Iron Metabolism and Requirements in Early Childhood: Do We Know Enough?: A Commentary by the ESPGHAN Committee on Nutrition

Anemia affects approximately 42% of children younger than 5 years in developing countries and approximately 17% in industrialized countries (1). The latter are often, but not exclusively, children of ethnic minorities or socioeconomically deprived. Not surprisingly, these prevalence rates are highest during periods of rapid growth (6–24 months of age). Although, there are many other nutritional and infectious (gastrointestinal) causes of anemia, iron deficiency is often a contributory factor in many of these cases. Few surveys of anemia have applied strict criteria for defining and characterizing iron deficiency anemia (IDA) (2–4). During the past decade, the possible association between iron deficiency, with or without anemia, and impaired cognitive and psychomotor development has been the subject of much concern. This concern has lead to establishing extensive intervention programs to prevent iron deficiency in many countries. Preventing iron deficiency also is a key issue in recommendations for infant feeding. Although iron is essential for optimum development in infants and children, we do not know the precise requirements or how to recognize milder forms of iron deficiency. Although we know the effect of severe deficiency and of toxic overdose, we know little about the association among iron supply and stores and the subtle effects of an inadequate iron supply. Iron deficiency may be defined in terms of reference ranges for hematologic and biochemical criteria derived from healthy populations, but we do not know how these reference thresholds correlate, if at all, with functional defects. The criteria for IDA are based on hemoglobin (defining anemia) and measures of iron metabolism and function, such as circulating ferritin (reflecting the size of iron stores), serum transferrin (reflecting iron transport capacity), zinc protoporphyrin (ZPP, reflecting defective hemoglobin synthesis), and serum transferrin receptors (TfR, reflecting cellular need for iron) (3). However, these indicators of iron status are particularly difficult to interpret in infants and young children because of the impact of coincident changes in physiology and metabolism during growth and development, and because of the impact of infection. For these reasons, the Committee on Nutrition recognizes a need to review critically the current literature with respect to the prevalence and consequences of iron deficiency and IDA in infants and children younger than 2 years. The main focus is on infants born at term in industrialized countries. IRON METABOLISM Iron metabolism during pregnancy adapts to ensure a supply to the placenta and fetus. Therefore, only when the mother is severely iron deficient does her iron status affect the newborn infant (4). The iron stores of the newborn also are influenced by the amount of blood transferred from placenta to fetus after delivery and before clamping the umbilical cord (5,6). This is why the cord should not be clamped until pulsation has stopped. Because most of the iron is transferred to the fetus toward the end of pregnancy, paralleling the rate of weight gain, preterm infants are born with smaller iron stores and have increased need for exogenous iron, in part also because of their rapid growth after birth (7). Newborn, healthy, term infants with normal birth weight are born with iron stores sufficient to cover the needs for growth during the first 6 months of life (8,9). During this period, the infant needs little, if any, exogenous iron, explaining why breast-fed infants and infants fed an infant formula with only 2 mg/L show no signs of depleted iron stores during the first half of infancy (10). Consistent with this, the amount of total body iron does not change, although iron stores and iron content per kilogram of body weight decrease during the first 4 to 6 months of life, as the infant grows (11). The low content of iron in human milk (0.2–0.4 mg/L) limits the iron losses of the mother, which is especially important if the mother is iron deficient and breast-feeding is prolonged. Populations of lactating mothers in whom menstruation is suppressed tend to be in better iron balance than populations of menstruating women (12). During the second half of infancy, the requirement for exogenous iron rapidly increases, to a concentration per kilogram of body weight higher than at any other time in life. The requirement of absorbed iron is about 0.1 mg/kg body weight daily, which is three times higher than that of menstruating pubertal girls (11,13). Homeostasis The major process responsible for modulating mammalian iron homeostasis is intestinal absorption, which is affected by the iron status of the individual, dietary factors, interorgan transport and uptake, and cellular use. The molecular mechanisms behind these processes are not fully understood, but a number of proteins are involved and changes in the abundance or activity of these proteins play a key role in iron homeostasis. Therefore, the role of iron regulatory proteins, which provide the molecular framework that coordinates regulation of iron metabolism, is beginning to be understood. Iron regulatory proteins bind to iron responsive elements in specific mRNA and regulate their use (14). In contrast with other trace elements, no regulated excretory pathway is involved in controlling the systemic body burden (15). The divalent metal transporter 1 is important for iron absorption. It transfers nonheme iron across the apical membrane into the enterocyte. Divalent metal transporter 1 can transport a wide variety of divalent metal ions, including manganese, cobalt, copper, zinc, cadmium, and lead. Nonheme iron is preferentially absorbed in the ferrous form (14). Reduction of ferric iron to ferrous iron is accomplished