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.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Study Section
Child Psychopathology and Developmental Disabilities Study Section (CPDD)
Program Officer
Raiten, Daniel J
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University of Michigan Ann Arbor
Schools of Medicine
Ann Arbor
United States
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Hua, Ying; Kaciroti, Niko; Jiang, Yaping et al. (2018) Inadequate iron stores in early term neonates. J Perinatol 38:1017-1021
Santos, Denise C C; Angulo-Barroso, Rosa M; Li, Ming et al. (2018) Timing, duration, and severity of iron deficiency in early development and motor outcomes at 9 months. Eur J Clin Nutr 72:332-341
Clark, Katy M; Li, Ming; Zhu, Bingquan et al. (2017) Breastfeeding, Mixed, or Formula Feeding at 9 Months of Age and the Prevalence of Iron Deficiency and Iron Deficiency Anemia in Two Cohorts of Infants in China. J Pediatr 181:56-61
Angulo-Barroso, Rosa M; Li, Ming; Santos, Denise C C et al. (2016) Iron Supplementation in Pregnancy or Infancy and Motor Development: A Randomized Controlled Trial. Pediatrics 137:
Lozoff, Betsy; Jiang, Yaping; Li, Xing et al. (2016) Low-Dose Iron Supplementation in Infancy Modestly Increases Infant Iron Status at 9 Mo without Decreasing Growth or Increasing Illness in a Randomized Clinical Trial in Rural China. J Nutr 146:612-21
Jones, A D; Zhao, G; Jiang, Y-P et al. (2016) Maternal obesity during pregnancy is negatively associated with maternal and neonatal iron status. Eur J Clin Nutr 70:918-24
Silver, Monica K; Li, Xiaoqing; Liu, Yuhe et al. (2016) Low-level prenatal lead exposure and infant sensory function. Environ Health 15:65
Zhao, Gengli; Xu, Guobin; Zhou, Min et al. (2015) Prenatal Iron Supplementation Reduces Maternal Anemia, Iron Deficiency, and Iron Deficiency Anemia in a Randomized Clinical Trial in Rural China, but Iron Deficiency Remains Widespread in Mothers and Neonates. J Nutr 145:1916-23
Mai, Xiaoqin; Tardif, Twila; Xu, Lin et al. (2015) Temporal processing in the auditory brainstem response by full-term 6-week- and 9-month-old infants. Sci Rep 5:12647
Armony-Sivan, Rinat; Shao, Jie; Li, Ming et al. (2012) No relationship between maternal iron status and postpartum depression in two samples in China. J Pregnancy 2012:521431