Iron Balance in the Neonate Carissa Cheng and Sandra Juul Neoreviews 2011;12;e148 DOI: 10.1542/neo.

12-3-e148

The online version of this article, along with updated information and services, is located on the World Wide Web at: http://neoreviews.aappublications.org/content/12/3/e148

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Iron Balance in the Neonate

Carissa Cheng, RD,* Sandra Juul, MD, PhD

Abstract
Iron is essential for growth and development, and deciency during gestation and infancy may have lifelong effects. Iron is necessary for oxygen transport, cellular respiration, myelination, neurotransmitter production, and cell proliferation. Iron deciency may decrease hippocampal growth and alter oxidative metabolism, neurotransmitter concentrations, and fatty acid and myelination proles throughout the brain. Excellent articles and reviews have been published on the effect of iron on cognitive development. This review highlights more recent ndings, focusing on the role of iron in brain development during gestation and early life, and discusses implications for practice in the neonatal intensive care unit.

Author Disclosure Ms Cheng and Dr Juul have disclosed no nancial relationships relevant to this article. This commentary does not contain a discussion of an unapproved/ investigative use of a commercial product/ device.

Objectives
1. 2. 3. 4. 5.

After completing this article, readers should be able to:

Name sites of iron absorption and regulation. List the consequences of iron deciency and excess for the neonate. Choose an appropriate tool for iron assessment. Discuss practical challenges to providing iron to neonates. List iron intake recommendations for preterm infants.

Background
Iron status of the neonate is a balance between iron accretion during gestation, iron utilization and loss, and iron acquired postnatally, either through enteral or parenteral routes (Fig. 1). Thus, maternal and fetal conditions as well as postnatal experiences affect neonatal iron status. Iron is a transition metal that readily converts between the ferrous (2) and ferric (3) oxidation states. In biochemical systems, iron is often found in the catalytic site of enzymes, where it facilitates redox reactions. Its redox properties provide protein function but can also be dangerous because inappropriate oxidation may cause cellular damage. Free iron in a biologic system can convert between oxidation states, generating free radicals. Polyunsaturated fatty acids, which are found in cell membranes, are especially susceptible to damage by free radicals. To protect the organism, iron is sequestered by proteins throughout absorption, transport, storage, and as it performs its physiologic functions. (1) Among other functions, iron is essential for development Abbreviations of the nervous system. Myelination, neurotransmission, dendritogenesis, and neurometabolism are dependent on iron. DMT1: divalent metal transporter-1 (2)(3)(4) Iron deciency during the late fetal and the early DcytB: duodenal cytochrome B infant periods may result in decreased cellular respiration in Epo: erythropoietin the hippocampus and frontal cortex, abnormal neurotransHCP-1: heme carrier protein 1 mitter concentrations, and alterations in fatty acid and myIRE/IRP: iron response element/iron regulatory protein elination proles. (2) Iron deciency in infancy may have a MCV: mean cell volume lasting impact on cognitive, socioemotional, and motor sTfR: soluble transferrin receptor functions. (4) The effects of iron deciency on brain strucTIBC: total iron binding capacity ture and function are interrelated; neuronal development ZnPP/H: zinc protoporphyrin-to-heme ratio affects behavior that, in turn, affects brain development. (4)

*Nutritional Sciences Program, University of Washington, Seattle, WA. Department of Pediatrics, Division of Neonatology, University of Washington, Seattle, WA. e148 NeoReviews Vol.12 No.3 March 2011

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Figure 1. Iron balance in the neonate is a balance between

iron input from prenatal placental transfer; enteral and parenteral iron intake; and transfusions and iron loss via phlebotomy, gastrointestinal loss, and iron use for growth.

degradation of the protein (Fig. 2F). This blocks iron release, and iron is incorporated into ferritin in the enterocyte, which is lost when the cells are sloughed. Hepcidin expression is increased in response to iron overload and inammation and is reduced in response to increased erythropoiesis, hypoxia, and iron deciency. (5) Hepcidin production is also reduced during pregnancy, allowing for increased maternal iron absorption. (6) In murine models, hepcidin regulation has been demonstrated by inammatory cytokines, bone morphogenetic protein signaling, and toll-like receptors. (9) A recent study in mice has demonstrated that H-ferritin, as well as hepcidin, is required for regulation of intestinal iron efux. (10)

Thus, having the appropriate amount of iron is essential because both deciency and excess can be harmful.

Transport
Ferric iron is transported through the bloodstream bound primarily to transferrin, a protein that has two iron-binding sites. (1) Some iron is also found associated with albumin or small molecules. In the bloodstream, transferrin is typically one third saturated with iron. Binding of free iron by proteins not only protects the body from damage by free radicals but also sequesters free iron from bacteria, which use host iron for reproduction. (5)

Absorption, Transport, and Storage of Iron in Infants

Absorption
The uptake of iron by the enterocyte is an important regulatory step in body iron content. Iron can be absorbed into the enterocyte as heme iron or nonheme iron (both ferrous and ferric forms). Heme iron is soluble in the duodenum and is absorbed as an intact metalloprotein via heme carrier protein 1 (HCP-1) (Fig. 2A). Ferrous iron is then released from heme via heme oxygenase. (5) Unbound iron is absorbed into the enterocyte in the ferrous or ferric form. In the duodenum, nonheme iron is converted to the ferrous (II) form by ascorbic acid and duodenal cytochrome B (DcytB) on the surface of the brush border (Fig. 2B). (6) Ferrous iron then binds to divalent metal transporter-1 (DMT1) and is transferred into the enterocyte. (5) Expression of DcytB and DMT1 are regulated by the iron content of the enterocyte (6) and transcription factors sensitive to hypoxia and intracellular iron concentration. (7) Ferric iron (III) binds chelators in the small intestine and is absorbed via a 3 integrin and mobilferrin pathway (Fig. 2C). (8) After entry into the enterocyte, ferric iron is reduced by paraferritin and binds mobilferrin. Ferrous iron from all three entry pathways is released into the intracellular iron pool and used for cellular metabolism, stored as ferritin, or transferred out of the enterocyte (Fig. 2D). (6) Iron is released by ferroportin at the basolateral membrane, where it is oxidized by hephaestin and binds to transferrin for transport (Fig. 2E). Iron release from the enterocyte into the bloodstream is a tightly regulated process. When the body is ironreplete, hepcidin binds ferroportin at the basolateral surface of the enterocyte, inducing internalization and

