Tranexamic Acid and Ethamsylate for Reducing Blood Loss in Patient Undergoing Lower Segment Cesarean Section at High Risk for Post-Partum Hemorrhage: A Pilot Study

Objective: To assess the efficacy of intravenous tranexamic acid and ethamsylate in reducing blood loss during and after elective lower segment cesarean delivery in patients at high risk for postpartum hemorrhage. Methods: A double-blind, randomized placebo-controlled study was undertaken of women undergoing elective lower-segment cesarean delivery of a full-term pregnancy at high risk for postpartum hemorrhage at Ain Sham University Maternity Hospital in Cairo, Egypt, between January 2019 and October 2019. Patients were randomly assigned (1:1) using computer-generated random numbers to receive either 1 g tranexamic acid and 1 gm ethamsylate or 5% glucose (placebo) just after delivery of the fetus. Prophylactic oxytocin was administered to all women. Preoperative and postoperative complete blood count, hematocrit values, and maternal weight were used to calculate the estimated blood loss (EBL) during the cesarean, which was the primary outcome. Results: Analyses included 32 women in each group. Our results showed that tranexamic acid and ethamsylate significantly reduced bleeding during and after cesarean delivery. The study group’s total blood loss (149.22 ± 54.74 ml) was significantly less than the control group (353.75 ± 115.56 ml) (p < 0.001). In our study, postoperative hemoglobin and hematocrit were significantly higher in the study group than the control group (p < 0.001); Reduction in hemoglobin and hematocrit were significantly less in the study group than the control group (p < 0.001). Conclusion: The use of tranexamic acid and ethamsylate during cesarean delivery can significantly reduce blood loss during and after cesarean delivery.


Background
Worldwide 15% of deliveries are done by cesarean [1]. Although cesarean delivery is planned to be a lifesaving procedure, diminishing both maternal and fetal morbidity and mortality [2], blood loss during cesarean is double that of vaginal delivery [3]. Postpartum hemorrhage (PPH) remains the main cause of maternal mortality and accounts for about one-fourth of all maternal deaths worldwide.
Its risk factors include previous PPH, multiple pregnancies, polyhydramnios, and macrosomia [4]. Most of these could be avoided through the use of prophylactic uterotonics by timely and appropriate management [5]. Therefore, medications such as oxytocin, ergometrine, prostaglandin F2α, and misoprostol (prostaglandin E1) are commonly used to minimize intraoperative and postoperative blood loss during cesarean delivery [6] [7]. In addition to this enhancement of chemical hemostasis, a complementary biochemical hemostatic effect might be expected from the complementary use of prohemostatic drugs as tranexamic acid or ethamsylate [8].
Tranexamic acid (TXA) is a synthetic derivative of the amino acid lysine that exerts its antifibrinolytic action through the reversible block of the lysine binding sites on plasminogen molecules. Intravenous administration of TXA has been routinely used for treating and preventing bleeding with good results [9].
During delivery, when the placenta separates from the uterine wall, sequential physiologic and hemostatic changes occur and decrease bleeding, including strong myometrial contraction, increased platelet activation, and a massive release of coagulant factors; at the same time, however, fibrinolytic activity increases [10]. While oxytocin administration facilitates the first mechanism, tranexamic acid administration might be able to counter the latter and thus enhances the hemostatic process [11]. Prophylactic TXA given before cesarean skin incision in women undergoing cesarean delivery, significantly decreases blood loss, including postpartum hemorrhage and severe postpartum hemorrhage, in addition to the standard prophylactic oxytocin given after delivery of the neonate [12]. So prophylactic TXA administration is effective and safe for postpartum hemorrhage prevention [13].
Ethamsylate is a synthetic hemostatic drug indicated in cases of capillary bleeding. It exerts a hemostatic effect by acting on the first step of hemostasis by improving platelet adhesiveness and restoring capillary resistance. It decreases bleeding time and enhances platelet aggregation. It reduces capillary bleeding when platelets are adequate. The drug exerts antihyaluronidase action and improves capillary wall stability. It inhibits PGI-2 synthesis and correct abnormal platelet function. Side effects include rash, headache, nausea, and fall in blood pressure only after intravenous administration [14]. The aim of the present study was to evaluate the efficacy and safety of intravenous tranexamic acid and ethamsylate in reducing blood loss during and after elective lower segment cesarean delivery in patients at high risk for postpartum hemorrhage.

