NIHR Signal Drug reduces deaths from bleeding after childbirth

Published on 22 August 2017

Tranexamic acid, given to women who bleed heavily after giving birth, reduced the risk of death by 31% when given within three hours.

This trial included 20,060 women with postpartum haemorrhage who were randomly assigned to receive tranexamic acid or placebo. This is the first large study to indicate that it is safe and implies it should be considered as an early drug option for postpartum haemorrhage. In keeping with other recent research, there was no increase in the risk of blood clots.

Tranexamic acid is a drug that stops clots breaking down. Current guidance recommends giving drugs that cause the womb to contract first, such as oxytocin, and using tranexamic acid if bleeding continues.

Most of the data in this study came from low and middle-income countries, with much higher incidence of postpartum haemorrhage and poorer maternal health outcomes than the UK. This means that reduction in the already low rates of such deaths in the UK might be small.

Drug reduces deaths from bleeding after childbirth

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Why was this study needed?

Obstetric haemorrhage (bleeding during pregnancy, labour or after giving birth) is the fourth largest cause of maternal deaths, with 13 deaths between 2012 and 2014 a rate of 0.56 per 100,000 maternities.

Postpartum haemorrhage (PPH) is a common type of major obstetric haemorrhage, occurring in 16% of deliveries. About 10% of women with major obstetric haemorrhage will need a hysterectomy after failure to limit bleeding.

Normally, the muscles of the womb contract after giving birth as the placenta separates from the womb. The blood vessels which had supplied the placenta are compressed and this helps to stop bleeding. Oxytocin is usually given after delivery of the baby to help this contraction. 

Tranexamic acid reduces the breakdown of blood clots. Evidence has shown that it reduces the risk of death from bleeding in adults after traumatic injury.

The researchers wanted to find out if giving tranexamic acid to women early on in PPH improved outcomes.

What did this study do?

The World Maternal Antifibrinolytic (WOMAN) trial involved 20,060 women with postpartum haemorrhage (PPH), defined as blood loss of:

  • more than 500ml after vaginal delivery
  • more than 1000ml after caesarean section
  • any amount that caused haemodynamic instability (inability to maintain blood pressure).

Women aged 16 years and over were randomly assigned to receive tranexamic acid 1g intravenously or matching placebo. All women received “usual” obstetric maternity care. A second dose could be given if bleeding continued or recurred.

Though 569 women from hospitals in the UK were included, the other 20 participating countries were of low- to middle-income, such as Ethiopia, Pakistan and Nigeria. “Usual care” may differ and the overall national death rates due to PPH are much lower in the UK.

What did it find?

  • Tranexamic acid reduced the risk of death from bleeding by 19%. There were 155 deaths (1.5%) in the tranexamic acid group compared with 191 (1.9%) in the placebo group, (risk ratio [RR] 0.81, 95% confidence interval [CI] 0.65 to 1.00). This reduction in risk was still seen after researchers adjusted the results to take into account the underlying risk of bleeding between patients (RR 0.78, 95% CI 0.62 to 0.98).
  • The benefits were greater in those given tranexamic acid earlier. If given before three hours the risk of death from bleeding was reduced by 31%: 89 deaths (1.2%) versus 127 (1.7%) in the placebo group (RR 0.69, 95% CI 0.52 to 0.91). Tranexamic acid did not reduce the risk of dying from bleeding if given more than three hours after birth, 66 deaths (2.6%) versus 63 (2.5%) (RR 1.07, 95% CI 0.76 to 1.51).
  • There was no difference between the groups in adverse events due to blood clots, such as deep vein thrombosis, pulmonary embolus, stroke or heart attack.

What does current guidance say on this issue?

The Royal College of Obstetricians’ Green-top Guideline from 2016 recommends that clinicians should consider the use of intravenous tranexamic acid, in addition to oxytocin at caesarean section to reduce blood loss in women at increased risk of postpartum haemorrhage (PPH). They and NICE guidance from 2014 also recommend considering the use of tranexamic acid in the management of PPH.

The World Health Organisation 2017 guidelines recommend tranexamic acid if oxytocin or other drugs that cause the womb to contract fail to stop bleeding or if the bleeding is partly due to trauma.

What are the implications?

Some uncertainty remains as to the potential impact on mortality in the UK as most of the data came from countries with higher incidence of postpartum haemorrhage (PPH) and poorer maternal health outcomes.

No effect was found of tranexamic acid on blood transfusion and hysterectomy rates but this is probably a reflection of the design of the study and will need further research in the UK context.

Of note, tranexamic acid is not currently licensed for the treatment of PPH in the UK.

Citation and Funding

WOMAN Trial Collaborators.  Effect of early tranexamic acid administration on mortality, hysterectomy, and other morbidities in women with post-partum haemorrhage (WOMAN): an international, randomised, double-blind, placebo-controlled trial. Lancet. 2017;389(10084):2105-16.

