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

Lead Research Organisation: London School of Hygiene & Tropical Medicine
Department Name: MRC Unit The Gambia at LSHTM


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.

Technical Summary

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.

Planned Impact

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.
Description Kings College London Collaboration with Dr Sophie Moore and team 
Organisation King's College London
Department Women's Health Academic Centre
Country United Kingdom 
Sector Academic/University 
PI Contribution I have taken on local mentorship and supervision of the Kings College London PhD candidate described further below, Isabella Stelle. Ms Stelle's primary supervisor is Dr Sophie Moore at Kings College London
Collaborator Contribution Ms Stelle has been an active member of the clinical trial team. She has played a key role in the regulatory and trial monitoring updates. She has assisted with all our interactions with the Gambian government medicines Control agency. She has helped with the writing of the clinical trial protocol and is the first author on the protocol paper which has been submitted to Wellcome Open https://wellcomeopenresearch.org/articles/7-16 In addition, she has completed the fieldwork for a qualitative study which was embedded in the main clinical trial (also described in the protocol paper linked above). The qualitative study assessed the acceptability of this iron supplementation efficacy trial in infants under six months of age in rural Gambia. The objectives were to: a) Explore mothers' (the main care providers') perspectives on the acceptability of iron supplementation in their young, breast-fed infants through in-depth interviews. b) Explore the acceptability of iron supplementation in young, breast-fed infants through focus group discussions with local stakeholders. c) To integrate quantitative and qualitative clinical intervention outcomes to explore the acceptability of iron supplementation in the young, breast-fed infant
Impact https://wellcomeopenresearch.org/articles/7-16
Start Year 2021
Description Wageningen University - Hans Verhoef 
Organisation Wageningen University & Research
Department Division of Human Nutrition
Country Netherlands 
Sector Academic/University 
PI Contribution We work closely with Dr Verhoef and have weekly meetings.
Collaborator Contribution Dr Hans Verhoef, Associate Professor at Wageneingen University is the statistician on this trial. He advised on the statistical analysis plan and checked all the calculations made for the publication. In addition, he has contributed to mentoring of the PhD student, Mamadou Bah, who is working on the trial.
Impact (1) Iron supplementation of breastfed Gambian infants from 6 weeks to 6 months of age: protocol for a randomised controlled trial. Stelle I, Bah M, Silverio SA, Verhoef H, Comma E, Prentice AM, Moore SE, Cerami C. Wellcome Open Res. 2022 Jan 18;7:16. doi: 10.12688/wellcomeopenres.17507.1. eCollection 2022. PMID: 36874582 (2) Early iron supplementation of exclusively breastfed African infants: a proof-of-principle, placebo-controlled, randomised, double-blinded efficacy trial Mamadou Bah, Isabella Stelle, Hans Verhoef, Alasana Saidykhan, Sophie E. Moore, Babucarr Susso, Andrew M. Prentice, Carla Cerami doi: https://doi.org/10.1101/2023.01.12.22284059 https://www.medrxiv.org/content/10.1101/2023.01.12.22284059v1
Start Year 2020
Description Community and participant feedback 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Study participants or study members
Results and Impact We returned to the communities (20 villages) were the study was done to report the results of the study.
Participants, their families and the general public were all invited.
These events were heavily attended.
Year(s) Of Engagement Activity 2023
Description Community meetings in Jara Soma on Iron deficiency in children 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact The Iron Babies trial team held over 20 community-based meetings. The purpose of the meetings was to engage community members, especially new mothers. Educational information about iron deficiency in young children was provided. Information about the "Iron Babies" trial was also given.
Year(s) Of Engagement Activity 2021