|Ahead of print publication
Comparative study of oxytocin versus tranexamic acid and ethamsylate in preventing primary postpartum hemorrhage in women undergoing lower-segment cesarean section
Sanjeev Singh1, Rachna Mishra2, Arti Singh3, Pavagada Shaifulla4
1 Department of Anaesthesiology and Intensive Care, CHS, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana; Department of Anaesthesiology and Intensive Care, SAMSRI, Lucknow, Uttar Pradesh, India
2 Department of Obstetrics and Gynecology, SAMSRI, Lucknow, Uttar Pradesh, India
3 Department of Public Health, School of Public Health, CHS, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana
4 Department of Medicine, Viswabhatathi Medical College, Kurnool, Andhra Pradesh, India
|Date of Submission||25-May-2022|
|Date of Decision||21-Jun-2022|
|Date of Acceptance||27-Jun-2022|
|Date of Web Publication||14-Jul-2022|
Department of Anaesthesiology and Intensive Care, Kwame Nkrumah University of Science and Technology, Kumasi
Source of Support: None, Conflict of Interest: None
Background: Worldwide, 21% of deliveries are by elective cesarean sections (C/S) as a procedure to reduce maternal and neonatal mortality and morbidity. Blood loss during C/Ss is more than vaginal delivery. Therefore, reducing blood loss during the C/Ss is essential and challenging for anesthesiologists and obstetricians. This study aimed to assess the efficacy of intravenous oxytocin versus tranexamic acid + ethamsylate (TXA + Eth) in reducing blood loss in pregnant women at high risk of primary PPH undergoing elective lower-segment cesarean section.
Materials and Methods: A single-center, prospective, randomized, and double-blind study was started after obtaining institutional ethical approval. The study involved women undergoing elective C/Ss at full-term pregnancy at high risk for primary postpartum hemorrhage (PPH) at the SAMSRI between September 2021 and March 2022. The study participants received an infusion of either oxytocin 10 International Unit or TXA 1 g + Eth 250 mg before the skin incision. The primary outcome was the blood loss calculation, alongside hemoglobin and hematocrit before and after the surgery. The secondary outcome was the percentage of participants who progressed into primary PPH and required blood transfusion.
Results: Analyses included 132 women in each group, and results showed that TXA + Eth significantly reduced bleeding during and after cesarean section in pregnant women at high risk for PPH. In oxytocin and TXA + Eth groups, postoperative blood loss was (613.7 ± 123.7 and 406.2 ± 116.5) ml, respectively, P < 0.001. The duration of surgery in oxytocin and TXA + Eth groups were (48.5 ± 9.3) and (44.3 ± 9.8) minutes, respectively (P = 0.287). The blood transfusion requirement in the oxytocin and TXA + Eth groups were 10.69% and 0.75%, respectively (P = 0.023). The PPH in the oxytocin and TXA + Eth groups were 2.30% and 0%, respectively (p < 0.017). Pre- and postoperative hemoglobin and hematocrit values at 24 h after cesarean section in the oxytocin (10.78 and 8.29) and (32.23 + 25.10) and TXA + Eth groups were (11.07 and 10.02) and (33.20 and 30.73), respectively (P < 0.001).
Conclusion: The use of TXA and Eth is safe and more effective than oxytocin in minimizing blood loss, and the demand for blood transfusion after cesarean section.
Keywords: Blood loss, cesarean section, ethamsylate, oxytocin, tranexamic acid
|How to cite this URL:|
Singh S, Mishra R, Singh A, Shaifulla P. Comparative study of oxytocin versus tranexamic acid and ethamsylate in preventing primary postpartum hemorrhage in women undergoing lower-segment cesarean section. Formos J Surg [Epub ahead of print] [cited 2022 Aug 14]. Available from: https://www.e-fjs.org/preprintarticle.asp?id=351000
| Introduction|| |
Elective cesarean section (C/S) is a planned, procedure through incisions of the abdomen wall and lower uterine segment of the mother. Elective C/S is performed at the fetal viability and when vaginal delivery does not augur well for the safety of the baby or mother or both. The acceptable C/S rate recommended by the World Health Organization (WHO) for world communities is between 10% and 15%. Cesarean levels above this range may be termed misuse of the procedure. The worldwide rate of C/S is 21% and is expected to increase to 29% by 2030. The rate of C/S in some states of India, such as Kerala, Andhra Pradesh, and Jammu and Kashmir, is above 40%.
