{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T06:25:21Z","timestamp":1787639121832,"version":"build-2736575974"},"reference-count":50,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T00:00:00Z","timestamp":1787616000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pediatr."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Iron deficiency is one of the most prevalent micronutrient deficiencies globally, affecting nearly 40% of children aged 6\u201359 months. Iron plays an essential role in early brain development, particularly in myelination, neurotransmitter synthesis and energy metabolism. Deficiency during critical developmental periods may impair cognitive, motor and behavioral outcomes. Although iron supplementation improves hematological parameters, its effects on brain myelination and neurodevelopmental outcomes in children aged 0\u20133 years remain unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>To evaluate the effects of iron supplementation administered during pregnancy or early childhood (0\u20133 years) on brain myelination and neurodevelopmental outcomes in children.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This systematic review protocol follows PRISMA 2020 and Cochrane Handbook recommendations and has been prospectively designed for registration in PROSPERO. We will search PubMed, EMbase, Scopus, CENTRAL, PsycINFO, CINAHL and Web of Science for randomized controlled trials, quasi-experimental studies, cohort studies, and observational studies evaluating iron supplementation in pregnant women or children aged 0\u20133 years. Interventions will include iron supplementation in any form and dosage, compared with placebo, standard care, or alternative interventions. Primary outcomes include cognitive, motor, language, executive function, memory and myelination outcomes assessed through validated neurodevelopmental tools and neuroimaging modalities. Secondary outcomes include adverse events. Risk of bias will be assessed using ROB 2 and ROBINS-I tools and certainty of evidence will be evaluated using the GRADE approach.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>This review will synthesize current evidence regarding the role of iron supplementation in brain myelination and neurodevelopment during early childhood. The findings may inform clinical practice and public health policy, particularly in low- and middle-income settings where iron deficiency is highly prevalent.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Clinical Trial Registration<\/jats:title>\n                    <jats:p>\n                      <jats:ext-link>https:\/\/www.crd.york.ac.uk\/PROSPERO\/view\/CRD420261388359<\/jats:ext-link>\n                      , Registration ID: CRD420261388359.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fped.2026.1891295","type":"journal-article","created":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T05:35:17Z","timestamp":1787636117000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Effect of iron supplementation on brain myelination and neurodevelopmental outcomes in children aged 0\u20133 years: a systematic review protocol"],"prefix":"10.3389","volume":"14","author":[{"given":"Anju","family":"Sinha","sequence":"first","affiliation":[{"name":"Division of Reproductive, Child Health and Nutrition, Indian Council of Medical Research","place":["New Delhi, India"]},{"name":"Department of Pediatrics, India ICMR- National Institute of Child Health and Development Research","place":["New Delhi, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yamini Priyanka","family":"Kuruba","sequence":"additional","affiliation":[{"name":"Division of Reproductive, Child Health and Nutrition, Indian Council of Medical Research","place":["New Delhi, India"]},{"name":"Department of Pediatrics, India ICMR- National Institute of Child Health and Development Research","place":["New Delhi, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pradeep","family":"Kumar","sequence":"additional","affiliation":[{"name":"Clinical Research Unit, All India Institute of Medical Sciences","place":["New Delhi, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rounik","family":"Thalukdar","sequence":"additional","affiliation":[{"name":"Division of Reproductive, Child Health and Nutrition, Indian Council of Medical Research","place":["New Delhi, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Subodh","family":"Gupta","sequence":"additional","affiliation":[{"name":"Department of Community