TRAnexamic Acid for Preventing Blood Loss Following a Cesarean Delivery in Women With Placenta pREVIA

Study Overview
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Brief Summary
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Several randomized, controlled trials, mostly involving women undergoing cesarean delivery, have shown that the prophylactic intravenous administration of 1 g of tranexamic acid after childbirth reduced blood loss. Most were small, single-centre trials with considerable methodologic limitations. It is important to emphasize that none of these RCTs has included women at increased risk of PPH such as placenta previa, a context in which the prevalence of moderate and severe blood loss is significantly higher and where the magnitude of the effect of TXA may highly differ compared to low risk women

Detailed Description
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TXA is a promising candidate drug, inexpensive and easy to administer, that can be easily added to the delivery management of women worldwide. Strong evidence that TXA reduces blood transfusion in elective and emergency surgery, outside obstetrics, has been available for many years, whatever the type of surgery (ie cardiac, orthopaedic, hepatic, urological, and vascular surgery). Tranexamic acid was recently shown to reduce bleeding-related mortality among women with postpartum hemorrhage, especially when the drug was administered shortly after delivery. A meta-analysis of data from individual patients including data from patients with trauma and women with postpartum hemorrhage suggested the importance of early treatment. Several randomized, controlled trials (RCTs), involving women undergoing cesarean delivery, as well have meta-analyses, have shown that the prophylactic intravenous administration of 1 g of tranexamic acid after childbirth reduced blood loss. Most of them were small, single- center trials with considerable methodologic limitations. Thus, no guidelines advocate the use of tranexamic acid to prevent blood loss after cesarean delivery. Moreover, it is important to emphasize that none of these RCTs has included women at increased risk of PPH such as placenta previa, a context in which the prevalence of moderate and severe blood loss is significantly higher and where the magnitude of the effect of TXA may highly differ compared to low risk women. The aim of our study is to conduct a large multicentre randomised, double blind placebo controlled trial to adequately assess the impact of TXA for preventing PPH following a cesarean delivery in women with placenta previa.

Official Title
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TRAnexamic Acid for Preventing Blood Loss Following a Cesarean Delivery in Women With Placenta pREVIA: a Multicenter Randomised, Double Blind Placebo Controlled Trial

Conditions
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Postpartum Hemorrhage

Intervention / Treatment
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* Drug: Tranexamic Acid / Sodium chloride


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age≥ 18 years Placenta previa defined by a placental edge below 20mm from internal cervical os diagnosed at the most recent transvaginal ultrasound examination before delivery, as per French guidelines Cesarean delivery before or during labor Gestational age at delivery ≥ 32 weeks + 0 Affiliated or beneficiary to a health security system Signed informed consent Exclusion Criteria: History of venous (deep vein thrombosis and/or pulmonary embolism) or arterial (angina pectoris, myocardial infarction, stroke) thrombotic event History of epilepsy or seizure Chronic or acute cardiovascular disease (including foramen oval, mitral stenosis, aortic stenosis, heart transplant, pulmonary hypertension); chronic or acute renal disease (including chronic or acute kidney failure with glomerular filtration rate <90 mL/min, renal transplantation), chronic active or acute liver disorder with hemorrhagic or thrombotic risk (including cirrhosis, portal hypertension, ASAT>3N, Budd-Chiari syndrome) Active autoimmune disease with thromboembolic risk (including lupus, antiphospholipid syndrome, Crohn's disease) Sickle cell disease (homozygous) Severe hemostasis disorder prothrombotic (Factor V Leiden mutation - homo or heterozygous; Activated protein C (APC) resistance, Protein C deficiency, Protein S deficiency - aside from pregnancy, Homocysteinemia, , Factor 2 mutation - homo or heterozygous, Deficiency in antithrombin 3), prohemorragic (von Willebrand disease requiring desmopressin treatment during delivery, thrombocytopenia (<30000/mm3), Glanzmann disease, hypofibrinogenemia (<1g/L) -aside from pregnancy) High prenatal suspicion of placenta accreta spectrum disorder according to the obstetrician in charge Placenta praevia diagnosed during delivery Abruptio placentae Significant bleeding (estimated blood loss>500ml) within 12 hours before cesarean delivery Eclampsia / HELLP syndrome In utero fetal death Administration of low-molecular-weight heparin or antiplatelet agents during the 7 days before delivery Tranexamic acid contraindication Sodium chloride contraindication Women under legal protection Poor understanding of the French language

