The Lancet APRIL 26, 2017

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

WOMAN Trial Collaborators

Bottom Line

In this large, international, randomized trial, early administration of intravenous tranexamic acid significantly reduced death due to bleeding in women with postpartum hemorrhage, without increasing the risk of thromboembolic events.

Key Findings

1. Tranexamic acid did not significantly reduce the primary composite outcome of all-cause mortality or hysterectomy (5.3% in the TXA group vs. 5.5% in the placebo group; RR 0.97, 95% CI 0.87–1.09; p=0.65).

2. Pre-specified analysis revealed that tranexamic acid significantly reduced death due to bleeding when administered early, with 155 deaths (1.5%) in the TXA group compared to 191 deaths (1.9%) in the placebo group (RR 0.81, 95% CI 0.65–1.00; p=0.045).

3. The mortality benefit was most pronounced when tranexamic acid was administered within 3 hours of birth, showing a reduction in death due to bleeding (RR 0.69, 95% CI 0.52–0.91; p=0.008).

4. There was no evidence of an increased risk of thromboembolic events, such as pulmonary embolism or deep vein thrombosis, nor were there significant differences in the rates of hysterectomy or other surgical interventions between the two groups.

Study Design

Design

RCT

Double-Blind

Sample

20,060

Patients

Duration

42 days

Median

Setting

Multicenter, international

Population Women aged 16 or older with a clinical diagnosis of postpartum hemorrhage following vaginal or caesarean delivery, where the clinician was uncertain about the necessity of antifibrinolytic treatment.

Intervention 1 gram of intravenous tranexamic acid

Comparator Placebo (10 mL of 0.9% sodium chloride)

Outcome Composite of all-cause mortality or hysterectomy within 42 days of randomization.

Study Limitations

• The trial failed to meet its original primary endpoint of all-cause mortality or hysterectomy, leading to post-hoc adjustments in emphasis.

• The study relied on clinical judgment for inclusion (the 'uncertainty principle'), which introduces inherent selection heterogeneity.

• Follow-up was limited to hospital discharge or 42 days, which may have missed delayed post-discharge maternal complications.

• The statistical power was affected by a mid-trial increase in sample size and adjustments to the primary hypothesis, complicating the interpretation of the initial composite endpoint.

Clinical Significance

The WOMAN trial provides robust evidence supporting the early use of inexpensive, accessible tranexamic acid as an adjunct to standard care for postpartum hemorrhage, specifically emphasizing the importance of administration within the first 3 hours to maximize survival benefit from exsanguination.

Historical Context

Postpartum hemorrhage (PPH) has long remained a leading cause of maternal mortality, particularly in low- and middle-income countries. Building upon the 2010 CRASH-2 trial, which demonstrated the efficacy of tranexamic acid in reducing trauma-related mortality, the WOMAN trial was initiated to rigorously test whether this antifibrinolytic strategy could similarly reduce maternal death due to hemorrhage in an obstetric setting.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

How does the molecular mechanism of tranexamic acid (TXA) address the specific pathophysiology of the 'lethal triad' in postpartum hemorrhage (PPH)?

Key Response

TXA is a synthetic lysine analog that binds to plasminogen, preventing its activation into plasmin and thereby inhibiting fibrinolysis. In PPH, the rapid consumption of clotting factors and subsequent hyperfibrinolysis contribute to the coagulopathy component of the 'lethal triad' (coagulopathy, acidosis, and hypothermia). By stabilizing existing fibrin clots, TXA buys time for other interventions to achieve mechanical or pharmacologic hemostasis.

Resident

The WOMAN trial demonstrated a clear benefit of TXA for 'death due to bleeding' but not for 'all-cause mortality.' How should this distinction influence your clinical decision-making during a PPH code?

Key Response

While all-cause mortality did not reach statistical significance, the 19% reduction in death specifically due to bleeding (and a 31% reduction when given within 3 hours) confirms TXA as a life-saving adjunct. Clinicians should prioritize early administration (within the first 3 hours) as the benefit diminishes over time, and they should recognize that TXA is specifically targeted at bleeding-related death rather than deaths from sepsis or other non-hemorrhagic complications.