Worldwide, one-fourth of all maternal deaths are caused by postpartum hemorrhage (PPH). Its most common risk factors include multiple pregnancies, macrosomia, polyhydramnios, and previous PPH. PPH could be avoided most of the time through the prophylactic use of uterotonics agents. Therefore, drugs such as ergometrine, oxytocin, misoprostol, carbetocin, and carboprost were tested previously to reduce perioperative blood loss during C/S., The British journal of Obstetricians and Gynecologists emphasizes slow intravenous use of oxytocin 5 International Unit (IU) after fetal labor to urge contractions of the uterus, and hence, decrease intraoperative blood loss and thereby PPH. Efforts are made to prevent and control perioperative hemorrhages in high-risk PPH candidates. Prophylactic antifibrinolytic and hemostatic therapy is another approach to reducing hemorrhage using prohemostatic drugs such as tranexamic acid (TXA) and ethamsylate (Eth). TXA is a synthetically derived amino acid lysine that exerts its antifibrinolytic action through the reversible block of the lysine binding sites on the proenzyme plasminogen molecule. TXA has been routinely used for preventing and treating bleeding with promising results.,
Eth is a commonly available synthetic hemostatic drug that exerts its effect by improving platelet adhesiveness and restoring capillary endothelial resistance. In addition, the drug exerts anti-hyaluronidase action and improves capillary wall stability. Thus, it reduces capillary bleeding when platelets are inadequate in the blood. It also inhibits Prostacyclin I2 synthesis and normalizes abnormal platelet function.,
Some studies conducted in the past have shown that the use of TXA reduces bleeding and PPH,, and in contrast, few studies have reported no significant reduction in active bleeding with the addition of TXA to misoprostol treatment. Dixon et al. reported no difference between activated partial thromboplastin time, prothrombin time (PT), fibrinogen, plasminogen activator inhibitor, and tissue plasminogen activator in placebo and TXA groups at 6 h after administration. Wilde et al. reported no difference in blood loss between patients treated with one and two doses of TXA. The World Maternal Antifibrinolytic (WOMAN) Trial Collaborators reported no benefit from TXA administered more than 3 h postpartum. There is a controversy in the literature about the dose, timing of administration, and effectiveness of TXA in pregnant women at high risk of PPH.,,, There is a paucity of clinical trials that investigated the role of Eth in either prophylaxis or treatment of PPH. This study aimed to assess the efficacy of intravenous oxytocin versus TXA + Eth in reducing blood loss in pregnant women at high risk of primary PPH undergoing elective lower-segment C/S in the immediate 24 h postsurgery.
| Methods|| |
This was a single-center, prospective, randomized, and a double-blind study conducted at SAMSRI, Lucknow, India, between September 2021 and March 2022 after approval from the Institutional Ethical Clearance Committee on Human Research (Number: OBGH/1837/R/2021-22) SAMSRI, Lucknow, India. Inclusion criteria for the study were women in the age group of 20–40 years, with no medical disorders, at 38–40 weeks of gestation are at high risk for PPH (with one or more risk factors for PPH such as macrosomic baby [weight >4.5 kg]), multiple pregnancies, polyhydramnios (AFI >25 cm), obesity (body mass index [BMI >30], previous history of PPH) and planned for elective lower-segment C/S. Exclusion criteria included anemia, acute kidney or liver diseases, history of convulsions, deep venous thrombosis, the bleeding tendency disseminated intravascular coagulopathy, prolonged bleeding time/PT/thrombin time, disturbances of color vision, abnormal placentation (such as placenta previa, abruption placenta, or morbidly adherent placenta), allergy to TXA or Eth.
PPH is defined as blood loss greater than 500 mL after vaginal delivery and 750 Ml after C/S. Primary PPH occurs within the first 24 h after C/S. Data from the pilot study conducted to calculate the study sample size revealed that the risk of postpartum blood loss ≥750 ml was 11.82% in women who received TXA 1 g + Eth 250 mg in contrast to 28.94% in women who received Oxytocin 10 IU alone. Calculation according to these values produced a minimal sample size of 120 cases per group. We derived a mean difference of 9% with an SD of 17% from our pilot data and calculated that women per group would be needed with a two-sided α error of 0.05 and power of 0.8. A 10% of dropout was also added to the sample size. The required sample size (n) = ([estimated 120 and dropout 12]) =132 cases per group.
