REVIEW ARTICLE

 

Tranexamic acid use in neonates and children: a narrative review of current evidence, and knowledge gaps

 

 

Joseline Nkhoma; Harrilene Apleni; Gontse Leballo; Palesa Motshabi Chakane; Moses Kebalepile

Department of Anaesthesiology, School of Clinical Medicine, Faculty of Health Sciences, University of Witwatersrand

Correspondence

 

 

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ABSTRACT

BACKGROUND: Neonatal anaemia is common, particularly in preterm and critically ill infants, and is frequently managed with red blood cell transfusion despite well-recognised associated morbidity. Patient blood management strategies aim to reduce transfusion exposure, and tranexamic acid (TXA) has emerged as a potential pharmacological adjunct. However, evidence supporting the use of TXA in neonates remains limited
METHODS: We conducted a comprehensive narrative review of peer-reviewed literature published between January 2015 and December 2025. Searches were performed in PubMed/MEDLINE, Scopus, and Web of Science using Medical Subject Headings and keyword combinations related to neonates, children, blood conservation strategies, and TXA. Eligible studies included systematic reviews, randomised controlled trials, observational cohort studies, and case reports evaluating TXA use in paediatric and neonatal populations across surgical, critical care, and selected medical contexts. Adult-only and animal studies were excluded. Findings were synthesised qualitatively
RESULTS: Seventeen studies met the inclusion criteria. Evidence consistently supports the use of TXA as part of multimodal blood-conservation strategies in elective paediatric surgery with predictable bleeding, particularly in craniosynostosis surgery, where reductions in blood loss and transfusion requirements were observed. In paediatric cardiac surgery and life-threatening haemorrhage, TXA may reduce bleeding and early mortality; however, benefits were less consistent in neonates. Evidence for TXA use in neonatal medical indications was sparse and inconclusive. Safety data suggest a dose- and context-dependent risk of seizures, with limited neonatal-specific adverse event reporting
CONCLUSION: TXA shows promise as a pharmacological blood conservation strategy in selected paediatric surgical populations, but evidence supporting its routine use in neonates remains limited. The unique haemostatic physiology, immature renal clearance, and neurological vulnerability of neonates necessitate cautious use. High-quality neonatal pharmacokinetic studies and prospective trials are urgently needed to define optimal dosing, safety, and efficacy before widespread adoption in neonatal practice

Keywords: neonatal anaemia; tranexamic acid; patient blood management; blood conservation strategies; neonatal surgery; transfusion

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INTRODUCTION

Anaemia is a major global health problem, affecting nearly one-third of the world's population,(1) and is associated with a disproportionate burden of morbidity and mortality in infants and children. Approximately 29% of newborns develop anaemia, with preterm infants, particularly those with extremely low birth weight (ELBW), at substantially higher risk.(1,2) Neonatal anaemia results from blood loss, reduced red blood cell (RBC) production, or increased RBC destruction.(3) In preterm and critically ill neonates, anaemia is often more severe, compromising tissue oxygen delivery and contributing to adverse short- and long-term outcomes.(4) These vulnerable infants frequently require perioperative blood transfusion; however, transfusion exposure is consistently associated with poorer outcomes. Transfused neonates have significantly higher morbidity compared with non-transfused infants (46.2% vs. 16.2%, p < 0.01).(5)

Anaemia, commonly defined using a haematocrit (HcT) threshold of 40%, has been identified as an independent predictor of in-hospital mortality.(6) Clinically, neonatal anaemia may present subtly but can progress to cerebral hypoxia and long-term neurodevelopmental impairment if severe.(7) More than 80% of ELBW infants receive at least one RBC transfusion during hospitalisation.(8,9) Blood conservation strategies have been reported to be efficacious, with a one-third reduction in blood loss and a significant decrease in transfusion requirements (41% vs. 73%; RR = 0.56; p = 0.001).(10) Therefore, optimising perioperative blood management is critical for improving neonatal out-comes.(6,11,12)

