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

Study Overview
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Brief Summary
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Multicentre, pragmatic, parallel group, pilot randomised controlled trial with an embedded factorial design.

Detailed Description
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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).

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

Conditions
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Pregnancy, Prolonged, Induced; Birth, Pregnancy Related

Intervention / Treatment
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* Procedure: Amniotic membrane sweep


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Factorial Assignment
Interventional Model Description: 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
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group A<br>Membrane sweep @ 39 weeks' gestation only | Procedure: Amniotic membrane sweep<br>* 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.<br>|
| Experimental: Group B<br>Membrane sweep @ 40 weeks' gestation only | Procedure: Amniotic membrane sweep<br>* 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.<br>|
| Experimental: Group C<br>Membrane sweep @ 39, 40 and 41 weeks' gestation or until onset of labour | Procedure: Amniotic membrane sweep<br>* 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.<br>|
| Experimental: Group D<br>Membrane sweep @ 40 and 41 weeks' gestation or until onset of labour | Procedure: Amniotic membrane sweep<br>* 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.<br>|
| No Intervention: Control Group<br>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). | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recruitment | Evaluation of the number and percentage of eligible women who are recruited and randomised to the study. Assessed by study-specific checklists. | Duration of the recruitment process (approximately 8 months ) | 
| Retention | 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. | At month 15 approximately | 
| Adherence with the trial interventions. | 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. | At month 15 approximately | 
| Evaluation of the randomisation process. | 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. | At month 15 approximately | 
| Evaluation of attrition rates | Evaluation of attrition rates assessed by study-specific checklists. Data will be extracted from routinely collected data. | At month 15 approximately | 
| Evaluation of the types of attrition | Evaluation of the types of attrition assessed by case report forms. Data will be extracted from routinely collected data. | At month 21 approximately | 
| Evaluation of the data collection process through study specific checklists | 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. | At month 21 approximately | 
| Estimate the main effect of individual intervention components and their interactions | 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. | At month 21 approximately | 
| Evaluation of the data analysis process | 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. | At month 21 approximately | 
| Evaluation of the EQ5D | Assessment of the mechanism of, timing of and delivery of the EQ5D through study specific checklists. | At month 21 approximately | 
| Feasibility of cost analyses process through analysis of study specific documentation. | 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. | At month 21 approximately | 
| Feasibility of the cost effectiveness analyses | Assessment of the mechanism and utilisation of the incremental cost-effectiveness ratio (ICER), through study specific checklists. | At month 21 approximately | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants achieving a spontaneous onset of labour | Labour which begins spontaneously. | From time of randomisation to commencement of spontaneous onset of labour or formal induction of labour or caesarean section (up to 5 weeks) | 
| Number of participants who underwent an induction of labour | Formal induction of labour using pharmacological or surgical methods. | From time of randomisation to commencement of formal induction of labour (up to 5 weeks). | 
| Number of participants achieving a spontaneous vaginal birth | Spontaneous vaginal birth | From time of randomisation to birth of baby (up to 5 weeks) | 
| Instrumental birth | Vaginal birth which is assisted with the use of instruments. | From time of randomisation to birth of baby (up to 5 weeks) | 
| Caesarean Section | Birth which is achieved through the surgical procedure caesarean section. | From time of randomisation to birth of baby (up to 5 weeks) | 
| Post-Partum Haemorrhage ≥ 500mls | Blood loss ≥ 500mls within the first 24 hours of the birth of a baby | From time of birth to 24 hours after the birth of baby. | 
| Antepartum haemorrhage requiring hospital admission | Bleeding from the genital tract, from 24+0 weeks of pregnancy and before the birth of the baby. | From 24+0 weeks of pregnancy to birth of baby (up to 18 weeks) | 
| Uterine hyperstimulation with/without fetal heart rate (FHR) changes | 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. | From time of randomisation to birth of baby (up to 5 weeks) | 
| Serious maternal death or morbidity | Serious maternal death or morbidity (e.g. uterine rupture, admission to intensive care unit, septicaemia) | From time of randomisation to six weeks postnatal (up to 11 weeks). | 
| Epidural analgesia | Introduction of a local anaesthetic into the epidural space of the vertebral canal. | From time of randomisation to birth of baby (up to 5 weeks) | 
| Augmentation of labour | 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) | From commencement of established labour to birth of baby (up to 2 days) | 
| Pyrexia in labour | Pyrexia that developed anytime after onset of labour. | From commencement of established labour to birth of baby (up to 2 days) | 
| Uterine rupture | All clinically signiﬁcant ruptures of unscarred or scarred uteri. Trivial scar dehiscence noted incidentally at the time of surgery will be excluded | From time of randomisation to birth of baby (up to 5 weeks) | 
| EQ5D-5L | EuroQol EQ5D-5L survey instrument. | From time of randomisation to six weeks postnatal (up to 11 weeks) | 
| Serious neonatal morbidity | e.g. seizures, birth asphyxia defined by trialists, neonatal encephalopathy, disability in childhood, Proven and suspected neonatal sepsis | From time of birth of baby to six weeks postnatal. | 
| Apgar score < 7 at five minutes. | 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 baby to five minutes of life. | 
| Cord PH < 7.20 | Umbilical cord blood gas test. | From birth of infant to collection of cord bloods after delivery of the placenta (an average of 15 minutes) | 
| Neonatal encephalopathy | 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. | From time of birth to six weeks postnatal. | 
| Perinatal death | The perinatal period is defined as commences at 22 completed weeks (154 days) of gestation and ends seven completed days after birth of baby. | From time of randomisation to seven completed days after birth of baby (up to 6 weeks) | 
| Admission to neonatal intensive care unit or equivalent | Admission of infant to neonatal intensive care unit or equivalent | From time of birth to six weeks postnatal. | 
| Length of time from membrane sweep to birth of baby. | Length of time from membrane sweep to birth of baby . | From time of membrane sweep to birth of baby (up to 4 weeks) | 
| Length of time from formal induction of labour to birth of baby. | Length of time from formal induction of labour to birth of baby. | From time of formal induction of labour to birth of baby (up to 2 weeks) | 
| Overall length of maternal hospital stay | Overall length of maternal hospital stay | From time of randomisation to six weeks postnatal (up to 11 weeks). | 
| Length of infant stay in neonatal intensive care unit or equivalent | Length of infant stay in neonatal intensive care unit or equivalent | From time of birth to six weeks postnatal. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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membrane sweep, feasibility study, randomised trial, pilot study, SWAT, pregnancy, induction of labour, post dates, prolonged pregnancy