Patient's experience with the Arabin cervical pessary during pregnancy: A questionnaire survey.

INTRODUCTION: The cervical pessary is used in women with precocious cervical ripening to prevent preterm birth. Up to now however, there have been no systematic studies on compliance and tolerance, which vary among different study cohorts.
MATERIAL AND METHODS: A questionnaire was administered to 166 women treated with the Arabin cervical pessary in one center. Data were analysed about the patient's experience before insertion (adequacy of information received), during treatment (follow-up, impact on daily life, perceived discomfort, side effects) and at the time of removal (pain, if the patient's expectations had been met regarding the treatment).
RESULTS: Information received before the insertion of the Arabin cervical pessary was considered adequate in 163/166 (98.2%) women. An increase in vaginal discharge was experienced by 70/166 (42.2%) women. Discomfort or other side effects were reported in 13.8% and 16.3% of cases, respectively. Overall, 77% of women reported an improved quality of life and 94% considered the follow-up during pregnancy adequate. Removal was moderately painful for 58/166 (35%) of women. Patient's expectations regarding the treatment were exceeded in the majority of cases (75.3%). In a final step, we compared our results to previous studies regarding the use of the pessary in singleton and twin pregnancies.
CONCLUSION: Although some trials report high rates of non-compliant patients, this could not be confirmed by our study. In contrast, most women reported having a positive experience and that they were motivated to continue the treatment when they were continuously followed by experienced clinicians.

Introduction

Globally, preterm birth was reported to have an incidence of 10.6% in 2014 [1], with a wide variation among continents and countries in terms of absolute numbers and rates of preterm births, and in absolute and relative numbers of perinatal and neonatal deaths [2]. Even within Europe, preterm birth rates ranged from 4.9% in Lithuania to 11.2% in Greece in 2015 [3].

Primary prevention of preterm birth would be desirable, but this demands the involvement of publicly funded and supported health policies without immediate benefits, such as smoke-free legislation [3], prevention of teenage pregnancies [4], promotion of healthy diets [5], or possibly the use of medications such as aspirin [6] or omega-3-fatty acids [7-9].

In contrast, secondary prevention of preterm birth describes treatment concepts when the first signs are already recognizable but expected to be reversable. Thereby, a short cervical length (CL) measured by transvaginal sonography is one of the earliest signs, and sonographic assessment of CL is therefore recommended to be applied in high-risk patients or even for screening of the general population [10]. Cervical cerclage, vaginal progesterone and a cervical pessary specially designed to prevent preterm birth are options that are discussed at present for secondary prevention in singleton and twin pregnancies. The question of which method should be chosen does not solely depend on the methods themselves but also whether these pregnant women are followed within dedicated preterm birth clinics by experienced clinicians. Di Renzo et al. in 2017 already recognized the need for clinical training regarding the application of cerclage and cerclage pessaries within the European guidelines for Preterm Birth [11]. However, an adequate practical training is neither described nor audited in many observational or randomized controlled trials.

During the past decade, the cervical pessary has been investigated in different settings in both singleton [12-17] and twin pregnancies [18-24]. It promotes an inclination of the uterocervical angle as visualized by MRI or clinically [25, 26]. This mechanism is supposed to reduce the pressure on the lower uterine segment at the level of the internal cervical os and the cervix as studied in vivo by a change in maternal position [27, 28], or in vitro by biomechanical engineering [29].

It has been suggested that clinical success also requires experience following a learning curve [30]. Appropriate training of physicians in pessary placement could help to reduce a patient’s discomfort during pessary insertion. Up to now, there have been incidental reports on the side effects of the cervical pessary, but women’s views and satisfaction rates have not yet been systematically investigated apart from the rates of early removal or discharge within randomized controlled trials (RCTs) [12–16, 18–22].

The discrepant rates of complaints, early removal, and success in preventing preterm birth within both singleton and twin pregnancies motivated us to investigate women’s experience with the cervical pessary within our own cohort over 10 years and to compare the results with publications where the consideration of a learning curve was not an issue.

Material and methods

At Careggi University Hospital in Florence, Italy, a total of 205 women were treated with the Arabin cervical pessary for prevention of preterm birth from June 2010 to June 2020. The treatment was performed by three clinicians who had received proper training. The average treatment per physician was 68.3 insertions in this series, with individual differences. For the two younger physicians, the first 30 applications of the device were supervised by the senior physician who had already had experience with pessary placement. Based on our hospital protocol, the cervical pessary was offered to women with a CL ≤25 mm before 26 weeks of gestation, with intact membranes. After the insertion of a cervical pessary there was a first follow-up vaginal exam after 48 hours to verify whether the pessary was still surrounding the cervix and had not been displaced, and then follow-up visits were performed by the same clinicians every 2–3 weeks. Only in the case of patients with an extremely short cervical length (<10 mm), an additional transvaginal ultrasound examination after one week was performed to exclude rapid progress of cervical shortening. As an additional treatment, vaginal progesterone was administered to all patients.

Retrospectively, the hospital’s electronic database was used to contact the total cohort. 34/205 women (16.6%) could not be contacted because they had changed their contact details and therefore they were not included in the study, while 5/205 (2%) refused to participate. The remaining 166 women were contacted by phone and gave verbal consent to the study. They were administered a questionnaire inquiring about their experience before the insertion (adequacy of the information received), during treatment (follow-up, impact on daily life, perceived discomfort and other side effects) and at the time of removal (presence of pain, degree to which the patient’s expectation about the treatment had been met). The questionnaire is available as (S1 File). Numerical rating scales (NRS) from 0 to 10 were used for vaginal discharge and pain. The pain-intensity level was assigned as follows: NRS: 0 = no pain, 1–3 = mild pain, 4–6 = moderate pain, and 7–10 = severe pain [31]. This study was approved by the Institutional Ethics Committee (Comitato Etico Regionale per la Sperimentazione Clinica della Regione Toscana; approval number: 18058). Because the study consisted of telephone interviews, the Ethics Committee, complying with our Institution’s guidelines, waived the requirement for written consent.