Physiological anaemia of infancy occurs in all neo-nates due to reduced erythropoietin (EPO) production, transition from foetal to adult haemoglobin, shortened RBC lifespan, and haemodilution with growth.(4) While this typically resolves without intervention in term neo-nates,(13) preterm neonates experience anaemia that is earlier, more profound, and prolonged, termed anaemia of prematurity, driven by immature erythropoiesis and bone marrow function.(14,15) Consequently, RBC transfusions are frequently required to support oxygen delivery in this population.(13)

Despite advances in transfusion medicine, neonatal transfusion practices remain highly variable, reflecting a lack of consensus on optimal thresholds and strategies.(16,17) Transfusion decisions are guided by gestational age, birth weight, haemodynamic status, and laboratory indices, with adjunctive tools such as echocardiography and near-infrared spectroscopy (NIRS) increasingly explored to refine clinical judgement.(3,18) However, transfusions carry substantial risks in neonates, including infection, transfusion-related lung injury (TRALI), circulatory overload, and associations with bronchopulmonary dysplasia (BPD), retinopathy of prematurity (ROP), intraventricular haemorrhage (IVH), and necrotising enterocolitis (NEC).(19-22) These risks highlight the need for safe and effective blood-conservation strategies, coupled with evidence-based practices.

Perioperative patient blood management (PBM) and blood conservation strategies aim to reduce blood loss and transfusion exposure by optimising preoperative anaemia, meticulous surgical and anaesthetic techniques, and goal-directed transfusion practices.(23-25) Many conventional blood-conservation methods are unsuitable in neonates due to limited blood volume and physiological reserve, underscoring the importance of potent pharmacological approaches.

Tranexamic acid (TXA), a synthetic lysine analogue that inhibits fibrinolysis, has emerged as a potent and key pharmacological blood-conservation strategy. TXA inhibits fibrinolysis by blocking the binding of plasminogen to fibrin, thereby preventing its conversion to plasmin and subsequent clot breakdown.(26,27) By preserving existing clots rather than promoting new clot formation, TXA enhances clot stability and reduces ongoing and excessive bleeding by targeting the final common pathway of haemorrhage.(28) While well established in paediatric and neonatal cardiac surgery,(29,30) TXA is increasingly used off-label in non-cardiac paediatric settings.(26,31) However, evidence regarding its safety, dosing, and effectiveness in neonates remains heterogeneous and incompletely synthesised.

This narrative review aims to synthesise the current evidence on the use of TXA as a pharmacological blood conservation strategy in paediatric patients, with a particular focus on neonates, and to identify key knowledge gaps to inform future research and clinical practice.

 

METHODS

Review design

This narrative review evaluated the perioperative and clinical application of TXA in paediatric patients, with particular emphasis on the neonatal population, highlighting current evidence and identifying existing knowledge gaps.

Literature search strategy

The review was conducted using a structured and transparent methodology by two reviewers (GL and MK). A focused search of peer-reviewed literature published between January 2015 and December 2025 was undertaken across three electronic databases: PubMed/MEDLINE, Scopus, and Web of Science. The search strategy combined Medical Subject Headings (MeSH) and relevant keywords, including neonates, newborns, blood conservation strategies, and tranexamic acid. The complete search strategy is presented in Table 1.

Eligibility criteria

EndNote 20 (Clarivate Analytics, Philadelphia, USA, 2022) was used to export study records identified across the different search engines, to identify and remove duplicate citations, and to manage the screening of titles, abstracts, and full-text articles. Peer-reviewed journal articles were included if they examined the use of TXA in children and neonates within the perioperative period, intensive care settings, or other relevant medical contexts where its use has been reported or proposed. Eligible study designs included systematic reviews, meta-analyses, narrative reviews, randomised controlled trials (RCTs), case reports, and observational cohort studies that evaluated TXA as a pharmacological blood conservation strategy. Only full-text articles published in English were included. Studies involving adult populations and animal models were excluded. Figure 1 illustrates the literature identification, screening, and study inclusion process.