Medicine, Mahatma Gandhi Institute of Medical Sciences","place":["Sewagram, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alok","family":"Pradhan","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Independent Consultant, Pediatrics","place":["New Delhi, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kushagra","family":"Shiromani","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, India ICMR- National Institute of Child Health and Development Research","place":["New Delhi, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeeva","family":"Shankar","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, India ICMR- National Institute of Child Health and Development Research","place":["New Delhi, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,25]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"101299","DOI":"10.1016\/j.eclinm.2022.101299","article-title":"Global, regional, and national burdens of common micronutrient deficiencies from 1990 to 2019: a secondary trend analysis based on the global burden of disease 2019 study","volume":"44","author":"Han","year":"2022","journal-title":"EClinicalMed"},{"key":"B2","doi-asserted-by":"publisher","first-page":"CD009085","DOI":"10.1002\/14651858.CD009085.pub2","article-title":"Intermittent iron supplementation for improving nutrition and development in children under 12 years of age","volume":"12","author":"De-Regil","year":"2011","journal-title":"Cochrane Database Syst Rev"},{"key":"B3","doi-asserted-by":"publisher","first-page":"463","DOI":"10.3389\/fphys.2019.00463","article-title":"Iron metabolism and brain development in premature infants","volume":"10","author":"Wang","year":"2019","journal-title":"Front Physiol"},{"key":"B4","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1007\/s00431-021-04181-1","article-title":"Neurological development and iron supplementation in healthy late-preterm neonates: a randomized double-blind controlled trial","volume":"181","author":"Luciano","year":"2022","journal-title":"Eur J Pediatr"},{"key":"B5","doi-asserted-by":"publisher","first-page":"1261","DOI":"10.1093\/ajcn\/84.6.1261","article-title":"Iron supplementation in early childhood: health benefits and risks","volume":"84","author":"Iannotti","year":"2006","journal-title":"Am J Clin Nutr"},{"key":"B6","doi-asserted-by":"publisher","first-page":"2001","DOI":"10.3390\/nu12072001","article-title":"The role of iron in brain development: a systematic review","volume":"12","author":"McCann","year":"2020","journal-title":"Nutrients"},{"key":"B7","doi-asserted-by":"publisher","first-page":"126","DOI":"10.3390\/ph12030126","article-title":"Multilevel impacts of iron in the brain: the cross talk between neurophysiological mechanisms, cognition, and social behavior","volume":"12","author":"Ferreira","year":"2019","journal-title":"Pharmaceuticals (Basel)"},{"key":"B8","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1002\/ijgo.14951","article-title":"The importance of iron deficiency in pregnancy on fetal, neonatal, and infant neurodevelopmental outcomes","volume":"162","author":"Georgieff","year":"2023","journal-title":"Int J Gynaecol Obstet"},{"key":"B9","doi-asserted-by":"publisher","first-page":"CD001444","DOI":"10.1002\/14651858.CD001444.pub2","article-title":"Iron therapy for improving psychomotor development and cognitive function in children under the age of three with iron deficiency anaemia","volume":"6","author":"Wang","year":"2013","journal-title":"Cochrane Database Syst Rev"},{"key":"B10","doi-asserted-by":"publisher","first-page":"118267","DOI":"10.1016\/j.neuroimage.2021.118267","article-title":"Investigation of the association between cerebral iron content and myelin content in normative aging using quantitative magnetic resonance neuroimaging","volume":"239","author":"Khattar","year":"2021","journal-title":"Neuroimage"},{"key":"B11","doi-asserted-by":"publisher","first-page":"757","DOI":"10.1038\/sj.jp.7211178","article-title":"Iron status and neurobehavioral development of premature infants","volume":"24","author":"Armony-Sivan","year":"2004","journal-title":"J Perinatol"},{"key":"B12","doi-asserted-by":"publisher","first-page":"e0287703","DOI":"10.1371\/journal.pone.0287703","article-title":"Effects of iron supplementation on cognitive development in school-age children: systematic review and meta-analysis","volume":"18","author":"Gutema","year":"2023","journal-title":"PLoS One"},{"key":"B13","doi-asserted-by":"publisher","first-page":"649S","DOI":"10.1093\/jn\/131.2.649S","article-title":"A