The total cohort and specific subgroups were analysed. In particular, we compared the answers given by Italian women compared to those of foreign nationality, and between women who delivered either before or after 34 weeks, because this more or less defines the success of the treatment, and an earlier delivery might have had an impact on the patient’s reported experience or expectations.

Statistical analysis was performed with Graph Pad INSTAT3 software package (San Diego, CA, USA). Continuous variables were expressed as mean and standard deviation; categorical variables were indicated by percentage. We used the chi-square test to compare the answers between the subgroups. A p-value of < 0.05 was considered significant.

Results

The characteristics of the study cohort of 166 patients that answered the questionnaire are demonstrated in Table 1.

Table 1

Mean characteristics of the study group of 166 women treated with the cervical pessary during an observation period of 10 years.

Characteristics	Mean ± SD
Age (years)	34.6 ± 5.3
Body mass index (kg/m2)	22.3 ± 3.6
	N. (%)
Ethnicity
White	152 (91.6%)
Asian	9 (5.4%)
Black	5 (3.0%)
Nulliparous	97 (58.4%)
Parous	69 (41.6%)
History of preterm birth	23 (13.9%)
Singleton pregnancy	118 (71%)
Multiple pregnancy:	48 (28.9%)
Twin pregnancies	43 (25.9%)
Triplet pregnancies	5 (3.0%)
Spontaneous preterm birth <34 weeks in the index pregnancy:	46/166 (27.7%)
Singleton pregnancies	26/118 (22.0%)
Twin pregnancies	16/43 (37.2%)
Triplet pregnancies	4/5 (80.0%)
pPROM with pessary in situ	19/166 (11.4%)
Singleton pregnancies	14/118 (11.9%)
Twin pregnancies	3/43 (7.0%)
Triplet pregnancies	2/5 (40.0%)

Table 2 summarizes the answers given by the patients. Information received before the insertion of the Arabin pessary was considered adequate in 163/166 cases (98.2%). An increase of vaginal discharge (mean NRS score 5.3), a side effect that is also indicated in the instructions, was experienced by 70/166 (42.2%) women. Discomfort or any other side effects were reported in a minority of cases (13.8% and 16.3%, respectively). Most women (128/166) reported an improved quality of life (77.1%) and even more (94.0%) considered the follow-up, always by the same physician, adequate (Table 2). Removal was moderately painful for 58/166 women (35%), with a mean NRS score of 6.7 ± 2.1. Patient’s expectations of treatment outcome were exceeded in the majority of cases (75.3%) and almost all patients (91.6%) reported that they would choose the pessary treatment again or recommend it to a friend in a similar situation (Table 2).

Table 2

Results of the questionnaire investigating maternal views and experiences before, during and after treatment with cervical pessary (n = 166).

Related issues	Possible answers
	n (%)
Adequate information before insertion	Yes	No
	163 (98.2%)	3 (1.8%)
Information received before insertion regarding possible increase in vaginal discharge	Yes	No
	128 (77.1%)	38 (22.9%)
Increased vaginal discharge during the treatment	Yes	No
	70 (42.2%)	96 (57.8%)
NRS (Mean ± SD)	5.3 ± 2.7
Any other side effects during the treatment	Yes	No
	27 (16.3%)	139 (83.7%)
Change in daily life during the treatment	Yes, positive	Yes, negative	No
	128 (77.1%)	11 (6.6%)	27 (16.3%)
Discomfort during the treatment	Yes	No
	23 (13.9%)	143 (86.1%)
Adequate follow-up	Yes	No	No response
	156 (94.0%)	4 (2.4%)	6 (3.6%)
Expectations regarding the treatment	Better than I expected	Worse than I expected	As I expected
	125 (75.3%)	17 (10.2%)	24 (14.5%)
Pain at removal	Yes	No
NRS (Mean ± SD)	58 (34.9%)	108 (65.1%)
	6.7 ± 2.1
In a similar situation would you chose the pessary treatment again or recommend it to a friend?	Yes	No
	152 (91.6%)	14 (8.4%)

NRS, numerical rating scale.

Our study population included 118 Italian and 48 foreign women. There were no significant differences in the answers given between the two subgroups, including side effects (p = 0.49), perceived adequacy of the information (p = 0.56) and of the follow-up received (p = 0.33). Among singleton pregnancies, 26/118 (22%) had a spontaneous preterm birth before 34 weeks, while 92/118 (78%) delivered after 34 weeks. 16/43 twin pregnancies (37%) and 4/5 triplet pregnancies (80%) delivered before 34 weeks secondary to spontaneous preterm labor. 3/166 patients (2%) underwent an iatrogenic preterm birth (two for vaginal bleeding in placenta previa, one for HELLP syndrome). One patient (0.6%) required early removal of the pessary due to discomfort. In general, women who delivered later (≥ 34 weeks) more frequently reported an improvement in their daily life, a better than expected experience, and a wish to re-use the device compared to women who delivered before 34 weeks (Table 3).

Table 3

Results of the subjective experience stratified for gestational age at delivery (before or after 34 weeks of gestation).

	< 34 weeks	≥ 34 weeks	p-value*
	50	116
	n (%)	n (%)
Adequate information before insertion	47 (94.0%)	116 (100.0%)	0.03
Information received before insertion regarding possible vaginal discharge	37 (74.0%)	91 (78.4%)	0.56
Increased vaginal discharge during the treatment	16 (32.0%)	54 (46.6%)	0.09
Any other side effects during the treatment	10 (20.0%)	17 (14.7%)	0.49
Positive changes in daily life during the treatment	29 (58.0%)	99 (85.3%)	0.007
Discomfort during the treatment	6 (12.0%)	17 (14.7%)	0.81
Adequate follow up	43 (86.0%)	113 (97.4%)	0.07
Experience was better than expected	25 (50.0%)	100 (86.2%)	< 0.001
Pain at removal	13 (26.0%)	45 (38.8%)	0.16
Would re-use Arabin pessary	38 (76.0%)	114 (98.3%)	<0.001

* chi square test.

