Pregnolia system.

The Pregnolia System is a novel medical device designed to quantitatively assess the biomechanical properties of the cervix through cervical stiffness. The system consists of a single-use sterile probe and a control unit as seen in Fig 3. The control unit is the active component composed of a power supply, foot switch for clinician control, and an integrated pump that generates a vacuum. The sterile probe is attached to the control device via a connector cable and air filters on the probe prevent microbiological contamination [32].

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Fig 3. Pregnolia device- control unit with foot switch and single-use sterile probe.

https://doi.org/10.1371/journal.pone.0311324.g003

The device requires the use of a vaginal speculum to clearly visualise the cervix. The device probe is placed at the 12 o’clock position on the cervix and the cervical stiffness measurement is operated by a foot switch, creating a weak vacuum which displaces the cervical tissue into the probe tip to a depth of 4mm. The softer the tissue, the less pressure required to deform the tissue [33]. The result is represented by the CSI shown on the control unit. The measurement is audio-guided for the clinician and indicates when the measurement has started, in progress and completed.

The device has instructions for use that outline appropriate clinical indications, contra-indications for use and clear instructions. All clinicians using the device will have read the instructions and completed the Pregnolia training instructional video.

Cervical stiffness assessment.

Cervical stiffness will be measured using the Pregnolia System. Following informed consent, with the woman in a supine position, the cervix is visualised by use of a sterile speculum and the single-use, sterile Pregnolia Probe is placed on the anterior lip of the cervix at 12 o’clock position. A recording of cervical stiffness is generated over maximum 60 seconds (typically ~15 seconds) and displayed as CSI in mbar. The measurement is repeated 3 consecutive times without any time lag. The clinician is audio-guided by the control unit which indicates when a reading has been taken.

The cervical stiffness readings will be stored on the Pregnolia Control Unit and documented for the participant once all study procedures have been completed. The cervical stiffness readings are blinded to the patient and the clinician who will perform the Bishop’s score assessment at the time of the study visit.

Any difficulty in obtaining readings will be documented on the case report form (CRF). Simple troubleshooting guidelines will be followed to optimize readings at the time of the study visit as per Pregnolia instructions (e.g avoiding kinks in connector cable and ensuring Luer locks are secure).

Bishops score assessment.

BS assessment will be undertaken by a sterile digital vaginal examination. The study site uses an electronic maternity notes software, and the BS is documented in a standard format. Five components of the vaginal examination will be documented as a score: cervical dilatation (cm), consistency of cervix, cervical canal length (cm), position of cervix and station of presenting part in relation to ischial spines, giving a potential score from 0 to 12.

This procedure will be undertaken by a member of the induction suite midwifery team as per routine unit practice, and their score will be documented in the patient’s electronic maternity records. The BS will be taken from the medical records and transferred to the CRF.

Feasibility outcomes.

Our feasibility outcomes of interest relate to whether the study procedure is acceptable, participant recruitment is achieved, data collection is feasible, and cervical stiffness assessment fidelity is maintained with adequate reliability and safety [34].

Our feasibility outcomes will be defined as follows;

1. Recruitment rate
   1. Measured as proportion of participants recruited compared to total number approached for recruitment in the study period
   2. Reasons for non-participation collected
2. Participant acceptability of cervical stiffness assessment at IOL
   1. Qualitative questionnaire following assessment
   2. Number of participant withdrawals throughout the study duration
3. Adherence to protocol and data collection
   1. Measured as number of protocol deviations
   2. Missing data
4. Cervical stiffness fidelity
   1. Ability to obtain triplicate cervical stiffness measurements
   2. Triplicate measurement reliability

Clinical outcomes.

Clinical outcome data will be collected in accordance with the “short-term” core outcome set for trials on IOL as determined by the international Delphi study [35,36]. Ability to capture this core data set in this feasibility study will inform data collection and study design for a larger definitive IOL study.

The primary clinical outcome will be vaginal delivery. Secondary maternal and neonatal outcomes will be recorded for descriptive analyses. Variables that are already recognised as informative for induction prediction modelling will be collected and included for descriptive analyses such as; maternal demographics, maternal obstetric parameters, induction methods and indications, cervical findings on digital examination and fetal parameters [8,23].

Sample size.

The Pregnolia System is a novel device with no published data providing cervical stiffness index results in primiparous women undergoing IOL. This will be the first study to provide this data and will guide how further research using this novel assessment tool can be most appropriately designed.

