[Abstract]
Background Preterm birth is the main cause of child death under 5years of age. The incidence of twin pregnancies is less than 2%, but the incidence of preterm delivery is 50% and the risk of neonatal death is 5 times higher in twin pregnancies than in singleton pregnancies. However, there is still no consensus on the effect of cervical pessary on preventing preterm delivery, prolonging the pregnancy cycle, and improving maternal and infant outcomes in patients with twin pregnancies.
Objectives To explore the effect of cervical pessary on the pregnancy outcome of unselected twin pregnancy patients.
Search Strategy Up to Jan 2022, researchers searched PubMed, EMBASE, COCHRANE, Web of Science, Wanfang, Weipu, and CNKI databases for research.
Study eligibility criteria Randomized controlled trials that compared cervical pessary with standard care (no pessary) or alternative interventions (conventional and standard treatment (e.g., Atoxiban therapy) or vaginal progesterone) in patients with twin pregnancies.
Study appraisal and synthesis methods.
Data Collection and Analysis Two authors independently extracted information related to the study characteristics and test results from each of the included literature, and used Revman 5.3 to analyze the data. Pooled relative risks with 95% confidence intervals were calculated. Cohrane collaborative tools were used to assess the risk of bias in individual studies.The main results were premature delivery at <34 weeks, preterm delivery <37 weeks, and abortion <28 weeks. Secondary results included spontaneous preterm delivery <34 weeks, spontaneous preterm delivery <34 weeks, spontaneous abortion <28 weeks, and preterm prelabour rupture of membranes <34 and preterm prelabour rupture of membranes, vaginal bleeding, chorioamnionitis, delivery week, vaginal infection, vaginal discharge, cesarean section, intrauterine death or stillbirth, neonatal death, low weight birth, very low weight birth, neonatal respiratory distress syndrome, neonatal intraventricular hemorrhage, necrotizing enterocolitis, retinopathy, sepsis.
Results The researchers included a total of 7 documents with a total of 3120 patients. Among them, 4 studies included pregnancy outcomes and neonatal outcomes for patients with cervix length <25mm, and 7 studies included pregnancy outcomes and neonatal outcomes for patients with cervix length <38mm. The results showed that cervical pessary increase the incidence of delivery week, vaginal discharge, and vaginal bleeding, which was statistically significant. For neonates, cervical pessary decreases the incidence of low-weight children, necrotizing enterocolitis and neonatal septicemia, which were statistically significant. Subgroup analysis results based on cervical length <38mm showed that cervical pessary could reduce the preterm birth rate before 34 weeks, the spontaneous preterm birth rate before 34 weeks, prolong the gestational week of delivery, reduce neonatal mortality, occurrence of neonatal necrotizing enterocolitis and neonatal sepsis. However, the incidence of events such as increased vaginal discharge and vaginal bleeding in the experimental group was significantly higher than that in the control group, and the results were statistically significant. The results of subgroup analysis based on the cervical length < 25mm showed that cervical pessary was better than the control group in reducing the preterm birth rate before 34 weeks, the spontaneous preterm birth rate before <34 weeks, and the incidence of low-birth-weight infants, and the results were statistically significant. Otherwise, the subgroup analysis based on merely Arabin cervical pessary prove merely Arabin cervical pessary has similar results.
Conclusion The cervical pessary can extend the gestational week of short-cervix twin pregnancy without clinical symptoms, reduce the premature birth rate before 34 weeks of gestation, improve pregnancy outcome, reduce neonatal mortality, reduce necrotizing enterocolitis incidence, neonatal sepsis incidence, and improve neonatal outcome. For patients with a cervical length less than 38mm, a cervical pessary can be performed to extend the gestational week. For patients with a cervical length less than 25mm, a cervical pessary can effectively prolong the gestational age and improve the maternal and fetal outcomes. The cervical pessary is safe for patients with twin pregnancies. Suggest that twin-preganct-patients with CL<38mm should consider take cervical pessary in advance. In terms of long-term efficacy, there is no evidence of cervical support placement on the long-term maternal prognosis. In terms of economic benefits, cervical support is better than vaginal progesterone, but this conclusion still needs more research to prove.
