Discussion
3.1Main findings and interpretation
The results found that the efficacy of cervical pessary in twin patients suggested that cervical support prolonged the gestational week of twin patients and reduced the incidence of low weight birth, NE and the incidence of neonatal sepsis. In 2012, the CL <25 mm can be considered as short cervix by singleton guidelines published by American Obstetricians and Gynecologists (ACOG)[21].However, there were also studies using a CL of less than the 25th percentile (<38mm)[22,23].Therefore, the researchers used these two sets of digital row subgroup analysis, respectively. The results suggested that in twin patients with <38mm of CL, cervical pessary reduced preterm birth <34 weeks, decreased rate of spontaneous premature delivery <34 weeks, prolonged delivery week, reduced neonatal mortality, neonatal necrotizing enterocolitis, and neonatal sepsis; For patients with CL <25mm, although the data are insufficient, limited data still suggest that cervical pessary is better than conventional treatment in reducing preterm birth rate <34 weeks, spontaneous preterm birth <34 weeks, and reducing the incidence of low-weight infants. Although, increased vaginal secretions and higher vaginal bleeding rate were higher in the experimental group when <38mm of the CL was observed, there was no significant difference in the incidence of vaginitis and chorioamnionitis compared with the control groups. This shows that cervical pessary can effectively reduce the rate of preterm birth before 34 weeks in twin patients with CL less than 38mm, effectively prolong pregnancy week, reduce neonatal mortality, neonatal necrotizing enterocolitis and neonatal sepsis, and effectively improve adverse maternal pregnancy outcome.
Considering type of cervical pessary, merely Arabin cervical pessary prolonged the gestational week of twin patients and reduced the incidence of low weight birth, necrotizing enterocolitis and neonatal sepsis, but it also increased the incidences of vaginal discharge, C-section and vaginal bleeding without any changed of vaginal infection and chorioamnionitis. The results suggested that in twin patients with <38mm of CL, cervical pessary reduced preterm birth <34 weeks, spontaneous preterm delivery before 34 weeks and incidence of PPROM, prolonged delivery week, decreased neonatal mortality, neonatal necrotizing enterocolitis, and neonatal sepsis, but increased the incidences of VD and VB; For patients with CL <25mm, although the data are insufficient, limited data still suggest that cervical pessary is better than conventional treatment in reducing preterm birth rate <34 weeks, spontaneous preterm birth <34 weeks, and reducing the incidence of low-weight infants. Although, increased vaginal secretions and higher vaginal bleeding rate were higher in the experimental group. Importantly, while Arabin cervical pessary do increase vaginal discharge and vaginal bleeding rate, but there is no difference of vaginal infection and chorioamnionitis, which means cervical pessary is safe to twin-pregnancy women. Comparing our data, different CL seems to do not influence the effect of cervical pessary, especially on sptb<34 weeks, ptb<34weeks and low birth weight, but patients with CL <38mm have great effect and less side effect. The effect of cervical pessary in CL<25 mm is still need more research.The results of the subgroup analysis were significantly improved after excluding Berghella 2017, and the level of evidence was also significantly increased, which proved that the subgroup analysis was effective.
3.2 Sensitivity analysis
During the course of the sensitivity analysis, the researchers found the phenomena of altered P values after the sensitivity analysis. After analyzing the sources of heterogeneity one by one, the researchers thought that the reasons for the heterogeneity were: 1. The data gap is too large; 2. There is a publication bias. 3.Existing bias in 7 research, particularly Berghella 2017.4. There are other potential unmeasured confounders. Researchers found several factors could cause confounders such as cervical surgery history, miscarriage history, difference race, the time of pregnancy or delivery, ART history, time of placing or removing cervical pessary, vaginal progesterone. Particularly, vaginal progesterone has been proven to prevent preterm birth. It is possible to cover the effect of cervical pessary. Otherwise, combined treatment of cervical pessary plus vaginal progesterone is uncertain. One retrospective cohort study of twin pregnancies draws a conclusion that cervical pessary combined with vaginal progesterone could prolonged pregnancy and reduce risk of adverse neonatal outcomes[24]. In 2020, a retrospective study of 57 patients with (dichorionic diamniotic twin (DCDA) showed that a cervical pessary combined with vaginal progesterone reduced the rate of preterm birth in patients [25]. There is one study showed that cervical pessary combined with vaginal progesterone could prolonged pregnancy, reduce prematurity rate and a low rate of perinatal complications[26]. However, a meta-analysis[27] and a RCT [28]in 2016 showed that combined treatment did not decrease the risk of preterm birth compared with cervical pessary in singletons with short CL. Therefore, it is not sure if vaginal progesterone could enhance or weaken the influence of cervical pessary to twin pregnancy. More clinical trials are needed to prove the efficiency of combined treatment. As for Berghella 2017, it was published as a small RCT research[29]. In stand of Arabin cervical pessary, Berghella choosed Bioteque cup cervical pessary included 46 women. After subgroup based on type of cervical pessary, comparing data, all the difference seems to indicate that the different type of cervical pessary had similar effects .However, Kyvernitakis believes that there are differences in the appearance of Bioteque and Arabin, and these may have different effects[30].
