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A variety of factors may be involved in the development and course of musculoskeletal (MSK) pain. We undertook a systematic review with meta-analysis to synthesize and evaluate the quality of evidence about childhood and adolescent factors associated with onset and persistence of MSK pain, and its related disability. Studies were identified from searches of electronic databases (PubMed, EMBASE, PsycINFO, CINAHL, and Web of Science), references of included studies, and the Pediatric Pain mail list. Two independent reviewers assessed study inclusion, completed data extraction, and evaluated the quality of evidence using a modified Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework. Thirty-six studies reporting on 21 cohorts were included. These studies examined 65 potential risk factors for onset of MSK pain and 43 potential prognosis factors for persistence of MSK pain. No study was identified that examined prognostic factors for MSK pain–related disability. High-quality evidence suggests that low socioeconomic status is a risk factor for onset of MSK pain in studies exploring long-term follow-up. Moderate-quality evidence suggests that negative emotional symptoms and regularly smoking in childhood or adolescence may be associated with later MSK pain. However, moderate-quality evidence also suggests that high body mass index, taller height, and having joint hypermobility are not risk factors for onset of MSK pain. We found other risk and prognostic factors explored were associated with low or very low quality of evidence. Additional well-conducted primary studies are needed to increase confidence in the available evidence, and to explore new childhood risk and prognostic factors for MSK pain.