Keywords: cervical pessary; pregnancy outcome; fetal outcome; preterm birth;preterm delivery;
Introduction
Studies have shown that the mortality rate for children under 5 years of age in China is 37%, with the main cause of death being complications from premature birth, accounting for about 17% of all deaths[1].Surviving preterm infants are at greater risk for short-term complications, with higher rates of respiratory distress syndrome, bronchopulmonary dysplasia, necrotizing enterocolitis, sepsis, intraventricular hemorrhage, paraventricular leukodystrophy, and retinopathy than in term-born neonates[2,3].The incidence of twin pregnancies is less than 2%, but the incidence of preterm delivery is 50% and the risk of neonatal death is 5 times higher in twin pregnancies than in singleton pregnancies[4,5].Cervical insufficiency as a cause of spontaneous preterm delivery in patients with twin pregnancies[6].
Currently, the main therapeutic measures regarding the prevention of preterm delivery in patients with twin pregnancies are the vaginal progesterone, cervical cerclage and cervical pessary. In the Clinical Guidelines for the Management of Twin Pregnancies published in China in 2020, it is clearly stated that in asymptomatic patients with twin pregnancies with a short cervix, the use of progestins can effectively reduce the risk of preterm delivery before 35 weeks of gestation[7].As for cervical cerclage, for singleton patients, this treatment is currently considered effective in preventing preterm birth[8],but for patients with twin pregnancies, the efficacy of the treatment remains controversial[7,9].
Originally used to treat pelvic organ prolapse, cervical pessary placement has been used to prevent preterm birth since 1990. Currently, the Arabin uterine support is widely used in the treatment of spontaneous preterm labor. It is designed with the intention not only to support and compress, but also to tilt the cervix and possibly rotate it towards the sacrum, mainly by supporting the inner cervical opening and preventing it from being overburdened with gravity[10].Currently studies show that cervical pessary placement is effective in reducing the rate of preterm birth in patients with singleton pregnancies[11,12],while cervical pessary placement remains controversial in patients with twin pregnancies. A retrospective analysis in 2016 showed that cervical pessary placement reduced the rate of preterm delivery before 37 and 34 weeks of gestation in patients with twin pregnancies[13].In 2019, an RCT trial suggested that cervical pessary placement reduces preterm birth rates and improves pregnancy outcomes in patients with twin pregnancies[14],but There were RCT experiments and meta-analyses that came to the opposite conclusion[15-17].
No specific and effective treatment exists to prevent preterm birth in the 2014 ACOG guidelines for twin women[18]. In 2019, the Canadian Association of Obstetricians and Gynecologists (SOGC) still believed that, even in twin patients with a short cervix, there was still no evidence that cervical pessary could effectively prevent premature birth[9]. China updated its guidelines in 2020 and did not give clear recommendations on the use of cervical pessary to prevent premature birth in twin patients. However, Chinese guidelines clearly support that vaginal progesterone can reduce the preterm birth and neonatal prevalence before 35 weeks in pregnant women with asymptomatic ultrasound showing a short cervix[7]. As for cervical cerclage, as an invasive treatment, its efficacy varies due to its different timing and indications. In 2014, ACOG noted that existing data demonstrated that ring ligation actually significantly increased preterm birth rates in asymptomatic twin pregnancies with CL <25mm[18]. The SOGC guidelines also indicate that cerclage increases asymptomatic preterm rates in twin pregnancies with CL <25mm, arguing that without physical evidence of physical examination, taking cerclage merely indicated by ultrasound hints of cervical shortening or previous second trimester abortion history increases the risk of preterm pregnancy.
In conclusion, there is still no consensus on the effect of cervical pessary on preventing preterm delivery, prolonging the pregnancy cycle, and improving maternal and infant outcomes in patients with twin pregnancies. In this article, we present a meta-analysis of the effects of cervical pessary placement on pregnancy outcomes in patients with twin pregnancies and discuss the effectiveness of cervical pessary placement in improving adverse pregnancy outcomes and neonatal outcomes.
