Effect of Prophylactic Intraoperative Tranexamic Acid on Postpartum Blood Loss Following Cesarean Section at a Single Center

Introduction

Postpartum hemorrhage (PPH) remains a significant obstetric emergency and is a leading cause of maternal mortality worldwide. The American College of Obstetricians and Gynecologists (ACOG) defines PPH as a cumulative blood loss of ≥1000 mL or any blood loss accompanied by symptoms or signs of hypovolemia within 24 hours of delivery (including intrapartum loss), regardless of delivery method (vaginal or peri-abdominal). However, a consensus published by the Network for the Advancement of Patient Blood Management, Haemostasis, and Thrombosis (NATA) classifies cumulative blood loss of ≥500 mL, regardless of delivery method, as primary PPH [1–3].

Globally, PPH accounts for an estimated 20% of all deliveries, with severe cases occurring in 1–3%. The worldwide prevalence is about 100 000 deaths per year [4]. In Indonesia, data from the Family Health Program of the Ministry of Health in 2022 reported 3500 maternal deaths, with 730 (20.9%) attributed to hemorrhage occurring in hospitals, 76 of which were in south Sumatra [5].

Tranexamic acid (TXA) is a synthetic reversible plasminogen inhibitor. TXA is approved for the management of heavy menstrual bleeding, but off-label use has been described, including for the control of postpartum hemorrhage. Use TXA as a hemorrhage preventative has been studied extensively in various surgical procedures. It is recognized for its effectiveness in reducing intraoperative hemorrhage; therefore, its use is recommended in surgery [3,6]. TXA inhibits the binding of plasminogen and plasmin to fibrin, thereby preserving blood clots from plasmin-mediated lysis. Its use has been shown to reduce hemorrhage-related mortality in women with PPH, particularly when administered intravenously for 30 to 60 seconds within 3 minutes immediately after cesarean section delivery. Intravenous TXA is commonly used in severely bleeding patients requiring massive transfusion protocols (MTP) or when hyper-fibrinolysis is demonstrated.

A randomized, double-blind, placebo-controlled study of 660 women who underwent elective cesarean sections showed the TXA group had less blood loss than in the placebo group, with no increase in thromboembolic events [7,8]. The WOMAN trial, a landmark study involving 20 060 women with PPH, demonstrated that TXA significantly reduced mortality due to PPH. Women receiving TXA (n=10 051) had a relative risk (RR) of 0.81 (95% confidence interval [CI]: 0.65–1.00; P=0.045) compared to the placebo group (n=10 009). A meta-analysis of data from the trial indicated a 10% reduction in survival benefit for every 15-minute delay in TXA administration, but this benefit disappeared when administered after 3 hours [3].

A literature review revealed scant data on the use of TXA as PPH prophylaxis during cesarean section in educational centers and hospitals in South Sumatra. This prompted us to investigate the effectiveness of TXA as a prophylactic agent for PPH in post-cesarean patients. This study aimed to compare postpartum blood loss following cesarean section in 88 women treated with either tranexamic acid or placebo at a single center.

Material and Methods

INCLUSION CRITERIA:

The study included pregnant women with a gestational age of ≥32 weeks who met the inclusion criteria: (1) age ≥18 years, (2) undergoing cesarean delivery, and (3) availability of pre-operative hemoglobin levels.

EXCLUSION CRITERIA:

The exclusion criteria were: (1) history of thrombosis (deep vein thrombosis and/or pulmonary embolism) or arterial disease (angina pectoris, myocardial infarction, or stroke), (2) history of epilepsy or seizures, (3) known cardiovascular, renal, or liver disorders, (4) sickle cell disease, (5) severe hemorrhage disease, (6) placenta previa, abnormal invasive placenta (placenta accreta/increta/percreta), placental abruption, (7) eclampsia or Hemolysis Elevated Liver Low Platelet (HELLP) syndrome, (8) intrauterine fetal death (IUFD), (9) administration of low-molecular-weight heparin or antiplatelet agents within a week before delivery, (10) history of hypersensitivity to TXA or concentrated hydrochloric acid, (11) failed vaginal delivery (stage II), and (12) cesarean delivery for second twins or second/third triplets after vaginal delivery of first twins [8].

SAMPLE:

We enrolled 88 subjects, with 44 in the TXA group and 44 in the placebo group. The minimum sample size was determined using the sample size estimate formula for analytical research with numerical data to ascertain the mean difference between 2 independent groups [10]. Using a confidence level of 95% (α=0.05, zα=1.96), a power level of 90% (β=0.1, zβ=1.28), and standard deviation of blood loss of 32.4 ml, and effect size (d) of 16.6 based on a previous study by Igboke et al [9], a minimum sample size of 40 was obtained for each group, resulting in a total of 80 patients. To account for potential dropouts, cancellations, or incomplete data, the sample size of each group was increased by 10%, leading to a total of 88 participants. Participants signed an informed consent form after receiving a detailed explanation of the study. They were then selected based on the inclusion and exclusion criteria.

