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Update: Should tranexamic acid be added to the standard of care in treating postpartum hemorrhage?

Introduction

Postpartum hemorrhage (PPH) is one of the leading causes of maternal death around the world.1-3 The maternal death prevalence in the United States due to PPH has been reported to be approximately 11% per year.3 Postpartum hemorrhage is defined as blood loss of greater than or equal 1000 mL or requiring a blood transfusion within 24 hours after vaginal or caesarean deliveries. However, the risk of PPH can emerge as late as 12 weeks after childbirth.1

There are a few different preventative and treatment options for PPH, including tranexamic acid (TXA). In childbirth, it has been reported that the concentration of tissue plasminogen activator increases due to tissue damage which can cause increased bleeding.4 Tranexamic acid is an antifibrinolytic agent and works as a reversible competitive inhibitor to bind to lysine receptors on plasminogen to inhibit its conversion to plasmin.5 Plasmin binds and activates the fibrin matrix. A reduction in plasmin activity by tranexamic acid leads to decreased bleeding. The only FDA-approved indications for TXA are for heavy menstrual bleeding and short-term prevention of hemophilia. Some TXA off-label uses include: trauma, severe risk of hemorrhage, gastrointestinal bleeding, non-traumatic subarachnoid hemorrhage, surgical operations (eg, elective cesarean sections, total knee arthroplasty, orthognathic surgery, cardiac surgery, spinal surgeries, and transurethral retrograde prostatectomy), hereditary angioedema, and PPH.

A frequently asked question (FAQ) was published in December 2017 (available here) and presented information on use of TXA as a treatment option for PPH after childbirth.6 The author discussed that there is a potential benefit for using TXA as treatment for PPH as shown by the results of the 2017 WOMAN trial, however further studies were still warranted.

Guideline Recommendations

The American College of Obstetricians and Gynecologists (ACOG) recommendations for prevention and management of PPH have not been updated since 2017.1 According to the guideline, uterotonic agent administration (ie oxytocin), uterine massage, and umbilical cord traction are still the most effective approaches when it comes to PPH prevention. Prophylactic oxytocin is recommended and remains the most effective medication with the fewest adverse effects and tranexamic acid can be considered when initial medical therapies fail.  

The World Health Organization (WHO) guideline for the prevention and treatment of PPH was published in 2012, with an update in 2018 focusing on uterotonic agents.7,8 The recommendations suggest using uterotonic agents (oxytocin is recommended in settings where multiple uterotonics are available) for prevention and treatment. The use of TXA is recommended for treating PPH in case of refractory or persistent trauma-related bleeding.7

In 2017, WHO released a recommendation about TXA use for the treatment of PPH.9 The recommendation was based on the evidence reported in the WOMAN trial. Early use of intravenous TXA (within 3 hours of birth) in addition to standard care was recommended for women with clinically diagnosed PPH following vaginal birth or cesarean section.

Literature Review

An updated search of the PubMed database was conducted in January 2022 to include recent randomized clinical trials (RCT) and meta-analyses (MA) evaluating the clinical outcomes of TXA in preventing and treating PPH in women regardless of delivery method; relevant articles are described in the Table below. Most of the recently published RCTs since 2017 were included in a recent MA (summarized below) and are not evaluated individually.10

The MA by Bellos et al aimed to assess the efficacy and safety of using TXA as a prophylactic agent in combination with known uterotonic agents versus using the uterotonic agent alone in women undergoing caesarean delivery.10 A majority of the RCTs included women who were at low risk of bleeding. The uterotonic agent that was used in all the trials was oxytocin. The result for the primary outcome for this MA, total blood loss, indicated that TXA administration was associated with significant blood loss reduction compared with placebo. Although this MA evaluated a large number of RCTs, none of them were conducted in the United States. Another limitation of this MA was the limited data surrounding post discharge follow-up which can be a concern regarding long-term safety of treatment.

Four additional RCTs that were not included in the MA evaluated the efficacy and safety of using TXA to prevent or treat PPH. The French TRAAP and TRAAP2 trials studied the role of TXA in preventing PPH after vaginal and caesarean deliveries, respectively.11,12 In the first TRAAP trial, investigators found that use of TXA did not significantly impact the primary outcome of PPH (defined as blood loss ≥500 mL) compared to placebo in vaginal deliveries.11 In TRAAP2, investigators found that TXA did result in a significantly lower incidence of the primary outcome of PPH (defined as estimated blood loss ≥1000 mL or red cell transfusion by day 2) compared to placebo in caesarean deliveries.12 In the United States, Ogunkua et al evaluated TXA as a prophylactic agent to reduce blood loss compared to placebo in women undergoing elective repeat caesarean delivery.13 There was no statistically significant difference between the TXA group and the placebo group for its primary outcome of mean calculated blood loss. Another RCT conducted by Oseni et al evaluated the effectiveness of preoperative TXA in reducing blood loss during caesarean section in Nigeria.14 There was a significant reduction in the amount of blood loss when TXA was administered in combination with a uterotonic agent versus administering the placebo.14