by the acidic milieu of gastric content, by the composition of the meal (see below), and by brush border ferric reductase. Absorption seems to be regulated in various ways. One way depends on the size of the iron stores in the body, that is, the stores regulator. Iron absorption is up-regulated by a factor of two to three in iron deficiency states when compared with iron replete states. It probably acts at the level of crypt-cell programming in response to the saturation of plasma transferrin with iron (16). An erythropoietic regulatory mechanism responds to the iron requirements for erythropoiesis. The amount of iron recently consumed in the diet also can modulate absorption. For several days after ingesting a dietary iron bolus, the absorptive enterocytes are blocked for further iron absorption, which may occur even in the presence of systemic iron deficiency (16). The type of iron given and the composition of the diet also affect iron absorption. The fractional absorption of heme iron, present only in meat, poultry, and fish, is considerably higher than absorption of nonheme iron (approximately 25% compared with 5–10%), and is less subjected to regulation (17). The iron status of the individual and dietary composition influence absorption of nonheme iron. Ascorbic acid is the most potent enhancer of nonheme iron absorption. The mechanism is probably reducing ferric to ferrous iron. Organic acids such as citric acid and fermented foods have an enhancing effect. Muscle foods (meat, fish, and seafood) also enhance absorption of nonheme iron through a “meat factor” (17), as yet unidentified. Foods may contain compounds (ligands) that strongly bind iron and therefore inhibit absorption, for example, phytates, mainly from whole grain cereals and soy protein, and phenolic compounds in tea, coffee, and cacao (18,19). Single-meal studies have shown a negative effect of calcium on iron absorption (20). However, other studies in 3- to 5-year-old children (21) and of long-term calcium supplements with meals (22) did not find a negative effect of calcium intake on iron absorption and iron status. Regulation of iron absorption seems to be immature during the first half of infancy (23). DETERMINATION OF IRON STATUS The World Health Organization defines the cutoff concentration for hemoglobin in defining anemia as 110 g/L until 5 years of age (24). This cutoff concentration is based on studies in young children and has been extrapolated to cover infancy because of lack of more appropriate data. However, several studies have indicated that this concentration may be too high. In a study of 1,175 8-month-old infants, Emond et al. (25) found that the fifth percentile for hemoglobin was 97 g/L and suggested that for British infants of this age, this value would be a more appropriate cutoff for anemia. Using the same approach, a cutoff of 100 g/L was suggested for children at 12 and 18 months of age (26). Similarly more than one third of healthy, term Swedish infants at 6 months of age had hemoglobin concentrations below 110 g/L, but less than 3% had s-ferritin less than 12 μg/L, indicating that very few infants had depleted iron stores (27). No significant differences in hemoglobin concentrations or any other indicator of iron status were found between breast-fed infants and infants fed formula with 2, 4, or 7 mg iron/L, suggesting that all groups were receiving adequate amounts of iron (10). In another study of healthy, term infants, 29%, 32%, and 20% were anemic using the 110 g/L cutoff at 2, 6, and 9 months, respectively (28). Only 3% of the infants in this study had s-ferritin concentrations below the cutoff (12 μg/L) at 9 months. When 105 g/L was used as the cutoff for hemoglobin concentration, the corresponding percentages were 15%, 5%, and 5%, respectively. In a recent randomized study of the effect of iron supplements on healthy, term, breast-fed Swedish and Honduran infants, 20% of Swedish infants who did not receive supplementation had hemoglobin concentrations less than 110 g/L and 29% had ferritin concentrations less than 12 μg/L at 9 months of age. The prevalence of iron deficiency defined as two of three abnormal iron status indexes (ferritin, mean corpuscular volume, and ZPP), with the following cutoff concentrations: ferritin less than 12 μg/L, mean corpuscular volume less than 70 fL, and ZPP higher than 80 μmol/mol heme was however below 3% and not further reduced in infants who were given daily iron supplements (1 mg iron/kg daily) between 4 or 6 and 9 months of age as compared with infants given placebo. Nor was there a difference in hemoglobin concentration at 9 months between the supplemented and the placebo groups (9). Factors other than iron status affect hemoglobin concentration. Even mild viral infections and vaccinations decrease hemoglobin concentration (29,30). Furthermore, even within the normal range, the hemoglobin concentration of an infant is influenced by genetic factors (31), including gender (32). We conclude that more appropriate cutoff values to define anemia in infants and young children are necessary and that current prevalence data must be interpreted with caution. No single standard test assesses iron deficiency in the absence of anemia. Different tests estimate different aspects of iron deficiency. S-ferritin is the most specific biochemical test because it correlates to total body iron stores, and a low s-ferritin concentration reflects depleted iron stores (33). However, apoferritin is an acute-phase reactant protein and is therefore elevated in inflammatory processes (34). Consequently s-ferritin concentration in the normal range reflects adequate iron stores only in the absence of inflammation. Therefore, of s-ferritin concentrations is in populations with a of infection. of s-ferritin also is difficult at times of rapid systemic iron such as during rapid growth The cutoff