Finally, we compared our results with respect to the side effects and clinical experience with details reported in studies on the use of the cervical pessary for prevention of preterm birth. We identified one retrospective study and ten RCTs that reported the rates of side effects such as vaginal discharge, discomfort, and pain. The results are demonstrated in Table 4 (studies on singletons) and Table 5 (studies on twins). Although two studies [12, 15] did not report data on training, we have observed a low rate (0–5%) of early removal due to pain or discomfort in studies on singleton pregnancies, including our own, where physicians have received practical training [13, 14, 16] (Table 4). The rate of early removal due to pain or discomfort was higher in the study on twin pregnancies by Norman et al. (11%) [21], where training was provided only by video or on a model. The incidence of vaginal discharge, the most frequent side effect of pessary described by patients (42% in our cohort), is highly variable among the studies (from 14 to 100% in singletons, and from 18 to 100% in twin pregnancies, Tables 4 and 5). Most studies [13–15, 17, 18, 20], including our own, specify that the side effect was an increase in vaginal discharge during treatment compared to before pessary placement (Tables 4 and 5). On the other hand, in three studies [12, 16, 22] reporting a 70–100% vaginal discharge rate during treatment, the authors do not specify if the discharge increased after the pessary was placed, but they only described a significantly higher rate of this symptom among patients with cervical pessary compared to controls.

Table 4

Comparison between studies on pessary use in singleton gestations in terms of side effects, experience and training of clinicians, and clinical results.

	Our study	Goya et al.	Hui et al.	Saccone et al.	Nicolaides et al.	Dugoff et al.	Ivandic et al.
		2012 [12]	2013 [15]	2017 [13]	2016 [14]	2018 [16]	2020 [17]
Investigated device	Arabin pessary	Arabin pessary	Arabin pessary	Arabin pessary	Arabin pessary	Bioteque cup pessaries	Arabin pessary
Number of subjects with pessary placed (n)	118	190	53	150	460	60	129
Teaching/ Audit details	Yes	Not specified	Not specified	Yes	Yes	Yes	Patients managed by preterm labor team.
	The treatment was performed by three clinicians who had received practical training in the placement of the device.			The physicians had received practical training in the placement of the device. Pessary insertion training consisted of a didactic session and a hands-on session.	The research-team members who inserted the pessaries had received practical training in the placement of the device.	In addition to didactic and hands-on training, all staff was required to demonstrate competence in pessary placement on a live model.
Vaginal discharge	51.7% (increased during treatment)	100%	47.2%	86.7%	10.5%	73.3%	14.0% (increased during treatment)
			(increased during treatment)	(increased during treatment)	(increased during treatment)
Early removal due to discomfort/pain	0.8%	<1%	0	0	5.4%	3%	5.1%
Discomfort during treatment	16.1%	Mean pain score: 4 (scale 0–10) during pessary insertion	7.5% pressure sensations	3.3%	11.4%	1.7% removal for discomfort during sexual intercourse	7.0%
			1.9% vaginal pain
Pain during removal (mean score on a 0–10 scale)	7.0	7	Not specified	Not specified	Not specified	Not specified	Painful in 28%
Clinical results	Incidence of PTB<34w: 22%	Cervical pessary associated with significant reduction of PTB < 34w and neonatal composite adverse outcomes in singleton pregnancies with CL ≤25 mm	Cervical pessary not associated with reduction of PTB <34 w in singleton pregnancies with CL<25 mm	Cervical pessary associated with significant reduction of PTB < 34w in asymptomatic singleton pregnancies with CL ≤25 mm	Cervical pessary not associated with reduction of PTB <34 w in singleton pregnancies with CL<25 mm	Cervical pessary not associated with reduction of PTB in singleton pregnancies with short CL<25mm	Incidence of PTB<34w: 28.7%

PTB, preterm birth. CL, cervical length.

Table 5

Comparison between studies on pessary use in twin gestations in terms of side effects, experience and training of clinicians, and clinical results.

	Our study	Goya et al.	Dang et al.	Liem et al.	Nicolaides et al.	Norman et al.
		2016 [19]	2019 [22]	2013 [18]	2016 [20]	2021 [21]
Investigated device	Arabin pessary	Arabin pessary	Arabin pessary	Arabin pessary	Arabin pessary	Arabin pessary
Number of subjects with pessary placed (n)	48	68	148	401	588	250
Teaching/ Audit details	Yes	Yes	Yes	No	No	Yes (by video)
	The treatment was performed by three clinicians who had received practical training in the placement of the device.	The central team in turn instructed the other centers in the use of the pessary	Well-trained staff involved in pessary treatment	No specific training was provided	Many research team doctors were involved in the insertion of the pessary and they did not receive supervised training in doing so	Inserting obstetricians watched a training video on pessary insertion, were provided with written guidance on pessary management, and (at their discretion) practiced pessary insertion on a model prior to first insertion
Vaginal discharge	18.7% (increased during treatment)	100%	70%	26% (increased during treatment)	42.1% (increased during treatment)	Not specified
Early removal due to discomfort/pain	0	Not specified	Not specified	5.7%	5%	11.3%
Discomfort during treatment	8.3%	Mean pain score: 4 (scale 0–10) during pessary insertion	Discomfort (17%)	4%	5.8%	11.3% (32.5% discomfort or pain during insertion)
			Pain 4%
Pain during removal (mean score on a 0–10 scale)	5.7	7	Not specified	Not specified	Not specified	Uncomfortable in 41.3%
Clinical results	Incidence of PTB<34w: 37%	Cervical pessary associated with significant reduction of PTB < 34w in twin pregnancies with short CL ≤25 mm	Cervical pessary associated with reduction of PTB < 34w and improved composite poor perinatal outcome in twin pregnancies with CL <28 mm	Cervical pessary associated with reduction of composite poor perinatal outcome in pregnancies with a CL< 38 mm between 16 and 20 w	Cervical pessary not associated with reduction of PTB <34w in unselected twin pregnancies.	Cervical pessary not associated with reduction of PTB <34w nor composite adverse neonatal outcome in twin pregnancies with CL ≤35 mm

PTB, preterm birth. CL, cervical length.

Discussion

One of the main findings of this study was that apart from vaginal discharge no significant discomfort or side effects were experienced by the vast majority of patients. Moreover, the level of patient satisfaction was high and only one patient required early removal due to discomfort.

