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Neonatal iron nutrition
Semin Neonatol 2001; 6: 425–435 doi:10.1053/siny.2001.0063, available online at http://www.idealibrary.com on
Neonatal iron nutrition Raghavendra Rao and Michael K. Georgieff
Division of Neonatology, Department of Pediatrics and Center for Neurobehavioral Development, University of Minnesota, Minneapolis, MN, USA
Key words: infant, newborn, infant, premature, iron/administration and dosage, iron/adverse effects, iron/deficiency, iron/toxicity
Preterm infants are prone to iron deficiency. Their total body iron content at birth is low and gets further depleted by clinical practices such as uncompensated phlebotomy losses and exogenous erythropoietin administration during the neonatal period. Early iron deficiency appears to adversely affect cognitive development in human infants. To maintain iron sufficiency and meet the iron demands of catch-up postnatal growth, iron supplementation is prudent in preterm infants. A dose of 2–4 mg/kg/day is recommended for preterm infants who are fed exclusively human milk. A dose of 6 mg/kg/day or more is needed with the use of exogenous erythropoietin or to correct preexisting iron deficiency. However, due to the poor antioxidant capabilities of preterm infants and the potential role of iron in several oxidant-related perinatal disorders, indiscriminate iron supplementation should be avoided. 2002 Elsevier Science Ltd
Introduction Iron and iron-containing proteins are involved in a myriad of synthetic and metabolic functions that are essential for normal cellular functioning and survival [1]. Iron deficiency during development adversely affects the growth and functioning of multiple organ systems including erythrocytes, heart, skeletal muscle and the gastrointestinal tract [2–6]. Perhaps the most concerning effect of iron deficiency is on the developing brain. Neurophysiological studies suggest that early iron deficiency has an adverse effect on cognitive functioning in human infants [7,8] that appears to be long-lasting [9–11]. No studies have specifically evaluated the effect of early iron deficiency on cognitive development in preterm infants, but the adverse effects are likely to be more severe because of the relative immaturity and rapid growth rate of the preterm brain. On the other hand, iron supplementation in preterm infants has to be undertaken cautiously due to the potential role of free iron as an oxidant stressor [12,13] and the limited Correspondence to: Michael K. Georgieff, M.D., Mayo Mail Code 39, 420 Delaware Street SE, Minneapolis, MN, 55455, USA. Tel.: +1 612 626 0644; Fax: +1 612 624 8176; E-mail: [email protected]
1084–2756/01/$-see front matter
antioxidant capacity of the preterm infant [14]. Iron delivery to the preterm infant should be based on sound physiological knowledge to strike a balance between iron deficiency and toxicity in order to achieve iron homeostasis.
Determinants of newborn iron status Even though placental iron transport begins during the first trimester of gestation [15], it is only during the third trimester that significant accretion occurs [16,17]. The total body iron content of infants born anytime during the third trimester is approximately 75 mg/kg body weight [16]. Two-thirds of total body iron present in the term infant is accreted during the third trimester, with storage organ iron contents progressively increasing during this period [17]. Seventy-five to 80% of total body iron is found in the red cell mass as hemoglobin (Hgb), 10% in iron-containing proteins in non-heme tissues (e.g. myoglobin and cytochromes) and the remaining 10–15% in storage forms in reticuloendothelial and parenchymal tissues (e.g. ferritin and hemosiderin) [18,19]. Conditions that may © 2002 Elsevier Science Ltd
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Table 1. Conditions affecting neonatal iron status Conditions having a negative effect Severe maternal iron deficiency (maternal Hgb <65 g/l) Placental insufficiency due to maternal hypertension Maternal diabetes mellitus (gestational and pre-existing) Antenatal and intranatal hemorrhage Feto-maternal transfusion, twin-to-twin transfusion (donor twin) Placenta previa or abruption Umbilical cord accidents (velamentous insertion, occlusion or slipped ligature) Prematurity Early clamping of the umbilical cord Postnatal hemorrhage Phlebotomy losses Gastrointestinal tract hemorrhage (e.g., Meckel’s diverticulum, milk protein intolerance) Exchange transfusion Use of r-HuEPO without iron supplementation Conditions having a positive effect Twin-to-twin transfusion (recipient twin) Delaying or stripping of the umbilical cord before clamping Erythrocyte transfusions Early iron supplementation
have an effect on the iron status of the newborn infant are listed in Table 1. Multiple factors affect the total body iron status of preterm infants, making them prone to early postnatal iron deficiency.
Factors influencing postnatal iron status in preterm infants Total body and liver iron contents, Hgb and serum ferritin concentration are lower in the preterm infant than in the full-term infant [6,17,20–26]. Small-for-gestational-age preterm infants may have normal concentrations of serum iron and transferrin (Tf) in the cord blood [27] but have lower organ iron contents [28]. Postnatally, the Hgb concentration decreases by 30–50% due to a combination of cessation of erythropoiesis, expansion of the vascular volume and hemolysis of fetal erythrocytes [6]. The iron released (3.4 mg/g Hgb) during hemolysis is stored for future use and is reflected by a transient increase in serum ferritin concentration [25,29,30]. The Hgb level reaches a lower and earlier nadir during physiologic anemia in preterm infants [26,31–33]. Erythropoiesis commences between 1 and 2 months in preterm infants, 1 to 3 months earlier than in term infants. With the onset of
erythropoiesis, the serum ferritin levels decrease rapidly [26,31,34]. Extremely-low-birth-weight (ELBW) infants may be in negative iron balance during the first 30 postnatal days without iron supplementation [35,36]. Without an external source of iron, non-transfused preterm infants have sufficient iron stores to sustain effective erythropoiesis only until they have doubled their birthweight [26]. The high rate of postnatal catch-up growth with its attendant increase in blood volume and Hgb requires additional postnatal iron accretion. To achieve hematological indices of iron sufficiency and physical growth comparable to full-term infants, preterm infants may have to increase their body iron content by three- to six-fold during infancy [37,38]. Inadequately compensated phlebotomy losses, exchange transfusions [39] and administration of recombinant human erythropoietin (r-HuEPO) further deplete the meager iron stores in preterm infants. r-HuEPO is administered in an attempt to promote erythropoiesis [40,41]. By decreasing the need for erythrocyte transfusions, this practice negatively affects body iron status by depriving preterm infants of this exogenous source of iron. The mandatory prioritization of iron for erythropoiesis [42] depletes the body iron stores, particularly when simultaneous external iron supplementation is not provided [43]. Serum ferritin
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[40,44] and iron levels decrease [44] and erythrocytes become hypochromic [40] following rHuEPO administration, even with high-dose iron supplementation. The decrease in iron levels is not dependent on the r-HuEPO dose [45]. On the positive side of the iron ledger, preterm infants frequently receive erythrocyte transfusions [33]. Most transfusions are given during the first 3 to 4 weeks of age, either to replace phlebotomy losses or to maintain a certain hematocrit level. The iron delivered through this route augments body iron stores. Serum ferritin levels increase during the first month of life in preterm infants who have received >2 transfusions and are fourfold higher in those receiving d7 transfusions [46]. Thus, multiply transfused ELBW infants may maintain high iron stores without iron supplementation up to 6 months of age [46–48]. Preterm infants who receive more than 100 ml of packed red cells have higher ferritin levels for a longer period than those who receive smaller volumes or no transfusions [47]. Ferritin levels as high as 500 g/l have been recorded [12]. On the other hand, a conservative transfusion practice, as is currently being done [33,49,50], might adversely affect the iron stores if adequate iron supplementation is not provided to preterm infants. Preterm infants who receive no transfusions have lower serum ferritin levels at 6 months, when compared with non-transfused full-term infants of similar age [47]. In summary, postnatal factors can either exacerbate the tenuous iron status of the prematurely born infant or conversely place the infant at risk of iron overload. The iron status of the extremely premature infant at discharge can vary widely from iron deficient to iron overloaded.
Preventing iron deficiency in preterm infants Overview Between 3% and 30% of full-term infants develop iron deficiency during infancy, usually during the second half of the first year [51–53]. The incidence is higher in preterm infants and is reported to be between 26% and 86% [31,32,54–56]. A ferritin level <10 g/l is seen in as many as 65% of preterm infants between 3 and 6 months, with the smallest infants being at the greatest risk of developing early iron deficiency [31]. The incidence
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of iron deficiency (ferritin <10 g/l, Tf saturation <10%) and iron deficiency anemia (Hgb <110 g/l) is higher in preterm infants from developing countries [54] and infants who are exclusively breast-fed without iron supplementation [55]. The diagnosis of iron deficiency during infancy is complex and lacks uniform diagnostic criteria [38]. As in other age groups, anemia occurs after the storage and non-storage tissue iron pools have already been depleted [42,57,58]. Prediction of body iron stores from the serum ferritin concentration has significant shortcomings (Table 2). However, since low ferritin levels are not found in any other condition, it is probably still the best indicator of low iron stores [29,37,59], especially if serial estimations are performed [6]. Cord blood transferrin receptor (TfR) level also has been advocated as an indicator of fetal iron stores [60]. However, compared to adults, TfR levels in infants correlate better with erythropoiesis than functional iron deficiency [6,61]. One method of preventing postnatal iron deficiency in the preterm infant is to ensure that the infant begins life with a full endowment of iron. In developing countries, cord serum iron levels in preterm infants born to severely iron-deficient mothers are low and correlate with the serum iron levels of the mother [62]. In such populations, neonatal iron status could likely be enhanced by improved maternal iron supplementation during gestation. Similarly, delaying the clamping of the umbilical cord at birth to allow additional placental erythrocyte transfusion has been advocated to improve iron stores [63]. The major route of iron loss in preterm infants during the neonatal period is through phlebotomy for laboratory investigations. ELBW infants may lose 26–64% of their total blood volume via phlebotomy, the majority during the early neonatal period [64]. Because infants have higher hemoglobin concentrations at birth, phlebotomy in the neonatal period results in a greater loss of iron when compared with phlebotomy of a similar volume of blood at an older age. Since such losses are being more conservatively replaced due to more restrictive transfusion criteria [49,50], the risk of developing iron deficiency is higher. Minimizing phlebotomy losses would be beneficial in such situations. In addition to measures that minimize blood loss, iron supplementation is necessary to prevent iron deficiency in preterm infants [38]. The time of initiation and the amount and route of iron
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Table 2. Advantages and disadvantages of serum ferritin in the diagnosis of iron deficiency during infancy Advantages Low ferritin levels are not found in any other condition [59,107] Ferritin levels correlate with iron intake [29] and with serum iron concentration [24] Low levels are associated with low Tf saturation [29] Level at 2 months of age predicts future risk of iron deficiency [31] Disadvantages Cord ferritin levels do not predict future risk of iron deficiency [29] Levels vary widely in preterm infants, especially in conditions of latent iron deficiency (low Tf saturation without anemia) [59] The immediate increase in ferritin levels after the commencement of iron supplementation is not a true reflection of body iron stores [59] In preterm infants, hematological evidence of iron deficiency may appear before depletion of serum ferritin [31,68] There is no correlation between serum ferritin levels and liver iron content during infancy, probably because of sequestration and delayed release of hepatic iron for erythropoiesis [76] All isoforms of ferritin may not be detected by the conventional laboratory methods, and the actual levels might be higher than what is detected Being an acute phase reactant, ferritin also is increased in inflammatory conditions [59,108]
