World Maternal Antifibrinolytic Trial_2
- Conditions
- Intrapartum - Moderate and Severe Anaemia
- Interventions
- Other: Placebo
- Registration Number
- NCT03475342
- Lead Sponsor
- London School of Hygiene and Tropical Medicine
- Brief Summary
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.
- Detailed Description
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.
We will also conduct a pre-planned cohort analysis of data from the WOMAN-2 trial to assess the effect of pain control and episiotomy on the risk of post-partum haemorrhage. Adrenaline is a potent stimulus for fibrinolysis. Adrenaline causes the release of tissue plasminogen activator (TPA) from the endothelium. In trauma victims, high adrenaline levels are associated with increased fibrinolysis, decreased clot strength and increased deaths due to bleeding. Childbirth is intensely painful and maternal adrenaline levels are two to six times higher during labour. Maternal adrenaline concentrations peak in the second and third stages of labour but then rapidly return to normal after birth. Pain control can reduce the maternal catecholamine response. We hypothesize that painful procedures such as episiotomy will significantly increase the risk of postpartum haemorrhage and that pain control will reduce the risk of PPH.
The exposures of interest are the presence or absence of pain control during labour and delivery and whether episiotomy was conducted prior to birth. Pain control will be categorised as present or absent but the type of pain control administered during labour will also be described and examined. The types of pain control recorded in the study are epidural, opioids, 'other', or a combination of opioids and other pain control. For the multivariable regression analysis, the pain control variable was converted into a binary variable indicating whether a participant received any pain control or not. Episiotomy will be categorised as present or absent according to the CRF. The main outcome variable will be a clinical diagnosis of PPH (binary: yes/no), defined as an estimated blood loss of more than 500 mL or any blood loss sufficient to compromise haemodynamic stability within 24 hours. Potential confounding factors will include maternal age, BMI, anaemia, history of PPH, antepartum hemorrhage, hypertensive disease, multiple gestation, parity, prophylactic uterotonics, duration of labor, induction and augmentation of labor, assisted delivery, gestational age, birth canal trauma, placental abruption, and macrosomia.
We will use multivariable logistic regression to examine the association between pain control and episiotomy and the risk of PPH after adjusting for confounding factors. We will describe our causal assumptions using a directed acyclic graph. We will examine the association between the exposures of interest and PPH with odds ratios and 95% confidence intervals. We will estimate odds ratios and 95% CI for the crude association between the exposures of interest and PPH and after controlling for confounding factors. We will check for collinearity using variance inflation factors. Finally, we will examine whether the effect of pain control and episiotomy on the risk of PPH is modified by tranexamic acid treatment. To do this we will conduct stratified analysis and calculate a p-value for heterogeneity using a likelihood ratio test.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- Female
- Target Recruitment
- 15068
- 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
- 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.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Placebo Placebo One Injection of the placebo which is 10 mL Sodium Chloride (0.9%) Tranexamic acid Tranexamic Acid One intravenous injection of tranexamic acid. Total dose 1 gram (10mL)
- Primary Outcome Measures
Name Time Method Postpartum Haemorrhage (cause will be described) 24 hours after administration of the trial medication or at discharge from hospital, whichever is earlier 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).