 

 

Risk of bias (quality) assessment

Given the substantial heterogeneity of study designs included in this narrative review; RCTs, systematic reviews, meta-analyses, observational studies, narrative reviews, and case reports, a single unified risk-of-bias tool was not applied. Instead, the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework was used to assess the overall certainty of evidence. GRADE was selected because it allows structured appraisal across diverse evidence types by considering key domains including risk of bias, inconsistency, indirectness, imprecision, and publication bias, rather than relying on design-specific tools that are not directly comparable across heterogeneous study designs.

Data extraction and synthesis

Following study selection, a narrative synthesis was undertaken to integrate findings across heterogeneous study designs, populations, and clinical contexts. The retained evidence clustered into distinct clinical domains. These results were synthesised qualitatively, and the strength and certainty of evidence were assessed descriptively, considering study design, risk of bias, consistency of findings, and applicability to paediatric and neonatal populations.

 

RESULTS

A structured literature search identified 60 peer-reviewed studies, of which three were duplicates. Following title and abstract screening, 34 studies were excluded as they primarily involved adult obstetric populations and did not meet the inclusion criteria. Full-text screening of the remaining articles identified 17 studies for inclusion in the narrative synthesis (Figure 1). These studies examined TXA use across elective surgical, cardiac, trauma, and massive haemorrhage contexts, as well as selected paediatric and neonatal medical contexts, with substantial variability in the certainty of the evidence across indications and age groups. The majority of included studies demonstrated moderate certainty of evidence according to the GRADE assessment (47%), while 29% were rated as very low certainty (Table 2). No included studies were assessed as having high certainty of evidence.

Across the retained studies, the evidence on tranexamic acid can be synthesised into four key clinical domains: (i) elective surgery with predictable bleeding, (ii) efficacy of tranexamic acid in reducing bleeding and transfusion requirements and life-threatening haemorrhage, (iii) safety outcomes, including seizures, thrombotic events, and renal effects, and (iv) neonatal medical indications for tranexamic acid use. Table 3 summarises the included studies, with particular emphasis on study design and key findings.

Elective surgery and bleeding

Moderate certainty evidence across multiple study designs, as assessed using the GRADE approach, including prospective single-centre cohorts, RCTs, and systematic reviews with meta-analyses, demonstrates consistent reductions in peri-operative allogeneic blood product use among neonatal and paediatric patients receiving TXA during cranial vault surgery.(32,35,47) A 2015 systematic review and meta-analysis of children undergoing craniosynostosis surgery, with a mean age ranging from 2 months to 4 years, reported a significant reduction in allogeneic blood transfusion volume in the TXA compared with controls (mean difference -111.6 mL, 95% CI -207.1 to -16.1 mL; = 51%; p = 0.002).(32)

In a single-centre prospective observational cohort study, Wood and colleagues evaluated 279 children aged 1 year or younger undergoing craniosynostosis surgery and demonstrated a significant reduction in intraopera-tive blood loss following implementation of a multimodal blood-conservation protocol.(47) This protocol included TXA administered at a loading dose of 20 mg/kg followed by an infusion of 10 mg/kg/h and was associated with substantially lower blood loss compared with standard care (6.6 mL vs. 24.8 mL, p < 0.001). However, as TXA formed part of a comprehensive strategy that also incorporated modified surgical techniques, preoperative EPO administration, local anaesthetic infiltration, and hypervolaemic haemodilution, the independent effect of TXA cannot be isolated.

In contrast, a retrospective study reported higher estimated blood loss (EBL) in patients who received TXA compared with those who did not (274 mL vs. 138 mL) in a cohort with a mean age of 3.4 ± 1.2 months.(38) This finding likely reflects confounding by indication, as TXA was preferentially administered to patients undergoing more complex or extensive procedures, highlighting the challenges of interpreting observational data in this setting.

