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 虽然与产前酒精暴露（PAE）相关的不良影响是众所周知的，但许多妇女 在怀孕期间继续大量饮酒，使他们的婴儿处于胎儿酒精谱系障碍的危险之中。 鉴于社会心理和信息干预措施的效力有限，人们对以下方面越来越感兴趣： 新的方法，如营养干预，可能更有效。动物研究表明， 在相当于人类第三个三个月期间补充胆碱可以减轻PAE对 增长和发展。然而，迄今为止，人类研究的结果并不一致， 难以解释。胆碱是一种必需的营养素，作为DNA甲基化的甲基供体， 神经传递素乙酰胆碱的一种成分，是细胞膜主要成分的前体。在 在一项R21可行性试验中，70名重度饮酒者被随机分配接受每日剂量为2g的胆碱或 从入组产前护理直至分娩期间接受安慰剂治疗。参与者从开普敦招募 南非开普敦的有色（混合血统）社区，在那里， 怀孕和胎儿酒精综合症是世界上最高的。胆碱治疗组的婴儿 比安慰剂组更有可能达到眨眼条件反射的标准。 胆碱组和安慰剂组的母亲出生时体型较小，但胆碱组的母亲出生时体型较小， 体重和头围在6.5个月时显著追赶增长，并持续至12个月。在 12个月时，胆碱组婴儿的识别记忆明显好于安慰剂组。 费根婴儿智力测试，众所周知，该测试对学龄儿童智商具有预测有效性。关键特征 包括更高的胆碱剂量（4.4倍的适当摄入量（AI），而以前的研究为1.7-2.5倍）。 人类研究）和在妊娠早期开始治疗。我们建议招募酗酒的孕妇 妇女从农村开普敦有色社区参加一个充分的权力，双盲，随机， 安慰剂对照胆碱补充试验（1），以评估母体胆碱的有效性 妊娠期间补充PAE以减轻PAE对三个主要结局的影响：婴儿识别 记忆力和出生后生长限制（体重和头围）;（2）评估这种方法的疗效 补充用于减轻酒精对以下次要结果的影响：婴儿眨眼 条件反射、出生后时间长短和信息处理速度;（3）从因果关系中运用创新方法 推断分析，以检查方案依从性作为治疗疗效变异的重要来源， 确定与不遵守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;（4）在探索性分析中，检查母亲是否 胆碱补充剂对饮食胆碱摄入量较低或营养不良的妇女特别有效。 status. !

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