Study design
We conducted an open-label feasibility RCT (Registration Number: NCT03199820) with individual randomisation to either sustained-release prostaglandin vaginal pessary (Propess) or cervical ripening balloon catheter (CRB) in the out-patient setting using a 1:1 allocation ratio. The trial took place in two UK maternity units: St Georges University Hospitals NHS Foundation Trust, South London (October 2017 to March 2019), and Medway University Hospital, Kent (February 2018 to October 2018). The trial protocol is publicly available at the clinical trials registry8. The trial was approved by the East of England - Cambridgeshire and Hertfordshire Research Ethics Committee (17/EE/0295).
Participants
Inclusion criteria were women aged ≥16 years, undergoing IOL at ≥37 weeks’ gestation, with intact membranes, able to give informed consent and deemed suitable for out-patient IOL according to local guidelines. Written information was provided to women regarding the available methods: IOL with sustained release dinoprostone (Propess), or cervical ripening balloon (CRB), both in the out-patient setting. Research teams at each site approached women to confirm eligibility and provided verbal and written information. Strict eligibility criteria have been developed for suitability of out-patient IoL against which research midwives screened for eligible participants and a medical practitioner confirmed that eligibility was met. A trained clinician obtained written informed consent. During the study the investigators noticed a shortfall of eligible women. Therefore, inclusion criteria were widened in 2018 at St. George’s Hospital to include women requiring induction of labour at term (37+0 weeks or more) with diet-controlled gestational diabetes, who were originally excluded.
Randomisation and masking
Eligible participants were randomly allocated with a 1:1 ratio to receive Propess or CRB. Randomisation was stratified by site and parity using variable block sizes (two and four). A research team member entered baseline data on a web-based database at study enrolment and then allocated the treatment (Propess or CRB) using the web-based randomisation program developed by King’s Clinical trial Unit (KCTU). Nature of the intervention mandated that trial participants, clinical care providers or outcome assessors could not be blinded to trial allocation. However, the data analysts were masked to allocation.
Procedures
After randomisation, a member of the research team administered the treatment method according to the recommendations of the manufacturer. Briefly, for induction of labour with Propess, 10mg insert was introduced in the posterior vaginal fornix close to the cervix, using only small amounts of water-soluble lubricants to aid insertion. The woman was advised to be recumbent for 20-30 minutes following insertion. For IoL with balloon catheter, recommendations by the manufacturer were followed. Briefly, the woman was positioned in the dorsal position and a vaginal speculum was inserted to gain cervical access. The cervix was cleaned appropriately to prepare for device insertion. The CRB was inserted into the cervix and advanced until both balloons entered the cervical canal. The uterine balloon was inflated with 40ml Sodium Chloride (0.9%). Once the uterine balloon was inflated, the device was pulled back until the balloon was against the internal cervical os. The vaginal balloon was now Inflated with 20ml NaCl (0.9%). The speculum was removed after the balloons were situated on each side of the cervix and the device was securely in place. More fluid was added to each balloon in turn, in 20ml increments until each balloon contains 80ml (maximum volume of fluid). Following this, clinical care was provided by clinical healthcare practitioners.
Women underwent monitoring of fetal condition and uterine activity by cardiotocography (CTG) according to the local protocol. CTG was discontinued once it was judged to be normal and the woman could go home. She was instructed to return to the hospital at an agreed time on the following morning, if the balloon catheter was spontaneously expelled or if she thought she was in labour, whichever was earlier. On the following morning/upon onset of labour the device (Propess or CRB) was removed, and artificial rupture of membranes (ARM) attempted (unless spontaneous rupture had occurred already).
The intended recruitment target was randomisation of 120 women between the two sites over a 12-month period. The primary objective was to assess the feasibility of conducting a randomised controlled trial (RCT). Secondary objectives were to identify most suitable clinical outcome measures, estimate service costs and monitor safety; as well as to determine women's willingness to be randomised, to determine the acceptability of using the balloon catheter, to examine women’s views on out-patient induction of labour and to assess women’s experience with these methods and their preference.
Women who declined to participate in the trial were invited to complete a short questionnaire exploring their main reasons for not participating. Verbal feedback was obtained for those who declined to complete the questionnaire. After they had given birth, the participants were asked to complete a questionnaire within 48 hours. The questionnaire was modified from one used in a previously published study4. This recorded women’s experience and acceptability of the two methods. All women who took part in the RCT were also invited to participate in a semi-structured interview at least four weeks after the birth. Partners were also invited with the women’s permission. The detailed methods and findings of the interviews as well as the post-natal questionnaire will be reported in a separate paper.
Participant demographics, clinical and patient-reported data were collected using an online database developed by KCTU. This included participant demographics, vital signs at trial entry, cervical Bishop score, birth details, maternal and fetal outcomes including adverse outcomes, use of pain relef measures at home and in the hospital, survey responses and decliner questionnaire responses.
The purpose of the health economic component was to pilot a data collection instrument for use in a future RCT and to conduct an exploration of the cost of the interventions under evaluation. A data collection instrument was developed according to the standard methods for economic evaluations. All relevant health-service resources were identified via a literature review and from lists developed in collaboration with the clinical research team. The best way to measure these resources was also examined and a data collection instrument was developed. The efficacy of the instrument was judged by the ease of completion by the research staff and it’s ability to provide the data needed to generate costs for a full economic evaluation.
The method for estimating the cost of the alternative interventions for this study required work in a feasibility stage because of the need to capture all aspects of induction. Service-use data were reviewed in order to establish the most accurate approach to estimating the cost and alternative methods were compared. The options for sources of unit costs for the intervention and associated resources were also explored, making use of nationally available costs and optimising links with the service use data.
Research teams undertook standard assessments of safety, with reporting of adverse events and serious adverse events following usual governance procedures for a clinical trial of an investigational medicinal product overseen by the UK Medicines and Healthcare Regulatory Agency (MHRA).
Statistical analysis
The analysis and presentation of results follows the recommendations of the CONSORT group9. All analyses followed the intention-to-treat principle: all randomly allocated women (and infants) were analysed according to the group they were allocated to, irrespective of the intervention they received. Demographic and clinical data were presented as n (%) for categorical variables, mean (SD) for normally distributed continuous variables, and median (IQR) or median (range) for other continuous variables. No statistical tests were performed as this was a feasibility study.
Role of funding source
The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.