In this feasibility study we will recruit for 12 months and expect to achieve a cohort of 100 participants. The study site has a high IOL capacity with on average 100 primiparous women being induced every month. We anticipate 50% to be eligible for the study and aim to achieve 50% recruitment. Previous IOL trials have struggled with recruitment, with over 70% declining participation [37]. However, in our feasibility study design the clinical indication and timing of IOL have already been determined and the participant is already expecting to undergo an IOL at the time of study recruitment. The study does not influence or change routine clinical practice therefore, we expect to achieve a moderate recruitment rate of 50%. Clearly determining the expected recruitment rate for this novel device is of paramount importance for future successful definitive study design.

At the study site, routine IOL appointments are from 8am-8pm with emergency indications being accommodated throughout the 24hr, 7-day service. In this feasibility study we understand that not all eligible women will be able to be approached given the 24hr 7-day nature of the service. We have planned for a 12-month recruitment period to allow for these challenges and aim to achieve a sample size of 100 participants. Ability to achieve this target number for this feasibility study with the small study team available will help inform the larger study design resource and team allocation for study recruitment and study visit procedures in this dynamic clinical setting.

This feasibility study will provide key data including an accurate recruitment rate demonstrating this population’s acceptability for the novel assessment in clinical practice, and an estimate of the variance for cervical stiffness using the Pregnolia System for pre-induction cervical assessment. Together this data can infer a larger study design for a predictive model for IOL outcome in this population [38–40].

Statistical analysis.

Descriptive statistics will be generated and presented as means (SD), median (IQR) and frequency of observations (percentages) with 95% confidence intervals as appropriate.

Reliability assessment of the Pregnolia System using Cronbach’s alpha and descriptive statistics with 95% confidence intervals will inform best use of the triplicate CSI measurements. Specifically exploring whether the first, average, median or lowest measurement of the three readings should be utilised in further analysis and most importantly inform best use of the CSI results in clinical practice.

Diagnostic performance of cervical stiffness assessments using the Pregnolia System for IOL outcome will be demonstrated through receiver operating characteristic (ROC) curves with area under the curve and 95% confidence intervals being calculated, as well as aiming to define the optimum cut-off value for predicting vaginal delivery. Alongside the primary clinical outcome of mode of delivery, other IOL outcomes of interest will include oxytocin requirement and duration, requirement for artificial rupture of membranes and total duration of rupture membranes, caesarean section for failed IOL, achieving established labour and >1 cervical ripening method required. Bishop’s score diagnostic performance data will also be generated for direct comparison.

If a positive signal between CSI and an IOL outcome is achieved, a multivariate analysis will be performed using logistic regression, including CSI and other variables related to IOL outcome, such as maternal age, gestational age and maternal weight at booking [23]. Results will be presented as odds ratios with 95% confidence intervals.

Acceptability of the device will be determined using participant questionnaires. Results will be collated and analysed providing descriptive statistics presented as means (SD), median (IQR) and frequency of responses (percentages). The participant experience of each study procedure is collected as a scale response from 1–10. A paired t-test with 95% confidence intervals will be used for comparison of participant experience between the different study procedures. A p value of <0.05 will determine significance.

Consent and criteria for withdrawal.

Consent to enter the study must be sought from each participant only after a full explanation has been given, an information leaflet offered, and time allowed for consideration. Signed participant consent will be obtained. The participant can decline to participate without giving reasons and this will not impact upon further care. All participants are free to withdraw at any time from the study without giving reasons and without prejudicing further care.

In addition, the CI may decide, for reasons of medical prudence, to withdraw a participant. In either event, the Sponsor will be notified and the date and reason(s) for the withdrawal will be documented in the participant source data. If a participant withdraws or is withdrawn, ideally, they should remain in the study for the collection of outcome data. If the participant states their wish not to contribute further data to the study, collected data will be removed from the study database and no further outcome date will be collected.

Monitoring and safety.

A Study Management Group (SMG) comprising the CI, principal investigator, co-applicants, and core study management staff meet at regular intervals throughout the course of the study and holds responsibility for the day-to-day running and management of the study. The need to stop the study will be determined by the SMG and the decision will be based upon data integrity and participant safety.

Any adverse events for this study will be recorded at each study visit on the study CRF. This is a non-interventional study we therefore do not anticipate many serious adverse events. The Pregnolia System is a licensed, CE-marked, non-invasive medical device and the risk of adverse events related to the measurement is small. The device has a very good safety profile, and the manufacturer has not received any serious adverse event reporting related to the medical device either in studies or clinical practice to date.

Ethical considerations and declarations.

The Seasonal Research Ethics Committee has given approval for this research (23/LO/0627). All patients have given written informed consent prior to entry to the study and are aware that participation is completely voluntary.

Status and timeline of the study.

This study is registered at ClinicalTrials.gov, identifier NCT05981469 and has been open for recruitment since 29^th September 2023. Recruitment is due to finish 30^th September 2024, and patient follow up complete in November 2024.