Study protocol. TRAAP - TRAnexamic Acid for Preventing postpartum hemorrhage after vaginal delivery: a multicenter randomized, double-blind, placebo-controlled trial

Loïc Sentilhes, Valérie Daniel, Astrid Darsonval, Philippe Deruelle, Delphine Vardon, Franck Perrotin, Camille Le Ray, Marie-Victoire Senat, Norbert Winer, Françoise Maillard, Catherine Deneux-Tharaux, Loïc Sentilhes, Valérie Daniel, Astrid Darsonval, Philippe Deruelle, Delphine Vardon, Franck Perrotin, Camille Le Ray, Marie-Victoire Senat, Norbert Winer, Françoise Maillard, Catherine Deneux-Tharaux

Abstract

Background: Postpartum hemorrhage (PPH) is a major cause of maternal mortality, accounting for one quarter of all maternal deaths worldwide. Estimates of its incidence in the literature vary widely, from 3 % to 15 % of deliveries. Uterotonics after birth are the only intervention that has been shown to be effective in preventing PPH. Tranexamic acid (TXA), an antifibrinolytic agent, has been investigated as a potentially useful complement to uterotonics for prevention because it has been proved to reduce blood loss in elective surgery, bleeding in trauma patients, and menstrual blood loss. Randomized controlled trials for PPH prevention after cesarean (n = 10) and vaginal (n = 2) deliveries show that women who received TXA had significantly less postpartum blood loss without any increase in their rate of severe adverse effects. However, the quality of these trials was poor and they were not designed to test the effect of TXA on the reduction of PPH incidence. Large, adequately powered, multicenter randomized controlled trials are required before the widespread use of TXA to prevent PPH can be recommended.

Methods and design: A multicenter, double-blind, randomized controlled trial will be performed. It will involve 4000 women in labor for a planned vaginal singleton delivery, at a term ≥ 35 weeks. Treatment (either TXA 1 g or placebo) will be administered intravenously just after birth. Prophylactic oxytocin will be administered to all women. The primary outcome will be the incidence of PPH, defined by blood loss ≥500 mL, measured with a graduated collector bag. This study will have 80 % power to show a 30 % reduction in the incidence of PPH, from 10.0 % to 7.0 %.

Discussion: In addition to prophylactic uterotonic administration, a complementary component of the management of third stage of labor acting on the coagulation process may be useful in preventing PPH. TXA is a promising candidate drug, inexpensive, easy to administer, and simple to add to the routine management of deliveries in hospitals. This large, adequately powered, multicenter, randomized placebo-controlled trial seeks to determine if the risk-benefit ratio favors the routine use of TXA after delivery to prevent PPH.

Trial registration: ClinicalTrials.gov NCT02302456 (November 17, 2014).