Tissue Uptake
For iron uptake in most tissues, transferrin binds to transferrin receptors on the surface of the cell, and the transferrin receptortransferrin complex is endocytosed. Protons are pumped into the endosome, lowering the pH and releasing iron from the transferrin. The free iron is released into the cell for use, and the transferrin is released back into the bloodstream. The number of transferrin receptors expressed on the cell surface is regulated by intracellular iron concentrations. In a low-iron state, expression of the transferrin receptor is increased and expression of ferritin is reduced. Conversely, when the intracellular iron concentration is high, expression of the transferrin receptor is reduced while expression of ferritin is increased. (5)

Storage
Approximately 75% of somatic iron is contained in hemoglobin, 15% in storage sites (liver, bone marrow, and spleen), and 10% in regulatory proteins. Iron is efciently recycled from senescent red blood cells. Erythrocytes are phagocytosed by macrophages in the spleen, where they are lysed and the protein is degraded. The released iron can either be stored in the macrophage or sent back into circulation bound to plasma transferrin. (5) Ferroportin
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Figure 2. Iron transport through the enterocyte. A. Heme iron is absorbed as an intact metalloprotein via heme carrier protein 1 (HCP-1). Ferrous iron is released from heme via heme oxygenase. B. Nonheme iron is converted to the ferrous form by ascorbic acid and duodenal cytochrome B (DcytB) on the surface of the brush border. Ferrous iron then binds to divalent metal transporter-1 (DMT1) and is transferred into the enterocyte. C. Ferric iron binds chelators in the small intestine and is absorbed via a 3 integrin and mobilferrin pathway. After entry into the enterocyte, ferric iron is reduced by paraferritin and binds mobilferrin. D. Ferrous iron from all three entry pathways is released into the intracellular iron pool and used for cellular metabolism, stored as ferritin, or transferred out of the enterocyte. E. Iron is released by ferroportin at the basolateral membrane, where it is oxidized by hephaestin and binds to transferrin for transport. F. When the body is iron-replete, hepcidin binds ferroportin (IREG1) at the basolateral surface of the enterocyte, inducing internalization and degradation of the protein.

is a transmembrane protein that transports iron from the inside to the outside of a cell. It is found on the surface of cells that store or transport iron, including enterocytes, hepatocytes, and macrophages in the reticuloendothelial system. Ferritin, a 24-subunit hollow protein sphere, is the primary iron storage protein. Ferritin concentration is regulated by intracellular iron content via the iron response element/iron regulatory protein (IRE/IRP) system. When iron content is low, the IRP binds the IRE on ferritin mRNA and blocks translation. For release from ferritin, iron is reduced to the ferrous form and exits through pores in the ferritin protein. On the cell surface,
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iron is reoxidized by ceruloplasmin for transport. (11) Iron loss is not regulated by the human body and occurs primarily by sloughing of iron-containing enterocytes or via blood loss in menstruating females.

Special Considerations for Infants

Regulatory mechanisms present in adults may not be fully developed in infants. In mice, ferroportin and DMT1 are not expressed on the enterocyte surface until late infancy, indicating that the structure for iron regulation continues to develop postnatally. This is also true in rats. Expression of DMT1 and ferroportin is not upregu-

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lated in iron-decient rat pups by 10 days of age but increases by 20 days. In humans, a randomized, controlled trial found that at 6 months of age, iron absorption was not different between iron-sufcient and -decient infants, but at 9 months of age, unsupplemented infants increased iron absorption. (12) This suggests that before 6 months of age, infants are unable to modulate iron absorption in response to iron status.

Behavioral changes also occur. These include poorer learning capacity (20) and spatial navigation (21) and increased hesitancy (21) and anxiety. (22) These changes may be irreversible because reversal of iron deciency after weaning did not improve decits in sensorimotor function, increased hesitancy to explore, and spatial learning. (21)

