Investigating the Effect of Melatonin on Short-Term Prognosis of Neonatal Hypoxic-Ischemic Encephalopathy: A Randomized Controlled Trial
-
Nahid Kiani
,
Maryam Shokouhi Solfi
,
Mohammad Kazem Sabzehei
,
Fatemeh Eghbalian
,
Nasrin Jiraiyaae
,
Behnaz Basiri
Abstract
Hypoxic-ischemic encephalopathy (HIE) is a leading cause of neonatal mortality with limited therapeutic options. This study evaluated the effect of melatonin on short-term outcomes in neonates with HIE. To determine whether adjunctive oral melatonin improves short-term clinical outcomes, including in-hospital survival, in neonates with HIE. A randomized controlled trial enrolled 80 neonates with HIE at Fatemieh Hospital, Hamadan, Iran (2021-2023). The intervention group (n=32) received standard treatment plus 10 mg/kg oral melatonin daily for 5 days, while the control group (n=48) received standard treatment alone. Outcomes included seizure frequency, hospital stay duration, time to initiate oral feeding, time to regain consciousness, adverse effects, and in-hospital survival. Baseline characteristics, HIE severity, medications for seizure control, and paraclinical/imaging findings were comparable between groups (all P>0.05). No significant adverse effects were observed. The intervention group had a higher survival rate (81.2%, 26/32) than the control group (52.1%, 25/48) (P=0.04). There were no significant differences in hospital length of stay, time to start feeding, or time to regain consciousness among surviving neonates (all P>0.05). Adjunctive melatonin may improve in-hospital survival in neonates with HIE and merits further evaluation as an additive therapy.
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7. Lynch H, Wurtman R, Moskowitz MA. Daily rhythm in human urinary melatonin. Science 1975;187:169-71.
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10. Reiter RJ, Tan DX, Fuentes-Broto L. Melatonin: a multitasking molecule. Prog Brain Res 2010;181:127-51.
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12. Sadanandan N, Cozene B, Cho J, Park YJ, Saft M, Gonzales-Portillo B, et al. Melatonin—a potent therapeutic for stroke and stroke-related dementia. Antioxidants (Basel) 2020;9:672.
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14. Prechtl HFR. Assessment methods for the newborn infant: a critical evaluation. In: Stratton P, editor. Psychobiology of human newborn. Chichester: Wiley; 1982: 21-52.
15. Wu YW, Gonzalez FF. Erythropoietin: a novel therapy for hypoxic–ischaemic encephalopathy? Dev Med Child Neurol 2015;57:34-39.
16. Babbo CCR, Mellet J, van Rensburg J. Neonatal encephalopathy due to suspected hypoxic ischemic encephalopathy: pathophysiology, current, and emerging treatments. World J Pediatr. 2024;20:1105-14.
17. 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.
18. Ouwehand S, Smidt LC, Dudink J, Benders MJ, de Vries LS, Groenendaal F, et al. Predictors of outcomes in hypoxic-ischemic encephalopathy following hypothermia: a meta-analysis. Neonatology 2020;117:411-27.
19. D'Angelo G, Cannavò L, Reiter RJ. Melatonin administration from 2000 to 2020 to human newborns with hypoxic-ischemic encephalopathy. Am J Perinatol 2020;37:1082-8.
20. Sinha B, Wu Q, Li W, Tu Y, Sirianni AC, Chen Y, et al. Protection of melatonin in experimental models of newborn hypoxic-ischemic brain injury through MT1 receptor. J Pineal Res 2018;64:e12443.
21. Tütüncüler F, Eskiocak S, Başaran UN, Ekuklu G, Ayvaz S, Vatansever U, et al. The protective role of melatonin in experimental hypoxic brain damage. Pediatr Int 2005;47:434-9.