Table: Clinical outcome for evaluating the use of tranexamic acid in postpartum hemorrhage.10-14 
Study DesignPopulationInterventionsPrimary OutcomeOther outcomes
Meta-analysis
Bellos 202110
 
MA of 36 RCTs		N=10,659 women who underwent cesarean delivery and received standard uterotonic agent (mostly oxytocin)IV TXA
 
Control (placebo, standard uterotonic agent)		Significant decrease in total blood loss in those who received TXA vs. placebo. (MD: -189.44 mL, 95% CI, -218.63 to -160.25)Blood loss of  > 1000mL: decreased risk of blood loss of  >1000 mL with TXA
(OR, 0.37; 95% CI, 0.22-0.60)
 
RBC transfusion:
significantly less frequent in women receiving prophylactic TXA
(OR, 0.41; 95% CI, 0.26-0.65)
 
Need of additional uterotonic agent administration:
significantly less common in
the TXA arm (OR, 0.36; 95% CI,
0.25-0.52)
 
Thromboembolic events:
No significant differences between TXA and placebo groups
Clinical trials
Sentilhes 201811
 
(TRAAP)
 
MC, DB, RCT		N=3891 women who had vaginal delivery of a live fetus at 35 or more weeks of gestation1g IV TXA (n=1945)
 
Control (placebo, standard uterotonic agent) (n=1946)		Blood loss of  ≥ 500 mL:
Blood loss was less in the TXA group (8.1%) compared to placebo (9.8%), but not statistically significant (RR, 0.83; 95% CI, 0.68 to 1.01; p=0.07)		Provider-assessed clinically significant PPH*:
Lower in the TXA vs. placebo (7.8% vs. 10.4% respectively; RR, 0.74; 95% CI, 0.61
to 0.91; p=0.004; adjusted p=0.04, post hoc)
 
Use of additional uterotonic agents for excessive bleeding:
Used less often in TXA group vs. placebo (7.2% vs. 9.7%; RR, 0.75; 95% CI, 0.61 to 0.92; p=0.006; adjusted p=0.04)
 
No significant differences between the 2 groups for incidence of thromboembolic events 3 months after delivery
Sentilhes 202112
 
(TRAAP2)
 
MC, DB, RCT		N=4431 women who had cesarean delivery before or during labor at 34 or more gestational weeks1g IV TXA (n=2222)
 
Control (placebo and prophylactic uterotonic agent) (n=2209)		CBL  > 1000 mL or RBC transfusion within 2 days after delivery:
Significantly less in the TXA group than placebo (26.7% vs. 31.6% respectively; adjusted RR, 0.84; 95% CI, 0.75 to 0.94; p=0.003).		EBL:
No significant difference between the 2 groups
Provider-assessed clinically significant PPH*:
No significant differences between the 2 groups
 
Use of additional uterotonic agents for excessive bleeding:
No significant differences between the 2 groups
 
Incidence of postpartum blood transfusion:
No significant differences between the 2 groups
 
Thromboembolic events 3 months after delivery:
More in TXA group vs. placebo (0.4% vs. 0.1% respectively; RR, 4.01; 95% CI, 0.85 to 18.92; p=0.08).
Ogunkua 202213
 
RCT, DB, SC		N=110 women with singleton pregnancy and undergoing an elective repeat cesarean delivery at 34 or more gestational weeks1g IV TXA (n=55)
 
NS (n=55)
 
All participants received prophylactic oxytocin		Mean CBL at 24 hours:
TXA: 2274 +/- 469 mL
 
Placebo 2407 +/- 388 mL; p > 0.05
CBL  ≥  2000 mL:
Significantly lower in TXA group (69%) vs. placebo (91%) (p=0.004)
 
EBL ≥ 1000 mL immediately following surgery:
No statistical differences between TXA vs. placebo; p=0.052
 
EBL ≥ 2000 mL immediately following surgery:
No statistical differences between TXA vs. placebo;
p > 0.05.
 
