Enhancing brain development by early iron supplementation of African infants: An enabling pilot study

Iron is crucial for brain development and early deficiencies during infancy can cause irreparable damage. Figures from the latest Global Burden of Disease analysis estimate that iron deficiency is more common than all other micronutrient deficiencies combined. This burden is concentrated in sub-Saharan Africa and South Asia.

Breast milk contains very little iron, so babies draw upon iron stores laid down in their liver during late foetal life. However, the babies of iron deficient mothers are born with a limited endowment of iron and can rapidly develop iron deficiency. We have recently shown that, by 5 months of age, almost 95% of rural Gambian infants have circulating iron levels below the lower limit of the US reference range. This indicates that these babies are profoundly iron deficienct.

The American Academy of Pediatrics (AAP) recommends iron supplementation in exclusively breastfed infants beginning at 4 months of age. AAP also recommends that babies born prematurely start supplementation at 2 weeks. Yet prior and on-going trials of iron supplementation in low-income settings have commenced supplementation much later (eg 8-9m in a large on-going trial in Bangladesh). Our data suggest that this will be too late to prevent early iron deficiency from impairing brain development. We therefore propose a large randomised controlled trial of early iron supplementation starting at 6wks of age.

In preparation for such a trial we need to conduct preliminary studies addressing the following questions: Can we effectively enhance circulating iron levels in early infancy by giving daily iron drops? Can we achieve this without undermining duration of exclusive breast feeding? Might the iron alter the balance of the babies' gut microbial flora and thereby cause diarrhoea? Might iron supplementation impair the absorption of zinc and copper and hence require a triple supplement?

These questions will be tested in a small enabling study that will inform the design of the intended full trial.

Growth and organisation of the human brain is maximally active in late fetal life and early infancy. Breast milk contains very little iron and babies born to iron deficient mothers lack the full endowment of hepatic iron that usually subsidises the needs for growth and brain development in early infancy. We have recently shown that, by 5m of age, breastfed infants in rural Africa have extremely low levels of circulating iron with 95% lying below the US reference range.
There is extensive evidence from human and animal studies that early iron deficiency causes irreversible deficits in psychomotor development and cognition. Hence, we plan to conduct a large-scale RCT that will introduce iron supplements much earlier than in prior and on-going trials. To inform a go/no go decision and to refine the trial design we first need to conduct an enabling trial that will address the following key questions: Can provision of a daily iron supplement as paediatric drops starting at 6wks of age reverse the profound decline in serum iron and other measures of iron status seen in rural African infants? Can we introduce supplementary iron without undermining exclusive breast-feeding? Would iron supplementation at this age alter the infant gut microbiome potentially causing diarrhoea? Does iron supplementation (through competition for divalent metal transport systems) impair zinc and/or copper status; and hence indicate a need for triple supplementation? These questions will be addressed in a pilot 'experimental medicine' two-arm RCT comparing daily iron versus placebo in 100 rural Gambian infants receiving intervention or placebo from 6wk to 5m.

Who might benefit from this research?

The ultimate beneficiaries of a positive outcome from the proposed large-scale RCT(s) of early iron supplementation (to be done after the successful completion of this trial development project) will be young infants in low income settings blighted by iron deficiency. If we can achieve a meaningful enhancement of psychomotor and cognitive development (+3% points or more), this would have direct benefit to the children themselves, to their families and future generations as well as enhancing the human capital of nations. This would only be achieved at scale it the evidence is strong enough to drive a change in recommended practice at the World Health Organisation (WHO) since most African countries adopt their guidance. Therefore, WHO can be viewed as the chief intermediate beneficiaries. Any change in policy would be trickled down to country offices and relevant governmental and non-governmental institutions. In the Gambia, these would be the National Nutrition Agency (NaNA) and the Department of Health and Social Welfare (DoHSW). Any change in policy would be implemented through altered guidance and, optimally, through procurement and distribution of supplies for distribution.

How might they benefit from this research?

For our research to have a global impact the proposed large-scale trial(s) would need to be designed and implemented with a view to meeting the highest standards of GRADE criteria. This will maximise our public health leverage through systematic reviews and meta-analysis and deposition of the results within the WHO eLENA system that informs expert groups convened to adjudicate on possible policy amendments.
Adoption by WHO and national governments is not the only way that infants might benefit. Even though many African countries would not currently have the capacity to implement nationwide supplement distribution, the mere change in policy could have significant impact by changing prescribing habits and on mothers' behaviours in regard to home supplements.