By Ninha Silva, MARCH Centre Blog Editor (MSc Public Health Candidate)
Around 100,000 women die every year globally as a result of severe bleeding after birth (postpartum haemorrhage). In 2010, an international and multidisciplinary team, coordinated by the London School of hygiene and Tropical Medicine (LSHTM), initiated the Woman Trial study, to test whether tranexamic acid, a blood clot stabiliser, could be used as a tool for fighting excessive bleeding soon after giving birth.
Based on the results of CRASH-2, the Woman Trial recruited a total of 20,060 women in 21 countries, from March 2010 to April 2016. Results of the study, published earlier this year in The Lancet show that, if used within 3 hours, tranexamic acid can reduce death due to bleeding by about a third.
To disseminate findings of the study and raise awareness, the WOMAN Trial and the Maternal, Adolescent, Reproductive & Child Health (MARCH) Centre, will be hosting today, 9th of November 2017, an event that brings together leading experts in maternal health from the UK, Pakistan and Nigeria. The event also marks the launch of the ‘Blood Clock’ art installation, open to the public until February 2018, at LSHTM.
In anticipation to the event, we spoke to Haleema Shakur-Still, Project Director and Principal Investigator of the Woman Trial.
Could you start by giving us some background? How did Woman Trial come to life?
So, a bit about background. I think it must have been at least 10 years ago. We were doing a trial in trauma – bleeding is the biggest killer of young people with trauma and primarily young men – and we were doing a study called CRASH-2, which was looking at tranexamic acid as a treatment for traumatic haemorrhage.
We were in Nigeria and doctors in emergency department, who were taking part in CRASH-2, trial said: “Why are you only looking at this drug in trauma? What about postpartum haemorrhage?”. And at the time – because postpartum haemorrhage doesn’t actually kill people here in the UK- to be honest, I knew nothing about it [postpartum haemorrhage]. At the time, I said: “You know, our primary focus area for research is trauma”. But they insisted that this was something we should look at and when we came back [to London] we started looking at the issue and I was totally amazed that, in this day and age, women were still dying in childbirth and that over 100,000 women every year die of postpartum haemorrhage.
I must confess, I was shocked. And was even more shocked at the total lack of research in this area. For some reason, we’ve hardly studied the normal processes that happen during pregnancy and at the time of birth. Much less what happens when you have a problem during pregnancy and birth. So, we started planning a trial to look at tranexamic acid as treatment for postpartum haemorrhage, before we even had results of the CRASH-2 trial.
When you say “we”, is this yourself and Ian Roberts?
Definitely not. One of the things that we get totally wrong in academia is that individuals do things. I have never recruited a single patient into the trial. Ian has never recruited a single patient into the trial. The only way you can do good research is through collaboration with others. And this is absolutely critical. Academic institutions really discourage this notion of collaboration because we are constantly being pushed as individuals to claim things for ourselves because that’s how we progress. But I think it is fundamentally wrong. And for me to say it’s my trial, or for Ian to say it’s his trial or either one of us to claim it, would be absolutely wrong because there are hundreds of doctors and midwives. Thousands! In fact, I did a back-of-the-envelope calculation, and to deliver the WOMAN Trial would have taken half a million people. So, this is why it’s really important that it’s the WOMAN Trial collaboration that gets the kudos for any work that we do. It’s not about us as individuals.
Thank you so much for that answer. So, how did the collaboration start? How did you start putting everyone together to get this amazing trial running?
Yes, to get the collaboration… in Nigeria we got doctors and midwives on board very quickly because women dying from postpartum haemorrhage is a daily occurrence for them. Throughout they kept saying to us: “Look, our women are different and we’re sick of seeing them coming into our emergency departments and into our labour wards and dying.” So, to get people on board was relatively easy because people everywhere want to make a difference to their people. You know, none of us want to see people coming and dying because there’s nothing we can do about it.
In the West, the reason why we don’t see women dying is because we are healthier, we are fitter, we don’t have to cope with the burden of infectious diseases, anaemia. So, although we might believe, in the West, that we have all the treatments available and all we have to do is give the treatments, I think that we still need to keep looking for better treatments, for places where women are still dying. The fact that women here aren’t dying any longer doesn’t mean we should be complacent. The devastation of having postpartum haemorrhage is enormous.
You just have to read some of the stories of women who have had difficult birth and postpartum haemorrhage. They end up with PTSD [post-traumatic stress disorder], and they end up losing their ability to have children in the future…through hysterectomies, blood transfusions. Can you imagine being so scared of dying? Because that’s what goes through not only the mind of the woman and their families, it’s also the doctors looking after them. Every time they have a woman with postpartum haemorrhage.
