Search tips
Search criteria 


Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Clin Perinatol. Author manuscript; available in PMC 2010 March 1.
Published in final edited form as:
PMCID: PMC2657918

Iron Therapy for Preterm Infants


Preterm infants are at risk for both iron deficiency and iron overload. The role of iron in multiple organ functions suggests that iron supplementation is essential for the preterm infant. Conversely, the potential for iron overload and the poorly developed anti-oxidant measures in the preterm infant argues against indiscriminate iron supplementation in this population. The purpose of this article is to review the predisposing factors and consequences of iron deficiency and iron overload in the preterm infant, the current recommendation for iron supplementation and its appropriateness, and describe potential management strategies that strike a balance between iron deficiency and iron toxicity.

Keywords: guidelines, infant, iron, iron overload, premature, therapy


The need for iron therapy in preterm infants has been debated at least since the 1950s [1]. The essential role for iron in various tissue functions and their propensity to develop iron deficiency suggest that iron supplementation is essential to the preterm infants. Conversely, the pro-oxidant role of non-protein bound iron and the poorly developed antioxidant measures in preterm infants cautions against aggressive iron supplementation in this population. It is not surprising that there are wide variations in iron supplementation practices among neonatal units [2].


Between 25% and 85% of preterm infants develop evidence of iron deficiency during infancy [38]. Unlike full term infants, in whom the condition typically occurs during the second half of infancy, preterm infants are at risk for developing iron deficiency during their first 6 postnatal months [59]. Gestationally more premature and smaller preterm infants are at greatest risk for developing iron deficiency at an earlier age [5,9,10]. Iron deficiency is more common in preterm infants from developing countries [4] and in those consuming human milk exclusively without supplementation.

Factors predisposing to iron deficiency

A number of factors combine to predispose the premature infant to negative iron balance. Iron is mostly accumulated during the third trimester of gestation [11]. Total body iron and hemoglobin (Hgb) contents, and serum and storage iron concentrations are lower in preterm infants [1113]. Conditions such as severe maternal iron deficiency [14], intrauterine growth restriction [12,15,16], and chronic blood loss during gestation can further compromise fetal iron endowment.

Postnatally, the meager iron stores can be rapidly depleted during the first 6–8 weeks, coinciding with the onset of erythropoiesis and rapid catch-up growth [1,5,15]. The Hgb nadir is lower and occurs earlier in more premature (gestational age 28–32 wk) infants when compared with those born at a gestational age of 33–36 wk [3]. However, beginning at 9 weeks and continuing until 12 months of age, Hgb concentrations are comparable in the two gestational age groups [3], implying the need for a more robust erythropoiesis and therefore, greater iron requirement in the more prematurely born infants.

Tissue iron stores are depleted sooner in those preterm infants demonstrating the greatest growth velocity [15]. This is seen particularly with more immature preterm infants who demonstrate the most rapid catch-up growth [1]. Interestingly, the iron status at birth does not influence postnatal growth rate [17], signifying that preterm infants will grow whether they are iron replete or not at birth. The high rate of postnatal catch-up growth with its attendant increases in blood volume and Hgb mass requires additional iron. Unless augmented by external sources, the endogenous iron stores of preterm infants at birth meet their iron demands only until the doubling of the birth weight, i.e., approximately until 2–3 months of age [18]. Chronic gastrointestinal hemorrhage and clinical practices, such as uncompensated phlebotomy losses and inadequate iron supplementation further deplete iron stores and increase iron requirements.

Consequences of iron deficiency

The effects of iron deficiency are pervasive and involve multiple organ systems. Poor physical growth, gastrointestinal disturbances, thyroid dysfunction, altered immunity and temperature instability has been attributed to iron deficiency in very low birth weight (VLBW, birth weight <1500 g) infants [19]. Anemia is typically a late sign and suggests significant depletion of iron stores. A major concern of early iron deficiency is its effect on the developing brain.

Potential effects of iron deficiency on neurodevelopment

Dietary iron deficiency during early infancy is associated with long-term neurodevelopmental impairments that appear to be irreversible in spite of iron supplementation (Reviewed in [20]). Long-term cognitive abnormalities have also been demonstrated in full-term infants with iron deficiency in the neonatal period [13,21].

A limited number of studies suggest that early iron deficiency may also adversely affect neurologic function and neurodevelopment in preterm infants. Compared with non-anemic, iron-replete infants, preterm infants with anemia (Hgb ≤10 g/dL) and low iron stores (serum ferritin ≤ 76 μg/L) had an increased number of abnormal neurologic reflexes at 37 wk postmenstrual age [22]. A recent study demonstrated more mild neurologic abnormalities, such as broad gait, dysdiadochokinesis or dysmetria at 5 years of age in preterm infants who received iron supplementation from 2 months of age, compared with those supplemented from 2 weeks after birth [23]. A trend toward poorer cognitive performance was also present in those supplemented late [23]. Thus, early iron deficiency appears to adversely affect neurodevelopment in preterm infants. Interestingly, unlike the cognitive deficits that tend to predominate in full-term infants with neonatal iron deficiency [13,21], motor deficits appear to predominate in preterm infants.


In the absence of genetic conditions, such as congenital hemochromatosis, iatrogenic factors are responsible for excessive iron accumulation in preterm infants. However, there are no specific data on the incidence of iron overload due to nutritional iron therapy in preterm infants.

Factors predisposing to iron overload

Multiple erythrocyte transfusions may lead to excess iron accumulation in preterm infants. Approximately 80% of VLBW and 95% of extremely low birth weight (ELBW, birth weight <1000 g) infants receive erythrocyte transfusions during their hospitalization [24]. Compared with adults, the mean life span of transfused erythrocytes is shorter in preterm infants [25]. The accelerated breakdown of erythrocytes may lead to excess iron accumulation [26] and a need for repeated transfusions. Each mL of transfused packed erythrocytes potentially delivers 0.5–1.0 mg of iron to the body [27,28]. Elevated serum iron and ferritin concentrations, and liver iron concentration are common after multiple transfusions in preterm infants [2931]. Preterm infants who have received multiple transfusions may maintain iron stores without iron supplementation up to 6 months of life [30,32,33].

