Exploratory Trial of Choline Supplementation for Fetal Alcohol Syndrome

补充胆碱治疗胎儿酒精综合症的探索性试验

• 批准号: 8242494
• 负责人: SANDRA W. JACOBSON
• 金额: $ 23.43万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-05 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8242494
• 关键词: Adherence; Adult; Adverse effects; Affect; Air; Alcohol abuse; Alcohol dependence; Alcohol-Related Disorders; Alcoholic beverage heavy drinker; Alcohols; Animal Model; Animals; Area; Auditory; Behavioral; Biological Assay; Biological Markers; Birth; Blinking; Body Weight; Brain; Brain Stem; Child; Choline; Cognitive; Cognitive deficits; Color; Communities; Conditioned Stimulus; Data; Development; Diet; Dietary History; Dietary Supplementation; Dietary intake; Disease; Double-Blind Method; Dysmorphology; Female of child bearing age; Fetal Alcohol Exposure; Fetal Alcohol Spectrum Disorder; Fetal Alcohol Syndrome; Fetal Growth; Fetal alcohol effects; Folate; Genetic Polymorphism; Growth; Heavy Drinking; High Prevalence; Hour; Hyperactive behavior; Impairment; Incidence; Infant; Intake; Intervention; Learning; Mediating; Mothers; National Institute on Alcohol Abuse and Alcoholism; Neurocognitive; Neurocognitive Deficit; Nutrient; Nutritional; Outcome Study; Pattern; Placebo Control; Placebos; Plasma; Population; Postpartum Period; Pregnancy; Pregnancy Trimesters; Pregnant Women; Prenatal care; Prevalence; Prevention; Protocols documentation; Public Health; Randomized; Randomized Clinical Trials; Rattus; Recruitment Activity; Research; Research Priority; Risk; Sampling; Severities; South Africa; Stimulus; Supplementation; Treatment Efficacy; Woman; alcohol consumption during pregnancy; alcohol exposure; base; cognitive function; cohort; conditioning; design; fetal; interest; meetings; neural circuit; neurobehavioral; pregnant; prenatal; prenatal intervention; prevent; psychosocial; tool; way finding

DESCRIPTION (provided by applicant): Descriptive studies have documented poor fetal growth, dysmorphology, and a range of neurobehavioral deficits in infants and children with fetal alcohol spectrum disorder (FASD). Although the adverse effects associated with fetal alcohol exposure are well-known and numerous psychosocial interventions have been attempted, many women continue to drink heavily during pregnancy. Because psychosocial interventions are frequently ineffective, NIAAA has highlighted "the potential of maternal dietary supplementation with choline, folate, and other nutrients to interact with alcohol to reduce the risk of FASD" as a priority research area. This proposal is designed to gather feasibility, adherence, and preliminary data on a promising pharmacological intervention that could prevent or mitigate the severity of fetal alcohol-related impairment. Since 1998, we have conducted research on children born to mothers recruited during pregnancy in the Cape Coloured (mixed ancestry) community in Cape Town, South Africa, where there is an unusually high incidence of alcohol abuse and dependence in women of child-bearing age, very heavy alcohol consumption during pregnancy, and one of the highest rates of fetal alcohol syndrome (FAS) in the world. We have identified a strikingly consistent effect of prenatal alcohol exposure on eyeblink conditioning (EBC), a Pavlovian paradigm that involves contingent temporal pairing of a conditioned stimulus (a tone) with an unconditioned stimulus (an air puff). Not a single child with full FAS met criterin for conditioning, compared with 75% of non-exposed controls. Two-thirds of the other heavily exposed children also failed to meet criterion for conditioning. Because infants reach the same terminal levels of conditioning as adults, EBC can provide an early indicator of alcohol-related impairment and an important tool for evaluating the efficacy of a prenatal intervention. Animal studies have shown that choline supplementation during the equivalent of the 3rd trimester of pregnancy can protect against or mitigate some of the damage incurred by fetal alcohol exposure on EBC and cognitive function. We propose to conduct a randomized, double-blind exploratory trial to examine the feasibility of implementing a choline supplementation intervention in pregnancy, assess acceptability and adherence to the intervention protocol by heavy drinkers, obtain data on plasma choline levels in supplemented mothers and placebo controls and on the prevalence of polymorphisms that substantially alter endogenous choline synthesis in this population, and collect preliminary data regarding the efficacy of the intervention in mitigating fetal alcohol effects on infant EBC and other alcohol- related cognitive deficits. Sixty heavy drinking pregnant women from the Cape Coloured community who initiate prenatal care at or before 20 weeks gestation will receive either choline supplementation (n = 30) or placebo (n = 30) twice daily until delivery. Maternal and infant nutritional intake will be evaluated by dietary history and biological assay. Infants will be assessed for birth size, growth, and EBC and neurocognitive function at 6.5 months postpartum. PUBLIC HEALTH RELEVANCE: Fetal alcohol syndrome (FAS) and other alcohol-related disorders are an important public health problem worldwide. Informational and psychosocial interventions are often ineffective with women who drink heavily during pregnancy. If this exploratory pharmacological trial demonstrates that the proposed intervention is feasible and provides preliminary evidence that choline supplementation during pregnancy can protect against or mitigate adverse effects of fetal alcohol exposure on eyeblink conditioning and other neurobehavioral outcomes, this study will provide the basis for conducting a large, fully powered randomized clinical trial. Development of an effective pharmacological intervention for pregnant women at risk for delivering an infant with fetal alcohol disorder would represent a major breakthrough in prevention of developmental deficits associated with this disorder.

