Induction of labour in pre-eclamptic women: a randomised trial comparing balloon catheter with oral misoprostol.

Lead Research Organisation: University of Liverpool
Department Name: Reproductive and Developmental Medicine

Abstract

High blood pressure in pregnancy (or preeclampsia) is a major cause of death worldwide, killing up to 80,000 pregnant women annually. For women with preeclampsia currently available therapies improve the outcome of the illness, but the final cure only comes with delivery of the baby. Prompt delivery, preferably by the vaginal route rather than by caesarean section, is therefore vital to achieve good maternal and neonatal outcomes. There are various methods available to start the woman?s labour, and it is crucial that the method used is both effective and safe for mother and baby. This is especially important in low resource settings where the underlying illness is often severe and there are few facilities for monitoring the mother and baby. The World Health Organisation currently recommends two low cost options ? oral misoprostol (OM) tablets and transcervical Foley catheterisation (TFC). Whilst in the former method a tablet is swallowed every two hours, in the latter a thin rubber (?Foley?) catheter is threaded through the neck of the womb and held in place with a small inflated balloon at its tip. Although OM has been widely studied, it is infrequently used in India. Furthermore, there is comparatively little research on the TFC and the two methods have never been directly compared despite their great promise. Current evidence suggests that OM may be faster but sometimes ?overcontract? the uterus, whilst TFC may be slower but safer.

We propose a study to be conducted in two large government hospitals in Nagpur, India. 800 women with preeclampsia will be randomly allocated to use OM (25mcg tablets 2hrly) or TFC (size 18F with a 50ml balloon for 12 hours) for their induction. The main outcome is the attainment of vaginal delivery within 24 hours, and a variety of other measures of maternal and neonatal morbidity including cost effectiveness will also be collected. Currently 15% of mothers with preeclampsia suffer stillbirths in this setting ? this trial will also examine whether the use of the balloon catheter can reduce this.

Recruitment rates in a recent study of preeclamptic women using the same team and site demonstrate that 800 women can be recruited in 2 years. The study will be managed on a daily basis by the successful team of Dr Mundle in GMC Nagpur and Gynuity Health Projects, one of the most successful low-resource setting clinical trial specialists in the world.

Technical Summary

Up to 80,000 pregnant women die annually from pre-eclampsia and eclampsia ? many of them in India where there are more maternal deaths than any other country. Current therapies reduce the morbidity associated with pre-eclampsia but the final cure only comes with delivery. Prompt delivery of the baby, preferably by the vaginal route following labour induction, is vital to achieve good maternal and neonatal outcomes. The need for an effective and safe induction method is especially important in low resource settings where the underlying illness is often severe and there are minimal facilities for monitoring of mother and baby. The WHO currently recommends one of two different interventions for low resource settings ? oral misoprostol (OM) and transcervical Foley catheterisation (TFC). Although OM has been widely studied, there is comparatively little research on the TCF. Neither are widely used and the two methods have never been directly compared. Current evidence suggests that OM may be faster but with more uterine hyperstimulation, whilst TFC may be slower but safer.

We propose an open label randomised trial of OM (25mcg tablets 2hrly) versus TFC (18F with 50ml balloon for 12 hours). The study will be conducted in two large government hospitals in Nagpur, India and will recruit women with preeclampsia who require induction of labour. Following informed consent, labour induction will be carried out using the selected method, followed by artificial membrane rupture and oxytocin infusion as required. The primary outcome is the attainment of vaginal delivery within 24 hours which is expected in 62% of women in the OM group. To detect an absolute reduction of 10% in this rate (i.e. 62% to 52%) with 80% power (two-sided a =0.05) we will require a sample of 768 women. This number will also have 80% power to detect a reduction in stillbirth rate from 15% (data from a recent study in the same site) to 8.5%. The secondary outcomes will include measures of maternal and neonatal morbidity up to the time of hospital discharge as well as a detailed economic evaluation.

Recruitment rates in a recent study of pre-eclamptic women using the same team and site demonstrate that 800 women can be recruited in 2 years. The study will be managed on a daily basis by the successful team of Dr Mundle in GMC Nagpur and Gynuity Health Projects, one of the most successful low-resource setting clinical trial specialists in the world.