After ethical approval, all 264 study participants were involved in a discussion on the nature of the study, and informed written consent was obtained on the day of their scheduled L/S C/S. To sample 264 participants who met the eligibility criteria were identified each weekday from the registry of the theater manager's surgical caseloads, a balloting system was used with a total of 30 sheets of papers equally assigned “In” and “Out” for them to pick one at the point of recruitment. Those who selected “In” were enrolled till the sample size of 264 was reached to give an equal chance to the study population. Randomization of participants among the two study groups was performed using a computer-generated randomization program. To double-blind, neither the investigator nor the patient knew about the study drugs. For both groups, a 50 ml syringe was used to dilute study drugs in 0.9% NaCl to make it 50 ml and infused at a rate of 50 ml/h before taking the skin incision with an infusion pump.
The day before surgery, all participants underwent a pre-anesthetic evaluation. A detailed examination of the cardiovascular, respiratory, and central nervous systems was performed. For all gravid, weight, nutritional status, and airway assessment by the Mallampatti scoring system were recorded. In addition, preoperative obstetric ultrasonography to check fetal heart rate and routine investigations such as platelet count, hemoglobin, hematocrit, and blood group/Rh typing were rechecked. The spinal anesthesia procedure was explained to the participants on the day of surgery, and written informed consent was obtained for anesthesia and the surgery.
Intravenous access was secured, and Ringer's lactate solution infusion started. Patients were then shifted to the operating room, after which routine noninvasive monitoring was applied and vital signs monitored. After preloading the gravid with Ringer's lactate 15 ml/kg, in a lateral position, lumbar puncture was performed at L3-–4 level with Quincke type pencil-point 25 G × 90 mm disposable spinal needle. Injection bupivacaine 0.5% (Anawin heavy from Neon, India) 1.75 ml solution was injected intrathecally over 30 s and then turned to a supine position. Then, the surgeon started painting and draping the operating field and took the skin incision after confirming an adequate level of sensory loss. As per the group allocation injection, TXA 1gm (Tranexanaman from Naman Global Impex Pvt. Ltd, India) + Eth 250 mg (Ethamo from Zydus India) or oxytocin, 10 IU (Evatocin from Neon, India) infusion in 50 ml 0.9% NaCl, at a rate of 50 ml/h was started before the start of the skin incision with an infusion pump.
Mean arterial pressure (MAP), heart rate (HR), and oxygen saturation were monitored regularly throughout the surgery. Any fall in the HR below 60 beats/min and MAP below 65 mmHg were considered bradycardia and hypotension, respectively, and treated with incremental doses of injection atropine 0.3 mg IV and injection of ephedrine 10 mg, respectively. If any patient developed any complications was treated appropriately and excluded from the study.
Our Institutional protocols for obstetric hemorrhage and blood transfusion are similar to California Maternal Quality Care Collaborative Toolkit to Transform Maternity Care protocol: If Hb is <6 g/dl transfusions are indicated irrespective of the cause and condition of the patient. If Hb is between 6 and 10 g/dl, the indication will depend on whether the patient is actively bleeding or having a history of previous excessive hemorrhage or having some medical condition where optimal Hb is >7 g/dl is required. The common goal for transfusion in the obstetric patient is to achieve Hemoglobin >8 g/dl. The decision for transfusion should not be made based on Hb estimation alone. In addition, indications for transfusion include symptomatic anemia (causing shortness of breath, dizziness, congestive heart failure, and decreased exercise tolerance), acute sickle cell crisis, acute blood loss of more than 30% of blood volume and anemia with vital signs >15% change or HR ≥110, BP ≤85/45, oxygen saturation (SpO2) <95%.
Two variants calculated blood loss. The primary outcome was the blood loss calculation by calculating the difference between the weight of dry and wet gauzes and drapes soaked in blood and suctioned blood, along with the difference between hemoglobin and hematocrit before and after the surgery. The secondary outcome was the percentage of participants who progressed into PPH and required blood transfusion. Participants were given a brief orientation regarding signs and symptoms of a thromboembolic event and instructed to contact the investigating team member in case of need. All participants were examined for thromboembolic signs on follow-up at the 1 and 4 weeks.
Descriptive statistics for measured variables are 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). Data of both groups were compared using a t-test (for quantitative parametric measures), Mann–Whitney's U-test (for quantitative nonparametric measures), and Fisher's exact tests (for categorical measures). P < 0.05 was considered statistically significant. Statistical analysis was performed using the Statistical Package for the Social Sciences SPSS -23.0; IBM, Armonk, NY, the USA for Windows was used.
| Results|| |
Two hundred and sixty-four women who received either oxytocin 10 IU or TXA 1gm + Eth 250 mg were recruited during the study period. However, data from 263 (99.63%) women were analyzed. One woman (0.37%) was excluded from the study analysis due to sample attrition in the oxytocin group. The age, BMI, and gestational age in oxytocin and TXA + Eth groups were (29.0 ± 4.4 and 28.5 ± 4.3 years), (28.5 ± 5.2 and 26.1 ± 5.6 kg/m2) and (38.92 ± 0.40 and 38.87 ± 0.40 weeks), respectively. There was no significant difference in demographic between the oxytocin and TXA + Eth groups (P > 0.05) [Table 1].