Although the serum iron concentration transiently increases after intravenous administration of iron in preterm infants [34], there are no data that this practice leads to iron overload at commonly used dosages. Similarly, there is no evidence for excess iron accumulation with enteral iron administration at doses typically used for supplementation [35,36].

Consequences of iron excess in preterm infants

As with iron deficiency, excess iron accumulation potentially affects multiple organ systems. Large doses of enteral iron administration were associated with hemolysis in preterm infants with vitamin E deficiency [37]. This nutritional deficiency is rare at present. There is an association between multiple erythrocyte transfusions and retinopathy of prematurity (ROP) [29,38] and bronchopulmonary dysplasia (BPD) [30,39]. The incidence and severity of both conditions correlate with the number and volume of erythrocyte transfusions [29,30]. While it is tempting to speculate that transfusion-related iron overload may be involved in the pathogenesis of these conditions, other studies have failed to provide such evidence [40].

Non-protein bound (“free”) iron mediated oxidative stress in the presence of poor antioxidant capabilities has been postulated to initiate or potentiate the progression of BPD and ROP through generation of reactive oxygen species (ROS) [30,39]. Multiple studies have demonstrated that the milieu in preterm infants is conducive for iron to exist in the pro-oxidant ferrous state and for the formation of ROS [3,26,39]. Additionally, although ferritin iron is protein-bound, there is potential for release of free iron from ferritin during oxidative stress [41].

Nevertheless, assigning a direct causative role for iron in BPD and ROP has been problematic. Infants developing these multi-factorial conditions tend to be more premature and sicker and thus, more likely to receive multiple transfusions. It has yet to be established in vivo that iron is directly involved with oxidative stress in preterm infants [27,30,38,42]. Increased serum iron concentration following multiple transfusions was not associated with lipid peroxidation in preterm infants with BPD [30], nor was increased hepatic iron concentration in multiply transfused preterm infants associated with hepatocyte injury [31]. Unfortunately, most of the assessments have been short-term and assessed oxidative stress soon after a single transfusion [27] or short duration of enteral iron administration [42,43]. Long-term studies are necessary to conclusively assess the risk of oxidative stress and tissue injury with cumulative doses of iron administration in preterm infants.

Potential effects of iron overload on neurodevelopment

Iron overload is postulated in the pathogenesis of ischemic brain injury and many neurodegenerative disorders in adults [44]. Similarly, increased non-protein bound iron and lipid peroxidation products have been demonstrated in the CSF of newborn infants with birth asphyxia [45]. These are non-nutritional effects of iron. Parkinson-like neurodegeneration in adulthood has been demonstrated in mice following enteral administration of large doses of iron (approximately 40 times that present in own mother’s milk) during the lactation period [46]. While this animal study is concerning, long-term neurodevelopmental deficits due to iron supplementation at typical doses have yet to be demonstrated in human infants.

In summary, the preterm infant is at risk of both iron deficiency and iron overload. Due the potential adverse impact of iron deficiency on developing organ systems, preventive and therapeutic measures appear to be crucial. Conversely, the potential for organ injury with excess iron suggests that iron therapy should be instituted carefully in the preterm infants.


Determining the iron requirements of preterm infants

The goal of nutrient delivery to preterm infants is to mimic the intrauterine accretion rate and maintain normal serum levels [47]. Using this analogy, a preterm infant would require a daily iron intake of 1.6–2.0 mg/kg intravenously [48] or 5–6 mg/kg enterally, since enteral iron absorption is approximately 30% [49]. However, such supplementation is neither practical nor physiological soon after birth. Enteral nutrition is not feasible soon after birth in most VLBW preterm infants. Unlike intrauterine life, growth and erythropoiesis cease soon after birth. Iron requirements are lower under those circumstances. Estimates of daily requirements based on a factorial approach [50] are also likely to be imprecise [51]. Well-executed, randomized controlled trials are probably the best method to determine the iron requirements of preterm infants. These trials have established the beneficial effect of iron supplementation via fortification of human milk, iron-fortified formula and medicinal iron in decreasing the risk of iron deficiency [8,16,5153]. However, most studies have evaluated only short-term benefits on hematological parameters. There is a paucity of information on the long-term effects of iron supplementation on hematological and non-hematological parameters, such as growth and neurodevelopment.


Fortification of human milk

The iron content of human milk is approximately 0.5 mg/L [54]. Whereas human milk meets the iron requirements of full-term infants during the first 4–6 months of age, additional iron is necessary to meet the needs of erythropoiesis and growth of preterm infants [16]. The iron status of preterm infants receiving non-fortified breast milk starts to deteriorate within 1 to 4 months [7,9,10]. Cow milk-based human milk fortifiers that are currently available in the United States contain 3.5–14.4 mg/L of iron and deliver 0.7–2.2 mg/kg d−1 of additional iron if milk consumption is 150 mL/kg d−1. Fortification with an iron-fortified human milk fortifier is associated with fewer erythrocyte transfusions than fortification with a low-iron fortifier [52]. Therefore, additional iron supplementation may be necessary if the latter is used. The currently available human milk-based human milk fortifier in the United States is also not fortified with iron and provides only 0.3 mg/kg d−1 of iron if daily milk consumption is 150 mL/kg.

Use of iron-fortified formula

Compared with a formula lacking iron, weaning to an iron-fortified formula improves Hgb and serum ferritin concentrations in preterm infants [16]. Preterm infants with birth weights <1800 g will not achieve iron sufficiency on a formula containing ≤3 mg/L [6]. Formulas containing 5–9 mg/L of iron appear to meet the iron requirements of erythropoiesis in healthy preterm infants during the first 6 months of life [55]. However, 18% of the infants receiving the 9 mg/L formula and 30% of those receiving the 5 mg/L formula developed iron deficiency (serum ferritin concentration <10 μg/L) between 4 and 8 months of age in that study [55]. The currently available infant formulas in the United States are fortified with 12.0–14.4 mg/L of iron and deliver 1.8–2.2 mg/kg d−1 when consumed at 150 ml/kg d−1. The discharge formulas have an iron content of 13 mg/L and provide approximately 2 mg/kg d−1 of iron.