review of studies on the effect of iron deficiency on cognitive development in children","volume":"131","author":"Grantham-McGregor","year":"2001","journal-title":"J Nutr"},{"key":"B14","doi-asserted-by":"publisher","first-page":"1038","DOI":"10.1016\/j.neuroimage.2012.07.037","article-title":"Investigating white matter development in infancy and early childhood using myelin water faction and relaxation time mapping","volume":"63","author":"Deoni","year":"2012","journal-title":"Neuroimage"},{"key":"B15","doi-asserted-by":"publisher","first-page":"136","DOI":"10.1002\/dneu.22552","article-title":"Advances in noninvasive myelin imaging","volume":"78","author":"Heath","year":"2018","journal-title":"Dev Neurobiol"},{"key":"B16","doi-asserted-by":"publisher","first-page":"649","DOI":"10.1001\/jamapediatrics.2024.1095","article-title":"Effect of low-dose iron supplementation on early development in breastfed infants","volume":"178","author":"Svensson","year":"2024","journal-title":"JAMA Pediatr"},{"key":"B17","doi-asserted-by":"publisher","first-page":"2472871","DOI":"10.1080\/07853890.2025.2472871","article-title":"Role of iron in brain development, aging, and neurodegenerative diseases","volume":"57","author":"Gao","year":"2025","journal-title":"Ann Med"},{"key":"B18","doi-asserted-by":"publisher","first-page":"n71","DOI":"10.1136\/bmj.n71","article-title":"The PRISMA 2020 statement: an updated guideline for reporting systematic reviews","volume":"372","author":"Page","year":"2021","journal-title":"Br Med J"},{"key":"B19","article-title":"Methodological expectations of cochrane intervention reviews","author":"Higgins","year":"2023","journal-title":"Cochrane"},{"key":"B20","volume-title":"Cochrane Handbook for Systematic Reviews of Interventions Version 6.4","author":"Higgins","year":"2023"},{"key":"B21","first-page":"167","article-title":"What is your research question? An introduction to the PICOT format for clinicians","volume":"56","author":"Riva","year":"2012","journal-title":"J Can Chiropr Assoc"},{"key":"B22","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1002\/9781119536604.ch23","article-title":"Chapter 23: including variants on randomized trials","volume-title":"Cochrane Handbook for Systematic Reviews of Interventions","author":"Higgins","year":"2019"},{"key":"B23","volume-title":"Experimental and Quasi-experimental designs for Generalized Causal Inference","author":"Shadish","year":"2002"},{"key":"B24","doi-asserted-by":"publisher","first-page":"103659","DOI":"10.1016\/j.ridd.2020.103659","article-title":"Individual longitudinal neurodevelopmental trajectories of children treated with hypothermia for perinatal asphyxia from 3 months to 5 years of age","volume":"102","author":"Dekkers","year":"2020","journal-title":"Res Dev Disabil"},{"key":"B25","doi-asserted-by":"publisher","first-page":"238","DOI":"10.1016\/j.jpeds.2022.01.010","article-title":"Effects of early iron supplementation on later neurodevelopmental outcomes in preterm infants","volume":"243","author":"Domell\u00f6f","year":"2022","journal-title":"J Pediatr"},{"key":"B26","doi-asserted-by":"publisher","first-page":"CD011302","DOI":"10.1002\/14651858.CD011302.pub3","article-title":"Wheat flour fortification with iron and other micronutrients for reducing anaemia and improving iron status in populations","volume":"2021","author":"Field","year":"2021","journal-title":"Cochrane Database Syst Rev"},{"key":"B27","doi-asserted-by":"publisher","first-page":"CD005095","DOI":"10.1002\/14651858.CD005095.pub2","article-title":"Enteral iron supplementation in preterm and low birth weight infants","volume":"2012","author":"Mills","year":"2012","journal-title":"Cochrane Database Syst Rev"},{"key":"B28","volume-title":"Treasure Island","author":"Palanikumar","year":"2022"},{"key":"B29","doi-asserted-by":"publisher","first-page":"S2","DOI":"10.1212\/WNL.0b013e3182872e5f","article-title":"NIH Toolbox for assessment of neurological and behavioral function","volume":"80","author":"Gershon","year":"2013","journal-title":"Neurology"},{"key":"B30","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1203\/01.PDR.0000047657.23156.55","article-title":"Iron deficiency anemia in infancy: long-lasting effects on auditory and visual system functioning","volume":"53","author":"Algar\u00edn","year":"2003","journal-title":"Pediatr Res"},{"key":"B31","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1038\/nrn.2018.1","article-title":"Imaging structural and