This project was funded by the London School of Hygiene and Tropical Medicine, an investigator initiated research grant by Pfizer Ltd, The Department of Health (grant number HICF-T2-0510-007), the Wellcome Trust (grant number WT094947) and the Bill & Melinda Gates Foundation (grant number OPP1095618).

Bibliography

CRASH-2 Collaborators, Shakur H, Roberts I, et al. Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a randomised, placebo-controlled trial. Lancet. 2010;376(9734):23–32.

Healthcare Improvement Scotland. Scottish Confidential Audit of Severe Maternal Morbidity. 9th Annual Report. Scotland: Healthcare Improvement Scotland; 2013.

Knight M, Nair M, Tuffnell D, et al. (Eds) on behalf of MBRRACE UK. Saving Lives, Improving Mothers’ Care. Surveillance of maternal deaths in the UK 2012–14 and lessons learned to inform maternity care from the UK and Ireland Confidential Enquiries into Maternal Deaths and Morbidity 2009–14. Oxford: National Perinatal Epidemiology Unit, University of Oxford; 2016.

Mavrides E, Allard S, Chandraharan E, et al on behalf of the Royal College of Obstetricians and Gynaecologists. Prevention and management of postpartum haemorrhage: Greentop Guideline No. 52. BJOG. 2016;124:e106-49.

MHRA. Summary of Product Characteristics. Tranexamic Acid. 100mg/ml solution for injection. London: Medicines and Healthcare Regulatory Agency; 2014.

Mousa HA, Blum J, Abou El Senoun G, et al. Treatment for primary postpartum haemorrhage. Cochrane Database of Syst Rev. 2014;(2):CD003249.

NHS Choices. What happens straight after birth? London: Department of Health; 2016.

NHS Digital. Hospital Maternity Activity, 2015-2016. Leeds; 2017,

NICE. Intrapartum care for healthy women and babies. CG190. London: National Institute for Health and Care Excellence; 2014.

WHO. Managing complications in pregnancy and childbirth: a guide for midwives and doctors – 2nd Ed. Geneva: World Health Organization; 2017.

Why was this study needed?

Obstetric haemorrhage (bleeding during pregnancy, labour or after giving birth) is the fourth largest cause of maternal deaths, with 13 deaths between 2012 and 2014 a rate of 0.56 per 100,000 maternities.

Postpartum haemorrhage (PPH) is a common type of major obstetric haemorrhage, occurring in 16% of deliveries. About 10% of women with major obstetric haemorrhage will need a hysterectomy after failure to limit bleeding.

Normally, the muscles of the womb contract after giving birth as the placenta separates from the womb. The blood vessels which had supplied the placenta are compressed and this helps to stop bleeding. Oxytocin is usually given after delivery of the baby to help this contraction. 

Tranexamic acid reduces the breakdown of blood clots. Evidence has shown that it reduces the risk of death from bleeding in adults after traumatic injury.

The researchers wanted to find out if giving tranexamic acid to women early on in PPH improved outcomes.

What did this study do?

The World Maternal Antifibrinolytic (WOMAN) trial involved 20,060 women with postpartum haemorrhage (PPH), defined as blood loss of:

  • more than 500ml after vaginal delivery
  • more than 1000ml after caesarean section
  • any amount that caused haemodynamic instability (inability to maintain blood pressure).

Women aged 16 years and over were randomly assigned to receive tranexamic acid 1g intravenously or matching placebo. All women received “usual” obstetric maternity care. A second dose could be given if bleeding continued or recurred.

Though 569 women from hospitals in the UK were included, the other 20 participating countries were of low- to middle-income, such as Ethiopia, Pakistan and Nigeria. “Usual care” may differ and the overall national death rates due to PPH are much lower in the UK.

What did it find?

  • Tranexamic acid reduced the risk of death from bleeding by 19%. There were 155 deaths (1.5%) in the tranexamic acid group compared with 191 (1.9%) in the placebo group, (risk ratio [RR] 0.81, 95% confidence interval [CI] 0.65 to 1.00). This reduction in risk was still seen after researchers adjusted the results to take into account the underlying risk of bleeding between patients (RR 0.78, 95% CI 0.62 to 0.98).
  • The benefits were greater in those given tranexamic acid earlier. If given before three hours the risk of death from bleeding was reduced by 31%: 89 deaths (1.2%) versus 127 (1.7%) in the placebo group (RR 0.69, 95% CI 0.52 to 0.91). Tranexamic acid did not reduce the risk of dying from bleeding if given more than three hours after birth, 66 deaths (2.6%) versus 63 (2.5%) (RR 1.07, 95% CI 0.76 to 1.51).
  • There was no difference between the groups in adverse events due to blood clots, such as deep vein thrombosis, pulmonary embolus, stroke or heart attack.

