A Review on the Role of Melatonin in Neonatal Sepsis Caused by Methicillin-Resistant Staphylococcus aureus

Document Type : Review Article

Authors

1 Department of Genetics, Faculty of Advanced Sciences and Technology, TeMS.C, Islamic Azad University, Tehran, Iran

2 Neonatal Health Research Center, Research Institute for Children’s Health, Shahid Beheshti University of Medical Sciences, Tehran, Iran

3 Department of Neonatology. NICU ward, Taleghani Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran

4 Department of Pediatrics, School of Medicine, Imam Hossein Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

5 Tehran University of Medical Sciences, Children’s Medical Center, Pediatric Center of Excellence, Tehran, Iran

10.22038/ijn.2025.92245.2796

Abstract

Background: Neonatal sepsis and encephalopathy are life-threatening conditions marked by excessive inflammation and oxidative stress, contributing to high morbidity and mortality in newborns. Melatonin, a multifunctional indoleamine with potent antioxidant, anti-inflammatory, and immunomodulatory properties, has emerged as a promising adjunctive therapy in neonatal care. This review summarizes current evidence on melatonin’s biological functions and its potential to reduce inflammation, oxidative damage, and improve neonatal outcomes.
Methods: A narrative review was conducted by searching PubMed, Scopus, Web of Science, and Google Scholar from 2000 to November 2025 using the keywords melatonin, neonatal sepsis, and methicillin-resistant Staphylococcus aureus (MRSA). Relevant experimental, preclinical, and clinical studies were identified, reviewed, and synthesized to provide an integrated overview of melatonin’s effects in neonatal sepsis and related inflammatory conditions.
Results: Preclinical studies indicate that melatonin downregulates pro-inflammatory cytokines (e.g., TNF-α, IL-6) while enhancing anti-inflammatory mediators such as IL-10. It also preserves mitochondrial function, mitigating oxidative injury and neuroinflammation. Early clinical trials report that melatonin administration in septic and asphyxiated neonates reduces inflammatory biomarkers, lowers oxidative stress, and is well tolerated without major adverse effects. Challenges remain, including the distinct pharmacokinetics of neonates, variable clearance rates, heterogeneous study populations, and limited sample sizes, which complicate dose optimization and definitive conclusions on efficacy and long-term safety.
Conclusion: Melatonin represents a safe and biologically potent adjunctive therapy for neonatal inflammatory disorders. Large-scale, multicenter randomized trials are warranted to establish standardized dosing, assess long-term neurodevelopmental outcomes, and confirm clinical efficacy in improving neonatal survival and recovery.
 