Publications

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Alfirevic Z (2014) Oral misoprostol for induction of labour. in The Cochrane database of systematic reviews

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Morris JL (2017) FIGO's updated recommendations for misoprostol used alone in gynecology and obstetrics. in International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics

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Nabi HA (2014) A hundred years of induction of labour methods. in European journal of obstetrics, gynecology, and reproductive biology

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Polk J; Weeks AD (2017) Textbook of Obstetrics and Gynaecology

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Weeks A (2016) New WHO antenatal care model-quality worth paying for? in Lancet (London, England)

 
Description Chair of the Data Monitoring Committee for the SOLVE Study (Randomised controlled trial of a synthetic osmotic cervical dilator for induction of labour in comparison to dinoprostone vaginal insert; ISRCTN: 20131893)
Geographic Reach National 
Policy Influence Type Participation in a advisory committee
Impact I am Chair of the SOLVE DMC that launched in 2017. It is funded by Medicem, the manufacturer of the osmotic dilator.
URL https://www.birmingham.ac.uk/research/activity/mds/trials/bctu/trials/womens/solve/index.aspx
 
Description PROBIT-F Trial Steering Committee (Prostaglandin insert (Propess) versus trans-cervical balloon catheter for out-patient labour induction: A randomised controlled trial of feasibility)
Geographic Reach National 
Policy Influence Type Participation in a advisory committee
 
Description WHO RP2 Research Assessment Panel
Geographic Reach Multiple continents/international 
Policy Influence Type Participation in a advisory committee
Impact The RP2 Panel is an invited group of 10 researchers in maternal and child health who assess all the WHO research projects in this area. They meet formally once a year in Geneva as well as reviewing research proposals via email. The projects all relate to research in low and middle income settings.
 
Description WHO Collaborating Centre for Research and Research Synthesis in Reproductive Health 
Organisation World Health Organization (WHO)
Department Department of Reproductive Health and Research
Country Global 
Sector Academic/University 
PI Contribution The Terms of Reference are: 1. Collaborate in research synthesis to support the translation of evidence-based research findings into WHO policy and services in the area of maternal and newborn health
Collaborator Contribution To advise on research proposals and protocols, contribute to Trial Steering Groups
Impact The WHO officers contribute to all the research proposals within the Sanyu Research Unit by commenting on the protocols. In addition, Julie Storr was a co-investigator on the BabyGel Study and Metin Gulmezoglu chaired the Steering Committee for INFORM study.
Start Year 2012
 
Description "Improving child birth outcomes; more stable, less stables". 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Professional Practitioners
Results and Impact I was invited to give the 'Annual Christmas Lecture' at Alder Hey Hospital.
Year(s) Of Engagement Activity 2017
 
Description Annual meeting of European WHO Collaborating Centres in Edinburgh 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Annual meeting of European WHO Collaborating Centres at which we each present our ongoing work.
Year(s) Of Engagement Activity 2018
 
Description British Maternal Fetal Medicine Society (BMFMS) - Annual Conference - June 2016 - Birmingham, UK - INFORM study - abstract "Induction of labour in hypertensive women in India: a randomised trial comparing the Foley catheter with oral misoprostol" 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact The British Maternal and Fetal Medicine Society holds an annual congress to which research investigators are invited to show case their research and research outputs. In 2016 Professor Andrew Weeks, one of the co-investigators on the INFORM study had an abstract accepted for the conference.
Year(s) Of Engagement Activity 2016
 
Description British Maternal Fetal Medicine Society (BMFMS) - Annual Conference - June 2016 - Birmingham, UK - PPH Butterfly study - abstract (02.5)"Induction of labour in hypertensive women in India: a randomised trial comparing the Foley catheter with oral misoprostol" 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact BMFMS aims to improve the standard of pregnancy care by disseminating knowledge, promoting and funding research, contributing to the development and implementation of high quality training and providing a forum where issues relevant to pregnancy care are discussed. The Society holds an annual conference which attracts O and G practitioners from across the UK, and internationally. An abstract was accepted at this conference on the PPH Butterfly medical device conceptual thinking and development.