In paediatric cardiac surgery with cardiopulmonary bypass (CPB), the results on TXA efficacy were less uniform. Observational comparative studies suggest that TXA was associated with lower overall blood product exposure when compared with historical antifibrinolytics or alternative agents.(36,44,46) These benefits were more consistently observed in infants and children beyond the immediate neonatal period. In neonates, however, transfusion requirements remained high irrespective of the antifibrinolytic agent used, including TXA or epsilon-aminocaproic acid (EACA).

Furthermore, a systematic review and Delphi consensus from the Paediatric Extracorporeal Membrane Oxygenation Anticoagulation Collaborative (PEACE) identified only a single neonatal study involving congenital heart disease in which tranexamic acid use was associated with reduced bleeding and transfusion requirements.(40) The evidence in neonates was heterogeneous, sparse, and inconclusive, highlighting the limited and low-certainty evidence in this population.

TXA efficacy in life-threatening bleeding and massive transfusion

Studies evaluating TXA efficacy in life-threatening haemorrhage, including trauma and massive transfusion scenarios, suggest a potential early benefit. A secondary analysis of a large prospective paediatric dataset demonstrated that early administration of antifibrinolytic agents, including TXA, was associated with reduced early (6-hour) mortality. (41) These results suggest a potential early survival benefit from attenuating hyperfibrinolysis during acute bleeding.

Nevertheless, TXA was administered as part of complex resuscitation bundles, and the observational nature of these analyses introduces substantial confounding by indication. Consequently, while these data support biological plausibility and align with trauma evidence, the certainty of benefit in paediatric trauma and massive haemorrhage remains low to moderate.

TXA and safety outcomes

Principal adverse effects associated with TXA include an increased risk of seizures, thromboembolic events, and renal complications. A narrative review exploring multimodal PBM strategies and antifibrinolytic profile of different pharmacotherapeutic agents reported no thromboembolic risk following TXA use.(33) A neonatal-specific study evaluating infants undergoing cardiac surgery with CPB and directly comparing TXA with EACA demonstrated no increase in seizure incidence in the low-dose TXA group.

In contrast, a higher seizure frequency was observed in the EACA cohort.(43) An increased risk of acute kidney injury (AKI) was reported in paediatric cohorts receiving EACA, whereas no associated increase in AKI was observed with TXA administration.(41)

Neonatal TXA use indications

Evidence for TXA use in neonatal medical haemorrhage remains limited and inconsistent. Reports involving conditions such as haemophilia, factor X deficiency, and thrombocytopenia have yielded conflicting findings. A single neonatal case report described an episode of hypercoagu-lability following TXA administration,(45) while available evidence in newborns with haemophilia has been insufficient to support routine use in this subgroup.(42) Similarly, studies investigating TXA for the prevention of IVH in ELBW neonates have demonstrated no clinically or statistically significant benefit.(48)

In contrast, a single case report of a neonate with factor X deficiency described resolution of gastrointestinal bleeding following tranexamic acid administration; however, the concurrent use of fresh frozen plasma limits attribution of efficacy to tranexamic acid alone.(34)

 

DISCUSSION

This narrative review evaluated the role of TXA as a pharmacological blood conservation strategy in paediatric patients, with particular emphasis on neonates. The overall body of evidence suggests that TXA has a clearly defined role in selected paediatric surgical populations, while its application in neonates remains limited by physiological complexity, inconsistent efficacy signals, and a paucity of neonatal-specific safety data.

