Impact of Valproate Therapy on Timing of Puberty in Adolescents with Childhood-onset Epilepsy

Background: Data regarding the timing of puberty in adolescents with childhood-onset epilepsy is scarce. This study aimed to explore whether pre-pubertal valproate intake negatively affects the timing of puberty.

Methods: In this cross-sectional study, adolescents with childhood-onset epilepsy were asked to report when they attained Tanner 2 thelarche and gonadarche, respectively, using a Tanner self-staging score. Girls aged 13-18 years and boys aged 14-18 years -the ages at which the definition of delayed puberty can be applied- were included. Data regarding the pre-pubertal period were recorded, including seizure frequency/month, longest seizure-free interval, valproate intake, and duration.

Results: Eighty-one PWE (48 boys and 33 girls) were included. Forty-nine patients received valproate during the pre-pubertal period. Only 18 patients (22.2 %) had delayed onset puberty (4 girls and 14 boys). Delayed menarche was identified in 7 girls. Patients with delayed onset puberty had significantly younger age at epilepsy onset and shorter pre-pubertal longest seizure-free interval than patients with normal onset (P = 0.01, for each). Furthermore, the percentage of patients who received pre-pubertal valproate was significantly higher in patients with delayed puberty (94.4 %) than in patients with normal onset puberty (50.7 %), with significantly longer treatment duration in the former group (P = 0.0006). Duration of pre-pubertal valproate intake was an independent predictor for delayed onset puberty (OR=1.36, 95 %CI =1.14-1.62) while female sex had a protective effect (OR=0.21, 95 %CI =0.04-0.92).

Conclusion: Pre-pubertal valproate intake might delay pubertal onset in both sexes with epilepsy. Serial assessment to track pubertal development across the adolescence period is highly needed.