PL.08 (Reference in conference abstract booklet) The PPH Butterfly: a new device to facilitate bimanual uterine compression for the treatment of postpartum haemorrhage
Weeks, A(1) Aflaifel, N(1),(2); Cunningham, C(1);Lambert, D (1); Fisher, A(1); Lavender, T(3); Watt, P(1)
(1)University of Liverpool, Liverpool, UK;
(2) University of Omer Al-Mukhtar, Al-Bayda, Libya;
(3) University of Manchester, Manchester, UK

Introduction Postpartum haemorrhage (PPH) remains a major cause of maternal mortality and simple, low-cost, nonpharmacological therapies are urgently needed. Bimanual
uterine compression (BMC) is effective, but is both painful and intrusive. The PPH Butterfly is designed to make uterine compression much less invasive. This will expand access to PPH therapies and provide 'surgical treatment' at an early stage in the PPH process.Methods The PPH Butterfly was designed by a multidisciplinary team and reviewed by public and clinical focus groups during its development. The device was compared to standard BMC in a cross-over study. Twenty clinicians with previous experience of BMC, and 22 without conducted two forms of uterine compression in succession, each for 5 min. The order was randomly allocated. The mannequin (Noelle, Gaumard Ltd) was supplied with an 'atonic uterus', modified to allow BMC and to include a pressure sensor. This assessed the amount of intrauterine pressure produced by the participants' compression.
After regulatory approvals, the device was tested in healthy postpartum women.Results Users and focus groups found the PPH Butterfly device acceptable and easily used. In the mannequin studies there was huge interpersonal variation in the amount of pressure generated, but no significant difference between the two techniques or groups of users. With both methods, intrauterine pressures declined over the 5 min of use.Conclusion The PPH Butterfly is simple to use, even among obstetric care providers with little experience, and produces equivalent pressures to standard BMC. Funding National Institute for Health Research (Invention for Innovation i4i programme)
Year(s) Of Engagement Activity 2016
 
Description GLOW conference debate chair 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact I am on the steering committee for the GLOW Society (Global Women's Health) that has a conference every 1-2 years. In this year conference in Cambridge I chaired a round-table discussion with female African scientists about the role of women in science.
Year(s) Of Engagement Activity 2018
 
Description Global Health CSG 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact I sit on the RCOG Global Maternal Health Clinical Study Group. This meets 3 times per year to co-ordinate global maternal health activity.
Year(s) Of Engagement Activity 2018
 
Description Global Women's Research Society(GLOW) Annual Conference, Manchester, UK. Oral presentation on INFORM Study 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Professor Andrew Weeks was invited to make an oral presentation on the INFORM study. This study looked at the "Induction of labour in pre-eclamptic women: a randomised trial comparing the Foley balloon catheter with oral misoprostol". Pre-eclampsia remains a significant problem for pregnant women in low resource settings. Drug regimens can achieve some improvement but the best course of action with the best outcomes is prompt delivery of the baby. Prof Weeks gave a synopsis of the study primary and secondary objectives. setting of the research (Nagpur, India), number of women recruited and randomised to the study (602), the primary outcome measure (Attainment of vaginal delivery within 24 hours). This study told us that misoprostol is the more successful of the two methods tested from both the clincians' perspective and also from the women's perspective. Women were interviewed about their expectations before their induction commenced and were then re-interviewed within 48 hours of their delivery to ask for their opinions on the induction process, their labour and delivery and their perspective on each of the two technologies used and women were asked for their overall impression of the whole induction/delivery experience. The women were also asked to express their ideas on what they would like to see changed in any future inductions.
Professor Weeks applied to the MRC for further funding to take this research forward to look at what the best clinical care protocol will be for pre-eclamptic women again in Nagpur. The results of this application will be known later in 2017.
Year(s) Of Engagement Activity 2016
 
Description INFORM Study dissemination meeting (Nagpur, India) 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Professional Practitioners
Results and Impact This was a 3-hour meeting in Nagpur to disseminate the results of the INFORM Study. 58 obstetricians, postgraduate students, midwives and local public health officials attended to hear the results. Talks were given by Professor Shuchita Mundle (General Medical College Nagpur; background to the study), Professor Andrew Weeks (University of Liverpool; study methods, results and future directions), and Dr Hillary Bracken (Gynuity Health Projects; cost effectiveness evaluation). A question and answer session afterwards covered the changes in local practice since the study ended, practitioners' preference for induction method, and their experiences of the study. The meeting was followed by a shared meal as a way of thanking the local team for their participation in the study.
Year(s) Of Engagement Activity 2016
 
Description International Federation of Gynaecology and Obstetrics (FIGO) World Congress, Vancouver, Canada October 2015 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact FIGO operates on a global level and is the only organisation that brings together professional societies of obstetricians and gynecologists on a global basis. Attendance at this conference had a two-fold purpose. The audience over the course of the 3 conference days attracts in excess of 1000 attendees, many operating at the highest levels of clinical practice and research within their own organisations. Therefore attendance and presentations made at this conference allows access to a significant number of fellow professionals who can go back and influence their policy and decision makers. Researchers can allow interact with fellow reserachers in bringing together ideas for further research.