A key finding emerging from this synthesis is that TXA appears most beneficial when used in procedural contexts with predictable, surgical bleeding and when incorporated into structured, multimodal PBM strategies. In these settings, TXA functions as an adjunct to haemostatic optimisation by attenuating surgery and CPB-triggered hyperfibrinolysis, thereby supporting early clot stability and reducing exposure to allogeneic transfusion when other contributors to bleeding (temperature, calcium, fibrinogen, platelets, surgical haemostasis) are simultaneously addressed.(49) Paediatric PBM frameworks emphasise that antifibrinolytics are most effective when combined with broader strategies such as preoperative anaemia management, minimisation of iatrogenic haemodilution, meticulous operative technique, point-of-care coagulation-guided transfusion, and targeted factor therapy, reinforcing that TXA is rarely a single-solution intervention.(33) Importantly, the more consistent benefit observed in older infants and children contrasts with the variability reported in neonates, which likely reflects developmental differences in haemostasis, circulating blood volume, and pharmacology. Neonates exhibit developmental haemostasis, including lower plasminogen concentrations at birth, age-dependent differences in fibrinolytic regulation, and immature renal clearance mechanisms.(50,51) These features may blunt the net antifibrinolytic effect achievable with TXA compared with older children in whom fibrinolysis and compensatory haemostatic mechanisms are more mature.(52) These challenges are amplified in high-complexity haemostatic environments such as CPB and ECMO where bleeding is multifactorial and not exclusively fibrinolytic. In such contexts, CPB-related bleeding in neonates is driven by a convergence of haemodilution (small circulating volume relative to prime), platelet dysfunction or consumption, inflammatory activation, and circuit-related perturbations of coagulation and fibrinolysis, alongside procedure-specific surgical bleeding risk.(53-55) Therefore, even if TXA successfully reduces fibrinolysis, the dominant haemostatic limitation may be platelet dysfunction or dilutional hypofibrinogenaemia, thereby constraining the isolated impact of TXA unless PBM elements that address these parallel pathways are implemented. Consistent with this mechanistic rationale, neonatal-focused clinical evidence has been more heterogeneous than broader paediatric datasets, and systematic reviews continue to highlight variability in effect estimates and outcomes across paediatric cardiac surgery populations.(56) This supports an interpretation that TXA's apparent benefit is context-dependent, with the strongest signal occurring where fibrinolysis is a principal driver of bleeding and where multimodal PBM reduces competing causes of haemorrhage.

The evidence base supporting TXA use outside elective surgical settings remains comparatively limited and less robust methodologically. While TXA appears biologically plausible in life-threatening haemorrhage and massive transfusion scenarios, available data are largely observational and embedded within complex resuscitation bundles.(57) The majority of supporting data in these contexts derive from adult trauma and obstetric populations, and from observational paediatric series rather than randomised neonatal trials.

As a result, causal attribution remains uncertain, and the magnitude of the TXA-specific benefit cannot be reliably quantified, particularly in neonates. Large landmark studies, such as the CRASH-2 and WOMAN trials,(58,59) demonstrated a mortality benefit with early TXA administration; however, their findings cannot be directly extrapolated to neonates given fundamental differences in haemostatic physiology, injury patterns, and competing causes of bleeding. While TXA remains a biologically rational adjunct in severe haemorrhage, the magnitude of benefit specific to TXA in non-elective neonatal settings cannot be reliably quantified with the current evidence base. This uncertainty underscores the need for prospective, context-specific studies and for cautious interpretation of observational data when TXA is used within bundled resuscitation strategies rather than as an isolated intervention Off-label TXA use for neonatal medical haemorrhage highlights a clinically important gap between perceived need and evidentiary support. Although TXA is mechanistically attractive as an antifibrinolytic, neonatal bleeding phenotypes are heterogeneous and frequently reflect developmental haemostasis and systemic illness rather than isolated hyperfibrinolysis. In the study included in the review by Yao et al. on early IVH prevention, early randomised evidence demonstrated biochemical suppression of fibrinolysis without a corresponding reduction in haemorrhage incidence.(48) This suggests that fibrinolysis is unlikely to be the dominant modifiable driver of IVH in very preterm infants and that TXA's effect may not translate into meaningful clinical benefit in this indication. Broader syntheses of IVH prevention interventions similarly do not support TXA as an effective preventive therapy, reinforcing that routine prophylactic use in this setting is not evidence-based.

