Supplementary appendix

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1 Supplementary appendix This appendix formed part of the original submission and has been peer reviewed. We post it as supplied by the authors. Supplement to: Hare DJ, Cardoso BR, Szymlek-Gay EA, Biggs B-A. Neurological effects of iron supplementation in infancy: finding the balance between health and harm in iron-replete infants. Lancet Child Adolesc Health 2017; published online Dec 1.

2 ONLINE APPENDIX FOR: Neurological effects of iron supplementation in infancy: Finding the balance between health and harm in iron-replete children. Dominic J. Hare, Bárbara Rita Cardoso, Ewa A. Szymlek-Gay and Beverley-Ann Biggs Table 1: Completed and ongoing (with published methods) RCTs of iron supplementation including 6-24-month old infants with primary or secondary neurodevelopmental reported, published since the systematic review and meta-analysis by Pasricha et al. 1 in Table 2: Recommended iron intakes and formula fortification recommendations from selected countries for infants. 1

3 Table 1: Completed and ongoing (with published methods) RCTs of iron supplementation including 6-24-month old infants with primary or secondary neurodevelopmental reported, published since the systematic review and meta-analysis by Pasricha et al. 1 in Country income classifications according to current World Bank data. CRP = C-reactive protein; Hb = haemoglobin; IDA = iron deficiency anaemia; LBW = low birth weight; LNS = lipid-based nutrient supplement; SF = serum ferritin Study Abdullah et al. 2 Toronto, Canada (urban; highincome). Angulo- Barroso et al. 3. Attanasio et al. 4 Berglund et al. 5 Experimental groups 1. Non-anaemic iron deficient infants (Hb 110 g/l; SF < 14 µg/l; CRP < 10 mg/l). 2. IDA (Hb < 110 g/l; SF < 14 µg/l; CRP < 10 mg/l). 3. Iron replete ((Hb 110 g/l; SF > 14 µg/l; CRP < 10 mg/l). All iron replete. 1. Placebo in pregnancy / placebo in infancy. 2. Placebo in pregnancy / iron in infancy. 3. Iron in pregnancy / placebo in infancy 4. Iron in pregnancy / iron in infancy. 1. No 2. Stimulation. 3. Micronutrient powder. 4. Stimulation + micronutrient powder. All non-anaemic marginally LBW (2 2.5 kg) 1. Placebo 2. 1 mg/kg/day iron 3. 2 mg/kg/day iron Intervention and duration Daily 6 mg elemental iron/kg in two doses or placebo; age months; 4-month Pregnancy: daily 0.4 mg folate, 300 mg ferrous sulfate (as oral supplement); enrolment to birth. Infancy: daily ~1 mg/kg elemental iron (as iron protein succinylate solution); age 6 weeks; 6 weeks 9 months Daily 12.5 mg iron (with 5 mg zinc, vitamin A 300 µg retinol equivalents, 160 µg folic acid, and 30 mg vitamin C; as micronutrient powder); age months at enrolment; 18-month Daily 1 mg/kg or 2 mg/kg iron (as ferrous succinate drops) in two doses, or placebo; age 6 weeks; 6 weeks 6 months Location Hebei Province, China (rural; upper-middleincome). Colombia (mixed urban and rural; upper-middleincome). Umeå and Stockhom, Sweden (urban; highincome). Neurodevelopmental measures and outcomes Measures: Mullen Scales of Early Learning at baseline and 4-months (primary); Infant Behaviour Questionnaire; Early Childhood Behaviour Questionnaire, or Children s Behaviour Questionnaire (secondary; age-dependent). Outcomes: Study in recruitment phase. Measures: Peabody Developmental Motor Scale, Second Edition at 9 months. Outcomes: Iron in infancy but not pregnancy improved gross motor scores (overall p < 0.001; reflexes p < 0.03; stationary p < 0.001; locomotion p <0.001). Iron in infancy improved motor scores by 0.3SD vs no supplementation or supplementation in pregnancy. Measures: Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III) at enrolment and months. Outcomes: No change in micronutrient powder groups from baseline Measures: Wechsler Preschool and Primary Scale of Intelligence, Third Edition; Child Behaviour Checklist at 3.5 years; compared against normal birthweight controls. Outcomes: No difference in intelligence between treatment groups or vs normal birth weight controls. Behavioural scores equivalently improved in 1 mg and 2 mg compared to normal birthweight controls and placebo (p = 0.027) Notes - Only non-anaemic iron deficient infants randomised for iron or placebo. - ClinicalTrials.gov identifier: NCT Linked to RCT of iron supplementation in pregnancy - Motor improvements independent of supplementation during pregnancy. - Psychosocial stimulation with and without micronutrient powders improved Bayley-III scores in cognition and receptive language. - Not stratified according to anaemia prevalence (46%). - No micronutrient placebo group. - IDA excluded; defined as Hb < 90 g/l. 2

