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

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.