At the 2015 meeting in Vancouver we presented 2 posters - one giving the 'breaking' results of the INFORM study (we were too late to put the results in the submitted abstract and so were ineligible for an oral presentation) and the other giving a progress report on the development of the PPH Butterfly (device design and mannequin studies).

The second purpose of this visit was to meet with fellow investigators working on the INFORM project. This gave many members of the trial management group (TMG) attending the conference the opportunity to discuss issues face-to-face (members of the TMG are located in New York (USA) Nagput (India) and Liverpool (UK). The logistics of setting up a TMG for this study together with the travel costs usually makes regular face-to-face communication very difficult. The team could also spend a great deal of time discussing future plans in relation to a INFORM 2 study.
Year(s) Of Engagement Activity 2015
 
Description Lecture on Normal Labour 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Undergraduate students
Results and Impact A lecture to the undergraduate SNOGS (Students in Neonatology, Obstetrics and Gynaecology Society) conference.
Year(s) Of Engagement Activity 2018
 
Description NIHR GCRF Stillbirth Advisory Board 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Policymakers/politicians
Results and Impact I am a member of the advisory group for the University of Manchester Stillbirth project (funded by NIHR Grand Challenges Research Fund). The project seeks to explore the causes of stillbirth in African countries.
Year(s) Of Engagement Activity 2018
 
Description Normal labour 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Undergraduate students
Results and Impact A lecture on normal labour to the Student Neonatal Obstetrics and Gynaecology Society (SNOGS) which i first set up in 2008 with medical students who were attached to me.
Year(s) Of Engagement Activity 2017
 
Description Obstetrics in 8 pictures 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Undergraduate students
Results and Impact A lecture on maternity care to the Student Neonatal Obstetrics and Gynaecology Society (SNOGS) which i first set up in 2008 with medical students who were attached to me.
Year(s) Of Engagement Activity 2017
 
Description Presentation at MRC Centenary event 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact The talk was very well received and many people came up to me afterwards to chat about maternal health (as well as to try abdominal palpation on the mannequins). The keynote speaker was Dr Lawrence McGinty (ITN Chief Science Correspondent) who spoke to me following the meeting about the possibility of doing a new piece about the importance of low cost technologies in maternal health.

Unbeknown to me there was also a blogger there who subsequently wrote about my presentation in a blog (https://sciencegremlin.wordpress.com/2013/06/23/maternity-care-in-low-resource-settings-the-art-of-achieving-good-outcomes-with-few-resources/).
Year(s) Of Engagement Activity 2013
URL http://news.liv.ac.uk/2013/06/21/video-liverpool-celebrates-100-years-of-the-medical-research-counci...
 
Description Presentation of INFORM Study results at a regional obstetric and gynaecology meeting in Rajkot, India 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact This is a regional obs / gynae meeting organised by FOGSI, the professional obs / gynae society of India. We had an hour-long symposium, one of very few of the 3-day conference in which all attendees came together in a single session. We covered the background to the study (Prof Tom Easterling of the University of Washington), the INFORM study methods and results (Dr Shuchita Mundle, General Medical College, Nagpur) and the cost analysis (Dr Hillary Bracken, Gynuity Health Projects).
Year(s) Of Engagement Activity 2016
URL http://yuvafogsi.rajkotobgynsociety.com/Programme/Scientific-Programme/4783
 
