|Year : 2021 | Volume
| Issue : 17 | Page : 40-46
Intravenous tranexamic acid for reducing blood loss during cesarean delivery: A double-blind, randomized-controlled trial
Ibrahim Salihu Halifa1, Timothy Abiola Olusesan Oluwasola2, Bukola Fawole2, Adesina Oladokun2
1 Department of Obstetrics and Gynecology, Federal Medical Centre, Nguru, Yobe State, Nigeria
2 Department of Obstetrics and Gynecology, University College Hospital, Ibadan and College of Medicine, University of Ibadan, Ibadan, Nigeria
|Date of Submission||24-Jun-2020|
|Date of Acceptance||05-Sep-2020|
|Date of Web Publication||24-Apr-2021|
Dr. Timothy Abiola Olusesan Oluwasola
Department of Obstetrics and Gynecology, College of Medicine, University of Ibadan, Ibadan
Source of Support: None, Conflict of Interest: None
Background: Cesarean delivery (CD) has been associated with an increased risk of postpartum hemorrhage (PPH) and maternal mortality. Tranexamic acid (TXA) has proven effective in managing hemorrhage, but its overall effect on blood loss during CD when given before skin incision is yet to be evaluated. Materials and Methods: We recruited 154 consenting pregnant women, scheduled for CDs at the University College Hospital, Ibadan, between October 1, 2015 and March 31, 2016. Participants were randomly allocated to receive either 1 g of TXA or placebo given intravenously, 10 min before skin incision. All participants had intravenous oxytocin postdelivery. Operative blood loss, as the primary outcome, was measured by weight and volume at entry into the peritoneal cavity, at the end of the surgery, and 2 h postsurgery. Results: Both groups, with 77 women each, had similar baseline characteristics, obstetrics history, and blood loss from skin incision to the peritoneal cavity. Blood loss from uterine incision to 2 h postsurgery was significantly lower among the TXA group (613.05 ± 195.63 ml vs. 751.17 ± 250.66 ml; P < 0.001). Neonatal outcomes and the need for additional uterotonics were similar in the two groups. Conclusion: TXA significantly reduced blood loss during CD with no adverse events. Routine use of TXA during CDs will further reduce the impact of PPH.
Keywords: Blood loss, cesarean delivery, postpartum hemorrhage, tranexamic acid, uterotonics
|How to cite this article:|
Halifa IS, Olusesan Oluwasola TA, Fawole B, Oladokun A. Intravenous tranexamic acid for reducing blood loss during cesarean delivery: A double-blind, randomized-controlled trial. N Niger J Clin Res 2021;10:40-6
|How to cite this URL:|
Halifa IS, Olusesan Oluwasola TA, Fawole B, Oladokun A. Intravenous tranexamic acid for reducing blood loss during cesarean delivery: A double-blind, randomized-controlled trial. N Niger J Clin Res [serial online] 2021 [cited 2021 Jun 19];10:40-6. Available from: https://www.mdcan-uath.org/text.asp?2021/10/17/40/314600
| Introduction|| |
Cesarean delivery (CD) is a commonly performed obstetric operation all over the world with an attendant increase in the risk of postpartum hemorrhage (PPH), usage of blood and blood products, as well as maternal morbidity and mortality., Thus, the selection of effective prevention and treatment for PPH is a major public health issue. PPH has remained a nightmare for obstetricians for centuries and currently accounts for more than 30% of all maternal deaths in Africa and Asia and for 25% of maternal mortalities worldwide.,,, Women who have severe PPH and survived (“near misses”) are significantly more likely to die in the year following the PPH.
