A Randomized, Double-Blind, Placebo-controlled Clinical Trial of Choline Supplementation during Pregnancy to Mitigate Adverse Effects of Prenatal Alcohol Exposure on Growth and Cognitive Development

怀孕期间补充胆碱以减轻产前酒精暴露对生长和认知发展的不利影响的随机、双盲、安慰剂对照临床试验

• 批准号: 10421048
• 负责人: ROBERT COLIN CARTER
• 金额: $ 81.28万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10421048
• 关键词: Acetylcholine; Address; Adherence; Adverse effects; Alcohol consumption; Alcoholic beverage heavy drinker; Alcohols; Animal Model; Animals; Area; Back; Behavioral; Birth; Body Weight; Brain; Cell membrane; Cellular Structures; Child; Choline; Choline Deficiency; Clinical; Cognition; Cognitive; Color; Communities; Controlled Clinical Trials; DNA Methylation; Data; Developmental Delay Disorders; Dietary Intervention; Dietary Supplementation; Dose; Double-Blind Method; Dysmorphology; Early treatment; Effectiveness; Enrollment; Feasibility Studies; Fetal Alcohol Exposure; Fetal Alcohol Spectrum Disorder; Fetal Alcohol Syndrome; Fetal Growth; Fetal alcohol effects; Folic Acid; Growth; Growth and Development function; Head circumference; Health; Heavy Drinking; High Prevalence; Human; Incidence; Infant; Intake; Intelligence; Intervention; Interview; Learning; Length; Measures; Methods; Mothers; Motor; National Institute on Alcohol Abuse and Alcoholism; Neurotransmitters; Nursing Research; Nutrient; Nutritional status; Participant; Phase; Physiological; Placebo Control; Placebos; Plasma; Postpartum Period; Pregnancy; Pregnant Women; Prenatal care; Prevalence; Protocols documentation; Randomized; Rattus; Reflex action; Research; Research Priority; Risk; Rural; Sampling; School-Age Population; Short-Term Memory; Source; South Africa; Supplementation; Testing; Third Pregnancy Trimester; Time; TimeLine; Treatment Efficacy; Universities; Variant; Visit; Weight; Woman; alcohol consumption during pregnancy; alcohol effect; alcohol exposure; animal data; antenatal care; arm; binge drinking; choline supplementation; cognitive development; cognitive function; design; dietary; effectiveness evaluation; eyeblink conditioning; feasibility trial; human study; implementation facilitation; implementation intervention; infant outcome; information processing; innovation; interest; maternal alcohol use; memory recognition; methyl group; neurobehavioral; non-compliance; novel strategies; placebo group; postnatal; primary outcome; processing speed; psychosocial; public health relevance; randomized placebo controlled trial; recruit; secondary outcome; sociodemographic factors; way finding

