Tranexamic acid has gone largely unused in maternity wards since its development in Japan in the 1960s. Now a massive international trial has shown that tranexamic acid decreased the risk of death from blood loss associated with childbirth by about a third.
Back in the 1960s, a female doctor in Japan created a powerful drug to help mothers who haemorrhage after childbirth. The medicine is inexpensive to make. It's safe to use. And it stops bleeding quickly by helping keep naturally forming blood clots intact. The drug's inventor, Utako Okamoto, hoped that the drug called tranexamic acid would be used to help save moms' lives.
Every year about 100,000 women around the world die of blood loss soon after a baby is born. It's the biggest cause of maternal death worldwide. "It was Okamoto's dream to save women," says Haleema Shakur, who directs clinical trials at the London School of Tropical Medicine and Hygiene. "But she couldn't convince doctors to test the drug on post-partum haemorrhaging." And so tranexamic acid has gone largely unused in maternity wards for decades. Until now.
In a massive international trial, Shakur and her collaborators have shown that tranexamic acid decreased the risk of death from blood loss associated with childbirth by about a third. (Previous studies have looked at the drug's use in reducing bleeding deaths after traumatic injuries.)
In the study, women who were diagnosed with heavy bleeding, or postpartum haemorrhage, after a vaginal birth or caesarean section received either the drug or a placebo. About 1.2% of women who got tranexamic acid within three hours of a haemorrhage died, compared with 1.7% of the women who got the placebo. Side effects weren't a serious problem. And the medicine didn't increase the risk of dying of other causes during the procedure, Shakur and her colleagues report.
The study included 20,000 women, in nearly 200 hospitals, across 21 countries, including rich ones, like the UK, and poorer ones, like Pakistan and Nigeria. The medicine is inexpensive. It cost about $3 in the UK, and a quarter of that in Pakistan, for instance. "If you can save a life for approximately $3, then I believe that's worth doing," Shakur says.
It's rare to have a new tool for helping women during childbirth, says Felicia Lester, an OB-GYN at the University of California – San Francisco, who also works in Uganda and Kenya. "I think the study is exciting," she says. "I'm usually cautious in saying that. But it looks like tranexamic acid has the potential to save lives."
The drug even helped women when doctors used it along with other common medications, such as oxytocin, says Margaret Kruk, a global health researcher at Harvard University. "Tranexamic acid offers an additional benefit above and beyond what is being done for women already," she says.
Now, though, the big question is how to make sure this drug is available for women who need it the most – women in the poor, remote areas of the world, where maternal mortality is the highest.
“That's, I think, the million dollar question," Kruk says. "We in global health have a number of tools that seem very effective in large clinical trials. But then when it comes time to use them for all women, we see very large gaps in implementation."
Summary
Background: Post-partum haemorrhage is the leading cause of maternal death worldwide. Early administration of tranexamic acid reduces deaths due to bleeding in trauma patients. We aimed to assess the effects of early administration of tranexamic acid on death, hysterectomy, and other relevant outcomes in women with post-partum haemorrhage.
Methods: In this randomised, double-blind, placebo-controlled trial, we recruited women aged 16 years and older with a clinical diagnosis of post-partum haemorrhage after a vaginal birth or caesarean section from 193 hospitals in 21 countries. We randomly assigned women to receive either 1 g intravenous tranexamic acid or matching placebo in addition to usual care. If bleeding continued after 30 min, or stopped and restarted within 24 h of the first dose, a second dose of 1 g of tranexamic acid or placebo could be given. Patients were assigned by selection of a numbered treatment pack from a box containing eight numbered packs that were identical apart from the pack number. Participants, care givers, and those assessing outcomes were masked to allocation. We originally planned to enrol 15 000 women with a composite primary endpoint of death from all-causes or hysterectomy within 42 days of giving birth. However, during the trial it became apparent that the decision to conduct a hysterectomy was often made at the same time as randomisation. Although tranexamic acid could influence the risk of death in these cases, it could not affect the risk of hysterectomy. We therefore increased the sample size from 15 000 to 20 000 women in order to estimate the effect of tranexamic acid on the risk of death from post-partum haemorrhage. All analyses were done on an intention-to-treat basis. This trial is registered with ISRCTN76912190 (Dec 8, 2008); ClinicalTrials.gov, number NCT00872469; and PACTR201007000192283.
Findings: Between March, 2010, and April, 2016, 20 060 women were enrolled and randomly assigned to receive tranexamic acid (n=10 051) or placebo (n=10 009), of whom 10 036 and 9985, respectively, were included in the analysis. Death due to bleeding was significantly reduced in women given tranexamic acid (155 [1·5%] of 10 036 patients vs 191 [1·9%] of 9985 in the placebo group, risk ratio [RR] 0·81, 95% CI 0·65–1·00; p=0·045), especially in women given treatment within 3 h of giving birth (89 [1·2%] in the tranexamic acid group vs 127 [1·7%] in the placebo group, RR 0·69, 95% CI 0·52–0·91; p=0·008). All other causes of death did not differ significantly by group. Hysterectomy was not reduced with tranexamic acid (358 [3·6%] patients in the tranexamic acid group vs 351 [3·5%] in the placebo group, RR 1·02, 95% CI 0·88–1·07; p=0·84). The composite primary endpoint of death from all causes or hysterectomy was not reduced with tranexamic acid (534 [5·3%] deaths or hysterectomies in the tranexamic acid group vs 546 [5·5%] in the placebo group, RR 0·97, 95% CI 0·87-1·09; p=0·65). Adverse events (including thromboembolic events) did not differ significantly in the tranexamic acid versus placebo group.
Interpretation: Tranexamic acid reduces death due to bleeding in women with post-partum haemorrhage with no adverse effects. When used as a treatment for postpartum haemorrhage, tranexamic acid should be given as soon as possible after bleeding onset.
Authors
WOMAN Trial Collaborators
[link url="http://www.npr.org/sections/goatsandsoda/2017/04/26/525639110/overlooked-drug-could-save-thousands-of-moms-after-childbirth"]NPR material[/link]
[link url="http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)30638-4/fulltext"]The Lancet article summary[/link]
[link url="http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)31111-X/fulltext"]The Lancet editorial[/link]