{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T00:46:23Z","timestamp":1793321183159,"version":"4.5.0"},"reference-count":45,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,5,20]],"date-time":"2025-05-20T00:00:00Z","timestamp":1747699200000},"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><jats:title>Background and objectives<\/jats:title><jats:p>Exclusively breastfed infants are at risk of iron deficiency due to the low iron content in breast milk. This study aims to evaluate the benefits and risks of daily oral iron supplementation on growth, cognitive outcomes, and hematologic parameters in these infants.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Data sources include Cochrane Central Register of Controlled Trials, PubMed, and Embase from inception to December, 2024. Randomized controlled trials were included. The Cochrane risk of bias tool was used to assess the methodological quality of included trials. The continuous outcomes were analyzed by calculating the mean difference (MD) and the binary categorical variables were analyzed using relative risk (RR) with 95% confidence intervals (CI).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>This study included 8 trials (685 participants) comparing iron supplementation to no iron. At 6 months of age, compared to infants who were exclusively breastfed without iron supplementation, those who received oral iron supplementation showed an increase in hemoglobin (Hb) levels (MD 0.42, 95% CI 0.19\u20130.66, <jats:italic>p<\/jats:italic>\u2009&amp;lt;\u20090.001, <jats:italic>I<\/jats:italic><jats:sup>2<\/jats:sup>\u2009=\u200976%) and a reduction in the incidence of iron deficiency (ID) (RR 0.38, 95% CI 0.15\u20131.00, <jats:italic>p<\/jats:italic>\u2009=\u20090.050, <jats:italic>I<\/jats:italic><jats:sup>2<\/jats:sup>\u2009=\u200929%) and iron-deficiency anemia (IDA) (RR 0.58, 95% CI 0.40\u20130.84, <jats:italic>p<\/jats:italic>\u2009=\u20090.004, <jats:italic>I<\/jats:italic><jats:sup>2<\/jats:sup>\u2009=\u20090). However, by 12 months of age, the supplementation had no effect on Hb levels, ID, the incidence of IDA or mental development index (MDI). Iron supplementation appeared to reduce weight gain (MD\u2009=\u2009\u22120.04, 95%CI \u22120.07 to \u22120.01, <jats:italic>p<\/jats:italic>\u2009=\u20090.004, <jats:italic>I<\/jats:italic><jats:sup>2<\/jats:sup>\u2009=\u20090) and head circumference gain (MD\u2009=\u2009\u22120.14, 95% CI \u22120.18 to \u22120.09, <jats:italic>p<\/jats:italic>\u2009&amp;lt;\u20090.001, <jats:italic>I<\/jats:italic><jats:sup>2<\/jats:sup>\u2009=\u200925%).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Limited available evidence suggests that iron supplementation is beneficial for hematologic parameters and the incidence of IDA in healthy exclusively breastfed infants. However, it may delay weight gain and head circumference growth.<\/jats:p><\/jats:sec><jats:sec><jats:title>Systematic Review Registration<\/jats:title><jats:p><jats:uri>https:\/\/www.crd.york.ac.uk\/prospero\/<\/jats:uri>, PROSPERO [CRD42024610082].<\/jats:p><\/jats:sec>","DOI":"10.3389\/fped.2025.1587457","type":"journal-article","created":{"date-parts":[[2025,5,20]],"date-time":"2025-05-20T10:17:20Z","timestamp":1747736240000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["Effect of iron supplementation in healthy exclusively breastfed infants: a systematic review and meta-analysis"],"prefix":"10.3389","volume":"13","author":[{"given":"Ke","family":"Tian","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenli","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rong","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,5,20]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1789","DOI":"10.1016\/S0140-6736(18)32279-7","article-title":"Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990\u20132017: a systematic analysis for the global burden of disease study 2017","volume":"392","author":"James","year":"2018","journal-title":"Lancet"},{"key":"B2","doi-asserted-by":"publisher","first-page":"e16","DOI":"10.1016\/S2214-109X(13)70001-9","article-title":"Global, regional, and national trends in haemoglobin concentration and prevalence of total and severe