Efficacy of Tranexamic Acid in Preventing Postpartum Haemorrhage After Elective Caesarean Section

RESEARCH QUESTION Does intravenous Tranexamic Acid (TXA) 10mg/kg plus Oxytocin 5 International Units (IU) result in a lower incidence of primary postpartum haemorrhage compared to Oxytocin alone after elective caesarean section.

RATIONALE FOR THE RESEARCH Postpartum haemorrhage (PPH) is a major cause of maternal mortality worldwide accounting for 25% of maternal deaths. In Zimbabwe, PPH is the second most common cause of death. Tranexamic acid (TXA) is widely used to reduce blood loss in elective surgery, bleeding trauma patients, and menorrhagia.

In addition to prophylactic uterotonic administration, TXA is a complementary component acting on the haemostatic process that can be used in the third stage of labour to prevent PPH. It is a promising intervention that is cheap, easy to administer and would be easy to add to routine delivery protocols in hospitals. It would also help to conserve precious resources by reducing the need for blood products, and expensive surgical interventions to manage PPH.

The investigators seek to determine the efficacy of TXA in reducing PPH during and after elective caesarean section.

RESEARCH OBJECTIVES

1. To assess the impact of TXA (10mg/kg) given 10 minutes prior to elective caesarean section on postpartum blood loss
2. To assess the potential adverse effects of TXA given 10 minutes prior to elective caesarean section Primary Outcome

* Incidence of PPH defined by blood loss equal to or exceeding 1000ml following elective caesarean section Secondary Outcomes
* Estimated blood loss during caesarean section
* Need for blood transfusion
* Use of additional uterotonics (such as oxytocin infusion or prostaglandins)
* TXA side effects
* Incidence of emergency surgery for PPH
* Duration of mother's postnatal hospital stay
* Neonatal outcome RESEARCH METHODOLOGY Research Design The aim of this study is to compare the effect of a low dose of TXA (10mg/kg) administered 10 minutes prior to elective caesarean section with prophylactic oxytocin administration, versus prophylactic oxytocin alone in an open label randomized clinical trial (RCT). An RCT is appropriate as it aims to reduce bias when testing this potentially new intervention.

Target Population Women undergoing elective caesarean sections at Harare and Parirenyatwa Hospitals based on set inclusion and exclusion criteria Inclusion criteria Pregnant woman with signed informed consent, who understand English and/or Shona, at estimated gestational age of 38 weeks or older, requiring Elective Caesarean Section, with a live intrauterine fetus.

Exclusion criteria Placental Abruption, emergency caesarean section, current or previous history of significant disease including heart disease, liver, renal disorders; known coagulopathy or history of deep venous thrombosis and/or pulmonary embolism, or arterial thrombosis (angina pectoris, myocardial infarction, stroke); history of epilepsy or seizures; autoimmune disease; sickle cell disease; severe haemorrhagic disease; intrauterine fetal demise; eclampsia/HELLP syndrome; administration of anticoagulants - clexane or antiplatelet agents in the week prior to delivery.

Sample Size A total sample size of 1,162 (581 per group) was calculated assuming a proportion of 2.1% PPH in the experimental group and 5.8% in the control group at 95% confidence interval and 90% power using Fleiss formula.

Subjects' state of physical health Healthy Intervention Participants receive either 10mg/kg of TXA 10 minutes prior to elective caesarean section with prophylactic oxytocin administration after delivery of the baby, versus prophylactic oxytocin alone after delivery of the baby.

Assessment Questionnaire (attached). Vital signs (heart rate, blood pressure, respiratory rate) noted before surgery, immediately after placental delivery, and 1 to 2 hours after birth Full blood count (FBC), Urea \& electrolytes (u\&e) and liver function tests (LFTs) performed a day before delivery (routinely performed) U\&e, LFTs and FBC assessed 48 hours after delivery. Estimated blood loss (EBL) using the difference in hematocrit values taken prior to and 48 hours after caesarean delivery.

The investigators will also note the standard EBL based on estimates made by the anaesthetist after assessment of patient's linen and abdominal swabs.

RISKS AND BENEFITS The common adverse effects include headaches (50.4 - 60.4%), backaches (20.7 - 31.4%), nasal sinus problem (25.4%), abdominal pain (12 - 19.8%), diarrhea (12.2%), fatigue (5.2%) and anaemia (5.6%).

The WOMAN Trial collaborators found that TXA actually reduces mortality due to bleeding in women with PPH with no adverse effects.

Tranexamic acid potentiates the blood clotting system and is used to treat and prevent bleeding. Use of TXA could potentially prevent PPH due to factors other than uterine atony, where uterotonics will not be effective.

