Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD)

抗癫痫药物的产妇结局和神经发育影响 (MONEAD)

• 批准号: 9910453
• 负责人: KIMFORD J MEADOR
• 金额: $ 318.07万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-30 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9910453
• 关键词: 6 year old; Academy; Address; Adverse effects; Affect; Age; Alcohols; American; Anatomy; Animal Testing; Antiepileptic Agents; Attention; Behavior; Behavioral; Benchmarking; Birth; Blood; Blood drug level result; Brain; Breast Feeding; Breastfed infant; Caring; Cerebral Dominance; Child; Cognition; Cognitive; Collection; Congenital Abnormality; Controlled Study; Creativeness; Data; Data Collection; Detection; Development; Dissociation; Dose; Drug Exposure; Drug Kinetics; Drug usage; Emotional; Enrollment; Epilepsy; Exhibits; Exposure to; Female of child bearing age; Fetal Alcohol Exposure; First Pregnancy Trimester; Fright; Funding; Future; Goals; Grant; Human; Human Milk; Hyperactive behavior; Impairment; Individual; Infant; Ingestion; Investigation; Investigational Drugs; Knowledge; Levetiracetam; Long-Term Effects; Measurement; Measures; Memory; Mental Depression; Modeling; Mothers; National Institute of Neurological Disorders and Stroke; Neurology; Neurons; Neuropsychological Tests; Neuropsychology; Outcome; Outcome Assessment; Population; Pregnancy; Pregnancy Outcome; Pregnant Women; Prospective cohort study; Regimen; Registries; Reporting; Research; Risk; Seizures; Sentinel; Synapses; Teratogenic effects; Testing; Therapeutic Intervention; Third Pregnancy Trimester; Umbilical Cord Blood; Umbilical cord structure; Woman; adverse outcome; age related; autism spectrum disorder; autistic behaviour; base; behavior measurement; behavioral outcome; cognitive ability; cohort; comorbidity; design; diaries; early pregnancy; fetal; fetal drug exposure; human data; improved; in utero; individual variation; inter-individual variation; lamotrigine; malformation; nervous system disorder; neurodevelopment; neurodevelopmental effect; novel; prenatal exposure; prevent; primary outcome; prospective; screening; secondary outcome; standardize measure; teratogenesis

Project Summary: There is a compelling need for prospective, properly controlled studies in women with epilepsy (WWE) during pregnancy to improve maternal and child outcomes. The proposed investigations are pertinent to the NINDS Epilepsy Research Benchmarks, address multiple gaps in our knowledge noted by the American Academy of Neurology, and transform care in WWE. This multicenter investigation employs a prospective, observational, parallel-group, cohort design with an established research team. The FDA requires animal testing of individual AEDs to detect risks of fetal exposure for anatomical teratogenesis (i.e., congenital malformation), but not for functional teratogenesis (i.e., cognitive and behavioral deficits). Further, multiple human AED pregnancy registries are investigating malformations, but not cognitive/behavioral outcomes. Determining the effects of fetal AED exposure on development of neuropsychological abilities requires prospective collection of potential confounding factors and testing of children years after exposure. Thus, it is not surprising that such studies are rare, and the risks for most AEDs have not been assessed. The MONEAD investigation provides a unique cohort of exposed and unexposed children who have been followed prospectively starting in early pregnancy with detailed data collection; MONEAD is the first study to assess the effects of quantitated AED-exposure on neurodevelopment during pregnancy and breastfeeding by directly assessing blood levels in mother, cord blood and infant. This is critical because several commonly used AEDs undergo marked clearance changes during pregnancy with marked individual variability in these changes. Such changes could obscure “dose” relationships reducing sensitivity of detecting adverse effects. MONEAD is also collecting data on the effects of breastfeeding while taking AEDs which includes blood levels in the child and a breastfeeding diary to directly delineate their exposure. This has never been done previously. The collection of AED levels and other pregnancy related factors is complete. In the proposed continuation grant, the children will undergo detailed neuropsychological testing at 2, 3, 4.5, and 6 years-old. The results will provide clear indications of AED risks to the immature brain for the presently most commonly used AEDs, and provide sentinel data on less commonly used AEDs to direct future studies. The Specific Aims are to determine the long-term effects of in utero and infant AED exposure in the children of WWE on: Aim 1: Cognitive outcomes (e.g., verbal abilities and other cognitive domains including novel measures of cerebral lateralization and creativity), Aim 2: Behavioral outcomes (e.g., adaptive and emotional/behavioral functioning, with measures of autistic behavior, attentional problems and hyperactivity), Aim 3: Determine if breastfeeding when taking AEDs adds additional risks. Hypotheses: Children exposed in utero to certain AEDs will exhibit concentration- dependent impairments in cognitive abilities and abnormal behavior. Continued AED exposure through breastfeeding will not add additional neurodevelopmental risk.

项目概要： 目前迫切需要在女性癫痫患者（WWE）中进行前瞻性、适当对照的研究， 怀孕，以改善孕产妇和儿童的结果。拟议的调查与NINDS有关 癫痫研究基准，解决美国人指出的我们知识中的多个空白 神经病学学院，并在WWE转换护理。本多中心研究采用前瞻性、观察性、 平行组，队列设计与一个既定的研究团队。FDA要求对个别AED进行动物试验， 检测胎儿暴露于解剖学致畸作用的风险（即，先天性畸形），但不适用于功能性 致畸作用（即，认知和行为缺陷）。此外，多个人类AED妊娠登记处正在调查 畸形，但不是认知/行为结果。确定胎儿AED暴露对发育的影响 神经心理学能力需要前瞻性收集潜在的混杂因素，并对儿童进行测试。 暴露后。因此，这并不奇怪，这样的研究是罕见的，大多数AED的风险还没有被评估。 MONEAD调查提供了一个独特的暴露和未暴露儿童队列， 前瞻性地从妊娠早期开始，收集详细的数据; MONEAD是第一项评估 通过直接评估孕妇和哺乳期妇女的血液水平来定量AED暴露对神经发育的影响。 母亲脐带血和婴儿这是至关重要的，因为几种常用的AED会发生明显的清除变化 在怀孕期间，这些变化具有明显的个体差异。这种变化可能会掩盖“剂量”关系 降低了检测不利影响的灵敏度。该基金还在收集关于母乳喂养影响的数据， 服用抗癫痫药物，包括儿童的血液水平和母乳喂养日记，以直接描述其暴露情况。这 这是以前从未做过的。AED水平和其他妊娠相关因素的收集已完成。在 根据拟议的延续补助金，这些儿童将在2岁、3岁、4.5岁和6岁时接受详细的神经心理测试。 研究结果将为目前最常用的AED对未成熟大脑的风险提供明确的指示。 AED，并提供不常用的AED的哨兵数据，以指导未来的研究。 具体目的是确定宫内和婴儿期AED暴露对以下儿童的长期影响： WWE：目标1：认知结果（例如，语言能力和其他认知领域，包括新的措施， 大脑偏侧化和创造力），目标2：行为结果（例如，适应和情绪/行为功能， 与自闭症行为，注意力问题和多动症的措施），目的3：确定是否母乳喂养时， 服用抗癫痫药物增加了额外的风险。假设：在子宫内暴露于某些AED的儿童会表现出浓度- 认知能力和异常行为的依赖性损伤。通过母乳喂养持续接触AED将 不会增加额外的神经发育风险。