- Secondary Outcome Measures
Name Time Method Postpartum blood loss 24 hours after administration of the trial medication or at discharge from hospital, whichever is earlier Clinical assessment
Interventions to control primary postpartum haemorrhage (medical and surgical) Day 42 or 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
Shock index 24 hours after administration of trial treatment or discharge from hospital, whichever is earlier Heart rate/systolic blood pressure
Receipt of blood product transfusion Day 42 or discharge of mother from hospital, whichever is earlier units and type
Thromboembolic events in breastfed babies Day 42 or discharge of mother from hospital, whichever is earlier as defined in protocol
Quality of Life (maternal) Day 42 or discharge from hospital, whichever is earlier Defined as per protocol
Vascular occlusive events Day 42 or discharge from hospital, whichever is earlier Any of the following:pulmonary embolism (PE), deep vein thrombosis (DVT), stroke, myocardial infarction
Organ disfunction Day 42 or discharge from hospital, whichever is earlier Any of the following: Cardiovascular, Respiratory, Renal, Hepatic, Neurological, Coagulation/ haematologic dysfunction
In hospital death Day 42 Cause and time of death will be described
Adverse events Day 42 Any untoward medical occurrence (other than expected complications)
Haemodynamic instability 24 hours after administration of trial treatment or discharge from hospital, whichever is earlier Defined as per protocol
Expected side effects of trial medication Day 42 or discharge from hospital, whichever is earlier nausea, vomiting, diarrhoea
Symptoms of anaemia Day 42 or discharge of mother from hospital, whichever is earlier measured using Quality of life Questionnaire and walk test
Length of hospital stay. Day 42 or discharge from hospital, whichever is earlier Days
Admission to and time spent in higher level facility Day 42 or discharge from hospital, whichever is earlier High Dependency and/or Intensive Care Units
Haemoglobin 24 hours after administration of the trial medication or at discharge from hospital, whichever is earlier Haemocue (Point of care test)
Exercise tolerance Day 42 or discharge from hospital, whichever is earlier 6 minute walk test
Sepsis Day 42 or discharge from hospital, whichever is earlier 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)
Status of baby/ies Day 42 or discharge of mother from hospital, whichever is earlier alive or dead
Trial Locations
- Locations (41)
Ilorin General Hospital
🇳🇬Ilorin, Nigeria
Chandka SMBBMU Sheikh Zaid Woman Hospital Unit 1
🇵🇰Larkana, Pakistan
Adeoyo Maternity Hospital
🇳🇬Ibadan, Nigeria
State Hospital
🇳🇬Oyo, Nigeria
Ayub Teaching Hospital (Unit A)
🇵🇰Abbottabad, Pakistan
Ayub Teaching Hospital (Unit C)
🇵🇰Abbottabad, Pakistan
Ayub Teaching Hospital Unit B
🇵🇰Abbottabad, Pakistan
Bahawalpur Victoria Hospital
🇵🇰Bahawalpur, Pakistan
Military Hospital
🇵🇰Islamabad, Pakistan
Civil Hospital
🇵🇰Karachi, Pakistan
Koohi Goth Hospital
🇵🇰Karachi, Pakistan
Jinnah Hospital
🇵🇰Lahore, Pakistan
Sir Ganga Ram Hospital Unit 2
🇵🇰Lahore, Pakistan
Muhammad Abdullahi Wase Specialist Hospital
🇳🇬Kano, Nigeria
Aziz Bhatti Teaching Hospital
🇵🇰Gujrat, Pakistan
Sir Ganga Ram Hospital Unit 4
🇵🇰Lahore, Pakistan
Amana Regional Referral Hospital,
🇹🇿Dar Es Salaam, Tanzania
Tumbi Regional Referral Hospital, Kibaha
🇹🇿Kibaha, Tanzania
Women and Newborn Hospital
🇿🇲Lusaka, Zambia
Mother & Child Hospital
🇳🇬Akure, Nigeria
Jinnah Postgraduate Medical Centre
🇵🇰Karachi, Pakistan
University of Medical Sciences Teaching Hospital
🇳🇬Akure, Nigeria
MCH PIMS
🇵🇰Islamabad, Pakistan
Services Hospital
🇵🇰Lahore, Pakistan
Sir Ganga Ram Hospital Unit 3
🇵🇰Lahore, Pakistan
Bolan Medical Centre
🇵🇰Quetta, Pakistan
Holy Family Hospital
🇵🇰Rawalpindi, Pakistan
Chandka SMBBMU Sheikh Zaid Woman Hospital Units 2 & 3
🇵🇰Lārkāna, Pakistan
Nishtar Hospital Unit 2
🇵🇰Multān, Pakistan
Benazir Bhutto Shaheed Hospital
🇵🇰Rawalpindi, Pakistan
Muhimbili National Hospital
🇹🇿Dar Es Salaam, Tanzania
Temeke Regional Referral Hospital
🇹🇿Dar Es Salaam, Tanzania
Dodoma Regional Referral Hospital
🇹🇿Dodoma, Tanzania
Mwananyamala Regional Referral Hospital
🇹🇿Kinondoni, Tanzania
Ladoke Akintola University of Technology Teaching Hospital
🇳🇬Ogbomoso, Nigeria
Sir Ganga Ram Hospital Unit 1
🇵🇰Lahore, Pakistan
Nishtar Hospital Unit 1
🇵🇰Multan, Pakistan
Federal Government Polyclinic
🇵🇰Rawalpindi, Pakistan
Nishtar Hospital Unit 3
🇵🇰Multān, Pakistan
Mount Meru Regional Referral Hospital
🇹🇿Arusha, Tanzania
Mbeya Zonal Referral Hospital
🇹🇿Mbeya, Tanzania