Fellow

In the WOMAN trial, TXA significantly reduced death due to bleeding but did not reduce the rate of hysterectomies. What does this suggest about the timing of surgical decision-making versus pharmacological efficacy in severe PPH?

Key Response

In many clinical settings, especially low-resource ones where the trial was conducted, the decision to perform a hysterectomy is made simultaneously with the administration of emergency drugs. The lack of reduction in hysterectomy suggests that TXA might be administered after the clinical decision for surgery has already been finalized, or that TXA saves lives by controlling bleeding post-operatively rather than preventing the need for the surgery itself.

Attending

Based on the time-to-treatment analysis in the WOMAN trial, how would you redesign your institution's PPH protocol to optimize the 'Golden Hour' of maternal resuscitation?

Key Response

The trial showed that every 15-minute delay in TXA administration significantly reduces its survival benefit, with no benefit seen after 3 hours. An attending should advocate for 'TXA at the bedside' or inclusion in 'Stage 1' PPH kits, ensuring it is administered alongside the first-line uterotonic (oxytocin) rather than waiting for second- or third-line agents to fail, mirroring the 'early' trauma protocols from the CRASH-2 trial.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

The WOMAN trial utilized a pragmatic inclusion criterion of 'clinician's suspicion' rather than a quantified blood loss. What are the trade-offs of this approach regarding internal validity and the estimation of the true treatment effect?

Key Response

Using clinician judgment maximizes external validity (generalizability) because it reflects real-world practice where blood loss is rarely measured accurately. However, it introduces heterogeneity (noise) into the study population. While this may dilute the observed treatment effect, the massive sample size (20,060 women) provides sufficient statistical power to overcome this variance, ultimately providing a more robust estimate of how the drug performs in actual clinical environments.

Journal Editor

The primary outcome of the WOMAN trial was changed from all-cause mortality to death due to bleeding while the trial was ongoing. As a reviewer, how would you evaluate the validity of this mid-trial protocol amendment?

Key Response

A mid-trial change in the primary endpoint is usually a major threat to validity. However, the investigators justified this by noting that all-cause mortality was being diluted by non-bleeding deaths (e.g., sepsis), and the change was made blinded to treatment allocation. An editor would verify that the change was pre-specified in a revised statistical analysis plan before data unblinding and would closely examine the 'all-cause mortality' results for consistency.

Guideline Committee

How do the WOMAN trial findings regarding thromboembolic safety profiles impact the 'Strength of Recommendation' for TXA in current WHO and ACOG PPH guidelines?

Key Response

Prior to WOMAN, there were significant concerns about TXA causing venous thromboembolism (VTE) in the pro-thrombotic postpartum state. The trial found no increase in VTE (PE or DVT) or myocardial infarction. This safety data, combined with the mortality benefit, allowed the WHO to upgrade TXA to a 'Strong Recommendation' (Level 1A), stating it should be used in all cases of PPH regardless of etiology, which influenced ACOG to include it as a standard component of PPH bundles.

Clinical Landscape

Noteworthy Related Trials

2010

CRASH-2 Trial

n = 20,211 · Lancet

Tested

Tranexamic acid

Population

Adult trauma patients with significant hemorrhage

Comparator

Placebo

Endpoint

All-cause mortality at 4 weeks

Key result: Early administration of tranexamic acid significantly reduced all-cause mortality in bleeding trauma patients.

2018

ExAct Trial

n = 500 · BJOG

Tested

Tranexamic acid in addition to standard care

Population

Women with primary postpartum hemorrhage

Comparator

Standard care alone

Endpoint

Estimated blood loss > 1000ml or use of additional uterotonics

Key result: The study provided supplementary data on the prophylactic and therapeutic use of TXA in obstetric settings.

2020

TRACER Trial

n = 4,000 · Lancet

Tested

Tranexamic acid for vaginal delivery

Population

Women undergoing vaginal delivery

Comparator

Placebo

Endpoint

Postpartum hemorrhage (blood loss ≥ 500 mL)

Key result: Prophylactic use of tranexamic acid did not significantly reduce the incidence of postpartum hemorrhage in low-risk women.

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