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: 10625834
• 负责人: ROBERT COLIN CARTER
• 金额: $ 73.01万
• 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/10625834
• 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; Risk Reduction; Rural; Sampling; School-Age Population; Short-Term Memory; Source; South Africa; Supplementation; Testing; Third Pregnancy Trimester; Time; 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; efficacy evaluation; eyeblink conditioning; feasibility trial; human study; implementation facilitation; implementation intervention; 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; timeline; 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. !

摘要 尽管与产前酒精暴露(PAE)相关的不良影响众所周知，但许多女性 怀孕期间继续大量饮酒，使他们的婴儿面临患胎儿酒精谱系障碍的风险。 鉴于心理社会和信息干预的有效性有限，人们对 新的方法，如营养干预，可能会更有效。动物研究表明， 在相当于人类妊娠晚期补充胆碱可以减轻PAE对 成长和发展。然而，到目前为止，对人类的研究结果并不一致， 很难解释。胆碱是一种必需的营养物质，是DNA甲基化的甲基供体，是 神经递质乙酰胆碱的一种成分，是细胞膜主要成分的前体。在……里面 在R21可行性试验中，70名酗酒者被随机分配到每天服用2g胆碱或 安慰剂从参加产前护理时到分娩。参与者是从开普敦招募的 南非开普敦的有色人种(混血)社区，在那里酗酒的发生率在 怀孕和胎儿酒精综合症是世界上最高的之一。接受胆碱治疗的手臂上的婴儿 与安慰剂组相比，他们更有可能达到眨眼条件的标准。两人所生的婴儿 接受胆碱和安慰剂治疗的母亲在出生时个子很小，但胆碱治疗组的母亲表现出 体重和头围有相当大的追赶增长，增长了6.5个月，一直持续到12个月。在… 12个月后，胆碱组婴儿的再认记忆明显好于安慰剂组 费根婴儿智力测验，众所周知，它对学龄期智商具有预测有效性。关键特征 这项研究包括更高的胆碱剂量(4.4倍充足摄入量(AI)，而之前的研究为1.7-2.5倍 人体研究)和在怀孕早期开始治疗。我们建议招收酗酒孕妇 来自开普敦有色人种农村社区的妇女参加一个完全有力量的，双盲，随机， 安慰剂对照胆碱补充试验(1)：评估母体胆碱的有效性 孕期补充以减轻PAE对三个主要结局的影响：婴儿认知 记忆和出生后生长受限(体重和头围)；(2)评估这一方法的效果 补充酒精可减轻以下次要后果：婴儿眨眼 条件反射、出生后长度和信息加工速度；(3)从因果关系出发创新方法 作为治疗疗效和疗效差异的重要来源检查方案依从性的推理分析 查明与不遵约有关的社会人口因素，以促进执行 在临床环境中的干预方案；以及(4)在探索性分析中，检查母亲是否 补充胆碱对饮食中胆碱摄入量较低或营养不良的妇女特别有效 状态。 好了！

项目成果

Propensity score analysis for a semi-continuous exposure variable: a study of gestational alcohol exposure and childhood cognition.

半连续暴露变量的倾向评分分析：妊娠期酒精暴露和儿童认知的研究。

• DOI: 10.1111/rssa.12716
• 发表时间: 2021
• 期刊: Journal of the Royal Statistical Society. Series A, (Statistics in Society)
• 作者: Hocagil,TugbaAkkaya;Cook,RichardJ;Jacobson,SandraW;Jacobson,JosephL;Ryan,LouiseM
• 通讯作者: Ryan,LouiseM