Materials and Methods
1.1 Literature Search
This study was conducted and reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement[19],and was registered with PROSPERO, number CRD42021275530.Two authors independently extracted all study data into a canonical form. When there is a difference of opinion, the two authors reach a consensus through negotiation.
Up to Jan 2022, researchers searched PubMed, EMBASE, COCHRANE, Web of Science, Wan fang, Wi Pu and CNKI databases, for example, in the PubMed database, they searched for ((((((((cervical) OR pessary) OR cervical pessary)) OR pessary[MeSH Terms])) AND ((((((prematurity) OR prematurity[MeSH Terms]) OR premature birth) OR premature birth[MeSH Terms]) OR Preterm delivery) OR Preterm delivery[MeSH Terms])) AND (((((Twin) OR pregnancy) OR Twin pregnancy[MeSH Terms]) OR Multiple pregnancy) OR Multiple pregnancy[MeSH Terms])) AND ((cervical length) OR short cervix). Investigators selected studies for inclusion that met the inclusion standards. Relevant publications were searched. Researchers also systematically reviewed the references of the literature included in the study. Clinical pregnancy outcomes and neonatal outcomes were collected in the cervical pessary group (experimental group) and the non-cervical pessary group (control group). Cervical cerclage was excluded at an early stage of the study for the following reasons: 1. Meta-analysis has been conducted in relevant studies[20] ; Cervical cerclage is more irritating to patients than cervical pessary, cervical pessary as a non-invasive means, combined with non-invasive conventional fetal preservation methods such as bed rest, atosiban, vaginal progesterone, etc., compared with conventional fetal care methods, lower heterogeneity, more reliable results.
Two reviewers reviewed each potential eligibility article separately, analyzed the quality of the studies according to the Corhrane scale, and extracted data. Two authors (W-Y and M-D)independently performed the original screening of all study titles and abstracts, excluding literature that was deemed irrelevant by both observers. The PRISMA flowchart provides more detailed information about the article selection process (picture 1: flowchart). The researchers recorded in detail the year of publication of the records, country, study type, number of participants, week of gestation and range of cervical length (CL) at the time of placement of the cervical pessary, and mode of treatment for both groups of patients (table 1: characteristics of the included studies).
1.2 Eligibility criteria
The purpose of the included study was to investigate the effect of cervical pessary placement on pregnancy outcomes in patients with twin pregnancies. The inclusion criteria were1. Patients with twin pregnancies who underwent gynecological trans-vaginal ultrasound after 16 weeks of gestation and underwent cervical pessary because of the short cervix. There were no special requirements for the mode of pregnancy (ART and non-ART), and medical history of patients with twin pregnancy), 2.Must be done for RCT studies, 3.The experimental group must be patients undergoing cervical pessary, which can be performed in combination with conventional and standard treatment (e.g.Atoxiban therapy) or vaginal progesterone, 4.The control group must be routine noninvasive treatment such as conventional therapy (such as atoxeban) or vaginal progesterone. The exclusion criteria were: 1. The patient underwent cervical cerclage at this pregnancy, 2. patients who needed to receive fetoscopy, 3. Exclusion abnormal fetal development, pregnancies of three and more fetuses, medically indicated preterm birth of medical origin (Twin-twin transfusion syndrome, severe preeclampsia, placenta abruption, placenta previa, prenatal bleeding); 4. non-RCT experiments.
1.3 Outcome measures and data item extraction
Two researchers extracted information related to the study characteristics and test results from each of the included literature. The main outcome was preterm delivery (ptd) before 34 weeks gestation, preterm delivery before 37 weeks, miscarriage a before 28 weeks(China officially defines miscarriage as occurring before 28 weeks’ gestation). Secondary outcomes included spontaneous preterm delivery(sptd) before 34 weeks, spontaneous preterm delivery before 37 weeks, spontaneous miscarriage before 28 weeks(SM), preterm prelabor rupture of membranes(PPROM),preterm prelabor rupture of membranes before 34 week, deliver week(DW),vaginal bleeding(VB),chorioamnionitis(C),vaginal infection(VI),vaginal discharge(VD),C-section, intrauterine death or stillbirth, neonatal death , low-birth weight (<2500g), very low birth weight (<1500g), Respiratory distress syndrome (RDS),Intraventricular hemorrhage(IVH),Necrotizing Enterocolitis (NE),Retinopathy (RE),Sepsis (S).