On that note, could you explain how postpartum haemorrhage related morbidity affects a country socially and economically? Because it affects not only individuals, but the society on the whole.
Oh absolutely. Postpartum haemorrhage, when it kills a woman, immediately you have a husband who has lost his wife, a mother who has lost her daughter, a father who has lost his daughter, and a child who having been born will be lucky to survive – because a child without a mother is at high risk of early death. So, the first thing is that the child has to survive. And if they survive, the impact of a mother dying just goes from generation to generation. I was lucky enough to interview a man in his 30s who had lost his mother to postpartum haemorrhage. He was about 12 years old when she died in child birth, giving birth to his sibling. And even now it is impacting his life. He is now married, he has a wife, and his wife had their first child. And he has vowed that he is not going to expose his wife to having another child because he does not want his wife to die in child birth. So, the fear of death, just goes on and on.
Could you tell me what are the common causes of postpartum haemorrhage? Why does it happen mainly?
The reason why women have postpartum haemorrhage – some women are at high risk of developing postpartum haemorrhage, but for the majority we have no idea. So, the high-risk factors include anaemia, which is really common in developing countries; having had postpartum haemorrhage before; having given birth to many children; the older age group, or even the younger age group – a young mother or an older mother. So, there are lots of risk factors, but for the majority we really don’t know.
Now moving to the study results, could you explain what were the main findings?
In the study, we were looking at what is the effect of tranexamic acid on a woman bleeding to death, of the causes of death, the need for hysterectomy, and other major morbidities. And what we showed was that tranexamic acid significantly reduced the risk of a mother bleeding to death. We’ve just done a new analysis that shows that other than the first hour, for every 15-minute delay the effect of the treatment reduces by about 10%. So, giving the treatment really early is absolutely critical. So as soon as possible after birth, as soon as you make a diagnosis of a postpartum haemorrhage you should be treating the woman and there should be no delay.
Your previous findings also showed that if given within three hours, tranexamic acid, reduces the risk of bleeding to death by a third…
Yes, within three hours, but that should not be the key message. See, the problem we have is that doctors believe that they have three hours to treat a woman, so they can wait…they can do everything else and wait. But that’s not the message. The message is: if you give it [tranexamic acid] really early – as soon as possible- you can reduce the risk of bleeding to death by almost 70%. With every 15-minute delay, you’re reducing that effect by 10%. The thirty percent is just an average over the three hours, because at three hours there’s almost no effect. So, it’s really important that we get that message across.
Tranexamic acid has been known and used for a long time, so why did it take so long for people to realise that it could be used to potentially save the lives of thousands of women around the world. Why only now?
That’s a really good question. Tranexamic acid was discovered by an academic couple, husband and wife team working in Japan in the 60s. At that time women were actually dying from postpartum haemorrhage in rich countries at the same rate as in the poor countries and the dream of Utako Okamoto – the female professor- was to stop women bleeding to death. So, they developed the drug.
As you know to get the drug licensed you have to do all kinds of clinical trials to prove efficacy and safety, but she was unable to convince the obstetricians in her country at that time to do the studies that were needed. So, the drug got sold out to a drug company and it was only licensed for bleeding in haemophilia tooth extraction – so the full potential of the drug was never exploited. And because it is now out of patent, it is a cheap drug and I don’t believe there’s been much commercial interest in it. So, if there is no commercial interest and without public funding, I doubt anybody would have actually investigated this further.
But the good thing was that there was a lot of small studies done in general surgeries that showed that tranexamic acid reduced bleeding and the need for blood transfusion. And it was based on those surgical trials that we looked at the drug on trauma and we saw there a reduction in mortality due to bleeding, again with time dependent effect. Without all those small academic trials that were done in surgery we wouldn’t have followed up with it in trauma. If it wasn’t for the doctors making the link between bleeding and trauma and bleeding and postpartum haemorrhage, we wouldn’t have done it. So, sometimes you need to have people outside of the speciality. Obstetricians, at that point would not have made the link. It took the trauma doctors to see the potential link between bleeding in trauma and bleeding from postpartum haemorrhage.
One of the things that I found fascinating was that your team met Dr Utako Okamoto, and from the start she said that the trial would work and have positive results. How important was this for the study?
True. She died right at the point we finished recruitment, so she never actually got to hear the results of the study. She truly believed that this drug would help women with postpartum haemorrhage, because that was her aim in developing the drug in the first place. The fact that we were able to prove this for her 50 years later, it’s just fantastic.
So, now that the trial is over, what changes can we expect to see? Do you foresee any changes and developments soon?