Differences in maternal clotting activity: D-dimer levels were lower in the TXA group than in the placebo group 24 hours after delivery (2.1±1.2 µg/mL vs. 4.3±2.4 µg/mL; p<0.001)
 
Neonatal outcomes:
No differences in
neonatal intensive care admissions, and the need for assisted ventilation
Oseni 202114
 
RCT, DB, SC		N=244 women who were to have emergency cesarean section at  >37 weeks but < 42 gestational weeks1g IV TXA (n=122)
 
NS (n=122)
 
All participants received oxytocin after delivery		Average intraoperative blood loss:
Less blood loss in TXA group vs. placebo (414 mL vs. 773.8 mL respectively) (p≤0.01)		CBL  ≥ 1000 mL: 2 (1.6%) patients in the TXA group vs. 12 (9.8%) in placebo group
 
Hemoglobin and hematocrit levels: Significant reduction in levels in the TXA group vs. placebo
*According to provider responses on a self-administered questionnaire
Abbreviations: CBL, calculated blood loss; CI, confidence interval; DB, double blind; EBL, estimated blood loss; IV=intravenous; MA, meta-analysis; MC, multicenter; MD, mean difference; NS, normal saline; OR, odds ratio; PPH, postpartum hemorrhage; RCT, randomized controlled trial; RR, relative risk; RBC, red blood cells; SC, single center; TXA=tranexamic acid.

Conclusion:

In summary, several recent publication findings appear conflicting as to whether or not TXA should be added to the standard of care in preventing and treating PPH. A recent MA has demonstrated benefit from administering TXA compared to placebo for treating PPH in patients undergoing caesarean delivery.  However, the authors suggest that more robust RCTs are needed to have stronger support for utilization of TXA in this patient population. Recent RCTs have demonstrated mixed results on the utility of TXA in both cesarean and vaginal deliveries. Moreover, the most recent ACOG and WHO guidelines are from 2017 and do not include the recently published trials discussed above; these guidelines provided recommendations for the use of TXA in the treatment of PPH within 3 hours of birth if initial therapies were to fail.  Whether tranexamic acid should be added to the standard of care in treating PPH is still dependent on patient-specific situations due to mixed results of currently available literature; the risks versus benefits should be weighed when considering TXA use for this indication.

References:

  1. Committee on Practice Bulletins-Obstetrics. Practice bulletin no. 183: Postpartum hemorrhage. Obstet Gynecol. 2017;130(4):e168-e186. doi:10.1097/AOG.0000000000002351
  2. Ahmadzia HK, Hynds EB, Amdur RL, Gimovsky AC, James AH, Luban NLC. National trends in tranexamic acid use in the peripartum period, 2015-2019. J Thromb Thrombolysis. 2020;50(3):746-752. doi:10.1007/s11239-020-02141-4
  3. Quantitative blood loss in obstetric hemorrhage: ACOG committee opinion, number 794. Obstet Gynecol. 2019;134(6):e150-e156. doi:10.1097/AOG.0000000000003564
  4. 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
  5. Chauncey JM, Wieters JS. Tranexamic Acid. In: StatPearls. Treasure Island (FL): StatPearls Publishing; July 28, 2021.
  6. Armgardt E. Should tranexamic acid be added to the standard of care in treating postpartum hemorrhage? University of Illinois at Chicago Drug Information Group. Published December 2017. Accessed February 4, 2022.  https://dig.pharmacy.uic.edu/faqs/2017-2/december-2017-faqs/
  7. WHO recommendations for the prevention and treatment of postpartum haemorrhage. Geneva: World Health Organization; 2012.
  8. WHO recommendations: uterotonics for the prevention of postpartum haemorrhage. Geneva: World Health Organization; 2018
  9. WHO recommendation on tranexamic acid for the treatment of postpartum haemorrhage. Geneva: World Health Organization; 2017.
  10. Bellos I, Pergialiotis V. Tranexamic acid for the prevention of postpartum hemorrhage in women undergoing cesarean delivery: an updated meta-analysis Published online Sep 25 2021. Am J Obstet Gynecol. 2021;S0002-9378(21)01053-X.
  11. Sentilhes L, Winer N, Azria E, et al. Tranexamic acid for the prevention of blood loss after vaginal delivery. N Engl J Med. 2018;379(8):731-742. doi:10.1056/NEJMoa1800942.
  12. Sentilhes L, Sénat MV, Le Lous M, et al. Tranexamic acid for the prevention of blood loss after cesarean delivery. N Engl J Med. 2021;384(17):1623-1634. doi:10.1056/NEJMoa2028788
  13. Ogunkua OT, Duryea EL, Nelson DB, et al. Tranexamic acid for prevention of hemorrhage in elective repeat cesarean delivery – A randomized study. Am J Obstet Gynecol MFM. 2022;(100573):100573. doi:10.1016/j.ajogmf.2022.100573
  14. Oseni RO, Zakari M, Adamou N, Umar UA. Effectiveness of preoperative tranexamic acid in reducing blood loss during caesarean section at Aminu Kano Teaching Hospital, Kano: a randomized controlled trial. Pan Afr Med J. 2021;39:34. doi:10.11604/pamj.2021.39.34.21938

Prepared by:
Waad Nader, PharmD candidate
University of Illinois at Chicago College of Pharmacy

Faria Munir, PharmD, MS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy

March 2022

The information presented is current as of February 4, 2022. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making