Abstract Although the adverse effects associated with prenatal alcohol exposure (PAE) are well known, many women continue to drink heavily during pregnancy, putting their infants at risk for fetal alcohol spectrum disorders. Given the limited effectiveness of psychosocial and informational interventions, there is a growing interest in new approaches, such as nutritional interventions, that may be more effective. Animal studies have shown that choline supplementation during the equivalent of the 3rd trimester in humans can mitigate effects of PAE on growth and development. However, findings from studies in humans to date have been inconsistent and difficult to interpret. Choline, an essential nutrient, serves as a methyl-group donor for DNA methylation and is a constituent of the neurotransmitter acetylcholine and a precursor to major components of cell membranes. In an R21 feasibility trial, 70 heavy drinkers were randomly assigned to receive a daily dose of 2g of choline or a placebo from time of enrollment in antenatal care until delivery. Participants were recruited from the Cape Coloured (mixed ancestry) community in Cape Town, South Africa, where the incidence of heavy drinking during pregnancy and fetal alcohol syndrome are among the highest in the world. Infants in the choline-treated arm were more likely to meet criterion for eyeblink conditioning than those in the placebo arm. Infants born to both the choline- and placebo-treated mothers were small at birth, but those in the choline arm showed considerable catch-up growth in weight and head circumference by 6.5 mo, which persisted through 12 mo. At 12 mo, infants in the choline arm showed markedly better recognition memory compared to placebo-treated on the Fagan Test of Infant Intelligence, which is known to have predictive validity for school-age IQ. Key features of this study included the higher choline dose (4.4 times adequate intake (AI), compared to 1.7-2.5 in previous human studies) and initiation of treatment early in pregnancy. We propose to recruit heavy drinking pregnant women from a rural Cape Coloured community to participate in a fully-powered, double-blind, randomized, placebo-controlled choline supplementation trial (1) to assess the effectiveness of maternal choline supplementation during pregnancy to mitigate effects of PAE on three primary outcomes: infant recognition memory and postnatal growth restriction (weight and head circumference); (2) to assess the efficacy of this supplementation for mitigating alcohol effects on the following secondary outcomes: infant eyeblink conditioning, postnatal length, and information processing speed; (3) to use innovative methods from causal inference analysis to examine protocol adherence as an important source of variation in treatment efficacy and to identify socio-demographic factors associated with non-compliance in order to facilitate implementation of the intervention protocol in clinical settings; and (4) in exploratory analyses, to examine whether maternal choline supplementation is particularly effective in women with lower dietary choline intake or poor nutritional status. !

抽象的 尽管与产前酒精暴露（PAE）相关的不良影响是众所周知的，但许多女性 在怀孕期间继续大量饮酒，使婴儿处于胎儿酒精谱系障碍的风险。 鉴于社会心理和信息干预的有效性有限，对 新方法，例如营养干预措施，可能更有效。动物研究表明 相当于人类的第三个孕期期间补充胆碱可以减轻PAE的影响 增长与发展。但是，迄今为止在人类研究的发现并不一致，并且 难以解释。胆碱是一种必需的营养素，用作DNA甲基化的甲基组供体，IS 神经递质乙酰胆碱的成分和细胞膜主要成分的前体。在 R21的可行性试验，随机分配了70名重型饮酒者，每天接受2g胆碱或一个 安慰剂从入学到产前护理到交付。参与者是从海角招募的 南非开普敦的有色人种（混合血统）社区，在那里大量饮酒的发生率 怀孕和胎儿酒精综合征是世界上最高的。胆碱治疗的手臂中的婴儿 比安慰剂臂中的人更有可能符合拒绝条件的标准。两者出生的婴儿 胆碱和安慰剂治疗的母亲出生时很小，但是胆碱手臂的人 6.5 mo的重量和头圆周围相当大的追赶增长，通过12个月持续存在。在 12月，与安慰剂治疗相比，胆碱臂中的婴儿表现出明显更好的识别记忆 Fagan对婴儿智能的测试，该测试对学龄智商具有预测有效性。关键功能 这项研究包括较高的胆碱剂量（足够摄入量的4.4倍（AI），而先前的1.7-2.5 人类研究）和怀孕早期治疗的开始。我们建议招募大量饮酒 来自乡村斗篷有色社区的妇女参加了一个完全动力的，双盲的，随机的， 安慰剂控制的胆碱补充试验（1）评估母体胆碱的有效性 怀孕期间的补充以减轻PAE对三个主要结果的影响：婴儿识别 记忆和产后生长限制（体重和头围）； （2）评估此功效 补充可减轻酒精对以下次级结果的影响：婴儿闪光 调理，产后长度和信息处理速度； （3）使用因果关系的创新方法 推理分析以检查方案依从性，作为治疗功效差异的重要来源 确定与不合规的社会人口统计学因素，以促进实施 临床环境中的干预方案； （4）在探索性分析中，以检查孕产妇是否是否 补充胆碱对于饮食降低胆碱摄入量或营养不良的女性特别有效 地位。 呢