WHO recommendation on tranexamic acid for the treatment of postpartum haemorrhage

WHO recommendation on tranexamic acid for the treatment of postpartum haemorrhage

WHO recommendation on tranexamic acid for the treatment of postpartum haemorrhage

WHO recommendation on tranexamic acid for the treatment of postpartum haemorrhage ISBN 978-92-4-155015-4

© World Health Organization 2017 Some rights reserved. This work is available under the Creative Commons Attribution-NonCommercialShareAlike 3.0 IGO licence (CC BY-NC-SA 3.0 IGO; https://creativecommons.org/licenses/by-nc-sa/3.0/ igo). Under the terms of this licence, you may copy, redistribute and adapt the work for non-commercial purposes, provided the work is appropriately cited, as indicated below. In any use of this work, there VKRXOGEHQRVXJJHVWLRQWKDW:+2HQGRUVHVDQ\VSHFLÀFRUJDQL]DWLRQSURGXFWVRUVHUYLFHV7KHXVHRI the WHO logo is not permitted. If you adapt the work, then you must license your work under the same or equivalent Creative Commons licence. If you create a translation of this work, you should add the following disclaimer along with the suggested citation: “This translation was not created by the World Health Organization (WHO). WHO is not responsible for the content or accuracy of this translation. The original English edition shall be the binding and authentic edition”. Any mediation relating to disputes arising under the licence shall be conducted in accordance with the mediation rules of the World Intellectual Property Organization. Suggested citation. WHO recommendation on tranexamic acid for the treatment of postpartum haemorrhage. Geneva: World Health Organization; 2017. Licence: CC BY-NC-SA 3.0 IGO. Cataloguing-in-Publication (CIP) data. CIP data are available at http://apps.who.int/iris. Sales, rights and licensing. To purchase WHO publications, see http://apps.who.int/bookorders. To submit requests for commercial use and queries on rights and licensing, see http://www.who.int/about/ licensing. Third-party materials. If you wish to reuse material from this work that is attributed to a third party, such DVWDEOHVÀJXUHVRULPDJHVLWLV\RXUUHVSRQVLELOLW\WRGHWHUPLQHZKHWKHUSHUPLVVLRQLVQHHGHGIRUWKDW reuse and to obtain permission from the copyright holder. The risk of claims resulting from infringement of any third-party-owned component in the work rests solely with the user. General disclaimers. The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of WHO concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted and dashed lines on maps represent approximate border lines for which there may not yet be full agreement. 7KHPHQWLRQRIVSHFLÀFFRPSDQLHVRURIFHUWDLQPDQXIDFWXUHUV·SURGXFWVGRHVQRWLPSO\WKDWWKH\DUH endorsed or recommended by WHO in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. All reasonable precautions have been taken by WHO to verify the information contained in this publication. However, the published material is being distributed without warranty of any kind, either expressed or implied. The responsibility for the interpretation and use of the material lies with the reader. In no event shall WHO be liable for damages arising from its use. Printed in Switzerland

Contents Acknowledgements Acronyms and abbreviations Executive Summary 1. Background 2. Methods 3. Evidence and recommendation 4. Research implications 5. Dissemination and implementation of the recommendation 6. Applicability issues 7. Updating the recommendation References Annex 1. External experts and WHO staff involved in the preparation of the guideline Annex 2. Critical and important outcomes for decision-making Annex 3: Summary and management of declared interests from GDG members Annex 4. Summary of the considerations related to the strength of the recommendations Annex 5. GRADE Tables 1 2 3 5 6 11 20 21 22 23 24 26 29 30 32 33

WHO recommendation on tranexamic acid for the treatment of postpartum haemorrhage

Acknowledgements The Department of Reproductive Health and Research of the World Health Organization gratefully acknowledges the contributions of many individuals and organizations to the updating of this recommendation. Work on this update was coordinated by Olufemi Oladapo, Joshua Vogel and A. Metin Gülmezoglu of the WHO Department of Reproductive Health and Research. WHO extends sincere thanks to Edgardo Abalos, Yap-Seng Chong, Catherine DeneuxTharaux, Bukola Fawole, Justus Hofmeyr, Caroline Homer, Pisake Lumbiganon, Suellen Miller, Ashraf Nabhan, Hiromi Obara, Zahida Qureshi, Rahat Qureshi and Helen West who served as members of the Guideline Development Group (GDG), and to James Neilson for chairing the technical consultation. We also thank Richard Adanu, Fernando Althabe, Sue Fawcus, Jamilu Tukur and Dilys Walker who were members of the External Review Group. WHO also gratefully acknowledges the contribution of the members of the Executive Guideline Steering Group. 7KHUHVH'RZVZHOODQG$QQD&XWKEHUWUHYLHZHGWKHVFLHQWLÀFHYLGHQFHSUHSDUHG the GRADE tables and drafted the narrative summary of evidence. Joshua Vogel and Olufemi Oladapo revised the narrative summaries and double-checked the corresponding GRADE tables. Joshua Vogel, Olufemi Oladapo, A. Metin Gülmezoglu and Mercedes Bonet commented on the draft document before it was reviewed by participants at the WHO technical consultation. The External Review Group peerUHYLHZHGWKHÀQDOGRFXPHQW We acknowledge the various organizations that were represented by observers DWWKHÀQDOWHFKQLFDOFRQVXOWDWLRQLQFOXGLQJ'HERUDK$UPEUXVWHU8QLWHG6WDWHV Agency for International Development), Kusum Thapa (Maternal and Child Survival Program/Jhpiego), Janna Patterson (Bill & Melinda Gates Foundation), Sally Tracy (International Confederation of Midwives), Gerard Visser (International Federation of Gynecology and Obstetrics) and Beverly Winikoff (Gynuity Health Projects). Haleema Shakur-Still (London School of Hygiene and Tropical Medicine) provided an overview RIWKHFRQGXFWDQGÀQGLQJVRIWKH:20$1WULDOEXWGLGQRWSDUWLFLSDWHLQWKH*'* GHOLEHUDWLRQV:HDSSUHFLDWHWKHFRQWULEXWLRQVRI:+25HJLRQDO2IÀFHVWDIIWRWKLV update – Mavjuda Babamuradova, Ramez Khairi Mahaini, Anoma Jayathilaka, Bremen De Mucio, Claudio Sosa, Mari Nagai and Léopold Ouedraogo. The United States Agency for International Development and the Department of 5HSURGXFWLYH+HDOWKDQG5HVHDUFKSURYLGHGÀQDQFLDOVXSSRUWIRUWKLVZRUN7KH YLHZVRIWKHIXQGLQJERG\KDYHQRWLQÁXHQFHGWKHFRQWHQWRIWKLVUHFRPPHQGDWLRQ

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WHO recommendation on tranexamic acid for the treatment of postpartum haemorrhage

Acronyms and abbreviations &, FRQÀGHQFHLQWHUYDO &5$6+ &OLQLFDO5DQGRPL]DWLRQRIDQ$QWLÀEULQRO\WLFLQ6LJQLÀFDQW+DHPRUUKDJH trial DOI FIGO ):& GDG GRC GRADE GSG ICM IPD LMIC LY MCA MPA MPH NNT PICO PPH RHR RR SDG TXA UN UNFPA USAID WHO :20$1 Declaration of Interest International Federation of Gynecology and Obstetrics )DPLO\:RPHQ·VDQG&KLOGUHQ·V+HDOWKD:+2FOXVWHU Guideline Development Group Guideline Review Committee Grading of Recommendations, Assessment, Development, and Evaluation Executive Guideline Steering Group International Confederation of Midwives individual participant data meta-analysis low- and middle-income country life-year WHO Department of Maternal, Newborn, Child and Adolescent Health Maternal and Perinatal Health & Preventing Unsafe Abortion (a team in :+2·V'HSDUWPHQWRI5HSURGXFWLYH+HDOWKDQG5HVHDUFK maternal and perinatal health number needed to treat population (P), intervention (I), comparison (C), outcome (O) postpartum haemorrhage [WHO Department of] Reproductive Health and Research relative risk Sustainable Development Goals tranexamic acid United Nations United Nations Population Fund United States Agency for International Development World Health Organization :RUOG0DWHUQDO$QWLÀEULQRO\WLFVWULDO

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WHO recommendation on tranexamic acid for the treatment of postpartum haemorrhage

Executive Summary Introduction 3RVWSDUWXPKDHPRUUKDJH33+LVFRPPRQO\GHÀQHGDVDEORRGORVVRIPORU more within 24 hours after birth, and it affects about 5% of all women giving birth around the world. Globally, nearly one quarter of all maternal deaths are associated with PPH, and in most low-income countries it is the main cause of maternal mortality. Improving care for women around the time of childbirth to prevent and treat PPH is a necessary step towards achievement of the health targets of the Sustainable Development Goals (SDGs). Efforts to prevent and reduce PPH-associated morbidity and mortality can reduce the profound inequities in maternal health globally. To achieve this, healthcare providers, health managers, policy makers and other stakeholders need up-to-date and evidence-based recommendations to inform clinical policies and practices. In 2017, the Executive Guideline Steering Group (GSG) on WHO maternal and perinatal health recommendations prioritized the updating of the existing WHO recommendation on the use of tranexamic acid (TXA) for PPH treatment in response to important new evidence on this intervention. This updated recommendation thus supersedes the previous recommendation on TXA for PPH treatment, which was issued in the 2012 WHO recommendations on prevention and treatment of PPH.

Target audience The primary audience includes health professionals who are responsible for developing national and local health protocols (particularly those related to PPH) and those directly providing care to pregnant women and their newborns, including midwives, nurses, general medical practitioners, obstetricians, managers of maternal and child health programmes, and relevant staff in ministries of health, in all settings.

Guideline development methods The updating of this recommendation was guided by standardized operating procedures in accordance with the process described in the WHO handbook for guideline development. The recommendation was initially developed using this process, QDPHO\LLGHQWLÀFDWLRQRIWKHSULRULW\TXHVWLRQDQGFULWLFDORXWFRPHVLLUHWULHYDO of the evidence, (iii) assessment and synthesis of evidence, (iv) formulation of the recommendation, and (v) planning for the dissemination, implementation, impact evaluation and updating of the recommendation. 7KHVFLHQWLÀFHYLGHQFHVXSSRUWLQJWKHUHFRPPHQGDWLRQZDVV\QWKHVL]HGXVLQJWKH Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) DSSURDFK7KHV\VWHPDWLFUHYLHZZDVXVHGWRSUHSDUHHYLGHQFHSURÀOHVIRUWKHSULoritized question. WHO convened an online technical consultation on 29 August 2017 where an international group of experts – the Guideline Development Group (GDG) – formulated and approved the recommendation.

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WHO recommendation on tranexamic acid for the treatment of postpartum haemorrhage

Recommendation The WHO technical consultation adopted one recommendation related to the use of TXA for the treatment of PPH. In formulating the recommendation, the GDG reviewed the balance between desirable and undesirable effects of TXA and overall quality of supporting evidence, values and preferences of stakeholders, resource requirements and cost-effectiveness, acceptability, feasibility and equity. To ensure that the recommendation is correctly understood and applied in practice, the contributing experts provided additional remarks. Guideline users should refer to these remarks, as well as to the evidence summary, if there is any doubt as to the basis for the recommendation and how best to implement it. The WHO recommendation on TXA for treatment of PPH is summarized in Table 1 below. Table 1: Updated WHO recommendation on tranexamic acid for the treatment of postpartum haemorrhage Early use of intravenous tranexamic acid (within 3 hours of birth) in addition to standard care is recommended for women with clinically diagnosed postpartum haemorrhage following vaginal birth or caesarean section. (Strong recommendation, moderate quality of evidence) Remarks ‡ Based on the dosing regimen used in the WOMAN trial, the GDG supports the administration of WUDQH[DPLFDFLG7;$DWDÀ[HGGRVHRIJPJPOLQWUDYHQRXVO\,9DWPOSHUPLQXWHLH administered over 10 minutes), with a second dose of 1 g IV if bleeding continues after 30 minutes, or if EOHHGLQJUHVWDUWVZLWKLQKRXUVRIFRPSOHWLQJWKHÀUVWGRVH 7KH:20$1WULDOGHÀQHG´FOLQLFDOO\GLDJQRVHGSRVWSDUWXPKDHPRUUKDJHµDVFOLQLFDOO\HVWLPDWHGEORRG loss of more than 500 ml after a vaginal birth or 1000 ml after caesarean section, or any blood loss VXIÀFLHQWWRFRPSURPLVHKDHPRG\QDPLFVWDELOLW\ Based on evidence from the WOMAN trial, the reference point for the start of the 3-hour window for starting TXA administration is time of birth. If time of birth is unknown, the best estimate of time of birth should be used as the reference point. As most deaths due to postpartum haemorrhage (PPH) occur ZLWKLQWKHÀUVWWRKRXUVDIWHUELUWKLWLVFULWLFDOWKDW7;$LVJLYHQDVVRRQDVSRVVLEOHWRDFKLHYH FOLQLFDOEHQHÀWV Analysis of the effects of timing of administration in the WOMAN trial, as well as an individual participant data (IPD) meta-analysis of 40 138 bleeding patients (including WOMAN trial participants), indicates that 7;$DGPLQLVWUDWLRQEH\RQGKRXUVGRHVQRWFRQIHUDQ\FOLQLFDOEHQHÀW)XUWKHUPRUHWKHSRLQWHVWLPDWHV of effect of TXA use beyond 3 hours on death for trauma or after PPH were both in the direction of KDUPDOEHLWQRWVWDWLVWLFDOO\VLJQLÀFDQWIRUZRPHQZLWK33+,QYLHZRIWKLVHYLGHQFHWKH*'*GRHVQRW support the use of TXA more than 3 hours after birth. Administration of TXA should be considered as part of the standard PPH treatment package. Standard FDUHLQWKHFRQWH[WRIWKLVUHFRPPHQGDWLRQLQFOXGHVURXWLQHFDUHIRU33+WUHDWPHQWLQFOXGLQJÁXLG replacement, medical (uterotonics), monitoring of vital signs, nonsurgical (e.g. bimanual compression, intrauterine balloon tamponade, nonpneumatic antishock garment, aortic compression) and surgical interventions (e.g. brace sutures, arterial ligation, or hysterectomy) in accordance with WHO guidelines or adapted local PPH treatment protocols. TXA should be used in all cases of PPH, regardless of whether the bleeding is due to genital tract trauma or other causes. 7KHXVHRI7;$VKRXOGEHDYRLGHGLQZRPHQZLWKDFOHDUFRQWUDLQGLFDWLRQWRDQWLÀEULQRO\WLFWKHUDS\ (including TXA) (e.g. a known thromboembolic event during pregnancy). 7KLVUHFRPPHQGDWLRQDSSOLHVRQO\WR,9XVH7KHHYDOXDWLRQRIEHQHÀWVDQGSRWHQWLDOKDUPVRIRWKHU routes of TXA administration is a research priority. Regardless of the level of health system resources, TXA should be recognized as a life-saving intervention and be made readily available for the management of PPH in settings where emergency obstetric care is provided.

