This study demonstrated that supplementation of breastfed infants with medicinal iron (ferrous sulfate) in a dose of 7 mg/d from 1 to 5.5 mo of age of caused some preservation of the iron endowment. But the effect was modest and did not extend beyond the period of supplementation. The small effect size was surprising, given that an earlier study had shown that on average 7.8% of supplemental iron (equal to 0.55 mg/d from intake of 7 mg/d) is absorbed by breastfed infants (19
In the present study, two infants (6 %) in the placebo group became iron deficient by 5.5 mo of age. This is consistent with the prevalence of iron deficiency reported for other industrialized countries (7
). One of the two infants developed IDA at 5.5 mo of age and appeared to have been born with diminished iron stores, as indicated by a PF of 60 μ
g/L at 1 mo of age. Tamura et al. (6
) have shown that infants born with low PF concentrations are at risk of impaired neuro-developmental outcome, possibly because of unrecognized iron deficiency during early infancy. Georgieff et al. (5
) found that such infants are in poor iron status at 9 mo of age. One infant in the Fe group developed probable IDA at 9 mo of age. In the second year of life, 6 infants developed ID, which was mild (without anemia) and was mostly transient.
An earlier study by Friel et al. (25
) with a design similar to the present study also found that iron supplementation of breastfed infants led to a slowing down of the decrease of PF. But contrary to the present study, Friel et al. (25
) found a significant effect of iron on hemoglobin but not on PF at the end of the supplementation period at 6 mo of age. Also in contrast to the present study, 33% of infants receiving placebo and 7% of infants receiving iron were iron deficient (PF<12 μ
g/L) at 6 months; 14% of infants receiving placebo had IDA at 6 months.
Given the potential of severe iron deficiency to cause long-term behavioral abnormalities (11
), efforts to prevent iron deficiency among breastfed infants are warranted. Preventive strategies include screening with selective supplementation, and universal supplementation. The purpose of the present study was to assess the feasibility and the effectiveness of universal supplementation. Iron deficiency among breastfed babies has been reported at 4 mo to 6 mo of age, but the earliest age at which it can occur in full-term infants is not known. We elected to start iron supplementation at 1 mo of age. Because complementary foods as possible sources of iron are not customarily fed at that early an age, we chose medicinal iron as the source of iron. Iron was given through 5.5 mo of age, an age by which complementary foods have customarily been introduced and are relied upon to provide iron to the infant. Because of financial constraints the present trial was able to assess only the effect of medicinal iron on iron status and not whether it prevents iron deficiency or has adverse effects.
The ferrous sulfate-multivitamin preparation was well tolerated by most study infants and was, with the exception of a tendency to more greenish stools, free of side effects. Ferrous sulfate has a metallic taste and infants are often said to be reluctant to take it. But in our study no mother reported consistent difficulty or inability to administer the study supplements. Although 3 infants (8%) had side effects, the effects were not consistent. The fact that our extensive stool and behavior data showed no differences between Fe and Plac suggests that ferrous sulfate given as part of a multivitamin preparation is tolerated without side effects by the great majority of infants. Dewey et al. (15
) reported a significant negative effect of iron supplementation on length gain among Swedish infants (but not among Honduran infants) between 4 and 9 months of age. In young Indonesian children (12 - 18 mo), Idjradinata et al. (14
) showed that iron supplementation slowed growth significantly. Iron supplementation of iron replete, but not of iron deplete, infants and children was reported by Majumdar et al. (16
) and by Lind et al. (17
) to reduce growth. On the other hand, in the study by Dijkhuizen et al. (26
) iron supplementation between 4 and 10 mo was found to have no effect on growth, but that study did not take into account the initial iron status of subjects. Thus it appears that the deleterious effects of iron are limited to infants with replete iron stores.
Infants in the present study had replete iron stores, but iron supplementation had no unequivocal effect on growth. In particular there was no suggestion of an effect on length gain. Subgroup analysis showed that Fe significantly decreased weight gain (but not length gain) of female infants. This leaves open the possibility that Fe has an effect on weight gain in females only. Another possibility is that interpretation of growth data in our male infants was compromised by the high birth weight of these infants, so that an effect may have been concealed in male infants as well as in the combined genders. Also, the study was powered to detect large effects on iron status and therefore could have missed a modest-size effect on growth. In the present study iron was given right before a feeding and not between feedings, which may have limited the amount of iron absorbed. Also, most infants received some other foods (cereal, formula) during the latter part of the intervention period (from 4 to 5.5 mo).
The present study had limitations. Due to limited sample size, the study could not determine whether iron supplementation prevents iron deficiency. Also, it had sufficient statistical power only to detect relatively large adverse effects but not modest-size effects, for example on growth. Infants who left the study early were not followed, which did not allow for intention-to-treat analysis. The study had a weakness in that by chance there was a substantial difference in weight and length of subjects at birth and throughout the intervention period. This weakened the interpretation of the growth data and may have confounded the iron status data. A strength of the study was that infants were observed longitudinally from 1 to 18 mo of age and that plasma ferritin was determined at 1 mo, which provided a measure of the iron endowment at birth.
Plasma ferritin showed strong tracking across ages, with significant correlations between values obtained as far apart as 17 mo. Hay et al. (10
) reported tracking of serum ferritin between 6 and 12 mo (r=0.34) but not between 6 mo and 24 mo or between 12 mo and 24 mo. Hernell and Lönnerdal (27
) reported “strong tracking” (no data given) of serum ferritin and other indicators of iron status. Gender-related differences have been described by other investigators. Hay et al. (10
) found significantly higher ferritin concentrations at 6 mo in girls than in boys. MCV was also higher in girls than boys at 6, 12 and 24 mo. Domellöf et al. (28
) found girls to have higher PF, Hgb and MCV and lower TfR than boys at 4 mo, 6 mo and 9 mo of age.
In conclusion, the present study has shown that iron supplementation of breastfed infants from an early age is feasible but is only moderately effective in temporarily preserving the infants’ iron endowment. Although no adverse effects if iron were detected, the study’s power to detect adverse effects was limited. Two infants who did not receive iron became iron deficient by 5.5 mo of age (one with anemia). Whether iron supplementation is effective in preventing iron deficiency would need to be studied in a larger cohort. However, because of the low prevalence of early iron deficiency, screening with selective treatment would seem to be a more suitable approach to the prevention of iron deficiency than universal supplementation.