Early iron supplementation of exclusively breastfed African infants: a proof-of-principle, placebo-controlled, randomised, double-blinded efficacy trial

SO_SCPLOWUMMARYC_SCPLOWO_ST_ABSBackgroundC_ST_ABSWe have previously shown that breastfed Gambian children have depleted their neonatal iron endowment before 6 months. We measured the effect of daily iron supplementation for 14 weeks on serum iron concentration and other iron markers among breastfed Gambian infants. MethodIn a double-blind trial, healthy exclusively breastfed rural Gambian infants aged 6 to 10 weeks were identified from vaccination clinics and local communities. Eligible children (n=101) were individually randomised to 14 weeks of daily supplementation with either iron (7{middle dot}5mg as ferrous sulphate in sorbitol solution) or placebo (sorbitol solution). The primary outcome was serum iron concentration after 99 days of supplementation (98 days intervention plus 1-day washout). We used intention-to-treat analysis with multiple imputation to replace missing values. This trial was registered with clinicaltrials.gov (NCT04751994). FindingsIron administration increased serum iron concentration (crude difference in means: 2.5 mol/L; 95%CI: 0{middle dot}6 to 4{middle dot}3mol/L, p=0.0091) and meaningfully improved additional markers of iron and haematological status. There were 10 serious adverse events (5 iron/5 placebo) and 106 non-serious adverse events (54 iron/52 placebo) with no deaths. There were no marked group differences in maternally-reported episodes of diarrhoea, fever, cough, skin infection, eye infection and nasal discharge. InterpretationIn exclusively breastfed infants, early introduction of iron supplements can enhance iron supply to rapidly developing tissues in early infancy and warrants further investigation in large-scale trials with additional measurements of functional outcomes and safety. FundingUK Department for International Development, Medical Research Council UK, National Institute for Health Research and Care Research, Wellcome Trust. Research in contextO_ST_ABSEvidence before the studyC_ST_ABSThe World Health Organisation (WHO) recommends that infants should be exclusively breastfed for 6 months. Human milk contains very little iron so exclusively breastfed infants are forced to utilise their birth endowment of liver ferritin and fetal haemoglobin to meet the needs of growth and tissue development. In low-income countries many infants are born prematurely, at low birthweight or to iron deficient mothers. These infants start life with low iron reserves and hence frequently become very iron deficient by 6 months of age. In many high-income countries it is recommended that such infants should receive iron supplements from soon after birth. Although not specifically precluded by WHOs recommendation on exclusive breastfeeding, the provision of supplements is widely viewed as being unnecessary and as undermining the ethos of the recommendation. Added value of this studyIn this proof-of-principle trial we demonstrated that providing 7{middle dot}5mg iron per day to exclusively breastfed Gambian infants from 6 weeks of age substantially improved all markers of iron status at 6 months of age. There were no signals of adverse effects on growth or on infections. Implications of all the available evidenceSerious iron deficiency in many exclusively breastfed infants in low-income countries impairs iron supply to rapidly developing tissues including immune and neural cells and the expanding erythroid pool. Early introduction of iron supplements can reverse this deficiency and warrants further testing in large-scale trials with additional measurements of functional outcomes and safety.