supplementation have yet to be conclusively determined. Preterm infants certainly require more iron, both in absolute amount and on a per kilogram bodyweight basis [37], than full-term infants because their iron stores are lower at birth and their total body iron content has to increase at a greater rate postnatally. The amount of iron found in breast milk or unsupplemented formula is not enough to support this large iron demand. The American Academy of Pediatrics recommends iron supplementation at a dose of 2–4 mg/kg/day, up to a maximum of 15 mg/day for preterm infants exclusively fed breast milk. Supplementation should begin at 2 months of age, or when the birth weight doubles, and continue throughout the first postnatal year [65]. Supplementation is not recommended for preterm infants receiving iron-fortified formula unless they are in negative iron balance prior to the commencement of iron supplementation or are receiving r-HuEPO. Those infants may need a dose as high as 6 mg/kg/day [36,65]. Some controversial issues associated with iron supplementation of preterm infants are discussed in the following subsections. Early vs late iron supplementation The optimal time for initiating iron supplementation has yet to determined. Preterm infants with birth weights between 1000 and 2000 g who
receive iron supplementation at a dose of 2 mg/kg/ day from 2 weeks of age tend to have less iron deficiency and need fewer erythrocyte transfusions during the first 2 to 3 months of age when compared with unsupplemented cohorts [31]. Even at this level, approximately 15% develop a ferritin level <10 g/l [31]. In a cohort of preterm infants with a birth weight of <1301 g, early iron supplementation at a dose of 2–4 mg/kg/day initiated at a mean age of 2 weeks reduced the incidence of iron deficiency and/or need for erythrocyte transfusions by 30% when compared with those in whom iron supplementation was initiated at a mean age of 2 months [21]. Infants who have not received erythrocyte transfusions beyond 2 weeks appear to benefit the most by early iron supplementation [21]. On the other hand, early iron administration does not prevent or ameliorate physiologic anemia [24]. Incorporation of supplemented iron is better when it is administered with the onset of erythropoiesis [66]. Even without supplementation, serum iron and Tf saturation peak at 3 weeks [32] and serum ferritin levels remain elevated during the first 4 to 6 weeks of life [29,30]. Finally, during the first month of life, enteral iron absorption appears to be poorly regulated and has the potential for resulting in high serum iron levels with higher doses of supplementation [35,36]. These studies would support delaying iron supplementation until 4 to 8 weeks. However, this practice in ELBW infants confers a significant risk of
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negative iron balance [35,36], the long-term effects of which are not known. In summary, early iron supplementation appears to be safe and effective in small preterm infants and is indicated in non-transfused very-low-birth-weight (VLBW) infants. Enteral vs parenteral iron supplementation The optimal method of iron supplementation has also been a subject of intense scrutiny. Parenteral iron supplementation, usually in the context of r-HuEPO therapy or as a part of parenteral nutrition, has been proven to be safe and effective [43,67–69]. Intravenous iron supplementation in a dose of 1 mg/kg/day simulates the intrauterine iron accretion rate and achieves positive iron balance in VLBW infants [67]. In ELBW infants, an infusion dose of 120 g/kg/day results in a positive retention of approximately 90 g/kg/day, with simultaneous elevation in serum ferritin and Tf saturation levels [70]. Depending upon bodyweight and past erythrocyte transfusion, approximately 18–68% of intravenously administered iron is incorporated into erythrocytes [66,71]. However, the low Tf levels and poor antioxidant defenses of preterm infants cautions against injudicious parenteral iron supplementation, especially during the early neonatal period [27]. Rapid infusions of iron are probably best avoided as they may result in transiently elevated serum iron levels that may overwhelm the total iron-binding capacity. Malondialdehyde levels are transiently elevated following parenteral iron infusion, indicating an oxidant stress, but the long-term significance of this finding is not clear [68]. Finally, because of its invasiveness, intravenous iron supplementation may be indicated only in those for whom enteral supplementation is not feasible. The preferred alternative to parenteral iron supplementation is dosing the element via the enteral route. With the exception of one report [72], enteral iron supplementation appears to be well-tolerated and does not appear to result in gastrointestinal distress in preterm infants [21,56,66,68,73]. The effectiveness of enteral iron supplementation depends on its absorption and retention [74]. Absorption rates of 0.3–74% have been reported, depending upon postnatal age of the preterm infant and mode of administration [26]. A value between
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Table 3. Factors affecting enteral iron absorption Factors enhancing absorption Postnatal age [74] Iron deficiency state [76] Administration between feeds [66] Administration with breast milk [73,74] Ascorbic acid or other organic acids in the diet [38] Factors suppressing absorption Recent erythrocyte transfusion [36] Administration with formula milk [66] Phytates and phenols in the diet [38] Factors probably not having an effect on absorption Gestational age, postconceptional age and body weight [26,73] r-HuEPO therapy [76]
30% and 40% is probably a more representative figure for absorption of enteral iron given between feeds [74–76]. Iron absorption in preterm infants fed iron-supplemented breast milk averages 34% [36]. Major factors that may affect enteral iron absorption are given in Table 3. Absorption and retention correlate with reticulocyte count [77]. Recent erythrocyte transfusions decrease enteral iron absorption [36], but do not completely abolish it [35]. Thus, as in older children and adults [78], low iron status appears to enhance enteral iron absorption in preterm infants. However, even preterm infants with reasonable total body iron sufficiency continue to absorb enterally administered iron, probably due to a perceived need for erythropoiesis and catch-up growth [76]. Interestingly, r-HuEPO treatment, while promoting erythropoiesis, does not enhance enteral iron absorption [76]. Rates of absorption correlate with the amount of iron administered during the first month of life [35,36], but beyond that period, the percent retained is inversely proportional to the amount supplemented [74]. The interaction of iron with other cations such as zinc, selenium, calcium and copper has been studied in detail. Zinc supplementation at a ratio of 4:1 with iron in the formula does not appear to affect iron absorption and erythrocyte incorporation [79]. Similarly, iron supplementation at 2 mg/kg/day does not appear to adversely affect either serum zinc levels [80] or absorption of selenium, a putative antioxidant [81]. The high calcium content of human milk fortifier does not appear to adversely affect enteral iron absorption [66]. There is indirect evidence that iron supplementation
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started at 4 weeks of age could result in altered copper metabolism, but its clinical relevance is unclear [82].
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Table 4. Iron concentration of breast milk and artificial formulas commonly used in the United States Product
Iron concentration (mg/l)
Iron delivery (mg/kg/d)1
0.472 12.2 14.6 3.56–14.47 13.3
0.07 1.8 2.2 0.53–2.28 2.0
The effect of r-HuEPO on iron status The robustness of the erythropoietic response in preterm infants receiving r-HuEPO depends on the amount of available iron. Iron supplementation not only enhances the response to r-HuEPO [43], but as shown in animal models [83,84], may also increase endogenous erythropoietin production. Administration of r-HuEPO without sufficient iron supplementation decreases serum ferritin levels as early as 14 days [69]. Such an effect is seen after 4 weeks of r-HuEPO therapy, even with iron supplementation in a dose of 3 mg/kg/day via the parenteral route [43]. The American Academy of Pediatrics recommends an oral supplementation of 6 mg/kg/day for preterm infants receiving r-HuEPO [65]. Even that amount may not be sufficient to maintain serum ferritin levels [85]. Simultaneous oral (9 mg/kg/day) and parenteral (2 mg/kg/day) iron supplementation appears to be advantageous in achieving iron sufficiency in preterm infants on r-HuEPO [68]. Pollak et al. postulated that oral supplementation meets the iron requirements of growth and phlebotomy losses, while parenteral supplementation subserves the iron needs of erythropoiesis [68]. In summary, it is difficult to meet the iron needs of r-HuEPOinduced erythropoiesis with either breast milk or iron-fortified formula without additional iron supplementation.
Iron supplementation of preterm infants fed breast milk The iron content of human milk is approximately 0.47 mg/l [86]. While some studies have reported higher iron concentrations in preterm colostrum and during the initial 4 to 8 weeks of lactation [87,88], this has not been substantiated by other studies [86,89,90]. Interestingly, the breast milk of women of low socioeconomic status in developing countries may have higher iron concentrations [87,90]. Unsupplemented breast milk will not support an intrauterine accretion rate of iron during the first month of life, even with 100% absorption [73,89]. The iron status of preterm infants fed
Breast milk Term formula with iron3 Preterm formula with iron4 Human milk fortifier5 Discharge formula9 1
Assuming an intake of 150 ml/kg/d. Represents both term and preterm human milk [86]. 3 Enfamil 20 with iron and Similac 20 with iron. 4 Enfamil Premature Formula 24 with iron and Similac Special Care with iron 24. 5 When added to 1 l of breast milk. 6 Similac Human Milk Fortifier and 7Enfamil Human Milk Fortifier. 8 Does not include iron content of the breast milk. 9 EnfaCare and Similac NeoSure (Enfamil and EnfaCare are registered trademarks of Mead Johnson Nutritionals, Evansville, IN, and Similac and NeoSure are registered trademarks of Ross Products Division, Abbott Laboratories, Inc, Columbus, OH, USA). 2
exclusively breast milk without iron supplementation starts to deteriorate by 1 to 4 months of age [35,36,55,91]. By 6 months, 86% have evidence of iron deficiency [55]. Breast milk iron concentration cannot be enhanced by maternal iron supplementation [86]. The American Academy of Pediatrics recommends that preterm infants fed exclusively breast milk be supplemented with 2–4 mg/kg/day of iron [65]. Supplementation at this level reduces the incidence of iron deficiency and iron-deficiency anemia during infancy [80]. The dose of ferrous sulfate is equally effective whether it is administered to the infant as medicinal drops or mixed with breast milk [73]. Human milk fortifiers that are currently available in the United States provide an additional 0.5–2.2 mg of iron/kg/day (Table 4). Iron fortification of preterm formula The majority of preterm infants in the USA are not fed exclusively breast milk beyond 3 months. The commonly used premature infant formulas in the USA are fortified with 14.6 mg/l of iron (Table 4). When consumed at 150 ml/kg/day, these formulas would deliver an iron intake of 2.2 mg/kg/day. A low-iron term formula containing 2–3 mg/l of iron would deliver only 0.3–0.45 mg/kg/day of iron. Preterm infants with birth weights <1800 g will
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not achieve iron sufficiency on a formula containing 3 mg/l or less [56]. An iron content of at least 5 mg/l appears to be essential to maintain iron sufficiency during the initial 6 months of life [58]. Nevertheless, approximately 14% of preterm infants receiving a formula with an iron content of 5–9 mg/l develop iron deficiency between 4 and 8 months [58]. Preterm infants with birth weights <1800 g who are infrequently transfused appear to benefit the most from a formula containing 15 mg/l of iron [56]. Preterm infants may tolerate a formula with as much as 21 mg/l of iron. However, such supplementation does not appear to confer any further hematologic or developmental advantage over formulas containing 12 mg/l [92].