1.4 Risk assessment of bias
Cochrane collaborative tools were used to assess the risk of bias in individual studies,including: 1.selection bias; 2. implement bias; 3. detection bias; 4. attribution bias; 5. reporting bias; 6. Other bias (including measuring bias; sampling bias and follow-up bias) (See details in the table2:bias of included literature assessment table).The quality of evidence for primary and
secondary outcomes was assessed by 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 other 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 apossibility 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.
1.5 Data processing and analysis
Researchers used Revman 5.3 to analyze the data. It belonged to two categorical outcome variables and relative rate (RR) was used as the effect indicator. For the outcome index belonging to the continuous variables, the standards mean difference (SMD) was used as the effect indicator.95% confidence interval was calculated to evaluate the strength of the association between cervical pessary and the risk of adverse pregnancy-related outcomes. The RR values were calculated by the Z test. The P-value of <0.05 was defined as meaningful. Random-effects and fixed-effects models were applied in this meta-analysis. To assess inter-study heterogeneity, the Q test was applied to calculate I2. The I2values were defined as 25%, 50%, and 75%, representing low, moderate, and high heterogeneity, respectively. When high heterogeneity was observed, random-effects models were used to pool results, and a fixed-effect model. When the heterogeneity is too high, there should be further excluded clinical and methodological heterogeneity, and a random effect model is used for analysis. If there was evidence of statistical heterogeneity (I2>50%), it is necessary to explore the possible sources by using sensitivity and subgroup analyses to search for evidence of bias or methodological differences among trials. Researchers used the exclusion method article by piece exclusion literature method for sensitivity analysis. Differences in the elimination results and the original merger results were also assessed. Publication bias was visually judged by drawing funnel plots.
Results
2.1 Results of literature search
A total of 7 literature studies have included 3120 patients, and 4 studies containing <25mm for CL.For patient pregnancy and neonatal outcomes, seven studies included pregnancy and neonatal outcomes for patients with CL <38mm.
2.2 Primary and secondary outcome summary
2.2.1.A meta analysis was performed for all of the literature
First, we performed meta analyses on all included literature to compare the efficacy of cervical support in improving pregnancy outcomes with neonatal outcomes (see table3: Summary Results 1 ),It was found that the patients in the experimental group (cervical pessary group) had a longer deliver week (RR 6.82, P<0.00001), higher incidence of vaginal discharge (RR12.96 , P<0.00001) and vaginal bleeding (RR 5.34, P<0.0001) than in the control group, which was statistically significant. As neonates, in experimental groups, the incidence of low birth weight (RR 4.14, P<0.00001), NE (RR2.45, P=0.01) and neonatal septicemia (RR2.21, P=0.03) were significantly lower than control group, which were statistically significant. Compared DW, vaginal discharge, vaginal bleeding, low birth weight, S, remarkable heterogeneity could be seen. The sensitivity analysis was performed article by article, and the exclusion literature name and the p values after analysis are shown in the figure below. The funnel map suggests publication bias in part of the study.
2.2.2 Subgroup analysis was performed based on the CL
During the process of literature inclusion, the researchers found differences in the CL of the included patients, and to avoid the outcome bias caused by different CL, the subgroup analysis was performed.
Results of the subgroup analysis based on CL <38mm rows are shown in table 4. It can be seen that cervical pessary was better than the control group of preventing spontaneous premature delivery before 34 weeks(RR2.18, P=0.03) and premature delivery before 34 weeks (RR2.9, P=0.004), prolonged delivery week (RR6.31, P<0.00001), reducing neonatal mortality(RR2.47, P0.01), neonatal necrotic enterocolitis (RR3.52, P=0.0004) and neonatal sepsis(RR2.21, P=0.03).All the results were statistically significant. However, the incidence of increased vaginal discharge and vaginal bleeding in the cervical pessary group was significantly higher than in the control group. Some studies funnel plots suggest publication bias.
