Next Generation Medical Management of Postpartum Hemorrhage

Author(s): Jaclyn M. Phillips, John N. van den Anker, Homa K. Ahmadzia*

Journal Name: Current Pharmaceutical Design

Volume 25 , Issue 5 , 2019

Become EABM
Become Reviewer
Call for Editor


Background: Postpartum hemorrhage remains a significant contributor to morbidity and mortality of women of childbearing age worldwide. Trends in both incidence and severity of postpartum hemorrhage are increasing which makes it imperative to identify drugs that could target prevention and/or treatment of these postpartum hemorrhages for women living in high, middle and low-income countries.

Methods: We have reviewed current advances in the medical management of postpartum hemorrhage focusing on non-uterotonic therapy. We specifically describe the use and mechanism of action of tranexamic acid (TXA) and fibrinogen concentrate. Furthermore, we address the existing data for using these medications in postpartum hemorrhage, highlighting both strengths and limitations.

Results: This review describes a new generation of medications that are promising for the prevention and/or treatment of postpartum hemorrhage. For patients at risk for significant hemorrhage, TXA has been shown to reduce intraoperative blood loss and can be given as a prophylactic agent. For the treatment of postpartum hemorrhage, early use of TXA has the potential to reduce mortality. In addition, some data exists supporting the use of fibrinogen concentrate, though more studies are required to help formulate guidelines for its use.

Conclusion: A promising new approach for the management of severe postpartum hemorrhage is using medications that alter coagulation. More data are needed to describe ideal patient populations, dosing, the time of administration, and infusion rate.

Keywords: Postpartum hemorrhage, obstetric hemorrhage, tranexamic acid, blood transfusion, disseminated intravascular coagulation (DIC), fibrinogen concentrate.

