This 50 year-old drug can tackle the leading cause of maternal death

Twenty-eight weeks into her first pregnancy, Rabia’s worst fears were realised. She went into labour, and the baby was stillborn. The bleeding started the next day.

“It was severe bleeding, uncontrolled,” Rabia recalls. “The doctors and nurses were changing the bed sheets after every two or three minutes. They were red with blood.”

She was at a hospital in her hometown of Taxila, north of the Pakistani capital Islamabad. The hospital was small and poorly equipped; it employed hardly any gynaecologists, and did not have the facilities to give Rabia a blood transfusion or to surgically explore the cause of the haemorrhage. As her condition worsened and the bleeding continued unabated, panicked medical staff referred her to a larger hospital, over an hour’s drive away, in the nearby city of Rawalpindi.

By the time she reached the next hospital, everything was a blur. She had lost so much blood that she was experiencing multiple organ failure: her kidneys, liver and lungs were all beginning to fail. In Pakistan, blood banks are generally in short supply, and on top of this Rabia has a rare blood type. In a race against the clock, doctors tested the blood of the relatives who had travelled with her.

Her husband desperately called friends, colleagues, anyone he could think of who could quickly get to the hospital. Those that matched gave blood, which was transfused into Rabia immediately. At the same time, doctors sought to stop the bleeding and warned her family that she might not survive. But, after ten days in hospital, she made a full recovery.

As she struggled to make sense of her experience, Rabia – who five years later is now 31 and studying for a PhD in environmental sciences – looked up every medical paper she could find about the horror she had experienced. As she read, she realised that she was one of the lucky ones. Postpartum haemorrhage is the leading cause of maternal death worldwide, responsible for around 100,000 deaths every year.

The condition is usually defined as blood loss of more than 500 ml within 24 hours of a vaginal birth, or more than 1,000 ml, together with signs of decreased blood circulation, following a caesarean.

While around 6 per cent of women giving birth all over the world – in rich and poor countries alike – develop postpartum haemorrhage, 99 per cent of deaths from it occur in low- and middle-income countries.

Put bluntly, if you develop postpartum haemorrhage in the UK or France, it is extremely unlikely you will die. If you develop it in Pakistan or Nigeria, there is a significant chance that you will. This disparity applies to maternal deaths across the board: 99 per cent of maternal deaths take place in low- and middle-income countries.

A level of bleeding after giving birth is normal, because a woman has to bleed when the placenta detaches. But for some women, this does not stop. Postpartum haemorrhage can have various causes, but by far the most common is uterine atony. In simple terms: during delivery, the uterus squeezes to push the baby out away from the uterine wall, to which it is attached via the placenta. All being well, the uterus would then contract and seal off the bleeding. Sometimes, that doesn’t happen, so the uterus remains dilated and blood flow is uncontrolled.

In other cases of postpartum haemorrhage, the placenta might not detach entirely. Or the uterus might rupture, causing bleeding inside and out. Or the vagina might be torn, which can cause severe bleeding.

Typical treatment for postpartum haemorrhage involves uterine massage, and drugs such as misoprostol, oxytocin or ergometrine, all of which help the uterus to contract. If this treatment doesn’t work, doctors might take surgical steps – manually removing trapped parts of the placenta, placing temporary sutures on the uterus, stitching external or internal lacerations on the vagina, or, in extreme cases, performing a hysterectomy and removing the uterus altogether.

It can be difficult to identify the cause of the bleeding; during the time this takes a woman may lose a critical amount of blood and, as Rabia did, suffer multiple organ failure. For many, this will cause irreversible damage or death.

It is notoriously difficult to obtain reliable statistics for maternal mortality; a 2015 report by the World Health Organization (WHO) noted that many countries “lack comprehensive systems” for recording these deaths and that “underreporting” is rife.

On the best estimates available, the global maternal mortality rate fell by 44 per cent in the 25 years from 1990 to 2015. While this is a vast improvement, it still means that around the world, more than 200 women die for every 100,000 who give birth.

In 2009, Haleema Shakur-Still and Ian Roberts, two research scientists at the London School of Hygiene and Tropical Medicine, began to wonder if they might be able to add a tool to the arsenal in the battle against maternal death. They had been working on a clinical trial of a drug called tranexamic acid. The drug, which makes it easier for the body to stem bleeding by stopping blood clots from breaking down, was out of patent and therefore cheap.

It had been invented by husband and wife Shosuke and Utako Okamoto in Japan in 1962. The Okamotos thought it might be a useful treatment for postpartum haemorrhage, but they could not convince local doctors to perform a clinical trial. Instead, tranexamic acid was picked up by a pharmaceutical company and used as a treatment for heavy periods and after tooth extractions.

Shakur-Still and Roberts’s trial, CRASH-2, tested its use on people who were bleeding badly from injuries. The results were striking. If the drug was given intravenously within three hours of injury, it reduced the risk of death by a third. As the two scientists worked with doctors around the world, the subject of postpartum haemorrhage came up again and again.

“Doctors in Nigeria were seeing women come into the emergency department having given birth elsewhere, and bleeding to death,” says Shakur-Still. “It’s so far removed from our experience here [in the UK] that I didn’t even believe that was a reality, until I started looking at the data.”

In March 2010, Shakur-Still and Roberts launched the WOMAN (World Maternal Antifibrinolytic) trial, working in 21 countries to test whether tranexamic acid might similarly reduce deaths from postpartum haemorrhage. The double-blinded trial enrolled 20,000 women with postpartum haemorrhage, randomly assigning them to receive either 1 g of intravenous tranexamic acid, or a matching placebo, in addition to usual care – which would typically consist of uterine massage, one or more of the drugs aimed at helping the uterus contract, or surgery.