The risk of iron overload in preterm infants Free iron is toxic to tissues through its role in oxidant-related injuries [14]. The progressive increase in serum iron-binding capacity during the third trimester of pregnancy [23,93] is probably an attempt to minimize the exposure of developing organ systems to free iron during this period of increased maternal-fetal iron delivery. Excessive iron supplementation in preterm infants creates the potential for oxidant injuries. The classic example is iron-induced hemolysis in vitamin E deficiency states [94]. The cord blood levels of iron-binding plasma proteins, ceruloplasmin and Tf are lower [27] and ascorbic acid levels higher in preterm infants [95]. This situation is conducive for iron to exist in the reduced ferrous state. Lower Tf levels and decreased iron-binding antioxidant capacity have been demonstrated in preterm infants with respiratory distress syndrome and chronic lung disease (CLD) [96] and periventricularintraventricular hemorrhage (PIVH) [13]. Elevated intraerythrocyte free iron concentrations are found under hypoxic conditions in preterm infants [97,98]. Cord blood samples containing low molecular weight iron have been demonstrated to degrade DNA in vitro [99]. A role for iron in the etiopathogenesis of neonatal oxidative diseases, such as retinopathy of prematurity (ROP), CLD, PIVH and necrotizing enterocolitis, has been postulated but has yet to be conclusively proved [12–14,46]. The exogenous sources of iron for the preterm infants are through erythrocyte transfusions and parenteral or enteral
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iron supplementation. It has been postulated that in the absence of adequate protective mechanisms, the ‘free’ iron leaked from damaged erythrocytes during transfusion may induce or potentiate oxidantrelated injuries [95]. There is an association between multiple erythrocyte transfusions and ROP [12,100] and CLD [46,95]. The incidence and severity of ROP correlates with serum ferritin levels [101]. Very high serum ferritin levels (500 g/l) have been observed in multiply transfused premature infants with ROP [12]. Elevated serum ferritin and ‘free’ iron have also been demonstrated in multiply transfused preterm infants developing CLD [46]. However, this elevated plasma free iron did not induce lipid peroxidation, as demonstrated by lipid hydroperoxide formation [102], or generation of thiobarbituric acid reacting substances [46] in these preterm infants. The confounding variable seems to be that sicker and more preterm infants are likely to receive multiple transfusions, which makes it difficult to assign transfusion-related iron toxicity as the sole etiology of these multifactorial disorders. Interestingly, conservative transfusion practices have not reduced the incidence of ROP or PIVH in ELBW infants [50]. Nevertheless, since multiply transfused preterm infants are likely to maintain iron sufficiency during the initial months of infancy [46–48], early iron supplementation is probably not necessary for them. Similarly, the relationship between parenteral or enteral iron supplementation and oxidant-related disorders is also not clear. Serum malondialdehyde levels transiently rise after intravenous iron administration but are not associated with evidence of permanent tissue lipid peroxidation in VLBW infants [68]. However, to ensure adequate iron binding by the plasma proteins, it is prudent to avoid rapid infusion rates or exceed a dose of 1–2 mg/kg/day. Finally, no studies have demonstrated oxidative injury following enteral iron supplementation. Preterm infants between 27 and 34 weeks gestation had no increase in iron overload and oxidative stress with a formula fortified with 8 mg/l of iron [103]. As mentioned above, enteral iron supplementation as high as 21 mg/l has not been associated with elevated malondialdehyde levels [92]. The gradual rate of enteral iron absorption likely allows effective Tf binding of iron in the circulation. Furthermore, high ferritin levels, as seen in multiply transfused preterm infants, are not seen in preterm infants receiving enteral
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iron supplementation [43,104]. Nevertheless, a threshold dose of iron likely exists beyond which the potential for adverse effects increases. This is especially true for ELBW infants during the initial 4 weeks of life, when their enteral iron absorption appears to be poorly regulated [35,36]. It is also important to simultaneously maintain adequate vitamin E [105] and ascorbic acid [102] levels in the serum to effectively prevent oxidant injuries.
Post discharge screening for iron deficiency in the preterm infant There is no single ideal age for screening for iron deficiency in preterm infants. Due to variations in clinical practice, the iron status of preterm infants differs widely at the time of discharge. Hence, it would probably be wise to assess hematological indices and serum ferritin at this time. As in other populations, the zinc protoporphyrin to heme [ZnPP/H] ratio at the time of discharge may be useful in diagnosing iron-deficient erythropoiesis and, accordingly, the need for additional iron [106]. A recheck of hematologic status at 6 months of age, rather than waiting until the more standard 9 months, is prudent for all preterm infants and should be combined with serum ferritin determination. Additional follow-up may be needed, depending upon the iron status at discharge, type of milk feeding and the adequacy of iron supplementation. Small preterm infants and infants who received unfortified human milk or a low-iron formula need closer evaluation. Infants whose phlebotomy losses were not adequately replaced by erythrocyte transfusions or who were given r-HuEPO as a substitute also need to be assessed for iron status at an earlier post-discharge date. Acknowledgements The authors gratefully acknowledge Ms Ginny Lyson for her editorial assistance in the preparation of the manuscript. Supported in part by a grant from the National Institutes of Health (NICHD-HD 29421).
References 1 Dallman PR. Biochemical basis for the manifestations of iron deficiency. Ann Rev Nutr 1986; 6: 13–40. 2 Mackler B, Grace R, Finch CA. Iron deficiency in the rat: effects on oxidative metabolism in distinct types of skeletal muscle. Pediatr Res 1984; 18: 499–500.
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3 Blayney L, Bailey-Wood R, Jacobs A, Henderson A, Muir J. The effects of iron deficiency on the respiratory function and cytochrome content or rat heart mitochondria. 1976; 39: 744–748. 4 Ercan O, Ulukutlu L, Ozbay G, Arda O. Intestinal effects of iron deficiency anemia in children. Turk J Pediatr 1991; 33: 85–98. 5 Berant M, Khourie M, Menzies IS. Effect of iron deficiency on small intestinal permeability in infants and young children. J Pediatr Gastroenterol Nutr 1992; 14: 17–20. 6 Aggett PJ. Trace elements of the micropremie. Clin Perinatol 2000; 27: 119–129. 7 deRegnier RA, Nelson CA, Thomas K, Wewerka S, Georgieff MK. Neurophysiologic evaluation of auditory recognition memory in healthy newborn infants and infants of diabetic mothers. J Pediatr 2000; 137: 777– 784. 8 Roncagliolo M, Garrido M, Walter T, Peirano P, Lozoff B. Evidence of altered central nervous system development in infants with iron deficiency anemia at 6 mo: delayed maturation of auditory brainstem responses. Am J Clin Nutr 1998; 68: 683–690. 9 Lozoff B. Perinatal iron deficiency and the developing brain. Pediatr Res 2000; 48: 137–139. 10 Lozoff B, Klein NK, Nelson EC, McClish DK, Manuel M, Chacon ME. Behavior of infants with iron-deficiency anemia. Child Dev 1998; 69: 24–36. 11 Walter T. Effect of iron-deficiency anaemia on cognitive skills in infancy and childhood. Bailliere’s Clin Haematol 1994; 7: 815–827. 12 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: 541–544. 13 Lackmann GM, Hesse L, Tollner U. Reduced ironassociated antioxidants in premature newborns suffering intracerebral hemorrhage. Free Radic Biol Med 1996; 20: 407–409. 14 Jansson LT. Iron, oxygen stress, and the preterm infant. In: Lonnerdal B (ed.) Iron Metabolism in Infants. Boca Raton, FL: CRC Press, 1990; 73–85. 15 Gulbis B, Jauniaux E, Decuyper J, Thiry P, Jurkovic D, Campbell S. Distribution of iron and iron-binding proteins in first-trimester human pregnancies. Obstet Gynecol 1994; 84: 2892–2893. 16 Widdowson EM, Spray CM. Chemical development in utero. Arch Dis Child 1951; 26: 205–214. 17 Singla PN, Gupta VK, Agarwal KN. Storage iron in human foetal organs. Acta Paediatr Scand 1985; 74: 701–706. 18 Josephs HW. Iron metabolism and the hypochromic anaemia of infancy. Medicine 1953; 32: 125–157. 19 Dallman PR, Siimes MA, Stekel A. Iron deficiency in infancy and childhood. Am J Clin Nutr 1980; 33: 86–118. 20 Ziegler EE, O’Donnell AM, Nelson SE, Fomon SJ. Body composition of the reference fetus. Growth 1976; 40: 329–341. 21 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.
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22 Abbas A, Snijders RJ, Sadullah S, Nicolaides KH. Fetal blood ferritin and cobalamin in normal pregnancy. Fetal Diagn Ther 1994; 9: 14–18. 23 Lackmann GM, Schnieder C, Bohner J. Gestational age-dependent reference values for iron and selected proteins of iron metabolism in serum of premature human neonates. Biol Neonate 1998; 74: 208–213. 24 Haga P. Plasma ferritin concentrations in preterm infants in cord blood and during the early anaemia of prematurity. Acta Paediatr Scand 1980; 69: 637–641. 25 Siimes AS, Siimes MA. Changes in the concentration of ferritin in the serum during fetal life in singletons and twins. Early Hum Dev 1986; 13: 47–52. 26 Ehrenkranz RA. Iron, folic acid, and vitamin B12. In: Tsang RC, Luca A, Uauy R, Zlotkin S (eds) Nutritional Needs of the Preterm Infant. Scientific Basis and Practical Guidelines. New York: Williams & Wilkins, 1993; 177– 194. 27 Scott PH, Berger HM, Kenward C, Scott P, Wharton BA. Effect of gestational age and intrauterine nutrition on plasma transferrin and iron in the newborn. Arch Dis Child 1975; 50: 796–798. 28 Georgieff MK, Mills, MM, Gordon K, Wobken JD. Reduced neonatal liver iron concentrations after uteroplacental insufficiency. J Pediatr 1995; 127: 308– 311. 29 Saarinen UM, Siimes MA. Serum ferritin in assessment of iron nutrition in healthy infants. Acta Paediatr Scand 1978; 67: 745–751. 30 Rios E, Lipschitz DA, Cook JD, Smith NJ. Relationship of maternal and infant iron stores as assessed by determination of plasma ferritin. Pediatrics 1975; 55: 694–699. 31 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. 32 Halliday HL, Lappin TR, McClure G. Iron status of the preterm infant during the first year of life. Biol Neonate 1984; 45: 228–235. 33 Strauss RG. Recombinant erythropoietin for the anemia of prematurity: Still a promise, not a panacea. J Pediatr 1997; 131: 653–655. 34 Messer RD, Russo AM, McWhirter WR, Sprangemeyer D, Halliday JW. Serum ferritin in term and preterm infants. Aust Paediatr J 1980; 16: 185–188. 35 Shaw JC. Iron absorption by the premature infant. The effect of transfusion and iron supplements on the serum ferritin levels. Acta Paediatr Scand (Suppl) 1982; 299: 83–89. 36 Dauncey MJ, Davies CG, Shaw JC, Urman J. The effect of iron supplements and blood transfusion on iron absorption by low birthweight infants fed pasteurized human breast milk. Pediatr Res 1978; 12: 899–904. 37 Siimes MA. Hematopoiesis and storage iron in infants. In: Lonnerdal B (ed.) Iron Metabolism in Infants. Boca Raton, FL: CRC Press, 1990; 33–62. 38 Wharton BA. Iron deficiency in children: detection and prevention. Br J Haematol 1999; 106: 270–280. 39 Siimes MA, Koerper MA, Licko V, Dallman PR. Ferritin turnover in plasma: an opportunistic use of blood
433
40
41
42
43
44
45
46 47
48
49
50
51 52 53
54
removed during exchange transfusion. Pediatr Res 1975; 9: 127–129. Meyer MP, Meyer JH, Commerford A, Hann FM, Sive AA, Moller G, et al. Recombinant human erythropoietin in the treatment of the anemia of prematurity: results of a double-blind, placebo-controlled study. Pediatrics 1994; 93: 918–923. Ohls RK, Osborne KA, Christensen RD. Efficacy and cost analysis of treating very low birth weight infants with erythropoietin during their first two weeks of life: a randomized, placebo-controlled trial. J Pediatr 1995; 126: 421–426. Guiang SF, III, Georgieff MK, Lambert DJ, Schmidt RL, Widness JA. Intravenous iron supplementation effect on tissue iron and hemoproteins in chronically phlebotomized lambs. Am J Physiol 1997; 273: R2124– 2131. Carnielli VP, Da Riol R, Montini G. Iron supplementation enhances response to high doses of recombinant human erythropoietin in preterm infants. Arch Dis Child 1998; 79: F44–48. Bader D, Blondheim O, Jonas R, Admoni O, AbendWinger M, Reich D, et al. Decreased ferritin levels, despite iron supplementation, during erythropoietin therapy in anaemia of prematurity. Acta Paediatr 1996; 85: 496–501. Chang L, Liu W, Liao C, Zhao X. Preventive effect of different dosage of recombinant human erythropoietin on anemia of premature infants. J Tongji Med Univ 1998; 18: 239–242. Cooke RW, Drury JA, Yoxall CW, James C. Blood transfusion and chronic lung disease in preterm infants. Eur J Pediatr 1997; 156: 47–50. Arad I, Konijn AM, Linder N, Goldstein M, Kaufmann NA. Serum ferritin levels in preterm infants after multiple blood transfusions. Am J Perinatol 1988; 5: 40–43. Ramasethu J, Gunter K, McClenny R, Luban N, Fletcher A. When is iron supplementation appropriate for extremely low birth weight infant? Pediatr Res 1997; 41: 239A. Widness JA, Seward VJ, Kromer IJ, Burmeister LF, Bell EF, Strauss RG. Changing patterns of red blood cell transfusion in very low birth weight infants. J Pediatr 1996; 129: 680–687. Maier RF, Sonntag J, Walka MM, Liu G, Metze BC, Obladen M. Changing practices of red blood cell transfusions in infants with birth weight less than 1000 g. J Pediatr 2000; 136: 220–224. Looker AC, Dallman PR, Carroll MD, Gunter EW, Johnson CL. Prevalence of iron deficiency in the United States. JAMA 1997; 277: 973–976. Kilbride J, Baker TG, Parapia LA, Khoury SA. Incidence of iron-deficiency anaemia in infants in a prospective study in Jordan. Eur J Haematol 2000; 64: 231–236. Raman L, Pawashe AB, Vasanthi G, Parvathi C, Vasumathi N, Rawal A. Plasma ferritin in the assessment of iron status of Indian infants. Indian Pediatr 1990; 27: 705–713. Borigato EV, Martinez FE. Iron nutritional status is improved in Brazilian preterm infants fed food cooked in iron pots. J Nutr 1998; 128: 855–859.