In contrast to the PECEP trial [12, 19], in which all the women treated with a cervical pessary had vaginal discharge, this symptom was only present in about 50% of our patients. Other clinical trials report an increase in vaginal discharge in women with pessary treatment compared to women without a pessary in pregnancy, with a highly variable rate reported in the pessary group, depending on the study: from 10.5 in Nicolaides et al. [14] to 73.3% in Dugoff et al. [16] and 86.7% in Saccone et al. [13]. On the other hand, pelvic discomfort is less frequently reported. The lower incidence of vaginal discharge (14%) among women with a pessary reported in the study by Ivandic et al. [17] compared to most RCTs may be explained by the retrospective nature of the study (taking part in a clinical trial may undermine patient confidence in the treatment, resulting in more dissatisfaction or anxiety regarding the treatment) and by the fact that they reported the occurrence of “significant” vaginal discharge.

Since increased vaginal discharge is the most common side effect of pessary treatment in most studies, the patient should be advised of this before the pessary is positioned. As our study shows, 77.1% of women reported that they had received adequate, comprehensive information about the possibility of vaginal discharge. Communication is an essential part of the treatment, as accurate counselling can be helpful in increasing patient’s compliance and satisfaction regarding the treatment.

In order to prevent the accumulation of vaginal fluids, we encourage the use of Arabin cervical pessaries which are characterized by perforations in the silicone ring that favour the release of vaginal discharge [23]. It is important to keep in mind that vaginal discharge due to the Arabin pessary is not a sign of infection and should not be treated with antibiotics, unless there is evidence of infection based on positive vaginal cultures.

Encouraging data in relation to the impact of the treatment on a patient’s daily life has emerged from our study. The fact that the majority of patients have reported positive changes in their lives during treatment may be in part related to the decreased concern about the risk of preterm birth. In addition, the presence of the pessary supporting the cervix may give relief of pressure sensations while walking or standing in some patients [26].

Patients of foreign nationality did not report a different experience with the treatment, or a different perception of the assistance and information received compared to Italian patients, while women who delivered before 34 weeks reported adequacy of the information received, positive changes in their daily life, a sense of satisfaction and consideration of a possible reuse of the device with a lower frequency compared to women who delivered after 34 weeks. This could be explained by the fact that childbirth occurred at low gestational ages and, consequently, in some women a negative experience related to the prematurity of their child may also have had an impact on the reported experience with the pessary.

This is the first study which has focused on the maternal experience regarding pessary treatment. A strength of this study is that all the women included in the study were assisted by operators who had been trained in proper pessary placement. This study also has limitations, which include the retrospective design, the absence of a control group and the fact that a pilot test to validate the questionnaire was not conducted. Moreover, we acknowledge that our study may be limited by recall bias, as the participants were asked to answer questions about past experiences and outcomes. Therefore, the accuracy of the answers provided may be less reliable when compared to data collected prospectively during research trials. To reduce recall bias, we used a carefully compiled questionnaire, with very specific questions, in order to maximize accuracy and completeness.

Conclusions

Although some randomized trials report high rates of non-compliant patients, this could not be confirmed by our data. In contrast, most women treated with the Arabin pessary for prevention of preterm birth reported a positive experience, and the main side effect was an increase in vaginal discharge. Women were motivated to continue with the treatment when they were continuously followed by experienced clinicians.

Questionnaire administered to the study population.

(DOCX)

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(SAV)

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7 Oct 2021

PONE-D-21-15296Patient’s experience with Arabin cervical pessary during pregnancy: a questionnaire surveyPLOS ONE

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Reviewer #1: Overall you have provided a reasonable summary of patient experience of treatment with Arabin pessary over a 10 year period from a single centre. However the authors make the assumption that clinical experience of healthcare specialists explains the difference in previously reported prospectively collected RCT results. The manuscript does not provide sufficient evidence to support this statement. Please revise.

To strengthen this manuscript more information about the clinical protocol, clinical outcomes and alternative therapies would be useful.

Minor comments:

Line 44: You have included ‘policies to reduce physical stress’ from your list of evidence-based supported healthcare programmes and used a reference from 1985 in support. There has since been plenty of evidence that physical stress / exercise in pregnancy reduces rates of preterm birth. Please justify/clarify this statement, provide additional evidence or consider removing ‘policies to reduce physical stress’ from your list of evidence-based supported healthcare programmes.

Line 63: Formatting of references changes for 27, please amend.

Line 55 suggest use of word ‘recognised’ instead of ‘demanded’. i.e. ‘Di Renzo et al. in 2017 recognised the need for clinical training for the insertion of cerclage and cerclage pessaries’

Line 77: please use a unit of measurement for 68.3 (? Insertions)

Line 78: what do you mean by second control after 48 hours? Please clarify.

Line 79: please provide a definition for extremely short cervical length? (i.e. <15mm, <5mm)

Line 80: When was an additional TVU performed – immediately, one week later?

Line 82: How did you know that 34 women had changed address? Please clarify how you contacted them and who contacted them before the questionnaire was sent out (i.e. their clinical team or a research team).

In table 4 please justify why you have not included Hui 2003, Daskalakis 2013 and Cabrera Garcia 2015.

In table 4 please explain what is meant by “extensive training” – column one.

Table 4 is difficult to read and not all the details are necessary – please could you make more concise – particularly the section on clinical results. Consider additional rows to compare information on cervical length and gestation for inclusion/insertion then include rates of sPTB.

Major comments

Methods: Please make the management protocol of these women clear. How were these women screened for treatment? Did they have follow up with the same individuals? How many times were they seen in their pregnancy? Was TVU was performed after the pessary was placed? Did the management protocol change over the 10 year period, and if so, how?

You make the point in your introduction that the clinical success with Arabin pessary follows a learning curve – which ‘has been completely neglected’ and experienced clinicians improve the satisfaction rate. This point is also reiterated in your abstract results “In a final step, we compared our results to previous studies suggesting that clinical experience of the health care specialists in charge may explain why the discrepancy of results”. How much experience prior to 2010 did your clinicians have with insertion of pessaries? If you provided a questionnaire to all the women included in this case series you may expect to see an improvement with satisfaction over time from 2010 to 2020, otherwise you fail to provide evidence for the need for experienced clinicians, unless they were highly experienced before 2010, however Arabin pessaries were not widely used. Please clarify how these three clinicians obtained their experience prior to 2010, and how is this different to the RCT training?

