WHO Recommendations on Prevention and Treatment of Postpartum Haemorrhage and the WOMAN Trial
15 June 2017: Postpartum haemorrhage (PPH) is defined as a blood loss of 500 ml or more within 24 hours after birth. 1 PPH is the leading cause of maternal mortality in low-income countries, and the primary cause of nearly one quarter of all maternal deaths globally.2 Most deaths resulting from PPH occur during the first 24 hours after birth; the majority of these could be avoided through the use of prophylactic uterotonics during the third stage of labour and by timely and appropriate management.
WHO’s current recommendation on use of tranexamic acid
In 2012, WHO published 32 recommendations for the prevention and treatment of postpartum haemorrhage.1 These recommendations were developed according to the WHO guideline development standards, including synthesis of available research evidence, use of the GRADE methodology, and formulation of recommendations by a guideline panel of international experts, which convened in March 2012.
At the time of the guideline panel meeting, there was no direct evidence on the effectiveness and safety of tranexamic acid when used for treatment of PPH. Literature searches identified no randomised trials that investigated tranexamic acid for treatment of PPH following vaginal birth. A Cochrane systematic review evaluating tranexamic acid versus placebo or no treatment for the prevention of PPH identified only two small trials (combined total of 453 women), neither of which examined the outcomes prioritised for guideline decision-making.3 Another systematic review of randomized trials of tranexamic acid for PPH prevention identified three trials (460 participants).4 Although a significant reduction in average postpartum blood loss was reported in women treated with tranexamic acid, the quality of the trials was poor. None of the trials had adequate allocation concealment and, even in aggregate, the trials were too small to assess the effects of tranexamic acid on the clinically important end points.
Consequently, the guideline panel considered this as indirect evidence and recommended the use of tranexamic acid for the treatment of PPH when uterotonics fail to control the bleeding or when the bleeding is thought to be partly due to trauma. Given the limitations in the evidence and other considerations including feasibility, acceptability, and resource requirement, the guideline panel made this a conditional (or “weak”) recommendation, in line with the framework that was applied for moving from evidence to recommendation. The implication of a conditional recommendation for clinicians is that different choices will be appropriate for individual patients, who will require assistance in arriving at a management decision consistent with her values, whereas for health managers, it implies that health policy decision will require substantial debate and involvement of various stakeholders. The corresponding remarks clarify that the evidence for this recommendation was supported by literature on its use in (non-obstetric) surgery and trauma, which shows tranexamic acid to be a safe option for the treatment of trauma-related bleeding. The panel also noted that a large, randomized controlled trial examining the effect of early administration of tranexamic acid on mortality, hysterectomy, and other morbidities in women with clinically diagnosed PPH was ongoing – the World Maternal Antifibrinolytic (WOMAN) Trial. 5
The World Maternal Antifibrinolytic (WOMAN) Trial
The findings of the WOMAN Trial were recently published in the Lancet (26 April 2017).6 Briefly, the WOMAN Trial was a randomised, double-blind, placebo-controlled trial, that recruited women aged 16 years and older with a clinical diagnosis of PPH (regardless of mode of delivery).
Nearly 200 hospitals in 21 countries participated in the trial, recruiting over 20,000 women. Women with clinically diagnosed PPH were randomly assigned to receive either 1 g intravenous tranexamic acid or matching placebo, in addition to usual care. If bleeding continued after 30 minutes, or stopped and restarted within 24 hours of the first dose, a second dose was used. The primary endpoint was a composite of death from all-causes or hysterectomy within 42 days of giving birth.
In total, 10,051 women received tranexamic acid and 10,009 received the placebo. The composite primary endpoint of death from all causes or hysterectomy was not reduced with tranexamic acid (5·3% vs 5·5%, RR 0·97, 95% CI 0·87-1·09; p=0·65). However, death due to bleeding was significantly reduced in women given tranexamic acid (1·5% vs 1·9%, RR 0·81, 95% CI 0·65–1·00; p=0·045), especially in women treated within 3 hours of giving birth (1·2% vs 1·7%, 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 (3·6% vs 3·5%, RR 1·02, 95% CI 0·88–1·07; p=0·84).
The trial authors concluded that tranexamic acid reduces death due to bleeding in women with clinically diagnosed PPH, and that early treatment appears to optimize benefit.
The WOMAN Trial Collaboration is to be commended for the successful completion of this important trial. Safe, effective and affordable PPH treatments are critical to saving the lives of pregnant women globally, and the findings of this trial have important implications for the delivery of high-quality maternity care.
WHO’s response to the results of WOMAN trial
WHO guideline development standards require that WHO recommendations are regularly updated to reflect the latest scientific evidence, particularly when new or important evidence that may substantially affect the strength or direction of existing recommendations becomes available.
In March 2017, WHO convened a new panel of international experts to oversee the prioritization and updating of WHO recommendations in maternal and perinatal health. From nearly 200 existing recommendations, this Executive Guideline Steering Group identified a subset of approximately 30 recommendations in most urgent need of updating. Amongst these, recommendations relating to PPH prevention and treatment (including the recommendation on the use of tranexamic acid for PPH treatment) were most highly prioritized.
Consequently, the WHO Department of Reproductive Health and Research is working with the Cochrane Pregnancy and Childbirth Group to fast-track the update of the existing Cochrane systematic review on treatment of primary postpartum haemorrhage, with priority given to the use of antifibrinolytics for PPH treatment. Once completed, WHO will convene a virtual technical consultation of international experts to review the current evidence, and update the existing WHO recommendation on tranexamic acid for PPH treatment as needed. While it is not possible to pre-judge the conclusions of this guideline panel, few PPH trials are powered to detect a difference in mortality and the results of the WOMAN trial is a welcome development. It is of note, however, that the existing WHO PPH recommendation (2012) does support the use of tranexamic acid for PPH treatment. WHO is expediting the updating of this recommendation, and anticipates its electronic publication by the third quarter of 2017.
- WHO recommendations on prevention and treatment of postpartum haemorrhage. 2012.
- Say L, Chou D, Gemmill A, Tunçalp Ö, Moller AB, Daniels J, Gülmezoglu AM, Temmerman M, Alkema L. Global causes of maternal death: a WHO systematic analysis. Lancet Glob Health. 2014;2(6):e323-33. doi: 10.1016/S2214-109X(14)70227-X.
- Novikova, N., Hofmeyr, G. J. Tranexamic Acid for preventing postpartum haemorrhage. Cochrane 2010
- Ferrer P et al. Anti-fibrinolytic agents in post partum haemorrhage: a systematic review. BMC Pregnancy Childbirth. 2009
- Shakur et al. The WOMAN Trial (World Maternal Antifibrinolytic Trial): tranexamic acid for the treatment of postpartum haemorrhage: an international randomised, double blind placebo controlled trial. 2010
- 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.