References

    1. World Health Organization . Managing complications in pregnancy and childbirth. Geneva: World Organization; 2000.
    1. Calvert C, Thomas SL, Ronsmans C, Wagner KS, Adler AJ, Filippi V. Identifying regional variation in the prevalence of postpartum haemorrhage: a systematic review and meta-analysis. PLoS One. 2012;7:e41114. doi: 10.1371/journal.pone.0041114.
    1. Deneux-Tharaux C, Dupont C, Colin C, Rabilloud M, Touzet S, Lansac J, Harvey T, Tessier V, Chauleur C, Pennehouat G, Morin X, Bouvier-Colle MH, Rudigoz R. Multifaceted intervention to decrease the rate of severe postpartum haemorrhage: the PITHAGORE6 cluster-randomised controlled trial. BJOG Int J Obstet Gynaecol. 2010;117:1278–87. doi: 10.1111/j.1471-0528.2010.02648.x.
    1. Kramer MS, Berg C, Abenhaim H, Dahhou M, Rouleau J, Mehrabadi A, Joseph KS. Incidence, risk factors, and temporal trends in severe postpartum hemorrhage. Am J Obstet Gynecol. 2013;209:449.e1–7. doi: 10.1016/j.ajog.2013.07.007.
    1. Bateman BT, Berman MF, Riley LE, Leffert LR. The epidemiology of postpartum hemorrhage in a large, nationwide sample of deliveries. Anesth Analg. 2010;110:1368–73. doi: 10.1213/ANE.0b013e3181d74898.
    1. Mathai M, Gülmezoglu AM, Hill S. Saving womens lives: Evidence-based recommendations for the prevention of postpartum haemorrhage. Bull World Health Organ. 2007;85:322–3.
    1. McCormick ML, Sanghvi HCG, Kinzie B, McIntosh N. Preventing postpartum hemorrhage in low-resource settings. Int J Gynaecol Obstet Off Organ Int Fed Gynaecol Obstet. 2002;77:267–75. doi: 10.1016/S0020-7292(02)00020-6.
    1. Goffinet F, Mercier F, Teyssier V, Pierre F, Dreyfus M, Mignon A, Carbonne B, Lévy G, Groupe de Travail des RPC sur l’HPP Postpartum haemorrhage: recommendations for clinical practice by the CNGOF (December 2004) Gynécol Obstét Fertil. 2005;33:268–74. doi: 10.1016/j.gyobfe.2005.03.016.
    1. American College of Obstetricians and Gynecologists Clinical Management Guidelines for Obstetrician-Gynecologists Number 76, October 2006: postpartum hemorrhage. Obstet Gynecol. 2006;108:1039–47. doi: 10.1097/00006250-200610000-00046.
    1. Royal College of Obstetricians and Gynaecologists . Prevention and management of postpartum haemorrhage. Guidelines no 52 London: RCOG; 2009.
    1. World Health Organization. Recommendations for the prevention and treatment of postpartum haemorrhage. WHO;2012.
    1. Begley CM, Gyte GML, Devane D, McGuire W, Weeks A. Active versus expectant management for women in the third stage of labour. Cochrane Database Syst Rev. 2015;3:CD007412. doi:10.1002/14651858.CD007412.pub4.
    1. Westhoff G, Cotter AM, Tolosa JE. Prophylactic oxytocin for the third stage of labour to prevent postpartum haemorrhage. Cochrane Database Syst Rev. 2013;10:CD001808.
    1. Deneux-Tharaux C, Sentilhes L, Maillard F, Closset E, Vardon D, Lepercq J, Goffinet F. Effect of routine controlled cord traction as part of the active management of the third stage of labour on postpartum haemorrhage: multicentre randomised controlled trial (TRACOR) BMJ. 2013;346:f1541. doi: 10.1136/bmj.f1541.
    1. Gülmezoglu AM, Lumbiganon P, Landoulsi S, Widmer M, Abdel-Aleem H, Festin M, Carroli G, Qureshi Z, Souza JP, Bergel E, Piaggio G, Goudar SS, Yeh J, Armbruster D, Singata M, Pelaez-Crisologo C, Althabe F, Sekweyama P, Hofmeyr J, Stanton M-E, Derman R, Elbourne D. Active management of the third stage of labour with and without controlled cord traction: a randomised, controlled, non-inferiority trial. Lancet. 2012;379:1721–7. doi: 10.1016/S0140-6736(12)60206-2.
    1. Lalonde A, Daviss BA, Acosta A, Herschderfer K. Postpartum hemorrhage today: ICM/FIGO initiative 2004–2006. Int J Gynaecol Obstet Off Organ Int Fed Gynaecol Obstet. 2006;94:243–53. doi: 10.1016/j.ijgo.2006.04.016.
    1. Hofmeyr GJ, Abdel-Aleem H, Abdel-Aleem MA. Uterine massage for preventing postpartum haemorrhage. Cochrane Database Syst Rev. 2013;7:CD006431.
    1. Novikova N, Hofmeyr GJ. Tranexamic acid for preventing postpartum haemorrhage. Cochrane Database Syst Rev. 2010;(7):CD007872. doi:10.1002/14651858.CD007872.pub2.
    1. Henry DA, Carless PA, Moxey AJ, O’Connell D, Stokes BJ, McClelland B, Laupacis A, Fergusson D. Anti-fibrinolytic use for minimising perioperative allogeneic blood transfusion. Cochrane Database Syst Rev. 2007;(4):CD001886.