It would be useful to include data showing the number of pessaries inserted per year and relative satisfaction rates. i.e. did clinician confidence improve with use over time and more pessaries offered – or was confidence always high and treatment rates remained equal each year?

In table 4 – at least 6 RCTs appear to have provided adequate training in the placement of the pessary. You have not commented on if these 6 RCTs report significantly different results of patient experience / Arabin failure to the RCTs that did not provide treatment or have not reported on evidence of training. At present I do not feel that the data you have provided supports this assertion. Please provide adequate evidence and consider alternative explanations for the variation in reported results.

You summarise the data on RCT in Arabin pessaries but it is unhelpful to put clinical results of singleton and twin studies in the same table. Please separate these tables into a singleton and twin tables to make clinical comparison more useful for the reader.

Additionally please specifically address in your study weaknesses the likely recall bias, if you are asking women to remember their experiences of quantities of vaginal discharge between 6 months and 10 years after treatment. How reliable do you think these results are when compared to data that was collected prospectively during research trials?

There is huge variation in reports of vaginal discharge? How are RCTs collecting information and reporting on vaginal discharge? Were they asking women if there was an increase before and after treatment (no matter how small) or were they asking if it was troublesome vaginal discharge (i.e. causing them to wear pads etc.). Please address possible reasons for this difference in your discussion.

Table 2 – the answers here are reporting percentages of yes and no. Please justify what the addition of a statistical p-value adds to this data and consider removal of this column. i.e. there is a statistical significant difference in the number of women who received information before insertion regarding possible discharge, but 22.9% of women did not receive information. Do you think clinically this is acceptable when 42.2% of women report vaginal discharge during treatment?

Taking part in a research trial may undermine patient confidence in the treatment, resulting in more dissatisfaction or anxiety with the treatment. This may therefore not be the be best comparison for your retrospective study – consider comparing your results to other retrospective studies of Arabin pessary experience from a single centre in your discussion to strengthen your findings and put them in context (e.g. Jelena Ivandic, Angharad Care, Laura Goodfellow, Borna Poljak, Andrew Sharp, Devender Roberts & Zarko Alfirevic (2020) Cervical pessary for short cervix in high risk pregnant women: 5 years experience in a single centre, The Journal of Maternal-Fetal & Neonatal Medicine, 33:8, 1370-1376, DOI: 10.1080/14767058.2018.1519018).

This study design does suffer with the innate weakness of recall bias. I feel it would improve the manuscript to include more data about the overall clinical experience with the pessary. i.e. the reasons for intervention (? All short cervix <25mm), length of cervix on insertion, gestation at insertion, if additional adjunctive treatment was used (i.e. progesterone), how many patients required removal of pessary, how many required alternative treatments (i.e. rescue cerclage) and rate of PPROM with pessary in situ.

Reviewer #2: The manuscript entitled "Patient’s experience with Arabin cervical pessary during pregnancy: a questionnaire survey" analyzes the compliance and tolerance of pregnant women wearing Arabin cervical pessary. The authors concluded that the results cannot fully confirm a positive attitude of women towards this pessary, but more evidence is needed to investigate this topic.

The manuscript presents an interesting topic that falls within the scope of the journal “Plos One”. The Methodology is well written and the tables are detailed. The results are well represented, and the discussion is fine as the limitations of the study are explained.

I suggest the authors to discuss, at least briefly, about the universal screening for preterm delivery by cervical length measurement during the mid trimester scan (PMID: 29536576).

Reviewer #3: The manuscript entitled "Patient’s experience with Arabin cervical pessary during pregnancy: a questionnaire survey" analyzes the compliance and tolerance of pregnant women wearing Arabin cervical pessary. The authors concluded that the results cannot fully confirm a positive attitude of women towards this pessary, but more evidence is needed to investigate this topic.

The manuscript presents an interesting topic that falls within the scope of the journal “Plos One”. The Methodology is well written and the tables are detailed. The results are well represented, and the discussion is fine as the limitations of the study are explained.

I suggest the authors to discuss, at least briefly, about the universal screening for preterm delivery by cervical length measurement during the mid trimester scan (PMID: 29536576).

Reviewer #4: I read with great interest the manuscript titled "Patient's experience with Arabin cervical pessary during pregnancy: a questionnaire survey" (PONE-D-21-15296).

The topic of this manuscript falls within the scope of Plos One.

I was particularly pleased to review this paper. In my honest opinion, the topic is interesting enough to attract the readers' attention. Moreover, the methodology is accurate, and the data analysis supports conclusions. Nevertheless, the authors should clarify some points and improve the discussion.

In general, the manuscript may benefit from several minor revisions, as suggested below:

- All the text needs a minor language revision to correct some typos and grammatical errors.

- I would suggest reporting indications for Arabin pessary use in the methods section, such as inclusion and exclusion criteria of patients who were eligible for Arabin pessary use.

- I would suggest providing some details about how the authors identified the articles reported in table 4.

- Lines 162-163. I would suggest clarifying this sentence better. It is unclear.

- Strengths and limitations should be better discussed. The "experience" of the operator is not a standardized definition and is not comparable with other studies. Therefore, statements supporting the role of operator experience cannot be supported by study results. Regarding study limitations, the main limitation is not reported and discussed by the authors: the recall bias. Based on study methods, study outcomes were assessed by interview and getting in touch with patients up to 20 years after pessary use, providing concerns regarding the risk of recall bias.

**********

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Reviewer #1: Yes: Dr Angharad Care

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23 Nov 2021

Reviewer #1: Overall you have provided a reasonable summary of patient experience of treatment with Arabin pessary over a 10 year period from a single centre. However the authors make the assumption that clinical experience of healthcare specialists explains the difference in previously reported prospectively collected RCT results. The manuscript does not provide sufficient evidence to support this statement. Please revise.