Keywords


  1. Kaweti G, Tamirat A, Feleke, T. Factors predicting treatment outcome of neonatal sepsis in Hawassa University Comprehensive Specialized Hospital, Southern Ethiopia: A retrospective cohort study. Iran J Neonatol. 15(1).
  2. Rajesh S, Divya B, Neelaveni D, Subathra N. Incidence of methicillin resistant Staphylococcus aureus infection in neonatal septicemia in a tertiary care hospital. Int J Curr Microbiol Appl Sci. 2017;6(5):2874-81.
  3. Bazregari M, Mirlashari J, Ranjbar H, Pouraboli B. Effect of clustered nursing care on sleep behaviors of the preterm neonates admitted to the neonatal intensive care unit. Iran J Neonatol. 2019;10(3).
  4. Sabagh K, Ghaljaei F. The interventional effect of quiet time protocol on the sleep status of premature neonates admitted to the NICU. Iran J Neonatol. 2024;15(2).
  5. Aboelnaga N, Elsayed SW, Abdelsalam NA, Salem S, Saif NA, Elsayed M, et al. Deciphering the dynamics of methicillin-resistant Staphylococcus aureus biofilm formation: from molecular signaling to nanotherapeutic advances. Cell Commun Signal. 2024;22(1):188.
  6. Fatmawati SA, Luh Kompyang SN, Hadriani H, Rizkaningsih R, Fajrillah K, Sohayla A, Jun CH. Creating an innovative curriculum for developmental care of premature infants in the NICU: Insights from a delphi study. Iran J Neonatol. 2025;16(1).
  7. Saeidi R. Beneficial Effects of Melatonin for the Newborn. Iran J Neonatol. 2024;15(4).
  8. Pang R, Meehan C, Maple G, Norris G, Campbell E, Tucker K, et al. Melatonin reduces brain injury following inflammation-amplified hypoxia-ischemia in a translational newborn piglet study of neonatal encephalopathy. J Pineal Res. 2024;76(4):e12962. 
  9. Wang Y, Bian Z, Wang Y. Biofilm formation and inhibition mediated by bacterial quorum sensing. Appl Microbiol Biotechnol. 2022;106(19-20):6365-6381.
  10. Balduini W, Weiss MD, Carloni S, Rocchi M, Sura L, Rossignol C, et al. Melatonin pharmacokinetics and dose extrapolation after enteral infusion in neonates subjected to hypothermia. J Pineal Res. 2019;66(4):e12565.
  11. Henderson R, Kim S, Lee E. Use of melatonin as adjunctive therapy in neonatal sepsis: A systematic review and meta-analysis. Complement Ther Med. 2018;39:131-136.
  12. Ibrahim AE, El Sallab SM, Hamed AM, El Ghareeb AH. Anti-inflammatory effect of melatonin therapy
    in sepsis. Alexandria Journal of Pediatrics. 2024;37(2):95-9.
  13. Adib M, Bakhshiani Z, Navaei F, Saheb Fosoul F, Fouladi S, Kazemzadeh H. Procalcitonin: a reliable marker for the diagnosis of neonatal sepsis. Iran J Basic Med Sci. 2012;15(2):777-782.
  14. Saeidi R, Kazemian M, Noripour S, Fallahi M, Alizadeh P, Kordkatouli M. Comparison of serum procalcitonin and c-reactive protein levels in late onset neonatal sepsis. Zahedan J Res Med Sci. 2025;27(27).
  15. Saeidi R, Shahfarhat A, Mohammadzadeh A, Gholami M. Role of immunotherapy (IVIG) in the treatment of neonatal sepsis.
  16. Salarvand S, Abdollahi A, Khaki PA, Shadehi MN, Dalili H, Nateghi S, Panahi Z, Nazar E. Microbial Etiology and Antibiotic Susceptibility of Samples from Neonatal Intensive Care Units Patients in a Tertiary Care Center in Iran. Iran J Neonatol. 2025;16(2).
  17. Habibi M, Bahadoran E, Fathollahzadeh P, Yazdi Z, Khorshidi NK, SamieeRad F. Prevalence and risk factors of retinopathy of prematurity in premature born infants. Iran J Neonatol. 2025;16(4).
  18. Amini S, Rezaei M, Pouladfar G, Ghasemi F, Jafarian H, Badiee P. Evaluation of the fluconazole prophylaxis against fungal colonization in the preterm neonates: A double-blind clinical trial. Iran J Neonatol. 2024;15(2).
  19. Saeidi R, Vevsizadeh M, Kordkatouli M. Effect of melatonin on immune system enhancement and pediatric infections: A systematic review. Immunoregulation. 2024;7(1).
  20. Xu L, Zhang W, Kwak M, Zhang L, Lee PCW, Jin JO. Protective effect of melatonin against polymicrobial sepsis is mediated by the anti-bacterial effect of neutrophils. Front Immunol. 2019;10:1371. 
  21. Hassan HN, Oraibi AH. Neonatal bilious vomiting as a predictor for neonatal intestinal obstruction. Iran J Neonatol. 2025;16(2).
