Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Melatonin use for neuroprotection in perinatal asphyxia: a randomized controlled pilot study




Melatonin has been shown to be neuroprotective in animal models. The objective of this study is to examine the effect of melatonin on clinical, biochemical, neurophysiological and radiological outcomes of neonates with hypoxic–ischemic encephalopathy (HIE).

Study Design:

We conducted a prospective trial on 45 newborns, 30 with HIE and 15 healthy controls. HIE infants were randomized into: hypothermia group (N=15; received 72-h whole-body cooling) and melatonin/hypothermia group (N=15; received hypothermia and five daily enteral doses of melatonin 10 mg kg−1). Serum melatonin, plasma superoxide dismutase (SOD) and serum nitric oxide (NO) were measured at enrollment for all infants (N=45) and at 5 days for the HIE groups (N=30). In addition to electroencephalography (EEG) at enrollment, all surviving HIE infants were studied with brain magnetic resonance imaging (MRI) and repeated EEG at 2 weeks of life. Neurologic evaluations and Denver Developmental Screening Test II were performed at 6 months.


Compared with healthy neonates, the two HIE groups had increased melatonin, SOD and NO. At enrollment, the two HIE groups did not differ in clinical, laboratory or EEG findings. At 5 days, the melatonin/hypothermia group had greater increase in melatonin (P<0.001) and decline in NO (P<0.001), but less decline in SOD (P=0.004). The melatonin/hypothermia group had fewer seizures on follow-up EEG and less white matter abnormalities on MRI. At 6 months, the melatonin/hypothermia group had improved survival without neurological or developmental abnormalities (P<0.001).


Early administration of melatonin to asphyxiated term neonates is feasible and may ameliorate brain injury.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it


Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3


  1. Kurinczuk JJ, White-Koning M, Badawi N . Epidemiology of neonatal encephalopathy and hypoxic-ischaemic encephalopathy. Early Hum Dev 2010; 86 (6): 329–338.

    Article  PubMed  Google Scholar 

  2. Lawn JE, Kerber K, Enweronu-Laryea C, Cousens S . 3.6 million neonatal deaths—what is progressing and what is not? Semin Perinatol 2010; 34 (6): 371–386.

    Article  PubMed  Google Scholar 

  3. Shankaran S . Neonatal encephalopathy: treatment with hypothermia. NeoReviews 2010; 11 (2): e85–e92.

    Article  Google Scholar 

  4. Jacobs SE, Berg M, Hunt R, Tarnow-Mordi WO, Inder TE, Davis PG . Cooling for newborns with hypoxic ischaemic encephalopathy. Cochrane Database Syst Rev 2013; 1: CD003311.

    Google Scholar 

  5. Brzezinski A . Melatonin in humans. N Engl J Med 1997; 336 (3): 186–195.

    Article  CAS  PubMed  Google Scholar 

  6. Tamura H, Nakamura Y, Terron MP, Flores LJ, Manchester LC, Tan DX et al. Melatonin and pregnancy in the human. Reprod Toxicol 2008; 25 (3): 291–303.

    Article  CAS  PubMed  Google Scholar 

  7. Weissbluth M . Melatonin increases cyclic guanosine monophosphate: biochemical effects mediated by porphyrins, calcium and nitric oxide. Relationships to infant colic and the sudden infant death syndrome. Med Hypotheses 1994; 42 (6): 390–392.

    Article  CAS  PubMed  Google Scholar 

  8. Chen YC, Tain YL, Sheen JM, Huang LT . Melatonin utility in neonates and children. J Formos Med Assoc 2012; 111 (2): 57–66.

    Article  CAS  PubMed  Google Scholar 

  9. Gitto E, Reiter RJ, Cordaro SP, La Rosa M, Chiurazzi P, Trimarchi G et al. Oxidative and inflammatory parameters in respiratory distress syndrome of preterm newborns: beneficial effects of melatonin. Am J Perinatol 2004; 21 (4): 209–216.

