Background
Rational
Active management of the third stage of labor for the prevention of postpartum hemorrhage
Tranexamic acid for the reduction of bleeding in medical contexts other than PPH
Tranexamic acid for PPH
Study [réf] | Country | Study design | Sample size | Study groups | Intervention | TXA Dosage/route | Primary outcome | Result | P value | Adverse effects |
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Gai et al. al, (2004) [30] | China | Multicenter, prospective, randomized controlled study | N = 180, primiparas | N = 91 (experimental) | Infusion of TXA 10 min before CS | 1 g IV for 5 min | Postpartum blood loss not clearly specified | 359.3 mL vs 439.3 mL | 0.002 | No thromboembolic or other side effects reported |
N = 89 (no placebo) | ||||||||||
Gohel et al., (2007) [31] | India | Prospective, randomized controlled study | N = 100, primiparas and multiparas | N = 50 (experimental) | Infusion of TXA 20 min before CS | 1 g IV for 5 min | Postpartum blood loss not clearly specified | 374.9 mL vs 472.8 mL | 0.003 | No thromboembolic or other side effects reported |
N = 50 (no placebo) | ||||||||||
Sekhavat et al., (2009) [32] | Iran | Prospective, randomized, placebo-controlled study | N = 90, primiparas | N = 45 (experimental) | Infusion of TXA 10 min before CS | 1 g IV for 5 min | Postpartum blood loss not clearly specific | 28.0 mL vs 37.1 mL | 0.001 | No thromboembolic or other side effects reported |
N = 45 (placebo) | ||||||||||
Gungorkuk et al., (2011) [33] | Turkey | Prospective, unicenter, double-blind, randomised controlled study | N = 666, primiparas and multiparas | N = 330 (experimental) | Infusion of TXA 10 min before CS | 1 g IV for 5 min | Estimated blood loss during CS. | 600.7 mL vs 499.9 mL | <0.001 | Gastrointestinal side effects (16.3 %) in the experimental group |
N = 330 (placebo) | ||||||||||
Gastrointestinal side effects not mentioned for the placebo group. | ||||||||||
No thromboembolic events | ||||||||||
Movafegh et al., 2011 [34] | Iran | Prospective, unicenter, double-blind, randomized controlled study | N = 100, primiparas and multiparas | N = 50 (experimental) | Infusion of TXA 20 min before CS | 10 mg/kg IV for 10 min | Postpartum blood loss not clearly specified | 262.5 mL vs 404.7 mL | <0.001 | No thromboembolic events |
N = 50 (placebo) | ||||||||||
Xu et al., 2013 [35] | China | Randomized, double-blind, placebo-controlled study | N = 174 primiparas | N = 88 (experimental) | Infusion of TXA 10 min before CS | 10 mg/kg IV for 5 min | Postpartum blood loss not clearly specified | 379 mL vs 441 mL | 0.02 | 2 thromboses occurred in each group. |
Gastrointestinal side effects occurred in 10 TXA patients versus one placebo patient | ||||||||||
N = 86 (placebo) | ||||||||||
Senturk et al., 2013 [36] | Turkey | Randomized, double-blind, placebo-controlled study | N = 223, primiparas and multiparas | N = 101 (experimental) | Infusion of TXA 10 min before CS | 10 mg/kg IV for 5 min | Postpartum blood loss not clearly specified | 272 mL vs 347 mL | 0.001 | No thromboembolic or gastrointestinal side effects |
N = 122 (placebo) | ||||||||||
Shahid A et al., 2013 [37] | Pakistan | Randomized double-blind placebo controlled study | N = 74 primiparas and multiparas | N = 38 (experimental) | Infusion of TXA 10 min before CS | 1 g IV for 10 min | Postpartum blood loss not clearly specified | 356 mL vs 710 mL | <0.001 | No thromboembolic side effects |
N = 36 (placebo) | ||||||||||
Abdel-Aleem et al., 2013 [38] | Egypt | Randomized, single center, open, controlled study | N = 740 primiparas and multiparas | N = 373 (experimental) | Infusion of TXA 10 min before CS | 1 g IV for 10 min | Blood loss two hours after delivery | 241.6 mL vs 510.6 mL | <0.001 | Gastrointestinal side effects (74.3 % versus 53.1 %; P = 0.0001) |
N = 367 (no placebo) | ||||||||||
No thromboembolic side effects | ||||||||||
Goswami et al., 2013 [39] | India | Randomized, single center, double-blinded placebo controlled study | N = 90 primiparas and multiparas | N = 30 (experimental 1) | Infusion of TXA 20 min before CS | Experimental 1: 10 mg/kg | Postpartum blood loss, not clearly specified | 376.8 mL vs 261.2 mL vs 527.2 mL | Not reported | No thromboembolic side effects |
N = 30 (experimental 2) | ||||||||||
Experimental 2: 15 mg/kg | ||||||||||
N = 30 (placebo) |
Study [réf] | Country | Study design | Sample size | Study groups | Interventions | TXA Dosage/route | Primary outcome | Result | P value | Adverse effects |
---|---|---|---|---|---|---|---|---|---|---|
