WOMAN: Tranexamic Acid for Postpartum Hemorrhage (2017)

“Tranexamic acid reduces death due to bleeding in women with post-partum haemorrhage with no evidence of adverse effects. Tranexamic acid should be used in all women with post-partum haemorrhage.”

— The WOMAN Trial Collaborators

1. Publication Details

  • Trial Title: 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.
  • Citation: WOMAN Trial Collaborators. Effect of early tranexamic acid administration on mortality, hysterectomy, and other morbidities in women with post-partum haemorrhage (WOMAN): an international, randomised, double-blind, placebo-controlled trial. Lancet. 2017;389(10084):2105-2116. doi:10.1016/S0140-6736(17)30638-4.
  • Published: May 27, 2017, in The Lancet.
  • Author: The WOMAN Trial Collaborators.
  • Funding: UK Department of Health; Wellcome Trust; Bill & Melinda Gates Foundation.

2. Keywords

Postpartum Hemorrhage (PPH), Tranexamic Acid, Antifibrinolytic, Maternal Mortality, Obstetrics, Hysterectomy.

3. The Clinical Question

In adult women with a clinical diagnosis of postpartum hemorrhage (PPH) (Population), does the early administration of tranexamic acid (Intervention) compared to placebo (Comparison) reduce death due to bleeding (Outcome)?

4. Background and Rationale

  • Existing Knowledge: Postpartum hemorrhage (PPH) is a leading cause of maternal death worldwide, particularly in low- and middle-income countries. Tranexamic acid (TXA), an antifibrinolytic agent, had been shown to safely reduce bleeding and mortality in trauma patients (CRASH-2 trial).
  • Knowledge Gap: PPH involves physiological processes of uterine contraction and placental separation, but excessive fibrinolysis can contribute to ongoing bleeding. It was unknown if TXA would be a safe and effective treatment to reduce mortality from PPH.
  • Proposed Hypothesis: The authors hypothesized that the early administration of tranexamic acid would reduce the risk of death due to bleeding in women with PPH.

5. Study Design and Methods

  • Design: A prospective, multicenter, international, randomized, double-blind, placebo-controlled trial.
  • Setting: 193 hospitals in 21 countries, predominantly in low- and middle-income settings.
  • Trial Period: Enrollment from March 2010 to April 2016.
  • Population:
    • Inclusion Criteria: Adult women (≥16 years) with a clinical diagnosis of primary PPH after vaginal birth or caesarean section.
    • Exclusion Criteria: Clinician was certain that tranexamic acid would either definitely be beneficial or definitely not be indicated.
  • Intervention: A fixed dose of 1 g of tranexamic acid intravenously. A second dose could be given if bleeding continued after 30 minutes or restarted within 24 hours.
  • Control: Matching placebo (saline) administered in the same manner.
  • Management Common to Both Groups: All other aspects of PPH management, including uterotonics, fluid resuscitation, and surgical interventions, were at the discretion of the local clinical team.
  • Power and Sample Size: The trial was powered to detect a 25% relative reduction in death due to bleeding, requiring 20,000 patients.
  • Outcomes:
    • Primary Outcome: A composite of death from all causes or hysterectomy within 42 days. The main component analyzed was death due to bleeding.
    • Secondary Outcomes: Included death due to bleeding, hysterectomy, thromboembolic events, and other morbidities.

6. Key Results

  • Enrollment and Baseline: 20,060 women were randomized (10,051 to tranexamic acid, 10,009 to placebo). The groups were well-matched at baseline.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome: The risk of death due to bleeding was significantly reduced in the tranexamic acid group compared to the placebo group (1.5% vs 1.9%; P=0.045). There was no significant difference in the composite of death or hysterectomy.
  • Secondary Outcomes: The benefit of tranexamic acid on death due to bleeding was greatest when given early (within 3 hours of birth). There was no increase in the risk of thromboembolic events with tranexamic acid.
  • Adverse Events: The rates of adverse events, including thromboembolic events, were similar between the two groups, confirming the safety of TXA.