    Article  PubMed  Google Scholar 

  10. Gitto E, Karbownik M, Reiter RJ, Xian Tan D, Cuzzocrea S, Chiurazzi P et al. Effects of melatonin treatment in septic newborns. Pediatr Res 2001; 50 (6): 756–760.

    Article  CAS  PubMed  Google Scholar 

  11. Gitto E, Romeo C, Reiter RJ, Impellizzeri P, Pesce S, Basile M et al. Melatonin reduces oxidative stress in surgical neonates. J Pediatr Surg 2004; 39 (2): 184–189.

    Article  CAS  PubMed  Google Scholar 

  12. Alonso-Alconada D, Alvarez A, Arteaga O, Martinez-Ibarguen A, Hilario E . Neuroprotective effect of melatonin: a novel therapy against perinatal hypoxia-ischemia. Int J Mol Sci 2013; 14 (5): 9379–9395.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Reiter RJ, Tan DX, Osuna C, Gitto E . Actions of melatonin in the reduction of oxidative stress: a review. J Biomed Sci 2000; 7 (6): 444–458.

    Article  CAS  PubMed  Google Scholar 

  14. Rodriguez C, Mayo JC, Sainz RM, AntolÃn I, Herrera F, MartÃn V et al. Regulation of antioxidant enzymes: a significant role for melatonin. J Pineal Res 2004; 36 (1): 1–9.

    Article  CAS  PubMed  Google Scholar 

  15. Reiter RJ, Calvo JR, Karbownik M, Qi W, Tan DX . Melatonin and its relation to the immune system and inflammation. Ann NY Acad Sci 2000; 917: 376–386.

    Article  CAS  PubMed  Google Scholar 

  16. Mohan N, Sadeghi K, Reiter RJ, Meltz ML . The neurohormone melatonin inhibits cytokine, mitogen and ionizing radiation induced NF-κB. Biochem Mol Biol Int 1995; 37 (6): 1063–1070.

    CAS  PubMed  Google Scholar 

  17. Radogna F, Diederich M, Ghibelli L . Melatonin: a pleiotropic molecule regulating inflammation. Biochem Pharmacol 2010; 80 (12): 1844–1852.

    Article  CAS  PubMed  Google Scholar 

  18. Mayo JC, Sainz RM, Tan DX, Hardeland R, Leon J, Rodriguez C et al. Anti-inflammatory actions of melatonin and its metabolites, N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK) and N1-acetyl-5-methoxykynuramine (AMK), in macrophages. J Neuroimmunol 2005; 165 (1-2): 139–149.

    Article  CAS  PubMed  Google Scholar 

  19. Kaur C, Sivakumar V, Lu J, Tang FR, Ling EA . Melatonin attenuates hypoxia-induced ultrastructural changes and increased vascular permeability in the developing hippocampus. Brain Pathol 2008; 18 (4): 533–547.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Carloni S, Perrone S, Buonocore G, Longini M, Proietti F, Balduini W . Melatonin protects from the long-term consequences of a neonatal hypoxic-ischemic brain injury in rats. J Pineal Res 2008; 44 (2): 157–164.

    Article  CAS  PubMed  Google Scholar 

  21. Robertson NJ, Faulkner S, Fleiss B, Bainbridge A, Andorka C, Price D et al. Melatonin augments hypothermic neuroprotection in a perinatal asphyxia model. Brain 2013; 136 (1): 90–105.

    Article  PubMed  Google Scholar 

  22. Sarnat HB, Sarnat MS . Neonatal encephalopathy following fetal distress. A clinical and electroencephalographic study. Arch Neurol 1976; 33 (10): 696–705.

    Article  CAS  PubMed  Google Scholar 

  23. Jacobs SE, Morley CJ, Inder TE, Stewart MJ, Smith KR, McNamara PJ et al. Whole-body hypothermia for term and near-term newborns with hypoxic-ischemic encephalopathy: a randomized controlled trial. Arch Pediatr Adolesc Med 2011; 165 (8): 692–700.