Consequences of Iron Deciency and Excess

Effects of Maternal and Perinatal Iron Deciency: Cell Culture and Animal Models
Approximately 80% of iron transfer to the fetus occurs during the third trimester of pregnancy. In rats, when maternal iron stores are inadequate, expression of placental transferrin receptor and IRE-regulated DMT1 increase to augment iron transfer to the fetus. An in vitro model of placental iron deciency shows similar results, with increased iron transfer from the apical to basolateral side of BeWo cells, a commercially available human placental cell line. (13) These mechanisms may mitigate the fetal effects of maternal iron deciency, but severe maternal iron deciency may affect fetal neurodevelopment irreversibly. Structural changes in iron-decient rodents include reduced myelin content, (14) shortened hippocampal dendritic arbors, (15) and reduction of proteins necessary for myelin compaction. (16) The degree of neuronal myelination of rat pups from mothers fed iron-decient and iron-supplemented diets during pregnancy and lactation were compared. The iron-decient rat pups had reduced brain and spinal cord myelination compared with iron-replete pups. (14) Similar results have been shown in iron-decient mice. (16) Maternal iron deciency is associated with reduced brain iron concentrations, altered dopamine metabolism, and changes in myelin fatty acid composition. (17) Decreased neuronal metabolic activity has also been observed in irondecient rats. Cytochrome c oxidase activity is reduced in the hippocampus, dentate gyrus, piriform cortex, medial dorsal thalamic nucleus, and the cingulate cortex of iron-decient rats, indicating that areas of the brain involved in memory processing are selectively affected by iron deciency. (18) Iron-decient rats also have reduced oligodendrocyte metabolic activity, as measured by activity of 2,3-cyclic nucleotide 3-phosphohydrolase, lower concentrations of myelin basic protein, alterations in fatty acid composition of hindbrain phospholipids, and reduced cytochrome oxidase activity compared with iron-sufcient rats. Iron deciency during gestation and early postnatal life both show these results. (19)

Effects of Maternal Iron Deciency: Human Data

The consequences of iron deciency on the human fetus are less well characterized because ethically sound, randomized, controlled trials in this population are difcult to design. However, some information on the effects of iron deciency can be gleaned from developing countries where iron deciency during pregnancy is common. Evidence is also available from the literature on iron supplementation during pregnancy. Because the placenta adapts to increased iron transfer to the fetus in the presence of maternal iron deciency, the fetus is relatively protected until severe maternal deciency develops. At birth, most studies have shown minimal differences in iron status (cord blood hemoglobin, serum iron, serum ferritin, and total iron-binding capacity [TIBC]) between iron-supplemented and nonsupplemented mothers, although serum ferritin tends to be higher in infants born to nonanemic mothers. (23) Follow-up evaluation suggests that maternal iron supplementation may protect the infant from developing iron deciency anemia. Infants born with low ferritin stores tend to continue to have lower iron stores than age- and weight-matched controls at 9 to 12 months of age. (24)

Neonatal and Infant Iron Deciency

Iron deciency in infancy appears to affect socioemotional, cognitive, and motor function negatively. Irondecient infants are less engaged with their environment and are more shy, hesitant, solemn, and difcult to soothe. (25) They demonstrate slower auditory neural transmission speed, (26) poorer recognition memory, (27) and slower motor function. The severity of iron deciency affects the degree of socioemotional behavioral differences. Socioemotional behavior was assessed among 77 infants ages 9 to 10 months who received iron supplementation for 3 months. Linear effects of iron status were found for shyness, orientation-engagement, soothability, positive affect, and latency to engagement with examiner. (25) Iron deciency in infancy has been associated with long-termnegativeoutcomes.Theseincludealteredsleepwake cycles at preschool age, (28) reduced learning
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capacity and positive task orientation in elementary-age children, (29) behavioral problems in adolescence, (30) and decits in executive function and recognition memory in young adulthood. (31) The effect of iron supplementation was evaluated in a blinded study of 77 term breastfed infants randomized to either 7.5 mg/day of elemental iron or placebo from 1 to 6 months of age. Iron supplementation resulted in signicantly higher visual acuity and psychomotor development index at 13 months of age, suggesting there may be some benet to supplementation in breastfed infants. (32) It has been questioned whether iron supplementation in breastfed infants might increase the risk of infection. A systematic review in 2002 found no evidence of increased infection in children receiving iron supplementation, although the risk of diarrhea was increased. Thirteen of the 28 studies in this review were conducted in infants, and a variety of iron supplementation methods, including parenteral iron, enteral iron, or iron-fortied formula, were included. (33) The American Academy of Pediatrics recommends that exclusively breastfed infants receive 1 mg/kg per day of iron at 4 months of age. (34)

toward better neurodevelopmental outcome in the children who received early iron supplementation, but it was underpowered.

Consequences of Iron Excess: Neonates and Infants

Like iron deciency, iron excess can have adverse effects. Iron is a pro-oxidant and may damage lipids, polysaccharides, DNA, and proteins through free radical formation. (1) Iron is more likely to cause peroxidation of polyunsaturated fatty acids when adequate antioxidants, especially vitamin E, are not available. (37) Because of these effects, concern has been raised that providing routine iron supplementation to iron-sufcient infants might negatively affect long-term development, although this was not borne out in a study supplementing iron-sufcient infants age 6 to 18 months who were followed until 10 years of age. (38)

Consequences of Iron Excess: Preterm Infants

Providing excess iron might be particularly harmful to preterm infants, who are at increased risk for oxidative injury for several reasons, including immature antioxidant defense systems. (39) Neonates tend to have low TIBC; high saturation of circulating transferrin; and low concentrations of ceruloplasmin, unbound transferrin, and albumin, all of which bind free iron. (40) Although no direct link has been shown between iron excess and disease in preterm infants, concerns have been raised about the potential for iron to cause increased oxidative stress, which may contribute to complications of prematurity such as retinopathy of prematurity (41) or bronchopulmonary dysplasia. (42) Short-term studies indicate that iron does not induce oxidative stress, as measured by isoprostanes and antioxidant status, when provided to stable, growing low-birthweight infants at doses ranging from 2 to 12 mg/kg per day or at a twice-daily dose of 9 mg per day. (43)(44) Risks associated with repeated blood transfusions have primarily been studied in patients who have thalassemia major. Treatment for this autosomal recessive disorder includes frequent transfusion, which is associated with increased accumulation of hepatic iron, cardiac complications, increased incidence and severity of infections, altered immune function, and endocrinopathies (eg, diabetes, hypothyroidism). (39) These term infants differ from preterm infants requiring multiple transfusions because the requirement for transfusions in preterm infants is largely due to phlebotomy losses. (45) The risk or benet of restrictive versus liberal transfusion guidelines is still not known. (46)(47) An increased risk of