Nigeria was the first country to come on board for the WOMAN trial. Around the country, 53 hospitals took part. University College Hospital (UCH) in Ibadan, a sprawling city in southern Nigeria, was the organisational centre.

The thing about postpartum haemorrhage, doctors say, is the chaos. It is a race against the clock to stop the bleeding and find the cause before the patient loses a critical amount of blood and goes into irreversible shock.

Nike Bello, a consultant in gynaecology and obstetrics at UCH Ibadan, has treated too many cases of severe postpartum haemorrhage to count. “[In some cases] we did every single step of surgery, one by one, and she still died. Even after we removed the uterus and ligated all the arteries,” she says. She works at a large, well-equipped government hospital, an expansive complex set back from a traffic-clogged road. The most severe cases end up here, women referred from more basic facilities, often having lost massive amounts of blood before arrival.

Those that stand out in Bello’s mind are the ones that lived. One woman came in having given birth elsewhere, bleeding from lacerations to her vagina. The wounds had been packed with gauze, but it had not stemmed the bleeding. The gauze was soaking red, blood dripping through. “I looked at the vagina and it was all avulsed, it was like someone took a razor to it and shredded it to bits,” says Bello. “I really can’t explain what they did.” Seeing how severe the blood loss was, she decided to take the woman to surgery immediately.

The anaesthetist intervened: there was no blood to replace what she was losing, he said, and what if she died in surgery? In Nigeria, the desperately underfunded healthcare system works on a pay-as-you-go model, where patients and their families must purchase anaesthetic, drugs or blood before medical procedures can be carried out. Payment can be deferred for surgery if a patient cannot afford it, but not for drugs.

The reasoning is that hospitals can absorb the cost of the doctors’ time on surgery but cannot afford to replace medicines that have not first been paid for. If blood banks have stock of the right blood type, patients must buy it before they can receive a transfusion. As there are limited supplies of blood, more often than not, they also have to find a donor. This woman’s family did not have the funds to purchase the blood, and needed to go home to look for more money, which could cause a fatal delay.

“We are saying that if we arrest the bleeding she might die – but if we don’t arrest the bleeding she will die,” Bello told the anaesthetist. “I would rather the patient dies while I am trying to save her than watch her die without trying.”

They took her to surgery. Bello sewed the multiple wounds on the vagina, but the other tissue around it began to tear. As she stitched, the family returned with enough money for four pints of blood. The transfusion was given, and the wounds were eventually sealed off. The woman’s life was saved.

Nigeria has one of the highest maternal mortality rates in the world; according to the WHO, the country accounts for 19 per cent of all maternal deaths worldwide. Around 800 women die for every 100,000 births. While this figure has lowered over the past two decades, it is still the worst in sub-Saharan Africa. Postpartum haemorrhage is the leading cause. As in other parts of the world, eclampsia – a complication resulting from high blood pressure – is a close second.

Even when a woman survives postpartum haemorrhage, it can have devastating consequences. Oladapo Olayemi, another consultant in obstetrics and gynaecology at UCH, once treated a nurse, an employee at the hospital, who haemorrhaged after giving birth to her first child. The bleeding was severe and nothing was working to make it stop.

As Olayemi operated, he realised he would have to remove her uterus in order to save her life. The woman survived, but for three months afterwards, she would not speak to him, ignoring him when she passed him in the corridor. “Childbearing is a major aspect of our social life,” says Olayemi. “It is seen as a social success to have children, and she only had one. This means you are reluctant to remove the uterus – you have to weigh saving her life. Sometimes you take that decision too late.”

Only 32 per cent of women in Nigeria deliver their babies with a skilled attendant; the vast majority deliver at home, at a basic health facility, or with a traditional midwife. This means that if a woman begins to haemorrhage, there can be long delays before she gets the right treatment. Often, by the time she reaches a large hospital like UCH, she will already have been to two or three smaller hospitals along the way.

This, added to the financial pressure of having to buy medicines and blood before treatment, is a serious logistical problem. Against this context, it is clear why doctors at UCH and elsewhere in Nigeria were eager to take part in the WOMAN trial. But given the scale of the challenges, could tranexamic acid help?

The trial ran for six years, during which time Utako Okamoto, the co-inventor of the drug, died (her husband, Shosuke, had died in 2004). When the results came out in April 2017, they vindicated the Okamotos’ original thesis that it could be effective for postpartum haemorrhage. If tranexamic acid was administered within three hours of birth, the risk of death reduced by 31 per cent, around a third. “It buys us time,” explains Bello. “It makes the bleeding slower, so you can replace blood and fix the problem.”

Before the trial, there were concerns that the drug – which encourages blood clotting – might have an adverse effect since pregnant and lactating women are already prone to blood clots. But the trial showed that it did not. “For us in Nigeria, [the results] are very significant,” says Bukola Fawole, a professor at UCH and Nigeria’s project lead on the WOMAN trial. “If postpartum haemorrhage accounts for 25 per cent of all maternal deaths, and if we utilise tranexamic acid in every woman who is bleeding sufficiently early, it will reduce almost a third of those deaths. For us, that is huge.”

The WHO updated its recommendation on using tranexamic acid for postpartum haemorrhage in light of the WOMAN trial. But almost two years after the results came out, the drug isn’t always easily available in the countries that need it most. Tranexamic acid is cheap, heat-resistant, easy to store and to produce, and it is proven to save lives. Why aren’t we using it everywhere?