Valproate is the most effective treatment for idiopathic generalised epilepsy. Current guidance precludes its use in women of childbearing potential, unless other treatments are ineffective or not tolerated, because of high teratogenicity. This risk was recently extended to men. New guidance will limit use both in men and women aged <55 years, resulting in withdrawal of valproate from men already taking it, as occurs for women. Whether there are risks of personal harm (including injury or death) associated with valproate withdrawal has not yet been quantified for men or women on valproate, meaning clinicians cannot reliably counsel either sex when discussing valproate withdrawal with them, despite that this concern may be at the forefront of patients’ and clinicians’ minds. We assessed whether there are any morbidity or mortality risks associated with valproate withdrawal in young men and women. We performed a retrospective cohort study of internationally derived electronic health data within the TriNetX Global Collaborative Network. Included were men and women aged 16–54 years with ≥1 epilepsy disease or symptom code between 01/12/2017–01/12/2018 and ≥2 valproate prescriptions over the preceding two years (01/01/2015–30/11/2017). 5-year propensity-matched risks of mortality and a range of morbidity outcomes were compared between those remaining on vs. withdrawn from valproate during the 01/12/2017–01/12/2018 recruitment period, regardless of whether switched to another antiseizure medication. Survival analysis was undertaken using Cox-proportional hazard models, generating hazard ratios (HRs) with 95% confidence intervals (CIs). 8,991 men and 5,243 women taking valproate were recruited. 28% of men and 36% of women were subsequently withdrawn from valproate. Valproate withdrawal was associated with significantly increased risks of emergency department attendance (HRs overall: 1.236 (CI 1.159–1.319), men: 1.181 (CI 1.083–1.288), women: 1.242 (CI 1.125–1.371)), hospital admission (HRs overall: 1.160 (CI 1.081–1.246), men: 1.132 (CI 1.027–1.249), women: 1.147 (CI 1.033–1.274)), falls (HRs overall: 1.179 (CI 1.041–1.336), men: 1.298 (CI 1.090–1.546)), injuries (HRs overall: 1.095 (CI 1.021–1.174), men: 1.129 (CI 1.029–1.239)), burns (HRs overall: 1.592 (CI 1.084–2.337)), and new-onset depression (HRs overall 1.323 (CI 1.119–1.565), women: 1.359 (CI 1.074–1.720)). The risk of these outcomes occurring was 1–7% higher in those withdrawn from valproate than in those remaining on valproate. Overall, valproate withdrawal was not associated with increased mortality. These results may help patients and clinicians have a more informed discussion about personal safety when considering valproate withdrawal.

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年轻男性和女性癫痫患者与丙戊酸戒断相关的发病率和死亡风险

丙戊酸是治疗特发性全身性癫痫最有效的药物。目前的指导意见禁止将其用于育龄妇女，除非其他治疗无效或无法耐受，因为其致畸性较高。这种风险最近已扩展到男性。新指南将限制年龄<55岁的男性和女性的使用，导致已经服用丙戊酸的男性撤回丙戊酸，就像女性一样。对于服用丙戊酸的男性或女性，是否存在与丙戊酸戒断相关的人身伤害（包括受伤或死亡）风险尚未量化，这意味着临床医生在与男性或女性讨论丙戊酸戒断时无法可靠地为他们提供建议，尽管这种担忧可能存在是患者和临床医生最关心的问题。我们评估了年轻男性和女性是否存在与丙戊酸钠戒断相关的发病或死亡风险。我们对 TriNetX 全球协作网络内的国际电子健康数据进行了回顾性队列研究。包括年龄 16-54 岁的男性和女性，在 01/12/2017-01/12/2018 之间患有 ≥1 种癫痫疾病或症状代码，并且在前两年（01/01/2015-30/11）服用过 ≥2 种丙戊酸处方。 /2017）。在2017年12月12日至2018年12月12日招募期间，对继续服用丙戊酸钠和停用丙戊酸钠的患者进行了5年倾向匹配的死亡风险和一系列发病结果的比较，无论是否改用另一种抗癫痫药物。使用 Cox 比例风险模型进行生存分析，生成具有 95% 置信区间 (CI) 的风险比 (HR)。招募了 8,991 名男性和 5,243 名女性服用丙戊酸。 28% 的男性和 36% 的女性随后停止使用丙戊酸钠。丙戊酸钠戒断与急诊科就诊风险显着增加相关（总体 HR：1.236（CI 1.159–1.319），男性：1.181（CI 1.083–1.288），女性：1.242（CI 1.125–1.371））、入院（总体 HR ：1.160 (CI 1.081–1.246)，男性：1.132 (CI 1.027–1.249)，女性：1.147 (CI 1.033–1.274))，跌倒（HR 总体：1.179 (CI 1.041–1.336)，男性：1.298 (CI 1.090– 1.546))、受伤（总体 HR：1.095 (CI 1.021–1.174)、男性：1.129 (CI 1.029–1.239))、烧伤（总体 HR：1.592 (CI 1.084–2.337)) 和新发抑郁症（总体 HR 1.323 (CI 1.119–1.565)，女性：1.359 (CI 1.074–1.720))。停用丙戊酸的患者发生这些结果的风险比继续使用丙戊酸的患者高 1-7%。总体而言，丙戊酸戒断与死亡率增加无关。这些结果可能有助于患者和临床医生在考虑丙戊酸钠戒断时对个人安全进行更明智的讨论。