22. Ahmed J, 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.
23. Pluta R, Furmaga-Jabłońska W, Januszewski S, Tarkowska A. Melatonin: a potential candidate for the treatment of experimental and clinical perinatal asphyxia. Molecules 2023;28:1105
24. Seabra ML, Bignotto M, Pinto LR, Tufik S. Randomized, double-blind clinical trial, controlled with placebo, of the toxicology of chronic melatonin treatment. J Pineal Res 2000;29:193-200.
25. Merchant N, Azzopardi D, Counsell S. Melatonin as a novel neuroprotectant in preterm infants—a double-blinded randomized controlled trial (MINT study). Arch Dis Child 2014;99:A43.
26. Ahmad QM, Chishti AL, Waseem N. Role of melatonin in management of hypoxic ischaemic encephalopathy in newborns: a randomized control trial. J Pak Med Assoc 2018;68:1233-1237.
27. Aly H, Elmahdy H, El-Dib M, Rowisha M, Awny M, El-Gohary T, et al. Melatonin use for neuroprotection in perinatal asphyxia: a randomized controlled pilot study. J Perinatol 2015;35:186-91.
28. Cuzzocrea S, Costantino G, Gitto E, Mazzon E, Fulia F, Serraino I, et al. Protective effects of melatonin in ischemic brain injury. J Pineal Res 2000;29:217-27.
29. Bouslama M, Renaud J, Olivier P. Melatonin prevents learning disorders in brain-lesioned newborn mice. Neuroscience 2007;150:712-9.
30. 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;31:343-9.
31. 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;136:90-105.
2. Aneja S, Sharma S. Hypoxic ischaemic encephalopathy in low resource settings—time to stop cooling? Lancet Glob Health 2021;9:e1187–8.
3. Naburi H, Pillay S, Houndjahoue F, Bandeira S, Kali G, Horn A, et al. A survey on the diagnosis and management of neonatal hypoxic ischaemic encephalopathy in sub-Saharan Africa. Sci Rep 2024;14:22046.
4. Murphy SL, Kochanek KD, Xu J, Arias E. Mortality in the United States, 2023. NCHS Data Brief, no. 521. Hyattsville, MD: National Center for Health Statistics; 2024.
5. Cainelli E, Vedovelli L, Mastretta E, et al. Long-term outcomes after neonatal hypoxic-ischemic encephalopathy in the era of therapeutic hypothermia: a longitudinal, prospective, multicenter case-control study in children without overt brain damage. Children (Basel) 2021;8:1076.
6. Peeples ES, Rao R, Dizon ML, Johnson YR, Joe P, Flibotte J, et al. Predictive models of neurodevelopmental outcomes after neonatal hypoxic-ischemic encephalopathy. Pediatrics 2021;147:e2020024837.
7. Lynch H, Wurtman R, Moskowitz MA. Daily rhythm in human urinary melatonin. Science 1975;187:169-71.
8. Lewy AJ, Wehr TA, Goodwin FK. Light suppresses melatonin secretion in humans. Science 1980;210:1267-9.
9. Tan DX, Manchester LC, Terron MP, Flores LJ, Reiter RJ. One molecule, many derivatives: a never-ending interaction of melatonin with reactive oxygen and nitrogen species? J Pineal Res 2007;42:28-42.
10. Reiter RJ, Tan DX, Fuentes-Broto L. Melatonin: a multitasking molecule. Prog Brain Res 2010;181:127-51.
11. Perrone S, Carloni S, Dell’Orto VG, Filonzi L, Beretta V, Petrolini C, et al. Hypoxic ischemic brain injury: animal models reveal new mechanisms of melatonin-mediated neuroprotection. Rev Neurosci 2024;35:331-9.
12. Sadanandan N, Cozene B, Cho J, Park YJ, Saft M, Gonzales-Portillo B, et al. Melatonin—a potent therapeutic for stroke and stroke-related dementia. Antioxidants (Basel) 2020;9:672.
