Effect of Melatonin on Interleukin‐6 and C‐Reactive Protein in Neonates Undergoing Surgery

ABSTRACT Background Neonatal surgery induces a significant systemic inflammatory response mediated by cytokines such as IL‐6 and CRP. Melatonin has well‐established antioxidant and anti‐inflammatory properties, but data in neonates remain limited. This study aimed to evaluate the effect of adjunctive oral melatonin on serum IL‐6 and CRP levels in neonates undergoing surgery. Methods This randomized, double‐blind, placebo‐controlled trial included 40 neonates under 1 month of age undergoing major abdominal surgery at Mofid Children's Hospital, Tehran (2023–2024). Positive blood culture before surgery was an exclusion criterion. Neonates received oral melatonin (0.1 mg/kg/day, n = 20) or placebo ( n = 20) for 3 days. IL‐6, CRP and WBC were measured at baseline and 72 h after the last dose. Blood cultures were repeated 72 h after surgery. Results Baseline characteristics were comparable. Post‐intervention, the melatonin group showed significantly lower IL‐6 ( p = 0.0102) and CRP ( p = 0.0156) levels compared to placebo. Within‐group analysis revealed that IL‐6 increased significantly in the placebo group ( p = 0.003), whereas the decrease in the melatonin group was not significant ( p = 0.09). CRP reduction was significant in the melatonin group ( p = 0.01) but not in the placebo group ( p = 0.65). WBC counts and hospital stay showed no significant differences. Postoperative positive blood cultures occurred in 35% of the placebo group versus 10% of the melatonin group ( p = 0.118). No adverse events were reported. Conclusion Perioperative melatonin was associated with significantly lower postoperative IL‐6 and CRP levels compared to placebo, with a favourable safety profile. These between‐group differences should be interpreted in the context of the within‐group findings, including the significant postoperative rise in IL‐6 in the placebo group. Larger multicenter trials are needed to confirm these findings.