Prenatal DHA & Neurofunctional Development

 描述（申请人提供）：二十二碳六烯酸（DHA）是神经发育所必需的。如果母亲在怀孕期间DHA储备充足，分娩时母亲的RBC-DHA将≥婴儿，即，DHA平衡。以前，我们将孕妇随机分配到安慰剂油或DHA（600 mg/天）。我们发现，大多数受试者没有达到DHA平衡（5%安慰剂，35% DHA），表明DHA不足，据报道，这限制了婴儿的神经发育。为了测试DHA不足是否限制了我们样本中的胎儿神经发育，我们应用了一种创新的分析方法来估计胎儿脑成熟。结果证实，母亲DHA不足显着约束胎儿自主脑年龄评分（fABAS）。我们的假设是，许多孕妇未能从饮食中获得足够的DHA，DHA不足会限制胎儿和婴儿的神经发育。长期目标是提供神经科学知识，以告知与产前DHA补充剂的使用和剂量、膳食脂肪酸的影响以及对后代神经发育的影响有关的公共卫生建议。这与NICHD的战略和科学愿景以及国家和国际卫生组织的使命是一致的，这些组织认识到产前暴露为未来的健康和疾病奠定了基础。我们建议在妊娠的最后两个三个月进行一项200或800 mg/天DHA的随机III期临床试验，以实现这些目标：目的1）增加母亲补充800 mg/天DHA的DHA平衡发生率。假设：剂量策略将导致显著的组间差异，在接受800 mg/天DHA补充剂的格鲁组中，DHA平衡发生率较高。目的2）确定未能达到DHA平衡是否会限制胎儿神经发育。假设：DHA不足将限制胎儿神经发育，如在32和36周GA时较低的胎儿心脏和大脑自主神经指数（HRV，fABAS）所证明的。目的3）确定胎儿神经发育评分是否能预测婴儿神经发育。假设：与较低的胎儿HRV和fABAS评分相关的DHA不足将具有编程效应，其表现为：1）1个月龄时对不频繁的听觉刺激的频带限制EEG功率较低，2）6个月和12个月时对熟悉的视觉刺激的习惯性降低，通过更大的ERP负性中枢（NC）成分和3）减少的持续注意力维持和更长的4- 10岁之间的总体眼潜伏期来证明。6个月与公众健康的相关性：目前，FDA没有建议在怀孕期间补充DHA。如果该提案的目标得以实现，它可能会导致有关补充DHA的适当使用和有效剂量以及怀孕期间饮食建议的明智建议，特别是在饮食营养状况不佳的人群中。

 DESCRIPTION (provided by applicant): Docosahexaenoic acid (DHA) is essential for neurodevelopment. If maternal DHA reserves are adequate during pregnancy, at parturition RBC-DHA of the mother would be ≥ the infant, i.e., DHA equilibrium. Previously, we randomized pregnant women to placebo oil or DHA (600 mg/day). We discovered that the majority of subjects did not achieve DHA equilibrium (5% placebo, 35% DHA), indicating DHA insufficiency, which has been reported to limit infant neurodevelopment. To test whether DHA insufficiency limited fetal neurodevelopment in our sample, we applied an innovative analysis method to estimate fetal brain maturation. Results confirmed that maternal DHA insufficiency significantly constrained fetal autonomic brain age scores (fABAS). Our hypothesis is that many pregnant women fail to get adequate DHA in their diet and that DHA insufficiency constrains fetal and infant neurodevelopment. The long-term goal is to provide the neuroscience to inform public health recommendations related to the use and dose of prenatal DHA supplementation, the influence of dietary fatty acids and the effect on offspring neurodevelopment. This is aligned with the strategic and scientific vision of NICHD and the mission of national and international health organizations that recognize that prenatal exposures set the stage for future health and disease. We propose a randomized Phase III clinical trial of 200 or 800 mg/day DHA during the last two trimesters of pregnancy to achieve these aims: Aim 1) Increase the incidence of DHA equilibrium with 800 mg/day maternal DHA supplementation. Hypothesis: The dosing strategy will result in significant group differences with a higher incidence of DHA equilibrium in the grou receiving 800 mg/day DHA supplementation. Aim 2) Establish whether failure to achieve DHA equilibrium constrains fetal neurodevelopment. Hypothesis: DHA insufficiency will constrain fetal neurodevelopment as evidenced by lower fetal cardiac and brain autonomic indices (HRV, fABAS) at 32 and 36 weeks GA. Aim 3) Determine if fetal neurodevelopmental scores predict infant neurodevelopment. Hypothesis: DHA insufficiency associated with lower fetal HRV and fABAS scores will have a programming effect evidenced by 1) lower band-limited EEG power at 1 month of age to infrequent auditory stimuli, 2) decreased habituation to familiar visual stimuli at 6 and 12 months, evidenced by a larger ERP negative central (NC) component and 3) reduced maintenance of sustained attention and longer overall ocular latency between 4-6 months. Relevance to Public Health: Currently, there are no FDA recommendations for DHA supplementation during pregnancy. If the aims of this proposal are achieved, it could lead to informed recommendations with respect to the appropriate use and effective dose of supplemental DHA and dietary recommendations during pregnancy, especially in populations where the nutritional status of the diet is suboptimal.