There was a significant difference between the oxytocin and TXA + Eth groups regarding postoperative blood loss (613.7 ± 123.7 and 406.2 ± 116.5) ml, respectively, P < 0.001. The duration of surgery (DOS) in oxytocin and TXA + Eth groups were (48.5 ± 9.3) and (44.3 ± 9.8) minutes, respectively. The DOS was less in TXA + Eth group but statistically insignificant between the two groups (P = 0.287) [Table 2].
|Table 2: Comparison of intraoperative variables among the two study groups|
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The blood transfusion requirement in the oxytocin and TXA + Eth groups were 10.69% and 0.75%, respectively. The blood transfusion during surgery was statistically significant between the two groups (P = 0.023). The PPH in the oxytocin and TXA + Eth groups were 2.30% and 0%, respectively, and the PPH case in the oxytocin group were significantly more (P < 0.017) [Table 3].
|Table 3: Comparison of postoperative blood transfusion among the two study groups|
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In our study, pre- and postoperative hemoglobin values at 2 h after C/S in the oxytocin and TXA + Eth groups were (10.78 and 11.07) and (9.33 and 10.81), respectively. Postoperative hemoglobin was significantly higher in the TXA + Eth Group 2 h after C/S than in the oxytocin group (P < 0.001). Furthermore, postoperative hematocrit was significantly higher in the TXA + Eth group than in the oxytocin group at 2 h after C/S (P < 0.001). These findings of hemoglobin and hematocrit support each other [Table 4] and [Figure 1].
|Table 4: Comparison of perioperative variables among the two study groups at 2 and 24 h after cesarean section|
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|Figure 1: Comparison of hemoglobin and hematocrit levels between the Oxytocin and Tranexamic acid + Ethamsylate groups|
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Pre- and post-operative hemoglobin and hematocrit values at 24 h after C/S in the oxytocin (10.78 and 8.29) and (32.23 + 25.10) and TXA + Eth groups were (11.07 and 10.02) and (33.20 and 30.73), respectively. However, postoperative hemoglobin was significantly higher in the TXA + Eth group 24 h after C/S than in the oxytocin group (P < 0.001). Furthermore, postoperative hematocrit was significantly higher in the TXA + Eth group than in the oxytocin group after 24 h after C/S (P < 0.001). These findings of hemoglobin and hematocrit support each other [Table 4]. None of our participants had any complications such as seizure, renal dysfunction, or thromboembolic signs during surgery and on the follow-up at the 1 and 4 weeks.
| Discussion|| |
Cesarean section, known as an abdominal delivery, is a lifesaving procedure for the safety of the baby or mother or both. More than one million C/S are performed worldwide yearly. The rate of C/S rose from 5.6% in 1970 to 32% in 2019 and is expected to increase to 39% by 2030. In Indian states, Jammu and Kashmir, Kerala, and Andhra Pradesh C/S rate is more than 40%.
Obstetric hemorrhage contributes to about 25% of maternal deaths worldwide, and PPH is a well-known complication that increases the abdominal re-exploration rate, blood transfusion requirements, length of hospitalization, and cost. Therefore, every effort is made to prevent and control bleeding in the perioperative period. Prophylactic antifibrinolytic and hemostatic therapy is one approach to reducing postoperative bleeding. In 2017, the WHO recommended using antifibrinolytic for the treatment of PPH in case oxytocin and other ecbolics fail to stop the hemorrhage during vaginal delivery, regardless of the cause.
Aprotinin was the only extensively evaluated natural antifibrinolytic agent before 2008. However, the blood conservation using antifibrinolytics in a randomized trial showed an increased risk of allergic reaction and thrombosis leading to death with aprotinin, limiting its use., Due to these complications, its use has been scaled down to the commonly available antifibrinolytics like TXA and epsilon-aminocaproic acid (EACA). They are synthetic, cheaper, and readily available. Although some studies do not show any difference between TXA and EACA, while others showed that TXA is a more potent blood-sparing agent than EACA,, these findings encouraged us to consider using TXA over EACA for pregnant women at high risk for PPH in this study.