anaemia in children and pregnant and non-pregnant women for 1995\u20132011: a systematic analysis of population-representative data","volume":"1","author":"Stevens","year":"2013","journal-title":"Lancet Glob Health"},{"key":"B3","doi-asserted-by":"publisher","first-page":"635","DOI":"10.1016\/S0022-3476(98)70352-X","article-title":"Prevention of iron-deficiency anemia: comparison of high- and low-iron formulas in term healthy infants after six months of life","volume":"132","author":"Walter","year":"1998","journal-title":"J Pediatr"},{"key":"B4","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1097\/MPG.0000000000000206","article-title":"Iron requirements of infants and toddlers","volume":"58","author":"Domell\u00f6f","year":"2014","journal-title":"J Pediatr Gastroenterol Nutr"},{"key":"B5","doi-asserted-by":"publisher","first-page":"233","DOI":"10.1016\/S0140-6736(20)32594-0","article-title":"Iron deficiency","volume":"397","author":"Pasricha","year":"2021","journal-title":"Lancet"},{"key":"B6","doi-asserted-by":"publisher","first-page":"1040","DOI":"10.1542\/peds.2010-2576","article-title":"Diagnosis and prevention of iron deficiency and iron-deficiency anemia in infants and young children (0\u20133 years of age)","volume":"126","author":"Baker","year":"2010","journal-title":"Pediatrics"},{"key":"B7","doi-asserted-by":"publisher","first-page":"2523","DOI":"10.3945\/jn.108.095406","article-title":"Iron deficiency in young children in low-income countries and new approaches for its prevention","volume":"138","author":"Lutter","year":"2008","journal-title":"J Nutr"},{"key":"B8","doi-asserted-by":"publisher","first-page":"687","DOI":"10.1056\/NEJM199109053251004","article-title":"Long-term developmental outcome of infants with iron deficiency","volume":"325","author":"Lozoff","year":"1991","journal-title":"N Engl J Med"},{"key":"B9","doi-asserted-by":"publisher","first-page":"E51","DOI":"10.1542\/peds.105.4.e51","article-title":"Poorer behavioral and developmental outcome more than 10 years after treatment for iron deficiency in infancy","volume":"105","author":"Lozoff","year":"2000","journal-title":"Pediatrics"},{"key":"B10","doi-asserted-by":"publisher","first-page":"1108","DOI":"10.1001\/archpedi.160.11.1108","article-title":"Double burden of iron deficiency in infancy and low socioeconomic status: a longitudinal analysis of cognitive test scores to age 19 years","volume":"160","author":"Lozoff","year":"2006","journal-title":"Arch Pediatr Adolesc Med"},{"key":"B11","first-page":"Cd001444","article-title":"Iron therapy for improving psychomotor development and cognitive function in children under the age of three with iron deficiency anaemia","volume":"2","author":"Logan","year":"2001","journal-title":"Cochrane Database Syst Rev"},{"key":"B12","doi-asserted-by":"publisher","first-page":"382","DOI":"10.1016\/S0022-3476(96)70070-7","article-title":"Iron-deficiency anemia and infant development: effects of extended oral iron therapy","volume":"129","author":"Lozoff","year":"1996","journal-title":"J Pediatr"},{"key":"B13","doi-asserted-by":"publisher","first-page":"2023","DOI":"10.3390\/nu6052023","article-title":"Iron stores of breastfed infants during the first year of life","volume":"6","author":"Ziegler","year":"2014","journal-title":"Nutrients"},{"key":"B14","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1016\/j.jpeds.2020.10.071","article-title":"A substantial proportion of 6- to 12-month-old infants have calculated daily absorbed iron below recommendations, especially those who are breastfed","volume":"231","author":"Abrams","year":"2021","journal-title":"J Pediatr"},{"key":"B15","doi-asserted-by":"publisher","first-page":"773","DOI":"10.1016\/j.clnu.2010.05.002","article-title":"Iron intake and iron status in breastfed infants during the first year of life","volume":"29","author":"Dube","year":"2010","journal-title":"Clin Nutr"},{"key":"B16","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1089\/bfm.2007.0002","article-title":"Full breastfeeding duration and risk for iron deficiency in U.S. infants","volume":"2","author":"Chantry","year":"2007","journal-title":"Breastfeed