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.

Study Overview

• Status: Completed
• Conditions: Intrapartum - Moderate and Severe Anaemia
• Intervention / Treatment: Drug: Tranexamic Acid; Other: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 15068
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Ian Roberts; Phone Number: +44(0)20-7958-8128; Email: woman2@lshtm.ac.uk
• Study Contact Backup: Name: Haleema Shakur-Still; Phone Number: +44(0)20-7958-8113

Study Locations

• Nigeria
  • Akure, Nigeria
    • Mother & Child Hospital
  • Akure, Nigeria
    • University of Medical Sciences Teaching Hospital
  • Ibadan, Nigeria
    • Adeoyo Maternity Hospital
  • Ilorin, Nigeria
    • Ilorin General Hospital
  • Kano, Nigeria
    • Muhammad Abdullahi Wase Specialist Hospital
  • Ogbomoso, Nigeria
    • Ladoke Akintola University of Technology Teaching Hospital
  • Oyo, Nigeria
    • State Hospital
• Pakistan
  • Abbottabad, Pakistan
    • Ayub Teaching Hospital (Unit A)
  • Abbottabad, Pakistan
    • Ayub Teaching Hospital (Unit C)
  • Abbottabad, Pakistan
    • Ayub Teaching Hospital Unit B
  • Bahawalpur, Pakistan
    • Bahawalpur Victoria Hospital
  • Gujrat, Pakistan
    • Aziz Bhatti Teaching Hospital
  • Islamabad, Pakistan
    • MCH PIMS
  • Islamabad, Pakistan
    • Military Hospital
  • Karachi, Pakistan
    • Civil Hospital
  • Karachi, Pakistan
    • Jinnah Postgraduate Medical Centre
  • Karachi, Pakistan
    • Koohi Goth Hospital
  • Lahore, Pakistan
    • Jinnah Hospital
  • Lahore, Pakistan
    • Services Hospital
  • Lahore, Pakistan
    • Sir Ganga Ram Hospital Unit 1
  • Lahore, Pakistan
    • Sir Ganga Ram Hospital Unit 2
  • Lahore, Pakistan
    • Sir Ganga Ram Hospital Unit 3
  • Lahore, Pakistan
    • Sir Ganga Ram Hospital Unit 4
  • Larkana, Pakistan
    • Chandka SMBBMU Sheikh Zaid Woman Hospital Unit 1
  • Lārkāna, Pakistan
    • Chandka SMBBMU Sheikh Zaid Woman Hospital Units 2 & 3
  • Multan, Pakistan
    • Nishtar Hospital Unit 1
  • Multān, Pakistan
    • Nishtar Hospital Unit 2
  • Multān, Pakistan
    • Nishtar Hospital Unit 3
  • Quetta, Pakistan
    • Bolan Medical Centre
  • Rawalpindi, Pakistan
    • Holy Family Hospital
  • Rawalpindi, Pakistan
    • Benazir Bhutto Shaheed Hospital
  • Rawalpindi, Pakistan
    • Federal Government Polyclinic
• Tanzania
  • Arusha, Tanzania
    • Mount Meru Regional Referral Hospital
  • Dar Es Salaam, Tanzania
    • Temeke Regional Referral Hospital
  • Dar Es Salaam, Tanzania
    • Muhimbili National Hospital
  • Dar Es Salaam, Tanzania
    • Amana Regional Referral Hospital,
  • Dodoma, Tanzania
    • Dodoma Regional Referral Hospital
  • Kibaha, Tanzania
    • Tumbi Regional Referral Hospital, Kibaha
  • Kinondoni, Tanzania
    • Mwananyamala Regional Referral Hospital
  • Mbeya, Tanzania
    • Mbeya Zonal Referral Hospital
• Zambia
  • Lusaka, Zambia
    • Women and Newborn Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; One Injection of the placebo which is 10 mL Sodium Chloride (0.9%)	Other: Placebo; Ampoules and packaging for both arms will be identical in appearance.; Other Names: (Sodium Chloride 0.9%)
Active Comparator: Tranexamic acid; One intravenous injection of tranexamic acid. Total dose 1 gram (10mL)	Drug: Tranexamic Acid; Ampoules and packaging for both arms will be identical in appearance.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Postpartum Haemorrhage (cause will be described)	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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Postpartum blood loss	Clinical assessment	24 hours after administration of the trial medication or at discharge from hospital, whichever is earlier
Haemodynamic instability	Defined as per protocol	24 hours after administration of trial treatment or discharge from hospital, whichever is earlier
Shock index	Heart rate/systolic blood pressure	24 hours after administration of trial treatment or discharge from hospital, whichever is earlier
Quality of Life (maternal)	Defined as per protocol	Day 42 or discharge from hospital, whichever is earlier
Expected side effects of trial medication	nausea, vomiting, diarrhoea	Day 42 or discharge from hospital, whichever is earlier
Exercise tolerance	6 minute walk test	Day 42 or discharge from hospital, whichever is earlier
Interventions to control primary postpartum haemorrhage (medical and surgical)	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	Day 42 or discharge from hospital, whichever is earlier
Receipt of blood product transfusion	units and type	Day 42 or discharge of mother from hospital, whichever is earlier
Vascular occlusive events	Any of the following:pulmonary embolism (PE), deep vein thrombosis (DVT), stroke, myocardial infarction	Day 42 or discharge from hospital, whichever is earlier
Symptoms of anaemia	measured using Quality of life Questionnaire and walk test	Day 42 or discharge of mother from hospital, whichever is earlier
Organ disfunction	Any of the following: Cardiovascular, Respiratory, Renal, Hepatic, Neurological, Coagulation/ haematologic dysfunction	Day 42 or discharge from hospital, whichever is earlier
Sepsis	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)	Day 42 or discharge from hospital, whichever is earlier
In hospital death	Cause and time of death will be described	Day 42
Length of hospital stay.	Days	Day 42 or discharge from hospital, whichever is earlier
Admission to and time spent in higher level facility	High Dependency and/or Intensive Care Units	Day 42 or discharge from hospital, whichever is earlier
Status of baby/ies	alive or dead	Day 42 or discharge of mother from hospital, whichever is earlier
Thromboembolic events in breastfed babies	as defined in protocol	Day 42 or discharge of mother from hospital, whichever is earlier
Haemoglobin	Haemocue (Point of care test)	24 hours after administration of the trial medication or at discharge from hospital, whichever is earlier
Adverse events	Any untoward medical occurrence (other than expected complications)	Day 42

