Ahead of International Clinical Trials Day, Haleema Shakur-Still, Emeritus Professor of Global Health Clinical Trials at the London School of Hygiene & Tropical Medicine, shares insights from The WOMAN Trials, highlighting the importance of clinical trials for addressing health inequalities, and the global, collaborative effort that drives the trials and their aims forward.
How did you first get into clinical trials and how did earlier experience lead to your work on The WOMAN Trial and WOMAN-2 Trial?
How I got into clinical trials… I used to be that nightmare child – the one who was always asking ‘but why’ and this has never stopped, even now… I trained as a nurse and loved being a nurse but was frustrated by the fact that for most of the treatments I was giving to my patients, there was no evidence to support most of what I was doing. I thought I could do better for patients by going into research.
I thought I could get answers through Biomedical Sciences by focussing on how cells, organs and systems function in the human body, which is relevant to understanding and treatment of human diseases. After a few years, I learnt that the time to get ideas from the laboratory to benefit patients took about a decade and most will fail to show benefit. However, at the same time, I was lucky to discover the field of clinical trials and immediately saw how well-designed randomised controlled trials could provide answers.
My first experience of clinical trials was in respiratory diseases – mostly small mechanistic and proof of concept trials. When I moved to LSHTM, I discovered the power of large simple trials, with CRASH-2 looking at tranexamic acid (TXA) for traumatic haemorrhage showing a reduction in mortality due to bleeding of about one third. The large trials such as CRASH-2, WOMAN, and WOMAN-2 can never be the work of a single person. It takes a massive team of people – a social movement – all wanting to find answers to human problem. I never see myself as the Principal Investigator but more a privileged part of a global team.
How can the WOMAN Trials and clinical trials more broadly help to address inequities in maternal health and maternal care?
In addition to the many inequalities that women suffer, there is very little research guiding the care of women. For decades, regulations have excluded ‘pregnant women’ and ‘women of child-bearing age’ from participating in clinical trials. But childbearing age could be from 10 to over 50, which is the majority of a woman’s life.
Many countries still exclude pregnant women from taking part in clinical trials. In the WOMAN trial, one country refused to approve the trial on the basis it was unethical to include ‘pregnant women’. The fact that we were looking at reducing mortality from postpartum haemorrhage (PPH) did not change their minds.
Our clinical trials aim to address a significant inequality by involving women who have been excluded from trials and do not have access to vital treatments.
The WOMAN-2 Trial is due to publish results later this year on the effectiveness of TXA for the prevention of PPH in women with anaemia. Why women with anaemia and what do you hope to achieve through the trial?
Why women with anaemia? Women with anaemia are at a massive disadvantage. As they are already anaemic, they cannot afford to lose any blood. Yet, at the same time, anaemia increases their risk of bleeding.
About 500 million women of reproductive age suffer with anaemia worldwide. There are severe consequences of anaemia during pregnancy for both the baby and the mother. For the baby, there is an increased risk of being born with low birthweight, being born too early, and increased risk of death. For the mother, she is at an increased risk of death during and after childbirth. Severe anaemia can lead to low circulating volume, increased strain on the heart, and increased risk of haemorrhage.
In a perfect world, all women would be treated for anaemia before they become pregnant. We prevent anaemia throughout their pregnancy so they go into giving birth as healthy as possible. This will take massive political will. With the WOMAN-2 trial, if we can reduce the risk of women bleeding after childbirth with TXA, we will reduce their chances of dying – so more mothers live. We know TXA can reduce the chances of women dying once haemorrhage starts, but if we can prevent haemorrhaging starting in the first place, that would be a fantastic intervention.
What are the current challenges and opportunities in research and practice with regard to the treatment and prevention of PPH?
There are too many challenges and opportunities to list here, but here are some of the main ones.
About 7 years ago, the WOMAN trial showed that TXA could reduce the risk of a woman bleeding to death after childbirth by about one third. TXA also reduced the need for surgery to control bleeding by well over one third. With this knowledge, you would imagine the world would be championing this treatment to make sure every woman who needs it, gets it. Yet, women are not receiving this treatment. Accelerating change to ensure every woman giving birth has access to the drug provides a huge opportunity to stop women dying in childbirth.
For many women, it is almost too late for them by the time they are diagnosed with a PPH. If we can prevent women developing PPH in the first place, that has the potential to save many more lives and prevent significant morbidity caused by bleeding. The WOMAN-2 trial, which is reporting later this year, hopes to provide the answer as to whether we can prevent PPH happening in the first place in women with moderate and severe anaemia, who are at high risk of PPH.
We were asked how women who give birth at home or in the community could benefit from TXA if they were to develop PPH, as well as how midwives could give TXA as soon as they diagnose PPH if it had to be given by an intravenous injection which required specialist additional training and equipment. To find ways to address these issues, we have been working on finding alternative routes to intravenous injection. The Pharmaco-TXA and WOMAN-PharmacoTXA trials have produced some promising evidence that there is huge potential for an intramuscular injection (like a vaccine) to work. The IM-WOMAN Trial, which has just started, will provide the definitive answer if an intramuscular injection is truly an option.
Women who suffer with anaemia have a higher risk of bleeding after childbirth and have a higher risk of dying. To date all focus has been nutrition, but the fact that women bleed every month and many suffer heavy menstrual loss that can contribute to developing anaemia is not being addressed. Treatment and prevention of anaemia should be a priority for research, policy and action to reduce maternal mortality caused by PPH.
In your time working in clinical trials, what human stories have moved you most and highlighted the urgency of the issues you are working on?
There are so many sadly. One which stood out particularly was when I was working on the WOMAN Trial, I was travelling between Lagos and Ibadan in Nigeria and saw a sign along the road which said ‘Motherless Baby Unit’. Three words that carry so much meaning.
I asked our local team if it was possible to arrange a visit to the Unit. Here, I saw the consequences of mothers who had died in childbirth. Many, many babies with no mothers being cared for in an institution. Seeing children deprived of their mother’s love and brought up to become independent as quickly as possible so that their working fathers could take them back; this really highlighted the urgency of finding ways of stopping mothers dying in childbirth. I was given permission to film some of the babies to show the impact of losing a mother. This was an important reminder of why I do trials – to improve the survival of mothers.
The other story is the one which gave birth to the WOMAN trial. During a training visit in 2006 for the CRASH-2 trial to National Hospital, Abuja, Nigeria, I was in the emergency department when a woman was brought. I could hear CPR being performed and then loud wailing. When I asked what was happening, the doctor said that the woman who had just arrived had died from PPH. She had given birth at a rural clinic and they could not stop the bleeding, so she was brought to the hospital. He said this was quite common. This was a shock to me. In the UK where I live, women rarely die after childbirth and it’s even rarer for a woman to die from PPH.
The doctor asked why we were only looking at TXA for trauma and not for PPH. The WOMAN Trial came about because of this unknown woman, whose family wailing I still hear to this day.