‡

‡

‡

‡

‡ ‡ ‡ ‡

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WHO recommendation on tranexamic acid for the treatment of postpartum haemorrhage

1. Background 33+LVFRPPRQO\GHÀQHGDVDEORRGORVVRIPORUPRUHZLWKLQKRXUVDIWHU birth, and affects about 5% of all women giving birth around the world.1,2 Globally, nearly one quarter of all maternal deaths are associated with PPH, and in most lowincome countries it is the main cause of maternal mortality.3 6HYHUH33+LVJHQHUDOO\GHÀQHGDVDEORRGORVVRIPORUPRUHDIWHUELUWK Severe maternal health conditions, such as organ dysfunction or death, generally occur following substantial blood loss that compromises maternal haemodynamic stability. Uterine atony is the most common cause of PPH and a leading cause of maternal mortality worldwide.3 Genital tract trauma (that is, vaginal or cervical lacerations), uterine rupture, retained placental tissue, or maternal bleeding disorders are frequently associated with PPH. Although the majority of women SUHVHQWLQJZLWK33+KDYHQRLGHQWLÀDEOHULVNIDFWRUJUDQGPXOWLSDULW\SURORQJHG labour and multiple gestation are obstetric conditions that are associated with an increased risk of bleeding after birth.4 In addition, anaemia is a common aggravating factor. The majority of PPH-associated deaths could be avoided by the use of prophylactic uterotonics during the third stage of labour and appropriate treatment. Thus, improving health care for women during childbirth to prevent and treat PPH is a necessary step towards achievement of the health targets of the Sustainable Development Goals (SDGs). Furthermore, 99% of all maternal deaths occur in lowand middle-income countries (LMICs). Efforts to prevent and reduce PPH-associated morbidity and mortality can thus reduce the profound inequities in maternal health globally. In support of this, health workers at all levels of care (particularly in LMICs) need to have access to appropriate medications and training in relevant procedures. Healthcare providers, health managers, policy-makers and other stakeholders also need up-to-date, evidence-based recommendations to inform clinical policies and practices, in order to enable improved healthcare outcomes. In 2012, WHO published 32 recommendations for the prevention and treatment of PPH, including a recommendation on the use of TXA for treatment of PPH.5 These recommendations were developed according to 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. In 2017, the Executive GSG on WHO maternal and perinatal health recommendations prioritized the updating of the existing WHO recommendation on the use of TXA for PPH treatment in response to important new evidence on this question. This updated recommendation thus supersedes the previous recommendation on TXA for PPH treatment, issued in the 2012 WHO recommendations on prevention and treatment of PPH.

Rationale and objectives TXA is a competitive inhibitor of plasminogen activation, and it can reduce bleeding E\LQKLELWLQJWKHHQ]\PDWLFEUHDNGRZQRIÀEULQRJHQDQGÀEULQFORWV6 It is in routine clinical use for reduction of blood loss in surgery and trauma, and it is listed on the WHO Essential Medicines List for management of anticoagulation.7 At the time of

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WHO recommendation on tranexamic acid for the treatment of postpartum haemorrhage

the GDG meeting on prevention and treatment of PPH in March 2012, there was no direct evidence on the effectiveness and safety of TXA when used for treatment of PPH. The GDG conditionally recommended the use of TXA for the treatment of PPH only when uterotonics fail to control the bleeding or when the bleeding is thought to be partly due to trauma. The GDG noted that a large, randomized controlled trial ²WKH:RUOG0DWHUQDO$QWLÀEULQRO\WLF:20$1WULDOH[DPLQLQJWKHHIIHFWRIHDUO\ administration of TXA on mortality, hysterectomy, and other morbidities in women with clinically diagnosed PPH – was ongoing.8 The WOMAN trial has now concluded, DQGWKHSULPDU\ÀQGLQJVZHUHSXEOLVKHGLQ$SULO9 In light of this new evidence, the Executive GSG prioritized the updating of the recommendation on TXA use for PPH treatment. $VSDUWRI:+2·VQRUPDWLYHZRUNRQVXSSRUWLQJHYLGHQFHLQIRUPHGSROLFLHV and practices, the Department of Reproductive Health and Research (RHR) has now updated the recommendation on the use of TXA for treatment of PPH. This recommendation provides a foundation for the sustainable implementation of the intervention globally.

Target audience The primary audience includes health professionals who are responsible for developing national and local health guidelines and protocols (particularly those related to PPH) and those directly providing care to women during labour and childbirth, including midwives, nurses, general medical practitioners, obstetricians, managers of maternal and child health programmes and relevant staff in ministries of health, in all settings. This recommendation will also be of interest to professional societies involved in the care of pregnant women, nongovernmental organizations concerned with promotion of people-centred maternal care, and implementers of maternal and child health programmes.

Scope of the recommendation The question for this recommendation was: in women with PPH (P), does administration of TXA for PPH treatment (I) compared to placebo, no treatment or other treatments (C), improve outcomes (O)? If so, what is the most appropriate period to administer TXA to improve outcomes? The population affected by this recommendation includes women who experience PPH in low-, middle- or highincome settings.

2. Methods This recommendation is an update of the existing recommendation relating to TXA use for PPH treatment, published in the WHO recommendations for prevention and treatment of postpartum haemorrhage (2012).5 7KHUHFRPPHQGDWLRQZDVÀUVWGHYHORSHGXVLQJVWDQGDUGL]HGRSHUDWLQJSURFHGXUHV in accordance with the process described in the WHO handbook for guideline development.10,QVXPPDU\WKHSURFHVVLQFOXGHGLLGHQWLÀFDWLRQRIWKHSULRULW\ question and critical outcomes, (ii) retrieval of the evidence, (iii) assessment and

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WHO recommendation on tranexamic acid for the treatment of postpartum haemorrhage

synthesis of evidence, (iv) formulation of the recommendation, and (v) planning for the dissemination, implementation, impact evaluation and updating of the recommendation. The WHO recommendation on TXA use for treatment of PPH was LGHQWLÀHGE\WKH([HFXWLYH*6*DVDKLJKSULRULW\IRUXSGDWLQJLQUHVSRQVHWRQHZ important evidence on this question. 7KHXSGDWLQJRIWKLVUHFRPPHQGDWLRQLQYROYHGÀYHPDLQJURXSVWRJXLGHWKH SURFHVVZLWKWKHLUVSHFLÀFUROHVDVGHVFULEHGLQWKHIROORZLQJVHFWLRQV

Contributors to the guideline Executive Guideline Steering Group (Executive GSG) The Executive GSG is an independent panel of external experts and relevant stakeholders from the six WHO regions. This group advises WHO on the prioritization of new and existing questions in maternal and perinatal health for recommendation development or updating.

WHO Steering Group The WHO Steering Group, comprising WHO staff members from the Departments of Reproductive Health and Research (RHR) and Maternal, Newborn, Child and Adolescent Health (MCA), managed the updating process. The Group drafted the key UHFRPPHQGDWLRQTXHVWLRQLQ3,&2IRUPDWLGHQWLÀHGWKHV\VWHPDWLFUHYLHZWHDPDQG guideline methodologist, as well as the guideline development and external review groups. In addition, the WHO Steering Group supervised the retrieval and syntheses of evidence, organized the Guideline Development Group meeting, drafted and ÀQDOL]HGWKHJXLGHOLQHGRFXPHQWDQGPDQDJHGWKHJXLGHOLQHGLVVHPLQDWLRQ implementation and impact assessment. The members of the Steering Group are presented in Annex 1.

Guideline Development Group 7KH:+26WHHULQJ*URXSLGHQWLÀHGDSRRORIDSSUR[LPDWHO\H[SHUWVDQGUHOHYDQW stakeholders from the six WHO regions to constitute the WHO Maternal and Perinatal Health Guideline Development Group (MPH-GDG). This is a diverse group of experts who are skilled in critical appraisal of research evidence; implementation of evidence-based recommendations; guideline development methods; and clinical practice, policy and programmes relating to maternal and perinatal health. Members RIWKH03+*'*DUHLGHQWLÀHGLQDZD\WKDWHQVXUHVJHRJUDSKLFUHSUHVHQWDWLRQ DQGJHQGHUEDODQFHDQGWKHUHZHUHQRVLJQLÀFDQWFRQÁLFWVRILQWHUHVW0HPEHUV· expertise cuts across thematic areas within maternal and perinatal health. From the MPH-GDG pool, 14 external experts and relevant stakeholders were invited to constitute the Guideline Development Group (GDG) for updating this recommendation. This wasis a diverse group of individuals with expertise in PPH research, guideline development methods, and clinical policy and programmes relating to PPH prevention and treatment. The GDG members convened for this recommendation were selected in a way that ensured geographic representation and gender balance, and there were no LPSRUWDQWFRQÁLFWVRILQWHUHVW7KH*URXSDSSUDLVHGWKHHYLGHQFHWKDWZDVXVHG to inform the recommendation, advised on the interpretation of this evidence,

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WHO recommendation on tranexamic acid for the treatment of postpartum haemorrhage

IRUPXODWHGWKHÀQDOUHFRPPHQGDWLRQEDVHGRQWKHGUDIWSUHSDUHGE\WKH6WHHULQJ *URXSDQGUHYLHZHGDQGDSSURYHGWKHÀQDOGRFXPHQW7KHPHPEHUVRIWKLV*URXS are presented in Annex 1.

External Review Group 7KLV*URXSLQFOXGHGÀYHWHFKQLFDOH[SHUWVZLWKVXIÀFLHQWLQWHUHVWLQWKHSURYLVLRQ RIHYLGHQFHEDVHGREVWHWULFFDUH1RQHRILWVPHPEHUVGHFODUHGDFRQÁLFWRI LQWHUHVW7KH*URXSUHYLHZHGWKHÀQDOGRFXPHQWWRLGHQWLI\DQ\HUURUVRIIDFW and commented on clarity of the language, contextual issues and implications for implementation. The Group ensured that the decision-making processes have considered and incorporated contextual values and preferences of potential users of the recommendations, healthcare professionals and policy makers. They did not change the recommendation that was formulated by the GDG. The members of the External Review Group are presented in Annex 1.

Systematic review team and guideline methodologists A Cochrane systematic review on this question was initiated, supported by the Cochrane Pregnancy and Childbirth Group. The WHO Steering Group reviewed and provided input into the protocol, and it worked closely with the Cochrane Pregnancy and Childbirth Group to appraise the evidence using the GRADE methodology. A representative of the Cochrane Pregnancy and Childbirth Group attended the GDG meeting to provide an overview of the available evidence and GRADE tables and to respond to technical queries from the GDG.

External partners and observers Representatives of the United States Agency for International Development (USAID), the Maternal and Child Survival Programme (MCSP)/Jhpiego, the Bill & Melinda Gates Foundation (BMGF), the International Confederation of Midwives (ICM), the International Federation of Gynecology and Obstetrics (FIGO) and Gynuity Health Projects participated in the GDG meeting as observers. These organizations, with a long history of collaboration with the RHR Department in guideline dissemination and implementation, are implementers of the updated recommendation. In addition, one of the WOMAN trial co-ordinators from the London School of Hygiene DQG7URSLFDO0HGLFLQH/6+70SURYLGHGDQRYHUYLHZRIWKHFRQGXFWDQGÀQGLQJVRI the WOMAN trial and responded to questions from the GDG, but did not participate in GDG deliberations nor revision of the recommendation. The list of observers who SDUWLFLSDWHGLQWKHÀQDOWHFKQLFDOFRQVXOWDWLRQLVSUHVHQWHGLQ$QQH[

,GHQWLÀFDWLRQRIFULWLFDORXWFRPHV The critical and important outcomes were aligned with the prioritized outcomes from the WHO recommendations on prevention and treatment of PPH (2012).5 These RXWFRPHVZHUHLQLWLDOO\LGHQWLÀHGWKURXJKDVHDUFKRINH\VRXUFHVRIUHOHYDQW published, systematic reviews and a prioritization of outcomes by the 2012 GDG panel. During the updating of this recommendation, a further two outcomes were LGHQWLÀHGE\WKH:+26WHHULQJ*URXSDQGWKH*'*DVFULWLFDORXWFRPHVIRUWKLV question: namely, maternal death (all causes) and maternal death due to bleeding. 7KXVDWRWDORIRXWFRPHVZHUHUDWHGDV¶FULWLFDO·DQGQLQHRXWFRPHVZHUH UDWHGDV¶LPSRUWDQW·IRUWKLVTXHVWLRQ$OORXWFRPHVZHUHLQFOXGHGLQWKHVFRSHRI

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WHO recommendation on tranexamic acid for the treatment of postpartum haemorrhage

this document for evidence searching, retrieval, grading and formulation of the recommendation. The list of critical and important outcomes is provided in Annex 2.

