Oral adjuvants supplemented to phototherapy as a therapeutic strategy for neonatal hyperbilirubinemia: a systematic review

Clinical Snapshot

Key Findings

• P Value: Statistical significance reported for fenofibrate across trials

• Effect Size: Variable by intervention: Lactobacillus reuteri showed greater 24-hour TSB reduction; fenofibrate demonstrated most consistent efficacy

• Primary Outcome: Total serum bilirubin reduction at 24 hours

• Nnt Or Sensitivity: Not calculable from available data due to heterogeneity

• Confidence Interval: Not reported in abstract

Clinical Application

Variable - probiotics and UDCA readily available; fenofibrate requires careful consideration given limited neonatal safety data Relevant to Australian NICUs; TGA approval status of specific adjuvants would need verification; aligns with RANZCOG neonatal care guidelines for phototherapy optimization Term neonates with uncomplicated hyperbilirubinemia in well-resourced healthcare settings

Abstract

INTRODUCTION: Neonatal jaundice is a common condition characterized by elevated serum bilirubin levels. Although usually benign, inadequate management may result in severe complications such as bilirubin encephalopathy and kernicterus. Phototherapy is the standard treatment; however, concerns regarding potential short- and long-term adverse effects have motivated the investigation of oral adjuvants as complementary therapies to accelerate bilirubin clearance and reduce phototherapy exposure. CONTENT: This systematic review followed PRISMA guidelines and was registered in PROSPERO (CRD420251071886). Randomized controlled trials published between 2010 and 2025 were included, evaluating full-term neonates (35-42 weeks, 2-4 kg) without Rh incompatibility. Searches were conducted in PubMed, Cochrane Central, Embase, and Web of Science. Of 193 identified records, 18 RCTs met eligibility criteria. The oral adjuvants assessed included probiotics, phenobarbital, ursodeoxycholic acid (UDCA), oral calcium, zinc sulfate, fenofibrate, and clofibrate. Lactobacillus reuteri demonstrated greater 24-hour reductions in total serum bilirubin (TSB) compared to controls, whereas Bifidobacterium strains primarily reduced phototherapy duration. Phenobarbital did not outperform phototherapy alone and was associated with longer hospitalization. UDCA showed substantial bilirubin reductions, although findings were heterogeneous. Zinc supplementation did not demonstrate consistent significant benefit. Fenofibrate produced statistically significant decreases in TSB across trials and showed the most consistent efficacy. Clofibrate also reduced bilirubin levels but with methodological variability and limited comparative data. SUMMARY: Oral adjuvants combined with phototherapy may enhance bilirubin reduction in term neonates, particularly fenofibrate. OUTLOOK: However, heterogeneity and potential bias limit definitive conclusions, emphasizing the need for large, multicenter randomized trials.

References

1. 1.Tavares, L. C., Santos Nascimento, E. G., Gouvêa de Oliveira, L., de Oliveira Nantes, L. A., Nóbrega Dos Santos, L., Pereira Lobato Brito, G., & de Oliveira, R. C. S. (2026). Oral adjuvants supplemented to phototherapy as a therapeutic strategy for neonatal hyperbilirubinemia: a systematic review. Journal of Perinatal Medicine. https://doi.org/10.1016/j.jacig.2024.100350