World Maternal Antifibrinolytic Trial_2 (WOMAN-2)

Tranexamic Acid for the Prevention of Postpartum Bleeding in Women With Anaemia: an International, Randomised, Double-blind, Placebo Controlled Trial.

Postpartum haemorrhage (PPH) is responsible for about 100,000 maternal deaths every year, almost all of which occur in low and middle income countries. When given within three hours of birth, tranexamic acid reduces deaths due to bleeding in women with PPH by almost one third. However, for many women, treatment of PPH is too late to prevent death and severe morbidities. Over one-third of pregnant women in the world are anaemic and many are severely anaemic. We now want to do the WOMAN-2 trial to see if giving tranexamic acid can prevent PPH and other severe outcomes in women with moderate and severe anaemia.

Anaemia is a cause and consequence of PPH. A cohort study in Assam, India found that women with moderate or severe anaemia had a greatly increased risk of PPH. Women with moderate anaemia had a 50% increased risk, whereas those with severe anaemia had a ten-fold increased risk of PPH. Anaemic women may be more susceptible to uterine atony due to impaired oxygen transport to the uterus. Anaemic women experience worse outcomes after PPH. An international survey of 275,000 women found that severe maternal outcomes after PPH were nearly three times more common in anaemic than in non-anaemic women. Even moderate bleeding can be life threatening in anaemic women. Excessive bleeding after childbirth worsens maternal anaemia, resulting in a vicious circle of bleeding and adverse outcomes. Fatigue due to anaemia severely limits a mothers' wellbeing and her ability to care for her children. Despite efforts to prevent anaemia, many women labour with perilously low haemoglobin levels Tranexamic acid (TXA) inhibits fibrinolysis by blocking the lysine binding sites on plasminogen. TXA reduces surgical bleeding and death due to bleeding in trauma patients. The WOMAN trial assessed the effects of TXA in 20,060 women with PPH. When given within three hours of birth, TXA reduced death due to bleeding by nearly one-third (RR=0.69, 95% CI 0.52 to 0.91, p=0.008). However, for many women, treatment is too late to prevent death from PPH. Most PPH deaths occur in the first hours after giving birth and women with anaemia are at greatly increased risk. Whilst there have been some trials of TXA for the prevention of PPH, most have serious flaws and none collected data on maternal health and wellbeing. There is currently no reliable evidence about the effectiveness and safety of TXA for preventing PPH. The WOMAN-2 trial will determine reliably the effects of TXA in anaemic women who give birth vaginally.

prevention, postpartum haemorrhage, moderate anaemia, severe anaemia, antifibrinolytic, tranexamic acid, pregnancy

A randomised, double blind, placebo controlled trial among 15,000 women with moderate or severe anaemia having given birth vaginally.

Masking was done by an independent clinical trials supply company. It will involve the removal of the original manufacturer's label and replacement with the clinical trial label bearing the randomisation number, which will be used as the pack identification. Apart from the randomisation number, all pack label texts will be identical for tranexamic acid and placebo.

Clinical assessment: This may be an estimated blood loss of more than 500 mL or any blood loss sufficient to compromise haemodynamic stability within 24 hours of delivery. Haemodynamic instability is based on clinical judgement and assessed using clinical signs (low systolic blood pressure, tachycardia, reduced urine output).

24 hours after administration of the trial medication or at discharge from hospital, whichever is earlier

24 hours after administration of the trial medication or at discharge from hospital, whichever is earlier

24 hours after administration of the trial medication or at discharge from hospital, whichever is earlier

Any of the following: uterotonics, removal of placenta/placenta fragments, intrauterine balloon tamponade, bimanual uterine compression, external aortic compression, non-pneumatic anti-shock garments, uterine artery embolisation, uterine compression suture, hysterectomy and laparotomy to control bleeding

Any of the following:pulmonary embolism (PE), deep vein thrombosis (DVT), stroke, myocardial infarction

Any of the following: Cardiovascular, Respiratory, Renal, Hepatic, Neurological, Coagulation/ haematologic dysfunction

diagnosis is based on the presence of both infection and a systemic inflammatory response syndrome (SIRS). SIRS requires two or more of the following: a) temperature <36°C or >38°C (b) heart rate >90 beats/min (c) respiratory rate >20 breaths/min (d) white blood cell count <4x109/L (<4000/mm³) or >12x109/L (>12,000/mm³)

Inclusion Criteria: Women with moderate or severe anaemia (haemoglobin level <100 g/L or packed cell volume <30%) after giving birth vaginally where the responsible clinician is substantially uncertain whether to use TXA Exclusion Criteria: Women who are not legally adult (<18 years) and not accompanied by a guardian Women with a known allergy to tranexamic acid or its excipients Women who experience postpartum haemorrhage before the umbilical cord is cut or clamped.

Data will be shared publicly when all planned analyses are completed by the Woman-2 Trial Collaborators. This will be hosted on freebird.lshtm.ac.uk

Data will be shared publicly when all planned analyses are completed by the Woman-2 Trial Collaborators.

Totally anonymised data (without random allocation, patient, country and site identifiers) will be freely available. Where random allocation codes, country/site identifiers are requested, appropriate pre-specified analysis plan will need to be submitted to the Trial Management Group for review and if necessary, appropriate Ethics Committee approval will be required.

Brenner A, Roberts I, Balogun E, Bello FA, Chaudhri R, Fleming C, Javaid K, Kayani A, Lubeya MK, Mansukhani R, Olayemi O, Prowse D, Vwalika B, Shakur-Still H. Postpartum haemorrhage in anaemic women: assessing outcome measures for clinical trials. Trials. 2022 Mar 18;23(1):220. doi: 10.1186/s13063-022-06140-z.

Ker K, Roberts I, Chaudhri R, Fawole B, Beaumont D, Balogun E, Prowse D, Pepple T, Javaid K, Kayani A, Arulkumaran S, Bates I, Shakur-Still H; WOMAN-2 trial collaborators. Tranexamic acid for the prevention of postpartum bleeding in women with anaemia: study protocol for an international, randomised, double-blind, placebo-controlled trial. Trials. 2018 Dec 29;19(1):712. doi: 10.1186/s13063-018-3081-x.