Results of the subgroup analysis based on the <25mm line of CL are shown in table 5.Due to insufficient data, comparisons were made only between premature delivery before 34 weeks (RR3.82, P=0.0001) , spontaneous premature delivery before 34 weeks (RR2.7, P=0.04), low weight birth (RR6.32 ,P<0.00001) and vary low weight birth (RR0.16, P0.87). Results showed that cervical pessary was better in reducing spontaneous preterm birth <34 weeks and preterm birth <34, decreased the born of lower weight infants, and the results were statistically significant. Some study funnel plots suggested publication bias.
2.2.3 Subgroup analysis was performed based on the type of cervical pessary.
Because of Bioteque cervical pessary in Berghella2017, which could cause performance bias, the result of subgroup analysis after excluding Berghella2017 show in table 6 that the patients in the experimental group (merely Arabin cervical pessary group) had a longer deliver week (RR6.82 P<0.00001), higher incidence of vaginal discharge (RR12.23, P<0.00001) , C-section (RR2.05, P=0.04), vaginal bleeding(RR 5.43, P<0.04),which was statistically significant. For neonates, In experimental groups, the incidences of low birth weight(RR 4.14, P<0.0001), NE(RR2.59, P=0.01) and S (RR2.61, P=0.009) were lower ,which was statistically significant. Remarkable heterogeneity could be seen. The sensitivity analysis was performed article by article, and the exclusion literature name and the p values after analysis are shown in the figure below. After sensitivity analysis, the ptd <34 weeks, DW, VD, PPROM, DE, low birth weight were statistically significant, and the P value of sptd <34 weeks and S changed, but were not statistically significant. The funnel map suggests publication bias in part of the study.
Results of the subgroup analysis based on CL <38mm rows are shown in table 7. It can be seen that Arabin cervical pessary was better than the control group of preventing ptd<34 (RR3.05, P=0.002) and sptd<34 (RR2.24, P=0.03),prolonged delivery week(RR2.24, P<0.03), increased VD (RR9, P<0.00001)and VB(RR5.34, P<0.00001), decreased incidence of PPROM (RR2.31, P<0.02),reducing neonatal mortality(RR6.02, P<0.006),the incidences of low birth weight(RR 4.14, P<0.00001), NE (RR3.68, P=0.0002), S(RR 2.61, P<0.009),which was statistically significant. Remarkable heterogeneity could be seen. The sensitivity analysis was performed article by article.Funnel plots show the publication bias in part of the studies.
Results of the subgroup analysis based on the CL<25mm are shown in table 8. Due to insufficient data, comparisons were made only between premature delivery before 34 weeks(RR3.82 ,P=0.001) , spontaneous premature delivery before 34 weeks(RR2.07, P=0.04), low weight birth (RR6.32, P<0.00001) and vary low weight birth (RR 0.16, P=0.87). Results showed that merely Arabin cervical pessary was better in reducing spontaneous preterm birth <34 weeks and preterm birth <34, decreased the born of lower weight infants, and the results were statistically significant. Some study funnel plots suggested publication bias. Remarkable heterogeneity could be seen. The sensitivity analysis was performed article by article, and the exclusion literature name and the p values after analysis are shown in the figure below. After sensitivity analysis, sptd<34 keep his statistically significant, but low birth weight was not.
2.3 Quality evaluation and bias evaluation
These literatures were assessed for the risk of bias (as table 2 and picture2). Considering the particularity of the study, that the patients in the experiment knew all about their intervention after participating in the experiment, the researchers default that patient’s blindness are low-risk, and only evaluate the blind method of the researchers and the results assessors. The high uncertain risk of Merced 2019,Norman 2021and Berghella 2017 are exposed as missing visits and bias burned when selected patients.Dang’s high uncertain risk is from missing visits,and it has uncertain selection bias and reporting bias. Berghella 2017 has high preform bias.The results of GRADE approach categorizing the certainty of the evidence are in table 3-8.During analysis,we found that the quality of evidences could be influenced by Berghella 2017 because of his bias from patients selection.besides,the bias from Merced 2019,Norman 2021 and Dang 2019 could influence the certificate evidence quality.All in all,the quality of evidences in table 3-5 is low.But after subgroup analysis, it is obvious that the quality of evidences has improved.