Clinical Trials Logo

Clinical Trial Details — Status: Completed

Administrative data

NCT number NCT03475342
Other study ID # WOMAN_2
Secondary ID 03475342
Status Completed
Phase Phase 3
First received
Last updated
Start date August 24, 2019
Est. completion date October 29, 2023

Study information

Verified date April 2023
Source London School of Hygiene and Tropical Medicine
Contact n/a
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial 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.


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 information / eligibility

Status Completed
Enrollment 15068
Est. completion date October 29, 2023
Est. primary completion date September 20, 2023
Accepts healthy volunteers No
Gender Female
Age group N/A and older
Eligibility 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 Design


Related Conditions & MeSH terms

  • Anemia
  • Intrapartum - Moderate and Severe Anaemia

Intervention

Drug:
Tranexamic Acid
Ampoules and packaging for both arms will be identical in appearance.
Other:
Placebo
Ampoules and packaging for both arms will be identical in appearance.

Locations

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

Sponsors (3)

Lead Sponsor Collaborator
London School of Hygiene and Tropical Medicine Bill and Melinda Gates Foundation, Wellcome Trust

Countries where clinical trial is conducted

Nigeria,  Pakistan,  Tanzania,  Zambia, 

Outcome

Type Measure Description Time frame Safety issue
Primary 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 Postpartum blood loss Clinical assessment 24 hours after administration of the trial medication or at discharge from hospital, whichever is earlier
Secondary Haemoglobin Haemocue (Point of care test) 24 hours after administration of the trial medication or at discharge from hospital, whichever is earlier
Secondary Haemodynamic instability Defined as per protocol 24 hours after administration of trial treatment or discharge from hospital, whichever is earlier
Secondary Shock index Heart rate/systolic blood pressure 24 hours after administration of trial treatment or discharge from hospital, whichever is earlier
Secondary Quality of Life (maternal) Defined as per protocol Day 42 or discharge from hospital, whichever is earlier
Secondary Expected side effects of trial medication nausea, vomiting, diarrhoea Day 42 or discharge from hospital, whichever is earlier
Secondary Exercise tolerance 6 minute walk test Day 42 or discharge from hospital, whichever is earlier
Secondary 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
Secondary Receipt of blood product transfusion units and type Day 42 or discharge of mother from hospital, whichever is earlier
Secondary 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
Secondary Symptoms of anaemia measured using Quality of life Questionnaire and walk test Day 42 or discharge of mother from hospital, whichever is earlier
Secondary Organ disfunction Any of the following: Cardiovascular, Respiratory, Renal, Hepatic, Neurological, Coagulation/ haematologic dysfunction Day 42 or discharge from hospital, whichever is earlier
Secondary 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
Secondary In hospital death Cause and time of death will be described Day 42
Secondary Length of hospital stay. Days Day 42 or discharge from hospital, whichever is earlier
Secondary 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
Secondary Status of baby/ies alive or dead Day 42 or discharge of mother from hospital, whichever is earlier
Secondary Thromboembolic events in breastfed babies as defined in protocol Day 42 or discharge of mother from hospital, whichever is earlier
Secondary Adverse events Any untoward medical occurrence (other than expected complications) Day 42