Prenatal Micronutrient Supplementation and Intellectual and Motor Function in Early School-aged Children in Nepal | Global Health | JAMA | JAMA Network
[Skip to Navigation]
Access to paid content on this site is currently suspended due to excessive activity being detected from your IP address Please contact the publisher to request reinstatement.
Lozoff B. Iron deficiency and child development.  Food Nutr Bull. 2007;28(4):(suppl)  S560-S57118297894PubMedGoogle Scholar
Georgieff MK. The role of iron in neurodevelopment: fetal iron deficiency and the developing hippocampus.  Biochem Soc Trans. 2008;36(pt 6):1267-127119021538PubMedGoogle ScholarCrossref
Rao R, Tkac I, Townsend EL, Gruetter R, Georgieff MK. Perinatal iron deficiency alters the neurochemical profile of the developing rat hippocampus.  J Nutr. 2003;133(10):3215-322114519813PubMedGoogle Scholar
Ward KL, Tkac I, Jing Y,  et al.  Gestational and lactational iron deficiency alters the developing striatal metabolome and associated behaviors in young rats.  J Nutr. 2007;137(4):1043-104917374674PubMedGoogle Scholar
Todorich B, Pasquini JM, Garcia CI, Paez PM, Connor JR. Oligodendrocytes and myelination: the role of iron.  Glia. 2009;57(5):467-47818837051PubMedGoogle ScholarCrossref
Beard JL. Why iron deficiency is important in infant development.  J Nutr. 2008;138(12):2534-253619022985PubMedGoogle Scholar
Ortiz E, Pasquini JM, Thompson K,  et al.  Effect of manipulation of iron storage, transport, or availability on myelin composition and brain iron content in 3 different animal models.  J Neurosci Res. 2004;77(5):681-68915352214PubMedGoogle ScholarCrossref
Lozoff B, Beard J, Connor J, Barbara F, Georgieff M, Schallert T. Long-lasting neural and behavioral effects of iron deficiency in infancy.  Nutr Rev. 2006;64(5 pt 2):S34-S4316770951PubMedGoogle ScholarCrossref
de Deungria M, Rao R, Wobken JD, Luciana M, Nelson CA, Georgieff MK. Perinatal iron deficiency decreases cytochrome c oxidase (CytOx) activity in selected regions of neonatal rat brain.  Pediatr Res. 2000;48(2):169-17610926291PubMedGoogle ScholarCrossref
Clardy SL, Wang X, Zhao W,  et al.  Acute and chronic effects of developmental iron deficiency on mRNA expression patterns in the brain.  J Neural Transm Suppl. 2006;(71):173-19617447428PubMedGoogle Scholar
Carlson ES, Stead JD, Neal CR, Petryk A, Georgieff MK. Perinatal iron deficiency results in altered developmental expression of genes mediating energy metabolism and neuronal morphogenesis in hippocampus.  Hippocampus. 2007;17(8):679-69117546681PubMedGoogle ScholarCrossref
Golub MS, Hogrefe CE, Germann SL, Capitanio JP, Lozoff B. Behavioral consequences of developmental iron deficiency in infant rhesus monkeys.  Neurotoxicol Teratol. 2006;28(1):3-1716343844PubMedGoogle ScholarCrossref
Siddappa AM, Georgieff MK, Wewerka S, Worwa C, Nelson CA, deRegnier RA. Iron deficiency alters auditory recognition memory in newborn infants of diabetic mothers.  Pediatr Res. 2004;55:1034-104115155871PubMedGoogle ScholarCrossref
Zhou SJ, Gibson RA, Crowther CA, Baghurst P, Makrides M. Effect of iron supplementation during pregnancy on the intelligence quotient and behavior of children at 4 y of age: long-term follow-up of a randomized controlled trial.  Am J Clin Nutr. 2006;83(5):1112-111716685054PubMedGoogle Scholar
Merialdi M, Caulfield LE, Zavaleta N, Figueroa A, DiPietro JA. Adding zinc to prenatal iron and folate tablets improves fetal neurobehavioral development.  Am J Obstet Gynecol. 1999;180(2 pt 1):483-4909988823PubMedGoogle ScholarCrossref
Hamadani JD, Fuchs GJ, Osendarp SJM, Huda SN, Grantham-McGregor SM. Zinc supplementation during pregnancy and effects on mental development and behaviour of infants: a follow-up study.  Lancet. 2002;360(9329):290-29412147372PubMedGoogle ScholarCrossref
Tamura T, Goldenberg RL, Ramey SL, Nelson KG, Chapman VR. Effect of zinc supplementation of pregnant women on the mental and psychomotor development of their children at 5 y of age.  Am J Clin Nutr. 2003;77(6):1512-151612791632PubMedGoogle Scholar
Christian P, Khatry SK, Katz J,  et al.  Effects of alternative maternal micronutrient supplements on low birth weight in rural Nepal: double blind randomised community trial.  BMJ. 2003;326(7389):571-57612637400PubMedGoogle ScholarCrossref
Christian P, West KP, Khatry SK,  et al.  Effects of maternal micronutrient supplementation on fetal loss and infant mortality: a cluster-randomized trial in Nepal.  Am J Clin Nutr. 2003;78(6):1194-120214668283PubMedGoogle Scholar
Tielsch JM, Khatry SK, Stoltzfus RJ,  et al.  Effect of routine prophylactic supplementation with iron and folic acid on preschool child mortality in southern Nepal: community-based, cluster-randomised, placebo-controlled trial.  Lancet. 2006;367(9505):144-15216413878PubMedGoogle ScholarCrossref