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Multicenter double-blind randomized controlled trial
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tranexamic acid<br>After the routine prophylactic IV or IM injection of the uterotonic used in the hospital protocol's -either oxytocin or carbetocin - (as recommended by the 2014 guidelines for prevention and management of postpartum hemorrhage from the CNGOF), the intervention will be the IV administration of a 10-ml blinded ampoule of the study drug (either TXA or placebo according to the randomisation sequence) to the patient within 3 minutes after birth, slowly (over 30-60 seconds), once the cord has been clamped | Drug: Tranexamic Acid / Sodium chloride<br>* After the routine prophylactic IV or IM injection of the uterotonic used in the hospital protocol's -either oxytocin or carbetocin - (as recommended by the 2014 guidelines for prevention and management of postpartum hemorrhage from the CNGOF), the intervention will be the IV administration of a 10-ml blinded ampoule of the study drug (either TXA or placebo according to the randomisation sequence) to the patient within 3 minutes after birth, slowly (over 30-60 seconds), once the cord has been clamped<br>|
| Placebo Comparator: Placebo<br>After the routine prophylactic IV or IM injection of the uterotonic used in the hospital protocol's -either oxytocin or carbetocin - (as recommended by the 2014 guidelines for prevention and management of postpartum hemorrhage from the CNGOF), the intervention will be the IV administration of a 10-ml blinded ampoule of the study drug (either TXA or placebo according to the randomisation sequence) to the patient within 3 minutes after birth, slowly (over 30-60 seconds), once the cord has been clamped | Drug: Tranexamic Acid / Sodium chloride<br>* After the routine prophylactic IV or IM injection of the uterotonic used in the hospital protocol's -either oxytocin or carbetocin - (as recommended by the 2014 guidelines for prevention and management of postpartum hemorrhage from the CNGOF), the intervention will be the IV administration of a 10-ml blinded ampoule of the study drug (either TXA or placebo according to the randomisation sequence) to the patient within 3 minutes after birth, slowly (over 30-60 seconds), once the cord has been clamped<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of red blood cell transfusion (binary outcome) between delivery of child and discharge from postpartum hospital stay. | Incidence of red blood cell transfusion (binary outcome) between delivery of child and discharge from postpartum hospital stay. | baseline | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| gravimetrically estimated blood loss | gravimetrically estimated blood loss by measuring the suction volume and swab weight (estimated blood loss = (weight of materials used + materials not used - weight of all materials before surgery)/1.05 + volume included in the suction container) | Baseline | 
| Occurrence of calculated blood loss > 1000ml. | Calculated blood loss = estimated blood volume × (preoperative Ht - postoperative Ht)/preoperative Ht (where estimated blood volume = weight (kg) × 85). Preoperative Ht will be the most recent Ht within 7 days before delivery. Postoperative Ht will be measured at day 2 postpartum | Baseline | 
| Occurrence of calculated blood loss > 1500ml. | calculated blood loss > 1500 ml | Baseline | 
| mean calculated blood loss | mean calculated blood loss | Baseline | 
| linically significant PPH | provider-assessed clinically significant PPH | Baseline | 
| shock index | mean shock index defined by the ratio of heart rate to systolic blood pressure | 15, 30, 45, 60 and 120 minutes after birth | 
| supplementary uterotonic treatment | supplementary uterotonic treatment | Baseline | 
| iron sucrose perfusion | iron sucrose perfusion until discharge | Baseline | 
| red blood cell units transfusion | number of red blood cell units transfused between delivery of child and discharge from postpartum hospital stay. | Baseline | 
| number of transfusion | proportion of women transfused between delivery of child and 24 hours postpartum | Baseline | 
| arterial embolisation | arterial embolisation or emergency surgery for PPH | Baseline | 
| maternal postpartum transfer | maternal postpartum transfer to a higher level of care | Baseline | 
| change in peripartum Hb | mean change in peripartum Hb (difference between most recent Hb within 7 days before surgery and at day 2 postpartum). | day 2 | 
| change in peripartum Ht | mean change in peripartum Ht (difference between most recent Ht within 7 days before surgery and at day 2 postpartum). | day 2 | 
| proportion of breastfeeding at hospital discharge | proportion of breastfeeding at hospital discharge | Baseline | 
| maternal death for any cause | maternal death for any cause | Baseline | 
| mild adverse reactions of TXA | mild adverse reactions of TXA for women (e.g.: nausea, vomiting, phosphenes, dizziness) | Hospitalization stay | 
| thromboembolic events | Occurrence of thromboembolic events and other severe unexpected adverse reactions (e.g incidence of deep vein thrombosis confirmed by radiological exams, pulmonary embolism confirmed by radiological exams, myocardial infarction, seizure, renal failure necessitating dialysis) | week 12 | 
| transfer to neonatal ICU | neonatal outcomes: transfer to neonatal ICU | Baseline | 
| Women's satisfaction and psychological status | Women's satisfaction and psychological status (self-administered questionnaire at day 2 postpartum and self-administered questionnaire sent by mail at 8 weeks). | Week 8; Week 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Postpartum hemorrhage, tranexamix acid, placenta previa