434
55 Iwai Y, Takanashi T, Nakao Y, Mikawa H. Iron status in low birth weight infants on breast and formula feeding. Eur J Pediatr 1986; 145: 63–65. 56 Hall RT, Wheeler RE, Benson J, Harris G, Rippetoe L. Feeding iron-fortified premature formula during initial hospitalization to infants less than 1800 grams birth weight. Pediatrics 1993; 92: 409–414. 57 Oski FA. Iron deficiency in infancy and childhood. N Engl J Med 1993; 329: 190–193. 58 Griffin IJ, Cooke RJ, Reid MM, McCormick KP, Smith JS. Iron nutritional status in preterm infants fed formulas fortified with iron. Arch Dis Child 1999; 81: F45–49. 59 Siimes MA, Addiego JE Jr, Dallman PR. Ferritin in serum: diagnosis of iron deficiency and iron overload in infants and children. Blood 1974; 43: 581–590. 60 Sweet DG, Savage G, Tubman TR, Lappin TR, Halliday HL. Study of maternal influences on fetal iron status at term using cord blood transferrin receptors. Arch Dis Child 2001; 84: F40–43. 61 Kling PJ, Roberts RA, Widness JA. Plasma transferrin receptor levels and indices of erythropoiesis and iron status in healthy term infants. J Pediatr Hematol Oncol 1998; 20: 309–314. 62 Singla PN, Chand S, Agarwal KN. Cord serum and placental tissue iron status in maternal hypoferremia. Am J Clin Nutr 1979; 32: 1462–1465. 63 Pisacane A. Neonatal prevention of iron deficiency. BMJ 1996; 312: 136–137. 64 Maier RF, Obladen M, Kattner E, Natzschka J, Messer J, Regazzoni BM, et al. High-versus low-dose erythropoietin in extremely low birth weight infants. J Pediatr 1998; 132: 866–870. 65 American Academy of Pediatrics, Committee on Nutrition. Nutritional needs of preterm infants. In: Kleinman RE (ed.) Pediatric Nutrition Handbook. Elk Grove Village, IL: American Academy of Pediatrics, 1998; 55–87. 66 McDonald MC, Abrams SA, Schanler RJ. Iron absorption and red blood cell incorporation in premature infants fed an iron-fortified infant formula. Pediatr Res 1998; 44: 507–511. 67 Friel J, Andrews W, Hall M, Rodway MS, Keith M, McCloy UC, et al. Intravenous iron administration to very-low-birth-weight newborns receiving total and partial parenteral nutrition. J Parenter Enteral Nutr 1995; 19: 114–118. 68 Pollak A, Hayde M, Hayn M, Herkner K, Lombard KA, Lubec G, et al. Effect of intravenous iron supplementation on erythropoiesis in erythropoietin treated premature infants. Pediatrics 2001; 107: 78–85. 69 Ohls RK, Harcum J, Schibler KR, Christensen RD. The effect of erythropoietin on the transfusion requirements of preterm infants weighing 750 grams or less: a randomized, double-blind, placebo-controlled study. J Pediatr 1997; 131: 661–665. 70 Friel JK, Penney S, Reid DW, Andrews WL. Zinc, copper, manganese, and iron balance of parenterally fed very low birth weight preterm infants receiving a trace element supplement. J Parenter Enteral Nutr 1988; 12: 382–386. 71 Zlotkin SH, Lay DM, Kjarsgaard J, Longley T. Determination of iron absorption using erythrocyte iron
R. Rao and M. K. Georgieff
72 73 74 75
76
77
78 79
80
81
82
83
84
85
86 87
incorporation of two stable isotopes of iron (57Fe and 58Fe) in very low birthweight premature infants. J Pediatr Gastroenterol Nutr 1995; 21: 190–199. Victorin LH, Olegard R. Iron in the preterm infant: a pilot study comparing Fe2+ and Fe3+ tolerance and effect. J Pediatr 1984; 105: 151–152. Moody GJ, Schanler RJ, Abrams SA. Utilization of supplemental iron by premature infants fed fortified human milk. Acta Pediatr 1999; 88: 763–767. Fomon SJ, Nelson SE, Ziegler EE. Retention of iron by infants. Annu Rev Nutr 2000; 20: 273–290. Ehrenkranz RA, Gettner PA, Nelli CM, Sherwonit EA, Williams JE, Pearson HA, et al. Iron absorption and incorporation into red blood cells by very low birth weight infants: studies with the stable isotope 58Fe. J Pediatr Gastroenterol Nutr 1992; 15: 270–278. Widness JA, Lombard KA, Ziegler EE, Serfass RE, Carlson SJ, Johnson KJ, et al. Erythrocyte incorporation and absorption of 58Fe in premature infants treated with erythropoietin. Pediatr Res 1997; 41: 416–423. Gorten MK, Hepner R, Workman JB. Iron metabolism in premature infants. I. Absorption and utilization of iron as measured by isotope studies. J Pediatr 1963; 63: 1063–1071. Andrews NC. Disorders of iron metabolism. N Engl J Med 1999; 341: 1986–1995. Friel JK, Serfass RE, Fennessey PV, Miller LV, Andrews WL, Simmons BS, et al. Elevated intakes of zinc in infant formulas do not interfere with iron absorption in premature infants. J Pediatr Gastroenterol Nutr 1998; 27: 312– 316. Salvioli GP, Faldella G, Alessandroni R, Lanari M, Benfenati L. Plasma zinc concentrations in iron supplemented low birthweight infants. Arch Dis Child 1986; 61: 346–348. Rudolph N, Preis O, Bitzos EI, Reale MM, Wong SL. Hematologic and selenium status of low-birth-weight infants fed formulas with and without iron. J Pediatr 1981; 99: 57–62. Barclay SM, Aggett PJ, Lloyd DJ, Duffty P. Reduced erythrocyte superoxide dismutase activity in low birth weight infants given iron supplements. Pediatr Res 1991; 29: 297–301. Bechensteen AG, Halvorsen S, Haga P, Cotes PM, Liestol K. Erythropoietin (Epo), protein and iron supplementation and the prevention of anaemia of prematurity: effects on serum immunoreactive Epo, growth and protein and iron metabolism. Acta Paediatr 1996; 85: 490–495. Peters C, Georgieff MK, de Alarcon PA, Cook RT, Burmeister LF, Lowe LS, et al. Effect of chronic erythropoietin administration on plasma iron in newborn lambs. Biol Neonate 1996; 70: 218–228. Meyer MP, Haworth C, Meyer JH, Commerford A. A comparison of oral and intravenous iron supplementation in preterm infants receiving recombinant erythropoietin. J Pediatr 1996; 129: 258–263. Dorea JG. Iron and copper in human milk. Nutrition 2000; 16: 209–220. Atinmo T, Omololu A. Trace element content of breastmilk from mothers of preterm infants in Nigeria. Early Hum Dev 1982; 6: 309–313.
Neonatal iron nutrition
88 Lemons JA, Moye L, Hall D, Simmons M. Differences in the composition of preterm and term human milk during early lactation. Pediatr Res 1982; 16: 113–117. 89 Mendelson RA, Anderson GH, Bryan MH. Zinc, copper and iron content of milk from mothers of preterm and full-term infants. Early Hum Dev 1982; 6: 145–151. 90 Trugo NM, Donangelo CM, Koury JC, Silva MI, Freitas LA. Concentration and distribution pattern of selected micronutrients in preterm and term milk from urban Brazilian mothers during early lactation. Eur J Clin Nutr 1988; 42: 497–507. 91 Tudehope DI, Mitchell F, Cowley DM. A comparative study of a premature infant formula and preterm breast milk for low birthweight infants. Aust Paediatr J 1986; 22: 199–205. 92 Andrews WL, Friel JK, Simmons B, Azziz K, Kwa PG, Downton G. Effect of two levels of iron supplementation of infant formulas on developmental outcome and iron nutrition in very low birth weight infants. Pediatr Res 1998; 42: 255A. 93 Chockalingham U, Murphy E, Ophoven JC, Georgieff MK. The influence of gestational age, size for dates, and prenatal steroids on cord transferrin levels in newborn infants. J Pediatr Gastroenterol Nutr 1987; 6: 276–280. 94 Williams ML, Shoot RJ, O’Neal PL, Oski FA. Role of dietary iron and fat on vitamin E deficiency anemia of infancy. N Engl J Med 1975; 292: 887–890. 95 Silvers KM, Gibson AT, Russell JM, Powers HJ. Antioxidant activity, packed cell transfusions, and outcome in premature infants. Arch Dis Child 1998; 78: F214–219. 96 Moison RM, Haasnoot AA, Van Zoeren-Grobben D, Berger HM. Plasma proteins in acute and chronic lung disease of the newborn. Free Radic Biol Med 1998; 25: 321–328. 97 Buonocore G, Zani S, Perrone S, Caciotti B, Bracci R. Intraerythrocyte nonprotein-bound iron and plasma malondialdehyde in the hypoxic newborn. Free Radic Biol Med 1998; 25: 766–770.
435
98 Buonocore G, Zani S, Sargentini I, Gioia D, Signorini C, Bracci R. Hypoxia-induced free iron release in the red cells of newborn infants. Acta Paediatr 1998; 87: 77–81. 99 Berger HM, Mumby S, Gutteridge JM. Ferrous ions detected in iron-overloaded cord blood plasma from preterm and term babies: implications for oxidative stress. Free Radic Res 1995; 22: 555–559. 100 Hesse L, Eberl W, Schlaud M, Poets CF. Blood transfusion. Iron load and retinopathy of prematurity. Eur J Pediatr 1997; 156: 465–470. 101 Romagnoli C, Zecca E, Gallini F, Girlando P, Zuppa AA. Do recombinant human erythropoietin and iron supplementation increase the risk of retinopathy of prematurity? Eur J Pediatr 2000; 159: 627–628. 102 Berger TM, Polidori MC, Dabbagh A, Evans PJ, Halliwell B, Morrow JD, et al. Antioxidant activity of vitamin C in iron-overloaded human plasma. J Biol Chem 1997; 272: 15656–15660. 103 van Zoeren Grobben D, Moison R, Haasnoot A, Berger H. Iron containing feeding formula and oxidative stress in preterm infants. Pediatr Res 1998; 43: 270A. 104 Shannon KM, Keith JF, 3rd, Mentzer WC, Ehrenkranz RA, Brown MS, Widness JA, et al. Recombinant human erythropoietin stimulates erythropoiesis and reduces erythrocyte transfusions in very low birth weight preterm infants. Pediatrics 1995; 95: 1–8. 105 Melhorn DK, Gross S. Vitamin E-dependent anemia in the premature infant. I. Effects of large doses of medicinal iron. J Pediatr 1971; 79: 569–580. 106 Winzerling JJ, Kling PJ. Iron deficient erythropoiesis in premature infants measured by blood zinc protoporphyrin/heme. J Pediatr 2001; 139: 134–136. 107 Harju E. Clinical pharmacokinetics of iron preparations. Clin Pharmacokinet 1989; 17: 69–89. 108 Witte DL. Can serum ferritin be effectively interpreted in the presence of the acute-phase response? Clin Chem 1991; 37: 484–485.
