Updated WHO recommendation on intravenous tranexamic acid for the treatment of post-partum haemorrhage

Post-partum haemorrhage is the leading cause of maternal mortality globally.1Say L Chou D Gemmill A et al.Global causes of maternal death: a WHO systematic analysis.Lancet Glob Health. 2014; 2: e323-e333Summary Full Text Full Text PDF PubMed Scopus (2859) Google Scholar The majority of deaths resulting from post-partum haemorrhage occur during the first 24 h after birth, most of which could be avoided by routine prevention through active management of the third stage of labour and prompt and effective management of post-partum haemorrhage, including the use of uterotonics and fluid replacement. Tranexamic acid, an antifibrinolytic drug, was identified as a promising candidate to be included in recommended packages for treatment of post-partum haemorrhage, since it has shown efficacy in reducing blood loss and mortality following surgical trauma.2Perel P Ker K Morales Uribe CH Roberts I Tranexamic acid for reducing mortality in emergency and urgent surgery.Cochrane Database Syst Rev. 2013; 1 (CD010245.)Crossref Scopus (81) Google Scholar This hypothesis led to the conduct of the largest trial of tranexamic acid for the treatment of post-partum haemorrhage to date, the World Maternal Antifibrinolytic (WOMAN) trial, which was published in April, 2017.3WOMAN Trial CollaboratorsEffect 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: 2105-2116Summary Full Text Full Text PDF PubMed Scopus (745) Google Scholar The WOMAN trial was a randomised, double-blind, placebo-controlled trial in which women with a clinical diagnosis of post-partum haemorrhage (regardless of mode of birth) were randomly assigned to a regimen of intravenous tranexamic acid or placebo. Nearly 200 hospitals in 21 high-income, middle-income, and low-income countries participated, recruiting over 20 000 women. The investigators concluded that early use (within 3 h of birth) of intravenous tranexamic acid reduces maternal death due to bleeding in women with clinically diagnosed post-partum haemorrhage, and that early treatment appears to optimise benefits. In response to the WOMAN Trial, a new Cochrane review was rapidly initiated to assess the effect of antifibrinolytic drugs (in additional to standard care) compared with standard (or usual) care alone for treatment of post-partum haemorrhage (Shakur H, unpublished). This review includes only two trials in which tranexamic acid was compared with standard care. Evidence from the WOMAN trial dominates the findings.3WOMAN Trial CollaboratorsEffect 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: 2105-2116Summary Full Text Full Text PDF PubMed Scopus (745) Google Scholar The other trial was conducted in eight obstetric units in France, and randomly assigned 152 women with post-partum haemorrhage (defined as more than 800 mL of blood lost) after vaginal birth to treatment with tranexamic acid or placebo.4Ducloy-Bouthors AS Jude B Duhamel A et al.High-dose tranexamic acid reduces blood loss in postpartum haemorrhage.Crit Care. 2011; 15: R117Crossref PubMed Scopus (220) Google Scholar An individual participant-data meta-analysis of 40 138 bleeding patients,5Gayet-Ageron A, Prieto-Merino D, Ker K, Shakur H, Ageron F-X, Roberts I. Impact of treatment delay on the effectiveness and safety of anti-fibrinolytics in acute severe haemorrhage: an individual patient data meta-analysis in 40 138 bleeding patients. Lancet (in press).Google Scholar that includes participants from both the WOMAN3WOMAN Trial CollaboratorsEffect 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: 2105-2116Summary Full Text Full Text PDF PubMed Scopus (745) Google Scholar and CRASH-2 trials,6CRASH-2 trial collaboratorsEffects 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: 23-32Summary Full Text Full Text PDF PubMed Scopus (2148) Google Scholar is an important complement to the findings of the Cochrane review. WHO recommendations are regularly updated to reflect the latest scientific evidence, particularly when new evidence that could affect the strength or direction of existing recommendations becomes available. With a view to updating the existing WHO recommendation, a Guideline Development Group (GDG) was convened in August, 2017, to review and consider the updated analysis, values, and preferences of stakeholders, resource requirements, cost-effectiveness, acceptability, feasibility, and equity with respect to treatment of post-partum haemorrhage with tranexamic acid. WHO has now published an updated recommendation on the use of tranexamic acid for treatment of post-partum haemorrhage,7WHOWHO recommendation on tranexamic acid for the treatment of postpartum