    1. 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. doi: 10.1136/bmj.e3054.
    1. CRASH-2 trial collaborators. Shakur H, Roberts I, Bautista R, Caballero J, Coats T, Dewan Y, El-Sayed H, Gogichaishvili T, Gupta S, Herrera J, Hunt B, Iribhogbe P, Izurieta M, Khamis H, Komolafe E, Marrero M-A, Mejía-Mantilla J, Miranda J, Morales C, Olaomi O, Olldashi F, Perel P, Peto R, Ramana PV, Ravi RR, Yutthakasemsunt S. 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;376:23–32. doi: 10.1016/S0140-6736(10)60835-5.
    1. Matteson KA, Rahn DD, Wheeler TL, 2nd, Casiano E, Siddiqui NY, Harvie HS, Mamik MM, Balk EM, Sung VW, Society of Gynecologic Surgeons Systematic Review Group Nonsurgical management of heavy menstrual bleeding: a systematic review. Obstet Gynecol. 2013;121:632–43. doi: 10.1097/AOG.0b013e3182839e0e.
    1. Sentilhes L, Lasocki S, Deruelle P, Perrotin F, Goffinet F, Deneux-Tharaux C. Tranexamic acid for the prevention and treatment of post-partum hemorrhage. Brit J Anaesth. in press 2015: doi:10.1093/bja/aeu448.
    1. Hellgren M. Hemostasis during normal pregnancy and puerperium. Semin Thromb Hemost. 2003;29:125–30. doi: 10.1055/s-2003-38897.
    1. Charbit B, Mandelbrot L, Samain E, Baron G, Haddaoui B, Keita H, Sibony O, Mahieu-Caputo D, Hurtaud-Roux MF, Huisse MG, Denninger MH, de Prost D. PPH Study Group: The decrease of fibrinogen is an early predictor of the severity of postpartum hemorrhage. J Thromb Haemost JTH. 2007;5:266–73. doi: 10.1111/j.1538-7836.2007.02297.x.
    1. Cortet M, Deneux-Tharaux C, Dupont C, Colin C, Rudigoz R-C, Bouvier-Colle M-H, Huissoud C. Association between fibrinogen level and severity of postpartum haemorrhage: secondary analysis of a prospective trial. Br J Anaesth. 2012;108:984–9. doi: 10.1093/bja/aes096.
    1. Ducloy-Bouthors A-S, Jude B, Duhamel A, Broisin F, Huissoud C, Keita-Meyer H, Mandelbrot L, Tillouche N, Fontaine S, Le Goueff F, Depret-Mosser S, Vallet B, EXADELI Study Group. Susen S. High-dose tranexamic acid reduces blood loss in postpartum haemorrhage. Crit Care Lond Engl. 2011;15:R117. doi: 10.1186/cc10143.
    1. Bouet PE, Ruiz V, Legendre G, Gillard P, Sentilhes L. High-dose tranexamic acid for treating postpartum haemorrhage after vaginal delivery. Brit J Anaesth. in press 2015: doi:10.1093/bja/aeu468.
    1. Shakur H, Elbourne D, Gülmezoglu M, Alfirevic Z, Ronsmans C, Allen E, Roberts I. The WOMAN Trial (World Maternal Antifibrinolytic Trial): Tranexamic acid for the treatment of postpartum haemorrhage: an international randomised, double blind placebo controlled trial. Trials. 2010;11:40. doi: 10.1186/1745-6215-11-40.
    1. Gai M, Wu L, Su Q, Tatsumoto K. Clinical observation of blood loss reduced by tranexamic acid during and after caesarean section: a multi-center, randomized trial. Eur J Obstet Gynecol Reprod Biol. 2004;112:154–7. doi: 10.1016/S0301-2115(03)00287-2.
    1. Gohel M, Patel P, Gupta A, Desai P. Efficacy of tranexamic acid in decreasing blood loss during and after cesarean section: a randomised case controlled prospective study. J Obstet Gynecol India. 2007;57:227–30.
    1. Sekhavat L, Tabatabaii A, Dalili M, Farajkhoda T, Tafti AD. Efficacy of tranexamic acid in reducing blood loss after cesarean section. J Matern-Fetal Neonatal Med Off J Eur Assoc Perinat Med Fed Asia Ocean Perinat Soc Int Soc Perinat Obstet. 2009;22:72–5.
    1. 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;28:233–40. doi: 10.1055/s-0030-1268238.
    1. Movafegh A, Eslamian L, Dorabadi A. Effect of intravenous tranexamic acid administration on blood loss during and after cesarean delivery. Int J Gynaecol Obstet Off Organ Int Fed Gynaecol Obstet. 2011;115:224–6. doi: 10.1016/j.ijgo.2011.07.015.
    1. 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;287:463–8. doi: 10.1007/s00404-012-2593-y.
    1. Sentürk MB, Cakmak Y, Yildiz G, Yildiz P. Tranexamic acid for cesarean section: a double-blind, placebo-controlled, randomized clinical trial. Arch Gynecol Obstet. 2013;287:641–5. doi: 10.1007/s00404-012-2624-8.
    1. Shahid A, Khan A. Tranexamic acid in decreasing blood loss during and after caesarean section. J Coll Physicians Surg Pak JCPSP. 2013;23:459–62.