  22. Gbagbeke K, Ejenavwo E, Naiho A, Igweh J. The role of neonatal procalcitonin and pro-inflammatory cytokines at birth in prediction of sepsis in neonates. WJBPHS. 2025;22(01):190-199
  23. Maralihalli M, Malashetty S. Usefulness of cerebrospinal fluid procalcitonin in diagnosis of neonatal meningitis. Iran J Neonatol. 2025;16(4).
  24. Maralihalli MB, Malashetty S. Usefulness of cerebrospinal fluid procalcitonin in diagnosis of neonatal meningitis. Iran J Neonatol. 2025;16(4):1-5.
  25. Lee HY, Hsu YL, Lee WY, Huang KH, Tsai ML, Chen CL, et al. Maternal infections, antibiotics, steroid use, and diabetes mellitus increase risk of early-onset sepsis in preterm neonates: A nationwide population-based study. Pathogens. 2025;14(1):89.
  26. Arias-Arellano S, Cáceres-Aucatoma F, Geyson D, Segarra-Galarza K. Factores de riesgo asociados a sepsis neonatal tardía [Risk factors associated with late-onset neonatal sepsis]. Rev Med Inst Mex Seguro Soc. 2019;57(4):226-231. Spanish.
  27. Low JM, Lee JH, Foote HP, Hornik CP, Clark RH, Greenberg RG. Incidence of group B streptococcus early-onset sepsis in term neonates with second-line prophylaxis maternal intrapartum antibiotics: a multicenter retrospective study. Am J Obstet Gynecol. 2024;230(6):673.e1-673.e8.
  28. Burgunder L, Heyrend C, Olson J, Stidham C, Lane RD, Workman JK, et al. Medication and fluid management of pediatric sepsis and septic shock. Paediatr Drugs. 2022;24(3):193-205. 
  29. Monteiro KKAC, Shiroma ME, Damous LL, Simões MJ, Simões RDS, Cipolla-Neto J, et al. Antioxidant actions of melatonin: A systematic review of animal studies. Antioxidants (Basel). 2024;13(4):439.
  30. Kopustinskiene DM, Bernatoniene J. Molecular mechanisms of melatonin-mediated cell protection and signaling in health and disease. Pharmaceutics. 2021;13(2):129.
  31. Chitimus DM, Popescu MR, Voiculescu SE, Panaitescu AM, Pavel B, et al. Melatonin's impact on antioxidative and anti-inflammatory reprogramming in homeostasis and disease. Biomolecules. 2020;10(9):1211. 
  32. Ferlazzo N, Andolina G, Cannata A, Costanzo MG, Rizzo V, Currò M, et al. Is melatonin the cornucopia of the 21st century? Antioxidants (Basel). 2020;9(11):1088. 
  33. Hardeland R. Redox biology of melatonin: Discriminating between circadian and noncircadian functions. Antioxid Redox Signal. 2022;37(10-12):704-725.
  34. Valliammai A, Sethupathy S, Priya A, Selvaraj A, Bhaskar JP, Krishnan V, et al. 5-Dodecanolide interferes with biofilm formation and reduces the virulence of Methicillin-resistant Staphylococcus aureus (MRSA) through up regulation of agr system. Sci Rep. 2019;9(1):13744. 
  35. Naser IJ. Antimicrobial and anti-biofilm activity of titanium dioxide nanoparticles alone and in combination with erythromycin against methicillin-resistant Staphylococcus aureus. JOPAS. 2022;21(4):276-281.
  36. Valliammai A, Sethupathy S, Ananthi S, Priya A, Selvaraj A, Nivetha V, et al. Proteomic profiling unveils citral modulating expression of IsaA, CodY and SaeS to inhibit biofilm and virulence in methicillin-resistant Staphylococcus aureus. Int J Biol Macromol. 2020:S0141-8130(20)33095-6.
  37. Saadati F, Shahryari S, Sani NM, Farajzadeh D, Zahiri HS, Vali H, et al. Effect of MA01 rhamnolipid on cell viability and expression of quorum-sensing (QS) genes involved in biofilm formation by methicillin-resistant Staphylococcus aureus. Sci Rep. 2022;12(1):14833.
  38. Selvaraj A, Jayasree T, Valliammai A, Pandian SK. Myrtenol attenuates MRSA biofilm and virulence by suppressing sarA expression dynamism. Front Microbiol. 2019;10:2027.
  39. Roy S, Chowdhury G, Mukhopadhyay AK, Dutta S, Basu S. Convergence of biofilm formation and antibiotic resistance in Acinetobacter baumannii Front Med (Lausanne). 2022;9:793615. 
  40. Tarocco A, Caroccia N, Morciano G, Wieckowski MR, Ancora G, Garani G, et al. Melatonin as a master regulator of cell death and inflammation: molecular mechanisms and clinical implications for newborn care. Cell Death Dis. 2019;10(4):317. 
  41. Aslam S, O'Dea M, Kelly LA, O'Neill A, McKenna E, Hurley T, et al. Melatonin alters innate immune function in infants with neonatal encephalopathy. Neonatology. 2023;120(3):325-333.
