 | 0 | Low |
| Perinatal death | 6 | 25/989 (2.5%) | 28/993 (2.8%) | 0.88 (0.51–1.53) | .66 | 1 | Moderate |
| Birthweight <1500 g | 3 , , | 58/805 (7.2%) | 69/807 (8.6%) | 0.71 (0.30–1.68) | .44 | 81 | Low |
| Birthweight <2500 g | 4 , | 158/876 (18.0%) | 200/880 (22.7%) | 0.73 (0.39–1.35) | .31 | 88 | Low |
| Apgar score <7 at 5 min | 1 | 27/465 (5.8%) | 29/467 (6.2%) | 0.94 (0.56–1.55) | .80 | NA | Moderate |
| Respiratory distress syndrome | 5 , , | 62/918 (6.8%) | 90/920 (9.8%) | 0.72 (0.36–1.43) | .35 | 73 | Low |
| Necrotizing enterocolitis | 4 , , , | 11/865 (1.3%) | 10/865 (1.2%) | 1.15 (0.47–2.79) | .76 | 0 | Low |
| Intraventricular hemorrhage | 5 , , | 17/918 (1.9%) | 14/920 (1.5%) | 1.16 (0.48–2.80) | .73 | 21 | Low |
| Neonatal sepsis | 5 , , | 49/918 (5.3%) | 56/920 (6.1%) | 0.80 (0.46–1.40) | .44 | 43 | Low |
| Retinopathy of prematurity | 4 , , , | 8/865 (0.9%) | 16/865 (1.8%) | 0.51 (0.10–2.59) | .42 | 56 | Very low |
| Bronchopulmonary dysplasia | 2 , | 13/210 (6.2%) | 17/208 (8.2%) | 0.76 (0.38–1.53) | .44 | 0 | Low |
| Any composite adverse neonatal outcome | 4 , , , | 69/865 (8.0%) | 114/865 (13.2%) | 0.59 (0.28–1.27) | .18 | 83 | Low |
| Admission to NICU | 4 | 81/739 (11.0%) | 82/745 (11.0%) | 1.01 (0.64–1.58) | .97 | 53 | Low |
| Mechanical ventilation | 1 | 40/465 (8.6%) | 33/467 (7.1%) | 1.22 (0.78–1.90) | .38 | NA | Moderate |
The use of pessary was associated with an increased risk of both vaginal discharge (RR, 2.15; 95% CI, 1.67−2.78; NNT for harm, 3; 95% CI, 2−3; 95% prediction interval of the RR, 1.04−4.45) and pelvic discomfort (RR, 3.28; 95% CI, 1.96−5.50; NNT for harm, 16; 95% CI, 11−26; 95% prediction interval of the RR, 1.96−5.49) (high-quality evidence for both outcomes). One study reported that pessary significantly reduced the frequency of tocolytic agent use (RR, 0.63; 95% CI, 0.50−0.81; NNT for benefit, 5; 95% CI, 3−10; moderate-quality evidence). There were no significant differences between the pessary and no pessary groups in other pregnancy and maternal outcomes, as well as in adverse perinatal outcomes (low-quality evidence for most outcomes).
Subgroup analyses of the effect of pessary on spontaneous preterm birth <34 weeks among singleton gestations with a cervical length ≤25 mm according to prespecified variables are presented in Table 3 . Overall, there was no evidence of a different effect related to concomitant use of vaginal progesterone ( P for interaction = .70), history of preterm birth ( P for interaction = .24), and cervical length ( P for interaction = .68). The frequency of spontaneous preterm birth <34 weeks was comparable in women who received a pessary plus vaginal progesterone and those who received only vaginal progesterone (15.2% vs 16.1%; RR, 0.91; 95% CI, 0.47−1.76). In addition, pessary was associated with a nonsignificant reduction in the risk of spontaneous preterm birth <34 weeks of gestation in women with at least 1 previous preterm birth (RR, 0.53; 95% CI, 0.23−1.20) and women with a cervical length ≤10 mm (RR, 0.58; 95% CI, 0.10−3.23).