haemorrhage. World Health Organization, Geneva2017Google Scholar which supersedes the 2012 recommendation.8WHOWHO recommendations for the prevention and treatment of postpartum haemorrhage. World Health Organization, Geneva2012Google Scholar WHO strongly recommends early use of intravenous tranexamic acid (within 3 h of birth), in addition to standard care for women with clinically diagnosed post-partum haemorrhage following vaginal birth or caesarean section. On the basis of the dosing regimen used in the WOMAN trial, the GDG supports treatment with tranexamic acid at a fixed dose of 1 g (100 mg/mL) intravenously at 1 mL/min (ie, given over 10 min), with a second dose of 1 g intravenously if bleeding continues after 30 min, or if bleeding restarts within 24 h of completing the first dose. In the context of this recommendation, “clinically diagnosed postpartum haemorrhage” refers to a clinically estimated blood loss of more than 500 mL after vaginal birth or 1000 mL after caesarean section, or any blood loss that is sufficient to compromise haemodynamic stability.3WOMAN Trial CollaboratorsEffect 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: 2105-2116Summary Full Text Full Text PDF PubMed Scopus (745) Google Scholar The GDG remarked that tranexamic acid should be given in all cases of post-partum haemorrhage, regardless of whether the bleeding is thought to be due to genital tract trauma or for other reasons, including uterine atony. This updated recommendation is broader than the previous recommendation of 2012, which advised that tranexamic acid be given for treatment of post-partum haemorrhage only if oxytocin and other uterotonics fail to stop bleeding, or if it is thought that the bleeding could be partly due to trauma. The GDG panel considered the benefits and potential harms of tranexamic acid, and emphasised the 3 h threshold (following birth), after which it should not be given. This judgment was based on the individual participant data meta-analysis of the effects of timing of administration,5Gayet-Ageron A, Prieto-Merino D, Ker K, Shakur H, Ageron F-X, Roberts I. Impact of treatment delay on the effectiveness and safety of anti-fibrinolytics in acute severe haemorrhage: an individual patient data meta-analysis in 40 138 bleeding patients. Lancet (in press).Google Scholar which indicates that delay in treatment appears to reduce benefit, decreasing by 10% for every 15 min delay, and with no benefit seen after 3 h. Giving tranexamic acid to women with post-partum haemorrhage beyond 3 h after birth is suspected to be potentially harmful. Importantly, giving the drug earlier after birth appears to increase benefit; hence it should be given as soon as possible for treatment of post-partum haemorrhage. Giving tranexamic acid should be considered as part of the standard treatment packages for post-partum haemorrhage, in accordance with WHO guidelines.7WHOWHO recommendation on tranexamic acid for the treatment of postpartum haemorrhage. World Health Organization, Geneva2017Google Scholar, 8WHOWHO recommendations for the prevention and treatment of postpartum haemorrhage. World Health Organization, Geneva2012Google Scholar This package includes fluid replacement, treatment with uterotonics, monitoring of vital signs, and non-surgical (eg, bimanual compression, intrauterine balloon tamponade, non-pneumatic antishock garment, external aortic compression) and surgical interventions (eg, brace sutures, arterial ligation, or hysterectomy). The sequential use of these interventions should start with less invasive interventions, moving towards more invasive interventions as required. Health facilities in which emergency obstetric care is provided need to have the necessary supplies and the necessary training for staff who attend births, so that tranexamic acid can be given safely by intravenous infusion. Treatment with tranexamic acid should be avoided in women with a clear contraindication to antifibrinolytic therapy (eg, a known thromboembolic event during pregnancy). This updated recommendation7WHOWHO recommendation on tranexamic acid for the treatment of postpartum haemorrhage. World Health Organization, Geneva2017Google Scholar applies to giving the drug intravenously only, since the benefits and potential harms of other routes of administration are not yet known and are a research priority. Wide and effective implementation of this recommendation would require all health systems, regardless of their level of resources, to recognise tranexamic acid as a life-saving intervention that should be made readily available for the management of post-partum haemorrhage wherever emergency obstetric care is provided. We declare no competing interests.