3.3 Current research
Twin gestations are different from singleton patients, because of their excessive uterine enlargement, intrauterine pressure increases too much, beyond the limit that the cervix can bear, easy to lead to cervical insufficiency, and then cause premature birth.
For twin patients, cervical pessary is still controversial. Leim2013 was the first to study the treatment effect of cervical support in twin pregnancy patients through RCT experiments, and proposed that cervical uterine care could not effectively prevent adverse perinatal outcome or premature birth in multiple pregnant women, but its subgroup analysis proved that cervical pessary of the cervix in twin patients can reduce adverse perinatal outcome of <38mmm[31].This provided later researchers with ideas to study the relationship between different cervical length and the efficiency of cervical pessary. In 2016, a retrospective analysis revealed that cervical pessary placement reduced the rate of preterm delivery that occurred before 36 and 34 weeks[13]. A network meta-analysis published in 2021 suggested that cervical pessary, progesterone and cerclage do not show a significant effect in reducing the rate of PTB or perinatal morbidity in twins[20].
Contradictory findings also exist in the RCT study. A RCT experiment published by Goya in 2015 for the first time that cervical pessary reduced the rate of preterm delivery by 34 weeks in twin patients with a CL <25mm[16].However, In 2016, Kypros believes that cervical pessary does not reduce the preterm rate in twin patients with cervical insufficiency[15]. In 2017, by comparing treated patients with cervical pessary, cervical cerclage and vaginal progesterone, a meta analysis proposed that only vaginal progesterone extended the gestational week, but not statistical significance[32]. In 2019, an RCT experiment proposed that cervical pessary reduced the rate of preterm birth and improved pregnancy outcomes in patients with twin gestation [14]. The latest meta analysis in 2020 does not support the use of cervical pessary to prevent premature birth or improve perinatal outcomes in twin short cervix and unselected twin pregnancies[17]. It can not deny that it[17] is inspired to singletons. However, this paper studied high-risk pregnant women, not twin pregnant women alone, and it included only two studies about twin pregnancy, the data are so grossly insufficient that leads to a bias in their findings. About Xiong YQ [33], I have read this document when I collected the literature, and it has some guiding significance for this research. However, the differences between this article and this paper are as follows 1.The control group differs,our study excluded patients with cervical cerclage, and Yi-Quan Xiong did not. 2. We contain 7 studies and 4 in Xiong . 3. In Xiong’s study, no subgroup analysis was performed based on cervical length, which may lead to biased results.
3.4 Long-term effects of cervical pessary
In terms of the long-term effects of cervical pessary, only Noor E [34]followed up participants for up to four years based on the Leim study. The results showed that the intervention group (CL<38mm), but no difference in abnormal growth and development outcomes between the two groups. Van published his RCT research which evaluated the effect of a cervical pessary on the outcome of subsequent pregnancies and maternal quality of life four years after twin pregnancy among 408 women [35].The results showed that no long term effects of pessary use on the outcome of subsequent pregnancies and maternal quality of life. However, there were a large number of missed visits in the study, so at present, there is still insufficient data to prove that cervical care can lead to long-term adverse outcomes in mothers.