Med"},{"key":"B17","doi-asserted-by":"publisher","first-page":"679","DOI":"10.1067\/mpd.2001.112895","article-title":"Iron supplementation of breast-fed Honduran and Swedish infants from 4 to 9 months of age","volume":"138","author":"Domell\u00f6f","year":"2001","journal-title":"J Pediatr"},{"key":"B18","doi-asserted-by":"publisher","first-page":"401","DOI":"10.1016\/S0031-3955(08)70033-6","article-title":"Iron and breastfeeding","volume":"48","author":"Griffin","year":"2001","journal-title":"Pediatr Clin North Am"},{"key":"B19","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1016\/j.jpeds.2016.10.041","article-title":"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","volume":"181","author":"Clark","year":"2017","journal-title":"J Pediatr"},{"key":"B20","doi-asserted-by":"publisher","first-page":"616S","DOI":"10.1093\/jn\/131.2.616S","article-title":"Iron and its relation to immunity and infectious disease","volume":"131","author":"Oppenheimer","year":"2001","journal-title":"J Nutr"},{"key":"B21","doi-asserted-by":"publisher","first-page":"760","DOI":"10.1038\/s41415-022-4359-7","article-title":"PRISMA 2020 updated guideline","volume":"232","author":"Dickson","year":"2022","journal-title":"Br Dent J"},{"key":"B22","doi-asserted-by":"publisher","first-page":"Cd008754","DOI":"10.1002\/14651858.CD008754.pub2","article-title":"Memory rehabilitation for people with multiple sclerosis","volume":"3","author":"das Nair","year":"2012","journal-title":"Cochrane Database Syst Rev"},{"key":"B23","doi-asserted-by":"publisher","first-page":"265","DOI":"10.1016\/j.jclinepi.2021.04.014","article-title":"Corrigendum to GRADE guidelines 6. Rating the quality of evidence-imprecision. J Clin Epidemiol 2011;64:1283\u20131293","volume":"137","author":"Guyatt","year":"2021","journal-title":"J Clin Epidemiol"},{"key":"B24","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: a randomized clinical trial","volume":"178","author":"Svensson","year":"2024","journal-title":"JAMA Pediatr"},{"key":"B25","doi-asserted-by":"publisher","first-page":"299","DOI":"10.3760\/cma.j.issn.0253-9624.2012.04.003","article-title":"The influence of preventive iron supplementation to iron nutritional status in breastfed infants","volume":"46","author":"Wang","year":"2012","journal-title":"Zhonghua Yu Fang Yi Xue Za Zhi"},{"key":"B26","doi-asserted-by":"publisher","first-page":"284","DOI":"10.1097\/00043426-200405000-00005","article-title":"Efficacy of daily and weekly iron supplementation on iron status in exclusively breast-fed infants","volume":"26","author":"Yurdak\u00f6k","year":"2004","journal-title":"J Pediatr Hematol Oncol"},{"key":"B27","doi-asserted-by":"publisher","first-page":"280","DOI":"10.1093\/tropej\/48.5.280","article-title":"Effects of three different iron supplementations in term healthy infants after 5 months of life","volume":"48","author":"Ermis","year":"2002","journal-title":"J Trop Pediatr"},{"key":"B28","doi-asserted-by":"publisher","first-page":"582","DOI":"10.1067\/S0022-3476(03)00301-9","article-title":"A double-masked, randomized control trial of iron supplementation in early infancy in healthy term breast-fed infants","volume":"143","author":"Friel","year":"2003","journal-title":"J Pediatr"},{"key":"B29","doi-asserted-by":"publisher","first-page":"176","DOI":"10.2471\/BLT.23.289942","article-title":"Early iron supplementation in exclusively breastfed gambian infants: a randomized controlled trial","volume":"102","author":"Bah","year":"2024","journal-title":"Bull World Health Organ"},{"key":"B30","doi-asserted-by":"publisher","first-page":"3249","DOI":"10.1093\/jn\/132.11.3249","article-title":"Iron supplementation affects growth and morbidity of breast-fed infants: results of a randomized trial in Sweden and Honduras","volume":"132","author":"Dewey","year":"2002","journal-title":"J Nutr"},{"key":"B31","doi-asserted-by":"publisher","first-page":"4380","DOI":"10.3390\/nu14204380","article-title":"Benefits and risks of early life iron supplementation","volume":"14","author":"McMillen","year":"2022","journal-title":"Nutrients"},{"key":"B32","doi-asserted-by":"publisher","first-page":"278","DOI":"10.1159\/000360352","article-title":"The WHO child growth standards","volume":"113","author":"de