7. Medical Statistics

  • Analysis Principle: An intention-to-treat analysis was performed.
  • Statistical Tests Used: The primary outcome was analyzed using a log-rank test.
  • Primary Outcome Analysis: The proportion of deaths due to bleeding was compared between the two groups.
  • Key Statistic(s) Reported: Relative Risk (RR) for death due to bleeding with tranexamic acid: 0.81 (95% CI, 0.65 to 1.00; P=0.045).
  • Interpretation of Key Statistic(s):
    • Relative Risk (RR):
      • Formula: Conceptually, RR = (Risk in Intervention Group) / (Risk in Control Group).
      • Calculation: The paper reports the RR as 0.81.
      • Clinical Meaning: An RR of 0.81 means there was a 19% lower relative risk of death due to bleeding in the tranexamic acid group compared to the placebo group.
    • Confidence Interval (CI):
      • Formula: Conceptually, CI = (Point Estimate) ± (Margin of Error).
      • Calculation: The reported 95% CI was 0.65 to 1.00.
      • Clinical Meaning: The confidence interval suggests the true effect could be anywhere from a 35% benefit to no effect. Because the upper bound just touches the line of no effect (1.0), the result is statistically significant at the p<0.05 level.
    • P-value:
      • Calculation: The reported p-value was 0.045.
      • Clinical Meaning: The p-value of 0.045 is less than the conventional threshold of 0.05, indicating that the observed difference is unlikely to be due to chance.
  • Clinical Impact Measures:
    • Absolute Risk Reduction (ARR):
      • Formula: ARR = (Risk in Control Group) – (Risk in Intervention Group).
      • Calculation: ARR = 1.9% – 1.5% = 0.4%.
      • Clinical Meaning: For every 1000 women with PPH treated with tranexamic acid, about 4 fewer died from bleeding.
    • Number Needed to Treat (NNT):
      • Formula: NNT = 1 / ARR.
      • Calculation: NNT = 1 / 0.004 = 250.
      • Clinical Meaning: Approximately 250 women with PPH need to be treated with tranexamic acid to prevent one additional death from bleeding.
  • Subgroup Analyses: A key analysis showed that the benefit was time-dependent, with a significant reduction in death due to bleeding when TXA was given within 3 hours of birth, but no benefit (and a trend toward harm) when given after 3 hours.

8. Strengths of the Study

  • Study Design and Conduct: This was a very large, international, multicenter, randomized, double-blind, placebo-controlled trial, representing the highest level of evidence.
  • Generalizability: The pragmatic design and inclusion of a large number of hospitals in diverse, low-resource settings make the findings highly generalizable to where the burden of PPH is greatest.
  • Patient-Centered Outcomes: The primary outcome of death due to bleeding is a crucial, patient-centered endpoint.

9. Limitations and Weaknesses

  • Internal Validity (Bias): No major limitations to internal validity.
  • External Validity (Generalizability): The findings are most applicable to settings with a similar baseline mortality from PPH.
  • Other: The primary composite outcome (death or hysterectomy) was not met, but the pre-specified analysis of the most important component (death due to bleeding) was positive.

10. Conclusion of the Authors

“Tranexamic acid reduces death due to bleeding in women with post-partum haemorrhage with no increase in adverse events. When used as a treatment for post-partum haemorrhage, tranexamic acid should be given as soon as possible after bleeding onset.”

11. To Summarize

  • Impact on Current Practice: The WOMAN trial was a landmark, practice-changing study. It provided definitive evidence that a simple, inexpensive, and safe drug can significantly reduce maternal mortality from PPH. It has led to the inclusion of tranexamic acid in international guidelines and its addition to the WHO Model List of Essential Medicines for this indication.
  • Specific Recommendations:
    • Patient Selection: For all adult women with a clinical diagnosis of postpartum hemorrhage.
    • Actionable Intervention: Administer 1 g of tranexamic acid intravenously as soon as possible after the onset of PPH (ideally within 3 hours).
    • Expected Benefit: A significant reduction in death due to bleeding, with an NNT of approximately 250.
  • What This Trial Does NOT Mean: This trial does not mean that TXA replaces other essential PPH interventions like uterotonics, uterine massage, and surgical management. It is an adjunctive therapy.
  • Implementation Caveats: The key to effectiveness is early administration. Efforts should be made to ensure TXA is readily available in all delivery settings.

12. Context and Related Studies

  • Building on Previous Evidence: This trial was a direct successor to the CRASH-2 trial (2010), which established the life-saving benefit of TXA in trauma patients. The WOMAN trial successfully extended this finding to the analogous condition of obstetric hemorrhage.
  • Influence on Subsequent Research: The WOMAN trial has largely settled the question of TXA for the treatmentof PPH. Subsequent research has focused on its role in the prevention of PPH in high-risk women.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: What is the optimal dose and route of administration? What is the role of TXA in preventing PPH in high-risk women?
  • Future Directions: Research is ongoing to evaluate the prophylactic use of TXA and to optimize its integration into PPH care bundles in various healthcare settings.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The question was of immense global health importance, testing a simple, affordable intervention for a leading cause of maternal death.
  • Methods: The study’s design was of the highest quality: a massive, international, multicenter, double-blind, placebo-controlled RCT.
  • Results: The trial had a clear and statistically significant positive result for its most important clinical outcome, death due to bleeding. The safety profile was excellent.
  • Conclusions and Applicability: The authors’ conclusion is strongly supported by the data. The results are highly applicable globally, especially in low- and middle-income countries where the burden of PPH is highest, and have provided a definitive, evidence-based mandate to incorporate early TXA administration into the standard of care.

16. Disclaimer and Contact

This summary is provided by the Academic Committee of ESBICM (ACE) to facilitate the understanding of this study; readers are advised to refer to the original trial document for a deeper understanding. If you find any information incorrect, or missing, or it needs an update or have a request for a specific critical care trial summary, kindly write to us at academics[at]esbicm.org.

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