Tranexamic Acid for Preventing Postpartum Haemorrhage Following a Vaginal Delivery

Study Overview
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Brief Summary
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The purpose of this study is to assess whether the administration of a low dose of tranexamic acid just after vaginal delivery can reduce the incidence of immediate postpartum hemorrhage, in women who receive a prophylactic administration of oxytocin.

Detailed Description
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Postpartum hemorrhage (PPH) is a major cause of maternal mortality, accounting for one quarter of all maternal deaths worldwide. Its incidence estimates in the literature vary widely, from 3% to 15% of deliveries. Uterotonics after birth are the only intervention that has been shown to be effective for PPH prevention. Tranexamic acid (TXA), an antifibrinolytic agent, has therefore been investigated as a potentially useful complement to uterotonics for prevention because it has been proved to reduce blood loss in elective surgery, bleeding in trauma patients, and menstrual blood loss. Randomized controlled trials for PPH prevention after cesarean (n=10) and vaginal (n=2) deliveries showed that women who had received TXA had a significantly lesser amount of postpartum blood loss without any increase in severe maternal adverse effect. However, overall, the quality of these trials was poor, and they were not designed to test the effect of TXA on the reduction of PPH incidence, nor on the incidence of rare but severe adverse effects. Large, adequately powered multicenter randomized controlled trials are required before the widespread use of TXA for preventing PPH can be recommended. The investigators propose a multicentre randomised, double-blind, placebo-controlled trial, with two parallel groups. Individual information on the trial will be provided to women in late pregnancy during prenatal visits. This information will be repeated when the women arrive in the delivery room; the women then will confirm their participation and provide informed written consent before delivery, when, in the opinion of the investigator, the woman is likely to have a vaginal delivery with a minimum of 4 cm of cervix dilatation. The intervention will be the intravenous administration of a 10-ml blinded ampoule of the study drug (either 1g TXA or placebo according to the randomisation order), slowly (over 30-60 seconds), within 2 minutes after birth and prophylactic oxytocin administration, and once the cord has been clamped. All other aspects of management of the third stage will be identical in both arms: Routine prophylactic intravenous injection of 5 IU oxytocin at delivery of the anterior shoulder or within 2 minutes after birth Placement of a graduated (100 mL graduation) collector bag just after birth, left in place until the birth attendant judges that bleeding has stopped, and always at least for 15 minutes. When a woman is included in the trial, a bag will be prepared and ready to be put in place as soon as the baby is born and placed on the mother's belly; if needed, a second staff person will be present to help in managing both the baby and the bag. This will make it possible to collect and measure vaginal blood loss objectively during the immediate postpartum. Manual removal of the placenta at 30 minutes after birth if not expelled in absence of bleeding. Rapid suturing of the episiotomy, in accordance with good clinical practices Systematic use of uterotonic drugs after third stage of labor is not recommended. Controlled cord traction (CCT) will be left at the discretion of the practitioner. If PPH occurs, standardised management will be provided according to the department's protocol. In particular, the use of TXA for the treatment of PPH will be allowed and left at the discretion of the practitioner according to the department's protocol. The duration of the participation of each patient included in the trial will be from inclusion through 3 months postpartum. The planned total duration of the trial will be 34 months including 23 months of patient inclusion

Official Title
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Tranexamic Acid for Preventing Postpartum Haemorrhage Following a Vaginal Delivery: a Multicenter Randomised Double Blind Placebo Controlled Trial

Conditions
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Immediate Postpartum Hemorrhage

Intervention / Treatment
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* Drug: Tranexamic Acid
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age≥ 18 years Planned vaginal delivery Term ≥ 35 weeks of gestation Singleton pregnancy Informed consent form signed Exclusion Criteria: History of venous (deep vein thrombosis and/or pulmonary embolism) or arterial (angina pectoris, myocardial infarction, stroke) thrombosis. History of epilepsy or seizure Any known cardiovascular, renal, liver disorders Auto-immune disease Sickle cell disease Severe hemorrhagic disease Placenta previa Abnormally invasive placenta (placenta accreta/increta/percreta) Abruptio placentae Eclampsia; hemolysis, elevated liver enzymes, low platelet count (HELLP) syndrome Multiple pregnancy In utero foetal death Administration of Low-Molecular-Weight Heparin or antiplatelet agents seven days before delivery Poor understanding of the French language

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TXA<br>Intravenous administration of 1g of tranexamic acid within 2 minutes after birth and prophylactic oxytocin administration | Drug: Tranexamic Acid<br>* Intravenous administration of a 10 mL solution containing 1g of tranexamic acid within 2 minutes of birth and routine prophylactic IV injection of oxytocin<br>|
| Placebo Comparator: Placebo<br>Intravenous administration of placebo within 2 minutes after birth and prophylactic oxytocin administration | Drug: Placebo<br>* Intravenous administration of 10 mL of 0.9% sodium chloride solution within 2 minutes of birth and routine prophylactic IV injection of oxytocin<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of PPH | Incidence of PPH defined by blood loss ≥ 500 ml, measured with a graduated collector bag | 24 hours after birth | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean blood loss at 15 minutes after birth | Measured with a collector bag left in place at least 15 minutes to have one measure of blood loss at the same time point in all women | 15 minutes after birth | 
| Mean total blood loss | Measured at collector bag removal | Up to 24 hours after birth | 
| Incidence of severe PPH | Incidence of PPH defined by blood loss ≥ 1000 ml, measured with a graduated collector bag | 24 hours after birth | 
| Need for supplementary uterotonic treatment | Proportion of women requiring supplementary uterotonic treatment including sulprostone | 24 hours after birth | 
| Postpartum transfusion | Proportion of women transfused in postpartum | Duration of postpartum hospital stay, an expected average of 3 days | 
| Need for invasive second-line procedures for PPH | Any of the following: arterial embolization, pelvic arterial ligation, uterine compression suture, hysterectomy | Duration of postpartum hospital stay, an expected average of 3 days | 
| Hemoglobin peripartum delta | Mean difference between the hemoglobin values before delivery and on the 2nd day postpartum in the absence of a transfusion of packed red blood cells. | 2 days postpartum | 
| Hematocrit peripartum delta | Mean difference between the hematocrit values before delivery and on the 2nd day postpartum in the absence of a transfusion of packed red blood cells | 2 days postpartum | 
| Hemodynamic tolerance | Heart rate, blood pressure | 15, 30, 45, 60 and 120 minutes after delivery | 
| Mild adverse effects | Nausea, vomiting, phosphenes, dizziness | Stay in labor ward, an expected average of 2 hours | 
| Tolerance lab tests | Urea, creatinemia, prothrombin time, active prothrombin time, fibrinogenemia, aspartate and alanine transaminase, total bilirubin | Day 2 postpartum | 
| Severe adverse effects | Deep venous thrombosis, pulmonary embolism, myocardial infarction, renal failure needing dialysis | Up to 12 weeks after delivery | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Immediate postpartum hemorrhage, tranexamic acid, prevention