Neonatal iron nutrition Raghavendra Rao and Michael K. Georgieff
Division of Neonatology, Department of Pediatrics and Center for Neurobehavioral Development, University of Minnesota, Minneapolis, MN, USA
Key words: infant, newborn, infant, premature, iron/administration and dosage, iron/adverse effects, iron/deficiency, iron/toxicity
Preterm infants are prone to iron deficiency. Their total body iron content at birth is low and gets further depleted by clinical practices such as uncompensated phlebotomy losses and exogenous erythropoietin administration during the neonatal period. Early iron deficiency appears to adversely affect cognitive development in human infants. To maintain iron sufficiency and meet the iron demands of catch-up postnatal growth, iron supplementation is prudent in preterm infants. A dose of 2–4 mg/kg/day is recommended for preterm infants who are fed exclusively human milk. A dose of 6 mg/kg/day or more is needed with the use of exogenous erythropoietin or to correct preexisting iron deficiency. However, due to the poor antioxidant capabilities of preterm infants and the potential role of iron in several oxidant-related perinatal disorders, indiscriminate iron supplementation should be avoided. 2002 Elsevier Science Ltd
Introduction Iron and iron-containing proteins are involved in a myriad of synthetic and metabolic functions that are essential for normal cellular functioning and survival [1]. Iron deficiency during development adversely affects the growth and functioning of multiple organ systems including erythrocytes, heart, skeletal muscle and the gastrointestinal tract [2–6]. Perhaps the most concerning effect of iron deficiency is on the developing brain. Neurophysiological studies suggest that early iron deficiency has an adverse effect on cognitive functioning in human infants [7,8] that appears to be long-lasting [9–11]. No studies have specifically evaluated the effect of early iron deficiency on cognitive development in preterm infants, but the adverse effects are likely to be more severe because of the relative immaturity and rapid growth rate of the preterm brain. On the other hand, iron supplementation in preterm infants has to be undertaken cautiously due to the potential role of free iron as an oxidant stressor [12,13] and the limited Correspondence to: Michael K. Georgieff, M.D., Mayo Mail Code 39, 420 Delaware Street SE, Minneapolis, MN, 55455, USA. Tel.: +1 612 626 0644; Fax: +1 612 624 8176; E-mail: [email protected]
1084–2756/01/$-see front matter
antioxidant capacity of the preterm infant [14]. Iron delivery to the preterm infant should be based on sound physiological knowledge to strike a balance between iron deficiency and toxicity in order to achieve iron homeostasis.
Determinants of newborn iron status Even though placental iron transport begins during the first trimester of gestation [15], it is only during the third trimester that significant accretion occurs [16,17]. The total body iron content of infants born anytime during the third trimester is approximately 75 mg/kg body weight [16]. Two-thirds of total body iron present in the term infant is accreted during the third trimester, with storage organ iron contents progressively increasing during this period [17]. Seventy-five to 80% of total body iron is found in the red cell mass as hemoglobin (Hgb), 10% in iron-containing proteins in non-heme tissues (e.g. myoglobin and cytochromes) and the remaining 10–15% in storage forms in reticuloendothelial and parenchymal tissues (e.g. ferritin and hemosiderin) [18,19]. Conditions that may © 2002 Elsevier Science Ltd
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Table 1. Conditions affecting neonatal iron status Conditions having a negative effect Severe maternal iron deficiency (maternal Hgb <65 g/l) Placental insufficiency due to maternal hypertension Maternal diabetes mellitus (gestational and pre-existing) Antenatal and intranatal hemorrhage Feto-maternal transfusion, twin-to-twin transfusion (donor twin) Placenta previa or abruption Umbilical cord accidents (velamentous insertion, occlusion or slipped ligature) Prematurity Early clamping of the umbilical cord Postnatal hemorrhage Phlebotomy losses Gastrointestinal tract hemorrhage (e.g., Meckel’s diverticulum, milk protein intolerance) Exchange transfusion Use of r-HuEPO without iron supplementation Conditions having a positive effect Twin-to-twin transfusion (recipient twin) Delaying or stripping of the umbilical cord before clamping Erythrocyte transfusions Early iron supplementation
have an effect on the iron status of the newborn infant are listed in Table 1. Multiple factors affect the total body iron status of preterm infants, making them prone to early postnatal iron deficiency.
Factors influencing postnatal iron status in preterm infants Total body and liver iron contents, Hgb and serum ferritin concentration are lower in the preterm infant than in the full-term infant [6,17,20–26]. Small-for-gestational-age preterm infants may have normal concentrations of serum iron and transferrin (Tf) in the cord blood [27] but have lower organ iron contents [28]. Postnatally, the Hgb concentration decreases by 30–50% due to a combination of cessation of erythropoiesis, expansion of the vascular volume and hemolysis of fetal erythrocytes [6]. The iron released (3.4 mg/g Hgb) during hemolysis is stored for future use and is reflected by a transient increase in serum ferritin concentration [25,29,30]. The Hgb level reaches a lower and earlier nadir during physiologic anemia in preterm infants [26,31–33]. Erythropoiesis commences between 1 and 2 months in preterm infants, 1 to 3 months earlier than in term infants. With the onset of
erythropoiesis, the serum ferritin levels decrease rapidly [26,31,34]. Extremely-low-birth-weight (ELBW) infants may be in negative iron balance during the first 30 postnatal days without iron supplementation [35,36]. Without an external source of iron, non-transfused preterm infants have sufficient iron stores to sustain effective erythropoiesis only until they have doubled their birthweight [26]. The high rate of postnatal catch-up growth with its attendant increase in blood volume and Hgb requires additional postnatal iron accretion. To achieve hematological indices of iron sufficiency and physical growth comparable to full-term infants, preterm infants may have to increase their body iron content by three- to six-fold during infancy [37,38]. Inadequately compensated phlebotomy losses, exchange transfusions [39] and administration of recombinant human erythropoietin (r-HuEPO) further deplete the meager iron stores in preterm infants. r-HuEPO is administered in an attempt to promote erythropoiesis [40,41]. By decreasing the need for erythrocyte transfusions, this practice negatively affects body iron status by depriving preterm infants of this exogenous source of iron. The mandatory prioritization of iron for erythropoiesis [42] depletes the body iron stores, particularly when simultaneous external iron supplementation is not provided [43]. Serum ferritin
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[40,44] and iron levels decrease [44] and erythrocytes become hypochromic [40] following rHuEPO administration, even with high-dose iron supplementation. The decrease in iron levels is not dependent on the r-HuEPO dose [45]. On the positive side of the iron ledger, preterm infants frequently receive erythrocyte transfusions [33]. Most transfusions are given during the first 3 to 4 weeks of age, either to replace phlebotomy losses or to maintain a certain hematocrit level. The iron delivered through this route augments body iron stores. Serum ferritin levels increase during the first month of life in preterm infants who have received >2 transfusions and are fourfold higher in those receiving d7 transfusions [46]. Thus, multiply transfused ELBW infants may maintain high iron stores without iron supplementation up to 6 months of age [46–48]. Preterm infants who receive more than 100 ml of packed red cells have higher ferritin levels for a longer period than those who receive smaller volumes or no transfusions [47]. Ferritin levels as high as 500 g/l have been recorded [12]. On the other hand, a conservative transfusion practice, as is currently being done [33,49,50], might adversely affect the iron stores if adequate iron supplementation is not provided to preterm infants. Preterm infants who receive no transfusions have lower serum ferritin levels at 6 months, when compared with non-transfused full-term infants of similar age [47]. In summary, postnatal factors can either exacerbate the tenuous iron status of the prematurely born infant or conversely place the infant at risk of iron overload. The iron status of the extremely premature infant at discharge can vary widely from iron deficient to iron overloaded.
Preventing iron deficiency in preterm infants Overview Between 3% and 30% of full-term infants develop iron deficiency during infancy, usually during the second half of the first year [51–53]. The incidence is higher in preterm infants and is reported to be between 26% and 86% [31,32,54–56]. A ferritin level <10 g/l is seen in as many as 65% of preterm infants between 3 and 6 months, with the smallest infants being at the greatest risk of developing early iron deficiency [31]. The incidence
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of iron deficiency (ferritin <10 g/l, Tf saturation <10%) and iron deficiency anemia (Hgb <110 g/l) is higher in preterm infants from developing countries [54] and infants who are exclusively breast-fed without iron supplementation [55]. The diagnosis of iron deficiency during infancy is complex and lacks uniform diagnostic criteria [38]. As in other age groups, anemia occurs after the storage and non-storage tissue iron pools have already been depleted [42,57,58]. Prediction of body iron stores from the serum ferritin concentration has significant shortcomings (Table 2). However, since low ferritin levels are not found in any other condition, it is probably still the best indicator of low iron stores [29,37,59], especially if serial estimations are performed [6]. Cord blood transferrin receptor (TfR) level also has been advocated as an indicator of fetal iron stores [60]. However, compared to adults, TfR levels in infants correlate better with erythropoiesis than functional iron deficiency [6,61]. One method of preventing postnatal iron deficiency in the preterm infant is to ensure that the infant begins life with a full endowment of iron. In developing countries, cord serum iron levels in preterm infants born to severely iron-deficient mothers are low and correlate with the serum iron levels of the mother [62]. In such populations, neonatal iron status could likely be enhanced by improved maternal iron supplementation during gestation. Similarly, delaying the clamping of the umbilical cord at birth to allow additional placental erythrocyte transfusion has been advocated to improve iron stores [63]. The major route of iron loss in preterm infants during the neonatal period is through phlebotomy for laboratory investigations. ELBW infants may lose 26–64% of their total blood volume via phlebotomy, the majority during the early neonatal period [64]. Because infants have higher hemoglobin concentrations at birth, phlebotomy in the neonatal period results in a greater loss of iron when compared with phlebotomy of a similar volume of blood at an older age. Since such losses are being more conservatively replaced due to more restrictive transfusion criteria [49,50], the risk of developing iron deficiency is higher. Minimizing phlebotomy losses would be beneficial in such situations. In addition to measures that minimize blood loss, iron supplementation is necessary to prevent iron deficiency in preterm infants [38]. The time of initiation and the amount and route of iron
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Table 2. Advantages and disadvantages of serum ferritin in the diagnosis of iron deficiency during infancy Advantages Low ferritin levels are not found in any other condition [59,107] Ferritin levels correlate with iron intake [29] and with serum iron concentration [24] Low levels are associated with low Tf saturation [29] Level at 2 months of age predicts future risk of iron deficiency [31] Disadvantages Cord ferritin levels do not predict future risk of iron deficiency [29] Levels vary widely in preterm infants, especially in conditions of latent iron deficiency (low Tf saturation without anemia) [59] The immediate increase in ferritin levels after the commencement of iron supplementation is not a true reflection of body iron stores [59] In preterm infants, hematological evidence of iron deficiency may appear before depletion of serum ferritin [31,68] There is no correlation between serum ferritin levels and liver iron content during infancy, probably because of sequestration and delayed release of hepatic iron for erythropoiesis [76] All isoforms of ferritin may not be detected by the conventional laboratory methods, and the actual levels might be higher than what is detected Being an acute phase reactant, ferritin also is increased in inflammatory conditions [59,108]
