Each year in Pakistan, about 20,000 women die from causes related to pregnancy and childbirth.1 Haemorrhage, which usually occurs in the post partum period, is responsible for around a third of these deaths.2 Other consequences of post partum haemorrhage (PPH) include the need for blood transfusion which is not always available or safe, and severe anaemia which can cause disabling fatigue and reduces a woman’s capacity to look after her children and to do any other work.
There are known effective treatments for preventing severe bleeding after childbirth and it is essential to ensure that all pregnant women have access to these.3 However, even with these treatments, many women do develop severe post partum bleeding and there is an urgent need for a safe and effective treatment that is inexpensive and easy to administer across a range of different healthcare settings. This editorial invites obstetricians, midwives and nurses throughout Pakistan and the world to join an international collaborative effort to identify such a treatment.
Tranexamic acid (TXA) is an anti-fibrinolytic drug that inhibits clot breakdown by blocking the lysine binding sites on plasminogen molecules.4 TXA is not a new drug and has been used for many years to treat menorrhagia and dental extraction in people with haemophilia. More recently, it has been used to reduce bleeding in elective surgical patients. Although there are many ongoing trials of TXA in elective surgery, the accumulated evidence already shows that TXA reduces bleeding. A recently updated systematic review of randomised trials of TXA in elective surgery found 65 randomised trials, including a total of 4,842 participants. TXA reduces blood transfusion by about one third [relative risk (RR)=0·61, 95% CI 0·53 to 0·70; p<0.001] with a trend towards reduced mortality that was not statistically significant (RR=0·60, 95% CI 0·33 to 1·10; p=0.10).5
Results from the CRASH-2 trial6 of TXA in bleeding trauma patients provide exciting grounds for optimism that TXA might reduce mortality and the need for hysterectomy in women with PPH. In the CRASH-2 trial, 20,211 adults with traumatic haemorrhage were randomised to either TXA (loading dose 1 gram over ten minutes followed by infusion of 1 gram over 8 hours) or matching placebo, with 99·6% follow-up. The risk of death due to bleeding was significantly reduced with TXA (RR= 0·85, 95%CI 0·76 to 0·96; p=0·008). Importantly, there was no increase in fatal or non-fatal vascular occlusive events (RR=0·84, 95% CI 0·68 to 1·0; p=0·08). All cause mortality was also significantly reduced with TXA (RR=0·91, 95% CI 0·85 to 0·97; p=0·004). The large numbers of patients studied, from hospitals in high, middle and low income countries, help these results to be generalised widely. Because TXA is inexpensive and easy to administer, it can easily be added to the normal medical and surgical management of trauma patients in the hospitals, world-wide.
The knowledge that TXA safely reduces mortality in traumatic haemorrhage raises the possibility that it might also be effective in PPH. To date, there have been only a few small trials of TXA in post partum bleeding, including in total less than 500 women.7 Although there was a significant reduction in post partum blood loss in women treated with TXA, the quality of the trials was poor. None had well concealed treatment allocation and even in aggregate they were too small to assess the effects of TXA on mortality, hysterectomy and thrombotic side effects. The recently updated PPH treatment guidelines prepared by the World Health Organization state that TXA may be used if other measures fail, but points out that the evidence base is poor and calls for further clinical trials of TXA in PPH.8
The World Maternal Antifibrinolytic (WOMAN) trial, coordinated by the London School of Hygiene and Tropical Medicine, University of London, has been launched in response to this important clinical uncertainty. WOMAN is a pragmatic, randomised, double blind, placebo controlled trial among women with a clinical diagnosis of post partum haemorrhage that determines reliably the effect of the early administration of TXA on death, hysterectomy and other morbidities (surgical interventions, blood transfusion and risk of non-fatal vascular events), in women with PPH.9 The trial has already recruited over 2500 eligible women in the hospitals in Africa, Asia, Latin America and Europe but many new collaborating centres are needed in order to reach the target sample size of 15,000 women.
The WOMAN trial has been approved by the Pakistan National Bioethics Committee and the Ministry of Health. Recruitment started in Pakistan in November 2010 at Obstetrics and Gynaecology (Obs/Gyn) Unit-I, Holy Family Hospital, Rawalpindi (Principal Investigator and Pakistan National Coordinator, Professor Rizwana Chaudhri). Four further units / hospitals have also joined this study, Obs/Gyn Unit II, Holy Family Hospital, Rawalpindi (Principal Investigator, Professor Fehmida Shaheen), Liaquat National Hospital, Karachi (Principal Investigator, Prof Haleema Hashmi), Mian Mohammad Trust Hospital, Faisalabad (Principal Investigator, Dr Ambreen Ikram) and Shalimar Hospital, Lahore (Principal Investigator; Dr Lubna Riaz Dar).
We hope that many more hospitals throughout Pakistan will join this collaboration.
Full details of the protocol and how to join the trial are available on the trial website (www.thewomantrial.lshtm.ac.uk), or by e-mailing TheWomanTrial@Lshtm.ac.uk. The success of the WOMAN trial depends on the collaboration of midwives, nurses and doctors from hospitals all around the world. The hope is that by working together we might identify a safe and effective treatment that could save the lives of tens of thousands of new mothers.
References
1. Hogan MC, Foreman KJ, Naghavi M, et al. Maternal mortality for 181 countries, 1980-2008: a systematic analysis of progress towards Millennium Development Goal 5. Lancet 2010; 375: 1609–1623.
2. Khan KS, Wojdyla D, Say L, Gülmezoglu AM, Van Look PFA. WHO analysis of causes of maternal death: a systematic review. Lancet 2006; 367:1066-1074.
3. WHO Recommendations for the prevention of postpartum haemorrhage. Geneva: World Health Organization, 2007.
4.Okamoto S, Hijikata-Okunomiya A, Wanaka K, Okada Y, Okamoto U. Enzyme controlling medicines: introduction. Semin Thromb Hemost 1997; 23: 493–501.
5. Henry D, Carless P, Moxey A, O'Connell D, Stokes B, Fergusson D, et al. Anti-fibrinolytic use for minimising perioperative allogeneic blood transfusion. Cochrane Database Syst Rev 2011, Issue 3. Art. No.: CD001886. DOI: 10.1002/14651858.CD001886.pub4.
6. CRASH-2 trial collaborators. 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, Issue 9734: p23-32.
7. Ferrer P, Roberts I, Sydenham E, Blackhall K, Shakur H. Anti-fibrinolytic agents in postpartum haemorrhage: a systematic review. BMC Pregnancy Childbirth 2009; 9: 29.
8. WHO guidelines for the management of postpartum haemorrhage and retained placenta. Geneva: World Health Organization, 2009.
9. Shakur H, Elbourne D, Gulmezoglu M, et al. 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. |