Onis","year":"2015","journal-title":"World Rev Nutr Diet"},{"key":"B33","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1159\/000332138","article-title":"Iron requirements in infancy","volume":"59","author":"Domell\u00f6f","year":"2011","journal-title":"Ann Nutr Metab"},{"key":"B34","doi-asserted-by":"publisher","first-page":"1588s","DOI":"10.3945\/ajcn.117.155846","article-title":"Iron assessment to protect the developing brain","volume":"106","author":"Georgieff","year":"2017","journal-title":"Am J Clin Nutr"},{"key":"B35","doi-asserted-by":"publisher","first-page":"e009441","DOI":"10.1136\/bmjopen-2015-009441","article-title":"Effect of iron supplementation on psychomotor development of non-anaemic, exclusively or predominantly breastfed infants: a randomised, controlled trial","volume":"5","author":"Chmielewska","year":"2015","journal-title":"BMJ Open"},{"key":"B36","doi-asserted-by":"publisher","first-page":"108","DOI":"10.1017\/S0029665121002858","article-title":"Iron deficiency during the first 1000 days of life: are we doing enough to protect the developing brain?","volume":"81","author":"McCarthy","year":"2022","journal-title":"Proc Nutr Soc"},{"key":"B37","doi-asserted-by":"publisher","first-page":"585","DOI":"10.3389\/fnhum.2013.00585","article-title":"Perinatal iron deficiency and neurocognitive development","volume":"7","author":"Radlowski","year":"2013","journal-title":"Front Hum Neurosci"},{"key":"B38","doi-asserted-by":"publisher","first-page":"108","DOI":"10.4274\/balkanmedj.galenos.2025.2024-11-24","article-title":"Neurodevelopmental impairments as long-term effects of iron deficiency in early childhood: a systematic review","volume":"42","author":"Theola","year":"2025","journal-title":"Balkan Med J"},{"key":"B39","doi-asserted-by":"publisher","first-page":"479","DOI":"10.1515\/revneuro-2015-0012","article-title":"An explanation of the pathophysiology of adverse neurodevelopmental outcomes in iron deficiency","volume":"26","author":"Bakoyiannis","year":"2015","journal-title":"Rev Neurosci"},{"key":"B40","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1016\/j.cell.2010.06.028","article-title":"Two to tango: regulation of mammalian iron metabolism","volume":"142","author":"Hentze","year":"2010","journal-title":"Cell"},{"key":"B41","doi-asserted-by":"publisher","first-page":"1327","DOI":"10.3390\/nu9121327","article-title":"Iron supplementation during pregnancy and infancy: uncertainties and implications for research and policy","volume":"9","author":"Brannon","year":"2017","journal-title":"Nutrients"},{"key":"B42","doi-asserted-by":"publisher","first-page":"102536","DOI":"10.1016\/j.bcmd.2021.102536","article-title":"Is the erythropoietin-erythroferrone-hepcidin axis intact in human neonates?","volume":"88","author":"Bahr","year":"2021","journal-title":"Blood Cells Mol Dis"},{"key":"B43","doi-asserted-by":"publisher","first-page":"62","DOI":"10.1016\/j.jpeds.2021.09.059","article-title":"Do extremely low gestational age neonates regulate iron absorption via hepcidin?","volume":"241","author":"German","year":"2022","journal-title":"J Pediatr"},{"key":"B44","doi-asserted-by":"publisher","first-page":"319","DOI":"10.1016\/j.mcna.2016.09.004","article-title":"Iron deficiency Anemia","volume":"101","author":"DeLoughery","year":"2017","journal-title":"Med Clin North Am"},{"key":"B45","doi-asserted-by":"publisher","first-page":"247","DOI":"10.1016\/j.hoc.2015.11.002","article-title":"The global burden of Anemia","volume":"30","author":"Kassebaum","year":"2016","journal-title":"Hematol Oncol Clin North Am"}],"container-title":["Frontiers in Pediatrics"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fped.2025.1587457\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,5,20]],"date-time":"2025-05-20T10:17:23Z","timestamp":1747736243000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fped.2025.1587457\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,20]]},"references-count":45,"alternative-id":["10.3389\/fped.2025.1587457"],"URL":"https:\/\/doi.org\/10.3389\/fped.2025.1587457","relation":{},"ISSN":["2296-2360"],"issn-type":[{"value":"2296-2360","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,5,20]]},"article-number":"1587457"}}