Timing, Duration and Severity of Infant Iron Deficiency: Developmental Impacts

描述（由申请人提供）：缺铁（ID）是世界上最常见的单一营养素紊乱，孕妇和婴儿的风险最高。由于先前研究中存在长期差异，对发育中的大脑和婴儿行为和发育的影响是最令人担忧的问题之一。然而，关于早期ID的因果关系、时间、持续时间和严重程度的基本问题仍然没有答案。拟议的研究将根据铁补充的时间（目标1）和持续时间（目标2）确定预防ID的发育/行为影响（即，出生前和/或出生后早期）。该研究将结果与ID的严重程度（目标3）相关，并考虑铁治疗的作用的可逆性，取决于时间（目标4）。我们预计，当ID发生时，或在大脑发育的不同阶段（主要是产前的增殖和生长阶段，以及主要在婴儿期的区域多样化和相互联系）预防/治疗时，会产生不同的神经行为效应。该项目需要2项随机对照试验（RCT）来支持产前和/或产后早期预防ID的因果推断。该项目建立在疾病预防控制中心支持的一项涉及中国农村孕妇的大型研究的基础上。在拟议的RCT中，婴儿的研究组为a）产前和产后早期铁，B）产前铁，c）产后早期铁，d）两者都不含（n = 500/组，研究结束时共2000例）。在出生时、6个月、12个月和24个月时评估铁状态和敏感感觉、运动、认知、语言和社会情感结局。组B）v. c）相对于d）的比较将确定预防出生前和出生后早期ID的不同效果（目标1，时机）。比较组a）产前和产后铁与B）或c）将确定早期补铁的持续时间是否具有不同的行为/发育效应（目的2）。目标1和2的结果将确定预防ID效应的最佳窗口以及母乳喂养的婴儿是否在6个月前受益于铁。将单独和组合分析每个年龄段的婴儿铁状态测量值，以确定不同发育领域受到不利影响的ID水平（严重程度，目标3）。如果没有贫血的ID的不良影响被记录在案，可能会有重大的政策影响;筛查目前只针对贫血。检测或多或少的脆弱领域也可能指向除了铁治疗之外的其他干预措施。为了确定可逆性效应，根据治疗年龄（目标4），将比较以下婴儿24个月时的结局：1）从未缺铁，2）出生时铁状态差并分配至出生后铁，3）在妊娠早期或妊娠中期接受治疗的母体IDA（贫血），4）在6个月时接受治疗的婴儿IDA，以及5）在12个月时接受治疗的IDA。该研究对现有方法-母乳喂养婴儿的补铁及其时间安排、不同年龄的筛查和治疗-进行了比较，其结果将与有关ID的全球实践和政策高度相关，因为ID对各地的贫困和/或少数民族妇女和婴儿的影响各不相同。

DESCRIPTION (provided by applicant): Iron deficiency (ID) is the most common single nutrient disorder in the world, and pregnant women and infants are at highest risk. With long-lasting differences in prior studies, effects on the developing brain and infant behavior and development are among the most worrisome concerns. However, fundamental questions about causality, timing, duration, and severity of early ID remain unanswered. The proposed study will determine developmental/ behavioral effects of preventing ID depending on timing (Aim 1) and duration (Aim 2) of iron supplementation (i.e., pre- and/or early postnatally). The study will relate outcomes to severity of ID (Aim 3) and consider reversibility of effects with iron therapy, depending on timing (Aim 4). We expect different neurobehavioral effects when ID occurs or is prevented/treated during different phases of brain development (proliferation and growth phase primarily prenatally and regional diversification and interconnection largely in infancy). The project entails 2 randomized controlled trials (RCTs) to support causal inferences about preventing ID pre- and/or early postnatally. The project builds on a large CDC- supported study involving pregnant women in rural China. Study groups of infants in the proposed RCTs combined are a) pre- and early postnatal iron, b) prenatal iron, c) early postnatal iron, and d) neither (n = 500/group, total 2000, at study end). Iron status and sensitive sensory, motor, cognitive, language, and social-emotional outcomes will be assessed at birth, 6,12, and 24 mo. Comparisons of groups b) v. c) relative to d) will identify differential effects of preventing ID pre- v. early postnatally (Aim 1, timing). Comparisons of groups a) pre- & postnatal iron v. b) or c) will determine whether the duration of early iron supplementation has differential behavioral/developmental effects (Aim 2). Results of Aims 1 & 2 will determine the best window to prevent ID effects and whether breast-fed infants benefit from iron before 6 mo. Infant iron status measures at each age will be analyzed individually and in combination to determine the level of ID at which different developmental domains are adversely affected (severity, Aim 3). If ill effects of ID without anemia are documented, there could be major policy implications; screening is currently only for anemia. Detecting more or less vulnerable domains may also point to other interventions in addition to iron therapy. To identify reversibile effects, depending on age of treatment (Aim 4), outcomes at 24 mo will be compared for infants 1) never iron-deficient, 2) poor iron status at birth and assigned to postnatal iron, 3) maternal IDA (anemia) treated in the 1st or 2nd trimester, 4) infant IDA treated at 6 mo, and 5) IDA treated at 12 mo. The study's comparisons of available approaches - iron supplementation and its timing in breast- fed infants, screening and treatment at different ages - will make the results highly relevant to global practice and policy regarding ID, which differentially affects poor and/or minority women and infants everywhere.