Membrane Sweeping to Prevent Post-term Pregnancy: The MILO Study (MILO)

Feasibility Study Protocol of a Pragmatic, Randomised Controlled Pilot Trial: Membrane Sweeping to Prevent Post-term Pregnancy: The MILO Study

Multicentre, pragmatic, parallel group, pilot randomised controlled trial with an embedded factorial design.

The primary aim of the MILO study is to inform the optimal design of a future definitive randomised trial to evaluate the effectiveness (including optimal timing and frequency) of membrane sweeping to prevent post-term pregnancy. We will also assess the acceptability and feasibility of the proposed trial interventions to clinicians and women (through focus group interviews). Methods/Design Multicentre, pragmatic, parallel group, pilot randomised controlled trial with an embedded factorial design. Pregnant women with a live, singleton fetus ≥ 38 weeks gestation, cephalic presentation, longitudinal lie, intact membranes, English speaking and ≥18 years of age will be randomised in a 2:1 ratio to: • Membrane sweep versus no membrane sweep Women allocated randomly to a sweep will then be randomised further (factorial component) to: early (from 39 weeks) versus late (from 40 weeks) sweep commencement; and a single verses weekly sweep The proposed feasibility study consists of four work packages i.e., (1) a multicentre, pilot randomised trial, 2) a health economic analysis and 3) a qualitative study (4) a study within the host trial (a SWAT).

membrane sweep, feasibility study, randomised trial, pilot study, SWAT, pregnancy, induction of labour, post dates, prolonged pregnancy

Women will initially be randomised in a 2:1 ratio to: • Membrane sweep (2) versus no membrane sweep (1). Those allocated to the intervention group will then be further randomised in a factorial fashion to A, B, C or D: A. Membrane sweep @ 39 weeks' gestation only B. Membrane sweep @ 40 weeks' gestation only C. Membrane sweep @ 39, 40 and 41 weeks' gestation or until onset of labour D. Membrane sweep @ 40 and 41 weeks' gestation or until onset of labour

Clinicians performing a membrane sweep cannot be blinded and it is not feasible to genuinely blind membrane sweeping for women. Therefore, neither clinicians administering the intervention nor women will be blinded to group assignment. Data will be reviewed by two assessors blinded to group allocation

Women in the control arm will not receive a membrane sweep and will receive usual care (as defined by local hospital protocols and vaginal examination to determine Bishop score only).

Amniotic membrane sweeping is defined as the manual detachment of the inferior pole of the amniotic membranes from the lower uterine segment. This is performed with consent by a clinician digitally through a circular motion during a vaginal examination. If the cervical os is closed massage of the cervix will be accepted.

Evaluation of the number and percentage of eligible women who are recruited and randomised to the study. Assessed by study-specific checklists.

Evaluation of the number and percentage of eligible women who are randomised, take part in and adhere to the study protocols. Data will be extracted from routinely collected data.

Evaluation of adherence with the trial interventions, and reasons for non-compliance assessed by study-specific checklists. Data will be extracted from routinely collected data and focus group interviews with clinicians and participants at six weeks post intervention.

Evaluation of effective allocation of participants to the intervention/control group assessed by study-specific checklists and evaluation of the randomisation protocol throughout the randomisation period.

Evaluation of attrition rates assessed by study-specific checklists. Data will be extracted from routinely collected data.

Evaluation of the types of attrition assessed by case report forms. Data will be extracted from routinely collected data.

Evaluated, statistically and narratively, by assessing the completeness of outcome measurements at baseline and postnatal (6 weeks) through study specific checklists. Researchers will manually examine the data collected. They will assess the proportion of complete data collection forms, the quality of data collected and the applicability of this data in facilitating pilot trial outcomes.

Estimates (with measures of uncertainty) of the main effect of individual intervention components and any interaction effect between the main effects of the embedded factorial design will be assessed and reported using regression analysis.

As this is a feasibility study formal hypothesis testing will not be undertaken. Researchers will manually examine the data collected. Evaluation of the data analysis process will be undertaken through the assessment of gaps and limitations to the analysis process measured by study-specific checklist. Findings will be reported through descriptive statistics and graphical summaries.

Assessment of the mechanism of, timing of and delivery of the EQ5D through study specific checklists.

Assessment of data collection tools to undertake cost effectiveness analysis through study specific documentation. Researchers will manually examine data to assess the mechanism of, timing of and delivery of the cost analysis tools.

Assessment of the mechanism and utilisation of the incremental cost-effectiveness ratio (ICER), through study specific checklists.

From time of randomisation to commencement of spontaneous onset of labour or formal induction of labour or caesarean section (up to 5 weeks)

Uterine hyperstimulation defined as uterine tachysystole (more than five contractions per ten minutes for at least twenty minutes) and uterine hypersystole/hypertonicity (a contraction lasting at least two minutes). These may or not be associated with changes in the fetal heart rate pattern (persistent decelerations, tachycardia or decreased short term variability.

Serious maternal death or morbidity (e.g. uterine rupture, admission to intensive care unit, septicaemia)

The stimulation of uterine contractions using pharmacologic methods or artificial rupture of membranes to increase their frequency and/or strength following the onset of spontaneous labor or contractions following spontaneous rupture of membranes (ACOG 2014)

All clinically significant ruptures of unscarred or scarred uteri. Trivial scar dehiscence noted incidentally at the time of surgery will be excluded

e.g. seizures, birth asphyxia defined by trialists, neonatal encephalopathy, disability in childhood, Proven and suspected neonatal sepsis

The Apgar score provides an accepted and convenient method for reporting the status of the newborn infant immediately after birth and the response to resuscitation if needed (ACOG 2015).

From birth of infant to collection of cord bloods after delivery of the placenta (an average of 15 minutes)

Severity of hypoxic ischaemic encephalopathy assessed using Sarnat staging; i)Stage 1 (mild): hyper-alertness, hyper-reflexia, dilated pupils, tachycardia, absence of seizures; ii)Stage 2 (moderate): lethargy, hyper-reflexia, miosis, bradycardia, seizures, hypotonia with weak suck and Moro reflexes; iii)Stage 3 (severe): stupor, flaccidity, small to mid-position pupils which react poorly to light, decreased stretch reflexes, hypothermia and absent Moro reflex.

The perinatal period is defined as "commences at 22 completed weeks (154 days) of gestation and ends seven completed days after birth of baby."

Inclusion Criteria: Pregnant women carrying a live singleton fetus ≥ 38 weeks completed gestation. (Gestational age will be calculated from the first day of the last menstrual period and an ultrasound examination carried out in the 2nd trimester) Longitudinal lie Cephalic presentation Intact amniotic ≥ 18 years of age on enrollment Exclusion Criteria: Not able to communicate in english contraindications to a vaginal examination contraindications to a vaginal birth

Finucane EM, Biesty L, Murphy D, Cotter A, Molloy E, O'Donnell M, Treweek S, Gillespie P, Campbell M, Morrison JJ, Alvarez-Iglesias A, Gyte G, Devane D. Feasibility study protocol of a pragmatic, randomised controlled pilot trial: membrane sweeping to prevent post-term pregnancy-the MILO Study. Trials. 2021 Feb 2;22(1):113. doi: 10.1186/s13063-021-05043-9.