| Subgroup | No. of trials | Pessary | No pessary | Relative risk (95% CI) | I 2 , % | Interaction P value |
|---|---|---|---|---|---|---|
| Concomitant use of vaginal progesterone | .70 | |||||
| No | 4 , | 31/521 (6.0%) | 67/518 (12.9%) | 0.70 (0.23–2.14) | 78 | |
| Yes | 3 | 62/408 (15.2%) | 67/417 (16.1%) | 0.91 (0.47–1.76) | 67 | |
| Obstetric history | .24 | |||||
| No previous preterm birth | 3 , , | 78/605 (12.9%) | 72/591 (12.2%) | 0.97 (0.54–1.76) | 71 | |
| ≥1 Previous preterm birth | 1 | 7/70 (10.0%) | 16/84 (19.0%) | 0.53 (0.23–1.20) | NA | |
| Cervical length | .68 | |||||
| ≤10 mm | 2 , | 28/111 (25.2%) | 25/83 (30.1%) | 0.58 (0.10–3.23) | 85 | |
| 11–25 mm | 2 , | 38/504 (7.5%) | 48/534 (9.0%) | 0.84 (0.56–1.27) | 0 |
Pessary vs no pessary in unselected multiple gestations
Two studies (1985 women and 3988 fetuses/infants) evaluated pessary vs no pessary in unselected multiple gestations: 1 in twin gestations (1177 women and 2354 fetuses/infants) and the other in both twin (790 women and 1580 fetuses/infants) and triplet (18 women and 54 fetuses/infants) gestations. The frequencies of spontaneous preterm birth and any preterm birth <34, <37, <32, and <28 weeks of gestation did not significantly differ between the study groups (most RRs from 0.92−1.07; high-quality evidence for preterm birth <37 weeks, moderate-quality evidence for preterm birth <34 and <32 weeks, and low- to moderate-quality evidence for preterm birth <28 weeks) ( Table 4 ).
| Outcome | No. of trials | Pessary | No pessary | Relative risk (95% CI) | P value | I 2 , % | Adjusted relative risk a (95% CI) | Quality of evidence |
|---|---|---|---|---|---|---|---|---|
| Pregnancy/maternal outcomes | ||||||||
| Spontaneous preterm birth <34 wk | 1 | 80/588 (13.6%) | 76/589 (12.9%) | 1.05 (0.79–1.41) | .72 | NA | NA | Moderate |
| Spontaneous preterm birth <37 wk | 1 | 205/588 (34.9%) | 197/589 (33.4%) | 1.04 (0.89–1.22) | .61 | NA | NA | High |
| Spontaneous preterm birth <32 wk | 1 | 42/588 (7.1%) | 45/589 (7.6%) | 0.93 (0.62–1.40) | .74 | NA | NA | Moderate |
| Spontaneous preterm birth <28 wk | 1 | 19/588 (3.2%) | 13/589 (2.2%) | 1.46 (0.73–2.94) | .28 | NA | NA | Low |
| Preterm birth <37 wk | 2 , | 546/989 (55.2%) | 560/996 (56.2%) | 0.98 (0.91–1.06) | .65 | 0 | NA | High |
| Preterm birth <34 wk | 1 | 98/588 (16.7%) | 92/589 (15.6%) | 1.07 (0.82–1.38) | .63 | NA | NA | Moderate |
| Preterm birth <32 wk | 2 , | 93/989 (9.4%) | 102/996 (10.2%) | 0.92 (0.70–1.20) | .53 | 0 | NA | Moderate |
| Preterm birth <28 wk | 2 , | 35/989 (3.5%) | 36/996 (3.6%) | 0.98 (0.60–1.59) | .93 | 10 | NA | Moderate |
| Chorioamnionitis | 2 , | 16/989 (1.6%) | 15/996 (1.5%) | 1.06 (0.52–2.14) | .88 | 0 | NA | Low |