Oh absolutely! Already within six months of the trial results coming out, the World Health Organisation, last week, announced that they had updated the treatment guidelines for postpartum haemorrhage. As you know the first thing you have to start with, is making sure that it is in the treatment guidelines. The drug is available in most countries, it’s relatively cheap, so availability in most countries shouldn’t be a problem because it’s licensed for so many other things. So, the key thing we have to make sure is that doctors who look after women with postpartum haemorrhage know the results of the trial, because women cannot benefit from the results if the doctor treating does not know about the results. So, the biggest challenge is to make sure that doctors know about it and that women and their families demand it.
For example, in the UK – with trauma – if a patient had a traumatic haemorrhage and didn’t receive tranexamic acid, as audit is done, the hospital will not get paid for that treatment episode. So, we have to find ways to make sure that women benefit from this treatment [tranexamic acid]. What we have to do is to make sure that there is a push from women, from organisations who look after women wellbeing, from ministries of health. For example, we met with the Ministry of Health in Nigeria, within few weeks of the results being available, and he wrote to all obstetricians in the country making them aware of the results and requesting that the treatment is implemented. In Pakistan, also within few weeks of the results being available, the Ministry of Health said that it should be in the treatment guidelines. So, already many things started to happen, but we have a long way before women start really benefiting.
When you say that the treatment guidelines for postpartum haemorrhage has been updated, do you also mean that tranexamic acid has also been included in the list of essential medicines?
The guidelines for postpartum haemorrhage and essential medicines are slightly different. Tranexamic acid is already in the list of essential medicines for trauma, so countries should be making it available already, but we know that many countries are still not making it available. On the other hand, a lot of the countries we are talking about, already have it available. So, availability should not be a problem. The problem is that if doctors are not demanding a drug, pharmacies won’t make it available. So, we need a push from doctors, they need to start prescribing it.
What are the best strategies to create knowledge and awareness amongst doctors that this drug is essential and can save thousands of lives?
The first thing, is to make sure that key opinion leaders know the results; second, we need to use different sources to promote information. We have used all the methods available. There isn’t a single method and that’s why we utilise things like films, radio and TV interviews, our lead collaborators in each country doing work with the media, to try and bring the results to the attention of the public. This is part of the reason why we commissioned the ‘Blood Clock’ because we are constantly looking for ways to engage with the public to make sure we use every opportunity to bring the results to the attention of doctors, midwives and the public.
That leads nicely to my next question. Could you tell us how Graham Tydeman got on board of this project?
We put a general call out for people to come out with ideas for an art installation that would illustrate the problem of postpartum haemorrhage, to highlight the results of the Woman Trial. And Graham came up with the idea of the ‘Blood Clock’. I think that the fact that he is an obstetrician gave him an advantage over most artists. He knows the global problem [postpartum haemorrhage] and he knows the problem personally because he sees it routinely in his daily work. I think that the fact that he used the blood clock to illustrate the problem was really important.
For how long will the installation be on display at LSHTM?
It will be here until February next year.
Will it be open to the public?
Yes. We have the security situation, but we do want to invite people to come in and see the exhibition, because it really does represent what happens. The amazing thing is that Graham was able to use all kinds of instruments and equipment that is associated with childbirth. For example, equipment that is used in caesarean section, equipment that is used to treat a woman that is bleeding from retained placenta and the baby cribs that were used for thousands of babies after birth. The blood flow tilts every six minutes; because every six minutes a woman dies from postpartum haemorrhage. The volume of the blood is also important, because this is the average at which a woman is a at high risk of death- it is about two and half litres, but in a developing country that would be much lower if, for example, the woman is anaemic. The installation is highly symbolic.
Do you have any final thoughts that you’d like to share?
There is just so much to change… What we know is – if a woman turns up to hospital having delivered her baby elsewhere or if she is in the hospital and bleeding – we now have really good evidence that we could reduce her risk of bleeding to death significantly by using a very cheap intervention. Sometimes we forget that it is easier to do something about ‘the bird hand’ – that is the woman in front of us. We know women die in the community from postpartum haemorrhage, many who we can do little about. But while we are waiting for things to change, to make life better for women and all in the community, let’s do what we know will work for the woman in front of us.
For me the key message is that sometimes we focus on just the negative, the political aspects that we can do little about, but we should focus on the fact that we can make some difference. There is not just one answer and we need a combination of things. If we add on all these things together – tranexamic acid as well as other treatments- we really will make a difference.
Postpartum haemorrhage is the main cause of maternal mortality in most Low-Income Countries and, globally, nearly one quarter of all maternal deaths are associated with Postpartum Haemorrhage. The Woman Trial findings and subsequent introduction of new recommendations and guidelines for treatment of Postpartum haemorrhage show that have the potential to change this reality.
Full results of the Woman Trial study are available here.
Image copyright: Women Trial website – http://womantrial.lshtm.ac.uk/