concentration for s-ferritin below which iron stores are depleted is 12 μg/L in children younger than 5 years of age (24). infants have s-ferritin concentrations at reflecting iron the in hemoglobin causes a further with a rapid decrease until concentration a at 9 to 12 months of age (33). During this period, infants have s-ferritin indicating smaller iron stores (11). Although s-ferritin concentrations during the first part of infancy to changes in iron stores, no data the cutoff for when iron stores are depleted with functional use the cutoff of μg/L for infants and young children, which is based on the of s-ferritin concentrations in a in the in which the fifth percentile indicated abnormal values In a British study with more than children, the fifth percentile was μg/L at and 12 months, and 12 μg/L at 18 months Therefore, in this age such are not based on functional such as the of iron in and concentrations below the cutoff do not depleted iron study of healthy Swedish infants 25% of infants had s-ferritin concentrations below 12 μg/L and no was found between low s-ferritin and low hemoglobin infants were with that formula and This study was part of the healthy infants from The prevalence of s-ferritin concentrations less than 12 μg/L in the was the same as in the that is a cutoff concentration of μg/L in the which infants, had ferritin concentrations below However, using only were as iron deficient and as IDA suggesting that a cutoff concentration at 12 μg/L for this age does not depleted iron The of infections after the age of 6 months further the use of s-ferritin in this age The value of using and saturation to iron deficiency also is and with higher concentrations in the are also higher after may decrease during infections and in these between healthy and also their in establishing or a of iron deficiency (15). protoporphyrin forms when iron supply is inadequate for heme with does not affect the ZPP to heme and is and for studies However, this indicator has not been or used in infants and young receptors is a recent to the of iron to the need for iron in human is a response during the development of iron deficiency. concentrations as iron stores before the of anemia. major of is that or inflammatory processes do not affect the The in concentration is also less than that of that have been on the have different cutoff Because of this and other aspects of the among studies is not fully data do not yet to the value of as an indicator of iron deficiency in infants and young studies that have used these for infants have only a low of infants with iron deficiency, which may the low between low s-ferritin and iron replete infants were shown to have higher concentrations than did indicating that reference concentrations probably are Therefore, it is too to the value of this The use of tests only the of single tests and is an in tests do not all with one another because reflects a different of iron IRON effects Iron is found the including the The content is at birth and with age to concentrations only after Iron is across the and to through the and other in other cellular iron is to involved in specific to iron has a role in and studies of the during have shown the highest concentrations of iron in the the the and the However, most of the iron, and transferrin mRNA and to in the and of the most iron regulatory protein within the human is found mainly in and on iron and metabolism in the from studies using the in which development to development in the human in that the of and is from birth to the age of in and from to 2 years in iron deficient between birth and days of age do not their content, iron that are iron deficient can do with iron deficiency and concern that iron deficiency during development in infants and young children may affect iron concentration and Although these changes are may to in The iron deficiency in the has been and therefore may not the iron deficiency with impaired development in infants and young However, even if these in the the consequences of iron deficiency on human function, the higher of iron deficiency by infants and young children, between 6 and 18 months of age, the for development IDA and in and show an association between IDA and impaired cognitive and psychomotor development in infants and young have a of because IDA is in this age Therefore, the issue is a significant Although, a association between IDA and cognitive development the and the of are not as During the past decade, the issue has been critically with respect to study intervention and age, and the used to studies the that IDA than iron deficiency is with a or psychomotor as by the of few studies have indicated that iron deficiency in the absence of anemia may also development effect is because more severe anemia has been with or psychomotor or Although the of from studies a association between IDA and development, these studies do not and are subject to many infants and children from of the and the that IDA is a for other factors that to be such as or at of or even growth and other nutritional may hemoglobin concentrations for a of the in and measures of the may be too to for the differences in and receive the of intervention are be in which infants are randomized to groups that receive iron or or be in which infants at an age are randomized to groups that receive various of iron in children younger than 2 years have to in and studies of that is, 2 to 6 months an anemic placebo and all a for three found no significant study in which 6 months, that the before was in a of infants with IDA compared with a reference and that did not one in and the other in The study to show an effect using the test to development, the latter found that the and psychomotor of children with anemia compared with children in the placebo Therefore, this study also that impaired development is these studies have no although the study