| PPROM | 2 , | 143/989 (14.5%) | 125/996 (12.6%) | 1.15 (0.92–1.44) | .21 | 0 | NA | Moderate |
| Vaginal discharge | 2 , | 342/966 (35.4%) | 115/970 (11.9%) | 2.96 (2.46–3.57) b | <.0001 | 96 | NA | High |
| Vaginal infection | 1 | 116/555 (20.9%) | 86/511 (16.8%) | 1.24 (0.97–1.60) | .09 | NA | NA | Moderate |
| Pelvic discomfort | 1 | 33/565 (5.8%) | 29/563 (5.2%) | 1.13 (0.70–1.84) | .61 | NA | NA | Moderate |
| Use of tocolytic agents | 1 | 74/401 (18.5%) | 92/407 (22.6%) | 0.82 (0.62–1.07) | .15 | NA | NA | Moderate |
| Cesarean delivery | 2 , | 632/989 (63.9%) | 559/996 (56.1%) | 1.13 (1.06–1.21) | .0004 | 0 | NA | High |
| Maternal death | 2 , | 1/989 (0.1%) | 0/996 (0.0%) | 3.04 (0.12–74.52) | .49 | NA | NA | Low |
| Perinatal outcomes | ||||||||
| Fetal death | 2 , | 22/1987 (1.1%) | 32/2001 (1.6%) | 0.69 (0.40–1.19) | .18 | 0 | 0.69 (0.34–1.39) | Moderate |
| Neonatal death | 2 , | 40/1987 (2.0%) | 42/2001 (2.1%) | 0.96 (0.62–1.48) | .85 | 0 | 0.93 (0.54–1.61) | Moderate |
| Perinatal death | 2 , | 62/1987 (3.1%) | 74/2001 (3.7%) | 0.84 (0.61–1.18) | .32 | 0 | 0.87 (0.57–1.33) | Moderate |
| Birthweight <1500 g | 2 , | 182/1987 (9.2%) | 182/2001 (9.1%) | 1.01 (0.83–1.23) | .94 | 0 | 1.00 (0.77–1.29) | Moderate |
| Birthweight <2500 g | 2 , | 1106/1987 (55.7%) | 1136/2001 (56.8%) | 0.98 (0.93–1.04) | .48 | 0 | 0.98 (0.92–1.05) | High |
| Respiratory distress syndrome | 2 , | 145/1958 (7.4%) | 129/1969 (6.6%) | 1.13 (0.90–1.41) | .31 | 0 | 1.14 (0.85–1.53) | Moderate |
| Necrotizing enterocolitis | 2 , | 16/1958 (0.8%) | 13/1969 (0.7%) | 1.24 (0.60–2.57) | .56 | 0 | 1.28 (0.58–2.81) | Low |
| Intraventricular hemorrhage | 2 , | 26/1958 (1.3%) | 22/1969 (1.1%) | 1.19 (0.67–2.09) | .55 | 0 | 1.19 (0.62–2.31) | Moderate |
| Neonatal sepsis | 2 , | 85/1958 (4.3%) | 91/1969 (4.6%) | 0.94 (0.70–1.25) | .67 | 0 | 0.94 (0.67–1.32) | Moderate |
| Retinopathy of prematurity | 1 | 12/1147 (1.0%) | 3/1146 (0.3%) | 4.00 (1.13–14.12) | .03 | NA | 3.50 (0.73–16.77) | Low |
| Bronchopulmonary dysplasia | 1 | 2/811 (0.2%) | 9/823 (1.1%) | 0.23 (0.05–1.04) | .06 | NA | 0.17 (0.02–1.40) | Low |
| Periventricular leukomalacia | 1 | 0/811 (0.0%) | 5/823 (0.6%) | 0.09 (0.01–1.67) | .11 | NA | 0.11 (0.01–2.09) | Low |
| Any composite adverse neonatal/perinatal outcome | 2 , | 196/1958 (10.0%) | 192/1969 (9.8%) | 1.03 (0.85–1.24) | .79 | 0 | 1.03 (0.81–1.32) | Moderate |
| Admission to NICU | 2 , | 457/1987 (23.0%) | 466/2001 (23.3%) | 0.96 (0.77–1.18) | .67 | 60 | 0.98 (0.82–1.18) | Moderate |
| Mechanical ventilation | 1 | 114/1147 (9.9%) | 97/1146 (8.5%) | 1.17 (0.91–1.52) | .22 | NA | 1.16 (0.82–1.64) | Moderate |
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