This study was a randomised, double blind, placebo controlled trial which was conducted from January 2016 through February 2017 at the Department of Obstetrics and Gynaecology, Udonthani Hospital, Udonthani, Thailand. The study was conducted after approval by the Ethical Research Committee of Udonthani Hospital No.18/2559. Women in labour who met the inclusion criteria were invited to participate. We explained the study methods and side effects of the drug to the patients then a written informed consent was obtained from all the participants. The inclusion criteria were age more than 18 years, gestational age between 36 and 42 weeks, singleton, a live fetus, cephalic presentation in the active phase of labour (cervical dilate more than 3 cm). Patients with high risk factors for PPH, such as polyhydramnios, fetal macrosomia, grand multiparity (five or more), chorioamnionitis and previous PPH were also included. Exclusion criteria included multiple pregnancy, dead fetus in utero, vacuum extraction, forceps extraction, placenta previa, placenta accreta syndrome, placental abruption, prior cesarean section, or any uterine scar, history of thromboembolic disease, heart disease, liver and renal disorders. The participants were randomly allocated into two groups to receive an intravenous infusion of TA (n=75) or a placebo (n=75). All participants were examined at admission with complete blood count, Blood Urea Nitrogen (BUN) and creatinine. They were then randomised into one of the two study groups using block randomisation by computer generated random number. Intervention drug was labeled and sealed in opaque envelopes. The experimental group’s drug contained 1 gm/10 mL TA diluted with 20 mL of normal saline and the placebo group’s drug contained 30 mL of normal saline. Investigators and patients were blinded to the contents of the intervention drug until the conclusion of the study. We used prophylactic injection of 10 units of oxytocin in both groups then either TA or a placebo was administered intravenously within one minute period at delivery in the anterior shoulder. Standard management of the third stages of labour were performed. The primary outcome measure was the volume of postpartum blood loss during the first two hours after delivery. The other outcomes included the incidence of PPH (more than 500 mL), severe PPH (more than 1,000 mL), need for blood transfusion, need for additional uterotonic drugs (200 μg intravenous methylergometrine and/or 800-1,000 μg misoprostol rectally and intravenous sulprostone) and side effects of TA injection. The mild adverse effects of TA (nausea/vomiting, diarrhea, pyrexia, headache) and the severe adverse effects of TA (deep vein thrombosis, pulmonary embolism, seizure, renal failure) were recorded [19]. Total amount of blood loss (mL) was determined as the sum of: 1) collective bag 2) The gravimetric of gauze (wet weight−dry weight) and 3) Diapers used during the first two hours postpartum (wet weight−dry weight)/1.05 [16,20]. The power calculation was based on the previous study. Twenty five percent reduction of volume of blood loss was used and the sample size calculation was performed by the formula for RCT for continuous data [21]. Mean in a treatment group is 261.50 and SD in a treatment group is 146.80. Mean in a control group is 349.98 and SD, in a control group is 188.85 [16]. The level of significance was considered to be 0.05 and power is 80%. Numbers of participant by calculation were 58 participants per groups. An additional 17 subjects per groups were recruited to study for possible drop out from study.

The study and control group data were compared using an unpaired Student t-test for continuous variable and chi-square and fisher’s exact tests were used for categorical variables. Mean difference with a 95% CI was calculated for magnitude of effect. Statistical analysis were performed using Stata13 (Stata Corp, College Station, TX). A p-value below 0.05 was considered statistically significant.

The study included 150 participants allocated in to two groups of 75 participants per group. Seventy two participants in the TA group and 69 participants in the placebo group completed this study. Three participants in the TA group and six participants in the placebo group were excluded from this study due to cesarean delivery from cephalopelvic disproportion [Table/Fig-1]. Both groups were comparable in patient characteristics and there was no significant difference in risk factors for PPH between the two groups except maternal body weight [Table/Fig-2]. The results for primary outcomes and secondary outcomes are presented in [Table/Fig-3]. Mean blood loss in the first two hours for the TA group was not significantly different from the placebo group (226.59±114.66 mL versus 234.05±142.41 mL, p=0.73). Adjusted mean difference was 4.61 mL (95% CI: -48.25 to 39.02).

[Table/Fig-1]:

Flow of participants through the trial.

The frequency of PPH was one case in the TA group and three cases in the placebo group (one case was severe PPH). More women in the placebo group (n=6) than in the experimental group (n=2) required additional uterotonic agents but not statistically significant. There was no major complication, (maternal mortality or surgical intervention) for PPH, in either group. Maternal adverse events are summarised in [Table/Fig-4]. Only one woman had a mild side effect (nausea) and no episode of thrombosis occurred in the women who received TA.

The PPH is the major direct cause of maternal death worldwide, especially in developing countries. The third stage of labour is an important period because placental delivery has a rapid degradation of fibrin due to the stimulation of the fibrinolytic system [22]. Many methods have been used to prevent excessive blood loss after vaginal delivery especially uterotonic agents.

Our study used TA in the third stage of labour for reducing the fibrinolysis process. However, our results demonstrate that the use of TA reduced postpartum blood loss but was not significant in the first two hours postpartum from the placebo group. The reason might be the action of the prophylactic oxytocin in the first two hours. It might have strongly enhanced the contraction of the uterus, so it masked the effect of the TA. However, this result is different from previous studies [16,17].

In the previous studies, Yang H et al., and Gungorduk K et al., reported that the volume of blood loss was decreased significantly after postpartum injection of 1 gm TA [16,17]. However, the Yang H et al., study had some limitations due to the small sample size and randomisation was not clearly mentioned.

Our study’s result is also different from the RCTs about TA in the management of PPH which showed the effectiveness of TA in the treatment of PPH [9, 16-18]. The reason could be, in case of PPH, the primary mechanism of uterine contraction to inhibit blood loss was not enough to prevent postpartum blood loss. Therefore, the TA antifibrinolytic action can help reduce postpartum blood loss. This was different from most vaginal delivery without PPH where uterine contraction can adequately stop the blood losses in a normal situation.

The frequency of PPH was one case in TA group and three cases in placebo group (with one case of severe PPH). More women in the placebo group than in the TA group required additional uterotonic agents but not statistically significant which might be due to the limitation of our sample size.

The strength of our study was the double blind, placebo controlled randomised design and was specified for vaginal delivery group. The dosage of one gram of TA was selected according to data from the previous study so the effect of different dosage of TA needs further evaluation.

The sample size was designed to evaluate the difference of blood loss volume between TA and control group, a larger sample size is needed to evaluate the difference of incidence of PPH between both groups. The postpartum haematocrit change was also designed to be measured in this study, however it was removed due to the missing data problem.

The addition of TA in vaginal delivery did not reduce the amount of postpartum blood loss in the first two hours compared to prophylaxis oxytocin only. The data from this study, which has the different results, should be included in the meta analysis with previous and upcoming studies for an accurate guideline on the benefit of TA in prophylaxis of PPH in vaginal delivery.

None of the authors has any conflict of interest relative to this work. This study did not receive pharmaceutical company support.

Trial Registry number: The study was conducted after approval by the Ethical Research Committee of Udonthani Hospital No.18/2559 and is registered in the Thai Clinical Trial Registry number: TCTR20161104004.