When supplementation is necessary, which is a better supplement to breast milk: low-iron or iron-fortified formula? In a recent article in AAP News,¹ Lawrence Gartner, MD, chair of the American Academy of Pediatrics (AAP) Group on Breastfeeding, suggested that breastfed infants 6 months or younger be supplemented with low-iron formula. Dr Gartner and others have taken this position on the theoretical grounds that the higher iron content of iron-fortified formula could saturate the breast milk protein lactoferrin, which plays a role in preventing the overgrowth of intestinal Escherichia coli.² If true, the hypothesis continues that this iron-lactoferrin interaction would result in increased intestinal growth of E coli. Although in vitro studies and studies in guinea pigs demonstrate the plausibility of this theory,^3,4 studies of breastfed human infants, supplemented with iron fortified and low-iron formula, are lacking. Furthermore, the clinical consequences of such an alteration, if demonstrated in humans, would require further examination.

Current guidelines on iron-fortified formula issued by the Committee on Nutrition of the AAP in 1989 specify that if infants are supplemented with formula, the formula should be fortified with iron as a strategy to prevent iron deficiency.⁵ Evidence suggests that the iron content of an infant's diet is the major determinant of iron deficiency,⁶ and that the significant decline of iron deficiency anemia among children in the United States is related to the shift from low-iron to iron-fortified formula.^7,8 Preventing iron deficiency anemia in infants is important, because anemia adversely affects development and behavior.^9,10

In this study, we compared the frequency of diarrhea in two groups of breastfed infants, one given low-iron formula and the other given iron-fortified formula. If increased iron has an undesirable impact on the infant's intestinal flora, as hypothesized, breastfed infants given iron-fortified formula should have more episodes of diarrhea than similar infants given low-iron formula.

METHODS

Sampling Frame

Exclusion Criteria

Nonresponse

For this analysis, we excluded women who failed to complete the demographic questionnaire (n = 60), as well, leaving 1743 mother-infant pairs. In any given month, we excluded infants who received neither breast milk nor formula; this exclusion had little impact on the sample size until month 12 (Table 1).

Table 1. Sample Size by Type of Feeding and Age of Child [View Table]

Population Characteristics

Data Collection

Classification of Predictor and Outcome Variables

Mothers were also asked, "How many times has your baby had diarrhea during the past 2 weeks?" Diarrhea was defined for the mother as three or more watery or semiwatery stools in a 24-hour period. Before this question, the mother had been asked to describe the infant's usual stool. We think this gave her a reference by which to distinguish between normally loose stools and diarrhea.

Analysis

To test whether the frequency of diarrhea episodes among breastfed infants differed between those supplemented with iron-fortified formula and those given low-iron formula, we divided the diarrhea rate in the iron-fortified formula group by the rate in the referent group, generating a rate ratio. If the ratio was close to 1.0, we would not reject the null hypothesis that breastfed infants fed with iron-fortified formula have the same frequency of diarrhea as those fed with low-iron formula. A rate ratio significantly greater than 1.0 would suggest that breastfed infants given iron-fortified formula are at greater risk of having diarrhea than their counterparts given low-iron formula. For completeness, we made the comparable calculation for infants given formula only.

The rates were adjusted for the infant's age and gender, mother's education, occupation, and smoking history, household size, household income, and day care use (Table 2). We performed the analysis with Poisson regression (generalized linear model), using the Genmod procedure of SAS for Windows, version 6.08 (SAS Institute, Inc, Cary, NC).

Table 2. Confounding Variables Used in Multivariate Analysis [View Table]

RESULTS

When we compared infants fed iron-fortified formula with those fed low-iron formula, there was no significant difference in the rates of diarrhea (Fig 2). Among infants who received both breast milk and formula, the rate ratio for fortified versus low-iron formula was 1.06 (P = .60; confidence interval, 0.84 to 1.34); among infants receiving formula only, the comparable rate ratio was 0.89 (P = .02; confidence interval, 0.80 to 0.99).

DISCUSSION

This study also found that among infants receiving formula only, iron-fortified formula provided a small but significant amount of protection against diarrhea when compared with low-iron formula. Other researchers looking at the iron intake of formula-fed infants and the development of diarrhea, in the past, have reported no association.^11,12

We did confirm the well-documented finding that infants given formula are at greater risk of having diarrhea than are breastfed infants.¹³ Our results also demonstrate that infants receiving both breast milk and formula have diarrhea more often than do infants receiving breast milk exclusively but less often than infants fed formula only. The demonstration of such a dose-response relationship indicates that this study design and sample size have the power to detect differences in clinical outcomes related to feeding practices.

The evidence presented by others to argue that iron may harm an infant's gastrointestinal tractnamely, differences in intestinal florawithout correlation with clinical outcome is not sufficient to recommend the use of low-iron formula. Indeed, we think there is no compelling medical evidence to support the use of low-iron formula in the general population. On the other hand, there is substantial evidence that iron-fortified formula has helped to prevent iron deficiency anemia in the United States. Thus, we urge continued support of the 1989 recommendations of the Committee on Nutrition of the AAP that low-iron formulas have no place in infant feeding and that any formula given to infants be fortified with iron.⁵