(YLGHQFHLGHQWLÀFDWLRQDQGUHWULHYDO $&RFKUDQHV\VWHPDWLFUHYLHZRQWKHHIÀFDF\RI7;$IRU33+WUHDWPHQWZDVLQLWLDWHG by the Cochrane Pregnancy and Childbirth Group, as an offshoot of the existing Cochrane review of treatment for PPH.11 This systematic review12 was the primary source of evidence for this recommendation. Randomized, controlled trials relevant to the key question were screened by the review authors, and data on relevant outcomes and comparisons were extracted LQWR5HYLHZ0DQDJHU5HY0DQVRIWZDUH7KH5HY0DQÀOHZDVUHWULHYHGIURP WKH&RFKUDQH3UHJQDQF\DQG&KLOGELUWK*URXSDQGFXVWRPL]HGWRUHÁHFWWKHNH\ comparisons and outcomes (those that were not relevant to the recommendation ZHUHH[FOXGHG7KHQWKH5HY0DQÀOHZDVH[SRUWHGWR*5$'(SURÀOHUVRIWZDUH (GRADEpro) and GRADE criteria were used to critically appraise the retrieved VFLHQWLÀFHYLGHQFH)LQDOO\HYLGHQFHSURÀOHVLQWKHIRUPRI*5$'(WDEOHVZHUH prepared for comparisons of interest, including the assessment and judgements for each outcome, and the estimated risks.

Quality assessment and grading of the evidence The quality assessment of the body of evidence for each outcome was performed using the GRADE approach.13 Using this approach, the quality of evidence for each RXWFRPHZDVUDWHGDV¶KLJK·¶PRGHUDWH·¶ORZ·RU¶YHU\ORZ·EDVHGRQDVHWRI HVWDEOLVKHGFULWHULD7KHÀQDOUDWLQJRITXDOLW\RIHYLGHQFHZDVGHSHQGHQWRQWKH IDFWRUVEULHÁ\GHVFULEHGEHORZ Study design limitations7KHULVNRIELDVZDVÀUVWH[DPLQHGDWWKHOHYHORI individual study and then across studies contributing to the outcome. For UDQGRPL]HGWULDOVTXDOLW\ZDVÀUVWUDWHGDV¶KLJK·DQGWKHQGRZQJUDGHGE\RQH ¶PRGHUDWH·RUWZR¶ORZ·OHYHOVGHSHQGLQJRQWKHPLQLPXPTXDOLW\FULWHULDPHW by the majority of the studies contributing to the outcome. Inconsistency of the results The similarity in the results for a given outcome was assessed by exploring the magnitude of differences in the direction and size of effects observed from different studies. The quality of evidence was not GRZQJUDGHGZKHQWKHGLUHFWLRQVRIWKHÀQGLQJVZHUHVLPLODUDQGFRQÀGHQFHOLPLWV overlapped, whereas quality was downgraded when the results were in different GLUHFWLRQVDQGFRQÀGHQFHOLPLWVVKRZHGPLQLPDORUQRRYHUODS Indirectness The quality of evidence was downgraded when there were serious or very serious concerns regarding the directness of the evidence, that is, whether there were important differences between the research reported and the context for which the recommendation was being prepared. Such differences were related, for instance, to populations, interventions, comparisons or outcomes of interest. Imprecision This assessed the degree of uncertainty around the estimate of effect. As this is often a function of sample size and number of events, studies with UHODWLYHO\IHZSDUWLFLSDQWVRUHYHQWVDQGWKXVZLGHFRQÀGHQFHLQWHUYDOVDURXQG effect estimates, were downgraded for imprecision.

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WHO recommendation on tranexamic acid for the treatment of postpartum haemorrhage

Publication bias Quality rating could also be affected by perceived or statistical evidence of bias to underestimate or overestimate the effect of an intervention as a result of selective publication based on study results. We considered downgrading evidence by one level for strong suspicion of publication bias.

Formulation of recommendations 7KH:+26WHHULQJ*URXSXVHGWKHHYLGHQFHSURÀOHVWRVXPPDULVHHYLGHQFH RQHIIHFWVRI7;$RQWKHSUHVSHFLÀHGRXWFRPHV7KHHYLGHQFHVXPPDU\DQG corresponding GRADE tables, other related documents for assessment of values and preferences, resource requirements and cost-effectiveness, acceptability, feasibility and equity were provided in advance to members of the GDG. The GDG members and other participants were then invited to attend an online technical consultation (see Annex 1 for the list of participants) organized by the Steering Group in Geneva, Switzerland, on 29 August 2017. During the technical consultation, the GDG members reviewed and discussed the balance between desirable and undesirable effects of TXA and the overall quality of supporting evidence, values and preferences of stakeholders, resource requirements and cost-effectiveness, DFFHSWDELOLW\IHDVLELOLW\DQGHTXLW\EHIRUHÀQDOL]LQJWKHUHFRPPHQGDWLRQDQG remarks.

Declaration of interests by external contributors According to WHO regulations, all experts must declare their relevant interests prior to participation in WHO guideline development processes and meetings. All GDG members were therefore required to complete a standard WHO Declaration of Interest (DOI) form before engaging in the guideline development process and before participating in the guideline-related meeting. The WHO Steering Group UHYLHZHGDOOGHFODUDWLRQVEHIRUHÀQDOL]LQJWKHH[SHUWV·LQYLWDWLRQVWRSDUWLFLSDWH :KHUHDQ\FRQÁLFWRILQWHUHVWZDVGHFODUHGWKH6WHHULQJ*URXSGHWHUPLQHGZKHWKHU VXFKFRQÁLFWVZHUHVHULRXVHQRXJKWRDIIHFWREMHFWLYHMXGJHPHQWRIWKHH[SHUWRQ the guideline development process and recommendation. To ensure consistency, WKH6WHHULQJ*URXSDSSOLHGWKHFULWHULDIRUDVVHVVLQJWKHVHYHULW\RIFRQÁLFWRI interests in the WHO Handbook for Guideline Development for all experts. All ÀQGLQJVIURPWKHUHFHLYHG'2,VWDWHPHQWVZHUHPDQDJHGLQDFFRUGDQFHZLWKWKH WHO DOI guidelines on a case-by-case basis and communicated to the experts. :KHUHDFRQÁLFWRILQWHUHVWZDVQRWFRQVLGHUHGVLJQLÀFDQWHQRXJKWRSRVHDQ\ULVN to the guideline development process or reduce its credibility, the experts were only UHTXLUHGWRRSHQO\GHFODUHVXFKFRQÁLFWDWWKHEHJLQQLQJRIWKH*'*PHHWLQJDQG no further actions were taken. $QQH[VKRZVDVXPPDU\RIWKH'2,VWDWHPHQWVDQGKRZGHFODUHGFRQÁLFWVRI interest were managed by the Steering Group.

Decision-making during the technical consultation During the technical consultation, the GDG reviewed and discussed the evidence VXPPDU\DQGVRXJKWFODULÀFDWLRQV,QDGGLWLRQWRHYDOXDWLQJWKHEDODQFHEHWZHHQ desirable and undesirable effects of TXA and the overall quality of the evidence, the GDG applied additional criteria based on the GRADE evidence-to-decision framework to determine the direction and strength of the recommendation. These criteria

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WHO recommendation on tranexamic acid for the treatment of postpartum haemorrhage

included values of stakeholders, resource implications, acceptability, feasibility and equity. Considerations were based on the experience and opinions of members of the GDG and supported by evidence from a literature search where available. +RZHYHUVSHFLÀFV\VWHPDWLFUHYLHZVRIHYLGHQFHIRUH[DPSOHTXDOLWDWLYHHYLGHQFH synthesis or detailed economic evaluation) were not performed to inform discussions on these criteria. Evidence-to-decision tables were used to describe and synthesize these considerations. 7KHGHFLVLRQZDVEDVHGRQFRQVHQVXVGHÀQHGDVWKHDJUHHPHQWE\WKUHHTXDUWHUV or more of the participants. None of the GDG members expressed opposition to the recommendation.

Document preparation Prior to the online technical consultation, the WHO Steering Group prepared a draft YHUVLRQRIWKH*5$'(HYLGHQFHSURÀOHVHYLGHQFHVXPPDU\DQGRWKHUGRFXPHQWV relevant to the deliberation of the GDG. The draft documents were made available to the participants of the technical consultation two weeks before the meeting for WKHLUFRPPHQWV'XULQJWKHPHHWLQJWKHVHGRFXPHQWVZHUHPRGLÀHGLQOLQHZLWK WKHSDUWLFLSDQWV·GHOLEHUDWLRQVDQGUHPDUNV)ROORZLQJWKHPHHWLQJPHPEHUVRI WKH:+26WHHULQJ*URXSGUDIWHGDIXOOJXLGHOLQHGRFXPHQWWRDFFXUDWHO\UHÁHFW the deliberations and decisions of the participants. The draft document was sent HOHFWURQLFDOO\WR*'*PHPEHUVDQGWKH([WHUQDO5HYLHZ*URXSIRUÀQDOUHYLHZDQG approval.

Peer review 7KHÀQDOGRFXPHQWZDVVHQWWRÀYHH[WHUQDOLQGHSHQGHQWH[SHUWVZKRZHUHQRW involved in the guideline panel for peer review. The WHO Steering Group evaluated the inputs of the peer reviewers for inclusion in this document. After the technical FRQVXOWDWLRQDQGSHHUUHYLHZWKHPRGLÀFDWLRQVPDGHE\WKH:+26WHHULQJ*URXS to the document were limited to correction of factual errors and improvement in language to address any lack of clarity.

3. Evidence and recommendation The following section outlines the recommendation and the corresponding narrative summary of evidence for the prioritized question. The GRADE table is presented in Annex 5. The evidence-to-decision table, summarizing the balance between desirable and undesirable effects and the overall quality of the supporting evidence, values and preferences of stakeholders, resource requirements, cost-effectiveness, acceptability, feasibility and equity that were considered in determining the strength and direction of the recommendation, is presented in Annex 4. The following recommendation was adopted by the GDG. Evidence on the effectiveness of the intervention was derived from one systematic review and was summarized in GRADE tables (Annex 5). The quality of the supporting evidence was UDWHGDV¶PRGHUDWH·IRUPRVWFULWLFDORXWFRPHV7RHQVXUHWKDWWKHUHFRPPHQGDWLRQ is correctly understood and appropriately implemented in practice, additional ¶UHPDUNV·UHÁHFWLQJWKHVXPPDU\RIWKHGLVFXVVLRQE\*'*DUHLQFOXGHGXQGHUWKH recommendation.

11

WHO recommendation on tranexamic acid for the treatment of postpartum haemorrhage

Early use of intravenous tranexamic acid (within 3 hours of birth) in addition to standard care is recommended for women with clinically diagnosed postpartum haemorrhage following vaginal birth or caesarean section. (Strong recommendation, moderate quality of evidence) Remarks ‡ Based on the dosing regimen used in the WOMAN trial, the GDG supports the DGPLQLVWUDWLRQRIWUDQH[DPLFDFLG7;$DWDÀ[HGGRVHRIJPJPO intravenously (IV) at 1 ml per minute (i.e. administered over 10 minutes), with a second dose of 1 g IV if bleeding continues after 30 minutes, or if bleeding restarts within 24 KRXUVRIFRPSOHWLQJWKHÀUVWGRVH 7KH:20$17ULDOGHÀQHG´FOLQLFDOO\GLDJQRVHGSRVWSDUWXPKDHPRUUKDJHµDVFOLQLFDOO\ estimated blood loss of more than 500 ml after a vaginal birth or 1000 ml after FDHVDUHDQVHFWLRQRUDQ\EORRGORVVVXIÀFLHQWWRFRPSURPLVHKDHPRG\QDPLFVWDELOLW\ Based on evidence from the WOMAN trial, the reference point for the start of the 3-hour window for starting TXA administration is time of birth. If time of birth is unknown, the best estimate of time of birth should be used as the reference point. As PRVWGHDWKVGXHWRSRVWSDUWXPKDHPRUUKDJHRFFXUZLWKLQWKHÀUVWWRKRXUVDIWHU ELUWKLWLVFULWLFDOWKDW7;$LVJLYHQDVVRRQDVSRVVLEOHWRDFKLHYHFOLQLFDOEHQHÀWV Analysis of the effects of timing of administration in the WOMAN trial, as well as an individual participant data (IPD) meta-analysis of 40 138 bleeding patients (including WOMAN trial participants), indicates that TXA administration beyond 3 hours does QRWFRQIHUDQ\FOLQLFDOEHQHÀW)XUWKHUPRUHWKHSRLQWHVWLPDWHVRIHIIHFWRI7;$XVH beyond 3 hours on death for trauma or after PPH were both in the direction of harm, DOEHLWQRWVWDWLVWLFDOO\VLJQLÀFDQWIRUZRPHQZLWK33+,QYLHZRIWKLVHYLGHQFHWKH GDG does not support the use of TXA more than 3 hours after birth. Administration of TXA should be considered as part of the standard postpartum haemorrhage treatment package. Standard care in the context of this recommendation LQFOXGHVURXWLQHFDUHIRU33+WUHDWPHQWLQFOXGLQJÁXLGUHSODFHPHQWPHGLFDO (uterotonics), monitoring of vital signs, nonsurgical (e.g. bimanual compression, intrauterine balloon tamponade, nonpneumatic antishock garment, aortic compression) and surgical interventions (e.g. brace sutures, arterial ligation or hysterectomy) in accordance with WHO guidelines or adapted local PPH treatment protocols. TXA should be used in all cases of PPH regardless of whether the bleeding is due to genital tract trauma or other causes. The use of TXA should be avoided in women with a clear contraindication to DQWLÀEULQRO\WLFWKHUDS\LQFOXGLQJ7;$HJDNQRZQWKURPERHPEROLFHYHQWGXULQJ pregnancy). 7KLVUHFRPPHQGDWLRQDSSOLHVRQO\WR,9XVH7KHHYDOXDWLRQRIEHQHÀWVDQGSRWHQWLDO harms of other routes of TXA administration is a research priority. Regardless of the level of health system resources, TXA should be recognized as a lifesaving intervention and be made readily available for the management of postpartum haemorrhage in settings where emergency obstetric care is provided.

