Neuroactive Steroids and Seizure Control during Pregnancy in Women with Epilepsy

癫痫女性怀孕期间的神经活性类固醇和癫痫发作控制

• 批准号: 7739995
• 负责人: Page Buckhannan Pennell
• 金额: $ 10.26万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7739995
• 关键词: Absence Epilepsy; Address; Affect; Age; Allopregnanolone; Animal Model; Animals; Anticonvulsants; Antiepileptic Agents; Blood specimen; Child health care; Clinical; Collection; Controlled Study; Data; Development; Disease; Enrollment; Epilepsy; Equilibrium; Estradiol; Exposure to; Female of child bearing age; Fetus; Frequencies; Gender; Gender Issues; General Population; Gonadal Steroid Hormones; Hour; Human; Lead; Life; Measurement; Mediating; Menstrual cycle; Metabolic; Mothers; Neurons; Outcome; Perinatal Exposure; Pharmaceutical Preparations; Plasma; Pregnancy; Pregnancy Trimesters; Premature Labor; Progesterone; Program Research Project Grants; Regulation; Research; Risk; Role; Sampling; Seizures; Serum; Specialized Center; Spontaneous abortion; Staging; Steroids; TNFRSF5 gene; Therapeutic Agents; Third Pregnancy Trimester; Time; United States; Woman; Work; base; improved; in utero; insight; neurosteroids; novel; novel therapeutic intervention; pregnant; prevent; prospective; public health relevance; relating to nervous system; reproductive; steroid analog; treatment strategy

DESCRIPTION (provided by applicant): Epilepsy is a common disorder, affecting approximately 1.3 million women of child-bearing age in the United States. Seizures during pregnancy can cause increased risks to both the mother and fetus. These risks have to be balanced against the known teratogenic effects of antiepileptic drugs (AEDs). During pregnancy, the sex steroid hormones estradiol and progesterone increase dramatically. Sex steroid hormones and the metabolic byproducts that are capable of modifying neural activity are classified as neuroactive steroids (NAS). Animal models demonstrate modulation of seizure activity by the NAS 17¿-estradiol (EST), progesterone (PROG), and allopregnanolone (ALLO). In women, fluctuations in these NAS have been implicated in seizure control in the non-pregnant state, with worsening seizures at certain times of the menstrual cycle (catamenial epilepsy). Human studies have demonstrated an increase in seizure frequency with elevated EST/PROG ratios and with declining or low PROG levels. This has not been studied during pregnancy in women with epilepsy. This proposed study will utilize serum samples (n=810 samples) already collected from 135 women with epilepsy during different stages of pregnancy during a Specialized Center of Research in Women and Gender Issues program project grant. These women were enrolled prospectively with tracking of seizures and medications. Collection of plasma samples occurred at multiple points in each trimester. Based on variable points of enrollment (< 20 weeks gestation), we have increased observations/samples in the later trimesters of pregnancy. Seizure frequency will be analyzed during the second and third trimesters of pregnancy and compared to the nonpregnant baseline for each subject. Consistent with the R03 mechanism, the current application will extend the analysis of these existing data/samples via measurement of the neuroactive steroids EST, PROG, and ALLO. The working hypotheses are 1) during pregnancy, changing concentrations of EST and PROG influence seizure control; 2) the progesterone metabolite, ALLO, mediates the seizure-reducing effect of PROG. The following will be analyzed in relationship to change in seizure frequency during pregnancy: EST/PROG ratio, the rate of rise of PROG, and the rate of rise of ALLO. Additionally, given that labor and delivery is a particularly vulnerable time for increased seizures; ALLO and PROG levels will be compared between women who had peripartum seizures and those who did not. This study can ultimately lead to a better understanding of the NAS regulation of seizure control during pregnancy. Insights gained from this study could provide the impetus for further development of NAS analogs, with treatment benefits extending to both genders and across all ages. During pregnancy, treatment with supplemental progesterone could allow for decreased levels of fetal exposure to AEDs in utero, with improved seizure control and reduced anatomical and neurodevelopmental teratogenicity. PUBLIC HEALTH RELEVANCE: Treating women with epilepsy during pregnancy requires a precarious balance of controlling the mother's seizures without exposing the developing fetus to more anticonvulsant medication than necessary. During pregnancy, the rising sex steroid hormones and their metabolic byproducts may directly influence seizure control; this study will analyze blood samples already obtained in women with epilepsy during pregnancy to examine whether women with increased seizures have alterations in neuroactive steroid levels. These findings could lead to the development of novel treatment strategies for women with epilepsy during pregnancy, such as use of supplemental progesterone, to improve mother and child health outcomes.

描述（由申请人提供）：癫痫是一种常见疾病，影响着美国约130万育龄妇女。怀孕期间的癫痫发作会增加母亲和胎儿的风险。这些风险必须与已知的抗癫痫药物致畸作用相平衡。在怀孕期间，性类固醇激素雌二醇和黄体酮急剧增加。性类固醇激素和能够改变神经活动的代谢副产物被归类为神经活性类固醇（NAS）。动物模型证明了NAS 17 -雌二醇（EST）、孕酮（PROG）和异孕酮（ALLO）对癫痫发作活动的调节作用。在妇女中，这些NAS的波动与非怀孕状态的癫痫发作控制有关，在月经周期的某些时间（双侧癫痫）发作加剧。人体研究表明，随着EST/PROG比值升高和PROG水平下降或降低，癫痫发作频率增加。这一点尚未在癫痫患者怀孕期间进行过研究。这项拟议的研究将利用在妇女和性别问题专门研究中心项目资助下从135名不同妊娠阶段的癫痫妇女中收集的血清样本（n=810份样本）。这些女性被纳入前瞻性研究，跟踪癫痫发作和药物治疗情况。在每个妊娠期的多个时间点采集血浆样本。基于可变入组点（妊娠< 20周），我们增加了妊娠后期的观察/样本。将分析每个受试者在妊娠中期和晚期的癫痫发作频率，并与非妊娠基线进行比较。与R03机制一致，目前的应用将通过测量神经活性类固醇EST、PROG和ALLO来扩展对这些现有数据/样本的分析。工作假设是：1)在怀孕期间，改变EST和PROG的浓度影响癫痫的控制；2)孕酮代谢物ALLO介导PROG的降癫痫作用。分析与妊娠期癫痫发作频率变化的关系：EST/PROG比值、PROG上升速率、ALLO上升速率。此外，鉴于分娩和分娩是癫痫发作增加的特别脆弱时期；ALLO和PROG水平将在有围产期发作和没有围产期发作的妇女之间进行比较。这项研究最终可以更好地理解NAS对妊娠期间癫痫发作控制的调节。从这项研究中获得的见解可以为进一步开发NAS类似物提供动力，其治疗益处可扩展到男女和所有年龄段。在怀孕期间，补充孕酮治疗可以降低胎儿在子宫内接触aed的水平，改善癫痫控制，减少解剖和神经发育致畸性。公共卫生相关性：治疗怀孕期间患有癫痫的妇女需要一个不稳定的平衡，既要控制母亲的癫痫发作，又不让发育中的胎儿服用不必要的抗惊厥药物。在怀孕期间，性类固醇激素及其代谢副产物的升高可能直接影响癫痫的控制；这项研究将分析已经获得的怀孕期间癫痫妇女的血液样本，以检查癫痫发作增加的妇女是否有神经活性类固醇水平的改变。这些发现可能会导致开发新的治疗策略，如使用补充孕酮，以改善母亲和儿童的健康结果。