supplementation have yet to be conclusively determined. Preterm infants certainly require more iron, both in absolute amount and on a per kilogram bodyweight basis [37], than full-term infants because their iron stores are lower at birth and their total body iron content has to increase at a greater rate postnatally. The amount of iron found in breast milk or unsupplemented formula is not enough to support this large iron demand. The American Academy of Pediatrics recommends iron supplementation at a dose of 2–4 mg/kg/day, up to a maximum of 15 mg/day for preterm infants exclusively fed breast milk. Supplementation should begin at 2 months of age, or when the birth weight doubles, and continue throughout the first postnatal year [65]. Supplementation is not recommended for preterm infants receiving iron-fortified formula unless they are in negative iron balance prior to the commencement of iron supplementation or are receiving r-HuEPO. Those infants may need a dose as high as 6 mg/kg/day [36,65]. Some controversial issues associated with iron supplementation of preterm infants are discussed in the following subsections. Early vs late iron supplementation The optimal time for initiating iron supplementation has yet to determined. Preterm infants with birth weights between 1000 and 2000 g who
receive iron supplementation at a dose of 2 mg/kg/ day from 2 weeks of age tend to have less iron deficiency and need fewer erythrocyte transfusions during the first 2 to 3 months of age when compared with unsupplemented cohorts [31]. Even at this level, approximately 15% develop a ferritin level <10 g/l [31]. In a cohort of preterm infants with a birth weight of <1301 g, early iron supplementation at a dose of 2–4 mg/kg/day initiated at a mean age of 2 weeks reduced the incidence of iron deficiency and/or need for erythrocyte transfusions by 30% when compared with those in whom iron supplementation was initiated at a mean age of 2 months [21]. Infants who have not received erythrocyte transfusions beyond 2 weeks appear to benefit the most by early iron supplementation [21]. On the other hand, early iron administration does not prevent or ameliorate physiologic anemia [24]. Incorporation of supplemented iron is better when it is administered with the onset of erythropoiesis [66]. Even without supplementation, serum iron and Tf saturation peak at 3 weeks [32] and serum ferritin levels remain elevated during the first 4 to 6 weeks of life [29,30]. Finally, during the first month of life, enteral iron absorption appears to be poorly regulated and has the potential for resulting in high serum iron levels with higher doses of supplementation [35,36]. These studies would support delaying iron supplementation until 4 to 8 weeks. However, this practice in ELBW infants confers a significant risk of
Neonatal iron nutrition
negative iron balance [35,36], the long-term effects of which are not known. In summary, early iron supplementation appears to be safe and effective in small preterm infants and is indicated in non-transfused very-low-birth-weight (VLBW) infants. Enteral vs parenteral iron supplementation The optimal method of iron supplementation has also been a subject of intense scrutiny. Parenteral iron supplementation, usually in the context of r-HuEPO therapy or as a part of parenteral nutrition, has been proven to be safe and effective [43,67–69]. Intravenous iron supplementation in a dose of 1 mg/kg/day simulates the intrauterine iron accretion rate and achieves positive iron balance in VLBW infants [67]. In ELBW infants, an infusion dose of 120 g/kg/day results in a positive retention of approximately 90 g/kg/day, with simultaneous elevation in serum ferritin and Tf saturation levels [70]. Depending upon bodyweight and past erythrocyte transfusion, approximately 18–68% of intravenously administered iron is incorporated into erythrocytes [66,71]. However, the low Tf levels and poor antioxidant defenses of preterm infants cautions against injudicious parenteral iron supplementation, especially during the early neonatal period [27]. Rapid infusions of iron are probably best avoided as they may result in transiently elevated serum iron levels that may overwhelm the total iron-binding capacity. Malondialdehyde levels are transiently elevated following parenteral iron infusion, indicating an oxidant stress, but the long-term significance of this finding is not clear [68]. Finally, because of its invasiveness, intravenous iron supplementation may be indicated only in those for whom enteral supplementation is not feasible. The preferred alternative to parenteral iron supplementation is dosing the element via the enteral route. With the exception of one report [72], enteral iron supplementation appears to be well-tolerated and does not appear to result in gastrointestinal distress in preterm infants [21,56,66,68,73]. The effectiveness of enteral iron supplementation depends on its absorption and retention [74]. Absorption rates of 0.3–74% have been reported, depending upon postnatal age of the preterm infant and mode of administration [26]. A value between
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Table 3. Factors affecting enteral iron absorption Factors enhancing absorption Postnatal age [74] Iron deficiency state [76] Administration between feeds [66] Administration with breast milk [73,74] Ascorbic acid or other organic acids in the diet [38] Factors suppressing absorption Recent erythrocyte transfusion [36] Administration with formula milk [66] Phytates and phenols in the diet [38] Factors probably not having an effect on absorption Gestational age, postconceptional age and body weight [26,73] r-HuEPO therapy [76]
30% and 40% is probably a more representative figure for absorption of enteral iron given between feeds [74–76]. Iron absorption in preterm infants fed iron-supplemented breast milk averages 34% [36]. Major factors that may affect enteral iron absorption are given in Table 3. Absorption and retention correlate with reticulocyte count [77]. Recent erythrocyte transfusions decrease enteral iron absorption [36], but do not completely abolish it [35]. Thus, as in older children and adults [78], low iron status appears to enhance enteral iron absorption in preterm infants. However, even preterm infants with reasonable total body iron sufficiency continue to absorb enterally administered iron, probably due to a perceived need for erythropoiesis and catch-up growth [76]. Interestingly, r-HuEPO treatment, while promoting erythropoiesis, does not enhance enteral iron absorption [76]. Rates of absorption correlate with the amount of iron administered during the first month of life [35,36], but beyond that period, the percent retained is inversely proportional to the amount supplemented [74]. The interaction of iron with other cations such as zinc, selenium, calcium and copper has been studied in detail. Zinc supplementation at a ratio of 4:1 with iron in the formula does not appear to affect iron absorption and erythrocyte incorporation [79]. Similarly, iron supplementation at 2 mg/kg/day does not appear to adversely affect either serum zinc levels [80] or absorption of selenium, a putative antioxidant [81]. The high calcium content of human milk fortifier does not appear to adversely affect enteral iron absorption [66]. There is indirect evidence that iron supplementation
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started at 4 weeks of age could result in altered copper metabolism, but its clinical relevance is unclear [82].
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Table 4. Iron concentration of breast milk and artificial formulas commonly used in the United States Product
Iron concentration (mg/l)
Iron delivery (mg/kg/d)1
0.472 12.2 14.6 3.56–14.47 13.3
0.07 1.8 2.2 0.53–2.28 2.0
The effect of r-HuEPO on iron status The robustness of the erythropoietic response in preterm infants receiving r-HuEPO depends on the amount of available iron. Iron supplementation not only enhances the response to r-HuEPO [43], but as shown in animal models [83,84], may also increase endogenous erythropoietin production. Administration of r-HuEPO without sufficient iron supplementation decreases serum ferritin levels as early as 14 days [69]. Such an effect is seen after 4 weeks of r-HuEPO therapy, even with iron supplementation in a dose of 3 mg/kg/day via the parenteral route [43]. The American Academy of Pediatrics recommends an oral supplementation of 6 mg/kg/day for preterm infants receiving r-HuEPO [65]. Even that amount may not be sufficient to maintain serum ferritin levels [85]. Simultaneous oral (9 mg/kg/day) and parenteral (2 mg/kg/day) iron supplementation appears to be advantageous in achieving iron sufficiency in preterm infants on r-HuEPO [68]. Pollak et al. postulated that oral supplementation meets the iron requirements of growth and phlebotomy losses, while parenteral supplementation subserves the iron needs of erythropoiesis [68]. In summary, it is difficult to meet the iron needs of r-HuEPOinduced erythropoiesis with either breast milk or iron-fortified formula without additional iron supplementation.
Iron supplementation of preterm infants fed breast milk The iron content of human milk is approximately 0.47 mg/l [86]. While some studies have reported higher iron concentrations in preterm colostrum and during the initial 4 to 8 weeks of lactation [87,88], this has not been substantiated by other studies [86,89,90]. Interestingly, the breast milk of women of low socioeconomic status in developing countries may have higher iron concentrations [87,90]. Unsupplemented breast milk will not support an intrauterine accretion rate of iron during the first month of life, even with 100% absorption [73,89]. The iron status of preterm infants fed
Breast milk Term formula with iron3 Preterm formula with iron4 Human milk fortifier5 Discharge formula9 1
Assuming an intake of 150 ml/kg/d. Represents both term and preterm human milk [86]. 3 Enfamil 20 with iron and Similac 20 with iron. 4 Enfamil Premature Formula 24 with iron and Similac Special Care with iron 24. 5 When added to 1 l of breast milk. 6 Similac Human Milk Fortifier and 7Enfamil Human Milk Fortifier. 8 Does not include iron content of the breast milk. 9 EnfaCare and Similac NeoSure (Enfamil and EnfaCare are registered trademarks of Mead Johnson Nutritionals, Evansville, IN, and Similac and NeoSure are registered trademarks of Ross Products Division, Abbott Laboratories, Inc, Columbus, OH, USA). 2
exclusively breast milk without iron supplementation starts to deteriorate by 1 to 4 months of age [35,36,55,91]. By 6 months, 86% have evidence of iron deficiency [55]. Breast milk iron concentration cannot be enhanced by maternal iron supplementation [86]. The American Academy of Pediatrics recommends that preterm infants fed exclusively breast milk be supplemented with 2–4 mg/kg/day of iron [65]. Supplementation at this level reduces the incidence of iron deficiency and iron-deficiency anemia during infancy [80]. The dose of ferrous sulfate is equally effective whether it is administered to the infant as medicinal drops or mixed with breast milk [73]. Human milk fortifiers that are currently available in the United States provide an additional 0.5–2.2 mg of iron/kg/day (Table 4). Iron fortification of preterm formula The majority of preterm infants in the USA are not fed exclusively breast milk beyond 3 months. The commonly used premature infant formulas in the USA are fortified with 14.6 mg/l of iron (Table 4). When consumed at 150 ml/kg/day, these formulas would deliver an iron intake of 2.2 mg/kg/day. A low-iron term formula containing 2–3 mg/l of iron would deliver only 0.3–0.45 mg/kg/day of iron. Preterm infants with birth weights <1800 g will
Neonatal iron nutrition
not achieve iron sufficiency on a formula containing 3 mg/l or less [56]. An iron content of at least 5 mg/l appears to be essential to maintain iron sufficiency during the initial 6 months of life [58]. Nevertheless, approximately 14% of preterm infants receiving a formula with an iron content of 5–9 mg/l develop iron deficiency between 4 and 8 months [58]. Preterm infants with birth weights <1800 g who are infrequently transfused appear to benefit the most from a formula containing 15 mg/l of iron [56]. Preterm infants may tolerate a formula with as much as 21 mg/l of iron. However, such supplementation does not appear to confer any further hematologic or developmental advantage over formulas containing 12 mg/l [92].