3.5 Efficacy and economic benefits of cervical pessary
In 2014, Leim concluded that the cost of treatment in the cervical pessary group was comparable to that of the control group when comparing costs alone. However, when the cervical length was less than 38 mm, the placement of a cervical pessary not only prolonged the gestational cycle and reduced adverse neonatal outcomes, but also, was less costly than in the control group [36]。In 2020, one study[37] has proposed that after comparing the efficacy and economic benefits of cervical pessary with vaginal progesterone, cervical care improved adverse pregnancy outcomes and reduced costs.The connection between pessary and his economic effect still requires sufficient data support.
3.6 Strengths and limitations
7 RCT studies were included with a total of 3120 patients who performed a subgroup analysis based on different CL and type of cervical pessary. The results proved that cervical pessary could prolong the delivery weeks. Particularly, it effectively reduces the preterm birth rate of twins before 34 weeks for patients with CL less than 38mm, effectively prolong gestational week, reduce neonatal mortality, neonatal necrotic enterocolitis, and neonatal sepsis, and effectively improve the adverse pregnancy outcome.
There are shortcomings in this research. First, even if more than 3,000 patients were included, the results were still affected by insufficient sample size and uneven sample distribution, resulting in altered results after sensitivity analysis. Second, only one of the seven studies included was about the efficacy comparison of cervical pessary placement and vaginal progesterone, which brought some bias to our study. At the same time, the researchers regretted that the inability to compare the treatment effect of cervical pessary with vaginal progesterone to prevent premature birth in twin patients had failed. Furthermore, only one study included was from Asia, and researchers similarly regret the inability to perform a race-based subgroup analysis. Otherwise, The subjects were unselected twin pregnancies and had no clear requirements for the mode of pregnancy (ART or non-ART) , choriogenin, medical history (with a history of miscarriage, delivery and cervical surgery), which may bias the results. For this part of the patients, additional attention is needed. Alternatively, timing differences in the inclusion literature exist to the current lack of uniform guidelines. It is seen that most of the pessary were placed between 16 – 24 weeks, but Merced was at 24 – 34 weeks. Norman choose patients with CL < 35mm. Those reasons for this difference is selection bias due to the different subjects selected each study.
3.7 Implications for practice and research
Despite the multiple regrets, our approach is scientific, and the results are valid. This paper reverses the conclusion proposed in the previous meta-analysis and guidelines that ”cervical pessary cannot effectively prolong gestational weeks and prevent preterm birth in twin pregnancies” and proves the effectiveness of cervical trust placement in patients with twin pregnancies.
Conclusion
  1. 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 neonatal enterocolitis incidence, neonatal sepsis incidence, and improve neonatal outcome.
  2. For patients with a cervical length less than 38mm, cervical pessary can be performed to extend the gestational week.
  3. For patients with cervical length less than 25mm, cervical pessary can effectively prolong the gestational age and improve the maternal and fetal outcome.
  4. Cervical pessary is safe for patients with twin pregnancies.
  5. Although, different CL seems to do not affect the effect of cervical pessary, especially on sptb<34 weeks, ptb<34 weeks and low birth weight, but patients with CL <38mm have great effect and less side effect, so we suggest that twin-pregant-patients with CL<38mm should consider take cervical pessary in advance. Patients with CL<25mm could take cervical pessary in order to prevent preterm birth before 34 weeks, but side effect of cervical pessary to patients with CL<25 mm is still need more research.
  6. In terms of long-term efficacy, there is no evidence of cervical support placement on the long-term maternal prognosis.
  7. In terms of economic benefits, cervical support is better than vaginal progesterone, but the conclusion still needs more research to prove.
  8. The influence from different type of cervical pessary needs more attention.
Acknowledgments
We are grateful to Mr.Wu, Mrs.Ma and Mrs Huang for their contribution to this article on data collecting,writing,and polishing this study.Mrs Wang approved this project and participated in all parts. Mrs Ma and Mrs Huang were helped in data collecting. Mr Wu polished this paper and provided several precious advises about data analysis.Mrs Huang recheck this paper at last. This study is not sponsored by any individuals or organizations,and there are no conflicts of interest or ethical challenges.
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