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A. Review Question z For women with postpartum haemorrhage (P), does administration of tranexamic acid in addition to standard care (I) compared to standard care alone (C), improve outcomes (O)? { If so, when is the most appropriate period to administer tranexamic acid to improve outcomes?

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WHO recommendation on tranexamic acid for the treatment of postpartum haemorrhage

B. Assessment Effects of the intervention What are the anticipated effects of administration of TXA in addition to standard care for PPH treatment? Research evidence Evidence on the use of TXA for treatment of PPH was extracted from a forthcoming Cochrane systematic review of two trials (20 212 women).12 This UHYLHZLQFOXGHGWULDOVWKDWFRPSDUHGWKHXVHRIDQ\ÀEULQRO\WLFGUXJZLWK QRWUHDWPHQWLQZRPHQZLWK33++RZHYHUQRHYLGHQFHZDVLGHQWLÀHGIRU interventions other than TXA. One multicentre trial was conducted in eight obstetric units in France with recruitment between 2005 and 2008.14 This trial randomized 152 women with PPH > 800 ml after a vaginal birth. The intervention group received a loading dose of 4 g TXA mixed with 50 ml saline, administered IV over 1 hour, followed by a maintenance dose of 1 g/hour for 6 hours. Women in the control group were given standard care only, as per the routine practice in participating facilities. The primary outcome was blood loss between randomization and 6 hours. The second (WOMAN trial) was a multicountry, multicentre, placebo-controlled randomised trial of 20 060 women in 193 hospitals, across 21 high-, middle- and low-income countries conducted between March 2010 and April 2016.9 The trial UDQGRPL]HGZRPHQZLWKFOLQLFDOO\GLDJQRVHG33+GHÀQHGDVFOLQLFDOO\HVWLPDWHG blood loss after a vaginal birth of > 500 ml, or > 1000 ml following a caesarean VHFWLRQRUDQ\EORRGORVVVXIÀFLHQWWRFRPSURPLVHKDHPRG\QDPLFVWDELOLW\DQG where the clinician responsible for care was uncertain as to whether or not to use TXA. In addition to usual care, women in the experimental group were initially given 1 g TXA IV in a 10 ml solution, at an approximate rate of 1 ml/minute, as soon as possible after randomization. A second dose was used if bleeding continued after 30 minutes or if it stopped and restarted within 24 hours after WKHÀUVWGRVH7KHFRQWURODUPUHFHLYHGSODFHERQRUPDOVDOLQHXVLQJWKHVDPH regimen. When the trial protocol was registered, the primary outcome was a composite of death from all causes or hysterectomy within 42 days. During the course of the study (but before results were available or any unblinding), the primary outcome was revised to maternal death due to bleeding, and the sample size increased. Evidence regarding this intervention is almost entirely derived from the WOMAN trial. Comparison: TXA (in addition to standard care) versus standard care alone The effects of TXA on critical outcomes for all women with PPH, regardless of KRZ33+ZDVGHÀQHGWKHPRGHRIELUWKRUWLPLQJRI33+DGPLQLVWUDWLRQDUH described below. ‡ Maternal mortality (all causes): Moderate certainty evidence suggests slightly fewer deaths in the group receiving TXA although this difference was not statistically VLJQLÀFDQWWZRVWXGLHVZRPHQYV RR 0.88, 95% CI 0.74 to 1.05).

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WHO recommendation on tranexamic acid for the treatment of postpartum haemorrhage

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Maternal mortality due to PPH: In both trials, clinicians were asked to record the primary cause of death. Moderate certainty evidence suggests that deaths that were considered to be due to bleeding were probably reduced in the TXA group (two studies, 20 172 women, 155/10 113 (1.5%) vs 191/10 059 (1.9%), RR 0.81, 95% CI 0.65 to 1.00). The number needed to treat (NNT) to prevent one maternal death due to bleeding is 258 (95% CI 133.2 to 4051.8). Severe maternal morbidity: The French trial reported multiple organ failure; there were no events in either arm and very few admissions to intensive care (one study, 152 women, 3/77 (3.9%) vs 5/74 (6.8%), RR 0.58 (95% CI 0.14 to 2.33). The number of women suffering any severe morbidity was not reported in the WOMAN trial report, EXWVSHFLÀFPRUELGLWLHVZHUHUHSRUWHG0RGHUDWHFHUWDLQW\HYLGHQFHVXJJHVWHGOLWWOH or no difference between groups for any of morbidity outcomes reported (respiratory failure: RR 0.87, 95% CI 0.67 to 1.12; seizure: two studies; RR 0.76, 95% CI 0.49 to 1.20; hepatic failure RR 0.96, 95% CI 0.58 to 1.60; cardiac failure: RR 0.95, 95% CI 0.73 to 1.23; renal failure: two studies; RR 1.09, 95% CI 0.85 to 1.39). Blood products transfusion (all): Moderate certainty evidence suggests there is very little or no difference between groups for transfusion of blood products, with more than half of the women in both arms of the WOMAN trial receiving a transfusion (two studies; RR 1.00, 95% CI 0.97 to 1.03). Additional blood loss: The French trial reported additional blood loss > 500 ml or > 1000 ml. Low-quality evidence suggests TXA probably reduces blood loss > 500 ml (RR 0.50, 95% CI 0.27 to 0.93, 151 women). Although the direction of effect was the VDPHIRUORVV!POWKHVWXG\KDGLQVXIÀFLHQWSRZHUWRGHPRQVWUDWHDGLIIHUHQFH between groups (4/77 women versus 8/74). Additional uterotonics: The vast majority of women in the WOMAN trial received uterotonics (99.3% vs 99.1%, two studies; RR 1.00, 95% CI 1.0 to 1.0). Surgical interventions: High or moderate certainty evidence suggests there is probably little difference between groups for most surgical interventions to control bleeding (hysterectomy (all): two studies; RR 1.01, 95% CI 0.88 to 1.17; ligature: RR 0.88, 95% CI 0.74 to 1.05; embolization: RR 0.82, 95% CI 0.42 to 1.62). High certainty evidence suggests laparotomy to control bleeding is reduced for women in the TXA group (0.8% vs 1.3%) (RR 0.64, 95% CI 0.49 to 0.85) while brace sutures are increased (RR 1.19, 95% CI 1.01 to 1.41). Invasive nonsurgical interventions: High certainty evidence suggests there is probably little or no difference in intrauterine tamponade (one study; RR 0.96, 95% CI 0.87 to 1.06) or manual removal of placenta: (one study; RR 0.95, 95% CI 0.87 to 1.04). Procedure-related complications: Moderate certainty evidence suggests there is probably little or no difference between groups for thromboembolic events (any maternal thromboembolic event: RR 0.88, 95% CI 0.54 to 1.43; deep venous thrombosis: two studies; RR 0.62 95% CI 0.20 to 1.88; pulmonary embolism RR 0.85, 95% CI 0.44 to 1.61; myocardial infarction: RR 0.66, 95% CI 0.11 to 3.97; stroke: RR 1.33, 95% CI 0.46 to 3.82). Neonatal adverse effects: Available neonatal outcome data were limited (data from WOMAN trial only). There were no neonatal thromboembolic events and no clear differences in deaths in breastfed neonates (eight deaths with TXA vs seven deaths with placebo) in the WOMAN trial. Longer-term outcomes: Available data on longer-term outcomes was limited (data from the WOMAN trial only). Outcomes in the WOMAN trial were measured up to hospital discharge or 42 days if still in hospital. There was no information on longerterm outcomes in women or babies. Subgroup analysis examining treatment effect by mode of birth (vaginal or caesarean) suggests no clear difference in effect on maternal death (all causes) and maternal death due to PPH for type of birth (moderate certainty of evidence).

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WHO recommendation on tranexamic acid for the treatment of postpartum haemorrhage

Comparison: TXA (in addition to standard care) versus standard care alone, by timing of TXA administration Evidence for this subgroup comparison was derived from a pre-planned subgroup analysis of the WOMAN trial. ‡ Maternal mortality due to PPH: There are subgroup differences for the timing of drug administration. Women receiving TXA less than 1 hour after birth had reduced risk of GHDWKIURPEOHHGLQJEXWWKHFRQÀGHQFHLQWHUYDOFURVVHGWKHOLQHRIQRHIIHFWOHVV than 1 hour: RR 0.80, 95% CI 0.55 to 1.16). Women receiving TXA 1 to 3 hours after birth were at reduced risk of death from bleeding (1 to 3 hours: RR 0.60, 95% CI 0.41 to 0.88) compared with women where more than 3 hours had elapsed before TXA was administered (more than 3 hours: RR 1.07, 95% CI 0.76 to 1.51). Maternal mortality (all cause): Compared to the control group, women receiving TXA less than 1 hour after birth had similar risks of death (any cause) (less than 1 hour: RR 0.98, 95% CI 0.72 to 1.33), as did women receiving TXA more than 3 hours after birth (more than 3 hours: RR 1.00, 95% CI 0.75 to 1.33). However, women receiving TXA 1 to 3 hours after birth were at reduced risk of death from all causes (1 to 3 hours: RR 0.69, 95% CI 0.49 to 0.96). Death or hysterectomy: Compared to the control group, women receiving TXA less than 1 hour after birth had similar risks of death or hysterectomy (less than 1 hour: RR 1.08, 95% CI 0.91 to 1.28), as did women receiving TXA more than 3 hours after birth (more than 3 hours: RR 1.01, 95% CI 0.82 to 1.25). However, women receiving TXA 1 to 3 hours after birth were at reduced risk of death or hysterectomy (1 to 3 hours: RR 0.80, 95% CI 0.63 to 1.00). Laparotomy for bleeding: Compared to the control group, women receiving TXA less than 1 hour after birth had reduced risk of laparotomy for bleeding (less than 1 hour: RR 0.48, 95% CI 0.29 to 0.79), as did women receiving TXA at 1 to 3 hours after birth (1 to 3 hours: RR 0.54, 95% CI 0.31 to 0.95). Women receiving TXA more than 3 hours after birth were not at reduced risk of laparotomy for bleeding (more than 3 hours: RR 0.89, 95% CI 0.59 to 1.35).

