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E-MOTIVE wins prestigious Trial of the Year Award

The landmark E-MOTIVE study, led by University of Birmingham researchers and coordinated by the Birmingham Clinical Trials Unit, as been awarded ‘David Sackett Trial of the Year Award’ by the Society of Clinical Trials, recognising the importance of the findings and the potential impact as the simple, low-cost approach is rolled out around the world, dramatically improving maternal health across the globe. The trial tested a package of low-cost interventions that resulted in a 60% reduction in heavy bleeding following childbirth.

Each year the award goes to a randomized, controlled trial published in the previous calendar year that is considered to improve the lot of humankind and provide the basis for substantial, beneficial change in healthcare, amongst other criteria.

“This has been the largest set of nominations for the Trial of the Year Award in all my time on the committee. We received numerous nominations for worthy trials, from around the world and across a large number of clinical disciplines – including obstetrics, emergency medicine, infectious disease, and cancer. We had a challenging time as a committee to choose a winner” said Andrew Cook, Chair of the SCT David Sackett Trial of the Year Committee.

Postpartum haemorrhage (PPH), or severe bleeding after birth, is the leading cause of maternal deaths worldwide. It affects an estimated 14 million women each year and results in around 70 000 deaths – mostly in low and middle-income countries – equivalent to 1 death every 6 minutes. The E-MOTIVE study found that objectively measuring blood loss using a simple, low-cost collection device called a ‘drape’ and bundling together WHO-recommended treatments – rather than offering them sequentially – reduced severe bleeding by 60%, and women were less likely to lose their life.

Dr Adam Devall collected the award, on behalf of the E-MOTIVE team, from the Society of Clinical Trials 45th Annual Meeting, in Boston, USA, and said: “I’m honoured to accept the Trial of the Year Award on behalf of the E-MOTIVE project. E-MOTIVE was a huge international team effort, and this award speaks to the dedication of teams at each of our 80+ sites. More high-quality clinical trial evidence is desperately needed for pregnancy and maternal health so we’re delighted to receive this recognition of our work and the impact it will have on deaths from PPH.”

Professor Arri Coomarasamy, who led the E-MOTIVE trial and is the Co-Director of the WHO Collaborating Centre on Global Women’s Health at the University of Birmingham said: “This new approach to treating postpartum haemorrhage could radically improve women’s chances of surviving childbirth globally, helping them get the treatment they need when they need it”.

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Understanding pregnancy: Accelerating the development of new therapies for pregnancy-specific conditions

During pregnancy, women and pregnant individuals who do not identify as women* can develop a range of pregnancy-specific conditions, such as preeclampsia and gestational diabetes, that can adversely affect both their own health and that of the developing foetus during the pregnancy. These conditions can affect the lifelong health of both mother and child. Despite the danger that these conditions present to mother and baby, there are few approved, safe and effective medicines to treat them, and limited investment in novel therapy development.

To map out key barriers and potential enablers of preclinical research and experimental medicine to support the development of new medicines for pregnancy-specific conditions, the Academy of Medical Sciences, Birmingham Health Partners, and Concept Foundation organised a multi-sectoral FORUM workshop in September 2023. People with lived experience joined representatives from academia, the commercial sector, clinical practice (including doctors and midwives), regulatory authorities, funding bodies, charities, and patient advocacy groups at the meeting.

The result of this workshop is a new report – Understanding pregnancy: Accelerating the development of new therapies for pregnancy-specific conditions – which highlights the need to raise awareness of the importance of research in pregnancy, and give women opportunities to participate.

> Understanding pregnancy: Accelerating the development of new therapies for pregnancy-specific conditions – view and download the report here

This work builds upon the BHP-led Pregnancy Policy Commission which in 2022 published its Healthy Mum, Healthy Baby, Healthy Future: The Case for UK Leadership in the Development of Safe, Effective and Accessible Medicines for Use in Pregnancy report, proposing a clear roadmap to improve the lives of millions of people, not just for women while they are pregnant, but for future generations.

Professor Peter Brocklehurst, Emeritus Professor at BHP founder member the University of Birmingham, commented: “We need to better understand the biological mechanisms of pregnancy-specific conditions so that we can develop therapies that target these processes. To do this, we need more health data and biological samples from women with those conditions.”