RANDOMIZATION AND CONCEALMENT:

Participants were randomly assigned to treatment groups using computer-generated random numbers using Research Randomizer^® software. Of the 88 participants, 44 were allocated to group A (TXA group), while the remaining were automatically assigned to group B (placebo group). Group A received 1 g of TXA intravenously over 30–60 seconds at the time of the initial incision, with oxytocin administered after the umbilical cord was clamped. Group B received 10 ml of saline for injection intravenously over 30–60 seconds at the time of the initial incision, with oxytocin administered after the umbilical cord was clamped.

Randomization in this study was performed by the teaching staff and chief resident of Obstetrics and Gynecology of a single center in Indonesia, who were not involved in the study. Masking was carried out by the hospital pharmacist, who did not disclose the results to the researchers. All envelopes containing injection drugs in 10-cc syringes were stored in lockers accessible to all members of the research team.

DATA COLLECTING:

The researchers assessed the amount of hemorrhage based on suction volume and gauze and underpad counts, minus the amount of washing fluid and amniotic volume [8,11,12]. The number of gauzes and underpads was assessed from pictograms. Pictograms are a simple tool to improve the accuracy of blood loss assessment in cesarean section and may be useful for low-resource hospitals that cannot provide complex instruments for accurate estimation. The pictogram has 7 clinical scenarios simulating a cesarean section and quantitatively estimated blood volume in milliliters based on a previous study by Cheerranichanunth et al [13].

The volume of washing fluid was measured in milliliters just before skin closure. Amniotic volume was estimated using the amniotic fluid index (AFI), measured in centimeters with a Samsung Hera 10 ultrasound device. This index, combined with the patient’s gestational age and the date of their last menstrual period, was used to determine a percentile value, which was then converted into milliliters using a percentile table.

STATISTICAL ANALYSIS:

All statistical analyses were conducted using SPSS Version 25 (IBM, Armonk, NY). The chi-square test with Fisher’s exact test as an alternative was used for comparisons between groups for categorical variables. The t test with the Mann-Whitney U test as an alternative was used for comparisons between groups for numerical variables. A P value of <0.05 was considered statistically significant.

Results

SUBJECT CHARACTERISTICS:

The women in our study had an average age of 30.7 years with an age range of 18–46 years. The average gestational age was 36.2 weeks, with a range of 32–41 weeks. The lowest body mass index (BMI) was 16.2 kg/m2 and the highest was 36.9 kg/m2, with an average BMI of 22.6 kg/m2. Most women were high school graduates (77.3%), and only 6 (6.8%) had an only elementary or middle school education. Statistical analysis revealed no significant differences between the TXA and placebo groups in terms of age (P=0.093), gestational age (P=0.398), body mass index (BMI) (P=0.445), or education level (P=0.056). A summary of the sociodemographic characteristics is presented in Table 1.

CHARACTERISTICS OF BLOOD LOSS:

The amount of hemorrhage in the underpads, suction, and gauze was assessed, as well as the amount of washing fluid and amniotic volume. Total hemorrhage was determined by subtracting the total amount of blood in the underpads, suction, and gauze from the amount of washing fluid and amniotic volume. Statistical analysis showed there was a significant difference in the amount of blood in the suction (P=0.044), the amount of blood in the gauze (P=0.014), and the total amount of fluid in the underpads, suction, and gauze (P=0.022) between the intervention and placebo groups. However, no significant differences were found in pre-operative Hb levels between the 2 groups (P = 0.361), postoperative Hb levels (P=0.133), or amniotic volume in ml (P=0.382) (Table 2).

EFFECTIVENESS OF TRANEXAMIC ACID ADMINISTRATION AND PLACEBO GROUP ON HEMOGLOBIN LEVELS:

We did not find any significant relationship between pre-operative (P=0.738) and postoperative (P=0.349) Hb levels between the 2 groups (Table 3).

EFFECTIVENESS OF TXA ADMINISTRATION AFTER CESAREAN SECTION IN PREVENTING POST-CESAREAN HEMORRHAGE:

Based on statistical analysis, there was a significant difference in the amount of PPH between samples given TXA and placebo (P=0.000). Patients who were given TXA had significantly less hemorrhaging than the placebo group (Table 4).

We found that TXA was significantly protective, reducing the risk of PPH by 87.5% compared to the placebo group (RR=0.125 [95% CI 0.016–0.958]; P=0.045) (Table 5).