Updated WHO Recommendation on Tranexamic Acid for the Treatment of Postpartum Haemorrhage Highlights and Key Messages from the World Health Organization’s 2017 Global Recommendation
WHO recommendation on tranexamic acid for the treatment of postpartum haemorrhage
Postpartum Hemorrhage ACOG PRACTICE BULLET IN Clinical Management Guidelines for Obstetrician–Gynecologists. 2017; 130.
Say L, Chou D, Gemmill A, et al. Global causes of maternal death: A WHO systematic analysis. Lancet Glob Health 2014; 2(6): e323-33.
Mehrabadi A, Hutcheon JA, Lee L, Liston RM, Joseph KS. Trends in postpartum hemorrhage from 2000 to 2009: A population-based study. BMC Pregnancy Childbirth 2012; 12: 108.
Bateman BT, Berman MF, Riley LE, Leffert LR. The epidemiology of postpartum hemorrhage in a large, nationwide sample of deliveries. Anesth Analg 2010; 110(5): 1368-73.
Neb H, Zacharowski K, Meybohm P. Strategies to reduce blood product utilization in obstetric practice. Curr Opin Anaesthesiol 2017; 30(3): 294-9.
Oyelese Y, Ananth CV. Postpartum Hemorrhage: Epidemiology, Risk Factors, and Causes Available:
Knight M, Callaghan WM, Berg C, et al. Trends in postpartum hemorrhage in high resource countries: A review and recommendations from the International Postpartum Hemorrhage Collaborative Group. BMC Pregnancy Childbirth 2009; 9: 55.
Shakur H, Beaumont D, Pavord S, Gayet-Ageron A, Ker K, Mousa HA. Antifibrinolytic drugs for treating primary postpartum haemorrhage. Cochrane Database Syst Rev 2018; 2: CD012964.
Widmer M, Piaggio G, Nguyen TMH, et al. Heat-Stable Carbetocin versus Oxytocin to Prevent Hemorrhage after Vaginal Birth. N Engl J Med 2018; 379(8): 743-52.
Pacheco LD, Saade GR, Costantine MM, Clark SL, Hankins GDV. An update on the use of massive transfusion protocols in obstetrics. Am J Obstet Gynecol Elsevier Inc 2016; 214: 340-4.
Lunde J, Stensballe J, Wikkelsø A, Johansen M, Afshari A. Fibrinogen concentrate for bleeding--a systematic review. Acta Anaesthesiol Scand 2014; 58(9): 1061-74.
Combs CA, Murphy EL, Laros RK Jr. Factors associated with hemorrhage in cesarean deliveries. Obstet Gynecol 1991; 77(1): 77-82.
Rath WH. Postpartum hemorrhage--update on problems of definitions and diagnosis. Acta Obstet Gynecol Scand 2011; 90(5): 421-8.
Schaap T, Bloemenkamp K, Deneux-Tharaux C, Knight M, Langhoff-Roos J, Sullivan E, et al. Defining definitions: A Delphi study to develop a core outcome set for conditions of severe maternal morbidity. BJOG 2019; 126(3): 394-401.
Beyerle A, Nolte MW, Solomon C, Herzog E, Dickneite G. Analysis of the safety and pharmacodynamics of human fibrinogen concentrate in animals. Toxicol Appl Pharmacol 2014; 280(1): 70-7.
McCormack PL. Tranexamic acid: A review of its use in the treatment of hyperfibrinolysis. Drugs 2012; 72(5): 585-617.
Shakur H, Roberts I, Bautista R, et al. Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): A randomised, placebo-controlled trial. Lancet 2010; 376(9734): 23-32.
Tranexamic Acid Package Insert. In: Pfizer Australia Pty Ltd 2010; 1-27.
Lethaby A, Farquhar C, Cooke I. Antifibrinolytics for heavy menstrual bleeding. Cochrane Database Syst Rev 2000; 4–7(4): CD000249.
Davies J, Kadir RA. Heavy menstrual bleeding: An update on management. Thromb Res 2017; 151(Suppl. 1): S70-7.
Novikova N, Hofmeyr GJ, Cluver C. Tranexamic acid for preventing postpartum haemorrhage. Cochrane Database Syst Rev 2015; (6): CD007872.
Simonazzi G, Bisulli M, Saccone G, Moro E, Marshall A, Berghella V. Tranexamic acid for preventing postpartum blood loss after cesarean delivery: A systematic review and meta-analysis of randomized controlled trials. Acta Obstet Gynecol Scand 2016; 95(1): 28-37.
Wang H-Y, Hong S-K, Duan Y, Yin H-M. Tranexamic acid and blood loss during and after cesarean section: A meta-analysis. J Perinatol 2015; 35(10): 818-25.
Ker K, Edwards P, Perel P, Shakur H, Roberts I. Effect of tranexamic acid on surgical bleeding: Systematic review and cumulative meta-analysis. BMJ 2012; 344: e3054.
Sentilhes L, Daniel V, Darsonval A, et al. Study protocol. TRAAP - TRAnexamic Acid for Preventing postpartum hemorrhage after vaginal delivery: A multicenter randomized, double-blind, placebo-controlled trial. BMC Pregnancy Childbirth 2015; 15: 135.