Forum participants identified the following six priority areas for next steps:

    1. A cross-sectoral and cross-speciality network or coalition, including women with lived experience, to provide a platform for collaboration and to coordinate efforts to promote the development of new medicines for pregnancy-specific conditions.
    2. Additional interdisciplinary research and cross-sector collaboration to address key knowledge gaps (including the biology of the placenta, of the early stages of pregnancy, and of pregnancy-specific conditions), to enable appropriate use of animal models and physiologically based pharmacokinetic (PBPK) modelling, and to leverage routinely collected health data and patient samples.
    3. The establishment of a more enabling environment for research in pregnancy, for example through development of a stronger research base and a more supportive regulatory environment.
    4. Greater engagement with women to raise awareness of the importance of research into pregnancy and of opportunities to participate in this research, including when women contact the healthcare system.
    5. Education and training of healthcare professionals, including midwives, to promote research in pregnancy.
    6. Advocacy to secure greater prioritisation of research in pregnancy (and women’s health more generally) by policymakers, funders, and higher education institutions.

The workshop was chaired by Professor Peter Brocklehurst FMedSci, Emeritus Professor of Women’s Health at the University of Birmingham, and Dr Pauline Williams CBE FMedSci, an independent pharmaceutical medicine consultant and former Senior Vice-President and Head of Global Health R&D at GlaxoSmithKline.

The Academy acknowledges that not all pregnant people identify as women. While the terms ‘woman’ and ‘mother’ are used here, many of the learnings from the workshop about obstetric/pregnancy-specific conditions are expected to be widely applicable. It is recognised that there will be specific experiences and challenges associated with obstetric conditions among pregnant individuals who do not identify as women that were not explored at the workshop given the lack of specific research in this area. 

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Epilepsy in pregnancy – new project to create personalised care for at-risk mums

Pregnant women with epilepsy could see a major improvement in the care they receive through a new cross-BHP project led by the University of Birmingham with Birmingham Women’s and Children’s Hospitals NHS Foundation Trust (BWC), which also aims to reduce maternal mortality risk.

The EpiSafe project, funded by the National Institute for Health and Care Research over five years, will create and trial an evidence-based, personalised care bundle specifically designed for pregnant women with epilepsy.

The team of researchers, led by Professor Shakila Thangaratinam from the University of Birmingham and BWC, will provide healthcare professionals with the tools and guidance they need to streamline the care they provide and allow for shared decision-making with women regarding their epilepsy and pregnancy.

The EpiSafe project will also study the long-term effects of newer anti-epileptic drugs (AEDs) on children’s development. Many mothers are prescribed these newer AEDs due to concerns with older medications, yet they often discontinue them out of fear of potential harm to their baby.

As part of this study, the researchers across BHP will bridge the knowledge gap by assessing the long-term neurodevelopmental outcomes of children exposed to newer AEDs during pregnancy. This research will empower pregnant women with epilepsy, enabling them to make informed decisions about the safe use of AEDs.

Professor Shakila Thangaratinam, Dame Hilda Lloyd Chair of Maternal and Perinatal Health at the University of Birmingham and Consultant Obstetrician at Birmingham Women’s and Children’s NHS Foundation Trust said:

“Epilepsy continues to be one of the main causes of mothers dying in pregnancy and postpartum period. Sadly, we are not observing a fall in maternal deaths. On the contrary, there has been a doubling of the rates of Sudden Unexpected Death in Epilepsy (SUDEP) in mothers between 2013-15 and 2019-21 in UK and Ireland.

“We know that the primary factors contributing to these poor maternal outcomes are the lack of specialist antenatal care and reduced compliance with anti-seizure medication. The EpiSafe programme of work has the potential to improve the care these women receive and save lives within this high-risk group.”

At the core of the EpiSafe programme are mothers with lived experiences of epilepsy from diverse backgrounds. They will play a pivotal role throughout the lifetime of the programme in shaping the development and roll-out of the EpiSafe bundle. Charity partners on the programme include Epilepsy Research Institute and Epilepsy Action, who will provide invaluable insight and guidance.

Dr John Allotey, Associate Professor in Epidemiology and Women’s Health at the University of Birmingham and project leader said: “By working with diverse groups of women with epilepsy and their families, professional bodies, organisations providing care for pregnant women with epilepsy, as well as dedicated epilepsy charities, we will develop an acceptable, relevant and accessible tool which identifies pregnant women with epilepsy who are at high risk and promotes safe use of AED.”

