The Safety of Iron
As discussed in the Prevalence, Causes, and Consequences tab, iron is an important mineral for human health and helps to generate energy in the body and ensure optimal neuro-development. Most minerals, including iron, can be toxic if intake is excessive of the recommended daily intake. Unsupervised children in the United States have over-dosed on their mother’s prenatal iron supplements so messages should be given to women during antenatal care to keep IFA supplements out of the reach of young children (see Program Guidance tab).
Iron is sequestered in the liver as a protective mechanism during infection because, like humans, many micro-organisms also need iron to live and thrive. The amount of freely-circulating iron in the body, not stored iron, puts individuals at-risk of increased infection. However, freely-circulating iron is usually low because iron absorption in the gut is tightly controlled in most individuals. People with the genetic disorder called hereditary hemochromatosis do not have this control mechanism and are at risk of what is often called “iron-overload”. Some white males of Northern European descent also absorb too much iron. Enteral (injected) iron also can lead to high levels of freely circulating iron.
Currently, there is uncertainty about the safety of giving iron to young children in malaria endemic areas. This is not a new concern (Oppenheimer, 1986), although this concern was resolved for oral iron in the 1990s. The USAID-funded International Nutritional Anemia Consultative Group (INACG) reviewed the evidence of the safety of giving oral iron to several age groups (infants, preschool children, school-age children, adults, and pregnant women). They reviewed 13 trials and found a weak relationship between increased risk of several outcomes of malaria and giving iron, but significant reductions in anemia.
Click here for more information about the 1999 INACG finding.
In 2006, a large study in Pemba, Zanzibar, where malaria transmission is high it was found that preschool children receiving iron and folic acid were at higher risk of hospitalization and mortality compared with infants receiving a placebo (Sazawal et al, 2006). However, in another study in rural Nepal, where malaria transmission is low, iron supplements did not cause increased morbidity or mortality (Tielsch et al, 2006). However, a sub-study in the Pemba study found that children with iron deficiency at the beginning of the study had no adverse outcomes when given iron and in fact benefited from receiving iron. The conclusion was that children who were iron replete (i.e., had adequate iron status) were the ones at risk from adverse outcomes when they received iron.
The study in Pemba and a consultation about the study findings led the World Health Organization (WHO, 2007) to recommend giving iron to iron-deficient children living in malaria-endemic regions. Because tests for iron deficiency and anemia are not available in most developing countries, WHO changed the recommendation and now advises on its website that children be given iron in conjunction with malaria prevention, diagnosis, and treatment programs. However, these recommendations continue to make it difficult to implement iron supplementation programs for young children that would help reduce the high burden of anemia because robust malaria control programs do not always exist. In the Africa region, where malaria and iron deficiency are both significant causes of anemia, anemia prevalence rates are over 70% in children 6-23 months in some countries.
In 2011, a symposium on giving iron to children was held at the annual meeting for the American Society for Nutrition. Click here to view the entire series of papers presented.
For more background information on this issue, read the overview by Harding et al, 2012. In the paper by Stoltzfus, 2012, practical recommendations are presented about giving iron where screening is not available:
- Iron status at birth is dependent on the size of the baby and the iron status of the mother—implement nutrition and health interventions (e.g., corticosteroids, IFA supplements, adequate food intake) to prevent preterm births and low birth weight; ensure total body iron at birth is optimal by through maternal IFA. supplements and delayed cord clamping which transfers iron from the mother to the infant at birth.
- Lower the dose of iron which will reduce the risk of morbidity but ensure children get some iron.
- Use food-based interventions such as giving iron in a micronutrient powder or fortified complementary food which will slow the absorption and reduce the dose of iron.
- Work to improve malaria control and treat malaria in young children.
Since the Pemba study, several analyses and studies have been conducted to add to the knowledge-base on the subject, although the findings do not clarify the situation and in some cases add to the confusion.
- In 2011, an updated Cochrane review of 68 trials found that iron supplementation alone or with anti-malaria treatment did not increase malaria risk or death with regular malaria surveillance and treatment programs in place. Trials that did not have active malaria surveillance showed a higher risk for clinical malaria among children receiving iron (Okebe et al, 2011). For a commentary on the first review see Roth et al, 2010.
- In 2012, in an area of Tanzania with high transmission of malaria, 785 children were enrolled at birth and monitored for parasitemia and illness, including malaria, for three years. Children who were iron-replete had significantly more malaria infection, morbidity, and mortality (Gwamaka et al, 2012).
- In 2013, a study in Pakistan was published (Soofi et al, 2013) that gave micronutrient powders with iron to children 6-18 months and found an increased proportion of days of diarrhea, increased incidence of bloody diarrhea, and increased reported chest-in-drawing. Incidence of febrile episodes, and admission to hospital for diarrhea, respiratory problems, and febrile episodes did not increase.
- The 2013 Lancet on Maternal and Child Nutrition examined studies on the benefit of giving iron to young children and found that in children younger than four years of age, there was evidence that iron deficiency affects motor development, but no consistent effect on mental development. The authors offer caveats their findings, however: the studies were complicated by the fact that there were only small improvements in iron status and may have been too short in duration which may have limited the effect.
Sorting out the context in which iron can be given to children will need more research. Before those studies are conducted and synthesized, the following considerations should be taken into account:
- Disaggregate areas by high and moderate-low malaria transmission areas which may differ within countries.
- Implement widespread screening of children using clinical signs to identify those with severe anemia and get them treated for malaria or other infections along with receiving iron.
- Strengthen deworming programs for children starting at one year of age.
- Educate mothers on danger signs for malaria and other infections to ensure immediate treatment and to withhold iron on the days the child is sick.