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Associate Professor, Department of Obstetrics and Gynecology, Warren Alpert Medical School of Brown University, Women and Infants Hospital, Providence, RI
Dr. Allen reports she is a Nexplanon trainer for Merck, and has served as a consultant for Bayer and Pharmanest.
Postpartum hemorrhage (PPH) traditionally has been defined as estimated blood loss in excess of 500 mL after vaginal delivery and in excess of 1,000 mL after a cesarean delivery. The newest definitions from the American College of Obstetricians and Gynecologists’ (ACOG) reVITALize program defines PPH as estimated blood loss ≥ 1,000 mL or blood loss accompanied by signs and symptoms of hypovolemia within 24 hours of birth (including intrapartum loss) regardless of route of delivery.1 In the United States, hemorrhage accounts for 11.4% of maternal deaths, the fourth most common cause after cardiovascular diseases, non-cardiovascular diseases, and infection; worldwide, it is the leading cause of maternal mortality.2 The rate of PPH increased in the United States from 2.3% in 1994 to 2.9% in 2006.3 This 26% increase primarily was the result of an increase in uterine atony.
Management of PPH involves a team approach, and ACOG recommends that all hospitals have standardized processes in place, including a massive transfusion protocol.4 Risk factors for PPH should be assessed upon admission. (See Table 1.) Primary causes of PPH that occur within the first 24 hours of birth include uterine atony, lacerations, retained placenta, placenta accreta/increta/percreta, acquired or inherited coagulation defects, and uterine inversion. Secondary causes of PPH that occur more than 24 hours after delivery and up to 12 weeks postpartum include subinvolution of the placental site, retained products of conception, infection, and inherited coagulation defects. For prevention of primary PPH, ACOG recommends oxytocin at the time of delivery, either 10 units intramuscular injection or a dilute intravenous solution (bolus dose 10 units).4
The management of PPH depends on the cause, with uterine atony comprising 70-80% of the cases. Management of uterine atony includes uterine massage, removal of intrauterine clots, and emptying the bladder to allow the uterus to contract. Oxytocin should be given and, typically, a second uterotonic, such as methylergonovine, 15-methyl prostaglandin F2a, or misoprostol, is necessary. Of note, tranexamic acid is a new agent that has entered the field for the treatment of PPH. Tranexamic acid reduces bleeding by inhibiting the enzymatic breakdown of fibrinogen and fibrin by plasmin.4 OB/GYNs will be familiar with the oral form of tranexamic acid (brand name Lysteda), which is used for the treatment of heavy menstrual bleeding. The intravenous formulation of tranexamic acid has been studied outside of pregnancy and was found to be effective in decreasing mortality in trauma patients with hemorrhage.5
Based on the data in trauma patients, the WOMAN (World Maternal Antifibrinolytic) trial was conducted in 193 hospitals in 21 countries (both developed and developing nations) to evaluate tranexamic acid for treatment of PPH.6 The study was a randomized, double-blind, placebo-controlled trial in women 16 years of age and older who had a clinical diagnosis of PPH after vaginal birth or cesarean delivery. Subjects were assigned randomly to receive 1 gram of tranexamic acid or placebo intravenously. If bleeding continued after 30 minutes or bleeding stopped and restarted within 24 hours, a second dose was permitted. The primary outcome was a composite of death from all causes or hysterectomy within 42 days of randomization. Secondary outcomes included deaths due to bleeding, thrombotic events, surgical interventions, and other complications.
Between March 2010 and April 2016, 20,060 women were randomized to tranexamic acid (n = 10,050) or placebo (n = 10,009). Of the 483 maternal deaths, 346 (72%) were due to bleeding. The risk of death due to bleeding was reduced in the tranexamic acid group compared to the placebo group (155 [1.5%] vs. 191 [1.9%]; relative risk [RR], 0.81; 95% confidence interval [CI], 0.65-1.00; P = 0.045). Deaths due to other causes, such as preeclampsia, pulmonary embolism, and sepsis, did not differ. The tranexamic acid was effective in reducing death due to hemorrhage if given within three hours of birth but not if given after more than three hours. Of the 709 women who underwent hysterectomy, 608 (86%) were on the day of randomization and 191 (27%) within 1 hour of randomization. The risk of hysterectomy was not reduced with tranexamic acid (358 [3.6%] vs. 351 [3.5%]; RR, 1.02; 95% CI, 0.88-1.07; P = 0.84). The risk of thrombosis and other adverse outcomes was no different between the two groups.
The authors of the WOMAN study concluded that tranexamic acid is effective in reducing deaths due to PPH and is most effective the earlier it is started. No effect was found on hysterectomies, likely because many clinicians in the study already had decided to perform hysterectomy at the time of randomization. This makes sense in the context of life-threatening hemorrhage that multimodal treatments would be initiated simultaneously. The authors concluded that tranexamic acid should be given alongside uterotonics because it is safe, effective, and there were no adverse effects. In its recent practice bulletin, ACOG concluded that 1 gram IV tranexamic acid should be considered for PPH when initial medical therapy fails.4 The dose may be repeated if bleeding persists after 30 minutes or restarts within 24 hours. However, most experts currently believe that using tranexamic acid for the prevention of PPH is still investigational.
Other techniques to control PPH after medical therapy include intrauterine tamponade with balloon systems (e.g., Bakri), 60 mL Foley catheter, or uterine packing. Ultimately, surgical intervention may be required including uterine artery embolization, vascular ligation, uterine compression sutures, or hysterectomy. One critical component of PPH management is early transfusion therapy. Maternal tachycardia and hypotension often occur only after significant blood loss in the healthy women for whom we care. One lesson learned from past maternal deaths is that inadequate early resuscitation leads to consumptive coagulopathy and other complications. Therefore, as soon as estimated blood loss approaches 1,500 mL, ACOG recommends preparing for blood transfusion, including packed red blood cells, fresh frozen plasma, and platelets.4 The current recommended initial ratio for transfusion in the setting of anticipated massive transfusion is 1:1:1 of packed red blood cells:fresh frozen plasma:platelets.7 Ultimately, treatment of PPH is a team effort and hospitals should prepare themselves by having an organized multidisciplinary response that is reinforced with hemorrhage drills and/or team training exercises. It is heartening that we have one more tool — tranexamic acid — to use to treat PPH. This agent may well play a role in reducing significant maternal morbidity and mortality in the United States.
Financial Disclosure: OB/GYN Clinical Alert’s editor, Jeffrey T. Jensen, MD, MPH, reports that he is a consultant for and receives grant/ research support from Bayer, Abbvie, ContraMed, and Merck; he receives grant/research support from Medicines 360, Agile, and Teva; and he is a consultant for MicroChips and Evofem. Peer reviewer Catherine Leclair, MD; nurse planners Marci Messerle Forbes, RN, FNP, and Andrea O’Donnell, FNP; AHC Media editorial group manager Terrey L. Hatcher; executive editor Leslie Coplin; and editor Journey Roberts report no financial relationships relevant to this field of study.