Yang et al., (2001) [40] | China | Multicenter, randomized controlled study | N = 400 primiparas | N = 94 (experimental 1) | Infusion of TXA after delivery of the fetal shoulders in the first 2 groups and infusion of AMBA in the third | 1 g IV. | Measurement of blood loss 2 h after delivery, without details about the measurement method | 243.3 mL vs 242.9 mL vs 308.1 mL vs 314.8 mL | <0.01 | Nausea (n = 2) |
0.5 g IV | ||||||||||
N = 92 (experimental 2) | ||||||||||
N = 92 (experimental 3) | 0.5 g IV | |||||||||
N = 87 (no placebo) | placebo | |||||||||
Gungorkuk et al., (2013) [41] | Turkey | Prospective, single-center, double-blinded, randomized controlled study | N = 439 primiparas and multiparas | N = 220 (experimental) N = 219 (placebo) | Infusion of TXA at delivery of the anterior shoulder | 1 g IV for 5 min | Mean blood loss during the third and fourth stages of labor - from the end of delivery to 2 h postpartum- measured as (weight of material used – weight of materials before use)/1.05 | 261.5 mL vs 349.9 mL | <0.001 | Gastrointestinal side effects (35.9 %) |
No thromboembolic event |
Severe maternal adverse events related to tranexamic acid
Objectives
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To assess the impact of TXA (1 g) after vaginal delivery on postpartum blood loss
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■ Primary outcome
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➢Incidence of PPH, defined by blood loss ≥ 500 mL, measured with a graduated collector bag
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■ Secondary outcomes
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➢Other outcome measures describing postpartum blood loss, such as mean measured total postpartum blood loss, incidence of severe PPH, defined by blood loss ≥ 1000 mL, proportion of women requiring supplementary uterotonic agent, transfusion, arterial embolization, or emergency surgery for PPH, and mean peripartum change in hemoglobin and hematocrit
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To assess the potential adverse effects of TXA (1 g) after vaginal delivery:
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■ The hemodynamic parameters, gastrointestinal side effects, renal, hepatic and coagulation function, venous or arterial thrombosis within 3 months following delivery.
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To assess women’s satisfaction and psychological status at D60
Methods and design
Recruitment and allocation
Inclusion criteria
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Age ≥ 18 years
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Planned vaginal delivery
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Term ≥ 35 weeks of gestation
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Singleton pregnancy
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Informed consent form signed
Exclusion criteria
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History of venous (deep vein thrombosis and/or pulmonary embolism) or arterial (angina pectoris, myocardial infarction, stroke) thrombosis
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History of epilepsy or seizure
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Any known cardiovascular, renal, or liver disorders
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Autoimmune disease
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Sickle cell disease
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Severe hemorrhagic disease
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Placenta previa
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Abnormally invasive placenta (placenta accreta/increta/percreta)
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Abruptio placentae
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Eclampsia, HELLP syndrome
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Multiple pregnancy
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In utero fetal death
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Administration of low-molecular-weight heparin or antiplatelet agents during the week before delivery
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Poor understanding of the French language
Intervention
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Routine prophylactic intravenous injection of 5 IU oxytocin at delivery of the anterior shoulder or within 2 min of birth, as recommended in the national clinical practice guidelines issued by the French College of Gynecologists and Obstetricians [50].
