Migraine in pediatric population: the role of biochemical markers.
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BACKGROUND: Diagnosis of migraine remains primarily clinical, and objective biological markers are lacking. Although biomarker research has expanded considerably in adults, evidence in pediatric populations remains fragmented and heterogeneous. This systematic review aimed to synthesize current data on biochemical markers in pediatric migraine and to evaluate their potential diagnostic, monitoring, prognostic, and treatment-response roles. METHODS: The review was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. PubMed, Embase and Scopus were searched up to January 1st, 2026. Studies investigating biochemical markers in individuals younger than 18 years diagnosed with episodic or chronic migraine according to International Classification of Headache Disorders 3rd edition (ICHD-3) criteria were included. Biomarkers assessed in blood, saliva, urine, cerebrospinal fluid, or stool were considered. Due to substantial heterogeneity in study design, sampling timing and laboratory methods, findings were synthesized narratively. RESULTS: Twenty-eight studies met inclusion criteria. Neuropeptides were the most extensively investigated biomarkers. Ictal elevation of calcitonin gene-related peptide (CGRP) was the most reproducible finding, supporting a disease-activity monitoring role, whereas interictal levels showed inconsistent results. Pituitary adenylate cyclase–activating polypeptide 38 (PACAP-38) and vasoactive intestinal peptide (VIP) demonstrated variable associations and may contribute within multimarker panels. Mitochondrial stress markers (growth differentiation factor-15, fibroblast growth factor-21 and hypoxia-inducible factor-1α) were elevated during attacks and in chronic migraine, suggesting links with metabolic stress and disease burden. MicroRNAs emerged as preliminary treatment-responsive candidates. Gut microbiota studies showed consistent β-diversity alterations and shifts in tryptophan metabolism; ratio-based kynurenine metabolites displayed promising diagnostic performance. Among inflammatory markers, tumor necrosis factor (TNF)-axis activation and interleukin (IL)-12p70 were the most reproducible signals. CONCLUSIONS: No single biomarker currently supports standalone clinical application. Pathway-based multimarker approaches may improve biological stratification and monitoring in pediatric migraine. CLINICAL TRIAL NUMBER: Not applicable.