Introduction 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, 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.

# Grading of Recommendations, Assessment, Development, and Evaluation (GRADE)
-ritized 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.

# 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)
Based on the dosing regimen used in the WOMAN trial, the GDG supports the administration of administered over 10 minutes), with a second dose of 1 g IV if bleeding continues after 30 minutes, or if loss of more than 500 ml after a vaginal birth or 1000 ml after caesarean section, or any blood loss 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 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 of effect of TXA use beyond 3 hours on death for trauma or after PPH were both in the direction of 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 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.
(including TXA) (e.g. a known thromboembolic event during pregnancy). 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.
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. 5 1. Background 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 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 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 6 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 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 administration of TXA on mortality, hysterectomy, and other morbidities in women with clinically diagnosed PPH -was ongoing. 8 The WOMAN trial has now concluded, 9 In light of this new evidence, the Executive GSG prioritized the updating of the recommendation on TXA use for PPH treatment. 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.
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 in accordance with the process described in the WHO handbook for guideline development. 10 question and critical outcomes, (ii) retrieval 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. The WHO recommendation on TXA use for treatment of PPH was important evidence on this question.

# 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 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 implementation and impact assessment. The members of the Steering Group are presented in Annex 1.

# Guideline Development Group
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 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 to inform the recommendation, advised on the interpretation of this evidence, 8 are presented in Annex 1.

# External Review Group
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 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 The critical and important outcomes were aligned with the prioritized outcomes from the WHO recommendations on prevention and treatment of PPH (2012). 5 These published, systematic reviews and a prioritization of outcomes by the 2012 GDG panel. During the updating of this recommendation, a further two outcomes were question: namely, maternal death (all causes) and maternal death due to bleeding. this document for evidence searching, retrieval, grading and formulation of the recommendation. The list of critical and important outcomes is provided in Annex 2.
by the Cochrane Pregnancy and Childbirth Group, as an offshoot of the existing Cochrane review of treatment for PPH. 11 This systematic review 12 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 comparisons and outcomes (those that were not relevant to the recommendation (GRADEpro) and GRADE criteria were used to critically appraise the retrieved 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 Study design limitations individual study and then across studies contributing to the outcome. For 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 overlapped, whereas quality was downgraded when the results were in different 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 effect estimates, were downgraded for imprecision.
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
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, 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 the guideline development process and recommendation. To ensure consistency, interests in the WHO Handbook for Guideline Development for all experts. All WHO DOI guidelines on a case-by-case basis and communicated to the experts.
to the guideline development process or reduce its credibility, the experts were only no further actions were taken. interest were managed by the Steering Group.

# Decision-making during the technical consultation
During the technical consultation, the GDG reviewed and discussed the evidence 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 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. 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.
-r 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 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 the deliberations and decisions of the participants. The draft document was sent approval.

# Peer review
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 to the document were limited to correction of factual errors and improvement in language to address any lack of clarity.

# 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 is correctly understood and appropriately implemented in practice, additional recommendation.

# 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)
Based on the dosing regimen used in the WOMAN trial, the GDG supports the 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 estimated blood loss of more than 500 ml after a vaginal birth or 1000 ml after 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 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 beyond 3 hours on death for trauma or after PPH were both in the direction of harm, 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 (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 pregnancy). 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.

# A. Review 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)?
If so, when is the most appropriate period to administer tranexamic acid to improve outcomes?

# 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 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 blood loss after a vaginal birth of > 500 ml, or > 1000 ml following a caesarean 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 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 described below.
Maternal mortality (all causes): Moderate certainty evidence suggests slightly fewer deaths in the group receiving TXA although this difference was not statistically RR 0.88, 95% CI 0.74 to 1.05).

# 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, 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 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).
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 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).

# Desirable effects
How substantial are the desirable anticipated effects of TXA + standard care vs standard care alone?

# 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 15 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 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

# 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 (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.

# Important uncertainty or variability

# Possibly important uncertainty or variability
Probably no important uncertainty or variability

# No important uncertainty or variability

# 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)?
due to bleeding and reducing the need for laparotomy to stop bleeding. Early 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

# 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 Description
Training 2 to 3 day practice-based training/practice drills for PPH management Supplies 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 Equipment None required.
Average time needed is 10 to 15 minutes for gaining IV access and administration of the drug (depending on other factors for monitoring the response of the woman to treatment as required for all cases of PPH.

# Supervision and monitoring Regular supervision and review by labour ward lead, especially

# 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. 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

# Resource requirements
How large are the resource requirements for administering TXA in addition to standard care for PPH treatment compared to standard care alone?
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, 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, 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.
Varies Reduced Probably reduced

# Probably no impact
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 be acceptable to key stakeholders (women, providers and policy makers) across would be generally acceptable.

# No Probably No Probably Yes Yes
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 infusions (similar to oxytocin infusion). Many hospitals already have access to TXA due to its common use for trauma and surgery. 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.

# 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 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 WHO staff. The executive summary will be translated into the six UN languages and 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.
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, meetings. Local professional societies play important roles in this process, and an inclusive and participatory process should be encouraged.
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 precedence.
The recommendation should be adapted into locally appropriate documents that are

# 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 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 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 recommendations on PPH prevention and treatment. The use of other locally agreed 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 severe maternal complications (including PPH) based on the near-miss and criterionbased clinical audit concepts. 22 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 Information on recommended indicators can also be obtained at the local level by interrupted time series or clinical audits.

# Updating the recommendation
-f 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 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.

# Annex 2. Critical and important outcomes for decision-making

# Key question Priority Outcomes
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)?

# Critical outcomes
Maternal death (all cause)