SIDE EFFECTS POST-CESAREAN SECTION ADMINISTRATION OF TXA:

TXA administration has moderate adverse effects (nausea, vomiting, and phosphenes) and severe adverse effects (deep vein thrombosis, pulmonary embolism, myocardial infarction, and renal failure). In the intervention group, moderate adverse effects were found in the form of nausea (11.4%), while the placebo group did not report any moderate adverse effects, but the difference was not significant (P=0.101) (Table 6). In addition, no severe adverse effects were found in either group.

Discussion

A clinical study was conducted to evaluate the effect of prophylactic intraoperative tranexamic acid (TXA) on postpartum blood loss in women undergoing cesarean sections at a single center. The mean age of pregnant women undergoing cesarean delivery was 30.7 years, with a range of 18 to 46 years. These findings align with those reported by Akinola et al, who observed an average age of 30.92 years among women undergoing cesarean section [14]. Similarly, Ryhdahl et al reported a mean age of 30 years, with a broader range of 13 to 61 years [15]. Meanwhile, Gyaase et al documented a slightly higher average age of 34 years, with a range of 15 to 49 years [16]. Pre-pregnancy obesity is a known risk factor for cesarean delivery. However, in that study, the lowest BMI was 16.2 kg/m2 and the highest was 36.9 kg/m2, with a mean BMI of 22.6 kg/m2. These results are consistent with Al-Kubaisy et al, who reported a mean BMI of 24.31 kg/m2 for women undergoing cesarean delivery, which is also still in the normal category. Research by Sanchez-Samaniego et al involving 965 women undergoing cesarean delivery reported that 495 of their samples (51.3%) had normal BMI [17]. Most participants in this study had a high school education. This result is comparable to the findings of Alshammari et al, who found high school was the most common educational level among women with cesarean deliveries [18]. A study conducted by Idris et al, which classified education levels into low (no formal education or elementary school), medium (junior and senior high school), and high (undergraduate education), reported that most mothers undergoing cesarean delivery had a medium education level [19]. In the present study, no significant differences were observed in age, gestational age, BMI, and education between the intervention and placebo groups. Therefore, it can be concluded that these sociodemographic characteristics did not influence the incidence of PPH in our study and supports the comparability of the 2 groups for analysis.

Measurement of PPH was performed using quantitative objective measures due to the inaccuracy of other methods [8,12]. The amount of hemorrhage in the underpads, suction, and gauze was subtracted from the washing fluid and amniotic volume to obtain the actual blood loss. We found significant differences in blood loss from suction, gauze, and total hemorrhage (underpads + suction + gauze) between the intervention and placebo groups. Blood loss in all 3 components was significantly lower in the intervention group than in the placebo group. These findings are in line with Hemapriya et al, who reported a significant reduction in intraoperative hemorrhage in women receiving TXA. In addition, the control group experienced a significant decrease in postoperative Hb levels when compared to the group that received tranexamic acid [20]. Omawumi et al also found that TXA significantly reduced blood loss during and after cesarean section (P <0.01), with lower total blood loss (TXA group: 624.88±200.76 ml vs placebo group: 864.24±229.09 ml, P=0.001) and higher post-cesarean packed cell volume (30.68%±2.80%) compared to the placebo group [21].

This study found no difference in amniotic volume in ml (P=0.382) between the intervention and placebo groups. Whittington et al examined the relationship between amniotic volume and the incidence of PPH, noting that pregnancies affected by oligohydramnios had higher risks of PPH (5.7% vs 1.7%, OR 2.94, 95% CI 1.31, 6.61), fetal malposition (5.7% vs 1.9%, OR 2.44, 95% CI 1.07, 5.59), and cesarean section (28.7% vs 13.5%, OR 2.07, 95% CI 1.41, 3.03) compared to those without oligohydramnios [22].

Finally, Hb levels were assessed before and after the procedure. The results showed no significant difference in pre-operative Hb levels (P=0.361) and postoperative Hb levels (P=0.133) between the intervention and placebo groups. We found no significant difference in pre-operative and postoperative Hb levels in either the intervention or placebo groups (P=0.738; P=0.349). Consequently, the protective effect of TXA on maintaining Hb levels could not be conclusively determined. Meanwhile, Hemapriya et al found that the control group had a significant decrease in postoperative Hb levels compared to women who received TXA [20,23]. In addition, a systematic study and meta-analysis conducted by Cheema et al analyzed 6 trials in high-risk patients and found that the decrease in Hb levels was lower among those administered TXA. The administration of TXA was associated with a significantly smaller reduction in Hb levels (MD: 0.63 g/dl; 95% CI, 0.53–0.74) [24]. However, Abdelazim et al found no significant difference between pre-operative Hb levels (11.6±6.4 gms%) and Hb levels immediately after surgery, at 12 hours, 24 hours, and 48 hours postoperatively, and up to 1 week after surgery. In addition, Baktiyani found that there was no relationship between pre-operative Hb levels before (r=0.034, P=0.742) and after surgery (r=−0102, P=0.322) with the amount of blood loss during surgery [25].

