产前暴露于抗癫痫药物与 4.5 岁时的创造性和执行功能的关联。
Association of Prenatal Exposure to Antiseizure Medications With Creative and Executive Function at Age 4.5 Years.
机构信息
From the Stanford University (K.J.M.), Palo Alto, CA; Pediatric Neuropsychology International (M.J.C.), Augusta; Emory University School of Medicine (D.W.L., E.G.), Atlanta, GA; The Emmes Company (A.G.M., C.A.B., C.R., A.C.), Rockville, MD; Piedmont University (S.S.), Athens, GA; University of Minnesota (A.K.B.), Minneapolis; University of Southern California (L.A.K.), Los Angeles; Brigham and Women's Hospital (P.E.V.), Harvard Medical School, Boston, MA; Northwestern University (E.E.G.), Chicago, IL; Minnesota Epilepsy Group (J.H.), Roseville; University of Cincinnati (J.C.), OH; Wake Forest University (M.S.), Winston-Salem, NC; Northwell Health (S.T.H.), Great Neck; Columbia University (A.M.P.), New York, NY; University of Washington (J.J.T.), Seattle; and University of Pittsburgh (P.B.P.), PA.
出版信息
Neurology. 2024 Jun 25;102(12):e209448. doi: 10.1212/WNL.0000000000209448. Epub 2024 May 29.
BACKGROUND AND OBJECTIVES
Neurodevelopmental effects of fetal antiseizure medication (ASM) exposure on creativity and executive functions are poorly understood. We previously found fetal valproate exposure to adversely affect measures of creativity and executive functions. In this study, we examine fetal exposure of newer ASMs on these functions in children of women with epilepsy (WWE) compared with children of healthy women (HW).
METHODS
The Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs study is a multicenter NIH-funded prospective observational cohort study of WWE and HW enrolled in pregnancy and their offsprings. This report examines blindly assessed creativity and executive functions in 4.5-year-old children of WWE vs HW. In addition, exposure-dependent ASM effects during the third trimester were examined in children of WWE, using a ratio of maximum observed ASM concentrations and ratio of defined daily dose (ratio DDD). For polytherapy, ratios were summed across ASMs. Linear regression models adjusted for multiple potential confounding factors were conducted for all analyses. The primary outcome for 4.5-year-old children was the Torrance Test of Creative Thinking-Figural Creativity Index. Secondary outcomes included the Global Executive Composite Score from the Behavior Rating Inventory of Executive Function-Preschool Version and subscales and other indexes of both measures.
RESULTS
The primary analysis included 251 children of WWE and 73 of HW. No differences in creativity or executive function were found between children of WWE vs HW. No ASM exposure-dependent effects were found for the creativity measures, but exposure-dependent effects for executive function were present for ratio ASM concentration and ratio DDD.
DISCUSSION
Our findings at 4.5 years show no differences in creative thinking between children of WWE vs HW (-3.2 [-9.0 to 2.7], = 0.286) or associations with fetal exposure to ASMs (-2.6 [-11.0 to 5.7], = 0.530). Secondary analyses revealed fetal exposure-dependent effects for executive function in children of WWE (7.0 [2.9-11.2], = 0.001), which are most marked for levetiracetam (12.9 [4.2-21.6], = 0.004). Our findings suggest that even for relatively safe ASMs, dosing needs to be adjusted to concentrations that prevent seizures, but balance risks to the fetus that high concentrations may pose.
TRIAL REGISTRATION INFORMATION
The study is registered at ClinicalTrials.gov as NCT01730170.
背景与目的
胎儿抗癫痫药物（ASM）暴露对创造力和执行功能的神经发育影响知之甚少。我们之前发现胎儿丙戊酸暴露会对创造力和执行功能的测量结果产生不利影响。在这项研究中，我们研究了新的 ASM 对癫痫女性（WWE）和健康女性（HW）后代这些功能的影响。
方法
MATERNAL OUTCOMES AND NEURODEVELOPMENTAL EFFECTS OF ANTIEPILEPTIC DRUGS 研究是一项由 NIH 资助的多中心前瞻性观察队列研究，纳入了癫痫女性（WWE）及其妊娠期间的后代，以及健康女性（HW）及其后代。本报告研究了 WWE 与 HW 后代 4.5 岁时的创造力和执行功能的盲法评估。此外，还通过观察到的最高 ASM 浓度与定义日剂量比（ratio DDD）的比值，研究了 WWE 后代在妊娠晚期时的依赖于暴露的 ASM 效应。对于联合治疗，比值是通过 ASM 相加得出的。所有分析均采用调整了多个潜在混杂因素的线性回归模型进行。4.5 岁儿童的主要结果是托兰斯创造性思维测验的图形创造性指数。次要结果包括行为评定量表中的执行功能学前版的总体执行综合评分以及子量表和其他两个指标。
结果
主要分析纳入了 251 名 WWE 后代和 73 名 HW 后代。WWE 后代和 HW 后代的创造力或执行功能没有差异。在创造力测量方面，未发现与 ASM 暴露相关的效应，但在执行功能方面，ASM 浓度比值和 DDD 比值存在依赖于暴露的效应。
讨论
我们在 4.5 岁时的发现表明，WWE 后代的创造性思维与 HW 后代之间没有差异（-3.2[-9.0 至 2.7]，=0.286），也与胎儿暴露于 ASM 之间没有关联（-2.6[-11.0 至 5.7]，=0.530）。二次分析显示，WWE 后代的执行功能存在依赖于胎儿暴露的效应（7.0[2.9-11.2]，=0.001），其中左乙拉西坦的效应最明显（12.9[4.2-21.6]，=0.004）。我们的研究结果表明，即使对于相对安全的 ASM，也需要根据预防癫痫发作的浓度来调整剂量，但要平衡高浓度可能对胎儿带来的风险。
试验注册信息
该研究在 ClinicalTrials.gov 注册，编号为 NCT01730170。
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