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Desirable effects How substantial are the desirable anticipated effects of TXA + standard care vs standard care alone? Judgement … 'RQ·WNQRZ … Varies … Trivial … Small … Moderate _ Large

Undesirable effects How substantial are the undesirable anticipated effects TXA + standard care vs standard care alone? Judgement … 'RQ·WNQRZ … Varies … Large … Moderate … Small _ Trivial

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WHO recommendation on tranexamic acid for the treatment of postpartum haemorrhage

Certainty of the evidence What is the overall certainty of the evidence of effects? Judgement … No included studies … Very low … Low _ Moderate … High

Additional considerations Additional evidence was obtained from a forthcoming individual patient data (IPD) on the impact of treatment delay on the effectiveness and safety of DQWLÀEULQRO\WLFVLQDFXWHVHYHUHKDHPRUUKDJH15 The IPD meta-analysed 40 138 bleeding patients (with 3 558 deaths recorded) who received TXA or placebo from WOMAN and CRASH-2 trials combined. The authors reported that deaths from PPH peaked at 2 to 3 hours after childbirth, and immediate treatment improved EOHHGLQJVXUYLYDO7UHDWPHQWGHOD\DSSHDUVWRUHGXFHEHQHÀW²WKHEHQHÀW DSSHDUVWRGHFUHDVHE\IRUHYHU\PLQXWHV·GHOD\ZLWKQREHQHÀWVHHQ after 3 hours. The point estimates of effect of TXA use beyond 3 hours on death for trauma or after PPH were both in the direction of harm, albeit not statistically VLJQLÀFDQWIRUZRPHQZLWK33+ Values and preferences Is there important uncertainty about, or variability in, how much women value the main outcomes? Typically, women, healthcare providers and policy-makers place a higher value on avoiding a maternal death, even when potentially associated with an increase in invasive surgical interventions, such as brace sutures. Therefore, women, healthcare providers and policy-makers in all settings are likely to place a high value on the reduction in the risk of maternal death due to bleeding. The GDG is FRQÀGHQWWKDWZRPHQKHDOWKFDUHSURYLGHUVDQGSROLF\PDNHUVLQDQ\VHWWLQJZLOO LQYDULDEO\SODFHDKLJKHUYDOXHRQWKLVEHQHÀWFRPSDUHGWRDQ\LQFRQYHQLHQFH (or drawbacks) that TXA use might cause to the woman, her baby or the health system. Stakeholders with different values in different contexts are unlikely to make different decisions when presented with these choices. Judgement … Important uncertainty or variability … Possibly important uncertainty or variability … Probably no important uncertainty or variability _ No important uncertainty or variability

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WHO recommendation on tranexamic acid for the treatment of postpartum haemorrhage

Balance of effects Does the balance between desirable and undesirable effects favour use of TXA in addition to standard care (intervention) or standard care alone (comparison)? 7KHUHLVHYLGHQFHWKDW7;$LVSUREDEO\EHQHÀFLDOLQUHGXFLQJPDWHUQDOGHDWKV due to bleeding and reducing the need for laparotomy to stop bleeding. Early WUHDWPHQWDSSHDUVWRRSWLPL]HEHQHÀW7KHUHGRHVQRWDSSHDUWREHHYLGHQFHRI PDWHUQDORUQHZERUQKDUPVRUVLJQLÀFDQWVLGHHIIHFWV:KLOHQRGLIIHUHQFHLQ newborn thromboembolic events were seen, in the WOMAN trial most women and babies were followed until discharge from the health facility, thus this evidence is PRUHOLNHO\UHSUHVHQWDWLYHRIWKHÀUVWIHZGD\VDIWHUELUWK Judgement … 'RQ·WNQRZ … Varies … Favours the standard care alone … Probably favours the standard care alone … Does not favour TXA + standard care or standard care alone … Probably favours TXA + standard care _ Favours TXA + standard care

Resources required What are the resource requirements for administering TXA in addition to standard care for PPH treatment? Research evidence None of the studies included in the Cochrane systematic review conducted a formal cost-effectiveness analysis.

Main resource requirements The use of TXA in addition to standard PPH treatment requires the existence of healthcare providers who have been trained in how to administer intravenous drugs. Resource Training Supplies Description 2 to 3 day practice-based training/practice drills for PPH management 1 to 2 g of TXA (varies between settings, with an approximate range of $1.00 to $5.70 per g) 16 IV infusion set Syringe/needle/swabs = approximately US$0.08 to $0.10 None required. Average time needed is 10 to 15 minutes for gaining IV access and administration of the drug (depending on other factors VXFKDVSURYLGHUVNLOOV+RZHYHUVXIÀFLHQWWLPHLVQHHGHG for monitoring the response of the woman to treatment as required for all cases of PPH. Regular supervision and review by labour ward lead, especially ZKHQÀUVWLQWURGXFHG

Equipment Time

Supervision and monitoring

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WHO recommendation on tranexamic acid for the treatment of postpartum haemorrhage

Additional considerations ‡ TXA is relatively cheap in most contexts, easy to administer, and it is often available in healthcare settings due to its use in trauma and surgery. Research evidence on costeffectiveness can be extrapolated from cost-effectiveness analysis of TXA for bleeding trauma patients.16 The study found that administering TXA to bleeding trauma patients within 3 hours of injury saved an estimated 372, 315 and 755 life-years (LYs) per 1 000 trauma patients in Tanzania, India and the UK respectively. The cost of giving TXA to 1 000 patients was $17 483 in Tanzania, $19 550 in India and $30 830 in the UK. The incremental cost of giving TXA versus not giving TXA was $18 025 in Tanzania, $20 670 in India and $48 002 in the UK. The estimated incremental cost per LY gained of administering TXA is $48, $66 and $64 in Tanzania, India and the UK respectively. Early administration of TXA to bleeding trauma patients is likely to be highly costeffective in low-, middle- and high-income settings. The use of TXA may also reduce subsequent costs related to surgical procedures for PPH treatment (such as laparotomy) as well as any complications associated with surgery. Out-of-pocket costs to individual women might be higher when TXA is added to VWDQGDUGFDUHIRU33+LQVHWWLQJVZKHUHZRPHQLQFXUÀQDQFLDOFRVWVIRUELUWKV

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Resource requirements How large are the resource requirements for administering TXA in addition to standard care for PPH treatment compared to standard care alone? Judgement … 'RQ·WNQRZ … Varies … Large costs … Moderate costs _ Negligible costs or savings … Moderate savings … Large savings

Certainty of evidence on required resources What is the certainty of the evidence on costs? Judgement _ No included studies … Very low … Low … Moderate … High

Cost-effectiveness Does cost-effectiveness favour TXA + standard care or standard care alone? Judgement … 'RQ·WNQRZ … Varies … … Favours the Probably standard favours the care alone standard care alone … Does not favour either the TXA + standard care or the standard care alone _ Probably favours TXA + standard care … Favours TXA +standard care

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WHO recommendation on tranexamic acid for the treatment of postpartum haemorrhage

Equity What would be the impact on health equity of TXA administration in addition to standard care for PPH treatment? Research evidence ‡ No direct evidence of the impact of the TXA administration in addition to standard care for PPH treatment on equity was found. However, indirect evidence from a review of barriers and facilitators to facility-based birth indicates that poor quality of care, DVHYLGHQWE\SRRUELUWKRXWFRPHVLVSUREDEO\DVLJQLÀFDQWEDUULHUWRWKHXSWDNHRI facility birth by women in LMICs.17

Additional considerations ‡ The 2015 WHO State of Inequality report indicates that women who are poor, leasteducated, and reside in rural areas have lower health intervention coverage and worse health outcomes than more advantaged women.18 Therefore, reducing maternal deaths due to bleeding through scaling up of TXA for PPH treatment could have a positive impact on health equity and improve outcomes among disadvantaged women, HVSHFLDOO\LQ/0,&VZKHUHWKHVHZRPHQDUHDWVLJQLÀFDQWO\KLJKHUULVNRI33+UHODWHG maternal deaths. Reducing the need for expensive, life-saving surgical interventions (such as laparotomy to stop bleeding in women with vaginal birth) through an IV medication would probably reduce inequities, especially in contexts where health services are covered through out-of-pocket means.

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Judgement … 'RQ·WNQRZ … Varies … Reduced … Probably reduced … Probably no impact _ Probably increased … Increased

Acceptability Is TXA (in addition to standard care) acceptable to key stakeholders (women and healthcare providers) for PPH treatment? The intervention is likely to be acceptable to both women and healthcare providers. TXA is administered in adequately equipped health facilities (providing emergency obstetric care) by a skilled healthcare provider via a standard IV infusion over a short period of time. There is no evidence of adverse maternal or QHRQDWDOHIIHFWV7KHEDODQFHEHWZHHQEHQHÀWVDQGKDUPVVXJJHVWVWKDW7;$ZLOO be acceptable to key stakeholders (women, providers and policy makers) across VHWWLQJV$QLQFUHPHQWDOFRVWZLWKVXEVWDQWLDOEHQHÀWVLQWHUPVRIVDYLQJOLYHV would be generally acceptable. Judgement … 'RQ·WNQRZ … Varies … No … Probably No _ Probably Yes … Yes

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WHO recommendation on tranexamic acid for the treatment of postpartum haemorrhage

Feasibility Is TXA feasible to implement in addition to standard care for PPH treatment? The use of IV TXA for treatment of PPH in healthcare facilities was regarded by the GDG as feasible. Standard IV infusion equipment is required, as well DVKHDOWKFDUHSURYLGHUVZLWKVXIÀFLHQWWUDLQLQJWRVDIHO\DGPLQLVWHU,9EROXV infusions (similar to oxytocin infusion). Many hospitals already have access to TXA due to its common use for trauma and surgery. Available preparations are compatible with recommended dosing regimens for PPH treatment. In many healthcare facilities (including in LMICs) no (or minimal) additional resources, infrastructure or training is required to commence using TXA for this indication. Administration of TXA should be relatively easy to integrate into standard PPH treatment packages. It is listed on the WHO Model List of Essential Medicines under medicines affecting coagulation. The successful implementation of the WOMAN trial in 193 hospitals in 21 countries, which recruited over 20 000 women, in itself can be considered a potential demonstration of the feasibility of implementing this intervention.9 The pragmatic nature of the trial, coupled with the variations in the capacities of participating institutions (from low to very high) also supports feasibility across low-, middle- and high-income settings. These hospitals are likely to implement a recommendation of TXA easily. However, given that evidence currently supports IV TXA for treatment, the intervention may not be feasible in settings where IV administrations are restricted to doctors working in high-level or referral facilities. Judgement … 'RQ·WNQRZ … Varies … No … Probably No _ Probably Yes … Yes

4. Research implications ‡ 7KH*'*LGHQWLÀHGWKDWIXUWKHUUHVHDUFKRQWKHXVHRI7;$IRU33+LVDSULRULW\ :KLOHWKHODUJHPXOWLFRXQWU\:20$1WULDOKDVDVVHVVHGWKHEHQHÀWVDQGKDUPV of IV TXA for PPH treatment, other research priorities include: ‡ What are the effects of TXA by other routes of administration (for example, oral, intramuscular, topical, buccal) when used for PPH treatment? ‡ What is the cost-effectiveness of TXA when used for PPH treatment? ‡ What is the optimal dosing regimen of TXA for PPH treatment? ‡ What are the longer-term effects (on women and breastfed newborns) of TXA when used for PPH treatment? ‡ What are the effects of oral or intravenous TXA when used for PPH prevention? 19

20

WHO recommendation on tranexamic acid for the treatment of postpartum haemorrhage

5. Dissemination and implementation of the recommendation Dissemination and implementation of the recommendation is to be considered by all actors involved in the provision of care for pregnant women at the international, national and local levels. There is a vital need to increase access and strengthen the capacity of health centres to provide high quality services for all women giving birth. It is therefore crucial that this recommendation is translated into PPH treatment packages and programmes at country and health-facility levels.

Recommendation dissemination and evaluation The recommendation will be disseminated through WHO regional and country RIÀFHVPLQLVWULHVRIKHDOWKSURIHVVLRQDORUJDQL]DWLRQV:+2FROODERUDWLQJFHQWUHV other United Nations agencies and nongovernmental organizations, among others. This recommendation will be also available on the WHO website and in the WHO Reproductive Health Library. To increase awareness of the recommendation, a short commentary will be published in a peer-reviewed journal. The recommendation ZLOOEHDOVRGLVVHPLQDWHGGXULQJPHHWLQJVRUVFLHQWLÀFFRQIHUHQFHVDWWHQGHGE\ WHO staff. The executive summary will be translated into the six UN languages and GLVVHPLQDWHGWKURXJKWKH:+2UHJLRQDORIÀFHV7HFKQLFDODVVLVWDQFHZLOOEHSURYLGHG WRDQ\:+2UHJLRQDORIÀFHZLOOLQJWRWUDQVODWHWKHIXOOUHFRPPHQGDWLRQLQWRDQ\RI the six UN languages.

Implementation considerations The successful introduction of evidence-based policies (related to the prevention and management of PPH) into national programmes and healthcare services depends on well planned and participatory, consensus-driven processes of adaptation and implementation. These processes may include the development or revision of existing national guidelines or protocols based on this document. TXA should be included as part of the standard package for PPH treatment. It should therefore be available at all times in the labour room of facilities providing emergency obstetric care. 'XHFRQVLGHUDWLRQVKRXOGEHJLYHQWRDQ\VSHFLÀFPDQXIDFWXUHU·VLQVWUXFWLRQVRQ precautions and contraindications. TXA for injection may be mixed with most solutions for infusion, such as electrolyte solutions, carbohydrate solutions, amino acid solutions and dextran solutions.20 TXA should be administered as a bolus IV injection over 10 minutes, as there is a potential risk of transient lowering of blood pressure. TXA should not be mixed with blood for transfusion, solutions containing penicillin or mannitol.20 It can be administered via the same IV cannula used for IV hydration or uterotonic administration. An enabling environment should be created for the use of TXA (for example, by widening its availability) in order to support changes in the behaviour of healthcare practitioners to enable the use of evidence-based practice. This includes technical support for local guideline implementers in the development of training manuals, ÁRZFKDUWVDQGTXDOLW\LQGLFDWRUVDVZHOODVWKHLUSDUWLFLSDWLRQLQVWDNHKROGHUV· meetings. Local professional societies play important roles in this process, and an inclusive and participatory process should be encouraged. 21

WHO recommendation on tranexamic acid for the treatment of postpartum haemorrhage

Health facilities where emergency obstetric care is provided need to have the necessary supplies and equipment, as well as the necessary training for staff attending births, so that TXA can be administered safely by IV infusion. The shelf life of TXA is generally three years, and can be stored at room temperature (15 to 30 degrees Celsius). The opened product must be used immediately. The PDQXIDFWXUHU·VLQVWUXFWLRQVRQVWRUDJHDQGXVHKRZHYHUVKRXOGDOZD\VEHJLYHQ precedence. The recommendation should be adapted into locally appropriate documents that are DEOHWRPHHWWKHVSHFLÀFQHHGVRIHDFKFRXQWU\DQGKHDOWKVHUYLFH0RGLÀFDWLRQVWR WKHUHFRPPHQGDWLRQVKRXOGEHMXVWLÀHGLQDQH[SOLFLWDQGWUDQVSDUHQWPDQQHU

6. Applicability issues Anticipated impact on the organization of care and resources Implementing this evidence-based recommendation can be achieved without substantive additional resources. The GDG noted that updating training curricula and providing training on the updated recommendation would increase the UHFRPPHQGDWLRQ·VLPSDFWDQGIDFLOLWDWHLWVLPSOHPHQWDWLRQ6WDQGDUGL]LQJ33+ treatment by including this recommendation into existing packages of care can encourage healthcare provider behaviour change.