Iron Deciency in Preterm Infants

Preterm infants are at increased risk for long-term consequences of iron deciency because they are born before the bulk of placental iron transfer. The human brain triples in weight as it develops between 24 and 44 weeks postconception. Areas of signicant development include the visual and auditory cortexes, capability for receptive language and executive function, and the neuronal basis for learning. Because neuronal development requires iron, these processes are vulnerable to iron deciency in the preterm infant. (2) Tsunenobu and associates (35) examined the correlation between umbilical cord ferritin values and performance on mental and psychomotor tests at 5 years of age. Children whose serum ferritin concentrations were in the lowest quartile at birth performed the worst. In the sample, 13% of the children (n278) were born preterm and 22% were small for gestational age. The percentage of low birthweight was highest in the lowest quartile of serum ferritin values. This study highlights the possibility that inadequate iron accretion during gestation may have long-term developmental effects. Steinmacher and colleagues (36) evaluated the neurodevelopment of a cohort of 5-year-old children who weighed less than 1,301 g at birth and had been randomized to early (as soon as enteral feedings reached 100 mL/kg per day) or late (61 days of age) iron supplementation. The follow-up study showed a trend
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apnea and severe brain hemorrhage or periventricular leukomalacia was reported in one single-center trial, (47) but this risk was not corroborated in a larger multicenter, randomized, controlled trial. (46) The long-term neurodevelopment measured 18 to 21 months after transfusion with restrictive or liberal guidelines showed no difference. (48)

Assessment of Iron Status

Assessing Iron Status in Adults
Traditional measures of iron status include hematocrit and hemoglobin, red cell indices, serum ferritin, serum iron, and TIBC. Each test identies iron availability at a different point in iron metabolism. The clinicians choice of test(s) for iron status is driven by the question being asked, coexisting factors that may affect the laboratory test, and the sensitivity and specicity of the test. Hemoglobin and hematocrit are the least sensitive measures of iron deciency. (49) Iron deciency anemia is microcytic and hypochromic. Low mean cell volume (MCV) is consistent with iron deciency but may also reect dysfunction of hemoglobin synthesis. (50) Serum ferritin reects iron stores. Low serum ferritin is specic for iron deciency. (51) However, ferritin is an acutephase protein and may increase during infection, masking low stores. Serum iron concentration identies advanced iron deciency but has low sensitivity. It is affected by iron intake and time of day, (49) is elevated in erythropoietic dysfunction, and decreased during infection or inammation. (50) The TIBC primarily reects the amount of available unbound transferrin and is elevated in iron deciency. Historically, TIBC was standard for measuring iron status, but it has been largely replaced by serum ferritin. Synthesis of the soluble transferrin receptor (sTfR) is increased when intracellular iron is insufcient. Increased sTfR is observed in iron deciency or when erythropoiesis elevates cellular iron needs. This test is specic for iron deciency in patients who are suspected to have nutritional iron deciency or anemia of chronic disease, but it is affected by hematologic disorders. (49)

higher than the other tests. This indicates that serum ferritin and MCV may be better screening tests for iron deciency than hemoglobin assessment. (52) Serum ferritin may be affected by length of gestation, sex, maternal iron status, maternal-fetal nutrient exchange, (51) hypoxemia, reduced placental perfusion in utero, (53) and inammation. (49) The effect of inammation is especially important in preterm infants, who have reduced iron stores and are at increased risk for infection. sTfR exhibits developmental changes in the rst 2 postnatal years, but sTfR and the ratio of sTfR to serum ferritin may be better markers than ferritin alone for detection of iron deciency. (54) Hemoglobin concentrations change during gestation and the rst few postnatal months. Hemoglobin rises from 11 to 12 g/dL (110 to 120 g/L) at 22 to 24 weeks to 13 to 14 g/dL (130 to 140 g/L) at term. As erythropoiesis slows after birth (due to reduced erythropoietin [Epo] production in response to increased oxygenation), the hemoglobin concentration drops, then rises again by 6 months as erythropoiesis increases again. The drop in hemoglobin concentration after birth is greater in preterm than term infants. By 4 to 8 weeks after birth, the average hemoglobin concentration of a preterm infant (1,500 g birthweight) is 8 g/dL (80 g/L).

Difculties in Assessing Infant Iron Status and Anemia of Prematurity

The gestational-appropriate development and hematopoietic changes that take place after birth include changes in hemoglobin concentration and red cell size. Iatrogenic changes also occur in preterm infants. The anemia of prematurity is a hypoproliferative, normochromic, normocytic anemia characterized by reduced production of Epo. (55) The decrease in Epo production is caused by the transition from a hypoxic intrauterine environment to the relatively hyperoxic extrauterine environment. In addition, fetal Epo is produced by the liver, which is relatively insensitive to hypoxia, whereas by term gestation, Epo is primarily produced by the kidney, which is more responsive to hypoxia. Additional contributors to anemia in the preterm infant include phlebotomy losses, the shortened red blood cell life span, iron deciency, and inammation. (45) At what point this anemia becomes pathologic and the appropriate clinical response to such a development is an area of ongoing research. Approximately 85% of extremely low-birthweight infants are transfused with adult red blood cells, further complicating the ability to assess iron status because circulating blood reects both the babys and the transfused adult cells.
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Assessing Iron Status in Infants