What does current guidance say on this issue?

The Royal College of Obstetricians’ Green-top Guideline from 2016 recommends that clinicians should consider the use of intravenous tranexamic acid, in addition to oxytocin at caesarean section to reduce blood loss in women at increased risk of postpartum haemorrhage (PPH). They and NICE guidance from 2014 also recommend considering the use of tranexamic acid in the management of PPH.

The World Health Organisation 2017 guidelines recommend tranexamic acid if oxytocin or other drugs that cause the womb to contract fail to stop bleeding or if the bleeding is partly due to trauma.

What are the implications?

Some uncertainty remains as to the potential impact on mortality in the UK as most of the data came from countries with higher incidence of postpartum haemorrhage (PPH) and poorer maternal health outcomes.

No effect was found of tranexamic acid on blood transfusion and hysterectomy rates but this is probably a reflection of the design of the study and will need further research in the UK context.

Of note, tranexamic acid is not currently licensed for the treatment of PPH in the UK.

Citation and Funding

WOMAN Trial Collaborators.  Effect of early tranexamic acid administration on mortality, hysterectomy, and other morbidities in women with post-partum haemorrhage (WOMAN): an international, randomised, double-blind, placebo-controlled trial. Lancet. 2017;389(10084):2105-16.

This project was funded by the London School of Hygiene and Tropical Medicine, an investigator initiated research grant by Pfizer Ltd, The Department of Health (grant number HICF-T2-0510-007), the Wellcome Trust (grant number WT094947) and the Bill & Melinda Gates Foundation (grant number OPP1095618).

Bibliography

CRASH-2 Collaborators, Shakur H, Roberts I, et al. Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a randomised, placebo-controlled trial. Lancet. 2010;376(9734):23–32.

Healthcare Improvement Scotland. Scottish Confidential Audit of Severe Maternal Morbidity. 9th Annual Report. Scotland: Healthcare Improvement Scotland; 2013.

Knight M, Nair M, Tuffnell D, et al. (Eds) on behalf of MBRRACE UK. Saving Lives, Improving Mothers’ Care. Surveillance of maternal deaths in the UK 2012–14 and lessons learned to inform maternity care from the UK and Ireland Confidential Enquiries into Maternal Deaths and Morbidity 2009–14. Oxford: National Perinatal Epidemiology Unit, University of Oxford; 2016.

Mavrides E, Allard S, Chandraharan E, et al on behalf of the Royal College of Obstetricians and Gynaecologists. Prevention and management of postpartum haemorrhage: Greentop Guideline No. 52. BJOG. 2016;124:e106-49.

MHRA. Summary of Product Characteristics. Tranexamic Acid. 100mg/ml solution for injection. London: Medicines and Healthcare Regulatory Agency; 2014.

Mousa HA, Blum J, Abou El Senoun G, et al. Treatment for primary postpartum haemorrhage. Cochrane Database of Syst Rev. 2014;(2):CD003249.

NHS Choices. What happens straight after birth? London: Department of Health; 2016.

NHS Digital. Hospital Maternity Activity, 2015-2016. Leeds; 2017,

NICE. Intrapartum care for healthy women and babies. CG190. London: National Institute for Health and Care Excellence; 2014.

WHO. Managing complications in pregnancy and childbirth: a guide for midwives and doctors – 2nd Ed. Geneva: World Health Organization; 2017.

Effect of early tranexamic acid administration on mortality, hysterectomy, and other morbidities in women with post-partum haemorrhage (WOMAN): an international, randomised, double-blind, placebo-controlled trial

Published on 1 May 2017

WOMAN Trial Collaborators

Lancet , 2017

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. FUNDING: London School of Hygiene & Tropical Medicine, Pfizer, UK Department of Health, Wellcome Trust, and Bill & Melinda Gates Foundation.

Several hospitals from each of the following countries participated in the trial: Cote d’Ivoire, Colombia, Egypt, Papua New Guinea, Ghana, Jamaica, Burkina Faso, Ethiopia, Bangladesh, Democratic Republic of Congo, Albania, Zambia, Nepal, Tanzania, UK, Sudan, Cameroon, Kenya, Uganda, Pakistan, Nigeria.

Expert commentary

Looking outside the silo of our own particular speciality, identifying the learning and appropriating the techniques developed by other specialities can lead to quantum leaps in care. Adopting the use of tranexamic acid from the management of haemorrhage in trauma to postpartum haemorrhage is a simple, effective, safe and affordable intervention which will reduce morbidity and mortality.

The challenge to healthcare commissioners and providers internationally is to promptly implement the early use of tranexamic acid into best practice care in both first and third world health systems.

Matthew Jolly, National Clinical Director for Maternity and Women's Health, Acute Medical Directorate, NHS England

Categories

  •   Cardiovascular system disorders, Fertility and childbirth, Medicines, Surgery