The evolving role of prophylactic use of tranexamic acid before cesarean section: balance between maternal benefits and unknown neonatal effects

Tranexamic acid (TXA), an antifibrinolytic agent, has recently been investigated as a potentially useful drug for both prevention and treatment of Primary Postpartum Hemorrhage (PPH). This article highlights the continuing evolvement of this antifibrinolytic medication in the broad field of anesthesiology, and more specifically, obstetric anesthesiology, focusing on three important aspects of TXA administration: the continuing studies and assessment of the potential benefits of TXA administration to minimize PPH in both non high risk and high risk parturients, the possible adverse effects of TXA on the mother, and finally the unknown risks of the administration of TXA to the neonate. Although there is promise in the use of TXA for prevention and treatment of PPH, large, high quality randomized controlled trials are necessary on all three of these aspects before its widespread use can be recommended safely. Until that time, it is imperative that the anesthesiologist be well informed on this delicate balance of potential benefit of TXA to the mother versus potential and unknown risk to the mother and neonate.


Introduction
Primary postpartum hemorrhage (PPH) is a major cause of maternal mortality, accounting for close to one-quarter of all maternal deaths worldwide [1]. Until recently, uterotonic medications, specifically oxytocin, have been the only drugs shown to decrease PPH. Given that PPH remains a major cause of maternal mortality worldwide, there is a need for additional treatments and interventions. Tranexamic acid (TXA), an antifibrinolytic agent, has recently been investigated as a potentially useful drug for both prevention and treatment of PPH [1]. It has also been shown to reduce blood loss in elective surgery, cardiac surgery, and trauma. It has also been used to reduce menstrual blood loss [1]. TXA appears to be a promising drug for prevention and treatment of PPH after both vaginal and cesarean deliveries. However, as studies are currently ongoing to assess these benefits and unknown risks, the anesthesiologist must be aware of the evolving knowledge of TXA in the obstetric setting in order to maximize the beneficial effects on the mother while concurrently minimizing any potential deleterious effects on the neonate.