functional brain development in early childhood","volume":"19","author":"Gilmore","year":"2018","journal-title":"Nat Rev Neurosci"},{"key":"B32","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1016\/j.neuroscience.2013.12.044","article-title":"The early development of brain white matter: a review of imaging studies in fetuses, newborns and infants","volume":"276","author":"Dubois","year":"2014","journal-title":"Neuroscience"},{"key":"B33","volume-title":"Bayley Scales of Infant and Toddler Development","author":"Bayley","year":"2015"},{"key":"B34","volume-title":"Adaptive Behavior Assessment System","author":"Harrison","year":"2015"},{"key":"B35","volume-title":"Contemporary Intellectual Assessment: Theories, Tests, and Issues","author":"Schneider","year":"2018"},{"key":"B36","article-title":"Litmaps","author":"Webster","year":"2016","journal-title":"Lit. Rev. Assist"},{"key":"B37","doi-asserted-by":"publisher","first-page":"l4898","DOI":"10.1136\/bmj.l4898","article-title":"Rob 2: a revised tool for assessing risk of bias in randomised trials","volume":"366","author":"Sterne","year":"2019","journal-title":"Br Med J"},{"key":"B38","article-title":"Chapter 25: assessing risk of bias in a non-randomized study","volume-title":"Cochrane Handbook for Systematic Reviews of Interventions Version 6.4","author":"Sterne","year":"2023"},{"key":"B39","year":"2024"},{"key":"B40","article-title":"Chapter 6: choosing effect measures and computing estimates of effect","volume-title":"Cochrane Handbook for Systematic Reviews of Interventions Version 6.4","author":"Higgins","year":"2023"},{"key":"B41","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1080\/15374416.2021.2007485","article-title":"Empirically-derived effect size distributions of interventions for young children on the autism spectrum","volume":"52","author":"Chow","year":"2023","journal-title":"J Clin Child Adolesc Psychol"},{"key":"B42","doi-asserted-by":"publisher","first-page":"l6890","DOI":"10.1136\/bmj.l6890","article-title":"Synthesis without meta-analysis (SWiM) in systematic reviews: reporting guideline","volume":"368","author":"Campbell","year":"2020","journal-title":"Br Med J"},{"key":"B43","article-title":"Chapter 9: summarizing study characteristics and preparing for synthesis","volume-title":"Cochrane Handbook for Systematic Reviews of Interventions Version 6.4","author":"McKenzie","year":"2023"},{"key":"B44","doi-asserted-by":"publisher","first-page":"557","DOI":"10.1136\/bmj.327.7414.557","article-title":"Measuring inconsistency in meta-analyses","volume":"327","author":"Higgins","year":"2003","journal-title":"Br Med J"},{"key":"B45","doi-asserted-by":"publisher","first-page":"629","DOI":"10.1136\/bmj.315.7109.629","article-title":"Bias in meta-analysis detected by a simple, graphical test","volume":"315","author":"Egger","year":"1997","journal-title":"Br Med J"},{"key":"B46","doi-asserted-by":"publisher","first-page":"785","DOI":"10.1111\/biom.12817","article-title":"Quantifying publication bias in meta-analysis","volume":"74","author":"Lin","year":"2018","journal-title":"Biometrics"},{"key":"B47","doi-asserted-by":"publisher","first-page":"924","DOI":"10.1136\/bmj.39489.470347.AD","article-title":"GRADE: an emerging consensus on rating quality of evidence and strength of recommendations","volume":"336","author":"Guyatt","year":"2008","journal-title":"Br Med J"},{"key":"B48","year":"2024"},{"key":"B49","volume-title":"Grading of Recommendations Assessment, Development and Evaluation","author":"Sch\u00fcnemann","year":"2013"},{"key":"B50","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1016\/j.jclinepi.2013.08.005","article-title":"Applying an equity lens to interventions: using PROGRESS ensures consideration of socially stratifying factors to illuminate inequities in health","volume":"67","author":"O'Neill","year":"2014","journal-title":"J Clin Epidemiol"}],"container-title":["Frontiers in Pediatrics"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fped.2026.1891295\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T05:35:23Z","timestamp":1787636123000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fped.2026.1891295\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,25]]},"references-count":50,"alternative-id":["10.3389\/fped.2026.1891295"],"URL":"https:\/\/doi.org\/10.3389\/fped.2026.1891295","relation":{},"ISSN":["2296-2360"],"issn-type":[{"value":"2296-2360","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,25]]},"article-number":"1891295"}}