Tranexamic Acid (TXA) in Obstetric Hemorrhage

Introduction: Postpartum hemorrhage (PPH) is the leading cause of maternal deaths with over 100,000 deaths per year. It occurs in 3-15% of deliveries, making up about 25% of all maternal deaths worldwide.[1-5] The three most common causes of PPH can be remembered as the three T’s: tone, tissue, and trauma. Tone refers to uterine atony, tissue referrers to retained placental tissue, and trauma refers to cervical or perineal lacerations. Uterine atony is the most common cause of PPH and can be treated with bimanual massage and uterotonics such as oxytocin, methergine, or misoprostol.[2,5] American College of Obstetrics and Gynecology (ACOG) and World Health Organization (WHO) currently recommend routine prophylaxis with the administration of oxytocin during the third stage of labor.[2,5]

PPH is defined as greater than 500mL of blood loss in vaginal deliveries.[1-3,5] Recognition of PPH is commonly delayed due to underestimation of blood loss. Tranexamic acid (TXA) gained significant popularity after publication of a large randomized placebo-controlled trial, CRASH-2, in 2010 which showed a significant reduction in death from hemorrhage in trauma patients (9.2% reduction in all-cause mortality, 95% CI .85-.97).[6] Since then, studies on TXA in obstetric hemorrhage have continued to evaluate its efficacy and safety profile.

Pharmacology: TXA is an antifibrinolytic that works by inhibiting lysine’s action on plasminogen and plasmin. This subsequently decreases degradation of the fibrin clot.[2,3,6] TXA obtains peak plasma concentrations immediately after intravenous administration and has a half life of approximately two hours.[1] Current recommendations suggest one gram should be given intravenously for PPH and a second gram can be given after 30 minutes if bleeding continues.[1,5]

Evidence: The WOMAN trial (published in Lancet, 2017) is the largest randomized, double blinded, placebo-controlled study to date that has evaluated the use of TXA in obstetric hemorrhage. It included over 20,000 women at almost 200 hospitals in 21 countries. One gram of TXA was given intravenously after vaginal delivery or c-section to the intervention group and was compared to the placebo group who receive 0.9% sodium chloride. There was a statistically significant reduction in bleeding in the intervention group with similar adverse events between groups. As a result, recommendations include giving TXA as soon as possible when PPH is suspected or anticipated. One limitation to this study’s generalizability is that it was conducted primarily in developing countries which account for a much larger proportion of PPH worldwide.[5]

Della Corte et al. recently published a systematic review and meta-analysis of randomized control trials in 2020 including only vaginal deliveries. Based on the results, authors concluded TXA reduces risk of hysterectomy and does not increase risk of thrombotic events.[1]

Sentilhes et al. are currently undergoing the TRAAP (TRAnexamic Acid for Preventing postpartum hemorrhage) Trial. It is a multicenter randomized, double-blinded, placebo-controlled trial that plans to enroll approximately 4,000 females in labor and will administer one gram TXA routinely immediately after birth and compare outcomes of PPH. Their hypothesis is that TXA will reduce PPH when given routinely without any increased risk of adverse effects.[3]

Cost: A study by Sudhof et al. evaluated the cost-effectiveness in the United States of routine administration of TXA in PPH. At the time of the study, which was published in 2019, the authors reported the of TXA to be $37.80 in the United States. Authors calculated an anticipated cost savings from routine use of TXA in the US to be $11.3 million per year by reducing rates of hysterectomy and PPH complications. TXA administration within three hours would triple cost savings and improve maternal outcomes.[4]

Conclusion: TXA is effective in reducing mortality and hysterectomy in PPH without increasing the risk of thromboembolism. Additionally, TXA is found to be a cost-effective adjunct by multiple trials. Future research is being conducted on the routine use of TXA in vaginal deliveries. The above literature, ACOG, and WHO recommend the use of TXA in treating PPH with a first dose of one gram intravenous followed by a second gram 30 minutes later if bleeding continues.

References

1. Della Corte L, Saccone G, Locci M. Tranexamic acid for treatment of primary postpartum hemorrhage after vaginal delivery: a systematic review and meta-analysis of randomized controlled trials. J Matern Fetal Neonatal Med. 2020;33(5):869-874.
2. Fahrenholtz, CG, Bonanno LS, Martin JB. Tranexamic acid as adjuvant treatment for postpartum hemorrhage: a systematic review protocol. JBI Database System Rev Implement Rep. 2019;17(8):1565-1572.
3. Sentilhes L, Daniel V, Darsonval A et al. Study protocol. TRAAP – TRAnexamic Acid for Preventing postpartum hemorrhage after vaginal delivery: a multicenter randomized, double-blind, placebo-controlled trial. BMC Pregnancy Childbirth. 2015;15:135.
4. Sudhof LS, Shainker SA, Einerson BD. Tranexamic acid in the routine treatment of postpartum hemorrhage in the United States: a cost-effectiveness analysis. Am J Obstet Gynecol. 2019;221(3):275.e1-275.e12
5. Woman Trial Collaborators. Effect of early tranexamic acid administration on mortality, hysterectomy, and other morbidities in women with post-partum haemorrhage (WOMAN): an international, randomized, double-blind, placebo-controlled trial. Lancet. 2017;389(10084):2105-2116.
6. Shakur H, Roberts I, Bautista R, Caballero J, Coats T, Yutthakasemsunt S, et al. Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH2): a randomised, placebo-controlled trial. Lancet 2010;376(9734):23–32.