Sentilhes L, Winer N, Azria E, et al. 1: Tranexamic acid for the prevention of postpartum hemorrhage after vaginal delivery: the TRAAP trial. N Engl J Med 2018; 379(8): 731-42.
Effect of Early Tranexamic Acid Administration on Mortality, Hysterectomy, and Other Morbidities in Women With Post-Partum Haemorrhage (WOMAN). Lancet 2017; 389(10084): 2105-16.
Jerath A, Yang QJ, Pang KS, et al. Tranexamic Acid Dosing for Cardiac Surgical Patients With Chronic Renal Dysfunction: A New Dosing Regimen. Anesth Analg 2018; 127(6): 1323-32.
Xu J, Gao W, Ju Y. Tranexamic acid for the prevention of postpartum hemorrhage after cesarean section: A double-blind randomization trial. Arch Gynecol Obstet 2013; 287(3): 463-8.
Ahmadzia HK, Lockhart EL, Thomas SM, et al. Using antifibrinolytics in the peripartum period - concern for a hypercoagulable effect? J Neonatal Perinatal Med 2017; 10(1): 1-7.
Da H, Pa C, Aj M, Connell OD, Bj S, Da F, et al. Anti-fibrinolytic use for minimising perioperative allogeneic blood transfusion ( Review ) Anti-fibrinolytic use for minimising perioperative allogeneic blood transfusion 2011; 3-5.
Frimat M, Decambron M, Lebas C, et al. Renal Cortical Necrosis in Postpartum Hemorrhage: A Case Series. Am J Kidney Dis 2016; 68(1): 50-7.
Sharma V, Fan J, Jerath A, et al. Pharmacokinetics of tranexamic acid in patients undergoing cardiac surgery with use of cardiopulmonary bypass. Anaesthesia 2012; 67(11): 1242-50.
Falana O, Patel G. Efficacy and safety of tranexamic acid versus ϵ-aminocaproic acid in cardiovascular surgery. Ann Pharmacother 2014; 48(12): 1563-9.
Martin K, Knorr J, Breuer T, et al. Seizures after open heart surgery: comparison of ε-aminocaproic acid and tranexamic acid. J Cardiothorac Vasc Anesth 2011; 25(1): 20-5.
Jensen NHL, Stensballe J, Afshari A. Comparing efficacy and safety of fibrinogen concentrate to cryoprecipitate in bleeding patients: A systematic review. Acta Anaesthesiol Scand 2016; 60(8): 1033-42.
Cortet M, Deneux-Tharaux C, Dupont C, et al. Association between fibrinogen level and severity of postpartum haemorrhage: secondary analysis of a prospective trial. Br J Anaesth 2012; 108(6): 984-9.
Charbit B, Mandelbrot L, Samain E, et al. The decrease of fibrinogen is an early predictor of the severity of postpartum hemorrhage. J Thromb Haemost 2007; 5(2): 266-73.
Levy JH, Welsby I, Goodnough LT. Fibrinogen as a therapeutic target for bleeding: A review of critical levels and replacement therapy. Transfusion 2014; 54(5): 1389-405.
Pacheco LD, Hankins GDV, Saad AF, Costantine MM, Chiossi G, Saade GR. Tranexamic acid for the management of obstetric hemorrhage. Obstet Gynecol 2017; 130(4): 765-9.
Fibrinogen Concentrate (Human) RiaSTAP Package Insert. In: CSL Behring LLC. 2009; pp. 1-11.
Seto S, Itakura A, Okagaki R, Suzuki M, Ishihara O. An algorithm for the management of coagulopathy from postpartum hemorrhage, using fibrinogen concentrate as first-line therapy. Int J Obstet Anesth Elsevier Ltd 2017; 32: 11-6.
Mengoli C, Franchini M, Marano G, et al. The use of fibrinogen concentrate for the management of trauma-related bleeding: A systematic review and meta-analysis. Blood Transfus 2017; 15(4): 318-24.
Wikkelsø AJ, Edwards HM, Afshari A, et al. Pre-emptive treatment with fibrinogen concentrate for postpartum haemorrhage: randomized controlled trial. Br J Anaesth 2015; 114(4): 623-33.
Aawar N, Alikhan R, Bruynseels D, et al. Fibrinogen concentrate versus placebo for treatment of postpartum haemorrhage: study protocol for a randomised controlled trial. Trials 2015; 16: 169.
Ducloy-Bouthors AS, Mignon A, Huissoud C, Grouin JM, Mercier FJ. Fibrinogen concentrate as a treatment for postpartum haemorrhage-induced coagulopathy: A study protocol for a randomised multicentre controlled trial. The fibrinogen in haemorrhage of DELivery (FIDEL) trial. Anaesth Crit Care Pain Med 2016; 35(4): 293-8.
Collins PW, Cannings-John R, Bruynseels D, et al. Viscoelastometric-guided early fibrinogen concentrate replacement during postpartum haemorrhage: OBS2, a double-blind randomized controlled trial. Br J Anaesth 2017; 119(3): 411-21.