Enteral administration is commonly used for supplementing iron to preterm infants. There are wide variations in the dose, initiation and duration of supplementation and iron compounds used for enteral supplementation [2]. The recommendations of various pediatric societies [47,56,57] are given in table 1. Iron supplementation is not recommended nor is it necessary during the transition period soon after birth [56]. An exogenous source of 2–4 mg/kg d−1 iron is recommended during the period of stable growth, beginning at 4–8 weeks and continuing until 12–15 months of age (Table 1). Whereas these recommendations provide useful guidelines for iron therapy in preterm infants, they may not be universally applicable as discussed below.

Table 1
Enteral Iron Intake Recommendations for Preterm Infants in Stable Clinical Condition

Dosage of elemental iron

At least 2–4 mg/kg d−1 of elemental iron is necessary to prevent iron deficiency in non-transfused VLBW infants [5,58]. However, their Hgb level does not reach that of full term infants by 9 months of age with such supplementation [58]. Even with 4–6 mg/kg d−1 of iron supplementation from 2 wk of age, iron deficiency is found at 2 months of age in approximately 15% of preterm infants with birth weight <1301 gm [8]. Preterm infants with lower birth weight and gestational age demonstrate more robust erythropoiesis and greater growth velocity than heavier and more mature counterparts [3]. At the same time their iron endowment at birth is lower. A scaled dosage based on gestational age and/or birth weight may be more appropriate [56,59]. Conversely, approximately 95% of ELBW infants receive erythrocyte transfusions [24] and are likely to have larger iron stores. Therefore, body iron stores should also be taken into consideration while deciding additional iron supplementation in ELBW infants. Preterm infants who are small-for-gestational age also may benefit from a higher dose of iron, as they potentially have lower total body iron concentration than appropriate-for-gestation counterparts [16].

Initiation of supplementation

The initiation of iron supplementation in preterm infants has been debated since the 1950s [1] and has ranged from 14 days to 10 weeks among the neonatal units [2]. The current recommendation is to begin supplementation from 4–8 wks of age, irrespective of gestational age or birth weight (Table 1).

However, beginning supplementation earlier may be prudent for the more immature preterm infants, many of who may be in negative iron balance by one month of age [9,33]. Compared with unsupplemented infants or who were supplemented from 4–8 wk of age, supplementing 2–5 mg/kg d−1 of iron from 2 weeks of age reduces the need for erythrocyte transfusions and the risk of iron deficiency between 2 and 6 months of age [5,8,53]. Cumulative iron intake with early supplementation was calculated to be > 3 times of late supplementation [8]. Hgb, serum iron and ferritin concentrations were higher and serum transferrin (Tf) receptor concentrations lower at 2 months of age with early iron supplementation [8,53], suggesting better iron stores at discharge. Early iron supplementation was tolerated well and was not associated with morbidities. A follow-up study demonstrated a lower incidence of mild motor signs and a trend towards better cognitive function at 5 years of age in those supplemented from 2 weeks [23], suggesting potential long-term benefits with early supplementation. The lack of long-term neurological morbidity also supports the safety of early iron supplementation.

On the other hand, the risk of iron-induced hemolysis in preterm infants with vitamin E deficiency is maximal during the first 6 weeks of life [37]. Serum iron and ferritin concentrations remain elevated during the first 4–6 wk of life even without supplementation. [3]. There is a potential for iron excess with higher doses of supplementation since enteral iron absorption appears to be poorly regulated during the first month of life in ELBW infants [9,10,51]. Furthermore, supplemental iron is better incorporated into red cells when it is administered after the onset of erythropoiesis [60]. These studies would support delaying iron supplementation until 4–6 wk.

Duration of supplementation

The duration of supplementation has varied from 6 to 12 months [2]. Most organizations recommend supplementation until 12–15 months of age (Table 1). The optimal duration of supplementation has yet to established in randomized controlled trials.

Choice of iron compound for supplementation

Ferrous sulfate is commonly used for supplementation, as well as for fortifying formula. It is inexpensive and widely available. Even though there are theoretical advantages for using non-ionic ferric compounds, studies have not established their superiority over ferrous sulfate vis-à-vis tolerance, efficacy and complications [61]. Moreover, whereas ferrous sulfate may be administered once daily [62], some of the other compounds require more frequent administration [61], which may compromise compliance.

Route of supplementation

Parenteral iron administration is not typically used for routine iron supplementation. As iron is not naturally excreted in stools or urine, almost all of the parenterally administered iron would be retained in the body. Intramuscular administration of iron is as efficacious as oral supplementation in ameliorating iron deficiency [63]. Nevertheless, the practice is discouraged because of associated pain and complications [64]. Intravenous iron administration is safe and more effective than enteral iron for supporting erythropoiesis [28,34,35]. Even though iron is accreted at a rate of 1.6–2.0 mg/kg d−1 during the third trimester [48], an intravenous dose of 120 μg/kg d−1 results in a positive iron balance [28], likely due to decreased iron requirements soon after birth. Between 18% and 68% of the intravenously administered iron is incorporated into erythrocytes within 2 weeks [60,65]. Intravenous administration is also thought to improve growth in preterm infants receiving rHuEPO [66]. Nevertheless, the transient elevation of malondialdehyde, a marker of lipid peroxidation, at the conclusion of iron infusions [34], cautions against routine supplementation through this route. The need for long-term intravenous access also makes it impractical for most infants.

