Systematic Review and Meta-Analysis of Abnormal Pubertal Timing in Children With Autism Spectrum Disorder (ASD)

This study aimed to synthesize evidence on the risk and patterns of abnormal pubertal timing, including precocious puberty (PP) and altered onset, in children with autism spectrum disorder (ASD) compared with typically developing (TD) peers. We conducted a systematic review and meta-analysis following the PRISMA guidelines, searching PubMed (n = 51), Web of Science (n = 91), and Cochrane Library (n = 19). After removing duplicates (n = 40), we screened 121 records and assessed 31 full-text articles, with 12 meeting the inclusion criteria (3 cohort studies on PP; 9 cohort studies on pubertal timing). Random-effects meta-analyses were performed to calculate pooled hazard ratios (HRs) for PP and standardized mean differences (SMDs) for pubertal timing. Study quality was assessed using the Newcastle-Ottawa Scale (NOS). Meta-analysis of three studies (42,017 ASD children; 3,424,004 TD children) revealed a significantly higher risk of PP in ASD children (pooled HR = 3.64; 95% CI: 1.42-9.34; P = 0.007), with an absolute risk difference of 1.13% (prevalence: 1.2% in ASD vs. 0.07% in TD), indicating that 88 ASD children would need monitoring to identify one additional case of PP; this risk was particularly pronounced in females with ASD. In contrast, nine studies (856 ASD children; 648 TD children) found no significant overall difference in pubertal timing (SMD = -0.22; 95% CI: -0.91-0.46; P = 0.52), despite high heterogeneity (I² = 96%). Funnel plot asymmetry suggested potential publication bias or methodological variations (e.g., confounder adjustments, diagnostic criteria). Sensitivity analysis confirmed the association between ASD and PP but highlighted instability in the effect size. Children with ASD exhibit a 3.6-fold increased relative risk of PP, particularly in females, though the absolute prevalence is low and the certainty of evidence is very low (per Grading of Recommendations Assessment, Development and Evaluation [GRADE] criteria), primarily due to high heterogeneity (I² = 91%-96%) and potential biases. No consistent differences in pubertal timing were observed between ASD and TD children, likely reflecting methodological inconsistencies. Clinicians should enhance vigilance for PP in ASD children, without the need for routine screening. Future studies should adopt standardized, multi-method assessments to refine these findings.