Two papers from the WOMAN Trials Collaborators, published in The Lancet today, reveal important evidence on the effects of the drug tranexamic acid (TXA) on postpartum haemorrhage (PPH) and life-threatening bleeding after childbirth.
The work was led by researchers, clinicians and support staff based at the London School of Hygiene & Tropical Medicine and centres in Nigeria (College of Medicine, University of Ibadan), Pakistan (Global Institute of Human Development, Shifa Tameer-e-Millat University), Tanzania (Muhimbili University of Health and Allied Sciences) and Zambia (Women and Newborn Hospital, Lusaka).
The papers also highlight the hugely negative impact that moderate and severe anaemia have on pregnant women and their babies, and could be significant in making progress towards reducing maternal deaths. Every year, around the world, about 70,000 women die from severe bleeding after childbirth, mostly in sub-Saharan Africa and South Asia.
The first study, an individual patient data (IPD) meta-analysis, assessed data on 54,404 women across five clinical trials and found that TXA substantially reduces life-threatening bleeding after childbirth, regardless of the type of birth (vaginal or caesarean) or the presence or absence of anaemia. The analysis showed that TXA cut the risk of life-threatening bleeding by nearly one quarter.
A second paper reports the results of the WOMAN-2 Trial, which enrolled 15,068 women with moderate or severe anaemia who had given birth vaginally in 34 hospitals across Nigeria, Tanzania, Zambia and Pakistan.
The trial was randomised, double blind and placebo-controlled, and examined whether TXA given within 15 minutes of the umbilical cord being clamped after birth could prevent clinically diagnosed PPH. This was defined as an estimated blood loss of more than 500ml, or any blood loss that causes haemodynamic instability – when the body is not able to maintain stable blood pressure and blood flow, putting vital organs at risk. The study found that women with moderate and severe anaemia had a much higher risk of PPH, but there was no reduction in the risk of PPH with TXA.
Dr Katharine Ker, lead author of the IPD meta-analysis, said: “Our analysis provides strong scientific evidence that TXA reduces life-threatening bleeding in women giving birth. In this case, life-threatening bleeding entails death or surgical interventions for bleeding within 24 hours of birth. In addition to this positive result, we found no evidence of any serious adverse effects from TXA.”
The IPD meta-analysis included the WOMAN and WOMAN-2 Trials, which recruited in low- and middle-income countries, as well as the TRAAP, TRAAP-2 and TXA-MFMU trials, which recruited women in high-income countries (France or USA).
The study found that life-threatening bleeding occurred in 178 (0.65% of 27,300) women in the TXA group versus 230 (0.85% of 27,093) women in the placebo group. There was no evidence that TXA increased thrombosis and there were fewer deaths within 24 hours and fewer deaths from bleeding in women in the TXA group.
The World Health Organization currently recommends TXA treatment for all women with a clinical PPH diagnosis, alongside other interventions, such as uterotonics. This was informed by the WOMAN Trial results from 2017, also coordinated by the WOMAN Trials Collaborators, which showed that TXA, given within three hours of birth, reduces bleeding deaths in women with PPH, regardless of the cause of the bleeding or mode of delivery.
Professor Ian Roberts, co-author of the IPD meta-analysis and co-lead of the WOMAN-2 Trial, said: “TXA is recommended for women with a diagnosis of PPH, but since women can bleed to death very soon after birth, we need to consider giving TXA even before a PPH in women at high risk of death. We were disappointed to find that TXA did not prevent PPH in anaemic women, but our data raises critical questions about the neglect of anaemia in efforts to reduce maternal deaths.”
The WOMAN-2 Trial showed that anaemic women have a greatly increased risk of PPH. The more severe the anaemia, the higher the risk of PPH and the sooner after birth the diagnosis is made. The trial found that 35% of PPH diagnoses were made before the trial treatment had been completed. It seems likely that many of these PPH diagnoses were made before TXA could have any effect.
Professor Roberts said: “It seems that in women with moderate and severe anaemia, bleeding occurs so rapidly and the mother’s ability to tolerate bleeding is so low, that either we are giving TXA too late to prevent PPH, or PPH cannot be prevented in these vulnerable women. It would therefore make sense to place much more importance on anaemia prevention and treatment.”
Data from the WOMAN-2 Trial, published last year in The Lancet Global Health, showed that women with severe anaemia are considerably more likely to die if they experience severe bleeding. Worldwide, half a billion women of reproductive age are anaemic and 20 million are severely anaemic. In Sub-Saharan Africa and South Asia half of all pregnant women are anaemic.
Professor Nike Bello, who led the trial in Nigeria, said: “Effective ways to prevent and treat anaemia are urgently needed. In countries like Nigeria, anaemia in pregnant women is chronic and often linked to poor nutrition and infections, such as malaria. The WOMAN-2 Trial shows that as the haemoglobin concentration of the blood falls, the risk of death and serious complications, including antepartum haemorrhage and abruption, increases steeply.”
Professor Haleema Shakur-Still, co-lead on the WOMAN-2 Trial, said: “The trial data also show that women with moderate and severe anaemia have a hugely increased risk of stillbirth. In the most severely anaemic women, the risk of stillbirth was over 30%. This is ten times higher than the risk in non-anaemic women in high-income countries. We must prevent moderate and severe anaemia in women giving birth.”
Looking ahead, the team are already working on the next major research questions. The I’M WOMAN Trial, which has so far recruited over 4,000 women in Nigeria, Tanzania and Pakistan, is evaluating the effect of giving TXA earlier – just before childbirth – on the risk of PPH.
I’M WOMAN is also looking at better ways to give TXA – intramuscularly, rather than intravenously. If TXA could be given intramuscularly, women giving birth outside of hospitals would have better access to TXA and healthcare workers would be able treat women faster in hospitals. This is crucial when a woman can bleed to death in a matter of minutes.
Professor Roberts said: “These two papers have major implications for obstetric care. TXA cuts life-threatening bleeding and healthcare professionals and policymakers worldwide must ensure it is available for all women who need it. But we must also tackle anaemia since this is a major cause of life-threatening bleeding and stillbirth.
“To cut maternal deaths, we must prevent and treat anaemia in women of childbearing age. Our WOMAN-3 Trial, currently at the planning stage, will examine the role of giving TXA during menstruation alongside the usual iron and multivitamins to treat anaemia.”
The WOMAN-2 Trial is funded by the Bill and Melinda Gates Foundation and the Wellcome Trust. The IPD meta-analysis research is funded by the Bill and Melinda Gates Foundation.