R. We thank the reviewer for the remark. We have removed the statement “..clinical experience of the health care specialists in charge may explain why the discrepancy of results” from the abstract and we have revised our statement in the introduction (line 65 of the clean version, now as follows: It has been suggested that clinical success also requires experience following a learning curve , ref. to Franca et al 2020 ). The large discrepancies in outcomes between studies can be explained by several reasons, including distinct selection criteria (e.g. different cut-off values of the cervical length in different studies), ethnic and cultural particularities. We believe that one point that is often neglected is the importance of training on how to handle the cervical pessary and that a proper training in pessary placement may facilitate less maternal discomfort during the insertion of the device by trained physicians. However, we agree with the reviewer that statements supporting the role of operator experience cannot be supported by our study results. Therefore, we removed the sentence: “There seems to be a negative association of increased early removal with the experience of the clinicians involved in the treatment and the practical training received”, and we only report instead that low rates (0-5%) of early removal due to pain or discomfort are observed in studies on singleton pregnancies, including ours, where physicians received practical training.

To strengthen this manuscript more information about the clinical protocol, clinical outcomes and alternative therapies would be useful. R. We agree with the reviewer, and we have now included in the Methods more details about the clinical protocol for pessary use at our Center and about additional treatment (progesterone). Data on outcome are reported in Table 1.

Minor comments:

Line 44: You have included ‘policies to reduce physical stress’ from your list of evidence-based supported healthcare programmes and used a reference from 1985 in support. There has since been plenty of evidence that physical stress / exercise in pregnancy reduces rates of preterm birth. Please justify/clarify this statement, provide additional evidence or consider removing ‘policies to reduce physical stress’ from your list of evidence-based supported healthcare programmes. R. We agree with the reviewer that physical exercise in pregnancy is recommended, even in women at risk for preterm birth, as it has shown to reduce the risk of PTD. The sentence was meant to refer to possible effects of mental and physical stress related to excessive workload in pregnancy. However, we have now removed the reference and the sentence because it was misleading.

Line 63: Formatting of references changes for 27, please amend. R. The formatting has been corrected.

Line 55 suggest use of word ‘recognised’ instead of ‘demanded’. i.e. ‘Di Renzo et al. in 2017 recognised the need for clinical training for the insertion of cerclage and cerclage pessaries’. R. The verb has been changed as suggested

Line 77: please use a unit of measurement for 68.3 (? Insertions) R. The unit has been specified

Line 78: what do you mean by second control after 48 hours? Please clarify.R. We meant a follow-up vaginal exam to verify the correct position of the pessary. We have now explained it more clearly in the sentence.

Line 79: please provide a definition for extremely short cervical length? (i.e. <15mm, <5mm) R. A definition has been provided (< 10 mm)

Line 80: When was an additional TVU performed – immediately, one week later? R. It is usually performed one week later in case of CL<10 mm, based on our clinical protocol. This is now specified in the methods.

Line 82: How did you know that 34 women had changed address? Please clarify how you contacted them and who contacted them before the questionnaire was sent out (i.e. their clinical team or a research team). R. We tried to call those women but the phone number we had was no longer in use, therefore we assumed that they had changed phone number and they were not included in the study.

In table 4 please justify why you have not included Hui 2003, Daskalakis 2013 and Cabrera Garcia 2015.R We thank the reviewer for the remark. We have now included the work by Hui 2013 in Table 4 (singletons). We did not include the work by Daskalakis 2013 because it is a review and we meant only to list the clinical studies in table 4. We have found a study protocol published by Cabrera Garcia in 2015 for a RCT (PESAPRO trial). However, we were not able to find the results of such trial.

In table 4 please explain what is meant by “extensive training” – column one. R. We have changed the term “extensive traning” with “practical training in the placement of the device”, by which we mean that the younger physicians were supervised by the senior physician (who already had experience with the pessary) for the first 30 applications of the pessary (with the senior physician checking the correct position of the pessary), before starting to place pessaries without supervision. Details of such training are now also included in the Methods (line 79-81 of the clean version).

Table 4 is difficult to read and not all the details are necessary – please could you make more concise – particularly the section on clinical results. Consider additional rows to compare information on cervical length and gestation for inclusion/insertion then include rates of sPTB. R. We thank the reviewer for the suggestions. We have modified the section on clinical results of table 4, which is now more concise. The results are now also more easily comparable between studies, and the different cut offs of CL are more clearly reported. We have also divided the original table in two tables separating studies on singletons (table 4) and twins (Table 5) to make clinical comparison more useful for the reader, as suggested by the reviewer (see major comments).

Major comments

Methods: Please make the management protocol of these women clear. How were these women screened for treatment? Did they have follow up with the same individuals? How many times were they seen in their pregnancy? Was TVU was performed after the pessary was placed? Did the management protocol change over the 10 year period, and if so, how? R. Pessary treatment was offered to women with a CL ≤25 mm before 26 weeks of gestation, who had intact membranes. After insertion, they were followed up by the same clinicians with obstetric visits every 2-3 weeks. TVU was performed after 1 week of pessary placement in case of CL<10 mm (see Methods). This protocol has been remained the same over the 10 year period. All the details about the protocol are now included in the methods.

You make the point in your introduction that the clinical success with Arabin pessary follows a learning curve – which ‘has been completely neglected’ and experienced clinicians improve the satisfaction rate. This point is also reiterated in your abstract results “In a final step, we compared our results to previous studies suggesting that clinical experience of the health care specialists in charge may explain why the discrepancy of results”. How much experience prior to 2010 did your clinicians have with insertion of pessaries? If you provided a questionnaire to all the women included in this case series you may expect to see an improvement with satisfaction over time from 2010 to 2020, otherwise you fail to provide evidence for the need for experienced clinicians, unless they were highly experienced before 2010, however Arabin pessaries were not widely used. Please clarify how these three clinicians obtained their experience prior to 2010, and how is this different to the RCT training? R. We thank the reviewer for the remarks. We have removed the statement “..the clinical experience of the health care specialists in charge may explain why the discrepancy of results” from the abstract, as we agree with the reviewer that our results do not provide sufficient evidence to support this statement. We also revised our statement in the introduction (line 65 of the clean version), reporting that “It has been suggested” that clinical success also requires experience following a learning curve (ref. to the study by Franca et al.2021).

