WOMAN-2: TXA has no role in postpartum hemorrhage

Despite being widely talked about in glowing terms, the original WOMAN trial was clearly negative, with no benefit in their primary outcome, and no change in all cause mortality, and therefore no hint of benefit. (There is a lot of confusion about what disease specific mortality means when this paper is discussed, but it only takes a moment or two of reflection to realize that if mortality is unchanged, the cause of death being written on the death certificate is completely irrelevant.) WOMAN-2 is mostly irrelevant in emergency providers, as it is focused on preventing rather than treating postpartum hemorrhage, but it is another very large TXA trial, and I think knowing this research can help inform your priors for TXA’s utility in other conditions. 

The paper

WOMAN-2 Trial Collaborators. The effect of tranexamic acid on postpartum bleeding in women with moderate and severe anaemia (WOMAN-2): an international, randomised, double-blind, placebo-controlled trial. Lancet. 2024 Oct 26;404(10463):1645-1656. doi: 10.1016/S0140-6736(24)01749-5. PMID: 39461792 NCT03475342

The Methods

WOMAN-2 is an international multicenter, double-blind, placebo-controlled RCT from 34 hospitals in Nigeria, Pakistan, Tanzania, and Zambia.

Patients

All women in labour and moderate to severe anemia (baseline hemoglobin less than 100 g/L) and no indication or contraindication to TXA. 

Intervention

Tranexamic acid (TXA) 1 gram IV within 15 minutes of the umbilical cord being clamped. 

Comparison

Matching placebo.

Outcome

“The primary outcome was a clinical diagnosis of postpartum haemorrhage, which might be an estimated blood loss of more than 500 mL or any blood loss sufficient to compromise haemodynamic stability within 24 h of randomisation.”

The Results

They include 15,068 women, with a mean hemoglobin of 83 g/L, and 13% with a baseline hemoglobin less than 70 g/L. It took a median of 5 minutes to give the TXA. Other baseline characteristics are basically what you would expect.

There was no difference in their primary outcome, with 7.0% of the TXA group and 6.6% of the placebo group experiencing postpartum hemorrhage (RR 1·05, 95% CI 0·94–1·19). 

“Deaths or near misses” occurred in 1.6% of the TXA group vs 1.8% of the placebo group. There were no differences in any of the secondary outcomes.

The only statistical difference was that TXA increased bleeding in women with antepartum hemorrhage. This data point is most likely the result of random chance, as are almost all subgroup findings, but it does fit with the theory that giving TXA late in bleeding is harmful. 

There were no vascular occlusive events (ie, pulmonary embolism, deep vein thrombosis, stroke, or myocardial infarction) reported in either group.

My thoughts

Although trials aren’t really “positive” or “negative”, this is about as negative as you can get. There is not even a hint of difference in any of the outcomes. 

For the most part, this is a well done trial, with limited sources of bias for the primary outcome. The only major concern I have is about their reporting of harms. We know trials always under-report harms. There are many reasons for this, but one of the biggest sources of bias is that trials often aren’t designed to look that hard for harms. This has been a major concern of mine from prior TXA research, and I think this trial very clearly demonstrates that this group is not great at capturing or recording harms. They have a cohort of over 15,000 women in the immediate postpartum period, and they didn’t find a single vascular occlusive event in the entire cohort? How is that possible?! The rate of PE and DVT alone is approximately 10-15 per 10,000 deliveries. (Maughan  2022) We should have had more than 20 in a study this large. The only way to have 0 events is to have your eyes closed. The reported harms have consistently been way too low in the published TXA research, and therefore we should be very very cautious in claiming that TXA is a safe medication. We just can’t trust this research to make that claim. 

The negative outcome of this trial is entirely predictable based on the existing literature looking at TXA for postpartum hemorrhage, as the literature we have to date is resoundingly negative. Unfortunately, fooled by their own rhetoric, these researchers went in the wrong direction. The initial WOMAN trial was negative, showing no benefit at all in actively bleeding patients. If TXA doesn’t work in bleeding patients, there was no way it was going to work in patients who weren’t even bleeding yet. This research group spun their initial negative trial as positive and tricked themselves. The problem with the initial WOMAN study was that the population was actually too healthy, with only a 2-3% mortality rate, and less than half the patients having even 1 L of blood loss. If TXA was going to have any chance of working, it would be in the massive hemorrhage patient, and that is where follow-up research should have focused. 