In the present study, 1 g of TXA was given intravenously at the time of the initial incision. In the intervention group, the actual amount of hemorrhage (the amount of hemorrhage in the underpads, suction, and gauze minus the amount of washing fluid and amniotic volume) was significantly less than in the placebo group. Major PPH (total hemorrhage >1000 ml) was also found to be less common in the intervention group (2.3% vs 18.2%). The administration of TXA to pregnant women before cesarean delivery is a protective factor for PPH [26,27]. We found that TXA reduced the incidence of PPH after a cesarean section by 87.5%. TXA was significantly protective, reducing the risk of PPH by 87.5% compared to the placebo group (RR=0.125 [95% CI 0.016–0.958]; P=0.045) in this study. Naeiji et al also reported that TXA reduced the average blood loss by 25.3% [23]. The average volume of intraoperative blood loss in the TXA group was significantly lower, with a difference of 132.7 ml, compared to the placebo group. The rate of hemorrhage >1000 ml, hemorrhage >500 ml, and the need for blood transfusion were also significantly lower in the TXA group. Oseni et al reported that there was a significant decrease in blood loss when pre-operative TXA was given to patients undergoing emergency cesarean section [28]. The average intraoperative blood loss in the TXA group was significantly less than in the control group (t=−16.18, P≤0.01). A study conducted by Neumann et al involving 212 women (TXA [n=106] and placebo [n=106]) reported that the estimated mean blood loss in the TXA group was significantly lower than in the placebo group (P<0.001) [29]. The estimated mean blood loss measured gravimetrically was also found to be significantly less in the TXA group than in the placebo group (P<0.001). A meta-analysis conducted by Cheema et al involving 50 randomized control trials reported that TXA can reduce the risk of blood loss >1000 mL, mean total blood loss, and the need for blood transfusion in low- and high-risk patients [24]. Notably, TXA was most beneficial when administered before the skin incision was made, rather than after cord clamping [30].

This study evaluated the occurrence of moderate and severe adverse effects between the TXA and placebo groups. None of the participants in either group experienced severe adverse effects. However, moderate adverse effects in the form of nausea were found only in the TXA group, although the difference was not statistically significant. Naeiji et al also reported no specific adverse effects associated with TXA administration [23]. This emphasizes that TXA has a good safety profile in women undergoing cesarean section and has no contraindications. A systematic review of 252 randomized clinical trials involving over 25 000 participants confirmed that lysine analogs, including TXA, can effectively reduce perioperative blood loss without serious adverse effects [3]. A randomized, placebo-controlled clinical trial conducted on 20 060 women with PPH across 193 hospitals in 21 countries between 2010 and 2016 also showed that adverse effects of TXA (including thromboembolic events) were not significantly higher than with use of placebo when patients received 1 g of TXA, while tranexamic acid could significantly reduce hemorrhage-related mortality in patients at this dose [31].

This study’s main strength lies in its rigorous methodology, including a double-blind, randomized clinical design, which minimizes the risk of bias and enhances the reliability of the findings. The use of quantitative measures for blood loss using calibrated surgical suction devices and pictograms, provides precise and objective data. Additionally, the inclusion and exclusion criteria were clearly defined, ensuring a well-selected study population relevant to the research question. However, there are several limitations to consider. The study was conducted at a single center, which may limit the generalizability of the findings to other settings or populations. The strict exclusion and inclusion criteria may have resulted in a homogenous study group that is not generalizable to the broader population of pregnant women. Thus, the results may not be generalizable to women with complicating factors beyond the focus of this study. The sample size, although adequate to detect differences in blood loss, might still be too small to uncover less common adverse effects of TXA or to assess outcomes across diverse demographic groups. Furthermore, the study’s scope was limited to immediate postoperative outcomes, lacking long-term follow-up to identify any delayed adverse effects or long-term benefits of TXA usage. Lastly, while efforts were made to control for confounding variables, other unmeasured factors related to individual patient health or institutional practices might have influenced the outcomes.

Conclusions

Intraoperative TXA administration significantly reduced blood loss and the risk of PPH in women undergoing cesarean sections. These findings support the routine use of TXA in cesarean management protocols to improve maternal safety and outcomes.