The project consists of six work packages to create the EpiSafe risk assessment and treatment pathway, that will facilitate early specialist epilepsy care for high-risk women. The team will also evaluate whether EpiSafe will help more women at high-risk access specialist epilepsy care early in pregnancy.

The Epilepsy Research Institute’s Director of Research Partnerships, Dr Caoimhe Twohig-Bennett, said: “The Institute launched last month with Reproduction & Hormones as one of our overarching strategic research theme. We are delighted to be collaborating on the EpiSafe project, to ensure safer care and reduced risks for pregnant women with epilepsy.“Central to the work of the Epilepsy Research Institute is a culture of advocating and actioning the research priorities of people affected by epilepsy through our Shape Network PPIE group. Members of the network have been pivotal in the development of this programme of research, and we look forward to their continued involvement as this important project progresses.”

Rajinder Flora, Assistant Director of NIHR’s Programme Grants for Applied Research (PGfAR), which funds the research, said: “Epilepsy causes 1 in 10 of all deaths during pregnancy in the UK, this new project aims to identify women with epilepsy who are at highest risk of seizures and create a treatment pathway for them.

“Funding research like this is vital to provide evidence-based personalised care for pregnant women with epilepsy”

The EpiSafe team also includes co-applicants from University of Liverpool, University of Manchester, Birmingham City University, University of Aberdeen and Belfast Health and Social Care trust, as well as partnerships with Kings Health Partnership and Murdoch Children’s Research initiative.

The EpiSafe work streams consist of:

  • Gathering all evidence needed to design the EpiSafe bundle,
  • Co-designing and testing the EpiSafe bundle by working with women and healthcare professionals,
  • A randomised controlled trial to see if using the EpiSafe bundle improves care, reduces seizures and complications in mother and baby,
  • Studying the longer-term development of children aged 7-11 exposed to AEDs before birth,
  • Studying the cost of using EpiSafe and its long-term impact, and
  • Planning appropriate involvement and engagement with women with epilepsy and their support networks.

Parliamentary event

At a parliamentary event to launch the project hosted by former Health Minister Baroness Cumberlege – who chaired key report on harmful side effects of some medicine – patients and researchers explained about how important this project is for ensuring that women across the UK get a say in managing epilepsy during pregnancy.

Addressing the event, Baroness Cumberlege said: “Being pregnant is a very important stage for every woman, conscious that if all goes well she is bringing new life into the world. The EpiSafe programme is crucial in creating evidenced based pathways which must ensure the voices and experience of women directly shape solutions. The success of this programme will only be realised if there is meaningful collaboration between researchers, clinicians, and women with epilepsy and their families. Cooperation is vital to spur change.

“All those involved in the care of pregnant women have a duty to safeguard the wellbeing of all mothers with chronic health needs. I will follow the progress of innovations borne from initiatives such as this closely, and with the help of others advocate tirelessly for their swift translation into enhanced standards of care.”

Giving progesterone in early pregnancy may reduce preeclampsia risk – preliminary study

Prescribing vaginal progesterone treatment early in pregnancy appears to reduce risk of developing preeclampsia – a potentially fatal condition – by approximately 39%, a recent research review suggests.

Collaborating through the Tommy’s National Centre for Miscarriage Research, Dr Pedro Melo from the University of Oxford, and Dr Adam Devall and Professor Arri Coomarasamy from BHP member the University of Birmingham have analysed the findings of 11 recent studies involving 11,640 women.

These studies were originally designed to explore the impact of progesterone on reducing miscarriage or preterm birth rates. In every study, data were also collected on whether the same treatment affected rates of preeclampsia or other high blood pressure (hypertensive) disorders in women during pregnancy.

The review, published in the British Journal of Obstetrics and Gynaecology, concludes that vaginal progesterone appears to reduce risk of hypertensive disorders in pregnancy, but only when treatment is started in the first trimester.

The review showed that, compared to a placebo, 400 mg of vaginal progesterone used twice a day was associated with a 39% reduction in preeclampsia and a 29% reduction in the rate of other hypertensive disorders such as gestational hypertension.

Starting progesterone early in pregnancy appears to be critical: no clear evidence was found through this review to suggest that starting progesterone in the second or third trimesters had an effect.

Frequency, quantity, and method of use are also important: 400 mg used twice daily as a vaginal capsule showed a benefit in reducing risk of preeclampsia and other hypertensive disorders but using 400 mg once a day did not.

