The short-term and long-term adverse effects of melatonin treatment in children and adolescents: a systematic review and GRADE assessment.

Autor:	Händel MN; The Danish Health Authority, 2300, Copenhagen, Denmark.; Research Unit OPEN, Department of Clinical Research, University of Southern Denmark, Odense, Denmark.; The Parker Institute, Bispebjerg and Frederiksberg Hospital, Frederiksberg, Denmark., Andersen HK; The Danish Health Authority, 2300, Copenhagen, Denmark., Ussing A; The Danish Health Authority, 2300, Copenhagen, Denmark., Virring A; Department of Child and Adolescent Psychiatry, Aarhus University Hospital, Psychiatry, Aarhus, Denmark., Jennum P; Danish Centre for Sleep Medicine, Department of Clinical Neurophysiology, Rigshospitalet, Copenhagen, Denmark., Debes NM; Department of Pediatrics, Copenhagen University Hospital - Herlev and Gentofte, Herlev, Denmark.; Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark., Laursen T; Department of Clinical Pharmacology, Aarhus University Hospital, Denmark., Baandrup L; Bispebjerg and Gentofte Departments, Mental Health Centre Copenhagen, Copenhagen University Hospital - the Mental Health Services of the Capital Region in Denmark & Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark., Gade C; Departments of Clinical Pharmacology and Clinical Medicine, Copenhagen University Hospital, Bispebjerg and Frederiksberg, University of Copenhagen, Denmark., Dettmann J; Department of Pediatrics, Copenhagen University Hospital - NOH, Hillerød, Denmark., Holm J; The Occupational Therapist Association, Denmark., Krogh C; The Danish Health Authority, 2300, Copenhagen, Denmark., Birkefoss K; The Danish Health Authority, 2300, Copenhagen, Denmark., Tarp S; The Danish Health Authority, 2300, Copenhagen, Denmark., Bliddal M; Research Unit OPEN, Department of Clinical Research, University of Southern Denmark, Odense, Denmark., Edemann-Callesen H; The Danish Health Authority, 2300, Copenhagen, Denmark.; Centre for Evidence-Based Psychiatry, Psychiatric Research Unit, Psychiatry Region Zealand, 4200, Slagelse, Denmark.
Jazyk:	angličtina
Zdroj:	EClinicalMedicine [EClinicalMedicine] 2023 Jul 06; Vol. 61, pp. 102083. Date of Electronic Publication: 2023 Jul 06 (Print Publication: 2023).
DOI:	10.1016/j.eclinm.2023.102083
Abstrakt:	Background: Currently, melatonin is used to treat children and adolescents with insomnia without knowing the full extent of the short-term and long-term consequences. Our aim was to provide clinicians and guideline panels with a systematic assessment of serious-and non-serious adverse events seen in continuation of melatonin treatment and the impact on pubertal development and bone health following long-term administration in children and adolescents with chronic insomnia. Methods: We searched PubMed, Embase, Cinahl and PsycINFO via Ovid, up to March 17, 2023, for studies on melatonin treatment among children and adolescents (aged 5-20 years) with chronic insomnia. The language was restricted to English, Danish, Norwegian, and Swedish. Outcomes were non-serious adverse events and serious adverse events assessed 2-4 weeks after initiating treatment and pubertal development and bone health, with no restriction on definition or time of measurement. Observational studies were included for the assessment of long-term outcomes, and serious and non-serious adverse events were assessed via randomised studies. The certainty of the evidence was assessed using Grades of Recommendation, Assessment, Development and Evaluation (GRADE). The protocol is registered with the Danish Health Authority. Findings: We identified 22 randomised studies with 1350 patients reporting on serious-and non-serious adverse events and four observational studies with a total of 105 patients reporting on pubertal development. Melatonin was not associated with serious adverse events, yet the number of patients experiencing non-serious adverse events was increased (Relative risk 1.56, 95% CI 1.01-2.43, 17 studies, I 2  = 47%). Three studies reported little or no influence on pubertal development following 2-4 years of treatment, whereas one study registered a potential delay following longer treatment durations (>7 years). These findings need further evaluation due to several methodological limitations. Interpretation: Children who use melatonin are likely to experience non-serious adverse events, yet the actual extent to which melatonin leads to non-serious adverse events and the long-term consequences remain uncertain. This major gap of knowledge on safety calls for caution against complacent use of melatonin in children and adolescents with chronic insomnia and for more research to inform clinicians and guideline panels on this key issue. Funding: The Danish Health Authority. The Parker Institute, Bispebjerg and Frederiksberg Hospital, supported by the Oak Foundation. Competing Interests: LB is a member of the Danish medication reimbursement committee. AV has previously received honoraria for lectures at AGB pharma, Takeda & Medice, and holds stocks at Novo Nordisk. All other authors declare no competing interests. Statements of conflicts of interests can be found for all members of the guideline panel, the external reviewer of the national clinical guideline, the reference–and project group at the Danish Health Authority website (www.sst.dk). (© 2023 The Authors.)
Databáze:	MEDLINE
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