Collaborators and Investigators

• Sponsor: London School of Hygiene and Tropical Medicine
• Collaborators: Bill and Melinda Gates Foundation; Wellcome Trust
• Investigators: Study Chair: Ian Roberts, Clinical Trials Unit, London School of Hygiene and Tropical Medicine; Study Chair: Haleema Shakur-Still, Clinical Trials Unit, London School of Hygiene and Tropical Medicine; Principal Investigator: Rizwana Chaudhri, National Coordinating Investigator, Shifa Tameer-e-Millat University, Pakistan; Principal Investigator: Folasade A Bello, National Coordinating Investigator, College of Medicine, University of Ibadan, Nigeria; Principal Investigator: Bellington Vwalika, National Coordinating Investigator, University of Zambia School of Medicine, Zambia; Principal Investigator: Projestine Muganyizi, National Coordinating Investigator, Muhimbili University of Health and Allied Sciences, Tanzania; Principal Investigator: Oladapo Olayemi, National Coordinating Investigator, College of Medicine, University of Ibadan, Nigeria

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): August 24, 2019
• Primary Completion (Actual): September 20, 2023
• Study Completion (Actual): October 29, 2023

Study Registration Dates

• First Submitted: February 23, 2018
• First Submitted That Met QC Criteria: March 16, 2018
• First Posted (Actual): March 23, 2018

Study Record Updates

• Last Update Posted (Actual): January 10, 2024
• Last Update Submitted That Met QC Criteria: January 5, 2024
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Keywords: pain; pregnancy; tranexamic acid; episiotomy; antifibrinolytic; prevention, postpartum haemorrhage; moderate anaemia; severe anaemia
• Additional Relevant MeSH Terms: Hematologic Diseases; Anemia; Molecular Mechanisms of Pharmacological Action; Fibrin Modulating Agents; Antifibrinolytic Agents; Hemostatics; Coagulants; Tranexamic Acid
• Other Study ID Numbers: WOMAN_2; 03475342 (Other Identifier: ISRCTN)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: 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
• IPD Sharing Time Frame: Data will be shared publicly when all planned analyses are completed by the Woman-2 Trial Collaborators.

IPD Sharing Access Criteria

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.

• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No