Monitoring and evaluating guideline implementation Implementation should be monitored at the health-service level as part of broader efforts to monitor and improve the quality of maternal and newborn care. For example, interrupted time series, clinical audits or criterion-based clinical audits can be used to obtain relevant data related to the management of PPH. Clearly GHÀQHGUHYLHZFULWHULDDQGLQGLFDWRUVDUHQHHGHGDQGWKHVHFRXOGEHDVVRFLDWHG with locally agreed targets. These can be aligned with the standards and indicators described in the WHO document Standards for improving quality of maternal and newborn care in health facilities.21 In 2012, the GDG of the WHO recommendations on prevention and treatment of PPH strongly recommended the use of coverage of prophylactic uterotonics as a process indicator for the monitoring of PPH prevention.5 This indicator provides DQRYHUDOODVVHVVPHQWRIDGKHUHQFHWRDNH\UHFRPPHQGDWLRQZLWKLQDOORI:+2·V recommendations on PPH prevention and treatment. The use of other locally agreed DQGPRUHVSHFLÀFLQGLFDWRUVIRUH[DPSOHWKHDVVHVVPHQWRIWKHXVHRIVSHFLÀF uterotonics or use of TXA for PPH treatment) may be necessary to obtain a more complete assessment of the quality of care related to the prevention and treatment RI33+:+2KDVGHYHORSHGVSHFLÀFJXLGDQFHIRUHYDOXDWLQJWKHTXDOLW\RIFDUHIRU severe maternal complications (including PPH) based on the near-miss and criterionbased clinical audit concepts.22 ,QFROODERUDWLRQZLWKWKH:+25+5DQG0&$'HSDUWPHQWV·PRQLWRULQJDQGHYDOXDWLRQ team, data on country and regional level implementation of the recommendation will be collected and evaluated in the short- to medium-term to evaluate the UHFRPPHQGDWLRQ·VLPSDFWRQWKHQDWLRQDOSROLF\RILQGLYLGXDO:+20HPEHU6WDWHV 22

WHO recommendation on tranexamic acid for the treatment of postpartum haemorrhage

Information on recommended indicators can also be obtained at the local level by interrupted time series or clinical audits.

7. Updating the recommendation 7KH([HFXWLYH*6*ZLOOFRQYHQHDQQXDOO\WRUHYLHZ:+2·VFXUUHQWSRUWIROLR of maternal and perinatal health recommendations, and to prioritize new and existing questions for recommendation development and updating. Accordingly, the recommendation on TXA use for the treatment of PPH will be reviewed and prioritized by the Executive GSG. In the event that new evidence (that could SRWHQWLDOO\LPSDFWWKHFXUUHQWHYLGHQFHEDVHLVLGHQWLÀHGWKHUHFRPPHQGDWLRQ PD\EHXSGDWHG,IQRQHZUHSRUWVRULQIRUPDWLRQLVLGHQWLÀHGWKHUHFRPPHQGDWLRQ may be revalidated. Following publication and dissemination of the updated recommendation, any concern about validity of the recommendation will be promptly communicated to the guideline implementers, in addition to plans to update the recommendation. WHO welcomes suggestions regarding additional questions for inclusion in the updated recommendation. Please email your suggestions to mpa-info@who.int.

23

WHO recommendation on tranexamic acid for the treatment of postpartum haemorrhage

References 1. Souza JP, Gülmezoglu AM, Vogel J, et al. Moving beyond essential interventions for reduction of maternal mortality (the WHO Multicountry Survey on Maternal and Newborn Health): a cross-sectional study. Lancet. 2013;381(9879):1747-55. 2. Carroli G, Cuesta C, Abalos E, Gulmezoglu AM. Epidemiology of postpartum haemorrhage: a systematic review. Best Pract Res Clin Obstet Gynaecol. 2008;22(6):999-1012. 3. Say L, Chou D, Gemmill A, et al. Global causes of maternal death: a WHO systematic analysis. Lancet Glob Health. 2014;2(6):e323-33. 4. Oyelese Y, Ananth CV. Postpartum hemorrhage: epidemiology, risk factors, and causes. Clin Obstet Gynecol. 2010;53(1):147-56. 5. WHO recommendations for the prevention and treatment of postpartum haemorrhage. Geneva: World Health Organization, 2012. 6. National Center for Biotechnology Information PCD, CID=5526. Tranexamic acid – compound summary for CID 5526. 2017 (https://pubchem.ncbi.nlm.nih.gov/ compound/5526, accessed 31 August 2017). 7. Report of the WHO Expert Committee on Selection and Use of Essential Medicines, 2017 (including the 20th WHO Model List of Essential Medicines and the 6th WHO Model List of Essential Medicines for Children). Geneva: World Health Organization, 2017. 8. Shakur H, Elbourne D, Gülmezoglu M, et al. The WOMAN Trial (World Maternal $QWLÀEULQRO\WLF7ULDOWUDQH[DPLFDFLGIRUWKHWUHDWPHQWRISRVWSDUWXP haemorrhage: an international randomised, double blind placebo controlled trial. Trials. 2010:11:40. 9. WOMAN Trial Collaborators. Effect of early tranexamic acid administration on mortality, hysterectomy, and other morbidities in women with post-partum haemorrhage (WOMAN): an international, randomised, double-blind, placebocontrolled trial. Lancet. 2017;389(10084):2105-16. 10. WHO handbook for guideline development (second edition). Geneva: World Health Organization; 2014. 0RXVD+$%OXP-$ERX(O6HQRXQ*6KDNXU+$OÀUHYLF=7UHDWPHQW for primary postpartum haemorrhage. Cochrane Database Syst Rev. 2014;(2):CD003249. 12. Shakur H, Beaumont D, Pavord S, Gayet-Ageron A, Ker K, Dowswell T, Mousa H. $QWLÀEULQRO\WLFGUXJVIRUWUHDWLQJSULPDU\SRVWSDUWXPKDHPRUUKDJH&RFKUDQH Database Syst Rev. 2017;(unpublished). 13. Balshem H, Helfand M, Schünemann HJ, et al. GRADE guidelines: 3. Rating the quality of evidence. J Clin Epidemiol. 2011;64(4):401-6. 14. Ducloy-Bouthors AS, Jude B, Duhamel A, et al. High-dose tranexamic acid reduces blood loss in postpartum haemorrhage. Crit Care. 2011;15(2):R117.

24

WHO recommendation on tranexamic acid for the treatment of postpartum haemorrhage

15. Gayet-Ageron A, Prieto-Merino D, Ker K, Shakur H, Ageron F-X, Roberts I. Impact RIWUHDWPHQWGHOD\RQWKHHIIHFWLYHQHVVDQGVDIHW\RIDQWLÀEULQRO\WLFVLQDFXWH severe haemorrhage: an individual patient data meta-analysis in 40 138 bleeding patients. Lancet. 2017; accepted for publication. 16. Guerriero C, Cairns J, Perel P, Shakur H, Roberts I, collaborators Ct. Costeffectiveness analysis of administering tranexamic acid to bleeding trauma patients using evidence from the CRASH-2 trial. PLoS One. 2011;6(5):e18987. 17. Bohren MA, Hunter EC, Munthe-Kaas HM, Souza JP, Vogel JP, Gülmezoglu AM. Facilitators and barriers to facility-based delivery in low- and middle-income countries: a qualitative evidence synthesis. Reprod Health. 2014;11(1):71. 18. State of inequality: reproductive, maternal, newborn and child health. Geneva: World Health Organization; 2015. 19. Novikova N, Hofmeyr GJ, Cluver C. Tranexamic acid for preventing postpartum haemorrhage. Cochrane Database Syst Rev. 2015;(6):CD007872. 20. EMC. Cyclokapron Injection. 15 March 2016 (https://www.medicines.org.uk/emc/ medicine/1489w5, accessed September 2017). 21. Standards for improving quality of maternal and newborn care in health facilities. Geneva: World Health Organization; 2016. 22. Evaluating the quality of care for severe pregnancy complications: The WHO near-miss approach for maternal health. Geneva: World Health Organization; 2011.

25

WHO recommendation on tranexamic acid for the treatment of postpartum haemorrhage

Annex 1. External experts and WHO staff involved in the preparation of the guideline A. Participants at the who technical consultation on TXA for the treatment of PPH Guideline Development Group Edgardo Abalos (unable to attend) Centro Rosarino de Estudios Perinatales (CREP) Rosario, Argentina Yap-Seng Chong Department of Obstetrics and Gynaecology National University Hospital Singapore Catherine Deneux-Tharaux Inserm U1153 Obstetrical, Perinatal and Pediatric Epidemiology Research Team Centre of Research in Epidemiology and Statistics Sorbonne Paris Cité Université Paris Descartes Paris, France Bukola Fawole Department of Obstetrics & Gynaecology College of Medicine University of Ibadan Ibadan, Nigeria Justus Hofmeyr Universities of the Witwatersrand and Walter Sisulu/Eastern Cape Department of Health East London, South Africa Caroline Homer (unable to attend) WHO Collaborating Centre for Nursing, Midwifery and Health Development Faculty of Health University of Technology Sydney, Australia Pisake Lumbiganon Department of Obstetrics and Gynaecology Faculty of Medicine Khon Kaen University Khon Kaen, Thailand Suellen Miller Department of Obstetrics, Gynecology & Reproductive Sciences Director, Safe Motherhood Program Bixby Center for Global Reproductive Health San Francisco, United States Ashraf Nabhan Department of Obstetrics and Gynecology Faculty of Medicine Ain Shams University Abbasia, Cairo, Egypt James Neilson 'HSDUWPHQWRI:RPHQ·VDQG&KLOGUHQ·V+HDOWK The University of Liverpool :RPHQ·V1+6)RXQGDWLRQ7UXVW Liverpool, United Kingdom Hiromi Obara JICA Health Policy Advisor /DR3HRSOH·V'HPRFUDWLF5HSXEOLF Zahida Qureshi Department of Obstetrics and Gynaecology School of Medicine University of Nairobi Nairobi, Kenya Rahat Qureshi Aga Khan University Department of Obstetrics and Gynecology Karachi, Pakistan Helen West The University of Liverpool :RPHQ·V1+6)RXQGDWLRQ7UXVW Liverpool, United Kingdom

26

WHO recommendation on tranexamic acid for the treatment of postpartum haemorrhage

Observers Deborah Armbruster United States Agency for International Development (USAID) Bureau for Global Health Washington DC, United States Kusum Thapa MCSP/Jhpiego USAID Grantee 1776 Massachusetts Ave Washington DC, United States Janna Patterson Maternal, Neonatal & Child Health Global Development Program Bill & Melinda Gates Foundation Seattle, Washington, United States Haleema Shakur-Still London School of Hygiene and Tropical Medicine London, United Kingdom Sally Tracy International Confederation of Midwives (ICM) Sydney University Sydney, Australia Gerard H.A. Visser International Federation of Gynecology and Obstetrics (FIGO) London, United Kingdom Beverley Winikoff Gynuity Health Projects New York, United States

Anoma Jayathilaka Family Health, Gender and Life Course :+25HJLRQDO2IÀFHIRU6RXWK(DVW$VLD New Delhi, India Ramez Khairi Mahaini (unable to attend) Reproductive and Maternal Health :+25HJLRQDO2IÀFHIRUWKH(DVWHUQ0HGLWHUUDQHDQ Cairo, Egypt Bremen De Mucio Sexual and Reproductive Health :+25HJLRQDO2IÀFHRIWKH$PHULFDV Montevideo, Uruguay Mari Nagai (unable to attend) Reproductive, Maternal, Newborn, Child and Adolescent Health Division of NCD and Health through Life-Course 5HJLRQDO2IÀFHIRUWKH:HVWHUQ3DFLÀF Manila, Philippines Léopold Ouedraogo (unable to attend) Reproductive Health Health Promotion Cluster (HPR) :+25HJLRQDO2IÀFHIRU$IULFD Brazzaville, Republic of Congo Claudio Sosa Sexual and Reproductive Health :+25HJLRQDO2IÀFHRIWKH$PHULFDV Montevideo, Uruguay

WHO Secretariat A. Metin Gülmezoglu Coordinator, RHR/MPA Maternal and Perinatal Health & Preventing Unsafe Abortion Department of Reproductive Health and Research Mercedes Bonet 0HGLFDO2IÀFHU5+503$ Maternal and Perinatal Health & Preventing Unsafe Abortion Department of Reproductive Health and Research Olufemi T. Oladapo 0HGLFDO2IÀFHU5+503$ Maternal and Perinatal Health & Preventing Unsafe Abortion Department of Reproductive Health and Research

