Increased risk of pyrexial illness with higher doses of iron supplementation.

The study conducted by da Silva et al. sets out to investigate the relative advantages and disadvantages of three different iron prophylactic regimens. The authors claim that the findings about an association of iron supplementation and enhanced vulnerability to infections are controversial, and they also claim that the groups of their study did not show differences in morbidity. A close look at the data provided by the authors reveals that, if one compares the group with 2 mg/kg/day of iron supplementation with the other groups, who had 1mg/kg/day iron or less, pooled into one group, the incidence of fever was significantly greater in the group with higher iron intake (28/36), compared to the incidence in the pooled group with half or less of this iron intake (42/77) (p = 0.03, chi-square test). The majority of comparisons (seven out of 10) in incidenceof infectiousdiseasesbetween the three groups reveals an (albeit not statistically significant) increased incidence in thegroupwith2mg/kg/dayof iron. Larger sample sizes may have revealed a statistically significant difference for each comparison. Such a difference becameevident in the largest randomized, controlled trial of iron supplementation by Sazawal et al. involving 24,076 children. That study, the largest to date, concluded that, in areas with high rates of malaria, iron and folic acid supplementation can result in a 12% increased risk of severe illness and death. Analysis of results for infection-related causes included confirmed febrile illness not meeting definitions for malaria (e.g., pneumonia, sepsis, meningitis, measles, pertussis) and revealed that, compared with placebo, the iron supplemented groups had a significantly higher risk for serious adverse events (1.32, 1.10-1.59), deaths (1.61, 1.03-2.52), andadmissions to hospital (1.28, 1.05-1.55) due to these causes. The findingswere significant enough for the data and safety monitoring board to stop the trial of iron and folic acid supplementation prematurely.Subgroupanalysis of this trial showed that theseeffects aremainly due to increased risk of infectious complications in children who were not iron-deficient at the beginning of the trial. Based on this trial, it is possible to conclude that prophylactic iron supplementation in children who are not iron-deficient in areas with high incidence of infectious diseases cannot be justified.