Fominskiy E, Nepomniashchikh VA, Lomivorotov VV, et al. Efficacy and safety of fibrinogen concentrate in surgical patients: a meta-analysis of randomized controlled trials. J Cardiothorac Vasc Anesth 2016; 30(5): 1196-204.
Wikkelsø A, Lunde J, Johansen M, et al. Fibrinogen concentrate in bleeding patients. Cochrane Database Syst Rev 2013; 8: CD008864.
Solomon C, Gröner A, Ye J, Pendrak I. Safety of fibrinogen concentrate: Analysis of more than 27 years of pharmacovigilance data. Thromb Haemost 2015; 113(4): 759-71.
Novoseven Package Insert. In: Novo Nordisk. 2014; pp. 1-17.
Franchini M, Lippi G, Franchi M. The use of recombinant activated factor VII in obstetric and gynaecological haemorrhage. BJOG 2007; 114(1): 8-15.
Magon N, Babu KM, Kapur K, Chopra S, Joneja GS. Recombinant activated factor VII in post partum haemorrhage. Niger Med J 2013; 54(5): 289-94.
Levi M, Levy JH, Andersen HF, Truloff D. Safety of recombinant activated factor VII in randomized clinical trials. N Engl J Med 2010; 363(19): 1791-800.
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): 731-42.
Gillissen A, Henriquez DDCA, Van Den Akker T, et al. The effect of tranexamic acid on blood loss and maternal outcome in the treatment of persistent postpartum hemorrhage: A nationwide retrospective cohort study. PLoS One 2017; 12(11): e0187555.
Abdel-Aleem H, Alhusaini TK, Abdel-Aleem MA, Menoufy M, Gülmezoglu AM. Effectiveness of tranexamic acid on blood loss in patients undergoing elective cesarean section: randomized clinical trial. J Matern Fetal Neonatal Med 2013; 26(17): 1705-9.
Gungorduk K, Yıldırım G, Asıcıoğlu O, Gungorduk OC, Sudolmus S, Ark C. Efficacy of intravenous tranexamic acid in reducing blood loss after elective cesarean section: A prospective, randomized, double-blind, placebo-controlled study. Am J Perinatol 2011; 28(3): 233-40.
Senturk MB, Cakmak Y, Yildiz G, Yildiz P. Tranexamic acid for cesarean section: A double-blind, placebo-controlled, randomized clinical trial. Arch Gynecol Obstet 2013; 287(4): 641-5.
Yang H, Zheng S, Shi C. Clinical study on the efficacy of tranexamic acid in reducing postpartum blood lose: A randomized, comparative, multicenter trial. Zhonghua Fu Chan Ke Za Zhi 2001; 36(10): 590-2.
Mirghafourvand M, Mohammad-Alizadeh S, Abbasalizadeh F, Shirdel M. The effect of prophylactic intravenous tranexamic acid on blood loss after vaginal delivery in women at low risk of postpartum haemorrhage: A double-blind randomised controlled trial. Aust N Z J Obstet Gynaecol 2015; 55(1): 53-8.
Gai MY, Wu LF, Su QF, Tatsumoto K. Clinical observation of blood loss reduced by tranexamic acid during and after caesarian section: A multi-center, randomized trial. Eur J Obstet Gynecol Reprod Biol 2004; 112(2): 154-7.
Ducloy-Bouthors A, Broisin F, Keita H, Fontaine S, Depret S, Legoeff F, et al. Tranexamic acid reduces blood loss in postpartum haemorrhage. Crit Care 2010; 14: 370.
Ahmed MR, Sayed Ahmed WA, Madny EH, Arafa AM, Said MM. Efficacy of tranexamic acid in decreasing blood loss in elective caesarean delivery. J Matern Fetal Neonatal Med 2015; 28(9): 1014-8.
Mayur G, Purvi P, Ashoo G, Pankaj D. Efficacy of tranexamic acid in decreasing blood loss during and after cesarean section: A randomized case controlled prospective study. J Obs Gynecol India 2007; 57: 227-30.
Movafegh A, Eslamian L, Dorabadi A. Effect of intravenous tranexamic acid administration on blood loss during and after cesarean delivery. Int J Gynaecol Obstet 2011; 115(3): 224-6.
Goswami U, Sarangi S, Gupta S, Babbar S. Comparative evaluation of two doses of tranexamic acid used prophylactically in anemic parturients for lower segment cesarean section: A double-blind randomized case control prospective trial. Saudi J Anaesth 2013; 7(4): 427-31.
Shahid A, Khan A. Tranexamic acid in decreasing blood loss during and after caesarean section. J Coll Physicians Surg Pak 2013; 23: 459-62.
Mannucci PM, Levi M. Prevention and treatment of major blood loss. N Engl J Med 2007; 356(22): 2301-11.

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2019
Published on: 02 June, 2019
Page: [549 - 555]
Pages: 7
DOI: 10.2174/1381612825666190320155337
Price: $65

Article Metrics

PDF: 50
PRC: 2