Systematic Review Team Therese Dowswell 'HSDUWPHQWRI:RPHQ·VDQG&KLOGUHQ·V+HDOWK The University of Liverpool :RPHQ·V1+6)RXQGDWLRQ7UXVW Crown Street Liverpool, United Kingdom

:+25HJLRQDO2IÀFHV Mavjuda Babamuradova Sexual and Reproductive Health Noncommunicable diseases and life-course :+25HJLRQDO2IÀFHIRU(XURSH Copenhagen, Denmark

27

WHO recommendation on tranexamic acid for the treatment of postpartum haemorrhage

Joao Paulo Souza (unable to attend) 0HGLFDO2IÀFHU5+503$ Maternal and Perinatal Health & Preventing Unsafe Abortion Department of Reproductive Health and Research Joshua P. Vogel 7HFKQLFDO2IÀFHU5+503$ Maternal and Perinatal Health & Preventing Unsafe Abortion Department of Reproductive Health and Research Maurice Bucagu (unable to attend) 0HGLFDO2IÀFHU0&$333 Policy, Planning and Programmes Department of Maternal, Newborn, Child and Adolescent Health Fran McConville (unable to attend) 7HFKQLFDO2IÀFHU0&$333 Policy, Planning and Programmes Department of Maternal, Newborn, Child and Adolescent Health Anayda Portela 7HFKQLFDO2IÀFHU0&$05' Research and Development Department of Maternal, Newborn, Child and Adolescent Health

C. External Review Group Richard M.K. Adanu School of Public Health University of Ghana Accra, Ghana Fernando Althabe Department of Maternal and Child Health Research Institute for Clinical Effectiveness and Health Policy Buenos Aires, Argentina Sue Fawcus Department of Obstetrics and Gynaecology University of Cape Town Cape Town, South Africa Jamilu Tukur Department of Obstetrics and Gynaecology Bayero University Kano, Nigeria Dilys Walker Department of Obstetrics, Gynecology & Reproductive Sciences UCSF School of Medicine University of California San Francisco, United States

B. WHO Steering Group A. Metin Gülmezoglu (WHO Department of Reproductive Health and Research) Olufemi T. Oladapo (WHO Department of Reproductive Health and Research) Anayda Portela (WHO Department of Maternal, Newborn, Child and Adolescent Health) Joshua Vogel (WHO Department of Reproductive Health and Research)

28

WHO recommendation on tranexamic acid for the treatment of postpartum haemorrhage

Annex 2. Critical and important outcomes for decision-making Key question For women with postpartum haemorrhage (P), does administration of tranexamic acid in addition to standard care (I) compared to standard care alone (C), improve outcomes (O)? Priority Outcomes

Critical outcomes ‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡ Maternal death (all cause)* Maternal death due to bleeding* $GGLWLRQDOEORRGORVV•PO $GGLWLRQDOEORRGORVV•PO Blood transfusion Additional uterotonics Invasive nonsurgical interventions Surgical interventions (including hysterectomy) 0DWHUQDOWHPSHUDWXUH•ƒ& Procedure-related complications Infections Severe morbidity Maternal transfer Reduction of time from decision-making to implementation Availability of drugs and treatment

Important outcomes ‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡ recommendation.

Accuracy in blood loss assessment Mean blood loss Postpartum anaemia Additional nonsurgical interventions (e.g. external aortic compression and compression garments) Artery embolization Nausea, vomiting or shivering 0DWHUQDOWHPSHUDWXUH•ƒ& Delayed initiation of breastfeeding Prolonged hospitalization

* Maternal death (all cause) and maternal death due to bleeding were added as critical outcomes for the update of this

29

WHO recommendation on tranexamic acid for the treatment of postpartum haemorrhage

Annex 3: Summary and management of declared interests from GDG members Name and expertise Declared interest contributed to the guideline development Edgardo Abalos Content expert and end-user Yap-Seng Chong Content expert and end-user Catherine DeneuxTharaux Content expert and end-user Therese Dowswell Guideline methodologist Bukola Fawole Content expert and end-user None declared 0DQDJHPHQWRIFRQÁLFWRILQWHUHVW

Not applicable

None declared

Not applicable

None declared

Not applicable

None declared

As one of the methodologists for this guideline, Therese Dowswell did not have voting rights at the meeting. 7KHFRQÁLFWZDVQRWFRQVLGHUHGVHULRXV enough to affect GDG membership or participation in the Technical Consultation. His perspectives on implementation of this intervention (resulting from WOMAN trial) were regarded as important. Not applicable

Professor Fawole was a country investigator (Nigeria) on the WOMAN trial. He has participated in previous GDGs, including the previous WHO GDG on prevention and treatment of postpartum haemorrhage (2012).

Justus Hofmeyr Content expert and end-user Caroline Homer Content expert and end-user

None declared

Co-Chair of National Antenatal Guidelines Expert Advisory Committee in Australia (2008 onwards)

7KHFRQÁLFWZDVQRWFRQVLGHUHGVHULRXV enough to affect GDG membership or participation in the Technical Consultation 7KHFRQÁLFWZDVQRWFRQVLGHUHGVHULRXV enough to affect GDG membership or participation in the Technical Consultation 7KHFRQÁLFWZDVQRWFRQVLGHUHGVHULRXV enough to affect GDG membership or participation in the Technical Consultation

Pisake Lumbiganon Content expert and end-user

Was a DSMB member of the WOMAN trial

Suellen Miller Content expert and end-user

3URI0LOOHU·VHPSOR\HU8QLYHUVLW\ of California, San Francisco) holds the trademark on a nonpneumatic antishock device (NASG) for PPH management None declared

Ashraf Nabhan Content expert and end-user

Not applicable

30

WHO recommendation on tranexamic acid for the treatment of postpartum haemorrhage

Name and expertise Declared interest contributed to the guideline development James Neilson Content expert and end-user Hiromi Obara Content expert and implementer Zahida Qureshi Content expert and end-user None declared

0DQDJHPHQWRIFRQÁLFWRILQWHUHVW

Not applicable

None declared

Not applicable

Professor Qureshi was a country investigator (Kenya) on the WOMAN trial. She has participated in previous GDGs, including the previous WHO GDG on prevention and treatment of postpartum haemorrhage (2012). None declared

7KHFRQÁLFWZDVQRWFRQVLGHUHGVHULRXV enough to affect GDG membership or participation in the Technical Consultation. Her perspectives on implementation of this intervention (resulting from WOMAN trial) were regarded as important. Not applicable

Rahat Qureshi Content expert and end-user Helen West Consumer representative

None declared

Not applicable

31

WHO recommendation on tranexamic acid for the treatment of postpartum haemorrhage

Annex 4. Summary of the considerations related to the strength of the recommendations Desirable effects Undesirable effects Certainty of the evidence 'RQ·W know 'RQ·W know No included studies Varies Varies Trivial Large Very low Small Moderate Low Moderate Small 9 Moderate 9 Large

9 Trivial High

Values and preferences

9 Important Possibly Probably no No uncertainty important important important or variability uncertainty or uncertainty or uncertainty variability variability or variability 'RQ·W know Varies Favours the comparison Probably favours the comparison Does not favour either the intervention or the comparison 9 Negligible costs or savings Low Probably favours the intervention 9 Favours the intervention

Balance of effects

Resources required

'RQ·W know 9 No included studies

Varies

Large costs

Moderate costs Very low

Moderate savings Moderate

Large savings High

Certainty of evidence of required resources

Costeffectiveness

'RQ·W know

Varies

Favours the comparison

Probably favours the comparison

Does not favour either the intervention or the comparison Probably no impact Probably No Probably No

9 Probably favours the intervention

Favours the intervention

Equity

'RQ·W know 'RQ·W know 'RQ·W know

Varies

Reduced

Probably reduced No No

9 Probably increased 9 Probably Yes Probably Yes

Increased Yes 9 Yes

Acceptability

Varies Varies

Feasibility

32

Annex 5. GRADE Tables

Question: Standard care plus tranexamic acid compared to standard care alone for treating primary postpartum haemorrhage

Setting: Data from two studies, one conducted in France (5 tertiary care centres and 3 secondary care obstetric centres: 152 women) and one multicentre RCT with 20 060 women (WOMAN trial).

WOMAN trial: Labour ward settings in high- (United Kingdom: 569 women), and low- and middle-income countries (Nigeria: 5711 women; Pakistan: 5282 women; Uganda: 2235 women; Kenya: 1031 women; Cameroon: 893 women; Sudan: 860 women; Tanzania: 538 women; Nepal: 533 women; Zambia: 496 women; Albania: 485 women; Democratic Republic of Congo: 457 women; Bangladesh: 325 women; Ethiopia: 302 women; Burkina Faso: 142 women; Jamaica: 73 women; Ghana: 41 women; Papua New Guinea: 38 women; Egypt: 33 women; Colombia: 8 women; Côte G·,YRLUHZRPHQ

Bibliography: 6KDNXU+%HDXPRQW'3DYRUG6*D\HW$JHURQ$.HU.'RZVZHOO70RXVD+$QWLÀEULQRO\WLFGUXJVIRUWUHDWLQJSULPDU\ postpartum haemorrhage. Cochrane Database Syst Rev. 2017;(unpublished). No. of patients Placebo or standard care alone Relative (95% CI) Effect Absolute (95% CI) Certainty Importance

Quality assessment

No. of Study studies design

Standard Risk of bias Inconsistency Indirectness Imprecision Other consider- care plus tranexamic ations acid

Maternal mortality (all causes) not serious a

2 none 227/10113 (2.2%)

randomised not serious trials

not serious

serious

256/10059 (2.5%)

RR 0.88 (0.74 to 1.05)

3 fewer per 1000 (from 1 more to 7 fewer)

۩۩۩{ MODERATE CRITICAL

Maternal mortality (due to PPH) not serious b

2 none

randomised not serious trials

not serious

serious

155/10113 (1.5%)

191/10059 (1.9%)

RR 0.81 (0.65 to 1.00)

4 fewer per 1000 (from 0 fewer to 7 fewer)

۩۩۩{ MODERATE CRITICAL

Severe maternal morbidity (maternal intensive care admission) none d

WHO recommendation on tranexamic acid for the treatment of postpartum haemorrhage

1 not serious

randomised serious trials

c

not serious

very serious

3/77 (3.9%)

5/74 (6.8%) RR 0.58 (0.14 to 2.33)

33

28 fewer per ۩{{{ 1000 VERY LOW CRITICAL (from 58 fewer to 90 more)

34 No. of patients Placebo or standard care alone Relative (95% CI) Absolute (95% CI) Effect Certainty Importance not serious a

Quality assessment

No. of Study studies design

Standard Risk of bias Inconsistency Indirectness Imprecision Other consider- care plus tranexamic ations acid serious none 108/10033 (1.1%) 124/9985 (1.2%)

Severe maternal morbidity (maternal respiratory failure) RR 0.87 (0.67 to 1.12) 2 fewer per 1000 (from 1 more to 4 fewer) ۩۩۩{ MODERATE CRITICAL

1

randomised not serious trials

not serious

Severe maternal morbidity (maternal seizure) not serious a

2 none 33/10110 (0.3%) 43/10059 (0.4%) RR 0.76 (0.49 to 1.20)

randomised not serious trials

not serious

serious

1 fewer per 1000 (from 1 more to 2 fewer)

۩۩۩{ MODERATE CRITICAL

Severe maternal morbidity (hepatic failure) not serious a

1 none 29/10033 (0.3%) 30/9985 (0.3%)

randomised not serious trials

not serious

serious

RR 0.96 (0.58 to 1.60)

0 fewer per 1000 (from 1 fewer to 2 more)

۩۩۩{ MODERATE CRITICAL

Severe maternal morbidity (cardiac failure) not serious a

WHO recommendation on tranexamic acid for the treatment of postpartum haemorrhage

1 none 110/10033 (1.1%)

randomised not serious trials

not serious

serious

115/9985 (1.2%)

RR 0.95 (0.73 to 1.23)

1 fewer per 1000 (from 3 fewer to 3 more)

۩۩۩{ MODERATE CRITICAL

Severe maternal morbidity (maternal renal failure) not serious a

2 none

randomised not serious trials

not serious

serious

129/10110 (1.3%)

118/10059 (1.2%)

RR 1.09 (0.85 to 1.39)

1 more per 1000 (from 2 fewer to 5 more)

۩۩۩{ MODERATE CRITICAL

Blood Products transfusion (all) not serious not serious none 5474/10113 (54.1%) 5446/10059 RR 1.00 (54.1%) (0.97 to 1.03) CRITICAL 0 fewer per ۩۩۩{ 1000 MODERATE (from 16 fewer to 16 more)

2

randomised not serious trials

serious

e

Quality assessment Placebo or standard care alone Relative (95% CI) Absolute (95% CI)

No. of patients

Effect

Certainty Importance

No. of Study studies design

Standard Risk of bias Inconsistency Indirectness Imprecision Other consider- care plus tranexamic ations acid

Additional blood loss > 500 ml not serious f

1

c

randomised serious trials

not serious

serious

none

12/77 (15.6%) 23/74 (31.1%)

RR 0.50 (0.27 to 0.93)

155 fewer per ۩۩{{ 1000 LOW (from 22 fewer to 227 fewer)