“The recent PROMISE and larger PRISM trials led to an exciting breakthrough in finding evidence that progesterone can reduce miscarriage risk in some women when used in the first trimester. This evidence led to updated NICE guidelines in 2021 recommending its use. But the signal we found in the data for progesterone’s effectiveness in reducing hypertensive disorders had not previously been demonstrated.

“These are exciting preliminary findings, but it must be stressed that they were secondary results of trials focusing on the use of progesterone for the prevention of miscarriage and preterm birth, not preeclampsia. We need a large randomised controlled trial focusing specifically on women and birthing people at risk of preeclampsia to confirm our hypothesis that progesterone supplementation may tackle abnormal implantation in this subgroup of people” said Dr Pedro Melo, lead author of the study at the Tommy’s National Centre for Miscarriage Research at the University of Birmingham and the Nuffield Department of Women’s and Reproductive Health at the University of Oxford.

Dr Adam Devall, Institute of Metabolism and Systems Research, University of Birmingham, added: “The preliminary finding from this study suggests vaginal micronised progesterone might reduce the risk of preeclampsia. The researchers are calling for a large multi-centre clinical trial to explore the effects of progesterone in women at risk of preeclampsia.”

The 11 studies analysed focused on groups of pregnant women who either had a history of recurrent pregnancy loss or had a threatened miscarriage (i.e., they were experiencing early pregnancy bleeding). The review recommends that future studies are needed to explore the link further, to find out whether the reductions of 29-39% are relevant to all women and birthing people and whether the effect could be larger for those who have risk factors for preeclampsia.

Preeclampsia is a condition that affects some pregnant women, usually during the second half of pregnancy or soon after their baby is delivered. Preeclampsia can lead to fetal growth restriction which can cause premature birth. If severe, it can be dangerous, sometimes even fatal, for mothers.

Progesterone plays an important role in implantation of the embryo as it helps make the tissue lining the uterus receptive to implantation. By giving vaginal progesterone, researchers believe it is possible to combat problems with the lining of the womb and partly correct abnormal implantation, helping support successful development of the blood vessels in the placenta. This would reduce the chance of developing conditions such as preeclampsia.

“This research further supports Tommy’s calls for women with a history of miscarriage and pregnancy bleeding to be given progesterone in the early stages of pregnancy. We must continue to keep exploring progesterone’s potential and improve understanding of what it can be used for, who it works best for, when, and how” explained Kate Davies, Research Director at Tommy’s.

Healthy Mum, Healthy Baby, Healthy Future – a year on, what progress has been made?

“We cannot allow another 40 years to pass by with no new medicines for pregnant women” – Professor Katie Morris reflects on BHP’s Pregnancy Policy Commission and its work since the publication of the Healthy Mum, Healthy Baby, Healthy Future report in 2022. 

Most pregnant women will have a healthy pregnancy and give birth to healthy babies. An increasing number of women, however, will either have one or more health conditions before they become pregnant which require on-going treatment, or they may develop complications of pregnancy which require treatment.

The care of these women is severely hampered by a lack of suitable medicines, that we definitively know to be safe and effective for use in pregnancy or during breastfeeding. As a consequence, women and babies worldwide continue to become sick and die during or immediately after pregnancy. Despite this, over the last 40 years, only two new medicines have been approved for use in pregnancy.

Birmingham Health Partners‘ 2021 report, ‘Safe and Effective Medicines for Use in Pregnancy: A Call to Action’ highlighted the absence of research and information on the safety of medicines in pregnancy. It also drew attention to the urgent health needs of this neglected group both nationally and internationally, and the potential for saving and improving millions of lives globally.

As a direct response to this report the University of Birmingham and Birmingham Health Partners convened a Policy Commission focussing on the UK, canvassing knowledge and opinions from key parties including patient groups, the pharmaceutical industry, scientists, clinicians, NHS leaders, regulators and insurers. It aimed to explore the scale of the problems that are preventing the evaluation and development of safe medicines for use in pregnancy and collected recommendations for how these could be overcome.

The Commission report was published in May 2022 and entitled “Healthy Mum, Healthy Baby, Healthy Future.” It made a series of eight recommendations related to advocacy, widening participation of pregnant women in clinical trials, updating information on existing medicines, de-risking the insurance process for clinical trials, incentivising industry to develop pregnancy specific medicines, establishing a UK-wide network of research centres, improving the use of routine data, and appointing a UK steering committee to deliver these recommendations.