The risk of iron overload in preterm infants Free iron is toxic to tissues through its role in oxidant-related injuries [14]. The progressive increase in serum iron-binding capacity during the third trimester of pregnancy [23,93] is probably an attempt to minimize the exposure of developing organ systems to free iron during this period of increased maternal-fetal iron delivery. Excessive iron supplementation in preterm infants creates the potential for oxidant injuries. The classic example is iron-induced hemolysis in vitamin E deficiency states [94]. The cord blood levels of iron-binding plasma proteins, ceruloplasmin and Tf are lower [27] and ascorbic acid levels higher in preterm infants [95]. This situation is conducive for iron to exist in the reduced ferrous state. Lower Tf levels and decreased iron-binding antioxidant capacity have been demonstrated in preterm infants with respiratory distress syndrome and chronic lung disease (CLD) [96] and periventricularintraventricular hemorrhage (PIVH) [13]. Elevated intraerythrocyte free iron concentrations are found under hypoxic conditions in preterm infants [97,98]. Cord blood samples containing low molecular weight iron have been demonstrated to degrade DNA in vitro [99]. A role for iron in the etiopathogenesis of neonatal oxidative diseases, such as retinopathy of prematurity (ROP), CLD, PIVH and necrotizing enterocolitis, has been postulated but has yet to be conclusively proved [12–14,46]. The exogenous sources of iron for the preterm infants are through erythrocyte transfusions and parenteral or enteral
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iron supplementation. It has been postulated that in the absence of adequate protective mechanisms, the ‘free’ iron leaked from damaged erythrocytes during transfusion may induce or potentiate oxidantrelated injuries [95]. There is an association between multiple erythrocyte transfusions and ROP [12,100] and CLD [46,95]. The incidence and severity of ROP correlates with serum ferritin levels [101]. Very high serum ferritin levels (500 g/l) have been observed in multiply transfused premature infants with ROP [12]. Elevated serum ferritin and ‘free’ iron have also been demonstrated in multiply transfused preterm infants developing CLD [46]. However, this elevated plasma free iron did not induce lipid peroxidation, as demonstrated by lipid hydroperoxide formation [102], or generation of thiobarbituric acid reacting substances [46] in these preterm infants. The confounding variable seems to be that sicker and more preterm infants are likely to receive multiple transfusions, which makes it difficult to assign transfusion-related iron toxicity as the sole etiology of these multifactorial disorders. Interestingly, conservative transfusion practices have not reduced the incidence of ROP or PIVH in ELBW infants [50]. Nevertheless, since multiply transfused preterm infants are likely to maintain iron sufficiency during the initial months of infancy [46–48], early iron supplementation is probably not necessary for them. Similarly, the relationship between parenteral or enteral iron supplementation and oxidant-related disorders is also not clear. Serum malondialdehyde levels transiently rise after intravenous iron administration but are not associated with evidence of permanent tissue lipid peroxidation in VLBW infants [68]. However, to ensure adequate iron binding by the plasma proteins, it is prudent to avoid rapid infusion rates or exceed a dose of 1–2 mg/kg/day. Finally, no studies have demonstrated oxidative injury following enteral iron supplementation. Preterm infants between 27 and 34 weeks gestation had no increase in iron overload and oxidative stress with a formula fortified with 8 mg/l of iron [103]. As mentioned above, enteral iron supplementation as high as 21 mg/l has not been associated with elevated malondialdehyde levels [92]. The gradual rate of enteral iron absorption likely allows effective Tf binding of iron in the circulation. Furthermore, high ferritin levels, as seen in multiply transfused preterm infants, are not seen in preterm infants receiving enteral
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iron supplementation [43,104]. Nevertheless, a threshold dose of iron likely exists beyond which the potential for adverse effects increases. This is especially true for ELBW infants during the initial 4 weeks of life, when their enteral iron absorption appears to be poorly regulated [35,36]. It is also important to simultaneously maintain adequate vitamin E [105] and ascorbic acid [102] levels in the serum to effectively prevent oxidant injuries.
Post discharge screening for iron deficiency in the preterm infant There is no single ideal age for screening for iron deficiency in preterm infants. Due to variations in clinical practice, the iron status of preterm infants differs widely at the time of discharge. Hence, it would probably be wise to assess hematological indices and serum ferritin at this time. As in other populations, the zinc protoporphyrin to heme [ZnPP/H] ratio at the time of discharge may be useful in diagnosing iron-deficient erythropoiesis and, accordingly, the need for additional iron [106]. A recheck of hematologic status at 6 months of age, rather than waiting until the more standard 9 months, is prudent for all preterm infants and should be combined with serum ferritin determination. Additional follow-up may be needed, depending upon the iron status at discharge, type of milk feeding and the adequacy of iron supplementation. Small preterm infants and infants who received unfortified human milk or a low-iron formula need closer evaluation. Infants whose phlebotomy losses were not adequately replaced by erythrocyte transfusions or who were given r-HuEPO as a substitute also need to be assessed for iron status at an earlier post-discharge date. Acknowledgements The authors gratefully acknowledge Ms Ginny Lyson for her editorial assistance in the preparation of the manuscript. Supported in part by a grant from the National Institutes of Health (NICHD-HD 29421).
References 1 Dallman PR. Biochemical basis for the manifestations of iron deficiency. Ann Rev Nutr 1986; 6: 13–40. 2 Mackler B, Grace R, Finch CA. Iron deficiency in the rat: effects on oxidative metabolism in distinct types of skeletal muscle. Pediatr Res 1984; 18: 499–500.
R. Rao and M. K. Georgieff
3 Blayney L, Bailey-Wood R, Jacobs A, Henderson A, Muir J. The effects of iron deficiency on the respiratory function and cytochrome content or rat heart mitochondria. 1976; 39: 744–748. 4 Ercan O, Ulukutlu L, Ozbay G, Arda O. Intestinal effects of iron deficiency anemia in children. Turk J Pediatr 1991; 33: 85–98. 5 Berant M, Khourie M, Menzies IS. Effect of iron deficiency on small intestinal permeability in infants and young children. J Pediatr Gastroenterol Nutr 1992; 14: 17–20. 6 Aggett PJ. Trace elements of the micropremie. Clin Perinatol 2000; 27: 119–129. 7 deRegnier RA, Nelson CA, Thomas K, Wewerka S, Georgieff MK. Neurophysiologic evaluation of auditory recognition memory in healthy newborn infants and infants of diabetic mothers. J Pediatr 2000; 137: 777– 784. 8 Roncagliolo M, Garrido M, Walter T, Peirano P, Lozoff B. Evidence of altered central nervous system development in infants with iron deficiency anemia at 6 mo: delayed maturation of auditory brainstem responses. Am J Clin Nutr 1998; 68: 683–690. 9 Lozoff B. Perinatal iron deficiency and the developing brain. Pediatr Res 2000; 48: 137–139. 10 Lozoff B, Klein NK, Nelson EC, McClish DK, Manuel M, Chacon ME. Behavior of infants with iron-deficiency anemia. Child Dev 1998; 69: 24–36. 11 Walter T. Effect of iron-deficiency anaemia on cognitive skills in infancy and childhood. Bailliere’s Clin Haematol 1994; 7: 815–827. 12 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: 541–544. 13 Lackmann GM, Hesse L, Tollner U. Reduced ironassociated antioxidants in premature newborns suffering intracerebral hemorrhage. Free Radic Biol Med 1996; 20: 407–409. 14 Jansson LT. Iron, oxygen stress, and the preterm infant. In: Lonnerdal B (ed.) Iron Metabolism in Infants. Boca Raton, FL: CRC Press, 1990; 73–85. 15 Gulbis B, Jauniaux E, Decuyper J, Thiry P, Jurkovic D, Campbell S. Distribution of iron and iron-binding proteins in first-trimester human pregnancies. Obstet Gynecol 1994; 84: 2892–2893. 16 Widdowson EM, Spray CM. Chemical development in utero. Arch Dis Child 1951; 26: 205–214. 17 Singla PN, Gupta VK, Agarwal KN. Storage iron in human foetal organs. Acta Paediatr Scand 1985; 74: 701–706. 18 Josephs HW. Iron metabolism and the hypochromic anaemia of infancy. Medicine 1953; 32: 125–157. 19 Dallman PR, Siimes MA, Stekel A. Iron deficiency in infancy and childhood. Am J Clin Nutr 1980; 33: 86–118. 20 Ziegler EE, O’Donnell AM, Nelson SE, Fomon SJ. Body composition of the reference fetus. Growth 1976; 40: 329–341. 21 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.
Neonatal iron nutrition
22 Abbas A, Snijders RJ, Sadullah S, Nicolaides KH. Fetal blood ferritin and cobalamin in normal pregnancy. Fetal Diagn Ther 1994; 9: 14–18. 23 Lackmann GM, Schnieder C, Bohner J. Gestational age-dependent reference values for iron and selected proteins of iron metabolism in serum of premature human neonates. Biol Neonate 1998; 74: 208–213. 24 Haga P. Plasma ferritin concentrations in preterm infants in cord blood and during the early anaemia of prematurity. Acta Paediatr Scand 1980; 69: 637–641. 25 Siimes AS, Siimes MA. Changes in the concentration of ferritin in the serum during fetal life in singletons and twins. Early Hum Dev 1986; 13: 47–52. 26 Ehrenkranz RA. Iron, folic acid, and vitamin B12. In: Tsang RC, Luca A, Uauy R, Zlotkin S (eds) Nutritional Needs of the Preterm Infant. Scientific Basis and Practical Guidelines. New York: Williams & Wilkins, 1993; 177– 194. 27 Scott PH, Berger HM, Kenward C, Scott P, Wharton BA. Effect of gestational age and intrauterine nutrition on plasma transferrin and iron in the newborn. Arch Dis Child 1975; 50: 796–798. 28 Georgieff MK, Mills, MM, Gordon K, Wobken JD. Reduced neonatal liver iron concentrations after uteroplacental insufficiency. J Pediatr 1995; 127: 308– 311. 29 Saarinen UM, Siimes MA. Serum ferritin in assessment of iron nutrition in healthy infants. Acta Paediatr Scand 1978; 67: 745–751. 30 Rios E, Lipschitz DA, Cook JD, Smith NJ. Relationship of maternal and infant iron stores as assessed by determination of plasma ferritin. Pediatrics 1975; 55: 694–699. 31 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. 32 Halliday HL, Lappin TR, McClure G. Iron status of the preterm infant during the first year of life. Biol Neonate 1984; 45: 228–235. 33 Strauss RG. Recombinant erythropoietin for the anemia of prematurity: Still a promise, not a panacea. J Pediatr 1997; 131: 653–655. 34 Messer RD, Russo AM, McWhirter WR, Sprangemeyer D, Halliday JW. Serum ferritin in term and preterm infants. Aust Paediatr J 1980; 16: 185–188. 35 Shaw JC. Iron absorption by the premature infant. The effect of transfusion and iron supplements on the serum ferritin levels. Acta Paediatr Scand (Suppl) 1982; 299: 83–89. 36 Dauncey MJ, Davies CG, Shaw JC, Urman J. The effect of iron supplements and blood transfusion on iron absorption by low birthweight infants fed pasteurized human breast milk. Pediatr Res 1978; 12: 899–904. 37 Siimes MA. Hematopoiesis and storage iron in infants. In: Lonnerdal B (ed.) Iron Metabolism in Infants. Boca Raton, FL: CRC Press, 1990; 33–62. 38 Wharton BA. Iron deficiency in children: detection and prevention. Br J Haematol 1999; 106: 270–280. 39 Siimes MA, Koerper MA, Licko V, Dallman PR. Ferritin turnover in plasma: an opportunistic use of blood
433
40
41
42
43
44
45
46 47
48
49
50
51 52 53
54
removed during exchange transfusion. Pediatr Res 1975; 9: 127–129. Meyer MP, Meyer JH, Commerford A, Hann FM, Sive AA, Moller G, et al. Recombinant human erythropoietin in the treatment of the anemia of prematurity: results of a double-blind, placebo-controlled study. Pediatrics 1994; 93: 918–923. Ohls RK, Osborne KA, Christensen RD. Efficacy and cost analysis of treating very low birth weight infants with erythropoietin during their first two weeks of life: a randomized, placebo-controlled trial. J Pediatr 1995; 126: 421–426. Guiang SF, III, Georgieff MK, Lambert DJ, Schmidt RL, Widness JA. Intravenous iron supplementation effect on tissue iron and hemoproteins in chronically phlebotomized lambs. Am J Physiol 1997; 273: R2124– 2131. Carnielli VP, Da Riol R, Montini G. Iron supplementation enhances response to high doses of recombinant human erythropoietin in preterm infants. Arch Dis Child 1998; 79: F44–48. Bader D, Blondheim O, Jonas R, Admoni O, AbendWinger M, Reich D, et al. Decreased ferritin levels, despite iron supplementation, during erythropoietin therapy in anaemia of prematurity. Acta Paediatr 1996; 85: 496–501. Chang L, Liu W, Liao C, Zhao X. Preventive effect of different dosage of recombinant human erythropoietin on anemia of premature infants. J Tongji Med Univ 1998; 18: 239–242. Cooke RW, Drury JA, Yoxall CW, James C. Blood transfusion and chronic lung disease in preterm infants. Eur J Pediatr 1997; 156: 47–50. Arad I, Konijn AM, Linder N, Goldstein M, Kaufmann NA. Serum ferritin levels in preterm infants after multiple blood transfusions. Am J Perinatol 1988; 5: 40–43. Ramasethu J, Gunter K, McClenny R, Luban N, Fletcher A. When is iron supplementation appropriate for extremely low birth weight infant? Pediatr Res 1997; 41: 239A. Widness JA, Seward VJ, Kromer IJ, Burmeister LF, Bell EF, Strauss RG. Changing patterns of red blood cell transfusion in very low birth weight infants. J Pediatr 1996; 129: 680–687. Maier RF, Sonntag J, Walka MM, Liu G, Metze BC, Obladen M. Changing practices of red blood cell transfusions in infants with birth weight less than 1000 g. J Pediatr 2000; 136: 220–224. Looker AC, Dallman PR, Carroll MD, Gunter EW, Johnson CL. Prevalence of iron deficiency in the United States. JAMA 1997; 277: 973–976. Kilbride J, Baker TG, Parapia LA, Khoury SA. Incidence of iron-deficiency anaemia in infants in a prospective study in Jordan. Eur J Haematol 2000; 64: 231–236. Raman L, Pawashe AB, Vasanthi G, Parvathi C, Vasumathi N, Rawal A. Plasma ferritin in the assessment of iron status of Indian infants. Indian Pediatr 1990; 27: 705–713. Borigato EV, Martinez FE. Iron nutritional status is improved in Brazilian preterm infants fed food cooked in iron pots. J Nutr 1998; 128: 855–859.