Review
Primary postpartum hemorrhage (PPH) is classically defined as blood loss of ≥500 mL for a vaginal delivery and ≥1000 mL for a cesarean delivery in the first 24 hours after delivery [2]. It is a major cause of maternal mortality and accounts for about one-quarter of all maternal deaths worldwide [1]. The leading cause of massive obstetric hemorrhage is uterine atony [3,4], but obstetric complications such as placental abruption, placenta accreta, and amniotic fluid embolism may also precipitate obstetric hemorrhage, often times complicated by consumptive coagulopathy [4]. Risk factors for PPH include previous PPH, obesity, prolonged labor, multiple pregnancies, prior caesarean delivery, primiparity, polyhydramnios, and macrosomia [5].
The coagulation and fibrinolytic systems are believed to be in a state of dynamic balance that maintains an intact vascular  [6]. During delivery, when the placenta separates from the uterine wall, physiologic and hemostatic changes occur sequentially to reduce bleeding: strong myometrial contractions, increased platelet activity, massive release of coagulation factors and consequently a parallel increase in fibrinolytic activity [7]. Tranexamic acid (TXA) is a potent antifibrinolytic agent that exerts its effects by blocking the link between plasminogen kringle 5 and lysine site of the fibrin heavy chain at one of the sites where antiplasmin and thrombin-activatable fibrinolysis inhibitor (TAFI) have their potential action. Thus, depending on the dose and the condition of the tertiary complex elements of the patient (tPA-Native Fibrin-plasminogen) and the secretion of the natural antifibrinolytic (antiplasmin depending on the liver function and TAFI depending on the thrombin secretion), tranexamic acid can supply a deficient natural antifibrinolysis or be competitive with it. This is one of the challenges of future trials to determine the optimal dose and the best timing of administration in the course of the fibrinolytic process.
The majority of the larger studies regarding TXA have been focused on broader categories of surgical patients. The Clinical Randomisation of an Antifibrinolytic in Significant Haemorrhage-2 (CRASH-2) trial randomized more than 20,000 adult trauma patients to receive empiric tranexamic acid within 8 hours of injury or placebo. The study not only found a significant decrease in all-cause mortality (14.5% vs 16%, relative risk: 0.91, 95% CI: 0.85-0.97, P=0.0035) as well as mortality due to hemorrhage (4.9% vs 5.7%) in the tranexamic acid group, but importantly showed no significant increase in thromboembolic complications in subjects receiving tranexamic acid [8].
With regards to studies specifically addressing TXA effects on prevention of PPH, a recent article by L. Sentilhes et al., published in the British Journal of Anesthesia found 10 published Randomized Controlled Trials (RCT) evaluating the efficacy of TXA in preventing PPH after elective non haemorrhagic caesarean delivery [1]. Their characteristics are summarized in a table created by L. Sentilhes and can be seen here in Table 1. The 10 published RCTs that have assessed the effects of TXA in preventing PPH during caesarean deliveries showed a significant reduction in blood loss in patients who received TXA and no increase in the incidence of adverse events [1] ( Table 1). Although these results are promising and support the use of TXA, it must be noted that majority of these RCTs included small sample sizes with inadequate power to fully assess the risk of adverse effects.
Of these 10 RCTs, one in particular, Goswami et al., demonstrated a decrease in estimated blood loss when tranexamic acid was used prophylactically before elective caesarean section in anemic patients [9]. In the study, it was found that even minimal blood loss reduction probably helped to avoid packed red blood cell transfusion in the two TXA groups compared to the placebo group [9]. The choice of this particular population of high risk obstetric parturients is of high importance. Even if the outcome of the currenty ongoing clinical trials reveals there is minimal benefit on mortality to using TXA on non high-risk patients, this particular study highlights the need for more focused studies on the targeted use of TXA in treating high risk obstetric patients. High risk obstetric patients specifically include the populations of anemic patients as well as mothers with high risk obstetric conditions including placental abruptions or abnormal placentation, including placenta accreta, increta, and percreta. Even minimal blood loss in these patients can have a far more devastating outcome on the patient and even a minimal reduction in bleeding can potentially be of great benefit.
There are very few studies specifically addressing the adverse effects or even the possible risks of TXA. A recent study by Kratzer et al., concluded that TXA administered at clinically relevant concentrations increases the propagation of neuronal excitation in the basolateral nucleus of the amygdala. The observed enhancement of neuronal excitation arises from reduced synaptic inhibition rather than from increased neuronal excitability [10]. TXA impairs neuronal inhibition by a postsynaptic antagonism against GABA A receptors. In contrast, TXA does not affect the excitatory glutamatergic synaptic transmission. Because inhibitors of GABA A receptors are known to act in a proconvulsant manner, this mechanism of action may explain the increased incidence of seizures in patients treated with TXA [10]. This study elucidates a potential mechanism for the neuronal excitation and subsequent seizures that have been seen with TXA administration.
Given the sparsity of studies of maternal adverse effects with TXA, it should not be surprising that there are even fewer assessing the potential risks to the neonate. A recent study by Yee et al., found the effective concentration of TXA in neonatal plasma (in vitro) that inhibits fibrinolysis is far lower than the concentration needed in adults [11]. These two aforementioned studies speak for caution regarding neonatal exposure: there is a potential mechanism for seizures, and in addition the neonate may be more sensitive to low drug levels. These studies point to the need for further studies to be done asssessing the serum levels associated with neonatal seizures. As a result, this places even more importance on the timing of TXA administration. Until that information is obtained, it may be imperitive to continue suggesting that the drug be held until the cord is clamped. Most of the RCTs that have been completed at this time have involved the administration of the TXA well before the cord is clamped. Neonatal exposure will occur when TXA is given before the cord is clamped, as TXA is known to cross the placenta [12].
However, the unknown potential neonatal effect on a predelivery administration of TXA could have more potential clarity given the results of a very recent study by Wesley et al., on the pharmacokinetics of TXA in neonatal cardiac surgerywith cardiopulmonary bypass [13]. This study was the first population pharmacokinetic analysis of TXA in neonates and young infants undergoing cardiac surgery. The most Their study also highlights that a single dose schedule used across all age ranges to achieve a desired plasma TXA concentration is unlikely to be effective [13]. Alternatively, a study by O. Gilad et al., evaluated the outcome of infants exposed to tranexamic acid during lactation. The results of their study found no increase in adverse longterm outcomes in infants exposed through breastfeeding to tranexamic acid. Their data, in conjunction with previous estimates of very low drug exposure, support continuation of breastfeeding in women treated with tranexamic acid [14]. This study compared to the prior two mentioned studies highlight the lack of concrete evidence of adverse effects of TXA on the neonate.

Conclusions
Although there is promise in the use of TXA for prevention and treatment of PPH, large, high quality RCTs are necessary before widespread usage can be supported and considered safe for administration. Of note, The World Maternal Antifibrinolytic Trial (WOMAN) trial, which is a large, international randomized placebo controlled study, is currently ongoing at this time to compare the impact of a 1 g dose of TXA at the onset of post-partum bleeding on mortality [15]. The results of this study should provide more evidence about the potential benefits of TXA to the mother.