We have now included more details about our experience (line 79-81 of the clean version): “for the two younger physicians, the first 30 applications of the device were supervised by the senior physician who already had experience with pessary placement.” The senior obstetrician had started placing pessary since 2008 (following the results of Arabin et al. Is treatment with vaginal pessaries an option in patients with a sonographically detected short cervix? J Perinat Med. 2003;31(2):122-33. which suggested that its use in patients at risk for PTB was cost-effective). We were unable to observe an improvement in patient’s satisfaction over time from 2010 to 2020, given the small number of patients per year in our study (e.j. only a total of 15 patients were included in the first three years 2010-2012)

It would be useful to include data showing the number of pessaries inserted per year and relative satisfaction rates. i.e. did clinician confidence improve with use over time and more pessaries offered – or was confidence always high and treatment rates remained equal each year? R. We were unable to observe an improvement with satisfaction over time from 2010 to 2020, given the small number of patients per year in our study (e.j. 15 patients were included in the first three years 2010-2012). The number of patients treated increased over the years, possibly suggesting: i) increased clinician’s confidence, and ii) increased evidence supporting pessary use coming from studies performed over the years.

In table 4 – at least 6 RCTs appear to have provided adequate training in the placement of the pessary. You have not commented on if these 6 RCTs report significantly different results of patient experience / Arabin failure to the RCTs that did not provide treatment or have not reported on evidence of training. At present I do not feel that the data you have provided supports this assertion. Please provide adequate evidence and consider alternative explanations for the variation in reported results. R. We thank the reviewer for the remark. We agree that we are not able to demonstrate a negative association of increased early removal with the experience of the clinicians (this statement was removed from the Results), also because some of the trials do not specify the rate of early removal, nor give any information on patient’s satisfaction rate. Therefore, we only “observed low rates (0-5%) of early removal due to pain or discomfort in studies on singleton pregnancies, including ours, where physicians received practical training”

You summarise the data on RCT in Arabin pessaries but it is unhelpful to put clinical results of singleton and twin studies in the same table. Please separate these tables into a singleton and twin tables to make clinical comparison more useful for the reader. R. We have now created two different tables for studies on singletons (table 4) and twins (table 5)

Additionally please specifically address in your study weaknesses the likely recall bias, if you are asking women to remember their experiences of quantities of vaginal discharge between 6 months and 10 years after treatment. How reliable do you think these results are when compared to data that was collected prospectively during research trials?

R. We agree with the reviewer that recall bias is an important limitation of our study, and we have addressed it in the discussion.

There is huge variation in reports of vaginal discharge? How are RCTs collecting information and reporting on vaginal discharge? Were they asking women if there was an increase before and after treatment (no matter how small) or were they asking if it was troublesome vaginal discharge (i.e. causing them to wear pads etc.). Please address possible reasons for this difference in your discussion: R. Unfortunately, details on how information about vaginal discharge was collected are quite scarce in the RCTs analyzed. The most detailed description of how women were counselled about the possibility of vaginal discharge was reported in the retrospective study by Ivandic et al (2018), who reported a 14% incidence of “significant vaginal discharge” with pessary. In our questionnaire, we asked the patients if they experienced an increase of vaginal discharge with the treatment (the question is now more clearly reported in table 2). We reviewed all the other studies: most of them (Saccone et al, Hui et al, Ivandic et al, Nicolaides et al, Liem et al.) specify that the side effect was “increased vaginal discharge” with treatment compared to before treatment (this is now specified in table 4 and 5). On the other hand, three studies (ref Goya et al ,Dugoff et al, Dang et al) ,which report a 70-100% vaginal discharge rate during treatment, do not specify if there was an increase after treatment, but only compared the rate of vaginal discharge between women with pessary and controls, reporting a statistically significant difference. We have included these comments in the Results.

Table 2 – the answers here are reporting percentages of yes and no. Please justify what the addition of a statistical p-value adds to this data and consider removal of this column. i.e. there is a statistical significant difference in the number of women who received information before insertion regarding possible discharge, but 22.9% of women did not receive information. Do you think clinically this is acceptable when 42.2% of women report vaginal discharge during treatment? R. We have removed the column with the p-value, as we agree that it does not add any relevant information. After reviewing the results of the questionnaire, the fact that 23% of our patients did not recall having received information about such a common side effect forced us to review the way we provide the counselling and to improve it.

Taking part in a research trial may undermine patient confidence in the treatment, resulting in more dissatisfaction or anxiety with the treatment. This may therefore not be the be best comparison for your retrospective study – consider comparing your results to other retrospective studies of Arabin pessary experience from a single centre in your discussion to strengthen your findings and put them in context (e.g. Jelena Ivandic, Angharad Care, Laura Goodfellow, Borna Poljak, Andrew Sharp, Devender Roberts & Zarko Alfirevic (2020) Cervical pessary for short cervix in high risk pregnant women: 5 years experience in a single centre, The Journal of Maternal-Fetal & Neonatal Medicine, 33:8, 1370-1376, DOI: 10.1080/14767058.2018.1519018). R We have reviewed the article by Ivandic et al, and added the reference to that paper in our manuscript. The comparison of their results with those of our study is also now included in the table. As stated above, the most detailed description of how women were counselled about vaginal discharge was reported in the retrospective study by Ivandic et al (2018), who reported a 14% incidence of “significant vaginal discharge” with pessary. This is now commented in the discussion.

This study design does suffer with the innate weakness of recall bias. I feel it would improve the manuscript to include more data about the overall clinical experience with the pessary. i.e. the reasons for intervention (? All short cervix <25mm), length of cervix on insertion, gestation at insertion, if additional adjunctive treatment was used (i.e. progesterone), how many patients required removal of pessary, how many required alternative treatments (i.e. rescue cerclage) and rate of PPROM with pessary in situ. R. We have now included the recall bias among the limitations of our study. In addition, based on the reviewer’s suggestion, we have specified the indications for the interventions (cut-off of CL and Gestational age: see details about clinical protocol for pessary treatment in the Methods section). As additional treatment, vaginal progesterone was administered to all singletons (see Methods). The overall rate of pPROM with pessary in situ was 11.4% (19/166) (now reported in table 1). The rate of removal is reported in table 4/5.