The tests used to assess iron status are affected by hematologic changes after birth. Thus, standard reference ranges must be interpreted with caution when evaluating the iron status of preterm and even term infants in the rst 6 months after birth. In a group of term 9- to 12-month-old infants who had iron deciency dened by sTfR greater than 2.45 mg/L, the sensitivity of hemoglobin (67%) was lower than that of serum ferritin (83%) and MCV (86%), while the specicity of hemoglobin was

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New Possibilities for Assessment of Iron Status of Infants

One candidate test for detection of iron-decient erythropoiesis is the zinc protoporphyrin-to-heme ratio (ZnPP/H). ZnPP/H measures the amount of zinc relative to iron incorporated into the protoporphyrin ring during heme synthesis. Figure 3 depicts the balance between the ZnPP molecule and heme. Because the body prioritizes iron for hematopoiesis, ZnPP/H is a sensitive indicator of iron deciency. The only known cause of increased formation of zinc protoporphyrin is increased iron-decient erythropoiesis. As a result, this test is specic for iron-decient erythropoiesis (not necessarily iron deciency) of any cause. (49) A density gradient can be used to separate denser, mature erythrocytes from their lighter, immature counterparts. Measuring the ZnPP/H on this top fraction may further increase the sensitivity of this test to identify conditions associated with impaired erythrocyte iron delivery. (56) The sensitivity and specicity of ZnPP/H in preterm and term infants, especially in special conditions such as nutritional inadequacy or zinc deciency, have not been clearly determined. A normal range for ZnPP/H of preterm infants has been proposed, (57) but the sample size was small.

tively affect the iron status of the preterm infant. Type of feeding (formula, human milk, soy-based formula, or use of fortier) also affects iron delivery. The intestinal epithelium develops rapidly after birth, stimulated by growth factors in amniotic uid, colostrum, and human milk. (58) Similarly, other tissues in the preterm infant are not fully developed. Although these do not have direct inuence on iron absorption, they may affect iron utilization in the preterm infant.

Iron Supplementation: Enteral

The optimal timing and dosage of iron supplementation for the preterm infant has been extensively studied. The American Academy of Pediatrics recently issued new iron recommendations, indicating that breastfed, iron-sufcient term infants typically have iron stores at birth that last until 4 months of age, when either ironcontaining complementary foods or an iron supplement should be introduced. (34) Preterm infants are born with less total iron stores and have signicant iatrogenic blood loss, necessitating earlier supplementation. Low-birthweight infants who begin iron supplementation (2 mg/kg per day) at 2 weeks of age have better iron status at 3 to 6 months of age than infants who only receive iron before 6 months if they develop iron deciency. (59) Two studies (60)(61) have tested whether early iron supplementation in very low-birthweight infants (early iron started at 14 days of age or when the infant was tolerating 100 mL/kg per day enteral feedings; late iron started at 61 days of age) improved serum ferritin at 2 months. Neither study showed a difference in serum ferritin at 2 months of age, but blood transfusions and iron deciency were reduced in one study. (60) The second study (61) was underpowered. (62) Arnon and associates (37) reported improved iron status of preterm infants at 4 and 8 weeks when iron supplementation began at 2 weeks rather than 4 weeks of age. No negative effects of early supplementation were reported. These studies indicate that early supplementation may be neutral at worst and helpful at best. Human milk is the best choice for term infants, but human milk alone does not provide adequate nutrients for the growing preterm infant. Iron absorption is affected by protein composition. Iron absorption from human milk, whey- or casein-based cow milk formulas, and soy formulas has been compared. Iron is best absorbed from human milk and is more readily available from whey-based than casein-based formula. (63)(64) Estimated availability of iron from soy-based formulas varies. The whey-to-casein ratio, (64) type of iron compound, (65) and amounts of ascorbic acid and phytates

Prevention and Treatment of Iron Deciency in the Preterm Infant

Preterm birth increases the risk for iron deciency. Cellular immaturities and reduced iron delivery may nega-

Figure 3. Zinc replaces iron in the center of protoporphyrin IX when iron is in low supply.
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(66) all affect availability. Although iron may be less readily available from soy-based formulas, it is similar to cow milk formulas in preventing iron deciency in infancy. However, soy-based infant formulas are not recommended for use in preterm infants (unless other formulas are contraindicated). Although iron is best absorbed from human milk, because the iron content of human milk is low, the total amount of iron an infant absorbs may be higher from formulas. The ideal amount of iron to provide in ironfortied formulas is still an area of investigation; most preterm formulas in the United States contain 1.8 mg/ 100 kcal. The estimated oral iron requirement for preterm infants is 2 to 4 mg/kg per day, which may be less in an infant receiving red blood cell transfusions. The American Academy of Pediatrics recommends that infants not receiving human milk receive an iron-fortied formula and that preterm infants receive at least 2 mg/kg per day of elemental iron from 1 to 12 months of age. (34)