434
55 Iwai Y, Takanashi T, Nakao Y, Mikawa H. Iron status in low birth weight infants on breast and formula feeding. Eur J Pediatr 1986; 145: 63–65. 56 Hall RT, Wheeler RE, Benson J, Harris G, Rippetoe L. Feeding iron-fortified premature formula during initial hospitalization to infants less than 1800 grams birth weight. Pediatrics 1993; 92: 409–414. 57 Oski FA. Iron deficiency in infancy and childhood. N Engl J Med 1993; 329: 190–193. 58 Griffin IJ, Cooke RJ, Reid MM, McCormick KP, Smith JS. Iron nutritional status in preterm infants fed formulas fortified with iron. Arch Dis Child 1999; 81: F45–49. 59 Siimes MA, Addiego JE Jr, Dallman PR. Ferritin in serum: diagnosis of iron deficiency and iron overload in infants and children. Blood 1974; 43: 581–590. 60 Sweet DG, Savage G, Tubman TR, Lappin TR, Halliday HL. Study of maternal influences on fetal iron status at term using cord blood transferrin receptors. Arch Dis Child 2001; 84: F40–43. 61 Kling PJ, Roberts RA, Widness JA. Plasma transferrin receptor levels and indices of erythropoiesis and iron status in healthy term infants. J Pediatr Hematol Oncol 1998; 20: 309–314. 62 Singla PN, Chand S, Agarwal KN. Cord serum and placental tissue iron status in maternal hypoferremia. Am J Clin Nutr 1979; 32: 1462–1465. 63 Pisacane A. Neonatal prevention of iron deficiency. BMJ 1996; 312: 136–137. 64 Maier RF, Obladen M, Kattner E, Natzschka J, Messer J, Regazzoni BM, et al. High-versus low-dose erythropoietin in extremely low birth weight infants. J Pediatr 1998; 132: 866–870. 65 American Academy of Pediatrics, Committee on Nutrition. Nutritional needs of preterm infants. In: Kleinman RE (ed.) Pediatric Nutrition Handbook. Elk Grove Village, IL: American Academy of Pediatrics, 1998; 55–87. 66 McDonald MC, Abrams SA, Schanler RJ. Iron absorption and red blood cell incorporation in premature infants fed an iron-fortified infant formula. Pediatr Res 1998; 44: 507–511. 67 Friel J, Andrews W, Hall M, Rodway MS, Keith M, McCloy UC, et al. Intravenous iron administration to very-low-birth-weight newborns receiving total and partial parenteral nutrition. J Parenter Enteral Nutr 1995; 19: 114–118. 68 Pollak A, Hayde M, Hayn M, Herkner K, Lombard KA, Lubec G, et al. Effect of intravenous iron supplementation on erythropoiesis in erythropoietin treated premature infants. Pediatrics 2001; 107: 78–85. 69 Ohls RK, Harcum J, Schibler KR, Christensen RD. The effect of erythropoietin on the transfusion requirements of preterm infants weighing 750 grams or less: a randomized, double-blind, placebo-controlled study. J Pediatr 1997; 131: 661–665. 70 Friel JK, Penney S, Reid DW, Andrews WL. Zinc, copper, manganese, and iron balance of parenterally fed very low birth weight preterm infants receiving a trace element supplement. J Parenter Enteral Nutr 1988; 12: 382–386. 71 Zlotkin SH, Lay DM, Kjarsgaard J, Longley T. Determination of iron absorption using erythrocyte iron
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77
78 79
80
81
82
83
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85
86 87
incorporation of two stable isotopes of iron (57Fe and 58Fe) in very low birthweight premature infants. J Pediatr Gastroenterol Nutr 1995; 21: 190–199. Victorin LH, Olegard R. Iron in the preterm infant: a pilot study comparing Fe2+ and Fe3+ tolerance and effect. J Pediatr 1984; 105: 151–152. Moody GJ, Schanler RJ, Abrams SA. Utilization of supplemental iron by premature infants fed fortified human milk. Acta Pediatr 1999; 88: 763–767. Fomon SJ, Nelson SE, Ziegler EE. Retention of iron by infants. Annu Rev Nutr 2000; 20: 273–290. Ehrenkranz RA, Gettner PA, Nelli CM, Sherwonit EA, Williams JE, Pearson HA, et al. Iron absorption and incorporation into red blood cells by very low birth weight infants: studies with the stable isotope 58Fe. J Pediatr Gastroenterol Nutr 1992; 15: 270–278. Widness JA, Lombard KA, Ziegler EE, Serfass RE, Carlson SJ, Johnson KJ, et al. Erythrocyte incorporation and absorption of 58Fe in premature infants treated with erythropoietin. Pediatr Res 1997; 41: 416–423. Gorten MK, Hepner R, Workman JB. Iron metabolism in premature infants. I. Absorption and utilization of iron as measured by isotope studies. J Pediatr 1963; 63: 1063–1071. Andrews NC. Disorders of iron metabolism. N Engl J Med 1999; 341: 1986–1995. Friel JK, Serfass RE, Fennessey PV, Miller LV, Andrews WL, Simmons BS, et al. Elevated intakes of zinc in infant formulas do not interfere with iron absorption in premature infants. J Pediatr Gastroenterol Nutr 1998; 27: 312– 316. Salvioli GP, Faldella G, Alessandroni R, Lanari M, Benfenati L. Plasma zinc concentrations in iron supplemented low birthweight infants. Arch Dis Child 1986; 61: 346–348. Rudolph N, Preis O, Bitzos EI, Reale MM, Wong SL. Hematologic and selenium status of low-birth-weight infants fed formulas with and without iron. J Pediatr 1981; 99: 57–62. Barclay SM, Aggett PJ, Lloyd DJ, Duffty P. Reduced erythrocyte superoxide dismutase activity in low birth weight infants given iron supplements. Pediatr Res 1991; 29: 297–301. Bechensteen AG, Halvorsen S, Haga P, Cotes PM, Liestol K. Erythropoietin (Epo), protein and iron supplementation and the prevention of anaemia of prematurity: effects on serum immunoreactive Epo, growth and protein and iron metabolism. Acta Paediatr 1996; 85: 490–495. Peters C, Georgieff MK, de Alarcon PA, Cook RT, Burmeister LF, Lowe LS, et al. Effect of chronic erythropoietin administration on plasma iron in newborn lambs. Biol Neonate 1996; 70: 218–228. Meyer MP, Haworth C, Meyer JH, Commerford A. A comparison of oral and intravenous iron supplementation in preterm infants receiving recombinant erythropoietin. J Pediatr 1996; 129: 258–263. Dorea JG. Iron and copper in human milk. Nutrition 2000; 16: 209–220. Atinmo T, Omololu A. Trace element content of breastmilk from mothers of preterm infants in Nigeria. Early Hum Dev 1982; 6: 309–313.
Neonatal iron nutrition
88 Lemons JA, Moye L, Hall D, Simmons M. Differences in the composition of preterm and term human milk during early lactation. Pediatr Res 1982; 16: 113–117. 89 Mendelson RA, Anderson GH, Bryan MH. Zinc, copper and iron content of milk from mothers of preterm and full-term infants. Early Hum Dev 1982; 6: 145–151. 90 Trugo NM, Donangelo CM, Koury JC, Silva MI, Freitas LA. Concentration and distribution pattern of selected micronutrients in preterm and term milk from urban Brazilian mothers during early lactation. Eur J Clin Nutr 1988; 42: 497–507. 91 Tudehope DI, Mitchell F, Cowley DM. A comparative study of a premature infant formula and preterm breast milk for low birthweight infants. Aust Paediatr J 1986; 22: 199–205. 92 Andrews WL, Friel JK, Simmons B, Azziz K, Kwa PG, Downton G. Effect of two levels of iron supplementation of infant formulas on developmental outcome and iron nutrition in very low birth weight infants. Pediatr Res 1998; 42: 255A. 93 Chockalingham U, Murphy E, Ophoven JC, Georgieff MK. The influence of gestational age, size for dates, and prenatal steroids on cord transferrin levels in newborn infants. J Pediatr Gastroenterol Nutr 1987; 6: 276–280. 94 Williams ML, Shoot RJ, O’Neal PL, Oski FA. Role of dietary iron and fat on vitamin E deficiency anemia of infancy. N Engl J Med 1975; 292: 887–890. 95 Silvers KM, Gibson AT, Russell JM, Powers HJ. Antioxidant activity, packed cell transfusions, and outcome in premature infants. Arch Dis Child 1998; 78: F214–219. 96 Moison RM, Haasnoot AA, Van Zoeren-Grobben D, Berger HM. Plasma proteins in acute and chronic lung disease of the newborn. Free Radic Biol Med 1998; 25: 321–328. 97 Buonocore G, Zani S, Perrone S, Caciotti B, Bracci R. Intraerythrocyte nonprotein-bound iron and plasma malondialdehyde in the hypoxic newborn. Free Radic Biol Med 1998; 25: 766–770.
435
98 Buonocore G, Zani S, Sargentini I, Gioia D, Signorini C, Bracci R. Hypoxia-induced free iron release in the red cells of newborn infants. Acta Paediatr 1998; 87: 77–81. 99 Berger HM, Mumby S, Gutteridge JM. Ferrous ions detected in iron-overloaded cord blood plasma from preterm and term babies: implications for oxidative stress. Free Radic Res 1995; 22: 555–559. 100 Hesse L, Eberl W, Schlaud M, Poets CF. Blood transfusion. Iron load and retinopathy of prematurity. Eur J Pediatr 1997; 156: 465–470. 101 Romagnoli C, Zecca E, Gallini F, Girlando P, Zuppa AA. Do recombinant human erythropoietin and iron supplementation increase the risk of retinopathy of prematurity? Eur J Pediatr 2000; 159: 627–628. 102 Berger TM, Polidori MC, Dabbagh A, Evans PJ, Halliwell B, Morrow JD, et al. Antioxidant activity of vitamin C in iron-overloaded human plasma. J Biol Chem 1997; 272: 15656–15660. 103 van Zoeren Grobben D, Moison R, Haasnoot A, Berger H. Iron containing feeding formula and oxidative stress in preterm infants. Pediatr Res 1998; 43: 270A. 104 Shannon KM, Keith JF, 3rd, Mentzer WC, Ehrenkranz RA, Brown MS, Widness JA, et al. Recombinant human erythropoietin stimulates erythropoiesis and reduces erythrocyte transfusions in very low birth weight preterm infants. Pediatrics 1995; 95: 1–8. 105 Melhorn DK, Gross S. Vitamin E-dependent anemia in the premature infant. I. Effects of large doses of medicinal iron. J Pediatr 1971; 79: 569–580. 106 Winzerling JJ, Kling PJ. Iron deficient erythropoiesis in premature infants measured by blood zinc protoporphyrin/heme. J Pediatr 2001; 139: 134–136. 107 Harju E. Clinical pharmacokinetics of iron preparations. Clin Pharmacokinet 1989; 17: 69–89. 108 Witte DL. Can serum ferritin be effectively interpreted in the presence of the acute-phase response? Clin Chem 1991; 37: 484–485.