Reviewer #2: The manuscript entitled "Patient’s experience with Arabin cervical pessary during pregnancy: a questionnaire survey" analyzes the compliance and tolerance of pregnant women wearing Arabin cervical pessary. The authors concluded that the results cannot fully confirm a positive attitude of women towards this pessary, but more evidence is needed to investigate this topic.

The manuscript presents an interesting topic that falls within the scope of the journal “Plos One”. The Methodology is well written and the tables are detailed. The results are well represented, and the discussion is fine as the limitations of the study are explained.

I suggest the authors to discuss, at least briefly, about the universal screening for preterm delivery by cervical length measurement during the mid trimester scan (PMID: 29536576). R. We thank the reviewer for the suggestion. In the introduction section, we have included a comment on the recommendation to universal cervical screening (line 52 of the clean version), and we have now added the reference to the work by Souka et al (2019), as suggested.

Reviewer #3: The manuscript entitled "Patient’s experience with Arabin cervical pessary during pregnancy: a questionnaire survey" analyzes the compliance and tolerance of pregnant women wearing Arabin cervical pessary. The authors concluded that the results cannot fully confirm a positive attitude of women towards this pessary, but more evidence is needed to investigate this topic.

The manuscript presents an interesting topic that falls within the scope of the journal “Plos One”. The Methodology is well written and the tables are detailed. The results are well represented, and the discussion is fine as the limitations of the study are explained.

I suggest the authors to discuss, at least briefly, about the universal screening for preterm delivery by cervical length measurement during the mid trimester scan (PMID: 29536576). ). R. We thank the reviewer for the suggestion. In the introduction section, we have included a comment on the recommendation to universal cervical screening (line 52 of the clean version), and we have now added the reference to the work by Souka et al (2019), as suggested.

Reviewer #4: I read with great interest the manuscript titled "Patient's experience with Arabin cervical pessary during pregnancy: a questionnaire survey" (PONE-D-21-15296).

The topic of this manuscript falls within the scope of Plos One.

I was particularly pleased to review this paper. In my honest opinion, the topic is interesting enough to attract the readers' attention. Moreover, the methodology is accurate, and the data analysis supports conclusions. Nevertheless, the authors should clarify some points and improve the discussion.

In general, the manuscript may benefit from several minor revisions, as suggested below:

- All the text needs a minor language revision to correct some typos and grammatical errors. R. The manuscript has now been reviewed by a native English speaker to correct any grammatical or typos errors.

- I would suggest reporting indications for Arabin pessary use in the methods section, such as inclusion and exclusion criteria of patients who were eligible for Arabin pessary use. R. We have now specified in the Methods section that cervical pessary was offered to women with a CL ≤25 mm before 26 weeks of gestation, who had intact membranes.

- I would suggest providing some details about how the authors identified the articles reported in table 4. R. We identified the studies on pessary that reported the rates of side effects such as vaginal discharge, discomfort, and pain. Therefore, we included all randomized clinical trials on pessary use, now reported in Table 4 (singletons) and Table 5 (twins) (as suggested by Reviewer #1). In addition, we included a retrospective study by Ivandic et al (2018), as requested by Reviewer #1, that describe the 5-years experience with pessary in a single center, and reported the rates of side effects. Details are now provided in the Results section.

- Lines 162-163. I would suggest clarifying this sentence better. It is unclear. R. We have now replaced the sentence with the following: “Most importantly, it should be remembered that vaginal discharge due to Arabin pessary is not a sign of infection and should not be treated with antibiotics.”

- Strengths and limitations should be better discussed. The "experience" of the operator is not a standardized definition and is not comparable with other studies. Therefore, statements supporting the role of operator experience cannot be supported by study results. Regarding study limitations, the main limitation is not reported and discussed by the authors: the recall bias. Based on study methods, study outcomes were assessed by interview and getting in touch with patients up to 20 years after pessary use, providing concerns regarding the risk of recall bias.

R 1. We thank the reviewer for the remark. We have removed the statement “clinical experience of the health care specialists in charge may explain why the discrepancy of results” from the abstract and we have revised our statement in the introduction (line 65 of the clean version, now as follows: It has been suggested that clinical success also requires experience following a learning curve, , ref. to Franca et al 2021). The large discrepancies in outcomes between studies can be explained by several reasons, including distinct selection criteria (e.g. different cut-off values of the cervical length in different studies), ethnic and cultural particularities. We also believe that one point that is often neglected is the importance of training on how to handle the cervical pessary. However, we agree with the reviewer that statements supporting the role of operator experience cannot be supported by study results. Therefore, we removed the sentence: “There seems to be a negative association of increased early removal with the experience of the clinicians involved in the treatment and the practical training received”, and we only report instead that low rates (0-5%) of early removal due to pain or discomfort are observed in studies on singleton pregnancies, including ours, where physicians received practical training.

2. We agree with the reviewer that recall bias is an important limitation of our study, and we have now addressed it in the discussion.

Submitted filename: Response to Reviewers.docx

Click here for additional data file.

13 Dec 2021

Patient’s experience with the Arabin cervical pessary during pregnancy: a questionnaire survey

PONE-D-21-15296R1

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Reviewer #3: The Authors addressed all the comments and significantly improved the quality of the manuscript.

I suggest acceptance in the present form

Regards

Reviewer #4: I read with great interest the manuscript titled "Patient's experience with Arabin cervical pessary during pregnancy: a questionnaire survey" (PONE-D-21-15296_R1).

The topic of this manuscript falls within the scope of Plos One.

I was particularly pleased to review this paper. In my honest opinion, the topic is interesting enough to attract the readers' attention. The methodology is accurate, and the data analysis supports conclusions. Moreover, authors addressed all suggested revisions, and I appreciated the manuscript improvement.

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22 Dec 2021

PONE-D-21-15296R1

Patient’s experience with the Arabin cervical pessary during pregnancy: a questionnaire survey

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I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

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