Iron supplementation in special circumstances

Iron supplementation during recombinant human erythropoietin (rHuEPO) therapy

Administration of rHuEPO promotes erythropoiesis and reduces the need for erythrocyte transfusions in preterm infants (see [67] for a review). Iron supplementation is necessary since rHuEPO administration depletes body iron stores [35,68]. A daily intake of 3–8 mg/kg of iron appears to be adequate for supporting erythropoiesis, is well-tolerated and does not appear to be associated with oxidative stress [35,66,67,69]. The Committee on Nutrition of the American Academy of Pediatrics recommends enteral supplementation of 6 mg/kg d−1 of elemental iron during rHuEPO administration [47]. However, this dose may not be sufficient to support erythropoiesis and maintain iron stores [70]. Simultaneous enteral (9 mg/kg d−1) and parenteral (2 mg/kg d−1) iron administration [34] or continuation of enteral iron therapy beyond rHuEPO administration [66] may be necessary to achieve this goal. Enteral doses as high as 18–36 mg/d (approximately 12–24 mg/kg d−1) have been used [71], but do not appear to provide additional benefits and may cause hematochezia [66].

Intravenous iron supplementation in a dose of 2–6 mg/kg or 20 mg/kg weekly may improve erythropoietic response and growth during rHuEPO therapy [70]. Such therapy may be useful in infants with low serum ferritin levels or in whom enteral nutrition has yet to be established. Intramuscular administration of 1 mg/kg d−1 or 12 mg/kg once weekly during rHuEPO therapy also appears to be effective [67,72]. Overall, a prudent approach may be to adjust the iron dose to maintain serum ferritin concentration >100 μg/L during rHuEPO therapy [73].

Iron supplementation in preterm infants with elevated serum ferritin concentrations

It is not unusual for preterm infants to have abnormally high serum ferritin concentrations (>350 μg/L). This may occur due to storage of excess iron following multiple transfusions (i.e., true iron overload) or sequestration of iron during periods of inflammation (i.e., iron redistribution). There are no specific guidelines with respect to iron supplementation of preterm infants with high serum ferritin concentrations. The increased risk of mortality and morbidity associated with iron supplementation in iron-replete infants and children [74] and the potential for additional iron accumulation due to the poor regulation of intestinal absorption [9,51,74] cautions against routine supplementation in these infants. Nevertheless, some of the preterm infants with elevated serum ferritin may simultaneously have iron-deficient erythropoiesis [51], suggesting an inability to release ferritin bound hepatic iron to the bone marrow. Therefore, it may be prudent to rule out iron-deficient erythropoiesis by determining the zinc protoporphyrin to heme (ZnPP/H) ratio and reticulocyte count [75] in infants with increased serum ferritin levels and consider iron supplementation on an individual basis. Preterm infants in whom iron supplementation has been withheld will likely benefit from periodic screening of their iron status as they may be at risk of iron deficiency during the post-discharge period. A recent study of small sample size demonstrated evidence of iron deficiency between 6 and 12 months corrected age in approximately 25% of preterm infants who had serum ferritin concentration >95th percentile of normal at discharge, in spite of receiving 2–4 mg/kg d−1 of iron [76].

Post-ingestion considerations

Absorption and retention

The absorption of iron from human milk is >50% and from cow milk based formulas is approximately 4–12% [77]. Absorption is better from whey-predominant formula than casein-based formula. Only 1–7% of iron in soy milk-based formula is absorbed [77].

The absorption and retention of enterally administered medicinal iron depends upon the postnatal age and iron status of the infant. Absorption is better if medicinal iron is supplemented with breast milk or between meals [49,60]. Isotope studies have demonstrated that approximately 25–30% of the administered iron is absorbed [9,49], irrespective of the iron endowment [51]. Approximately 10–25% of the iron supplemented between feeding is incorporated into erythrocytes within 2 weeks [60,65].

Adjuvant therapies to enhance the efficacy of enteral iron supplementation

Ascorbic acid and other organic acids in the diet favor absorption. However, there are no specific recommendations for administering these or other nutrients during iron supplementation. Although rHuEPO promotes incorporation of absorbed iron into erythrocytes, it does not enhance enteral iron absorption [78].

Gastrointestinal tolerance

Iron-fortified infant formulas are well tolerated in full-term infants and may be used as the first feeding when breast milk is not available [77]. Gastrointestinal symptoms, such as cramping, gastroesophageal reflux and flatulence that are attributed to ingestion of iron have not been borne out by controlled studies of iron-fortified formulas [79]. Similarly, medicinal iron in doses of 2–10 mg/kg d−1 is well tolerated by preterm infants [5,8,42,53]. However, clinically significant hematochezia without necrotizing enterocolitis occurred in 17% of preterm infants receiving 8–16 mg/kg d−1 of elemental iron, necessitating cessation of supplementation [66]. Whether hematochezia was due to iron per se or to other factors (for example, allergy to cow milk protein) was not established. In most instances iron therapy could be resumed upon the resolution of hematochezia [66]. Other studies have reported tolerance of 18–36 mg/d of iron supplementation without gastrointestinal side effects [71].

Interaction of iron with other minerals

As many divalent cations share common transport mechanisms [80], there is a potential for interaction between iron and other minerals. The effect on zinc and copper has been studied in detail. Zinc supplementation does not appear to impede iron absorption at a ratio of 4:1 in formula [81]. Similarly, there was no effect of 2 mg/kg d−1 of iron supplementation on serum zinc levels [82] or selenium absorption [83]. Iron absorption from fortified breast milk appears to be intact in spite of the high calcium content of the fortifier [60]. Even though iron supplementation appears to alter copper metabolism, its clinical relevance is unclear at present [51].

Oxidative stress with enteral iron supplementation

In vitro studies have demonstrated increased free radical and lipid peroxidation products in formula and human milk after addition of medicinal iron [84]. There are no in vivo studies demonstrating 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 [85]. Enteral iron supplementation in doses of 3–10 mg/kg d−1 was not associated with markers of oxidative stress in plasma and urine of stable VLBW infants [42,43]. Nevertheless, a threshold dose of iron likely exists beyond which the potential for oxidative stress increases.