Subtle modifications take place in both fibrinolytic agents and coagulation factors before and after delivery. All through pregnancy and after delivery, plasma concentrations of clotting factors increase, but after placental delivery, fibrinogen and fibrin are swiftly degraded, whereas plasminogen activators and fibrin degradation products increase following the activation of the fibrinolytic system, thus minimizing the possibility of blood to clot. Tranexamic acid (TXA), an antifibrinolytic agent, directly inhibits the activation of plasminogen by binding to receptor sites of the plasminogen molecule, thereby reducing hemorrhage by preventing breakdown rather than promoting new clot formation, although higher doses are required to reduce the formation of plasmin. This was reflected in the results from previous randomized controlled trials and reviews.,,,
In Sub-Saharan Africa, due to poor health-seeking behaviors, emergency CDs are commonly performed intervention as most parturients present late. Aside the associated occasional significant blood loss, procuring blood for transfusion during such emergency situations could be challenging because of poor blood bank services. In addition, most parturients presenting in such situations often had other predisposing factors for uterine atony such as anemia or sepsis (from prolonged obstructed labor or prolonged rupture of membranes). Since intravenous TXA, with the onset of action of 5–10 min and duration of action of up to 3 h, can be administered before surgery, it is expected to potentiate the beneficial effect of oxytocin which has a shorter duration of action and is usually administered for the prevention of PPH after the delivery of the baby.
Most of the previous studies on TXA were centered on elective CDs which are often performed in carefully selected and well-optimized patients. Our main thrust in this study was to determine the overall effect of TXA on blood loss during CDs (especially emergency CDs) and also to assess its role on the reduction of blood loss when administered before the skin incision.
| Materials and Methods|| |
This was a randomized, double-blind, placebo-controlled trial of 154 women who underwent elective or emergency cesarean deliveries (CDs) at the University College Hospital (UCH), Ibadan, between October 1, 2015 and March 31, 2016. The Joint Ethics Committee of the University of Ibadan/UCH reviewed and approved the study. The trial was registered in the Pan African Clinical Trial Registry as PACTR 201804002955302. The UCH is the premier and the largest teaching hospital in Nigeria, located within the largest city in West Africa and has an average of 2500 deliveries per annum.
Women with severe medical and surgical complications involving the heart, liver or kidneys, blood disorders, allergy to TXA, known risk factors for PPH such as previous CD, multiple pregnancy, placenta previa, morbidly adherent placenta, previous myomectomy, coexisting uterine fibroid in pregnancy, history of thromboembolic disorder, or risk factors for thromboembolic disorder such as sickle cell diseases were excluded from the study.
The sample size was determined with the assumption that a difference of 120 ml of total blood loss would be clinically important between the two groups. It was calculated that 70 participants would be required per group in order to detect this difference with 80% power and 5% probability of type 1 error. The CONSORT diagram illustrating the flow of participants during the study is as presented in [Figure 1].
|Figure 1: Consort diagram for the flow of participants throughout the study|
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Generation of sequence
The sequence of randomization was generated and held by a statistician using a computer program. The codes were given to a pharmacist not related to the trial who prepared the syringes containing the trial treatment using the randomization list. Each syringe contained either 10 ml of TXA (1 g) or 10 ml of normal saline; both liquids are colorless, so the syringes containing the drugs were indistinguishable from those containing placebo. The pharmacist, who had the randomization sequence, placed the drug and placebo into sequentially numbered envelopes in groups of 4 at a time. Each set of envelopes, thus, contained two 10 ml syringes containing the trial drug and two 10 ml syringes containing the placebo. The order was only known to the pharmacist who performed the packing, sealing, and numbering of the envelopes. The envelopes were kept in a specially designed box in the labor ward theater. The study participants and the investigators were blinded to the randomization codes.
Consenting study participants were randomly allocated to receive either 10 ml of the trial drug or placebo given intravenously over 10 min. This was done 10 min before skin incision. Each participant was assigned a uniquely numbered syringe containing either TXA or placebo. Blood loss was then measured by weight and volume during three periods: from skin incision to entry into the peritoneal cavity, from uterine incision to the end of the surgery, and from the end of the surgery to 2 h postsurgery. To ensure accurate measurement of blood loss, a combination of direct measurement and gravimetric methods were used. The difference in packed cell volume levels before and after the surgery was determined.
