Effects of phenobarbitone on neonatal hyperbilirubinemia, a systematic review and meta-analysis of randomized controlled trial

Abstract

Background: The management of neonatal jaundice is relatively straightforward; however, hemodynamic insults may still occur, particularly in very low birth weight infants. While phototherapy is effective, it may lead to prolonged hospitalization and potential adverse effects. This study investigates the efficacy of phenobarbitone in preventing neonatal hyperbilirubinemia in both term and preterm neonates.

Method: We conducted a comprehensive search of PubMed, Web of Science, Embase, Cochrane Library, Scopus, and CINAHL to identify relevant articles published up to January 23, 2025. Study selection followed the PRISMA guidelines, and assessments of the risk of bias were performed. Data analysis was conducted using Review Manager 5.3, with mean difference (MD) and 95% confidence intervals (CI) calculated for continuous variables, while risk ratios (RR) were estimated for binary variables. We included randomized controlled trials (RCTs) that investigated the effects of phenobarbitone on neonatal hyperbilirubinemia. The primary outcomes assessed were phototherapy duration, the need for exchange transfusion, peak bilirubin levels, the need of phototherapy, and cumulative weight loss. The extracted data encompassed key study characteristics along with an evaluation of the risk of bias 1.0 tool and Level of Evidence was summarized using GRADE guidelines.

Result: A total of 41 articles were identified through searches of six databases. After removing duplicates, 23 articles remained. Based on title and abstract screening, 15 were excluded. An additional 3 articles were excluded for not meeting the inclusion criteria. Five studies, including 590 newborns, were identified and included in the meta-analysis. This meta-analysis discovered significant changes in phototherapy duration, measured in hours (mean difference (MD) -24.51 (95% CI -34.08, -14.94), p < 0.01) with low heterogeneity, exchange transfusion(Risk ratio(RR) 0.32 (95% CI 0.16, 0.61), p < 0.01) with low heterogeneity, peak bilirubin level(MD -2.35 (95% CI -2.96, -1.74), p < 0.01) with low heterogeneity, need of phototherapy (RR 0.75 (95% CI 0.66, 0.85), p < 0.01) with low heterogeneity. There was not a significant change in weight loss (MD 0.15 (95% CI -0.76, 1.07), p = 0.74) with low heterogeneity. Only one of these studies reported side effects of phenobarbitone (Pediatric Res 51:399A, 2002).

Conclusion: Phenobarbitone might be applied in unconjugated neonatal hyperbilirubinemia to reduce the peek bilirubin level, phototherapy duration, and reduce the chance of exchange transfusion and phototherapy treatment.

Prospero registration number: CRD42025636128.

Keywords: Meta-analysis; Neonatal hyperbilirubinemia; Phenobarbitone; Phototherapy; RCTs (randomized controlled trials).