Delaying the clamping the umbilical cord 30–180 sec after birth improves iron status [86]. However, data are insufficient to recommended this practice as a general policy, given the potential impact of a large volume expansion on the fragile cerebral circulation of the preterm infant. Limiting phlebotomy losses, avoiding cow milk and using iron pots for cooking [4] are other preventive measures that may improve the iron status of preterm infants. Of note, it is not possible to enhance iron concentration of the breast milk with maternal iron supplementation after birth [54].


Timing and frequency of screening

Periodic assessment of Hgb or hematocrit is recommended for screening the iron nutritional status of full term infants, with an initial screening between 9 and 12 months of age and a second screening 6 months later (i.e., between 15 and 18 months) [87]. Although there are no specific recommendations for preterm infants, it is considered prudent to them at approximately 4 months [87]. As many preterm infants develop iron deficiency prior to that age [8,15], screening at 2 months or at discharge, whichever is earlier, appears prudent. In one study, serum ferritin <50 μg/L at 2 months predicted future risk of iron deficiency in preterm infants [5]. Determining ZnPP/H ratio at the time of discharge may be useful for diagnosing iron deficient erythropoiesis and need for additional iron [75]. A recheck of hematological status at 6 months of age, instead of the recommended 9 months, may also be beneficial. An individualized follow-up schedule based on the iron status at discharge, growth velocity, type of milk feeding and dose of iron supplementation would be ideal.

Biomarkers of iron nutritional status

Many laboratory tests are available to comprehensively assess the iron nutritional status (See [88] for a review). However, their usefulness for diagnosing iron adequacy or deficiency is limited in preterm infants, as gestational age-specific normal values have yet to be established for most biomarkers [88]. Furthermore, many laboratory markers are confounded by normal developmental changes [89,90], associated morbidities (e.g. inflammation) and therapies (e.g. rHuEPO administration and transfusions).

Diagnosis and treatment of iron deficiency

Hgb below the age-specific norm, serum ferritin <10–12 μg/L and transferrin saturation <10–17% have been considered suggestive of iron deficiency anemia in preterm infants during the first 2–6 months of age [5,8,53]. A relative increase of the absolute reticulocyte count by >50% one week after starting iron supplementation has also been considered suggestive of preexisting iron deficiency [8]. There are no universally accepted treatment protocols for iron deficiency in preterm infants. Oral administration of 3–6 mg/kg d−1 of elemental iron for 3 months is recommended in confirmed cases of iron deficiency anemia [87]. A scaled dosing of 3–12 mg/kg d−1, adjusted according to the ZnPP/H ratio has been demonstrated to improve erythropoiesis without causing oxidative stress in preterm infants [43].

Potential risk of neuronal injury with rapid iron replenishment

Animal studies have demonstrated upregulation of iron receptors and transporters in the brain regions during fetal and neonatal iron deficiency [91]. Thus, there is a potential for increased cerebral uptake and neuronal injury with excess amounts of iron supplementation [46]. Therefore, rapid correction of iron deficiency using erythrocyte transfusions or large doses of iron should be avoided.


Setting guidelines for erythrocyte transfusions based on specific hematological parameters would potentially avoid iron excess. However, there are practical difficulties in adhering to the practice [40], as transfusions are often administered for non-hematological reasons. Use of rHuEPO in lieu of transfusions may be another strategy. Nevertheless, most studies have demonstrated only a modest decrease in the frequency of erythrocyte transfusions with rHuEPO use [67]. Furthermore, a conservative transfusion practice or rHuEPO administration in lieu of transfusion may negatively affect the iron stores after discharge [32].

There are no specific recommendations for managing preterm infants with transfusion-related elevated serum ferritin concentrations. Periodic monitoring of the iron status may suffice, as the increased serum ferritin concentrations spontaneously normalizes within 2 months corrected age in most instances [76] due to a combination of cessation of erythrocyte transfusions, accelerating growth and regulation of enteral iron absorption [9]. A cocktail of antioxidants and iron chelators has been demonstrated to reduce hepatocyte injury and serum ferritin concentration in neonatal hemochromatosis [92]. However, such therapies have not been studied in transfusion-related hyperferritinemia and may not be necessary, since hepatocyte injury has not been demonstrated with the increased iron deposition in preterm infants [31]. Addition of lactoferrin to formula or human milk decreases the levels of iron-induced oxidative products in vitro [84]. This potential benefit has yet to be established in vivo. There is a theoretical benefit in administering rHuEPO, especially if there is co-existing iron-deficient erythropoiesis, as rHuEPO decreases serum ferritin concentrations without inducing lipid peroxidation or altering antioxidant enzyme activities in preterm infants [93].


Iron deficiency and iron excess are significant nutritional problems in the preterm infant. The potential risk of neurodevelopmental impairments due to iron deficiency warrants frequent screening and preventive measures via fortification of breast milk or use of iron-fortified formula. Iron supplementation also appears to be effective and safe. Nevertheless, there are unresolved issues concerning the practice. Iron overload remains a significant concern in multiply transfused sick preterm infants because of their poorly developed anti-oxidant mechanisms. The management of preterm infant with iron overload has not been well studied. Careful monitoring and support during the newborn and post-discharge periods is necessary due to the highly variable iron status of preterm infants. There is a need to develop gestational age-specific laboratory markers for comprehensively assessing iron nutritional status. Most studies on iron status and iron supplementation were conducted before the era of improved survival of smaller and gestationally more immature preterm infants. Well-controlled randomized trials are necessary to establish iron therapy guidelines for these infants. Research is also necessary to establish the mechanism of absorption and regulation of iron homeostasis during typical development.


The authors thank Jennifer L.M. Super, RD, LD for assistance with the iron content of formula and additives, and Caitlyn Nystedt for assistance with manuscript preparation.

This work was supported by grant HD 29421-14 from the National Institutes of Health


Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.