Description Royal College of Obstetricians and Gynaecologists (RCOG) - Annual Conference (June 2016) - Birmingham, UK - Poster Presentation - "Induction of labour in pre-eclamptic women: a randomised trial comparing the Foley balloon catheter with oral misoprostol: results" INFORM STUDY 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact O2.5 (Conference abstract booklet reference)
Study title: ""Induction of labour in hypertensive women in India: a randomised trial comparing the Foley catheter with oral misoprostol" INFORM study
Poster title: "Induction of labour in pre-eclamptic women: a randomised trial comparing the Foley balloon catheter with oral misoprostol: results"
Mundle, S (1); Bracken, H(2); Faragher, B(3); Alfirevic, Z(4); Winikoff, B(2); Weeks, A (4)
(1) Government Medical College, Nagpur, India;
(2) Gynuity Health Projects, New York, NY, USA;
(3) Liverpool School of Tropical Medicine, Liverpool, UK;
(4) University of Liverpool, Liverpool, UK
Introduction
Between 40 000 and 80 000 women die annually from hypertension in pregnancy. Prompt delivery, preferably by vaginal route, is vital for good maternal and neonatal outcomes.
Two low-cost interventions-oral misoprostol tablets and transcervical Foley catheterisation-are recommended for use in low-resource settings, but their relative risks and benefits are not known.
Methods In all, 602 women with a live fetus requiring delivery for pre-eclampsia or hypertension were randomly assigned to cervical ripening with oral misoprostol 25 lg every 2 hours
(maximum of 12 doses) or transcervical Foley catheter (size 18 F with 30-mL balloon). This remained until active labour started, the Foley catheter fell out, or 12 hours had elapsed. Induction continued with artificial membrane rupture and oxytocin. Funded by MRC.
Results More women in the misoprostol arm had a vaginal birth within 24 hours (57.0% versus 47.0%; P = 0.014). Women induced with misoprostol were more likely to have a vaginal birth (59.3% versus 49.7%; P = 0.017) and with a shorter time to delivery (771 min versus 861 min; P = 0.013). Oxytocin requirements were higher in the Foley arm. Rates of uterine hyperstimulation were very low in both groups (0.7% versus 0.3%; P = 0.566) and no differences were seen in neonatal morbidity. More women in the misoprostol group would use the same method in the future should they require another induction (82.8% versus 72.0%; P = 0.006).
Conclusion Oral misoprostol 25 lg was more effective and more acceptable to women than a transcervical Foley catheter for induction of labour in women requiring delivery because of preeclampsia or hypertension.
Year(s) Of Engagement Activity 2016
 
Description The INFORM Study results 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact I gave an invited lecture at the ISSHP (International Society for the study of hypertension in pregnancy) in Amsterdam entitled: Trials in low-resourced setting. The INFORM study (oral misoprostol versus balloon induction in women with PIH or Preeclampsia).
Year(s) Of Engagement Activity 2018
 
Description WHO Collaborating Centres annual meeting in Edinburgh 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact This was the annual meeting of the WHO Collaborating Centres in Maternal and Child Health for Europe. I presented the work of our centre in Liverpool.
Year(s) Of Engagement Activity 2018
 
Description Women's Voices in African Low Income Settings 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact This was a working group set up to take forward the concept of PPI (Patient and public involvement) in research in low income settings. Interested parties came from Leicester, London, Liverpool and Uganda to develop a funding application.
Year(s) Of Engagement Activity 2018
 
Description www.misoprostol.org website 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Health professionals
Results and Impact I set up www.misoprostol.org in 2001 with a colleague in order to disseminate evidence-based dosage recommendations for misoprostol. The University of Liverpool has funded 2 major relaunches - one in 2005 and one currently in progress. It now contains 169 documents and 58 pages and includes the FIGO guidelines, an extensive bibliography of over 1800 references, and information on availability, dangers and protocols. Dosage posters are also available for download and the main pages are translated into Dutch, Spanish and Russian.

The website is used extensively throughout the world. It currently receives around 16,500 visits per month (an increase of 45% from 2011) and tops the Google search for misoprostol. Visitors to the site come from all over the world: for example in September 2013 the top 15 countries were India, Mexico, Australia, Brazil, Germany, Canada, UK, South Africa, Czech Republic, Turkey, Indonesia, United Arab Emirates, Poland, Columbia and Kenya. Most visitors are directed from search engines, but 10% directly type 'www.misoprostol.org'. 74% of the visits are to the home page or main dosage page. The website is also referenced in guidelines including the Royal College of Obstetricians and Gynaecologists guideline on Late Intrauterine Fetal Death and Stillbirth.


The website is widely referenced (see above) but as we are not present at the time of decision making we do not have any direct evidence of the way in which it has affected misoprostol use.
Year(s) Of Engagement Activity Pre-2006,2006,2007,2008,
URL http://www.misoprostol.org