Tranexamic Acid May Not Prevent Hemorrhage After C-Section

Prophylactic tranexamic acid (TXA) during cesarean delivery did not lead to a lower risk of maternal death or blood transfusion, a randomized trial found.

Among 11,000 women in 31 U.S. hospitals assigned to TXA or placebo after umbilical cord clamping, the primary outcome of maternal death or blood transfusion occurred in 3.6% of the TXA group and 4.3% of the placebo group (adjusted relative risk 0.89, 95.26% CI 0.74-1.07, P=0.19), reported Luis Pacheco, MD, of the University of Texas Medical Branch in Galveston, and colleagues.

Intraoperative blood loss of more than 1 liter occurred in 7.5% of the TXA group and 8.0% of the placebo group (RR 0.91, 95% CI 0.79-1.05), the researchers said in the New England Journal of Medicine. There was one maternal death in the placebo group.

"The bottom line of the studies is that tranexamic acid does not decrease the risk or the necessity to receive blood products," Pacheco told MedPage Today. "So as of now, our conclusion is that there is not enough data to recommend the use of tranexamic acid to prevent obstetrical hemorrhage, because it does not translate into clinically significant improvements."

But physicians "should be cautious" when they interpret these results, noted Homa Ahmadzia, MD, MPH, of George Washington University in Washington, D.C., who wasn't involved with the study.

"I think there were some some trends towards benefit [with TXA], but we need to continue looking at... maybe earlier use and a larger trial to see if there's true benefits in hemorrhage morbidity reduction," she told MedPage Today. "I think the logical question from this trial is going to be, if it didn't show a huge impact, if it didn't show major reduction, maybe we gave it too late."

TXA in the context of other surgeries, like heart operations and liver transplants, has been shown to decrease perioperative bleeding. It has also been studied within the context of treating established or ongoing obstetrical hemorrhage, which accounts for 28.1% of maternal deaths worldwide and is the second most common cause of pregnancy-related death in the U.S.

Based on a previous large, randomized international trial, a number of groups including the American College of Obstetricians and Gynecologists and the World Health Organization have recommended its early use (within 3 hours of delivery) for women with obstetric or postpartum hemorrhage.

But according to Pacheco, its effectiveness in preventing obstetric hemorrhage remains unclear. "To prevent hemorrhage, I guess everyone was waiting for this study to see if recommendations would change, and then we would actually move towards a more active use of prophylactic TXA," he said. "And that's not going to happen, because this study didn't show any benefit."

Previous studies, such as TRAAP and TRAAP2, were smaller and used estimated blood loss as their primary outcome, he said. TRAAP2, which evaluated the use of 1 gram of TXA within 3 minutes after C-section, found a decrease of 100 milliliters in blood loss, "but that doesn't mean anything clinically if it doesn't translate to, let's say, the need to transfuse blood products to someone or [the] need to re-operate," Pacheco said. "So we looked at something more tangible."

Pacheco said his group looked at C-section specifically because it is one of the most common major surgeries performed in the U.S. and the risk of hemorrhage, compared with vaginal delivery, is higher.

Study Details

Patients (maternal age around 30; around 39% white; mean BMI 35.7 for both groups) undergoing C-section were randomly assigned to receive either 1 gram TXA diluted in saline or IV saline (placebo). About half of the C-sections were scheduled in each group. TXA was administered within 3 minutes after umbilical cord clamping in 91.8% of participants. Mean gestational age at delivery was 38.3 weeks.

The primary outcome was a composite of maternal death or blood transfusion before hospital discharge or 7 days post-partum, whichever came first. The major secondary outcome was intraoperative blood loss of more than 1 liter, as assessed in the anesthesia record and operative report. Key secondary outcomes included a composite of treatments related to bleeding and other complications within 7 days post partum, such as surgical or radiologic procedures to control bleeding, infectious complications within 6 weeks, and thromboembolic events.

After excluding 217 patients who received open-label TXA (because of excessive intraoperative bleeding, for example), the adjusted RR of a primary outcome event was 0.84 (95.26% CI 0.68-1.03).

Interventions for bleeding complications occurred in 16.1% of the participants in the TXA group and 18% of the placebo group. Pre- to post-operative hemoglobin levels changed -1.8 g per deciliter and -1.9 g per deciliter, respectively.

Postpartum infectious complications occurred in 3.2% of the TXA group and 2.5% of the placebo group. There were no material between-group differences in major safety outcomes, including thromboembolic events or seizures, the authors said.

Participants received 1 gram of IV TXA over 10 minutes immediately after umbilical cord clamping. "Because tranexamic acid was administered after umbilical cord clamping, the benefit of earlier administration (before incision), if any, is unknown," the authors stated. Pacheco said the FDA has not approved the use of TXA prior to clamping the umbilical cord because of lack of data on safety to the fetus, making it hard to evaluate pre-delivery TXA treatment.

But Ahmadzia said she suspected many physicians were already giving TXA pre-delivery in some cases, and that a larger study may capture potential benefits of earlier administration. TXA has "been around for decades," she noted. "And in cardiac surgery for babies, they give it and the concentrations are so much higher, and these babies don't have seizure or clots." The OPTIMUM OB-TXA trial will look at the optimal timing, route, and dose of TXA prior to umbilical cord clamping, she noted.

Study limitations included the administration of TXA only after cord clamping, the small percentage of delayed administration (after the 3-minute window), and the exclusion of patients at high risk for thromboembolic phenomena. However, "risk of thromboembolic events (venous or arterial) was not higher in the tranexamic acid group than in the placebo group," the authors pointed out.

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