ASSOCIATION BETWEEN ADHD, METHYLPHENIDATE, AND PRECOCIOUS PUBERTY: A NATIONWIDE COHORT STUDY

Abstract Background A few studies reported the associations between ADHD and precocious puberty. Based on animal studies, Methylphenidate (MPH) can alter the timing of puberty and the change varies by sex. Aims & Objectives We conducted a cohort study to investigate the association between ADHD, MPH, and precocious puberty, with considering of the potential moderating effects by different neuropsychiatric disorders and sex. Method To compare the risk of precocious puberty between ADHD and non-ADHD cases, we conducted Cox regression analysis with ADHD as exposure and time-to-precocious puberty as outcomes adjusting for sex, ASD, tics, obsessive– compulsive disorder, anxiety disorder, intellectual disability, and epilepsy. We performed moderation analyses to examine the potential moderating effects by sex and comorbidities. To compare the risk of precocious puberty between MPH uesrs and non-MPH users in patients with ADHD, we conducted Cox regression analysis with MPH as exposure and time-to-precocious puberty as outcomes adjusting for sex and the six neuropsychaitric comorbidities. We also performed a moderation analysis to examine the potential moderating effects by sex. Results Patients with ADHD had a significantly greater risk of precocious puberty than patients without ADHD, with an aHR of 2.01 (95% CI 1.91, 2.11). In the sex-stratified analysis, precocious puberty was still significantly more prevalent in ADHD group than in non-ADHD group in either stratum of males or females, with aHRs of 2.05 and 1.99, respectively. Regarding the effect modification, sex, specifically female, moderated the association between ADHD and precocious puberty, with a relative excess risk due to interaction (RERI) 8.56 (95% CI 7.48,9.64). Tics also served as an effect modifier on either additive (RERI -1.24, 95% CI -1.78, -0.70) or multiplicative scale (aHR -0.70, 95% CI -1.02, -0.38). Similar findings were found when intellectual disability was set as an effect modifier, with RERI -0.70 (95% CI -1.02, - 0.38) and value of ratio on multiplicative scale being 0.62 (95% CI 0.50, 0.77). This means that ADHD has a greater impact on the risk of precocious puberty in patients without tics or without intellectual disability than in patients with tics or with intellectual disability. No significant effect modification was found for the other comorbidities within the scope of additive effect modification. While comparing the effect of MPH on risk of precocious puberty in patients with ADHD, MPH users had significantly lower rate of precocious puberty than non-MPH users, with aHR 0.63 and 95% CI 0.57-0.70. If considering the moderation analysis of sex, being female was served as an effect modifier on both additive (RERI -4.38, 95% CI -5.51, -3.25) and multiplicative scales (aHR 0.54, 95% CI 0.43, 0.67). It means that the preventive effect of MPH on precocious puberty in patients with ADHD was greater in females than in males. Discussion & Conclusion Patients with ADHD are at greater risk for precocious puberty, regardless of sex. Girls with ADHD are at particularly high risk of developing precocious puberty. Comorbid tics or intellectual disability appear to have an antagonistic effect on the association between ADHD and precocious puberty. Treatment with MPH lower the risk of precocious puberty in ADHD, especially in girls with ADHD.