Context: Hyperbilirubinemia is a common cause for diagnostic work-up and therapeutic intervention in neonates and needs a convenient, quick, and safe treatment modality. Phototherapy is the most common treatment for neonatal jaundice; however, complementary treatment is still needed. Despite the identification of the enzymatic pathways of bilirubin catabolism, few pharmacological interventions have been found to be effective in reducing bilirubin, along with traditional phototherapy. This review was conducted to evaluate recent pharmacotherapies as adjuvants to phototherapy for the treatment of neonatal indirect hyperbilirubinemia (IHB). Evidence Acquisition: This study was carried out through a literature search with the keywords of Infant, Newborn, and Indirect Hyperbilirubinemia, combined with Drug Therapy, in PubMed, Scopus, International Statistical Institute, Web of Science, Cochrane, and Embase databases. This study included relevant articles (i.e., randomized controlled trials, observational studies, guidelines, and reviews) written in English and published between 2012 - 2022. Results: This narrative review first assessed the relevant articles to define IHB and its etiology. Then, the efficacy and side effects of recent pharmacologic agents as adjuvants to phototherapy were discussed. Additionally, this study reviewed the efficacy and safety of drugs prescribed to neonates to prevent jaundice. Conclusions: The best drug for adjuvant pharmacotherapy, in addition to phototherapy, for neonatal jaundice has not still been identified. The use of probiotics, prebiotics, synbiotics, and ursodeoxycholic acid (UDCA) in adjuvant to phototherapy has been recently increasing, and beneficial results were observed in most studies. The use of agar, charcoal, fibrate, and phenobarbital had a minor therapeutic role in recent years. There were conflicting results about the efficacy of herbal agents in neonatal jaundice. The use of intravenous immunoglobulin (IVIG), metalloporphyrin, and albumin is also limited to severe or immune-related IHB cases. The prescription of the aforementioned drugs sometimes had different results. Therefore, further research in this regard is necessary.