  42. El-Kabbany ZA, El-Farghali OG, Khafagy SM, Shaaban HA, Osman HH, Metwally MH. Melatonin as an adjuvant therapy in preterm infants with neonatal sepsis, randomized trial. Gaz Egypt Paediatr Assoc. 2020;68(1):2.
  43. Hu Y, Wang Z, Pan S, Zhang H, Fang M, Jiang H, et al. Melatonin protects against blood-brain barrier damage by inhibiting the TLR4/ NF-κB signaling pathway after LPS treatment in neonatal rats. Oncotarget. 2017;8(19):31638-31654. 
  44. Yazdani A, Adeel B, Gul S. Effects of melatonin as adjuvant therapy in treatment of neonatal sepsis. insights-journal of health and rehabilitation Учредители: Health and Research Insights. 2024;2(2):548-553.
  45. Pavlyshyn Н, Sarapuk I, Kozak K. The relationship of melatonin concentration in preterm infants and adverse outcomes in the late neonatal period. Biochem Med (Zagreb). 2023;33(1):010706.
  46. Pang R, Advic-Belltheus A, Meehan C, Fullen DJ, Golay X, Robertson NJ. Melatonin for neonatal encephalopathy: From bench to bedside. Int J Mol Sci. 2021;22(11):5481.
  47. Ahmed J, Pullattayil S AK, Robertson NJ, More K. Melatonin for neuroprotection in neonatal encephalopathy: A systematic review & meta-analysis of clinical trials. Eur J Paediatr Neurol. 2021;31:38-45.
  48. Berger HR, Nyman AKG, Morken TS, Widerøe M. Transient effect of melatonin treatment after neonatal hypoxic-ischemic brain injury in rats. PLoS One. 2019;14(12):e0225788. 
  49. Cardinali DP. An assessment of melatonin's therapeutic value in the hypoxic-ischemic encephalopathy of the newborn. Front Synaptic Neurosci. 2019;11:34. 
  50. Mohamadzadeh A, Farhat A, Khodashenas E, Adineh M, Vaezi A., Taji P, et al. Therapeutic hypothermia by cold intravenous fluid and short outcome in asphyxiated newborn. Iran J Neonatol. 2025;16(2): 9-13.
  51. Häusler S, Robertson NJ, Golhen K, van den Anker J, Tucker K, Felder TK. Melatonin as a therapy for preterm brain injury: What is the evidence? Antioxidants (Basel). 2023;12(8):1630. 
  52. Carloni S, Proietti F, Rocchi M, Longini M, Marseglia L, D'Angelo G, et al. Melatonin pharmacokinetics following oral administration in preterm neonates. Molecules. 2017;22(12):2115
  53. Merchant NM, Azzopardi DV, Hawwa AF, McElnay JC, Middleton B, Arendt J, et al. Pharmacokinetics of melatonin in preterm infants. Br J Clin Pharmacol. 2013;76(5):725-733.
  54. Marseglia L, Gitto E, Laschi E, Giordano M, Romeo C, Cannavò L, et al. Antioxidant effect of melatonin in preterm newborns. Oxid Med Cell Longev. 2021;2021:6308255.
  55. Saeidi R, Alizadeh P, Kazemian M, Noripour S, Fallahi M. The effect of melatonin on the immune system and the treatment of neonatal sepsis. Patient Saf Qual Improve J. 2025;13(4):235-239.
  56. Gitto E, Marseglia L, Manti S, D’Angelo G, Barberi I, Salpietro C, et al. Protective role of melatonin in neonatal diseases. Oxid Med Cell Long 2013;2013(1):980374.
  57. Gitto E, Karbownik M, Reiter RJ, Tan DX, Cuzzocrea S, Chiurazzi P, et al. Effects of melatonin treatment in septic newborns. Pediatr Res. 2001;50(6):756-760. 
  58. El Frargy M, El-Sharkawy HM, Attia GF. Use of melatonin as an adjuvant therapy in neonatal sepsis. J Neonatal Perinatal Med. 2015;8(3):227-232. 
  59. El-Gendy FM, El-Hawy MA, Hassan MG. Beneficial effect of melatonin in the treatment of neonatal sepsis. J Matern Fetal Neonatal Med. 2018;31(17):2299-2303. 
  60. Abdelbar AT, Mohammed Rashad ML, Mohammed Ali Elsharkawy MM. Significance of plasma melatonin as a diagnostic marker in full-term with late onset sepsis. Zagazig Univ Med J. 2024;30(5):1929-1937.
  61. He F, Wu X, Zhang Q, Li Y, Ye Y, Li P, et al. Bacteriostatic potential of melatonin: Therapeutic standing and mechanistic insights. Front Immunol. 2021;12:683879.
  62. Sun Z, Yu C, Zhang Z, Hu C, Li X, Dong X, et al. Efficacy of melatonin as adjunctive therapy for sepsis: A meta-analysis of randomized controlled trials. Complement Ther Med. 2025;89:103147.
  63. Pavlyshyn Н, Sarapuk I, Kozak K. The relationship of melatonin concentration in preterm infants and adverse outcomes in the late neonatal period. Biochem Med (Zagreb). 2023;33(1):010706.