CRITICAL

Additional blood loss > 1000 ml not serious d

1 very serious none 4/77 (5.2%) 8/74 (10.8%) RR 0.48 (0.15 to 1.53)

randomised serious trials

c

not serious

56 fewer per 1000 (from 57 more to 92 fewer)

۩{{{ VERY LOW CRITICAL

Additional uterotonics not serious not serious none 10032/10106 (99.3%) 9964/10058 RR 1 (99.1%) (1 to 1) 0 fewer per 1000 (from 0 fewer to 0 fewer) ۩۩۩۩ HIGH CRITICAL

2

randomised not serious trials

not serious

Surgical intervention (hysterectomy) not serious not serious none 358/10109 (3.5%) 352/10059 (3.5%) RR 1.01 (0.88 to 1.17) 0 fewer per 1000 (from 4 fewer to 6 more) ۩۩۩۩ HIGH CRITICAL

2

randomised not serious trials

not serious

Surgical intervention (ligature) not serious a

2 none

randomised not serious trials

not serious

serious

225/10109 (2.2%)

255/10059 (2.5%)

RR 0.88 (0.74 to 1.05)

3 fewer per 1000 (from 1 more to 7 fewer)

۩۩۩{ MODERATE CRITICAL

Surgical intervention (embolization) not serious serious a

WHO recommendation on tranexamic acid for the treatment of postpartum haemorrhage

2

randomised not serious trials

not serious

none

15/10109 (0.1%)

18/10059 (0.2%)

RR 0.82 (0.42 to 1.62)

0 fewer per 1000 (from 1 fewer to 1 more)

۩۩۩{ MODERATE CRITICAL

35

36 No. of patients Placebo or standard care alone Relative (95% CI) Absolute (95% CI) Effect Certainty Importance not serious not serious none 82/10032 (0.8%) 127/9985 (1.3%) RR 0.64 (0.49 to 0.85) 5 fewer per 1000 (from 2 fewer to 6 fewer) ۩۩۩۩ HIGH CRITICAL not serious not serious none 300/10032 (3.0%) 250/9985 (2.5%) RR 1.19 (1.01 to 1.41) 5 more per 1000 (from 0 fewer to 10 more) ۩۩۩۩ HIGH CRITICAL not serious not serious none 705/10032 (7.0%) 729/9985 (7.3%) RR 0.96 (0.87 to 1.06) 3 fewer per 1000 (from 4 more to 9 fewer) ۩۩۩۩ HIGH CRITICAL not serious not serious none 918/10032 (9.2%) 961/9985 (9.6%) RR 0.95 (0.87 to 1.04) 5 fewer per 1000 (from 4 more to 13 fewer) ۩۩۩۩ HIGH CRITICAL not serious a

Quality assessment

No. of Study studies design

Standard Risk of bias Inconsistency Indirectness Imprecision Other consider- care plus tranexamic ations acid

Surgical intervention (laparotomy)

1

randomised not serious trials

not serious

Surgical intervention (brace sutures)

1

randomised not serious trials

not serious

Invasive non-surgical intervention (intrauterine tamponade)

1

randomised not serious trials

not serious

Invasive non-surgical intervention (manual removal of placenta)

WHO recommendation on tranexamic acid for the treatment of postpartum haemorrhage

1

randomised not serious trials

not serious

Procedure-related complication (any maternal thromboembolic event) serious none 30/10033 (0.3%) 34/9985 (0.3%) RR 0.88 (0.54 to 1.43) 0 fewer per 1000 (from 1 more to 2 fewer) ۩۩۩{ MODERATE CRITICAL

1

randomised not serious trials

not serious

Procedure-related complication (deep venous thrombosis) not serious serious a

2

randomised not serious trials

not serious

none

5/10110 (0.0%)

8/10059 (0.1%)

RR 0.62 (0.20 to 1.88)

0 fewer per 1000 (from 1 fewer to 1 more)

۩۩۩{ MODERATE CRITICAL

Quality assessment Placebo or standard care alone Relative (95% CI) Absolute (95% CI)

No. of patients

Effect

Certainty Importance

No. of Study studies design

Standard Risk of bias Inconsistency Indirectness Imprecision Other consider- care plus tranexamic ations acid

Procedure-related complication (pulmonary embolism) not serious a

1 none 17/10033 (0.2%) 20/9985 (0.2%) RR 0.85 (0.44 to 1.61)

randomised not serious trials

not serious

serious

0 fewer per 1000 (from 1 fewer to 1 more)

۩۩۩{ MODERATE CRITICAL

Procedure-related complication (myocardial infarction) not serious a

1 none 2/10033 (0.0%) 3/9985 (0.0%) RR 0.66 (0.11 to 3.97)

randomised not serious trials

not serious

serious

0 fewer per 1000 (from 0 fewer to 1 more)

۩۩۩{ MODERATE CRITICAL

Procedure-related complication (stroke) not serious a

1 none 8/10033 (0.1%) 6/9985 (0.1%)

randomised not serious trials

not serious

serious

RR 1.33 (0.46 to 3.82)

0 fewer per 1000 (from 0 fewer to 2 more)

۩۩۩{ MODERATE CRITICAL

Procedure-related complication (neonatal thromboembolic event) not serious none g

1 0/10033

randomised not serious trials

not serious

very serious

0/9985

No events

No events

۩۩{{ LOW

CRITICAL

Procedure-related complication (death of breastfed baby) not serious a

1 none

randomised not serious trials

not serious

serious

8/10033 (0.1%)

7/9985 (0.1%)

RR 1.14 (0.41 to 3.14)

0 fewer per 1000 (from 0 fewer to 2 more)

No baby ۩۩۩{ MODERATE outcomes in WHO but this could be seen as a procedure related complication

WHO recommendation on tranexamic acid for the treatment of postpartum haemorrhage

CI:&RQÀGHQFHLQWHUYDORR: Risk ratio; MD: Mean difference

37

38

Explanations

D:LGHFRQÀGHQFHLQWHUYDOFURVVLQJWKHOLQHRIQRHIIHFW

E:LGHFRQÀGHQFHLQWHUYDOWKDWLQFOXGHVWKHOLQHRIQRHIIHFW

c. Single study with design limitations (no blinding)

G)HZHYHQWVVPDOOVDPSOHVL]HDQGZLGHFRQÀGHQFHLQWHUYDOFURVVLQJWKHOLQHRIQRHIIHFW

e. Moderate statistical heterogeneity and may be clinical heterogeneity

f. Single study with small sample size

WHO recommendation on tranexamic acid for the treatment of postpartum haemorrhage

g. No events

Question: Standard care plus tranexamic acid compared to placebo or standard care alone for treating primary postpartum haemorrhage (subgroup time from birth)

Setting: Data from one multicentre RCT with 20 060 women (WOMAN trial). Labour ward settings in high- (United Kingdom: 569 women), and lowand middle-income countries (Nigeria: 5711 women; Pakistan: 5282 women; Uganda: 2235 women; Kenya: 1031 women; Cameroon: 893 women; Sudan: 860 women; Tanzania: 538 women; Nepal: 533 women; Zambia: 496 women; Albania: 485 women; Democratic Republic of Congo: 457 women; Bangladesh: 325 women; Ethiopia: 302 women; Burkina Faso: 142 women; Jamaica: 73 women; Ghana: 41 women; Papua New Guinea: 38 ZRPHQ(J\SWZRPHQ&RORPELDZRPHQ&{WHG·,YRLUHZRPHQ

Bibliography6KDNXU+%HDXPRQW'3DYRUG6*D\HW$JHURQ$.HU.'RZVZHOO70RXVD+$QWLÀEULQRO\WLFGUXJVIRUWUHDWLQJSULPDU\ postpartum haemorrhage. Cochrane Database Syst Rev. 2017;(unpublished).

Quality assessment Placebo or standard care alone

No. of patients Relative (95% CI)

Effect Absolute (95% CI)

Certainty

Importance

No. of Study studies design

Standard Risk of bias Inconsistency Indirectness Imprecision Other consider- care plus tranexamic ations acid

Maternal mortality due to bleeding (subgroup time from birth) – less than 1 hour not serious a

1 none 49/4846 (1.0%)

randomised not serious trials

not serious

serious

60/4726 (1.3%)

RR 0.80 (0.55 to 1.16)

3 fewer per 1000 (from 2 more to 6 fewer)

۩۩۩{ MODERATE CRITICAL

Maternal mortality due to bleeding (subgroup time from birth) – 1 to 3 hours not serious not serious none 40/2674 (1.5%) 67/2682 (2.5%) RR 0.60 (0.41 to 0.88) 10 fewer per 1000 (from 3 fewer to 15 fewer) ۩۩۩۩ HIGH CRITICAL

1

randomised not serious trials

not serious

Maternal mortality due to bleeding (subgroup time from birth) – more than 3 hours not serious serious a

WHO recommendation on tranexamic acid for the treatment of postpartum haemorrhage

1

randomised not serious trials

not serious

none

66/2514 (2.6%)

63/2569 (2.5%)

RR 1.07 (0.76 to 1.51)

2 more per 1000 (from 6 fewer to 13 more)

۩۩۩{ MODERATE CRITICAL

39

40 No. of patients Placebo or standard care alone Relative (95% CI) Absolute (95% CI) Effect Certainty Importance not serious a

Quality assessment

No. of Study studies design

Standard Risk of bias Inconsistency Indirectness Imprecision Other consider- care plus tranexamic ations acid serious none 80/4846 (1.7%) 80/4726 (1.7%) RR 0.98 (0.72 to 1.33) 0 fewer per 1000 (from 5 fewer to 6 more)

Maternal mortality (all cause) (subgroup time from birth) – less than 1 hour ۩۩۩{ MODERATE CRITICAL

1

randomised not serious trials

not serious

Maternal mortality (all cause) (subgroup time from birth) – 1 to 3 hours not serious not serious none 57/2674 (2.1%) 83/2682 (3.1%) RR 0.69 (0.49 to 0.96) 10 fewer per 1000 (from 1 fewer to 16 fewer) ۩۩۩۩ HIGH CRITICAL

1

randomised not serious trials

not serious

Maternal mortality (all cause) (subgroup time from birth) – more than 3 hours not serious a

1 none 90/2514 (3.6%) 92/2569 (3.6%)

randomised not serious trials

not serious

serious

RR 1.00 (0.75 to 1.33)

0 fewer per 1000 (from 9 fewer to 12 more)

۩۩۩{ MODERATE CRITICAL

Composite outcome: death or hysterectomy by subgroups (timing) – less than 1 hour not serious a

WHO recommendation on tranexamic acid for the treatment of postpartum haemorrhage

1 none 253/4844 (5.2%)

randomised not serious trials

not serious

serious

229/4726 (4.8%)

RR 1.08 (0.91 to 1.28)

4 more per 1000 (from 4 fewer to 14 more)

۩۩۩{ MODERATE CRITICAL

Composite outcome: death or hysterectomy by subgroups (timing) – 1 to 3 hours not serious b

1 none

randomised not serious trials

not serious

serious

122/2672 (4.6%)

154/2682 (5.7%)

RR 0.80 (0.63 to 1.00)

11 fewer per 1000 (from 0 fewer to 21 fewer)

۩۩۩{ MODERATE CRITICAL

Composite outcome: death or hysterectomy by subgroups (timing) – more than 3 hours not serious serious a

1

randomised not serious trials

not serious

none

159/2514 (6.3%)

161/2569 (6.3%)

RR 1.01 (0.82 to 1.25)

1 more per 1000 (from 11 fewer to 16 more)

۩۩۩{ MODERATE

CRITICAL

Quality assessment Placebo or standard care alone Relative (95% CI) Absolute (95% CI)

No. of patients

Effect

Certainty

Importance

No. of Study studies design

Standard Risk of bias Inconsistency Indirectness Imprecision Other consider- care plus ations tranexamic acid

Laparotomy for bleeding (subgroups by timing) – less than 1 hour not serious not serious none 22/4844 (0.5%) 45/4726 (1.0%) RR 0.48 (0.29 to 0.79) 5 fewer per 1000 (from 2 fewer to 7 fewer) ۩۩۩۩ HIGH CRITICAL

1

randomised not serious trials

not serious

Laparotomy for bleeding (subgroups by timing) – 1 to 3 hours not serious not serious none 19/2672 (0.7%) 35/2682 (1.3%) RR 0.54 (0.31 to 0.95) 6 fewer per 1000 (from 1 fewer to 9 fewer) ۩۩۩۩ HIGH CRITICAL

1

randomised not serious trials

not serious

Laparotomy for bleeding (subgroups by timing) – more than 3 hours not serious a

1

randomised not serious trials

not serious

serious

none

41/2514 (1.6%)

47/2569 (1.8%)

RR 0.89 (0.59 to 1.35)

2 fewer per 1000 (from 6 more to 8 fewer)

۩۩۩{ MODERATE

CRITICAL

CI:&RQÀGHQFHLQWHUYDORR: Risk ratio

Explanations

a. Wide 95% CI crossing the line of no effect

WHO recommendation on tranexamic acid for the treatment of postpartum haemorrhage

b. Wide 95% CI including the line of no effect

41

For more information, please contact: Department of Reproductive Health and Research E-mail: reproductivehealth@who.int www.who.int/reproductivehealth Maternal, Newborn, Child and Adolescent Health E-mail: mncah@who.int www.who.int/maternal_child_adolescent World Health Organization Avenue Appia 20, CH-1211 Geneva 27 Switzerland ISBN 978 92 4 155015 4