    Article  PubMed  Google Scholar 

  24. Fourtillan JB, Brisson AM, Fourtillan M, Ingrand I, Decourt JP, Girault J . Melatonin secretion occurs at a constant rate in both young and older men and women. Am J Physiol Endocrinol Metab 2001; 280 (1): E11–E22.

    Article  CAS  PubMed  Google Scholar 

  25. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Nebot C, Moutet M, Huet P, Xu JZ, Yadan JC, Chaudiere J . Spectrophotometric assay of superoxide dismutase activity based on the activated autoxidation of a tetracyclic catechol. Anal Biochem 1993; 214 (2): 442–451.

    Article  CAS  PubMed  Google Scholar 

  27. Biagioni E, Mercuri E, Rutherford M, Cowan F, Azzopardi D, Frisone MF et al. Combined use of electroencephalogram and magnetic resonance imaging in full-term neonates with acute encephalopathy. Pediatrics 2001; 107 (3): 461–468.

    Article  CAS  PubMed  Google Scholar 

  28. Barkovich AJ, Hajnal BL, Vigneron D, Sola A, Partridge JC, Allen F et al. Prediction of neuromotor outcome in perinatal asphyxia: evaluation of MR scoring systems. AJNR Am J Neuroradiol 1998; 19 (1): 143–149.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Miller SP, Ramaswamy V, Michelson D, Barkovich AJ, Holshouser B, Wycliffe N et al. Patterns of brain injury in term neonatal encephalopathy. J Pediatr 2005; 146 (4): 453–460.

    Article  PubMed  Google Scholar 

  30. Frankenburg WK, Dodds J, Archer P, Shapiro H, Bresnick B . The Denver II: a major revision and restandardization of the Denver Developmental Screening Test. Pediatrics 1992; 89 (1): 91–97.

    CAS  PubMed  Google Scholar 

  31. Hallioglu O, Topaloglu AK, Zenciroglu A, Duzovali O, Yilgor E, Saribas S . Denver developmental screening test II for early identification of the infants who will develop major neurological deficit as a sequalea of hypoxic-ischemic encephalopathy. Pediatr Int 2001; 43 (4): 400–404.

    Article  CAS  PubMed  Google Scholar 

  32. Kumar A, Ramakrishna SV, Basu S, Rao GR . Oxidative stress in perinatal asphyxia. Pediatr Neurol 2008; 38 (3): 181–185.

    Article  PubMed  Google Scholar 

  33. Tomas-Zapico C, Coto-Montes A . A proposed mechanism to explain the stimulatory effect of melatonin on antioxidative enzymes. J Pineal Res 2005; 39 (2): 99–104.

    Article  CAS  PubMed  Google Scholar 

  34. Thorat VN, Suryakar AN, Sardeshmukh AS, Sarawade SS . Oxidants and antioxidants in hypoxic ischaemic encephalopathy. Indian J Clin Biochem 2004; 19 (2): 32–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Kakita H, Hussein MH, Kato S, Yamada Y, Nagaya Y, Asai H et al. Hypothermia attenuates the severity of oxidative stress development in asphyxiated newborns. J Crit Care 2012; 27 (5): 469–473.

    Article  CAS  PubMed  Google Scholar 

  36. Fulia F, Gitto E, Cuzzocrea S, Reiter RJ, Dugo L, Gitto P et al. Increased levels of malondialdehyde and nitrite/nitrate in the blood of asphyxiated newborns: reduction by melatonin. J Pineal Res 2001; 31 (4): 343–349.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations


Corresponding author

Correspondence to H Aly.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Aly, H., Elmahdy, H., El-Dib, M. et al. Melatonin use for neuroprotection in perinatal asphyxia: a randomized controlled pilot study. J Perinatol 35, 186–191 (2015).

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


Quick links