Tranexamic acid for preventing postpartum blood loss at cesarean delivery: is evidence sufficient?

We congratulate Simonazzi et al. for their excellent systematic review regarding the use of tranexamic acid (TXA) to prevent postpartum blood loss after a cesarean delivery. All randomized controlled trials (RCTs) have found that TXA significantly decreases postpartum blood loss 1. Consequently, this meta-analysis showed that TXA, in addition to the standard prophylactic oxytocin, decreases blood loss. More interestingly, TXA was also reported to significantly decrease the incidence of postpartum hemorrhage (PPH), severe PPH, and blood transfusion. Simonazzi et al. recommend routine use of TXA before skin incision for all cesarean deliveries despite the safety concerns regarding the risk of thrombotic events 1. We agree with Simonazzi et al. that TXA appears to be a promising drug for the prevention of PPH after cesarean delivery 1, 2. Nevertheless, we strongly believe that the current level of evidence supporting its efficacy is insufficient, as are the data about its benefit–harm ratio 2. Contrary to Simonazzi et al., who stated that “the included studies were of high quality with a low risk of bias” 1, all other authors who have recently performed meta-analyses on this topic have underlined that the quality of the data was low to moderate with high risk of bias 3, 4. It is also noteworthy that there is a wide heterogeneity among the three meta-analyses in reporting risk of bias (as low, high or unclear risk) based on the same attributes (selection, performance, detection, attrition, reporting, and other biases) of the same included studies using the Cochrane Collaboration's Risk of Bias Tool 1, 3, 4. These discrepancies and difficulties in assessing bias reflect the overall low quality of the available data 2-4. Moreover, blood loss was not assessed by a validated methodology, the definition of PPH was nonstandard, policy of blood transfusion was never described, some secondary outcomes (and sometimes even primary outcomes) were not pre-specified and were rarely assessed beyond 24 h postpartum, and the adverse events were hardly assessed after hospital discharge. These limitations cause a lack of confidence in results and particularly in the estimated effect size. Besides, mean difference of blood loss [160.27 mL or 136.75 mL depending on the trial design) 1] may not be clinically relevant. Finally, studies were underpowered to assess the safety profile for both the fetus [severe adverse neonatal effects may occur with TXA, which is known to cross the placenta, when administered at least 10 min before the cesarean incision 2] and the mother. Recently published data suggest that antifibrinolytic agents might increase the risk of renal cortical necrosis 5. In conclusion, caution and robust evidence are necessary before recommending the use of TXA in routine clinical practice for the prevention of PPH after cesarean section in view of the number of eligible women and the potential for an increase in thrombotic events in postpartum women who are in a hypercoagulable state.