COSTS AND COMPENSATION Study participants will not receive any compensation. The cost of TXA shall not be incurred by the study participants. They will bear their usual admission and caesarean section costs that they would otherwise have borne had they not participated in the study.

INFORMED CONSENT All subjects or legally authorized representatives for minors are expected to be give informed consent.

CONFIDENTIALITY ASSURANCES Information collected from the participants shall be confidential, will be assigned a code and no personal identifiers will be used. Information collected will be stored in a secure place only accessible to the researcher and assistants, as well as on a password-protected laptop computer. Consent forms will be kept for three years after the completion of the investigation unless stipulated otherwise by the Medical Research Council of Zimbabwe.

CONFLICTS OF INTERESTS The study is being carried out in partial fulfillment of the degree of Masters of Medicine in Obstetrics and Gynaecology. No other gains are to be obtained from carrying out the study.

COLLABORATIVE AGREEMENTS N/A INTENDED USE OF RESULTS The results of the study will be submitted to the College of Health Sciences as part of the requirements for completion of the degree of Masters of Medicine in Obstetrics and Gynaecology, and may be considered for publications to add to the current body of knowledge on the use of TXA.

• Tranexamic Acid (Drug), also known as TXA: TXA (10mg/kg) solution for injection from the vial will be diluted with 100 - 200ml electrolyte solution such as Normal Saline, Ringers solution, dextrose/water for injection on the same day it is to be used (i.e. when anaesthetist notes the patient has been randomized to receive TXA). Intravenous administration should be at a rate of 100mg or fraction thereof over at least 1 minute - usually at least 5 minutes. Standard practice is to administer over 20 minutes. Administration is to be done at least 10 minutes prior to skin incision.
• Oxytocin (Drug), also known as Prophylactic oxytocin: 5IU of oxytocin are administered intravenously slowly once the baby has been delivered at caesarean section.

Primary outcomes

• Number of Participants With Postpartum Haemorrhage (PPH) [Up to 48 hours post-caesarean section]: PPH based on Haematocrit calculation and PPH based on Haemoglobin calculation

Secondary outcomes

• Estimated Blood Loss [At caesarean section]: Blood loss during caesarean section based on visual estimation and calculation.
• Amount of Blood Transfused [At caesarean section up to 48 hours post-caesarean section]: Requirement by participant of blood transfusion
• Number of Participants With Use of Additional Uterotonics [At caesarean section up to 48 hours post-caesarean section]: Number of participants who received additional uterotonics such as an oxytocin infusion or prostaglandin (misoprostol).
• Number of Participants With Tranexamic Acid Side Effects [From intravenous infusion of the drug up to 48 hours post-caesarean section]: Number of participants with adverse effects related to tranexamic acid use
• Number of Participants Requiring Emergency Surgery for PPH [At caesarean section up to 48 hours post-caesarean section]: Number of participants requiring emergency surgical procedures to manage any PPH that occurs
• Number of Days of Participants' Hospital Stay [From date of randomization until the day 2 post-caesarean section (date of discharge from hospital) or date of death whichever comes earlier]: The number of days the participant stayed in hospital from the date of admission to date of discharge from hospital.
• Neonatal Outcome - Weight [From date of delivery of neonate by caesarean section until day 2 post-caesarean section (the date of discharge from hospital) or date of death whichever comes earlier]: Neonatal birth weight in grams
• Neonatal Outcome - APGAR Score of the Neonates at 1 Minute and 5 Minutes After Delivery [Scores at 1 minute from time of delivery and at 5 minutes after delivery]: APGAR (Appearance, Pulse, Grimace, Activity, Respiration) scores out of 10 at 1 minute and 5 minutes. A measure of the physical condition of a newborn infant. It is obtained by adding points (maximum score of 2, 1, or 0 as minimum score) for Appearance (0 - blue/pale, 1 - pink body, blue extremities, 2 - pink); Pulse (0 - absent heart rate, 1 - below 100 beats per minute, 2 - over 100 beats per minute), Grimace (Reflex irritability - 0 - floppy, 1 - minimal response to stimulation, 2- prompt response to stimulation), Activity (muscle tone: 0 - absent, 1 - Flexed arms and legs, 2 - active), Respiration ( 0 - absent, 1 - slow or irregular, 2 - vigorous cry). APGAR score at 1minute or 5 minute can be a minimum of of 0 (0+0+0+0+0) or maximum of 10 (2 for each parameter above).
• Neonatal Outcome - Number of Neonates Admitted to the Neonatal Unit [From date of delivery of neonate by caesarean section until day 2 post-caesarean section (the date of discharge from hospital) or date of death whichever comes earlier]: Number of neonates requiring admission to the neonatal unit from time of delivery at caesarean section
• Neonatal Outcome - Number of Neonates Diagnosed With Jaundice [From date of delivery of neonate by caesarean section until day 2 post-caesarean section (the date of discharge from hospital) or date of death whichever comes earlier]: Number of neonates with clinical jaundice (yellowing of the skin or whites of the eyes)
• Neonatal Outcome - Thromboembolic Event [From date of delivery of neonate by caesarean section until day 2 post-caesarean section (the date of discharge from hospital) or date of death whichever comes earlier]: Number of neonatal thromboembolic events
• Neonatal Outcome - Death [From date of delivery of neonate by caesarean section until day 2 post-caesarean section (the date of discharge from hospital) or date of death whichever comes earlier]: Neonatal death that occurs

