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
- 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.
- For patients with a cervical length less than 38mm, cervical pessary
can be performed to extend the gestational week.
- For patients with cervical length less than 25mm, cervical pessary can
effectively prolong the gestational age and improve the maternal and
fetal outcome.
- Cervical pessary is safe for patients with twin pregnancies.
- 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.
- 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 the conclusion still needs more research to prove.
- 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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Picture 1:flowchart