Melatonin in Newborn Infants Undergoing Surgery: A Pilot Study on Its Effects on Postoperative Oxidative Stress

**Background:** Surgery induces excessive oxidative stress through local and systemic inflammatory responses. Melatonin possesses both direct free radical scavenging properties and indirect antioxidant effects via activation of antioxidant enzymes. Transient melatonin deficiency has been described in neonatal surgical patients. This study aimed to evaluate whether exogenous melatonin supplementation before surgery reduces perioperative oxidative stress in newborns.

**Methods:** This evaluator-blinded, randomized controlled pilot trial enrolled 23 newborn infants (gestational age >34 weeks) requiring surgery at the Neonatology Unit of AOU 'G. Martino' in Messina. Exclusion criteria included sepsis, inborn errors of metabolism, perinatal hypoxia, maternal mental disorders, or surgery scheduled in the afternoon/night. Ten newborns received a single oral dose of melatonin 0.5 mg/kg (MEL group) via nasogastric tube in the morning before surgery; 13 newborns received 0.5 mL of 5% glucose solution (untreated group). Plasma samples (0.2 mL) were collected 1 hour before and 1 hour after surgery. Melatonin concentrations were measured using LC-MS/MS. Oxidative stress biomarkers included non-protein-bound iron (NPBI, μmol/dL), advanced oxidation protein products (AOPP, μmol/dL), and F2-isoprostanes (F2-IsoPs, pg/mL). Statistical analysis used SPSS version 25.0 with Student's t-test for parametric data and chi-squared test for non-parametric data; p < 0.05 was considered significant.

**Key Results:** Plasma melatonin concentrations were significantly higher in the MEL group versus untreated group both preoperatively (1265.50 ± 717.03 vs. 23.23 ± 17.71 pg/mL; p < 0.0001) and postoperatively (1465.20 ± 538.38 vs. 56.47 ± 37.18 pg/mL; p < 0.0001). In the untreated group, melatonin significantly increased from pre- to postoperative period (23.23 ± 17.71 vs. 56.47 ± 37.18 pg/mL; p = 0.006). In the MEL group, mean blood concentrations of NPBI significantly decreased from pre- to postoperative (4.69 ± 3.85 vs. 1.65 ± 1.18 μmol/dL; p = 0.049), F2-IsoPs significantly decreased (128.40 ± 92.30 vs. 50.25 ± 47.47 pg/mL; p = 0.037), and AOPP significantly decreased (65.18 ± 15.50 vs. 43.98 ± 17.92 μmol/dL; p = 0.022). In the untreated group, only NPBI showed a significant decrease postoperatively; F2-IsoPs and AOPP showed no significant differences. No side effects were reported.

**Clinical Implications:** This pilot study demonstrates that endogenous melatonin increases physiologically after surgical stress in neonates, suggesting a defensive response, but this increase is insufficient to adequately counteract oxidative damage. Exogenous melatonin administration (0.5 mg/kg orally) before surgery produced a more than 100-fold increase in plasma melatonin concentration and significantly reduced lipid peroxidation (F2-IsoPs) and protein oxidation (AOPP), as well as non-protein-bound iron, a marker of oxidative stress potential. These findings suggest melatonin may protect newborns from deleterious oxidative consequences of surgery. Limitations include small sample size, heterogeneity in pathologies requiring surgery, and variable postnatal ages at surgery. Larger, more homogeneous studies are needed to establish whether reduced oxidative stress translates to clinical benefits such as reduced postoperative pain, fewer infectious complications, faster nutritional recovery, or shorter hospitalization.