13. Welin AK, Svedin P, Lapatto R, Sultan B, Hagberg H, Gressens P, et al. Melatonin reduces inflammation and cell death in white matter in the mid-gestation fetal sheep following umbilical cord occlusion. Pediatr Res 2007;61:153-8.
14. Prechtl HFR. Assessment methods for the newborn infant: a critical evaluation. In: Stratton P, editor. Psychobiology of human newborn. Chichester: Wiley; 1982: 21-52.
15. Wu YW, Gonzalez FF. Erythropoietin: a novel therapy for hypoxic–ischaemic encephalopathy? Dev Med Child Neurol 2015;57:34-39.
16. Babbo CCR, Mellet J, van Rensburg J. Neonatal encephalopathy due to suspected hypoxic ischemic encephalopathy: pathophysiology, current, and emerging treatments. World J Pediatr. 2024;20:1105-14.
17. 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.
18. Ouwehand S, Smidt LC, Dudink J, Benders MJ, de Vries LS, Groenendaal F, et al. Predictors of outcomes in hypoxic-ischemic encephalopathy following hypothermia: a meta-analysis. Neonatology 2020;117:411-27.
19. D'Angelo G, Cannavò L, Reiter RJ. Melatonin administration from 2000 to 2020 to human newborns with hypoxic-ischemic encephalopathy. Am J Perinatol 2020;37:1082-8.
20. Sinha B, Wu Q, Li W, Tu Y, Sirianni AC, Chen Y, et al. Protection of melatonin in experimental models of newborn hypoxic-ischemic brain injury through MT1 receptor. J Pineal Res 2018;64:e12443.
21. Tütüncüler F, Eskiocak S, Başaran UN, Ekuklu G, Ayvaz S, Vatansever U, et al. The protective role of melatonin in experimental hypoxic brain damage. Pediatr Int 2005;47:434-9.
22. Ahmed J, 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.
23. Pluta R, Furmaga-Jabłońska W, Januszewski S, Tarkowska A. Melatonin: a potential candidate for the treatment of experimental and clinical perinatal asphyxia. Molecules 2023;28:1105
24. Seabra ML, Bignotto M, Pinto LR, Tufik S. Randomized, double-blind clinical trial, controlled with placebo, of the toxicology of chronic melatonin treatment. J Pineal Res 2000;29:193-200.
25. Merchant N, Azzopardi D, Counsell S. Melatonin as a novel neuroprotectant in preterm infants—a double-blinded randomized controlled trial (MINT study). Arch Dis Child 2014;99:A43.
26. Ahmad QM, Chishti AL, Waseem N. Role of melatonin in management of hypoxic ischaemic encephalopathy in newborns: a randomized control trial. J Pak Med Assoc 2018;68:1233-1237.
27. Aly H, Elmahdy H, El-Dib M, Rowisha M, Awny M, El-Gohary T, et al. Melatonin use for neuroprotection in perinatal asphyxia: a randomized controlled pilot study. J Perinatol 2015;35:186-91.
28. Cuzzocrea S, Costantino G, Gitto E, Mazzon E, Fulia F, Serraino I, et al. Protective effects of melatonin in ischemic brain injury. J Pineal Res 2000;29:217-27.
29. Bouslama M, Renaud J, Olivier P. Melatonin prevents learning disorders in brain-lesioned newborn mice. Neuroscience 2007;150:712-9.
30. 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;31:343-9.
31. 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;136:90-105.
| Files | ||
| Issue | Vol 64 No 1 (2026) | |
| Section | Original Articles | |
| Keywords | ||
| Neonates Hypoxic-ischemic encephalopathy Melatonin Survival rate Hospitalization | ||
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How to Cite
1.
Kiani N, Shokouhi Solfi M, Sabzehei MK, Eghbalian F, Jiraiyaae N, Basiri B. Investigating the Effect of Melatonin on Short-Term Prognosis of Neonatal Hypoxic-Ischemic Encephalopathy: A Randomized Controlled Trial. Acta Med Iran. 2026;64(1).