At this point, we have a ton of data on TXA in postpartum hemorrhage, and it is very clear that it does not work. As mentioned, the original WOMAN trial was clearly negative, with no difference in the primary outcome of all cause mortality or hysterectomy (5.3% vs 5.5%, RR 0.97, 95% CI 0.87-1.09) and no difference in all cause mortality (2.3% vs 2.6%). (WOMAN collaborators 2017) The TRAAP trial also looked at prevention of PPH, randomizing 3891 low risk women after vaginal delivery to either 1 gram of TXA or placebo, and there were no difference in the primary outcome of blood loss of at least 500 mL (8.1% vs 9.8%, p=0.07, RR 0.83; 95% CI 0.68-1.01). (Sentilhes 2018) TRAAP 2 looked at the prevention of PPH after c-section in 4551 women. (Senthilies 2021) This is the only trial that is statistically positive, with a primary outcome of estimated blood loss greater than 1,000 mL or blood transfusion within 2 days of delivery occurring in 27% of the TXA group and 32% of the placebo group. However, despite this statistically positive disease oriented outcome, it is pretty clearly a negative trial, demonstrating absolutely no difference in any of the clinical outcomes. The measured difference in blood loss between the groups was only 30 mL – clinically irrelevant. There was no difference in the number of women needing transfusions (1.6% vs 1.4%), the amount transfused (3.1 vs 3.2 units), clinically significant PPH as assessed by the doctor, ICU use, follow up hemoglobin, or need for invasive procedures. For everything important to the patients, there was absolutely no difference. Finally, we have a much bigger RCT comparing TXA to placebo in 11,000 women after cesarean section, and it was negative for the primary outcome of death or blood transfusion (3.6% vs 4.3%, p=0.19). (Pacheco 2023) 

In other words, we now have 5 very large trials of TXA for PPH, and none of them show a clinically important benefit. Considering the clear under-reporting of harms, there is no way that TXA should be used routinely either to prevent or to treat post-partum hemorrhage. 

As far as the overall utility of TXA, I don’t think a prevention trial should move the needle much, but this adds to the trend: every single high quality trial since CRASH-2 has shown no clinical benefit from TXA. The more data we see, the more convinced I am that we need a full replication of the CRASH-2 trial.

Bottom line

The WOMAN 2 trial is a large double-blind RCT that shows no benefit of TXA in the prevention of postpartum hemorrhage, which fits with all of the existing literature demonstrating no role for TXA in the management of postpartum hemorrhage. We still cannot comment on the role of TXA in massive post-partum hemorrhage, as none of the research to date has really captured that group of patients.

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Other FOAMed

3 misunderstandings about WOMAN (TXA in postpartum hemorrhage)

Does TXA work for everything? For anything?

Management of postpartum hemorrhage

Evidence based medicine is easy

The EBM bibliography

Evidence based medicine resources

EBM deep dives

References

Pacheco LD, Clifton RG, Saade GR, et al; Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal–Fetal Medicine Units Network. Tranexamic Acid to Prevent Obstetrical Hemorrhage after Cesarean Delivery. N Engl J Med. 2023 Apr 13;388(15):1365-1375. doi: 10.1056/NEJMoa2207419. PMID: 37043652

Maughan BC, Marin M, Han J, Gibbins KJ, Brixey AG, Caughey AB, Kline JA, Jarman AF. Venous Thromboembolism During Pregnancy and the Postpartum Period: Risk Factors, Diagnostic Testing, and Treatment. Obstet Gynecol Surv. 2022 Jul;77(7):433-444. doi: 10.1097/OGX.0000000000001043. PMID: 35792687

Sentilhes L, Winer N, Azria E, Sénat MV, Le Ray C, Vardon D, Perrotin F, Desbrière R, Fuchs F, Kayem G, Ducarme G, Doret-Dion M, Huissoud C, Bohec C, Deruelle P, Darsonval A, Chrétien JM, Seco A, Daniel V, Deneux-Tharaux C; Groupe de Recherche en Obstétrique et Gynécologie. Tranexamic Acid for the Prevention of Blood Loss after Vaginal Delivery. N Engl J Med. 2018 Aug 23;379(8):731-742. doi: 10.1056/NEJMoa1800942. PMID: 30134136

Sentilhes L, Sénat MV, Le Lous M, Winer N, Rozenberg P, Kayem G, Verspyck E, Fuchs F, Azria E, Gallot D, Korb D, Desbrière R, Le Ray C, Chauleur C, de Marcillac F, Perrotin F, Parant O, Salomon LJ, Gauchotte E, Bretelle F, Sananès N, Bohec C, Mottet N, Legendre G, Letouzey V, Haddad B, Vardon D, Madar H, Mattuizzi A, Daniel V, Regueme S, Roussillon C, Benard A, Georget A, Darsonval A, Deneux-Tharaux C; Groupe de Recherche en Obstétrique et Gynécologie. Tranexamic Acid for the Prevention of Blood Loss after Cesarean Delivery. N Engl J Med. 2021 Apr 29;384(17):1623-1634. doi: 10.1056/NEJMoa2028788. PMID: 33913639

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 (London, England). 2017; PMID: 28456509

WOMAN-2 Trial Collaborators. The effect of tranexamic acid on postpartum bleeding in women with moderate and severe anaemia (WOMAN-2): an international, randomised, double-blind, placebo-controlled trial. Lancet. 2024 Oct 26;404(10463):1645-1656. doi: 10.1016/S0140-6736(24)01749-5. PMID: 39461792