Tielsch JM, Khatry SK, Stoltzfus RJ,  et al.  Effect of daily zinc supplementation on child mortality in southern Nepal: a community-based, cluster randomised, placebo-controlled trial.  Lancet. 2007;370(9594):1230-123917920918PubMedGoogle ScholarCrossref
Bracken BA, McCallum RS. Universal Nonverbal Intelligence Test. Itasca, IL: Riverside; 1998
McCallum S, Bracken B, Wasserman J. Essentials of Nonverbal Assessment. New York, NY: John Wiley & Sons Inc; 2001
Bull R, Scerif G. Executive functioning as a predictor of children's mathematics ability: inhibition, switching, and working memory.  Dev Neuropsychol. 2001;19(3):273-29311758669PubMedGoogle ScholarCrossref
Wechsler D. The Wechsler Intelligence Scale for Children—Third Edition (WISC-III). San Antonio, Texas: Psychological Corp; 1991
Konishi S, Nakajima K, Uchida I, Sekihara K, Miyashita Y. No-go dominant brain activity in human inferior prefrontal cortex revealed by functional magnetic resonance imaging.  Eur J Neurosci. 1998;10(3):1209-12139753190PubMedGoogle ScholarCrossref
Henderson SE, Sugden DA. Movement Assessment Battery for Children. London, England: Psychological Corp; 1992
Caldwell B, Bradley R. Home Observation for the Measurement of the Environment. Little Rock: University of Arkansas; 1984
Raven JC, Court JH, Raven J. Manual for Raven's Progressive Matrices and Vocabulary Scales. Oxford, England: Oxford Psychologists Press Ltd; 1992
de Onis M, Onyango AW, Borghi E, Siyam A, Nishida C, Siekmann J. Development of a WHO growth reference for school-aged children and adolescents.  Bull World Health Organ. 2007;85(9):660-66718026621PubMedGoogle ScholarCrossref
Snedecor GW, Cochran WG. Statistical Methods. 7th ed. Ames: Iowa State University Press; 1980:chap 13
Diggle PJ, Liang KY, Zeger SL. Analysis of Longitudinal Data. Oxford, England: Oxford University Press; 1994:chap 3, 7
Dreyfuss ML, Stoltzfus RJ, Shrestha JB,  et al.  Hookworms, malaria and vitamin A deficiency contribute to anemia and iron deficiency among pregnant women in the plains of Nepal.  J Nutr. 2000;130(10):2527-253611015485PubMedGoogle Scholar
Christian P, Shrestha J, LeClerq SC,  et al.  Supplementation with micronutrients in addition to iron and folic acid does not further improve the hematologic status of pregnant women in rural Nepal.  J Nutr. 2003;133(11):3492-349814608063PubMedGoogle Scholar
Connor JR. Evidence for iron mismanagement in the brain in neurological disorders. In: Connor JR, ed. Metals and Oxidative Damage in Neurological Disorders. New York, NY: Plenum Press; 1997:23-39
Olivares M, Pizarro F, Ruz M. New insights about iron bioavailability inhibition by zinc.  Nutrition. 2007;23(4):292-29517350802PubMedGoogle ScholarCrossref
Whittaker P. Iron and zinc interactions in humans.  Am J Clin Nutr. 1998;68(2):(suppl)  442S-446S9701159PubMedGoogle Scholar
Li Q, Yan H, Zeng L,  et al.  Effects of maternal multimicronutrient supplementation on the mental development of infants in rural western China: follow-up evaluation of a double-blind, randomized, controlled trial.  Pediatrics. 2009;123(4):e685-e69219336358PubMedGoogle ScholarCrossref
Tofail F, Persson LA, El Arifeen S,  et al.  Effects of prenatal food and micronutrient supplementation on infant development: a randomized trial from the Maternal and Infant Nutrition Interventions, Matlab (MINIMat) study.  Am J Clin Nutr. 2008;87(3):704-71118326610PubMedGoogle Scholar
McGrath N, Bellinger D, Robins J, Msamanga GI, Tronick E, Fawzi WW. Effect of maternal multivitamin supplementation on the mental and psychomotor development of children who are born to HIV-1-infected mothers in Tanzania.  Pediatrics. 2006;117(2):e216-e22516452331PubMedGoogle ScholarCrossref
Gillian BJ. The Impact of Vitamin A Supplementation In Utero and in Infancy on the Psycho-motor Development of School-Aged Children in Rural Nepal [thesis]. Baltimore, MD: Johns Hopkins University; 2009
Malouf M, Grimley EJ, Areosa SA. Folic acid with or without vitamin B12 for cognition and dementia.  Cochrane Database Syst Rev. 2003;4(4):CD00451414584018PubMedGoogle Scholar
Wehby GL, Murray JC. The effects of prenatal use of folic acid and other dietary supplements on early child development.  Matern Child Health J. 2008;12(2):180-18717554612PubMedGoogle ScholarCrossref
Roza SJ, van Batenburg-Eddes T, Steegers EA,  et al.  Maternal folic acid supplement use in early pregnancy and child behavioural problems: the Generation R Study.  Br J Nutr. 2010;103(3):445-45219772683PubMedGoogle ScholarCrossref
Original Contribution
December 22 2010