1. Halvorsen S, Seip M. Erythrocyte production and iron stores in premature infants during the first months of life; the anemia of prematurity-etiology, pathogenesis, iron requirement. Acta Paediatr. 1956 Nov;45(6):600–617. [PubMed]
2. Barclay SM, Lloyd DJ, Duffty P, Aggett PJ. Iron supplements for preterm or low birthweight infants. Arch Dis Child. 1989 Nov;64(11):1621–1622. [PMC free article] [PubMed]
3. Halliday HL, Lappin TR, McClure G. Iron status of the preterm infant during the first year of life. Biol Neonate. 1984;45(5):228–235. [PubMed]
4. Borigato EV, Martinez FE. Iron nutritional status is improved in Brazilian preterm infants fed food cooked in iron pots. J Nutr. 1998;128(5):855–859. [PubMed]
5. Lundstrom U, Siimes MA, Dallman PR. At what age does iron supplementation become necessary in low-birth-weight infants? J Pediatr. 1977;91(6):878–883. [PubMed]
6. 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(3):409–414. [PubMed]
7. 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(1–2):63–65. [PubMed]
8. 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(4):700–706. [PubMed]
9. 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. [PubMed]
10. 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(9):899–904. [PubMed]
11. Widdowson EM, Spray CM. Chemical development in utero. Arch Dis Child. 1951;26:205–214. [PMC free article] [PubMed]
12. 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(1):47–52. [PubMed]
13. Siddappa AM, Rao R, Long JD, Widness JA, Georgieff MK. The assessment of newborn iron stores at birth: a review of the literature and standards for ferritin concentrations. Neonatology. 2007;92(2):73–82. [PMC free article] [PubMed]
14. Singla PN, Chand S, Agarwal KN. Cord serum and placental tissue iron status in maternal hypoferremia. Am J Clin Nutr. 1979;32(7):1462–1465. [PubMed]
15. Haga P. Plasma ferritin concentrations in preterm infants in cord blood and during the early anaemia of prematurity. Acta Paediatr Scand. 1980;69(5):637–641. [PubMed]
16. Olivares M, Llaguno S, Marin V, Hertrampf E, Mena P, Milad M. Iron status in low-birth-weight infants, small and appropriate for gestational age. A follow-up study. Acta Paediatr. 1992 Oct;81(10):824–828. [PubMed]
17. Sichieri R, Fonseca VM, Hoffman D, Trugo NM, Moura AS. Lack of association between iron status at birth and growth of preterm infants. Rev Saude Publica. 2006 Aug;40(4):641–647. [PubMed]
18. Aggett PJ, Barclay S, Whitley JE. Iron for the suckling. Acta Paediatr Scand Suppl. 1989;361:96–102. [PubMed]
19. Aggett PJ. Trace elements of the micropremie. Clinics in Perinatology. 2000;27(1):119–129. vi. [PubMed]
20. Lozoff B, Georgieff MK. Iron deficiency and brain development. Semin Pediatr Neurol. 2006 Sep;13(3):158–165. [PubMed]
21. Tamura T, Goldenberg RL, Hou J, et al. Cord serum ferritin concentrations and mental and psychomotor development of children at five years of age. J Pediatr. 2002 Feb;140(2):165–170. [PubMed]
22. Armony-Sivan R, Eidelman AI, Lanir A, Sredni D, Yehuda S. Iron status and neurobehavioral development of premature infants. J Perinatol. 2004 Dec;24(12):757–762. [PubMed]
23. Steinmacher J, Pohlandt F, Bode H, Sander S, Kron M, Franz AR. Randomized trial of early versus late enteral iron supplementation in infants with a birth weight of less than 1301 grams: neurocognitive development at 5.3 years’ corrected age. Pediatrics. 2007 Sep;120(3):538–546. [PubMed]
24. 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 Nov;129(5):680–687. [PubMed]
25. Bard H, Widness JA. The life span of erythrocytes transfused to preterm infants. Pediatr Res. 1997 Jul;42(1):9–11. [PubMed]
26. Hirano K, Morinobu T, Kim H, et al. Blood transfusion increases radical promoting non-transferrin bound iron in preterm infants. Arch Dis Child Fetal Neonatal Ed. 2001 May;84(3):F188–193. [PMC free article] [PubMed]
27. Dani C, Martelli E, Bertini G, et al. Effect of blood transfusions on oxidative stress in preterm infants. Arch Dis Child Fetal Neonatal Ed. 2004 Sep;89(5):F408–411. [PMC free article] [PubMed]
28. Friel JK, Andrews WL, Hall MS, et al. Intravenous iron administration to very-low-birth-weight newborns receiving total and partial parenteral nutrition. JPEN J Parenter Enteral Nutr. 1995 Mar-Apr;19(2):114–118. [PubMed]
29. 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(4):541–544. [PubMed]
30. Cooke RW, Drury JA, Yoxall CW, James C. Blood transfusion and chronic lung disease in preterm infants. Eur J Pediatr. 1997;156(1):47–50. [PubMed]
31. Ng PC, Lam CW, Lee CH, et al. Hepatic iron storage in very low birthweight infants after multiple blood transfusions. Arch Dis Child Fetal Neonatal Ed. 2001 Mar;84(2):F101–105. [PMC free article] [PubMed]
32. 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(1):40–43. [PubMed]
33. Shaw JC. Trace metal requirements of preterm infants. Acta Paediatr Scand Suppl. 1982;296:93–100. [PubMed]
34. Pollak A, Hayde M, Hayn M, et al. Effect of intravenous iron supplementation on erythropoiesis in erythropoietin treated premature infants. Pediatr. 2001;107(1):78–85. [PubMed]
