From Pages to Practice
From 1980 to 2008, the annual number of maternal deaths (during pregnancy, childbirth, or in the 42 days after delivery) worldwide decreased from approximately 500,000 to 350,000. Much of this improvement was due to advances in medicine, including the use of uterotonic agents such as oxytocin to decrease rates of postpartum hemorrhage. However, rates of maternal mortality have not decreased equally worldwide. In some countries, such as Zimbabwe, the yearly number of maternal deaths increased during the same period. Some of the differences can be explained by the inability to deliver appropriate health care, including oxytocin, which is not heat-stable and must be kept refrigerated.
In this week’s issue of NEJM, two multicenter randomized trials evaluated the efficacy of different strategies to decrease rates of postpartum hemorrhage. In the double-blind, noninferiority Carbetocin Hemorrhage Prevention (CHAMPION) trial, investigators randomized nearly 30,000 pregnant women in 10 countries to receive intramuscular injection of carbetocin or oxytocin to prevent postpartum hemorrhage immediately after vaginal delivery. Carbetocin is a heat-stable analogue of oxytocin, so unlike oxytocin, it can be delivered to remote areas without requiring refrigeration. Both agents were kept on ice to ensure double-blinding. For one primary outcome — the proportion of women with blood loss of at least 500 mL or the use of additional uterotonic agents — carbetocin was noninferior to oxytocin (14.5% vs. 14.4%). Carbetocin did not meet the prespecified noninferiority criterion for the other primary outcome — the proportion of women with blood loss of at least 1000ml (1.51% vs. 1.45%, respectively), but the incidence of blood loss greater than 1000 mL was lower than expected, so the trial was underpowered for this outcome.
In the Tranexamic Acid for Preventing Postpartum Hemorrhage Following Vaginal Delivery (TRAAP) trial, 4000 women scheduled to undergo vaginal delivery were randomized to receive either tranexamic acid or placebo administered intravenously, along with oxytocin immediately after delivery. Tranexamic acid is a antifibrinolytic agent that is heat-stable and inexpensive and has been shown to reduce bleeding-related mortality when administered postpartum, especially shortly after delivery. In the TRAAP trial, tranexamic acid did not significantly decrease the rate of the primary outcome — postpartum hemorrhage of at least 500 mL (8.1% in the tranexamic acid group vs. 9.8% in the placebo group, P=0.07).
In an accompanying editorial, Haleema Shakura-Still, MSc, and Ian Roberts, PhD, note that because the TRAAP trial was performed in low-risk women in France, we cannot exclude the possibility that tranexamic acid will have a clinically significant effect on postpartum hemorrhage in higher risk patients, such as women with anemia, who make up a higher portion of the population in low- and middle-income countries. Further work is needed to determine tranexamic acid is beneficial in high-risk populations. In the meantime, heat-stable carbetocin can be offered as an effective alternative to oxytocin for prevention of postpartum hemorrhage in regions without access to cold storage.