The Case

A 27-year-old primiparous woman arrives at the emergency department after a prolonged labor at home; she is fully dilated and crowning. She has no significant health history and is only taking prenatal vitamins.

Obstetrics and pediatrics are called stat, but the patient rapidly delivers in the emergency department—a healthy 6-pound, 8-ounce girl with only a first-degree laceration. Pediatrics arrives quickly and provides neonatal assessment. Obstetrics, however, is busy doing an emergency cesarean delivery.

Shortly after the delivery of the placenta, the patient has brisk vaginal bleeding. Her vital signs are normal and stable. Lab tests are requested, and the nurse has already given oxytocin 10 mg IM and started an IV. Knowing that uterine atony is the number-one cause of postpartum hemorrhage (PPH), you start performing fundal massage. While waiting for obstetrics to show up, you think about drugs other than oxytocin that could be used for PPH (methylergonovine, misoprostol, and prostaglandins), and you remember reading something about tranexamic acid (TXA).

Background

TXA is a synthetic analog of the amino acid lysine and acts as an antifibrinolytic agent. It binds to lysine receptor sites on plasminogen, blocking its action on fibrin. The ultimate result is that the fibrin matrix structure is maintained and bleeding is reduced.

PPH is defined by the World Health Organization as “a cumulative blood loss of greater than or equal to 1,000 mL or blood loss accompanied by signs or symptoms of hypovolemia within 24 hours after the birth process.” PPH is one of the leading causes of maternal mortality around the world.¹

The American College of Obstetricians and Gynecologists published guidelines for the management of PPH, including the use of TXA. It gives TXA a Level B recommendation: “Given the mortality reduction findings, tranexamic acid should be considered in the setting of obstetric hemorrhage when initial medical therapy fails.”²

Clinical Question

In women with PPH, does TXA improve survival?

Reference

WOAN 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.

• Population: Women older than 16 years with a diagnosis of PPH after vaginal birth (>500 mL blood loss) or cesarean delivery (>1,000 mL blood loss) or blood loss causing hemodynamic instability and the clinician was uncertain whether to use TXA.
  • Exclusions: If the clinician felt that TXA would clearly be or not be beneficial.
• Intervention: 1 g TXA slowly infused with the optional second 1 g dose if bleeding continued for 30 minutes or more or stopped and restarted within 24 hours.
• Comparison: Placebo.
• Outcome:
  • Primary: All-cause mortality or hysterectomy within 42 days.
  • Secondary: Mortality due to bleeding, thromboembolic events, surgical interventions, other complications, adverse events, quality-of-life measurements, and thromboembolic events in breastfed babies.

Authors’ Conclusions

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

Key Results

They enrolled 20,021 women in the trial. Maternal death occurred in 2.4 percent of all women within 24 hours, and 9 percent of the deaths were within one hour after randomization.

For the primary outcome of all-cause mortality or hysterectomy, there was not a statistical difference (see Table 1).

(click for larger image) Table 1: Key Results from the WOMAN Trial

EBM Commentary

1) Inclusion Criteria: The inclusion criteria in this study were vague. Clinical diagnosis of PPH was based on a subjective estimation of blood loss. Hemodynamic instability was not defined, and the clinician had to be unsure whether to use TXA.

2) Power Calculation: The trial was originally powered for a 25 percent relative reduction (1 percent absolute) in all-cause mortality or hysterectomy. After the trial started, they figured out the decision to do a hysterectomy usually was made at the same time as randomization. Therefore, they recalculated the sample size for a 25 percent relative reduction (0.75 percent absolute) in all-cause mortality. As a result, the sample size increased from 15,000 to 20,000.

Trials are often criticized for being underpowered but not for being overpowered. Trials are usually designed to find a difference between two things, and if you have a large enough trial, you will find a statistical difference because no two things are identical. Despite having more than 20,000 women, they did not find a difference in all-cause mortality.

3) Subgroup Analyses: A number of subgroup analyses for the primary composite outcome were considered a priori. The only statistical difference observed was if TXA was given in less than three hours postpartum. This result should be viewed with skepticism because subgroup analyses are considered hypothesis-generating and should not be overinterpreted.

4) Fragility of the Study: The fragility index is a way to measure the robustness of the results obtained.³ It is calculated by converting one patient (treatment or control) from a “non-event” to an “event.” In this case, how many women would have to have a different outcome for the study not to be statistically significant (P ≥ 0.05)?

This was a negative trial for the primary outcome of all-cause mortality or hysterectomy. However, there was a statistical difference in death due to bleeding. But the fragility index of this secondary outcome was zero, which emphasizes the lack of robustness of the WOMAN trial.⁴

The fragility index for the subgroup analysis of the secondary outcome of bleeding mortality treated in less than three hours is nine. This means if nine women switched from an event to a non-event in either group, the results of this hypothesis-generating result would no longer be considered statistically significant.

5) External Validity: The vast majority of these patients came from developing countries. It is unclear what resources their health care system had to address PPH compared to the United States and if these results could be applied to our health care system.

Bottom Line

This study does not provide good evidence that TXA improves survival in women with PPH.

Case Resolution

The fundal massage and oxytocin seem to work, and the bleeding slows. The patient is still hemodynamically stable when the obstetrical team arrives. She is transferred to the postpartum unit for further management and does not receive TXA.

Thank you to Nick Papalia, MD, who is currently completing his third year of obstetrics and gynecology residency at the University of Calgary in Alberta, for his help with this review.

Remember to be skeptical of anything you learn, even if you heard it on the Skeptics’ Guide to Emergency Medicine

References

1. 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.
2. Committee on Practice Bulletins-Obstetrics. Practice bulletin no. 183: postpartum hemorrhage. Obstet Gynecol. 2017;130(4):e168-e186.
3. Nickson C. Fragility index. Life in the Fast Lane website. Accessed June 20, 2018.
4. Fragility index calculator. ClinCalc website. Accessed June 20, 2018.