Sex: Female, accepts healthy volunteers

Inclusion Criteria:

* Pregnant woman with signed informed consent***
* Understand English and/or Shona
* Estimated gestational age of 38 weeks or older
* Requiring Elective Caesarean Section defined as caesarean section performed before onset of labour
* Live intrauterine fetus

  * The study will enrol participants who are Pregnant and who have a signed informed Consent form. Some of the pregnant women may be minors as they are occasionally included in patients planned for elective caesarean section for varying indications. Their inclusion also will make the results of the trial generalizable to elective caesarean section patients attended to at the two study hospitals. Consent will be sought from a legally authorized representative such as the parent or guardian.

Exclusion Criteria:

* Placental Abruption
* Emergency caesarean section
* Current or previous history of significant disease including heart disease, liver, renal disorders
* Known coagulopathy or history of deep venous thrombosis and/or pulmonary embolism, or arterial thrombosis (angina pectoris, myocardial infarction, stroke)
* History of epilepsy or seizures
* Autoimmune disease
* Sickle cell disease
* Severe haemorrhagic disease
* Intrauterine fetal demise
* Eclampsia/HELLP syndrome
* Administration of anticoagulants - clexane or antiplatelet agents in the week prior to delivery

Participant flow

Outcome results

• Number of Participants With Postpartum Haemorrhage (PPH) (Primary), Count of participants, Participants: Group A 48; Group B 54 (p 0.549)
• Estimated Blood Loss (Secondary), Mean, ml: Group A 483.73 +/- 182.56; Group B 479.61 +/- 139.49 (p 0.789)
• Amount of Blood Transfused (Secondary), Median, units of blood given: Group A 1.5 (1 to 2); Group B 2.5 (2 to 3) (p <0.05)
• Number of Participants With Use of Additional Uterotonics (Secondary), Count of participants, Participants: Group A 38; Group B 32 (p <0.05)
• Number of Participants With Tranexamic Acid Side Effects (Secondary), Count of participants, Participants: Group A 7; Group B 3
• Number of Participants Requiring Emergency Surgery for PPH (Secondary), Count of participants, Participants: Group A 0; Group B 2
• Number of Days of Participants' Hospital Stay (Secondary), Median, days: Group A 5 (4 to 5); Group B 5 (4 to 5)
• Neonatal Outcome - Weight (Secondary), Mean, grams: Group A 3087.85 +/- 523.98; Group B 3109.98 +/- 513.13
• Neonatal Outcome - APGAR Score of the Neonates at 1 Minute and 5 Minutes After Delivery (Secondary), Median, units on a scale up to 10: Group A 8 (8 to 9); Group B 9 (8 to 9)
• Neonatal Outcome - Number of Neonates Admitted to the Neonatal Unit (Secondary), Count of participants, Participants: Group A 33; Group B 23
• Neonatal Outcome - Number of Neonates Diagnosed With Jaundice (Secondary), Count of participants, Participants: Group A 1; Group B 0
• Neonatal Outcome - Thromboembolic Event (Secondary), Count of participants, Participants: Group A 0; Group B 0
• Neonatal Outcome - Death (Secondary), Count of participants, Participants: Group A 1; Group B 1

Adverse events

Time frame: Adverse event data was collected up to the time the patient and baby were discharged from hospital which on average is on the third day post-caesarean section.

Other adverse events by term

Limitations and caveats: The a priori power was not been achieved as the target sample size had not yet been achieved due to reasons beyond the scope of the study. The study had no placebo and was not blinded.

• Study Protocol and Statistical Analysis Plan (PDF, 2019-06-30)

• Tsungai Chipato, MBChB FRCOG, Study chair, Professor of Obstetrics and Gynaecology
• Taazadza Nhemachena, MBChB MMED, Study chair, Lecturer and Consultant
• Chipo Gwanzura, MBChB, Principal investigator, Registrar