The side effects of antifibrinolytics like TXA include seizures, and renal dysfunction., For example, Martin et al. reported that 4.6% of patients had seizures who received 2 g TXA at the beginning of surgery and then a continuous infusion of 0.5 g/h till the end of surgery. It is worth noting that these women were exposed to a very high dose of TXA. In contrast, we used 1 g of TXA as a continuous infusion. Seizure and renal dysfunction were not reported in our study. However, the manufacturer's package insert indicates that TXA may cause focal and generalized seizures.
Clinical randomization of an antifibrinolytic in a significant hemorrhage-2 (CRASH-2) study showed that the use of TXA 3 h after injury was associated with an increase in mortality, which suggests administering TXA at the earliest possible. Therefore, in agreement with the CRASH-2 study, TXA was started before the skin incision in this study.
Torky et al., 2021, compared the effectiveness of TXA + Eth with placebo in reducing blood loss during elective C/S and concluded that both the drugs effectively reduce blood loss than placebo. Overall, the findings of our study match the findings of the study mentioned above. In our study, postoperative blood loss in oxytocin and TXA + Eth groups was 613.7 and 406.2 ml, respectively, and this was statistically significant less in the TXA + Eth group compared to the oxytocin group (P < 0.001). In addition, the hemoglobin (1.44 gm/dl) and hematocrit (4.66%) were higher in the TXA group. These values were statistically significant high in the TXA + Eth group compared to the oxytocin group. This is consistent with the recommendations of The British Journal of Obstetricians and Gynecologists that TXA effectively reduces blood loss during vaginal delivery.
In contrast, Diop et al. 2020 reported that controlling PPH with TXA + misoprostol and placebo + misoprostol was (56.9% TXA) and (60.2% placebo), respectively (P = 0.59). TXA showed an insignificant synergistic result compared to placebo in their study, which may be due to the different routes of drug administration and study design. They administered TXA orally, which may not confer the same effect as intravenous administration of TXA due to slow oral absorption and less bioavailability.
The present study showed that the DOS was shorter in the TXA + Eth group ranging from 29.0 to 59.0 (44.3) minutes, than in the oxytocin group ranging from 26.0 to 61.0 (48.5) minutes. Furthermore, the current result concurs with the study of Suryakumari and Parveen as they revealed that DOS was reduced in TXA + Eth groups due to less bleeding and wastage of less time to secure bleeder. However, in their study, DOS was statistically significant, P < 0.05, in contrast to statistically insignificant (P = 0.287) in our study.
Our study supports the WOMAN Trial, strengthening the place of TXA in PPH. WOMAN trial compared 1 gm TXA or placebo and concluded TXA decreased death due to bleeding (155 [1.5%] vs. 191 [1.9%]) and laparotomy for bleeding was also reduced (82 [0.8%] vs. 127 [1.3%], relative risk 0.64; 95% confidence interval 0.49-0.85; P = 0.002) after vaginal delivery and C/S with no adverse effects. There was a significant difference between the oxytocin and TXA + Eth groups in postoperative blood loss (613.7 ± 123.7 and 406.2 ± 116.5) ml, respectively, P < 0.001. Supported by pre and postoperative values of hemoglobin and hematocrit at 24 h after C/S were (10.78 and 8.29) and (32.23 and 25.10) in the oxytocin group (11.07 and 10.02) and (33.20 and 30.73) in TXA + Eth group, respectively (P < 0.001).
There is a paucity of clinical trials investigating the role of Eth in either prophylaxis or treatment of PPH. Our study was the first to use TXA and Eth to reduce blood loss in the elective lower-segment C/S in pregnant women at high risk for PPH, giving it a pilot nature.
| Conclusion|| |
The current results demonstrated that TXA and Eth could be safely used to reduce bleeding during C/S in pregnant women at high risk for PPH. TXA + Eth appears to be a safe and effective option in treating obstetric hemorrhage. Further research with large numbers of patients with different dosage and administration routes is preferable to compare each route's efficacy.
All the data are available within the manuscript. In addition, the datasets used and analyzed during the current study are available from the corresponding author based on reasonable request.
The authors declare that this paper is their original work and has never been published. However, all directly quoted material has been appropriately referenced.
Special thanks to expert panel members: Associate professor Ahmed Ibrahim (M.A., MPhil, PhD.) Department of English for their contributions to Proofreading, Dr. Meera Battra (MD, PhD.) Department of Medical statistics for statistical support and Dr. Mithlesh Govil (MBBS, MS) Department of Obstetrics and Gynecology for study coordination and assistance with research approvals. From SAMSRI, Lucknow, India.
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]