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From * Epidemic Intelligence Service, Epidemiology Program
Office, and Division of Nutrition and Physical Activity, National
Center for Chronic Disease Prevention and Health Promotion, Centers for
Disease Control and Prevention, Atlanta, Georgia; and § Office of
Scientific Analysis and Support, Center for Food Safety and Applied
Nutrition, Food and Drug Administration, Washington, DC.
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
ACKNOWLEDGMENTS
ABBREVIATIONS
REFERENCES
ABSTRACT 
Background. Concern has been raised by infant feeding experts that supplementing breastfed infants with iron-fortified formula rather than low-iron formula may have an undesirable impact on their gastrointestinal flora. Thus far, there have been no clinical studies to address this issue directly. We compared the reported frequency of diarrhea for breastfed infants given iron-fortified formula with those fed low-iron formula.
Methods. Mothers participating in a mail panel provided feeding and diarrhea information on their infants at 2, 3, 4, 5, 6, 7, 9, and 12 months (n = 1743). Infants were grouped into five feeding categories: (1) breast milk only, (2) breast milk and low-iron formula, (3) breast milk and iron-fortified formula, (4) low-iron formula only, and (5) iron-fortified formula only. We calculated the number of diarrheal episodes per week for each feeding category and used rate ratios to estimate the relative impact of low-iron and iron-fortified formulas.
Results. Among infants who received both breast milk and formula, the rate ratio for iron-fortified formula versus low-iron formula was 1.06 (confidence interval, 0.84 to 1.34), indicating that the type of formula a breastfed infant receives does not significantly affect the frequency of diarrhea.
Conclusions. We found no evidence to support the hypothesis that breastfed infants given iron-fortified formula are at greater risk of having diarrhea. This, in addition to the fact that iron-fortified formula has played a major role in preventing childhood iron deficiency anemia, supports the current recommendation that any formula given to infants be fortified with iron. infant food, diarrhea, breastfeeding, iron.
INTRODUCTION
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
The Infant Feeding Practices Study is a panel study of US mother-infant pairs followed from late pregnancy through the infant's first year. The Food and Drug Administration conducted the study between 1993 and 1994. The agency used a consumer mail panel as the sampling frame and sent prenatal intake questionnaires to 3155 households identified as including pregnant women.Exclusion Criteria
A woman was ineligible for the study at the time of the prenatal questionnaire if she was either not pregnant or her due date was more than 3 months away. A woman was ineligible for the study after the prenatal questionnaire for any of the following reasons: (1) her infant weighed less than 5 lb at birth; (2) she gave birth to multiple infants; (3) she had medical problems that prevented her from feeding the infant for more than 1 week; (4) her infant stayed in the intensive care unit for more than 3 days; (5) her infant had medical problems that affected feeding; (6) she or her infant died at any time during the data collection period; and (7) her infant was born too early for the neonatal questionnaire to be administered on time. Five hundred forty women were excluded from the study because they met ineligibility criteria. This gave a sample base of 2615 women.Nonresponse
A woman was considered a nonrespondent if she failed to complete the first (prenatal) or second (birth screener) questionnaire or if she failed to complete the first two questionnaires sent after the infant's birth (n = 812). We did not eliminate a mother from the study for failure to complete a subsequent questionnaire. The response rate was 69% (1803 of 2615).
Table 1.
Sample Size by Type of Feeding and Age of Child
Population Characteristics
To better understand the characteristics of our sample, we compared them with a nationally representative population of mothers participating in the National Maternal and Infant Health Survey. In comparison, our cohort consisted of mothers who were: (1) more from middle- and upper-income groups, (2) predominantly white, (3) older, (4) more likely to be married, (5) more likely to take prenatal classes, and (6) less likely to drink alcohol or smoke.Data Collection
The Food and Drug Administration used the prenatal questionnaire, which was administered from 90 to 42 days before the mother's due date, to collect information on the mother's health, employment situation, and infant feeding plans. The birth screener questionnaire, administered shortly after the mother gave birth, included questions on the health of the infant and anthropometric indices at birth. A third (neonatal) questionnaire was administered when the child was 1 month old; information about the infant's birth and subsequent feeding was collected. The remaining questionnaires collected information about feeding, health status, allergies, and the infant's social situation and were administered at months 2, 3, 4, 5, 6, 7, 9, and 12. We used data from months 2 through 12 for the analysis presented here.Classification of Predictor and Outcome Variables
Each month, the mother was asked whether she had breastfed her infant and whether she had given formula to the infant in the previous 7 days. If she had given her infant formula, she was asked whether that formula was iron fortified. We grouped infants into one of five feeding categories: (1) breast milk only, (2) breast milk and iron-fortified formula, (3) breast milk and low-iron formula, (4) iron-fortified formula only, or (5) low-iron formula only.Analysis
We summed the number of cases of diarrhea (some mothers reported more than one for some 2-week periods) for all periods in which we had responses and divided by 2 (because of the 2-week reporting period) to define the number of diarrhea episodes per infant-week. We examined the five feeding categories described previously in two different groupings. First, to create a framework within which to interpret our results, we compared the rate of diarrhea for three groups: breast milk only, breast milk with formula, and formula only. In this case, the breast milk-only group served as the referent. Next, we compared the rate of diarrhea among infants receiving iron-fortified or low-iron formula in both the breast milk-with-formula and formula-only groups. Here, low-iron formula was the referent group.
Table 2.
Confounding Variables Used in Multivariate Analysis
RESULTS
indicates P < .001 compared with rate for breast milk only; and *, episodes per week, adjusted for age and gender of infant, household income, mother's education, occupation, and smoking history, household size,
and use of day care.
DISCUSSION 
Fig. 2.
Rate of diarrhea by formula type within two major feeding groups. indicates not significant compared with breastfed infants given
iron-fortified formula; 
, P = .02 compared with
formula-only infants given iron-fortified formula; and *, episodes
per week, adjusted for age and gender of infant, household income,
mother's education, occupation, and smoking history, household size,
and use of day care. 
, Iron-fortified; 
, low iron.
[View Larger Version of this Image (42K GIF file)]
namely, 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
FOOTNOTES
Received for publication Mar 5, 1996; accepted May 21, 1996.
Reprint requests to (P.D.S.) Centers for Disease Control and Prevention, Mail Stop K-25, Division of Nutrition and Physical Activity, 4770 Buford Hwy, Atlanta, GA 30341-3724.
ACKNOWLEDGMENTS
We thank Dr Kelley Scanlon, Dr Caryn Bern, and Dr Frederick Trowbridge for their careful review and comments on this manuscript. We also thank Dr Bern for sharing her expertise on matters regarding diarrhea in infancy.
ABBREVIATIONS
AAP, American Academy of Pediatrics.
REFERENCES
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