Prenatal Micronutrient Supplementation and Intellectual and Motor Function in Early School-aged Children in Nepal

Author Affiliations

Author Affiliations: Center for Human Nutrition, Department of International Health, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland (Drs Christian, Murray-Kolb, Katz, and Tielsch and Mr LeClerq); Departments of Nutritional Sciences (Dr Murray-Kolb), Educational and School Psychology and Special Education (Dr Schaefer), and Psychology (Dr Cole), Pennsylvania State University, University Park; and Nepal Nutrition Intervention Project–Sarlahi, Nepal Eye Hospital Complex, Kathmandu, Nepal (Dr Khatry and Mr LeClerq).

JAMA. 2010;304(24):2716-2723. doi:10.1001/jama.2010.1861

Context Iron and zinc are important for the development of both intellectual and motor skills. Few studies have examined whether iron and zinc supplementation during gestation, a critical period of central nervous system development, affects children's later functioning.

Objective To examine intellectual and motor functioning of children whose mothers received micronutrient supplementation during pregnancy.

Design, Setting, and Participants Cohort follow-up of 676 children aged 7 to 9 years in June 2007–April 2009 who had been born to women in 4 of 5 groups of a community-based, double-blind, randomized controlled trial of prenatal micronutrient supplementation between 1999 and 2001 in rural Nepal. Study children were also in the placebo group of a subsequent preschool iron and zinc supplementation trial.

Interventions Women whose children were followed up had been randomly assigned to receive daily iron/folic acid, iron/folic acid/zinc, or multiple micronutrients containing these plus 11 other micronutrients, all with vitamin A, vs a control group of vitamin A alone from early pregnancy through 3 months postpartum. These children did not receive additional micronutrient supplementation other than biannual vitamin A supplementation.

Main Outcome Measures Children's intellectual functioning, assessed using the Universal Nonverbal Intelligence Test (UNIT); tests of executive function, including go/no-go, the Stroop test, and backward digit span; and motor function, assessed using the Movement Assessment Battery for Children (MABC) and finger-tapping test.

Results The difference across outcomes was significant (Bonferroni-adjusted P < .001) for iron/folic acid vs control but not for other supplement groups. The mean UNIT T score in the iron/folic acid group was 51.7 (SD, 8.5) and in the control group was 48.2 (SD, 10.2), with an adjusted mean difference of 2.38 (95% confidence interval [CI], 0.06-4.70; P = .04). Differences were not significant between the control group and either the iron/folic acid/zinc (0.73; 95% CI, −0.95 to 2.42) or multiple micronutrient (1.00; 95% CI, −0.55 to 2.56) groups. In tests of executive function, scores were better in the iron/folic acid group relative to the control group for the Stroop test (adjusted mean difference in proportion who failed, −0.14; 95% CI, −0.23 to −0.04) and backward digit span (adjusted mean difference, 0.36; 95% CI, 0.01-0.71) but not for the go/no-go test. The MABC score was lower (better) in the iron/folic acid group compared with the control group but not after adjustment for confounders (mean difference, −1.47; 95% CI, −3.06 to 0.12; P = .07). Finger-tapping test scores were higher (mean difference, 2.05; 95% CI, 0.87-3.24; P = .001) in the iron/folic acid group.

Conclusion Aspects of intellectual functioning including working memory, inhibitory control, and fine motor functioning among offspring were positively associated with prenatal iron/folic acid supplementation in an area where iron deficiency is prevalent.

Trial Registration Identifier: NCT00115271