from strongly a are used to the of in to In a study of infants from randomized to of mg/L) or mg/L) formula from 1 to 2 months of life, were found in psychomotor at 9 and 12 months. However, these were no at months. The of many children from at months the of this study recent studies In one children were fed milk or formula (12 mg/L) from months until 18 months of age. groups were fed milk until months of age. Using the infants who the formula significant at months but not at 18 months Because there are many more in the nutritional supply of these infants than to iron this was One such may be the to affect In the second and most recent children were randomized to receiving milk or to one of two infant with mg/L or 12 mg/L iron, from 9 to 18 months of age, when the iron status and development were Although infants fed the formula with the highest iron concentration had the highest no significant difference was found among the groups in prevalence of anemia and as by the test This study was to and psychomotor and indicators of iron status at 18 months in infants fed formula with infants fed Therefore, iron deficiency was not in the was it defined or at the of the Because iron status in these and other recent studies was not or because criteria were used to define iron deficiency, is a of these studies have the of in infants with children who had IDA during infancy on tests of and at 5 years of age and even years of age than did who were iron of the iron deficiency was or no of iron deficiency during from the Health in found that hemoglobin concentrations at 9 months of age were with and at 5 years of age that on tests for children with IDA in infancy after the of deficiency. However, as other with iron deficiency may be responsible for these recent that data by the for and and that anemia increased the of mild or for in hemoglobin concentration This effect was after controlling for the effects of birth and age. In low level and very low birth weight increased the of 12 and respectively Because the children in the study were different from the study children had more the size of the effect may be considerably smaller in a at studies only but do not that anemia causes mild or this study may be in the long-term of and with Iron and Iron is an essential for normal development and iron deficiency in life can affect and function, which the association between iron deficiency and In to effects on cognitive iron deficiency also may affect infant infants months were as more more and less may the which to impaired cognitive factor be an increased lead absorption in iron deficiency, because lead is to affect studies have shown that lead absorption in iron deficiency which may to the association of iron deficiency and increased serum lead concentrations found in studies of infants and children is of the divalent metal transporter 1 However, even if given the role of iron in development and function, a between IDA and impaired cognitive development be from the of Iron studies have suggested an association between iron deficiency and Iron reduced the of mechanisms have not been number of studies found that several are affected during iron deficiency, especially and activity of study of infants and young children between 6 months and years of age found no difference in the between infants who were iron deficient and infants who were iron replete In many no differences have been shown in the prevalence of infections when infants and young children who are and Iron deficiency may because are depleted of iron but no data from studies Nor is there that iron or iron supplementation is a factor for is in The effect in with iron deficiency without anemia is less In severe anemia, the to regulate body when to also is This effect has been with an in concentrations One study found increased in the of children who were iron deficient that to normal after with iron This that the often in severely children at in from iron deficiency. IRON Although no that iron stores a to the individual, a daily intake of iron may have negative with respect to absorption of other effects and in in which iron absorption is increased The recent of the divalent metal transporter 1 the between absorption of iron and divalent of most for infants and young children are and with iron content may have a negative effect on and zinc absorption. In absorption of iron with absorption of zinc and copper, and iron intake in reduced serum In a study of term, healthy infants, an infant formula with an iron content of 7 mg/L in a significant decrease in serum (27). Iron is a and in a intake may However, no studies such effects in healthy, term In studies have shown an association between and size of iron stores and iron intake this association be through of However, there is no of and the for infants and young children is Iron is an essential with important in life. IDA has effects on and and iron deficiency in the absence of anemia has effects on is not The literature does not show a between IDA and impaired cognitive development, even if such an association is based on studies of the role of iron in development and further is measures should be to prevent iron deficiency, for example, using formula when formula is of whole milk until the end of the first of life, and The prevalence of iron deficiency during the first 2 years of life not be until we have a better of the homeostasis and regulation of iron metabolism during this of We do not know and cutoff values to use to iron deficiency during the first 2 years. The cutoff values in use with respect to anemia 110 and depleted iron stores 12 μg/L) the prevalence of anemia and of iron deficiency. the possible effects of iron deficiency on cognitive development, and better intervention studies are studies at of iron deficiency are for reasons, and also have the that of iron can be by by of other factors, or by nutritional