4 Chmielewska et al. 6 Colombo et al. 7 Iannotti et al. 8 All iron replete infants. - Placebo. - Iron supplemented. All iron replete infants. 1. Zinc, iron and copper 2. Iron and copper 1. Placebo month 3. 6-month Daily ~1 mg/kg iron (as iron pyrophosphate + maltodextrin powder mixed with breastmilk or formula; 7 mg 7 kg, 10 mg 7-10 kg; 15 mg > 10 kg); age 4 months; 5-month Daily 10 mg zinc (as sulfate), 0.5 mg copper (as oxide), with/without 10 mg iron (as ferrous sulfate; as mixed oral liquid supplement); 12-month Daily 9 mg iron (+ 22 vitamins/minerals; as LNS) in two doses; age 6-11 months; 3- or 6-month Warsaw, Poland (urban; highincome) Villa El Salvador, Peru (semiurban; uppermiddleincome) Cap Haitien, Haiti (urban; low-income). Measures: Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III; primary; 12, 24, 36 months); Child Behaviour Checklist (secondary; 3 years). Outcomes: Study in recruitment phase. Measures: Bayley Scales of Infant and Toddler Development, Second Edition (Bayley-II; 6, 12, 18 months); A-not-B error task (9, 12 months); freeplay attention tasks (12, 18 months). Outcomes: No change from baseline in either group. Measures: WHO motor development milestones (child crawling on hands and knees, child standing with assistance, child walking with assistance, child stands alone, child walks alone); motherreported and enumeratorobserved at monthly visits. - All participants exclusively or predominantly breastfed. - ClinicalTrials.gov identifier: NCT Study of zinc supplementation on neurodevelopment. - - IDA prevalence not reported. Lozoff et al. 9 Prado et al 10. Pulakka et al. 11 All iron replete. Initial: 1. Iron fortified. 2. Low iron. Reclassification: 1. Iron supplemented. 2. No iron. 1. Iron + folic acid in pregnancy only. 2. Micronutrient powder in pregnancy only. 3. LNP in pregnancy + LNP in infancy. 1. Control. 2. LNS. Initial intervention: iron fortified formula (12.7 mg/l); low-iron formula (2.3 mg/l); minimum consumption 250 ml/day; age 6- months; 6-month Reclassified as iron supplemented or no added iron. Daily 6 mg iron (+ 22 vitamins/minerals; as LNS); age 6-months; 12-month Daily 20 mg iron (+ 22 vitamins/minerals; as LNS); age 6- Chile (urbanisation not reported; high-income) Somanya- Kpong, Ghana (semiurban; lowermiddleincome). Mangochi, Malawi (urban; lowincome) Outcomes: No change in developmental outcomes between trial arms. Measures: Behaviour and Attitude Checklist; Child Behaviour Checklist, Spanish Edition, positive affect and social interaction testing; Trier Social Stress Test for Children at 10 years. Outcomes: Examiner rating of superior cooperative, confident, persistent after failure, coordinated, direct and reality-oriented in speech and working harder after praise behaviours in iron supplemented group vs no iron (p < 0.05). Measures: 6 motor milestones based on WHO Multicentre Growth Reference Study; 2 language and 2 personalsocial milestones based on Malawi Developmental Assessment Tool at 18 months. Outcomes: Higher number of LNS group able to walk unassisted at 12 months vs iron + folic acid in pregnancy only group (p = 0.025). No other differences. Measures: Physical activity (measured by ActiGraph GT3X+ over 1 week) at 18-months year follow-up of RCT; % participation. - Original study carried out , enrolment criteria changed to include exclusively breastfed. - Effects difficult to interpret due to study design. - IDA status of children randomised to experimental groups. - Infants receiving LNS are a subgroup of maternal LNS (other maternal groups included iron + folic acid/micronutrient powder). - Participant iron status not reported. - Control group born to mothers who 3

