Background: Premature neonates with documented sepsis who undergo surgery face heightened systemic inflammation, crucially mediated by interleukin-6 (IL-6). Given their low endogenous melatonin levels and melatonin’s known anti-inflammatory properties, this study aimed to evaluate the impact of adjunctive melatonin on IL-6 and other inflammatory markers in premature neonates with positive blood cultures or documented sepsis undergoing surgery.
Materials and Methods: This randomized controlled pilot study at Mofid Children’s Hospital (2023-2024) included 9 preterm neonates with positive blood cultures who were scheduled for surgery. They were randomized to receive either melatonin (0.1 mg/kg/day, n=6) or a placebo (n=3) orally for three days (pre- to post-surgery). Blood samples at baseline (T0) and two days post-surgery (T1) were collected to assess serum IL-6 and C-reactive protein (CRP) levels and white blood cell (WBC) counts. Repeat blood cultures were also performed. Data were analyzed using SPSS software, version 26 at a significance level of P<0.05. 
Results: Baseline (T0) characteristics were comparable. Post-intervention (T1), the melatonin group showed significant reductions in CRP levels (T0: 9.333±7.828 mg/dL vs T1: 2.167±0.831 mg/dL; P=0.027) and WBC counts (T0: 13.933±3.741×103/μL vs T1: 9.933±2.196 ×103/μL; P=0.027), while the placebo group showed no significant changes. Although IL-6 decreased in both groups, it did not reach statistical significance. All melatonin-treated neonates achieved negative blood cultures, compared to 33% in the placebo group. 
Conclusion: The use of adjunctive melatonin in preterm neonates with documented sepsis undergoing surgery suggests a reduction in systemic inflammation (CRP, WBC) and lower bloodstream infection rates. While the reduction in IL-6 was not statistically significant, these findings indicate melatonin’s potential as a safe and effective adjunctive therapy; however, further large-scale studies are warranted.