    1. 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 Off J Eur Assoc Perinat Med Fed Asia Ocean Perinat Soc Int Soc Perinat Obstet. 2013;26:1705–9.
    1. 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;7:427–31. doi: 10.4103/1658-354X.121077.
    1. 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;36:590–2.
    1. Gungorduk K, Asıcıoğlu O, Yıldırım G, Ark C, Tekirdağ Aİ, Besımoglu B. Can intravenous injection of tranexamic acid be used in routine practice with active management of the third stage of labor in vaginal delivery? A randomized controlled study. Am J Perinatol. 2013;30:407–13.
    1. Ferrer P, Roberts I, Sydenham E, Blackhall K, Shakur H. Anti-fibrinolytic agents in post partum haemorrhage: a systematic review. BMC Pregnancy Childbirth. 2009;9:29. doi: 10.1186/1471-2393-9-29.
    1. Koo JR, Lee YK, Kim YS, Cho WY, Kim HK, Won NH. Acute renal cortical necrosis caused by an antifibrinolytic drug (tranexamic acid) Nephrol Dial Transplant Off Publ Eur Dial Transpl Assoc Eur Ren Assoc. 1999;14:750–2.
    1. Odabaş AR, Cetinkaya R, Selçuk Y, Kaya H, Coşkun U. Tranexamic-acid-induced acute renal cortical necrosis in a patient with haemophilia A. Nephrol Dial Transplant Off Publ Eur Dial Transpl Assoc Eur Ren Assoc. 2001;16:189–90.
    1. Levin M-D, Betjes MGH, V d Kwast TH, Wenberg BL, Leebeek FWG. Acute renal cortex necrosis caused by arterial thrombosis during treatment for acute promyelocytic leukemia. Haematologica. 2003;88:ECR21.
    1. Charytan C, Purtilo D. Glomerular capillary thrombosis and acute renal failure after epsilon-amino caproic acid therapy. N Engl J Med. 1969;280:1102–4. doi: 10.1056/NEJM196905152802006.
    1. Purtilo DT, Constantian HM, DeGirolami E. Letter: Epsilon-aminocaproic acid in haematuria. Lancet. 1975;1:755. doi: 10.1016/S0140-6736(75)91674-8.
    1. Jackson E, Curtis KM, Gaffield ME. Risk of venous thromboembolism during the postpartum period: a systematic review. Obstet Gynecol. 2011;117:691–703. doi: 10.1097/AOG.0b013e31820ce2db.
    1. Peitsidis P, Kadir RA. Antifibrinolytic therapy with tranexamic acid in pregnancy and postpartum. Expert Opin Pharmacother. 2011;12:503–16. doi: 10.1517/14656566.2011.545818.
    1. Sentilhes L, Vayssière C, Mercier FJ, Aya AG, Bayoumeu F, Bonnet MP, Deneux-Taraux C, Djoudi R, Dolley P, Dreyfus M, Ducroux-Schouwey C, Dupont C, François A, Gallot D, Haumonté JB, Huissoud C, Kayem G, Keita-Meyer H, Langer B, Mignon A, Morel O, Parant O, Pelage JP, Phan E, Rossignol M, Tessier V, Goffinet F. Hémorragie du post-partum: recommandations pour la pratique clinique — Texte des recommandations (texte court) J Gynecol Obstet Biol Reprod. 2014;43:1170–9. doi: 10.1016/j.jgyn.2014.10.009.
    1. Dildy GA, Paine AR, George NC, Velasco C. Estimating blood loss: can teaching significantly improve visual estimation? Obstet Gynecol. 2004;104:601–6. doi: 10.1097/01.AOG.0000137873.07820.34.
    1. Duthie SJ, Ven D, Yung GL, Guang DZ, Chan SY, Ma HK. Discrepancy between laboratory determination and visual estimation of blood loss during normal delivery. Eur J Obstet Gynecol Reprod Biol. 1991;38:119–24. doi: 10.1016/0028-2243(91)90188-Q.
    1. Glover P. Blood loss at delivery: how accurate is your estimation? Aust J Midwifery Prof J Aust Coll Midwives Inc. 2003;16:21–4.
    1. Razvi K, Chua S, Arulkumaran S, Ratnam SS. A comparison between visual estimation and laboratory determination of blood loss during the third stage of labour. Aust N Z J Obstet Gynaecol. 1996;36:152–4. doi: 10.1111/j.1479-828X.1996.tb03273.x.
    1. Stafford I, Dildy GA, Clark SL, Belfort MA. Visually estimated and calculated blood loss in vaginal and cesarean delivery. Am J Obstet Gynecol. 2008;199:519.e1–7. doi: 10.1016/j.ajog.2008.04.049.
    1. Joseph KS, Rouleau J, Kramer MS, Young DC, Liston RM, Baskett TF, Maternal Health Study Group of the Canadian Perinatal Surveillance System Investigation of an increase in postpartum haemorrhage in Canada. BJOG Int J Obstet Gynaecol. 2007;114:751–9. doi: 10.1111/j.1471-0528.2007.01316.x.
    1. Lutomski JE, Byrne BM, Devane D, Greene RA. Increasing trends in atonic postpartum haemorrhage in Ireland: an 11-year population-based cohort study. BJOG Int J Obstet Gynaecol. 2012;119:306–14. doi: 10.1111/j.1471-0528.2011.03198.x.

Source: PubMed

Patrocinadores e Colaboradores

Condições médicas

Intervenções de drogas

3
Se inscrever