5 Surkan et al Placebo. 2. Iron + folic acid 3. Zinc 4. Iron + folic acid +zinc months; 12-month Daily 12.5 mg iron, 50 µg folic acid, with/without 10 mg zinc (both as tablets dissolved in breast milk or water); age 4-17 months; approx. 12-month Sarlahi, Nepal (rural; lowincome). Outcomes: No difference between groups. Measure: Temperament component of Infant Characteristics Questionnaire. Outcomes: No change from baseline. received either iron + folic acid or iron + folic acid + 16 additional micronutrients. - LNS group born to mothers receiving daily LNS during pregnancy to 6-months post partum. - Irregular data collection intervals. - Anaemia prevalence 42%, no neurodevelopmental effects when stratified by IDA status. 4

6 Table 2: Recommended iron intakes and formula fortification recommendations from selected countries for infants. a in addition to introduction of iron-rich foods. b based on average weight of 9.2 kg at 9 months of age. c based on average weight of 12.3 kg at 2 years of age. d reported as an indicator of available product only. Advisory body Recommended dietary iron intake Recommended iron supplementation/ fortification a American Academy of Pediatrics Committee on Nutrition Food and Nutrition Board of the Institute of Medicine of the National Academy of Science European Society for Paediatric Gastroenterology Hepatology and Nutrition European Food Safety Authority National Health and Medical Research Council (Australia); Ministry of Health (New Zealand) Health Canada, Canadian Paediatric Society, Dietitians of Canada, and Breastfeeding Committee for Canada - 4 months to introduction of solid foods: 1 mg/kg/day - 6 to 12 months: 11 mg/day (1.2 mg/kg/day b ) - 1 to 3 years: 7 mg/day (0.6 mg/kg/day c ) - Preterm, 0 to 12 months: 2 mg/kg/day - 7 to 12 months: 1.2 mg/kg/day - 1 to 3 years: 0.6 mg/kg/day - 6 to 12 months: mg/kg/day - 1 to 3 years: mg/kg/day - Low birth weight, < 6 months: 1-3 mg/kg/day - 6 to 12 months: 0.8 mg/kg/day a years: 0.6 mg/kg/day mg/l (as formula) mg/kg (as cereal) Date of most recent recommendation Not defined mg/l (as formula, up to 6 months of age) - Introduction of ironcontaining foods at 6 months - No recommendation on fortified cereals. - No specific recommended level to 12 months: 11 mg/day (1.2 mg/kg/day b ) - 1 to 3 years: 9 mg/day (0.7 mg/kg/day c ) - If weaned before 12 months should receive iron fortified formula mg/l Not defined 4-13 mg/l d World Health Organization - 6 to 24 months: mg/day ( mg/kg/day b ) for three consecutive months a year where anemia prevalence 40% Drops/syrups