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molecular control of mammalian iron metabolism. Cell. 2004;117: 285297 2. Georgieff MK. Nutrition and the developing brain: nutrient priorities and measurement. Am J Clin Nutr. 2007;85:614S 620S 3. Lozoff B, Beard J, Connor J, Felt B, Georgieff M, Schallert T. Long-lasting neural and behavioral effects of iron deciency in infancy. Nutr Rev. 2006;64:S34 S43 4. Lozoff B, Georgieff M. Iron deciency and brain development. Semin Pediatr Neurol. 2006;13:158 165 5. Andrews NC, Schmidt PJ. Iron homeostasis. Annu Rev Physiol. 2007;69:69 85 6. McArdle HJ, Andersen HS, Jones H, Gambling L. Copper and iron transport across the placenta: regulation and interactions. J Neuroendocrinol. 2008;20:427 431 7. Shah YM, Matsubara T, Ito S, Yim SH, Gonzalez FJ. Intestinal hypoxia-inducible transcription factors are essential for iron absorption following iron deciency. Cell Metab. 2009;9:152164 8. Conrad ME, Umbreit JN. Pathways of iron absorption. Blood Cell Mol Dis. 2002;29:336 355 9. Koening C, Miller J, Nelson J, et al. Toll-like receptors mediate induction of hepcidin in mice infected with Borrelia burgdorferi. Blood. 2009;114:19131918 10. Vanoaica L, Darshan D, Richman L, Schumann K, Kuhn LC. Intestinal ferritin H is required for an accurate control of iron absorption. Cell Metab. 2010;12:273282 11. Anderson GJ, Frazer DM. Hepatic iron metabolism. Semin Liver Dis. 2005;25:420 432 12. Domellof M, Lonnerdal B, Abrams SA, Hernell O. Iron absorption in breast-fed infants: effects of age, iron status, iron supplements, and complementary foods. Am J Clin Nutr. 2002;76: 198 204 13. Gambling L, Danzeisen R, Gair S, et al. Effect of iron deciency on placental transfer of iron and expression of iron transport proteins in vivo and in vitro. Biochem J. 2001;356:883 889 14. Yu GSM, Steinkirchner TM, Rao GA, Larkin EC. Effect of prenatal iron deciency on myelination in rat pups. Am J Pathol. 1986;125:620 624 15. Jorgenson LA, Wobken JD, Georgieff MK. Perinatal iron deciency alters apical dendritic growth in hippocampal CA1 pyramidal neurons. Dev Neurosci. 2003;25:412 420 16. Ortiz E, Pasquini JM, Thompson K, et al. Effect of manipulation of iron storage, transport, or availability on myelin composition and brain iron content in three different animal models. J Neurosci Res. 2004;77:681 689 17. Kwik-Uribe CL, Gietzen D, German JB, Golub MS, Keen CL. Chronic marginal iron intakes during early development in mice result in persistent changes in dopamine metabolism and myelin composition. J Nutr. 2000;130:28212830 18. de Deungria M, Rao R, Wobken JD, Luciana M, Nelson CA, Georgieff MK. Perinatal iron deciency decreases cytochrome c oxidase (CytOx) activity in selected regions of neonatal rat brain. Pediatr Res. 2000;48:169 176 19. Beard JL, Wiesinger JA, Connor JR. Pre- and postweaning iron deciency alters myelination in Sprague-Dawley rats. Dev Neurosci. 2003;25:308 315 20. Yehuda S, Youdim ME, Mostofsky DI. Brain iron-deciency causes reduced learning capacity in rats. Pharmacol Biochem Behav. 1986;25:141144
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Iron Supplementation: Parenteral

Parenteral iron has been considered as an option for patients who are unable to absorb adequate iron enterally. It has been used effectively to improve iron status and promote erythropoiesis in preterm infants. However, parenteral iron is not as safe as enteral iron. Risks include neonatal sepsis, (67) iron overload, (68) and anaphylaxis. (69) Consensus on the best iron solution, dosage, and route of administration has not been reached. Dosage, timing, route of administration, and use with Epo has varied in studies of preterm infants. (70)(71) In utero iron accretion is estimated at 1.6 to 2.0 mg/kg per day during the third trimester. (72) It has been suggested that a parenteral iron dose of 1 mg/kg per day may meet iron needs; (71) this dose has been successfully used in preterm infants also receiving recombinant Epo.

American Board of Pediatrics Neonatal-Perinatal Medicine Content Specications

Understand the mechanism and gestational timing of placental transfer of iron to the fetus and its effect on iron stores in newborn infants. Recognize the causes of iron deciency anemia and various prevention measures. Recognize the clinical and diagnostic features, laboratory ndings, management, and long-term consequences of iron deciency anemia.

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21. Felt B, Beard J, Schallert T, et al. Persistent neurochemical and