Material and Methods
This was a prospective double-blind randomized controlled clinical trial study Institutional review and ethical board approval were obtained, and all participants provided informed written consent following a discussion on the nature of the study as well as the expected value, outcome, and possible adverse effects.
On the day of their scheduled surgery, participants were randomly assigned in a 1:1 ratio to receive either intravenous tranexamic acid and ethamsylate or intravenous glucose (placebo) given just after delivery of the fetus during cesarean delivery. Randomization was performed using computer-generated random numbers. Neither the surgeon nor the investigator was aware whether the patient received tranexamic acid and ethamsylate or placebo (double-blinded technique). Placebo was the same in size, color, and shape to the original drug.
A full medical history was obtained from all participants. Obstetric ultrasonography and laboratory tests were performed, including prothrombin time, complete blood count, and liver and kidney function tests. Maternal body weight and vital signs (heart rate, blood pressure) were checked 30 minutes before surgery.
Patients assigned randomly into one of two groups: group 1 (the case group); suckers, towels, and pads placed under women buttocks then weighting the towels and pads to allow objective measurement of blood loss. Vital data (pulse and blood pressure) was monitored postoperatively, complete blood count test was performed 24 hours after delivery.
Each patient in the study was tested for the following endpoints; operative blood loss (measured by suckers, towels, and pads placed under women buttocks just after delivery and weighting the pads and towels to allow objective measurement of blood loss), the need for blood transfusion, pre-and post-operative hemoglobin and hematocrit (peripartum change) and if PPH occurs, measurement of vaginal blood loss objectively.
Upon discharge, patients who received tranexamic acid were given a brief orientation regarding symptoms and signs of a thromboembolic event and were instructed to contact the investigators if any occurred. All patients were examined for thromboembolic signs at the 1-and 4-week follow-up visits.
Descriptive statistics for measured variables expressed as a range, mean and standard deviation (for metric data); range, median and inter-quartile range (for discrete data); and number and proportions (for categorical data

Results
70 pregnant women were enrolled. Six women were excluded from the study; 3 women with a history of venous thrombosis, 2 women had medical disorders (cardiac and hepatic diseases) and 1 woman had abnormal placentation (morbidly adherent placenta). 64 women were included in the final analysis, divided randomly into two groups; 32 women in the study group (tranexamic acid and ethamsylate) and 32 women in the control group (placebo).
There was no significant difference as regard patient characteristics (age, weight, BMI, and gestational age) between study and control groups [ Table 1].
There was a significant difference between two groups as regards postoperative examination (pulse, pads, drains) and need for blood transfusion. The study group's total blood loss: (149.22 ± 54.74 ml) was significantly less than control group (353.75 ± 115.56 ml) (p < 0.001) [ Table 2; Figure 1].
In our study postoperative hemoglobin was significantly higher in the study group than the control group (p < 0.001); Reduction in Hemoglobin was significantly    Table 3; Figure 2]. Also, postoperative hematocrit was significantly higher in study group than control group (p < 0.001): reduction in hematocrit was significantly less in the study group than in control group (33.2 to 32.4 vs 32.2 to 28.1) (p < 0.001) [ Table 4; Figure 3].

Discussion
The present study has demonstrated that intraoperative intravenous administra- control group (12.57 + 1.33 in the tranexamic group and 11.74 + 1.14 in the control group (p = 0.002). Tranexamic acid was not associated with any side effects or complications [16].
In 2011, the CRASH-2 trial [17] showed that early administration of tranexamic acid significantly decreases mortality in trauma patients with hemorrhage.
As a result of this trial, the drug was included in the WHO Model List of Essential Medicines [18]. In obstetric and gynecologic practice, tranexamic acid is most commonly used in the management of pregnancy-associated bleeding (threatened abortion and placenta previa) and idiopathic menorrhagia [9].

Conclusion
Our results demonstrated that tranexamic acid and ethamsylate can be used safely to reduce bleeding during and after CS, and its use was not associated with any maternal and neonatal side effects. Tranexamic acid and ethamsylate appear to be a safe and effective option in the treatment of obstetric hemorrhage. In addition, the limited available evidence supports the need for a well-designed adequately powered clinical trial to test their benefit as a prophylactic agent.

Authors' Contributions
All authors had put the plan, collecting data, participate in the surgical procedure and follow up of the patients.

Ethical Consideration
Institutional review board (IRB) approval: The protocol was discussed by the ethical scientific committee of Ain Shams University Maternity Hospital.

Subject Confidentiality
All evaluation forms, reports, laboratory specimens, and other records that leave the site would not comprise unique personal data to maintain subject confidentiality.

Consent Procedure
The Investigator made a great concern that a correct informed consent process was in place to make sure that potential research subjects were fully addressed about the nature and objectives of this clinical trial, the potential hazards and gains of study participation, and also their rights as research subjects. The Investigator took the written, signed an informed consent from each participant before performing any study-specific technique on the participant. The investigator retained the forms of original signed informed consents. All data and materials are available on request with agreement for publication.