For inherited bleeding disorders and other neonatal medical haemorrhage indications, the literature remains limited and is largely composed of small series and isolated reports, typically in conjunction with concurrent haemostatic therapies.(34,42,45)In haemophilia, major international guidance positions antifibrinolytics as adjuncts, particularly for mucosal bleeding and dental/ENT procedures, rather than definitive stand-alone therapy, which further supports cautious interpretation of apparent "TXA success" in case-based neonatal reports where factor replacement or other haemostatic optimisation is occurring simultaneously.(60) Collectively, these findings support the conclusion that routine TXA use for neonatal medical haemorrhage cannot currently be recommended, and that future research should prioritise clearly defined haemorrhage phenotypes, standardised co-interventions, and prospective evaluation to isolate TXA-specific effects.

Safety considerations remain central to TXA use in neonates, particularly given the vulnerability of the developing brain and the immaturity of renal clearance pathways. Among reported adverse events, neurological complications, most notably seizures, represent the most consistent safety signal associated with TXA exposure. The available evidence suggests that seizure risk is dose-dependent and context-specific, with neonatal-specific studies using low-dose regimens not demonstrating the same risk profile observed in larger paediatric cohorts.(56) Importantly, no consistent association between TXA and thromboembolic events has been demonstrated, and renal adverse effects appear more prominent with alternative antifibrinolytic agents. Nevertheless, the absence of strong safety signals must be interpreted in light of the limited statistical power of existing neonatal studies, which are typically under-represented, heterogeneous, and not designed to detect rare adverse events.

Given that TXA is predominantly renally eliminated, and that neonatal glomerular filtration and tubular handling mature over the first weeks of life, inter-individual variability in drug exposure remains a legitimate concern, particularly in critically ill neonates or those with evolving renal dysfunction.(61)

Collectively, these considerations reinforce the view that TXA should not be regarded as a universal or benign solution for neonatal bleeding. Rather, it should be considered a context-specific adjunct, used selectively within broader blood conservation strategies, and guided by neonatal physiology, exposure-conscious dosing, and careful neurological and renal surveillance. Extrapolation from adult or older paediatric data, particularly with respect to safety, should be approached cautiously until adequately powered neonatal studies become available.

 

CONCLUSIONS

Neonatal anaemia and transfusion exposure remain major contributors to morbidity in preterm and critically ill infants. Pharmacological blood conservation strategies are therefore highly desirable. TXA demonstrates clear benefit in selected paediatric surgical populations; however, its role in neonates remains incompletely defined. Current evidence does not support routine neonatal use outside carefully selected surgical contexts, and significant uncertainty persists regarding optimal dosing, efficacy, and safety.

Until high-quality neonatal-specific data are available, TXA use in neonates should be cautious, individualised, and embedded within comprehensive patient blood management strategies. Addressing the identified evidence gaps is essential to ensure that TXA, if adopted more widely in neonatal care, improves outcomes without introducing avoidable harm.

 

FUTURE DIRECTIONS

This review identified several critical gaps that warrant prioritisation. Neonatal-specific pharmacokinetic and pharmacodynamic studies are urgently needed to define safe and effective dosing regimens. Prospective trials focusing on clinically meaningful outcomes, including transfusion exposure, neurological events, renal injury, and mortality, are essential before TXA can be routinely recommended in neonatal practice.

Author Contribution:

The following authors equally contributed to the project conceptualisation (PC), data curation (DC), results synthesis (RS), and the writing of the manuscript (WM).

• Dr Joseline Nkhoma - PC, DC, RS, WM

• Dr Harrilene Apleni - PC, DC, RS, WM

• Dr Gontse Leballo - PC, DC, RS, WM

• Professor Palesa Motshabi Chakane - PC, DC, RS, WM

• Dr Moses Kebalepile* - PC, DC, RS, WM

Funding: This research received no external funding.

Conflicts of Interest: The authors declare no conflicts of interest

 

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Correspondence:
Moses Kebalepile
Moses.kebalepile@wits.ac.za