behavioral abnormalities in adulthood despite early iron supplementation for perinatal iron deciency anemia in rats. Behav Brain Res. 2006;171:261270 22. Beard JL, Erikson KM, Jones BC. Neurobehavioral analysis of developmental iron deciency in rats. Behav Brain Res. 2002;134: 517524 23. Hokama T, Takenaka S, Hirayama K, et al. Iron status of newborns born to iron decient anaemic mothers. J Trop Pediatr. 1996;42:7577 24. Georgieff MK, Wewerka SW, Nelson CA, deRegnier RA. Iron status at 9 months of infants with low iron stores at birth. J Pediatr. 2002;141:405 409 25. Lozoff B, Clark K, Jing Y, Armony-Sivan R, Angelilli M, Jacobson S. Dose-response relationships between iron deciency with or without anemia and infant social-emotional behavior. J Pediatr. 2008;152:696 702 26. Roncagliolo M, Garrido M, Walter T, Peirano P, Lozoff B. Evidence of altered central nervous system development in infants with iron deciency anemia at 6 mo: delayed maturation of auditory brainstem responses. Am J Clin Nutr. 1998;68:683 690 27. Carter RC, Jacobson JL, Burden MJ, et al. Iron deciency anemia and cognitive function in infancy. Pediatrics. 2010;126: e427 e434 28. Peirano PD, Algarin CR, Garrido MI, Lozoff B. Iron deciency anemia in infancy is associated with altered temporal organization of sleep states in childhood. Pediatr Res. 2007;62:715719 29. Palti H, Meijer A, Adler B. Learning achievement and behavior at school of anemic and non-anemic infants. Early Hum Dev. 1985;10:217223 30. Corapci F, Calatroni A, Kaciroti N, Jimenez E, Lozoff B. Longitudinal evaluation of externalizing and internalizing behavior problems following iron deciency in infancy. J Pediatr Psychol. 2010;35:296 305 31. Lukowski AF, Koss M, Burden MJ, et al. Iron deciency in infancy and neurocognitive functioning at 19 years: evidence of long-term decits in executive function and recognition memory. Nutr Neurosci. 2010;13:54 70 32. Friel JK, Aziz K, Andrews WL, Harding SV, Courage ML, Adams RJ. A double-masked, randomized control trial of iron supplementation in early infancy in healthy term breast-fed infants. J Pediatr. 2003;143:582586 33. Gera T, Sachdev HP. Effect of iron supplementation on incidence of infectious illness in children: systematic review. BMJ. 2002;325:1142 34. Baker RD, Greer FR. Clinical report diagnosis and prevention of iron deciency and iron-deciency anemia in infants and young children (0 3 years of age). Pediatrics. 2010;126:1040 1050 35. Tsunenobu T, Goldenberg RL, Hou J, et al. Cord serum ferritin concentrations and mental and psychomotor development of children at ve years of age. J Pediatr. 2002;140:165170 36. Steinmacher J, Pohlandt F, Bode H, Sander S, Kron M, Franz AR. Randomized trial of early versus late enteral iron supplementation in infants with a birth weight of less than 1301 grams: neurocognitive development at 5.3 years corrected age. Pediatrics. 2007; 120:538 546 37. Arnon S, Regev RH, Bauer S, et al. Vitamin E levels during early iron supplementation in preterm infants. Am J Perinatol. 2009;26:387392 38. Gahagan S, Yu S, Kaciroti N, Castillo M, Lozoff B. Linear and ponderal growth trajectories in well-nourished, iron-sufcient ine156 NeoReviews Vol.12 No.3 March 2011

fants are unimpaired by iron supplementation. J Nutr. 2009;139: 2106 2112 39. Ozment CP, Turi JL. Iron overload following red blood cell transfusion and its impact on disease severity. Biochim Biophys Acta. 2009;1790:694 701 40. Collard K. Iron homeostasis in the neonate. Pediatrics. 2009; 123:1208 1216 41. Inder TE, Clemett RS, Austin NC, Graham P, Darlow BA. High iron status in very low birth weight infants is associated with an increased risk of retinopathy of prematurity. J Pediatr. 1997; 131:541544 42. Silvers KM, Gibson AT, Russell JM, Powers HJ. Antioxidant activity, packed cell transfusions, and outcome in premature infants. Arch Dis Child Fetal Neonatal Ed. 1998;78:F214 F219 43. Braekke K, Bechensteen AG, Halvorsen BL, Blomhoff R, Haaland K, Staff AC. Oxidative stress markers and antioxidant status after oral iron supplementation to very low birth weight infants. J Pediatr. 2007;151:2328 44. Miller SM, McPherson RJ, Juul SE. Iron sulfate supplementation decreases zinc protoporphyrin to heme ratio in premature infants. J Pediatr. 2006;148:44 48 45. Widness JA. Pathophysiology of anemia during the neonatal period, including anemia of prematurity. NeoReviews. 2008;9:e520 46. Kirpalani H, Whyte RK, Andersen C, et al. The Premature Infants in Need of Transfusion (PINT) study: a randomized, controlled trial of a restrictive (low) versus liberal (high) transfusion threshold for extremely low birth weight infants. J Pediatr. 2006; 149:301307 47. Bell EF, Strauss RG, Widness JA, et al. Randomized trial of liberal versus restrictive guidelines for red blood cell transfusion in preterm infants. Pediatrics. 2005;115:16851691 48. Whyte RK, Kirpalani H, Asztalos EV, et al. Neurodevelopmental outcome of extremely low birth weight infants randomly assigned to restrictive or liberal hemoglobin thresholds for blood transfusion. Pediatrics. 2009;123:207213 49. Labbe RF, Dewanji A. Iron assessment tests: transferrin receptor vis-a-vis zinc protoporphyrin. Clin Biochem. 2004;37:165174 50. Worwood M. The laboratory assessment of iron statusan update. Clin Chim Acta Int J Clin Chem. 1997;259:323 51. Siddappa AM, Rao R, Long JD, Widness JA, Georgieff MK. The assessment of newborn iron stores at birth: a review of the literature and standards for ferritin concentrations. Neonatology. 2007;92:73 82 52. Vendt N, Talvik T, Kool P, et al. Reference and cut-off values for serum ferritin, mean cell volume, and hemoglobin to diagnose iron deciency in infants aged 9 to 12 months. Medicina (Kaunas). 2007;43:698 702 53. Chockalingam UM, Murphy E, Ophoven JC, Weisdorf SA, Georgieff MK. Cord transferrin and ferritin values in newborn infants at risk for prenatal uteroplacental insufciency and chronic hypoxia. J Pediatr. 1987;111:283286 54. Olivares M, Walter T, Cook JD, Hertrampf E, Pizarro F. Usefulness of serum transferrin receptor and serum ferritin in diagnosis of iron deciency in infancy. Am J Clin Nutr. 2000;72: 11911195 55. Bishara N, Ohls RK. Current controversies in the management of the anemia of prematurity. Semin Perinatol. 2009;33:29 34 56. Blohowiak SE, Chen ME, Repyak KS, et al. Reticulocyte enrichment of zinc protoporphyrin/heme discriminates impaired iron supply during early development. Pediatr Res. 2008;64:63 67