7 References: 1. Pasricha S-R, Hayes E, Kalumba K, Biggs B-A. Effect of daily iron supplementation on health in children aged 4 23 months: a systematic review and meta-analysis of randomised controlled trials. Lancet Glob. Health 2013; 1: e77-e Abdullah K, Thorpe KE, Mamak E, et al. Optimizing early child development for young children with non-anemic iron deficiency in the primary care practice setting (OptEC): study protocol for a randomized controlled trial. Trials 2015; 16: Angulo-Barroso RM, Li M, Santos D, et al. Iron Supplementation in Pregnancy or Infancy and Motor Development: A Randomized Controlled Trial. Pediatrics 2016; 137: e Attanasio OP, Fernández C, Fitzsimons EOA, Grantham-McGregor SM, Meghir C, Rubio-Codina M. Using the infrastructure of a conditional cash transfer program to deliver a scalable integrated early child development program in Colombia: cluster randomized controlled trial. BMJ 2014; 349: g Berglund SK, Westrup B, Domellöf M. Iron Supplementation Until 6 Months Protects Marginally Low-Birth-Weight Infants From Iron Deficiency During Their First Year of Life. J. Pediatr. Gastroenterol. Nutr. 2015; 60: Chmielewska A, Chmielewski G, Domellöf M, Lewandowski Z, Szajewska H. Effect of iron supplementation on psychomotor development of non-anaemic, exclusively or predominantly breastfed infants: a randomised, controlled trial. BMJ Open 2015; 5: e Colombo J, Zavaleta N, Kannass KN, et al. Zinc Supplementation Sustained Normative Neurodevelopment in a Randomized, Controlled Trial of Peruvian Infants Aged 6 18 Months. J. Nutr. 2014; 144: Iannotti LL, Dulience S, Green J, et al. Linear growth increased in young children in an urban slum of Haiti: a randomized controlled trial of a lipid-based nutrient supplement. Am. J. Clin. Nutr. 2014; 99: Lozoff B, Castillo M, Clark KM, Smith JB, Sturza J. Iron Supplementation in Infancy Contributes to More Adaptive Behavior at 10 Years of Age. J. Nutr. 2014; 144: Prado EL, Adu-Afarwuah S, Lartey A, et al. Effects of pre- and post-natal lipid-based nutrient supplements on infant development in a randomized trial in Ghana. Early Hum. Dev. 2016; 99: Pulakka A, Cheung YB, Maleta K, et al. Effect of 12-month intervention with lipidbased nutrient supplement on the physical activity of Malawian toddlers: a randomised, controlled trial. Br. J. Nutr. 2017; 117: Surkan PJ, Charles M, Katz J, et al. The Role of Zinc and Iron-Folic Acid Supplementation on Early Child Temperament and Eating Behaviors in Rural Nepal: A Randomized Controlled Trial. PLoS One 2015; 10: e

8 13. Baker RD, Greer FR, Nutrition Co. Clinical Report Diagnosis and Prevention of Iron Deficiency and Iron-Deficiency Anemia in Infants and Young Children (0 3 Years of Age). Pediatrics 2010; 126: Trumbo P, Yates AA, Schlicker S, Poos M. Dietary Reference Intakes: Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc. J. Am. Diet. Assoc. 2001; 101: Domellöf M, Braegger C, Campoy C, et al. Iron Requirements of Infants and Toddlers. J. Pediatr. Gastroenterol. Nutr. 2014; 58: EFSA Panel on Dietetic Products NaA. Scientific Opinion on nutrient requirements and dietary intakes of infants and young children in the European Union. EFSA J. 2013; 11: Nutrient Reference Values for Australia and New Zealand. Canberra: National Health and Medical Research Council, Australian Government Department of Health and Ageing, New Zealand Ministry of Health, Critch JN, Society C, and Committee N. Nutrition for healthy term infants, six to 24 months: An overview. Paediatr. Child Health 2014; 19: Guideline: Daily Iron Supplementation in Infants and Children. Geneva: World Health Organization,