Long-term Effects and Safety of DHA Supplementation in Toddlerhood for Children born Preterm

项目总结/摘要 在美国，十分之一的儿童早产，因此长期认知缺陷的风险很高， 学习成绩差。虽然ω-3二十二碳六烯酸（DHA）膳食补充剂已经被 被吹捧为促进早产儿的认知发展，最近的几项研究表明， 提示长期不良反应的证据。长期目标是确保干预措施有助于 早产儿在学校的成功是安全和有效的。本申请的目的是确定 补充DHA对一般认知能力、语言和执行功能的长期影响，以及 为了检验治疗效果的遗传学解释，通过继续跟踪全盲儿童， 一项名为Omega Tots的随机安慰剂对照试验。核心假设是早产儿 在1岁时随机接受180天DHA治疗的儿童， 与随机接受安慰剂的儿童相比，9-10岁儿童的执行功能受损更严重。的理由 对DHA补充剂的长期影响的仔细检查将提供有价值的 澄清DHA作为促进儿童神经发育的干预措施的适当性 早产儿将通过追求2个具体目标来检验中心假设：1）确定长期效应 通过比较一般认知能力，语言和多个方面， 在9-10岁时DHA组和安慰剂组之间的执行功能。2)确定变异性在脂肪代谢中的作用 酸代谢遗传学研究补充DHA对短期和长期结果的影响， 并进一步关注2个先前发表的FADS 2遗传变异。根据目标1，方法将是 创新的前瞻性队列的儿童从欧米茄托特谁将参加详细的，在人 9-10岁的评估，包括盲评估员的评估以及家长和教师的结果报告。 对于目标2，基于SNP的遗传力方法将检查脂肪酸代谢基因的作用， 储存的血液或唾液来解释观察到的治疗效果。该研究具有创新性， 申请人的意见，因为它代表了一个实质性的偏离现状，通过进行强有力的， 对儿童的一般认知发展、语言和执行功能进行多信息人随访评估 参与DHA补充试验的大型儿童队列，以及有史以来第一次整合， 考虑脂肪酸代谢遗传学作为短期和长期不良反应的可能解释因素 方面的影响.预期的结果是确定1岁时补充DHA对认知功能的影响。 能力，语言，和执行功能的多个方面在9-10岁，和新的见解的作用，具体的 遗传因素作为短期和长期效应的解释机制。预计这一贡献将 重要的是，如果DHA补充剂对美国人的神经发育有持续的不良影响， 对于早产儿，这些发现将直接为补充剂的临床建议提供信息。

PROJECT SUMMARY/ABSTRACT One in 10 children in the U.S. is born preterm and consequently at high risk for long-term cognitive deficits and poor academic performance. While omega-3 docosahexaenoic fatty acid (DHA) dietary supplements have been touted to promote cognitive development in children born preterm, several recent studies have produced suggestive evidence of long-term adverse effects. The long-term goal is to ensure that interventions to help children born preterm succeed in school are safe and effective. The objective of this application is to determine the long-term effects of DHA supplementation on general cognitive ability, language, and executive function, and to examine genetic explanations for treatment effects, by continuing to follow the children from the fully blind, randomized, placebo-controlled trial called Omega Tots. The central hypothesis is that children born preterm who were randomized to 180 days of DHA at age 1 will exhibit poorer general cognitive ability, greater language deficits, and more impaired executive function at age 9-10 versus children randomized to placebo. The rationale for this project is that a careful examination of the long-term effects of DHA supplementation will offer valuable clarification about the appropriateness of DHA as an intervention to promote neurodevelopment among children born preterm. The central hypothesis will be tested by pursuing 2 specific aims: 1) Determine the long-term effect of DHA supplementation at age 1 year by comparing general cognitive ability, language, and multiple facets of executive function between the DHA and placebo arms at age 9-10. 2) Determine the role of variability in fatty acid metabolism genetics en masse on the effect of DHA supplementation on short and long-term outcomes, and further focus on 2 previously published FADS2 genetic variants. Under Aim 1, the approach will be an innovative prospective cohort of children from Omega Tots who will participate in detailed, in-person assessments at age 9-10 including evaluation by blind assessors and parent and teacher reports of outcomes. For Aim 2, SNP-based heritability methods will examine the role of fatty acid metabolism genes as measured in stored blood or saliva to explain observed treatment effects. The proposed research is innovative, in the applicant's opinion, because it represents a substantive departure from the status quo by conducting robust, multi-informant follow-up assessment of general cognitive development, language and executive function of a large child cohort who participated in a DHA supplementation trial, as well as integrating, for the first time ever, consideration of fatty acid metabolism genetics as possible explanatory factors for short and long-term adverse effects. The expected outcome is the determination of the effects of DHA supplementation at age 1 on cognitive ability, language, and multiple facets of executive function at age 9-10, and new insight into the role of specific genetic contributors as explanatory mechanisms for short and long-term effects. This contribution is expected to be significant because, if DHA supplementation has persistent, adverse effects on the neurodevelopment of US children born preterm, such findings would directly inform clinical recommendations about supplementation.