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57. Juul SE, Zerzan JC, Strandjord TP, Woodrum DE. Zinc
protoporphyrin/heme as an indicator of iron status in NICU patients. J Pediatr. 2003;142:273278 58. Buccigrossi V, De Marco G, Bruzzese E, et al. Lactoferrin induces concentration-dependent functional modulation of intestinal proliferation and differentiation. Pediatr Res. 2007;61:410 414 59. Lundstrom U, Siimes MA, Dallman PR. At what age does iron supplementation become necessary in low-birth-weight infants? J Pediatr. 1977;91:878 883 60. Franz AR, Mihatsch WA, Sander S, Kron M, Pohlandt F. Prospective randomized trial of early versus late enteral iron supplementation in infants with a birth weight of less than 1301 grams. Pediatrics. 2000;106:700 706 61. Sankar MJ, Saxena R, Mani K, Agarwal R, Deorani AK, Paul VK. Early iron supplementation in very low birth weight infantsa randomized controlled trial. Acta Paediatr. 2009;98:953958 62. Bharti B, Bharti S. Early iron supplementation for very low birth weight preterm newborns: statistical vs. clinical signicance!! Acta Paediatr. 2009;98:1704 1705 63. Bosscher D, Van Caillie-Bertrand M, Robberecht H, Van Dyck K, Van Cauwenbergh R, Deelstra H. In vitro availability of calcium, iron, and zinc from rst-age infant formulae and human milk. J Pediatr Gastroenterol Nutr. 2001;32:54 58 64. Drago SR, Valencia ME. Inuence of components of infant

formulas on in vitro iron, zinc, and calcium availability. J Agricul Food Chem. 2004;52:32023207 65. Hendricks GM, Guo MR, Kindstedt PS. Solubility and relative absorption of copper, iron, and zinc in two milk-based liquid infant formulae. Int J Food Sci Nutr. 2001;52:419 428 66. Davidsson L, Galan P, Kastenmayer P, et al. Iron bioavailability studied in infants: the inuence of phytic acid and ascorbic acid in infant formulas based on soy isolate. Pediatr Res. 1994;36:816 822 67. Barry DMJ, Reeve AW. Increased incidence of gram-negative neonatal sepsis with intramuscular iron administration. Pediatrics. 1977;60:908 912 68. Ben Hariz M, Goulet O, De Potter S, et al. Iron overload in children receiving prolonged parenteral nutrition. J Pediatr. 1993; 123:238 241 69. Hamstra RD, Block MH, Schocket AL. Intravenous iron dextran in clinical medicine. JAMA. 1980;243:1726 1731 70. Pollak A, Hayde M, Hayn M, et al. Effect of intravenous iron supplementation on erythropoiesis in erythropoietin-treated premature infants. Pediatrics. 2001;107:78 85 71. Friel JK, Andrews WL, Hall MS, et al. Intravenous iron administration to very-low-birth-weight newborns receiving total and partial parenteral nutrition. JPEN J Parenter Enteral Nutr. 1995; 19:114 118 72. Shaw JCL. Parenteral nutrition in the management of sick low birthweight infants. Pediatr Clin North Am. 1973;20:333358

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NeoReviews Quiz
11. The uptake of iron by the enterocyte is an important regulatory step in body iron homeostasis. Of the following, the absorption of heme iron in the enterocyte is primarily regulated by: A. B. C. D. E. Beta-3 integrin. Divalent metal transporter-1. Duodenal cytochrome B. Heme carrier protein 1. Paraferritin.

12. The release of iron from the enterocyte into the bloodstream is a tightly regulated process, inuenced by the iron status of the body. Of the following, the release of iron from the enterocyte into the bloodstream is primarily regulated by: A. B. C. D. E. Ferroportin. Hephaestin. Mobilferrin. Paraferritin. Transferrin.

13. Preterm infants are at increased risk for long-term neurodevelopmental consequences of iron deciency because they are deprived of placental iron transfer from shortened gestation. Conversely, preterm infants are also at increased risk for potential oxidative complications of iron excess from repeated blood transfusions. Assessment of iron status, therefore, is important in the nutritional management of preterm infants. Of the following, the most specic blood test of iron status in preterm infants is the measurement of: A. B. C. D. E. Erythropoietin. Ferritin. Hemoglobin. Soluble transferrin receptor. Total iron-binding capacity.

14. In iron deciency, another trace element is incorporated into the protoporphyrin ring of the heme molecule. This observation has led to the development of a new test that can be used as a sensitive marker of iron-decient erythropoiesis. Of the following, the candidate trace element used as a measure of iron-decient erythropoiesis is: A. B. C. D. E. Chromium. Copper. Manganese. Selenium. Zinc.

15. The optimal timing and dosage of iron supplementation for preterm infants has been studied extensively. Of the following, the best suggested postnatal age for starting iron supplementation (2.0 mg/kg per day) in preterm infants is at: A. B. C. D. E. Birth. 2 weeks. 4 weeks. 2 months. 4 months.

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Iron Balance in the Neonate Carissa Cheng and Sandra Juul Neoreviews 2011;12;e148 DOI: 10.1542/neo.12-3-e148

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including high resolution figures, can be found at: http://neoreviews.aappublications.org/content/12/3/e148 This article cites 72 articles, 22 of which you can access for free at: http://neoreviews.aappublications.org/content/12/3/e148#BIBL This article, along with others on similar topics, appears in the following collection(s): Fetus and Newborn Infant http://neoreviews.aappublications.org/cgi/collection/fetus_newb orn_infant Nutrition and Nutritional Disorders http://neoreviews.aappublications.org/cgi/collection/nutritional_ disorders Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: /site/misc/Permissions.xhtml Information about ordering reprints can be found online: /site/misc/reprints.xhtml

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