Over the last year, members of the Commission have been working to develop the steering group and engage with industry and insurance companies to drive forward these recommendations. There are challenges in driving this agenda forwards which can be broadly described as a de-prioritisation of women’s health, and particularly pregnancy, by industry and in the delivery of clinical trials related to workforce and capacity.

Without combined efforts from all stakeholders; public, scientific, clinical, industry, regulatory and governmental sectors, we will not see any progress. The first step will be through co-ordinated efforts via the recently formed steering committee and renewed approaches for engagement with industry and insurance providers.

We cannot allow another 40 years to pass by with no new medicines for pregnant women.

Together these stakeholders must advocate for change, respond to research and funding issues, and, where necessary, work to change official guidance or law to enable progress in this much neglected area.

The UK is well placed to become a global pioneer of maternal health research innovation. We have the health infrastructure of our NHS, with its birth-to-death records. Our medicines regulator is able to fast-track drug development and make changes to streamline the process, as well as working globally with Europe, the US and other regions. We are already a global hub for insurance – and we can support and build on this to add to our potential in becoming a leader in clinical studies for medicines in pregnancy.

There is an urgent need for action to address the underserved area of medicines use in pregnancy. Without it, women and babies will continue to die when they could be saved. They will continue to experience long-term health effects, disability and distress, which might be avoided. It is no longer ethical to deny pregnant women and their unborn babies access to safe, modern medicines that the rest of the population enjoys.

Single-stranded suture threads could prevent pregnancy infection complications, finds C-STICH trial

Women at risk of pregnancy loss who need a specialist surgical procedure are at a lower risk of infection if the procedure is carried out using a single-stranded suture thread, results from the C-STICH clinical trial found.

The trial was the largest of its type and is published in the Lancet. It involved more than 2,000 expectant mothers who needed a procedure called a cerclage, where a purse string suture is placed around the cervix (the neck of the womb) during pregnancy. Women were randomly allocated to have the surgical procedure performed using either a single-stranded thread or a braided thread.

Researchers tested whether there would be any difference in miscarriage or stillbirth, due to an increased risk of infection, from using a braided suture thread. The research, funded by the NIHR, demonstrated that single-stranded sutures could potentially improve outcomes for mothers at risk of preterm birth.

The team led by researchers from Birmingham Women’s and Children’s Hospitals (BWC) and the University of Birmingham – both founder-members of BHP – found that the mothers treated with single-stranded threads had no differences in pregnancy loss or preterm birth but reported fewer instances of infection and sepsis. This could have important implications for the health outcomes of mothers and babies who are treated with a cervical cerclage in their pregnancy.

Dr Vicky Hodgetts-Morton, NIHR Clinical Lecturer in Obstetrics at the University of Birmingham and Birmingham Women’s Hospital explained the implications of the trial results. Dr Hodgetts-Morton said:

“Preterm birth is a significant problem, complicating approximately one in ten pregnancies around the world. The consequences of preterm birth may be significant with some babies being born too early to survive, and those that survive are at increased risk of health complications. One cause for preterm birth is cervical insufficiency, occurring in 0.5% to 1% of pregnant women for which the placement of a vaginal cervical cerclage can be an effective treatment.

“Suture thread choice has the potential to improve how well a cerclage works in preventing miscarriage, stillbirth and preterm birth. Both single stranded and braided threads are commonly used to perform cerclages and our findings show no differences in pregnancy loss and preterm birth. The C-STICH trial results did show an increased risk of infections in labour and around the time of delivery with braided threads and this supported our hypothesis that a single stranded thread could reduce the risk of infection developing during the pregnancy.”

Mr Philip Toozs-Hobson, Chief Investigator of the C-STICH project and Consultant Gynaecologist at the Birmingham Women’s Hospital said:

“We are extremely grateful to all the women who trusted us by taking part in the study and also the dedication of the research teams at of the 72 maternity units who made the trial happen. Our aim, as ever, is to improve women’s experience in pregnancy through safer childbirth and to help the NHS achieve their target of reducing both pre-term birth and cerebral palsy. This work has added to our understanding relating to infection and sepsis.”

The study also highlighted that while single stranded suture threads led to better outcomes around infection, clinicians mentioned that such suture threads were subjectively more difficult to remove and more often required surgery to help remove under a general anaesthetic.