35. Carnielli VP, Da Riol R, Montini G. Iron supplementation enhances response to high doses of recombinant human erythropoietin in preterm infants. Arch Dis Child Fetal Neonatal Ed. 1998;79(1):F44–48. [PMC free article] [PubMed]
36. Shannon KM, Keith JF, 3rd, Mentzer WC, et al. Recombinant human erythropoietin stimulates erythropoiesis and reduces erythrocyte transfusions in very low birth weight preterm infants [see comments] Pediatrics. 1995;95(1):1–8. [PubMed]
37. Melhorn DK, Gross S. Vitamin E-dependent anemia in the premature infant. I. Effects of large doses of medicinal iron. J Pediatr. 1971 Oct;79(4):569–580. [PubMed]
38. Hesse L, Eberl W, Schlaud M, Poets CF. Blood transfusion. Iron load and retinopathy of prematurity. Eur J Pediatr. 1997 Jun;156(6):465–470. [PubMed]
39. Silvers KM, Gibson AT, Russell JM, Powers HJ. Antioxidant activity, packed cell transfusions, and outcome in premature infants. Archives of Diseases in Children. 1998;78:F214–F219. [PMC free article] [PubMed]
40. Brooks SE, Marcus DM, Gillis D, Pirie E, Johnson MH, Bhatia J. The effect of blood transfusion protocol on retinopathy of prematurity: A prospective, randomized study. Pediatrics. 1999 Sep;104(3 Pt 1):514–518. [PubMed]
41. Bolann BJ, Ulvik RJ. Release of iron from ferritin by xanthine oxidase. Role of the superoxide radical. Biochem J. 1987 Apr 1;243(1):55–59. [PubMed]
42. Braekke K, Bechensteen AG, Halvorsen BL, Blomhoff R, Haaland K, Staff AC. Oxidative stress markers and antioxidant status after oral iron supplementation to very low birth weight infants. J Pediatr. 2007 Jul;151(1):23–28. [PubMed]
43. Miller SM, McPherson RJ, Juul SE. Iron sulfate supplementation decreases zinc protoporphyrin to heme ratio in premature infants. J Pediatr. 2006 Jan;148(1):44–48. [PubMed]
44. Berg D, Youdim MB. Role of iron in neurodegenerative disorders. Top Magn Reson Imaging. 2006 Feb;17(1):5–17. [PubMed]
45. Shouman BO, Mesbah A, Aly H. Iron metabolism and lipid peroxidation products in infants with hypoxic ischemic encephalopathy. J Perinatol. 2008 Mar 6; [PubMed]
46. Kaur D, Peng J, Chinta SJ, et al. Increased murine neonatal iron intake results in Parkinson-like neurodegeneration with age. Neurobiol Aging. 2007 Jun;28(6):907–913. [PubMed]
47. American Academy of Pediatrics, Committee on Nutrition. Nutritional needs of the preterm infant. In: Kleinman RE, editor. Pediatric nutrition handbook. 5. Chapel Hill, NC: American Academy of Pediatrics; 2004. pp. 23–54.
48. Fletcher J, Suter PE. The transport of iron by the human placenta. Clin Sci. 1969 Apr;36(2):209–220. [PubMed]
49. Fomon SJ, Nelson SE, Ziegler EE. Retention of iron by infants [In Process Citation] Annu Rev Nutr. 2000;20:273–290. [PubMed]
50. Oski FA. Iron deficiency in infancy and childhood [see comments] N Engl J Med. 1993;329(3):190–193. [PubMed]
51. Lonnerdal B, Kelleher SL. Iron metabolism in infants and children. Food Nutr Bull. 2007 Dec;28(4 Suppl):S491–499. [PubMed]
52. Berseth CL, Van Aerde JE, Gross S, Stolz SI, Harris CL, Hansen JW. Growth, efficacy, and safety of feeding an iron-fortified human milk fortifier. Pediatrics. 2004 Dec;114(6):e699–706. [PubMed]
53. Arnon S, Shiff Y, Litmanovitz I, et al. The efficacy and safety of early supplementation of iron polymaltose complex in preterm infants. Am J Perinatol. 2007 Feb;24(2):95–100. [PubMed]
54. Dorea JG. Iron and copper in human milk. Nutrition. 2000;16(3):209–220. [PubMed]
55. Griffin IJ, Cooke RJ, Reid MM, McCormick KP, Smith JS. Iron nutritional status in preterm infants fed formulas fortified with iron. Arch Dis Child Fetal Neonatal Ed. 1999;81(1):F45–49. [PMC free article] [PubMed]
56. Nutrition Committee, Canadian Pediatric Society. Nutrition needs and feeding of premature infants. Can Med Assoc J. 1995;152(11):1765–1785. [PMC free article] [PubMed]
57. Committee on Nutrition of the Preterm Infant, European Society of Paediatric Gastroenterology and Nutrition. Nutrition and feeding of preterm infants. Acta Paediatr Scand. 1987;suppl 336:1–14. [PubMed]
58. Siimes MA, Jarvenpaa AL. Prevention of anemia and iron deficiency in very low-birth-weight infants. J Pediatr. 1982;101(2):277–280. [PubMed]
59. Siimes MA. Iron requirement in low birthweight infants. Acta Paediatr Scand Suppl. 1982;296:101–103. [PubMed]
60. 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(4):507–511. [PubMed]
61. Naude S, Clijsen S, Naulaers G, Daniels H, Vanhole C, Devlieger H. Iron supplementation in preterm infants: a study comparing the effect and tolerance of a Fe2+ and a nonionic FeIII compound. J Clin Pharmacol. 2000 Dec;40(12 Pt 2):1447–1451. [PubMed]
62. Zlotkin S, Arthur P, Antwi KY, Yeung G. Randomized, controlled trial of single versus 3-times-daily ferrous sulfate drops for treatment of anemia. Pediatrics. 2001 Sep;108(3):613–616. [PubMed]
63. Heese HD, Smith S, Watermeyer S, Dempster WS, Jakubiec L. Prevention of iron deficiency in preterm neonates during infancy. S Afr Med J. 1990;77(7):339–345. [PubMed]
64. Barry DM, Reeve AW. Increased incidence of gram-negative neonatal sepsis with intramuscula iron administration. Pediatrics. 1977 Dec;60(6):908–912. [PubMed]
