Ideal time for administration of prophylactic tranexamic acid for reducing blood loss and preventing postpartum hemorrhage in cesarean delivery in a tertiary health care centre: A single-centre, double-blind, randomized controlled non-inferiority trial.

Post-partum hemorrhage is characterized by a cumulative blood volume loss (encompassing both intrapartum and postpartum bleeding) equal to or exceeding 500 ml subsequent to a vaginal delivery, or 1000 ml following a cesarean delivery. Alternatively, it includes blood loss accompanied by clinical manifestations of hypovolemia, such as increased heart rate, low blood pressure, rapid breathing, reduced urine output, dizziness, pallor, or changes in mental alertness, all occurring within 24 hours of the childbirth process**.** Worldwide post-partum hemorrhage accounts for 27% of maternal deaths. Some countries have reported this figure as high as 60%. It is the most important cause of maternal mortality & morbidity especially in the middle and low income countries. In India, deaths due to PPH were reported to be 38%(RGI-SRS 2001-2003). Some of the risk factors contributing to the occurrence of Post partum hemorrhage include Body Mass Index (BMI) >35, anemia (Hb <10.5g/dl), leiomyomas, adenomyosis, induced labor, labor prolonged >12hours, oxytocin use, multiple pregnancies, parity >5, polyhydramnios, fetal macrosomia (>4Kg), history of PPH, history of previous cesarean section and placenta previa**.** It is crucial to emphasize that the existence of these risk factors does not assure the occurrence of PPH; however, they might elevate the probability. Top of FormIdentifying these risk factors and implementing appropriate preventive measures, including close monitoring during labor, judicious use of interventions, and readiness to manage complications, can contribute to the prevention and effective management of postpartum hemorrhage.

In 2017, the WOMAN Trial, showed that Tranexamic acid when given early, within 3hours of birth, decreases deaths due to PPH by one-third. promptly**.** In a matter of months following this pivotal trial, the World Health Organization (WHO) revised the directives for managing PPH. The updated guidance advocates the prompt administration of intravenous tranexamic acid, within a three-hour window from childbirth, alongside standard care, for women diagnosed with PPH after either vaginal or cesarean delivery**.** In accordance with the dosage regimen employed in the study, it is advised to administer a 1g dose of intravenous (IV) tranexamic acid (100mg/ml) over a 10-minute period, with a subsequent 1g IV dose if bleeding persists after 30 minutes or resumes within 24 hours**.** Though it has been postulated that this drug may act to prevent PPH, currently the evidence supporting this is insufficient and needs further studies**.** In a recent meta-analysis, that included 50 randomized control trials evaluating the role of administering Tranexamic acid prophylactically to reduce post-partum hemorrhage in low and high risk women who underwent caesarean delivery**.** The study concluded that tranexamic acid decreases the risk of blood loss >1000ml in both high & low risk women. It might also reduce the mean total blood loss in both groups, the effect being more pronounced in the high risk group compared to the low risk population. A subgroup analysis examining the timing of administering tranexamic acid for blood loss exceeding 1000 ml was conducted. Among the 15 studies, tranexamic acid was administered before skin incision, while in 3 studies, it was given after birth or cord clamping. According to the analysis, trials in which tranexamic acid was administered before skin incision exhibited a more favorable outcome (Relative Risk, 0.33; 95% Confidence Interval, 0.25-0.44; I2=0%) compared to those in which the drug was administered after birth or cord clamping (Relative Risk, 0.86; 95% Confidence Interval, 0.79-0.93; I2=0%; p value < 0.001).While numerous small trials have shown the positive effect of prophylactic tranexamic acid, two of the largest trial with a total of 4431 & 11000 participants reported unsubstantial benefit in decreasing the risk of PPH in the low risk population**.** This contrasting result can partly be attributed to the timing of tranexamic acid administration which was after cord clamping in both the studies. Studies focusing on the timing of administration TXA are lacking to accept or refute these findings. Additional studies are needed to conclude on the ideal time for prophylactic tranexamic acid for reducing blood loss and preventing PPH in women undergoing caesarean deliveries. At present, to the best of our knowledge, there is no study directly comparing the effects of this drug when given before skin incision to that after cord clamping. This research will be the inaugural endeavor of its nature to assess the decrease in blood loss in caesarean deliveries by comparing the timing of prophylactic tranexamic acid administration.This research endeavor seeks to execute a randomized, double-blind, non-inferiority trial, to assess and compare the effectiveness of prophylactic tranexamic acid administered at two distinct time points in reducing blood loss. The overarching aim is to ascertain the optimal timing for the administration of tranexamic acid to prevent post-partum hemorrhage (PPH) in cesarean deliveries.