描述（由申请人提供）：描述性研究记录了患有胎儿酒精谱系障碍 (FASD) 的婴儿和儿童存在胎儿生长不良、形态畸形和一系列神经行为缺陷。尽管与胎儿酒精暴露相关的不利影响是众所周知的，并且已经尝试了许多心理社会干预措施，但许多妇女在怀孕期间仍然大量饮酒。由于心理社会干预措施常常无效，NIAAA 强调了“母亲饮食补充胆碱、叶酸和其他营养素与酒精相互作用以降低 FASD 风险的潜力” 优先研究领域。该提案旨在收集一项有希望的药物干预措施的可行性、依从性和初步数据，该干预措施可以预防或减轻胎儿酒精相关损害的严重程度。自 1998 年以来，我们对南非开普敦开普有色人种（混血）社区招募的母亲在怀孕期间所生的孩子进行了研究，该社区育龄妇女酗酒和依赖的发生率异常高，怀孕期间饮酒量非常大，也是世界上胎儿酒精综合症 (FAS) 发病率最高的地区之一。我们发现产前酒精暴露对眨眼条件反射（EBC）有惊人一致的影响，这是一种巴甫洛夫范式，涉及条件刺激（音调）与非条件刺激（吹气）的偶然时间配对。没有一个患有完全 FAS 的儿童符合调节标准，而未暴露对照组的这一比例为 75%。其他严重暴露的儿童中三分之二也未能达到调节标准。由于婴儿达到与成人相同的调节终末水平，EBC 可以提供酒精相关损伤的早期指标，也是评估产前干预效果的重要工具。动物研究表明，在妊娠第三个月补充胆碱可以预防或减轻胎儿酒精暴露对 EBC 和认知功能造成的一些损害。我们建议进行一项随机、双盲探索性试验，以检验妊娠期间实施胆碱补充干预措施的可行性，评估重度饮酒者对干预方案的可接受性和依从性，获得补充母亲和安慰剂对照组的血浆胆碱水平数据，以及显着改变该人群内源性胆碱合成的多态性的患病率数据，并收集有关功效的初步数据 减轻胎儿酒精对婴儿 EBC 和其他酒精相关认知的影响的干预措施 赤字。来自 Cape Colored 社区的 60 名酗酒孕妇在妊娠 20 周或之前开始产前护理，每天两次接受胆碱补充剂 (n = 30) 或安慰剂 (n = 30)，直至分娩。将通过饮食史和生物测定来评估母亲和婴儿的营养摄入量。将评估婴儿的出生尺寸、生长情况、 产后 6.5 个月的 EBC 和神经认知功能。 公共卫生相关性：胎儿酒精综合症 (FAS) 和其他酒精相关疾病是全球重要的公共卫生问题。对于怀孕期间酗酒的女性来说，信息和社会心理干预往往无效。如果这项探索性药理学试验证明所提出的干预措施是可行的，并提供初步证据表明怀孕期间补充胆碱可以预防或减轻胎儿酒精暴露对眨眼条件反射和其他神经行为结果的不利影响，那么这项研究将为进行大型、全面的随机临床试验提供基础。为有胎儿酒精障碍婴儿风险的孕妇开发有效的药物干预措施，将是预防与该疾病相关的发育缺陷的重大突破。