65. Zlotkin SH, Lay DM, Kjarsgaard J, Longley T. Determination of iron absorption using erythrocyte iron incorporation of two stable isotopes of iron (57Fe and 58Fe) in very low birthweight premature infants. J Pediatr Gastroenterol Nutr. 1995;21(2):190–199. [PubMed]
66. Bader D, Kugelman A, Maor-Rogin N, et al. The role of high-dose oral iron supplementation during erythropoietin therapy for anemia of prematurity. J Perinatol. 2001 Jun;21(4):215–220. [PubMed]
67. Aher S, Ohlsson A. Late erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants. Cochrane Database Syst Rev. 2006;(3):CD004868. [PubMed]
68. Fujiu T, Maruyama K, Koizumi T. Oral iron supplementation in preterm infants treated with erythropoietin. Pediatr Int. 2004 Dec;46(6):635–639. [PubMed]
69. Ridley FC, Harris J, Gottstein R, Emmerson AJ. Is supplementary iron useful when preterm infants are treated with erythropoietin? Arch Dis Child. 2006 Dec;91(12):1036–1038. [PMC free article] [PubMed]
70. 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(2):258–263. [PubMed]
71. Bechensteen AG, Haga P, Halvorsen S, et al. Erythropoietin, protein, and iron supplementation and the prevention of anaemia of prematurity. Arch Dis Child. 1993 Jul;69(1 Spec):19–23. [PMC free article] [PubMed]
72. Kivivuori SM, Virtanen M, Raivio KO, Viinikka L, Siimes MA. Oral iron is sufficient for erythropoietin treatment of very low birth-weight infants. Eur J Pediatr. 1999 Feb;158(2):147–151. [PubMed]
73. Carbonell-Estrany X, Figueras-Aloy J, Alvarez E. Erythropoietin and prematurity--where do we stand? J Perinat Med. 2005;33(4):277–286. [PubMed]
74. Domellof M. Iron requirements, absorption and metabolism in infancy and childhood. Curr Opin Clin Nutr Metab Care. 2007 May;10(3):329–335. [PubMed]
75. Winzerling JJ, Kling PJ. Iron-deficient erythropoiesis in premature infants measured by blood zinc protoporphyrin/heme. J Pediatr. 2001 Jul;139(1):134–136. [PubMed]
76. deRegnier R-A, Shah MD, Wiles C, Georgieff MK. First year outcome of hyperferremia in multiply transfused preterm infants. [abstract E-PAS2008:633774.6]. Abstracts2View Online Program of the Pediatric Academic Societies and Asian Society for Pediatric Research Joint Meeting; Honolulu, HI. 2008.
77. American Academy of Pediatrics CoN. Iron fortification of infant formulas. Pediatrics. 1999;104(1 Pt 1):119–123. [PubMed]
78. Widness JA, Lombard KA, Ziegler EE, et al. Erythrocyte incorporation and absorption of 58Fe in premature infants treated with erythropoietin. Pediatr Res. 1997;41(3):416–423. [PubMed]
79. Nelson SE, Ziegler EE, Copeland AM, Edwards BB, Fomon SJ. Lack of adverse reactions to iron-fortified formula. Pediatrics. 1988 Mar;81(3):360–364. [PubMed]
80. Garrick MD, Dolan KG, Horbinski C, et al. DMT1: a mammalian transporter for multiple metals. Biometals. 2003 Mar;16(1):41–54. [PubMed]
81. Friel JK, Serfass RE, Fennessey PV, et al. Elevated intakes of zinc in infant formulas don not interfere with iron absorption in premature infants. Journal of Pediatric Gastroenterology & Nutrition. 1998;27(3):312–316. [PubMed]
82. Salvioli GP, Faldella G, Alessandroni R, Lanari M, Benfenati L. Plasma zinc concentrations in iron supplemented low birthweight infants. Arch Dis Child. 1986;61(4):346–348. [PMC free article] [PubMed]
83. 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(1):57–62. [PubMed]
84. Raghuveer TS, McGuire EM, Martin SM, et al. Lactoferrin in the preterm infants’ diet attenuates iron-induced oxidation products. Pediatr Res. 2002 Dec;52(6):964–972. [PubMed]
85. van Zoeren Grobben D, Moison R, Haasnoot A, Berger H. Iron containing feeding formula and oxidative stress in preterm infants. Pediatric Research. 1998;43:270A.
86. Rabe H, Reynolds G, Diaz-Rossello J. A systematic review and meta-analysis of a brief delay in clamping the umbilical cord of preterm infants. Neonatology. 2008;93(2):138–144. [PubMed]
87. American Academy of Pediatrics, Committee on Nutrition. Iron deficiency. In: Kleinman RE, editor. Pediatric nutrition handbook. 5. Chapel Hill, NC: American Academy of Pediatrics; 2004. pp. 299–312.
88. Beard J, deRegnier RA, Shaw MD, Rao R, Georgieff M. Diagnosis of Iron Deficiency in Infants. Lab Med. 2007;38(2):103–108.
89. Griffin IJ, Reid MM, McCormick KP, Cooke RJ. Zinc protoporphyrin/haem ratio and plasma ferritin in preterm infants. Arch Dis Child Fetal Neonatal Ed. 2002 Jul;87(1):F49–51. [PMC free article] [PubMed]
90. Lott DG, Zimmerman MB, Labbe RF, Kling PJ, Widness JA. Erythrocyte zinc protoporphyrin is elevated with prematurity and fetal hypoxemia. Pediatrics. 2005 Aug;116(2):414–422. [PubMed]
91. Siddappa AJ, Rao RB, Wobken JD, et al. Iron deficiency alters iron regulatory protein and iron transport protein expression in the perinatal rat brain. Pediatr Res. 2003 May;53(5):800–807. [PubMed]
92. Flynn DM, Mohan N, McKiernan P, et al. Progress in treatment and outcome for children with neonatal haemochromatosis. Arch Dis Child Fetal Neonatal Ed. 2003 Mar;88(2):F124–127. [PMC free article] [PubMed]
93. Akisu M, Tuzun S, Arslanoglu S, Yalaz M, Kultursay N. Effect of recombinant human erythropoietin administration on lipid peroxidation and antioxidant enzyme(s) activities in preterm infants. Acta Med Okayama. 2001 Dec;55(6):357–362. [PubMed]