Failure of the uterus or our understanding?

Written by Professor Ian Roberts, Professor of Epidemiology at LSHTM and co-lead of the WOMAN-2 Trial.

On 15 January 2024, a new fact will enter the world. It will take the form of just a few numbers but will potentially shed new light on the field of maternal health and why women die in childbirth. At 09:00 that morning, two statisticians sitting back-to-back in a cramped office overlooking Malet Street in central London will receive the codes revealing which women received the trial treatment – tranexamic acid – and who got placebo in the WOMAN-2 Trial, a trial that I have co-led for the last seven years.

The WOMAN-2 Trial will show whether tranexamic acid, a cheap, generic drug, can prevent life threatening bleeding after childbirth. Every year, worldwide, 14 million women suffer severe bleeding, also known as postpartum haemorrhage or PPH, and 70,000 women die. Anyone who has heard the crying of a newborn in a room silenced by a maternal death, will know the urgency of these results.

Dr Nike times the contraction of a woman to be sure that it is frequent and strong enough before she sends the patient to the labor ward.
In Nigeria, Dr Nike Bello times the contraction of a woman to be sure that it is frequent and strong enough before she sends the patient to the labour ward.

On 15 January, my co-investigator Professor Haleema Shakur-Still and I will be pacing nervously like expectant parents. Once the codes are linked to the outcome data on the 15,000 women across four countries who enrolled in the trial, the statisticians will run independent analyses. Heartbeats later, the result of seven years’ work by hundreds of doctors and midwives around the world will stutter onto their screens.

According to the WHO, the main cause of PPH is the failure of the uterus to contract after birth. The unborn baby “breathes” through the placenta, a plump pillow of flesh that clings like an octopus to the wall of the uterus, sliding its tentacles deep into the mother’s body searching for pools of oxygenated blood. Every beat of the mother’s heart sends waves of fresh blood crashing into these pools – almost a litre of blood per minute. But after birth, when the placenta releases its grip, this riptide of blood must be staunched, or the mother will bleed to death. To reach the placenta, her blood vessels weave through a wall of interlacing muscle fibres. When the placenta detaches, these fibres contract, clamping down on bleeding vessels, like a clenched fist on a wet sponge. The WHO believes that PPH happens because the uterus is too weak to squeeze. If the doctor feels an enlarged uterus in a woman with PPH, the uterus is assumed be at fault. This uterine “atony” is said to account for 70% of PPH cases.

Uterine atony and oxytocin

The theory of uterine atony is obstetric lore passed down from professors to students for centuries. However, there is a not much evidence to support it. Studies that have actually measured uterine tone – by placing a pressure monitor inside the uterus – have found that tone cannot be assessed by feeling the belly, and there is no correlation between tone and bleeding.

The discovery of drugs that make the uterus contract gave a commercial boost to the atony theory. In 1906, Henry Dale identified oxytocin, the hormone produced by the mother that causes her uterus to contract and, in 1953, Vincent De Vigneaud of Cornell University worked out how to synthesise it. De Vigneaud won a Nobel Prize and oxytocin became a blockbuster.

The WHO still recommends that every woman giving birth should get an oxytocin injection to prevent bleeding, with a second dose given if she has a PPH. It claims that this would prevent most PPH deaths but again without any evidence. There have been no trials of oxytocin for the treatment of PPH, even though it has serious side effects.

While De Vigneaud was working on oxytocin, in Japan, Utako Okamoto and her husband Shosuke were also searching for drugs to cut maternal bleeding deaths. Their research took quite a different tack and focused on blood. Plasmin is a powerful enzyme that dissolves blood clots. Fear, pain, and tissue damage lead to its release and this can result in the failure of the blood to clot. This coagulation failure is a common cause of severe bleeding in major surgery and accident victims. Utako asked whether the same mechanism could be responsible for severe bleeding after childbirth. In 1962, the Okamotos reported the invention of tranexamic acid, a powerful plasmin inhibitor. Their invention hardly caused a ripple. Utako tried to get obstetricians to test tranexamic acid as a treatment for PPH, but they were not interested.

Tranexamic acid gains traction

But as years passed, tranexamic acid got noticed. First by women, which led to it becoming the “go to” drug for heavy menstrual bleeding and then by surgeons who found that it cut surgical bleeding by one third. In 2010, we published the results of the CRASH-2 trial showing that giving tranexamic acid to accident victims cuts bleeding deaths by one third. When I found that Utako was alive and still working in Kobe at the age of 92, I went to thank her for her lifesaving discovery. She quizzed me about the pending WOMAN Trial of tranexamic acid for the treatment of PPH. (By then, we had started the trial that she had tried to conduct half a century earlier.)

In 2017, the WOMAN Trial showed that tranexamic acid also cuts PPH deaths, even when bleeding is said to be due to uterine atony. Finally, tranexamic acid was included in WHO guidelines. Tranexamic acid is now recognised as the only proven lifesaving treatment for PPH. Utako died at the age of 98, a few weeks before the WOMAN Trial was completed.

Could anaemia be a key factor?

This year, preliminary data from 10,000 women enrolled in the WOMAN-2 Trial showed that anaemia greatly increases the risk of uterine atony. Worldwide, half a billion young women are anaemic. Untreated heavy menstrual bleeding is one of the main causes, along with poor diet and infections. Most PPH deaths are in countries where anaemia is common.

Anaemic blood is thin and runny and does not clot properly, but anaemia has never been shown to reduce uterine tone. Could bleeding be the cause of a distended uterus? Tranexamic acid supports coagulation by preventing blood clot breakdown. It has no effect on uterine tone.

In the WOMAN-2 Trial, we are trying to find out if tranexamic acid can prevent PPH. If we find less uterine atony in woman given tranexamic acid it will strongly suggest that bleeding causes a distended uterus – and not the other way around.

Survivors of PPH are often told how their uterus failed them. Now we have the chance to find out if the “failure” is in fact in our understanding.