Weight measurement was done using an Avery Berkel IM Series Retail Scale (UK), with standard weighing abilities. The vulva pads were “Comfit” sanitary pads (Femina Hygienical Company, Lagos under the license of K. LOKUMAL, London, United Kingdom) which were purchased for the participants' use at no extra cost. The sequence of estimating blood loss was as follows: (i) abdominal packs were used from the point of skin incision to entry into the peritoneal cavity; (ii) separate set of abdominal and gauze packs were used from uterine incision to the end of the surgery; (iii) blood loss from uterine incision to the end of the surgery was also meticulously suctioned into the calibrated suction bottle (amniotic fluids were suctioned separately when necessary); (iv) all abdominal packs and gauzes used during surgery were weighed and the known dry weights subtracted; and (v) the sanitary pads used within 2 h postoperation were also weighed and the known dry weights were subtracted. It was assumed that 1 ml of blood weighs approximately 1 g such that the balance, in grams, was equated to total loss in milliliters (ml). Total blood loss immediately after surgery was calculated by adding blood volume in (i) to the calculated blood volume in (ii) and (iii) while blood loss 2 h after surgery was calculated from (v) and the volume of blood was recorded in the datasheet.
The primary outcome was the total amount of blood loss during CDs, whereas secondary outcomes included the changes in the vital signs intraoperatively and up to 2 h postoperatively. Other secondary outcomes were vaginal bleeding during the first 2 postoperative hours (amount of vaginal bleeding was calculated according to the weight of soaked pads used after CD), need for additional uterotonics, need for other surgical measures to stop bleeding (B-Lynch, uterine artery ligation, internal iliac artery ligation, hysterectomy, and/or transfusion of blood or blood products), 24 h postoperative hematocrit values, as well as maternal and neonatal side effects of medications administered.
Data were collected, tabulated, and then statistically analyzed using the Statistical Package for the Social Sciences version 23.0 (IBM, Armonk, NY, USA). Continuous variables were presented as mean and standard deviation (±SD), whereas categorical variables were presented as numbers and percentages. Chi-square statistic was used to determine the relationship categorical variables, whereas independent t-test was used to compare the mean values of quantitative variables among the groups, and risk ratios (RRs), 95% confidence intervals (CIs), and two-sided P values were calculated for the binary outcomes. Statistical analysis was performed on an intention-to-treat basis, and the level of statistical significance was set at P < 0.05.
| Results|| |
During the study period, 194 women were assessed for eligibility; 39 were excluded for failure to meet the eligibility criteria, whereas one woman declined to consent for personal reasons [Figure 1]. The remaining 154 women were enrolled and randomly allocated to receive either TXA or placebo–77 in each arm. The baseline characteristics and obstetrics history were similar between the two groups [Table 1] and [Table 2].
[Table 3] shows the comparison of blood loss between the two groups. In the period from skin incision to entry into the peritoneal cavity, estimated blood loss was similar between the TXA and control groups (58.06 ± 21.95 vs. 57.42 ± 28.14; t-test = 0.157, P = 0.88). However, blood loss from uterine incision to the end of CD was significantly lower in the TXA group compared to the placebo group, (mean blood loss 486.27 ± 175.63 versus 632.89 ± 240.42; t-test = 4.321, P < 0.001). Overall, the total volume of blood loss from skin incision to 2 h postpartum was significantly lower in the TXA group compared to the placebo group (613.05 ± 195.63 ml vs. 751.17 ± 250.66 ml; t-test = 3.812 P < 0.001). Abnormal fetal heart pattern was the most common indication for having a CD in the two groups of patients, followed by obstructed labor and maternal requests. The indications for CD, cadre of surgeon, types of anesthesia, and duration of surgery were similar in the two groups.