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Placement of a graduated (100 mL graduation) collector bag just after birth, left in place for at least 15 min and then until the birth attendant judges that bleeding has stopped. 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 [14].
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Manual removal of the placenta at 30 min after birth if not expelled, in the absence of bleeding.
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Rapid suturing of the episiotomy, in accordance with good clinical practices.
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Systematic use of uterotonic drugs after the third stage of labor is not recommended.
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Controlled cord traction (CCT) will be left to the discretion of the practitioner since its use in the management of placental expulsion has been shown to have no significant effect on the incidence of PPH or other markers of postpartum blood loss [14].
Outcome measures
Primary outcome measure
Secondary outcomes
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Secondary outcome measures describing postpartum blood loss
Clinical
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mean measured blood loss at 15 min after birth (the collector bag must be left in place at least 15 min to have one measure of blood loss at the same time point for all women)
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mean measured total postpartum blood loss (at bag removal)
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incidence of severe PPH, defined by measured blood loss ≥ 1000 mL.
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proportion of women requiring supplementary uterotonic treatment, including sulprostone
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incidence of postpartum transfusion (until discharge)
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incidence of arterial embolization and emergency surgery for PPH.
Laboratory
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mean change in peripartum hemoglobin (difference between Hb before delivery and at D2)
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mean change in peripartum hematocrit (difference between Ht before delivery and on D2).
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The occurrence of potential adverse effects of TXA:
Clinical
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Hemodynamic parameters (heart rate, blood pressure) 15, 30, 45, 60 and 120 min after delivery.
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the occurrence of potential mild adverse effects of TXA in the delivery room:
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■ nausea
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■ vomiting
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■ phosphenes
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■ dizziness
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the occurrence of potential severe adverse effects of TXA up to three months of postpartum:
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■ deep vein thrombosis, if the diagnosis is confirmed by Doppler ultrasound
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■ pulmonary embolism, if the diagnosis is confirmed by radiological examinations.
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■ myocardial infarction
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■ seizure
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■ renal failure needing dialysis
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■ any other unexpected adverse events.
Laboratory
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urea and creatinemia, prothrombin time (PT), active prothrombin time (aPTT), aspartate and alanine transaminase, and total bilirubin at D2
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Women’s satisfaction and psychological status
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These will be assessed by a self-administered questionnaire on day 2 postpartum and by mail on day 60.
Statistical analysis
Feasibility
Sample size
Timetable
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6 months for ethics approval, signatures of agreements between the participating centers and training the staff in the management methods required by the protocol for the third stage of labor.
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23 months for the trial, with an inclusion period of 16 months and a follow-up period of 3 months.
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5 months after the end of the inclusion period will be devoted to finalizing the data collection and entry, database cleaning, and analysis.
Ethics committee approval
Data management
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1 completed by the clinical research technician from the obstetric file: woman’s characteristics, course of the pregnancy, labor, and delivery
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1 completed by the clinical research technician about the postpartum events after leaving the delivery room, and the results of the blood count on D2
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1 questionnaire about women’s satisfaction on D2 postpartum, completed by the women, with responses entered secondarily in the electronic file by the clinical research technician.
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1 questionnaire about the women’s satisfaction and psychological status on D60 postpartum, sent by the technician to the women and completed by them, with responses entered secondarily in the electronic file by the clinical research technician.
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1 questionnaire about the occurrence of thromboembolic and any other unexpected events at 12 weeks in postpartum, completed by the clinical research technician during a telephone interview with the woman, with responses secondarily entered in the electronic file by the technician.
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Compliance with the research protocol and the procedures defined therein
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Verification of the patients’ informed consents, for all women included
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Examination of the source documents and their comparison with the data reported in the electronic case report files (CRFs), for the accuracy and consistency of the data and the missing data, performed on a random sample of 10 % of participating women.
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End-of-trial visit: archiving of research documents.