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

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，使婴儿面临胎儿酒精谱系障碍的风险。 鉴于心理社会和信息干预措施的有效性有限，人们越来越感兴趣 新方法，例如营养干预措施，可能更有效。动物研究表明 在相当于人类妊娠第三个月期间补充胆碱可以减轻 PAE 对 成长和发展。然而，迄今为止对人类的研究结果并不一致， 很难解释。胆碱是一种必需营养素，作为 DNA 甲基化的甲基供体， 神经递质乙酰胆碱的成分和细胞膜主要成分的前体。在 在 R21 可行性试验中，70 名酗酒者被随机分配接受每日 2 克胆碱剂量或 从参加产前保健直至分娩期间均使用安慰剂。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，该地区酗酒的发生率 怀孕和胎儿酒精综合症是世界上最严重的。接受胆碱治疗的婴儿手臂 与安慰剂组相比，他们更有可能满足眨眼条件反射的标准。双方所生婴儿 接受胆碱和安慰剂治疗的母亲出生时身材较小，但胆碱组的母亲表现出 体重和头围显着追赶性增长 6.5 个月，并持续了 12 个月。在 12个月后，与安慰剂治疗组相比，胆碱组的婴儿表现出明显更好的识别记忆 费根婴儿智力测试，众所周知，该测试对学龄期智商具有预测有效性。主要特点 这项研究的内容包括更高的胆碱剂量（4.4 倍的充足摄入量 (AI)，而之前的研究为 1.7-2.5 倍） 人类研究）并在怀孕早期开始治疗。我们建议招募酗酒孕妇 来自开普有色人种农村社区的妇女参加一项全权、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 怀孕期间补充，以减轻 PAE 对三个主要结局的影响：婴儿认知 记忆力和产后生长受限（体重和头围）； (2) 评估该方法的有效性 补充剂可减轻酒精对以下次要结果的影响：婴儿眨眼 调理、产后长度和信息处理速度； （三）运用因果创新方法 推理分析以检查方案遵守情况作为治疗效果变化的重要来源， 查明与不遵守情况相关的社会人口因素，以促进实施 临床环境中的干预方案； (4) 在探索性分析中，检查母亲是否 补充胆碱对于膳食胆碱摄入量较低或营养不良的女性特别有效 状态。 ！

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. !