As shown in [Table 4], 29 (18.8%) of all the participants had a need for additional uterotonics, however the distribution was similar in the two groups. In addition, seven (7; 4.5%) of the study participants required blood transfusion, out of which only one was in the TXA group (RR: 0.17; 95% CI = 0.02–1.35, P = 0.05). The TXA group had a significantly higher value of mean postoperative hematocrit (expressed as packed cell volume in percentage) compared to the placebo group (34.54 ± 3.35 vs. 32.53 ± 3.13, P < 0.001), although the preoperative hematocrit values were similar between the study groups (35.06 ± 3.16 vs. 34.64 ± 3.2, P = 0.42) [Table 5].
|Table 4: Need for additional uterotonics and blood transfusion between the study groups|
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|Table 5: Comparison of pre- and postoperativepacked cell volumes in the study groups|
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Irrespective of the type of CD, the TXA group had less mean blood loss compared to the placebo arm of the study. Among those who had elective CD, the mean blood loss was 733.05 ± 194.47 ml in the placebo group compared to 603.95 ± 211.36 ml in the TXA group, P < 0.001). Similarly, among those who had emergency CDs, the mean blood loss was 758.84 ± 269.97 ml in the placebo group and 617.75 ± 190.88 ml in the intervention group; P < 0.001.
Three patients experienced nausea, of which two were in the TXA group, whereas the remaining one was in the placebo group, whereas the only two women who experienced dizziness were in the TXA group [Table 6]. An equal proportion of women experienced vomiting in both groups. The neonatal outcomes were similar with respect to the mean APGAR scores at 5 min in the two groups: 9.13 ± 1.18 versus 9.17 ± 1.08, P = 0.83 for TXA and placebo groups, respectively. The babies' birth weights were also similar between both groups: 3.03 ± 0.59 kg versus 3.00 ± 0.54 kg; P = 0.67.
| Discussion|| |
The administration of TXA to women who underwent CD reduced total blood loss from skin incision to 2 h postpartum. The blood loss from uterine incision to the end of the CD was significantly lower in the TXA group compared to the placebo group. This is similar to the findings of previous authors who stated in different reports that administration of 10 mg/kg TXA reduced bleeding during the period from the end of CD to 2 h postpartum.,, However, the quantity of blood loss from skin incision to entry into the peritoneal cavity was similar in the two groups. Although this may be due to the pharmacokinetics of the drugs and delay onset of action before the skin incision, it has helped to establish that major impact of TXA in reducing blood loss results majorly from its activities on the uterus. In addition, the time interval between skin incision and entering the peritoneal cavity was very short.
The current study has shown that TXA significantly reduced total estimated blood loss by an average of 138 ml, which is higher than 88 ml reported by Gai et al. and 101 ml reported by Gungorduk et al., Most of the previous authors worked among participants scheduled for elective CD and who were unlikely to be at risk for PPH when compared to emergency CDs. In addition, the need for additional uterotonics, as expected, was higher in the placebo group, thus supporting the theory that TXA has the potential to reduce the need for additional uterotonics and this is in tandem with earlier documentation by Gungorduk et al. Moreover, fewer participants in the TXA group had a need for blood transfusion implying that TXA may play significant positive roles in reducing the need for blood transfusion. The cumulative impact of giving intravenous TXA before CD was reflected on its ability to reduce total blood loss, need for additional uterotonics, and blood transfusion.
The side effects of TXA medication were documented majorly as gastrointestinal in nature.,, In this study, nausea, vomiting, and dizziness were observed among a few of the participants with dizziness appearing to be significantly associated with TXA although the figures were too small to make appropriate deductions. However, neonatal outcomes were similar in the two groups of participants implying that TXA has no adverse effect on the neonates in the current dose schedule.
While it was noted that the study was underpowered in addressing safety issues for TXA, the minor side effects including gastrointestinal manifestations, which were mild and reversible, were higher in the TXA group than the control group. Although these minor side effects were of lesser importance compared to possible thromboembolic events, it is essential to balance the clinical effects of TXA in reducing blood loss without disabling symptoms.
| Conclusion|| |
TXA significantly reduced overall total blood loss during CDs. In addition, the need for additional uterotonics, although statistically insignificant, was lower in the TXA group, and yet, this group had a significant higher postoperative hematocrit values. It was, thus, concluded that TXA is effective and safe in reducing blood loss and preventing postpartum bleeding in CDs. In a developing country like Nigeria, TXA which is cheap and readily available could be an option for reducing PPH – a major threat to potential mothers.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]